Field assessment of active ingredient quantity in pharmaceutical tablets with limited calibration of near infrared spectra: An application to ciprofloxacin tablets.

Portable near-infrared (NIR) spectrophotometers have emerged as valuable tools for identifying substandard and falsified pharmaceuticals (SFPs). Integration of these devices with chemometric and machine learning models enhances their ability to provide quantitative chemical insights. However, different NIR spectrophotometer models vary in resolution, sensitivity, and responses to environmental factors such as temperature and humidity, necessitating instrument-specific libraries that hinder the wider adoption of NIR technology. This study addresses these challenges and seeks to establish a robust approach to promote the use of NIR technology in post-market pharmaceutical analysis. We developed support vector machine and partial least squares regression models based on binary mixtures of lab-made ciprofloxacin and microcrystalline cellulose, then applied the models to ciprofloxacin dosage forms that were assayed with high performance liquid chromatography (HPLC). A receiver operating characteristic (ROC) analysis was performed to set spectrophotometer independent NIR metrics to evaluate ciprofloxacin dosage forms as "meets standard," "needs HPLC assay," or "fails standard." Over 200 ciprofloxacin tablets representing 50 different brands were evaluated using spectra acquired from three types of NIR spectrophotometer with 85% of the prediction agreeing with HPLC testing. This study shows that non-brand-specific predictive models can be applied across multiple spectrophotometers for rapid screening of the conformity of pharmaceutical active ingredients to regulatory standard.

Mitigating the impact of gelatin capsule variability on detection of substandard and falsified pharmaceuticals with near-IR spectroscopy.

Portable NIR spectrometers are effective in detecting authentic pharmaceutical products in intact capsule formulations, which can be used to screen for substandard or falsified versions of those authentic products. However, the chemometric models are trained on libraries of authentic products, and are generally unreliable for detection of quality problems in products from outside their training set, even for products that are nominally the same active pharmaceutical ingredient and same dosage as products in the training set. As part of our research directed at developing better non-brand-specific strategies for pharmaceutical screening, we investigated the impact of capsule composition on NIR modeling. We found that capsule features like gelatin type, color, or thickness, give rise to a similar amount of variance in the NIR spectra as the type of API stored within the capsules. Our results highlight the efficacy of orthogonal projection to latent structures in mitigating the impacts of different types of capsules on the accuracy of NIR chemometric models for classification and regression analysis of lab-made samples. The models showed good performance for classification of field-collected doxycycline capsules as good or bad quality when an NIR-based % w/w metric was used, identifying five samples that were adulterated with talc. However, the % w/w was systematically underestimated, so when evaluating the capsules based on their absolute API content according to the monograph standard, the classification accuracy decreased from 100% to 70%. The underestimation was attributed to an unforeseen variability in the quantities and types of excipients present in the capsules.

Enhancing drug checking services for supply monitoring: perspectives on implementation in syringe service programs in the USA.

BACKGROUND: Shifts in the US drug supply, including the proliferation of synthetic opioids and emergence of xylazine, have contributed to the worsening toll of the overdose epidemic. Drug checking services offer a critical intervention to promote agency among people who use drugs (PWUD) to reduce overdose risk. Current drug checking methods can be enhanced to contribute to supply-level monitoring in the USA, overcoming the selection bias associated with existing supply monitoring efforts and informing public health interventions. METHODS: As a group of analytical chemists, public health researchers, evaluators, and harm reductionists, we used a semi-structured guide to facilitate discussion of four different approaches for syringe service programs (SSPs) to offer drug checking services for supply-level monitoring. Using thematic analysis, we identified four key principles that SSPs should consider when implementing drug checking programs. RESULTS: A number of analytical methods exist for drug checking to contribute to supply-level monitoring. While there is likely not a one-size-fits-all approach, SSPs should prioritize methods that can (1) provide immediate utility to PWUD, (2) integrate seamlessly into existing workflows, (3) balance individual- and population-level data needs, and (4) attend to legal concerns for implementation and dissemination. CONCLUSIONS: Enhancing drug checking methods for supply-level monitoring has the potential to detect emerging threats in the drug supply and reduce the toll of the worsening overdose epidemic.

Assessment of two brands of fentanyl test strips with 251 synthetic opioids reveals "blind spots" in detection capabilities.

BACKGROUND: Fentanyl test strips (FTS) are a commonly deployed tool in drug checking, used to test for the presence of fentanyl in street drug samples prior to consumption. Previous reports indicate that in addition to fentanyl, FTS can also detect fentanyl analogs like acetyl fentanyl and butyryl fentanyl, with conflicting reports on their ability to detect fentanyl analogs like Carfentanil and furanyl fentanyl. Yet with hundreds of known fentanyl analogs, there has been no large-scale study rationalizing FTS reactivity to different fentanyl analogs. METHODS: In this study, 251 synthetic opioids-including 214 fentanyl analogs-were screened on two brands of fentanyl test strips to (1) assess the differences in the ability of two brands of fentanyl test strips to detect fentanyl-related compounds and (2) determine which moieties in fentanyl analog chemical structures are most crucial for FTS detection. Two FTS brands were assessed in this study: BTNX Rapid Response and WHPM DanceSafe. RESULTS: Of 251 screened compounds assessed, 121 compounds were detectable at or below 20,000 ng/mL by both BTNX and DanceSafe FTS, 50 were not detectable by either brand, and 80 were detectable by one brand but not the other (n = 52 BTNX, n = 28 DanceSafe). A structural analysis of fentanyl analogs screened revealed that in general, bulky modifications to the phenethyl moiety inhibit detection by BTNX FTS while bulky modifications to the carbonyl moiety inhibit detection by DanceSafe FTS. CONCLUSIONS: The different "blind spots" are caused by different haptens used to elicit the antibodies for these different strips. By utilizing both brands of FTS in routine drug checking, users could increase the chances of detecting fentanyl analogs in the "blind spot" of one brand.

Development and validation of a liquid chromatography tandem mass spectrometry method for the analysis of 53 benzodiazepines in illicit drug samples.

An LC-MS/MS method for the analysis of 53 benzodiazepines, including various designer benzodiazepines, was developed. The developed method was applied to a total of 79 illicit street drug samples collected in Chicago, IL. Of these samples, 68 (84%) had detectable amounts of at least one benzodiazepine. Further, of the 53 benzodiazepines included in the developed method just 14 were measured in samples. Clonazolam, a potent designer benzodiazepine and derivative of clonazepam, was the most frequently measured benzodiazepine in 63% of samples and was measured in the highest concentrations. Other benzodiazepines measured in more than 10% of samples included clonazepam, alprazolam, flualprazolam, and oxazepam. Mixtures of benzodiazepines were frequently measured in samples, with just 24% of samples containing just one benzodiazepine. To determine the response of benzodiazepines on a rapid, point-of-use drug checking tool, all 53 benzodiazepine standards were screened on a lateral flow immunoassay benzodiazepine test strip. Sixty eight percent of standards gave a positive BTS response at a concentration of 20 µg/mL, demonstrating BTS have response to a wide variety of benzodiazepines, including many designer benzodiazepines. A comparison of this data to previous data reported for the same samples demonstrated all samples containing a benzodiazepine also had an opioid present, with fentanyl being present in 94% of benzodiazepine samples. These results highlight high rates of polysubstance drug presence in Chicago, IL illicit drug samples, posing an increased risk of drug overdoses in people who use drugs.

Current attitudes toward drug checking services and a comparison of expected with actual drugs present in street drug samples collected from opioid users.

BACKGROUND: The opioid epidemic continues to be associated with high numbers of fatalities in the USA and other countries, driven mainly by the inclusion of potent synthetic opioids in street drugs. Drug checking by means of various technologies is being increasingly implemented as a harm reduction strategy to inform users about constituent drugs in their street samples. We assessed how valued drug checking services (DCS) would be for opioid street drug users given the ubiquity of fentanyl and related analogs in the drug supply, the information they would most value from drug checking, and compared expected versus actual constituent drugs in collected samples. METHODS: A convenience sample of opioid street drug users (N = 118) was recruited from two syringe service exchange programs in Chicago between 2021 and 2022. We administered brief surveys asking about overdose history, whether fentanyl was their preferred opioid, and interest in DCS. We also collected drug samples and asked participants what drug(s) they expected were in the sample. Provided samples were analyzed using LC-MS technology and the results compared to their expected drugs. RESULTS: Participants reported an average of 4.4 lifetime overdoses (SD = 4.8, range = 0-20) and 1.1 (SD = 1.8, range = 0-10) past-year overdoses. A majority (92.1%) believed they had recently used drugs containing fentanyl whether intentionally or unintentionally. Opinions about the desirability of fentanyl were mixed with 56.1% indicating they did not and 38.0% indicating they did prefer fentanyl over other opioids, mainly heroin. Attitudes toward DCS indicated a general but not uniform receptiveness with a majority indicating interest in DCS though sizeable minorities believed DCS was "too much trouble" (25.2%) or there was "no point" in testing (35.4%). Participants were especially inaccurate identifying common cutting agents and potentiating drugs such as diphenhydramine in their samples (sensitivity = .17). CONCLUSIONS: Results affirmed street drug users remain interested in using DCS to monitor their drugs and such services should be more widely available. Advanced checking technologies that provide information on the relative quantities and the different drugs present in a given sample available at point-of-care, would be most valuable but remain challenging to implement.

Providers' Perceptions Versus Practices Inform Pediatric Colorectal Enhanced Recovery After Surgery Implementation.

INTRODUCTION: There are many barriers to the implementation of an enhanced recovery after surgery (ERAS) pathway. The aim of this study was to compare surgeon and anesthesia perceptions with current practices prior to the initiation of an ERAS protocol in pediatric colorectal patients and to use that information to inform ERAS implementation. METHODS: This was a mixed method single institution study of barriers to implementation of an ERAS pathway at a free-standing children's hospital. Anesthesiologists and surgeons at a free-standing children's hospital were surveyed regarding current practices of ERAS components. A retrospective chart review was performed of 5- to 18-y-old patients undergoing colorectal procedures between 2013 and 2017, followed by the initiation of an ERAS pathway, and a prospective chart review for 18 mo postimplementation. RESULTS: The response rate was 100% (n = 7) for surgeons and 60% (n = 9) for anesthesiologists. Preoperative nonopioid analgesics and regional anesthesia were rarely used. Intraoperatively, 54.7% of patients had a fluid balance of <10 cc/kg/h and normothermia was achieved in only 38.7%. Mechanical bowel prep was frequently utilized (48%). Median nil per os time was significantly longer than required at 12 h. Postoperatively, 42.9% of surgeons reported that patients could have clears on postoperative day zero, 28.6% on postoperative day one, and 28.6% after flatus. In reality, 53.3% of patients were started on clears after flatus, with a median time of 2 d. Most surgeons (85.7%) expected patients to get out of bed once awake from anesthesia; however, median time that patients were out of bed was postoperative day one. While most surgeons reported frequent use of acetaminophen and/or ketorolac, only 69.3% received any nonopioid analgesic postoperatively, with only 41.3% receiving two or more nonopioid analgesics. Nonopioid analgesia showed the highest rates of improvement from retrospective to prospective: preoperative use of analgesics increased from 5.3% to 41.2% (P < 0.0001), postoperative use of acetaminophen increased by 27.4% (P = 0.5), Toradol by 45.5% (P = 0.11), and gabapentin by 86.7% (P < 0.0001). Postoperative nausea/vomiting prophylaxis with >1 class of antiemetic increased from 8% to 47.1% (P < 0.001). The length of stay was unchanged (5.7 versus 4.4 d, P = 0.14). CONCLUSIONS: For the successful implementation of an ERAS protocol, perceptions versus reality must be assessed to determine current practices and identify barriers to implementation.

Validated method for the analysis of 22 illicit drugs and their metabolites via liquid chromatography tandem mass spectrometry (LC-MS/MS) in illicit drug samples collected in Chicago, IL.

Drug checking services are being utilized worldwide to provide people who use drugs information on the composition and contents of their drugs as a tool for harm reduction and accidental overdose prevention. Existing drug checking services use a variety of techniques including immunoassay strips and spectroscopic techniques like FTIR and Raman. Few services utilize LC-MS based methods for primary or secondary analysis and few methods exist for direct analysis of illicit drugs. To address this, an LC-MS/MS method was developed for 22 illicit drugs and cutting agents using LC-MS/MS with application to 124 illicit drug samples that were collected from Chicago, IL. Samples were also analyzed using fentanyl and benzodiazepine immunoassay test strips. Fentanyl test strips gave a positive result for 86% of samples with only one sample showing a positive result on a benzodiazepine test strip. LC-MS/MS analysis of samples show that opioids were the most commonly quantified in 96% of samples, followed by stimulants at 12% and benzodiazepines at 1%. Fentanyl was measured in 91% of samples, co-occurring with heroin in 58% of opioid-containing samples. A comparison of the gold-standard LC-MS/MS results to fentanyl test strips shows a high level of accuracy for the fentanyl test strips, with just 5% of samples being classified as false negatives and no false positives. These results demonstrate the strengths and benefits of LC-MS/MS when incorporated as a secondary analysis tool for drug checking.

Discrimination of Substandard and Falsified Formulations from Genuine Pharmaceuticals Using NIR Spectra and Machine Learning.

Near-infrared (NIR) spectroscopy is a promising technique for field identification of substandard and falsified drugs because it is portable, rapid, nondestructive, and can differentiate many formulated pharmaceutical products. Portable NIR spectrometers rely heavily on chemometric analyses based on libraries of NIR spectra from authentic pharmaceutical samples. However, it is difficult to build comprehensive product libraries in many low- and middle-income countries due to the large numbers of manufacturers who supply these markets, frequent unreported changes in materials sourcing and product formulation by the manufacturers, and general lack of cooperation in providing authentic samples. In this work, we show that a simple library of lab-formulated binary mixtures of an active pharmaceutical ingredient (API) with two diluents gave good performance on field screening tasks, such as discriminating substandard and falsified formulations of the API. Six data analysis models, including principal component analysis and support-vector machine classification and regression methods and convolutional neural networks, were trained on binary mixtures of acetaminophen with either lactose or ascorbic acid. While the models all performed strongly in cross-validation (on formulations similar to their training set), they individually showed poor robustness for formulations outside the training set. However, a predictive algorithm based on the six models, trained only on binary samples, accurately predicts whether the correct amount of acetaminophen is present in ternary mixtures, genuine acetaminophen formulations, adulterated acetaminophen formulations, and falsified formulations containing substitute APIs. This data analytics approach may extend the utility of NIR spectrometers for analysis of pharmaceuticals in low-resource settings.

Securing the Chain of Custody and Integrity of Data in a Global North-South Partnership to Monitor the Quality of Essential Medicines.

Substandard and falsified (SF) pharmaceuticals account for an estimated 10% of the pharmaceutical supply chain in low- and middle-income countries (LMICs), where a lack of regulatory and laboratory resources limits the ability to conduct effective post-market surveillance and allows SF products to penetrate the supply chain. The Distributed Pharmaceutical Analysis Laboratory (DPAL) was established in 2014 to expand testing of pharmaceutical dosage forms sourced from LMICs; DPAL is an alliance of academic institutions throughout the United States and abroad that provides high-quality, validated chemical analysis of pharmaceutical dosage forms sourced from partners in LMICs. Results from analysis are reported to relevant regulatory agencies and are used to inform purchasing decisions made by in-country stakeholders. As the DPAL program has expanded to testing more than 1,000 pharmaceutical dosage forms annually, challenges have surfaced regarding data management and sample tracking. Here, we describe a pilot project between DPAL and ARTiFACTs that applies the blockchain to organize and manage key data generated during the DPAL workflow, including a sample's progress through the workflow, its physical location, provenance of metadata, and lab reputability. Recording time and date stamps with these data will create a permanent and verifiable chain of custody for samples. This secure, distributed ledger will be linked to an easy-to-use dashboard, allowing stakeholders to view results and experimental details for each sample in real time and verify the integrity of DPAL analysis data. Introducing this blockchain-based system as a pilot will allow us to test the technology with real users analyzing real samples. Feedback from users will be recorded and necessary adjustments will be made to the system before the implementation of blockchain across all DPAL sites. Anticipated benefits of implementing the blockchain technology for managing DPAL data include efficient management for routing work, increasing throughput, creating a chain of custody for samples and their data in alignment with the distributed nature of DPAL, and using the analysis results to detect patterns of quality within and across brands of products and develop enhanced sampling techniques and best practices.

Iron Quantum Dots Electro-Assembling on Vulcan XC-72R: Hydrogen Peroxide Generation for Space Applications.

Highly dispersed iron-based quantum dots (QDs) onto powdered Vulcan XC-72R substrate were successfully electrodeposited by the rotating disk slurry electrodeposition (RoDSE) technique. Our findings through chemical physics characterization revealed that the continuous electron pathway interaction between the interface metal-carbon is controlled. The rotating ring-disk electrode (RRDE) and the prototype generation unit (PGU) of in-situ H2O2 generation in fuel cell experiments revealed a high activity for the oxygen reduction reaction (ORR) via two-electron pathway. These results establish the Fe/Vulcan catalyst at a competitive level for space and terrestrial new materials carriers, specifically for the in-situ H2O2 production. Transmission electron microscopy (TEM) analysis reveals the well-dispersed Fe-based quantum dots with a particle size of 4 nm. The structural and chemical-physical characterization through induced coupled plasma-optical emission spectroscopy (ICP-OES), transmission scanning electron microscopy (STEM), X-ray diffraction (XRD), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and X-ray absorption spectroscopy (XAS); reveals that, under atmospheric conditions, our quantum dots system is a Fe2+/3+/Fe3+ combination. The QDs oxidation state tunability was showed by the applied potential. The obtention of H2O2 under the compatibility conditions of the drinking water resources available in the International Space Station (ISS) enhances the applicability of this iron- and carbon-based materials for in-situ H2O2 production in future space scenarios. Terrestrial and space abundance of iron and carbon, combined with its low toxicity and high stability, consolidates this present work to be further extended for the large-scale production of Fe-based nanoparticles for several applications.

Geospatial mapping and resource utilization tool in support of a national smoke-free public housing rule.

OBJECTIVE: To advance public health support for the U.S. Department of Housing and Urban Development's smoke-free rule, the Centers for Disease Control and Prevention collaborated with the Georgia Institute of Technology to develop a geospatial mapping tool. The objective was to create a tool state and local public health agencies could use to tailor smoke-free educational materials and cessation interventions for specific public housing development resident populations. RESULTS: The resulting "Extinguish Tool" includes an interactive map of U.S. public housing developments (PHDs) and healthcare facilities that provides detailed information on individual PHDs, their proximity to existing healthcare facilities, and the demographic characteristics of residents. The tool also estimates the number of PHD residents who smoke cigarettes and calculates crude estimates of the potential economic benefits of providing cessation interventions to these residents. The geospatial mapping tool project serves as an example of a collaborative and innovative public health approach to protecting the health and well-being of the nation's two million public housing residents, including 760,000 children, from the harms of tobacco smoking and secondhand smoke exposure in the places where they live, play, and gather.

The effect of resident involvement on bariatric surgical outcomes: an ACS-NSQIP analysis.

BACKGROUND: Surgical residency training programs in the United States are modeled on the principle of graduated responsibility. Residents are given greater responsibility and autonomy in the operating room and during perioperative care as they gain surgical skills and progress through their training. The impact of this method of surgical training on patient outcomes remains unknown. The purpose of this study is to compare early patient morbidity and mortality after bariatric surgery in cases with and without resident participation using the American College of Surgeons National Surgical Quality Improvement Program database. METHODS: All patients undergoing bariatric surgery from 2006 through 2010 were identified within the American College of Surgeons National Surgical Quality Improvement Program database. These patients were divided into three groups based on resident involvement in their surgery (no resident, senior-level resident, and junior-level resident). The effect of resident involvement and postgraduate year level on 30-d morbidity and mortality was investigated using composite outcomes, including cardiac events (acute myocardial infarction or cardiac arrest requiring cardiopulmonary resuscitation), pulmonary events (pneumonia, prolonged intubation, or unplanned reintubation), wound (superficial surgical site infection, deep surgical site infection, organ-space infection, or dehiscence), septic events (sepsis and septic shock), clotting events (pulmonary embolism and deep venous thrombosis), and renal events (urinary tract infection and acute kidney injury requiring dialysis). Length of hospital stay, unplanned return to the operating room, and 30-d mortality were also investigated. RESULTS: A total of 19,616 patients underwent bariatric surgery from the year 2006 through 2010; 8960 (45.7%) procedures were performed with resident involvement, with 5406 (36.7%) of these cases involving a senior-level resident. Operations involving a senior-level resident were more likely to experience postoperative cardiac events (P < 0.006), pulmonary events (P = 0.03), wound events (P = 0.01), septic events (P < 0.002), renal events (P ≤ 0.01), prolonged operative time (P < 0.0001), and a prolonged length of hospital stay (P < 0.0001) than those that involved either no resident or a junior-level resident. CONCLUSIONS: Although bariatric operations involving senior-level residents have more statistically significant morbidity outcomes, these morbidity outcomes are related more to perioperative care rather than intraoperative resident involvement. This suggests that more emphasis on perioperative progressive responsibility may be needed to match operative oversight.

The Influence of Palliative Care Consultation on Health-Care Resource Utilization During the Last 2 Months of Life: Report From an Integrated Palliative Care Program and Review of the Literature.

BACKGROUND: We reviewed 104 consecutive deaths of veterans receiving care in the Dayton VA Medical Center from October 10, 2015 to April 11, 2016. The purpose of our study was to test our hypothesis that palliative care consultation would be associated with reduced health care resource utilization for individuals approaching end of life. METHODS: Medical records were reviewed and data entry recorded on a spreadsheet. Non-parametric statistical methods were used to compare four outcome variables from veterans with palliative care consultation (PCC) vs. those without PCC. These variables included the number of ED visits, hospitalizations, hospital days, and ICU days all during the last two months of life. Predictor variables included PCC vs. no PCC and PCC before vs. PCC during the last two months of life. The study sample was comprised of 102 patients after excluding two outlier cases with ethical challenges in surrogate decision-making. RESULTS: Of the 102 consecutive veteran deaths, palliative care consultation was associated with a lower number of ICU days during the last two months of life. For 96 veterans with PCC, the frequency of ED visits and acute care hospitalizations, as well as the number of ICU and hospital days, were all significantly less after PCC compared to before PCC during the last two months of life. The timing of PCC had no effect on the outcomes of interest. CONCLUSION: Palliative care consultation has a notable effect on health care resource utilization during the last two months of life.

Impact of Appropriate Use on the Estimated Radiation Risk to Men and Women Undergoing Radionuclide Myocardial Perfusion Imaging.

UNLABELLED: The impact of appropriate use criteria (AUC) for myocardial perfusion imaging (MPI) with SPECT on the estimated lifetime attributable risk (LAR) of cancer is unknown. METHODS: A cohort of 1,511 consecutive patients who underwent clinically indicated (99m)Tc-setamibi MPI were categorized into appropriate/uncertain (n = 823) versus inappropriate (n = 688) use groups according to the 2009 AUC and were prospectively followed for 27 ± 10 mo. Logistic regression models were used to determine the annualized probability of major adverse cardiac events (MACE) of cardiac death or myocardial infarction and the probability of revascularization within 6 mo of MPI, accounting for relevant covariates. We determined LAR for each subject on the basis of accepted risk estimates. We calculated MPI's benefit-to-risk ratios, defined by the annualized predicted MACE-to-LAR ratio and the predicted 6-mo-revascularization-to-LAR ratio. RESULTS: During follow-up, there were 22 MACE and 29 6-mo revascularizations. The administered radioactivity and effective radiation doses absorbed were similar between the study groups. Patients with inappropriate MPI had significantly higher LAR (median, 0.08% vs. 0.06%, P < 0.001), lower predicted MACE-to-LAR ratio (median, 1.5 vs. 4.3, P < 0.001), and lower predicted 6-mo-revascularization-to-LAR ratio (median, 5.4 vs. 15.5, P < 0.001). Women had higher LAR (median, 0.08% vs. 0.07%, P < 0.001) and lower predicted MACE-to-LAR ratio (median, 1.9 vs. 3.3, P < 0.001) and 6-mo-revascularization-to-LAR ratio (median, 4.4 vs. 17.5, P < 0.001). However, appropriate/uncertain use negated the difference between men and women in LAR (P = 0.94) and the predicted MACE-to-LAR ratio (P = 0.97). CONCLUSION: Inappropriate MPI use is associated with excess cancer risk and lower MPI's benefit-to-risk ratio. Appropriate/uncertain use neutralizes the sex gap in LAR with MPI.

Appropriate use criteria for SPECT myocardial perfusion imaging: Are they appropriate for women?

BACKGROUND: Several studies have reported that women are more likely to receive inappropriate SPECT myocardial perfusion imaging (MPI), suggesting gender disparity in AUC determination. We investigated the impact of gender on the diagnostic and prognostic utility of AUC. METHODS AND RESULTS: We analyzed a multi-site prospective cohort of 1511 consecutive patients (43.5% women) who underwent outpatient, community-based SPECT-MPI. Subjects were stratified into gender groups and appropriateness subgroups, and followed for 27 ± 10 months for cardiac death, myocardial infarction, and coronary revascularization. Women were more likely to receive inappropriate MPI (60.7% vs 33.8%, P < .001). Irrespective of appropriateness, women were less likely to have an abnormal MPI (6.1% vs 14.9%, P < .001), even after adjusting for clinical covariates [odds ratio = 0.40 (95% confidence interval = 0.26-0.60), P < .001]. Irrespective of appropriateness, women were at lower risk for MACE (composite of cardiac death, myocardial infarction, or coronary revascularization) after adjusting for clinical and imaging covariates [hazard ratio = 0.49 (95% confidence interval = 0.28-0.86), P = .01]. There was no interaction between gender and appropriateness group as a determinant of abnormal MPI or MACE (interaction P values ≥ .26), indicating that female gender was associated with similar relative risk of an abnormal MPI and MACE irrespective of appropriateness group. Abnormal MPI was similarly predictive of increased hazard of MACE in both genders, regardless of appropriateness (interaction P values ≥ .46). CONCLUSION: In this multi-site cohort, there was no demonstrable gender-based differential impact of AUC on the diagnostic or prognostic utility of SPECT-MPI. The study validates the methods used in determining risk in the AUC algorithm and endorses the widespread application of AUC in men and women.

Impact of insurance carrier, prior authorization, and socioeconomic status on appropriate use of SPECT myocardial perfusion imaging in private community-based office practice.

BACKGROUND: The impact of health insurance carrier and socioeconomic status (SES) on the adherence to appropriate use criteria (AUC) for radionuclide myocardial perfusion imaging (MPI) is unknown. HYPOTHESIS: Health insurance carrier's prior authorization and patient's SES impact adherence to AUC for MPI in a fee-for-service setting. METHODS: We conducted a prospective cohort study of 1511 consecutive patients who underwent outpatient MPI in a multi-site, office-based, fee-for-service setting. The patients were stratified according to the 2009 AUC into appropriate/uncertain appropriateness and inappropriate use groups. Insurance status was categorized as Medicare (does not require prior authorization) vs commercial (requires prior authorization). Socioeconomic status was determined by the median household income in the ZIP code of residence. RESULTS: The proportion of patients with Medicare was 33% vs 67% with commercial insurance. The rate of inappropriate use was higher among patients with commercial insurance vs Medicare (55% vs 24%; P < 0.001); this difference was not significant after adjusting for confounders known to impact AUC determination (odds ratio: 1.06, 95% confidence interval: 0.62-1.82, P = 0.82). The mean annual household income in the residential areas of patients with inappropriate use as compared to those with appropriate/uncertain use was $72 000 ± 21 000 vs $68 000 ± 20 000, respectively (P < 0.001). After adjusting for covariates known to impact AUC determination, SES (top vs bottom quartile income area) was not independently predictive of inappropriate MPI use (odds ratio: 0.9, 95% confidence interval: 0.53-1.52, P = 0.69). CONCLUSIONS: Insurance carriers prior authorization and SES do not seem to play a significant role in determining physicians adherence to AUC for MPI.

Mitotic asynchrony induces transforming growth factor-ß1 secretion from airway epithelium.

We recently proposed that mitotic asynchrony in repairing tissue may underlie chronic inflammation and fibrosis, where immune cell infiltration is secondary to proinflammatory cross-talk among asynchronously repairing adjacent tissues. Building on our previous finding that mitotic asynchrony is associated with proinflammatory/fibrotic cytokine secretion (e.g., transforming growth factor [TGF]-ß1), here we provide evidence supporting cause-and-effect. Under normal conditions, primary airway epithelial basal cell populations undergo mitosis synchronously and do not secrete proinflammatory or profibrotic cytokines. However, when pairs of nonasthmatic cultures were mitotically synchronized at 12 hours off-set and then combined, the mixed cell populations secreted elevated levels of TGF-ß1. This shows that mitotic asynchrony is not only associated with but is also causative of TGF-ß1 secretion. The secreted cytokines and other mediators from asthmatic cells were not the cause of asynchronous regeneration; synchronously mitotic nonasthmatic epithelia exposed to conditioned media from asthmatic cells did not show changes in mitotic synchrony. We also tested if resynchronization of regenerating asthmatic airway epithelia reduces TGF-ß1 secretion and found that pulse-dosed dexamethasone, simvastatin, and aphidicolin were all effective. We therefore propose a new model for chronic inflammatory and fibrotic conditions where an underlying factor is mitotic asynchrony.

Impact of appropriate use on the prognostic value of single-photon emission computed tomography myocardial perfusion imaging.

BACKGROUND: Appropriate use criteria (AUC) have been developed to aid in the optimal use of single-photon emission computed tomography (SPECT)-myocardial perfusion imaging (MPI), a technique that is a mainstay of risk assessment for ischemic heart disease. The impact of appropriate use on the prognostic value of SPECT-MPI is unknown. METHODS AND RESULTS: A prospective cohort study of 1511 consecutive patients undergoing outpatient, community-based SPECT-MPI was conducted. Subjects were stratified on the basis of the 2009 AUC for SPECT-MPI into an appropriate or uncertain appropriateness group and an inappropriate group. Patients were prospectively followed up for 27±10 months for major adverse cardiac events of death, death or myocardial infarction, and cardiac death or myocardial infarction. In the entire cohort, the 167 subjects (11%) with an abnormal scan experienced significantly higher rates of major adverse cardiac events and coronary revascularization than those with normal MPI. Among the 823 subjects (54.5%) whose MPIs were classified as appropriate (779, 51.6%) or uncertain (44, 2.9%), an abnormal scan predicted a multifold increase in the rates of death (9.2% versus 2.6%; hazard ratio, 3.1; P=0.004), death or myocardial infarction (11.8% versus 3.3%; hazard ratio, 3.3; P=0.001), cardiac death or myocardial infarction (6.7% versus 1.7%; hazard ratio, 3.7; P=0.006), and revascularization (24.7% versus 2.7%; hazard ratio, 11.4; P<0.001). Among the 688 subjects (45.5%) with MPI classified as inappropriate, an abnormal MPI failed to predict major adverse cardiac events, although it was associated with a high revascularization rate. Furthermore, appropriate MPI use provided incremental prognostic value beyond myocardial perfusion and ejection fraction data. CONCLUSIONS: When performed for appropriate indications, SPECT-MPI continues to demonstrate high prognostic value. However, inappropriate use lacks effectiveness for risk stratification, further emphasizing the need for optimal patient selection for cardiac testing.