Synthesis and biological profile of substituted hexahydrofuro[3,4-b]furans, a novel class of bicyclic acyl-acyl carrier protein (ACP) thioesterase inhibitors.

BACKGROUND: Weed control is a significant challenge for farmers around the globe. Of the various methods available for combatting weeds, small molecules remain the most effective and versatile technology to date. In the search for novel chemical entities with new modes of action toward herbicide-resistant weeds, we have investigated hexahydrofuro[3,4-b]furan-based acyl-acyl carrier protein (ACP) thioesterase inhibitors inspired by X-ray co-crystal structure-based modeling studies. RESULTS: By exploiting scaffold hopping concepts and molecular modeling studies we were able to identify new hexahydrofuro[3,4-b]furan-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity. CONCLUSION: The present work covers a series of novel herbicidal lead structures that possess a hexahydrofuro[3,4-b]furan scaffold as a structural key feature, carrying ortho-substituted aryloxy side chains. Based on an optimized synthetic approach a broad structure-activity relationship (SAR) study was carried out. The new compounds emerging from our modeling-inspired structural variations show good acyl-ACP thioesterase inhibition in line with promising initial herbicidal activity. Glasshouse trials showed that the hexahydrofuro[3,4-b]furans outlined herein display good control of cold and warm season grass-weed species in pre-emergence application. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors also showed promising efficacy against warm season weeds that are difficult to control. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Towards algorithm auditing: managing legal, ethical and technological risks of AI, ML and associated algorithms.

-Business reliance on algorithms is becoming ubiquitous, and companies are increasingly concerned about their algorithms causing major financial or reputational damage. High-profile cases include Google's AI algorithm for photo classification mistakenly labelling a black couple as gorillas in 2015 (Gebru 2020 In The Oxford handbook of ethics of AI, pp. 251-269), Microsoft's AI chatbot Tay that spread racist, sexist and antisemitic speech on Twitter (now X) (Wolf et al. 2017 ACM Sigcas Comput. Soc. 47, 54-64 (doi:10.1145/3144592.3144598)), and Amazon's AI recruiting tool being scrapped after showing bias against women. In response, governments are legislating and imposing bans, regulators fining companies and the judiciary discussing potentially making algorithms artificial 'persons' in law. As with financial audits, governments, business and society will require algorithm audits; formal assurance that algorithms are legal, ethical and safe. A new industry is envisaged: Auditing and Assurance of Algorithms (cf. data privacy), with the remit to professionalize and industrialize AI, ML and associated algorithms. The stakeholders range from those working on policy/regulation to industry practitioners and developers. We also anticipate the nature and scope of the auditing levels and framework presented will inform those interested in systems of governance and compliance with regulation/standards. Our goal in this article is to survey the key areas necessary to perform auditing and assurance and instigate the debate in this novel area of research and practice.

Understanding the impact of COVID-19 on antibiotic use in Canadian primary care: a matched-cohort study using EMR data.

BACKGROUND: Inappropriate or overuse of antibiotic prescribing in primary care highlights an opportunity for antimicrobial stewardship (AMS) programs aimed at reducing unnecessary use of antimicrobials through education, policies and practice audits that optimize antibiotic prescribing. Evidence from the early part of the pandemic indicates a high rate of prescribing of antibiotics for patients with COVID-19. It is crucial to surveil antibiotic prescribing by primary care providers from the start of the pandemic and into its endemic stage to understand the effects of the pandemic and better target effective AMS programs. METHODS: This was a matched pair population-based cohort study that used electronic medical record (EMR) data from the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). Participants included all patients that visited their primary care provider and met the inclusion criteria for COVID-19, respiratory tract infection (RTI), or non-respiratory or influenza-like-illness (negative). Four outcomes were evaluated (a) receipt of an antibiotic prescription; (b) receipt of a non-antibiotic prescription; (c) a subsequent primary care visit (for any reason); and (d) a subsequent primary care visit with a bacterial infection diagnosis. Conditional logistic regression was used to evaluate the association between COVID-19 and each of the four outcomes. Each model was adjusted for location (rural or urban), material and social deprivation, smoking status, alcohol use, obesity, pregnancy, HIV, cancer and number of chronic conditions. RESULTS: The odds of a COVID-19 patient receiving an antibiotic within 30 days of their visit is much lower than for patients visiting for RTI or for a non-respiratory or influenza-like-illnesses (AOR = 0.08, 95% CI[0.07, 0.09] compared to RTI, and AOR = 0.43, 95% CI[0.38, 0.48] compared to negatives). It was found that a patient visit for COVID-19 was much less likely to have a subsequent visit for a bacterial infection at all time points. CONCLUSIONS: Encouragingly, COVID-19 patients were much less likely to receive an antibiotic prescription than patients with an RTI. However, this highlights an opportunity to leverage the education and attitude change brought about by the public health messaging during the COVID-19 pandemic (that antibiotics cannot treat a viral infection), to reduce the prescribing of antibiotics for other viral RTIs and improve antibiotic stewardship.

The Effect of a Direct Fed Microbial on Liveweight and Milk Production in Dairy Cattle.

This longitudinal study aimed to quantify the effects of dietary supplementation of a direct-fed microbial (DFM) consisting of three lactobacilli isolates on milk yield, milk fat and protein yields, somatic cell count (SCC), and liveweight in a single dairy herd in Australia. A total of 150 dairy cows were randomly selected based on parity and days in milk and divided into two groups: control (n = 75) and DFM treatment (n = 75). Throughout the study, the two groups of cows were housed separately in a dry lot yard, and each group had their own feeding area. For the DFM treatment group, selected cows in mid-lactation were supplemented with 10 mL/cow/day of the DFM via top dressing of the feed for the remainder of the lactation and through the dry period, extending into subsequent lactation. The control group had no supplementation. The milk yield and liveweight were recorded daily. Milk samples were collected every two months for milk component analysis (fat, protein, and somatic cell count [SCC]). The DFM-treated cows gained more liveweight across the study (19.40 kg, 95% CI 0.44 kg; 38.30 kg, p = 0.05) compared to the control cows. In the second production year, the DFM-treated cows mobilized more liveweight (-6.06 kg, 95% CI -10.49 kg; -1.61 kg, p = 0.01) and produced more milk (0.39 L/d 95% CI 0.10; 0.89, p = 0.05). Over a full lactation, DFM cows yielded at least 258 L (95% CI 252 L; 265 L) more milk than controls. No significant differences were found in fat and protein yield or SCC. This study suggests that consistent and ongoing supplementation with a Lacticaseibacillus- and Lentilactobacillus-based DFM could have a positive effect on milk production, but further research is needed to understand the underlying mechanism.

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors.

The present work covers novel herbicidal lead structures that contain a 2,3-dihydro[1,3]thiazolo[4,5-b]pyridine scaffold as structural key feature carrying a substituted phenyl side chain. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity against commercially important weeds in broadacre crops, e.g., wheat and corn. The desired substituted 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines were prepared via an optimized BH3-mediated reduction involving tris(pentafluorophenyl)borane as a strong Lewis acid. Remarkably, greenhouse trials showed that some of the target compounds outlined herein display promising control of grass weed species in preemergence application, combined with a dose response window that enables partial selectivity in certain crops.

Prevalence and management of dyslipidemia in primary care practices in Canada.

OBJECTIVE: To estimate the prevalence of dyslipidemia and to describe its management in Canadian primary care. DESIGN: Retrospective cohort study using primary care electronic medical record data. SETTING: Canada. PARTICIPANTS: Adults aged 40 years or older who saw a Canadian Primary Care Sentinel Surveillance Network contributor between January 1, 2018, and December 31, 2019. MAIN OUTCOME MEASURES: Presence or absence of dyslipidemia as identified by a validated case definition and the treatment status of patients identified as having dyslipidemia based on having been prescribed a lipid-lowering agent (LLA). RESULTS: In total, 50.0% of the 773,081 patients 40 years of age or older who had had a primary care visit in 2018 or 2019 were identified as having dyslipidemia. Dyslipidemia was more prevalent in patients 65 or older (61.5%), in males (56.7%) versus females (44.7%), and in those living in urban areas (50.0%) versus rural areas (45.2%). In patients with documented dyslipidemia, 42.8% had evidence of treatment with an LLA. Stratifying patients by Framingham risk score revealed that those in the high-risk category were more likely to have been prescribed an LLA (65.0%) compared with those in the intermediate-risk group (48.7%) or the low-risk group (22.8%). The strongest determinants of receiving LLA treatment for dyslipidemia include sex, with males being 1.95 times more likely to have been treated compared with females (95% CI 1.91 to 1.98; P<.0001); and body mass index, with those with obesity having a significantly increased likelihood of being treated with an LLA (adjusted odds ratio of 1.36, 95% CI 1.32 to 1.41; P<.0001). CONCLUSION: This study provides an updated look at the prevalence and treatment of dyslipidemia among Canadians. Half of patients aged 40 years or older have dyslipidemia, with an even higher prevalence observed among adults aged 65 years or older, males, and those with obesity or other chronic conditions. There are still gaps in treatment among those with documented dyslipidemia, principally among those calculated to have high or intermediate Framingham risk scores. Particular attention should also be paid to those at higher risk for not receiving treatment, including female patients and those within normal body mass index ranges.

Discovery and optimization of spirocyclic lactams that inhibit acyl-ACP thioesterase.

BACKGROUND: There are various methods to control weeds, that represent considerable challenges for farmers around the globe, although applying small molecular compounds is still the most effective and versatile technology to date. In the search for novel chemical entities with new modes-of-action that can control weeds displaying resistance, we have investigated two spirocyclic classes of acyl-ACP thioesterase inhibitors based on X-ray co-crystal structures and subsequent modelling studies. RESULTS: By exploiting scaffold-hopping and isostere concepts, we were able to identify new spirolactam-based lead structures showing promising activity in vivo against commercially important grass weeds in line with strong target affinity. CONCLUSION: The present work covers a series of novel herbicidal lead structures that contain a spirocyclic lactam as a structural key feature carrying ortho-substituted benzyl or heteroarylmethylene side chains. These new compounds show good acyl-ACP thioesterase inhibition in line with strong herbicidal activity. Glasshouse trials showed that the spirolactams outlined herein display promising control of grass-weed species in pre-emergence application combined with dose-response windows that enable partial selectivity in wheat and corn. Remarkably, some of the novel acyl-ACP thioesterase-inhibitors showed efficacy against resistant grass weeds such as Alopecurus myosuroides and Lolium spp. on competitive levels compared with commercial standards. © 2024 Society of Chemical Industry.

Mortality surrogates in combined pulmonary fibrosis and emphysema.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) with coexistent emphysema, termed combined pulmonary fibrosis and emphysema (CPFE) may associate with reduced forced vital capacity (FVC) declines compared to non-CPFE IPF patients. We examined associations between mortality and functional measures of disease progression in two IPF cohorts. METHODS: Visual emphysema presence (>0% emphysema) scored on computed tomography identified CPFE patients (CPFE/non-CPFE: derivation cohort n=317/n=183, replication cohort n=358/n=152), who were subgrouped using 10% or 15% visual emphysema thresholds, and an unsupervised machine-learning model considering emphysema and interstitial lung disease extents. Baseline characteristics, 1-year relative FVC and diffusing capacity of the lung for carbon monoxide (D LCO) decline (linear mixed-effects models), and their associations with mortality (multivariable Cox regression models) were compared across non-CPFE and CPFE subgroups. RESULTS: In both IPF cohorts, CPFE patients with ≥10% emphysema had a greater smoking history and lower baseline D LCO compared to CPFE patients with <10% emphysema. Using multivariable Cox regression analyses in patients with ≥10% emphysema, 1-year D LCO decline showed stronger mortality associations than 1-year FVC decline. Results were maintained in patients suitable for therapeutic IPF trials and in subjects subgrouped by ≥15% emphysema and using unsupervised machine learning. Importantly, the unsupervised machine-learning approach identified CPFE patients in whom FVC decline did not associate strongly with mortality. In non-CPFE IPF patients, 1-year FVC declines ≥5% and ≥10% showed strong mortality associations. CONCLUSION: When assessing disease progression in IPF, D LCO decline should be considered in patients with ≥10% emphysema and a ≥5% 1-year relative FVC decline threshold considered in non-CPFE IPF patients.

CenTime: Event-conditional modelling of censoring in survival analysis.

Survival analysis is a valuable tool for estimating the time until specific events, such as death or cancer recurrence, based on baseline observations. This is particularly useful in healthcare to prognostically predict clinically important events based on patient data. However, existing approaches often have limitations; some focus only on ranking patients by survivability, neglecting to estimate the actual event time, while others treat the problem as a classification task, ignoring the inherent time-ordered structure of the events. Additionally, the effective utilisation of censored samples-data points where the event time is unknown- is essential for enhancing the model's predictive accuracy. In this paper, we introduce CenTime, a novel approach to survival analysis that directly estimates the time to event. Our method features an innovative event-conditional censoring mechanism that performs robustly even when uncensored data is scarce. We demonstrate that our approach forms a consistent estimator for the event model parameters, even in the absence of uncensored data. Furthermore, CenTime is easily integrated with deep learning models with no restrictions on batch size or the number of uncensored samples. We compare our approach to standard survival analysis methods, including the Cox proportional-hazard model and DeepHit. Our results indicate that CenTime offers state-of-the-art performance in predicting time-to-death while maintaining comparable ranking performance. Our implementation is publicly available at https://github.com/ahmedhshahin/CenTime.

Validation of adult asthma case definitions for primary care sentinel surveillance.

BACKGROUND: Most asthma diagnoses and patient care take place in primary care settings. Electronic medical records (EMRs) offer an opportunity to utilize technology to improve asthma diagnosis and care. The purpose of this study was to create and validate separate case definitions for suspected and confirmed asthma in primary care EMRs, to enable surveillance, benchmarking, and quality improvement in primary care settings. The objective of this study was to develop a case definition for suspected and confirmed asthma for use in a primary care sentinel surveillance system. METHODS: A single chart abstractor conducted a manual audit of 776 randomly selected patient charts from an academic primary care practice EMR in Kingston, Ontario. Following the single chart abstractor classification, a consensus on chart classification as "not asthma", "suspected asthma", or "confirmed asthma" was achieved between the abstractor, a family physician, and a respirologist using Canadian Thoracic Society (CTS) criteria. Case definition algorithms based on billing codes, clinical data elements and medications were applied to the site's Canadian Primary Care Sentinel Surveillance Network (CPCSSN) data for the same charts and compared to abstractor classifications to determine each algorithm's measurement properties. RESULTS: The prevalence of suspected and confirmed asthma were 7.3% (n = 54) and 2.4% (n = 18), respectively. None of the proposed case definitions could differentiate between suspected and confirmed asthma. One algorithm consisting of billing, clinical, and medication elements had the highest Youden's Index for either suspected or confirmed asthma. The algorithm had a sensitivity of 81%, a specificity of 96%, positive predictive value of 71%, negative predictive value of 98%, and a Youden's Index of 0.77 for combined suspected or confirmed asthma cases. CONCLUSION: An EMR case definition for suspected or confirmed adult asthma has been validated for use in CPCSSN. Implementation of this case definition will enable the development of a surveillance electronic tool (eTool) for adult asthma that can foster quality improvement.

A Study in Scaffold Hopping: Discovery and Optimization of Thiazolopyridines as Potent Herbicides That Inhibit Acyl-ACP Thioesterase.

In the search for new chemical entities that can control resistant weeds by addressing novel modes of action (MoAs), we were interested in further exploring a compound class that contained a 1,8-naphthyridine core. By leveraging scaffold hopping methodologies, we were able to discover the new thiazolopyridine compound class that act as potent herbicidal molecules. Further biochemical investigations allowed us to identify that the thiazolopyridines inhibit acyl-acyl carrier protein (ACP) thioesterase (FAT), with this being further confirmed via an X-ray cocrystal structure. Greenhouse trials revealed that the thiazolopyridines display excellent control of grass weed species in pre-emergence application coupled with dose response windows that enable partial selectivity in certain crops.

A hybrid CNN-RNN approach for survival analysis in a Lung Cancer Screening study.

In this study, we present a hybrid CNN-RNN approach to investigate long-term survival of subjects in a lung cancer screening study. Subjects who died of cardiovascular and respiratory causes were identified whereby the CNN model was used to capture imaging features in the CT scans and the RNN model was used to investigate time series and thus global information. To account for heterogeneity in patients' follow-up times, two different variants of LSTM models were evaluated, each incorporating different strategies to address irregularities in follow-up time. The models were trained on subjects who underwent cardiovascular and respiratory deaths and a control cohort matched to participant age, gender, and smoking history. The combined model can achieve an AUC of 0.76 which outperforms humans at cardiovascular mortality prediction. The corresponding F1 and Matthews Correlation Coefficient are 0.63 and 0.42 respectively. The generalisability of the model is further validated on an 'external' cohort. The same models were applied to survival analysis with the Cox Proportional Hazard model. It was demonstrated that incorporating the follow-up history can lead to improvement in survival prediction. The Cox neural network can achieve an IPCW C-index of 0.75 on the internal dataset and 0.69 on an external dataset. Delineating subjects at increased risk of cardiorespiratory mortality can alert clinicians to request further more detailed functional or imaging studies to improve the assessment of cardiorespiratory disease burden. Such strategies may uncover unsuspected and under-recognised pathologies thereby potentially reducing patient morbidity.

Value in Primary Care: Evidence from the Canadian Primary Care Sentinel Surveillance Network.

Primary care antimicrobial stewardship programs are virtually non-existent. Using electronic medical record (EMR) data for an interrupted time series study, the authors examined the relationship between antibiotic prescriptions for acute respiratory tract infections (RTIs) and the COVID-19 pandemic. The main outcome of the study was to gauge the proportion of RTI encounters with an antibiotic prescription. The pre-pandemic RTI antibiotic prescribing rate was 27.8%. During the COVID-19 pandemic, prescribing dropped significantly by 9.4% (p < 0.001). Almost 750,000 fewer patients could potentially avoid receiving an antibiotic prescription for RTI. The authors also discuss the value of EMR data; their use can help develop insights for health system improvement.

Impact of remuneration, extrinsic and intrinsic incentives on interprofessional primary care teams: protocol for a rapid scoping review.

INTRODUCTION: Interprofessional teams and funding and payment provider arrangements are key attributes of high-performing primary care. Several Canadian jurisdictions have introduced team-based models with different payment models. Despite these investments, the evidence of impact is mixed. This has raised questions about whether team-based primary care models are being implemented to facilitate team collaboration and effectiveness. Thus, we present a protocol for a rapid scoping review to systematically map, synthesise and summarise the existing literature on the impact of provider remuneration mechanisms and extrinsic and intrinsic incentives in team-based primary care. This review will answer three research questions: (1) What is the impact of provider remuneration models on team, patient, provider and system outcomes in primary care?; (2) What extrinsic and intrinsic incentives have been used in interprofessional primary care teams?; and (3) What is the impact of extrinsic and intrinsic team-based incentives on team, patient, provider and system outcomes? METHODS AND ANALYSIS: We will conduct a rapid scoping review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews guidelines. We will search electronic databases (Medline, Embase, CINAHL, PsycINFO, EconLit) and grey literature sources (Google Scholar, Google). This review will consider all empirical studies and full-text English-language articles published between 2000 and 2022. Reviewers will independently perform the literature search, data extraction and synthesis of included studies. The Mixed Methods Appraisal Tool will be used to appraise the quality of evidence. The literature will be synthesised, summarised and mapped to themes that answer the research question of this review. ETHICS AND DISSEMINATION: Ethics approval is not required. Findings from this study will be written for publication in an open-access peer-review journal and presented at national and international conferences. Knowledge users are part of the research team and will assist with disseminating findings to the public, clinicians, funders and professional associations.

Inspired by Nature: Isostere Concepts in Plant Hormone Chemistry.

Chemical concepts such as isosteres and scaffold hopping have proven to be powerful tools in agrochemical innovation processes. They offer opportunities to modify known molecular lead structures with the aim to improve a range of parameters, including biological efficacy and spectrum, physicochemical properties, stability, and toxicity. While recent biochemical insights into plant-specific receptors and signaling pathways trigger the discovery of the first lead structures, the disclosure of such a new chemical structure sparks a broad range of synthesis activities giving rise to diverse chemical innovation and often a considerable boost in biological activity. Herein, recent examples of isostere concepts in plant-hormone chemistry will be discussed, outlining how synthetic creativity can broaden the scope of natural product chemistry and giving rise to new opportunities in research fields such as abiotic stress tolerance and growth promotion.

Using Administrative Data in Primary Care to Evaluate the Effectiveness of a Continuing Professional Development Program Focused on the Management of Patients Living With Obesity.

INTRODUCTION: There are guidelines for referral to medical and/or surgical weight loss interventions (MSWLI) in Ontario; however, only about one-third of eligible patients in our region are being referred for consideration of MSWLI. METHODS: A planning committee, including a registered dietician, psychiatrist, endocrinologist, bariatric surgeon, family physician, and educationalists, developed an interdisciplinary continuing professional development (CPD) program focused on practical approaches to the management of patients living with obesity. The Kirkpatrick model was used to evaluate the educational outcomes of the CPD program specifically focusing on Level-2, -3, and -4 outcomes based on self-reported questionnaire and health administrative data. RESULTS: Eighteen primary care providers from the CPD program agreed to participate in this study, and 16 primary care providers (89%) completed the postintervention questionnaire and granted us access to their MSWLI referral data; 94% of study participants reported changes to their knowledge, comfort, and confidence (Level 2), as well as expected change in their future behaviour (Level 3) following the CPD program. However, there was no change in Kirkpatrick Level-4 outcomes, despite more than 90% of participants indicating that they will be making changes to their practice after the program. DISCUSSION: The CPD program in our study was overwhelmingly well received and participants reported knowledge (Level 2) and behavioural (Level 3) changes following participation; however, there was no detectable change in their clinical practice (Level 4). The methodology described in our proof-of-concept study can be modified and adopted to evaluate Level-4 outcomes in other studies of effectiveness of CPD interventions.

Baseline Inappropriate Antibiotic Use in Primary Care Patients with Viral Respiratory Tract Infections with 2019 and 2020.

Context: Respiratory tract infection (RTI) is the leading cause of avoidable antimicrobial use in primary care. How the COVID-19 pandemic has impacted antibiotic prescribing practices across Canada is unknown. The purpose of this study was to examine rates of antibiotic prescribing for RTI in primary care during the first year of the pandemic (2020), compared to baseline in 2019. Study Design and Analysis: Cross sectional study. Dataset: Canadian Primary Care Sentinel Surveillance Network electronic medical record data from sites in British Columbia, Alberta, Manitoba, Ontario, Quebec, Nova Scotia and Newfoundland. Population Studied: Patients that met the case definition criteria for an RTI or a Urinary Tract Infection (UTI) in 2019, and in 2020. Outcome measures: We examined oral antibiotic prescribing for patients who were identified as having a primary care visit for RTI. The same analysis was repeated for urinary tract infection (UTI) as a tracer condition. The antibiotic use considered avoidable for RTI was defined by Choosing Wisely Canada. Results: A total of 1,692,876 patients with a valid birth year and sex and at least one visit to primary care in 2019 and 2020 were included. Patient visits for RTI decreased from 2.3% in 2019 to 1.6% in 2020 (p<.0001), as did patient visits for UTI (1.1% vs 0.7%, p<.0001). In 2019, 28.0% of patients visits for RTI were prescribed an antibiotic, and this proportion decreased significantly to 20.6% in 2020 (<.0001). The drop in antibiotic prescriptions for RTI was driven by a decrease in prescribing for common cold (13.6% vs. 11.3%, <.0001) and for acute bronchitis/asthma (15.2% vs. 7.3%, p<.0001). In comparison, antibiotic prescribing for visits related to UTI increased marginally between 2019 and 2020 (71.6% vs. 72.3%, p=0.007). Conclusions: A significant decrease in antibiotic prescribing for RTI across primary care was observed during the first year of the COVID-19 pandemic, likely related to the changes in epidemiology and care delivery models in primary care. CPCSSN can provide pan-Canadian surveillance of antibiotic prescribing practices in primary care that can be used for provider feedback and quality improvement.