Mechanisms of cannabinoid tolerance.

Cannabis has been used recreationally and medically for centuries, yet research into understanding the mechanisms of its therapeutic effects has only recently garnered more attention. There is evidence to support the use of cannabinoids for the treatment of chronic pain, muscle spasticity, nausea and vomiting due to chemotherapy, improving weight gain in HIV-related cachexia, emesis, sleep disorders, managing symptoms in Tourette syndrome, and patient-reported muscle spasticity from multiple sclerosis. However, tolerance and the risk for cannabis use disorder are two significant disadvantages for cannabinoid-based therapies in humans. Recent work has revealed prominent sex differences in the acute response and tolerance to cannabinoids in both humans and animal models. This review will discuss evidence demonstrating cannabinoid tolerance in rodents, non-human primates, and humans and our current understanding of the neuroadaptations occurring at the cannabinoid type 1 receptor (CB1R) that are responsible tolerance. CB1R expression is downregulated in tolerant animals and humans while there is strong evidence of CB1R desensitization in cannabinoid tolerant rodent models. Throughout the review, critical knowledge gaps are indicated and discussed, such as the lack of a neuroimaging probe to assess CB1R desensitization in humans. The review discusses the intracellular signaling pathways that are responsible for mediating CB1R desensitization and downregulation including the action of G protein-coupled receptor kinases, ß-arrestin2 recruitment, c-Jun N-terminal kinases, protein kinase A, and the intracellular trafficking of CB1R. Finally, the review discusses approaches to reduce cannabinoid tolerance in humans based on our current understanding of the neuroadaptations and mechanisms responsible for this process.

Mice lacking proSAAS display alterations in emotion, consummatory behavior and circadian entrainment.

ProSAAS is a neuroendocrine protein that is cleaved by neuropeptide-processing enzymes into more than a dozen products including the bigLEN and PEN peptides, which bind and activate the receptors GPR171 and GPR83, respectively. Previous studies have suggested that proSAAS-derived peptides are involved in physiological functions that include body weight regulation, circadian rhythms and anxiety-like behavior. In the present study, we find that proSAAS knockout mice display robust anxiety-like behaviors in the open field, light-dark emergence and elevated zero maze tests. These mutant mice also show a reduction in cued fear and an impairment in fear-potentiated startle, indicating an important role for proSAAS-derived peptides in emotional behaviors. ProSAAS knockout mice exhibit reduced water consumption and urine production relative to wild-type controls. No differences in food consumption and overall energy expenditure were observed between the genotypes. However, the respiratory exchange ratio was elevated in the mutants during the light portion of the light-dark cycle, indicating decreased fat metabolism during this period. While proSAAS knockout mice show normal circadian patterns of activity, even upon long-term exposure to constant darkness, they were unable to shift their circadian clock upon exposure to a light pulse. Taken together, these results show that proSAAS-derived peptides modulate a wide range of behaviors including emotion, metabolism and the regulation of the circadian clock.

Clinician Attitudes and Beliefs Associated with More Aggressive Diagnostic Testing.

BACKGROUND: Variation in clinicians' diagnostic test utilization is incompletely explained by demographics and likely relates to cognitive characteristics. We explored clinician factors associated with diagnostic test utilization. METHODS: We used a self-administered survey of attitudes, cognitive characteristics, and reported likelihood of test ordering in common scenarios; frequency of lipid and liver testing in patients on statin therapy. Participants were 552 primary care physicians, nurse practitioners, and physician assistants from practices in 8 US states across 3 regions, from June 1, 2018 to November 26, 2019. We measured Testing Likelihood Score: the mean of 4 responses to testing frequency and self-reported testing frequency in patients on statins. RESULTS: Respondents were 52.4% residents, 36.6% attendings, and 11.0% nurse practitioners/physician assistants; most were white (53.6%) or Asian (25.5%). Median age was 32 years; 53.1% were female. Participants reported ordering tests for a median of 20% (stress tests) to 90% (mammograms) of patients; Testing Likelihood Scores varied widely (median 54%, interquartile range 43%-69%). Higher scores were associated with geography, training type, low numeracy, high malpractice fear, high medical maximizer score, high stress from uncertainty, high concern about bad outcomes, and low acknowledgment of medical uncertainty. More frequent testing of lipids and liver tests was associated with low numeracy, high medical maximizer score, high malpractice fear, and low acknowledgment of uncertainty. CONCLUSIONS: Clinician variation in testing was common, with more aggressive testing consistently associated with low numeracy, being a medical maximizer, and low acknowledgment of uncertainty. Efforts to reduce undue variations in testing should consider clinician cognitive drivers.

Impact of Statewide Prevention and Reduction of Clostridioides difficile (SPARC), a Maryland public health-academic collaborative: an evaluation of a quality improvement intervention.

To evaluate changes in Clostridioides difficile incidence rates for Maryland hospitals that participated in the Statewide Prevention and Reduction of C. difficile (SPARC) collaborative. Pre-post, difference-in-difference analysis of non-randomised intervention using four quarters of preintervention and six quarters of postintervention National Healthcare Safety Network data for SPARC hospitals (April 2017 to March 2020) and 10 quarters for control hospitals (October 2017 to March 2020). Mixed-effects negative binomial models were used to assess changes over time. Process evaluation using hospital intervention implementation plans, assessments and interviews with staff at eight SPARC hospitals. Maryland, USA. All Maryland acute care hospitals; 12 intervention and 36 control hospitals. Participation in SPARC, a public health-academic collaborative made available to Maryland hospitals, with staggered enrolment between June 2018 and August 2019. Hospitals with higher C. difficile rates were recruited via email and phone. SPARC included assessments, feedback reports and ongoing technical assistance. Primary outcomes were C. difficile incidence rate measured as the quarterly number of C. difficile infections per 10 000 patient-days (outcome measure) and SPARC intervention hospitals' experiences participating in the collaborative (process measures). SPARC invited 13 hospitals to participate in the intervention, with 92% (n=12) participating. The 36 hospitals that did not participate served as control hospitals. SPARC hospitals were associated with 45% greater C. difficile reduction as compared with control hospitals (incidence rate ratio=0.55, 95% CI 0.35 to 0.88, p=0.012). Key SPARC activities, including access to trusted external experts, technical assistance, multidisciplinary collaboration, an accountability structure, peer-to-peer learning opportunities and educational resources, were associated with hospitals reporting positive experiences with SPARC. SPARC intervention hospitals experienced 45% greater reduction in C. difficile rates than control hospitals. A public health-academic collaborative might help reduce C. difficile and other hospital-acquired infections in individual hospitals and at state or regional levels.

Accuracy of Practitioner Estimates of Probability of Diagnosis Before and After Testing.

Importance: Accurate diagnosis is essential to proper patient care. Objective: To explore practitioner understanding of diagnostic reasoning. Design, Setting, and Participants: In this survey study, 723 practitioners at outpatient clinics in 8 US states were asked to estimate the probability of disease for 4 scenarios common in primary care (pneumonia, cardiac ischemia, breast cancer screening, and urinary tract infection) and the association of positive and negative test results with disease probability from June 1, 2018, to November 26, 2019. Of these practitioners, 585 responded to the survey, and 553 answered all of the questions. An expert panel developed the survey and determined correct responses based on literature review. Results: A total of 553 (290 resident physicians, 202 attending physicians, and 61 nurse practitioners and physician assistants) of 723 practitioners (76.5%) fully completed the survey (median age, 32 years; interquartile range, 29-44 years; 293 female [53.0%]; 296 [53.5%] White). Pretest probability was overestimated in all scenarios. Probabilities of disease after positive results were overestimated as follows: pneumonia after positive radiology results, 95% (evidence range, 46%-65%; comparison P < .001); breast cancer after positive mammography results, 50% (evidence range, 3%-9%; P < .001); cardiac ischemia after positive stress test result, 70% (evidence range, 2%-11%; P < .001); and urinary tract infection after positive urine culture result, 80% (evidence range, 0%-8.3%; P < .001). Overestimates of probability of disease with negative results were also observed as follows: pneumonia after negative radiography results, 50% (evidence range, 10%-19%; P < .001); breast cancer after negative mammography results, 5% (evidence range, <0.05%; P < .001); cardiac ischemia after negative stress test result, 5% (evidence range, 0.43%-2.5%; P < .001); and urinary tract infection after negative urine culture result, 5% (evidence range, 0%-0.11%; P < .001). Probability adjustments in response to test results varied from accurate to overestimates of risk by type of test (imputed median positive and negative likelihood ratios [LRs] for practitioners for chest radiography for pneumonia: positive LR, 4.8; evidence, 2.6; negative LR, 0.3; evidence, 0.3; mammography for breast cancer: positive LR, 44.3; evidence range, 13.0-33.0; negative LR, 1.0; evidence range, 0.05-0.24; exercise stress test for cardiac ischemia: positive LR, 21.0; evidence range, 2.0-2.7; negative LR, 0.6; evidence range, 0.5-0.6; urine culture for urinary tract infection: positive LR, 9.0; evidence, 9.0; negative LR, 0.1; evidence, 0.1). Conclusions and Relevance: This survey study suggests that for common diseases and tests, practitioners overestimate the probability of disease before and after testing. Pretest probability was overestimated in all scenarios, whereas adjustment in probability after a positive or negative result varied by test. Widespread overestimates of the probability of disease likely contribute to overdiagnosis and overuse.

2019 Update on Medical Overuse: A Review.

IMPORTANCE: Medical overuse is an important cause of patient harm and medical waste. OBSERVATION: This structured literature review of English-language articles supplemented by examination of tables of contents of high-impact journals published in 2018 identified articles related to medical overuse. Articles were appraised for their methodologic quality, clinical relevance, and influence on patients. Of 1499 candidate articles, 839 addressed medical overuse. Of these, 117 were deemed to be most significant, with the 10 highest-ranking articles selected by author consensus. The most important articles on medical overuse identified issues with testing, including that procalcitonin does not affect antibiotic duration in patients with lower respiratory tract infection (4.2 vs 4.3 days); incidentalomas are present in 22% to 38% of common magnetic resonance imaging or computed tomography studies; 9% of women dying of stage IV cancer are still screened with mammography; and computed tomography lung cancer screening offers stable benefit and higher rates of harm for patients at lower risk. Articles related to overtreatment reported that urgent care clinics commonly overprescribe antibiotics (in 39% of all visits, patients received antibiotics) and that treatment of subclinical hypothyroidism had no effect on clinical outcomes. Three studies highlighted services that should be questioned, including using opioids for chronic noncancer pain (meta-analysis found no clinically significant benefit), stress ulcer prophylaxis for intensive care unit patients (mortality, 31.1% with pantoprazole vs 30.4% with placebo), and supplemental oxygen for patients with normal oxygen levels (mortality relative risk, 1.21; 95% CI, 1.03-1.43). A policy article found that state medical liability reform was associated with reduced invasive testing for coronary artery disease, including 24% fewer angiograms. CONCLUSIONS AND RELEVANCE: The findings suggest that many tests are overused, overtreatment is common, and unnecessary care can lead to patient harm. This review of these 2018 findings aims to inform practitioners who wish to reduce overuse and improve patient care.

Cannabinoids: Current and Future Options to Treat Chronic and Chemotherapy-Induced Neuropathic Pain.

Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN.

2018 Update on Pediatric Medical Overuse: A Review.

Importance: Efforts to combat medical overuse have gained traction in recent years, but success has been intermittent and shortcomings have been recognized. A commitment to a strong evidence base is needed to more broadly engage clinicians and reduce overuse. Observations: A structured MEDLINE search and a manual review of tables of contents from selected high-impact journals was performed to identify original research published in 2017 relevant to pediatric overuse. Articles were scored from low to high for 3 categories: quality of methods, magnitude of potential harm, and number of patients potentially harmed. The top-scoring articles presented in this review highlight examples of safe reductions in treatment intensity, including in the setting of cancer, appendicitis, acute respiratory tract infection, and elective anesthesia. This year's articles also provide cautionary examples of rational interventions adopted without a full understanding of potential harms, including pharmacologic migraine therapies, docosahexaenoic acid supplementation for preterm neonates, tight glycemic control for individuals with critically illness, and prophylactic antibiotics for children with vesicoureteral reflux. Conclusions and Relevance: The articles represent high-quality, original research from 2017 that may help mitigate overuse. These works should be fundamental to the maturation of the pediatric overuse field.

Improving Incident Reporting Among Physician Trainees.

BACKGROUND: Preventable medical harm is a leading cause of death in the United States. Incident reporting systems have been identified as the primary method to capture medical error and harm. Incidents are rarely reported, particularly among physician trainees. METHODS: We conducted a single-center, quasi-experimental study to examine the effect of education on the importance of and how to file an incident report for physician trainees on reporting rates. Trainees were provided laminated plastic instructions, and reporting was reinforced with weekly patient safety rounds. In addition, trainees completed anonymous surveys preintervention and postintervention to determine barriers to reporting. A χ test compared the number of reports preintervention and postintervention. RESULTS: For 6 months, 73 resident physicians participated in the study. Median incident reports entered by trainees increased from 1 report per month during the preintervention period to 10 reports per month after the intervention (P = 0.005). The most common barriers to reporting incidents before intervention were not knowing how to report (72.6%), what to report (56.2%), and lack of time (42.5%). A total of 13.7% reported fear of retaliation. Most incident reports were due to delay in patient care (40.9%) and medical errors (33.3%). CONCLUSIONS: Real-time education and regular reinforcement increased incident reporting among resident physicians. This educational approach may increase incidence reporting in other institutions.

2018 Update on Medical Overuse.

Importance: Overuse of medical care is a well-recognized problem in health care, associated with patient harm and costs. We sought to identify and highlight original research articles published in 2017 that are most relevant to understanding medical overuse. Observations: A structured review of English-language articles published in 2017 was performed, coupled with examination of tables of contents of high-impact journals to identify articles related to medical overuse in adult care. Manuscripts were appraised for their quality, clinical relevance, and impact. A total of 1446 articles were identified, 910 of which addressed medical overuse. Of these, 111 articles were deemed to be the most relevant based on originality, methodologic quality, and scope. The 10 most influential articles were selected by author consensus. Findings included that unnecessary electrocardiograms are common (performed in 22% of patients at low risk) and can lead to a cascade of services, lipid monitoring rarely affects care, patients who were overdiagnosed with cancer experienced anxiety and criticism about not seeking treatment, calcium and vitamin D supplementation does not reduce hip fracture (relative risk, 1.09; 95% CI, 0.85-1.39), and pregabalin does not improve symptoms of sciatica but frequently has adverse effects (40% of patients experienced dizziness). Antipsychotic medications increased the severity of delirium in patients receiving hospice care and were associated with an increased risk of death (hazard ratio, 1.7; P = .003), and robotic-assisted radical nephrectomy was without benefits by being slower and more costly than laparoscopic surgery. High-sensitivity troponin testing often yielded false-positive results, as 16% of patients with positive troponin results in a US hospital had a myocardial infarction. One-third of patients who received a diagnosis of asthma had no evidence of asthma. Restructuring the electronic health record was able to reduce unnecessary testing (from 31.3 to 13.9 low-value tests performed per 100 patient visits). Conclusions and Relevance: Many current practices were found to represent overuse, with no benefit and potential harms. Other services were used inappropriately. Reviewing these findings and extrapolating to their patients will enable health care professionals to improve the care they provide.

Use of diagnostic stewardship practices to improve urine culturing among SHEA Research Network hospitals.

This survey investigated interventions used by acute-care hospitals to reduce the detection of asymptomatic bacteriuria. Half of the respondents reported using reflex urine cultures but with varied urinalysis criteria and perceived outcomes. Other diagnostic stewardship interventions for urine culture ordering and specimen quality were less common.

2017 Update on Medical Overuse: A Systematic Review.

Importance: Overuse of medical care is a well-recognized problem. Objective: To identify and highlight original research articles published in 2016 that are most relevant to understanding medical overuse or strategies to reduce it. Evidence Review: A structured review of English-language articles on PubMed published in 2016 coupled with examination of tables of contents of high-impact journals to identify articles related to medical overuse in adults. These articles were appraised for their importance to medicine. Findings: This study considered 2252 articles, 1224 of which addressed medical overuse. Of these, 122 were deemed most relevant based on originality, methodologic quality, and number of patients potentially affected. The 10 most influential articles were selected by author consensus. Select findings from the studies include the lack of benefit of transesophageal echocardiography in the workup of cryptogenic stroke, increasing use of computed tomography in the emergency department from 2.2% to 9.4% from 2001 to 2010, and carotid ultrasonography and revascularization being performed for uncertain or inappropriate indications with 95% frequency. Likewise, services for which harms are likely to outweigh benefits include treatment for early-stage prostate cancer, which provides no mortality benefit but increases absolute risk of erectile dysfunction by 10% to 30%, oxygen for patients with moderate chronic obstructive pulmonary disease, surgery for meniscal tear with mechanical symptoms, and nutritional interventions for inpatients with malnutrition. This review highlights 2 methods for reducing overuse: clinician audit and feedback with peer comparison for antibiotic use (reduction in inappropriate antibiotic use from 20% to 4%) and a practical and sensible shared decision-making tool for low-risk chest pain (reduction in emergency department workup from 52% to 37%). Conclusions and Relevance: The body of empirical work continues to expand related to medical services that are provided for inappropriate or uncertain indications. Engaging patients in conversations aimed at shared decision making and giving practitioners feedback about their performance relative to peers appear to be useful in reducing overuse.

Synthetic Cannabinoid Activity Against Colorectal Cancer Cells.

Introduction: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, and new therapeutic strategies are still required. Here we screened a synthetic cannabinoid library to identify compounds that uniformly reduce the viability of seven CRC cell lines. Material and Methods: Seven distinct CRC cell lines were treated with 10 µM cannabinoid compounds (from a library of 370 molecules) for 48 h, and cell viability was subsequently measured with MTS assay. Dose-response curves were conducted for compounds that were found to reproducibly reduce cell viability of one or more cell lines. Results: We identified 10 compounds from the library that were able to reduce cell viability of CRC cell lines (with an IC50 ≤ 30 µM). Of these compounds, seven were specific for CRC cells, and six were effective in all CRC cell lines tested. Treatment with traditional phytocannabinoids (THC or CBD) was either ineffective or much less potent and only partially efficacious. Treatment with antagonists for the known cannabinoid receptors (alone or in combination) failed to block the activity of the most potent of identified compounds. Conclusion: We identified three families of cannabinoid compounds that reduce CRC cell viability through a noncanonical receptor mechanism. Future modification of these compounds may lead to the development of novel therapies to treat this disease.

Frequency of Adverse Events Before, During, and After Hospital Admission.

OBJECTIVES: Adverse events (AEs) are unintended physical injuries resulting from or contributed to by medical or surgical care. We determined the frequency and type of AEs before, during, and after hospital admission. METHODS: We conducted a cohort study of 296 adult hospital patients. We used the standardized Institute for Healthcare Improvement Global Trigger Tool for Measuring Adverse Events to review the medical records of the hospital patients for occurrence, timing relative to hospital admission, severity, and preventability of AEs. We also identified the primary physiologic system affected by the AE. RESULTS: Among 296 patients, we identified 338 AEs. AEs occurred with similar frequency before (n = 148; 43.8%) and during hospital admission (n = 162; 47.9%). Fewer AEs occurred after discharge (n = 28; 8.3%). Half of all AEs (n = 169; 50.0%) were severe, whereas 47.9% (n = 162) were preventable. CONCLUSIONS: AEs occur with similar frequency before and during hospitalization and may contribute more to hospital admissions than previously recognized. These findings suggest that efforts to improve patient safety should include outpatient settings in addition to the more commonly targeted acute care settings.

2016 Update on Medical Overuse: A Systematic Review.

Importance: Overuse of medical care is an increasingly recognized problem in clinical medicine. Objective: To identify and highlight original research articles published in 2015 that are most likely to reduce overuse of medical care, organized into 3 categories: overuse of testing, overtreatment, and questionable use of services. The articles were reviewed and interpreted for their importance to clinical medicine. Evidence Review: A structured review of English-language articles on PubMed published in 2015 and review of tables of contents of relevant journals to identify potential articles that related to medical overuse in adults. Findings: Between January 1, 2015, and December 31, 2015, we reviewed 1445 articles, of which 821 addressed overuse of medical care. Of these, 112 were deemed most relevant based on their originality, methodologic quality, and number of patients potentially affected. The 10 most influential articles were selected by consensus using the same criteria. Findings included a doubling of specialty referrals and advanced imaging for simple headache (from 6.7% in 2000 to 13.9% in 2010); unnecessary hospital admission for low-risk syncope, often leading to adverse events; and overly frequent colonoscopy screening for 34% of patients. Overtreatment was common in the following areas: 1 in 4 patients with atrial fibrillation at low risk for thromboembolism received anticoagulation; 94% of testosterone replacement therapy was administered off guideline recommendations; 91% of patients resumed taking opioids after overdose; and 61% of patients with diabetes were treated to potentially harmfully low hemoglobin A1c levels (<7%). Findings also identified medical practices to question, including questionable use of treatment of acute low-back pain with cyclobenzaprine and oxycodone/acetaminophen; of testing for Clostridium difficile with molecular assays; and serial follow-up of benign thyroid nodules. Conclusions and Relevance: The number of articles on overuse of medical care nearly doubled from 2014 to 2015. The present review promotes reflection on the top 10 articles and may lead to questioning other non-evidence-based practices.

Choosing Wisely in Healthcare Epidemiology and Antimicrobial Stewardship.

OBJECTIVE To identify Choosing Wisely items for the American Board of Internal Medicine Foundation. METHODS The Society for Healthcare Epidemiology of America (SHEA) elicited potential items from a hospital epidemiology listserv, SHEA committee members, and a SHEA-Infectious Diseases Society of America compendium with SHEA Research Network members ranking items by Delphi method voting. The SHEA Guidelines Committee reviewed the top 10 items for appropriateness for Choosing Wisely. Five final recommendations were approved via individual member vote by committees and the SHEA Board. RESULTS Ninety-six items were proposed by 87 listserv members and 99 SHEA committee members. Top 40 items were ranked by 24 committee members and 64 of 226 SHEA Research Network members. The 5 final recommendations follow: 1. Don't continue antibiotics beyond 72 hours in hospitalized patients unless patient has clear evidence of infection. 2. Avoid invasive devices (including central venous catheters, endotracheal tubes, and urinary catheters)and, if required, use no longer than necessary. They pose a major risk for infections. 3. Don't perform urinalysis, urine culture, blood culture, or Clostridium difficile testing unless patients have signs or symptoms of infection. Tests can be falsely positive leading to overdiagnosis and overtreatment. 4. Do not use antibiotics in patients with recent C. difficile without convincing evidence of need. Antibiotics pose a high risk of C. difficile recurrence. 5. Don't continue surgical prophylactic antibiotics after the patient has left the operating room. Five runner-up recommendations are included. CONCLUSIONS These 5 SHEA Choosing Wisely and 5 runner-up items limit medical overuse. Infect Control Hosp Epidemiol 2016;37:755-760.

Update on Medical Practices That Should Be Questioned in 2015.

IMPORTANCE: Overuse of medical care, consisting primarily of overdiagnosis and overtreatment, is a common clinical problem. OBJECTIVES: To identify and highlight articles published in 2014 that are most likely to influence medical overuse, organized into the categories of overdiagnosis, overtreatment, and methods to avoid overuse, and to review these articles and interpret them for their importance to clinical medicine. EVIDENCE REVIEW: A structured review of English-language articles in PubMed published in 2014 and a review of tables of contents of relevant journals to identify potential articles that related to medical overuse in adults. FINDINGS: We reviewed 910 articles, of which 440 addressed medical overuse. Of these, 104 were deemed most relevant based on the presentation of original data, quality of methods, magnitude of clinical effect, and number of patients potentially affected. The 10 most influential articles were selected by author consensus using the same criteria. Findings included lack of benefit for screening pelvic examinations (positive predictive value <5%), carotid artery screening (no reduction in stroke), and thyroid ultrasonography (15-fold increase in thyroid cancer). The harms of cancer screening included unnecessary surgery and complications. Head computed tomography was an overused diagnostic test (clinically significant findings in 4% [7 of 172] of head computed tomographic scans). Overtreatment included acetaminophen for low back pain, perioperative aspirin use, medications to increase high-density lipoprotein cholesterol level, stenting for renal artery stenosis, and prolonged opioid use after surgery (use >90 days in 3% [1229 of 39,140] of patients). CONCLUSIONS AND RELEVANCE: Many common medical practices should be reconsidered. It is anticipated that our review will promote reflection on these 10 articles and lead to questioning of other non-evidence-based practices.

Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.

BACKGROUND: The declining efficacy of existing antibiotics potentially jeopardises outcomes in patients undergoing medical procedures. We investigated the potential consequences of increases in antibiotic resistance on the ten most common surgical procedures and immunosuppressing cancer chemotherapies that rely on antibiotic prophylaxis in the USA. METHODS: We searched the published scientific literature and identified meta-analyses and reviews of randomised controlled trials or quasi-randomised controlled trials (allocation done on the basis of a pseudo-random sequence-eg, odd/even hospital number or date of birth, alternation) to estimate the efficacy of antibiotic prophylaxis in preventing infections and infection-related deaths after surgical procedures and immunosuppressing cancer chemotherapy. We varied the identified effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions) and estimated the additional number of infections and infection-related deaths per year in the USA for each scenario. We estimated the percentage of pathogens causing infections after these procedures that are resistant to standard prophylactic antibiotics in the USA. FINDINGS: We estimate that between 38·7% and 50·9% of pathogens causing surgical site infections and 26·8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA. A 30% reduction in the efficacy of antibiotic prophylaxis for these procedures would result in 120,000 additional surgical site infections and infections after chemotherapy per year in the USA (ranging from 40,000 for a 10% reduction in efficacy to 280,000 for a 70% reduction in efficacy), and 6300 infection-related deaths (range: 2100 for a 10% reduction in efficacy, to 15,000 for a 70% reduction). We estimated that every year, 13,120 infections (42%) after prostate biopsy are attributable to resistance to fluoroquinolones in the USA. INTERPRETATION: Increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. More data are needed to establish how antibiotic prophylaxis recommendations should be modified in the context of increasing rates of resistance. FUNDING: DRIVE-AB Consortium.