Red flags to screen for vertebral fracture in patients presenting with low-back pain.

EDITORIAL NOTE: See https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD014461.pub2/full for a more recent review that covers this topic and has superseded this review. BACKGROUND: Low-back pain (LBP) is a common condition seen in primary care. A principal aim during a clinical examination is to identify patients with a higher likelihood of underlying serious pathology, such as vertebral fracture, who may require additional investigation and specific treatment. All 'evidence-based' clinical practice guidelines recommend the use of red flags to screen for serious causes of back pain. However, it remains unclear if the diagnostic accuracy of red flags is sufficient to support this recommendation. OBJECTIVES: To assess the diagnostic accuracy of red flags obtained in a clinical history or physical examination to screen for vertebral fracture in patients presenting with LBP. SEARCH METHODS: Electronic databases were searched for primary studies between the earliest date and 7 March 2012. Forward and backward citation searching of eligible studies was also conducted. SELECTION CRITERIA: Studies were considered if they compared the results of any aspect of the history or test conducted in the physical examination of patients presenting for LBP or examination of the lumbar spine, with a reference standard (diagnostic imaging). The selection criteria were independently applied by two review authors. DATA COLLECTION AND ANALYSIS: Three review authors independently conducted 'Risk of bias' assessment and data extraction. Risk of bias was assessed using the 11-item QUADAS tool. Characteristics of studies, patients, index tests and reference standards were extracted. Where available, raw data were used to calculate sensitivity and specificity with 95% confidence intervals (CI). Due to the heterogeneity of studies and tests, statistical pooling was not appropriate and the analysis for the review was descriptive only. Likelihood ratios for each test were calculated and used as an indication of clinical usefulness. MAIN RESULTS: Eight studies set in primary (four), secondary (one) and tertiary care (accident and emergency = three) were included in the review. Overall, the risk of bias of studies was moderate with high risk of selection and verification bias the predominant flaws. Reporting of index and reference tests was poor. The prevalence of vertebral fracture in accident and emergency settings ranged from 6.5% to 11% and in primary care from 0.7% to 4.5%. There were 29 groups of index tests investigated however, only two featured in more than two studies. Descriptive analyses revealed that three red flags in primary care were potentially useful with meaningful positive likelihood ratios (LR+) but mostly imprecise estimates (significant trauma, older age, corticosteroid use; LR+ point estimate ranging 3.42 to 12.85, 3.69 to 9.39, 3.97 to 48.50 respectively). One red flag in tertiary care appeared informative (contusion/abrasion; LR+ 31.09, 95% CI 18.25 to 52.96). The results of combined tests appeared more informative than individual red flags with LR+ estimates generally greater in magnitude and precision. AUTHORS' CONCLUSIONS: The available evidence does not support the use of many red flags to specifically screen for vertebral fracture in patients presenting for LBP. Based on evidence from single studies, few individual red flags appear informative as most have poor diagnostic accuracy as indicated by imprecise estimates of likelihood ratios. When combinations of red flags were used the performance appeared to improve. From the limited evidence, the findings give rise to a weak recommendation that a combination of a small subset of red flags may be useful to screen for vertebral fracture. It should also be noted that many red flags have high false positive rates; and if acted upon uncritically there would be consequences for the cost of management and outcomes of patients with LBP. Further research should focus on appropriate sets of red flags and adequate reporting of both index and reference tests.

A novel methodological framework was described for detecting and quantifying overdiagnosis.

OBJECTIVES: Methods to quantify overdiagnosis of screen detected cancer have been developed, but methods for quantifying overdiagnosis of noncancer conditions (whether symptomatic or asymptomatic) have been lacking. We aimed to develop a methodological framework for quantifying overdiagnosis that may be used for asymptomatic or symptomatic conditions and used gestational diabetes mellitus as an example of how it may be applied. STUDY DESIGN AND SETTING: We identify two earlier definitions for overdiagnosis, a narrower prognosis-based definition and a wider utility-based definition. Building on the central importance of the concepts of prognostic information and clinical utility of a diagnosis, we consider the following questions: within a target population, do people found to have a disease using one diagnostic strategy but found not to have the disease using another diagnostic strategy (so called 'additional diagnoses'), have an increased risk of adverse clinical outcomes without treatment (prognosis evidence), and/or a decreased risk of adverse outcomes with treatment (utility evidence)? RESULTS: Using Causal Directed Acyclic Graphs and fair umpires, we illuminate the relationships between diagnostics strategies and the frequency of overdiagnosis. We then use the example of gestational diabetes mellitus to demonstrate how the Fair Umpire framework may be applied to estimate overdiagnosis. CONCLUSION: Our framework may be used to quantify overdiagnosis in noncancer conditions (and in cancer conditions) and to guide further studies on this topic.

I need an exact margin measurement for this basal cell carcinoma!

BACKGROUND/OBJECTIVES: Pathology laboratories are required to determine or estimate the measurement uncertainty for all quantitative results, but there is no literature on the uncertainty in margin measurements for skin cancer excisions. METHODS: Six pathologists measured 4-14 histological margins in each of 10 basal cell carcinoma. RESULTS: The mean of measurements from all the margins from all the cases was 1.8 mm (range 0 and 6 mm). Regarding the overall variance in margin measurements across the ten cases, 25% was from variation within cases (differences in margin measurement for a given case, because of different margins and different pathologists measuring each margin, SD 0.7 mm). For a given case, we estimate that 95% of margin measurements would fall approximately within±1.4 mm of the mean measurement for that case. When only pathologists' closest margin for each case were included (for the six cases with uninvolved margins), 6% of the overall variance was from differences within cases (because of different pathologists' measurements of the closest margin, SD 0.2 mm). For a given case without an involved margin, 95% of closest margin measurements would fall approximately within±0.5 mm of the mean closest measurement for that case. CONCLUSIONS: Clinicians should be aware there is uncertainty in reported histological margins.

Assessing the Potential for Patient-led Surveillance After Treatment of Localized Melanoma (MEL-SELF): A Pilot Randomized Clinical Trial.

IMPORTANCE: Patient-led surveillance is a promising new model of follow-up care following excision of localized melanoma. OBJECTIVE: To determine whether patient-led surveillance in patients with prior localized primary cutaneous melanoma is as safe, feasible, and acceptable as clinician-led surveillance. DESIGN, SETTING, AND PARTICIPANTS: This was a pilot for a randomized clinical trial at 2 specialist-led clinics in metropolitan Sydney, Australia, and a primary care skin cancer clinic managed by general practitioners in metropolitan Newcastle, Australia. The participants were 100 patients who had been treated for localized melanoma, owned a smartphone, had a partner to assist with skin self-examination (SSE), and had been routinely attending scheduled follow-up visits. The study was conducted from November 1, 2018, to January 17, 2020, with analysis performed from September 1, 2020, to November 15, 2020. INTERVENTION: Participants were randomized (1:1) to 6 months of patient-led surveillance (the intervention comprised usual care plus reminders to perform SSE, patient-performed dermoscopy, teledermatologist assessment, and fast-tracked unscheduled clinic visits) or clinician-led surveillance (the control was usual care). MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of eligible and contacted patients who were randomized. Secondary outcomes included patient-reported outcomes (eg, SSE knowledge, attitudes, and practices, psychological outcomes, other health care use) and clinical outcomes (eg, clinic visits, skin surgeries, subsequent new primary or recurrent melanoma). RESULTS: Of 326 patients who were eligible and contacted, 100 (31%) patients (mean [SD] age, 58.7 [12.0] years; 53 [53%] men) were randomized to patient-led (n = 49) or clinician-led (n = 51) surveillance. Data were available on patient-reported outcomes for 66 participants and on clinical outcomes for 100 participants. Compared with clinician-led surveillance, patient-led surveillance was associated with increased SSE frequency (odds ratio [OR], 3.5; 95% CI, 0.9 to 14.0) and thoroughness (OR, 2.2; 95% CI, 0.8 to 5.7), had no detectable adverse effect on psychological outcomes (fear of cancer recurrence subscale score; mean difference, -1.3; 95% CI, -3.1 to 0.5), and increased clinic visits (risk ratio [RR], 1.5; 95% CI, 1.1 to 2.1), skin lesion excisions (RR, 1.1; 95% CI, 0.6 to 2.0), and subsequent melanoma diagnoses and subsequent melanoma diagnoses (risk difference, 10%; 95% CI, -2% to 23%). New primary melanomas and 1 local recurrence were diagnosed in 8 (16%) of the participants in the intervention group, including 5 (10%) ahead of routinely scheduled visits; and in 3 (6%) of the participants in the control group, with none (0%) ahead of routinely scheduled visits (risk difference, 10%; 95% CI, 2% to 19%). CONCLUSIONS AND RELEVANCE: This pilot of a randomized clinical trial found that patient-led surveillance after treatment of localized melanoma appears to be safe, feasible, and acceptable. Experiences from this pilot study have prompted improvements to the trial processes for the larger trial of the same intervention. TRIAL REGISTRATION: http://anzctr.org.au Identifier: ACTRN12616001716459.

Can patient-led surveillance detect subsequent new primary or recurrent melanomas and reduce the need for routinely scheduled follow-up? A protocol for the MEL-SELF randomised controlled trial.

BACKGROUND: Most subsequent new primary or recurrent melanomas might be self-detected if patients are trained to systematically self-examine their skin and have access to timely medical review (patient-led surveillance). Routinely scheduled clinic visits (clinician-led surveillance) is resource-intensive and has not been shown to improve health outcomes; fewer visits may be possible if patient-led surveillance is shown to be safe and effective. The MEL-SELF trial is a randomised controlled trial comparing patient-led surveillance with clinician-led surveillance in people who have been previously treated for localised melanoma. METHODS: Stage 0/I/II melanoma patients (n = 600) from dermatology, surgical, or general practice clinics in NSW Australia, will be randomised (1:1) to the intervention (patient-led surveillance, n = 300) or control (usual care, n = 300). Patients in the intervention will undergo a second randomisation 1:1 to polarised (n = 150) or non-polarised (n = 150) dermatoscope. Patient-led surveillance comprises an educational booklet, skin self-examination (SSE) instructional videos; 3-monthly email/SMS reminders to perform SSE; patient-performed dermoscopy with teledermatologist feedback; clinical review of positive teledermoscopy through fast-tracked unscheduled clinic visits; and routinely scheduled clinic visits following each clinician's usual practice. Clinician-led surveillance comprises an educational booklet and routinely scheduled clinic visits following each clinician's usual practice. The primary outcome, measured at 12 months, is the proportion of participants diagnosed with a subsequent new primary or recurrent melanoma at an unscheduled clinic visit. Secondary outcomes include time from randomisation to diagnosis (of a subsequent new primary or recurrent melanoma and of a new keratinocyte cancer), clinicopathological characteristics of subsequent new primary or recurrent melanomas (including AJCC stage), psychological outcomes, and healthcare use. A nested qualitative study will include interviews with patients and clinicians, and a costing study we will compare costs from a societal perspective. We will compare the technical performance of two different models of dermatoscope (polarised vs non-polarised). DISCUSSION: The findings from this study may inform guidance on evidence-based follow-up care, that maximises early detection of subsequent new primary or recurrent melanoma and patient wellbeing, while minimising costs to patients, health systems, and society. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000176864 . Registered on 18 February 2021.

Informing Women About Overdetection in Breast Cancer Screening: Two-Year Outcomes From a Randomized Trial.

BACKGROUND: Supporting well-informed decisions about breast cancer screening requires communicating that inconsequential disease may be detected, leading to overdiagnosis and overtreatment. Having previously shown that telling women about overdetection improved informed choice, we investigated effects on screening knowledge and participation over 2 years. METHODS: We conducted a community-based, parallel-group, randomized controlled trial in Australia. Participants were women aged 48-50 years, without personal or strong family history of breast cancer, who had not undergone mammography in the past 2 years. We randomly assigned 879 women to receive the intervention decision aid (evidence-based information on overdetection, breast cancer mortality reduction, and false-positives) or control decision aid (identical but without overdetection information). We interviewed 838 women postintervention and recontacted them for follow-up at 6 months and 1 and 2 years. Main outcomes for this report are screening knowledge and participation. RESULTS: We interviewed 790, 746, and 712 participants at 6 months, 1, and 2 years, respectively. The intervention group demonstrated superior knowledge throughout follow-up. After 2 years, conceptual knowledge was adequate in 123 (34.4%) of 358 women in the intervention group compared with 71 (20.1%) of 354 control participants(odds ratio = 2.04, 95% confidence interval = 1.46 to 2.85). Groups were similar in total screening participation (200 [55.1%] vs 204 [56.0%]; = 0.97, 95% confidence interval = 0.73 to 1.29). CONCLUSIONS: A brief decision aid produced lasting improvement in women's understanding of potential consequences of screening, including overdetection, without changing participation rates. These findings support the use of decision aids for breast cancer screening.

The potential for overdiagnosis and underdiagnosis because of blood pressure variability: a comparison of the 2017 ACC/AHA, 2018 ESC/ESH and 2019 NICE hypertension guidelines.

OBJECTIVE: To estimate the extent that BP measurement variability may drive over- and underdiagnosis of 'hypertension' when measurements are made according to current guidelines. METHODS: Using data from the National Health and Nutrition Examination Survey and empirical estimates of within-person variability, we simulated annual SBP measurement sets for 1 000 000 patients over 5 years. For each measurement set, we used an average of multiple readings, as recommended by guidelines. RESULTS: The mean true SBP for the simulated population was 118.8 mmHg with a standard deviation of 17.5 mmHg. The proportion overdiagnosed with 'hypertension' after five sets of office or nonoffice measurements using the 2017 American College of Cardiology guideline was 3-5% for people with a true SBP less than 120 mmHg, and 65-72% for people with a true SBP 120-130 mmHg. These proportions were less than 1% and 14-33% using the 2018 European Society of Hypertension and 2019 National Institute for Health and Care Excellence guidelines (true SBP <120 and 120-130 mmHg, respectively). The proportion underdiagnosed with 'hypertension' was less than 3% for people with true SBP at least 140 mmHg after one set of office or nonoffice measurements using the 2017 American College of Cardiology guideline, and less than 18% using the other two guidelines. CONCLUSION: More people are at risk of overdiagnosis under the 2017 American College of Cardiology guideline than the other two guidelines, even if nonoffice measurements are used. Making clinical decisions about cardiovascular prediction based primarily on absolute risk, minimizes the impact of blood pressure variability on overdiagnosis.

Correction to: Estimation of treatment preference effects in clinical trials when some participants are indifferent to treatment choice.

In the original publication of this article [1], the number "- 0.49" in the below sentence in the Results section should be changed to "-3.23", and this typo does not affect the wider conclusions.

Correction: Prognostic impact of systolic blood pressure variability in people with diabetes.

[This corrects the article DOI: 10.1371/journal.pone.0194084.].

Patients' Views About Skin Self-examination After Treatment for Localized Melanoma.

IMPORTANCE: Skin self-examination (SSE) is a key factor in the early detection of melanoma, and many new and recurrent melanomas are first detected by patients themselves or their family members. OBJECTIVE: To explore the views of patients with melanoma regarding SSE in general, as well as their attitudes toward using novel digital technologies to support their own SSE. DESIGN, SETTING, AND PARTICIPANTS: Qualitative study with semistructured interviews that were conducted from June 20 to December 12, 2016, with 37 individuals in Sydney, Australia, who were previously treated for a first primary localized melanoma during 2014 and had not had a recurrence or new primary melanoma in the time since treatment. MAIN OUTCOMES AND MEASURES: Patients' views and experiences, analyzed thematically. RESULTS: A total of 37 patients (11 women and 26 men; median age, 67 years [interquartile range, 59.5-72 years]) were interviewed. Participants perceived SSE as important for the early identification of local recurrence or new primary melanomas. Despite this belief, participants did not report undertaking full-body SSE on a regular basis. Factors that influenced their low engagement in thorough SSE included lack of self-efficacy, reliance on clinician consultations as the primary means of melanoma detection, and fear of cancer recurrence. Regarding the use of digital technology to assist with SSE, the key motivating factors in favor of such tools were the ability to track changes in lesions over time and the use of automated reminders to undertake SSE. Deterrents included a lack of confidence in undertaking SSE and in using new technology. CONCLUSIONS AND RELEVANCE: Patients with melanoma are aware of the importance of thorough skin examinations. However, a lack of confidence in their ability to undertake SSE and reliance on clinicians as the primary means of melanoma detection may inhibit patients from undertaking regular and thorough SSE. Patients may benefit from new digital technologies that assist them in undertaking SSE, provided they have appropriate education and technical support.

Legacy effects of statins on cardiovascular and all-cause mortality: a meta-analysis.

OBJECTIVES: To assess evidence for 'legacy' (post-trial) effects on cardiovascular disease (CVD) mortality and all-cause mortality among adult participants of placebo-controlled randomised controlled trials (RCTs) of statins. DESIGN: Meta-analysis of aggregate data. SETTING/PARTICIPANTS: Placebo-controlled statin RCTS for primary and secondary CVD prevention. METHODS: Data sources: PubMed, Embase from inception and forward citations of Cholesterol Treatment Trialists' Collaborators RCTs to 16 June 2016. STUDY SELECTION: Two independent reviewers identified all statin RCT follow-up reports including ≥1000 participants, and cardiovascular and all-cause mortality. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. MAIN OUTCOMES: Post-trial CVD and all-cause mortality. RESULTS: We included eight trials, with mean post-trial follow-up ranging from 1.6 to 15.1 years, and including 13 781 post-trial deaths (6685 CVD). Direct effects of statins within trials were greater than legacy effects post-trials. The pooled data from all eight studies showed no evidence overall of legacy effects on CVD mortality, but some evidence of legacy effects on all-cause mortality (p=0.01). Exploratory subgroup analysis found possible differences in legacy effect for primary prevention trials compared with secondary prevention trials for both CVD mortality (p=0.15) and all-cause mortality (p=0.02). Pooled post-trial HR for the three primary prevention studies demonstrated possible post-trial legacy effects on CVD mortality (HR=0.87; 95% CI 0.79 to 0.95) and on all-cause mortality (HR=0.90; 95% CI 0.85 to 0.96). CONCLUSIONS: Possible post-trial statin legacy effects on all-cause mortality appear to be driven by the primary prevention studies. Although these relative benefits were smaller than those observed within the trial, the absolute benefits may be similar for the two time periods. Analysis of individual patient data from follow-up studies after placebo-controlled statin RCTs in lower-risk populations may provide more definitive evidence on whether early treatment of subclinical atherosclerosis is likely to be beneficial.

Use of shared care and routine tests in follow-up after treatment for localised cutaneous melanoma.

BACKGROUND: Patients may decide to undertake shared care with a general practitioner (GP) during follow-up after treatment for localised melanoma. Routine imaging tests for surveillance may be commonly used despite no evidence of clinical utility. This study describes the frequency of shared care and routine tests during follow-up after treatment for localised melanoma. METHODS: We randomly sampled 351 people with localised melanoma [American Joint Cancer Committee (AJCC) substages 0 - II] who had not had recurrent or new primary melanoma diagnosed from a total of 902 people diagnosed and treated for localised melanoma at a specialist centre in 2014. We interviewed participants by telephone about their experience of follow-up in the past year, and documented the proportion of patients who were undertaking shared care follow-up with a GP. We also recorded the frequency and type of investigations during follow-up. We calculated weighted estimates that are representative of the full inception cohort. RESULTS: Of the 351 people who were invited to participate, 230 (66%) people consented to the telephone interview. The majority undertook shared care follow-up with a GP (61%). People who choose to have shared care follow-up with a GP are more likely to be male (p = 0.006), have lower AJCC stage (p for trend = 0.02), reside in more remote areas (p for trend< 0.001), and are less likely to have completed secondary school (p < 0.001). Few people saw a non-doctor health practitioner as part of their follow-up (9%). Many people report undergoing tests for melanoma, much of which may be routine tests for surveillance (37%). CONCLUSIONS: The majority of people treated for a first primary localised melanoma at a specialist centre, without recurrent or new melanoma, choose to undertake shared care follow-up with a GP. Many appear to have routine diagnostic imaging as part of their melanoma surveillance.

Prognostic impact of systolic blood pressure variability in people with diabetes.

OBJECTIVE: Blood pressure variability (BPV) has been associated with risk of cardiovascular events in observational studies, independently of mean BP levels. In states with higher autonomic imbalance, such as in diabetes, the importance of BP variability may theoretically be even greater. We aimed to investigate the incremental value of BPV for prediction of cardiovascular and all-cause mortality in patients with type 2 diabetes. METHODS: We identified 9,855 patients without pre-existing cardiovascular disease who did not change BP-lowering treatment during the observation period from a Swedish primary health care cohort of patients with type 2 diabetes. BPV was summarized as the standard deviation (SD), coefficient of variation (CV), or variation independent of mean (VIM). Patients were followed for a median of 4 years and associations with cardiovascular and all-cause mortality were investigated using Cox proportional hazards models. RESULTS: BPV was not associated with cardiovascular specific or all-cause mortality in the total sample. In patients who were not on BP-lowering drugs during the observation period (n = 2,949), variability measures were associated with all-cause mortality: hazard ratios were 1.05, 1.04 and 1.05 for 50% increases in SD, CV and VIM, respectively, adjusted for Framingham risk score risk factors, including mean BP. However, the addition of the variability measures in this subgroup only led to very minimal improvement in discrimination, indicating they may have limited clinical usefulness (change in C-statistic ranged from 0.000-0.003 in all models). CONCLUSIONS: Although BPV was independently associated with all-cause mortality in diabetes patients in primary care who did not have pre-existing cardiovascular disease or BP-lowering drugs, it may be of minimal clinical usefulness above and beyond that of other routinely measured predictors, including mean BP.

Patient Preferences for Follow-up After Recent Excision of a Localized Melanoma.

Importance: The standard model of follow-up posttreatment of localized melanoma relies on clinician detection of recurrent or new melanoma, through routinely scheduled clinics (clinician-led surveillance). An alternative model is to increase reliance on patient detection of melanoma, with fewer scheduled visits and increased support for patients' skin self-examination (SSE) (eg, using smartphone apps to instruct, prompt and record SSE, and facilitate teledermatology; patient-led surveillance). Objective: To determine the proportion of adults treated for localized melanoma who prefer the standard scheduled visit frequency (as per Australian guideline recommendations) or fewer scheduled visits (adapted from the Melanoma Follow-up [MELFO] study of reduced follow-up). Design, Setting, and Participants: This survey study used a telephone interview for surveillance following excision of localized melanoma at an Australian specialist center. We invited a random sample of 400 patients who had completed treatment for localized melanoma in 2014 to participate. They were asked about their preferences for scheduled follow-up, and experience of follow-up in the past 12 months. Those with a recurrent or new primary melanoma diagnosed by the time of interview (0.8-1.7 years since first diagnosis) were asked about how it was first detected and treated. SSE practices were also assessed. Main Outcomes and Measures: Proportion preferring standard vs fewer scheduled clinic visits, median delay between detection and treatment of recurrent or new primary melanoma, and SSE practices. Results: Of the 262 people who agreed to be interviewed, the mean (SD) age was 64.3 (14.3) years, and 93 (36%) were women. Among the 230 people who did not have a recurrent or new primary melanoma, 149 vs 81 preferred the standard vs fewer scheduled clinic visits option (70% vs 30% after adjusting for sampling frame). Factors independently associated with preferring fewer visits were a higher disease stage, melanoma on a limb, living with others, not having private health insurance, and seeing a specialist for another chronic condition. The median delay between first detection and treatment of recurrent or new primary melanoma was 7 and 3 weeks, respectively. Only 8% missed a scheduled visit, while 40% did not perform SSE or did so at greater than 3-month intervals. Conclusions and Relevance: Some patients with melanoma may prefer fewer scheduled visits, if they are supported to do SSE and there is rapid clinical review of anything causing concern (patient-led surveillance).