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ObjectivesTo estimate data loss and bias in studies of Clinical Practice Research Datalink (CPRD) data that restrict analyses to Read codes, omitting anything recorded as text.DesignMatched case–control study.SettingPatients contributing data to the CPRD.Participants4915 bladder and 3635 pancreatic, cancer cases diagnosed between 1 January 2000 and 31 December 2009, matched on age, sex and general practitioner practice to up to 5 controls (bladder: n=21 718; pancreas: n=16 459). The analysis period was the year before cancer diagnosis.Primary and secondary outcome measuresFrequency of haematuria, jaundice and abdominal pain, grouped by recording style: Read code or text-only (ie, hidden text). The association between recording style and case–control status (χ2 test). For each feature, the odds ratio (OR; conditional logistic regression) and positive predictive value (PPV; Bayes’ theorem) for cancer, before and after addition of hidden text records.ResultsOf the 20 958 total records of the features, 7951 (38%) were recorded in hidden text. Hidden text recording was more strongly associated with controls than with cases for haematuria (140/336=42% vs 556/3147=18%) in bladder cancer (χ2 test, p<0.001), and for jaundice (21/31=67% vs 463/1565=30%, p<0.0001) and abdominal pain (323/1126=29% vs 397/1789=22%, p<0.001) in pancreatic cancer. Adding hidden text records corrected PPVs of haematuria for bladder cancer from 4.0% (95% CI 3.5% to 4.6%) to 2.9% (2.6% to 3.2%), and of jaundice for pancreatic cancer from 12.8% (7.3% to 21.6%) to 6.3% (4.5% to 8.7%). Adding hidden text records did not alter the PPV of abdominal pain for bladder (codes: 0.14%, 0.13% to 0.16% vs codes plus hidden text: 0.14%, 0.13% to 0.15%) or pancreatic (0.23%, 0.21% to 0.25% vs 0.21%, 0.20% to 0.22%) cancer.ConclusionsOmission of text records from CPRD studies introduces bias that inflates outcome measures for recognised alarm symptoms. This potentially reinforces clinicians’ views of the known importance of these symptoms, marginalising the significance of ‘low-risk but not no-risk’ symptoms.

Open-source automated insulin delivery (AID) systems are used by many patients with type 1 diabetes. Data are needed on the efficacy and safety of an open-source AID system. In this multicenter, open-label, randomized, controlled trial, we assigned patients with type 1 diabetes in a 1:1 ratio to use an open-source AID system or a sensor-augmented insulin pump (control). The patients included both children (defined as 7 to 15 years of age) and adults (defined as 16 to 70 years of age). The AID system was a modified version of AndroidAPS 2.8 (with a standard OpenAPS 0.7.0 algorithm) paired with a preproduction DANA-i insulin pump and Dexcom G6 CGM, which has an Android smartphone application as the user interface. The primary outcome was the percentage of time in the target glucose range of 70 to 180 mg per deciliter (3.9 to 10.0 mmol per liter) between days 155 and 168 (the final 2 weeks of the trial). A total of 97 patients (48 children and 49 adults) underwent randomization (44 to open-source AID and 53 to the control group). At 24 weeks, the mean (±SD) time in the target range increased from 61.2±12.3% to 71.2±12.1% in the AID group and decreased from 57.7±14.3% to 54.5±16.0% in the control group (adjusted difference, 14 percentage points; 95% confidence interval, 9.2 to 18.8; P<0.001), with no treatment effect according to age (P = 0.56). Patients in the AID group spent 3 hours 21 minutes more in the target range per day than those in the control group. No severe hypoglycemia or diabetic ketoacidosis occurred in either group. Two patients in the AID group withdrew from the trial owing to connectivity issues. In children and adults with type 1 diabetes, the use of an open-source AID system resulted in a significantly higher percentage of time in the target glucose range than the use of a sensor-augmented insulin pump at 24 weeks. (Supported by the Health Research Council of New Zealand; Australian New Zealand Clinical Trials Registry number, ACTRN12620000034932.).

Background Expediting cancer diagnosis may be achieved by targeted decreases in referral thresholds to increase numbers of patients referred for urgent investigation. Methods Clinical Practice Research Datalink data from England for 150,921 adults aged ≥40 were used to identify participants with features of possible cancer equating to risk thresholds ≥1%, ≥2% or ≥3% for breast, lung, colorectal, oesophago-gastric, pancreatic, renal, bladder, prostatic, ovarian, endometrial and laryngeal cancers. Results The mean age of participants was 60 (SD 13) years, with 73,643 males (49%). In 2016, 8576 consultation records contained coded features having a positive predictive value (PPV) of ≥3% for any of the 11 cancers. This equates to a rate of 5682/100,000 patients compared with 4601/100,000 Suspected Cancer NHS referrals for these cancers from April 2016–March 2017. Nine thousands two hundred ninety-one patient-consultation records had coded features equating to a ≥2% PPV, 8% more than met PPV ≥ 3%. Similarly, 19,517 had features with a PPV ≥ 1%, 136% higher than for PPV ≥ 3%. Conclusions This study estimated the number of primary-care patients presenting at lower thresholds of cancer risk. The resource implications of liberalising this threshold to 2% are modest and manageable. The details across individual cancer sites should assist planning of English cancer services.

Objectives To explore the potential impacts of incorporating prebiopsy magnetic resonance imaging into primary care as a triage test within the prostate cancer diagnostic pathway. Subjects and methods Decision analytic modelling with decision trees was utilised for this early economic evaluation. A conceptual model was developed reflecting the common primary care routes to diagnosis for prostate cancer: opportunistic, asymptomatic prostate‐specific antigen (PSA) screening or symptomatic presentation. The use of multiparametric MRI (mpMRI) or biparametric MRI (bpMRI) as a primary care triage test following an elevated PSA result was evaluated. A health system perspective was adopted with a time horizon of 12 months. Health effects were expressed in terms of utilities drawn from the literature. The primary outcome was prostate cancer diagnosis. Evidence used to inform the model was drawn from published primary studies, systematic reviews, and secondary analyses of primary and secondary care datasets. Results Base case analysis showed that the PSA pathway was dominated by both mpMRI‐ and bpMRI‐based pathways for patients undergoing opportunistic screening and symptomatic assessment. bpMRI pathways had greater improvement in cost and utility than mpMRI pathways in both clinical scenarios. Significantly more MRI scans would be performed using the modelled approach (66 626 scans vs. 37 456 scans per 100 000 patients per annum), with fewer subsequent urgent suspected cancer referrals for both mpMRI (38% reduction for screening and symptomatic patients) and bpMRI (72% reduction for screening; 71% for symptomatic) pathways, and a small increase in number of missed cancer diagnoses. Deterministic sensitivity analyses, varying each parameter to its upper and lower 95% confidence intervals, showed no significant change in the dominance of the MRI‐based prostate cancer diagnostic pathways. Conclusion Using prostate MRI as a second‐level triage test for suspected prostate cancer in primary care could reduce health service costs without a detrimental effect on patient utility.

AbstractObjectiveTo quantify the predictive value of unexpected weight loss for cancer according to patient’s age, sex, smoking status, and concurrent clinical features (symptoms, signs, and abnormal blood test results).DesignDiagnostic accuracy study (update).SettingData from Clinical Practice Research Datalink electronic health records linked to the National Cancer Registration and Analysis Service in primary care, England.Participants326 240 adults (≥18 years) with a code for unexpected weight loss from 1 January 2000 to 31 December 2019.Main outcome measuresCancer diagnosis in the six months after the earliest weight loss code (index date). Codes for additional clinical features were identified in the three months before to one month after the index date. Diagnostic accuracy measures included positive and negative likelihood ratios, positive predictive values, and diagnostic odds ratios.ResultsOf 326 240 adults with unexpected weight loss, 184 270 (56.5%) were women, 176 508 (54.1%) were aged ≥60 years, and 176 053 (54.0%) were ever smokers. 15 624 (4.8%) had a diagnosis of cancer within six months of the index date, of whom 15 051 (96.3%) were aged ≥50 years. The positive predictive value for cancer was above the 3% threshold recommended by the National Institute for Health and Care Excellence for urgent investigation in men aged ≥50 years and women aged ≥60 years. 17 additional clinical features were associated with cancer in younger men with unexpected weight loss, and eight in women. Positive likelihood ratios in men ranged from 1.43 (95% confidence interval 1.30 to 1.58) for fatigue to 21.00 (8.59 to 51.37) for rectal mass, and in women from 1.28 (1.16 to 1.41) for back pain to 19.46 (12.69 to 29.85) for pelvic mass. Abnormal blood test results associated with cancer included low albumin (positive likelihood ratio 3.24, 3.13 to 3.35) and raised platelets (3.48, 3.35 to 3.62), total white cell count (3.01, 2.89 to 3.14), and C reactive protein (3.13, 3.05 to 3.20). However, no normal blood test result in isolation ruled out cancer. Clinical features co-occurring with unexpected weight loss were associated with multiple cancer sites.ConclusionThe risk of cancer in younger adults with unexpected weight loss presenting to primary care is <3% and does not merit investigation under current UK guidelines. However, in men aged ≥50 years, women aged ≥60 years, and younger patients with concurrent clinical features, the risk of cancer warrants referral for invasive investigation. Clinical features typically associated with specific cancer sites are markers of several cancer types when they occur with unexpected weight loss.Readers’ noteThis article is an updated version of a previously published BMJ paper that has since been retracted.

AbstractObjectiveTo quantify the predictive value of unexpected weight loss (WL) for cancer according to patient’s age, sex, smoking status, and concurrent clinical features (symptoms, signs, and abnormal blood test results).DesignDiagnostic accuracy study.SettingClinical Practice Research Datalink electronic health records data linked to the National Cancer Registration and Analysis Service in primary care, England.Participants63 973 adults (≥18 years) with a code for unexpected WL from 1 January 2000 to 31 December 2012.Main outcome measuresCancer diagnosis in the six months after the earliest weight loss code (index date). Codes for additional clinical features were identified in the three months before to one month after the index date. Diagnostic accuracy measures included positive and negative likelihood ratios, positive predictive values, and diagnostic odds ratios.ResultsOf 63 973 adults with unexpected WL, 37 215 (58.2%) were women, 33 167 (51.8%) were aged 60 years or older, and 16 793 (26.3%) were ever smokers. 908 (1.4%) had a diagnosis of cancer within six months of the index date, of whom 882 (97.1%) were aged 50 years or older. The positive predictive value for cancer was above the 3% threshold recommended by the National Institute for Health and Care Excellence for urgent investigation in male ever smokers aged 50 years or older, but not in women at any age. 10 additional clinical features were associated with cancer in men with unexpected WL, and 11 in women. Positive likelihood ratios in men ranged from 1.86 (95% confidence interval 1.32 to 2.62) for non-cardiac chest pain to 6.10 (3.44 to 10.79) for abdominal mass, and in women from 1.62 (1.15 to 2.29) for back pain to 20.9 (10.7 to 40.9) for jaundice. Abnormal blood test results associated with cancer included low albumin levels (4.67, 4.14 to 5.27) and raised values for platelets (4.57, 3.88 to 5.38), calcium (4.28, 3.05 to 6.02), total white cell count (3.76, 3.30 to 4.28), and C reactive protein (3.59, 3.31 to 3.89). However, no normal blood test result in isolation ruled out cancer. Clinical features co-occurring with unexpected WL were associated with multiple cancer sites.ConclusionThe risk of cancer in adults with unexpected WL presenting to primary care is 2% or less and does not merit investigation under current UK guidelines. However, in male ever smokers aged 50 years or older and in patients with concurrent clinical features, the risk of cancer warrants referral for invasive investigation. Clinical features typically associated with specific cancer sites are markers of several cancer types when they occur with unexpected WL.

Diagnosing cancer may be expedited by decreasing referral risk threshold. Clinical Practice Research Datalink participants (≥40 years) had a positive predictive value (PPV) ≥3% feature for breast, lung, colorectal, oesophagogastric, pancreatic, renal, bladder, prostatic, ovarian, endometrial or laryngeal cancer in 2016. The numbers of participants with features representing a 1–1.99% or 2–2.99% PPV for same cancer in the previous year were reported, alongside the time difference between meeting the ≥3% criteria and the lower threshold criteria. A total of 8616 participants had a PPV ≥3% feature, of whom 365 (4.2%) and 1147 (13.3%), respectively, met 2–2.99% and 1–1.99% criteria in the preceding year. The median time difference was 131 days (Interquartile Range (IQR) 27 to 256) for the 2–2.99% band and 179 days (IQR 58 to 289) for the 1–1.99% band. Results were heterogeneous across cancer sites. For some cancers, participants may progress from presenting lower- to higher-risk features before meeting urgent referral criteria; however, this was not usually the case. The details of specific features across multiple cancer sites will allow for a tailored approach to future reductions in referral thresholds, potentially improving the efficiency of urgent cancer referrals for the benefit both of individuals and the National Health Service (NHS).

By positional cloning techniques, we have identified the gene that is disrupted in the jcpk and bpk mouse models for polycystic kidney disease. This gene is the mouse homolog of the Drosophila Bicaudal C gene. Both of these mutations have been mapped to a very short stretch of Chromosome (Chr) 10. By sequencing the bicaudal C gene, Bicc1, in these models, it was found that the jcpk mutation results in a shortened and abnormal transcript, whereas the bpk mutation results in an abnormal 3' coding region. In Drosophila, this gene encodes a protein known to influence developmental processes. The mammalian homolog contains three KH (K homology) domains and a SAM (sterile alpha motif) domain and is expressed in the developing embryo, indicating that it may be important in RNA-binding and/or protein interactions during embryogenesis.

AbstractObjectiveTo quantify the predictive value of unexpected weight loss (WL) for cancer according to patient’s age, sex, smoking status, and concurrent clinical features (symptoms, signs, and abnormal blood test results).DesignDiagnostic accuracy study.SettingClinical Practice Research Datalink electronic health records data linked to the National Cancer Registration and Analysis Service in primary care, England.Participants63 973 adults (≥18 years) with a code for unexpected WL from 1 January 2000 to 31 December 2012.Main outcome measuresCancer diagnosis in the six months after the earliest weight loss code (index date). Codes for additional clinical features were identified in the three months before to one month after the index date. Diagnostic accuracy measures included positive and negative likelihood ratios, positive predictive values, and diagnostic odds ratios.ResultsOf 63 973 adults with unexpected WL, 37 215 (58.2%) were women, 33 167 (51.8%) were aged 60 years or older, and 16 793 (26.3%) were ever smokers. 908 (1.4%) had a diagnosis of cancer within six months of the index date, of whom 882 (97.1%) were aged 50 years or older. The positive predictive value for cancer was above the 3% threshold recommended by the National Institute for Health and Care Excellence for urgent investigation in male ever smokers aged 50 years or older, but not in women at any age. 10 additional clinical features were associated with cancer in men with unexpected WL, and 11 in women. Positive likelihood ratios in men ranged from 1.86 (95% confidence interval 1.32 to 2.62) for non-cardiac chest pain to 6.10 (3.44 to 10.79) for abdominal mass, and in women from 1.62 (1.15 to 2.29) for back pain to 20.9 (10.7 to 40.9) for jaundice. Abnormal blood test results associated with cancer included low albumin levels (4.67, 4.14 to 5.27) and raised values for platelets (4.57, 3.88 to 5.38), calcium (4.28, 3.05 to 6.02), total white cell count (3.76, 3.30 to 4.28), and C reactive protein (3.59, 3.31 to 3.89). However, no normal blood test result in isolation ruled out cancer. Clinical features co-occurring with unexpected WL were associated with multiple cancer sites.ConclusionThe risk of cancer in adults with unexpected WL presenting to primary care is 2% or less and does not merit investigation under current UK guidelines. However, in male ever smokers aged 50 years or older and in patients with concurrent clinical features, the risk of cancer warrants referral for invasive investigation. Clinical features typically associated with specific cancer sites are markers of several cancer types when they occur with unexpected WL.