Patient versus physician preferences for lipid-lowering drug therapy: A discrete choice experiment.

BACKGROUND: The emergence of proprotein convertase subtilisin/kexin type 9 inhibitors offered dyslipidemia patients an alternative to statins for lipid-lowering treatment. Understanding patient and physician preferences for lipid-lowering drugs may promote shared decision-making and improve treatment outcomes. METHODS: This study utilized an online discrete choice experiment (DCE) to assess the relative importance (RI) of six attributes related to lipid-lowering drugs, including frequency of administration, mode of administration, reduction of low-density lipoprotein cholesterol (LDL-C) level, risk of myopathy, risk of liver damage, and out-of-pocket monthly cost. Respondents were recruited from dyslipidemia patients and cardiovascular physicians in China. A mixed logit model and latent class analysis were employed to estimate the preference coefficient, marginal willingness to pay (mWTP), and RI of attributes. Ethical approval has been obtained for this study. RESULTS: A total of 708 patients and 507 physicians participated in the survey. Patients prioritized the 'risk of liver damage' (RI = 23.6%) with 'mode of administration' (RI = 19.2%) and 'frequency of administration' (RI = 18.8%) following closely. Contrarily, physicians prioritized the 'reduction of LDL-C level' (RI = 33.5%), followed by 'risk of liver damage' (RI = 26.0%) and 'risk of myopathy' (RI = 16.1%). Patients placed a higher value on 'frequency of administration' (p < .001) and 'mode of administration' (p < .001) compared to physicians, while physicians valued 'reduction of LDL-C level' (p < .001) and 'risk of myopathy' (p = .012) more than patients. Physicians exhibited higher mWTP than patients for all attributes except frequency and mode of administration. The LCA revealed three distinct patient classes: focus on oral administration, focus on hepatic safety and frequency and focus on hepatic safety and cost. Likewise, three physician classes were identified: frequency-insensitive, efficacy-focused and safety-focused. CONCLUSIONS: The preferences for lipid-lowering drug therapy differed between patients and physicians in China. Physicians should take into account patients' preferences and provide personalized treatment when they formulate lipid-lowering treatment plans. PATIENT OR PUBLIC CONTRIBUTION: Patients participated in the questionnaire design process. They engaged in a focus group discussion to determine attributes and levels and also participated in a pilot survey to assess the comprehensibility of the questionnaires. Additionally, patients were involved in the DCE survey to express their preferences. The findings of patient preference for lipid-lowering drug therapy will promote shared decision-making and optimize the treatment regimen.

Inpatient antibacterial use trends and patterns, China, 2013-2021.

Objective: To analyse trends and patterns in inpatient antibacterial use in China's tertiary and secondary hospitals between 2013 and 2021. Methods: The analysis involved quarterly data from hospitals covered by China's Center for Antibacterial Surveillance. We obtained information on hospital characteristics (e.g. province, a de-identified hospital code, hospital level and inpatient days) and antibacterial characteristics (e.g. generic name, drug classification, dosage, administration route and usage volume). We quantified antibacterial use as the number of daily defined doses per 100 patient-days. The analysis took into account the World Health Organization's (WHO's) Access, Watch, Reserve classification of antibiotics. Findings: Between 2013 and 2021, overall antibacterial use in inpatients decreased significantly from 48.8 to 38.0 daily defined doses per 100 patient-days (P < 0.001). In 2021, the variation between provinces was almost twofold: 29.1 daily defined doses per 100 patient-days in Qinghai versus 55.3 in Tibet. The most-used antibacterials in both tertiary and secondary hospitals throughout the study period were third-generation cephalosporins, which comprised around one third of total antibacterial use. Carbapenems entered the list of most-used antibacterial classifications in 2015. The most frequently used antibacterials in WHO's classification belonged to the Watch group: usage increased significantly from 61.3% (29.9/48.8) in 2013 to 64.1% (24.4/38.0) in 2021 (P < 0.001). Conclusion: Antibacterial use in inpatients decreased significantly during the study period. However, the rising proportion of last-resort antibacterials used is concerning, as is the large gap between the proportion of antibacterials used belonging to the Access group and WHO's global target of no less than 60%.

Antibiotics for lower respiratory tract infection in children presenting in primary care in England (ARTIC PC): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Antibiotic resistance is a global public health threat. Antibiotics are very commonly prescribed for children presenting with uncomplicated lower respiratory tract infections (LRTIs), but there is little evidence from randomised controlled trials of the effectiveness of antibiotics, both overall or among key clinical subgroups. In ARTIC PC, we assessed whether amoxicillin reduces the duration of moderately bad symptoms in children presenting with uncomplicated (non-pneumonic) LRTI in primary care, overall and in key clinical subgroups. METHODS: ARTIC PC was a double-blind, randomised, placebo-controlled trial done at 56 general practices in England. Eligible children were those aged 6 months to 12 years presenting in primary care with acute uncomplicated LRTI judged to be infective in origin, where pneumonia was not suspected clinically, with symptoms for less than 21 days. Patients were randomly assigned in a 1:1 ratio to receive amoxicillin 50 mg/kg per day or placebo oral suspension, in three divided doses orally for 7 days. Patients and investigators were masked to treatment assignment. The primary outcome was the duration of symptoms rated moderately bad or worse (measured using a validated diary) for up to 28 days or until symptoms resolved. The primary outcome and safety were assessed in the intention-to-treat population. The trial is registered with the ISRCTN Registry (ISRCTN79914298). FINDINGS: Between Nov 9, 2016, and March 17, 2020, 432 children (not including six who withdrew permission for use of their data after randomisation) were randomly assigned to the antibiotics group (n=221) or the placebo group (n=211). Complete data for symptom duration were available for 317 (73%) patients; missing data were imputed for the primary analysis. Median durations of moderately bad or worse symptoms were similar between the groups (5 days [IQR 4-11] in the antibiotics group vs 6 days [4-15] in the placebo group; hazard ratio [HR] 1·13 [95% CI 0·90-1·42]). No differences were seen for the primary outcome between the treatment groups in the five prespecified clinical subgroups (patients with chest signs, fever, physician rating of unwell, sputum or chest rattle, and short of breath). Estimates from complete-case analysis and a per-protocol analysis were similar to the imputed data analysis. INTERPRETATION: Amoxicillin for uncomplicated chest infections in children is unlikely to be clinically effective either overall or for key subgroups in whom antibiotics are commonly prescribed. Unless pneumonia is suspected, clinicians should provide safety-netting advice but not prescribe antibiotics for most children presenting with chest infections. FUNDING: National Institute for Health Research.

The feasibility and acceptability of assessing and managing sarcopenia and frailty among older people with upper limb fracture.

BACKGROUND: sarcopenia and frailty are associated with increased risk of falls and fractures. This study evaluated the feasibility of assessing sarcopenia and frailty among older people attending fracture clinics. METHODS: patients aged 65+ years with an arm fracture attending fracture clinics in one UK city were recruited. Sarcopenia was assessed using gait speed, grip strength, skeletal muscle mass index SMI, SARC-F questionnaire and the European Working Group on Sarcopenia in Older People (EWGSOP) I and II criteria. Frailty was assessed using Fried Frailty Phenotype (FFP), FRAIL scale, PRISMA-7, electronic Frailty Index (e-FI), Clinical Frailty Score (CFS) and Study of Osteoporotic Fracture. The sensitivity and specificity of each tool was calculated against the EWGSOP II criteria (sarcopenia) and FFP (frailty). Patients identified to have either condition were referred for Comprehensive Geriatric Assessment (CGA). Interviews with 13 patients and nine staff explored the acceptability of this process. RESULTS: hundred patients (Mean age 75 years) were recruited. Most sarcopenia and frailty assessments were quick with complete data collection and were acceptable to patients and staff. Sarcopenia was identified among 4-39% participants depending on the tool and frailty among 9-25%. Both conditions were more common among men than women with all tools. The SARC-F and PRISMA-7 had the best sensitivity (100 and 93%, respectively) and specificity (96 and 87%). CGA among 80% of referred participants led to three interventions per participant (e.g. medication changes and investigations). CONCLUSION: SARC-F and PRISMA-7 are recommended for use in fracture clinics to screen for sarcopenia and frailty.

Patient blood management interventions do not lead to important clinical benefits or cost-effectiveness for major surgery: a network meta-analysis.

BACKGROUND: Patient blood management (PBM) interventions aim to improve clinical outcomes by reducing bleeding and transfusion. We assessed whether existing evidence supports the routine use of combinations of these interventions during and after major surgery. METHODS: Five systematic reviews and a National Institute of Health and Care Excellence health economic review of trials of common PBM interventions enrolling participants of any age undergoing surgery were updated. The last search was on June 1, 2019. Studies in trauma, burns, gastrointestinal haemorrhage, gynaecology, dentistry, or critical care were excluded. The co-primary outcomes were: risk of receiving red cell transfusion and 30-day or hospital all-cause mortality. Treatment effects were estimated using random-effects models and risk ratios (RR) with 95% confidence intervals (CIs). Heterogeneity assessments used I2. Network meta-analyses used a frequentist approach. The protocol was registered prospectively (PROSPERO CRD42018085730). RESULTS: Searches identified 393 eligible randomised controlled trials enrolling 54 917 participants. PBM interventions resulted in a reduction in exposure to red cell transfusion (RR=0.60; 95% CI 0.57, 0.63; I2=77%), but had no statistically significant treatment effect on 30-day or hospital mortality (RR=0.93; 95% CI 0.81, 1.07; I2=0%). Treatment effects were consistent across multiple secondary outcomes, sub-groups and sensitivity analyses that considered clinical setting, type of intervention, and trial quality. Network meta-analysis did not demonstrate additive benefits from the use of multiple interventions. No trial demonstrated that PBM was cost-effective. CONCLUSIONS: In randomised trials, PBM interventions do not have important clinical benefits beyond reducing bleeding and transfusion in people undergoing major surgery.

The Prevalence of Diabetes in Autistic Persons: A Systematic Review.

BACKGROUND: It has been proposed that autistic individuals are at an increased risk of type 1 and type 2 diabetes. Improved understanding of diabetes prevalence in autistic persons will help inform resource allocation for diabetes-related public health measures for this patient group. OBJECTIVE: To conduct a systematic review of published literature pertaining to type 1 and type 2 diabetes prevalence in autistic individuals, including comparison with their non-autistic peers. METHODS: Eligibility criteria included studies investigating the prevalence of diabetes in autistic individuals, as well as having been published in the English language. A systematic search of online databases (MEDLINE, PsycINFO, CINAHL, EMBASE and PubMed) was conducted on 4th April 2020. Additional approaches included the ancestry method, grey literature searches and expert consultation. Studies were qualitatively analysed with reporting quality appraised. RESULTS: 19 eligible studies were identified, 7 of which provided type-specific diabetes prevalence data. Of 15 studies that included a non-autistic control group, 9 reported a higher diabetes prevalence among autistic persons, with a statistically significant difference in 4 studies. Studies demonstrating a higher diabetes prevalence in autistic groups had higher average study population sizes and reporting quality ratings. CONCLUSION: It is uncertain whether diabetes is significantly more prevalent in autistic persons relative to their non-autistic peers, though larger studies suggest a trend in this direction. Nevertheless, diabetes is a significant public health issue for the autistic community, which may require a tailored approach for identification and management. Prospero database registration number: CRD42019122176.

Investigating time, strength, and duration of measures in controlling the spread of COVID-19 using a networked meta-population model.

Policy makers around the world are facing unprecedented challenges in making decisions on when and what degrees of measures should be implemented to tackle the COVID-19 pandemic. Here, using a nationwide mobile phone dataset, we developed a networked meta-population model to simulate the impact of intervention in controlling the spread of the virus in China by varying the effectiveness of transmission reduction and the timing of intervention start and relaxation. We estimated basic reproduction number and transition probabilities between health states based on reported cases. Our model demonstrates that both the time of initiating an intervention and its effectiveness had a very large impact on controlling the epidemic, and the current Chinese intense social distancing intervention has reduced the impact substantially but would have been even more effective had it started earlier. The optimal duration of the control measures to avoid resurgence was estimated to be 2 months, although would need to be longer under less effective controls.

A comparison of the clinical effectiveness and cost of specialised individually delivered parent training for preschool attention-deficit/hyperactivity disorder and a generic, group-based programme: a multi-centre, randomised controlled trial of the New Forest Parenting Programme versus Incredible Years.

The objective of this study is to compare the efficacy and cost of specialised individually delivered parent training (PT) for preschool children with attention-deficit/hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). This is a multi-centre three-arm, parallel group randomised controlled trial conducted in National Health Service Trusts. The participants included in this study were preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. New Forest Parenting Programme (NFPP)-12-week individual, home-delivered ADHD PT programme; Incredible Years (IY)-12-week group-based, PT programme initially designed for children with behaviour problems were the interventions. Primary outcome-Parent ratings of child's ADHD symptoms (Swanson, Nolan & Pelham Questionnaire-SNAP-IV). Secondary outcomes-teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputations). Intervention and other costs were estimated using standardized approaches. NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms [mean difference - 0.009 95% CI (- 0.191, 0.173), p = 0.921] or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms [- 0.189 95% CI (- 0.380, 0.003), p = 0.053]. NFPP significantly reduced parent-rated conduct problems compared to TAU across scales (p values < 0.05). No significant benefits of IY over TAU were seen for parent-rated SNAP, ADHD symptoms [- 0.16 95% CI (- 0.37, 0.04), p = 0.121] or parent-rated conduct problems (p > 0.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1591 versus £2103). Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches.

An internet-delivered handwashing intervention to modify influenza-like illness and respiratory infection transmission (PRIMIT): a primary care randomised trial.

BACKGROUND: Handwashing to prevent transmission of respiratory tract infections (RTIs) has been widely advocated, especially during the H1N1 pandemic. However, the role of handwashing is debated, and no good randomised evidence exists among adults in non-deprived settings. We aimed to assess whether an internet-delivered intervention to modify handwashing would reduce the number of RTIs among adults and their household members. METHODS: We recruited individuals sharing a household by mailed invitation through general practices in England. After consent, participants were randomised online by an automated computer-generated random number programme to receive either no access or access to a bespoke automated web-based intervention that maximised handwashing intention, monitored handwashing behaviour, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs. We enrolled participants into an additional cohort (randomised to receive intervention or no intervention) to assess whether the baseline questionnaire on handwashing would affect handwashing behaviour. Participants were not masked to intervention allocation, but statistical analysis commands were constructed masked to group. The primary outcome was number of episodes of RTIs in index participants in a modified intention-to-treat population of randomly assigned participants who completed follow-up at 16 weeks. This trial is registered with the ISRCTN registry, number ISRCTN75058295. FINDINGS: Across three winters between Jan 17, 2011, and March 31, 2013, we enrolled 20,066 participants and randomly assigned them to receive intervention (n=10,040) or no intervention (n=10,026). 16,908 (84%) participants were followed up with the 16 week questionnaire (8241 index participants in intervention group and 8667 in control group). After 16 weeks, 4242 individuals (51%) in the intervention group reported one or more episodes of RTI compared with 5135 (59%) in the control group (multivariate risk ratio 0·86, 95% CI 0·83-0·89; p<0·0001). The intervention reduced transmission of RTIs (reported within 1 week of another household member) both to and from the index person. We noted a slight increase in minor self-reported skin irritation (231 [4%] of 5429 in intervention group vs 79 [1%] of 6087 in control group) and no reported serious adverse events. INTERPRETATION: In non-pandemic years, an effective internet intervention designed to increase handwashing could have an important effect in reduction of infection transmission. In view of the heightened concern during a pandemic and the likely role of the internet in access to advice, the intervention also has potential for effective implementation during a pandemic. FUNDING: Medical Research Council.

Identification of Extracolonic Pathologies by Computed Tomographic Colonography in Colorectal Cancer Symptomatic Patients.

BACKGROUND & AIMS: Symptoms suggestive of colorectal cancer may originate outside the colorectum. Computed tomographic colonography (CTC) is used to examine the colorectum and abdominopelvic organs simultaneously. We performed a prospective randomized controlled trial to quantify the frequency, nature, and consequences of extracolonic findings. METHODS: We studied 5384 patients from 21 UK National Health Service hospitals referred by their family doctor for the investigation of colorectal cancer symptoms from March 2004 through December 2007. The patients were assigned randomly to groups that received the requested test (barium enema or colonoscopy, n = 3574) or CTC (n = 1810). We determined the frequency and nature of extracolonic findings, subsequent investigations, ultimate diagnosis, and extracolonic cancer diagnoses 1 and 3 years after testing patients without colorectal cancer. RESULTS: Extracolonic pathologies were detected in 959 patients by CTC (58.7%), in 42 patients by barium enema analysis (1.9%), and in no patients by colonoscopy. Extracolonic findings were investigated in 142 patients (14.2%) and a diagnosis was made for 126 patients (88.1%). Symptoms were explained by extracolonic findings in 4 patients analyzed by barium enema (0.2%) and in 33 patients analyzed by CTC (2.8%). CTC identified 72 extracolonic neoplasms, however, barium enema analysis found only 3 (colonoscopy found none). Overall, CTC diagnosed extracolonic neoplasms in 72 of 1634 patients (4.4%); 26 of these were malignant (1.6%). There were significantly more extracolonic malignancies detected than expected 1 year after examination, but these did not differ between patients evaluated by CTC (22.2/1000 person-years), barium enema (26.5/1000 person-years; P = .43), or colonoscopy (32.0/1000 person-years; P = .88). CONCLUSIONS: More than half of the patients with symptoms of colorectal cancer are found to have extracolonic pathologies by CTC analysis. However, the proportion of patients found to have extracolonic malignancies after 1 year of CTC examination is not significantly greater than after barium enema or colonoscopy examinations. International Standard Randomised Controlled Trials no: 95152621.isrctn.com.

Effectiveness of steam inhalation and nasal irrigation for chronic or recurrent sinus symptoms in primary care: a pragmatic randomized controlled trial.

BACKGROUND: Systematic reviews support nasal saline irrigation for chronic or recurrent sinus symptoms, but trials have been small and few in primary care settings. Steam inhalation has also been proposed, but supporting evidence is lacking. We investigated whether brief pragmatic interventions to encourage use of nasal irrigation or steam inhalation would be effective in relieving sinus symptoms. METHODS: We conducted a pragmatic randomized controlled trial involving adults (age 18-65 yr) from 72 primary care practices in the United Kingdom who had a history of chronic or recurrent sinusitis and reported a "moderate to severe" impact of sinus symptoms on their quality of life. Participants were recruited between Feb. 11, 2009, and June 30, 2014, and randomly assigned to 1 of 4 advice strategies: usual care, daily nasal saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions. The primary outcome measure was the Rhinosinusitis Disability Index (RSDI). Patients were followed up at 3 and 6 months. We imputed missing data using multiple imputation methods. RESULTS: Of the 961 patients who consented, 871 returned baseline questionnaires (210 usual care, 219 nasal irrigation, 232 steam inhalation and 210 combined treatment). A total of 671 (77.0%) of the 871 participants reported RSDI scores at 3 months. Patients' RSDI scores improved more with nasal irrigation than without nasal irrigation by 3 months (crude change -7.42 v. -5.23; estimated adjusted mean difference between groups -2.51, 95% confidence interval -4.65 to -0.37). By 6 months, significantly more patients maintained a 10-point clinically important improvement in the RSDI score with nasal irrigation (44.1% v. 36.6%); fewer used over-the-counter medications (59.4% v. 68.0%) or intended to consult a doctor in future episodes. Steam inhalation reduced headache but had no significant effect on other outcomes. The proportion of participants who had adverse effects was the same in both intervention groups. INTERPRETATION: Advice to use steam inhalation for chronic or recurrent sinus symptoms in primary care was not effective. A similar strategy to use nasal irrigation was less effective than prior evidence suggested, but it provided some symptomatic benefit. TRIAL REGISTRATION: ISRCTN, no. 88204146.

Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial.

BACKGROUND: Otitis media with effusion is a common problem that lacks an evidence-based nonsurgical treatment option. We assessed the clinical effectiveness of treatment with a nasal balloon device in a primary care setting. METHODS: We conducted an open, pragmatic randomized controlled trial set in 43 family practices in the United Kingdom. Children aged 4-11 years with a recent history of ear symptoms and otitis media with effusion in 1 or both ears, confirmed by tympanometry, were allocated to receive either autoinflation 3 times daily for 1-3 months plus usual care or usual care alone. Clearance of middle-ear fluid at 1 and 3 months was assessed by experts masked to allocation. RESULTS: Of 320 children enrolled, those receiving autoinflation were more likely than controls to have normal tympanograms at 1 month (47.3% [62/131] v. 35.6% [47/132]; adjusted relative risk [RR] 1.36, 95% confidence interval [CI] 0.99 to 1.88) and at 3 months (49.6% [62/125] v. 38.3% [46/120]; adjusted RR 1.37, 95% CI 1.03 to 1.83; number needed to treat = 9). Autoinflation produced greater improvements in ear-related quality of life (adjusted between-group difference in change from baseline in OMQ-14 [an ear-related measure of quality of life] score -0.42, 95% CI -0.63 to -0.22). Compliance was 89% at 1 month and 80% at 3 months. Adverse events were mild, infrequent and comparable between groups. INTERPRETATION: Autoinflation in children aged 4-11 years with otitis media with effusion is feasible in primary care and effective both in clearing effusions and improving symptoms and ear-related child and parent quality of life. TRIAL REGISTRATION: ISRCTN, No. 55208702.

Computed tomographic colonography versus barium enema for diagnosis of colorectal cancer or large polyps in symptomatic patients (SIGGAR): a multicentre randomised trial.

BACKGROUND: Barium enema (BE) is widely available for diagnosis of colorectal cancer despite concerns about its accuracy and acceptability. Computed tomographic colonography (CTC) might be a more sensitive and acceptable alternative. We aimed to compare CTC and BE for diagnosis of colorectal cancer or large polyps in symptomatic patients in clinical practice. METHODS: This pragmatic multicentre randomised trial recruited patients with symptoms suggestive of colorectal cancer from 21 UK hospitals. Eligible patients were aged 55 years or older and regarded by their referring clinician as suitable for radiological investigation of the colon. Patients were randomly assigned (2:1) to BE or CTC by computer-generated random numbers, in blocks of six, stratified by trial centre and sex. We analysed the primary outcome-diagnosis of colorectal cancer or large (≥10 mm) polyps-by intention to treat. The trial is an International Standard Randomised Controlled Trial, number 95152621. FINDINGS: 3838 patients were randomly assigned to receive either BE (n=2553) or CTC (n=1285). 34 patients withdrew consent, leaving for analysis 2527 assigned to BE and 1277 assigned to CTC. The detection rate of colorectal cancer or large polyps was significantly higher in patients assigned to CTC than in those assigned to BE (93 [7.3%] of 1277 vs 141 [5.6%] of 2527, relative risk 1.31, 95% CI 1.01-1.68; p=0.0390). CTC missed three of 45 colorectal cancers and BE missed 12 of 85. The rate of additional colonic investigation was higher after CTC than after BE (283 [23.5%] of 1206 CTC patients had additional investigation vs 422 [18.3%] of 2300 BE patients; p=0.0003), due mainly to a higher polyp detection rate. Serious adverse events were rare. INTERPRETATION: CTC is a more sensitive test than BE. Our results suggest that CTC should be the preferred radiological test for patients with symptoms suggestive of colorectal cancer. FUNDING: NIHR Health Technology Assessment Programme, NIHR Biomedical Research Centres funding scheme, Cancer Research UK, EPSRC Multidisciplinary Assessment of Technology Centre for Healthcare, and NIHR Collaborations for Leadership in Applied Health Research and Care.

Computed tomographic colonography versus colonoscopy for investigation of patients with symptoms suggestive of colorectal cancer (SIGGAR): a multicentre randomised trial.

BACKGROUND: Colonoscopy is the gold-standard test for investigation of symptoms suggestive of colorectal cancer; computed tomographic colonography (CTC) is an alternative, less invasive test. However, additional investigation after CTC is needed to confirm suspected colonic lesions, and this is an important factor in establishing the feasibility of CTC as an alternative to colonoscopy. We aimed to compare rates of additional colonic investigation after CTC or colonoscopy for detection of colorectal cancer or large (≥10 mm) polyps in symptomatic patients in clinical practice. METHODS: This pragmatic multicentre randomised trial recruited patients with symptoms suggestive of colorectal cancer from 21 UK hospitals. Eligible patients were aged 55 years or older and regarded by their referring clinician as suitable for colonoscopy. Patients were randomly assigned (2:1) to colonoscopy or CTC by computer-generated random numbers, in blocks of six, stratified by trial centre and sex. We analysed the primary outcome-the rate of additional colonic investigation-by intention to treat. The trial is an International Standard Randomised Controlled Trial, number 95152621. FINDINGS: 1610 patients were randomly assigned to receive either colonoscopy (n=1072) or CTC (n=538). 30 patients withdrew consent, leaving for analysis 1047 assigned to colonoscopy and 533 assigned to CTC. 160 (30.0%) patients in the CTC group had additional colonic investigation compared with 86 (8.2%) in the colonoscopy group (relative risk 3.65, 95% CI 2.87-4.65; p<0.0001). Almost half the referrals after CTC were for small (<10 mm) polyps or clinical uncertainty, with low predictive value for large polyps or cancer. Detection rates of colorectal cancer or large polyps in the trial cohort were 11% for both procedures. CTC missed 1 of 29 colorectal cancers and colonoscopy missed none (of 55). Serious adverse events were rare. INTERPRETATION: Guidelines are needed to reduce the referral rate after CTC. For most patients, however, CTC provides a similarly sensitive, less invasive alternative to colonoscopy. FUNDING: NIHR Health Technology Assessment Programme, NIHR Biomedical Research Centres funding scheme, Cancer Research UK, EPSRC Multidisciplinary Assessment of Technology Centre for Healthcare, and NIHR Collaborations for Leadership in Applied Health Research and Care.

Detection of extracolonic pathologic findings with CT colonography: a discrete choice experiment of perceived benefits versus harms.

PURPOSE: To determine the maximum rate of false-positive diagnoses that patients and health care professionals were willing to accept in exchange for detection of extracolonic malignancy by using computed tomographic (CT) colonography for colorectal cancer screening. MATERIALS AND METHODS: After obtaining ethical approval and informed consent, 52 patients and 50 health care professionals undertook two discrete choice experiments where they chose between unrestricted CT colonography that examined intra- and extracolonic organs or CT colonography restricted to the colon, across different scenarios. The first experiment detected one extracolonic malignancy per 600 cases with a false-positive rate varying across scenarios from 0% to 99.8%. One experiment examined radiologic follow-up generated by false-positive diagnoses while the other examined invasive follow-up. Intracolonic performance was identical for both tests. The median tipping point (maximum acceptable false-positive rate for extracolonic findings) was calculated overall and for both groups by bootstrap analysis. RESULTS: The median tipping point for radiologic follow-up occurred at a false-positive rate greater than 99.8% (interquartile ratio [IQR], 10 to >99.8%). Participants would tolerate at least a 99.8% rate of unnecessary radiologic tests to detect an additional extracolonic malignancy. The median tipping-point for invasive follow-up occurred at a false-positive rate of 10% (IQR, 2 to >99.8%). Tipping points were significantly higher for patients than for health care professionals for both experiments (>99.8 vs 40% for radiologic follow-up and >99.8 vs 5% for invasive follow-up, both P < .001). CONCLUSION: Patients and health care professionals are willing to tolerate high rates of false-positive diagnoses with CT colonography in exchange for diagnosis of extracolonic malignancy. The actual specificity of screening CT colonography for extracolonic findings in clinical practice is likely to be highly acceptable to both patients and health care professionals. Online supplemental material is available for this article.

Depression follow-up monitoring with the PHQ-9: an open cluster-randomised controlled trial.

BACKGROUND: Outcome monitoring of depression treatment is recommended but there is a lack of evidence on patient benefit in primary care. AIM: To test monitoring depression using the Patient Health Questionnaire (PHQ-9) with patient feedback. DESIGN AND SETTING: An open cluster-randomised controlled trial was undertaken in 141 group practices. METHOD: Adults with new depressive episodes were recruited through record searches and opportunistically. The exclusion criteria were as follows: dementia; psychosis; substance misuse; and suicide risk. The PHQ-9 was administered soon after diagnosis, and 10-35 days later. The primary outcome was the Beck Depression Inventory (BDI-II) score at 12 weeks. The secondary outcomes were as follows: BDI-II at 26 weeks; Work and Social Adjustment Scale (WSAS) and EuroQol EQ-5D-5L quality of life at 12 and 26 weeks; antidepressant treatment; mental health and social service contacts; adverse events, and Medical Interview Satisfaction Scale (MISS) over 26 weeks. RESULTS: In total, 302 patients were recruited to the intervention arm and 227 to the controls. At 12 weeks, 254 (84.1%) and 199 (87.7%) were followed-up, respectively. Only 40.9% of patients in the intervention had a GP follow-up PHQ-9 recorded. There was no significant difference in BDI-II score at 12 weeks (mean difference -0.46; 95% confidence interval [CI] = -2.16 to 1.26; adjusted for baseline depression, baseline anxiety, sociodemographic factors, and clustering by practice). EQ-5D-5L quality-of-life scores were higher in the intervention arm at 26 weeks (adjusted mean difference 0.053; 95% CI = 0.013 to 0.093. A clinically significant difference in depression at 26 weeks could not be ruled out. No significant differences were found in social functioning, adverse events, or satisfaction. In a per-protocol analysis, antidepressant use and mental health contacts were significantly greater in patients in the intervention arm with a recorded follow-up PHQ-9 (P = 0.025 and P = 0.010, respectively). CONCLUSION: No evidence was found of improved depression outcome at 12 weeks from monitoring. The findings of possible benefits over 26 weeks warrant replication, investigating possible mechanisms, preferably with automated delivery of monitoring and more instructive feedback.

Patient-reported outcome measures for monitoring primary care patients with depression: the PROMDEP cluster RCT and economic evaluation.

Background: Guidelines on the management of depression recommend that practitioners use patient-reported outcome measures for the follow-up monitoring of symptoms, but there is a lack of evidence of benefit in terms of patient outcomes. Objective: To test using the Patient Health Questionnaire-9 questionnaire as a patient-reported outcome measure for monitoring depression, training practitioners in interpreting scores and giving patients feedback. Design: Parallel-group, cluster-randomised superiority trial; 1 : 1 allocation to intervention and control. Setting: UK primary care (141 group general practices in England and Wales). Inclusion criteria: Patients aged ≥ 18 years with a new episode of depressive disorder or symptoms, recruited mainly through medical record searches, plus opportunistically in consultations. Exclusions: Current depression treatment, dementia, psychosis, substance misuse and risk of suicide. Intervention: Administration of the Patient Health Questionnaire-9 questionnaire with patient feedback soon after diagnosis, and at follow-up 10-35 days later, compared with usual care. Primary outcome: Beck Depression Inventory, 2nd edition, symptom scores at 12 weeks. Secondary outcomes: Beck Depression Inventory, 2nd edition, scores at 26 weeks; antidepressant drug treatment and mental health service contacts; social functioning (Work and Social Adjustment Scale) and quality of life (EuroQol 5-Dimension, five-level) at 12 and 26 weeks; service use over 26 weeks to calculate NHS costs; patient satisfaction at 26 weeks (Medical Informant Satisfaction Scale); and adverse events. Sample size: The original target sample of 676 patients recruited was reduced to 554 due to finding a significant correlation between baseline and follow-up values for the primary outcome measure. Randomisation: Remote computerised randomisation with minimisation by recruiting university, small/large practice and urban/rural location. Blinding: Blinding of participants was impossible given the open cluster design, but self-report outcome measures prevented observer bias. Analysis was blind to allocation. Analysis: Linear mixed models were used, adjusted for baseline depression, baseline anxiety, sociodemographic factors, and clustering including practice as random effect. Quality of life and costs were analysed over 26 weeks. Qualitative interviews: Practitioner and patient interviews were conducted to reflect on trial processes and use of the Patient Health Questionnaire-9 using the Normalization Process Theory framework. Results: Three hundred and two patients were recruited in intervention arm practices and 227 patients were recruited in control practices. Primary outcome data were collected for 252 (83.4%) and 195 (85.9%), respectively. No significant difference in Beck Depression Inventory, 2nd edition, score was found at 12 weeks (adjusted mean difference -0.46, 95% confidence interval -2.16 to 1.26). Nor were significant differences found in Beck Depression Inventory, 2nd Edition, score at 26 weeks, social functioning, patient satisfaction or adverse events. EuroQol-5 Dimensions, five-level version, quality-of-life scores favoured the intervention arm at 26 weeks (adjusted mean difference 0.053, 95% confidence interval 0.013 to 0.093). However, quality-adjusted life-years over 26 weeks were not significantly greater (difference 0.0013, 95% confidence interval -0.0157 to 0.0182). Costs were lower in the intervention arm but, again, not significantly (-£163, 95% confidence interval -£349 to £28). Cost-effectiveness and cost-utility analyses, therefore, suggested that the intervention was dominant over usual care, but with considerable uncertainty around the point estimates. Patients valued using the Patient Health Questionnaire-9 to compare scores at baseline and follow-up, whereas practitioner views were more mixed, with some considering it too time-consuming. Conclusions: We found no evidence of improved depression management or outcome at 12 weeks from using the Patient Health Questionnaire-9, but patients' quality of life was better at 26 weeks, perhaps because feedback of Patient Health Questionnaire-9 scores increased their awareness of improvement in their depression and reduced their anxiety. Further research in primary care should evaluate patient-reported outcome measures including anxiety symptoms, administered remotely, with algorithms delivering clear recommendations for changes in treatment. Study registration: This study is registered as IRAS250225 and ISRCTN17299295. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/42/02) and is published in full in Health Technology Assessment; Vol. 28, No. 17. See the NIHR Funding and Awards website for further award information.

Depression is common, can be disabling and costs the nation billions. The National Health Service recommends general practitioners who treat people with depression use symptom questionnaires to help assess whether those people are getting better over time. A symptom questionnaire is one type of patient-reported outcome measure. Patient-reported outcome measures appear to benefit people having therapy and mental health care, but this approach has not been tested thoroughly in general practice. Most people with depression are treated in general practice, so it is important to test patient-reported outcome measures there, too. In this study, we tested whether using a patient-reported outcome measure helps people with depression get better more quickly. The study was a 'randomised controlled trial' in general practices, split into two groups. In one group, people with depression completed the Patient Health Questionnaire, or 'PHQ-9', patient-reported outcome measure, which measures nine symptoms of depression. In the other group, people with depression were treated as usual without the Patient Health Questionnaire-9. We fed the results of the Patient Health Questionnaire-9 back to the people with depression themselves to show them how severe their depression was and asked them to discuss the results with the practitioners looking after them. We found no differences between the patient-reported outcome measure group and the control group in their level of depression; their work or social life; their satisfaction with care from their practice; or their use of medicines, therapy or specialist care for depression. However, we did find that their quality of life was improved at 6 months, and the costs of the National Health Service services they used were lower. Using the Patient Health Questionnaire-9 can improve patients' quality of life, perhaps by making them more aware of improvement in their depression symptoms, and less anxious as a result. Future research should test using a patient-reported outcome measure that includes anxiety and processing the answers through a computer to give practitioners clearer advice on possible changes to treatment for depression.

Internet and Telephone Support for Discontinuing Long-Term Antidepressants: The REDUCE Cluster Randomized Trial.

Importance: There is significant concern regarding increasing long-term antidepressant treatment for depression beyond an evidence-based duration. Objective: To determine whether adding internet and telephone support to a family practitioner review to consider discontinuing long-term antidepressant treatment is safe and more effective than a practitioner review alone. Design, Setting, and Participants: In this cluster randomized clinical trial, 131 UK family practices were randomized between December 1, 2018, and March 31, 2022, with remote computerized allocation and 12 months of follow-up. Participants and researchers were aware of allocation, but analysis was blind. Participants were adults who were receiving antidepressants for more than 1 year for a first episode of depression or more than 2 years for recurrent depression who were currently well enough to consider discontinuation and wished to do so and who were at low risk of relapse. Of 6725 patients mailed invitations, 330 (4.9%) were eligible and consented. Interventions: Internet and telephone self-management support, codesigned and coproduced with patients and practitioners. Main Outcomes and Measures: The primary (safety) outcome was depression at 6 months (prespecified complete-case analysis), testing for noninferiority of the intervention to under 2 points on the 9-item Patient Health Questionnaire (PHQ-9). Secondary outcomes (testing for superiority) were antidepressant discontinuation, anxiety, quality of life, antidepressant withdrawal symptoms, mental well-being, enablement, satisfaction, use of health care services, and adverse events. Analyses for the main outcomes were performed on a complete-case basis, and multiple imputation sensitivity analysis was performed on an intention-to-treat basis. Results: Of 330 participants recruited (325 eligible for inclusion; 178 in intervention practices and 147 in control practices; mean [SD] age at baseline, 54.0 [14.9] years; 223 women [68.6%]), 276 (83.6%) were followed up at 6 months, and 240 (72.7%) at 12 months. The intervention proved noninferior; mean (SD) PHQ-9 scores at 6 months were slightly lower in the intervention arm than in the control arm in the complete-case analysis (4.0 [4.3] vs 5.0 [4.7]; adjusted difference, -1.1; 95% CI, -2.1 to -0.1; P = .03) but not significantly different in an intention-to-treat multiple imputation sensitivity analysis (adjusted difference, -0.9 (95% CI, -1.9 to 0.1; P = .08). By 6 months, antidepressants had been discontinued by 66 of 145 intervention arm participants (45.5%) who provided discontinuation data and 54 of 129 control arm participants (41.9%) (adjusted odds ratio, 1.02; 95% CI, 0.52-1.99; P = .96). In the intervention arm, antidepressant withdrawal symptoms were less severe, and mental well-being was better compared with the control arm; differences were small but significant. There were no significant differences in the other outcomes; 28 of 179 intervention arm participants (15.6%) and 22 of 151 control arm participants (14.6%) experienced adverse events. Conclusions and Relevance: In this cluster randomized clinical trial of adding internet and telephone support to a practitioner review for possible antidepressant discontinuation, depression was slightly better with support, but the rate of discontinuation of antidepressants did not significantly increase. Improvements in antidepressant withdrawal symptoms and mental well-being were also small. There were no significant harms. Family practitioner review for possible discontinuation of antidepressants appeared safe and effective for more than 40% of patients willing and well enough to discontinue. Trial Registration: ISRCTN registry Identifiers: ISRCTN15036829 (internal pilot trial) and ISRCTN12417565 (main trial).

The economic burden of antibiotic resistance: A systematic review and meta-analysis.

INTRODUCTION: Antibiotic resistance (ABR) has substantial global public health concerns. This systematic review aimed to synthesise recent evidence estimating the economic burden of ABR, characterised by study perspectives, healthcare settings, study design, and income of the countries. METHODS: This systematic review included peer-reviewed articles from PubMed, Medline, and Scopus databases, and grey literature on the topic of the economic burden of ABR, published between January 2016 and December 2021. The study was reported in line with 'Preferred Reporting Items for Systematic Review and Meta-Analysis' (PRISMA). Two reviewers independently screened papers for inclusion first by title, then abstract, and then the full text. Study quality was assessed using appropriate quality assessment tools. Narrative synthesis and meta-analyses of the included studies were conducted. RESULTS: A total of 29 studies were included in this review. Out of these studies, 69% (20/29) were conducted in high-income economies and the remainder were conducted in upper-and-middle income economies. Most of the studies were conducted from a healthcare or hospital perspective (89.6%, 26/29) and 44.8% (13/29) studies were conducted in tertiary care settings. The available evidence indicates that the attributable cost of resistant infection ranges from -US$2,371.4 to +US$29,289.1 (adjusted for 2020 price) per patient episode; the mean excess length of stay (LoS) is 7.4 days (95% CI: 3.4-11.4), the odds ratios of mortality for resistant infection is 1.844 (95% CI: 1.187-2.865) and readmission is 1.492 (95% CI: 1.231-1.807). CONCLUSION: Recent publications show that the burden of ABR is substantial. There is still a lack of studies on the economic burden of ABR from low-income economies, and lower-middle-income economies, from a societal perspective, and in relation to primary care. The findings of this review may be of value to researchers, policymakers, clinicians, and those who are working in the field of ABR and health promotion. SYSTEMATIC REVIEW REGISTRATION: CRD42020193886.