Qualitative study to explore the perspectives and mental health experiences of first episode psychosis patients and their caregivers in North India.

BACKGROUND: The onset of psychosis brings unfamiliar experiences that can be disturbing for patients and their caregivers. Few studies from India (only one from North India) have examined these experiences from the perspective of the patient and caregiver. We explored experiences of first episode psychosis (FEP) patients and their caregivers within a North Indian context. METHOD: Semi-structured interviews were conducted in 2019 with ten FEP patients and their caregivers (total n=20) receiving out-patient care in a tertiary care centre. Topic guides focused on concerns/complaints, symptoms, help-seeking, and barriers and facilitators to treatment. Interviews were audio recorded, transcribed, and analysed using qualitative content analysis. RESULTS: Main categories of responses from patients and caregivers included: initial complaints for seeking help, initial emotional response, barriers to seeking treatment, perceived dysfunction and improvement, experienced stigma, understanding about illness, early follow-up, preventive measures and awareness programs. Caregivers undergo myriad of emotional reactions including anger, anxiety, guilt, and confusion. Symptoms other than psychotic symptoms were the primary complaint upon seeking help, and there was lack of understanding about the psychosocial model of care (role of medications acknowledged with little awareness regarding psychosocial interventions in recovery). Persisting occupational dysfunction despite perceived symptomatic improvement was described by both patients and caregivers. CONCLUSION: North Indian patients with FEP lack awareness of symptoms. Therefore, onus for seeking help often falls on their caregivers. Psychoeducation from first contact with services and increasing awareness about psychotic illness within the community might help address lack of awareness about symptoms, mental health services, early signs of relapse, and importance of psychosocial interventions in achieving functional recovery.

Pilot study to test the feasibility and clinical efficacy of a psychosocial care programme for patients with psychosis in low-resource settings.

BACKGROUND: Home-based psychosocial care has the potential to improving outcomes in patients with schizophrenia and related disorders (SCZ). There is lack of India data for such care in early psychosis. We developed the "Saksham" programme, a bespoke self-managed home-based psychosocial care model, available in two formats: manual-based and mobile-application based. With the anticipated success of recruitment of early psychosis cases in our setting, we plan to test the such intervention in this population in future trials. AIM: To assess the feasibility of the Saksham programme intervention in people with SCZ and its clinical efficacy as an adjunct to treatment as usual. METHODS: Seventy-five patient-caregiver pairs (total n=150) were recruited. Patients received either: treatment-as-usual (TAU) (n=25), manual-based Saksham intervention+TAU (n=25), or app-based Saksham intervention+TAU (n=25). Feasibility (i.e. acceptability, practicality, demand, implementation and integration) was assessed at three-months. Participants were assessed for psychopathology, illness-severity, cognition, functioning, disability, and caregiver-coping at baseline, one-month, and three-month. The percentage changes over time were compared across three groups. RESULTS: More found the mobile application-based intervention acceptable and easy-to-use than the manual-based intervention (92 % vs 68 %, and 76 % vs 68 %, respectively). Psychopathology and caregiver-burden improved significantly in all three groups (p<0.05). Cognition, disability, functioning, and caregiver burden improved significantly in the two Saksham intervention groups, with greater improvement in the Saksham app group (p<0.05). CONCLUSION: Home-based intervention is feasible and acceptable in a low-resource setting, with preliminary evidence for effectiveness. These findings need corroboration with randomised controlled trials in early psychosis to ameliorate course of illness.

Protocol-based assessment and management of first episode psychosis: Comparison of short and medium-term outcomes in psychopathology, quality of life, functioning and family burden across two sites in India.

BACKGROUND: Standard assessment and management protocols exist for first episode psychosis (FEP) in high income countries. Due to cultural and resource differences, these need to be modified for application in low-and middle-income countries. AIMS: To assess the applicability of standard assessment and management protocols across two cohorts of FEP patients in North and South India by examining trajectories of psychopathology, functioning, quality of life and family burden in both. METHOD: FEP patients at two sites (108 at AIIMS, North India, and 115 at SCARF, South India) were assessed using structured instruments at baseline, 3, 6 and 12 months. Standard management protocols consisted of treatment with antipsychotics and psychoeducation for patients and their families. Generalised estimating equation (GEE) modelling was carried out to test for changes in outcomes both across and between sites at follow-up. RESULTS: There was an overall significant improvement in both cohorts for psychopathology and other outcome measures. The trajectories of improvement differed between the two sites with steeper improvement in non-affective psychosis in the first three months at SCARF, and affective symptoms in the first three months at AIIMS. The reduction in family burden and improvement in quality of life were greater at AIIMS than at SCARF during the first three months. CONCLUSIONS: Despite variations in cultural contexts and norms, it is possible to implement FEP standard assessment and management protocols in North and South India. Preliminary findings indicate that FEP services lead to significant improvements in psychopathology, functioning, quality of life, and family burden within these contexts.

Global prevalence and trends in hypertension and type 2 diabetes mellitus among slum residents: a systematic review and meta-analysis.

OBJECTIVE: First, to obtain regional estimates of prevalence of hypertension and type 2 diabetes in urban slums; and second, to compare these with those in urban and rural areas. DESIGN: Systematic review and meta-analysis. ELIGIBILITY CRITERIA: Studies that reported hypertension prevalence using the definition of blood pressure ≥140/90 mm Hg and/or prevalence of type 2 diabetes. INFORMATION SOURCES: Ovid MEDLINE, Cochrane CENTRAL and EMBASE from inception to December 2020. RISK OF BIAS: Two authors extracted relevant data and assessed risk of bias independently using the Strengthening the Reporting of Observational Studies in Epidemiology guideline. SYNTHESIS OF RESULTS: We used random-effects meta-analyses to pool prevalence estimates. We examined time trends in the prevalence estimates using meta-regression regression models with the prevalence estimates as the outcome variable and the calendar year of the publication as the predictor. RESULTS: A total of 62 studies involving 108 110 participants met the inclusion criteria. Prevalence of hypertension and type 2 diabetes in slum populations ranged from 4.2% to 52.5% and 0.9% to 25.0%, respectively. In six studies presenting comparator data, all from the Indian subcontinent, slum residents were 35% more likely to be hypertensive than those living in comparator rural areas and 30% less likely to be hypertensive than those from comparator non-slum urban areas. LIMITATIONS OF EVIDENCE: Of the included studies, only few studies from India compared the slum prevalence estimates with those living in non-slum urban and rural areas; this limits the generalisability of the finding. INTERPRETATION: The burden of hypertension and type 2 diabetes varied widely between countries and regions and, to some degree, also within countries. PROSPERO REGISTRATION NUMBER: CRD42017077381.

Trends in 30-day readmissions following hospitalisation for heart failure by sex, socioeconomic status and ethnicity.

Background: Reducing the high patient and economic burden of early readmissions after hospitalisation for heart failure (HF) has become a health policy priority of recent years. Methods: An observational study linking Hospital Episode Statistics to socioeconomic and death data in England (2002-2018). All first hospitalisations with a primary discharge code for HF were identified. Quasi-poisson models were used to investigate trends in 30-day readmissions by age, sex, socioeconomic status and ethnicity. Findings: There were 698,983 HF admissions, median age 81 years [IQR 14].In-hospital deaths reduced by 0.7% per annum (pa), whilst additional deaths at 30-days remained stable at 5%. Age adjusted 30-day readmissions (21% overall), increased by 1.4% pa (95% CI 1.3-1.5). Readmissions for HF (6%) and 'other cardiovascular disease (CVD)' (3%) remained stable, but readmissions for non-CVD causes (12%) increased at a rate of 2.6% (2.4-2.7) pa. Proportions were similar by sex but trends diverged by ethnicity. Black groups experienced an increase in readmissions for HF (1.8% pa, interaction-p 0.03) and South Asian groups had more rapidly increasing readmission rates for non-CVD causes (interaction-p 0.04). Non-CVD readmissions were also more prominent in the least (15%; 15-15) compared to the most affluent group (12%; 12-12). Strongest predictors for HF readmission were Black ethnicity and chronic kidney disease, whilst cardiac procedures were protective. For non-CVD readmissions, strongest predictors were non-CVD comorbidities, whilst cardiologist care was protective. Interpretation: In HF, despite readmission reduction policies, 30-day readmissions have increased, impacting the least affluent and ethnic minority groups the most. Funding: NIHR.

Is convalescent plasma futile in COVID-19? A Bayesian re-analysis of the RECOVERY randomized controlled trial.

BACKGROUND: Randomized trials are generally performed from a frequentist perspective, which can conflate absence of evidence with evidence of absence. The RECOVERY trial evaluated convalescent plasma for patients hospitalized with coronavirus disease 2019 (COVID-19) and concluded that there was no evidence of an effect. Re-analysis from a Bayesian perspective is warranted. METHODS: Outcome data were extracted from the RECOVERY trial by serostatus and time of presentation. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, sceptical, and pessimistic) was performed, calculating the posterior probability for: any benefit, an absolute risk difference of 0.5% (small benefit, number needed to treat 200), and an absolute risk difference of one percentage point (modest benefit, number needed to treat 100). RESULTS: Across all patients, when analysed with a vague prior, the likelihood of any benefit or a modest benefit with convalescent plasma was estimated to be 64% and 18%, respectively. The estimated chance of any benefit was 95% if presenting within 7 days of symptoms, or 17% if presenting after this. In patients without a detectable antibody response at presentation, the chance of any benefit was 85%. However, it was only 20% in patients with a detectable antibody response at presentation. CONCLUSIONS: Bayesian re-analysis suggests that convalescent plasma reduces mortality by at least one percentage point among the 39% of patients who present within 7 days of symptoms, and that there is a 67% chance of the same mortality reduction in the 38% who are seronegative at the time of presentation. This is in contrast to the results in people who already have antibodies when they present. This biologically plausible finding bears witness to the advantage of Bayesian analyses over misuse of hypothesis tests to inform decisions.

The impact of user fees on health services utilization and infectious disease diagnoses in Neno District, Malawi: a longitudinal, quasi-experimental study.

BACKGROUND: User fees have generally fallen out of favor across Africa, and they have been associated with reductions in access to healthcare. We examined the effects of the introduction and removal of user fees on outpatient attendances and new diagnoses of HIV, malaria, and tuberculosis in Neno District, Malawi where user fees were re-instated at three of 13 health centres in 2013 and subsequently removed at one of these in 2015. METHODS: We conducted two analyses. Firstly, an unadjusted comparison of outpatient visits and new diagnoses over three periods between July 2012 and October 2015: during the period with no user fees, at the re-introduction of user fees at four centres, and after the removal of user fees at one centre. Secondly, we estimated a linear model of the effect of user fees on the outcome of interest that controlled for unobserved health centre effects, monthly effects, and a linear time trend. RESULTS: The introduction of user fees was associated with a change in total attendances of -68 % [95 % CI: -89 %, -12 %], similar reductions were observed for new malaria and HIV diagnoses. The removal of user fees was associated with an increase in total attendances of 352 % [213 %, 554 %] with similar increases for malaria diagnoses. The results were not sensitive to control group or model specification. CONCLUSIONS: User fees for outpatient healthcare services present a barrier to patients accessing healthcare and reduce detection of serious infectious diseases.

Global women's health: current clinical trials in low- and middle-income countries.

BACKGROUND: Clinical trials in low- and middle-income countries (LMICs) are necessary to develop evidence-based approaches to improve women's health. Understanding what research is currently being conducted will allow the identification of research gaps, avoidance of duplication, planning of future studies, collaboration amongst research groups, and geographical targeting for research investments. OBJECTIVES: To provide an overview of active women's health trials in LMICs. SEARCH STRATEGY: The World Health Organization's International Clinical Trials Registry Platform was searched for trials registered between 1 April 2012 and 31 March 2014. SELECTION CRITERIA: Selected trials were randomised, conducted in LMICs, active, and with a women's health intervention or a significant outcome for the woman. DATA COLLECTION AND ANALYSIS: Two reviewers extracted data. Analysis included geographical spread, speciality areas, pre-enrolment registration, study size, and funders. MAIN RESULTS: Of the 8966 records, 509 were eligible for inclusion. Gynaecology trials made up 57% of the research, whereas the remaining 43% of trials were in obstetrics. Research activity focused on fertility (17%), the antenatal period (15%), benign gynaecology (14%), intrapartum care (9%), and pre-invasive disease and cancers (8%). The majority of trials (84%) took place in middle-income countries (MICs). In low-income countries (LICs) 83% of research investigated obstetrics, and in MICs 60% of research investigated gynaecology. Most trials (80%) had a sample size of 500 or fewer participants. The median size of trials in LICs was 815 compared with 128 in MICs. Pre-enrolment registration occurred in 54% of trials. The majority (62%) of trials were funded locally. AUTHORS' CONCLUSIONS: Many LMICs are active in women's health research. The majority of registered trials are located in MICs; however, the trials in LICs are often larger. The focus of research in MICs may be driven by local priorities and funding, with fertility being highly researched. In LICs, pregnancy is the focus, perhaps reflecting the international prioritisation of maternal health.

A qualitative exploration of the motives behind the decision to order a liver function test in primary care.

BACKGROUND: The number of tests ordered in primary care continues to increase influenced by a number of factors not all of which are concerned with diagnosis and management of disease. Liver function tests (LFTs) are a good example of inexpensive tests that are frequently ordered in patients with non-specific symptoms. They remain among the most frequently ordered tests despite their lack of specificity yet the full range of motives behind the decision to order an LFT remains unexplored. AIMS: To gain an understanding of the family practitioner's (FP) medical and non-medical motives for ordering an LFT and the influence of various social and technical factors on this decision. METHODS: We interviewed FPs across six practices who were participating in a prospective study of the efficacy of an abnormal LFT to indicate the development of a serious liver disease. Following content analysis of the data from the semi-structured interviews we used the 'attitude-social influence-efficacy' model to categorise the determinants of test ordering behaviour. RESULTS: Factors influencing an FP's decision to order a test were grouped into two broad categories; the first is 'internal' including expectation of efficacy and general attitude towards LFTs. The second group is 'external' and consists of themes of social influence, tests characteristics and defensive medicine. CONCLUSIONS: Whilst our sample acknowledged the clinical use of LFTs such as the routine monitoring of medication and liver-specific diagnostic purposes we also found that social and behavioural reasons are strong motivators to order an LFT and may take precedence over clinical factors.

Birmingham and Lambeth Liver Evaluation Testing Strategies (BALLETS): a prospective cohort study.

OBJECTIVE: To evaluate mildly abnormal liver function test (LFT) results in general practice among patients who do not have known liver disease. DESIGN: Prospective cohort study of people with abnormal LFT results identified in primary care. Participants were intensively investigated using a common protocol and followed up for 2 years. Substudies investigated the psychological sequelae of abnormal test results, clinicians' reasons for testing, decision options when LFT results were abnormal and early detection of liver fibrosis. SETTING: Eleven primary-care practices: eight in Birmingham and three in Lambeth. PARTICIPANTS: Adults with abnormal LFT results who did not have pre-existing or obvious liver disease. Eight analytes were included in the panel of LFTs. MAIN OUTCOME MEASURES: Statistical tests were used to identify the interactions between clinical features, the initial pattern of abnormal LFT results and (1) specific viral, genetic and autoimmune diseases, such as viral hepatitis, haemochromatosis and primary biliary cirrhosis; (2) a range of other serious diseases, such as metastatic cancer and hypothyroidism; (3) 'fatty liver' not associated with the above; and (4) the absence of detectable disease. RESULTS: Fewer than 5% of people with abnormal LFT results had a specific disease of the liver, and many of these were unlikely to need treatment. The diagnostic potential of the LFT panel is largely subsumed into just two analytes: alanine aminotransferase (ALT) and alkaline phosphatase (ALP). Gamma-glutamyltransferase (GGT) offers a small increase in sensitivity at the margin at the cost of a large loss of specificity. Eighty-four per cent of abnormal LFT results remain abnormal on retesting 1 month later. In many cases, carrying out a definitive or specific test will be more efficient than repeating LFTs, with a view to specific testing only if the test remains abnormal. An ultrasound diagnosis of 'fatty liver' was present in nearly 40% of patients with abnormal LFTs and a small amount of weight loss over 2 years was associated with a reduced incidence of liver fat. There was a J-shaped relationship between alcohol intake and fatty liver in men. An abnormal LFT result causes temporary anxiety, which does not appear to promote sustained behaviour change. CONCLUSIONS: Liver disease is rare among people with abnormal LFT results in primary care. Only two analytes (ALT and ALP) are helpful in identifying the majority of liver disease. GGT adds little information in return for a high false-positive rate but it is sensitive to alcohol intake. LFT results seldom revert from abnormal to normal over a 1-month period, and modelling shows that repeating an abnormal LFT panel, as recommended in the current guidelines, is inefficient. LFTs are often undertaken to meet perceived patient need for a blood test, but as they are neither specific nor indicative of any particular disease they are among the least suitable tests for this purpose. Obesity and raised ALT provide strong evidence for a presumptive diagnosis of 'fatty' liver. Abnormal LFTs and 'fatty' liver provoke only short-term anxiety and neither is associated with sustained weight loss. Even a small amount of weight loss reduces liver fat. FUTURE WORK RECOMMENDATIONS: (1) the cases of 'fatty liver' and controls should be followed up in the long term to identify features that predict development of hepatosteatosis and then cirrhosis; (2) the acceptability of replacing the traditional six- to eight-analyte LFT panel with a drop down menu including the ALT/ALP combination should be evaluated. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The findings of the Mid-Staffordshire Inquiry do not uphold the use of hospital standardized mortality ratios as a screening test for 'bad' hospitals.

The Mid-Staffordshire Public Inquiry has published its findings. The initial investigations were triggered by an elevated hospital standardized mortality ratio (HSMR). This shows that the HSMR is being used as a screening test for substandard care; whereby hospitals that fail the test are scrutinized, whilst those that pass the test are not. But screening tests are often misunderstood and misused and so it is prudent to critically examine the HSMR before casting it in the role of a screening test for 'bad' hospitals. A screening test should be valid, have adequate performance characteristics and a clear post-test action plan. The HSMR is not a valid screening test (because the empirical relationship between clinically avoidable mortality and the HSMR is unknown). The HSMR has a poor performance profile (10 of 11 elevated HSMRs would be false alarms and 10 of 11 poorly performing hospitals would escape attention). Crucially, the aim of a post-test investigation into an elevated HSMR is unclear. The use of the HSMR as a screening test for clinically avoidable mortality and thereby substandard care, although well intentioned, is seriously flawed. The findings of the Mid-Staffordshire Public Inquiry have no bearing on this conclusion because a 'bad' hospital cannot uphold a bad screening test. Nonetheless, HSMRs continue to pose a grave public challenge to hospitals, whilst the unsatisfactory nature of the HSMR remains a largely unacknowledged and unchallenged private affair. This asymmetric relationship is inappropriate, unhelpful, costly and potentially harmful. The use of process measures remains a valid way to measure quality of care.

Patient experiences of colonoscopy, barium enema and CT colonography: a qualitative study.

Previous studies of patient experience with bowel screening tests, in particular CT colonography (CTC), have superimposed global rating scales and not explored individual experience in detail. To redress this, we performed qualitative interviews in order to characterize patient expectations and experiences in depth. Following ethical permission, 16 patients undergoing CTC, 18 undergoing colonoscopy and 15 undergoing barium enema agreed to a semi-structured interview by a health psychologist. Interviews were recorded, responses transcribed and themes extracted with the aim of assimilating individual experiences to facilitate subsequent development and interpretation of quantitative surveys of overall satisfaction with each diagnostic test. Transcript analysis identified three principal themes: physical sensations, social interactions and information provision. Physical sensations differed for each test but were surprisingly well tolerated overall. Social interactions with staff were perceived as very important in colouring the whole experience, particularly in controlling the feelings of embarrassment, which was critical for all procedures. Information provision was also an important determinant of experience. Verbal feedback was most common during colonoscopy and invariably reassuring. However, patients undergoing CTC received little visual or verbal feedback and were often confused regarding the test outcome. Barium enema had no specific advantage over other tests. Qualitative interviews provided important perspectives on patient experience. Our data demonstrated that models describing the quality of medical encounters are applicable to single diagnostic episodes. Staff interactions and information provision were particularly important. We found advantages specific to both CTC and colonoscopy but none for barium enema. CTC could benefit greatly from improved information provision following examination.

An epistemology of patient safety research: a framework for study design and interpretation. Part 1. Conceptualising and developing interventions.

This is the first of a four-part series of articles examining the epistemology of patient safety research. Parts 2 and 3 will describe different study designs and methods of measuring outcomes in the evaluation of patient safety interventions, before Part 4 suggests that "one size does not fit all". Part 1 sets the scene by defining patient safety research as a challenging form of service delivery and organisational research that has to deal (although not exclusively) with some very rare events. It then considers two inter-related ideas: a causal chain that can be used to identify where in an organisation's structure and/or processes an intervention may impact; and the need for preimplementation evaluation of proposed interventions. Finally, the paper outlines the authors' pragmatist ontological stance to patient safety research, which sets the philosophical basis for the remaining three articles.

An epistemology of patient safety research: a framework for study design and interpretation. Part 3. End points and measurement.

This article builds on the previous two articles in this series, which focused on an evaluation framework and study designs for patient safety research. The current article focuses on what to measure as evidence of safety and how these measurements can be undertaken. It considers four different end points, highlighting their methodological advantages and disadvantages: patient outcomes, fidelity, intervening variables and clinical error. The choice of end point depends on the nature of the intervention being evaluated and the patient safety problem it has been designed to address. This paper also discusses the different methods of measuring error, reviewing best practice and paying particular attention to case note review. Two key issues with any method of data collection are ensuring construct validity and reliability. Since no end point or method of data collection is infallible, the present authors advocate the use of multiple end points and methods where feasible.

An epistemology of patient safety research: a framework for study design and interpretation. Part 2. Study design.

This is the second in a four-part series of articles detailing the epistemology of patient safety research. This article concentrates on issues of study design. It first considers the range of designs that may be used in the evaluation of patient safety interventions, highlighting the circumstances in which each is appropriate. The paper then provides details about an innovative study design, the stepped wedge, which may be particularly appropriate in the context of patient safety interventions, since these are expected to do more good than harm. The unit of allocation in patient safety research is also considered, since many interventions need to be delivered at cluster or service level. The paper also discusses the need to ensure the masking of patients, caregivers, observers and analysts wherever possible to minimise information biases and the Hawthorne effect. The difficulties associated with masking in patient safety research are described and suggestions given on how these can be ameliorated. The paper finally considers the role of study design in increasing confidence in the generalisability of study results over time and place. The extent to which findings can be generalised over time and place should be considered as part of an evaluation, for example by undertaking qualitative or quantitative measures of fidelity, attitudes or subgroup effects.

An epistemology of patient safety research: a framework for study design and interpretation. Part 4. One size does not fit all.

This is the final article in the series on the epistemology of patient safety research, and considers the selection of study design and end points during the planning of an evaluation. The key message of this series is that "one size does not fit all": the nature of the evaluation will depend on logistical and pragmatic constraints, a priori assessment of the probability of benefits and harms, the plausible scale of these effects and the target audience for the results. This paper also discusses the advantages of mixed method designs. The strength of any conclusions can be increased if different end points concur and the authors therefore advocate assessment of the effect of the intervention on different end points across the generic causal chain linking structure, process and outcome. The use of both qualitative and quantitative methods is also advocated to help explain findings, generate theory and help contextualise results. We show how a bayesian framework can be used to synthesise evidence from a number of different sources and why this approach may be particularly appropriate for the evaluation of patient safety interventions.

Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions.

OBJECTIVE: To investigate discrepancies between direct comparison and adjusted indirect comparison in meta-analyses of new versus conventional pharmaceutical interventions. STUDY DESIGN AND SETTING: Results of direct comparison were compared with results of adjusted indirect comparison in three meta-analyses of new versus conventional drugs. The three case studies are (1) bupropion versus nicotine replacement therapy for smoking cessation, (2) risperidone versus haloperidol for schizophrenia, and (3) fluoxetine versus imipramine for depressive disorders. RESULTS: In all the three cases, effects of new drugs estimated by head-to-head trials tend to be greater than that by adjusted indirect comparisons. The observed discrepancies could not be satisfactorily explained by the play of chance or by bias and heterogeneity in adjusted indirect comparison. This observation, along with analysis of possible systematic bias in the direct comparisons, suggested that the indirect method might have produced less biased results. Simulations found that adjusted indirect comparison may counterbalance bias under certain circumstances. CONCLUSION: Adjusted indirect comparison could be used to cross-examine the validity and applicability of results from head-to-head randomized trials. The hypothesis that adjusted indirect comparison may provide less biased results than head-to-head randomized trials needs to be investigated by further research.