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The Centre for Evidence-Based Medicine (CEBM) at Oxford University develops, promotes and disseminates better evidence for health care.
Leadership training in healthcare: a systematic umbrella review.
The importance of effective clinical leadership has been reflected in an increase in leadership development programmes. However, there remains a lack of consensus regarding the optimal structure, content and evaluation of such programmes. This review synthesised evidence from reviews of leadership development interventions for healthcare professionals published prior to October 2024, including content, methods, evaluation strategies and impact. Title, abstract and full-text screening were conducted in duplicate by two reviewers. Data extraction was piloted by two reviewers and conducted by a single reviewer. Quality appraisal was conducted using the Risk of Bias in Systematic Reviews tool by a single reviewer, with generative artificial intelligence serving as the second reviewer. 86 systematic and non-systematic reviews met inclusion criteria. Regarding educational methods, leadership training effectiveness was associated with experiential learning, mixed-methods approaches, coaching or mentoring, longitudinal designs, goal-setting, and 360-degree feedback. Group learning and interprofessional education were noted for fostering teamwork. Programmes tailored to participants' needs and organisational contexts showed better outcomes. Content reported to be effective included interpersonal skills, self-awareness, emotional intelligence, leadership theory, communication and teamwork. Evaluations primarily relied on self-reported measures. Training outcomes were largely positive at the individual level, with participants reporting increased confidence and competence. Organisational and clinical outcomes were less frequently assessed. The long-term impact on patient outcomes and return on investment remains uncertain. Leadership development programmes were found to enhance individual competencies. However, evidence supporting long-term, system-wide impact remains limited due to reliance on self-reported evaluations and a lack of standardised evaluation approaches.
Assessing the feasibility and impact of clinical trial trustworthiness checks via an application to Cochrane Reviews: Stage 2 of the INSPECT-SR project
Background and Objectives: The aim of the INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project is to develop a tool to identify problematic RCTs in systematic reviews. In stage 1 of the project, a list of potential trustworthiness checks was created. The checks on this list must be evaluated to determine which should be included in the INSPECT-SR tool. Methods: We attempted to apply 72 trustworthiness checks to randomized controlled trials (RCTs) in 50 Cochrane reviews. For each, we recorded whether the check was passed, failed, or possibly failed or whether it was not feasible to complete the check. Following application of the checks, we recorded whether we had concerns about the authenticity of each RCT. We repeated each meta-analysis after removing RCTs flagged by each check and again after removing RCTs where we had concerns about authenticity to estimate the impact of trustworthiness assessment. Trustworthiness assessments were compared to Risk of Bias and Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessments in the reviews. Results: Ninety-five RCTs were assessed. Following application of the checks, assessors had some or serious concerns about the authenticity of 25% and 6% of the RCTs, respectively. Removing RCTs with either some or serious concerns resulted in 22% of meta-analyses having no remaining RCTs. However, many checks proved difficult to understand or implement, which may have led to unwarranted skepticism in some instances. Furthermore, we restricted assessment to meta-analyses with no more than five RCTs (54% contained only 1 RCT), which will distort the impact on results. No relationship was identified between trustworthiness assessment and Risk of Bias or GRADE. Conclusion: This study supports the case for routine trustworthiness assessment in systematic reviews, as problematic studies do not appear to be flagged by Risk of Bias assessment. The study produced evidence on the feasibility and impact of trustworthiness checks. These results will be used, in conjunction with those from a subsequent Delphi process, to determine which checks should be included in the INSPECT-SR tool. Plain Language Summary: Systematic reviews collate evidence from randomized controlled trials (RCTs) to find out whether health interventions are safe and effective. However, it is now recognized that the findings of some RCTs are not genuine, and some of these studies appear to have been fabricated. Various checks for these “problematic” RCTs have been proposed, but it is necessary to evaluate these checks to find out which are useful and which are feasible. We applied a comprehensive list of “trustworthiness checks” to 95 RCTs in 50 systematic reviews to learn more about them and to see how often performing the checks would lead us to classify RCTs as being potentially inauthentic. We found that applying the checks led to concerns about the authenticity of around 1 in three RCTs. However, we found that many of the checks were difficult to perform and could have been misinterpreted. This might have led us to be overly skeptical in some cases. The findings from this study will be used, alongside other evidence, to decide which of these checks should be performed routinely to try to identify problematic RCTs, to stop them from being mistaken for genuine studies and potentially being used to inform health care decisions.
The impact of inter-infection time on antimicrobial resistance profiles in women with multiple urinary tract infections over time.
BACKGROUND: Urinary tract infection (UTI) treatment in primary care is increasingly complicated by antimicrobial resistance (AMR), and antimicrobial susceptibility profiles are rarely available to prescribers at the point of prescription. Susceptibility profiles from previous urine culture results could inform prescribing, but little is known about associations between previous and current susceptibilities and the impact of time between infections (inter-infection time) on these associations. METHODS: We analysed routinely collected healthcare records of women ≥16 years in Oxfordshire, UK, who had two or more culture-positive urine specimens consistent with a UTI between 2013 and 2019. We used generalized additive logistic models to estimate associations between resistance to each of eight commonly prescribed antibiotics at first UTI and at second UTI, and their interaction with inter-infection time, adjusted for age and calendar year. RESULTS: In 10 216 women, significant associations were observed between AMR at first and second UTIs. For all antibiotics, these were largest for short inter-infection times. Pivmecillinam resistance at first UTI (OR: 41.70; 95% CI: 27.70-62.80), followed by fosfomycin (OR: 19.90; CI: 13.66-28.92) and ciprofloxacin resistance (OR: 19.65; 95% CI: 16.30-23.75), were strongly associated with resistance to the same antibiotic at the second UTI for inter-infection times ≤3 months. Lower magnitude associations were observed for other antibiotics. For UTIs caused by Escherichia coli only, these associations were generally larger. CONCLUSIONS: In a cohort of women experiencing UTIs, AMR at the first UTI and inter-infection time were key determinants of AMR in the second UTI. This information could inform empirical antimicrobial treatment to limit treatment failure in women with recurrent UTI.
Epidemiology and microbiology of recurrent UTI in women in the community in Oxfordshire, UK
Background: Recurrent urinary tract infection (rUTI) contributes to significant morbidity and antibiotic usage. Objectives: To characterize the age of women experiencing rUTI, the microbiology of rUTIs, and the risk of further rUTIs in Oxfordshire, UK. Patients and methods: We retrospectively analysed de-identified linked microbiology and hospital admissions data (Infections in Oxfordshire Research Database), between 2008 and 2019, including positive urine cultures from women aged ≥16 years in community settings. We defined rUTI as ≥2 positive urine cultures within 6 months or ≥3 within 12 months. Results: Of 201 927 women with urine culture performed, 84 809 (42%) had ≥1 positive culture, and 15 617 (18%) of these experienced ≥1 rUTI over a median (IQR) follow-up of 6 (3-9) years. Women with rUTI were 17.0 (95% CI: 16.3-17.7) years older on average. rUTI was commonest (6204; 40%) in those aged 70-89 years. Post-rUTI, the risk of further UTI within 6 months was 29.4% (95% CI: 28.7-30.2). Escherichia coli was detected in 65% of positive cultures. Among rUTIs where the index UTI was E. coli associated, the second UTI was also E. coli associated in 81% of cases. Conclusions: rUTIs represent a substantial healthcare burden, particularly in women >60 years. One-third of women experiencing rUTI have a further microbiologically confirmed UTI within 6 months.
Risk of repeat self-harm among individuals presenting to healthcare services: development and validation of a clinical risk assessment model (OxSET)
Background A self-harm episode is a major risk factor for repeat self-harm. Existing tools to assess and predict repeat self-harm have major methodological limitations, and few are externally validated. Objective To develop and validate a risk assessment model of repeat self-harm up to 6 months after an episode of non-fatal self-harm that resulted in an emergency visit to hospital or specialised care. Methods Using Swedish national registers, we identified 53 172 people aged≥10 years who self-harmed during 2008–2012. We allocated 37 523 individuals to development (2820 or 7.5% repeat self-harm incidents within 6 months) and 15 649 to geographic validation (1373 repeat episodes) samples, based on region of residence. In a temporal validation of people who self-harmed during 2018–2019, we identified 25 036 individuals (2886 repeat episodes). We fitted a multivariable accelerated failure time model to predict risk of repeat self-harm. Findings In the external validations (n=40 685), rates of repeat self-harm were 8.8%–11.5% over 6 months. The final model retained 17 factors. Calibration and discrimination were similar in both validation samples, with observed-to-expected ratio=1.15 (95% CI=1.09 to 1.21) and c-statistic=0.72 (95% CI=0.70 to 0.73) in the geographical validation. At 6 months and a 10% risk cutoff, sensitivity was 51.5% (95% CI=48.8% to 54.2%) and specificity was 80.7% (95% CI=80.1% to 81.4%) in geographic validation; corresponding values were 56.9% (95% CI=55.1% to 58.7%) and 76.0% (95% CI=75.5% to 76.6%) in temporal validation. Discrimination was slightly worse at the 1-month prediction horizon (c-statistics of 0.66–0.68). Conclusions Using mostly routinely collected data, simple risk assessment models and tools can provide acceptable levels of accuracy for repeat of self-harm. Clinical implications This risk model (OXford SElf-harm repeat tool) may assist clinical decision-making.
Impact and outcomes of the Emerging Leaders Programme: A mixed-methods evaluation of a leadership development programme for healthcare professionals
Background: The significance of effective medical leadership in enhancing healthcare outcomes has been widely acknowledged. This study evaluates the Emerging Leaders Programme, a multidisciplinary leadership development initiative for healthcare professionals at a UK Hospital Trust. Methods: The evaluation spanned three cohorts (2017-2019) and a total of 54 participants, employing mixed methods to assess participant reactions, learning, behaviour changes and organisational impact. Quantitative pre-/post-measures included the Primary Colours Questionnaire (PCQ), Medical Leadership Competency Framework Questionnaire (MLCFQ) and Brief Resilience Scale (BRS), while qualitative data were gathered via free-text comments and long-term follow-up interviews. Results: The programme had high satisfaction ratings, with particularly positive feedback relating to the multidisciplinary cohort and experiential learning via Quality Improvement projects. Findings indicated improvements in participants' leadership skills, knowledge, confidence and job satisfaction. Organisational outcomes included increased organisational interest in quality improvement and individual career progression. Conclusion: The results highlight the value of a structured leadership programme in developing healthcare leaders and driving organisational improvements, with long-term effects. Recommendations for future programmes include multidisciplinary involvement, experiential learning, inspiring speakers and embedded mixed-methods evaluation.
Risk of death by suicide following self-harm presentations to healthcare: development and validation of a multivariable clinical prediction rule (OxSATS)
BACKGROUND: Assessment of suicide risk in individuals who have self-harmed is common in emergency departments, but is often based on tools developed for other purposes. OBJECTIVE: We developed and validated a predictive model for suicide following self-harm. METHODS: We used data from Swedish population-based registers. A cohort of 53 172 individuals aged 10+ years, with healthcare episodes of self-harm, was split into development (37 523 individuals, of whom 391 died from suicide within 12 months) and validation (15 649 individuals, 178 suicides within 12 months) samples. We fitted a multivariable accelerated failure time model for the association between risk factors and time to suicide. The final model contains 11 factors: age, sex, and variables related to substance misuse, mental health and treatment, and history of self-harm. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines were followed for the design and reporting of this work. FINDINGS: An 11-item risk model to predict suicide was developed using sociodemographic and clinical risk factors, and showed good discrimination (c-index 0.77, 95% CI 0.75 to 0.78) and calibration in external validation. For risk of suicide within 12 months, using a 1% cut-off, sensitivity was 82% (75% to 87%) and specificity was 54% (53% to 55%). A web-based risk calculator is available (Oxford Suicide Assessment Tool for Self-harm or OxSATS). CONCLUSIONS: OxSATS accurately predicts 12-month risk of suicide. Further validations and linkage to effective interventions are required to examine clinical utility. CLINICAL IMPLICATIONS: Using a clinical prediction score may assist clinical decision-making and resource allocation.
Variation in duration of repeat prescriptions: a primary care cohort study in England
Background Many patients receive repeat prescriptions for routine medications used to treat chronic conditions. Doctors typically issue repeat prescriptions with durations ranging from 28 to 84 days. There is currently no national guidance in England for the optimal prescription duration for routine medications. Aim To evaluate current prescription durations for five common routine medications in England; explore and visualise geographical variation; and identify practice factors that are associated with shorter prescribing duration to inform policy making. Design and setting A retrospective cohort study of NHS primary care prescribing data in England from December 2018 to November 2019. Method The prescription duration was analysed for five common routine medications in England; ramipril, atorvastatin, simvastatin, levothyroxine, and amlodipine. Variation was assessed between regional clinical commissioning groups (CCGs), and practice factors associated with different durations were identified. Results Of the common medications included, 28-day prescriptions accounted for 48.5% (2.5 billion) tablets/ capsules issued, while 43.6% were issued for 56 days. There was very wide regional variation (7.2%–95.0%) in the proportion of 28-day prescriptions issued by CCGs. Practice dispensing status was the most likely predictor of prescription duration; dispensing practices had a higher 28-day prescribing proportion than non-dispensing practices. The proportion of patients with chronic conditions and the electronic health record system used by a practice were also associated with prescription duration. Conclusion This analysis of OpenPrescribing data showed that repeat prescriptions of 28 days are common for patients taking routine medications for chronic conditions, particularly in dispensing practices. This provides data to inform the policy debate on current practice. Configuration of electronic health record systems offer an opportunity to implement and evaluate new policies on repeat prescription duration in England.
UMBRELLA protocol: systematic reviews of multivariable biomarker prognostic models developed to predict clinical outcomes in patients with heart failure.
BACKGROUND: Heart failure (HF) is a chronic and common condition with a rising prevalence, especially in the elderly. Morbidity and mortality rates in people with HF are similar to those with common forms of cancer. Clinical guidelines highlight the need for more detailed prognostic information to optimise treatment and care planning for people with HF. Besides proven prognostic biomarkers and numerous newly developed prognostic models for HF clinical outcomes, no risk stratification models have been adequately established. Through a number of linked systematic reviews, we aim to assess the quality of the existing models with biomarkers in HF and summarise the evidence they present. METHODS: We will search MEDLINE, EMBASE, Web of Science Core Collection, and the prognostic studies database maintained by the Cochrane Prognosis Methods Group combining sensitive published search filters, with no language restriction, from 1990 onwards. Independent pairs of reviewers will screen and extract data. Eligible studies will be those developing, validating, or updating any prognostic model with biomarkers for clinical outcomes in adults with any type of HF. Data will be extracted using a piloted form that combines published good practice guidelines for critical appraisal, data extraction, and risk of bias assessment of prediction modelling studies. Missing information on predictive performance measures will be sought by contacting authors or estimated from available information when possible. If sufficient high quality and homogeneous data are available, we will meta-analyse the predictive performance of identified models. Sources of between-study heterogeneity will be explored through meta-regression using pre-defined study-level covariates. Results will be reported narratively if study quality is deemed to be low or if the between-study heterogeneity is high. Sensitivity analyses for risk of bias impact will be performed. DISCUSSION: This project aims to appraise and summarise the methodological conduct and predictive performance of existing clinically homogeneous HF prognostic models in separate systematic reviews.Registration: PROSPERO registration number CRD42019086990.
Signals of Adverse Reactions to Herbal Medicines: Evidence and Document Analysis Based on a Scoping Review
Background: To date, signals of adverse reactions to herbal medicines have not been systematically reviewed, limiting pharmacovigilance of herbal medicines because of a lack of data. Objectives: We sought to analyse the available evidence on signals involving herbal medicines and to determine to what extent they had been documented at the European Union (EU) level and in the USA. Methods: We used the results of a published scoping review of interventional and non-interventional studies that reported signals of adverse reactions to drugs. We assigned Anatomical Therapeutic Chemical classification to all drugs, and identified herbal medicines when they fell under the Anatomical Therapeutic Chemical V90. We ascertained the presence of the adverse reaction, or related adverse reactions, for each signal in reference documents for healthcare professionals: the US Botanical Safety Handbook and the EU monographs and US Dietary Supplement Fact Sheets; and in those for consumers: the US Dietary Supplement Label Database. We summarised the data descriptively, treating US documents as one and comparing harms across pairs of US and EU documents by signal. Documents were deemed concordant if they both included the same or related adverse reactions, or if neither did. We also compared adverse reactions across US documents for healthcare professionals with those for consumers. Results: Of the 10,861 signals covered by the scoping review, 53 (0.49%) concerned herbal medicines, all based on case reports. Reference documents from both the US and EU were available for 37 signals. Most of the documents were concordant (73%), and ten (27%) were discordant: six adverse reactions were mentioned only in US documents, three only in EU monographs, and one was warned against in US documents but not in EU documents. Twenty-one signals could be followed up in the Botanical Safety Handbook and Dietary Supplement Fact Sheets. Most (68%) US documents for healthcare professionals were concordant. When the Botanical Safety Handbook and Dietary Supplement Fact Sheets did not include an adverse reaction, neither did the Dietary Supplement Label Database. However, when they did, only 20% of the labels for consumers did too. The proportion of labels mentioning adverse reactions otherwise available in documents intended for healthcare professionals ranged widely, reflecting differences across multiple labels for the same products. Conclusions: Very few signals of adverse reactions from the wider scoping review concerned herbal medicines, and were all based on case reports. Information was mostly concordant across documents in the EU and USA. As manufacturers are solely responsible for the contents of the Dietary Supplement Label Database, regulatory oversight may be required to ensure that consistent and comprehensive information on the harms of herbal medicines is made available to consumers in the USA.
Pramipexole augmentation for the acute phase of treatment-resistant, unipolar depression: a placebo-controlled, double-blind, randomised trial in the UK
Background: About 30% of patients with depression treated with antidepressant medication do not respond sufficiently to the first agents used. Pramipexole might usefully augment antidepressant medication in such cases of treatment-resistant depression, but data on its effects and tolerability are scarce. We aimed to assess the efficacy and tolerability of pramipexole augmentation of ongoing antidepressant treatment, over 48 weeks, in patients with treatment-resistant depression. Methods: We did a multicentre, double-blind, placebo-controlled randomised trial in which adults with resistant major depressive disorder were randomly assigned (1:1; using an online randomisation system) to 48 weeks of pramipexole (titrated to 2·5 mg) or placebo added to their ongoing antidepressant medication. The study was conducted in nine National Health Service Trusts in England. Participants, investigators, and researchers involved in recruitment and assessment were masked to group allocation, and the central pharmacy team dispensing the medication was not masked. The primary outcome was change from baseline to week 12 in the total score of the 16-item Quick Inventory of Depressive Symptomology self-report version (QIDS-SR16). The primary analysis was performed on the intention-to-treat population that included all eligible, randomly assigned participants. People with lived experience were involved in the design, oversight, and interpretation of the study. The trial was registered with ISCTRN (ISRCTN84666271) and EudraCT (2019-001023-13) and is complete. Findings: Between Feb 16 and May 29, 2024, 217 participants attended a screening visit, of whom 66 were excluded due to ineligibility. 151 participants were randomly assigned (75 to the pramipexole group and 75 to the placebo group, after one participant was found to be ineligible after randomisation). 84 (56%) participants were female and 66 (44%) were male and the mean age of participants was 44·9 years (SD 14·0). Ethnicity data were not available. The mean QIDS-SR16 total score at baseline was 16·4 (SD 3·4) in the pramipexole group and 16·2 (3·5) in the placebo group. The mean dose of pramipexole received at week 12 was 2·3 mg (SD 0·45). Adjusted mean decrease from baseline to week 12 of the QIDS-SR16 total score was 6·4 (SD 4·9) for the pramipexole group and 2·4 (4·0) for the placebo group; the mean difference between groups was −3·91 (95% CI −5·37 to −2·45; p<0·0001). Termination of trial treatment due to adverse events was more frequent in the pramipexole group (15 participants [20%]) than in the placebo group (four participants [5%]), with reported adverse events consistent with known side-effects of pramipexole, in particular nausea, headache, and sleep disturbance or somnolence. Interpretation: In this trial involving participants with treatment-resistant depression, pramipexole augmentation of antidepressant treatment, at a target dose of 2·5 mg, demonstrated a reduction in symptoms relative to placebo at 12 weeks but was associated with some adverse effects. These results suggest that pramipexole is a clinically effective option for reducing symptoms in patients with treatment-resistant depression. Future trials directly comparing pramipexole with existing treatments for this disorder are needed. Funding: National Institute of Health and Care Research, Efficacy and Mechanism Evaluation Programme.
A framework for the development and implementation of open trauma guidelines: A Delphi consensus validation
Introduction: Lower limb open fractures are severe injuries that can lead to long-term sequelae. Clinical guidelines for managing these patients are associated with expedited treatment and better outcomes. However, few countries have implemented guidelines for open lower limb fractures. The aim of this study was to develop and validate a framework for the introduction of clinical guidelines in settings that do not have one at present. Methods: Using the qualitative analysis for the Limitations to the Implementation of Open Trauma Guidelines (LINEAGE) study, a framework proposal was designed. This included 4 clusters of inter-related concepts, including clinician, team, health and cultural factors. To validate this framework a modified Delphi study was devised. The elements of the framework were translated into 12 statements that were compiled in a Delphi questionnaire. A panel of orthopaedic and plastic surgeons was assembled to obtain structured feedback and assess the degree of consensus regarding the framework proposal. Results: Using purposive sampling, 43 clinicians enrolled in an international expert panel, including 20 orthopaedic and 23 plastic surgeons based in countries with no guidelines at present. Following three Delphi rounds, 11 out of the 12 assessed statements achieved the threshold for validation. The single statement that did not reach consensus status was then removed from the framework. Discussion: Frameworks are a well-described aid in implementation science, being able to describe complexity and propose strategies for improvement. We present the first validated framework for the development and implementation of open fracture guidelines.
Enhancing global clinical trial transparency for better health outcomes for all
Background: In 2022, WHO’s World Health Assembly adopted resolution WHA75.8, emphasizing the critical role of clinical trials in generating high-quality evidence and promoting equitable access to health interventions globally. In response, rapid landscape reviews were conducted to assess global clinical trial regulations, capacities, and funding distribution. Methods The analysis synthesized regulatory frameworks from 94 countries, institutional capacity data from the WHO International Clinical Trial Registry Platform (ICTRP), and funding data from World RePORT for trials registered between 2018-2022. Gaps in data availability and quality were assessed. Results Most countries reference international ethical guidelines, with universal requirements for ethics approval and informed consent. However, only 66% mandate public trial registration, and 40% require results reporting, with stark disparities between high- and low-income countries. High-income countries host over half of global trials; low-income countries contribute less than 1% despite high disease burden. Clinical trials sponsored by non-commercial entities are particularly scarce in low- and middle-income countries. Funding remains concentrated in the Americas and European regions, primarily driven by major funders such as the National Institutes of Health in the United States of America and European Commission. Significant data accessibility challenges persist due to incomplete registry records, inconsistent standards, lack of harmonized identifiers, and limited bulk data access. Recommendations Urgent actions include reinforcing international standards for trial registries, harmonizing data fields, improving registry interoperability, leveraging unique identifiers, enhancing multilingual accessibility, auditing data quality, pooling analytical resources, promoting open data policies, and investing in registry infrastructure and trained personnel. Conclusion Addressing data gaps and inequities in clinical trial ecosystems requires concerted action by global stakeholders. Improved data transparency and interoperability are essential to guide equitable research investments, foster coordination, and strengthen clinical trial capacity worldwide.
SARS-CoV-2 and the role of close contact in transmission: a systematic review
Background: SARS-CoV-2 transmission has been reported to be associated with close contact with infected individuals. However, the mechanistic pathway for transmission in close contact settings is unclear. Our objective was to identify, appraise and summarise the evidence from studies assessing the role of close contact in SARS-CoV-2 transmission. Methods: : This review is part of an Open Evidence Review on Transmission Dynamics of SARS-CoV-2. We conduct ongoing searches using WHO Covid-19 Database, LitCovid, medRxiv, PubMed and Google Scholar; assess study quality based on the QUADAS-2 criteria and report important findings on an ongoing basis. Results: : We included 278 studies: 258 primary studies and 20 systematic reviews. The settings for primary studies were predominantly in home/quarantine facilities (39.5%) and acute care hospitals (12%). The overall reporting quality of the studies was low-to-moderate. There was significant heterogeneity in design and methodology. The frequency of attack rates (PCR testing) varied between 2.1-75%; attack rates were highest in prison and wedding venues, and in households. The frequency of secondary attack rates was 0.3-100% with rates highest in home/quarantine settings. Three studies showed no transmission if the index case was a recurrent infection. Viral culture was performed in four studies of which three found replication-competent virus; culture results were negative where index cases had recurrent infections. Eighteen studies performed genomic sequencing with phylogenetic analysis – the completeness of genomic similarity ranged from 77-100%. Findings from systematic reviews showed that children were significantly less likely to transmit SARS-CoV-2 and household contact was associated with a significantly increased risk of infection. Conclusions: The evidence from published studies demonstrates that SARS-CoV-2 can be transmitted in close contact settings. The risk of transmission is greater in household contacts. There was a wide variation in methodology. Standardized guidelines for reporting transmission in close contact settings should be developed.
Viral cultures, cycle threshold values and viral load estimation for assessing SARS-CoV-2 infectiousness in haematopoietic stem cell and solid organ transplant patients: a systematic review
Background: Solid organ and haematopoietic stem cell transplant recipients are more vulnerable to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) than non-transplant recipients due to immunosuppression, and may pose a continued transmission risk, especially within hospital settings. Detailed case reports including symptoms, viral load and infectiousness, defined by the presence of replication-competent viruses in culture, provide an opportunity to examine the relationship between clinical course, burden and contagiousness, and provide guidance on release from isolation. Objectives: To investigate the relationship between serial SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) value or cycle of quantification value, or other measures of viral burden and the likelihood and duration of the presence of infectious virus based on viral culture, including the influence of age, sex, underlying pathologies, degree of immunosuppression, and/or vaccination on this relationship, in transplant recipients. Methods: LitCovid, medRxiv, Google Scholar and the World Health Organization COVID-19 database were searched from 1st November 2019 to 26th October 2022. Studies reporting relevant data (results from serial RT-PCR testing and viral culture data from the same respiratory samples) for transplant recipients with SARS-CoV-2 infection were included in this systematic review: Methodological quality was assessed using five criteria, and the data were synthesized narratively and graphically. Results: Thirteen case reports and case series reporting on 41 transplant recipients (22 renal, five cardiac, one bone marrow, two liver, one bilateral lung and 10 blood stem cell) were included in this review. A relationship was observed between proxies of viral burden and likelihood of shedding replication-competent SARS-CoV-2. Three individuals shed replication-competent viruses for >100 days after symptom onset. Lack of standardization of testing and reporting platforms precludes establishing a definitive viral burden cut-off. However, the majority of transplant recipients stopped shedding replication-competent viruses when the Ct value was >30 despite differences across platforms. Conclusions: Viral burden is a reasonable proxy for infectivity when considered within the context of the clinical status of each patient. Standardized study design and reporting are essential to standardize guidance based on an increasing evidence base.