Anti-Vascular Endothelial Growth Factor Drugs Compared With Panretinal Photocoagulation for the Treatment of Proliferative Diabetic Retinopathy: A Cost-Effectiveness Analysis.

OBJECTIVES: This study aimed to evaluate the cost-effectiveness of anti-vascular endothelial growth factor drugs (anti-VEGFs) compared with panretinal photocoagulation (PRP) for treating proliferative diabetic retinopathy (PDR) in the United Kingdom. METHODS: A discrete event simulation model was developed, informed by individual participant data meta-analysis. The model captures treatment effects on best corrected visual acuity in both eyes, and the occurrence of diabetic macular edema and vitreous hemorrhage. The model also estimates the value of undertaking further research to resolve decision uncertainty. RESULTS: Anti-VEGFs are unlikely to generate clinically meaningful benefits over PRP. The model predicted anti-VEGFs be more costly and similarly effective as PRP, generating 0.029 fewer quality-adjusted life-years at an additional cost of £3688, with a net health benefit of -0.214 at a £20 000 willingness-to-pay threshold. Scenario analysis results suggest that only under very select conditions may anti-VEGFs offer potential for cost-effective treatment of PDR. The consequences of loss to follow-up were an important driver of model outcomes. CONCLUSIONS: Anti-VEGFs are unlikely to be a cost-effective treatment for early PDR compared with PRP. Anti-VEGFs are generally associated with higher costs and similar health outcomes across various scenarios. Although anti-VEGFs were associated with lower diabetic macular edema rates, the number of cases avoided is insufficient to offset the additional treatment costs. Key uncertainties relate to the long-term comparative effectiveness of anti-VEGFs, particularly considering the real-world rates and consequences of treatment nonadherence. Further research on long-term visual acuity and rates of vision-threatening complications may be beneficial in resolving uncertainties.

End of life and death of residents: Experiences and practices of care facility directors in Portuguese residential care facilities.

Residential care facilities (RCFs) are places where older people live and usually die. This exploratory qualitative study aims to describe the experiences and practices of the directors of Portuguese RCFs regarding residents' end of life and death. Data were obtained from 17 care facility directors (CFDs) who participated in three focus groups. Thematic data analysis was performed. The CFDs described their practices and experiences framed within three moments in the life journey of the residents in RCFs: admission and living in RCF; end of life and death; postmortem and new admission - continuing and occupying the vacancy. The results suggest that end of life and death are only addressed in the last days/hours of life of the resident. However, the CFDs' approach throughout the stay of the residents in the RCF could allow for the expression of their wishes and wills, which could facilitate a good and dignified death.

Treatment effect modification due to comorbidity: Individual participant data meta-analyses of 120 randomised controlled trials.

BACKGROUND: People with comorbidities are underrepresented in clinical trials. Empirical estimates of treatment effect modification by comorbidity are lacking, leading to uncertainty in treatment recommendations. We aimed to produce estimates of treatment effect modification by comorbidity using individual participant data (IPD). METHODS AND FINDINGS: We obtained IPD for 120 industry-sponsored phase 3/4 trials across 22 index conditions (n = 128,331). Trials had to be registered between 1990 and 2017 and have recruited ≥300 people. Included trials were multicentre and international. For each index condition, we analysed the outcome most frequently reported in the included trials. We performed a two-stage IPD meta-analysis to estimate modification of treatment effect by comorbidity. First, for each trial, we modelled the interaction between comorbidity and treatment arm adjusted for age and sex. Second, for each treatment within each index condition, we meta-analysed the comorbidity-treatment interaction terms from each trial. We estimated the effect of comorbidity measured in 3 ways: (i) the number of comorbidities (in addition to the index condition); (ii) presence or absence of the 6 commonest comorbid diseases for each index condition; and (iii) using continuous markers of underlying conditions (e.g., estimated glomerular filtration rate (eGFR)). Treatment effects were modelled on the usual scale for the type of outcome (absolute scale for numerical outcomes, relative scale for binary outcomes). Mean age in the trials ranged from 37.1 (allergic rhinitis trials) to 73.0 (dementia trials) and percentage of male participants range from 4.4% (osteoporosis trials) to 100% (benign prostatic hypertrophy trials). The percentage of participants with 3 or more comorbidities ranged from 2.3% (allergic rhinitis trials) to 57% (systemic lupus erythematosus trials). We found no evidence of modification of treatment efficacy by comorbidity, for any of the 3 measures of comorbidity. This was the case for 20 conditions for which the outcome variable was continuous (e.g., change in glycosylated haemoglobin in diabetes) and for 3 conditions in which the outcomes were discrete events (e.g., number of headaches in migraine). Although all were null, estimates of treatment effect modification were more precise in some cases (e.g., sodium-glucose co-transporter-2 (SGLT2) inhibitors for type 2 diabetes-interaction term for comorbidity count 0.004, 95% CI -0.01 to 0.02) while for others credible intervals were wide (e.g., corticosteroids for asthma-interaction term -0.22, 95% CI -1.07 to 0.54). The main limitation is that these trials were not designed or powered to assess variation in treatment effect by comorbidity, and relatively few trial participants had >3 comorbidities. CONCLUSIONS: Assessments of treatment effect modification rarely consider comorbidity. Our findings demonstrate that for trials included in this analysis, there was no empirical evidence of treatment effect modification by comorbidity. The standard assumption used in evidence syntheses is that efficacy is constant across subgroups, although this is often criticised. Our findings suggest that for modest levels of comorbidities, this assumption is reasonable. Thus, trial efficacy findings can be combined with data on natural history and competing risks to assess the likely overall benefit of treatments in the context of comorbidity.

Comorbidity and health-related quality of life in people with a chronic medical condition in randomised clinical trials: An individual participant data meta-analysis.

BACKGROUND: Health-related quality of life metrics evaluate treatments in ways that matter to patients, so are often included in randomised clinical trials (hereafter trials). Multimorbidity, where individuals have 2 or more conditions, is negatively associated with quality of life. However, whether multimorbidity predicts change over time or modifies treatment effects for quality of life is unknown. Therefore, clinicians and guideline developers are uncertain about the applicability of trial findings to people with multimorbidity. We examined whether comorbidity count (higher counts indicating greater multimorbidity) (i) is associated with quality of life at baseline; (ii) predicts change in quality of life over time; and/or (iii) modifies treatment effects on quality of life. METHODS AND FINDINGS: Included trials were registered on the United States trials registry for selected index medical conditions and drug classes, phase 2/3, 3 or 4, had ≥300 participants, a nonrestrictive upper age limit, and were available on 1 of 2 trial repositories on 21 November 2016 and 18 May 2018, respectively. Of 124 meeting these criteria, 56 trials (33,421 participants, 16 index conditions, and 23 drug classes) collected a generic quality of life outcome measure (35 EuroQol-5 dimension (EQ-5D), 31 36-item short form survey (SF-36) with 10 collecting both). Blinding and completeness of follow up were examined for each trial. Using trials where individual participant data (IPD) was available from 2 repositories, a comorbidity count was calculated from medical history and/or prescriptions data. Linear regressions were fitted for the association between comorbidity count and (i) quality of life at baseline; (ii) change in quality of life during trial follow up; and (iii) treatment effects on quality of life. These results were then combined in Bayesian linear models. Posterior samples were summarised via the mean, 2.5th and 97.5th percentiles as credible intervals (95% CI) and via the proportion with values less than 0 as the probability (PBayes) of a negative association. All results are in standardised units (obtained by dividing the EQ-5D/SF-36 estimates by published population standard deviations). Per additional comorbidity, adjusting for age and sex, across all index conditions and treatment comparisons, comorbidity count was associated with lower quality of life at baseline and with a decline in quality of life over time (EQ-5D -0.02 [95% CI -0.03 to -0.01], PBayes > 0.999). Associations were similar, but with wider 95% CIs crossing the null for SF-36-PCS and SF-36-MCS (-0.05 [-0.10 to 0.01], PBayes = 0.956 and -0.05 [-0.10 to 0.01], PBayes = 0.966, respectively). Importantly, there was no evidence of any interaction between comorbidity count and treatment efficacy for either EQ-5D or SF-36 (EQ-5D -0.0035 [95% CI -0.0153 to -0.0065], PBayes = 0.746; SF-36-MCS (-0.0111 [95% CI -0.0647 to 0.0416], PBayes = 0.70 and SF-36-PCS -0.0092 [95% CI -0.0758 to 0.0476], PBayes = 0.631. CONCLUSIONS: Treatment effects on quality of life did not differ by multimorbidity (measured via a comorbidity count) at baseline-for the medical conditions studied, types and severity of comorbidities and level of quality of life at baseline, suggesting that evidence from clinical trials is likely to be applicable to settings with (at least modestly) higher levels of comorbidity. TRIAL REGISTRATION: A prespecified protocol was registered on PROSPERO (CRD42018048202).

Hierarchical network meta-analysis models for synthesis of evidence from randomised and non-randomised studies.

BACKGROUND: With the increased interest in the inclusion of non-randomised data in network meta-analyses (NMAs) of randomised controlled trials (RCTs), analysts need to consider the implications of the differences in study designs as such data can be prone to increased bias due to the lack of randomisation and unmeasured confounding. This study aims to explore and extend a number of NMA models that account for the differences in the study designs, assessing their impact on the effect estimates and uncertainty. METHODS: Bayesian random-effects meta-analytic models, including naïve pooling and hierarchical models differentiating between the study designs, were extended to allow for the treatment class effect and accounting for bias, with further extensions allowing for bias terms to vary depending on the treatment class. Models were applied to an illustrative example in type 2 diabetes; using data from a systematic review of RCTs and non-randomised studies of two classes of glucose-lowering medications: sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists. RESULTS: Across all methods, the estimated mean differences in glycated haemoglobin after 24 and 52 weeks remained similar with the inclusion of observational data. The uncertainty around these estimates reduced when conducting naïve pooling, compared to NMA of RCT data alone, and remained similar when applying hierarchical model allowing for class effect. However, the uncertainty around these effect estimates increased when fitting hierarchical models allowing for the differences in study design. The impact on uncertainty varied between treatments when applying the bias adjustment models. Hierarchical models and bias adjustment models all provided a better fit in comparison to the naïve-pooling method. CONCLUSIONS: Hierarchical and bias adjustment NMA models accounting for study design may be more appropriate when conducting a NMA of RCTs and observational studies. The degree of uncertainty around the effectiveness estimates varied depending on the method but use of hierarchical models accounting for the study design resulted in increased uncertainty. Inclusion of non-randomised data may, however, result in inferences that are more generalisable and the models accounting for the differences in the study design allow for more detailed and appropriate modelling of complex data, preventing overly optimistic conclusions.

Addition of long-acting beta2 agonists or long-acting muscarinic antagonists versus doubling the dose of inhaled corticosteroids (ICS) in adolescents and adults with uncontrolled asthma with medium dose ICS: a systematic review and network meta-analysis.

BACKGROUND: Inhaled corticosteroids (ICS) are the mainstay treatment for persistent asthma. Escalating treatment is required when asthma is not controlled with ICS therapy alone, which would include, but is not limited to, adding a long-acting beta2-agonist (LABA) or a long-acting muscarinic antagonist (LAMA) or doubling the dose of ICS. OBJECTIVES: To assess the efficacy and safety of adding a LABA or LAMA to ICS therapy versus doubling the dose of ICS in adolescents and adults whose asthma is not well controlled on medium-dose (MD)-ICS using a network meta-analysis (NMA), and to provide a ranking of these treatments according to their efficacy and safety. SEARCH METHODS: We searched the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, Global Health, ClinicalTrials.gov, and the World Health Organization ICTRP for pre-registered randomised controlled trials (RCTs) from January 2008 to 19 December 2022. SELECTION CRITERIA: We searched for studies including adolescents and adults with uncontrolled asthma who had been treated with or were eligible for MD-ICS, comparing it to high-dose (HD)-ICS, ICS/LAMA, or ICS/LABA. We excluded cluster- and cross-over RCTs. Studies were of at least 12 weeks duration. DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis according to a previously published protocol. We used Cochrane's Screen4ME workflow to assess search results. We used Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome is asthma exacerbations (moderate and severe). MAIN RESULTS: We included 38,276 participants from 35 studies (median duration 24 weeks (range 12 to 78); mean age 44.1; 38% male; 69% white; mean forced expiratory volume in one second 2.1 litres and 68% of predicted). MD- and HD-ICS/LABA likely reduce and MD-ICS/LAMA possibly reduces moderate to severe asthma exacerbations compared to MD-ICS (hazard ratio (HR) 0.70, 95% credible interval (CrI) 0.59 to 0.82; moderate certainty; HR 0.59, 95% CrI 0.46 to 0.76; moderate certainty; and HR 0.56, 95% CrI 0.38 to 0.82; low certainty, respectively), whereas HD-ICS probably does not (HR 0.94, 95% CrI 0.70 to 1.24; moderate certainty). There is no clear evidence to suggest that any combination therapy or HD-ICS reduces severe asthma exacerbations compared to MD-ICS (low to moderate certainty). This study suggests no clinically meaningful differences in the symptom or quality of life score between dual combinations and monotherapy (low to high certainty). MD- and HD-ICS/LABA increase or likely increase the odds of Asthma Control Questionnaire (ACQ) responders at 6 and 12 months compared to MD-ICS (odds ratio (OR) 1.47, 95% CrI 1.23 to 1.76; high certainty; and OR 1.59, 95% CrI 1.31 to 1.94; high certainty at 6 months; and OR 1.61, 95% CrI 1.22 to 2.13; moderate certainty and OR 1.55, 95% CrI 1.20 to 2.00; high certainty at 12 months, respectively). MD-ICS/LAMA probably increases the odds of ACQ responders at 6 months (OR 1.32, 95% CrI 1.11 to 1.57; moderate certainty). No data were available at 12 months. There is no clear evidence to suggest that HD-ICS increases the odds of ACQ responders or improves the symptom or qualify of life score compared to MD-ICS (very low to high certainty). There is no evidence to suggest that ICS/LABA or ICS/LAMA reduces asthma-related or all-cause serious adverse events (SAEs) compared to MD-ICS (very low to high certainty). HD-ICS results in or likely results in little or no difference in the included safety outcomes compared to MD-ICS as well as HD-ICS/LABA compared to MD-ICS/LABA. The pairwise meta-analysis shows that MD-ICS/LAMA likely reduces all-cause adverse events (AEs) and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS (risk ratio (RR) 0.86, 95% confidence interval (CI) 0.77 to 0.96; 4 studies, 2238 participants; moderate certainty; and RR 0.51, 95% CI 0.26 to 0.99; 4 studies, 2239 participants; absolute risk reduction 10 fewer per 1000 participants; moderate certainty, respectively). The NMA evidence is in agreement with the pairwise evidence on treatment discontinuation due to AEs, but very uncertain on all-cause AEs, due to imprecision and heterogeneity. AUTHORS' CONCLUSIONS: The review findings suggest that MD- or HD-ICS/LABA and MD-ICS/LAMA reduce moderate to severe asthma exacerbations and increase the odds of ACQ responders compared to MD-ICS whereas HD-ICS probably does not. The evidence is generally stronger for MD- and HD-ICS/LABA than for MD-ICS/LAMA primarily due to a larger evidence base. There is no evidence to suggest that ICS/LABA, ICS/LAMA, or HD-ICS/LABA reduces severe asthma exacerbations or SAEs compared to MD-ICS. MD-ICS/LAMA likely reduces all-cause AEs and results in a slight reduction in treatment discontinuation due to AEs compared to MD-ICS. The above findings may assist in deciding on a treatment option during the stepwise approach of asthma management. Longer-term safety of higher than medium-dose ICS needs to be addressed in phase 4 or observational studies given that the median duration of included studies was six months.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.

Removing chemical and biological pollutants from swine wastewater through constructed wetlands aiming reclaimed water reuse.

Reusing reclaimed wastewater is needed to fight water scarcity, reduce freshwater consumption and conserve water resources, but one must ensure that hazardous substances are fully removed/eliminate before that reuse. The potential of lab-scale constructed wetlands (CWs) for the removal of chemical and biological contaminants from livestock wastewater, while maintaining nutrient levels for fertilization, was assessed, evaluating changes in microbial communities, with particular focus on potential pathogens. CW microcosms with two different substrates (lava rock or light expanded clay aggregate), both planted with Phragmites australis, were tested. After 15 days of treatment, removal rates were higher than 80% for Cd, Cr, Cu, Fe, Pb and Zn, in general with no significant differences between the two different substrates. Organic matter and nutrients were also removed but their levels still allowed the used of the treated wastewater as a fertilizer Removal of bacterial contamination was estimated through enumeration of cultivable bacteria. High removal rates of fecal indicator bacteria were observed, reaching >95% for enterococci and >98% for enterobacteria after 15 days of treatment, decreasing hazardous biological contaminants initially present in the wastewater. In addition, the microbial communities in the initial and treated wastewater, and in the plant roots bed substrate, were characterized by using 16SrRNA gene amplicon sequencing. Microbial communities in the CW systems showed a clear shift comparatively with the initial wastewater showing system adaptation and removal potentialities. This also revealed an important removal of the most represented potential pathogenic genus, Clostridium, which relative abundance decreased from 33% to 1% through the treatment. Overall, CWs showed potential to be efficient in removing chemical and biological contaminants, while maintaining moderated levels of nutrients, allowing the reuse of reclaimed water in agriculture, namely as fertilizer. Current results will contribute for the optimization and use of CWs for a sustainable treatment of liquid wastes, promoting the circular economy.

A Systematic Review of the Reminiscence Functions Scale and Implications for Use with Older Adults.

OBJECTIVES: The Reminiscence Functions Scale (RFS) is a widely used robust instrument. While reminiscence-based intervention is one of the most effective nonpharmacological interventions for older adults. This systematic review provides a comprehensive synthesis of the literature that used RFS with older adults, summarizes the main outcomes, and highlights implications for practice. METHODS: This systematic review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were eligible if they used RFS and included older adults. Studies were searched from 1993, the year RFS was first published. Electronic databases were searched (Scopus, PsycNET, and Web of Science), from which 44 eligible studies were identified. RESULTS: Four themes were identified: i) predictive value of reminiscence functions regarding well-being, ii) increased frequency of teach/inform and death preparation functions in older adults, iii) key roles of reminiscence functions in coping with critical life events, iv) reminiscence-based interventions should promote positive memories. CONCLUSIONS: The RFS outcomes may improve reminiscence-based interventions, since the functions of reminiscence are key players in older adults daily life. CLINICAL IMPLICATIONS: Reminiscence-based interventions should promote positive memories, which are associated with improved well-being. Particularly, it seems a good practice when supporting older adults regarding critical and traumatic events.

Assessing trial representativeness using serious adverse events: an observational analysis using aggregate and individual-level data from clinical trials and routine healthcare data.

BACKGROUND: The applicability of randomised controlled trials of pharmacological agents to older people with frailty/multimorbidity is often uncertain, due to concerns that trials are not representative. However, assessing trial representativeness is challenging and complex. We explore an approach assessing trial representativeness by comparing rates of trial serious adverse events (SAE) to rates of hospitalisation/death in routine care. METHODS: This was an observational analysis of individual (125 trials, n=122,069) and aggregate-level drug trial data (483 trials, n=636,267) for 21 index conditions compared to population-based routine healthcare data (routine care). Trials were identified from ClinicalTrials.gov . Routine care comparison from linked primary care and hospital data from Wales, UK (n=2.3M). Our outcome of interest was SAEs (routinely reported in trials). In routine care, SAEs were based on hospitalisations and deaths (which are SAEs by definition). We compared trial SAEs in trials to expected SAEs based on age/sex standardised routine care populations with the same index condition. Using IPD, we assessed the relationship between multimorbidity count and SAEs in both trials and routine care and assessed the impact on the observed/expected SAE ratio additionally accounting for multimorbidity. RESULTS: For 12/21 index conditions, the pooled observed/expected SAE ratio was <1, indicating fewer SAEs in trial participants than in routine care. A further 6/21 had point estimates <1 but the 95% CI included the null. The median pooled estimate of observed/expected SAE ratio was 0.60 (95% CI 0.55-0.64; COPD) and the interquartile range was 0.44 (0.34-0.55; Parkinson's disease) to 0.87 (0.58-1.29; inflammatory bowel disease). Higher multimorbidity count was associated with SAEs across all index conditions in both routine care and trials. For most trials, the observed/expected SAE ratio moved closer to 1 after additionally accounting for multimorbidity count, but it nonetheless remained below 1 for most. CONCLUSIONS: Trial participants experience fewer SAEs than expected based on age/sex/condition hospitalisation and death rates in routine care, confirming the predicted lack of representativeness. This difference is only partially explained by differences in multimorbidity. Assessing observed/expected SAE may help assess the applicability of trial findings to older populations in whom multimorbidity and frailty are common.

Methods to assess evidence consistency in dose-response model based network meta-analysis.

Network meta-analysis (NMA) simultaneously estimates multiple relative treatment effects based on evidence that forms a network of treatment comparisons. Heterogeneity in treatment definitions, such as dose, can lead to a violation of the consistency assumption that underpins NMA. Model-based NMA (MBNMA) methods have been proposed that allow functional dose-response relationships to be estimated within an NMA, which avoids lumping different doses together and thereby reduces the likelihood of inconsistency. Dose-response MBNMA relies on appropriate specification of the dose-response relationship as well as consistency of relative effects. In this article we describe methods to check for inconsistency in dose-response MBNMA models. Global and local (node-splitting) tests for inconsistency are described that account for studies with ≥3 arms that are typical in dose-finding trials. We show that consistency needs to be assessed with respect to the choice of dose-response function. We illustrate the methods using a network comparing biologics for moderate-to-severe psoriasis. By comparing results from an Emax and an exponential dose-response function we show that failure to correctly characterise the dose-response can introduce apparent inconsistency. The number of comparisons for which node-splitting is possible is also shown to be dependent on the complexity of the selected dose-response function. We highlight that the nature of dose-finding studies, which typically compare multiple doses of the same agent, provide limited scope to assess inconsistency, but these study designs help guard against inconsistency in the first place. We demonstrate the importance of assessing consistency to obtain robust relative effects to inform drug-development and policy decisions.

Appraising the Costs of Genomic Testing for Histology-Independent Technologies: An Illustrative Example for NTRK Fusions.

OBJECTIVES: Histology-independent (HI) technologies are authorized for patients with advanced or metastatic cancer if they express a particular biomarker regardless of its position in the body. Although this represents an important advancement in cancer treatment, genomic testing to identify eligible individuals for HI technologies will require substantial investment and impact their cost-effectiveness. Estimating these costs is complicated by several issues, which affect not only the overall cost of testing but also the distribution of testing costs across tumor types. METHODS: Key issues that should be considered when evaluating the cost of genomic testing to identify those eligible for HI technologies are discussed. These issues are explored in illustrative analyses where costs of genomic testing for NTRK fusions in England for recently approved HI technologies are estimated. RESULTS: The prevalence of mutation, testing strategy adopted, and current testing provision affect the cost of identifying eligible patients. The illustrative analysis estimated the cost of RNA-based next-generation sequencing to identify 1 individual with an NTRK fusion ranged between £377 and £282 258. To improve cost-effectiveness, testing costs could be shared across multiple technologies. An estimated additional ∼4000 patients would need to be treated with other HI therapies for testing in patients with advanced or metastatic cancer to be cost-effective. CONCLUSIONS: The cost of testing to identify individuals eligible for HI technologies affect the drug's cost-effectiveness. The cost of testing across tumor types varies owing to heterogeneity in the mutation's prevalence and current testing provision. The cost-effectiveness of HI technologies may be improved if testing costs could be shared across multiple agents.

Effectiveness and tolerability of dual and triple combination inhaler therapies compared with each other and varying doses of inhaled corticosteroids in adolescents and adults with asthma: a systematic review and network meta-analysis.

BACKGROUND: Current guidelines recommend a higher-dose inhaled corticosteroids (ICS) or adding a long-acting muscarinic antagonist (LAMA) when asthma is not controlled with medium-dose (MD) ICS/long-acting beta2-agonist (LABA) combination therapy. OBJECTIVES: To assess the effectiveness and safety of dual (ICS/LABA) and triple therapies (ICS/LABA/LAMA) compared with each other and with varying doses of ICS in adolescents and adults with uncontrolled asthma. SEARCH METHODS: We searched multiple databases for pre-registered randomised controlled trials (RCTs) of at least 12 weeks of study duration from 2008 to 18 February 2022. SELECTION CRITERIA: We searched studies, including adolescents and adults with uncontrolled asthma who had been treated with, or were eligible for, MD-ICS/LABA, comparing dual and triple therapies. We excluded cluster- and cross-over RCTs. DATA COLLECTION AND ANALYSIS: We conducted a systematic review and network meta-analysis according to the previously published protocol. We used Cochrane's Screen4ME workflow to assess search results and Grading of Recommendations Assessment, Development and Evaluation (GRADE) to assess the certainty of evidence. The primary outcome was steroid-requiring asthma exacerbations and asthma-related hospitalisations (moderate to severe and severe exacerbations). MAIN RESULTS: We included 17,161 patients with uncontrolled asthma from 17 studies (median duration 26 weeks; mean age 49.1 years; male 40%; white 81%; mean forced expiratory volume in 1 second (MEF 1)1.9 litres and 61% predicted). The quality of included studies was generally good except for some outcomes in a few studies due to high attrition rates. Medium-dose (MD) and high-dose (HD) triple therapies reduce steroid-requiring asthma exacerbations (hazard ratio (HR) 0.84 [95% credible interval (CrI) 0.71 to 0.99] and 0.69 [0.58 to 0.82], respectively) (high-certainty evidence), but not asthma-related hospitalisations, compared to MD-ICS/LABA. High-dose triple therapy likely reduces steroid-requiring asthma exacerbations compared to MD triple therapy (HR 0.83 [95% CrI 0.69 to 0.996], [moderate certainty]). Subgroup analyses suggest the reduction in steroid-requiring exacerbations associated with triple therapies may be only for those with a history of asthma exacerbations in the previous year but not for those without. High-dose triple therapy, but not MD triple, results in a reduction in all-cause adverse events (AEs) and likely reduces dropouts due to AEs compared to MD-ICS/LABA (odds ratio (OR) 0.79 [95% CrI 0.69 to 0.90], [high certainty] and 0.50 [95% CrI 0.30 to 0.84], [moderate certainty], respectively). Triple therapy results in little to no difference in all-cause or asthma-related serious adverse events (SAEs) compared to dual therapy (high certainty). The evidence suggests triple therapy results in little or no clinically important difference in symptoms or quality of life compared to dual therapy considering the minimal clinically important differences (MCIDs) and HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA. AUTHORS' CONCLUSIONS: Medium-dose and HD triple therapies reduce steroid-requiring asthma exacerbations, but not asthma-related hospitalisations, compared to MD-ICS/LABA especially in those with a history of asthma exacerbations in the previous year. High-dose triple therapy is likely superior to MD triple therapy in reducing steroid-requiring asthma exacerbations. Triple therapy is unlikely to result in clinically meaningful improvement in symptoms or quality of life compared to dual therapy considering the MCIDs. High-dose triple therapy, but not MD triple, results in a reduction in all-cause AEs and likely reduces dropouts due to AEs compared to MD-ICS/LABA. Triple therapy results in little to no difference in all-cause or asthma-related SAEs compared to dual therapy. HD-ICS/LABA is unlikely to result in any significant benefit or harm compared to MD-ICS/LABA, although long-term safety of higher rather than MD- ICS remains to be demonstrated given the median duration of included studies was six months. The above findings may assist deciding on a treatment option when asthma is not controlled with MD-ICS/LABA.

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the absolute amount of bleeding. It is a very common condition in women of reproductive age, affecting 2 to 5 of every 10 women. Diverse treatments, either medical (hormonal or non-hormonal) or surgical, are currently available for HMB, with different effectiveness, acceptability, costs and side effects. The best treatment will depend on the woman's age, her intention to become pregnant, the presence of other symptoms, and her personal views and preferences. OBJECTIVES: To identify, systematically assess and summarise all evidence from studies included in Cochrane Reviews on treatment for heavy menstrual bleeding (HMB), using reviews with comparable participants and outcomes; and to present a ranking of the first- and second-line treatments for HMB. METHODS: We searched for published Cochrane Reviews of HMB interventions in the Cochrane Database of Systematic Reviews. The primary outcomes were menstrual bleeding and satisfaction. Secondary outcomes included quality of life, adverse events and the requirement of further treatment. Two review authors independently selected the systematic reviews, extracted data and assessed quality, resolving disagreements by discussion. We assessed review quality using the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) 2 tool and evaluated the certainty of the evidence for each outcome using GRADE methods. We grouped the interventions into first- and second-line treatments, considering participant characteristics (desire for future pregnancy, failure of previous treatment, candidacy for surgery). First-line treatments included medical interventions, and second-line treatments included both the levonorgestrel-releasing intrauterine system (LNG-IUS) and surgical treatments; thus the LNG-IUS is included in both groups. We developed different networks for first- and second-line treatments. We performed network meta-analyses of all outcomes, except for quality of life, where we performed pairwise meta-analyses. We reported the mean rank, the network estimates for mean difference (MD) or odds ratio (OR), with 95% confidence intervals (CIs), and the certainty of evidence (moderate, low or very low certainty). We also analysed different endometrial ablation and resection techniques separately from the main network: transcervical endometrial resection (TCRE) with or without rollerball, other resectoscopic endometrial ablation (REA), microwave non-resectoscopic endometrial ablation (NREA), hydrothermal ablation NREA, bipolar NREA, balloon NREA and other NREA. MAIN RESULTS: We included nine systematic reviews published in the Cochrane Library up to July 2021. We updated the reviews that were over two years old. In July 2020, we started the overview with no new reviews about the topic. The included medical interventions were: non-steroidal anti-inflammatory drugs (NSAIDs), antifibrinolytics (tranexamic acid), combined oral contraceptives (COC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecified endometrial ablation (EA) and LNG-IUS. We grouped the interventions as follows. First-line treatments Evidence from 26 studies with 1770 participants suggests that LNG-IUS results in a large reduction of menstrual blood loss (MBL; mean rank 2.4, MD -105.71 mL/cycle, 95% CI -201.10 to -10.33; low certainty evidence); antifibrinolytics probably reduce MBL (mean rank 3.7, MD -80.32 mL/cycle, 95% CI -127.67 to -32.98; moderate certainty evidence); long-cycle progestogen reduces MBL (mean rank 4.1, MD -76.93 mL/cycle, 95% CI -153.82 to -0.05; low certainty evidence), and NSAIDs slightly reduce MBL (mean rank 6.4, MD -40.67 mL/cycle, -84.61 to 3.27; low certainty evidence; reference comparator mean rank 8.9). We are uncertain of the true effect of the remaining interventions and the sensitivity analysis for reduction of MBL, as the evidence was rated as very low certainty. We are uncertain of the true effect of any intervention (very low certainty evidence) on the perception of improvement and satisfaction. Second-line treatments Bleeding reduction is related to the type of hysterectomy (total or supracervical/subtotal), not the route, so we combined all routes of hysterectomy for bleeding outcomes. We assessed the reduction of MBL without imputed data (11 trials, 1790 participants) and with imputed data (15 trials, 2241 participants). Evidence without imputed data suggests that hysterectomy (mean rank 1.2, OR 25.71, 95% CI 1.50 to 439.96; low certainty evidence) and REA (mean rank 2.8, OR 2.70, 95% CI 1.29 to 5.66; low certainty evidence) result in a large reduction of MBL, and NREA probably results in a large reduction of MBL (mean rank 2.0, OR 3.32, 95% CI 1.53 to 7.23; moderate certainty evidence). Evidence with imputed data suggests hysterectomy results in a large reduction of MBL (mean rank 1.0, OR 14.31, 95% CI 2.99 to 68.56; low certainty evidence), and NREA probably results in a large reduction of MBL (mean rank 2.2, OR 2.87, 95% CI 1.29 to 6.05; moderate certainty evidence). We are uncertain of the true effect for REA (very low certainty evidence). We are uncertain of the effect on amenorrhoea (very low certainty evidence). Evidence from 27 trials with 4284 participants suggests that minimally invasive hysterectomy results in a large increase in satisfaction (mean rank 1.3, OR 7.96, 95% CI 3.33 to 19.03; low certainty evidence), and NREA also increases satisfaction (mean rank 3.6, OR 1.59, 95% CI 1.09 to 2.33; low certainty evidence), but we are uncertain of the true effect of the remaining interventions (very low certainty evidence). AUTHORS' CONCLUSIONS: Evidence suggests LNG-IUS is the best first-line treatment for reducing menstrual blood loss (MBL); antifibrinolytics are probably the second best, and long-cycle progestogens are likely the third best. We cannot make conclusions about the effect of first-line treatments on perception of improvement and satisfaction, as evidence was rated as very low certainty. For second-line treatments, evidence suggests hysterectomy is the best treatment for reducing bleeding, followed by REA and NREA. We are uncertain of the effect on amenorrhoea, as evidence was rated as very low certainty. Minimally invasive hysterectomy may result in a large increase in satisfaction, and NREA also increases satisfaction, but we are uncertain of the true effect of the remaining second-line interventions, as evidence was rated as very low certainty.

A method for assessing robustness of the results of a star-shaped network meta-analysis under the unidentifiable consistency assumption.

BACKGROUND: In a star-shaped network, pairwise comparisons link treatments with a reference treatment (often placebo or standard care), but not with each other. Thus, comparisons between non-reference treatments rely on indirect evidence, and are based on the unidentifiable consistency assumption, limiting the reliability of the results. We suggest a method of performing a sensitivity analysis through data imputation to assess the robustness of results with an unknown degree of inconsistency. METHODS: The method involves imputation of data for randomized controlled trials comparing non-reference treatments, to produce a complete network. The imputed data simulate a situation that would allow mixed treatment comparison, with a statistically acceptable extent of inconsistency. By comparing the agreement between the results obtained from the original star-shaped network meta-analysis and the results after incorporating the imputed data, the robustness of the results of the original star-shaped network meta-analysis can be quantified and assessed. To illustrate this method, we applied it to two real datasets and some simulated datasets. RESULTS: Applying the method to the star-shaped network formed by discarding all comparisons between non-reference treatments from a real complete network, 33% of the results from the analysis incorporating imputed data under acceptable inconsistency indicated that the treatment ranking would be different from the ranking obtained from the star-shaped network. Through a simulation study, we demonstrated the sensitivity of the results after data imputation for a star-shaped network with different levels of within- and between-study variability. An extended usability of the method was also demonstrated by another example where some head-to-head comparisons were incorporated. CONCLUSIONS: Our method will serve as a practical technique to assess the reliability of results from a star-shaped network meta-analysis under the unverifiable consistency assumption.

Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by persistent respiratory symptoms and airflow limitation. Acute exacerbations punctuate the natural history of COPD and are associated with increased morbidity and mortality and disease progression. Chronic airflow limitation is caused by a combination of small airways (bronchitis) and parenchymal destruction (emphysema), which can impact day-to-day activities and overall quality of life. In carefully selected patients with COPD, long-term, prophylactic use of antibiotics may reduce bacterial load, inflammation of the airways, and the frequency of exacerbations. OBJECTIVES: To assess effects of different prophylactic antibiotics on exacerbations, quality of life, and serious adverse events in people with COPD in three separate network meta-analyses (NMAs), and to provide rankings of identified antibiotics. SEARCH METHODS: To identify eligible randomised controlled trials (RCTs), we searched the Cochrane Airways Group Specialised Register of trials and clinical trials registries. We conducted the most recent search on 22 January 2020. SELECTION CRITERIA: We included RCTs with a parallel design of at least 12 weeks' duration evaluating long-term administration of antibiotics prophylactically compared with other antibiotics, or placebo, for patients with COPD. DATA COLLECTION AND ANALYSIS: This Cochrane Review collected and updated pair-wise data from two previous Cochrane Reviews. Searches were updated and additional studies included. We conducted three separate network meta-analyses (NMAs) within a Bayesian framework to assess three outcomes: exacerbations, quality of life, and serious adverse events. For quality of life, we collected data from St George's Respiratory Questionnaire (SGRQ). Using previously validated methods, we selected the simplest model that could adequately fit the data for every analysis. We used threshold analysis to indicate which results were robust to potential biases, taking into account each study's contributions to the overall results and network structure. Probability ranking was performed for each antibiotic class for exacerbations, quality of life, and serious adverse events. MAIN RESULTS: Characteristics of studies and participants Eight trials were conducted at multiple sites that included hospital clinics or academic health centres. Seven were single-centre trials conducted in hospital clinics. Two trials did not report settings. Trials durations ranged from 12 to 52 weeks. Most participants had moderate to severe disease. Mean age ranged from 64 years to 73 years, and more males were recruited (51% to 100%). Forced expiratory volume in one second (FEV1) ranged from 0.935 to 1.36 L. Most participants had previous exacerbations. Data from 12 studies were included in the NMAs (3405 participants; 16 treatment arms including placebo). Prophylactic antibiotics evaluated were macrolides (azithromycin and erythromycin), tetracyclines (doxycyclines), quinolones (moxifloxacin) and macrolides plus tetracyclines (roxithromycin plus doxycycline). Risk of bias and threshold analysis Most studies were at low risk across domains, except detection bias, for which only seven studies were judged at low risk. In the threshold analysis for exacerbations, all comparisons in which one antibiotic was compared with another were robust to sampling variation, especially macrolide comparisons. Comparisons of classes with placebo were sensitive to potential bias, especially macrolide versus placebo, therefore, any bias in the comparison was likely to favour the active class, so any adjustment would bring the estimated relative effect closer to the null value, thus quinolone may become the best class to prevent exacerbations. Exacerbations Nine studies were included (2732 participants) in this NMA (exacerbations analysed as time to first exacerbation or people with one or more exacerbations). Macrolides and quinolones reduced exacerbations. Macrolides had a greater effect in reducing exacerbations compared with placebo (macrolides: hazard ratio (HR) 0.67, 95% credible interval (CrI) 0.60 to 0.75; quinolones: HR 0.89, 95% CrI 0.75 to 1.04), resulting in 127 fewer people per 1000 experiencing exacerbations on macrolides. The difference in exacerbations between tetracyclines and placebo was uncertain (HR 1.29, 95% CrI 0.66 to 2.41). Macrolides ranked first (95% CrI first to second), with quinolones ranked second (95% CrI second to third). Tetracyclines ranked fourth, which was lower than placebo (ranked third). Contributing studies were considered as low risk of bias in a threshold analysis. Quality of life (SGRQ) Seven studies were included (2237 participants) in this NMA. SGRQ scores improved with macrolide treatment compared with placebo (fixed effect-fixed class effect: mean difference (MD) -2.30, 95% CrI -3.61 to -0.99), but the mean difference did not reach the minimally clinical important difference (MCID) of 4 points. Tetracyclines and quinolones did not improve quality of life any more than placebo, and we did not detect a difference between antibiotic classes. Serious adverse events Nine studies were included (3180 participants) in the NMA. Macrolides reduced the odds of a serious adverse event compared with placebo (fixed effect-fixed class effect: odds ratio (OR) 0.76, 95% CrI 0.62 to 0.93). There was probably little to no difference in the effect of quinolone compared with placebo or tetracycline plus macrolide compared with placebo. There was probably little to no difference in serious adverse events between quinolones or tetracycline plus macrolide. With macrolide treatment 49 fewer people per 1000 experienced a serious adverse event compared with those given placebo. Macrolides ranked first, followed by quinolones. Tetracycline did not rank better than placebo. Drug resistance Ten studies reported drug resistance. Results were not combined due to variation in outcome measures. All studies concluded that prophylactic antibiotic administration was associated with the development of antimicrobial resistance. AUTHORS' CONCLUSIONS: This NMA evaluated the safety and efficacy of different antibiotics used prophylactically for COPD patients. Compared to placebo, prolonged administration of macrolides (ranked first) appeared beneficial in prolonging the time to next exacerbation, improving quality of life, and reducing serious adverse events. No clear benefits were associated with use of quinolones or tetracyclines. In addition, antibiotic resistance was a concern and could not be thoroughly assessed in this review. Given the trade-off between effectiveness, safety, and risk of antibiotic resistance, prophylactic administration of antibiotics may be best reserved for selected patients, such as those experiencing frequent exacerbations. However, none of the eligible studies excluded patients with previously isolated non-tuberculous mycobacteria, which would contraindicate prophylactic administration of antibiotics, due to the risk of developing resistant non-tuberculous mycobacteria.

Probiotic Greek yogurt: effect of the addition of prebiotic fat substitutes on the physicochemical characteristics, probiotic survival, and sensory acceptance.

In this research communication we evaluate the impact of the addition of prebiotic components (inulin, polydextrose, and modified starch, 40 g/l) as fat substitutes on the physicochemical characteristics, probiotic survival, and sensory acceptance of probiotic (Lacticaseibacillus casei 01, 108 CFU/ml) Greek yogurts during storage (7 °C, 28 d). All formulations had probiotic counts higher than 107 CFU/ml during storage and simulated gastrointestinal conditions (SGIC). The prebiotic components increased the probiotic survival to the enteric phase of the SGIC, with inulin producing the most pronounced effect. Inulin addition resulted in products with lower pH values and consistency and higher titratable acidity during storage, with negative impact on the sensory acceptance (flavor, texture, and overall impression) at the end of the storage period. Modified starch addition impacted negatively on the acceptance of the products (appearance, flavor, texture, and overall impression). Polydextrose addition resulted in products with lower consistency, but similar sensory acceptance to the full-fat yogurt. It can be concluded that it is possible to prepare potentially synbiotic Greek yogurts by desorption technique using L. casei as probiotic culture and inulin, polydextrose or modified starch as prebiotic components, with the utilization of polydextrose being advisable.

Psychological treatments for post-traumatic stress disorder in adults: a network meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a potentially chronic and disabling disorder affecting a significant minority of people exposed to trauma. Various psychological treatments have been shown to be effective, but their relative effects are not well established. METHODS: We undertook a systematic review and network meta-analyses of psychological interventions for adults with PTSD. Outcomes included PTSD symptom change scores post-treatment and at 1-4-month follow-up, and remission post-treatment. RESULTS: We included 90 trials, 6560 individuals and 22 interventions. Evidence was of moderate-to-low quality. Eye movement desensitisation and reprocessing (EMDR) [standardised mean difference (SMD) -2.07; 95% credible interval (CrI) -2.70 to -1.44], combined somatic/cognitive therapies (SMD -1.69; 95% CrI -2.66 to -0.73), trauma-focused cognitive behavioural therapy (TF-CBT) (SMD -1.46; 95% CrI -1.87 to -1.05) and self-help with support (SMD -1.46; 95% CrI -2.33 to -0.59) appeared to be most effective at reducing PTSD symptoms post-treatment v. waitlist, followed by non-TF-CBT, TF-CBT combined with a selective serotonin reuptake inhibitor (SSRI), SSRIs, self-help without support and counselling. EMDR and TF-CBT showed sustained effects at 1-4-month follow-up. EMDR, TF-CBT, self-help with support and counselling improved remission rates post-treatment. Results for other interventions were either inconclusive or based on limited evidence. CONCLUSIONS: EMDR and TF-CBT appear to be most effective at reducing symptoms and improving remission rates in adults with PTSD. They are also effective at sustaining symptom improvements beyond treatment endpoint. Further research needs to explore the long-term comparative effectiveness of psychological therapies for adults with PTSD and also the impact of severity and complexity of PTSD on treatment outcomes.

Research Review: Psychological and psychosocial treatments for children and young people with post-traumatic stress disorder: a network meta-analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) is a potentially chronic and disabling disorder that affects a significant minority of youth exposed to trauma. Previous studies have concluded that trauma-focused cognitive behavioural therapy (TF-CBT) is an effective treatment for PTSD in youth, but the relative strengths of different psychological therapies are poorly understood. METHODS: We undertook a systematic review and network meta-analyses of psychological and psychosocial interventions for children and young people with PTSD. Outcomes included PTSD symptom change scores post-treatment and at 1-4-month follow-up, and remission post-treatment. RESULTS: We included 32 trials of 17 interventions and 2,260 participants. Overall, the evidence was of moderate-to-low quality. No inconsistency was detected between direct and indirect evidence. Individual forms of TF-CBT showed consistently large effects in reducing PTSD symptoms post-treatment compared with waitlist. The order of interventions by descending magnitude of effect versus waitlist was as follows: cognitive therapy for PTSD (SMD -2.94, 95%CrI -3.94 to -1.95), combined somatic/cognitive therapies, child-parent psychotherapy, combined TF-CBT/parent training, meditation, narrative exposure, exposure/prolonged exposure, play therapy, Cohen TF-CBT/cognitive processing therapy (CPT), eye movement desensitisation and reprocessing (EMDR), parent training, group TF-CBT, supportive counselling and family therapy (SMD -0.37, 95%CrI -1.60 to 0.84). Results for parent training, supportive counselling and family therapy were inconclusive. Cohen TF-CBT/CPT, group TF-CBT and supportive counselling had the largest evidence base. Results regarding changes in PTSD symptoms at follow-up and remission post-treatment were uncertain due to limited evidence. CONCLUSIONS: Trauma-focused cognitive behavioural therapy, in particular individual forms, appears to be most effective in the management of PTSD in youth. EMDR is effective but to a lesser extent. Supportive counselling does not appear to be effective. Results suggest a large positive effect for emotional freedom technique, child-parent psychotherapy, combined TF-CBT/parent training, and meditation, but further research is needed to confirm these findings as they were based on very limited evidence.

Cost-effectiveness of psychological interventions for children and young people with post-traumatic stress disorder.

BACKGROUND: PTSD in youth may lead to long-lasting psychological implications, educational difficulties and increased healthcare costs. Psychological interventions have been shown to be effective in its management. The objective of this study was to assess the cost-effectiveness of a range of psychological interventions for children and young people with PTSD. METHODS: A decision-analytic model was constructed to compare costs and quality-adjusted life years (QALYs) of 10 psychological interventions and no treatment for children and young people with PTSD, from the perspective of the National Health Service and personal social services in England. Effectiveness data were derived from a systematic review and network meta-analysis. Other model input parameters were based on published sources, supplemented by expert opinion. RESULTS: Cognitive therapy for PTSD, a form of individual trauma-focused cognitive behavioural therapy (TF-CBT), appeared to be the most cost-effective intervention for children and young people with PTSD (with a probability of .78 amongst the 11 evaluated options at a cost-effectiveness threshold of £20,000/QALY), followed by narrative exposure (another form of individual TF-CBT), play therapy, and other forms of individual TF-CBT. After excluding cognitive therapy from the analysis, narrative exposure appeared to be the most cost-effective option with a .40 probability of being cost-effective amongst the remaining 10 options. EMDR, parent training and group TF-CBT occupied middle cost-effectiveness rankings. Family therapy and supportive counselling were less cost-effective than other active interventions. There was limited evidence for some interventions, in particular cognitive therapy for PTSD and parent training. CONCLUSIONS: Individual forms of TF-CBT and, to a lesser degree, play therapy appear to be cost-effective in the treatment of children and young people with PTSD. Family therapy and supportive counselling are unlikely to be cost-effective relative to other interventions. There is a need for well-conducted studies that examine the long-term clinical and cost-effectiveness of a range of psychological treatments for children and young people with PTSD.