[Development of criteria for the prospective assessment of the need for updating guideline recommendations: The AGIL criteria]. / Entwicklung von Kriterien für die prospektive Einschätzung des Aktualisierungsbedarfs von Leitlinienempfehlungen: AGIL-Kriterien.

BACKGROUND: Evidence-based guideline and vaccination recommendations should continuously be updated to appropriately support health care decisions. However, resources for updating guidelines are often limited. The aim of this project was to develop a list of criteria for the prospective assessment of the need for updating individual guideline or vaccination recommendations, which can be applied from the time a guideline or guideline update is finalised. METHODS: In this article we describe the development of the AGIL criteria (Assessment of Guidelines for Updating Recommendations). The AGIL criteria were developed by experienced scientists and experts in the field of guideline development in a multi-step process. The five steps included: 1) development of an initial list of criteria by the project team; 2) online survey of guideline experts on the initial version of the criteria list; 3) revision of the criteria list based on the results of the online survey; 4) workshop on the criteria list at the EbM Congress 2023; 5) creation of version 1.0 of the AGIL criteria based on the workshop results. RESULTS: The initial list included the following three criteria: 1) relevance of the question 2) availability of new relevant evidence, and 3) impact of potentially new evidence. The response rate of the online survey for fully completed questionnaires was 31.0% (N=195; 630 guideline experts were contacted by email). For 90.3% (n=176) of the respondents, the criteria list included all essential aspects for assessing the need for updating guideline recommendations. More than three quarters of respondents rated the importance of the three criteria as "very important" or "important" (criteria 1-3: 75.3%, 86.1%, 85.2%) and - with the exception of criterion 1 - comprehensibility as "very comprehensible" or "comprehensible" (criteria 1-3: 58.4%, 75.9%, 78.5%). The results of the online survey and the workshop generally confirmed the three criteria with their two sub-questions. The incorporation of all feedback resulted in the AGIL criteria (version 1.0), recapping: 1) relevance of the question regarding a) PICO components and b) other factors, e.g. epidemiological aspects; 2) availability of new evidence a) on health-related benefits and harms and b) on other decision factors, e.g. feasibility, acceptability; 3) impact of new evidence a) on the certainty of evidence on which the recommendation is based and b) on the present recommendation, e.g. DISCUSSION: The moderate response rate of the online survey may have limited its representativeness. Nevertheless, we consider the response rate to be satisfactory in this research context. The inclusion of many experts in the online survey and the EbM Congress workshop is a strength of the project and supports the quality of the results. CONCLUSIONS: The AGIL criteria provide a structured guidance for the prospective assessment of the need for updating individual guideline recommendations and other evidence-based recommendations. The implementation and evaluation of the AGIL criteria 1.0 in a field test is planned.

Safety and effectiveness of vaccines against COVID-19 in children aged 5-11 years: a systematic review and meta-analysis.

BACKGROUND: To date, more than 761 million confirmed SARS-CoV-2 infections have been recorded globally, and more than half of all children are estimated to be seropositive. Despite high SARS-CoV-2 infection incidences, the rate of severe COVID-19 in children is low. We aimed to assess the safety and efficacy or effectiveness of COVID-19 vaccines approved in the EU for children aged 5-11 years. METHODS: In this systematic review and meta-analysis, we included studies of any design identified through searching the COVID-19 L·OVE (living overview of evidence) platform up to Jan 23, 2023. We included studies with participants aged 5-11 years, with any COVID-19 vaccine approved by the European Medicines Agency-ie, mRNA vaccines BNT162b2 (Pfizer-BioNTech), BNT162b2 Bivalent (against original strain and omicron [BA.4 or BA.5]), mRNA-1273 (Moderna), or mRNA-1273.214 (against original strain and omicron BA.1). Efficacy and effectiveness outcomes were SARS-CoV-2 infection (PCR-confirmed or antigen-test confirmed), symptomatic COVID-19, hospital admission due to COVID-19, COVID-19-related mortality, multisystem inflammatory syndrome in children (MIS-C), and long-term effects of COVID-19 (long COVID or post-COVID-19 condition as defined by study investigators or per WHO definition). Safety outcomes of interest were serious adverse events, adverse events of special interest (eg, myocarditis), solicited local and systemic events, and unsolicited adverse events. We assessed risk of bias and rated the certainty of evidence (CoE) using the Grading of Recommendations Assessment, Development and Evaluation approach. This study was prospectively registered with PROSPERO, CRD42022306822. FINDINGS: Of 5272 screened records, we included 51 (1·0%) studies (n=17 [33%] in quantitative synthesis). Vaccine effectiveness after two doses against omicron infections was 41·6% (95% CI 28·1-52·6; eight non-randomised studies of interventions [NRSIs]; CoE low), 36·2% (21·5-48·2; six NRSIs; CoE low) against symptomatic COVID-19, 75·3% (68·0-81·0; six NRSIs; CoE moderate) against COVID-19-related hospitalisations, and 78% (48-90, one NRSI; CoE very low) against MIS-C. Vaccine effectiveness against COVID-19-related mortality was not estimable. Crude event rates for deaths in unvaccinated children were less than one case per 100 000 children, and no events were reported for vaccinated children (four NRSIs; CoE low). No study on vaccine effectiveness against long-term effects was identified. Vaccine effectiveness after three doses was 55% (50-60; one NRSI; CoE moderate) against omicron infections, and 61% (55-67; one NRSI; CoE moderate) against symptomatic COVID-19. No study reported vaccine efficacy or effectiveness against hospitalisation following a third dose. Safety data suggested no increased risk of serious adverse events (risk ratio [RR] 0·83 [95% CI 0·21-3·33]; two randomised controlled trials; CoE low), with approximately 0·23-1·2 events per 100 000 administered vaccines reported in real-life observations. Evidence on the risk of myocarditis was uncertain (RR 4·6 [0·1-156·1]; one NRSI; CoE low), with 0·13-1·04 observed events per 100 000 administered vaccines. The risk of solicited local reactions was 2·07 (1·80-2·39; two RCTs; CoE moderate) after one dose and 2·06 (1·70-2·49; two RCTs; CoE moderate) after two doses. The risk of solicited systemic reactions was 1·09 (1·04-1·16; two RCTs; CoE moderate) after one dose and 1·49 (1·34-1·65; two RCTs; CoE moderate) after two doses. The risk of unsolicited adverse events after two doses (RR 1·21 [1·07-1·38]; CoE moderate) was higher among mRNA-vaccinated compared with unvaccinated children. INTERPRETATION: In children aged 5-11 years, mRNA vaccines are moderately effective against infections with the omicron variant, but probably protect well against COVID-19 hospitalisations. Vaccines were reactogenic but probably safe. Findings of this systematic review can serve as a basis for public health policy and individual decision making on COVID-19 vaccination in children aged 5-11 years. FUNDING: German Federal Joint Committee.

Algorithm-based pain management for people with dementia in nursing homes.

BACKGROUND: People with dementia in nursing homes often experience pain, but often do not receive adequate pain therapy. The experience of pain has a significant impact on quality of life in people with dementia, and is associated with negative health outcomes. Untreated pain is also considered to be one of the causes of challenging behaviour, such as agitation or aggression, in this population. One approach to reducing pain in people with dementia in nursing homes is an algorithm-based pain management strategy, i.e. the use of a structured protocol that involves pain assessment and a series of predefined treatment steps consisting of various non-pharmacological and pharmacological pain management interventions. OBJECTIVES: To assess the effects of algorithm-based pain management interventions to reduce pain and challenging behaviour in people with dementia living in nursing homes. To describe the components of the interventions and the content of the algorithms. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's register, MEDLINE, Embase, PsycINFO, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Web of Science Core Collection (ISI Web of Science), LILACS (Latin American and Caribbean Health Science Information database), ClinicalTrials.gov and the World Health Organization's meta-register the International Clinical Trials Registry Portal on 30 June 2021. SELECTION CRITERIA: We included randomised controlled trials investigating the effects of algorithm-based pain management interventions for people with dementia living in nursing homes. All interventions had to include an initial pain assessment, a treatment algorithm (a treatment plan consisting of at least two different non-pharmacological or pharmacological treatment steps to reduce pain), and criteria to assess the success of each treatment step. The control groups could receive usual care or an active control intervention. Primary outcomes for this review were pain-related outcomes, e.g. the number of participants with pain (self- or proxy-rated), challenging behaviour (we used a broad definition that could also include agitation or behavioural and psychological symptoms assessed with any validated instrument), and serious adverse events. DATA COLLECTION AND ANALYSIS: Two authors independently selected the articles for inclusion, extracted data and assessed the risk of bias of all included studies. We reported results narratively as there were too few studies for a meta-analysis. We used GRADE methods to rate the certainty of the results. MAIN RESULTS: We included three cluster-randomised controlled trials with a total of 808 participants (mean age 82 to 89 years). In two studies, participants had severe cognitive impairment and in one study mild to moderate impairment. The algorithms used in the studies varied in the number of treatment steps. The comparator was pain education for nursing staff in two studies and usual care in one study. We judged the risk of detection bias to be high in one study. The risk of selection bias and performance bias was unclear in all studies. Self-rated pain (i.e. pain rated by participants themselves) was reported in two studies. In one study, all residents in the nursing homes were included, but fewer than half of the participants experienced pain at baseline, and the mean values of self-rated and proxy-rated pain at baseline and follow-up in both study groups were below the threshold of pain that may require treatment. We considered the evidence from this study to be very low-certainty and therefore are uncertain whether the algorithm-based pain management intervention had an effect on self-rated pain intensity compared with pain education (MD -0.27, 95% CI -0.49 to -0.05, 170 participants; Verbal Descriptor Scale, range 0 to 3). In the other study, all participants had mild to moderate pain at baseline. Here, we found low-certainty evidence that an algorithm-based pain management intervention may have little to no effect on self-rated pain intensity compared with pain education (MD 0.4, 95% CI -0.58 to 1.38, 246 participants; Iowa Pain Thermometer, range 0 to 12). Pain was rated by proxy in all three studies. Again, we considered the evidence from the study in which mean pain scores indicated no pain, or almost no pain, at baseline to be very low-certainty and were uncertain whether the algorithm-based pain management intervention had an effect on proxy-rated pain intensity compared with pain education. For participants with mild to moderate pain at baseline, we found low-certainty evidence that an algorithm-based pain management intervention may reduce proxy-rated pain intensity in comparison with usual care (MD -1.49, 95% CI -2.11 to -0.87, 1 study, 128 participants; Pain Assessment in Advanced Dementia Scale-Chinese version, range 0 to 10), but may not be more effective than pain education (MD -0.2, 95% CI -0.79 to 0.39, 1 study, 383 participants; Iowa Pain Thermometer, range 0 to 12). For challenging behaviour, we found very low-certainty evidence from one study in which mean pain scores indicated no pain, or almost no pain, at baseline. We were uncertain whether the algorithm-based pain management intervention had any more effect than education for nursing staff on challenging behaviour of participants (MD -0.21, 95% CI -1.88 to 1.46, 1 study, 170 participants; Cohen-Mansfield Agitation Inventory-Chinese version, range 7 to 203). None of the studies systematically assessed adverse effects or serious adverse effects and no study reported information about the occurrence of any adverse effect. None of the studies assessed any of the other outcomes of this review. AUTHORS' CONCLUSIONS: There is no clear evidence for a benefit of an algorithm-based pain management intervention in comparison with pain education for reducing pain intensity or challenging behaviour in people with dementia in nursing homes. We found that the intervention may reduce proxy-rated pain compared with usual care. However, the certainty of evidence is low because of the small number of studies, small sample sizes, methodological limitations, and the clinical heterogeneity of the study populations (e.g. pain level and cognitive status). The results should be interpreted with caution. Future studies should also focus on the implementation of algorithms and their impact in clinical practice.

Structured Care Protocols to Reduce Behavior That Challenges in People With Dementia: A Systematic Review.

OBJECTIVES: People with dementia often express behavior that challenges, such as agitation and aggression. Structured care protocols aim to identify common causes of behavior and facilitate the selection of appropriate treatments. The protocols comprise different steps including specific assessments and related nonpharmacologic and pharmacologic treatments. We aim to assess the effects of such protocols to reduce behavior that challenges. DESIGN: Systematic review according to the methods of Cochrane and registered in PROSPERO (CRD42020155706). SETTING AND PARTICIPANTS: People with dementia living in nursing homes. METHODS: The systematic search (September 2020) included databases (MEDLINE, CINAHL, Cochrane Library) and other sources. Two reviewers independently performed the study selection, data extraction, and quality assessment for all included studies. A narrative synthesis was conducted owing to the small number of studies and the heterogeneity of instruments. RESULTS: Four studies with 596 participants were included. Three studies compared a version of the Serial Trial Intervention, with control groups receiving education about behavior that challenges. One study compared 2 versions of the intervention. The methodologic quality was moderate. For behavior that challenges, there was little to no effect of structured care protocols (4 studies). Two studies found little to no effect on pain and quality of life. Structured care protocols may reduce discomfort (2 studies). None of the studies reported adverse effects. The certainty of evidence was low to moderate. Implementation fidelity of the structured care protocols was limited, although this was not assessed in all of the studies. CONCLUSION AND IMPLICATIONS: Structured care protocols seem not to be more beneficial than education for reducing behavior that challenges or pain, but may reduce discomfort in people with dementia in nursing homes. Based on the small number of studies, the results should be interpreted with caution. Further research should focus on the feasibility and implementation of structured care protocols.

Psychological and social consequences of non-invasive prenatal testing (NIPT): a scoping review.

BACKGROUND: Genomics-based noninvasive prenatal tests (NIPT) allow screening for chromosomal anomalies such as Down syndrome (trisomy 21). The technique uses cell-free fetal DNA (cffDNA) that circulates in the maternal blood and is detectable from 5 weeks of gestation onwards. Parents who choose to undergo this relatively new test (introduced in 2011) might be aware of its positive features (i.e. clinical safety and ease of use); however, they might be less aware of the required decisions and accompanying internal conflicts following a potential positive test result. To show the evidence on psychological and social consequences of the use of NIPT, we conducted a scoping review. METHODS: We systematically searched four electronic databases (MEDLINE (Ovid), Cochrane Library (Wiley), CINAHL (EBSCO) and PsychINFO (EBSCO)) for studies that investigated the psychological or social consequences of the use of NIPT by pregnant women or expecting parents. The search was limited to studies published between 2011 and August 8, 2018. We identified 2488 studies and, after removal of duplicates, screened 2007 titles and abstracts, and then assessed 99 articles in full text (both screenings were done independently in duplicate). We included 7 studies in our analysis. RESULTS: Five studies assessed anxiety, psychological distress and/or decisional regret among women with validated psychological tests like the Spielberger State Trait-Anxiety Inventory (STAI), the Pregnancy-Related Anxiety Questionnaire-Revised (PRAQ-R), the Kessler Psychological Distress Scale (K6) or the Decisional Regret Scale (DRS). Two studies assessed women's experiences with and feelings after NIPT in interviews or focus groups. The included studies were heterogeneous in location, study setting, inclusion criteria, outcome assessment, and other characteristics. CONCLUSIONS: Only few studies on psychological consequences of NIPT have been identified. The studies assessed only short-term psychological consequences of NIPT at baseline and/or after receiving the results or after giving birth. Studies show that short term anxiety decreased when women received negative NIPT results and that decisional regret was generally low. We could not identify studies on long term consequences of NIPT, as well as studies on women's partners' short and long term outcomes, nor on social consequences of NIPT.

Methodological review showed correct absolute effect size estimates for time-to-event outcomes in less than one-third of cancer-related systematic reviews.

OBJECTIVES: To evaluate in how many cancer-related Cochrane reviews hazard ratio (HR)-based absolute effects in summary of findings (SoF) tables have been correctly calculated and reported. STUDY DESIGN AND SETTING: We identified all Cochrane cancer intervention reviews that reported an HR for at least one outcome and provided a SoF table, published between January 2011 and December 2017 in the Cochrane Database of Systematic Reviews. RESULTS: In 28 reviews (29%) of 96 included Cochrane reviews, absolute effects in the SoF tables were calculated in a correct manner. In 23 reviews (24%), absolute effects had been correctly calculated, but there was no explanation given why authors calculated event-free survival (e.g., overall survival) throughout the review but reported number of events in SoF tables (e.g., death). Twelve reviews (13%) provided incorrect absolute effects. For seven reviews (7%), it was unclear if absolute effects were correctly calculated. In 26 (27%) reviews, no absolute effects based on the given HR were calculated. CONCLUSIONS: In less than one-third of cancer-related Cochrane reviews, absolute effect size estimates were correctly calculated and reported. There is a need for guidance on how to calculate and report absolute effect estimates based on HR data.

[A reporting tool for practice guidelines in health care: the RIGHT statement]. / Ein Instrument zur Erstellung von Leitlinienberichten: das RIGHT-Statement.

The quality of reporting practice guidelines is often poor, and there is no widely accepted guidance or standards for such reporting in health care. The international RIGHT (Reporting Items for practice Guidelines in HealThcare) Working Group was established to address this gap. The group followed an existing framework for developing guidelines for health research reporting and the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network approach. A checklist and an explanation and elaboration statement were developed. The RIGHT checklist includes 22 items that are considered essential for good reporting of practice guidelines: basic information (items 1 to 4), background (items 5 to 9), evidence (items 10 to 12), recommendations (items 13 to 15), review and quality assurance (items 16 and 17), funding and declaration and management of interests (items 18 and 19), and other information (items 20 to 22). The RIGHT checklist can assist developers in reporting guidelines, support journal editors and peer reviewers when considering guideline reports, and help health care practitioners understand and implement a guideline.

Regulation of autotrophic CO2 fixation in the archaeon Thermoproteus neutrophilus.

Thermoproteus neutrophilus, a hyperthermophilic, chemolithoautotrophic, anaerobic crenarchaeon, uses a novel autotrophic CO(2) fixation pathway, the dicarboxylate/hydroxybutyrate cycle. The regulation of the central carbon metabolism was studied on the level of whole cells, enzyme activity, the proteome, transcription, and gene organization. The organism proved to be a facultative autotroph, which prefers organic acids as carbon sources that can easily feed into the metabolite pools of this cycle. Addition of the preferred carbon sources acetate, pyruvate, succinate, and 4-hydroxybutyrate to cultures resulted in stimulation of the growth rate and a diauxic growth response. The characteristic enzyme activities of the carbon fixation cycle, fumarate hydratase, fumarate reductase, succinyl coenzyme A (CoA) synthetase, and enzymes catalyzing the conversion of succinyl-CoA to crotonyl-CoA, were differentially downregulated in the presence of acetate and, to a lesser extent, in the presence of other organic substrates. This regulation pattern correlated well with the differential expression profile of the proteome as well as with the transcription of the encoding genes. The genes encoding phosphoenolpyruvate (PEP) carboxylase, fumarate reductase, and four enzymes catalyzing the conversion of succinyl-CoA to crotonyl-CoA are clustered. Two putative operons, one comprising succinyl-CoA reductase plus 4-hydroxybutyrate-CoA ligase genes and the other comprising 4-hydroxybutyryl-CoA dehydratase plus fumarate reductase genes, were divergently transcribed into leaderless mRNAs. The promoter regions were characterized and used for isolating DNA binding proteins. Besides an Alba protein, a 18-kDa protein characteristic for autotrophic Thermoproteales that bound specifically to the promoter region was identified. This system may be suitable for molecular analysis of the transcriptional regulation of autotrophy-related genes.