Does Reinforcement Learning Improve Outcomes for Critically Ill Patients? A Systematic Review and Level-of-Readiness Assessment.

OBJECTIVE: Reinforcement learning (RL) is a machine learning technique uniquely effective at sequential decision-making, which makes it potentially relevant to ICU treatment challenges. We set out to systematically review, assess level-of-readiness and meta-analyze the effect of RL on outcomes for critically ill patients. DATA SOURCES: A systematic search was performed in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection, Elsevier/SCOPUS and the Institute of Electrical and Electronics Engineers Xplore Digital Library from inception to March 25, 2022, with subsequent citation tracking. DATA EXTRACTION: Journal articles that used an RL technique in an ICU population and reported on patient health-related outcomes were included for full analysis. Conference papers were included for level-of-readiness assessment only. Descriptive statistics, characteristics of the models, outcome compared with clinician's policy and level-of-readiness were collected. RL-health risk of bias and applicability assessment was performed. DATA SYNTHESIS: A total of 1,033 articles were screened, of which 18 journal articles and 18 conference papers, were included. Thirty of those were prototyping or modeling articles and six were validation articles. All articles reported RL algorithms to outperform clinical decision-making by ICU professionals, but only in retrospective data. The modeling techniques for the state-space, action-space, reward function, RL model training, and evaluation varied widely. The risk of bias was high in all articles, mainly due to the evaluation procedure. CONCLUSION: In this first systematic review on the application of RL in intensive care medicine we found no studies that demonstrated improved patient outcomes from RL-based technologies. All studies reported that RL-agent policies outperformed clinician policies, but such assessments were all based on retrospective off-policy evaluation.

Dental Abnormalities in Osteogenesis Imperfecta: A Systematic Review.

Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by fragile bones and skeletal deformities. Individuals with OI may have dental abnormalities such as dentinogenesis imperfecta (DI) type I, malocclusions, and unerupted or missing teeth. This review comprehensively examines these dental abnormalities to assess their prevalence among the OI population and explore potential differences across different clinical types of OI and pathogenic variants. In accordance with the PRISMA guidelines, a systematic literature search in PubMed, Embase, and Web of Science was conducted that included articles up to June 2024. Out of 672 articles screened, 34 were included. The included studies confirmed that dental abnormalities are prevalent in OI, with DI prevalence ranging from approximately 20 to 48%. Those with a more severe skeletal phenotype (OI type III/IV) exhibited more dental abnormalities than those with a milder skeletal phenotype (OI type I). Notably, OI type V individuals generally do not have DI, although a few isolated cases have been reported. The prevalence of occlusion types varied: Class I occlusion ranged from 14.8 to 50% and Class II malocclusion ranged from 0 to 37.5%, while Class III malocclusion from 4.1 to 84%. This differs from the general population, where Class III malocclusion is typically the least common. Open bites, cross-bites, and unerupted and missing teeth are also commonly reported, particularly in OI types III and IV. This review emphasizes the need for comprehensive dental examinations in OI due to the high prevalence of dental abnormalities. Additionally, the review draws attention to the lack of clear guidelines for diagnosing DI.

The ethical dimension of personal health monitoring in the armed forces: a scoping review.

BACKGROUND: Personal Health Monitoring (PHM) has the potential to enhance soldier health outcomes. To promote morally responsible development, implementation, and use of PHM in the armed forces, it is important to be aware of the inherent ethical dimension of PHM. In order to improve the understanding of the ethical dimension, a scoping review of the existing academic literature on the ethical dimension of PHM was conducted. METHODS: Four bibliographical databases (Ovid/Medline, Embase.com, Clarivate Analytics/Web of Science Core Collection, and Elsevier/SCOPUS) were searched for relevant literature from their inception to June 1, 2023. Studies were included if they sufficiently addressed the ethical dimension of PHM and were related to or claimed relevance for the military. After selection and extraction, the data was analysed using a qualitative thematic approach. RESULTS: A total of 9,071 references were screened. After eligibility screening, 19 articles were included for this review. The review identifies and describes three categories reflecting the ethical dimension of PHM in the military: (1) utilitarian considerations, (2) value-based considerations, and (3) regulatory responsibilities. The four main values that have been identified as being of concern are those of privacy, security, trust, and autonomy. CONCLUSIONS: This review demonstrates that PHM in the armed forces is primarily approached from a utilitarian perspective, with a focus on its benefits, without explicit critical deliberation on PHM's potential moral downsides. Also, the review highlights a significant research gap with a specific lack of empirical studies focussing specifically on the ethical dimension of PHM. Awareness of the inherent ethical dimension of PHM in the military, including value conflicts and how to balance them, can help to contribute to a morally responsible development, implementation, and use of PHM in the armed forces.

The Use of Deep Learning and Machine Learning on Longitudinal Electronic Health Records for the Early Detection and Prevention of Diseases: Scoping Review.

BACKGROUND: Electronic health records (EHRs) contain patients' health information over time, including possible early indicators of disease. However, the increasing amount of data hinders clinicians from using them. There is accumulating evidence suggesting that machine learning (ML) and deep learning (DL) can assist clinicians in analyzing these large-scale EHRs, as algorithms thrive on high volumes of data. Although ML has become well developed, studies mainly focus on engineering but lack medical outcomes. OBJECTIVE: This study aims for a scoping review of the evidence on how the use of ML on longitudinal EHRs can support the early detection and prevention of disease. The medical insights and clinical benefits that have been generated were investigated by reviewing applications in a variety of diseases. METHODS: This study was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A literature search was performed in 2022 in collaboration with a medical information specialist in the following databases: PubMed, Embase, Web of Science Core Collection (Clarivate Analytics), and IEEE Xplore Digital Library and computer science bibliography. Studies were eligible when longitudinal EHRs were used that aimed for the early detection of disease via ML in a prevention context. Studies with a technical focus or using imaging or hospital admission data were beyond the scope of this review. Study screening and selection and data extraction were performed independently by 2 researchers. RESULTS: In total, 20 studies were included, mainly published between 2018 and 2022. They showed that a variety of diseases could be detected or predicted, particularly diabetes; kidney diseases; diseases of the circulatory system; and mental, behavioral, and neurodevelopmental disorders. Demographics, symptoms, procedures, laboratory test results, diagnoses, medications, and BMI were frequently used EHR data in basic recurrent neural network or long short-term memory techniques. By developing and comparing ML and DL models, medical insights such as a high diagnostic performance, an earlier detection, the most important predictors, and additional health indicators were obtained. A clinical benefit that has been evaluated positively was preliminary screening. If these models are applied in practice, patients might also benefit from personalized health care and prevention, with practical benefits such as workload reduction and policy insights. CONCLUSIONS: Longitudinal EHRs proved to be helpful for support in health care. Current ML models on EHRs can support the detection of diseases in terms of accuracy and offer preliminary screening benefits. Regarding the prevention of diseases, ML and specifically DL models can accurately predict or detect diseases earlier than current clinical diagnoses. Adding personally responsible factors allows targeted prevention interventions. While ML models based on textual EHRs are still in the developmental stage, they have high potential to support clinicians and the health care system and improve patient outcomes.

Systematic Review and Comparison of Publicly Available ICU Data Sets-A Decision Guide for Clinicians and Data Scientists.

OBJECTIVE: As data science and artificial intelligence continue to rapidly gain traction, the publication of freely available ICU datasets has become invaluable to propel data-driven clinical research. In this guide for clinicians and researchers, we aim to: 1) systematically search and identify all publicly available adult clinical ICU datasets, 2) compare their characteristics, data quality, and richness and critically appraise their strengths and weaknesses, and 3) provide researchers with suggestions, which datasets are appropriate for answering their clinical question. DATA SOURCES: A systematic search was performed in Pubmed, ArXiv, MedRxiv, and BioRxiv. STUDY SELECTION: We selected all studies that reported on publicly available adult patient-level intensive care datasets. DATA EXTRACTION: A total of four publicly available, adult, critical care, patient-level databases were included (Amsterdam University Medical Center data base [AmsterdamUMCdb], eICU Collaborative Research Database eICU CRD], High time-resolution intensive care unit dataset [HiRID], and Medical Information Mart for Intensive Care-IV). Databases were compared using a priori defined categories, including demographics, patient characteristics, and data richness. The study protocol and search strategy were prospectively registered. DATA SYNTHESIS: Four ICU databases fulfilled all criteria for inclusion and were queried using SQL (PostgreSQL version 12; PostgreSQL Global Development Group) and analyzed using R (R Foundation for Statistical Computing, Vienna, Austria). The number of unique patient admissions varied between 23,106 (AmsterdamUMCdb) and 200,859 (eICU-CRD). Frequency of laboratory values and vital signs was highest in HiRID, for example, 5.2 (±3.4) lactate values per day and 29.7 (±10.2) systolic blood pressure values per hour. Treatment intensity varied with vasopressor and ventilatory support in 69.0% and 83.0% of patients in AmsterdamUMCdb versus 12.0% and 21.0% in eICU-CRD, respectively. ICU mortality ranged from 5.5% in eICU-CRD to 9.9% in AmsterdamUMCdb. CONCLUSIONS: We identified four publicly available adult clinical ICU datasets. Sample size, severity of illness, treatment intensity, and frequency of reported parameters differ markedly between the databases. This should guide clinicians and researchers which databases to best answer their clinical questions.

Outcomes of Combined Peritoneal and Local Treatment for Patients with Peritoneal and Limited Liver Metastases of Colorectal Origin: A Systematic Review and Meta-Analysis.

BACKGROUND: Almost half of all colorectal cancer (CRC) patients will experience metastases at some point, and in the majority of cases, multiple organs will be involved. If the peritoneum is involved in addition to the liver, the current guideline-driven treatment options are limited. The reported overall survival ranges from 6 to 13 months for the current standard of care (systemic treatment). This study aimed to evaluate morbidity and clinical long-term outcomes from a combined local treatment of hepatic metastases with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) used to treat peritoneal metastases. METHODS: A systematic search was performed in PubMed, Embase.com, Web of Science, and Cochrane. Studies evaluating the clinicopathologic data of patients who had both peritoneal and hepatic metastases treated with CRS-HIPEC were included provided sufficient data on the primary outcomes (overall and disease-free survival) were presented. The quality of included studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS). RESULTS: Patients treated for peritoneal and liver metastases (PMLM group) had a pooled mean survival of 26.4 months (95% confidence interval [CI] 22.4-30.4 months), with a 3-year survival rate of 34% (95% CI 26.7-42.0%) and a 5-year survival rate of 25% (95% CI 17.3-33.8%). Surgical complications occurred more frequently for these patients than for those with peritoneal metastasis only (40% vs 22%; p = 0.0014), but the mortality and reoperation rates did not differ significantly. CONCLUSION: This systematic review showed that CRS and HIPEC combined with local treatment of limited liver metastasis for selected patients is feasible, although with increased morbidity and an association with a long-term survival rate of 25%, which is unlikely to be achievable with systemic treatment only.

Relation between the food environment and oral health-systematic review.

BACKGROUND: There is increasing evidence that the food environment, i.e. the availability, accessibility, price and promotion of foods and beverages, has a significant influence on oral health through food consumption. With this systematic literature review, we systematically summarize the available evidence on relations between the food environment and oral health outcomes in children and adults. METHODS: English-language studies were identified through a systematic literature search, executed by a medical information specialist, on OVID/Medline, Embase, Web of Science and CINAHL. Title and abstract screening, full-text screening and quality assessment [using the Quality Assessment with Diverse Studies (QuADS) tool] were done independently by two authors. RESULTS: Twenty-three studies were included, of which 1 studied the consumer food environment (food labeling), 3 the community food environment (e.g. number of food stores in the community), 5 the organizational food environment (availability of healthy foods and beverages in schools), 2 the information environment (television advertisements) and 13 government and industry policies related to the food environment (e.g. implementation of a sugar-sweetened beverage tax). Almost all studies found that unhealthy food and beverage environments had adverse effects on oral health, and that policies improving the healthiness of food and beverage environments improved-or would improve in case of a modeling study-oral health. CONCLUSIONS: This systematic literature review provides evidence, although of low to moderate quality and available in a low quantity only, that several aspects of the food environment, especially policies affecting the food environment, are associated with oral health outcomes.

The efficacy of whole human genome capture on ancient dental calculus and dentin.

OBJECTIVES: Dental calculus is among the richest known sources of ancient DNA in the archaeological record. Although most DNA within calculus is microbial, it has been shown to contain sufficient human DNA for the targeted retrieval of whole mitochondrial genomes. Here, we explore whether calculus is also a viable substrate for whole human genome recovery using targeted enrichment techniques. MATERIALS AND METHODS: Total DNA extracted from 24 paired archaeological human dentin and calculus samples was subjected to whole human genome enrichment using in-solution hybridization capture and high-throughput sequencing. RESULTS: Total DNA from calculus exceeded that of dentin in all cases, and although the proportion of human DNA was generally lower in calculus, the absolute human DNA content of calculus and dentin was not significantly different. Whole genome enrichment resulted in up to four-fold enrichment of the human endogenous DNA content for both dentin and dental calculus libraries, albeit with some loss in complexity. Recovering more on-target reads for the same sequencing effort generally improved the quality of downstream analyses, such as sex and ancestry estimation. For nonhuman DNA, comparison of phylum-level microbial community structure revealed few differences between precapture and postcapture libraries, indicating that off-target sequences in human genome-enriched calculus libraries may still be useful for oral microbiome reconstruction. DISCUSSION: While ancient human dental calculus does contain endogenous human DNA sequences, their relative proportion is low when compared with other skeletal tissues. Whole genome enrichment can help increase the proportion of recovered human reads, but in this instance enrichment efficiency was relatively low when compared with other forms of capture. We conclude that further optimization is necessary before the method can be routinely applied to archaeological samples.

The Prevalence, Dental Complications, and Effects of Infant Oral Mutilation.

OBJECTIVE: The aim of this scoping review on infant oral mutilation (IOM) was to study the prevalence, dental complications, and immediate and long-term effects of this practice, in addition to providing a systematic overview on existing knowledge and analysis of identified knowledge gaps on IOM. METHODS: Five electronic bibliographic databases (OVID/Medline, Embase.com, Clarivate Analytics/Web of Science Core Collection, SCOPUS, and Global Index Medicus) were searched for relevant studies. Data were entered in a bespoke data-charting form. The risk of bias was assessed by 2 independent reviewers. RESULTS: A total of 478 studies were identified from the search, out of which 42 studies were included in this review. Of the 42 studies, 19 were prevalence studies published between 1969 and 2019 which were additionally assessed for the risk of bias. We found the prevalence of IOM in Uganda was 2% to 30%; Ethiopia, 12% to 86%; Sudan, 10%; Kenya, 61% to 87%; and Tanzania 0% to 24%. Based on the prevalence studies, we observed that the most common factor motivating IOM was diarrhoea. The immediate effects of IOM were found to be infection, bleeding, anaemia, pneumonia, septicaemia, osteomyelitis, meningitis, tetanus, and blood-borne diseases, with some infants dying from these effects. Missing canines, enamel hypoplasia, malformations, abnormal eruption of permanent teeth, occlusal discrepancies, midline shift, chronic periapical infections, rotations, canine transposition, or odontomas were the long-term effects found in relation to IOM. CONCLUSIONS: IOM is a practice with serious immediate and long-term consequences that is mainly performed in East Africa (or by people originated from this region) in children aged 4 to 8 months. Most frequently affected are the deciduous canines and mostly the mandibular teeth. It is important to create professional and public awareness of the procedure in low- and high-income countries. Furthermore, there is a need for more research on the prevalence of IOM in Africa and other areas of the world to determine the long-term consequences of the practice.

The evidence base for the optimal antibiotic treatment duration of upper and lower respiratory tract infections: an umbrella review.

BACKGROUND: Many trials, reviews, and meta-analyses have been performed on the comparison of short versus long antibiotic treatment in respiratory tract infections, generally supporting shorter treatment. The aim of this umbrella review is to assess the soundness of the current evidence base for optimal antibiotic treatment duration. METHODS: A search in Ovid MEDLINE, Embase, and Clarivate Analytics Web of Science Core Collection was performed on May 1, 2024, without date and language restrictions. Systematic reviews addressing treatment durations in community-acquired pneumonia (CAP), acute exacerbation of chronic obstructive pulmonary disease (AECOPD), hospital-acquired pneumonia (HAP), acute sinusitis, and streptococcal pharyngitis, tonsillitis, or pharyngotonsillitis were included. Studies from inpatient and outpatient settings were included; reviews in paediatric populations were excluded. Outcomes of interest were clinical and bacteriological cure, microbiological eradication, mortality, relapse rate, and adverse events. The quality of the reviews was assessed using the AMSTAR 2 tool, risk of bias of all included randomised controlled trials (RCTs) using the Cochrane risk-of-bias tool (version 1), and overall quality of evidence according to GRADE. FINDINGS: We identified 30 systematic reviews meeting the criteria; they were generally of a low to critically low quality. 21 reviews conducted a meta-analysis. For CAP outside the intensive care unit (ICU; 14 reviews, of which eight did a meta-analysis) and AECOPD (eight reviews, of which five did a meta-analysis), there was sufficient evidence supporting a treatment duration of 5 days; evidence for shorter durations is scarce. Evidence on non-ventilator-associated HAP is absent, despite identifying three reviews (of which one did a meta-analysis), since no trials were conducted exclusively in this population. For sinusitis the evidence appears to support a shorter regimen, but more evidence is needed in the population who actually require antibiotic treatment. For pharyngotonsillitis (eight reviews, of which six did a meta-analysis), sufficient evidence exists to support short-course cephalosporin but not short-course penicillin when dosed three times a day. INTERPRETATION: The available evidence for non-ICU CAP and AECOPD supports a short-course treatment duration of 5 days in patients who have clinically improved. Efforts of the scientific community should be directed at implementing this evidence in daily practice. High-quality RCTs are needed to underpin even shorter treatment durations for CAP and AECOPD, to establish the optimal treatment duration of HAP and acute sinusitis, and to evaluate shorter duration using an optimal penicillin dosing schedule in patients with pharyngotonsillitis. FUNDING: None.

Implementation barriers and facilitators of remote monitoring, remote consultation and digital care platforms through the eyes of healthcare professionals: a review of reviews.

OBJECTIVES: Digital transformation in healthcare is a necessity considering the steady increase in healthcare costs, the growing ageing population and rising number of people living with chronic diseases. The implementation of digital health technologies in patient care is a potential solution to these issues, however, some challenges remain. In order to navigate such complexities, the perceptions of healthcare professionals (HCPs) must be considered. The objective of this umbrella review is to identify key barriers and facilitators involved in digital health technology implementation, from the perspective of HCPs. DESIGN: Systematic umbrella review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. DATA SOURCES: Embase.com, PubMed and Web of Science Core Collection were searched for existing reviews dated up to 17 June 2022. Search terms included digital health technology, combined with terms related to implementation, and variations in terms encompassing HCP, such as physician, doctor and the medical discipline. ELIGIBILITY CRITERIA: Quantitative and qualitative reviews evaluating digital technologies that included patient interaction were considered eligible. Three reviewers independently synthesised and assessed eligible reviews and conducted a critical appraisal. DATA EXTRACTION AND SYNTHESIS: Regarding the data collection, two reviewers independently synthesised and interpreted data on barriers and facilitators. RESULTS: Thirty-three reviews met the inclusion criteria. Barriers and facilitators were categorised into four levels: (1) the organisation, (2) the HCP, (3) the patient and (4) technical aspects. The main barriers and facilitators identified were (lack of) training (n=22/33), (un)familiarity with technology (n=17/33), (loss of) communication (n=13/33) and security and confidentiality issues (n=17/33). Barriers of key importance included increased workload (n=16/33), the technology undermining aspects of professional identity (n=11/33), HCP uncertainty about patients' aptitude with the technology (n=9/33), and technical issues (n=12/33). CONCLUSIONS: The implementation strategy should address the key barriers highlighted by HCPs, for instance, by providing adequate training to familiarise HCPs with the technology, adapting the technology to the patient preferences and addressing technical issues. Barriers on both HCP and patient levels can be overcome by investigating the needs of the end-users. As we shift from traditional face-to-face care models towards new modes of care delivery, further research is needed to better understand the role of digital technology in the HCP-patient relationship.

The influence of disparities on intensive care outcomes in children with respiratory diseases: A systematic review.

CONTEXT: The negative effects of socioeconomic, environmental and ethnic inequalities on childhood respiratory diseases are known in the development of persistent asthma and can result in adverse outcomes. However, little is known about the effects of these disparities on pediatric intensive care unit (PICU) outcomes in respiratory diseases. OBJECTIVE: The purpose of this systematic review is to evaluate the literature on disparities in socioeconomic, environmental and ethnic determinants and PICU outcomes. We hypothesize that these disparities negatively influence the outcomes of children's respiratory diseases at the PICU. METHODS: A literature search (in PubMed, Embase.com and Web of Science Core Collection) was performed up to September 30, 2022. Two authors extracted the data and independently evaluated the risk of bias with appropriate assessment methods. Articles were included if the patients were below 18 years of age (excluding neonatal intensive care unit admissions), they concerned respiratory diseases and incorporated socioeconomic, ethnic or environmental disparities. RESULTS: Eight thousand seven hundred fourty-six references were reviewed, and 15 articles were included; seven articles on the effect of socioeconomic status, five articles on ethnicity, one on the effect of sex and lastly two on environmental factors. All articles but one showed an unfavorable outcome at the PICU. CONCLUSION: Disparities in socioeconomic (such as a low-income household, public health insurance), ethnic and environmental factors (such as exposure to tobacco smoke and diet) have been assessed as risk factors for the severity of children's respiratory diseases and can negatively influence the outcomes of these children admitted and treated at the PICU.

Oral-Functioning Questionnaires in Patients with Head and Neck Cancer: A Scoping Review.

Background: Oral-functioning impairment can negatively affect the quality of life (QoL) of head and neck cancer (HNC) patients after receiving radiotherapy (RT). Assessment of patient-reported oral functioning throughout treatment can improve patient care. This scoping review aims to propose a definition for oral functioning for HNC patients and to map out the available questionnaires measuring patient-reported oral functioning in RT-treated HNC patients. Methods: A literature search in relevant databases was performed. Each questionnaire was scored on the domains validity, reliability, and responsiveness. Furthermore, the items from the questionnaires were analyzed to define the common denominators for oral functioning in HNC patients. Results: Of the 6434 articles assessed, 16 met the inclusion criteria and employed 16 distinct instruments to evaluate QoL. No questionnaire covered all oral-health-related QoL items nor assessed all aspects of validity, reliability, and responsiveness. Chewing, speaking, and swallowing were the common denominators for oral functioning. Conclusions: Based on the included studies, we suggest using the VHNSS 2.0 questionnaire to assess oral functioning in HNC patients. Furthermore, we suggest to more clearly define oral functioning in HNC patients by focusing on masticatory function (chewing and grinding), mouth opening, swallowing, speaking, and salivation.

A systematic review with meta-analysis of biomarkers for detection of pulmonary arterial hypertension.

Rationale: The blood is a rich source of potential biomarkers for the diagnosis of idiopathic and hereditary pulmonary arterial hypertension (iPAH and hPAH, referred to as "PAH"). While a lot of biomarkers have been identified for PAH, the clinical utility of these biomarkers often remains unclear. Here, we performed an unbiased meta-analysis of published biomarkers to identify biomarkers with the highest performance for detection of PAH. Methods: A literature search (in PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and Wiley/Cochrane Library) was performed up to 28 January 2021. Primary end points were blood biomarker levels in PAH versus asymptomatic controls or patients suspected of pulmonary hypertension (PH) with proven normal haemodynamic profiles. Results: 149 articles were identified by the literature search. Meta-analysis of 26 biomarkers yielded 17 biomarkers that were differentially expressed in PAH and non-PH control subjects. Red cell distribution width, low density lipid-cholesterol, d-dimer, N-terminal prohormone of brain natriuretic protein (NT-proBNP), interleukin-6 (IL-6) and uric acid were biomarkers with the largest observed differences, largest sample sizes and a low risk of publication bias. Receiver operating characteristic curves and sensitivity/specificity analyses demonstrated that NT-proBNP had a high sensitivity, but low specificity for PAH. For the other biomarkers, insufficient data on diagnostic accuracy with receiver operating characteristic curves were available for meta-analysis. Conclusion: This meta-analysis validates NT-proBNP as a biomarker with high sensitivity for PAH, albeit with low specificity. The majority of biomarkers evaluated in this meta-analysis lacked either external validation or data on diagnostic accuracy. Further validation studies are required as well as studies that test combinations of biomarkers to improve specificity.

Exploring the development, evaluation and implementation of complex health interventions to prevent early childhood caries in preschool children: A scoping review protocol.

OBJECTIVE: This scoping review aims to identify complex health interventions (CHI's) to prevent early childhood caries (ECC), explore the level of complexity of the identified CHI's, and explore the details of their development, evaluation, and implementation. INTRODUCTION: Many interventions to prevent ECC have multiple interacting components and can be seen as CHI's. Recent reviews on these interventions have found inconclusive effects, which may be due to differences in the development, evaluation, and implementation of CHI's. INCLUSION CRITERIA: This scoping review will consider clinical trials reporting CHI's to prevent ECC that starts during pregnancy or in the first year of life. Studies in the English language will be included regardless of the country of origin, sociocultural setting, or context. METHODS: This review will follow the Joanna Briggs Institute methodology for scoping reviews. An initial search of PubMed identified keywords and Medical Subject Headings terms. A second search of PubMed, Embase, Clarivate Analytics/Web of Science Core Collection, ClinicalTrials.gov, and the Wiley/Cochrane Library will follow. Two independent reviewers will perform title and abstract screening, retrieve and review full-text studies, and extract data. The reference lists of all included sources will be screened for additional CHI's or relevant publications about a specific CHI. Data charting will be utilised based on study characteristics and intervention complexity. A 39-item instrument will be used to explore the details in the description of the CHI's development, evaluation, and implementation. The results will be presented in tables, visual outputs, and a narrative summary in response to the review questions. DISCUSSION: The proposed review will generate evidence which may provide a direction for the future design of studies on CHI's to prevent ECC and more complete information for those who want to adopt successful interventions to prevent ECC.

Ancient dental calculus preserves signatures of biofilm succession and interindividual variation independent of dental pathology.

Dental calculus preserves oral microbes, enabling comparative studies of the oral microbiome and health through time. However, small sample sizes and limited dental health metadata have hindered health-focused investigations to date. Here, we investigate the relationship between tobacco pipe smoking and dental calculus microbiomes. Dental calculus from 75 individuals from the 19th century Middenbeemster skeletal collection (Netherlands) were analyzed by metagenomics. Demographic and dental health parameters were systematically recorded, including the presence/number of pipe notches. Comparative data sets from European populations before and after the introduction of tobacco were also analyzed. Calculus species profiles were compared with oral pathology to examine associations between microbiome community, smoking behavior, and oral health status. The Middenbeemster individuals exhibited relatively poor oral health, with a high prevalence of periodontal disease, caries, heavy calculus deposits, and antemortem tooth loss. No associations between pipe notches and dental pathologies, or microbial species composition, were found. Calculus samples before and after the introduction of tobacco showed highly similar species profiles. Observed interindividual microbiome differences were consistent with previously described variation in human populations from the Upper Paleolithic to the present. Dental calculus may not preserve microbial indicators of health and disease status as distinctly as dental plaque.

Differential preservation of endogenous human and microbial DNA in dental calculus and dentin.

Dental calculus (calcified dental plaque) is prevalent in archaeological skeletal collections and is a rich source of oral microbiome and host-derived ancient biomolecules. Recently, it has been proposed that dental calculus may provide a more robust environment for DNA preservation than other skeletal remains, but this has not been systematically tested. In this study, shotgun-sequenced data from paired dental calculus and dentin samples from 48 globally distributed individuals are compared using a metagenomic approach. Overall, we find DNA from dental calculus is consistently more abundant and less contaminated than DNA from dentin. The majority of DNA in dental calculus is microbial and originates from the oral microbiome; however, a small but consistent proportion of DNA (mean 0.08 ± 0.08%, range 0.007-0.47%) derives from the host genome. Host DNA content within dentin is variable (mean 13.70 ± 18.62%, range 0.003-70.14%), and for a subset of dentin samples (15.21%), oral bacteria contribute > 20% of total DNA. Human DNA in dental calculus is highly fragmented, and is consistently shorter than both microbial DNA in dental calculus and human DNA in paired dentin samples. Finally, we find that microbial DNA fragmentation patterns are associated with guanine-cytosine (GC) content, but not aspects of cellular structure.

Intrinsic challenges in ancient microbiome reconstruction using 16S rRNA gene amplification.

To date, characterization of ancient oral (dental calculus) and gut (coprolite) microbiota has been primarily accomplished through a metataxonomic approach involving targeted amplification of one or more variable regions in the 16S rRNA gene. Specifically, the V3 region (E. coli 341-534) of this gene has been suggested as an excellent candidate for ancient DNA amplification and microbial community reconstruction. However, in practice this metataxonomic approach often produces highly skewed taxonomic frequency data. In this study, we use non-targeted (shotgun metagenomics) sequencing methods to better understand skewed microbial profiles observed in four ancient dental calculus specimens previously analyzed by amplicon sequencing. Through comparisons of microbial taxonomic counts from paired amplicon (V3 U341F/534R) and shotgun sequencing datasets, we demonstrate that extensive length polymorphisms in the V3 region are a consistent and major cause of differential amplification leading to taxonomic bias in ancient microbiome reconstructions based on amplicon sequencing. We conclude that systematic amplification bias confounds attempts to accurately reconstruct microbiome taxonomic profiles from 16S rRNA V3 amplicon data generated using universal primers. Because in silico analysis indicates that alternative 16S rRNA hypervariable regions will present similar challenges, we advocate for the use of a shotgun metagenomics approach in ancient microbiome reconstructions.