Intestinal microbiome and metabolome signatures in patients with chronic granulomatous disease.

BACKGROUND: Chronic granulomatous disease (CGD) is caused by defects in any 1 of the 6 subunits forming the nicotinamide adenine dinucleotide phosphate oxidase complex 2 (NOX2), leading to severely reduced or absent phagocyte-derived reactive oxygen species production. Almost 50% of patients with CGD have inflammatory bowel disease (CGD-IBD). While conventional IBD therapies can treat CGD-IBD, their benefits must be weighed against the risk of infection. Understanding the impact of NOX2 defects on the intestinal microbiota may lead to the identification of novel CGD-IBD treatments. OBJECTIVE: We sought to identify microbiome and metabolome signatures that can distinguish individuals with CGD and CGD-IBD. METHODS: We conducted a cross-sectional observational study of 79 patients with CGD, 8 pathogenic variant carriers, and 19 healthy controls followed at the National Institutes of Health Clinical Center. We profiled the intestinal microbiome (amplicon sequencing) and stool metabolome, and validated our findings in a second cohort of 36 patients with CGD recruited through the Primary Immune Deficiency Treatment Consortium. RESULTS: We identified distinct intestinal microbiome and metabolome profiles in patients with CGD compared to healthy individuals. We observed enrichment for Erysipelatoclostridium spp, Sellimonas spp, and Lachnoclostridium spp in CGD stool samples. Despite differences in bacterial alpha and beta diversity between the 2 cohorts, several taxa correlated significantly between both cohorts. We further demonstrated that patients with CGD-IBD have a distinct microbiome and metabolome profile compared to patients without CGD-IBD. CONCLUSION: Intestinal microbiome and metabolome signatures distinguished patients with CGD and CGD-IBD, and identified potential biomarkers and therapeutic targets.

Surgical Treatments for Epilepsies in Children Aged 1-36 Months: A Systematic Review.

BACKGROUND AND OBJECTIVES: Early life epilepsies (epilepsies in children 1-36 months old) are common and may be refractory to antiseizure medications. We summarize findings of a systematic review commissioned by the American Epilepsy Society to assess evidence and identify evidence gaps for surgical treatments for epilepsy in children aged 1-36 months without infantile spasms. METHODS: EMBASE, MEDLINE, PubMed, and the Cochrane Library were searched for studies published from 1/1/1999 to 8/19/21. We included studies reporting data on children aged 1 month to ≤36 months undergoing surgical interventions or neurostimulation for epilepsy and enrolling ≥10 patients per procedure. We excluded studies of infants with infantile spasms or status epilepticus. For effectiveness outcomes (seizure freedom, seizure frequency), studies were required to report follow-up at ≥ 12 weeks. For harm outcomes, no minimum follow-up was required. Outcomes for all epilepsy types, regardless of etiology, were reported together. RESULTS: Eighteen studies (in 19 articles) met the inclusion criteria. Sixteen prestudies/poststudies reported on efficacy, and 12 studies addressed harms. Surgeries were performed from 1979 to 2020. Seizure freedom for infants undergoing hemispherectomy/hemispherotomy ranged from 7% to 76% at 1 year after surgery. For nonhemispheric surgeries, seizure freedom ranged from 40% to 70%. For efficacy, we concluded low strength of evidence (SOE) suggests some infants achieve seizure freedom after epilepsy surgery. Over half of infants undergoing hemispherectomy/hemispherotomy achieved a favorable outcome (Engel I or II, International League Against Epilepsy I to IV, or >50% seizure reduction) at follow-up of >1 year, although studies had key limitations. Surgical mortality was rare for functional hemispherectomy/hemispherotomy and nonhemispheric resections. Low SOE suggests postoperative hydrocephalus is uncommon for infants undergoing nonhemispheric procedures for epilepsy. DISCUSSION: Although existing evidence remains sparse and low quality, some infants achieve seizure freedom after surgery and ≥50% achieve favorable outcomes. Future prospective studies in this age group are needed. In addition to seizure outcomes, studies should evaluate other important outcomes (developmental outcomes, quality of life [QOL], sleep, functional performance, and caregiver QOL). TRIAL REGISTRATION INFORMATION: This systematic review was registered in PROSPERO (CRD42021220352) on March 5, 2021.

Pharmacologic and Dietary Treatments for Epilepsies in Children Aged 1-36 Months: A Systematic Review.

BACKGROUND AND OBJECTIVES: Early life epilepsies are common and often debilitating, but no evidence-based management guidelines exist outside of those for infantile spasms. We conducted a systematic review of the effectiveness and harms of pharmacologic and dietary treatments for epilepsy in children aged 1-36 months without infantile spasms. METHODS: We searched EMBASE, MEDLINE, PubMed, and the Cochrane Library for studies published from January 1, 1999, to August 19, 2021. Using prespecified criteria, we identified studies reporting data on children aged 1-36 months receiving pharmacologic or dietary treatments for epilepsy. We did not require that studies report etiology-specific data. We excluded studies of neonates, infantile spasms, and status epilepticus. We included studies administering 1 of 29 pharmacologic treatments and/or 1 of 5 dietary treatments reporting effectiveness outcomes at ≥ 12 weeks. We reviewed the full text to find any subgroup analyses of children aged 1-36 months. RESULTS: Twenty-three studies met inclusion criteria (6 randomized studies, 2 nonrandomized comparative studies, and 15 prestudies/poststudies). All conclusions were rated low strength of evidence. Levetiracetam leads to seizure freedom in some infants (32% and 66% in studies reporting seizure freedom), but data on 6 other medications were insufficient to permit conclusions about effectiveness (topiramate, lamotrigine, phenytoin, vigabatrin, rufinamide, and stiripentol). Three medications (levetiracetam, topiramate, and lamotrigine) were rarely discontinued because of adverse effects, and severe events were rare. For diets, the ketogenic diet leads to seizure freedom in some infants (rates 12%-37%), and both the ketogenic diet and modified Atkins diet reduce average seizure frequency, but reductions are greater with the ketogenic diet (1 RCT reported a 71% frequency reduction at 6 months for ketogenic diet vs only a 28% reduction for the modified Atkins diet). Dietary harms were not well-reported. DISCUSSION: Little high-quality evidence exists on pharmacologic and dietary treatments for early life epilepsies. Future research should isolate how treatments contribute to outcomes, conduct etiology-specific analyses, and report patient-centered outcomes such as hospitalization, neurodevelopment, functional performance, sleep quality, and patient and caregiver quality of life. TRIAL REGISTRATION INFORMATION: This systematic review was registered in PROSPERO (CRD42021220352) on March 5, 2021.

Inulin fibre promotes microbiota-derived bile acids and type 2 inflammation.

Dietary fibres can exert beneficial anti-inflammatory effects through microbially fermented short-chain fatty acid metabolites^1,2, although the immunoregulatory roles of most fibre diets and their microbiota-derived metabolites remain poorly defined. Here, using microbial sequencing and untargeted metabolomics, we show that a diet of inulin fibre alters the composition of the mouse microbiota and the levels of microbiota-derived metabolites, notably bile acids. This metabolomic shift is associated with type 2 inflammation in the intestine and lungs, characterized by IL-33 production, activation of group 2 innate lymphoid cells and eosinophilia. Delivery of cholic acid mimics inulin-induced type 2 inflammation, whereas deletion of the bile acid receptor farnesoid X receptor diminishes the effects of inulin. The effects of inulin are microbiota dependent and were reproduced in mice colonized with human-derived microbiota. Furthermore, genetic deletion of a bile-acid-metabolizing enzyme in one bacterial species abolishes the ability of inulin to trigger type 2 inflammation. Finally, we demonstrate that inulin enhances allergen- and helminth-induced type 2 inflammation. Taken together, these data reveal that dietary inulin fibre triggers microbiota-derived cholic acid and type 2 inflammation at barrier surfaces with implications for understanding the pathophysiology of allergic inflammation, tissue protection and host defence.

Neuropeptide regulation of non-redundant ILC2 responses at barrier surfaces.

Emerging studies indicate that cooperation between neurons and immune cells regulates antimicrobial immunity, inflammation and tissue homeostasis. For example, a neuronal rheostat provides excitatory or inhibitory signals that control the functions of tissue-resident group 2 innate lymphoid cells (ILC2s) at mucosal barrier surfaces1-4. ILC2s express NMUR1, a receptor for neuromedin U (NMU), which is a prominent cholinergic neuropeptide that promotes ILC2 responses5-7. However, many functions of ILC2s are shared with adaptive lymphocytes, including the production of type 2 cytokines8,9 and the release of tissue-protective amphiregulin (AREG)10-12. Consequently, there is controversy regarding whether innate lymphoid cells and adaptive lymphocytes perform redundant or non-redundant functions13-15. Here we generate a new genetic tool to target ILC2s for depletion or gene deletion in the presence of an intact adaptive immune system. Transgenic expression of iCre recombinase under the control of the mouse Nmur1 promoter enabled ILC2-specific deletion of AREG. This revealed that ILC2-derived AREG promotes non-redundant functions in the context of antiparasite immunity and tissue protection following intestinal damage and inflammation. Notably, NMU expression levels increased in inflamed intestinal tissues from both mice and humans, and NMU induced AREG production in mouse and human ILC2s. These results indicate that neuropeptide-mediated regulation of non-redundant functions of ILC2s is an evolutionarily conserved mechanism that integrates immunity and tissue protection.

Non-redundant functions of group 2 innate lymphoid cells.

Protective immunity relies on the interplay of innate and adaptive immune cells with complementary and redundant functions. Innate lymphoid cells (ILCs) have recently emerged as tissue-resident, innate mirror images of the T cell system, with which they share lineage-specifying transcription factors and effector machinery1. Located at barrier surfaces, ILCs are among the first responders against invading pathogens and thus could potentially determine the outcome of the immune response2. However, so far it has not been possible to dissect the unique contributions of ILCs to protective immunity owing to limitations in specific targeting of ILC subsets. Thus, all of the available data have been generated either in mice lacking the adaptive immune system or with tools that also affect other immune cell subsets. In addition, it has been proposed that ILCs might be dispensable for a proper immune response because other immune cells could compensate for their absence3-7. Here we report the generation of a mouse model based on the neuromedin U receptor 1 (Nmur1) promoter as a driver for simultaneous expression of Cre recombinase and green fluorescent protein, which enables gene targeting in group 2 ILCs (ILC2s) without affecting other innate and adaptive immune cells. Using Cre-mediated gene deletion of Id2 and Gata3 in Nmur1-expressing cells, we generated mice with a selective and specific deficiency in ILC2s. ILC2-deficient mice have decreased eosinophil counts at steady state and are unable to recruit eosinophils to the airways in models of allergic asthma. Further, ILC2-deficient mice do not mount an appropriate immune and epithelial type 2 response, resulting in a profound defect in worm expulsion and a non-protective type 3 immune response. In total, our data establish non-redundant functions for ILC2s in the presence of adaptive immune cells at steady state and during disease and argue for a multilayered organization of the immune system on the basis of a spatiotemporal division of labour.

Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection.

Nociceptive pain is a hallmark of many chronic inflammatory conditions including inflammatory bowel diseases (IBDs); however, whether pain-sensing neurons influence intestinal inflammation remains poorly defined. Employing chemogenetic silencing, adenoviral-mediated colon-specific silencing, and pharmacological ablation of TRPV1+ nociceptors, we observed more severe inflammation and defective tissue-protective reparative processes in a murine model of intestinal damage and inflammation. Disrupted nociception led to significant alterations in the intestinal microbiota and a transmissible dysbiosis, while mono-colonization of germ-free mice with Gram+Clostridium spp. promoted intestinal tissue protection through a nociceptor-dependent pathway. Mechanistically, disruption of nociception resulted in decreased levels of substance P, and therapeutic delivery of substance P promoted tissue-protective effects exerted by TRPV1+ nociceptors in a microbiota-dependent manner. Finally, dysregulated nociceptor gene expression was observed in intestinal biopsies from IBD patients. Collectively, these findings indicate an evolutionarily conserved functional link between nociception, the intestinal microbiota, and the restoration of intestinal homeostasis.

Interventions for malnutrition in hospitalized adults: A systematic review and meta-analysis.

BACKGROUND: Malnutrition is associated with poor outcomes in hospitalized adults. We aimed to assess the effectiveness of hospital-initiated interventions for patients with malnutrition. METHODS: Data sources included MEDLINE, Embase, Cochrane Library from January 1, 2000 to June 3, 2021. We included randomized controlled trials (RCTs) assessing interventions for hospitalized adults diagnosed or identified as at-risk for malnutrition using malnutrition screening and diagnostic assessment tools. Individual reviewers extracted study data and performed quality checks for accuracy. Meta-analysis was conducted using a random-effects model with variance correction. We assessed the overall strength of evidence at the outcome level. The risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool. RESULTS: We found 11 RCTs that assessed two types of interventions: specialized nutrition care (8 RCTs) and increased protein provision (3 RCTs). The pooled findings of 11 RCTs found moderate strength of evidence that specialized nutrition care and increased protein provision reduced mortality by 21% (relative risk [RR]: 0.79, 95% confidence interval [CI]: 0.63-0.98; absolute risk reduction [ARR]: -0.02, 95% CI: -0.03 to -0.00). Pooled estimates indicated a nonsignificant decrease of 0.18 days in the length of stay (9 RCTs) and a 10% reduction in readmissions (7 RCTs). No eligible RCTs assessed parenteral or enteral nutrition. CONCLUSION: Certain malnutrition-focused hospital-initiated interventions (e.g., specialized nutrition care and increased protein provision) reduce mortality and may improve the quality of life among patients at risk for or diagnosed with malnutrition. Future trials are needed to assess the effectiveness of parenteral and enteral nutrition.

Utilizing a reductionist model to study host-microbe interactions in intestinal inflammation.

BACKGROUND: The gut microbiome is altered in patients with inflammatory bowel disease, yet how these alterations contribute to intestinal inflammation is poorly understood. Murine models have demonstrated the importance of the microbiome in colitis since colitis fails to develop in many genetically susceptible animal models when re-derived into germ-free environments. We have previously shown that Wiskott-Aldrich syndrome protein (WASP)-deficient mice (Was-/-) develop spontaneous colitis, similar to human patients with loss-of-function mutations in WAS. Furthermore, we showed that the development of colitis in Was-/- mice is Helicobacter dependent. Here, we utilized a reductionist model coupled with multi-omics approaches to study the role of host-microbe interactions in intestinal inflammation. RESULTS: Was-/- mice colonized with both altered Schaedler flora (ASF) and Helicobacter developed colitis, while those colonized with either ASF or Helicobacter alone did not. In Was-/- mice, Helicobacter relative abundance was positively correlated with fecal lipocalin-2 (LCN2), a marker of intestinal inflammation. In contrast, WT mice colonized with ASF and Helicobacter were free of inflammation and strikingly, Helicobacter relative abundance was negatively correlated with LCN2. In Was-/- colons, bacteria breach the mucus layer, and the mucosal relative abundance of ASF457 Mucispirillum schaedleri was positively correlated with fecal LCN2. Meta-transcriptomic analyses revealed that ASF457 had higher expression of genes predicted to enhance fitness and immunogenicity in Was-/- compared to WT mice. In contrast, ASF519 Parabacteroides goldsteinii's relative abundance was negatively correlated with LCN2 in Was-/- mice, and transcriptional analyses showed lower expression of genes predicted to facilitate stress adaptation by ASF519 in Was-/-compared to WT mice. CONCLUSIONS: These studies indicate that the effect of a microbe on the immune system can be context dependent, with the same bacteria eliciting a tolerogenic response under homeostatic conditions but promoting inflammation in immune-dysregulated hosts. Furthermore, in inflamed environments, some bacteria up-regulate genes that enhance their fitness and immunogenicity, while other bacteria are less able to adapt and decrease in abundance. These findings highlight the importance of studying host-microbe interactions in different contexts and considering how the transcriptional profile and fitness of bacteria may change in different hosts when developing microbiota-based therapeutics. Video abstract.

Interventions to Reduce Hospital Length of Stay in High-risk Populations: A Systematic Review.

Importance: Many strategies to reduce hospital length of stay (LOS) have been implemented, but few studies have evaluated hospital-led interventions focused on high-risk populations. The Agency for Healthcare Research and Quality (AHRQ) Learning Health System panel commissioned this study to further evaluate system-level interventions for LOS reduction. Objective: To identify and synthesize evidence regarding potential systems-level strategies to reduce LOS for patients at high risk for prolonged LOS. Evidence Review: Multiple databases, including MEDLINE and Embase, were searched for English-language systematic reviews from January 1, 2010, through September 30, 2020, with updated searches through January 19, 2021. The scope of the protocol was determined with input from AHRQ Key Informants. Systematic reviews were included if they reported on hospital-led interventions intended to decrease LOS for high-risk populations, defined as those with high-risk medical conditions or socioeconomically vulnerable populations (eg, patients with high levels of socioeconomic risk, who are medically uninsured or underinsured, with limited English proficiency, or who are hospitalized at a safety-net, tertiary, or quaternary care institution). Exclusion criteria included interventions that were conducted outside of the hospital setting, including community health programs. Data extraction was conducted independently, with extraction of strength of evidence (SOE) ratings provided by systematic reviews; if unavailable, SOE was assessed using the AHRQ Evidence-Based Practice Center methods guide. Findings: Our searches yielded 4432 potential studies. We included 19 systematic reviews reported in 20 articles. The reviews described 8 strategies for reducing LOS in high-risk populations: discharge planning, geriatric assessment, medication management, clinical pathways, interdisciplinary or multidisciplinary care, case management, hospitalist services, and telehealth. Interventions were most frequently designed for older patients, often those who were frail (9 studies), or patients with heart failure. There were notable evidence gaps, as there were no systematic reviews studying interventions for patients with socioeconomic risk. For patients with medically complex conditions, discharge planning, medication management, and interdisciplinary care teams were associated with inconsistent outcomes (LOS, readmissions, mortality) across populations. For patients with heart failure, clinical pathways and case management were associated with reduced length of stay (clinical pathways: mean difference reduction, 1.89 [95% CI, 1.33 to 2.44] days; case management: mean difference reduction, 1.28 [95% CI, 0.52 to 2.04] days). Conclusions and Relevance: This systematic review found inconsistent results across all high-risk populations on the effectiveness associated with interventions, such as discharge planning, that are often widely used by health systems. This systematic review highlights important evidence gaps, such as the lack of existing systematic reviews focused on patients with socioeconomic risk factors, and the need for further research.

Ethical Considerations in Dementia Diagnosis and Care: AAN Position Statement.

Alzheimer disease and other dementias present unique practical challenges for patients, their families, clinicians, and health systems. These challenges reflect not only the growing public health effect of dementia in an aging global population, but also more specific ethical complexities including early loss of patients' capacity to make decisions regarding their own care, the stigma often associated with a dementia diagnosis, the difficulty of balancing concern for patients' welfare with respect for patients' remaining independence, and the effect on the physical, emotional, and financial well-being of family caregivers. Caring for patients with dementia requires respecting patient autonomy while acknowledging progressively diminishing decisional capacity and continuing to provide care in accordance with other core ethical principles (beneficence, justice, and nonmaleficence). Whereas these ethical principles remain unchanged, neurologists must reconsider how to apply them given changes across multiple domains including our understanding of disease, clinical and legal tools for addressing manifestations of illness, our expanding awareness of the crucial role of family caregivers in providing care and maintaining patient quality of life, and societal conceptions of dementia and individuals' personal expectations for aging. This revision to the American Academy of Neurology's 1996 position statement summarizes ethical considerations that often arise in caring for patients with dementia; although it addresses how such considerations influence patient management, it is not a clinical practice guideline.

Improving the utility of evidence synthesis for decision makers in the face of insufficient evidence.

OBJECTIVE: To identify and suggest strategies to make insufficient evidence ratings in systematic reviews more actionable. STUDY DESIGN AND SETTING: A workgroup comprising members from the Evidence-Based Practice (EPC) Program of the Agency for Healthcare Research and Quality convened throughout 2020. We conducted iterative discussions considering information from three data sources: a literature review for relevant publications and frameworks, a review of a convenience sample of past systematic reviews conducted by the EPCs, and an audit of methods used in past EPC technical briefs. RESULTS: We identified five strategies for supplementing systematic review findings when evidence on benefits or harms is expected to be, or found to be, insufficient: 1) reconsider eligible study designs, 2) summarize indirect evidence, 3) summarize contextual and implementation evidence, 4) consider modelling, and 5) incorporate unpublished health system data in the evidence synthesis. While these strategies may not increase the strength of evidence, they may improve the utility of reports for decision makers. Adopting these strategies depends on feasibility, timeline, funding, and expertise of the systematic reviewers. CONCLUSION: Throughout the process of evidence synthesis of early scoping, protocol development, review conduct, and review presentation, authors can consider these five strategies to supplement evidence with insufficient rating to make it more actionable for end-users.

Ethical Perspectives on Costly Drugs and Health Care: AAN Position Statement.

High drug prices have created substantial challenges for patients, physicians, health systems, and payers. High drug prices can affect patient care in many ways, including limiting access to treatment, increasing the burden of administrative tasks, and contributing to physician burnout. Exorbitant drug pricing poses direct challenges for distributive justice, which is concerned with fairly distributing benefits and burdens across society. In this position statement, we discuss ethical concerns raised by high drug costs, primarily focusing on concerns around distributive justice. We consider forms of rationing, approaches to allocation, potential complexities in real-life application, and structural forces contributing to high drug costs. Finally, we consider potential policy solutions and ramifications for individual clinicians.

Translating an evidence-based clinical pathway into shareable CDS: developing a systematic process using publicly available tools.

OBJECTIVE: To develop a process for translating semi-structured clinical decision support (CDS) into shareable, computer-readable CDS. MATERIALS AND METHODS: We developed a systematic and transparent process using publicly available tools (eGLIA, GEM Cutter, VSAC, and the CDS Authoring Tool) to translate an evidence-based clinical pathway (CP) into a Clinical Quality Language (CQL)-encoded CDS artifact. RESULTS: We produced a 4-phase process for translating a CP into a CQL-based CDS artifact. CP content was extracted using GEM into discrete clinical concepts, encoded using standard terminologies into value sets on VSAC, evaluated against workflows using a wireframe, and finally structured as a computer readable CDS artifact using CQL. This process included a quality control step and intermediate products to support transparency and reuse by other CDS developers. DISCUSSION: Translating a CP into a shareable, computer-readable CDS artifact was accomplished through a systematic process. Our process identified areas of ambiguity and gaps in the CP, which generated improvements in the CP. Collaboration with clinical subject experts and the CP development team was essential for translation. Publicly available tools were sufficient to support most translation steps, but expression of certain complex concepts required manual encoding. CONCLUSION: Standardized development of CDS from a CP is feasible using a systematic 4-phase process. CPs represent a potential reservoir for developers of evidence-based CDS. Aspects of CP development simplified portions of the CDS translation process. Publicly available tools can facilitate CDS development; however, enhanced tool features are needed to model complex CDS statements.

Medical Care of Adults With Down Syndrome: A Clinical Guideline.

Importance: Down syndrome is the most common chromosomal condition, and average life expectancy has increased substantially, from 25 years in 1983 to 60 years in 2020. Despite the unique clinical comorbidities among adults with Down syndrome, there are no clinical guidelines for the care of these patients. Objective: To develop an evidence-based clinical practice guideline for adults with Down syndrome. Evidence Review: The Global Down Syndrome Foundation Medical Care Guidelines for Adults with Down Syndrome Workgroup (n = 13) developed 10 Population/Intervention/ Comparison/Outcome (PICO) questions for adults with Down syndrome addressing multiple clinical areas including mental health (2 questions), dementia, screening or treatment of diabetes, cardiovascular disease, obesity, osteoporosis, atlantoaxial instability, thyroid disease, and celiac disease. These questions guided the literature search in MEDLINE, EMBASE, PubMed, PsychINFO, Cochrane Library, and the TRIP Database, searched from January 1, 2000, to February 26, 2018, with an updated search through August 6, 2020. Using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology and the Evidence-to-Decision framework, in January 2019, the 13-member Workgroup and 16 additional clinical and scientific experts, nurses, patient representatives, and a methodologist developed clinical recommendations. A statement of good practice was made when there was a high level of certainty that the recommendation would do more good than harm, but there was little direct evidence. Findings: From 11 295 literature citations associated with 10 PICO questions, 20 relevant studies were identified. An updated search identified 2 additional studies, for a total of 22 included studies (3 systematic reviews, 19 primary studies), which were reviewed and synthesized. Based on this analysis, 14 recommendations and 4 statements of good practice were developed. Overall, the evidence base was limited. Only 1 strong recommendation was formulated: screening for Alzheimer-type dementia starting at age 40 years. Four recommendations (managing risk factors for cardiovascular disease and stroke prevention, screening for obesity, and evaluation for secondary causes of osteoporosis) agreed with existing guidance for individuals without Down syndrome. Two recommendations for diabetes screening recommend earlier initiation of screening and at shorter intervals given the high prevalence and earlier onset in adults with Down syndrome. Conclusions and Relevance: These evidence-based clinical guidelines provide recommendations to support primary care of adults with Down syndrome. The lack of high-quality evidence limits the strength of the recommendations and highlights the need for additional research.

Machine learning for screening prioritization in systematic reviews: comparative performance of Abstrackr and EPPI-Reviewer.

BACKGROUND: Improving the speed of systematic review (SR) development is key to supporting evidence-based medicine. Machine learning tools which semi-automate citation screening might improve efficiency. Few studies have assessed use of screening prioritization functionality or compared two tools head to head. In this project, we compared performance of two machine-learning tools for potential use in citation screening. METHODS: Using 9 evidence reports previously completed by the ECRI Institute Evidence-based Practice Center team, we compared performance of Abstrackr and EPPI-Reviewer, two off-the-shelf citations screening tools, for identifying relevant citations. Screening prioritization functionality was tested for 3 large reports and 6 small reports on a range of clinical topics. Large report topics were imaging for pancreatic cancer, indoor allergen reduction, and inguinal hernia repair. We trained Abstrackr and EPPI-Reviewer and screened all citations in 10% increments. In Task 1, we inputted whether an abstract was ordered for full-text screening; in Task 2, we inputted whether an abstract was included in the final report. For both tasks, screening continued until all studies ordered and included for the actual reports were identified. We assessed potential reductions in hypothetical screening burden (proportion of citations screened to identify all included studies) offered by each tool for all 9 reports. RESULTS: For the 3 large reports, both EPPI-Reviewer and Abstrackr performed well with potential reductions in screening burden of 4 to 49% (Abstrackr) and 9 to 60% (EPPI-Reviewer). Both tools had markedly poorer performance for 1 large report (inguinal hernia), possibly due to its heterogeneous key questions. Based on McNemar's test for paired proportions in the 3 large reports, EPPI-Reviewer outperformed Abstrackr for identifying articles ordered for full-text review, but Abstrackr performed better in 2 of 3 reports for identifying articles included in the final report. For small reports, both tools provided benefits but EPPI-Reviewer generally outperformed Abstrackr in both tasks, although these results were often not statistically significant. CONCLUSIONS: Abstrackr and EPPI-Reviewer performed well, but prioritization accuracy varied greatly across reports. Our work suggests screening prioritization functionality is a promising modality offering efficiency gains without giving up human involvement in the screening process.

16S rRNA sequencing analysis: the devil is in the details.

User-friendly computational tools for 16S ribosomal RNA (rRNA) sequencing analysis enable researchers who are not bioinformaticians to analyze and interpret sequencing data from microbial communities. These tools' easy-to-use interfaces belie the sophisticated and rapidly-evolving science of their underlying algorithms. When analyzing 16S data from a simple microbiome experiment, we found that superficially unimportant decisions about the bioinformatic pipeline led to results with radically different biological interpretations. We share these results as a cautionary tale whose moral is that, in 16S analysis, the devil is in the details. Wet bench researchers should therefore strongly consider partnering with bioinformaticians or computational biologists when analyzing 16S data.

More Guidelines than states: variations in U.S. lead screening and management guidance and impacts on shareable CDS development.

BACKGROUND: Pediatric lead exposure in the United States (U.S.) remains a preventable public health crisis. Shareable electronic clinical decision support (CDS) could improve lead screening and management. However, discrepancies between federal, state and local recommendations could present significant challenges for implementation. METHODS: We identified publically available guidance on lead screening and management. We extracted definitions for elevated lead and recommendations for screening, follow-up, reporting, and management. We compared thresholds and level of obligation for management actions. Finally, we assessed the feasibility of development of shareable CDS. RESULTS: We identified 54 guidance sources. States offered different definitions of elevated lead, and recommendations for screening, reporting, follow-up and management. Only 37 of 48 states providing guidance used the Center for Disease Control (CDC) definition for elevated lead. There were 17 distinct management actions. Guidance sources indicated an average of 5.5 management actions, but offered different criteria and levels of obligation for these actions. Despite differences, the recommendations were well-structured, actionable, and encodable, indicating shareable CDS is feasible. CONCLUSION: Current variability across guidance poses challenges for clinicians. Developing shareable CDS is feasible and could improve pediatric lead screening and management. Shareable CDS would need to account for local variability in guidance.

Treatments for Poststroke Motor Deficits and Mood Disorders: A Systematic Review for the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Guidelines for Stroke Rehabilitation.

Background: Early rehabilitation after stroke is essential to help reduce disability. Purpose: To summarize evidence on the benefits and harms of nonpharmacologic and pharmacologic treatments for motor deficits and mood disorders in adults who have had stroke. Data Sources: English-language searches of multiple electronic databases from April 2009 through July 2018; targeted searches to December 2018 for studies of selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors. Study Selection: 19 systematic reviews and 37 randomized controlled trials addressing therapies for motor deficits or mood disorders in adults with stroke. Data Extraction: One investigator abstracted the data, and quality and GRADE assessment were checked by a second investigator. Data Synthesis: Most interventions (for example, SSRIs, mental practice, mirror therapy) did not improve motor function. High-quality evidence did not support use of fluoxetine to improve motor function. Moderate-quality evidence supported use of cardiorespiratory training to improve maximum walking speed and repetitive task training or transcranial direct current stimulation to improve activities of daily living (ADLs). Low-quality evidence supported use of robotic arm training to improve ADLs. Low-quality evidence indicated that antidepressants may reduce depression, whereas the frequency and severity of antidepressant-related adverse effects was unclear. Low-quality evidence suggested that cognitive behavioral therapy and exercise, including mind-body exercise, may reduce symptoms of depression and anxiety. Limitation: Studies were of poor quality, interventions and comparators were heterogeneous, and evidence on harms was scarce. Conclusion: Cardiorespiratory training, repetitive task training, and transcranial direct current stimulation may improve ADLs in adults with stroke. Cognitive behavioral therapy, exercise, and SSRIs may reduce symptoms of poststroke depression, but use of SSRIs to prevent depression or improve motor function was not supported. Primary Funding Source: U.S. Department of Veterans Affairs, Veterans Health Administration.