Risk of Pancreatitis After Endoscopic Ultrasound-Guided Fine-Needle Aspiration of Pancreatic Cystic Lesions: A Systematic Review and Meta-Analysis.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is frequently used to risk-stratify pancreatic cystic lesions (PCLs). Rising PCL incidence and developments in tissue acquisition and specimen analysis necessitate updated appraisal of EUS-FNA safety, particularly the risk of postprocedure pancreatitis, the most common EUS-FNA-related adverse event. Our systematic review aims to accurately quantify the risk of EUS-FNA-related pancreatitis to best inform decisions regarding EUS-FNA's optimal role in PCL workup. METHODS: We performed systematic searches in 4 databases from inception to April 2024 for original English-language studies investigating EUS-FNA-related pancreatitis. We extracted data on demographics and EUS-FNA-related pancreatitis risk, severity, and risk factors. These were meta-analyzed through the DerSimonian Laird Method using a random-effects model. Meta-regression of pancreatitis risk was performed to delineate associations with clinical and procedural characteristics. RESULTS: Sixty-four studies comprised 8,086 patients and reported 110 EUS-FNA-related pancreatitis events. Pooled risk of EUS-FNA-related pancreatitis was 1.4% (95% confidence intervals, -0.8% to 3.5%; I2 = 0.00), which was predominantly of mild severity (67%) and uniformly nonfatal. Pancreatitis risk lacked significant association with sample size, age, sex, cyst size, needle caliber, or passes, although we noted trends toward higher risk in studies published after 2015, those using higher gauge needles (19 G vs 22 G/25 G), and those performing EUS-guided through-the-needle biopsy. DISCUSSION: We note with high certainty that pancreatitis after EUS-FNA of PCLs is infrequent and mild in severity with no mortality in the included cohort. EUS-guided through-the-needle biopsy may serve as a significant risk factor for EUS-FNA-related pancreatitis risk; however, further studies are needed to delineate other predisposing characteristics.

Experimental assessment of elemental analyzer isotope ratio mass spectrometry normalization methodologies for environmental stable isotopes.

RATIONALE: In stable isotope mass spectrometry, isotope delta values are normalized to internationally recognized reference scales using a combination of certified and in-house isotope reference materials. Numerous techniques exist for performing this normalization, but these methodologies need to be experimentally assessed to compare their effect on reproducibility of isotope results. METHODS: We tested normalization methods by the number of reference materials used, their matrix, their isotope range, and whether normalization required extrapolating beyond the isotope range. We analyzed eight commercially available isotope reference materials on a ThermoFinnigan Delta-V isotope ratio mass spectrometer (IRMS) and an Elementar VisION IRMS for nitrogen and carbon isotope composition via solid combustion with an elemental analyzer and computed every possible isotope normalization (n = 612). Additionally, we assessed how sample matrix affected linearity effects on both instruments using five in-house reference materials. RESULTS: Normalizations exhibited the best performance when the reference materials spanning an isotope range of at least 20‰ were matrix matched with the samples and did not require extrapolation beyond the calibration curve. When these conditions were not met, the number of reference materials used had a significant effect on accuracy, with normalizations composed of two reference materials exhibiting particularly inconsistent performance at isotope ranges below 20‰. Linearity effects were found to exceed instrument precision by two orders of magnitude irrespective of matrix type and were not predicted by working gas diagnostics. CONCLUSIONS: Interlaboratory comparability of isotope results is improved when operators of elemental analyzer isotope ratio mass spectrometry (EAIRMS) systems select reference materials spanning an isotope range of at least 20‰. Additionally, using three or more isotopic reference materials, avoiding extrapolation beyond the range of the normalization curve, and matching the matrix of the reference materials to the samples improve normalizations.

Assessing Right Ventricle Over Time in Patients on Veno-Venous Extracorporeal Membrane Oxygenation: Insights From Serial Echocardiography.

Extracorporeal membrane oxygenation (ECMO) is often used in acute respiratory distress syndrome (ARDS) with refractory hypoxemia. There is limited literature highlighting the development of right ventricular (RV) failure while on ECMO. We conducted a retrospective multicenter observational study including 70 patients who were placed on veno-venous (VV)-ECMO for respiratory failure at Mayo Clinic, Jacksonville, and Mayo Clinic, Rochester, between January 2018 and June 2022 and had at least two post-ECMO transthoracic echoes. The primary outcomes were the incidence and progression of RV dysfunction and dilatation. The secondary outcome was in-patient mortality. Among 70 patients in our cohort, 60.6% had a normal RV function at the time of ECMO placement, whereas only 42% had a normal RV function at the second post-ECMO echo. On multinomial regression, a moderate decrease in RV function was associated with ECMO flow (odds ratio [OR] = 2.32, p = 0.001) and ECMO duration (OR = 1.01, p = 0.01). A moderately dilated RV size was also associated with ECMO flow (OR = 2.62, p < 0.001) and ECMO duration (OR = 1.02, p = 0.02). An increasing degree of RV dysfunction was associated with worse outcomes. Our study showed that the increasing duration and flow of VV-ECMO correlated with progressive RV dilatation and dysfunction, which were associated with poor survival.

Gender Differences in Authorship and Quality of Anesthesia Clinical Practice Guidelines From 2016 to 2020 Using the Appraisal of Guidelines for Research and Evaluation II Instrument.

INTRODUCTION: Women continue to be underrepresented in academic anesthesiology. This study assessed guidelines in anesthesia journals over the past 5 years, evaluating differences in woman-led versus man-led guidelines in terms of author gender, quality, and changes over time. We hypothesized that anesthesia guidelines would be predominately man-led, and that there would be differences in quality between woman-led versus man-led guidelines. METHODS: All clinical practice guidelines published in the top 10 anesthesia journals were identified as per Clarivate Analytics Impact Factor between 2016 and 2020. Fifty-one guidelines were included for author, gender, and quality analysis using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Each guideline was assessed across 6 domains and 23 items and given an overall score, overall quality score, and overall rating/recommendation. Stratified and trend analyses were performed for woman-led versus man-led guidelines. RESULTS: Fifty out of 51 guidelines were included: 1 was excluded due to unidentifiable first-author gender. In total, 255 of 1052 (24%) authors were women, and woman-led guidelines (woman-first author) represented 12 of 50 (24%) overall guidelines. Eighteen percent (9 of 50) of guidelines had all-male authors, and a majority (26 of 50, 52%) had less than one-third of female authors. The overall number and percentage of woman-led guidelines did not change over time. There was a significantly higher percentage of female authors in woman-led versus man-led guidelines, median 39% vs 20% (P = .012), as well as a significantly higher number of female coauthors in guidelines that were woman-led median 3.5 vs 1.0, P = .049. For quality, there was no significant difference in the overall rating or objective quality of woman- versus man-led guidelines. However, there was a significant increase in the overall rating of all the guidelines over time (P = .010), driven by the increase in overall rating among man-led guidelines, P = .002. The overall score of guidelines did not increase over time; however, they increased in man-led but not woman-led guidelines. There was no significant correlation between the percentage of female authors per guideline and either overall score or overall rating. CONCLUSIONS: There is a substantial disparity in the number of women leading and contributing to guidelines which has not improved over time. Woman-led guidelines included more women and a higher percentage of women. There was no difference in quality of guidelines by first-author gender or percentage of female authors. Further systematic and quota-driven sponsorship is needed to promote gender equity, diversity, and inclusion in anesthesia guidelines.

Differential effects of disulfide bond formation in TEM-1 versus CTX-M-9 ß-lactamase.

To investigate how disulfide bonds can impact protein energy landscapes, we surveyed the effects of adding or removing a disulfide in two ß-lactamase enzymes, TEM-1 and CTX-M-9. The homologs share a structure and 38% sequence identity, but only TEM-1 contains a native disulfide bond. They also differ in thermodynamic stability and in the number of states populated at equilibrium: CTX-M-9 is two-state whereas TEM-1 has an additional intermediate state. We hypothesized that the disulfide bond is the major underlying determinant for these observed differences in their energy landscapes. To test this, we removed the disulfide bridge from TEM-1 and introduced a disulfide bridge at the same location in CTX-M-9. This modest change to sequence modulates the stabilities-and therefore populations-of TEM-1's equilibrium states and, more surprisingly, creates a novel third state in CTX-M-9. Unlike TEM-1's partially folded intermediate, this third state is a higher-order oligomer with reduced cysteines that retains the native fold and is fully active. Sub-denaturing concentrations of urea shifts the equilibrium to the monomeric form, allowing the disulfide bond to form. Interestingly, comparing the stability of the oxidized monomer with a variant lacking cysteines reveals the disulfide is neither stabilizing nor destabilizing in CTX-M-9, in contrast with the observed stabilization in TEM-1. Thus, we can conclude that engineering disulfide bonds is not always an effective stabilization strategy even when analogous disulfides exist in more stable structural homologs. This study also illustrates how homo-oligomerization can result from a small number of mutations, suggesting complex formation might be easily accessed during a protein family's evolution.

PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy.

PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer.

An Evaluation of Spin in the Abstracts of Systematic Reviews and Meta-analyses on the Treatment of Psoriasis: A Cross-sectional Analysis.

Spin is a way of reporting that distorts the true findings; we sought to investigate the prevalence of spin in systematic review abstracts on psoriasis treatments and whether study characteristics were associated with spin. We searched MEDLINE and Embase to obtain our sample. Screening and data extraction were performed in a masked duplicate fashion. Each included study was evaluated for the 9 most severe types of spin and other study characteristics. The methodological quality was assessed to explore potential relationships between spin and study quality. Search queries returned 3200 articles, which included 173 systematic reviews. Spin was present in systematic review abstracts. Preventing spin is essential for improving future systematic reviews.

A decade of systematic reviews: an assessment of Weill Cornell Medicine's systematic review service.

Background: The Weill Cornell Medicine, Samuel J. Wood Library's Systematic Review (SR) service began in 2011, with 2021 marking a decade of service. This paper will describe how the service policies have grown and will break down our service quantitatively over the past 11 years to examine SR timelines and trends. Case Presentation: We evaluated 11 years (2011-2021) of SR request data from our in-house documentation. In the years assessed, there have been 319 SR requests from 20 clinical departments, leading to 101 publications with at least one librarian collaborator listed as co-author. The average review took 642 days to publication, with the longest at 1408 days, and the shortest at 94 days. On average, librarians spent 14.7 hours in total on each review. SR projects were most likely to be abandoned at the title/abstract screening phase. Several policies have been put into place over the years in order to accommodate workflows and demand for our service. Discussion: The SR service has seen several changes since its inception in 2011. Based on the findings and emerging trends discussed here, our service will inevitably evolve further to adapt to these changes, such as machine learning-assisted technology.

Dynamic postural control in injured collegiate cross-country runners is not associated with running-related injury.

BACKGROUND: Biomechanical factors have been associated with running-related injury, but associations are unclear. Dynamic postural stability may be a factor related to injury that has not been studied extensively. RESEARCH QUESTION: Does dynamic postural control differ in those with a history of running-related injury or those who go on to sustain a running-related injury? METHODS: Sixty-five (45 injured; 20 uninjured) and fifty-eight (13 injured; 45 uninjured) collegiate cross-country runners were available for our retrospective and prospective analyses. Time to stabilization and dynamic postural stability index were collected during two separate jump landing tasks (forward and lateral direction) for each leg. Retrospective injury was tabulated by a running history survey. Prospective injuries were recorded by a licensed athletic trainer during the competitive season. Differences in postural stability were compared between injured and uninjured groups and between limbs using two-way ANOVA's. An overall group by leg comparison was completed for each task. RESULTS: The non-dominant limb demonstrated better postural stability indices regardless of injury history. An interaction was observed between limbs and history of injury for the anterior-posterior time to stabilization for the lateral task. The non-dominant limb demonstrated better medio-lateral postural stability indices and time to stabilization during the lateral task, regardless of prospective injury. SIGNIFICANCE: Dynamic postural stability was reduced in the dominant limb, but no clear differences were seen between injured and uninjured runners. This suggests dynamic postural stability may be altered in individuals with a history of a running-related injury, but no relationship to subsequent injury was substantiated. Further work is needed to understand how dynamic postural stability may be related to running-related injury.

Social determinants of mental health: the roles of traumatic events, financial strain, housing instability, food insecurity, and commute time.

OBJECTIVE: To identify social determinants of mental health embedded within college students' living and learning conditions. PARTICIPANTS: Participants included 215 mostly undergraduate (95%) business students at a diverse, urban west coast public university (48% women; mean age 24). METHODS: Participants completed an online self-report survey measuring affective state, global mental health, anxious and depressive symptoms, as well as social determinants of mental health. Data were analyzed using multiple regression controlling for self-esteem, gender, and race/ethnicity. RESULTS: Results suggest that higher family income is positively related to mental health, whereas more adverse events (e.g., assault, robbery, serious illness or injury), food insecurity, and commute time are negatively related to mental health. Moderation results indicate a moderate buffering effect of belonging on global mental health among students who experience zero adverse events. CONCLUSIONS: Social determinants can shed light on student's precarious living and learning conditions and resultant effects on students' mental health.

Spin within systematic review abstracts on antiplatelet therapies after acute coronary syndrome: a cross-sectional study.

OBJECTIVES: Spin is a reporting practice in which study results are misrepresented by overestimating efficacy or underestimating harm. Prevalence of spin varies between clinical specialties, and estimates are based almost entirely on clinical trials. Little is known about spin in systematic reviews. DESIGN: We performed a cross-sectional analysis searching MEDLINE and Embase for systematic reviews and meta-analyses pertaining to antiplatelet therapies following acute coronary syndrome on 2 June 2020. Data were extracted evaluating the presence of spin and study characteristics, including methodological quality as rated by A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2). All data extraction was conducted in a masked, duplicate manner from 2 June 2020 to 26 June 2020. PARTICIPANTS AND SETTING: Not applicable. PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed abstracts of systematic reviews on antiplatelet therapy following acute coronary syndrome and evaluated the prevalence of the nine most severe types of spin. We additionally explored associations between spin and certain study characteristics, including quality. RESULTS: Our searches returned 15 263 articles, and 185 systematic reviews met inclusion criteria. Of these 185 reviews, 31.9% (59/185) contained some form of spin in the abstract. Seven forms of spin (1, 2, 3, 4, 5, 7 and 9) among the nine most severe were identified. No instances of types 6 or 8 were found. There were no statistically significant relationships between spin and the evaluated study characteristics or AMSTAR-2 appraisals. CONCLUSIONS: Spin was present in abstracts for systematic reviews and meta-analyses; subsequent studies are needed to identify correlations between spin and specific study characteristics. There were no statistically significant associations between spin and study characteristics or AMSTAR-2 ratings; however, implementing changes will ensure that spin is reduced in the field of cardiology as well as other fields of medicine.

Single-mode distributed feedback lasing using photonic bandgaps to suppress degenerate modes.

We present a method for achieving single-mode distributed feedback lasing, using photonic bandgaps (PBGs) to suppress degenerate lasing modes. These PBGs arise from direct-Bragg coupling and exchange-Bragg coupling due to a passive waveguide placed in proximity to a uniform-grating-active-waveguide lasing structure. Analytic solutions at lasing threshold for this dual-waveguide, four-port structure reveal a high normalized gain margin (e.g., ΔαL = 0.86) accompanied by a low power flatness (e.g., F = 0.001) along the active region, outperforming the λ/4-shifted DFB laser structure. This single-mode lasing mechanism is compelling for both III/V and III/V-on-silicon platforms.

Evaluation of spin in the abstracts of systematic reviews and meta-analyses relating to postoperative nausea and vomiting.

INTRODUCTION: Spin - the beautification of study results to emphasise benefits or minimise harms - is a deceptive reporting strategy with the potential to affect clinical decision-making adversely. Few studies have investigated the extent of spin in systematic reviews. Here, we sought to address this gap by evaluating the presence of the nine most severe forms of spin in the abstracts of systematic reviews on treatments for postoperative nausea and vomiting (PONV). PONV has the potential to increase hospital costs and patient burden, adversely affecting outcomes. METHODS: We developed search strategies for MEDLINE and Embase to identify systematic reviews focused on PONV. Following title and abstract screening of the reviews identified during the initial search, those that met inclusion criteria were evaluated for the presence of spin and received a revised AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews) appraisal by two investigators in a masked, duplicate manner. Study characteristics for each review were also extracted in duplicate. RESULTS: Our systematic search returned 3513 studies, of which 130 systematic reviews and meta-analyses were eligible for data extraction. We found that 29.2% of included systematic reviews contained spin (38/130). Eight of the nine types of spin were identified, with spin type 3 ('selective reporting of or overemphasis on efficacy outcomes or analysis favouring the beneficial effect of the experimental intervention') being the most common. Associations were found between spin and funding source. Spin was more likely in the abstracts of privately funded than nonfunded studies, odds ratio (OR) 2.81 [95% confidence interval (CI), 0.66 to 11.98]. In the abstracts of studies not mentioning funding spin was also more likely than in nonfunded studies, OR 2.30 (95% CI, 0.61 to 8.70). Neither of these results were statistically significant. Significance was found in the association between the presence of spin and AMSTAR-2 ratings: 'low' quality studies were less likely to contain spin than 'high' quality, OR 0.24 (95% CI, 0.07 to 0.88): 'critically low' studies were also less likely to contain spin than 'high' quality studies, OR 0.21 (95% CI, 0.07 to 0.65). There were no other associations between spin and the remaining extracted study characteristics or AMSTAR-2 ratings. CONCLUSION: Spin was present in greater than 29% of abstracts of systematic reviews and meta-analyses regarding PONV. Various stakeholders must take steps to improve the reporting quality of abstracts on PONV.

A dynamical systems view of neuroethology: Uncovering stateful computation in natural behaviors.

State-dependent computation is key to cognition in both biological and artificial systems. Alan Turing recognized the power of stateful computation when he created the Turing machine with theoretically infinite computational capacity in 1936. Independently, by 1950, ethologists such as Tinbergen and Lorenz also began to implicitly embed rudimentary forms of state-dependent computation to create qualitative models of internal drives and naturally occurring animal behaviors. Here, we reformulate core ethological concepts in explicitly dynamical systems terms for stateful computation. We examine, based on a wealth of recent neural data collected during complex innate behaviors across species, the neural dynamics that determine the temporal structure of internal states. We will also discuss the degree to which the brain can be hierarchically partitioned into nested dynamical systems and the need for a multi-dimensional state-space model of the neuromodulatory system that underlies motivational and affective states.

Regional synapse gain and loss accompany memory formation in larval zebrafish.

Defining the structural and functional changes in the nervous system underlying learning and memory represents a major challenge for modern neuroscience. Although changes in neuronal activity following memory formation have been studied [B. F. Grewe et al., Nature 543, 670-675 (2017); M. T. Rogan, U. V. Stäubli, J. E. LeDoux, Nature 390, 604-607 (1997)], the underlying structural changes at the synapse level remain poorly understood. Here, we capture synaptic changes in the midlarval zebrafish brain that occur during associative memory formation by imaging excitatory synapses labeled with recombinant probes using selective plane illumination microscopy. Imaging the same subjects before and after classical conditioning at single-synapse resolution provides an unbiased mapping of synaptic changes accompanying memory formation. In control animals and animals that failed to learn the task, there were no significant changes in the spatial patterns of synapses in the pallium, which contains the equivalent of the mammalian amygdala and is essential for associative learning in teleost fish [M. Portavella, J. P. Vargas, B. Torres, C. Salas, Brain Res. Bull 57, 397-399 (2002)]. In zebrafish that formed memories, we saw a dramatic increase in the number of synapses in the ventrolateral pallium, which contains neurons active during memory formation and retrieval. Concurrently, synapse loss predominated in the dorsomedial pallium. Surprisingly, we did not observe significant changes in the intensity of synaptic labeling, a proxy for synaptic strength, with memory formation in any region of the pallium. Our results suggest that memory formation due to classical conditioning is associated with reciprocal changes in synapse numbers in the pallium.

Quality of recent clinical practice guidelines in anaesthesia publications using the Appraisal of Guidelines for Research and Evaluation II instrument.

Clinical practice guidelines are a valuable resource aiding medical decision-making based on scientific evidence. In anaesthesia, guidelines are increasing in both number and scope, influencing individual practice and shaping local departmental policy. The aim of this review is to assess the quality of clinical practice guidelines published in high impact anaesthesia journals over the past 5 yr using the internationally validated Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A literature search was conducted in Scopus to identify all guidelines published in the top 10 anaesthesia journals as per Clarivate Analytics Impact Factor from 2016 and 2020. Fifty-one guidelines were included for analysis by five independent appraisers using AGREE II. Each guideline was assessed across six domains and 23 items. Individual domain scores were calculated with a threshold agreed via consensus to represent high-quality guidelines. There was a significant increase in overall score over time (P=0.041), driven by Domain 3 (Rigour of Development, P=0.046). The raw overall score for Domain 3, however, was low. The other domains performed as expected based on previous studies, with Domains 1, 4, and 6 achieving high scores and Domains 2 and 5 incurring poor ratings. Most guidelines studied involved international collaboration but emerged from a single professional society. Use of an appraisal tool was stated as high but poorly detailed. The improvement in the overall score of guidelines and rigour of development is promising; however, only seven guidelines met high-quality criteria, suggesting room for improvement for the overall integrity of guidelines in anaesthesia.

Systematic review of current natural language processing methods and applications in cardiology.

Natural language processing (NLP) is a set of automated methods to organise and evaluate the information contained in unstructured clinical notes, which are a rich source of real-world data from clinical care that may be used to improve outcomes and understanding of disease in cardiology. The purpose of this systematic review is to provide an understanding of NLP, review how it has been used to date within cardiology and illustrate the opportunities that this approach provides for both research and clinical care. We systematically searched six scholarly databases (ACM Digital Library, Arxiv, Embase, IEEE Explore, PubMed and Scopus) for studies published in 2015-2020 describing the development or application of NLP methods for clinical text focused on cardiac disease. Studies not published in English, lacking a description of NLP methods, non-cardiac focused and duplicates were excluded. Two independent reviewers extracted general study information, clinical details and NLP details and appraised quality using a checklist of quality indicators for NLP studies. We identified 37 studies developing and applying NLP in heart failure, imaging, coronary artery disease, electrophysiology, general cardiology and valvular heart disease. Most studies used NLP to identify patients with a specific diagnosis and extract disease severity using rule-based NLP methods. Some used NLP algorithms to predict clinical outcomes. A major limitation is the inability to aggregate findings across studies due to vastly different NLP methods, evaluation and reporting. This review reveals numerous opportunities for future NLP work in cardiology with more diverse patient samples, cardiac diseases, datasets, methods and applications.

Supporting Consensus Statements: Considerations and Recommendations for a Systematic Review Service.

Increasingly, a critical eye has been placed on the methodological quality of consensus statements. As expert systematic review (SR) methodologists, librarians are often called on to support consensus statement work. Using the Weill Cornell Medicine Samuel J. Wood Library's SR Service experience as a guide, the aim of this paper is to answer three main questions regarding librarians supporting consensus statement work: (1) What is a consensus statement? (2) What is consensus statement methodology and how does this compare to practice guidelines? (3) What are important and practical points to consider when supporting this kind of request?

Dnmt3a-mutated clonal hematopoiesis promotes osteoporosis.

Osteoporosis is caused by an imbalance of osteoclasts and osteoblasts, occurring in close proximity to hematopoietic cells in the bone marrow. Recurrent somatic mutations that lead to an expanded population of mutant blood cells is termed clonal hematopoiesis of indeterminate potential (CHIP). Analyzing exome sequencing data from the UK Biobank, we found CHIP to be associated with increased incident osteoporosis diagnoses and decreased bone mineral density. In murine models, hematopoietic-specific mutations in Dnmt3a, the most commonly mutated gene in CHIP, decreased bone mass via increased osteoclastogenesis. Dnmt3a-/- demethylation opened chromatin and altered activity of inflammatory transcription factors. Bone loss was driven by proinflammatory cytokines, including Irf3-NF-κB-mediated IL-20 expression from Dnmt3a mutant macrophages. Increased osteoclastogenesis due to the Dnmt3a mutations was ameliorated by alendronate or IL-20 neutralization. These results demonstrate a novel source of osteoporosis-inducing inflammation.