Blood and guts: how the intestinal microbiome shapes hematopoiesis and treatment of hematologic disease.

ABSTRACT: Over the past 10 years, there has been a marked increase in recognition of the interplay between the intestinal microbiome and the hematopoietic system. Despite their apparent distance in the body, a large literature now supports the relevance of the normal intestinal microbiota to steady-state blood production, affecting both hematopoietic stem and progenitor cells as well as differentiated immune cells. Microbial metabolites enter the circulation where they can trigger cytokine signaling that influences hematopoiesis. Furthermore, the state of the microbiome is now recognized to affect outcomes from hematopoietic stem cell transplant, immunotherapy, and cellular therapies for hematologic malignancies. Here we review the mechanisms by which microbiotas influence hematopoiesis in development and adulthood as well as the avenues by which microbiotas are thought to impact stem cell transplant engraftment, graft-versus-host disease, and efficacy of cell and immunotherapies. We highlight areas of future research that may lead to reduced adverse effects of antibiotic use and improved outcomes for patients with hematologic conditions.

Over but not gone: lingering epigenetic effects of COVID-19.

'Long COVID' affects nearly one in five adults who have had coronavirus disease 2019 (COVID-19), yet the mechanisms underlying this disorder remain poorly understood. In a new study, Cheong et al. show that the epigenetic and transcriptional state of myeloid immune cells and their progenitors are durably altered in patients following severe COVID-19.

Dismantling the tumoral cloak of self-protection.

Tumors protect themselves from immune clearance by promoting extramedullary hematopoiesis. A new study in PLOS Biology provides insights into the mechanisms underlying this process, which may hold the key to disrupting generation of the immunosuppressive tumor microenvironment.

Glucocorticoid response to naturalistic interactions between children and dogs.

Although research has shown that pets appear to provide certain types of social support to children, little is known about the physiological bases of these effects, especially in naturalistic contexts. In this study, we investigated the effect of free-form interactions between children (ages 8-10 years) and dogs on salivary cortisol concentrations in both species. We further investigated the role of the child-dog relationship by comparing interactions with the child's pet dog to interactions with an unfamiliar dog or a nonsocial control condition, and modeled associations between survey measures of the human-animal bond and children's physiological responses. In both children and dogs, salivary cortisol decreased from pre- to post-interaction; the effect was strongest for children interacting with an unfamiliar dog (compared to their pet dog) and for the pet dogs (compared to the unfamiliar dog). We found minimal evidence for associations between cortisol output and behaviors coded from video, but children scoring higher on survey measures of the human-animal bond exhibited the greatest reductions in cortisol when interacting with dogs. Self-reported loneliness was not related to cortisol or the human-animal bond, but measures of both loneliness and the human-animal bond were higher among children who participated after the onset of the COVID-19 pandemic, relative to those who participated before the pandemic. This study builds on previous work that investigated potential stress-buffering effects of human-animal interaction during explicit stressors and demonstrates important physiological correlates of naturalistic interactions between children and dogs, similar to those that occur in daily life.

High-depth next-generation sequencing panel testing in the evaluation of arteriovenous malformations.

Arteriovenous malformations (AVMs) are vascular lesions in which an overgrowth of blood vessels of varying sizes develops with one or more direct connections between the arterial and venous circulation. We performed a retrospective review of a cohort of 54 patients with AVMs referred to our clinical genomic laboratory for high-depth next-generation sequencing (NGS) panel of Disorders of Somatic Mosaicism (DoSM). Thirty-seven of 54 patients were female (68.5%). Among the 54 cases, 37 (68.5%) cases had pathogenic and/or likely pathogenic (P/LP) variants identified, two cases (3.7%) had variants of uncertain clinical significance, and the remaining 15 cases (27.8%) had negative results. MAP2K1 variants were found in 12 cases, followed by eight cases with KRAS variants and seven with TEK variants, and the remainder being identified in several other genes on the panel. Among the 37 positive cases, 32 cases had somatic alterations only; the remaining five cases had at least one germline P/LP variant, including four cases with PTEN and one with RASA1. Of note, two cases had the unexpected co-existence of two P/LP variants. In summary, this study illustrated the molecular diagnostic yield (68.5%) of this cohort of patients with a clinical indication of AVMs by our high-depth DoSM NGS panel.

Extensive blaschkoid hypopigmentation in a girl with MED12-related disorder.

MED12-related disorders represent a spectrum of rare neurodevelopmental disorders causing intellectual disability, dysmorphic features, and other systemic abnormalities. We report a case of a 21-month-old girl with extensive hypopigmentation following Blaschko lines attributed to underlying MED12-related disorder.

Forecasting hydrologic controls on juvenile anadromous fish out-migration with process-based modeling and machine learning.

River herring (Alosa sp.) are ecologically and economically foundational species in freshwater streams, estuaries, and oceanic ecosystems. The migration between fresh and saltwater is a key life stage of river herring, where the timing and magnitude of out-migration by juveniles can be limited when streams dry and hydrologic connectivity is lost. Operational decisions by water managers (e.g., restricting community water use) can impact out-migration success; however, these decisions are largely made without reliable predictions of outmigration potential across the migration season. This research presents a model to generate short-term forecasts of the probability of herring out-migration loss. We monitored streamflow and herring out-migration for 2 years at three critical runs along Long Island Sound (CT, USA) to develop empirical understandings of the hydrologic controls on out-migration. We used calibrated Soil and Water Assessment Tool hydrologic models of each site to generate 10,000 years of daily synthetic meteorological and streamflow records. These synthetic meteorological and streamflow data were used to train random forest models to provide rapid within-season forecasts of out-migration loss from two simple predictors: current spawning reservoir depth and the previous 30-day precipitation total. The resulting models were approximately 60%-80% accurate with a 1.5-month lead time and 70-90% accurate within 2 weeks. We anticipate that this tool will support regional decisions on spawning reservoir operations and community water withdrawals. The architecture of this tool provides a framework to facilitate broader predictions of the ecological consequences of streamflow connectivity loss in human-impacted watersheds.

Geropsychology training at the doctoral level: a program evaluation case example.

While the older adult population continues to grow, psychologists specializing in geropsychology remain a small fraction of the workforce. Facing this reality, it is essential for training programs to better monitor whether their students receive adequate training to serve older adults. The current study describes a brief, logistically feasible, and cost-effective program evaluation conducted within one APA-accredited clinical psychology doctoral program. The evaluation consisted of an online survey of doctoral students (n = 99) that explored their field training experiences with older adults, coursework related to aging, and their overall interest in working with older adults. Students reported significantly less coursework and significantly less field work focused on serving older adults when compared to other age groups. However, students reported a high level of interest in learning about aging, with a total of 73.74% of participants (n = 73) reporting at least some current interest. A number of institutional actions resulted from this evaluation, which demonstrate how a brief evaluation can yield data that is practically useful. This case example provides a useful model for others to follow, and may support other institutions' efforts to evaluate, monitor, and make potential improvements to aging-related training in their own programs.

Plasma IL-2 and Symptoms Response after Acute Gluten Exposure in Subjects With Celiac Disease or Nonceliac Gluten Sensitivity.

INTRODUCTION: Treated patients with celiac disease (CeD) and nonceliac gluten sensitivity (NCGS) report acute, transient, incompletely understood symptoms after suspected gluten exposure. To determine whether (i) blinded gluten exposure induces symptoms, (ii) subjects accurately identify gluten exposure, and (iii) serum interleukin-2 (IL-2) levels distinguish CeD from NCGS subjects after gluten exposure. METHODS: Sixty subjects (n = 20 treated, healed CeD; n = 20 treated NCGS; n = 20 controls) were block randomized to a single, double-blind sham (rice flour) or 3-g gluten challenge with 72-hours follow-up. Twelve serial questionnaires (100 mm visual analog scale; pain, bloating, nausea, and fatigue) and 10 serial plasma samples were collected. Mucosal permeability was assessed using both urinary lactulose-13C mannitol ratios and endoscopic mucosal impedance. RESULTS: Thirty-five of 40 (83%) subjects with CeD and NCGS reported symptoms with gluten (8 CeD, 9 NCGS) and sham (9 CeD, 9 NCGS) compared with 9 of 20 (45%) controls after gluten (n = 6) and sham (n = 3). There was no significant difference in symptoms among groups. Only 2 of 10 subjects with CeD and 4 of 10 NCGS identified gluten, whereas 8 of 10 subjects with CeD and 5 of 10 NCGS identified sham. A significant plasma IL-2 increase occurred only in subjects with CeD after gluten, peaking at 3 hours and normalizing within 24 hours postchallenge despite no significant intestinal permeability change from baseline. DISCUSSION: Symptoms do not reliably indicate gluten exposure in either subjects with CeD or NCGS. IL-2 production indicates a rapid-onset gluten-induced T-cell activation in CeD despite long-standing treatment. The effector site is unknown, given no increased intestinal permeability after gluten.

Atopic asthma as a potentially significant but unrecognized risk factor for Kawasaki disease in children.

OBJECTIVES: Childhood asthma is known to be associated with risks of both respiratory and non-respiratory infections. Little is known about the relationship between asthma and the risk of Kawasaki disease (KD). We assessed associations of asthma status and asthma phenotype (e.g. atopic asthma) with KD. METHODS: We performed a population-based retrospective case-control study, using KD cases between January 1, 1979, and December 31, 2016, and two matched controls per case. KD cases were defined by the American Heart Association diagnostic criteria. Asthma status prior to KD (or control) index dates was ascertained by the two asthma criteria, Predetermined Asthma Criteria (PAC) and Asthma Predictive Index (API, a surrogate phenotype of atopic asthma). We assessed whether 4 phenotypes (both PAC + and API+; PAC + only; API + only, and non-asthmatics) were associated with KD. RESULTS: There were 124 KD cases during the study period. The group having both PAC + and API + was significantly associated with the increased odds of KD, compared to non-asthmatics (odds ratio [OR] 4.3; 95% CI: 1.3 - 14.3). While asthma defined by PAC was not associated with KD, asthma defined by PAC positive with eosinophilia (≥4%) was significantly associated with the increased odds of KD (OR: 6.7; 95% CI: 1.6 - 28.6) compared to non-asthmatics. Asthma status defined by API was associated with KD (OR = 4.7; 95% CI: 1.4-15.1). CONCLUSIONS: Atopic asthma may be associated with increased odds of KD. Further prospective studies are needed to determine biological mechanisms underlying the association between atopic asthma and increased odds of KD.

Robotic vs. minimally invasive mitral valve repair: A 5-year comparison of surgical outcomes.

BACKGROUND: Minimally invasive mitral valve repair (MVr) is commonly performed. Data on the outcomes of robotic MVr versus nonrobotic minimally invasive MVr are lacking. We sought to compare the short-term and mid-term outcomes of robotic and nonrobotic MVr. METHODS: We reviewed all patients who underwent robotic MVr (n = 424) or nonrobotic MVr via right mini-thoracotomy (n = 86) at Mayo Clinic, Rochester, MN, from January 2015 to February 2020. Data on baseline and operative characteristics, operative and long-term outcomes were analyzed. Patients were matched 1:1 using propensity scores. RESULTS: Sixty-nine matched pairs were included in the study. The median age was 59 years (interquartile range [IQR]: 54-69) and 75% (n = 103) were male. Baseline characteristics were similar after matching. Robotic and nonrobotic MVr had similar operative characteristics, except that robotic had longer cross-clamp times (57 [48-67] vs. 47 [37-58] min, p < .001) and more P2 resections (83% vs. 68%, p = .05) compared to nonrobotic MVr. There was no difference in operative outcomes between groups. Hospital stay was shorter after robotic MVr (4 [3-4] vs. 4 [4-6] days, p = .003). After a median follow-up of 3.3 years (IQR, 2.1-4.5), there was no mortality in either group, and there was no difference in freedom from mitral valve reoperations between robotic and nonrobotic MVr (5 years: 97.1% vs. 95.7%, p = .63). Follow-up echocardiogram analysis predicted excellent freedom from recurrent moderate-or-severe mitral regurgitation at 3 years after robotic and nonrobotic MVr (90% vs. 92%, p = .18, respectively). CONCLUSIONS: Both short-term and mid-term outcomes of robotic and nonrobotic minimally invasive mitral repair surgery are comparable.

Community-Based Study of Celiac Disease Autoimmunity Progression in Adults.

BACKGROUND & AIMS: Celiac disease can develop at any age, but outcomes of adults with positive results from serologic tests for tissue transglutaminase antibodies (tTGA) without endoscopic determination of celiac disease (called celiac autoimmunity) have not been thoroughly evaluated. We investigated the proportion of adults with celiac autoimmunity at a community medical center and their progression to celiac disease. METHODS: We analyzed waste blood samples from a community clinic from 15,551 adults for tTGA and, if titer results were above 2 U/mL, for endomysial antibody. The blood samples had been collected at 2 time points (median interval, 8.8 years) from 2006 through 2017. We collected data from the clinic on diagnoses of celiac disease based on duodenal biopsy analysis. RESULTS: Of the serum samples collected at the first time point, 15,398 had negative results for tTGA, and 153 had positive results for tTGA (>4 U/mL). Based on medical records, 6 individuals received a diagnosis of celiac disease, for a cumulative incidence of celiac disease diagnosis of 0.06% (95% confidence interval, 0.01-0.11). Forty-nine (0.32%) individuals with a negative result from the first serologic test for tTGA had a positive result from the second test. Among the 153 adults who were tTGA positive at the first time point, 31 (20%) had a subsequent diagnosis of celiac disease, 81 (53%) remained positive for tTGA without a clinical diagnosis of celiac disease, and 41 (27%) had negative test results for tTGA at the second time point. Higher initial tTGA titers, female sex, and a history of hypothyroidism and autoimmune disease were associated with increased risks of subsequent diagnosis of celiac disease. Interestingly, adults whose first blood sample had a positive test result but second blood sample had a negative result for tTGA were older, had lower-than-average initial tTGA titer results, and had a higher mean body mass index than adults whose blood samples were positive for tTGA at both time points and adults later diagnosed with celiac disease. CONCLUSIONS: In an analysis of serum samples collected from a community clinic an average of 8.8 years apart, we found that fewer than 1% of adults with negative results from an initial test for tTGA have a positive result on a second test. Of adults with positive results from the test for tTGA, only 20% are later diagnosed with celiac disease; the remaining individuals maintain persistent increases in tTGA without diagnoses of celiac disease or have negative results from second tests.

Reproductive Characteristics and Pregnancy Outcomes in Hidden Celiac Disease Autoimmunity.

INTRODUCTION: Untreated symptomatic celiac disease (CD) adversely affects female reproduction; however, the effect of hidden CD autoimmunity is uncertain. METHODS: We identified women who were not previously diagnosed with CD and tested positive for tissue transglutaminase and endomysial antibodies between 2006 and 2011 in a community-based retrospective cohort study. We evaluated (i) the rate of adverse pregnancy outcomes and medical complications of pregnancy in successful singleton deliveries and (ii) reproductive characteristics in seropositive women without a clinical diagnosis of CD and age-matched seronegative women. RESULTS: Among 17,888 women whose serum samples were tested for CD autoimmunity, 215 seropositive and 415 seronegative women were included. We reviewed 231 and 509 live singleton deliveries of 117 seropositive and 250 seronegative mothers, respectively. Menarche and menopausal age, gravidity, parity, and age at first child were similar in seropositive and seronegative women. CD seropositivity was not associated with an increased risk of maternal pregnancy complications. Maternal seropositivity was associated with small for gestational age in boys (OR 3.77, 95% CI: 1.47-9.71; P = 0.006), but not in girls (OR 0.57, 95% CI: 0.15-2.17; P = 0.41). CD serum positivity was not associated with prematurity, small for gestational age (birth weight <10th percentile), or 5-minute Apgar score of less than 7. DISCUSSION: Although underpowered, the present study did not show any difference in reproductive characteristics or rates of adverse pregnancy outcomes in women with and without CD autoimmunity, except for birth weight in male offspring. Larger studies are needed to determine the effects of CD autoimmunity on female reproduction.

A diagnostic codes-based algorithm improves accuracy for identification of childhood asthma in archival data sets.

OBJECTIVE: While a single but truncated ICD code (493) had been widely used for identifying asthma in asthma care and research, it significantly under-identifies asthma. We aimed to develop and validate a diagnostic codes-based algorithm for identifying asthmatics using Predetermined Asthma Criteria (PAC) as the reference. METHODS: This is a retrospective cross-sectional study which utilized two different coding systems, the Hospital Adaptation of the International Classification of Diseases, Eighth Revision (H-ICDA) and the International Classification of Diseases, Ninth Revision (ICD-9). The algorithm was developed using two population-based asthma study cohorts, and validated in a validation cohort, a random sample of the 1976-2007 Olmsted County Birth Cohort. Performance of the diagnostic codes-based algorithm for ascertaining asthma status against manual chart review for PAC (gold standard) was assessed by determining both criterion and construct validity. RESULTS: Among eligible 267 subjects of the validation cohort, 50% were male, 70% white, and the median age at last follow-up was 17 (interquartile range, 8.7-24.4) years. Asthma prevalence by PAC through manual chart review was 34%. Sensitivity and specificity of the codes-based algorithm for identifying asthma were 82% and 98% respectively. Associations of asthma-related risk factors with asthma status ascertained by the code-based algorithm were similar to those by the manual review. CONCLUSIONS: The diagnostic codes-based algorithm for identifying asthmatics improves accuracy of identification of asthma and can be a useful tool for large scale studies in a setting without automated chart review capabilities.

Impact of postoperative complications after cardiac surgery on long-term survival.

PURPOSE: The impact of postoperative complications on long-term survival is not well characterized. We sought to study the prevalence of postoperative complications after cardiac surgery and their impact on long-term survival. METHODS: Operative survivors (n = 26,221) who underwent coronary artery bypass grafting (CABG) (n = 13,054, 49.8%), valve surgery (n = 8667, 33.1%) or combined CABG and valve surgery (n = 4500, 17.2%) from 1993 to 2019 were included in the study. Records were reviewed for postoperative complications and long-term survival. Propensity-match analysis was performed between patients who did and did not have a postoperative complication. The associations between postoperative complications and survival were assessed using a Cox-proportional model. RESULTS: Complications occurred in 17,463 (66.6%) of 26,221 operative survivors. A total of 17 postoperative complications were analyzed. Postoperative blood product use was the commonest (n = 12,397, 47.3%), followed by atrial fibrillation (n = 8399, 32.0%), prolonged ventilation (n = 2336, 8.9%), renal failure (n = 870, 3.3%), reoperation for bleeding (n = 859, 3.3%) and pacemaker/ICD insertion (n = 795, 3.0%). Stroke (hazard ratio [HR]: 1.55; 95% confidence interval [CI]: 1.36-1.77), renal failure (HR: 1.45; 95% CI: 1.33-1.58) and pneumonia (HR: 1.23; 95% CI: 1.11-1.36) had the strongest impact on long-term survival. Long-term survival decreased as the number of postoperative complications increased. CONCLUSIONS: Postoperative complications after cardiac surgery significantly impact outcomes that extend beyond the postoperative period. Stroke, renal failure, and pneumonia are particularly associated with poor long-term survival.

Long-term Incidence of Kawasaki Disease in a North American Community: A Population-Based Study.

To assess the longitudinal incidence of Kawasaki disease (KD) within the well-defined predominantly White population of Olmsted County, MN. This retrospective cohort study used a population-based medical record linkage system and manual chart reviews to identify children with KD in Olmsted County, MN between January 1, 1979-December 31, 2016. Age- and gender-adjusted incidence rates were calculated using the 2010 U.S. White population. 124 children with KD were confirmed during the study period (median age 3.5, 61% male, 85% White, 9% Asian). The overall age- and gender-adjusted incidence rates for all ages and < 5 years old were 9.8 and 21.4 per 100,000 person-years, respectively. There was an overall increase in incidence up to 1994 followed by plateau, except among children between the ages of 1-5 years. There was also an overall increase in incidence among females compared to males. 24% of children had cardiac complications. While the overall incidence of KD in Olmsted County appears to be stable since 1994, the incidence of KD in subgroups of children 1-5 years old and females seems to have increased. Given the rising trends and one-quarter of children developing cardiac complications, further studies identifying factors driving these trends are warranted.

Hematopoiesis and the bacterial microbiome.

Recent studies have revealed that the intestinal bacterial microbiome plays an important role in the regulation of hematopoiesis. A correlation between adverse hematologic effects and imbalance of the intestinal microbiome, or dysbiosis, is evident in several human conditions, such as inflammatory bowel disease, obesity, and, critically, in the setting of antibiotic exposure. Here we review the effects of gut dysbiosis on the hematological compartment and our current understanding of the mechanisms through which changes in the bacterial microbiome affect hematopoiesis.

Management of Coronary Artery Aneurysms at the Time of Surgical Revascularization.

BACKGROUND: Coronary artery aneurysms (CAAs) represent a rare pathology occurring in 1.5%-5% of routine coronary angiograms. Limited data exist on the management of CAA at the time of cardiac surgery. MATERIALS AND METHODS: A single-institution retrospective review was performed on 53 patients who underwent cardiac surgery in the setting of atherosclerotic CAA between 1993 and 2015. Patients were stratified based on treatment strategy: exclusion and distal bypass (n = 26) versus revascularization alone (n = 27). Comparisons were made with respect to mortality, need for further/concomitant interventions, and long-term cardiac function including myocardial infarctions and congestive heart failure. RESULTS: A total of 53 patients underwent cardiac surgery in the setting of CAA disease. Management strategies included ligation and bypass in 26 patients and distal bypass only in 27 patients (with four of the patients in this group undergoing coronary stenting across the aneurysm). There were no significant differences in patient demographics between the two groups. No significant difference was found in either 30-d (P = 0.74) or long-term mortality when exclusion of the CAA was performed compared with revascularization alone (P = 0.20). More exclusion procedures were performed earlier in the experience (median surgical date 2000), whereas revascularization alone predominated later in the experience (median surgical date 2007; P ≤ 0.001). CONCLUSIONS: The practice of CAA exclusion, while still performed in selected cases, has largely been supplanted in patients undergoing revascularization. Exclusion does not appear to offer any advantage over isolated revascularization, supporting the current trends in managing this rare condition.

Effect of a Gluten-free Diet on Quality of Life in Patients With Nonclassical Versus Classical Presentations of Celiac Disease.

BACKGROUND: Celiac disease (CD) often presents with symptoms of diarrhea and malabsorption, termed classical CD. However, it can also present as nonclassical CD, which is commonly associated with nongastrointestinal symptoms. Studies suggest that nonclassical CD tends to have less severe symptoms than classical CD, which may affect both adherence to a gluten-free diet (GFD) and psychological stress. Therefore, we compared adherence to a GFD and psychological measures, including quality of life (QOL) and somatization, between patients with nonclassical and classical presentations of CD. METHODS: Patients at a tertiary care center with biopsy-proven CD, who completed a Talley Bowel Disease Questionnaire and the Short Form-36 at diagnosis and who had been on a GFD for at least 1 year, were included in this study. Patients were further surveyed to assess gastrointestinal symptoms, QOL, Somatization Symptom Checklist (SSC), and adherence to a GFD. Results were compared between patients with classical versus nonclassical CD presentation. RESULTS: Among 122 patients included in this study, 62 had classical CD and 60 had nonclassical CD. At diagnosis, health-related QOL was lower in the classical CD group than in the nonclassical CD group. After following a GFD, both groups had improved QOL after following a GFD, and body mass index significantly increased in both groups. Most subscales of QOL, SSC scores, and adherence to the GFD were similar between the groups, except the Short Form-36 Mental Component summary scores that were still lower in the classical CD (48.4 vs. 52.6 nonclassical CD group; P=0.03). CONCLUSIONS: Despite QOL at diagnosis being higher in those with nonclassical CD versus lower in those with classical CD, both groups had improved QOL and achieved a similar QOL after following a GFD.

mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert).

A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term G(Alert). Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(Alert) functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.