Predator-induced transgenerational plasticity of parental care behaviour in male three-spined stickleback fish across two generations.

Parental care is a critical determinant of offspring fitness, and parents adjust their care in response to ecological challenges, including predation risk. The experiences of both mothers and fathers can influence phenotypes of future generations (transgenerational plasticity). If it is adaptive for parents to alter parental care in response to predation risk, then we expect F1 and F2 offspring who receive transgenerational cues of predation risk to shift their parental care behaviour if these ancestral cues reliably predict a similarly risky environment as their F0 parents. Here, we used three-spined sticklebacks (Gasterosteus aculeatus) to understand how paternal exposure to predation risk prior to mating alters reproductive traits and parental care behaviour in unexposed F1 sons and F2 grandsons. Sons of predator-exposed fathers took more attempts to mate than sons of control fathers. F1 sons and F2 grandsons with two (maternal and paternal) predator-exposed grandfathers shifted their paternal care (fanning) behaviour in strikingly similar ways: they fanned less initially, but fanned more near egg hatching. This shift in fanning behaviour matches shifts observed in response to direct exposure to predation risk, suggesting a highly conserved response to pre-fertilization predator exposure that persists from the F0 to the F1 and F2 generations.

The transgenerational consequences of paternal social isolation and predation exposure in threespined sticklebacks.

Parents routinely encounter stress in the ecological environment that can affect offspring development (transgenerational plasticity: TGP); however, parents' interactions with conspecifics may alter how parents respond to ecological stressors. During social buffering, the presence of conspecifics can reduce the response to or increase the speed of recovery from a stressor. This may have cascading effects on offspring if conspecifics can mitigate parental responses to ecological stress in ways that blunt the transmission of stress-induced transgenerational effects. Here, we simultaneously manipulated both paternal social isolation and experience with predation risk prior to fertilisation in threespined stickleback (Gasterosteus aculeatus). We generated offspring via in-vitro fertilisation to allow us to isolate paternal effects mediated via sperm alone (i.e. in the absence of paternal care). If social buffering mitigates TGP induced by paternal exposure to predation risk, then we expect the transgenerational effects of predation exposure to be weaker when a conspecific is present compared to when the father is isolated. Offspring of predator-exposed fathers showed reduced anxiety-like behaviour and tended to be captured faster by the predator. Fathers who were socially isolated also had offspring that were captured faster by a live predator, suggesting that paternal social isolation may have maladaptive effects on how offspring respond to ecological stressors. Despite additive effects of paternal social isolation and paternal predation risk, we found no evidence of an interaction between these paternal treatments, suggesting that the presence of a conspecific did not buffer fathers and/or offspring from the effects of predation risk. Our results suggest that socially induced stress is an important, yet underappreciated, mediator of TGP and can elicit transgenerational effects even in species that do not form permanent social groups. Future studies should therefore consider how the parental social environment can affect both within and trans-generational responses to ecological stressors.

Social Environment Influences the Temporal Dynamics of Sneak-Spawning in a Fish with Alternative Reproductive Tactics.

AbstractSeveral predictions of sperm competition theory are not well supported empirically. One potential reason is that most current theory and empirical research ignore how the social environment influence the temporal dynamics of mating. We propose that understanding these dynamics is key to understanding sexual selection and improving the predictive power of theory. To demonstrate the importance of these dynamics, we quantify how males' social role, interactions among males, and current social environment influence the timing of mating in Symphodus ocellatus, a species with three alternative male reproductive tactics. Nesting males spawn synchronously with females; sneakers and satellites sneak-spawn with some time delay. Satellites also cooperate with nesting males. We found that satellites have shorter sneak-spawning delays than sneakers, a benefit of their cooperation with nesting males. Sneak-spawning delays decreased with increasing nest activity for sneakers but not for satellites, suggesting that sneakers may benefit from increased sperm competition intensity. Current sperm competition models ignore this potential benefit, which may be why the prediction that males should decrease investment when sperm competition involves more than two males is not well supported. Our study provides insight into mechanisms that drive variation in the timing of spawning, which could explain mismatches between theoretical and empirical results.

Racial Disparities in Pediatric Inflammatory Bowel Disease Care: Differences in Outcomes and Health Service Utilization Between Black and White Children.

OBJECTIVE: To describe racial inequities in pediatric inflammatory bowel disease care and explore potential drivers. METHODS: We undertook a single-center, comparative cohort study of newly diagnosed Black and non-Hispanic White patients with inflammatory bowel disease, aged <21 years, from January 2013 through 2020. Primary outcome was corticosteroid-free remission (CSFR) at 1 year. Other longitudinal outcomes included sustained CSFR, time to anti-tumor necrosis factor therapy, and evaluation of health service utilization. RESULTS: Among 519 children (89% White, 11% Black), 73% presented with Crohn's disease and 27% with ulcerative colitis. Disease phenotype did not differ by race. More patients from Black families had public insurance (58% vs 30%, P < .001). Black patients were less likely to achieve CSFR 1-year post diagnosis (OR: 0.52, 95% CI:0.3-0.9) and less likely to achieve sustained CSFR (OR: 0.48, 95% CI: 0.25-0.92). When adjusted by insurance type, differences by race to 1-year CSFR were no longer significant (aOR: 0.58; 95% CI: 0.33, 1.04; P = .07). Black patients were more likely to transition from remission to a worsened state, and less likely to transition to remission. We found no differences in biologic therapy utilization or surgical outcomes by race. Black patients had fewer gastroenterology clinic visits and 2-fold increased odds for emergency department visits. CONCLUSIONS: We observed no differences by race in phenotypic presentation and medication usage. Black patients had half the odds of achieving clinical remission, but a degree of this was mediated by insurance status. Understanding the cause of such differences will require further exploration of social determinants of health.

Vertical transmission of horizontally acquired social information in sticklebacks: implications for transgenerational plasticity.

There is growing evidence that offspring receive information about their environment vertically, i.e. from their parents (environmental parental effects or transgenerational plasticity). For example, parents exposed to predation risk may produce offspring with heightened antipredator defences. At the same time, organisms can gain information about the environment horizontally, from conspecifics. In this study, we provide some of the first evidence that horizontally acquired social information can be transmitted vertically across generations. Three-spined stickleback (Gasterosteus aculeatus) fathers produced larval offspring with altered antipredator behaviour when fathers received visual and olfactory cues from predator-chased neighbours. Although fathers did not personally witness their neighbours being chased (i.e. they never saw the predator), changes in offspring traits were similar to those induced by direct paternal exposure to predation risk. These findings suggest that two different non-genetic pathways (horizontal transfer of social information, vertical transfer via sperm-mediated paternal effects) can combine to affect offspring phenotypes. The implications of simultaneous horizontal and vertical transmission are widely appreciated in the context of disease and culture; our results suggest that they could be equally important for the maintenance of phenotypic variation and could have profound consequences for the rate at which information flows within and across generations.

An Integrative Framework for Understanding the Mechanisms and Multigenerational Consequences of Transgenerational Plasticity.

Transgenerational plasticity (TGP) occurs when the environment experienced by a parent influences the development of their offspring. In this article, we develop a framework for understanding the mechanisms and multi-generational consequences of TGP. First, we conceptualize the mechanisms of TGP in the context of communication between parents (senders) and offspring (receivers) by dissecting the steps between an environmental cue received by a parent and its resulting effects on the phenotype of one or more future generations. Breaking down the problem in this way highlights the diversity of mechanisms likely to be involved in the process. Second, we review the literature on multigenerational effects and find that the documented patterns across generations are diverse. We categorize different multigenerational patterns and explore the proximate and ultimate mechanisms that can generate them. Throughout, we highlight opportunities for future work in this dynamic and integrative area of study.

Sex-specific plasticity across generations II: Grandpaternal effects are lineage specific and sex specific.

Transgenerational plasticity (TGP) occurs when the environment encountered by one generation (F0) alters the phenotypes of one or more future generations (e.g. F1 and F2). Sex selective TGP, via specific lineages or to only male or female descendants, has been underexplored in natural systems, and may be adaptive if it allows past generations to fine-tune the phenotypes of future generations in response to sex-specific life-history strategies. We sought to understand if exposing males to predation risk can influence grandoffspring via sperm in three-spined stickleback Gasterosteus aculeatus. We specifically tested the hypothesis that grandparental effects are transmitted in a sex-specific way down the male lineage, from paternal grandfathers to F2 males. We reared F1 offspring of unexposed and predator-exposed F0 males under 'control' conditions and used them to generate F2s with control grandfathers, a predator-exposed maternal grandfather (i.e. predator-exposed F0 males to F1 daughters to F2s), a predator-exposed paternal grandfather (i.e. predator-exposed F0 males to F1 sons to F2s) or two predator-exposed grandfathers. We then assayed male and female F2s for a variety of traits related to antipredator defence. We found little evidence that transgenerational effects were mediated to only male descendants via the paternal lineage. Instead, grandpaternal effects depended on lineage and were mediated largely across sexes, from F1 males to F2 females and from F1 females to F2 males. When their paternal grandfather was exposed to predation risk, female F2s were heavier and showed a reduced change in behaviour in response to a simulated predator attack relative to grandoffspring of control, unexposed grandparents. In contrast, male F2s showed reduced antipredator behaviour when their maternal grandfather was exposed to predation risk. However, these patterns were only evident when one grandfather, but not both grandfathers, was exposed to predation risk, suggesting the potential for non-additive interactions across lineages. If sex-specific and lineage effects are common, then grandparental effects are likely underestimated in the literature. These results draw attention to the importance of sex-selective inheritance of environmental effects and raise new questions about the proximate and ultimate causes of selective transmission across generations.

Sex-specific plasticity across generations I: Maternal and paternal effects on sons and daughters.

Intergenerational plasticity or parental effects-when parental environments alter the phenotype of future generations-can influence how organisms cope with environmental change. An intriguing, underexplored possibility is that sex-of both the parent and the offspring-plays an important role in driving the evolution of intergenerational plasticity in both adaptive and non-adaptive ways. Here, we evaluate the potential for sex-specific parental effects in a freshwater population of three-spined sticklebacks Gasterosteus aculeatus by independently and jointly manipulating maternal and paternal experiences and separately evaluating their phenotypic effects in sons versus daughters. We tested the adaptive hypothesis that daughters are more responsive to cues from their mother, whereas sons are more responsive to cues from their father. We exposed mothers, fathers or both parents to visual cues of predation risk and measured offspring antipredator traits and brain gene expression. Predator-exposed fathers produced sons that were more risk-prone, whereas predator-exposed mothers produced more anxious sons and daughters. Furthermore, maternal and paternal effects on offspring survival were non-additive: offspring with a predator-exposed father, but not two predator-exposed parents, had lower survival against live predators. There were also strong sex-specific effects on brain gene expression: exposing mothers versus fathers to predation risk activated different transcriptional profiles in their offspring, and sons and daughters strongly differed in the ways in which their brain gene expression profiles were influenced by parental experience. We found little evidence to support the hypothesis that offspring prioritize their same-sex parent's experience. Parental effects varied with both the sex of the parent and the offspring in complicated and non-additive ways. Failing to account for these sex-specific patterns (e.g. by pooling sons and daughters) would have underestimated the magnitude of parental effects. Altogether, these results draw attention to the potential for sex to influence patterns of intergenerational plasticity and raise new questions about the interface between intergenerational plasticity and sex-specific selective pressures, sexual conflict and sexual selection.

Within-group relatedness is correlated with colony-level social structure and reproductive sharing in a social fish.

In group-living species, the degree of relatedness among group members often governs the extent of reproductive sharing, cooperation and conflict within a group. Kinship among group members can be shaped by the presence and location of neighbouring groups, as these provide dispersal or mating opportunities that can dilute kinship among current group members. Here, we assessed how within-group relatedness varies with the density and position of neighbouring social groups in Neolamprologus pulcher, a colonial and group-living cichlid fish. We used restriction site-associated DNA sequencing (RADseq) methods to generate thousands of polymorphic SNPs. Relative to microsatellite data, RADseq data provided much tighter confidence intervals around our relatedness estimates. These data allowed us to document novel patterns of relatedness in relation to colony-level social structure. First, the density of neighbouring groups was negatively correlated with relatedness between subordinates and dominant females within a group, but no such patterns were observed between subordinates and dominant males. Second, subordinates at the colony edge were less related to dominant males in their group than subordinates in the colony centre, suggesting a shorter breeding tenure for dominant males at the colony edge. Finally, subordinates who were closely related to their same-sex dominant were more likely to reproduce, supporting some restraint models of reproductive skew. Collectively, these results demonstrate that within-group relatedness is influenced by the broader social context, and variation between groups in the degree of relatedness between dominants and subordinates can be explained by both patterns of reproductive sharing and the nature of the social landscape.

Reproductive sharing in relation to group and colony-level attributes in a cooperative breeding fish.

The degree to which group members share reproduction is dictated by both within-group (e.g. group size and composition) and between-group(e.g. density and position of neighbours) characteristics. While many studies have investigated reproductive patterns within social groups, few have simultaneously explored how within-group and between-group social structure influence these patterns. Here, we investigated how group size and composition, along with territory density and location within the colony, influenced parentage in 36 wild groups of a colonial, cooperatively breeding fish Neolamprologus pulcher. Dominant males sired 76% of offspring in their group, whereas dominant females mothered 82% of offspring in their group. Subordinate reproduction was frequent, occurring in 47% of sampled groups. Subordinate males gained more paternity in groups located in high-density areas and in groups with many subordinate males. Dominant males and females in large groups and in groups with many reproductively mature subordinates had higher rates of parentage loss, but only at the colony edge. Our study provides, to our knowledge,the first comprehensive quantification of reproductive sharing among groups of wild N. pulcher, a model species for the study of cooperation and social behaviour. Further, we demonstrate that the frequency of extra-pair parentage differs across small social and spatial scales.

A comparative study of an innate immune response in Lamprologine cichlid fishes.

Social interactions facilitate pathogen transmission and increase virulence. Therefore, species that live in social groups are predicted to suffer a higher pathogen burden, to invest more heavily in immune defence against pathogens, or both. However, there are few empirical tests of whether social species indeed invest more heavily in immune defence than non-social species. In the current study, we conducted a phylogenetically controlled comparison of innate immune response in Lamprologine cichlid fishes. We focused on three species of highly social cichlids that live in permanent groups and exhibit cooperative breeding (Julidochromis ornatus, Neolamprologus pulcher and Neolamprologus savoryi) and three species of non-social cichlids that exhibit neither grouping nor cooperative behaviour (Telmatochromis temporalis, Neolamprologus tetracanthus and Neolamprologus modestus). We quantified the innate immune response by injecting wild fishes with phytohaemagglutinin (PHA), a lectin that causes a cell-mediated immune response. We predicted that the three highly social species would show a greater immune reaction to the PHA treatment, indicating higher investment in immune defence against parasites relative to the three non-social species. We found significant species-level variation in immune response, but contrary to our prediction, this variation did not correspond to social system. However, we found that immune response was correlated with territory size across the six species. Our results indicate that the common assumption of a positive relationship between social system and investment in immune function may be overly simplistic. We suggest that factors such as rates of both in-group and out-group social interactions are likely to be important mediators of the relationship between sociality and immune function.

Understanding beyond grasping propositions: a discussion of chess and fish.

In this paper, we argue that, contra Strevens (2013), understanding in the sciences is sometimes partially constituted by the possession of abilities; hence, it is not (in such cases) exhausted by the understander's bearing a particular psychological or epistemic relationship to some set of structured propositions. Specifically, the case will be made that one does not really understand why a modeled phenomenon occurred unless one has the ability to actually work through (meaning run and grasp at each step) a model simulation of the underlying dynamic.

Patient-Reported Outcomes Correlate With Microbial Community Composition Independent of Mucosal Inflammation in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel diseases (IBDs) involve an aberrant host response to intestinal microbiota causing mucosal inflammation and gastrointestinal symptoms. Patient-reported outcomes (PROs) are increasingly important in clinical care and research. Our aim was to examine associations between PROs and fecal microbiota in patients 0 to 22 years of age with IBD. METHODS: A longitudinal, prospective, single-center study tested for associations between microbial community composition via shotgun metagenomics and PROs including stool frequency and rectal bleeding in ulcerative colitis (UC) and abdominal pain and stool frequency in Crohn's disease (CD). Mucosal inflammation was assessed with fecal calprotectin. A negative binomial mixed-effects model including clinical characteristics and fecal calprotectin tested for differentially abundant species and metabolic pathways by PROs. RESULTS: In 70 CD patients with 244 stool samples, abdominal pain correlated with increased relative abundance of Haemophilus and reduced Clostridium spp. There were no differences relative to calprotectin level. In 23 UC patients with 76 samples, both rectal bleeding and increased stool frequency correlated with increased Klebsiella and reduced Bacteroides spp. Conversely, UC patients with lower calprotectin had reduced Klebsiella. Both UC and CD patients with active symptoms exhibited less longitudinal microbial community stability. No differences in metabolic pathways were observed in CD. Increased sulfoglycolysis and ornithine biosynthesis correlated with symptomatic UC. CONCLUSIONS: Microbial community composition correlated with PROs in both CD and UC. Metabolic pathways differed relative to PROs in UC, but not CD. Data suggest that microbiota may contribute to patient symptoms in IBD, in addition to effects of mucosal inflammation.

Human iPSC-derived hepatocyte system models cholestasis with tight junction protein 2 deficiency.

Background & Aims: The truncating mutations in tight junction protein 2 (TJP2) cause progressive cholestasis, liver failure, and hepatocyte carcinogenesis. Due to the lack of effective model systems, there are no targeted medications for the liver pathology with TJP2 deficiency. We leveraged the technologies of patient-specific induced pluripotent stem cells (iPSC) and CRISPR genome-editing, and we aim to establish a disease model which recapitulates phenotypes of patients with TJP2 deficiency. Methods: We differentiated iPSC to hepatocyte-like cells (iHep) on the Transwell membrane in a polarized monolayer. Immunofluorescent staining of polarity markers was detected by a confocal microscope. The epithelial barrier function and bile acid transport of bile canaliculi were quantified between the two chambers of Transwell. The morphology of bile canaliculi was measured in iHep cultured in the Matrigel sandwich system using a fluorescent probe and live-confocal imaging. Results: The iHep differentiated from iPSC with TJP2 mutations exhibited intracellular inclusions of disrupted apical membrane structures, distorted canalicular networks, altered distribution of apical and basolateral markers/transporters. The directional bile acid transport of bile canaliculi was compromised in the mutant hepatocytes, resembling the disease phenotypes observed in the liver of patients. Conclusions: Our iPSC-derived in vitro hepatocyte system revealed canalicular membrane disruption in TJP2 deficient hepatocytes and demonstrated the ability to model cholestatic disease with TJP2 deficiency to serve as a platform for further pathophysiologic study and drug discovery. Lay summary: We investigated a genetic liver disease, progressive familial intrahepatic cholestasis (PFIC), which causes severe liver disease in newborns and infants due to a lack of gene called TJP2. By using cutting-edge stem cell technology and genome editing methods, we established a novel disease modeling system in cell culture experiments. Our experiments demonstrated that the lack of TJP2 induced abnormal cell polarity and disrupted bile acid transport. These findings will lead to the subsequent investigation to further understand disease mechanisms and develop an effective treatment.

Neurologic Complications due to Severe Micronutrient Deficiencies in an American Adolescent.

Micronutrient deficiencies are a major global health problem but are less common in developed nations. If left unidentified and untreated, micronutrient deficiencies can lead to serious, sometimes irreversible, sequelae such as with vitamin A deficiency and vision loss. Providers should recognize these issues not only in chronically ill and hospitalized patients but in those with non-illness-related malnutrition due to parent/child-selected restricted diets. Herein, we present a case of unrecognized chronic, severe, malnutrition due to severe behavioral food selectivity with associated neurologic deficits due to hypovitaminosis (vitamins A and B2 ). With adequate enteral nutrition and vitamin repletion, our patient's neurologic deficits have partially recovered.

The interplay between sperm-mediated and care-mediated paternal effects in threespine sticklebacks.

The environment experienced by one generation can influence the phenotypes of future generations. Because parental cues can be conveyed to offspring at multiple points in time, ranging from fertilization to posthatching/parturition, offspring can potentially receive multiple cues from their parents via different mechanisms. We have relatively little information regarding how different mechanisms operate in isolation and in tandem, but it is possible, for example, that offspring phenotypes induced by nongenetic changes to gametes may be amplified by, mitigated by, or depend upon parental care. Here, we manipulated paternal experience with predation risk prior to fertilization in threespine stickleback, Gasterosteus aculeatus, and then examined the potential of paternal care to mitigate and/or amplify sperm-mediated paternal effects. Specifically, we compared (1) offspring of predator-exposed fathers who were reared without paternal care, (2) offspring of predator-exposed fathers who were reared with paternal care, (3) offspring of control (unexposed) fathers who were reared without paternal care and (4) offspring of control fathers who were reared with paternal care. We found that offspring of predator-exposed fathers were less active and had higher cortisol following a simulated predator attack. Although predator-exposed males shifted their paternal care behaviours - reduced fanning early in egg development and increased fanning right before egg hatching compared to control males - this shift in paternal behavior did not appear to affect offspring traits. This suggests that paternal care neither amplifies nor compensates for these phenotypic effects induced by sperm and that nongenetic changes induced by sperm may occur independently of nongenetic changes induced by paternal care. Overall, these results underscore the importance of considering how parents may have multiple nongenetic mechanisms by which they can influence offspring.

The specificity of sperm-mediated paternal effects in threespine sticklebacks.

Parental effects may help offspring respond to challenging environments, but whether parental exposure to different environmental challenges induces similar responses in offspring is largely unknown. We compared the offspring of threespine stickleback (Gasterosteus aculeatus) fathers who had been exposed to a potentially threatening stimulus (net), a native predator (sculpin), or who had been left unexposed (control). Relative to offspring of control fathers, offspring of sculpin-exposed fathers were more responsive (greater change in activity) to a simulated sculpin predator attack, while offspring of net-exposed fathers were less responsive (fewer antipredator behaviors) and showed altered stress responses compared to the control. To evaluate whether parental exposure primes offspring to respond to specific stimuli (e.g., offspring of net-exposed fathers respond most strongly to a net), we then exposed offspring of each paternal treatment to nets, native sculpin models, or non-native trout models. Paternal treatment did not influence offspring response to different stimuli; instead, offspring were generally more responsive to the native sculpin predator compared to nets or non-native trout predator, suggesting that sticklebacks have innate predator recognition of native predators. Collectively, these results underscore that, while parental exposure to non-ecologically relevant stressors elicits effects in intergenerational studies, these findings may not mirror those produced when parents encounter ecologically relevant stressors. Knowing that parental effects can be predator-specific furthers our understanding of the ways in which parental effects may evolve to be adaptive and suggests the potential for transgenerational plasticity to affect how animals respond to human induced environmental change, including non-native predators.

Favorable Outcomes and Anti-TNF Durability After Addition of an Immunomodulator for Anti-Drug Antibodies in Pediatric IBD Patients.

BACKGROUND: Anti-drug antibodies (ADAs) to anti-tumor necrosis factor alpha (anti-TNF) drugs are associated with increased drug clearance and loss of response. We aimed to assess the effectiveness of starting an immunomodulator (IM) drug in patients with newly detected ADAs on anti-TNF monotherapy. METHODS: We reviewed the medical records of pediatric patients with inflammatory bowel disease on infliximab or adalimumab monotherapy with first-time detection of significant ADAs between 2014 and 2018. Patients who started an IM within 3 months of ADA detection were compared with those who did not (No-IM). Outcomes included steroid-free clinical and biochemical remission on the same anti-TNF , anti-TNF durability, and ADA reversal. RESULTS: We identified 89 patients with ADAs: 30 IM patients and 59 No-IM patients. The initial anti-TNF was stopped shortly after ADA detection in 36% of the No-IM patients vs none of the IM patients, driving longer survival on the initial anti-TNF in the IM group (P = 0.005). At 12 months, steroid-free clinical and biochemical remission on the same anti-TNF occurred in 53.9% of the IM group vs 26.8% in the No-IM group (P = 0.025). Drug levels rose higher (P = 0.003) and ADA levels fell farther (P = 0.037) in the IM group than in the No-IM group. Baseline ADA level predicted ADA reversal in the No-IM patients with an area under the receiver operating characteristic of 0.79 (P = 0.006). An ADA level <329 ng/mL had a 76.2% sensitivity and an 83.3% specificity for ADA reversal without IM. CONCLUSIONS: Pediatric patients with inflammatory bowel disease on anti-TNF monotherapy who started an IM for significant ADA levels exhibited longer anti-TNF durability and a higher likelihood of steroid-free clinical and biochemical remission on the same anti-TNF. Patients not treated with an IM were unlikely to reverse ADAs >329 ng/mL.

Quality Improvement Methodology Optimizes Infliximab Levels in Pediatric Patients with Inflammatory Bowel Disease.

Achieving and maintaining target serum trough infliximab levels improves outcomes in children and young adults with inflammatory bowel disease. Our goal was to improve adherence to an infliximab therapy guideline. The primary aim was to increase the percentage of patients with infliximab levels ≥5 µg/mL and results checked in the last 12 months from 73% to ≥80% from July 2017 to January 2018. METHODS: We participated in Intermediate Improvement Science Series, a course at Cincinnati Children's Hospital Medical Center designed to catalyze change using quality improvement methodology. We implemented interventions through plan-do-study-act cycles. Our outcome measure was balanced by 2 process measures to determine what actions impacted improvement. These measures included the percentage of infusion plans revised in response to a drug level <5 µg/mL and the proportion of plans for which a follow-up drug level was ordered. RESULTS: We increased the percentage of infusion plans revised before the next infusion from 63% to 87% and the percentage of plans that had an appropriate drug level recheck from 61% to 83% from July 2017 to January 2018. We increased the percentage of patients with an infliximab level >5 µg/mL, and results checked in the last 12 months, from 73% to 80%. CONCLUSIONS: Quality improvement methodology was effective in improving provider adherence to infliximab therapeutic drug monitoring guidelines. Improvement in adherence to guidelines directly improved the percentage of patients achieving target infliximab levels at any time during infliximab therapy.

Effect of a Practice-wide Anti-TNF Proactive Therapeutic Drug Monitoring Program on Outcomes in Pediatric Patients with Inflammatory Bowel Disease.

BACKGROUND: Reports on the feasibility and effectiveness of translating proactive, antitumor necrosis factor (TNF) therapeutic drug monitoring (TDM) for inflammatory bowel disease into practice-wide quality improvement (QI) are lacking. We aimed to determine whether a TDM QI program improved outcomes at a large academic pediatric gastroenterology practice. METHODS: We instituted local anti-TNF TDM practice guidelines to proactively monitor and optimize drug levels (goal >5 µg/mL). We conducted a retrospective single-center cohort analysis of patient outcomes before (pre-TDM) and after (post-TDM) guideline institution and assessed the independent effect by multivariable regression. Primary outcome was sustained clinical remission (SCR22-52), defined as physician global assessment (PGA) of inactive from 22 to 52 weeks and off corticosteroids at 52 weeks. RESULTS: We identified 108 pre-TDM and 206 post-TDM patients. The SCR22-52 was achieved in 42% of pre-TDM and 59% of post-TDM patients (risk difference, 17.6%; 95% CI, 5.4-29%; P = 0.004). The post-TDM group had an increased adjusted odds of achieving SCR22-52 (odds ratio, 2.03; 95% CI, 1.27-3.26; P = 0.003). The adjusted risk of developing high titer antidrug antibodies (ADAs) was lower in the post-TDM group (hazard ratio, 0.18; 95% CI, 0.09-0.35; P < 0.001). Although the risk of anti-TNF cessation for any reason was not significantly different, there was a lower adjusted risk of cessation related to any detectable ADA in the post-TDM group (hazard ratio, 0.45; 95% CI, 0.26-0.77; P = 0.003). CONCLUSIONS: A practice-wide proactive anti-TNF TDM QI program improved key clinical outcomes at our institution, including sustained clinical remission, incidence of high titer ADA, and anti-TNF cessation related to ADA.