Population-based rare variant detection via pooled exome or custom hybridization capture with or without individual indexing.
Rare genetic variation in the human population is a major source of pathophysiological variability and has been implicated in a host of complex phenotypes and diseases. Finding disease-related genes harboring disparate functional rare variants requires sequencing of many individuals across many genomic regions and comparing against unaffected cohorts. However, despite persistent declines in sequencing costs, population-based rare variant detection across large genomic target regions remains cost prohibitive for most investigators. In addition, DNA samples are often precious and hybridization methods typically require large amounts of input DNA. Pooled sample DNA sequencing is a cost and time-efficient strategy for surveying populations of individuals for rare variants. We set out to 1) create a scalable, multiplexing method for custom capture with or without individual DNA indexing that was amenable to low amounts of input DNA and 2) expand the functionality of the SPLINTER algorithm for calling substitutions, insertions and deletions across either candidate genes or the entire exome by integrating the variant calling algorithm with the dynamic programming aligner, Novoalign. We report methodology for pooled hybridization capture with pre-enrichment, indexed multiplexing of up to 48 individuals or non-indexed pooled sequencing of up to 92 individuals with as little as 70 ng of DNA per person. Modified solid phase reversible immobilization bead purification strategies enable no sample transfers from sonication in 96-well plates through adapter ligation, resulting in 50% less library preparation reagent consumption. Custom Y-shaped adapters containing novel 7 base pair index sequences with a Hamming distance of ≥2 were directly ligated onto fragmented source DNA eliminating the need for PCR to incorporate indexes, and was followed by a custom blocking strategy using a single oligonucleotide regardless of index sequence. These results were obtained aligning raw reads against the entire genome using Novoalign followed by variant calling of non-indexed pools using SPLINTER or SAMtools for indexed samples. With these pipelines, we find sensitivity and specificity of 99.4% and 99.7% for pooled exome sequencing. Sensitivity, and to a lesser degree specificity, proved to be a function of coverage. For rare variants (≤2% minor allele frequency), we achieved sensitivity and specificity of ≥94.9% and ≥99.99% for custom capture of 2.5 Mb in multiplexed libraries of 22-48 individuals with only ≥5-fold coverage/chromosome, but these parameters improved to ≥98.7 and 100% with 20-fold coverage/chromosome. This highly scalable methodology enables accurate rare variant detection, with or without individual DNA sample indexing, while reducing the amount of required source DNA and total costs through less hybridization reagent consumption, multi-sample sonication in a standard PCR plate, multiplexed pre-enrichment pooling with a single hybridization and lesser sequencing coverage required to obtain high sensitivity.


[Cryotherapy III, Bibliographic review. Our experience (I)].
To perform a bibliographic review of the main features of cryotherapy as a therapeutic option in the managemente of prostate cancer and to report our initial experience. We employed the Endocare Fast-Trac system (Medipro) with 2,4 mm needles implanted in a single maneouvre without rack or transrectal US transducer support. Two cycles of freezing--hawing were employed, with apex backward movement when necessary. Freezing cycle duration was between 7-10 minutes or more. The Onik maneouvre-injection of saline into the Denonvillier's space--diminishes the risk of rectal injury and fistula allowing reaching posterior limits of the ica-ball beyond the prostatic capsule. We treated 20 patients. Follow-up was between 30-36 months. 58% of the patients had unilateral prostate cancer, 42% bilateral. In accordance to the classic definition 9 patients were classified as low risk of extraprostatic disease, 6 medium risk and 5 high risk; using number of positive cores as the criterion for risk 5, 6 and 9 were low, medium and high risk respectively. Per protocol prostate biopsies were performed in 18 patients 6, 12 and 24 months after treatment. Two patients underwent a second treatment due to persistence of cancer cells in the 6-month biopsy (11%). 3-month PSA nadirs after a total of 21 cryo treatments administered were < 0,2 ng/cc in 15 cases (78,9%), < 0,5 ng/cc in 17 (89,4%) and < or = 1.0 ng/cc in 18 (94,7%); it was over 1 ng/cc in only 5,6%. 30 month PSA for the same cutoff values was 27.8%, 50.0%, 66.6% and 33.3%, respectively. Prostate cancer cells were detected in the 12-month biopsies of 5.5% cases. All 24-month biopsies were negative. We observed scrotal edema, hematoma, perineal pain and constipation which lasted 2-3 weeks. 1 patient suffered injury of the mucosa at the prostatic urethra, which did not result in rectal fistula and was treated with bladder catheter for 3 months. 4 patients had erectile dysfunction before treatment. All others presented erectile dysfunction after treatment; 3 of them (20%) recovered rigidity enough to have intercourse over the 30 month period. No urethral sloughing or acute urinary retention appeared and all patients are continent. Prostatic cryosurgery is an effective, minimally invasive procedure for the treatment of prostate cancer with very low surgical risk, low morbidity and almost null mortality.


Application of the Discrete Element Method for Manufacturing Process Simulation in the Pharmaceutical Industry.
Process simulation using mathematical modeling tools is becoming more common in the pharmaceutical industry. A mechanistic model is a mathematical modeling tool that can enhance process understanding, reduce experimentation cost and improve product quality. A commonly used mechanistic modeling approach for powder is the discrete element method (DEM). Most pharmaceutical materials have powder or granular material. Therefore, DEM might be widely applied in the pharmaceutical industry. This review focused on the basic elements of DEM and its implementations in pharmaceutical manufacturing simulation. Contact models and input parameters are essential elements in DEM simulation. Contact models computed contact forces acting on the particle-particle and particle-geometry interactions. Input parameters were divided into two types-material properties and interaction parameters. Various calibration methods were presented to define the interaction parameters of pharmaceutical materials. Several applications of DEM simulation in pharmaceutical manufacturing processes, such as milling, blending, granulation and coating, were categorized and summarized. Based on this review, DEM simulation might provide a systematic process understanding and process control to ensure the quality of a drug product.


Intakes of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis: Results from five cohort studies.
Caffeine is thought to be neuroprotective by antagonizing the adenosine A2A receptors in the brain and thereby protecting motor neurons from excitotoxicity. We examined the association between consumption of caffeine, coffee and tea and risk of amyotrophic lateral sclerosis (ALS). Longitudinal analyses based on over 1,010,000 males and females in five large cohort studies (the Nurses' Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study). Cohort-specific multivariable-adjusted risk ratios (RR) and 95% confidence intervals (CI) estimates of ALS incidence or death were estimated by Cox proportional hazards regression and pooled using random-effects models. Results showed that a total of 1279 cases of ALS were documented during a mean of 18 years of follow-up. Caffeine intake was not associated with ALS risk; the pooled multivariable-adjusted RR comparing the highest to the lowest quintile of intake was 0.96 (95% CI 0.81-1.16). Similarly, neither coffee nor tea was associated with ALS risk. In conclusion, the results of this large study do not support associations of caffeine or caffeinated beverages with ALS risk.


The vascular niche in next generation microphysiological systems.
In recent years, microphysiological system (MPS, also known as, organ-on-a-chip or tissue chip) platforms have emerged with great promise to improve the predictive capacity of preclinical modeling thereby reducing the high attrition rates when drugs move into trials. While their designs can vary quite significantly, in general MPS are bioengineered in vitro microenvironments that recapitulate key functional units of human organs, and that have broad applications in human physiology, pathophysiology, and clinical pharmacology. A critical next step in the evolution of MPS devices is the widespread incorporation of functional vasculature within tissues. The vasculature itself is a major organ that carries nutrients, immune cells, signaling molecules and therapeutics to all other organs. It also plays critical roles in inducing and maintaining tissue identity through expression of angiocrine factors, and in providing tissue-specific milieus (i.e., the vascular niche) that can support the survival and function of stem cells. Thus, organs are patterned, maintained and supported by the vasculature, which in turn receives signals that drive tissue specific gene expression. In this review, we will discuss published vascularized MPS platforms and present considerations for next-generation devices looking to incorporate this critical constituent. Finally, we will highlight the organ-patterning processes governed by the vasculature, and how the incorporation of a vascular niche within MPS platforms will establish a unique opportunity to study stem cell development.


Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease.
Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.


School Administrator Perceptions of Cyberbullying Facilitators and Barriers to Preventive Action: A Qualitative Study.
Schools are often held responsible for preventing or addressing cyberbullying, yet little is known about school administrator perceptions of cyberbullying and the challenges they face in addressing this public health issue. The goal of this study is to examine school administrators' perceptions of the facilitators of cyberbullying and barriers to primary and secondary prevention strategies. Public school administrators ( N = 36) participated in in-depth interviews about bullying and discussed their experiences with cyberbullying and their perceptions of cyberbullying facilitators and barriers to prevention. Three main themes arose from the analysis: (1) cyberbullying as a major challenge; (2) facilitators of cyberbullying and barriers to preventive action, including parents and technology; and (3) prevention efforts, including unclear jurisdiction for action, primary versus secondary prevention efforts, and technology attributes that facilitate school response to bullying. Although administrators perceive cyberbullying as a major challenge facing their schools, they are often unsure about appropriate primary and secondary prevention efforts. Relationships with parents and police complicate response and prevention as schools attempt to navigate unclear jurisdiction. Additionally, technology presents a challenge to schools because it is seen as an enabler of cyberbullying, a facilitator of prevention, and a necessary part of education efforts. Lack of research on prevention strategies, parents' knowledge and attitudes, and confusion about responsibility for addressing cyberbullying are barriers to action. Findings suggest administrators could benefit from additional clarity on which strategies are most effective for primary prevention of cyberbullying, and that prevention strategies should proactively involve parents to promote effective collaboration with schools.


Apoptosis-dependent and -independent mechanisms mediate the phagocytic recognition/clearance of the HL60-A1 transfectants with prolonged survival.
The phagocytic recognition and clearance of the recruited inflammatory cells with prolonged survival play a pivotal role in relieving tissue inflammation and maintaining tissue homeostasis. Transgenic mice expressing Bcl-2 in mature neutrophils demonstrated that Bcl-2 attenuated neutrophil apoptosis, while the homeostasis of the neutrophil population was essentially unaffected. This result suggests that clearance of neutrophils with prolonged survival operates independently from apoptosis. Owing to the constitutive and inducible expression of Bcl-2 homologue, A1 in human neutrophils and the intolerance of preparation for the isolated human neutrophils with prolonged survival, the human promyelocytic HL60-A1 transfectants were established to study the mechanism of phagocytic recognition/clearance of the cells with prolonged survival. The non-apoptotic cells with prolonged survival were enriched by serum withdrawal for five days and negatively isolated by annexin V-binding beads. Then, the cells were labeled with a fluorogenic marker. Monocyte-derived macrophages (MDM) were co-cultured to perform the phagocytosis assay, and flow cytometry was employed to determine the phagocytic index. In the serum-free condition, the phagocytic index of HL60-A1 transfectants was little different from that of the HL60-EGFP control, despite showing a significantly lower degree of apoptosis. While the phagocytic index of HL60-EGFP control was significantly correlated with the degree of apoptosis, the index of the HL60-A1 transfectants was less relevant to it. The phagocytic index for the annexin V-positive cells did not distinguish the two cell types. However, the phagocytic index for the annexin V-negative cells from the HL60-A1 transfectants was increased with age in days. Preincubation of MDM with the scavenger receptor inhibitor, Oxi-LDL, and the inhibitory antibodies against alphavbeta3, CD14 and CD36 surface molecules could attenuate the phagocytic recognition of the annexin V-positive HL60 cells but not the annexin V-negative A1 transfectants with prolonged survival. This study thus suggests that a mechanism unrelated to apoptosis exists, which mediates the phagocytic clearance of the non-apoptotic cells with prolonged survival and may be associated with A1 function in the myeloid cells.


The Oxford medial unicompartmental knee replacement using a minimally-invasive approach.
This prospective study describes the complications and survival of the first 688 Phase 3 Oxford medial unicompartmental knee replacements implanted using a minimally-invasive technique by two surgeons and followed up independently. None was lost to follow-up. We had carried out 132 of the procedures more than five years ago. The clinical assessment of 101 of these which were available for review at five years is also presented. Nine of the 688 knees were revised: four for infection, three for dislocation of the bearing and two for unexplained pain. A further seven knees (1%) required other procedures: four had a manipulation under anaesthesia, two an arthroscopy and one a debridement for superficial infection. The survival rate at seven years was 97.3% (95% confidence interval 5.3). At five years, 96% of the patients had a good or excellent American Knee Society score, the mean Oxford knee score was 39 and the mean flexion was 133 degrees. This study demonstrates that the minimally-invasive Oxford unicompartmental knee replacement is a reliable and effective procedure.


Assessment of atherosclerosis: the role of flow-mediated dilatation.
Evidence suggests that endothelial dysfunction is on the causal pathway for both atherogenesis and destabilization of established plaques. In this review, the role of flow-mediated dilatation (FMD) as a non-invasive method to assess endothelial function is discussed. Technical modifications and development of analysis software have significantly improved the variability of the method. Following a strict standardized protocol enables reproducible measurements to be achieved and export of the technique from specialized laboratories to population studies and multicentre settings. Endothelial function assessed by FMD has been shown to be affected by cardiovascular risk factors, to be related to structural arterial disease and to cardiovascular outcome, validating its use for studying the pathophysiology of arterial disease. Numerous studies have also demonstrated that it is responsive to physiological and pharmacological interventions. Flow-mediated dilatation provides unique opportunities in drug development programmes to assess an early rapidly responsive signal of risk or benefit, complementing endpoints of structural arterial disease and cardiovascular outcomes that take much longer and are more expensive.


Dose to heart substructures is associated with non-cancer death after SBRT in stage I-II NSCLC patients.
To investigate potential associations between dose to heart (sub)structures and non-cancer death, in early stage non-small cell lung cancer (NSCLC) patients treated with stereotactic body radiation therapy (SBRT). 803 patients with early stage NSCLC received SBRT with predominant schedules of 3×18Gy (59%) or 4×12Gy (19%). All patients were registered to an average anatomy, their planned dose deformed accordingly, and dosimetric parameters for heart substructures were obtained. Multivariate Cox regression and a sensitivity analysis were used to identify doses to heart substructures or heart region with a significant association with non-cancer death respectively. Median follow-up was 34.8months. Two year Kaplan-Meier overall survival rate was 67%. Of the deceased patients, 26.8% died of cancer. Multivariate analysis showed that the maximum dose on the left atrium (median 6.5Gy EQD2, range=0.009-197, HR=1.005, p-value=0.035), and the dose to 90% of the superior vena cava (median 0.59Gy EQD2, range=0.003-70, HR=1.025, p-value=0.008) were significantly associated with non-cancer death. Sensitivity analysis identified the upper region of the heart (atria+vessels) to be significantly associated with non-cancer death. Doses to mainly the upper region of the heart were significantly associated with non-cancer death. Consequently, dose sparing in particular of the upper region of the heart could potentially improve outcome, and should be further studied.


Incidence and preoperative predictors for major complications following radical nephroureterectomy.
Radical nephroureterectomy (RNU) is the referent standard for managing bulky, invasive, or high grade upper-tract urothelial carcinoma (UTUC). The UTUC patient population, however, generally harbor medical comorbidities thereby placing them at risk of surgical complications. This study reviews a large international cohort of RNU patients to define the risk of major complications and preoperative factors associated with their occurrence. Patients undergoing RNU at 14 academic medical centers between 2002 and 2015 were retrospectively reviewed. Preoperative clinical, demographic, operative, and comorbidity indices were recorded. The modified Clavien-Dindo index was used to grade complications occurring within 30 days of surgery. The association between preoperative variables and major complications occurring after RNU was determined by multivariable logistic regression. One thousand two hundred and sixty-six patients (707 men; 559 women) with a median age of 70 years and BMI of 27 kg/m2 were included. Over three-quarters of the cohort was white, 50.1% had baseline chronic kidney disease (CKD) ≥ stage III, 22.4% had a Charlson comorbidity index (CCI) score >5, and 17.1% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2. Overall, 413 (32.6%) experienced a complication including 103 (8.1%) with a major event. Specific distribution of major complications included 49 Clavien III, 44 Clavien IV, and 10 Clavien V. On univariate analysis, patient age (P=0.006), hypertension (P=0.002), diabetes mellitus (P=0.023), CKD stage (P<0.001), American Society of Anesthesiologists (ASA) score (P=0.022), ECOG (P<0.001), and CCI (P<0.001) all were associated with major complications. On multivariate analysis, ECOG ≥2 (OR 2.38, 95% CI, 1.46-3.90), P=0.001), CCI >5 (OR 3.45, 95% CI, 1.41-8.33, P=0.007), and CKD stage ≥3 (OR 3.64, P=0.008) were independently associated with major complications. Major complications following RNU occurred in almost 10% of patients. Impaired preoperative performance status and baseline CKD are preoperative variables associated with these major post-surgical adverse event. These easily measurable indices warrant consideration and discussion prior to proceeding with RNU.


The MSBase pregnancy, neonatal outcomes, and women's health registry.
Family planning and pregnancy decisions are key considerations in the management of women with multiple sclerosis (MS), who are typically diagnosed between the ages of 20-40 years. Despite a strong evidence base that pregnancy is not harmful for women with MS, many knowledge gaps remain. These include: best management strategies through pregnancy in the era of highly effective disease-modifying therapies (DMT); foetal risks associated with DMT exposure in utero or in relation to breastfeeding; knowledge base around the use of assisted reproductive technologies; the long-term impact of pregnancy on disease outcomes, as well as the impact of long-term DMT use on women's health and cancer risk. Here, we describe the new MSBase pregnancy, neonatal outcomes and women's health registry. We provide the rationale for, and detailed description of, the variables collected within the registry, together with data acquisition details. The present paper will act as a reference document for future studies.


Postoperative experiences of pain and distress in elderly patients. An explorative study.
The aim of this study was to explore postoperative experiences of pain and distress in elderly patients, as well as interventions aimed at reducing these conditions, on three occasions. The study group was composed of 100 patients who had undergone elective surgery in two orthopedic and two general surgical units. Of the 50 patients in the orthopedic units, 26 had undergone hip arthroplasty and 24 knee arthroplasty: of the 50 patients in the general surgical units, 23 had had breast cancer surgery, and 27 abdominal surgery. The patients were interviewed, using a structured interview format, on three occasions; at the ward on the first and second day after surgery, and by telephone about ten days after discharge from hospital. Within both the sensory and the emotional dimensions, logistic regression analyses showed that the dependent variables of pain and distress were significantly related above all to type of surgery and sense of coherence (SOC). In a cluster analysis, three meaningful clusters of patients were obtained. The patients in the different profiles showed variations in their experiences of pain and distress. The 12 patients with the least favorable scores had weaker SOC than the patients in the other profiles. It is concluded that type of surgery and psychological factors influenced patients' experiences of pain and distress after undergoing surgery. These experiences should be reduced by identifying risk patients, and improving assistance and support in the nursing ward, and also when patients have returned home.


Socioeconomic inequalities in newborn care during facility and home deliveries: a cross sectional analysis of data from demographic surveillance sites in rural Bangladesh, India and Nepal.
In Bangladesh, India and Nepal, neonatal outcomes of poor infants are considerably worse than those of better-off infants. Understanding how these inequalities vary by country and place of delivery (home or facility) will allow targeting of interventions to those who need them most. We describe socio-economic inequalities in newborn care in rural areas of Bangladesh, Nepal and India for all deliveries and by place of delivery. We used data from surveillance sites in Bangladesh, India and from Makwanpur and Dhanusha districts in Nepal, covering periods from 2001 to 2011. We used literacy (ability to read a short text) as indicator of socioeconomic status. We developed a composite score of nine newborn care practices (score range 0-9 indicating infants received no newborn care to all nine newborn care practices). We modeled the effect of literacy and place of delivery on the newborn care score and on individual practices. In all study sites (60,078 deliveries in total), use of facility delivery was higher among literate mothers. In all sites, inequalities in newborn care were observed: the difference in new born care between literate and illiterate ranged 0.35-0.80. The effect of literacy on the newborn care score reduced after adjusting for place of delivery (range score difference literate-illiterate: 0.21-0.43). Socioeconomic inequalities in facility care greatly contribute to inequalities in newborn care. Improving newborn care during home deliveries and improving access to facility care are a priority for addressing inequalities in newborn care and newborn mortality.


Statins use and coronary artery plaque composition: results from the International Multicenter CONFIRM Registry.
The effect of statins on coronary artery plaque features beyond stenosis severity is not known. Coronary CT angiography (CCTA) is a novel non-invasive method that permits direct visualization of coronary atherosclerotic features, including plaque composition. We evaluated the association of statin use to coronary plaque composition type in patients without known coronary artery disease (CAD) undergoing CCTA. From consecutive individuals, we identified 6673 individuals (2413 on statin therapy and 4260 not on statin therapy) with no known CAD and available statin use status. We studied the relationship between statin use and the presence and extent of specific plaque composition types, which was graded as non-calcified (NCP), mixed (MP), or calcified (CP) plaque. The mean age was 59 ± 11 (55% male). Compared to the individuals not taking statins, those taking statins had higher prevalence of risk factors and obstructive CAD. In multivariable analyses, statin use was associated with increased the presence of MP [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.27-1.68), p < 0.001] and CP (OR 1.54, 95% CI 1.36-1.74, p < 0.001), but not NCP (OR 1.11, 95% CI 0.96-1.29, p = 0.1). Further, in multivariable analyses, statin use was associated with increasing numbers of coronary segments possessing MP (OR 1.52, 95% CI 1.34-1.73, p < 0.001) and CP (OR 1.52, 95% CI 1.36-1.70, p < 0.001), but not coronary segments with NCP (OR 1.09, 95% CI 0.94-1.25, p = 0.2). Statin use is associated with an increased prevalence and extent of coronary plaques possessing calcium. The longitudinal effect of statins on coronary plaque composition warrants further investigation.


IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.
Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.