Comparison of Medical Tape Performance Using Skin Response Quantitative Measurements on Healthy Volunteers.

BACKGROUND: Medical tapes can lead to skin damage upon removal in susceptible patients with fragile skin and at higher risk of developing tissue injury. PURPOSE: We compared the effect of medical tapes with silicone-based versus acrylate-based adhesives on the back or volar forearm stratum corneum using analytical techniques to assess skin condition and potential damage post product removal on 88 healthy volunteers. METHODS: Two studies were conducted in separate facilities (Study 1: 3M In-house Clinical Facility, St. Paul, Minnesota; Study 2: DermiCo, LLC, Broomall, Pennsylvania). Four commercially available tapes were the same in both studies, two for each type of adhesive. We evaluated adhesion to the skin, total proteins and corneocytes removed by the tapes, changes in transepidermal water loss (TEWL), and induction of the inflammatory cytokine interleukin-1 alpha (IL-1a). RESULTS: One of the silicone tapes displayed the strongest adhesion at 24 hours, and one of the acrylate tapes had the lowest adhesion, showing differences in performance within adhesive categories. The adhesion forces did not correlate with the amount of total protein or corneocytes removed. Silicone adhesives removed less total protein and corneocytes than acrylate adhesives. Silicone adhesives did not alter TEWL, whereas acrylate adhesives significantly raised TEWL. There were no differences in interleukin-1alpha induction. CONCLUSION: The silicone adhesive tapes were less disruptive to the skin barrier than the acrylate adhesive tapes, even in healthy volunteers whose skin is not as fragile as what is observed in typical patients. This type of data could guide clinical product usage decisions.

Impact of the 2021 CKD-EPI eGFR Equation on Kidney Care Referral Criteria in Ontario, Canada: A Population-based Cross-sectional Study.

Background: In some jurisdictions, individuals become eligible or recommended for referral for different types of kidney care using criteria based on their estimated glomerular filtration rate (eGFR). Historically, GFR was estimated with an equation developed in 2009, which included a Black race term. An updated, race-free equation was developed in 2021. It is unclear how adoption of the 2021 equation will influence the number of individuals meeting referral criteria to receive different types of kidney care. Objective: To develop population-based estimates on how the number of individuals meeting the eGFR-based referral criteria to receive three different types of kidney care (nephrologist consultation, care in a multi-care specialty clinic, kidney transplant evaluation) changes when the 2021 versus 2009 equation is used to calculate eGFR. Design: Population-based, cross-sectional study. Setting: Ontario, Canada's most populous province with 14.2 million residents as of 2021. Less than 5% of Ontario's residents self-identify as being of Black race. Patients: Adults with at least one outpatient serum creatinine measurement in the 2 years prior to December 31, 2021. Measurements: Referral criteria to 3 different types of kidney care: nephrologist consultation, multi-care specialty clinic, and evaluation for a kidney transplant. The eGFR thresholds used to define referral eligibility or recommendation for these kidney health services were based on guidelines from Ontario's provincial renal agency. Methods: The number of individuals meeting referral criteria for the 3 different healthcare services was compared between the 2009 and 2021 equations, restricted to individuals not yet receiving that level of care. As individual-level race data were not available, estimates were repeated, randomly assigning a Black race status to 1%, 5%, and 10% of the population. Results: We had an outpatient serum creatinine measurement available for 1 048 110 adults. Using the 2009 equation, 37 345 individuals met the criteria to be referred to a nephrologist, 10 019 met the criteria to receive care in a multi-care specialty clinic, and 10 178 met the criteria to be referred for kidney transplant evaluation. Corresponding numbers with the 2021 equation (and the percent relative to the 2009 equation) were 26 645 (71.3%), 9009 (89.9%), and 8615 (84.6%) individuals, respectively. These numbers were largely unchanged when Black race was assumed in up to 10% of the population. Limitations: Referral criteria based solely on urine albumin-to-creatinine ratio were not assessed. Self-reported race data were unavailable. Conclusions: For healthcare planning, in regions where a minority of the population is Black, a substantial number of individuals may no longer meet referral criteria for different types of kidney healthcare following adoption of the new 2021 eGFR equation.

Contexte: Dans certaines régions, les individus sont dirigés vers différents types de soins rénaux, ou y deviennent admissibles, selon des critères fondés sur le débit de filtration glomérulaire estimé (DFGe). Historiquement, le DFG était estimé avec une équation développée en 2009 comportant un terme qui tenait compte du fait d'être une personne de race noire. Une nouvelle équation sans mention de la race a été développée en 2021. Il est difficile de savoir comment l'adoption de l'équation de 2021 influencera le nombre de personnes qui répondront aux critères pour recevoir divers types de soins rénaux. Objectifs: Établir des estimations populationnelles de la variation du nombre de personnes qui répondent aux critères d'orientation fondés sur le DFGe pour recevoir trois différents types de soins rénaux (consultation avec un néphrologue, soins dans une clinique multidisciplinaire spécialisée, évaluation pour une transplantation rénale) selon que le DFGe est calculé avec l'équation de 2021 ou de 2009. Conception: Étude populationnelle transversale rétrospective. Cadre: L'Ontario, la province la plus peuplée du Canada avec 14,2 millions d'habitants en 2021. Moins de 5 % des résidents de l'Ontario s'identifient comme étant de race noire. Sujets: Des adultes avec au moins une mesure de la créatinine sérique en ambulatoire au cours des deux ans précédant le 31 décembre 2021. Mesures: Les critères d'orientation vers trois différents types de soins rénaux : consultation avec un néphrologue, soins en clinique multidisciplinaire spécialisée et évaluation pour une transplantation rénale. Les seuils de DFGe utilisés pour définir l'admissibilité à ­ ou l'orientation vers ­ ces services de santé rénale étaient fondés sur les lignes directrices de l'agence provinciale de soins rénaux de l'Ontario. Méthodologie: On a comparé les nombres d'individus répondant aux critères d'orientation pour les trois différents services de santé, calculés avec les équations de 2009 et de 2021, en se limitant aux personnes qui ne recevaient pas encore de tels soins. Les données individuelles sur la race n'étant pas disponibles, les estimations ont été répétées en attribuant aléatoirement un statut de race noire à 1 %, à 5 % et à 10 % de la population étudiée. Résultats: Une mesure de la créatinine sérique en ambulatoire était disponible pour un total de 1 048 110 adultes. Avec l'équation de 2009, 37 345 personnes répondaient aux critères pour être dirigées vers un néphrologue, 10 019 répondaient aux critères pour recevoir des soins dans une clinique multidisciplinaire spécialisée et 10 178 répondaient aux critères pour être évaluées pour une transplantation rénale. Avec l'équation de 2021, ces mêmes nombres de personnes (pourcentage par rapport à l'équation de 2009) étaient respectivement 26 645 (71,3 %), 9 009 (89,9 %) et 8 615 (84,6 %). Des chiffres qui sont demeurés majoritairement inchangés même en assumant une proportion de jusqu'à 10 % de personnes de race noire dans la population. Limites: Les critères d'orientation fondés uniquement sur le rapport albumine/créatinine urinaire n'ont pas été évalués. Les données autodéclarées sur la race n'étaient pas disponibles. Conclusion: Pour la planification des soins de santé, dans les régions où une minorité de la population est noire, un nombre important de personnes pourraient ne plus répondre aux critères d'orientation vers différents types de soins rénaux après l'adoption de l'équation de 2021 pour le calcul du DFGe.

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.g., ß-carbon), and other reactive species can form following initial bioactivation, although these alternative pathways tend to decrease rather than enhance carcinogenic potency. The activation pathway, oxidative dealkylation, is a common reaction in drug metabolism and evidence indicates that the carbonyl byproduct, e.g., formaldehyde, does not contribute to the toxic properties of N-nitrosamines. Nitric oxide (NO), a side product of denitrosation, can similarly be discounted as an enhancer of N-nitrosamine toxicity based on carcinogenicity data for substances that act as NO-donors. However, not all N-nitrosamines are potent rodent carcinogens. In a significant number of cases, there is a potency overlap with non-N-nitrosamine carcinogens that are not in the Cohort of Concern (CoC; high-potency rodent carcinogens comprising aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds), while other N-nitrosamines are devoid of carcinogenic potential. In this context, mutagenicity is a useful surrogate for carcinogenicity, as proposed in the ICH M7 (R2) (2023) guidance. Thus, in the safety assessment and control of N-nitrosamines in medicines, it is important to understand those complementary attributes of mechanisms of mutagenicity and structure-activity relationships that translate to elevated potency versus those which are associated with a reduction in, or absence of, carcinogenic potency.

Early intranasal medication administration in out-of-hospital cardiac arrest: Two randomized simulation trials.

Objective: Intranasal medications have been proposed as adjuncts to out-of-hospital cardiac arrest (OHCA) care. We sought to quantify the effects of intranasal medication administration (INMA) in OHCA workflows. Methods: We conducted separate randomized OHCA simulation trials with lay rescuers (LRs) and first responders (FRs). Participants were randomized to groups performing hands-only cardiopulmonary resuscitation (CPR)/automated external defibrillator with or without INMA during the second analysis phase. Time to compression following the second shock (CPR2) was the primary outcome and compression quality (chest compression rate (CCR) and fraction (CCF)) was the secondary outcome. We fit linear regression models adjusted for CPR training in the LR group and service years in the FR group. Results: Among LRs, INMA was associated with a significant increase in CPR2 (mean diff. 44.1 s, 95% CI: 14.9, 73.3), which persisted after adjustment (p = 0.005). We observed a significant decrease in CCR (INMA 95.1 compressions per min (cpm) vs control 104.2 cpm, mean diff. -9.1 cpm, 95% CI -16.6, -1.6) and CCF (INMA 62.4% vs control 69.8%, mean diff. -7.5%, 95% CI -12.0, -2.9). Among FRs, we found no significant CPR2 delays (mean diff. -2.1 s, 95% CI -15.9, 11.7), which persisted after adjustment (p = 0.704), or difference in quality (CCR INMA 115.5 cpm vs control 120.8 cpm, mean diff. -5.3 cpm, 95% CI -12.6, 2.0; CCF INMA 79.6% vs control 81.2% mean diff. -1.6%, 95% CI -7.4, 4.3%). Conclusions: INMA in LR resuscitation was associated with diminished resuscitation performance. INMA by FR did not impede key times or quality.

Validation of the East London Retinopathy of Prematurity algorithm to detect treatment-warranted retinopathy of prematurity: a cohort study.

AIM: To validate the East London Retinopathy of Prematurity algorithm (EL-ROP) in a cohort of infants at risk of developing retinopathy of prematurity (ROP). METHODS: The EL-ROP algorithm was applied retrospectively to routinely collected data from two tertiary neonatal units in England on infants eligible for ROP screening. The EL-ROP recommendation, to screen or not, was compared with the development of treatment-warranted ROP (TW-ROP) for each infant. The main outcome measures were (1) EL-ROP's sensitivity for predicting the future development of TW-ROP and (2) potential to reduce ROP screening examinations. RESULTS: Data from 568 infants were included in the trial. The median (IQR) birth weight (g) was 875 (704 - 1103) and gestational age (weeks) was 27.0 (25.4 - 29.0). Maternal ethnicity was black (33%) and non-black (67%). 58(10%) developed TW-ROP and in every case this was predicted by the EL-ROP algorithm. It's sensitivity was 100% (95% CI 94-100%) specificity: 44% (95% CI 39-48%) positive predictive value: 17% (95%CI 16-18%), negative predictive value: 100%. CONCLUSIONS: EL-ROP has been validated in a cohort of infants from two tertiary neonatal units in England. Further validation is required before its clinical usefulness can be assessed.

Effectiveness of a Fourth COVID-19 mRNA Vaccine Dose Against the Omicron Variant in Solid Organ Transplant Recipients.

BACKGROUND: The effectiveness of booster doses of COVID-19 vaccines in solid organ transplant recipients is unclear. We conducted a population-based matched cohort study using linked administrative healthcare databases from Ontario, Canada to estimate the marginal vaccine effectiveness of a fourth versus third dose of the BNT162b2 and mRNA-1273 vaccines against clinically important outcomes (ie, hospitalization or death) and infection during the era of the Omicron variant. METHODS: We matched 3120 solid organ transplant recipients with a third COVID-19 vaccine dose (reference) to 3120 recipients with a fourth dose. Recipients were matched on the third dose date (±7 d). We used a multivariable Cox proportional hazards model to estimate the marginal vaccine effectiveness with outcomes occurring between December 21, 2021 and April 30, 2022. RESULTS: The cumulative incidence of COVID-19-related hospitalization or death was 2.8% (95% confidence interval [CI], 2.0-3.7) in the third dose group compared with 1.1% (95% CI, 0.59-1.8) in the fourth dose group after 84 d of follow-up (P < 0.001). The adjusted marginal vaccine effectiveness was 70% (95% CI, 47-83) against clinically important outcomes and 39% (95% CI, 21-52) against SARS-CoV-2 infection. CONCLUSIONS: Compared with a third dose, a fourth dose of the COVID-19 vaccine was associated with improved protection against hospitalization, death, and SARS-CoV-2 infection during the Omicron era. Results highlight the importance of a booster COVID-19 vaccine dose in solid organ transplant recipients.

Brain signatures of chronic gut inflammation.

Gut inflammation is thought to modify brain activity and behaviour via modulation of the gut-brain axis. However, how relapsing and remitting exposure to peripheral inflammation over the natural history of inflammatory bowel disease (IBD) contributes to altered brain dynamics is poorly understood. Here, we used electroencephalography (EEG) to characterise changes in spontaneous spatiotemporal brain states in Crohn's Disease (CD) (n = 40) and Ulcerative Colitis (UC) (n = 30), compared to healthy individuals (n = 28). We first provide evidence of a significantly perturbed and heterogeneous microbial profile in CD, consistent with previous work showing enduring and long-standing dysbiosis in clinical remission. Results from our brain state assessment show that CD and UC exhibit alterations in the temporal properties of states implicating default-mode network, parietal, and visual regions, reflecting a shift in the predominance from externally to internally-oriented attentional modes. We investigated these dynamics at a finer sub-network resolution, showing a CD-specific and highly selective enhancement of connectivity between the insula and medial prefrontal cortex (mPFC), regions implicated in cognitive-interoceptive appraisal mechanisms. Alongside overall higher anxiety scores in CD, we also provide preliminary support to suggest that the strength of chronic interoceptive hyper-signalling in the brain co-occurs with disease duration. Together, our results demonstrate that a long-standing diagnosis of CD is, in itself, a key factor in determining the risk of developing altered brain network signatures.

Revisiting the Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals.

N-Nitrosamines are a class of indirect acting mutagens, as their metabolic degradation leads to the formation of the DNA-alkylating diazonium ion. Following up on the in-silico identification of thousands of nitrosamines that can potentially be derived from small molecule drugs and their known impurities described in a previous publication, we have now re-analyzed this dataset to apply EMA's Carcinogenic Potency Categorization Approach (CPCA) introduced with the 16th revision of their Q&A document for Marketing Authorization Holders. We find that the majority of potential nitrosamines from secondary amine precursors belongs to potency categories 4 and 5, corresponding to an acceptable daily intake of 1500 ng, whereas nitrosamines from tertiary amine precursors distribute more evenly among all categories, resulting in a substantial number of structures that are assigned the more challenging acceptable intakes of 18 ng/day and 100 ng/day for potency categories 1 and 2, respectively. However, the nitrosative dealkylation pathway for tertiary amine is generally far slower than the direct nitrosation on secondary amines, with a direct nitrosation mechanism suspected only for structures featuring electron-rich (hetero)aromatic substituents. This allows for greater focus towards those structures that require further review, and we demonstrate that their number is not substantial. In addition, we reflect on the nitrosamine risk posed by secondary amine API impurities and demonstrate that based on the ICH Q3A/B identification threshold unknown impurities may exist that could be transformed to relevant amounts of NA. We also demonstrate that the analytical sensitivity required for the quantification of high potency nitrosamines can be problematic especially for high dose APIs. In summary, the regulatory framework rolled out with the latest Q&A document represents a substantial improvement compared with the previous situation, but further refinement through interaction between manufacturers, regulators, not-for-profit and academic institutions will be required to ensure patient access to vital medicines without compromising safety.

The catalytic subunit of DNA-PK regulates transcription and splicing of AR in advanced prostate cancer.

Aberrant androgen receptor (AR) signaling drives prostate cancer (PC), and it is a key therapeutic target. Although initially effective, the generation of alternatively spliced AR variants (AR-Vs) compromises efficacy of treatments. In contrast to full-length AR (AR-FL), AR-Vs constitutively activate androgenic signaling and are refractory to the current repertoire of AR-targeting therapies, which together drive disease progression. There is an unmet clinical need, therefore, to develop more durable PC therapies that can attenuate AR-V function. Exploiting the requirement of coregulatory proteins for AR-V function has the capacity to furnish tractable routes for attenuating persistent oncogenic AR signaling in advanced PC. DNA-PKcs regulates AR-FL transcriptional activity and is upregulated in both early and advanced PC. We hypothesized that DNA-PKcs is critical for AR-V function. Using a proximity biotinylation approach, we demonstrated that the DNA-PK holoenzyme is part of the AR-V7 interactome and is a key regulator of AR-V-mediated transcription and cell growth in models of advanced PC. Crucially, we provide evidence that DNA-PKcs controls global splicing and, via RBMX, regulates the maturation of AR-V and AR-FL transcripts. Ultimately, our data indicate that targeting DNA-PKcs attenuates AR-V signaling and provide evidence that DNA-PKcs blockade is an effective therapeutic option in advanced AR-V-positive patients with PC.

Large cross-effect dynamic nuclear polarisation enhancements with kilowatt inverting chirped pulses at 94 GHz.

Dynamic nuclear polarisation (DNP) is a process that transfers electron spin polarisation to nuclei by applying resonant microwave radiation, and has been widely used to improve the sensitivity of nuclear magnetic resonance (NMR). Here we demonstrate new levels of performance for static cross-effect proton DNP using high peak power chirped inversion pulses at 94 GHz to create a strong polarisation gradient across the inhomogeneously broadened line of the mono-radical 4-amino TEMPO. Enhancements of up to 340 are achieved at an average power of a few hundred mW, with fast build-up times (3 s). Experiments are performed using a home-built wideband kW pulsed electron paramagnetic resonance (EPR) spectrometer operating at 94 GHz, integrated with an NMR detection system. Simultaneous DNP and EPR characterisation of other mono-radicals and biradicals, as a function of temperature, leads to additional insights into limiting relaxation mechanisms and give further motivation for the development of wideband pulsed amplifiers for DNP at higher frequencies.

Design of the elusive proteinaceous oxygen donor copper site suggests a promising future for copper for MRI contrast agents.

We report the preparation and spectroscopic characterization of a highly elusive copper site bound exclusively to oxygen donor atoms within a protein scaffold. Despite copper generally being considered unsuitable for use in MRI contrast agents, which in the clinic are largely Gd(III) based, the designed copper coiled coil displays relaxivity values equal to, or superior than, those of the Gd(III) analog at clinical field strengths. The creation of this new-to-biology proteinaceous CuOx-binding site demonstrates the power of the de novo peptide design approach to access chemistry for abiological applications, such as for the development of MRI contrast agents.

How do current police practices impact trauma care in the prehospital setting? A scoping review.

Objective: In the United States, police are often important co-responders to 911 calls with emergency medical services for medical emergencies. To date, there remains a lack of a comprehensive understanding of the mechanisms by which police response modifies time to in-hospital medical care for traumatically injured patients. Further, it remains unclear if differentials exist within or between communities. A scoping review was performed to identify studies evaluating prehospital transport of traumatically injured patients and the role or impact of police involvement. Methods: PubMed, SCOPUS, and Criminal Justice Abstracts databases were utilized to identify articles. English-language, US-based, peer-reviewed articles published on or prior to March 30, 2022 were eligible for inclusion. Results: Of 19,437 articles initially identified, 70 articles were selected for full review and 17 for final inclusion. Key findings included (1) current law enforcement practices involving scene clearance introduce the potential for delayed patient transport but to date there is little research quantifying delays; (2) police transport protocols may decrease transport times; and (3) there are no studies examining the potential impact of scene clearance practices at the patient or community level. Conclusions: Our results highlight that police are often the first on scene when responding to traumatic injuries and have an active role via scene clearance or, in some systems, patient transport. Despite the significant potential for impact on patient well-being, there remains a paucity of data examining and driving current practices.

Design and Synthesis of Functionally Active 5-Amino-6-Aryl Pyrrolopyrimidine Inhibitors of Hematopoietic Progenitor Kinase 1.

Immune activating agents represent a valuable class of therapeutics for the treatment of cancer. An area of active research is expanding the types of these therapeutics that are available to patients via targeting new biological mechanisms. Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of immune signaling and a target of high interest for the treatment of cancer. Herein, we present the discovery and optimization of novel amino-6-aryl pyrrolopyrimidine inhibitors of HPK1 starting from hits identified via virtual screening. Key components of this discovery effort were structure-based drug design aided by analyses of normalized B-factors and optimization of lipophilic efficiency.

Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV)-CTN 314.

The Correlates of Healthy Aging in Geriatric HIV (CHANGE HIV) study, CTN 314, is the first Canadian cohort of people living with HIV aged 65 years and older. The cohort was established with the purpose of characterizing the multidimensional health status of this population and identifying factors influencing healthy aging. The study builds on the World Health Organization (WHO) Aging and Health conceptual framework, generating a comprehensive profile of health domains (physical, social, mental health, cognitive function, and quality of life), health determinants (biologic, personal, and environmental), and HIV-specific factors that may interact with and influence health in people aging with HIV. The data for the first 353 participants are presented, focusing on sociodemographic factors, comorbidities, coinfections, frailty, cognitive function, loneliness, and resilience using a sex/gender stratified analysis. The cohort thus far is 91% men and the median age is 70 years (range from 65 to 85). Several vulnerabilities were observed, including a high prevalence of comorbidities and frailty. Women especially faced financial insecurity and precarious social structures; a large proportion live alone and only 6% are married or in steady relationships. Identifying strategies to address these vulnerabilities will empower people aging with HIV to optimize their health, quality of life, and independence.

Third-order motifs are sufficient to fully and uniquely characterize spatiotemporal neural network activity.

Neuroscientific analyses balance between capturing the brain's complexity and expressing that complexity in meaningful and understandable ways. Here we present a novel approach that fully characterizes neural network activity and does so by uniquely transforming raw signals into easily interpretable and biologically relevant metrics of network behavior. We first prove that third-order (triple) correlation describes network activity in its entirety using the triple correlation uniqueness theorem. Triple correlation quantifies the relationships among three events separated by spatial and temporal lags, which are triplet motifs. Classifying these motifs by their event sequencing leads to fourteen qualitatively distinct motif classes that embody well-studied network behaviors including synchrony, feedback, feedforward, convergence, and divergence. Within these motif classes, the summed triple correlations provide novel metrics of network behavior, as well as being inclusive of commonly used analyses. We demonstrate the power of this approach on a range of networks with increasingly obscured signals, from ideal noiseless simulations to noisy experimental data. This approach can be easily applied to any recording modality, so existing neural datasets are ripe for reanalysis. Triple correlation is an accessible signal processing tool with a solid theoretical foundation capable of revealing previously elusive information within recordings of neural networks.

Targeting RNA with small molecules-A safety perspective.

RNA is a major player in cellular function, and consequently can drive a number of disease pathologies. Over the past several years, small molecule-RNA targeting (smRNA targeting) has developed into a promising drug discovery approach. Numerous techniques, tools, and assays have been developed to support this field, and significant investments have been made by pharmaceutical and biotechnology companies. To date, the focus has been on identifying disease validated primary targets for smRNA drug development, yet RNA as a secondary (off) target for all small molecule drug programs largely has been unexplored. In this perspective, we discuss structure, target, and mechanism-driven safety aspects of smRNAs and highlight how these parameters can be evaluated in drug discovery programs to produce potentially safer drugs.

An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis.

BACKGROUND AND AIMS: Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. METHODS: We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. RESULTS: MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10-9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10-19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10-6]. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10-8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. CONCLUSIONS: Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.

A Method Using Longitudinal Laboratory Data to Predict Future Intestinal Complication in Patients with Crohn's Disease.

BACKGROUND: Stenosis, fistulization, and perforation of the bowel are severe outcomes which can occur in patients with Crohn's disease. Accurate prediction of these events may enable clinicians to alter treatment strategies and avoid these outcomes. AIMS: To study the correlation between longitudinal laboratory testing and subsequent intestinal complications in patients with Crohn's disease. METHODS: An observational cohort of patients with Crohn's disease at a single center were analyzed between 01/01/1994 and 06/30/2016. A complication was defined as the development of an intestinal fistula, stenosis, or perforation. Exploratory analysis using Cox regression was performed to select the best statistical method to represent longitudinal laboratory data. Cox regression was used to identify laboratory variables independently associated with the development of a subsequent complication. A clinical scoring tool was designed. RESULTS: In 246 patients observed over a median of 5.72 years, 134 complications occurred. Minimum or maximum value in a preceding window period of one year was most strongly associated with subsequent complication. A Longitudinal Laboratory score of ≥ 2 (maximum albumin level < 39 g/L = 1, maximum mean cell volume < 88 fL = 1, minimum platelet count > 355 × 109/L = 1, minimum C reactive protein > 5 mg/L = 1) was 62% sensitive and 91% specific in identifying patients who develop a subsequent complication. CONCLUSION: A consistent reduction in serum albumin and mean cell volume, and a consistent increase in platelet count and C reactive protein were associated with a subsequent complication in patients with Crohn's disease. Longitudinal laboratory tests may be used as described in this paper to provide a rational for earlier escalation of therapy.

Retrospective analysis of the potential use of virtual control groups in preclinical toxicity assessment using the eTOX database.

Virtual Control Groups (VCGs) based on Historical Control Data (HCD) in preclinical toxicity testing have the potential to reduce animal usage. As a case study we retrospectively analyzed the impact of replacing Concurrent Control Groups (CCGs) with VCGs on the treatment-relatedness of 28 selected histopathological findings reported in either rat or dog in the eTOX database. We developed a novel methodology whereby statistical predictions of treatment-relatedness using either CCGs or VCGs of varying covariate similarity to CCGs were compared to designations from original toxicologist reports; and changes in agreement were used to quantify changes in study outcomes. Generally, the best agreement was achieved when CCGs were replaced with VCGs with the highest level of similarity; the same species, strain, sex, administration route, and vehicle. For example, balanced accuracies for rat findings were 0.704 (predictions based on CCGs) vs. 0.702 (predictions based on VCGs). Moreover, we identified covariates which resulted in poorer identification of treatment-relatedness. This was related to an increasing incidence rate divergence in HCD relative to CCGs. Future databases which collect data at the individual animal level including study details such as animal age and testing facility are required to build adequate VCGs to accurately identify treatment-related effects.