Inhibition of Receptor-Interacting Protein Kinase 1 in Chronic Plaque Psoriasis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study.

INTRODUCTION: Receptor-interacting protein kinase 1 (RIPK1), a key mediator of inflammation through necroptosis and proinflammatory cytokine production, may play a role in the pathogenesis of immune-mediated inflammatory diseases such as chronic plaque psoriasis. An experimental medicine study of RIPK1 inhibition with GSK2982772 immediate-release formulation at doses up to 60 mg three times daily in mild to moderate plaque psoriasis indicated that efficacy may be improved with higher trough concentrations of GSK2982772. METHODS: This multicenter, randomized, double-blind, placebo-controlled, repeat-dose study (NCT04316585) assessed the efficacy, safety, pharmacokinetics, and pharmacodynamics of 960 mg GSK2982772 (once-daily modified-release formulation) in patients with moderate to severe plaque psoriasis. Twenty-nine patients were randomized 2:1 to GSK2982772 (N = 19) or placebo (N = 10) for 12 weeks. RESULTS: GSK2982772 was well tolerated with trough concentrations greater than tenfold higher than the previous phase 1 study with immediate release. Despite near complete RIPK1 target engagement in blood and modest reduction in circulating inflammatory cytokines, the proportion of patients achieving 75% improvement from baseline in Psoriasis Area Severity Index score at week 12 was similar between GSK2982772 and placebo (posterior median 1.8% vs 4.9%, respectively), with an estimated median treatment difference of - 2.3%. This analysis incorporated historical placebo data through the use of an informative prior distribution on the placebo arm. Week 4 changes in skin biopsy gene expression suggested sufficient local drug exposure to elicit a pharmacodynamic response. CONCLUSION: Administration of the RIPK1 inhibitor GSK2982772 to patients with moderate to severe plaque psoriasis did not translate into meaningful clinical improvements.

Psoriasis is thought to be caused by problems with the immune system, including possibly receptor-interacting protein kinase 1 (RIPK1), which plays an important role in the development of inflammation. A previous study suggested that the drug, GSK2982772, which interferes with RIPK1, might improve symptoms in patients with psoriasis. This study examined whether higher doses of GSK2982772 than previously studied would be beneficial for patients with psoriasis. The study found that the severity of psoriasis was similar in patients treated with GSK2982772 for 12 weeks as in those who did not receive the drug, indicating that GSK298772 did not improve psoriasis.

Airway Involvement and Intervention in Non-ACE-Inhibitor-Induced Angioedema.

OBJECTIVES: Characterize the presentation of patients with non-angiotensin-converting enzyme inhibitor (ACEI)-induced angioedema and determine risk factors associated with patient disposition and possible need for airway intervention. METHODS: The medical records of adult patients in the Emergency Department (ED) and diagnosed with non-ACEI-induced angioedema over 4.5 years were included. Demographics, vital signs, etiology, timeline, presenting symptoms, physical exam including flexible laryngoscopy, medical management, and disposition were examined. Statistical analyses were conducted using SPSS V 23.0 software calculating and comparing means, standard deviations, medians, and correlation of categorical and ordinate variables. RESULTS: A total of 181 patients with non-ACEI-induced angioedema were evaluated with flexible laryngoscopy by otolaryngology. Notably, 11 patients (6.1%) required airway intervention and were successfully intubated. Statistically significant factors (p ≤ 0.05) associated with airway intervention included the diastolic blood pressure (DBP) and mean arterial pressure (MAP) (p = 0.006 and 0.01 respectively), symptoms of dysphonia (p = 0.018), the presence of oropharyngeal, supraglottic, and hypopharyngeal edema (p ≤ 0.001 for each site), and the number of edematous anatomic subsites documented on physical exam (p < 0.001). Other patient demographics, prior history of angioedema, heart rate, systolic blood pressure, symptom onset, number of symptoms at presentation, and medication administered in the ED did not correlate with airway intervention. CONCLUSION: Dysphonia, DBP, MAP, anatomic location of edema and edema in multiple sites are associated with airway intervention and a higher level of care in non-ACEI-induced angioedema and can be useful in risk assessment in patient management. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:2282-2287, 2024.

Effects of a school-based physical activity intervention on cardiometabolic health 5 years after cessation.

BACKGROUND: While there have been several school-based physical activity (PA) interventions targeting improvement in cardiovascular disease (CVD) risk factors, few have assessed long-term effects. The aim of this paper was therefore to determine intervention effects on CVD risk factors 5 years after cessation. METHODS: Two schools were assigned to intervention (n = 125) or control (n = 134). The intervention school offered 210 min/week more PA than the control school over two consecutive years (fourth and fifth grades). Follow-up assessment was conducted 5-year post-intervention (10th grade) where 180-210 (73%-85%) children provided valid data. Outcomes were CVD risk factors: triglyceride, total-to-high-density-lipoprotein-cholesterol ratio (TC:HDL ratio), insulin resistance, blood pressure (BP), waist circumference, and cardiorespiratory fitness (VO2peak ). Variables were analyzed individually and as a composite score through linear mixed models, including random intercepts for children. RESULTS: Analyses revealed significant sustained 5-year intervention effects for HDL (effect sizes [ES] = 0.22), diastolic BP (ES = 0.48), VO2peak (ES = 0.29), and composite risk score (ES = 0.38). These effects were similar to the immediate results following the intervention. In contrast, while TC:HDL ratio initially decreased post-intervention (ES = 0.27), this decrease was not maintained at 5-year follow-up (ES = 0.09), whereas WC was initially unchanged post-intervention (ES = 0.02), but decreased at 5-year follow-up (ES = 0.44). CONCLUSION: The significant effects of a 2-year school-based PA intervention remained for CVD risk factors 5 years after cessation of the intervention. As cardiometabolic health can be maintained long-term after school-based PA, this paper demonstrates the sustainability and potential of schools in the primary prevention of future CVD risk in children.

Group exercise membership is associated with forms of social support, exercise identity, and amount of physical activity.

Exploring whether the mechanisms underlying the positive relationship between group exercise and physical activity are forms of social support - emotional, validation, informational, instrumental, and companionship and exercise identity. Participants (n=506; M age = 34.3) completed a 235-item questionnaire assessing physical activity, exercise identity, social support, and other determinants of physical activity. Exploratory path analysis was used to model group exercise membership, forms of social support, exercise identity, and metabolic equivalent (MET) minutes/wk. Women and men had similar yet varying results. For women, group exercise membership was significantly associated with MET-minutes/wk (ß = 0.11) and exercise identity (ß = 0.17). There was a significant association between exercise identity and MET-minutes/wk (ß = 0.38). Women perceived belonging to an exercise group provides emotional (ß = 0.36), validation (ß = 0.25), informational (ß = 0.35), instrumental (ß = 0.19), and companionship (ß = 0.46) support. Validation (ß = 0.11), informational (ß = 0.21), and companionship (B = 0.17) were significantly associated with exercise identity for women. For men, group exercise membership was not significantly associated with MET-minutes/wk or exercise identity. Exercise identity was significantly associated with MET-minutes/wk (ß = 0.46). Men perceived belonging to their group provides emotional (ß = 0.31), validation (ß = 0.32), informational (ß = 0.33), and companionship (ß = 0.34). Validation (ß = 0.22), informational (ß = 0.30), and emotional (ß = 0.23) were significantly associated with exercise identity for men. Belonging to an exercise group is associated with forms of social support that strengthen exercise identity.

Optimization of a Series of RIPK2 PROTACs.

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) is an important kinase of the innate immune system. Herein, we describe the optimization of a series of RIPK2 PROTACs which recruit members of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC optimization strategy focused on reducing the lipophilicity of the early lead which resulted in the identification of analogues with improved solubility and increased human and rat microsomal stability. We identified a range of IAP binders that were successfully incorporated into potent RIPK2 PROTACs with attractive pharmacokinetic profiles. Compound 20 possessed the best overall profile with good solubility, potent degradation of RIPK2, and associated inhibition of TNFα release. A proof-of-concept study utilizing a slow release matrix demonstrated the feasibility of a long-acting parenteral formulation with >1 month duration. This represents an attractive alternative dosing paradigm to oral delivery, especially for chronic diseases where compliance can be challenging.

OTS167 blocks FLT3 translation and synergizes with FLT3 inhibitors in FLT3 mutant acute myeloid leukemia.

Internal tandem duplication (-ITD) mutations of Fms-like tyrosine kinase 3 (FLT3) provide growth and pro-survival signals in the context of established driver mutations in FLT3 mutant acute myeloid leukemia (AML). Maternal embryonic leucine zipper kinase (MELK) is an aberrantly expressed gene identified as a target in AML. The MELK inhibitor OTS167 induces cell death in AML including cells with FLT3 mutations, yet the role of MELK and mechanisms of OTS167 function are not understood. OTS167 alone or in combination with tyrosine kinase inhibitors (TKIs) were used to investigate the effect of OTS167 on FLT3 signaling and expression in human FLT3 mutant AML cell lines and primary cells. We describe a mechanism whereby OTS167 blocks FLT3 expression by blocking FLT3 translation and inhibiting phosphorylation of eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and eukaryotic translation initiation factor 4B (eIF4B). OTS167 in combination with TKIs results in synergistic induction of FLT3 mutant cell death in FLT3 mutant cell lines and prolonged survival in a FLT3 mutant AML xenograft mouse model. Our findings suggest signaling through MELK is necessary for the translation and expression of FLT3-ITD, and blocking MELK with OTS167 represents a viable therapeutic strategy for patients with FLT3 mutant AML.

Once-weekly prophylaxis regimen of nonacog alfa in patients with hemophilia B: an analysis of timing of bleeding event onset.

In a pivotal, multicenter, open-label study, 25 patients aged 12-54 years with moderately severe/severe hemophilia B received on-demand nonacog alfa (6 months; dose at investigator's discretion) followed by once-weekly prophylaxis with nonacog alfa 100 IU/kg (12 months). During prophylaxis, patients had a median spontaneous annualized bleeding rate (sABR) of 1.0 and significant reductions in ABR (P < 0.0001). This post hoc analysis examined the time of onset of spontaneous bleeding events (sBEs) and spontaneous target joint bleeding events (sTJBEs). The postdosing day (D) of onset of sBEs observed during prophylaxis and steady-state FIX activity data (FIX:C) between 144 and 196 h postdose were collected at weeks 26 and 78. Twelve patients (48%) had no sBEs; the remaining 13 (52%) had the following onset of sBEs: less than 1 D (0%), 1 to less than 2D (5%), 2 to less than 3 D (22%), 3 to less than 4 D (9%), 4 to less than 5D (22%), 5 to less than 6D (23%), 6 to less than 7D (11%), and at least 7D (8%). Reductions in sBEs and sTJBEs during on-demand versus prophylaxis treatment were experienced by all 13 patients. Target joint sABR during prophylaxis was 0 for 5/13 patients. ABR reduction ranged from 66.1% (27.2→9.2) to 97.8% (46.2→1.0); sTJBE reductions ranged from 6.2% (2.1→2.0) to 100% (from 40.1, 19.1, 3.9, 9.0, 6.1--0). During prophylaxis, 47% (8/17) of trough FIX activity samples were more than 2%. In sBE patients, ABR and number of TJBEs were reduced with once-weekly nonacog alfa. When sBEs occurred, they followed no apparent pattern for day of occurrence. Clinicaltrials.gov identifier: NCT01335061.

Correction to Identification of Quinoline-Based RIP2 Kinase Inhibitors with an Improved Therapeutic Index to the hERG Ion Channel.

[This corrects the article DOI: 10.1021/acsmedchemlett.8b00344.].

Understanding Pharmacokinetic Disconnect in Preclinical Species for 4-Aminoquinolines: Consequences of Low Permeability and High P-glycoprotein Efflux Ratio on Rat and Dog Oral Pharmacokinetics.

Receptor Interacting Protein 2 (RIP2) kinase inhibitors have been reported for therapeutic opportunities in inflammatory bowel diseases such as Ulcerative Colitis and Crohn's disease. During lead optimization, team identified 4-aminoquinoline series and several compounds from this series were investigated in rat and dog pharmacokinetic studies. While compounds such as GSKA and GSKB demonstrated acceptable pharmacokinetics in rat and dog, further progression of these compounds was halted due to adverse findings in advanced safety studies. Structurally similar analogues incorporating polarity at C-7 position of 4-aminoquinoline resulted in identification of GSKC - GSKF. Interestingly, following oral administration to rat at similar low dose, GSKC - GSKF demonstrated significantly low systemic drug exposure compared to GSKA and GSKB (3-17-fold difference). However, in dog, dose normalized oral systemic exposure for GSKC - GSKF was comparable to GSKA and GSKB (within 2-fold). A series of studies were conducted to understand the disconnect which highlighted that an intrinsic reduction in permeability and high P-glycoprotein (P-gp) efflux ratio for C-7 substituted analogues were driving pharmacokinetic disconnect between rat and dog. Oral absorption was minimally impacted in dog by P-gp mediated efflux compared to rat because the leakier gastrointestinal tract in dog likely overcomes this effect.

Real-world outcomes associated with standard half-life and extended half-life factor replacement products for treatment of haemophilia A and B.

: Standard-of-care treatment for haemophilia A or B is to maintain adequate coagulation factor levels through clotting factor administration. The current study aimed to evaluate annualised bleeding rates (ABR) and treatment adherence for haemophilia A or B patients receiving standard half-life (SHL) vs. extended half-life (EHL) factor replacement products. We analysed data from the Adelphi Disease-Specific Programmes, a health record-based survey of United States and European haematologists. Analysis included 651 males with moderate-to-severe haemophilia A or B (the United States, n = 132; Europe, n = 519). The haemophilia A analysis included 501 patients (SHL, n = 435; EHL, n = 66). In the combined United States/European population, mean (SD) ABR was 1.7 (1.69) for the SHL group and 1.8 (2.00) for the EHL group. A total of 72% of patients receiving SHL factor VIII and 75% of patients receiving EHL factor VIII in the combined population were fully adherent (no doses missed of the last 10 doses), as reported by physicians. The haemophilia B analysis included 150 patients (SHL, n = 114; EHL, n = 36). The mean (SD) ABR in the combined population was 2.1 (2.16) for patients receiving SHL factor IX (FIX) and 1.4 (1.48) for patients receiving EHL FIX. The percentage of fully adherent patients (physician-reported) was similar in both treatment groups (SHL FIX, 68%; EHL FIX, 73%). In this preliminary real-world survey in a relatively small sample of patients, measures of ABR and adherence between SHL and EHL products were evaluated. Additional real-world research on prescribing patterns, SHL vs. EHL effectiveness, and adherence is warranted.

Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2.

Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

Adverse Events and Discontinuation Rates Associated with Sirolimus Treatment in Adult Renal Transplant Patients in Latin America vs Non-Latin American Countries.

BACKGROUND: Sirolimus is approved for prophylaxis of organ rejection following renal transplantation. Rates of treatment-emergent adverse events (TEAEs) leading to sirolimus discontinuation differ geographically. METHODS: Rates of TEAEs, serious AEs (SAEs), and discontinuations were evaluated in 3 clinical trials of conversion from calcineurin inhibitors to sirolimus. Posttransplantation, patients were treated over 4 years (study 1), over 1 year (study 2), and over 2 years (study 3). TEAEs, SAEs, and discontinuation rates were compared between Latin America (LATAM) vs North America (NA) and Europe/rest of world (EU/ROW). Data from studies 2 and 3, with similar times to conversion, were pooled. RESULTS: Study 1 comprised 551 patients (LATAM, n=189); studies 2/3 comprised 395 (LATAM, n=111). LATAM patients were significantly younger than NA or EU/ROW patients in study 1 and studies 2/3 (P < .0001), with a lower proportion of white patients and higher proportion of patients of other races in LATAM vs NA (P < .0001) and EU/ROW (P = .02) groups. Almost all patients reported TEAEs. Discontinuation because of medical events was significantly lower (P < .05) in LATAM vs NA or EU/ROW. Hypercholesterolemia and hypertriglyceridemia were more common, and anemia and peripheral edema less common in LATAM; diarrhea and proteinuria did not differ by region. Types of AEs leading to discontinuation did not differ by region. CONCLUSION: LATAM renal transplant recipients converted to sirolimus were more likely to remain on therapy than patients in other regions.

Conservative Management of Pneumatosis Intestinalis and Portal Venous Gas After Pediatric Liver Transplantation.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare pathologic finding in pediatric liver transplant (PLT) recipients. The presentation and course of PI can range from asymptomatic and clinically benign to life threatening, with no consensus regarding management of PI in children. We aim to review the clinical presentation and radiologic features of PLT recipients with PI and to report the results of conservative management. METHODS: A retrospective medical chart review was conducted on PLT recipients between November 1995 and May 2016. Parameters evaluated at PI diagnosis included pneumatosis location, presence of free air or portal venous gas (PVG), symptoms, laboratory findings, and medication regimen. RESULTS: PI developed in 10 of 130 PLT patients (7.7%) between 8 days and 7 years (median: 113 days) posttransplant. Five of the patients were male, and the median age was 2 years (range, 1-17 years). PI was located in 1 to 2 abdominal quadrants in 6 patients, and 3 patients had PVG. At diagnosis, all patients were on steroids and immunosuppressant medication and 6 patients had a concurrent infection. Laboratory findings were unremarkable. Symptoms were present in 7 patients. Nine patients were managed conservatively, and 1 patient received observation only. All patients had resolution of PI at a median of 7 days (range, 2-14 days). CONCLUSIONS: PI can occur at any time after PLT and appears to be associated with steroid use and infectious agents. If PI/PVG is identified and the patient is clinically stable, initiation of a standard management algorithm may help treat these patients conservatively, thus avoiding surgical intervention.

Non-attendance at diabetes outpatient appointments: a systematic review.

BACKGROUND: Non-attendance at diabetes outpatient appointments is a sizeable problem worldwide and has been associated with suboptimal health outcomes. We aimed to describe the characteristics, health outcomes and reasons given for non-attendance at doctor- or nurse-led diabetes appointments, and interventions to improve attendance. METHODS: PubMed, EMBASE, CINAHL and PsychInfo were searched from database inception to February 2019. Included articles were peer-reviewed, published in English, related to adults or young people with type 1 or type 2 diabetes, and addressed one of the above aspects of non-attendance. Studies were excluded if reporting on other types of diabetes or reviewing attendance at structured education, retinal screening, paediatric, antenatal, podiatry or dietetic clinics. RESULTS: Thirty-four studies of varied designs were identified (15 observational, 1 randomized control trial, 9 qualitative, 5 surveys, 4 service improvements). The definition of non-attendance varied. Younger adults, smokers and those with financial pressures were less likely to attend. Non-attendance was associated with higher HbA1c ; other outcomes were varied but typically worse in non-attenders. Reasons for non-attendance in qualitative studies fell into three categories: balancing the costs and benefits of attendance, coping strategies, and the relationships between the person with diabetes and healthcare professionals. Interventions included appointment management strategies, service improvements, patient navigators and WebCam appointments. CONCLUSIONS: Non-attendance is only partially explained by logistical issues. Qualitative studies suggest complex psychosocial factors are involved. Interventions have progressed from simple appointment reminders in an attempt to address some of the psycho-social determinants, but more work is needed to improve attendance.

Myxobolus spp. (Cnidaria: Myxozoa) in introduced yellow perch Perca flavescens (Mitchill, 1814).

We surveyed introduced yellow perch Perca flavescens (Mitchill, 1814) from the Willamette River, OR, USA, to determine if these fish have co-introduced myxosporean parasites. Mature parasite myxospores were observed in brains of 3/19 fish, and were morphologically and molecularly consistent with Myxobolus neurophilus (Guilford 1963), a parasite known from yellow perch in their native range. We identified another Myxobolus species from the gill filaments of 1/22 fish. The spores from the gill filaments were oval-shaped, 11.7 (10.7-12.3) µm long × 8.6 (7.7-9.0) µm wide × 5.2 (4.6-5.6) µm thick, with two oval-shaped polar capsules 5.7 (5.1-6.5) µm × 2.7 (2.4-3.2) µm, each containing a polar tubule with 8-9 turns. Small-subunit ribosomal DNA sequences from each of four plasmodia were identical, and 4.0% different (over 1800 nucleotides) from the closest known myxosporeans. Interestingly, these sequences had overlapping peaks in their chromatograms, which suggested that DNA from multiple species was present. Hence, we isolated and sequenced three individual myxospores and found that they too had mixed chromatograms, which indicated presence of at least two sequence types of small-subunit ribosomal DNA in each spore (GenBank accession MK592012, MK592013), a rare character among described myxosporeans. The spore morphology, morphometry, tissue tropism, and DNA sequence supported a diagnosis of a novel species, Myxobolus doubleae n. sp. This parasite is unknown from yellow perch in its native range, despite extensive historical surveys, which suggests that introduced yellow perch might have acquired an endemic Myxobolus species via spillback from another fish host.

Discovery of Pyrazolocarboxamides as Potent and Selective Receptor Interacting Protein 2 (RIP2) Kinase Inhibitors.

Herein we report the discovery of pyrazolocarboxamides as novel, potent, and kinase selective inhibitors of receptor interacting protein 2 kinase (RIP2). Fragment based screening and design principles led to the identification of the inhibitor series, and X-ray crystallography was used to inform key structural changes. Through key substitutions about the N1 and C5 N positions on the pyrazole ring significant kinase selectivity and potency were achieved. Bridged bicyclic pyrazolocarboxamide 11 represents a selective and potent inhibitor of RIP2 and will allow for a more detailed investigation of RIP2 inhibition as a therapeutic target for autoinflammatory disorders.

Interrelationship between depression, anxiety, pain, and treatment adherence in hemophilia: results from a US cross-sectional survey.

PURPOSE: Depression, anxiety, pain, and treatment adherence have reciprocal effects not characterized extensively in hemophilia. This study explored the relationships between depression, anxiety, chronic pain, and treatment adherence in adults with hemophilia. PATIENTS AND METHODS: Adults with self-reported hemophilia A or B completed the cross-sectional IMPACT QoL II survey. Depression (9-item Patient Health Questionnaire [PHQ-9]), anxiety (7-item Generalized Anxiety Disorder scale [GAD-7]), chronic pain (Faces Pain Scale-Revised [FPS-R]), social support (Duke UNC Functional Social Support questionnaire), level of pain control, clotting factor treatment adherence (VERITAS-Pro or -PRN), and previous depression/anxiety were analyzed. RESULTS: Among 200 participants (male, 77.3%; female, 22.8%), 54% had PHQ-9 and 52% had GAD-7 scores indicating moderate to severe depression or anxiety without diagnosis of either disorder. Participants with PHQ-9 scores ≥10 (moderate to severe depression) were more likely to have lower treatment adherence than those with PHQ-9 scores <10 (P<0.05). Participants with PHQ-9 or GAD-7 scores ≥10 were more likely to report uncontrolled pain and less social support versus PHQ-9 or GAD-7 scores <10 (χ2 P<0.05). Significant correlations were found between PHQ-9 and GAD-7 (P<0.0001), PHQ-9 and FPS-R (P=0.0004), PHQ-9 and VERITAS (P=0.01), GAD-7 and FPS-R (P=0.02), and GAD-7 and VERITAS (P=0.001). CONCLUSION: Depression and anxiety are underdiagnosed in hemophilia. Depression is associated with anxiety, pain, and lower treatment adherence. While treatment providers play an important role in diagnosis, social workers may play a pivotal role in depression and anxiety screening. This study highlights the importance of regular screening and treatment for these disorders.

Discovery of a First-in-Class Receptor Interacting Protein 2 (RIP2) Kinase Specific Clinical Candidate, 2-((4-(Benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl Dihydrogen Phosphate, for the Treatment of Inflammatory Diseases.

RIP2 kinase has been identified as a key signal transduction partner in the NOD2 pathway contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule inhibitors of RIP2 kinase or its signaling partners on the NOD2 pathway that are suitable for advancement into the clinic have yet to be described. Herein, we report our discovery and profile of the prodrug clinical compound, inhibitor 3, currently in phase 1 clinical studies. Compound 3 potently binds to RIP2 kinase with good kinase specificity and has excellent activity in blocking many proinflammatory cytokine responses in vivo and in human IBD explant samples. The highly favorable physicochemical and ADMET properties of 3 combined with high potency led to a predicted low oral dose in humans.

Outcome of within-host competition demonstrates that parasite virulence doesn't equal success in a myxozoan model system.

Within-host competition can affect outcomes of infections when parasites occupy the same niche. We investigated within-host competition and infection outcomes in Chinook salmon exposed to two genotypes of Ceratonova shasta (myxozoan parasite). We assessed i) virulence (host mortality, median days to death), ii) within-host competition (abundance in host), and iii) success (spore production, proportion of myxospore-producing hosts) following concurrent and sequential exposures to single or mixed-genotype treatments. In single treatments, genotype-I replicated faster, and caused higher and earlier host mortality (higher virulence) but genotype-II produced more myxospores (higher success). In mixed treatments, costs of competition were observed for both genotypes evidenced by reduced replication or myxospore production following concurrent exposures, but only the less-virulent genotype suffered costs of competition when hosts were exposed to genotypes sequentially. To understand potential host effects on competition outcomes, we characterized systemic (spleen) and local (intestine) cytokine and immunoglobulin expression in single and mixed infections. We observed delayed systemic and immunosuppressive responses to the virulent genotype (I), rapid, localized and non-suppressive responses to the less-virulent genotype (II), and a combination of responses to mixed-genotypes. Thus, competition outcomes favoring the virulent genotype may be partially explained by the localized response to genotype-II that facilitates myxospore production (success) offsetting the systemic response to genotype-I that results in early inflammation and immunosuppression (that increases onset of mortality). This evidence for different but simultaneous responses to each genotype suggests selection should favor the exclusion of the weaker competitor and the evolution of increased virulence in the stronger competitor because the outcome was generally more costly for the less-virulent genotype. With caveats, our results are relevant for understanding infection outcomes in commercially and ecologically important salmonids in C. shasta endemic regions where mixed infections are commonplace.

Comparing the expected refractive status from immersion biometry and the achieved refractive status post-cataract surgery

Objective: To investigate the accuracy of Immersion A-Scan Biometry by comparing the relationship between the predicted refractive status from the biometric data with the achieved refractive status determined from objective/subjective refraction. Design and Methodology: Sixty patients were recruited from the Trinidad Eye Hospital (TEH) who was scheduled to undergo cataract surgery. The method of ocular biometry measurement used in this study was Immersion A-scan Biometry using the Aviso: The Ultrasound Platform. The biometric data was then recorded along with the expected refractive status based on the SRK-T formula used to calculate the power of the intra-occular lens (IOL) to be implanted. Results: Out of the 60 patients used, phacoemulsification surgery was performed on 33 right eyes and 27 left eyes. The goal of emmetropia after surgery was achieved in 32 patients among the 60 patients. The 28 patients that were unable to achieve emmetropia brought awareness to the assumptions of errors within the biometric data. The visual acuity was improved significantly in all patients after the phacoemulsification surgery. Conclusion: The study confirmed that there is no significant difference between the refractive status predicted from Immersion A-scan biometry with the refractive status achieved post cataract surgery.