Prevalence of omalizumab resistant chronic urticaria and real world effectiveness of dupilumab in omalizumab refractory chronic urticaria patients: a single center experience.

Chronic urticaria (CU) is characterized by wheals, angioedema, or both lasting for ≥ 6 weeks with chronic spontaneous urticaria (CSU) being the most common subtype. Omalizumab-resistant CSU cases represent an unmet clinical need. In this study, we aimed to assess the prevalence and predictors of omalizumab failure in a large cohort of CU patients and assess the effectiveness of dupilumab for omalizumab-recalcitrant CU. Of 338 CU patients, 33 received omalizumab. 69.7% (23 patients) were responders and 30.3% (10 patients) non-responders. Bivariate regression demonstrated that female sex (adjusted OR [aOR] = 1.53; 95%CI = 1.14-2.06), higher baseline UAS7 (aOR = 1.05; 95%CI = 1.01-1.09) and older age (controlling for sex) (aOR = 1.00; 95%CI = 1.00, 1.01) were associated with omalizumab failure. Of 10 omalizumab-refractory patients, three were well controlled with cyclosporine (all children), whereas the seven adults failed on average 5.6 ± 2.6 therapies including cyclosporine. All 7 achieved a complete response with dupilumab with time to response varying between 1 to 6 months. While our results suggest a favourable efficacy of dupilumab omalizumab-resistant cases, future confirmatory studies are required.

A Systematic Review on Treatment Outcomes of Striae.

BACKGROUND: Striae are fine lines on the body that occur following rapid skin stretching (i.e., following pregnancy, puberty, weight change). The aim of this systematic review was to assess the current literature on treatment outcomes associated with striae. OBJECTIVE: (1) To assess the efficacy and safety of different treatment options reported for striae and (2) to determine the most efficient treatment options for each subtype of striae. METHODS: A systematic search was performed on MEDLINE, Embase, and PubMed with no publication date or language restrictions. All articles with original data and treatment outcomes were included. RESULTS: One hundred fifty-one studies on the treatment of striae met inclusion criteria (83% female, mean age at diagnosis = 30.2), and 4,806 treatment outcomes of striae were described. Energy-based devices were the most reported modality (56%; n = 2,699/4,806), followed by topicals (19%; n = 919/4,806) and combinations (12%; n = 567/4,806). The highest rates of complete response were injection-based devices for striae distensae (7%; n = 12/172), CO 2 lasers for striae alba (4%; n = 12/341), and platelet-rich plasma injections for striae rubra (31%; n = 4/13). CONCLUSION: Treatment options for striae are varied, likely indicating a lack of effective treatments due to the diversity in striae subtypes. Improved outcomes in striae management may be achieved with additional research on factors that predict treatment response.

Comparison of Preoperative Alpha-blockade for Resection of Paraganglioma and Pheochromocytoma.

OBJECTIVE: Phenoxybenzamine (nonselective, noncompetitive alpha-blocker) is the preferred drug for preoperative treatment of pheochromocytoma, but doxazosin (selective, competitive alpha-blocker) may be equally effective. We compared the efficacy of doxazosin vs phenoxybenzamine. METHODS: We conducted a prospective study of patients undergoing pheochromocytoma or paraganglioma resection by randomizing pretreatment with phenoxybenzamine or doxazosin at a single tertiary referral center. The high cost of phenoxybenzamine led to high crossover to doxazosin. Randomization was halted, and a consecutive historical cohort of phenoxybenzamine patients was included for a case-control study design. The efficacy of alpha-blockade was assessed with preinduction infusion of incremental doses of phenylephrine. The primary outcomes were mortality, cardiovascular complications, and intensive care unit admission. The secondary outcomes were hemodynamic instability index (proportion of operation outside of hemodynamic goals), adequacy of blockade by the phenylephrine titration test, and drug costs. RESULTS: Twenty-four patients were prospectively enrolled (doxazosin, n = 20; phenoxybenzamine, n = 4), and 15 historical patients treated with phenoxybenzamine were added (total phenoxybenzamine, n = 19). No major cardiovascular complications occurred in either group. The phenylephrine dose-response curves showed less blood pressure rise in the phenoxybenzamine than in the doxazosin group (linear regression coefficient = 0.008 vs 0.018, P = .01), suggesting better alpha-blockade in the phenoxybenzamine group. The median hemodynamic instability index was 14% vs 13% in the phenoxybenzamine and doxazosin groups, respectively (P = .56). The median highest daily cost of phenoxybenzamine was $442.20 compared to $5.06 for doxazosin. CONCLUSION: Phenoxybenzamine may blunt intraoperative hypertension better than doxazosin, but this difference did not translate to fewer cardiovascular complications and is offset by a considerably increased cost.

Trace Key Mechanistic Features of the Arsenite Sequestration Reaction with Nanoscale Zerovalent Iron.

Nanoscale zerovalent iron (nZVI) is considered as a highly efficient material for sequestrating arsenite, but the origin of its high efficacy as well as the chemical transformations of arsenite during reaction is not well understood. Here, we report an in situ X-ray absorption spectroscopy (XAS) study to investigate the complex mechanism of nZVI reaction with arsenite under anaerobic conditions at the time scale from seconds to days. The time-resolved XAS analysis revealed a gradual oxidation of AsIII to AsV in the course of minutes to hours in both the solid and liquid phase for the high (above 0.5 g/L) nZVI dose system. When the reaction time increased up to 60 days, AsV became the dominant species. The quick-scanning extended X-ray absorption fine structure (QEAXFS) was introduced to discover the transient intermediate at the highly reactive stage, and a small red-shift in As K-edge absorption edge was observed. The QEAXFS combined with density functional theory (DFT) calculation suggested that the red-shift is likely due to the electron donation in a Fe-O-As complex and possible active sites of As sequestrations include Fe(OH)4 and 4-Fe cluster. This is the first time that the transient reaction intermediate was identified in the As-nZVI sequestration system at the fast-reacting early stage. This study also demonstrated usefulness of in situ monitoring techniques in environmental water research.

Quality of Life Following Molecular Marker Testing for Indeterminate Thyroid Nodules.

OBJECTIVE: Thyroid cancer has a disproportionately negative effect on the quality of life (QOL) compared to malignancies with a worse prognosis. The QOL of patients with indeterminate thyroid nodules has not been previously evaluated. We aimed to assess the impact of molecular test results on the QOL of patients with indeterminate thyroid nodules. METHODS: A short version of the Thyroid-Related Patient-Reported Outcome (ThyPro-39) was used to assess the QOL of patients who underwent thyroid fine needle aspiration (FNA) biopsy throughout UCLA Health from May, 2016, to June, 2017. All patients with indeterminate biopsy results underwent molecular testing with either Afirma Gene Expression Classifier or ThyroSeq v2 at the time of the initial biopsy. The QOL associated with symptoms of goiter, anxiety, depression, and impaired daily life were analyzed. RESULTS: Of 825 consented patients, 366 completed the assessment (44.4% response rate). FNA results included 76% benign, 7% malignant, and 17% indeterminate. There were no differences in QOL between patients with a benign FNA and patients with an indeterminate result with benign molecular testing. In patients with an indeterminate FNA, symptoms of goiter (20.5 versus 10.4; P = .033) and depression (33.3 versus 21.0; P = .026) were worse for patients with suspicious versus benign molecular test results; however, no significant differences were observed in anxiety or impaired daily life. CONCLUSION: A benign molecular test result may provide reassurance for patients with indeterminate thyroid nodules that the risk of malignancy is low. Long-term follow-up is necessary to determine if benign molecular test results maintain improved QOL.

Fexofenadine and Rosuvastatin Pharmacokinetics in Mice with Targeted Disruption of Organic Anion Transporting Polypeptide 2B1.

Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the Slco2b1 gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wild-type (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC0-last) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced C max by 80% and 88%, respectively, while the AUC0-last values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine C max and AUC0-last values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT: A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.

Apixaban and Rosuvas--tatin Pharmacokinetics in Nonalcoholic Fatty Liver Disease.

There is little known about the impact of nonalcoholic fatty liver disease (NAFLD) on drug metabolism and transport. We examined the pharmacokinetics of oral apixaban (2.5 mg) and rosuvastatin (5 mg) when administered simultaneously in subjects with magnetic resonance imaging-confirmed NAFLD (N = 22) and healthy control subjects (N = 12). The area under the concentration-time curve to the last sampling time (AUC0-12) values for apixaban were not different between control and NAFLD subjects (671 and 545 ng/ml × hour, respectively; P = 0.15). Similarly, the AUC0-12 values for rosuvastatin did not differ between the control and NAFLD groups (25.4 and 20.1 ng/ml × hour, respectively; P = 0.28). Furthermore, hepatic fibrosis in NAFLD subjects was not associated with differences in apixaban or rosuvastatin pharmacokinetics. Decreased systemic exposures for both apixaban and rosuvastatin were associated with increased body weight (P < 0.001 and P < 0.05, respectively). In multivariable linear regression analyses, only participant weight but not NAFLD, age, or SLCO1B1/ABCG2/CYP3A5 genotypes, was associated with apixaban and rosuvastatin AUC0-12 (P < 0.001 and P = 0.06, respectively). NAFLD does not appear to affect the pharmacokinetics of apixaban or rosuvastatin.

Innovations in Bariatric Surgery.

Surgery has consistently been demonstrated to be the most effective long-term therapy for the treatment of obesity. However, despite excellent outcomes with current procedures, most patients with obesity- and weight-related comorbidities who meet criteria for surgical treatment choose not to pursue surgery out of fear of operative risks and complications or concerns about high costs. Novel minimally invasive procedures and devices may offer alternative solutions for patients who are hesitant to pursue standard surgical approaches. These procedures may be used for primary treatment of obesity, early intervention for patients approaching morbid obesity, temporary management prior to bariatric surgery, or revision of bypass surgery associated with weight regain. Novel bariatric procedures can in general be divided into four categories: endoluminal space-occupying devices, gastric suturing and restrictive devices, absorption-limiting devices, and neural-hormonal modulating devices. Many of these are only approved as short-term interventions, but these devices may be effective for patients desiring low-risk procedures or a transient effect. We will see the expansion of indications and alternatives for metabolic surgery as these techniques gain approval.

Host genetic background impacts modulation of the TLR4 pathway by RON in tissue-associated macrophages.

Toll-like receptors (TLRs) enable metazoans to mount effective innate immune responses to microbial and viral pathogens, as well as to endogenous host-derived ligands. It is understood that genetic background of the host can influence TLR responsiveness, altering susceptibility to pathogen infection, autoimmunity and cancer. Macrophage stimulatory protein (MSP), which activates the receptor tyrosine kinase recepteur d'origine nantais (RON), promotes key macrophage functions such as motility and phagocytic activity. MSP also acts via RON to modulate signaling by TLR4, which recognizes a range of pathogen or endogenous host-derived molecules. Here, we show that RON exerts divergent control over TLR4 activity in macrophages from different mouse genetic backgrounds. RON potently modulated the TLR4 response in macrophages from M2-prone FVB mice, as compared with M1-skewed C57Bl6 mice. Moreover, global expression analysis revealed that RON suppresses the TLR4-dependent type-I interferon gene signature only in FVB macrophages. This leads to attenuated production of the potent inflammatory mediator, tumor necrosis factor-α. Eliminating RON kinase activity markedly decreased carcinogen-mediated tumorigenesis in M2/Th2-biased FVB mice. We propose that host genetic background influences RON function, thereby contributing to the variability in TLR4 responsiveness in rodents and, potentially, in humans. These findings provide novel insight into the complex interplay between genetic context and immune function.

The multiple shark Ig H chain genes rearrange and hypermutate autonomously.

Sharks and skates are representatives of the earliest vertebrates with an immune system based on V(D)J rearrangement. They possess a unique Ig gene organization consisting of 15 to >50 individual IgM loci, each with one VH, two DH, one JH, and one set of constant region exons. The present study attempts to understand how multiple Ig genes are regulated with respect to rearrangement initiation and to targeting during somatic hypermutation. The linkage of three single-copy IgH genes was determined, and single-cell genomic PCR studies in a neonatal animal were used to examine any relationship between relative gene position and likelihood of rearrangement. Our results show that one to three IgH genes are activated independently of linkage or allelic position and the data best fit with a probability model based on the hypothesis that V(D)J rearrangement occurs as a sequence of trials within the B cell. In the neonatal cell set, two closely related IgH, G2A, and G2B, rearranged at similar frequencies, and their membrane forms were expressed at similar levels, like in other young animals. However, older animals displayed a bias in favor of the G2A isotype, which suggests that although rearrangement at G2A and G2B was randomly initiated during primary repertoire generation, the two very similar IgM sequences appear to be differentially expressed with age and exposure to Ag. We performed genomic single-cell PCR on B cells from an immunized individual to study activation-induced cytidine deaminase targeting and found that hypermutation, like V(D)J rearrangement, occurred independently among the many shark IgH.

Teledermatology in remote Indigenous populations: Lessons learned and paths to explore, an experience from Canada (Québec) and Australia.

Objective: Recent introduction of a provincially funded and administered teledermatology platform in Quebec presents a major opportunity to improve healthcare delivery to rural Indigenous communities where healthcare is suboptimal. In this study, we assessed approaches, challenges, solutions, and outcomes in implementing teledermatology in rural Indigenous communities of Australia and Canada. Methods: A narrative review was performed using journal articles and grey literatures to assess challenges encountered in Canadian and Australian teledermatology programs in rural Indigenous communities. We then conducted a focused search to identify solutions and outcomes to these challenges. We identified four main areas of focus for implementing teledermatology: financial, cultural, legal, and provider competency. Results: Main financial concerns included identifying the cost-to-benefit ratio of teledermatology and financial benefits of the store-and-forward system compared to videoconferencing. Delivery of teledermatology through culturally considerate services is crucial to mend the mistrust felt by Indigenous people toward mainstream health services. From a legal standpoint, patient confidentiality and physician liability must be considered. A uniform teledermatology platform and physician competency in both telemedicine and dermatology are needed to ensure standard of care. Conclusion: Teledermatology initiatives represent great opportunities to improve healthcare services to rural Indigenous populations.

Long-term effects of primary hyperparathyroidism and parathyroidectomy on kidney function.

IMPORTANCE: Limited evidence supports kidney dysfunction as an indication for parathyroidectomy in asymptomatic primary hyperparathyroidism (PHPT). OBJECTIVE: To investigate the natural history of kidney function in PHPT and whether parathyroidectomy alters renal outcomes. DESIGN: Matched control study. SETTING: A vertically integrated health care system serving 4.6 million patients in Southern California. PARTICIPANTS: 6058 subjects with PHPT and 16 388 matched controls, studied from 2000 to 2016. EXPOSURES: Biochemically confirmed PHPT with varying serum calcium levels. MAIN OUTCOMES: Estimated glomerular filtration rate (eGFR) trajectories were compared over 10 years, with cases subdivided by severity of hypercalcemia: serum calcium 2.62-2.74 mmol/L (10.5-11 mg/dL), 2.75-2.87 (11.1-11.5), 2.88-2.99 (11.6-12), and >2.99 (>12). Interrupted time series analysis was conducted among propensity-score-matched PHPT patients with and without parathyroidectomy to compare eGFR trajectories postoperatively. RESULTS: Modest rates of eGFR decline were observed in PHPT patients with serum calcium 2.62-2.74 mmol/L (−1.0 mL/min/1.73 m2/year) and 2.75-2.87 mmol/L (−1.1 mL/min/1.73 m2/year), comprising 56% and 28% of cases, respectively. Compared with the control rate of −1.0 mL/min/1.73 m2/year, accelerated rates of eGFR decline were observed in patients with serum calcium 2.88-2.99 mmol/L (−1.5 mL/min/1.73 m2/year, P < .001) and >2.99 mmol/L (−2.1 mL/min/1.73 m2/year, P < .001), comprising 9% and 7% of cases, respectively. In the propensity score­matched population, patients with serum calcium >2.87 mmol/L exhibited mitigation of eGFR decline after parathyroidectomy (−2.0 [95% CI: −2.6 to −1.5] to −0.9 [95% CI: −1.5 to 0.4] mL/min/1.73 m2/year). CONCLUSIONS AND RELEVANCE: Compared with matched controls, accelerated eGFR decline was observed in the minority of PHPT patients with serum calcium >2.87 mmol/L (11.5 mg/dL). Parathyroidectomy was associated with mitigation of eGFR decline in patients with serum calcium >2.87 mmol/L.

Safety of COVID-19 mRNA vaccination and effects of SARS-CoV-2 infection in children and adults with mast cell disorders.

Mastocytosis is characterized by abnormal clonal mast cell proliferation. Given the paucity of data in patients with mastocytosis, it is crucial to assess the safety of COVID-19 vaccines in this population. We aimed to assess the risk of allergic reactions and the effect of COVID-19 infection among patients with mastocytosis. Participants were recruited from Canada and Israel between December 2021 and May 2022. Consenting participants were administered standardized questionnaires querying whether they were infected with COVID-19, if they received the first and second dose vaccines, and post-vaccination side effects including allergic reactions (urticaria/angioedema, current rash flaring, need for updosing medications, or respiratory symptoms) and common side effects including injection site reaction (ISR) and flu-like symptoms. Forty participants with mastocytosis were administered a standardized questionnaire (median age = 9, 59% male). Amongst all participants, 16 (39%) reported COVID-19 infection and most (75%) reported flu-like symptoms, 3 (19%) were asymptomatic, 1 suffered from shortness of breath/chest pain and 1 from facial flushing. Of the 25 participants who were eligible for vaccination (≥ 5 years old), 80% received a first-dose vaccine and 68% received a second-dose vaccine. Of those who received the first-dose vaccine, most (60%) remained asymptomatic, 20% developed flu-like symptoms, 20% had an ISR, and 1 patient had an allergic reaction (urticaria and swelling). Of those who received the second-dose vaccine, most (53%) were asymptomatic, and 1 had an allergic reaction. No significant difference was found between side effects of both vaccine doses. No reactions fulfilled the criteria for anaphylaxis in either dose. This study reveals that among patients with mastocytosis, COVID-19 vaccine and infection were well-tolerated in the majority of cases.

Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.

Error-prone DNA repair activity during somatic hypermutation in shark B lymphocytes.

Sharks are representatives of the earliest vertebrates that possess an immune system utilizing V(D)J recombination to generate Ag receptors. Their Ab repertoire diversity is based in part on a somatic hypermutation process that introduces adjacent nucleotide substitutions of 2-5 bp. We have isolated mutant nonfunctional Ig rearrangements and intronic flank sequences to characterize the nonselected, intrinsic properties of this phenomenon; changes unique to shark were observed. Duplications and deletions were associated with N additions, suggesting participation of a DNA polymerase with some degree of template independence during the repair of DNA breaks initiated by activation-induced cytidine deaminase. Other mutations were consistent with some in vitro activities of mammalian translesion DNA polymerase η: tandem base substitutions, strand slippage, and small insertions/deletions. The nature of substitution patterns shows that DNA lesions at shark Ig genes recruit DNA repair factors with a species-specific repertoire of activities. We speculate that the tandem mutations are introduced by direct sequential misinsertions and that, in shark B cells, the mispairs tend to be extended rather than proofread. Despite extensive changes undergone by some mutants, the physical range of mutational activity remained restricted to VDJ and within the first 2-kb portion of the 6.8-kb J-C intron, perhaps a self-regulating aspect of activation-induced cytidine deaminase action that is conserved in evolution.

Description and Disposition of Patients With Cancer Accessing a Novel, Pharmacist-Led Cannabis Consultation Service.

PURPOSE: The Cannabis Consultation Service (CCS) is an innovative pharmacist-led resource at the Sunnybrook Odette Cancer Centre. Its mandate is to provide education and guide patients through access and appropriate use of high-quality plant-derived cannabinoids (PDCs). Our objective was to describe the CCS, explain its processes, and characterize patient disposition with respect to use of PDCs. METHODS: We retrospectively reviewed the charts of patients referred to the CCS from July 13, 2020, to March 05, 2021. We used descriptive statistics to report on the patient population and service metrics. RESULTS: During the 34-week period, 96 patients accessed the CCS (median age, 61 years). The top reasons for CCS consultation were management of cancer pain, insomnia, and general interest. Medical cannabis was supported as an option in 44/96 patients. Reasons for not supporting PDC use included lack of indication, potential drug interaction/contraindication, or requiring treatment with first-line therapy. Of the 40 patients requiring a medical document, 22 initiated therapy. The most common product used was a 2:50 THC:CBD (Tetrahydrocannabinol:Cannabidiol) cannabis oil. At the date of last contact, few patients remained on therapy because of lack of benefit, patient choice, and/or hesitancy. CONCLUSION: Despite patients with cancer having interest in seeking PDCs for symptom management, only a few initiated and continued therapy. Pharmacists have an opportunity to advise patients and the oncology team on the risks and benefits of PDCs. These results can be used to support the development of medical cannabis programs by oncology centers and focus future research priorities.

Partial Stenosis and Complete Punctal Closure Following Topical Netarsudil Use for Glaucoma.

PURPOSE: To describe patients who developed partial or complete punctal closure after the use of topical netarsudil in the treatment of glaucoma, with documented reversal of symptoms on drug cessation. PATIENTS AND METHODS: This is a retrospective, single-center case series including patients treated with topical netarsudil who were documented to have developed punctal disease ipsilateral to the eye(s) being treated. A literature review was also performed to identify other similar reports. RESULTS: A total of 10 patients were included in the study. Six patients developed partial punctal stenosis and 4 patients developed complete closure of the puncta in 1 or both eye(s) ipsilateral to the use of the topical medication. None of the patients developed punctal disease on the non-netarsudil side. The time from initiation of netarsudil to the documentation of punctal disease ranged from 5-32.2 months (18.41±9.94). In the patients with complete punctal closure, discontinuation of the topical medication led to clinical reappearance of the punctal opening, ranging from 31-83 days after drug cessation (45.75±21.57). In 8 cases, discontinuation of netarsudil resulted in improved epiphora and degree of punctal stenosis on clinical examination. CONCLUSIONS: The use of topical netarsudil for glaucoma may lead to punctal stenosis and complete punctal closure. These side effects of netarsudil are relevant to therapeutic considerations for glaucoma patients.