Bruton's tyrosine kinase inhibition for the treatment of allergic disorders.

IgE signaling through its high-affinity receptor FcεRI is central to the pathogenesis of numerous allergic disorders. Oral inhibitors of Bruton's tyrosine kinase (BTKis), which are currently Food and Drug Administration-approved for treating B cell malignancies, broadly inhibit the FcεRI pathway in human mast cells and basophils, and therefore may be effective allergen-independent therapies for a variety of allergic diseases. The application of these drugs to the allergy space was previously limited by the low kinase selectivity and subsequent toxicities of early-generation compounds. Fortunately, next-generation, highly selective BTKis in clinical development appear to have more favorable risk-benefit profiles, and their likelihood of being Food and Drug Administration-approved for an allergy indication is increasing. Recent clinical trials have indicated the remarkable and rapid efficacy of the second-generation BTKi acalabrutinib in preventing clinical reactivity to peanut ingestion in adults with peanut allergy. In addition, next-generation BTKis including remibrutinib effectively reduce disease activity in patients with antihistamine-refractory chronic spontaneous urticaria. Finally, several BTKis are currently under investigation in early clinical trials for atopic dermatitis and asthma. In this review, we summarize recent data supporting the use of these drugs as novel therapies in food allergy, anaphylaxis, urticaria, and other allergic disorders. We also discuss safety data derived from trials using both short-term and chronic dosing of BTKis.

Efficacy of immunotherapy with combination of cryotherapy and topical imiquimod for treatment of Kaposi sarcoma.

Multiple treatment modalities for Kaposi sarcoma (KS) have been reported, including chemotherapy, radiation therapy, surgical excision, electrochemotherapy, and cryotherapy. Common topical treatments include timolol, imiquimod, and alitretinoin. We searched our institutional database for patients with ICD-9 or 10 codes for KS seen by a dermatologist with experience in KS management from July 1, 2004 to January 1, 2022. We screened patient charts to include patients who received combination therapy of cryotherapy followed by topical imiquimod three times a week for 2 months (n = 9). Patients were followed in the clinic every 3 months. Time to resolution was assessed by photographic evidence of resolution as determined by a dermatologist and corroborated with clinical documentation in patient charts. Median age (IQR) at KS diagnosis was 58 (27.5) years. All patients were male (n = 9, 100%). Majority were white (n = 7, 78%) and non-Hispanic (n = 8, 89%). Five (56%) had classic KS, one (11%) had HIV-associated KS, and three (33%) were HIV-negative men who have sex with men. Median time to resolution was 30.5 weeks, with a median of two treatments. In our study, 93% (n = 42/45) of lesions and 89% (n = 8/9) of patients experienced complete resolution during a median (range) duration of follow-up of 58 (13-209) weeks. Side effects were limited to pain during cryotherapy, occasional blister formation after cryotherapy, and mild inflammation due to imiquimod. No infections were observed. Combination therapy of cryotherapy and topical imiquimod may be an efficacious and comparatively low-risk treatment for limited, cutaneous KS.

Host and primary tumor factors for the development of multiple cutaneous squamous cell carcinomas among a retrospective cohort in Rhode Island.

INTRODUCTION: Risk factors for a primary cutaneous squamous cell carcinoma (CSCC) are well-established; however, the host and primary tumor risk factors for subsequent CSCC have not been fully explored. METHODS: We performed a retrospective chart review of patients diagnosed with CSCC in an academic dermatology clinic in Rhode Island from 2016-2019. Logistic regression was used to evaluate the associations between host factors and multiple CSCC and between primary tumor characteristics and the risk of subsequent CSCC. Adjusted odds ratios (aORs) and 95% CIs were calculated. RESULTS: A total of 1312 patients with CSCC diagnoses were included. Host risk factors significantly associated with multiple CSCCs included: aged >80 years (aOR, 2.18; 95% CI, 1.46-3.31); history of: solid organ transplant (aOR, 2.41; 95% CI, 1.20-4.80); skin cancer (aOR, 1.96; 95% CI, 1.52-2.54); other cancer (aOR, 1.49; 95% CI, 1.11-2.00); family history of skin cancer (aOR, 1.36; 95% CI, 1.03-1.78); and actinic keratosis (aOR, 1.52; 95% CI, 1.18-1.95). Tumor location, diameter, histologic differentiation, and treatment were not significant predictors of subsequent CSCCs. LIMITATIONS: Study patients were predominantly White and from a single institution, limiting the generalizability of results. CONCLUSIONS: Certain host characteristics were associated with the development of subsequent CSCC, which may inform clinical guidelines for follow-up.

Cutaneous Sporothrix globosa infection mimicking cryptococcosis in a patient with history of kidney transplant.

Sporotrichosis is a subacute-to-chronic infection caused by Sporothrix species, a dimorphic fungus. Virulence varies by Sporothrix species and presentation can be region dependent. The patient had a history of immunosuppression as a result of a kidney transplant, and presented with a high disease burden on histopathological examination, but responded well to itraconazole. The case suggests considering Sporothrix speciation in immunocompromised patients to best determine treatment modality and duration.

The feasibility of academic detailing for acute oral pain management in outpatient dentistry: A pilot study.

BACKGROUND: Opioids are overprescribed in the outpatient dental setting. Therefore, opportunities exist for opioid stewardship. OBJECTIVES: The purpose of this pilot study was to test the feasibility of an academic detailing (AD) intervention to promote appropriate prescribing of opioids in outpatient dentistry. METHODS: We implemented an AD intervention targeting management of acute oral pain in a Midwestern Veterans Affairs outpatient dental facility. The intervention targeted dentists who actively prescribed opioids at the time of the study. The pilot study tested feasibility, adoption, and acceptance of the AD campaign. Visit-based prescribing rates were obtained from the Veterans Health Administration's Corporate Data Warehouse for baseline and postintervention using difference-in-differences analyses to detect potential changes in health service outcomes. RESULTS: Results indicate moderate levels of feasibility through participation rates (n = 5, 55.5%) and high levels of organizational readiness for change (average of 88.6% agree to strongly agree). Furthermore, fidelity of the AD intervention was high. Adoption measures show moderate indication of motivation to change, and trends suggest that participating dentists decreased their visit-based opioid prescribing rates (P > 0.05). CONCLUSION: The intervention demonstrated feasibility with some indications of adoption of intervention techniques and decrease in opioid prescribing. We further recommend working closely with frontline providers to gather feedback and buy-in before scaling and implementing the AD campaign.

Inflammatory phenotype modulation in the respiratory tract and systemic circulation of e-cigarette users: a pilot study.

Over 40 million people use e-cigarettes worldwide, but the impact of chronic e-cigarette use on health has not been adequately defined. In particular, effects of e-cigarette aerosol inhalation on inflammation and host defenses across the body are not fully understood. We conducted a longitudinal cohort pilot study to explore changes in the inflammatory state and monocyte function of e-cigarette users (n = 20) versus healthy controls (n = 13) and to evaluate effects of e-cigarette use reduction on the same. Saliva, sputum, and blood were obtained from e-cigarette users at baseline and after a 2-wk intervention of decreased e-cigarette use. Overall, across 38 proteins quantified by multiplex, airway samples from e-cigarette users tended to have decreased levels of immunomodulatory proteins relative to healthy controls, whereas levels of cytokines, chemokines, and growth factors in the circulation tended to be elevated. Specifically, e-cigarette users had lower levels of IL-1 receptor antagonist (IL-1Ra) in saliva (P < 0.0001), with higher IL-1Ra and growth-regulated oncogene (GRO) levels in sputum (P < 0.01 and P < 0.05, respectively), and higher levels of both TNFß (P < 0.0001) and VEGF (P < 0.0001) in plasma. Circulating monocytes from e-cigarette users had alterations in their inflammatory phenotype in response to reduced e-cigarette use, with blunted IL-8 and IL-6 release upon challenge with bacterial lipopolysaccharide (P < 0.001 and P < 0.05, respectively), suggesting a decreased ability to appropriately respond to bacterial infection. Based on these findings, chronic inhalation of e-cigarette aerosols alters the inflammatory state of the airways and systemic circulation, raising concern for the development of both inflammatory and infectious diseases in chronic users of e-cigarettes.

Trends in Use of Midodrine in the ICU: A Single-Center Retrospective Case Series.

OBJECTIVES: Midodrine is an oral alpha-agonist approved for orthostatic hypotension. The use of midodrine as a vasopressor sparing agent has steadily increased in the ICU despite limited evidence for its safety in that setting. We describe the trends in use and reported side effects and complications of midodrine in multidisciplinary ICUs of a tertiary care institution. DESIGN: Single-center retrospective case series. SETTING: Medical and surgical ICU patients from January 2011 to October 2016 at Mayo Clinic, Rochester. PATIENTS: Adult patients admitted to any ICU who received midodrine for hypotension were eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We reviewed the mean arterial pressures and cumulative vasopressor dose before and after midodrine administration and assessed for reported complications. During the study period, a total of 1,119 patients were initiated on midodrine, 56% in surgical ICUs, 42% in medical ICUs, and 2% in a mixed medical and surgical neurology ICU. There was a significant decrease in the number of patients on vasopressors 24 hours after initiation of midodrine (663 to 344; p < 0.001); among the patients that remained on vasopressors, there was a significant decrease in the median cumulative vasopressor dose (p = 0.002). There was a significant increase in median mean arterial pressure 24 hours after initiation of midodrine among patients who were not on vasopressors (65-68; p < 0.01). Asymptomatic bradycardia (heart rate < 50 beats/min) was the most common side effect (n = 172 patients, median 39 beats/min). Two patients developed bowel ischemia after initiation of midodrine that prompted discontinuation of midodrine in one case. Evaluating trends of utilization, the off-label use of midodrine has increased steadily over the years across ICUs. CONCLUSIONS: Our results suggest that midodrine is being increasingly used as an adjunct to increase mean arterial pressure and facilitate weaning of vasopressors in the ICU. Prospective trials are required to further establish the appropriate timing, efficacy, safety, and cost-effectiveness of midodrine use in ICU patients.

Comparison of Intranasal Dexmedetomidine and Oral Pentobarbital Sedation for Transthoracic Echocardiography in Infants and Toddlers: A Prospective, Randomized, Double-Blind Trial.

BACKGROUND: Acquisition of transthoracic echocardiographic (TTEcho) images in children often requires sedation. The optimal sedative for TTEcho has not been determined. Children with congenital heart disease are repeatedly exposed to sedatives and anesthetics that may affect brain development. Dexmedetomidine, which in animals alters brain structure to a lesser degree, may offer advantages in this vulnerable population. METHODS: A prospective, randomized, double-blind trial enrolled 280 children 3-24 months of age undergoing outpatient TTEcho, comparing 2.5 µg·kg intranasal dexmedetomidine to 5 mg·kg oral pentobarbital. Rescue sedation, for both groups, was intranasal dexmedetomidine 1 µg·kg. The primary outcome was adequate sedation within 30 minutes without rescue sedation, assessed by blinded personnel. Secondary outcomes included number of sonographer pauses, image quality in relation to motion artifacts, and parental satisfaction. RESULTS: Success rates with a single dose were not different between sedation techniques; 85% in the pentobarbital group and 84% in the dexmedetomidine group (P = .8697). Median onset of adequate sedation was marginally faster with pentobarbital (16.5 [interquartile range, 13-21] vs 18 [16-23] minutes for dexmedetomidine [P = .0095]). Time from drug administration to discharge was not different (P = .8238) at 70.5 (64-83) minutes with pentobarbital and 70 (63-82) minutes with dexmedetomidine. Ninety-five percent of sedation failures with pentobarbital and 100% of dexmedetomidine failures had successful rescue sedation with intranasal dexmedetomidine. CONCLUSIONS: Intranasal dexmedetomidine was comparable to oral pentobarbital sedation for TTEcho sedation in infants and did not increase the risk of clinically important adverse events. Intranasal dexmedetomidine appears to be an effective "rescue" sedative for both failed pentobarbital and dexmedetomidine sedation. Dexmedetomidine could be a safer option for repeated sedation in children, but further studies are needed to assess long-term consequence of repeated sedation in this high-risk population.

Obliterative bronchiolitis associated with rheumatoid arthritis: analysis of a single-center case series.

BACKGROUND: Rheumatoid arthritis (RA) is a systemic autoimmune condition characterized by erosive inflammation of the joints. One rare pulmonary manifestation is obliterative bronchiolitis (OB), a small airways disease characterized by the destruction of bronchiolar epithelium and airflow obstruction. METHODS: We retrospectively reviewed the clinical data of patients with rheumatoid arthritis-associated obliterative bronchiolitis (RA-OB) from 01/01/2000 to 12/31/2015. Presenting clinical features, longitudinal pulmonary function testing, radiologic findings, and independent predictors of all-cause mortality were assessed. RESULTS: Forty one patients fulfilled criteria for diagnosis of RA-OB. There was notable female predominance (92.7%) with a mean age of 57 ± 15 years. Dyspnea was the most common presenting clinical symptom. Median FEV1 was 40% (IQR 31-52.5) at presentation, with a mean decline of - 1.5% over a follow-up period of thirty-three months. Associated radiologic findings included mosaic attenuation and pulmonary nodules. A majority of patients (78%) received directed therapy including long-acting inhalers, systemic corticosteroids or other immunosuppressive agents, and macrolide antibiotics. All-cause mortality was 27% over a median follow-up of sixty-two months (IQR 32-113). No distinguishable predictors of survival at presentation were found. CONCLUSIONS: RA-OB appears to have a stable clinical course in the majority of patients despite persistent symptoms and severe obstruction based on presenting FEV1.

Altered Acoustic Startle Reflex, Prepulse Inhibition, and Peripheral Brain-Derived Neurotrophic Factor in Morphine Self-Administered Rats.

Background: Previous studies suggested that opiate withdrawal may increase anxiety and disrupt brain-derived neurotrophic factor function, but the effects of i.v. morphine self-administration on these measures remain unclear. Methods: Adult male Sprague-Dawley rats were implanted with a catheter in the jugular vein. After 1 week of recovery, the animals were allowed to self-administer either i.v. morphine (0.5 mg/kg per infusion, 4 h/d) or saline in the operant conditioning chambers. The acoustic startle reflex and prepulse inhibition were measured at a baseline and on self-administration days 1, 3, 5, and 7 (1- and 3-hour withdrawal). Blood samples were collected on self-administration days 3, 5, and 7 from separate cohorts of animals, and the levels of brain-derived neurotrophic factor and corticosterone were assayed using the enzyme-linked immunosorbent assay method. Results: Compared with the saline group, the morphine self-administration group showed hyper-locomotor activity and reduced defecation during the self-administration. The morphine self-administration increased acoustic startle reflex at 1-hour but not 3-hour withdrawal from morphine and disrupted prepulse inhibition at 3-hour but not 1-hour withdrawal. The blood brain-derived neurotrophic factor levels were decreased in the morphine self-administration group at self-administration days 3 and 5, while the corticosterone levels remained unchanged throughout the study. Conclusions: The current findings suggest that spontaneous withdrawal from i.v. morphine self-administration may have transient effects on acoustic startle, sensorimotor gating, and peripheral brain-derived neurotrophic factor levels, and these changes may contribute to the adverse effects of opiate withdrawal.

Pulmonary mucormycosis: clinical features and outcomes.

PURPOSE: Mucormycosis encompasses a group of opportunistic fungal infections caused by Zygomycetes, order Mucorales. Mucormycosis can manifest as rhino-orbito-cerebral, pulmonary, gastrointestinal, cutaneous, and disseminated infections. Pulmonary mucormycosis is the second most common presentation. This manuscript characterizes the demographics, clinical presentation, diagnostic procedures, radiologic findings, therapeutic interventions, and outcome in pulmonary mucormycosis. METHODS: We retrospectively reviewed clinical data of 35 patients with pulmonary mucormycosis from 2000 to 2015. Microbiologic diagnosis was based on positive culture from a sterile site or findings on histopathology consistent with mucormycosis. Independent predictors of 28-day mortality were assessed using logistic regression. Survival curves were estimated using Kaplan-Meier method. RESULTS: There was male predominance with a mean age of 55 ± 15 years. Analysis of predisposing conditions revealed the prevailing presence of malignancy. Sixty-six percent of patients were receiving immunosuppressive agents. Common presenting clinical findings were fever, neutropenia, dyspnea, and cough. Radiologic findings included pleural effusion and nodules. All patients received medical therapy and 43% underwent additional surgical intervention. Twenty eight day mortality was 29% with concurrent bacteremia found as the sole independent predictor. Similar survival from pulmonary mucormycosis was noted over time. CONCLUSIONS: Pulmonary mucormycosis is an opportunistic angioinvasive fungal infection. Physicians must have a high level of suspicion in immunocompromised patients with fever and respiratory symptoms refractory to antibiotics. A low threshold should be had for performing an invasive procedure to gain reliable diagnosis, as early, aggressive medical and surgical interventions are needed for successful treatment.

Sedation methods for transthoracic echocardiography in children with Trisomy 21-a retrospective study.

BACKGROUND: Many children with Trisomy 21 have neurologic or behavioral problems that make it difficult for them to remain still during noninvasive imaging studies, such as transthoracic echocardiograms (TTEcho). Recently, intranasal dexmedetomidine sedation has been introduced for this purpose. However, dexmedetomidine has been associated with bradycardia. Children with Trisomy 21 have been reported to have a higher risk of bradycardia and airway obstruction with sedation or anesthesia compared to children without Trisomy 21. OBJECTIVE: Our aim was to quantify the incidence of age-defined bradycardia and other adverse effects in patients with Trisomy 21 under sedation for TTEcho using a variety of sedation and anesthesia techniques available and utilized at our institution in this challenging patient population, including intranasal dexmedetomidine, oral pentobarbital, general anesthesia with propofol, and general anesthesia with sevoflurane. Our primary hypothesis was that intranasal dexmedetomidine sedation would result in a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens. METHODS: This is a retrospective, observational study of 147 consecutive patients with Trisomy 21 who were sedated or anesthetized for transthoracic echocardiography. Efficacy of sedation was defined as no need for rescue sedation or conversion to an alternate technique. Lowest and highest heart rate, systolic blood pressure, oxygen saturation, and PR interval from formal electrocardiograms were extracted from the electronic medical record. These data were compared to age-defined normal values to determine adverse events. RESULTS: Four methods of sedation or anesthesia were utilized to perform sedated transthoracic echocardiography: general anesthesia with sevoflurane by mask, general anesthesia with sevoflurane induction followed by intravenous propofol maintenance, oral pentobarbital, and intranasal dexmedetomidine. Intranasal dexmedetomidine 2.5 mcg·kg-1 was an effective sedative as a single dose for TTEcho in 37 of 41 (90%) cases. Oral pentobarbital 5 mg·kg-1 as a single dose for young children with Trisomy 21 was effective in 55 of 75 (73%) cases. Intranasal dexmedetomidine sedation was not associated with a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens, when compared to oral pentobarbital for patients under 2 years of age and general anesthesia for children 3 years and older. The two general anesthesia groups showed lowest heart rates of 66.9 ± 15.9 min-1 for sevoflurane and 69.0 ± 11.5 min-1 for sevoflurane-propofol. Hypotension was present in all groups ranging between an incidence of 56% in the sevoflurane group to 11% in the oral pentobarbital group. Oxygen saturation and clinically significant desaturation occurred in 14% of the oral pentobarbital group. CONCLUSION: Intranasal dexmedetomidine sedation was not associated with a significantly higher risk of bradycardia in patients with Trisomy 21, compared with other sedative or anesthetic regimens.

Mechanical effects of left ventricular midwall fibrosis in non-ischemic cardiomyopathy.

BACKGROUND: Left ventricular (LV) mid-wall fibrosis (MWF), which occurs in about a quarter of patients with non-ischemic cardiomyopathy (NICM), is associated with high risk of pump failure. The mid LV wall is the site of circumferential myocardial fibers. We sought to determine the effect of MWF on LV myocardial mechanics. METHODS: Patients with NICM (n = 116; age: 62.8 ± 13.2 years; 67% male) underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR) and were categorized according to the presence (+) or absence (-) of MWF. Feature tracking (FT) CMR was used to assess myocardial deformation. RESULTS: Despite a similar LVEF (24.3 vs. 27.5%, p = 0.20), patients with MWF (32 [24%]) had lower global circumferential strain (Ɛcc: -6.6% vs. -9.4 %, P = 0.004), but similar longitudinal (Ɛll: -7.6 % vs. -9.4 %, p = 0.053) and radial (Ɛrr: 14.6% vs. 17.8% p = 0.18) strain. Compared with - MWF, + MWF was associated with reduced LV systolic, circumferential strain rate (-0.38 ± 0.1 vs. -0.56 ± 0.3 s(-1), p = 0.005) and peak LV twist (4.65 vs. 6.31°, p = 0.004), as well as rigid LV body rotation (64 % vs. 28 %, P <0.001). In addition, +MWF was associated with reduced LV diastolic strain rates (DSRcc: 0.34 vs. 0.46 s(-1); DSRll: 0.38 vs. 0.50s(-1); DSRrr: -0.55 vs. -0.75 s(-1); all p <0.05). CONCLUSIONS: MWF is associated with reduced LV global circumferential strain, strain rate and torsion. In addition, MWF is associated with rigid LV body rotation and reduced diastolic strain rates. These systolic and diastolic disturbances may be related to the increased risk of pump failure observed in patients with NICM and MWF.