Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

Clinical relevance of doubtful reactions in patch testing: A single-centre retrospective study.

BACKGROUND: Doubtful reactions in patch testing are infrequently reported in the literature; however, recent reports have suggested they be assessed with the same scrutiny as stronger reactions. OBJECTIVE: Assess the clinical relevance of doubtful reactions in patch testing. METHODS: Retrospective study of 1514 patients comprehensively patch tested via the NACDG standard series and additional allergens based on history. The clinical relevance of each reaction was graded based on the NACDG scale: definite, probable, possible, past, unknown and irritant. Reactions were considered 'unique' if an additional mild-to-strong reaction to the same chemical at a different concentration was not observed. RESULTS: 68.9% (1043) of patients demonstrated at least 1 doubtful reaction. Of 4453 total doubtful reactions, 92.2% (4106) were unique. Only 3.3% (137) and 12.2% (500) of these were determined to be of definite or probable clinical relevance respectively. 'Fragrance' was the most common allergen family present among the unique definite doubtful reactions (37). However, 24 (64.9%) of these also had a stronger reaction to another fragrance. Cocamidopropyl betaine was the second most frequent allergen demonstrating definite doubtful reactions (27) and unique in 85.2% (23) of cases. Methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) was most prevalent (36) but less frequently unique (58.3%, 21). CONCLUSIONS: Doubtful reactions may not be as impactful to clinical decision making as theorised in the literature. Few demonstrate definite clinical significance, and many have related stronger reactions that capture them for clinical purposes. Identification of doubtful reactions to cocamidopropyl betaine and MCI/MI may be of greatest significance as they most frequently were not supported by stronger reactions.

Allergic contact dermatitis to salicylic acid: A case series of relevant sensitization.

INTRODUCTION: Allergic contact dermatitis (ACD) to salicylic acid (SA) is widely unreported. Furthermore, cross-reactivity between SA and other salicylates has not been reported despite well-documented in-group salicylate cross-reactivity. OBJECTIVE: To describe our clinic's experience patch testing to SA, highlighting seven cases of relevant reactions and concomitant reactivity with other salicylates. METHODS: Results of patch testing to 5% SA in petrolatum between 1 January 2020, and 9 February 2024, are reported. Seven cases of relevant reactions to SA are detailed. RESULTS: A total of 489 patients (27.5%) were tested to SA, 21 of which were positive: 7 doubtful (+/-), 14 weak positive (+), and no strong/extreme positive reactions. Four irritant reactions were documented. Of the 14 weak positive (+) reactions, 7 had definite or probable clinical relevance, 5 of which also reacted to other salicylates. CONCLUSIONS: ACD to SA is likely underreported due to a lack of testing. In our experience, testing SA 5% petrolatum is tolerable without significant irritation. Cross-reactivity between SA and other salicylates is probable. Though SA appears to be the primary sensitizer in some cases, more studies are needed to understand its possible role as a marker for salicylate allergy.

Are "clean" products safe for children? An analysis of contact allergens in "clean" children's products from a popular retailer.

BACKGROUND: Considering consumer trends toward the use of "clean" personal care products and increasing recognition of childhood allergic contact dermatitis, we sought to characterize the allergen profile of such children's products. METHODS: Ingredients of baby washes/shampoos, bubble baths, and moisturizers identified using the "Clean Baby" filter on Target®'s online marketplace were analyzed for relevant pediatric contact allergens. RESULTS: Product compositions declared fragrance in 82% of products, Compositae in 46%, cocamidopropyl betaine in 45%, glucosides in 37%, propylene glycol in 12%, lanolin in 1%, and no allergens in 9%-methylisothiazolinone and formaldehyde were not found. CONCLUSION: Children are greatly impacted by atopic dermatitis and skin barrier dysfunction, which underscores a need for greater public awareness of sensitizing and irritating ingredients, particularly regarding pediatric personal care products.

Antibody-mediated activation of the FGFR1/Klothoß complex corrects metabolic dysfunction and alters food preference in obese humans.

Fibroblast growth factor 21 (FGF21) controls metabolic organ homeostasis and eating/drinking behavior via FGF receptor 1/Klothoß (FGFR1/KLB) complexes expressed in adipocytes, pancreatic acinar cells, and the nervous system in mice. Chronic administration of recombinant FGF21 or engineered variants improves metabolic health in rodents, nonhuman primates, and humans; however, the rapid turnover of these molecules limits therapeutic utility. Here we show that the bispecific anti-FGFR1/KLB agonist antibody BFKB8488A induced marked weight loss in obese cynomolgus monkeys while elevating serum adiponectin and the adipose expression of FGFR1 target genes, demonstrating its action as an FGF21 mimetic. In a randomized, placebo-controlled, single ascending-dose study in overweight/obese human participants, subcutaneous BFKB8488A injection caused transient body weight reduction, sustained improvement in cardiometabolic parameters, and a trend toward reduction in preference for sweet taste and carbohydrate intake. These data suggest that specific activation of the FGFR1/KLB complex in humans can be used as therapy for obesity-related metabolic defects.

Childhood cancer survivorship and late effects: The landscape in India in 2020.

Survivorship care is a major area of focus in the holistic management of childhood cancer with current knowledge and information almost exclusively from high-income countries. In this review, we summarize the state of scientific knowledge, service delivery, advocacy initiatives, and research efforts in this field in India. Twenty-one single-center studies published until today (20 in the last decade) confirm some of the well-documented issues in childhood cancer survivors and highlight the high prevalence of hepatitis B and hepatitis C infection in our survivors. Heterogeneity in methodology, outcome metrics, and quality precludes drawing further conclusions, and the ongoing multicenter Indian Pediatric Oncology Group study would address this. Besides the usual model of follow-up clinics in hospital settings, innovative models of service delivery led by not-for-profit organizations are being developed. Advocacy initiatives driven by survivors and support groups are also under way. All of these portend a promising future.

A national survey of admission practices for late preterm infants in England.

BACKGROUND: Infants born at 34(+0) to 36(+6) weeks gestation are defined as 'late preterm' infants. It is not clear whether these babies can be managed on the postnatal ward (PNW) or routinely need to be admitted to the neonatal unit after birth. AIM: To conduct a national survey of admission practice for late preterm and low birth weight infants directly to the PNW after birth in England. METHODS: All neonatal units were identified from the Standardised Electronic Neonatal Database (SEND). Individual units were contacted and data collected on their admission practice. RESULTS: All 180 neonatal units in England responded. 49, 84 and 47 Units were Special Care Units (SCUs), Local Neonatal Units (LNUs) and Neonatal Intensive Care Units (NICUs) respectively. 161 units (89%) had written guidelines in relation to direct PNW admission for late preterm infants.The mean gestational age of infants admitted directly to the PNW was significantly lower in LNUs compared to SCUs and NICUs compared to LNUs. Mean birth weight limit for direct PNW admission was significantly lower in NICUs compared to SCUs.72 units had PNW nursery nurses. There was no significant difference in gestational age or birth weight limit for direct PNW admission in the presence of PNW nursery nurses. CONCLUSIONS: Admission practices of late preterm infants directly to the PNW varies according to designation of neonatal unit in England. Further studies are needed to establish the factors influencing these differences.

The Diagnostic Value of Delayed-Type Reactions to Perennial Aeroallergens for Atopic Disease.

Background: Delayed-type reactions to aeroallergens have been observed, however, their clinical significance continues to be debated. Objective: We assessed the prevalence and significance of delayed-type reactions to aeroallergens in atopic patients. Methods: Retrospective study including 266 patients with history or evidence of atopic disease (atopic dermatitis [AD], allergic rhinitis, and/or allergic asthma) and tested via either the intradermal skin test (IDT) or atopy patch test for common aeroallergens, specifically house dust mites (Dermatophagoides farinae, Dermatophagoides pteronyssinus) and perennial molds (Aspergillus fumigatus, Penicillium notatum). All patients were tested via IDT with both immediate (15 minute) and delayed (2 and 4 days) readings. Delayed reading was considered positive if the IDT injection site demonstrated at least 5 mm induration 48 hours after inoculation. Results: In total, 195 (73.3%) patients demonstrated an immediate-type reaction, whereas 118 (44.4%) had a delayed-type reaction. In total, 75 (28.2%) patients experienced both immediate- and delayed-type reactions, 43 (16.2%) reacted delayed-type only, and 85.3% of delayed-type reactions to individual aeroallergens were associated with eczematous lesions predominantly in air-exposed areas. Conclusion: Delayed-type reactions to aeroallergens are prevalent and clinically significant as a component of extrinsic AD and atopic diseases. The data support delayed reading of the IDT to guide diagnosis and management in these patients.

Characterization of Pediatric Patch Testing: A Retrospective Review, 2020-2023.

Background: Recent evidence shows similar rates of allergic contact dermatitis (ACD) among children and adults despite children accounting for less than 10% of patch testing subjects. With a need for in-depth analyses of pediatric ACD, we herein characterize a pediatric cohort at a large North American patch testing center. Methods: A retrospective chart review was conducted for 135 patients ages 1-17 years who underwent patch testing from July 2020 from August 2023. Data were stratified by age 1-5, 6-11, and 12-17 years. Significance-Prevalence Index Numbers (SPIN) were calculated. Results: A total of 86% were sensitized, 40% had a relevant reaction, and positivity rates were equal between males and females. Top allergens by SPIN differed with age, but overall were linalool hydroperoxides (SPIN = 11.01), propylene glycol (10.30), limonene hydroperoxides (10.27), fragrance mix I (5.62), and lanolin (4.90). In total, 14% of the top allergens were not represented on the North American Contact Dermatitis Group standard series. Of those tested to personal products, 45% had positive reactions and 72% of which were relevant. Conclusions: Emulsifiers and fragrances were the most relevant allergen categories, with the impact of emulsifiers not previously reported. ACD may affect males and females equally in this population. Supplemental allergens and personal products tested "as-is" contribute to conclusive pediatric patch testing.

Effects of Quinidine or Rifampin Co-administration on the Single-Dose Pharmacokinetics and Safety of Rilzabrutinib (PRN1008) in Healthy Participants.

This open-label, phase 1 study was conducted with healthy adult participants to evaluate the potential drug-drug interaction between rilzabrutinib and quinidine (an inhibitor of P-glycoprotein [P-gp] and CYP2D6) or rifampin (an inducer of CYP3A and P-gp). Plasma concentrations of rilzabrutinib were measured after a single oral dose of rilzabrutinib 400 mg administered on day 1 and again, following a wash-out period, after co-administration of rilzabrutinib and quinidine or rifampin. Specifically, quinidine was given at a dose of 300 mg every 8 hours for 5 days from day 7 to day 11 (N = 16) while rifampin was given as 600 mg once daily for 11 days from day 7 to day 17 (N = 16) with rilzabrutinib given in the morning of day 10 (during quinidine dosing) or day 16 (during rifampin dosing). Quinidine had no significant effect on rilzabrutinib pharmacokinetics. Rifampin decreased rilzabrutinib exposure (the geometric mean of Cmax and AUC0-∞ decreased by 80.5% and 79.5%, respectively). Single oral doses of rilzabrutinib, with or without quinidine or rifampin, appeared to be well tolerated. These findings indicate that rilzabrutinib is a substrate for CYP3A but not a substrate for P-gp.

Oncofertility and Pregnancy in Adolescent and Young Adult Cancers: Physicians' Knowledge and Preferences in India.

PURPOSE: The treatment outcomes of adolescent and young adult (AYA) cancers have improved with advanced oncology care. Hence, fertility preservation (FP) and post-therapy pregnancies (PTPs) become vital issues. MATERIALS AND METHODS: An online survey link with 17 questions regarding oncofertility and PTPs was circulated among oncologists to assess the knowledge, understand the oncofertility care patterns, and seek suggestions to improve oncofertility services. RESULTS: The median age of 179 respondents, predominantly medical oncologists (68.7%), was 37 years (IQR, 10; range, 29-74), working in academic centers (39%) having a median experience of 4 years (IQR, 4; range, 1-42); 23 (12.8%) had dedicated AYA cancer units. Although a quarter (19%-24%) of respondents discussed fertility issues in >90% of AYA patients with cancer, only a tenth (8%-11%) refer >90% for FP, with significantly higher (P < .05) discussions and referrals in males and by more experienced oncologists (P < .05). Forty-six (25.6%) were not well versed with international guidelines for FP. Most (122, 68.1%) oncologists knew about the referral path for semen cryopreservation; however, only 46% were knowledgeable about additional complex procedures. One hundred and ten (61.5%) oncologists never or rarely altered the systemic treatment for FP. Prominent barriers to FP were ignorance, lack of collaboration, and fear of delaying cancer treatment. Lead thrust areas identified to improve FP practices are education, and enhanced and affordable access to FP facilities. Seventy-four (41.3%) respondents knew about international guidelines for PTPs; however, only half (20%) of them often monitored fertility outcomes in survivors. Oncologists have conflicting opinions and uncertainties regarding pregnancy safety, assisted reproductive techniques, breastfeeding, and pregnancy outcomes among survivors. CONCLUSION: Oncologists are uncertain about the guidelines, FP practices, referral pathways, and PTPs. Multipronged approaches to improve awareness and provision for affordable oncofertility facilities are needed to enhance AYA cancer outcomes in India, which will be applicable to other low- and middle-income countries too.

Efficacy and Safety of Rilzabrutinib in Pemphigus: PEGASUS Phase 3 Randomized Study.

TRIAL DESIGN: Pemphigus is a rare but life-threatening autoimmune disease requiring long-term treatment that minimizes corticosteroid (CS) exposure while providing consistent disease control. The phase 2 pemphigus study of oral, reversible, covalent Bruton tyrosine kinase inhibitor rilzabrutinib demonstrated rapid and sustained efficacy with well-tolerated safety. METHODS: Adults (aged 18-80 years) were randomized 1:1 to 400 mg rilzabrutinib (n = 65) or placebo (n = 66) twice daily (with CS ≤ 0.5 mg/kg/d) for 37 weeks in the phase 3 PEGASUS study in moderate-to-severe pemphigus vulgaris/pemphigus foliaceus. RESULTS: The primary endpoint of complete remission from week 29 to week 37 with the amended endpoint CS dose ≤10 mg/d was not significant for 13 of 54 (24%) rilzabrutinib versus 10 of 55 (18%) placebo patients with PV (P = .45). Secondary endpoints showed numerical but nonsignificant improvements with rilzabrutinib (vs placebo) in reduced CS use, prolonged complete remission duration, and faster time to first complete remission. CONCLUSIONS: Overall, rilzabrutinib was well-tolerated, with similar adverse events reported in both groups. Using minimal CS dose ≤10 mg/d and excluding remote observations, the primary efficacy endpoint was not met. However, results from a prespecified sensitivity analysis using CS dose ≤5 mg/d, considering all observations, and including all patients support Bruton tyrosine kinase inhibition as a viable therapeutic approach for pemphigus.

Measuring practice preference variation for quality improvement in neonatal respiratory care.

OBJECTIVES: The authors sought to measure and compare practice preference variation in neonatal respiratory care within and between neonatal intensive care units (NICUs) using the Neonatology Survey of Interdisciplinary Groups in Healthcare Tool (NSIGHT). STUDY DESIGN: Eleven NICUs completed the NSIGHT between 2019 and 2021. Net preference was measured by mean response; agreement was ranked by standard distribution of response values. Heat maps showed comparisons between NICUs and disciplines. RESULTS: NICUs and individuals agreed most often on use of pressure support with mandatory ventilation and on use of non-invasive positive pressure ventilation for apnea. High preference variation surrounded decisions for invasive ventilation versus continuous positive airway pressure for extremely low birth weight infants. Preference difference was most frequent between neonatologists and nurses. CONCLUSIONS: Patterns of practice preference variation in neonatal respiratory care are specific to clinical scenario. Measuring preference variation may inform psychology of change and strengthen quality improvement efforts.

Relationships between maternal ethnicity, gestational age, birth weight, weight gain, and severe retinopathy of prematurity.

OBJECTIVE: To develop an algorithm that allows advanced identification of infants requiring treatment for retinopathy of prematurity (ROP). STUDY DESIGN: A retrospective observational study was performed at 2 tertiary neonatal units serving a multiethnic population in the UK, using data on 929 infants eligible for ROP screening. The relationships between study variables and the risk of developing ROP requiring treatment were analyzed using multiple logistic regression. RESULTS: After applying exclusion criteria, data from 589 infants were analyzed; of these, 57 required laser treatment. The proportion of treated infants was 5.9% of those born to black mothers, 9.39% of those born to white mothers, and 12.8% of those born to Asian mothers (P = .047). Multiple logistic regression showed that gestational age, birth weight, maternal ethnicity, and early weight gain were predictors for the development of ROP requiring treatment, with maternal ethnicity having greater predictive power compared with early weight gain. We developed an algorithm for predicting the development of ROP requiring treatment with sensitivity, specificity, and positive and negative predictive values of 100%, 65.7%, 23.8%, and 100%, respectively. CONCLUSION: Gestational age, birth weight, early weight gain, and maternal ethnicity are important predictors for the development of ROP requiring treatment. In a multiethnic population, an algorithm to predict development of ROP requiring treatment should include maternal ethnicity. If confirmed through prospective studies, this algorithm could reduce the number of opthalmologic examinations performed for ROP screening.

Growth retardation due to panhypopituitarism and central diabetes insipidus following Russell's viper bite.

Russell's viper envenomation and its related complications, especially acute kidney injury, is an important cause of morbidity and mortality in tropical developing countries of South Asia. Unusual complications, especially hypopituitarism, are rare and probably missed due to lack of clinical suspicion and diagnostic facilities. We report a rare presentation of growth retardation resulting from hypopituitarism due to Russell's viper envenomation along with central diabetes insipidus. Awareness of the fact that hypopituitarism may occur in this clinical setting is necessary for early diagnosis and treatment, especially among general care practitioners taking care of these patients.