Stepwise genetic approach for the diagnosis of primary ciliary dyskinesia in highly consanguineous populations.

BACKGROUND: The American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia (PCD) consider the presence of a bi-allelic pathogenic variant confirmatory for the diagnosis of PCD, with genetic testing recommended when other confirmatory diagnostic tests are less accessible. We present our experience with genetic testing as first line with a proposed algorithm for high consanguinity populations. METHODS: Patients with a suspected diagnosis of PCD underwent genetic testing according to a diagnostic algorithm composed of three steps: (1) patients with a previously known causative familial/Bedouin tribal pathogenic variant completed direct testing for a single variant; (2) if the initial test was negative or there was no known pathogenic variant, a PCD genetic panel was completed; (3) if the panel was negative, whole exome sequencing (WES) was completed. RESULTS: Since the implementation of the protocol, diagnosis was confirmed by genetic testing in 21 patients. The majority of them were of Bedouin origin (81%) and had a positive history of consanguinity (65%). Nine patients (43%) had a sibling with a confirmed diagnosis. Most patients (15/21, 71%) were diagnosed by direct pathogenic variant testing and the remainder by genetic panel (19%) and WES (10%). Disease-causing variants were found in nine genes, with DNAL1 (24%) and DNAAF3, DNAAF5, ZMYND10 (14% each) as the most prevalent ones. CONCLUSIONS: In highly consanguineous regions, a stepwise genetic testing approach is recommended. This approach may be particularly useful in areas where the ability to obtain confirmatory diagnostic tests through other modalities is less accessible.

Does cryotherapy decrease the local recurrence rate in the treatment of an aneurysmal bone cyst? A comparative assessment.

Curettage with or without the use of adjuvants is the standard of care in the treatment of an aneurysmal bone cyst (ABC). Historically, our approach combined curettage, high-speed burr drilling, and cryoablation. However, treatments varied based on age, tumor location, and surgeon preference. We asked: (1) Does cryoablation in addition to curettage and burr drilling decrease the local recurrence rates? (2) Are there any risk factors for the local recurrence rate? (3) Does cryoablation improve postsurgical functional outcomes in these patients? Patients treated for an ABC, between January 2006 and December 2019 were included in this retrospective analysis. Patient and surgical characteristics, such as age, gender, tumor location, type of treatment, time of follow-up, recurrence rate, and functional outcome measured by the Musculoskeletal Tumor Society Score 1993 (MSTS93) score were compared between those treated with and without cryoablation. Both groups, without cryoablation (n = 88) and with cryoablation (n = 42), showed no significant difference in local recurrence rates (9.1% vs. 7.1%, p = 0.553) and functional outcomes as measured by the MSTS93 score (28.9 vs. 27.8, p = 0.262). Risk factors analyzed did not significantly affect local recurrence risk, except for secondary ABC diagnosis (p = 0.017). The cryoablation group had a more extended follow-up (45.6 vs. 73.2 months, p < 0.001), reflecting a shift in practice over time. We found no significant difference in local recurrence rate or functional outcome in patients treated with or without cryoablation. Formal curettage with additional high-speed burr drilling provides effective tumor control and favorable functional outcomes, negating the need for adjuvant cryoablation.

Air Pollution and Meteorological Conditions Significantly Associated With Vernal Keratoconjunctivitis Exacerbations.

Purpose: Vernal keratoconjunctivitis (VKC) is a severe chronic allergic inflammation of the ocular surface with episodes of acute exacerbations, that primarily affects children and young adults. Although the etiology and pathogenesis of VKC remain unclear, studies have suggested that environmental factors may be involved. This study aims to investigate the association between exposure to meteorological and environmental factors and the incidence of VKC exacerbations. Methods: This study was conducted in southern Israel, which is a semi-arid, hot, and dry climate with frequent dust storms. Patients diagnosed with VKC were recruited for the study. VKC exacerbations were identified as the need for medical intervention. Pollutants measured included nitrogen dioxide (NO2), ozone (O3), particulate matter (PM10 and PM2.5), sulfur dioxide (SO2), relative humidity (RH), temperature, and solar radiation (SR). To assess the association between VKC exacerbations and exposure to different pollutants, a case-crossover analysis was conducted. We also stratified the analysis by sex, age, ethnicity, immigration status, and social state score. Results: Our results demonstrated that the pollutants NO2, O3, and PM10 were associated with VKC exacerbations with odds ratio (OR) = 2.17 (95% confidence interval [CI] =1.40 to 3.04), OR = 2.28 (95% CI = 1.30 to 3.39), and OR = 1.89 (95% CI = 1.06 to 2.74). Other pollutants PM2.5, temperature, and solar radiation were also independently associated with incidence of exacerbations with OR = 1.15 (95% CI = 0.87 to 1.50), OR = 1.75 (95% CI = 1.16 to 2.65), and OR = 1.37 (95% CI = 1.01 to 1.63) and had varying effects in different demographic strata. Conclusions: The environmental parameters, NO2, O3, PM10, PM2.5, temperature, and solar radiation were found to be significantly associated with VKC exacerbations, with NO2, O3, and PM10 showing the strongest associations. Our findings suggest that environmental factors should be considered when developing strategies to prevent and manage VKC exacerbations.

Erdafitinib treatment in metastatic urothelial carcinoma: a real-world analysis.

Background: Erdafitinib, a fibroblast growth factor receptor (FGFR) inhibitor is a standard post chemotherapy advanced treatment line for metastatic urothelial carcinoma harboring FGFR2/3 genomic alterations. It was approved based on a phase 2 clinical trial, revealing a 40% response rate, and 13.8 months overall survival. These FGFR genomic alterations are uncommon. Thus, real-world data on erdafitinb use is scant. We herein describe erdafitinib treatment outcome in a real world patient cohort. Methods: We retrospectively reviewed the data of patients treated with erdafitinib from 9 Israeli medical centers. Results: Twenty-five patients with metastatic urothelial carcinoma (median age 73, 64% male, 80% with visceral metastases) were treated with erdafitinib between January 2020 to October 2022. A clinical benefit (complete response 12%, partial response 32%, stable disease 12%) was seen in 56%. Median progression-free survival was 2.7 months, and median overall survival 6.73 months. Treatment related toxicity ≥ grade 3 occurred in 52%, and 32% discontinued therapy due to adverse events. Conclusions: Erdafitinib therapy is associated with a clinical benefit in the real world setting, and associated with similar toxicity as reported in prospective clinical trials.

An implantable system for long-term assessment of atrial fibrillation substrate in unanesthetized rats exposed to underlying pathological conditions.

Atrial fibrillation (AF) is a progressive arrhythmia with underlying mechanisms that are not fully elucidated, partially due to lack of reliable and affordable animal models. Here, we introduce a system for long-term assessment of AF susceptibility (substrate) in ambulatory rats implanted with miniature electrodes on the atrium. Rats were subjected to excessive aldosterone (Aldo) or solvent only (Sham). An additional group was exposed to myocardial infarction (MI). AF substrate was tested two- and four-weeks post implantation and was also compared with implanted rats early post-implantation (Base). Aldo and MI increased the AF substrate and atrial fibrosis. In the MI group only, AF duration was correlated with the level of atrial fibrosis and was inversely correlated with systolic function. Unexpectedly, Shams also developed progressive AF substrate relative to Base individuals. Further studies indicated that serum inflammatory markers (IL-6, TNF-alpha) were not elevated in the shams. In addition, we excluded anxiety\depression due to social-isolation as an AF promoting factor. Finally, enhanced biocompatibility of the atrial electrode did not inhibit the gradual development of AF substrate over a testing period of up to 8 weeks. Overall, we successfully validated the first system for long-term AF substrate testing in ambulatory rats.