A Multidisciplinary Approach to Improve the Management of Immune-Checkpoint Inhibitor-Related Pneumonitis.

Purpose: Treatment with immune-checkpoint inhibitors (ICIs) can be associated with a wide spectrum of immune-related adverse events (irAEs). Among irAEs, immune-mediated pneumonitis (im-PN) is a rare but potentially life-threatening side effect. TPrompt multidisciplinary diagnosis and effective management of im-PN may be essential to avoid severe complications and allowing resumation of therapy. Patients and Methods: We collected a case series of skin (melanoma, cutaneous squamous cell carcinoma-CSCC), lung, and mesothelioma cancer patients (pts), treated with ICI at the Center for Immuno-Oncology University Hospital of Siena, Italy, and diagnosed with im-PN. Clinical and radiologic data were thoroughly collected, as well as bronchoalveolar lavage (BAL) samples; im-PN was graded using CTCAE v. 5.0. Radiological patterns were reported according to the Fleischner Society classification. Results: From January 2014 to February 2023, 1004 patients with melanoma (522), CSCC (42), lung (342) or mesothelioma (98) were treated with ICI (619 monotherapy; 385 combination). Among treated patients, 24 (2%) developed an im-PN and 58% were symptomatic. Im-PN were classified as grades G1 (10) and G2 (14). Prompt steroid treatment led to complete resolution of im-PN in 21 patients, with a median time to resolution of 14 weeks (range: 0.4-51). Twelve patients resumed ICI therapy once fully-recovered and 2 experienced a recurrence that completely resolved with steroids after resumption of treatment. Three radiologic patterns were identified: organizational pneumonia-like (67%), pulmonary eosinophilia (29%), and hypersensitivity pneumonitis (4%). Furthermore, BAL analysis performed in 8 (33%) patients showed an inflammatory lymphocytic infiltrate, predominantly consisting of foam cell-like macrophage infiltrates in 6 cases. Notably, transmission electron microscopy evaluation performed in 2 patients revealed a scenario suggestive of a drug-mediated toxicity. Conclusion: Im-PN is a rare but challenging side effect of ICI therapy, with variable time of onset and with heterogeneous clinical and radiological presentations. A multidisciplinary assessment is mandatory to optimize the clinical management of im-PN.

Genetic and Phenotypic Characterization of Xanthomonas Species Pathogenic in Wheat in Uruguay.

Bacterial diseases affecting wheat production in Uruguay are an issue of growing concern yet remain largely uninvestigated in the region. Surveys of 61 wheat fields carried out from 2017 to 2019 yielded a regional collection of 63 strains identified by 16S rRNA gene analysis as Xanthomonas spp. A real-time PCR protocol with species-specific primers previously reported allowed the identification of 44 strains as X. translucens, the causal agent of bacterial leaf streak (BLS) in wheat and other cereal crops. Multilocus sequence analysis of four housekeeping genes (dnaK, fyuA, gyrB, and rpoD) revealed that these strains were most closely related to X. translucens pv. undulosa, the pathovar that is most commonly associated with BLS of wheat. Multilocus sequence typing was applied to examine the genetic diversity of X. translucens strains. Strains were assigned to four different sequence types, three of which were previously reported globally. Additionally, 17 Xanthomonas strains not belonging to X. translucens were obtained from diseased wheat leaves. Phylogenetic analysis showed that these strains are closely related to X. prunicola and clustered together with previously uncharacterized Xanthomonas strains isolated from wheat in Minnesota. In planta pathogenicity assays carried out on a BLS-susceptible wheat cultivar showed that X. translucens pv. undulosa strains caused brown necrosis symptoms typical of BLS, whereas non-translucens Xanthomonas sp. strains elicited an atypical symptom of dry necrosis. These findings suggest that local wheat fields are affected by X. translucens pv. undulosa and by a new wheat pathogen within the Xanthomonas genus.

An Integrative Approach for the Characterization of Plant-Pathogenic Streptomyces spp. Strains Based on Metabolomic, Bioactivity, and Phylogenetic Analysis.

Actinomycetes are generally recognized as a diverse group of gram-positive, mycelium-forming, soil bacteria that play an important role in mineralization processes and plant health, being Streptomyces the most well-known genus from this group. Although plant pathogenicity is a rare attribute in this genus, some species have significant impact worldwide due to their ability to cause important crop diseases such as potato common scab (CS). In this work, an integrative approach was applied to investigate the pathogenic potential of Streptomyces spp. isolates obtained from a local collection of actinomycetes isolated from potato fields. Secretion of phytotoxic compounds was verified in most pathogenic strains from our collection (27 out of 29), and we followed metabolomic analysis to investigate those phytotoxins. We first evaluated the production of the known phytotoxins thaxtomin A (TXT) and desmethylmensacarcin (DMSN) in phytotoxic Streptomyces spp. by HPLC analysis, resulting in 17 TXT and 6 DMSN producers. In addition, NMR-based metabolomic models were able to classify strains according to their phytotoxicity, and metabolomic data was also used to infer chemotaxonomy within pathogenic species. A correlation between phylogeny and the production of distinct phytotoxins was found, supporting the idea that there are "species specific" metabolites produced by this genus. The recently discovered polyketide DMSN was associated unequivocally with S. niveiscabiei strains and was not produced by other species in the growth conditions employed. Two S. niveiscabiei and two S. puniciscabiei phytotoxic strains that did not produce TXT nor DMSN suggest the production of other kind of metabolites involved in phytotoxicity, and allowed the prioritization of these strains for further chemical studies. Indeed, we found two S. niveiscabiei strains whose supernatants were not phytotoxic in the radish assay, suggesting other pathogenic mechanisms involved. We believe our work will be useful to help understand relations between metabolites and phylogenetic clades within actinomycetes.

Convergence, Accommodation, Fusion, and Stereopsis: What Keeps the Eyes Aligned in Intermittent Exotropia?

PURPOSE: To investigate the relationships between angle of deviation, fusional convergence and divergence amplitude, AC/A ratio, near point of convergence (NPC), and myopia-phoria in intermittent exotropia (IXT). METHODS: 93 patients with IXT, divided into two groups, were recruited in the study. In Group A (73 patients), fusional convergence and divergence amplitudes, NPC, and AC/A ratio were studied and compared with a control group. In Group B (in 20 patients), myopia-phoria while switching from monocular to binocular view was studied with an infrared video retinoscopy and compared with a control group. RESULTS: In Group A, positive fusional amplitudes, NPC, and AC/A ratio of IXT patients did not differ from those of normals. Negative fusional amplitudes were significantly higher in the patient group than in the control group. In Group B, myopic shift was statistically significantly higher in the patient group and there was a statistically significant positive correlation between myopic shift and angle of strabismus. CONCLUSIONS: Apart from the role of fusional convergence which accounts for myopia-phoria, that of the other binocular functions in the control at near of IXT and conversely their specific role in the pathogenesis of IXT remain unclear and the cause of divergent infantile strabismus is still unknown.

Pseudoamblyopia in Congenital Cyclotropia.

PURPOSE: To study the effect of surgery on amblyopia and suppression associated with congenital cyclovertical strabismus. METHODS: The fixation pattern was investigated with microperimetry before and soon after surgery in ten consecutive children operated for congenital superior oblique palsy at the S. Martino Hospital, Belluno, Italy, between September 2014 and December 2015. Changes in visual performance in terms of best-corrected visual acuity (BCVA) and stereopsis between the day before and one week after surgery were also evaluated. No other amblyopia treatment has been administered during the time study. RESULTS: Surgical correction of the excyclodeviation in congenital SO palsy determined monocular and binocular sensory consequences: monocularly, in the cyclodeviated amblyopic eye, BCVA (0.46-0.03 LogMAR; p < 0.0001) and the fixation pattern improved, as demonstrated by microperimetry examination. Binocularly, stereopsis improved or emerged while suppression at the Worth four-dot test disappeared. CONCLUSIONS: In the absence of further amblyopic factors such as coexisting constant vertical and/or horizontal deviation and anisometropia, the amblyopia encountered in congenital SO palsy may resolve soon after the surgical alignment. Therefore, it may be considered and defined "pseudoamblyopia."