IL-10 predicts incident neuroinflammatory disease and proviral load dynamics in a large Brazilian cohort of people living with human T-lymphotropic virus type 1.

Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.

Influence of Different Apical Foramen Morphologies on the Accuracy of Four Electronic Foramen Locators.

OBJECTIVE: The aim of this study was to evaluate the accuracy of the Root ZX II (RZX), Raypex 6 (RAY), EPex Pro (EPEX), and CanalPro (CNP) electronic foramen locators (EFLs) in different foraminal morphologies (fully formed foramen, immature foramen with parallel walls, and immature foramen with divergent walls); this article also evaluated the influence of different penetration levels (0.0 mm and -1.0 mm). MATERIALS AND METHODS: Thirty single-rooted human premolars were accessed and had their cervical/middle thirds prepared with SX ProTaper files. The apical foramens (AF) were standardized to 250 µm and the initial root canal length (RCL1) was measured under 16x magnification with aid of a digital caliper. Using the alginate model, electronic measurements (EM) were taken 1.0 mm up to AF (EM1/-1) and at AF (EM1/0), always using adjusted hand K-files. The root apexes were then cross-sectioned 3.0 mm from the foramen; then, new RCL (RCL2) and electronic measurements were performed (EM2/-1 and EM2/0.0). Finally, retropreparations were performed with instruments SX ProTaper files introduced 4.0 mm in the apicocervical direction. Then new RCL (RCL3) and electronic measurements (EM3/-1 and EM3/0) were performed. STATISTICAL ANALYSIS: Values were tabulated and tested for normality using the Shapiro-Wilk test, which yielded nonparametric distributions of the data. Data were subjected to the Kruskal-Wallis and Dunn tests to estimate possible differences between devices as a function of foramen morphology and/or apical limit. The significance level was set at 5.0%. RESULTS: In general, the EFLs were accurate in determining the RCL. Statistically significant differences were observed between EPEX and RAY at 0.0, when measuring the divergent AF canals (p < 0.05). Regarding the different foramen morphologies in each EFL, RZX and EPEX showed no interference (p > 0.05), whereas RAY and CNP had lower accuracy levels at 0.0 with divergent AF (p < 0.05). CONCLUSION: The four devices evaluated are accurate to determine the RCL in the conditions tested. The apical limit of penetration did not have significant influence on their accuracy. Conversely, the presence of divergence in the AF walls negatively influenced de RAY and CNP precisions at the foraminal level.

HTLV-1-Associated Myelopathy (HAM) Incidence in Asymptomatic Carriers and Intermediate Syndrome (IS) Patients.

Several studies suggest that HTLV-1 infection may be associated with a wider spectrum of neurological and clinical manifestations that do not meet diagnostic criteria for HAM. These conditions may later progress to HAM or constitute an intermediate clinical form: intermediate syndrome (IS), a mid-point between asymptomatic HTLV-1 carriers and those with full myelopathy. Thus, we determined the incidence of HAM cases in the HTLV-1-asymptomatic and IS patients, and the clinical/laboratory associated markers. A total of 204 HTLV-1-positive patients were included in this study, divided into two groups: Group 1, including 145 asymptomatic HTLV-1 subjects (ASY), and Group 2, including 59 patients with inflammatory clinical symptoms in more than three systems and a high proviral load (PVL). During a 60-month follow-up time, with the age ranging from 47 to 79 years, ten patients of the fifty-nine initially diagnosed as IS developed HAM (iHAM), and two patients of the initial 145 ASY developed HAM directly. Women were more prevalent in all groups. For the iHAM patients, the age ranged from 20 to 72 years, with a mean of 53 (±15 SD). Older age was associated with the development of HAM, higher PVL and IS; however, there was no any specific symptom or clinical sign, that was associated with risk for iHAM. In conclusion, IS cases could be an early phase of development of HAM. These findings show the presence of higher incidence probabilities in our cohort than previously reported.

ASSESSMENT OF SIMULATED SURGICAL DEXTERITY AFTER MODIFIABLE EXTERNAL EXPOSURES AMONG NOVICE VERSUS EXPERIENCED VITREORETINAL SURGEONS.

PURPOSE: To evaluate novice and senior vitreoretinal surgeons after various exposures. Multiple comparisons ranked the importance of these exposures for surgical dexterity based on experience. METHODS: This prospective cohort study included 15 novice and 11 senior vitreoretinal surgeons (<2 and >10 years' practice, respectively). Eyesi-simulator tasks were performed after each exposure. Day 1, placebo, 2.5 mg/kg caffeine, and 5.0 mg/kg caffeine; day 2, placebo, 0.2 mg/kg propranolol, and 0.6 mg/kg propranolol; day 3, baseline simulation, breathalyzer readings of 0.06% to 0.10% and 0.11% to 0.15% blood alcohol concentrations; day 4, baseline simulation, push-up sets with 50% and 85% repetitions maximum; and day 5, 3-hour sleep deprivation. Eyesi-generated score (0-700, worst-best), out-of-tolerance tremor (0-100, best-worst), task completion time (minutes), and intraocular pathway (in millimeters) were measured. RESULTS: Novice surgeons performed worse after caffeine (-29.53, 95% confidence interval [CI]: -57.80 to -1.27, P = 0.041) and alcohol (-51.33, 95% CI: -80.49 to -22.16, P = 0.001) consumption. Alcohol caused longer intraocular instrument movement pathways (212.84 mm, 95% CI: 34.03-391.65 mm, P = 0.02) and greater tremor (7.72, 95% CI: 0.74-14.70, P = 0.003) among novices. Sleep deprivation negatively affected novice performance time (2.57 minutes, 95% CI: 1.09-4.05 minutes, P = 0.001) and tremor (8.62, 95% CI: 0.80-16.45, P = 0.03); however, their speed increased after propranolol (-1.43 minutes, 95% CI: -2.71 to -0.15 minutes, P = 0.029). Senior surgeons' scores deteriorated only following alcohol consumption (-47.36, 95% CI: -80.37 to -14.36, P = 0.005). CONCLUSION: Alcohol compromised all participants despite their expertise level. Experience negated the effects of caffeine, propranolol, exercise, and sleep deprivation on surgical skills.

Branch retinal artery occlusion with paracentral acute middle maculopathy related to a COVID-19 infection in a patient with Anosmia.

PURPOSE: To report a case of paracentral acute middle maculopathy (PAMM) due to branch retinal artery occlusion (BRAO) as a complication of COVID-19. METHODS: A case report evaluated through spectral-domain optical coherence tomography (SD-OCT), fluorescein angiography, and OCT angiography. RESULTS: A 55-year-old man complained of blurred vision in the right eye. He presented with anosmia and tested positive for COVID-19 one week before. Fundus examination revealed a superior temporal whitening of the retina, SD-OCT showed a hyperreflective band-like lesion on the nuclear layer consistent with PAMM. CONCLUSION: COVID-19 infection involves inflammatory and thrombotic events. Even patients with just anosmia may have complications such as BRAO associated with PAMM.

Could Cesarean Delivery Help Prevent Mother-to-Child Transmission of Human T-Lymphotropic Virus Type 1?

BACKGROUND: Mother-to-child transmission (MTCT) of human T-lymphotropic virus type 1 (HTLV-1) is an important route of transmission that can cause lifelong infection. There is high morbidity and mortality due to adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy (HAM), and other inflammatory disorders. These conditions develop in nearly 10% of people with HTLV-1 infection, with a higher risk if infection occurs early in life. Identification of risk factors can inform targeted measures to reduce HTLV-1 MTCT. This study aimed to investigate the potential of cesarean delivery to prevent HTLV-1 MTCT. METHODS: We performed a review of the cases of women and their offspring under regular follow-up at the HTLV-1 outpatient clinic at the Institute of Infectious Diseases Emilio Ribas. RESULTS: A total of 177 HTLV-1-infected women and 369 adult offspring were investigated. Overall, 15% of the children were positive for HTLV-1 and 85% were negative. Regarding vertical transmission, we found that a breastfeeding duration of >6 months was associated with MTCT. Moreover, maternal proviral load was not associated with transmission, but high educational level and cesarean delivery were identified as protective factors. CONCLUSIONS: HTLV-1 MTCT was associated with mother's age at delivery of >25 years, low educational level, prolonged breastfeeding, and vaginal delivery.

Deep-sea Ophiuroidea (Echinodermata) collected during the TALUD cruises in western Mexico.

Deep-sea ophiuroids from western Mexico have been documented since 1899, but mostly by non-Mexican expeditions. TALUD is a Mexican project designed to study the deep-sea fauna from Mexico. As part of it, the present contribution provides for the first time detailed information about the taxonomy and distribution, as well as images, of deep-sea ophiuroids from western Mexico, representing a useful taxonomic identification tool for Ophiuroidea from the eastern Pacific. A total of 38 species of ophiuroid (35 identified at species level, one at genus level, and two as confer) were collected from 83 stations located at 123‒2,309 m depth. At a regional scale, several new species records are presented: six for western Baja California, five for western Baja California Sur, two for the Gulf of California, four for Jalisco, 14 for Colima, and five for Guerrero. Geographic (six) and bathymetric (seven) distribution ranges of species are extended. An updated list of deep-sea ophiuroids (61 species) from western Mexico is provided together with an identification key to species collected during this survey. In addition, nine records of deep-sea ophiuroids for the Mexican Pacific are unproven, doubtful or invalid. We corroborated the presence of Ophiacantha eurypoma and Ophiacantha pacifica in the study area and added Amphiura gymnogastra as the first record for Mexico. We propose to transfer Ophiacantha phragma to Ophiolimna on account of it having both granules and spines on the dorsal disc and striated arm plates. TALUD cruises collected 57 % of the total deep-sea species known to occur off Mexico, making it the most important survey of deep-sea Ophiuroidea carried out in western Mexico to date.

Characterization of Peptaibols Produced by a Marine Strain of the Fungus Trichoderma endophyticum via Mass Spectrometry, Genome Mining and Phylogeny-Based Prediction.

Trichoderma is recognized as a prolific producer of nonribosomal peptides (NRPs) known as peptaibols, which have remarkable biological properties, such as antimicrobial and anticancer activities, as well as the ability to promote systemic resistance in plants against pathogens. In this study, the sequencing of 11-, 14- and 15-res peptaibols produced by a marine strain of Trichoderma isolated from the ascidian Botrylloides giganteus was performed via liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-MS/MS). Identification, based on multilocus phylogeny, revealed that our isolate belongs to the species T. endophyticum, which has never been reported in marine environments. Through genome sequencing and genome mining, 53 biosynthetic gene clusters (BGCs) were identified as being related to bioactive natural products, including two NRP-synthetases: one responsible for the biosynthesis of 11- and 14-res peptaibols, and another for the biosynthesis of 15-res. Substrate prediction, based on phylogeny of the adenylation domains in combination with molecular networking, permitted extensive annotation of the mass spectra related to two new series of 15-res peptaibols, which are referred to herein as "endophytins". The analyses of synteny revealed that the origin of the 15-module peptaibol synthetase is related to 18, 19 and 20-module peptaibol synthetases, and suggests that the loss of modules may be a mechanism used by Trichoderma species for peptaibol diversification. This study demonstrates the importance of combining genome mining techniques, mass spectrometry analysis and molecular networks for the discovery of new natural products.

Discovery of dual PKS involved in sclerotiorin biosynthesis in Penicillium meliponae using genome mining and gene knockout.

Fungi of the genus Penicillium section Sclerotiora have as their main characteristic the presence of orange-pigmented mycelium, which is associated with sclerotiorin, a chlorinated secondary metabolite of the azaphilone subclass of polyketides. Sclerotiorin presents anti-diabetes, antioxidant, anti-inflammatory, anti-Alzheimer, antiviral, and antimicrobial activities, which has always attracted the attention of researchers worldwide. During our ongoing search for azaphilone-producing Amazonian fungi, the strain of Penicillium MMSRG-058 was isolated as an endophyte from the roots of Duguetia stelechantha and showed great capacity for producing sclerotiorin-like metabolites. Using multilocus phylogeny, this strain was identified as Penicillium meliponae. Moreover, based on the genome mining of this strain through the reverse approach, a cluster of putative biosynthetic genes (BGC) responsible for the biosynthesis of sclerotiorin-like metabolites (scl cluster) was identified. The knockout of the sclA (highly reducing PKS) and sclI (non-reducing PKS) genes resulted in mutants with loss of mycelial pigmentation and terminated the biosynthesis of sclerotiorin-like metabolites: geumsanol B, chlorogeumsanol B, 7-deacetylisochromophilone VI, isochromophilone VI, ochrephilone, isorotiorin, and sclerotiorin. Based on these results, a biosynthetic pathway was proposed considering the homology of BGC scl genes with the azaphilone BGCs that have already been functionally characterized.

Retinal microvascular abnormalities, cotton wool-like lesions, and macular edema following COVID-19 in a patient previously vaccinated with AstraZeneca and idiopathic myopathy.

In this case study, the authors describe peculiar bilateral cotton wool-like retinal lesions associated with macular edema in a patient with COVID-19 who was vaccinated with a single dose of AstraZeneca one month earlier. This patient had no pulmonary or systemic cardiovascular complications from COVID-19, as reported in other papers that found retinal lesions. However, the patient was diagnosed with idiopathic myopathy when discovering the SARS-CoV-2 infection. The patient was a 22-year-old white female with no previous history of morbidity, complaining of blurred vision in both eyes seven days after testing positive for SARS-CoV-2 by PCR (using nasal and oral swab) and confirmed through ELISA blood test (IgM positive). There was no ancillary test revealing diabetes mellitus. The patient presented with scattered whitish cotton wool-like lesions and a few hemorrhages on the posterior pole in fundus examination. On spectral domain optical coherence tomography (SD-OCT), there were hyperreflective lesions in the nerve fiber layer, ganglion cell layer, inner nuclear layer, and inner and outer plexiform layers at the site corresponding to the whitish cotton wool-like lesions in the posterior fundus photos. Moreover, the macula of both eyes had intraretinal and subretinal fluid, reversible with corticosteroid therapy. In conclusion, COVID-19 has been associated with capillary disorders at different target sites such as retina, lungs, and central nervous system. Similarly, vaccination against SARS-CoV-2 has been linked to retinal complications in the literature; however, cotton wool-like lesions have not yet been reported. There are many questions yet to be answered about the implications of COVID-19 infection and its vaccines.

On a small collection of mysids (Crustacea, Peracarida, Mysida) from the southern Gulf of California, western Mexico, with the description of new species of Mysidium and Cubanomysis.

Four species of Mysida were collected in the southwestern Gulf of California, Mexico, including a new species of Mysidium (Mysidium), Metamysidopsis frankfiersi, Siriella gracilis, and a new species of Cubanomysis. The new species of Mysidium is the eleventh species in this genus, with species represented along both coasts of the Americas. It is the third species occurring in the eastern Pacific. The new species of Cubanomysis is the third species in this genus; the other two occur in California and in the western Atlantic.

Systemic cytokines and GlycA discriminate disease status and predict corticosteroid response in HTLV-1-associated neuroinflammation.

BACKGROUND: HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) is an incapacitating neuroinflammatory disorder for which no disease-modifying therapy is available, but corticosteroids provide some clinical benefit. Although HAM/TSP pathogenesis is not fully elucidated, older age, female sex and higher proviral load are established risk factors. We investigated systemic cytokines and a novel chronic inflammatory marker, GlycA, as possible biomarkers of immunopathogenesis and therapeutic response in HAM/TSP, and examined their interaction with established risk factors. PATIENTS AND METHODS: We recruited 110 People living with HTLV-1 (PLHTLV-1, 67 asymptomatic individuals and 43 HAM/TSP patients) with a total of 946 person-years of clinical follow-up. Plasma cytokine levels (IL-2, IL-4, IL-6, IL-10, IL-17A, IFN-γ, TNF) and GlycA were quantified by Cytometric Bead Array and 1NMR, respectively. Cytokine signaling and prednisolone response were validated in an independent cohort by nCounter digital transcriptomics. We used multivariable regression, machine learning algorithms and Bayesian network learning for biomarker identification. RESULTS: We found that systemic IL-6 was positively correlated with both age (r = 0.50, p < 0.001) and GlycA (r = 0.45, p = 0.00049) in asymptomatics, revealing an 'inflammaging" signature which was absent in HAM/TSP. GlycA levels were higher in women (p = 0.0069), but cytokine levels did not differ between the sexes. IFN-γ (p = 0.007) and IL-17A (p = 0.0001) levels were increased in untreated HAM/TSP Multivariable logistic regression identified IL-17A and proviral load as independent determinants of clinical status, resulting in modest accuracy of predicting HAM/TSP status (64.1%), while a machine learning-derived decision tree classified HAM/TSP patients with 90.7% accuracy. Pre-treatment GlycA and TNF levels significantly predicted clinical worsening (measured by Osame Motor Disability Scale), independent of proviral load. In addition, a poor prednisolone response was significantly correlated with higher post-treatment IFN-γ levels. Likewise, a transcriptomic IFN signaling score, significantly correlated with previously proposed HAM/TSP biomarkers (CASP5/CXCL10/FCGR1A/STAT1), was efficiently blunted by in vitro prednisolone treatment of PBMC from PLHTLV-1 and incident HAM/TSP. CONCLUSIONS: An age-related increase in systemic IL-6/GlycA levels reveals inflammaging in PLHTLV-1, in the absence of neurological disease. IFN-γ and IL-17A are biomarkers of untreated HAM/TSP, while pre-treatment GlycA and TNF predict therapeutic response to prednisolone pulse therapy, paving the way for a precision medicine approach in HAM/TSP.

Redescription of Paguristes aztatlanensis Glassell, 1937 and description of a new species of the genus Paguristes Dana, 1851 (Anomura, Paguroidea, Diogenidae) from western Mexico.

A redescription of Paguristes aztatlanensis Glassell, 1937 is presented together with the description of Paguristes turkayi n. sp. from the Mexican Pacific. Paguristes turkayi n. sp. is close to P. digueti and P. sanguinimanus, but can be separated from these two species by the following: P. turkayi features a slender rostrum; the ocular peduncles are proportionally larger relative to the shield in P. turkayi n. sp. than in P. digueti, but proportionally shorter than in P. sanguinimanus; the anterodorsal plates of the carapace are unarmed in Paguristes turkayi n. sp. and P. sanguinimanus (versus armed with small teeth in P. digueti); in P. turkayi n. sp., the palm and carpus of the chelipeds bear fewer but larger spines and tufts of very long setae, while in P. digueti and P. sanguinimanus the chelipeds are armed with many small spines and very short setae.

Pelagic amphipods (Crustacea: Amphipoda: Hyperiidea) in western Mexico. 7. Superfamily Platysceloidea. Family Oxycephalidae.

Twelve species of the family Oxycephalidae were collected during a deep-water survey off western Mexico: four species of Rhabdosoma, three species of Streetsia, two species of Oxycephalus, and one species each of Cranocephalus, Glossocephalus, and Leptocotis. In total, 321 specimens were collected, 114 males and 207 females, in 33 sampling localities in the Gulf of California (28) and off southwestern Mexico (5). Two species dominated in the samples and co-occurred in 17 of the 33 samples containing hyperiids: Oxycephalus clausi (24 localities, 152 specimens) and Rhabdosoma whitei (20 localities, 121 specimens). Considering this study and previous records, a total of 16 of the 18 described species of Oxycephalidae (89%) have been reported from western Mexico. Distribution of this new material off western Mexico is provided together with update data on species occurrence in the eastern Pacific.

Hyperiids (Amphipoda, Hyperiidea) collected during the TALUD cruises in western Mexico. 5. Family Amphithyridae, with the description of a new species of Amphithyropsis Zeidler.

In order to complete the information related to the little studied deep-sea planktonic fauna of western Mexico, samples from a wide depth range (surface to 1550 m depth) were obtained using different gear. Six species and 108 individuals of hyperiid amphipods of the family Amphithyridae were collected at 26 localities, including a new species of Amphithyropsis Zeidler, 2016, which is herein described based on an adult male and a gravid female. Other species include Amphithyrus bispinosus Claus, 1879, the most abundant and frequently collected species (70 specimens at 17 localities), A. muratus Volkov, 1982 (11 specimens at 8 localities), A. sculpturatus Claus, 1879 (14 specimens at 7 localities), Paralycaea gracilis Claus, 1879 (10 specimens from 6 localities), and P. hoylei Stebbing, 1888 (one specimen from one locality). Worldwide and regional distributions are provided for each species.

Pelagic amphipods (Crustacea: Amphipoda: Hyperiidea) in western Mexico. 3. Family Lestrigonidae.

Thirteen species belonging to five genera of pelagic amphipods of the family Lestrigonidae were collected during a deep-water survey off western Mexico: four species of Hyperietta, two species of Hyperioides, five species of Lestrigonus, and one species each of Phronimopsis and Themistella. This represents 93% of all known species of Lestrigonidae world-wide. A total of 1092 specimens were obtained in 40 sampling localities in the Gulf of California (35) and off southwestern Mexico (5). Although sampling methodology was rather heterogeneous, two species, Hyperioides sibaginis and Lestrigonus bengalensis, were particularly abundant (336 and 562 specimens) and frequent (present in 24 and 31 localities) in the samples, representing 82% of the total catch. The southernmost distribution limit of Hyperietta stebbingi is extended to off SW Mexico. Of the 13 species that were collected during this survey, 10 and 8 species co-occurred at two sampling localities in the SE Gulf of California.