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.

To warrant clinical adoption AI models require a multi-faceted implementation evaluation.

Despite artificial intelligence (AI) technology progresses at unprecedented rate, our ability to translate these advancements into clinical value and adoption at the bedside remains comparatively limited. This paper reviews the current use of implementation outcomes in randomized controlled trials evaluating AI-based clinical decision support and found limited adoption. To advance trust and clinical adoption of AI, there is a need to bridge the gap between traditional quantitative metrics and implementation outcomes to better grasp the reasons behind the success or failure of AI systems and improve their translation into clinical value.

Complications after total wrist arthroplasty.

We reviewed the incidence and management of complications after total wrist arthroplasty, as reported in the literature, with so-called fourth-generation implants and other recent designs. While early intraoperative and postoperative complications, including fractures, tendon lacerations, infection, nerve compression, tendonitis, stiffness and chronic regional pain syndrome, had an acceptable incidence, late complications, such as periprosthetic osteolysis and implant loosening, occurred more frequently. Implant survival at 10 years was in the range of 70%-80% in most publications. Several of the implants have been modified or withdrawn. Instability and dislocation were frequent after a pyrocarbon spacer. Failed arthroplasties can be salvaged by revision arthroplasty or total wrist arthrodesis. Revision arthroplasty has a lower survival rate than primary arthroplasty and does not clearly offer important significant advantages over total wrist arthrodesis in terms of patient-reported outcome measures. Further development of prosthetic design, new materials and more knowledge on patient-related risk factors are needed.

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.

Total Wrist Arthroplasty: An International Perspective.

Concerns about implant durability and technical difficulty continue to make total wrist arthroplasties a specialized procedure with a narrow scope of indications. As a result, more routinely performed total or partial wrist arthrodesis continues to maintain popularity over arthroplasty. However, wrist motion preservation is undoubtedly preferable for patients and current literature is trending to more favorable outcomes for total wrist arthroplasties. In the setting of the evolving role of wrist arthroplasties in clinical practice, it is important to focus on providing hand surgeons a practical approach to incorporating total wrist arthroplasty into the treatment toolbox available to them when treating patients with painful wrist arthritis.

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.

Realistic Physiological Options to Increase Grain Legume Yield under Drought.

Increasing yield resiliency under water deficits remains a high priority for crop improvement. In considering the yield benefit of a plant trait modification, two facts are often overlooked: (1) the total amount of water available to a crop through a growing season ultimately constrains growth and yield cannot exceed what is possible with the limited amount of available water, and (2) soil water content always changes over time, so plant response needs to be considered within a temporally dynamic context of day-to-day variation in soil water status. Many previous evaluations of drought traits have implicitly considered water deficit from a "static" perspective, but while the static approach of stable water deficit treatments is experimentally congruous, the results are not realistic representations of real-world drought conditions, where soil water levels are always changing. No trait always results in a positive response under all drought scenarios. In this paper, we suggest two key traits for improving grain legume yield under water deficit conditions: (1) partial stomata closure at elevated atmospheric vapor pressure deficit that results in soil water conservation, and (2) lessening of the high sensitivity of nitrogen fixation activity to soil drying.

Ecotoxicity of single and mixture of perfluoroalkyl substances (PFOS and PFOA) in soils to the earthworm Aporrectodea caliginosa.

Per and polyfluoroalkyl substances (PFAS) are persistent compounds that are massively used in industry, consumer goods and fire-fighting foams. Soil contamination by PFAS is a major environmental concern, and there is a lack of knowledge on both their ecotoxicological mechanisms and the concentrations that induce adverse effects especially to non-target organisms, particularly in the case of PFAS mixtures. This study contributes to filling these gaps by assessing and modelling the effects of PFAS (in single and in mixtures for PFOS and PFOA at different environmental doses) on juvenile endogeic earthworms of a common species in European soils (Aporrectodea caliginosa) at different levels of biological organization (sub-individual and individual). The results showed for the first time combined strong ecotoxicological effects of PFAS on earthworm survival, integumental integrity, growth, sexual maturity and on genomic stability notably with the induction of DNA breaks associated with no abnormal oxidative DNA-lesion levels. Our results demonstrated significant effects at 0.3 mg kg-1 and additive effects in case of mixtures.

Intracranial Dural Arteriovenous Fistulas.

Dural arteriovenous fistulas (DAVFs) are abnormal communications between meningeal arteries and dural venous sinuses and/or cortical veins. Although many fistulas are benign and do not require treatment, some may carry a significant risk of bleeding or cause symptoms and warrant treatment. This review provides a review of various aspects of intracranial DAVFs including epidemiology, pathophysiology, clinical presentation, imaging characteristics, classification, natural history, and management options. By exploring these topics, we aim to enhance understanding of this condition and facilitate patient care.

Sex hormone-binding globulin levels and development of hypertension in middle-aged men and women.

OBJECTIVE: To investigate the association between sex hormone-binding globulin (SHBG) levels, change in blood pressure and development of hypertension. METHODS: In a community-based study, we examined 2816 middle-aged participants with focus on cardiometabolic risk factors in 2002-2005. A representative sample of 1954 men and women was invited to follow-up in 2012-2014 and 1327 were included in a second study visit. Mean follow-up time was 9.7 years. Blood pressure was measured according to the guidelines from the seventh Joint National Committee of Hypertension, and new cases of hypertension were recorded. SHBG was measured at baseline. The association between SHBG, blood pressure and new cases of hypertension was investigated using linear regression analyses and logistic regression analyses after excluding individuals treated with blood pressure-lowering drugs. RESULTS: Mean SBP and DBP at follow-up was 123 and 72 mmHg, respectively, and mean increase from baseline was 5.8 and 2.9 mmHg. During the follow-up time, 167 new cases of hypertension (16.1%) were identified. One standard deviation (SD) increase in SHBG at baseline was inversely associated with the risk to develop hypertension at follow-up (OR = 0.74, 95% CI 0.58-0.95) in the fully adjusted model. Moreover, one SD increase in SHBG was associated with a decrease in mean SBP (delta = -1.5 mmHg, 95% CI - 2.2 to -0.8) and DBP (delta = - 1.0 mmHg, 95% CI - 1.5 to -0.4), after adjusting for covariates. CONCLUSION: SHBG levels are inversely associated with development of hypertension and change in blood pressure levels independent of major risk factors.

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.

Impact of Decalcification, Cold Ischemia, and Deglycosylation on Performance of Programmed Cell Death Ligand-1 Antibodies With Different Binding Epitopes: Comparison of 7 Clones.

Programmed cell death ligand-1 (PD-L1) expression levels in patients' tumors have demonstrated clinical utility across many cancer types and are used to determine treatment eligibility. Several independently developed PD-L1 immunohistochemical (IHC) predictive assays are commercially available and have demonstrated different levels of staining between assays, generating interest in understanding the similarities and differences between assays. Previously, we identified epitopes in the internal and external domains of PD-L1, bound by antibodies in routine clinical use (SP263, SP142, 22C3, and 28-8). Variance in performance of assays utilizing these antibodies, observed following exposure to preanalytical factors such as decalcification, cold ischemia, and duration of fixation, encouraged additional investigation of antibody-binding sites, to understand whether binding site structures/conformations contribute to differential PD-L1 IHC assay staining. We proceeded to further investigate the epitopes on PD-L1 bound by these antibodies, alongside the major clones utilized in laboratory-developed tests (E1L3N, QR1, and 73-10). Characterization of QR1 and 73-10 clones demonstrated that both bind the PD-L1 C-terminal internal domain, similar to SP263/SP142. Our results also demonstrate that under suboptimal decalcification or fixation conditions, the performance of internal domain antibodies is less detrimentally affected than that of external domain antibodies 22C3/28-8. Furthermore, we show that the binding sites of external domain antibodies are susceptible to deglycosylation and conformational structural changes, which directly result in IHC staining reduction or loss. The binding sites of internal domain antibodies were unaffected by deglycosylation or conformational structural change. This study demonstrates that the location and conformation of binding sites, recognized by antibodies employed in PD-L1 diagnostic assays, differ significantly and exhibit differing degrees of robustness. These findings should reinforce the need for vigilance when performing clinical testing with different PD-L1 IHC assays, particularly in the control of cold ischemia and the selection of fixation and decalcification conditions.