Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design.

BACKGROUND: Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. METHODS: We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0-1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. FINDINGS: Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8-4·6) for radiographic progression-free survival and 4·4 years (3·5-5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41-0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69-0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34-0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59-0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. INTERPRETATION: Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. FUNDING: Janssen-Cilag, Ipsen, Sanofi, and the French Government.

Bibliometric analysis and description of research trends on transforaminal full-endoscopic approach on the spine for the last two-decades.

OBJECTIVE: The study aims to assess the current development status of transforaminal full-endoscopic spine surgery (TFES) by exploring and analyzing the published literature to obtain an overview of this field and discover the evolution and emerging topics that are underrepresented. METHODS: Using Bibliometrix, CiteSpace, and VOSviewer, we analyzed the bibliometric data selected from the Web of Science Core Collection between January 2002 and November 2022. The descriptive and evaluative analyses of authors, institutes, countries, journals, keywords, and references are compiled. The quantity of research productivity was measured by the number of publications that were published. A quality indicator was thought to be the number of citations. In the bibliometric analysis of authors, areas, institutes, and references, we calculated and ranked the research impact by various metrics, such as the h-index and m-index. RESULTS: A total of 628 articles were identified in the field of TFES by the 18.73% annual growth rate of research on the subject from 2002 to 2022, constituting the documents are by 1961 authors affiliated with 661 institutions in 42 countries or regions and published in 117 journals. The USA (n = 0.20) has the highest international collaboration rate, South Korea has the highest H-index value (h = 33), and China is ranked as the most productive country (n = 348). Brown univ., Tongji univ., and Wooridul Spine represented the most productive institutes ranked by the number of publications. Wooridul Spine Hospital demonstrated the highest quality of paper publication. The Pain Physician had the highest h-index (n = 18), and the most cited journal with the earliest publication year in the area of FEDS is Spine (t = 1855). CONCLUSION: The bibliometric study showed a growing trend of research on transforaminal full-endoscopic spine surgery over the past 20 years. It has shown a significant increase in the number of authors, institutions, and international collaborating countries. South Korea, the United States, and China dominate the related areas. A growing body of evidence has revealed that TFES has leapfrogged from its infancy stage and gradually entered a mature development stage.

Visualization of the Final Stage of Sintering in Nanoceramics with Atomic Resolution.

The deep understanding of the sintering mechanism is pivotal to optimizing denser ceramics production. Although several models explain the sintering satisfactorily on the micrometric scale, the extrapolation for nanostructured systems is not trivial. Aiming to provide additional information about the particularities of the sintering at the nanoscale, we performed in situ experiments using high-resolution transmission electron microscopy (HRTEM). We studied the pore elimination process in a ZrO2 thin film and identified a high anisotropic pore elimination. Interestingly, there is a redistribution of the atoms from the rough surface in the solid-gas surface, followed by the atom attachment in a faceted surface. Finally, we found evidence of the pore acting as a pin, reducing the GB mobility. These findings certainly can contribute to enhance the kinetic models to describe the densification process of systems at the nanoscale.

Rapid Communication: oxidative stress induced by mixed exposure to glyphosate and silver nanoparticles.

The aim of this study was to examine oxidative stress induced by the binary mixture of silver nanoparticles (AgNP) and glyphosate (Gly) in Daphnia magna by measurement of reactive oxygen species (ROS) production, glutathione (GSH) levels, enzyme activities of catalase (CAT) and superoxide dismutase (SOD) as well as malondialdehyde (MDA) content. Acute exposure of Daphnia magna to binary mixture of AgNP and Gly resulted in significant biochemical responses indicative of oxidative damage. This response seemed to be related to imbalance in enzymatic/non-enzymatic antioxidant enzymes associated with intracellular overproduction of ROS and significant increase in MDA levels, indicating that the integrity and function of the cell membrane was damaged. These changes adversely affected the fitness and survival of Daphnia magna and negatively influenced offspring growth and reproduction.

Adjuvant radiotherapy versus early salvage radiotherapy plus short-term androgen deprivation therapy in men with localised prostate cancer after radical prostatectomy (GETUG-AFU 17): a randomised, phase 3 trial.

BACKGROUND: Adjuvant radiotherapy reduces the risk of biochemical progression in prostate cancer patients after radical prostatectomy. We aimed to compare adjuvant versus early salvage radiotherapy after radical prostatectomy, combined with short-term hormonal therapy, in terms of oncological outcomes and tolerance. METHODS: GETUG-AFU 17 was a randomised, open-label, multicentre, phase 3 trial done at 46 French hospitals. Men aged at least 18 years who had an Eastern Cooperative Oncology Group performance status of 1 or less, localised adenocarcinoma of the prostate treated with radical prostatectomy, who had pathologically-staged pT3a, pT3b, or pT4a (with bladder neck invasion), pNx (without pelvic lymph nodes dissection), or pN0 (with negative lymph nodes dissection) disease, and who had positive surgical margins were eligible for inclusion in the study. Eligible patients were randomly assigned (1:1) to either immediate adjuvant radiotherapy or delayed salvage radiotherapy at the time of biochemical relapse. Random assignment, by minimisation, was done using web-based software and stratified by Gleason score, pT stage, and centre. All patients received 6 months of triptorelin (intramuscular injection every 3 months). The primary endpoint was event-free survival. Efficacy and safety analyses were done on the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT00667069. FINDINGS: Between March 7, 2008, and June 23, 2016, 424 patients were enrolled. We planned to enrol 718 patients, with 359 in each study group. However, on May 20, 2016, the independent data monitoring committee recommended early termination of enrolment because of unexpectedly low event rates. At database lock on Dec 19, 2019, the overall median follow-up time from random assignment was 75 months (IQR 50-100), 74 months (47-100) in the adjuvant radiotherapy group and 78 months (52-101) in the salvage radiotherapy group. In the salvage radiotherapy group, 115 (54%) of 212 patients initiated study treatment after biochemical relapse. 205 (97%) of 212 patients started treatment in the adjuvant group. 5-year event-free survival was 92% (95% CI 86-95) in the adjuvant radiotherapy group and 90% (85-94) in the salvage radiotherapy group (HR 0·81, 95% CI 0·48-1·36; log-rank p=0·42). Acute grade 3 or worse toxic effects occurred in six (3%) of 212 patients in the adjuvant radiotherapy group and in four (2%) of 212 patients in the salvage radiotherapy group. Late grade 2 or worse genitourinary toxicities were reported in 125 (59%) of 212 patients in the adjuvant radiotherapy group and 46 (22%) of 212 patients in the salvage radiotherapy group. Late genitourinary adverse events of grade 2 or worse were reported in 58 (27%) of 212 patients in the adjuvant radiotherapy group versus 14 (7%) of 212 patients in the salvage radiotherapy group (p<0·0001). Late erectile dysfunction was grade 2 or worse in 60 (28%) of 212 in the adjuvant radiotherapy group and 17 (8%) of 212 in the salvage radiotherapy group (p<0·0001). INTERPRETATION: Although our analysis lacked statistical power, we found no benefit for event-free survival in patients assigned to adjuvant radiotherapy compared with patients assigned to salvage radiotherapy. Adjuvant radiotherapy increased the risk of genitourinary toxicity and erectile dysfunction. A policy of early salvage radiotherapy could spare men from overtreatment with radiotherapy and the associated adverse events. FUNDING: French Health Ministry and Ipsen.

Antimicrobial activity of Lactobacillus fermentum TcUESC01 against Streptococcus mutans UA159.

Dental caries is a multifactorial chronic-infection disease, which starts with a bacterial biofilm formation caused mainly by Streptococcus mutans. The use of probiotics has shown numerous health benefits, including in the fight against oral diseases. Strains of Lactobacillus fermentum have already shown probiotic potential against S. mutans, but there are still few studies. Thus, the aim of our study was to evaluate the antimicrobial activity of the inoculum and metabolites produced by L. fermentum TcUESC01 against S. mutans UA159. For this, a growth curve of L. fermentum was performed and both the inoculum and the metabolites formed in the fermentation were tested against the growth of S. mutans UA159 in agar diffusion tests, and only its metabolites were tested to determine the minimum inhibitory concentration, minimal bactericidal concentration and inhibition of cell adhesion. Inhibition of biofilm formation, pH drop and proton permeability were also tested with the metabolites. The zone of inhibition began to be formed at 14 h and continued until 16 h. The inoculum containing L. fermentum also showed zone of inhibition. The MIC for the metabolites was 1280 mg/mL and the MBC was obtained with a concentration higher than the MIC equal to 5120 mg/mL. Half of the MIC concentration (640 mg/mL) was required to inhibit S. mutans adhesion to the surface of the microplates. In the biofilm analyzes, the treatment with the metabolites in the tested concentration was not able to reduce biomass, insoluble glucans and alkali soluble compared to the control biofilm (p > 0.05). The metabolites also did not affect acid production and acid tolerance of S. mutans cells in biofilms compared to saline group (p > 0.05). Lactic acid (50.38%) was the most abundant organic acid produced by L. fermentum. This is the first report showing that the metabolites produced by the Lactobacillus fermentum TcUESC01 have a potential to be used as an antimicrobial agent against S. mutans, showing anti-adherence and bactericidal activity against planktonic cells of S. mutans. Thus, further studies should be carried out in order to better understand the antimicrobial activity of metabolites of L. fermentum TCUESC01.

Crystalline phase-dependent toxicity of aluminum oxide nanoparticles toward Daphnia magna and ecological risk assessment.

Aluminum oxide nanoparticles (Al2O3 NPs) can be found in different crystalline phases, and with the emergence of nanotechnology there has been a rapid increase in the demand for Al2O3 NPs in different engineering areas and for consumer products. However, a careful evaluation of the potential environmental and human health risks is required to assess the implications of the release of Al2O3 NPs into the environment. Thus, the objective of this study was to investigate the toxicity of two crystalline phases of Al2O3 NPs, alpha (α-Al2O3 NPs) and eta (η-Al2O3 NPs), toward Daphnia magna and evaluate the risk to the aquatic ecology of Al2O3 NPs with different crystalline phases, based on a probabilistic approach. Different techniques were used for the characterization of the Al2O3 NPs. The toxicity toward Daphnia magna was assessed based on multiple toxicological endpoints, and the probabilistic species sensitivity distribution (PSSD) was used to estimate the risk of Al2O3 NPs to the aquatic ecology. The results obtained verify the toxic potential of the NPs toward D. magna even in sublethal concentrations, with a more pronounced effect being observed for η-Al2O3 NPs. The toxicity is associated with an increase in the reactive oxygen species (ROS) content and deregulation of antioxidant enzymatic/non-enzymatic enzymes (CAT, SOD and GSH). In addition, changes in MDA levels were observed, indicating that D. magna was under oxidative stress. The most prominent chronic toxic effects were observed in the organisms exposed to η-Al2O3 NPs, since the lowest LOEC was 3.12 mg/L for all parameters, while for α-Al2O3 NPs the lowest LOEC was 6.25 mg/L for longevity, growth and reproduction. However, the risk assessment results indicate that, based on a probabilistic approach, Al2O3 NPs (alpha, gamma, delta, eta and theta) only a very limited risk to organisms in surface waters.

Toxicity of binary mixtures of Al2O3 and ZnO nanoparticles toward fibroblast and bronchial epithelium cells.

The objective of this study was to examine the cytotoxic effects of binary mixtures of Al2O3 and ZnO NPs using mouse fibroblast cells (L929) and human bronchial epithelial cells (BEAS-2B) as biological test systems. The synergistic, additive, or antagonistic behavior of the binary mixture was also investigated. In toxicity experiments, cellular morphology, mitochondrial function (MTT assay), apoptosis, nuclear size and shape, clonogenic assays, and damage based upon oxidative stress parameters were assessed under control and NPs exposure conditions. Although Abbott modeling results provided no clear evidence of the binary mixture of Al2O3 and ZnO NPs exhibiting synergistic toxicity, some specific assays such as apoptosis, nuclear size and shape, clonogenic assay, activities of antioxidant enzymatic enzymes catalase, superoxide dismutase, and levels of glutathione resulted in enhanced toxicity for the mixtures with 1 and 1.75 toxic units (TU) toward both cell types. Data demonstrated that co-presence of Al2O3 and ZnO NPs in the same environment might lead to more realistic environmental conditions. Our findings indicate cytotoxicity of binary mixtures of Al2O3 and ZnO NPs produced greater effects compared to toxicity of either individual compound.

Oncologic Outcomes of Adjuvant versus Salvage Radiotherapy after Prostatectomy.

INTRODUCTION: The benefit of adjuvant radiotherapy (AR) or salvage radiotherapy (SR) after prostatectomy is still unclear. We wanted to compare both types of radiotherapy after prostatectomy in terms of oncological and functional results. METHODS: We included 173 patients treated at a single center between January 2005 and December 2008. All patients were treated with the same radiotherapy protocol (3D conformal radiotherapy accelerator 6 mV, 66 GY). AR was defined as radiotherapy initiated in a patient with a PSA level <0.2 ng/mL after prostatectomy otherwise it was defined as SR. No patients received neoadjuvant therapy prior to prostatectomy (whether hormone therapy or chemotherapy). Patients in the SR group had a PSA level ≥0.2 ng/mL during the treatment in accordance with the Phoenix criteria. The lymph nodes were irradiated if the patient had no lymph node dissection and if the risk of nodal involvement was >10%. Both groups were compared in terms of biological progression-free, metastasis-free, and overall survival (OS) using log-rank tests. Moreover, acute and late urinary and gastrointestinal toxicity were also compared. RESULTS: One hundred and fifty-seven patients underwent an open retropubic prostatectomy whereas 16 underwent a laparoscopy (6 subperitoneal and 10 transperitoneal). Eighty-six patients had AR with a median time of 6.7 months after surgery and 87 had SR with a median time of 21.4 months after surgery. Median follow-up was 6.7 years. Metastasis-free survival (MFS) was better in the AR than in the SR group (p = 0.01, 6-year MFS 95 and 89%, respectively). OS was also better in the AR than in the SR group (p = 0.02, 6-year OS 100 vs. 95%, respectively). AR was associated with better survival with no biochemical recurrence (85 vs. 63%, p < 0.00001). There was no significant difference between groups for acute or late urinary or gastrointestinal toxicity. CONCLUSION: Our study suggests that patients treated by AR have better results in terms of OS, disease-specific survival, survival without metastatic recurrence, and survival without biochemical recurrence compared with SR. Toxicity was comparable between both groups.

Long-term Outcomes and Patterns of Relapse Following High-dose Elective Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Nodes in Prostate Cancer: OLIGOPELVIS (GETUG-P07).

Androgen deprivation therapy (ADT) is a mainstay of treatment for metastatic prostate cancer, while additional salvage radiotherapy may offer prolonged remission for patients with regional node relapses. We report 5-yr outcomes from OLIGOPELVIS (GETUG-P07), an open-label phase 2 trial assessing long-term outcomes and patterns of relapse after 6-mo ADT and elective nodal radiotherapy (ENRT) in men with pelvic nodal oligorecurrence (<6 lesions) of prostate cancer. Progression was defined as two consecutive prostate-specific antigen (PSA) levels above the level at inclusion and/or clinical progression according to Response Evaluation Criteria in Solid Tumors v1.1 and/or death from any cause. Sixty-seven patients were recruited. Median follow-up was 6.1 yr (95% confidence interval 5.9-6.3). Rates of grade 2+ toxicities among patients without progression at 3, 4, and 5 yr were 15%, 9%, and 4% for genitourinary toxicities, and 2%, 3%, and 4% for gastrointestinal toxicities, respectively. The 5-yr progression-free, biochemical relapse-free, and ADT-free survival rates were 39%, 31%, and 64%, respectively. In total, 45 patients experienced progression, which was PSA-only progression in seven cases. Among the other 38 patients, local clinical progression occurred in 18%, progression to N1 stage in 29%, to M1a stage in 50%, to M1b stage in 32%, and to M1c stage in 11%. Finally, combined ENRT and ADT appeared to prolong tumor control with limited toxicity. At 5 yr, one-third of the patients had not experienced biochemical relapse. The major site of relapse was the para-aortic lymph nodes. PATIENT SUMMARY: We evaluated long-term results for high-dose radiotherapy in patients with recurrence of prostate cancer in pelvic lymph nodes. We found that this treatment provided prolonged tumor control without significant toxicity. One-third of the patients were still in complete remission after 5 years.

Individual and combined multigenerational effects induced by polystyrene nanoplastic and glyphosate in Daphnia magna (Strauss, 1820).

In this study, the acute and multigenerational effects of the individual and combined toxicity of polystyrene nanoplastic (PSNP - 15.6, 31.2 62.5, 125, 250 and 500 mg/L) and glyphosate (Gly - 6.2, 12.5, 25, 50, 100 and 200 mg/L) on the freshwater crustacean Daphnia magna were investigated. The acute toxicity interactions were predicted mathematically using Abbott's model and multiple toxicological endpoints. In the multigenerational tests, we evaluated the effects in filial (F1 and F2) generations of daphnids after parental (F0) exposure to Gly and PSNP, as individual compounds and as a mixture, during their life history. Based on Abbott's model, the combined individual toxicities of Gly and PSNP are increased when they are present as a mixture. This indicates synergy between the components of the mixture, especially in the case of co-exposure to Gly and PSNP in higher equitoxic proportions. The mixture of PSNP and Gly caused an increase in immobility and ROS production and decrease in swimming activity. Multigenerational responses indicated that the exposure of F0 daphnids to Gly and PSNP as a mixture induced effects in the F1 and F2 reproduction parameters in the recovery tests. Thus, the results reported herein provide important information on the interaction of hydrophilic organic and nanoplastic pollutants in aqueous ecosystems. This will be useful in future studies on the toxicity of mixtures and multigenerational effects and provide a basis for management decisions aimed at the protection of environmental health.

Chagas Immunochromatographic Rapid Test in the Serological Diagnosis of Trypanosoma cruzi Infection in Wild and Domestic Canids.

Canis lupus familiaris (domestic dog) represents a reliable sentinel for the occurrence of a well-established transmission cycle of Trypanosoma cruzi among wild mammals in the surroundings and, consequently, where the risk of human infection exists. Serological diagnosis is the chosen method to identify T. cruzi infection in dogs that, in Brazil, rarely present positive parasitological tests. The use of recombinant chimeric parasitic antigens results in a sensitive and specific serological diagnostic test in contrast to the use of crude T. cruzi antigens. Our objective was to evaluate the Chagas/Bio-Manguinhos Lateral Flow Immunochromatographic Rapid Test (Chagas-LFRT) for the diagnosis of T. cruzi infection in domestic dogs and the potential of application of this diagnostic platform to wild canid species. Two recombinant proteins (IBMP-8.1 and IBMP-8.4) that displayed the best performance in the enzyme immunoassay (ELISA) in previous studies were tested in a platform with two diagnostic bands. A panel of 281 dog serum samples was evaluated: 133 positive for T. cruzi by serological diagnosis, including 20 samples with positive blood cultures belonging to different discrete typing units (DTUs); 129 negative samples; and 19 samples from dogs infected by other trypanosomatids: Leishmania infantum, Trypanosoma rangeli, Trypanosoma caninum and Crithidia mellificae, in addition to samples infected by Anaplasma platys, Dirofilaria immitis and Erlichia sp. that were employed to evaluate eventual cross-reactions. We also evaluated the Chagas-LFRT to detect T. cruzi infection in 9 serum samples from six wild canid species. We observed that the intensity pattern of the bands was directly proportional to the serological titer observed in IFAT. The sensitivity was 94%, the specificity was 91% according to the ROC curve, and the defined cutoff was an optical density of 4.8. The agreement obtained was considered substantial by the kappa analysis (84%). From T. cruzi positive hemoculture samples, 88.9% were positive by Chagas-LFRT. The test was efficient in recognizing infections by five of the six T. cruzi DTUs. Cross-reactions were not observed in infections by L. infantum, T. rangeli, T. caninum and D. immitis; however, they were observed in sera of dogs infected by Crithidia mellificae, Anaplasma sp. and Erlichia sp. A strong reaction was observed when serum samples from wild canids were submitted to the Protein A affinity test, confirming its applicability for these species. This test will allow rapid preventive actions in areas with high risk to the emergence of Chagas disease in a safer, reliable, low-cost and immediate manner, without the need for more complex laboratory tests.

Phytochemical profile of Brazilian grapes (Vitis labrusca and hybrids) grown on different rootstocks.

Important factors may influence the bioactive compounds in grapes, including scion-rootstock interaction. Therefore, the bioactive compounds and antioxidant activity in grape skin and pulp fractions of 'Isabel Precoce', 'BRS Carmem', 'BRS Cora', 'BRS Violeta' and 'IAC 138-22 Máximo' were assessed. These cultivars, from genetic improvement programs in Brazil, have good adaptation to subtropical and tropical climate conditions, and can be widely used by winegrowers aiming at adding value to the grape. All grapevines were grafted onto 'IAC 766' and 'IAC 572' rootstocks under tropical conditions in Brazil. The highest concentration of bioactive compounds was found in skins of 'BRS Violeta', followed by 'IAC 138-22 Máximo', both grafted onto 'IAC 766'. There was a strong correlation between phenolic content and antioxidant properties, since antioxidant activity also decreased in the sequence: 'BRS Violeta' > 'IAC 138-22 Máximo' > 'BRS Cora' > 'BRS Carmem' > 'Isabel Precoce'. Skin from hybrid grapes ('BRS Violeta', 'IAC 138-22 Máximo', 'BRS Cora' and 'BRS Carmem') grafted in both rootstocks contains higher levels of (poly)phenolic compounds and antioxidant activity than 'Isabel Precoce' (V. labrusca). Skin from 'BRS Violeta' grafted onto 'IAC 766' stand out from the others due to their high content of bioactive compounds.

Case Report: Functional Analysis and Neuropsychological Evaluation of Dyshormonogenetic Fetal Goiter in Siblings Caused by Novel Compound Hyterozygous TPO Gene Mutations.

Introduction: It is rare for a euthyroid mother to carry a child with a fetal goiter. However, cases of congenital hypothyroidism (CH) caused by thyroid dyshormonogenesis have been reported. Even though gene mutations associated with fetal goiter have been reported in a few studies, the effects on intellectual development have not been investigated. This study aimed to characterize and investigate the underlying genetic mechanism of CH and neuropsychological development and growth of two siblings with CH-induced fetal goiters. Case report: Two male siblings from a non-consanguineous marriage with CH and fetal goiter were diagnosed by ultrasonography at 32- and 26-weeks of gestation. This condition was confirmed by cordocentesis in the first pregnancy (TSH: 135 µIU/ml). The mother was euthyroid, and no intra-amniotic levothyroxine treatment was performed. Peripheral blood DNA was screened for TPO mutations. The new deletion p.Cys296Alafs*21 and the p.Arg665Trp mutation, inherited from heterozygous parents, were identified in both patients. Functional analysis showed both mutations reduced the TPO enzyme activity and impaired the membrane localization. The p.Cys296Alafs*21 mutation produces a protein product with a drastically reduced molecular weight. Additionally, a complete clinical and neuropsychological evaluation was also performed. The WISC IV test was employed to provide an overall measure of the siblings' cognitive and intellectual abilities. No growth retardation was detected in either child. In general, both children showed normal neuropsychological development; however, they exhibited slight reduction of Processing Speed Index scores, which are sensitive to neurological and attentional factors and motor maturation activity. Notably, the younger sibling obtained significantly low scores in the Operational Memory Index, a measure of attention capacity and psychoneurological immaturity. Conclusion: We described a new TPO compound heterozygosity that severely impaired the TPO activity and membrane localization leading to severe CH and fetal goiter. This is the first report showing the neuropsychological evaluation in patients with dyshormonogenetic fetal goiter. More studies are needed to understand the neurodevelopmental outcomes of neonates with CH-induced fetal goiters.

Indication and Contraindication of Endoscopic Transforaminal Lumbar Decompression.

BACKGROUND: The indications and contraindications to the endoscopic transforaminal approach for lumbar spinal stenosis are not well defined. METHODS: We performed a Kaplan-Meier durability survival analysis of patients with the following types of spinal stenosis: type I, central canal; type II, lateral recess; type III, foraminal; and type IV, extraforaminal. The 304 patients comprised 140 men and 164 women, with an average age of 51.68 ± 15.78 years. The average follow-up was 45.3 years (range, 18-90 years). The primary clinical outcome measures were the Oswestry Disability Index, visual analog scale, and the modified Macnab criteria. RESULTS: Of 304 study patients, 70 had type I (23.0%) stenosis, 42 type II (13.7%), 151 type III (49.7%), and 41 type IV (13.5%). Excellent outcomes were obtained in 114 patients (37.5%), good in 152 (50.0%), fair in 33 (10.9%), and poor in 5 (1.6%). Kaplan-Meier durability analysis of the clinical treatment benefit with the endoscopic transforaminal decompression surgery showed statistically significance differences (P < 0.0001) on log-rank (Mantel-Cox) χ2 testing between the estimated median (50% percentile) survival times of type I (28 months), type II (53 months), type III (32 months), and type IV (66 months). CONCLUSIONS: We recommend stratifying patients based on the underlying compressive disease and the skill level of the endoscopic spine surgeon to decide preoperatively whether more difficult central or complex foraminal stenotic lesions should be considered for alternative endoscopic approaches.

Crithidia mellificae infection in different mammalian species in Brazil.

Crithidia mellificae, a monoxenous trypanosomatid considered restricted to insects, was recently reported to infect a bat. Herein, C. mellificae has been demonstrated to have a wider range of vertebrate hosts and distribution in Brazilian biomes than once thought. Parasites isolated from haemocultures were characterized using V7V8 SSU rDNA and glyceraldehyde 3-phosphate dehydrogenase genes. Coatis (Nasua nasua) in the Cerrado; marmosets (Callithrix sp.) and bats (Carollia perspicillata, Myotis lavali, M. izecksohni, Artibeus lituratus) in the Atlantic Forest; crab-eating foxes (Cerdocyon thous) and ocelot (Leopardus pardalis) in the Pantanal biomes were infected by trypanosomatids that displayed choanomastigote forms in haemoculture in Giemsa-stained slide smears. Molecular characterization and phylogenetic inference confirmed the infection of C. mellificae in these animals. Moreover, slight differences in C. mellificae sequences were observed. Crithidia mellificae growth curves were counted at 27°C, 36°C and 37°C, and the morphotypes were able to grow and survive for up to 16 days. Serological titers for C. mellificae were observed in nonhuman primates, demonstrating that this parasite is able to induce a humoral immune response in an infected mammal. These results showed that host specificity in trypanosomatids is complex and far from understood.

OLIGOPELVIS GETUG P07, a Multicenter Phase II Trial of Combined High-dose Salvage Radiotherapy and Hormone Therapy in Oligorecurrent Pelvic Node Relapses in Prostate Cancer.

BACKGROUND: Oligorecurrent pelvic nodal relapse in prostatic cancer is a challenge for regional salvage treatments. Androgen depriving therapies (ADTs) are a mainstay in metastatic prostate cancer, and salvage pelvic radiotherapy may offer long ADT-free intervals for patients harboring regional nodal relapses. OBJECTIVE: To assess the efficacy of the combination of ADT and salvage radiotherapy in men with oligorecurrent pelvic node relapses of prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: We performed an open-label, phase II trial of combined high-dose intensity-modulated radiotherapy and ADT (6 mo) in oligorecurrent (five or fewer) pelvic node relapses in prostate cancer, detected by fluorocholine positron-emission tomography computed tomography imaging. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 2-yr progression-free survival defined as two consecutive prostate-specific antigen levels above the level at inclusion and/or clinical evidence of progression as per RECIST 1.1 and/or death from any cause. RESULTS AND LIMITATIONS: Between August 2014 and July 2016, 67 patients were recruited in 15 centers. Half of the patients had received prior prostatic irradiation. The median age was 67.7 yr. After a median follow-up of 49.4 mo, 2- and 3-yr progression-free survival rates were 81% and 58%, respectively. Median progression-free survival was 45.3 mo. The median biochemical relapse-free survival (BRFS) was 25.9 mo. At 2 and 3 yr, the BRFS rates were 58% and 46%, respectively. Grade 2 + 2-yr genitourinary and gastrointestinal toxicities were 10% and 2%, respectively. CONCLUSIONS: Combined high-dose salvage pelvic radiotherapy and ADT appeared to prolong tumor control in oligorecurrent pelvic node relapses in prostate cancer with limited toxicity. After 3 yr, nearly half of patients were in complete remission. Our study showed initial evidence of benefit, but a randomized trial is required to confirm this result. PATIENT SUMMARY: In this report, we looked at the outcomes of combined high-dose salvage pelvic radiotherapy and 6-mo-long hormone therapy in oligorecurrent pelvic nodal relapse in prostatic cancer. We found that 46% of patients presenting with oligorecurrent pelvic node relapses in prostate cancer were in complete remission after 3 yr following combined treatment at the cost of limited toxicity.

Durability of Endoscopes Used During Routine Lumbar Endoscopy: An Analysis of Use Patterns, Common Failure Modes, Impact on Patient Care, and Contingency Plans.

BACKGROUND: Successful implementation of endoscopic spinal surgery programs hinges on reliable performance and case cost similar to traditional decompression surgeries of the lumbar spine. MATERIALS AND METHODS: To improve the statistical power of studying the durability of endoscopes with routine lumbar endoscopy, the authors performed a retrospective survey study among endoscopic spine surgeons by email and chat groups on social media networks WhatsApp and WeChat. Descriptive and correlative statistics were done on the surgeon's responses recorded in multiple-choice questions. Surgeons were asked about their clinical experience with spinal endoscopy, training background, the types of lumbar endoscopic decompression they perform by approach, their preferred decompression instruments, and their experience with endoscopic equipment failure. RESULTS: A total of 485 surgeons responded, of whom 85 submitted a valid survey recording, rendering a completion rate of 27.1%. These 85 respondents reported a case volume of 12,650 lumbar endoscopies within the past year and, to date, had performed a total of 120,150 spinal endoscopies over their collective career years. The majority of respondents performed endoscopic surgery for herniated disc (65.9%) vs spinal stenosis (34.1%) in a hospital setting, preferentially employing the transforaminal (76.5%), interlaminar (51.8%), and unilateral biportal endoscopic (UBE; 15.3%) approach technique. The most commonly used endoscopic spine systems were Wolf/Riwo Spine (38.8%), Joimax (36.5%), Storz (24.7%), unspecified Chinese brand (22.4%), Maxmore (15.3%), Spinendos (12.9%), Elliquence (10.6%), unspecified Korean brand (7.1%), and asap Endosystems GmbH (2.4%). The most frequent failure mode of the endoscope reported by survey respondents was a blurry image (71.8%), followed by the loss of focus (21.2%), the loss of illumination of the surgical site (18.8%), and the failure of the irrigation/suction system integrated into the endoscope (4.7%). Most respondents thought they had problems with the lens (67.1%), the fiberglass light conductor (23.5%), the prism (16.5%), or the rod system (4.7%). Motorized high-speed power burrs and hand reamers and trephines were the reported favorite decompression tools that were presumably associated with the endoscope's failure. The majority of respondents (49.5%) performed up to 50 endoscopies before the endoscope had to be either exchanged or repaired. Another 15.3% of respondents reported their endoscope lasted between 101 and 200 cases and only 12.9% reported more than 300 cases. Besides abuse during surgery (25.9%), bad handling by staff was the most common suspected reason (45.9%), followed by the wrong sterilization technique (21.2%). Some 23.5% of respondents noted that the endoscope failed during their surgery. In that case, 66.3% asked for a replacement endoscope, and 36.1% completed the surgery with the broken endoscope. However, 10.8% stopped and another 6% of respondents woke the patient up and rescheduled the surgery to complete the decompression at another time. CONCLUSIONS: Spinal endoscopes used during routine lumbar decompression surgeries for herniated disc and spinal stenosis have an estimated life cycle between 50 and 100 surgeries. Abusive use by surgeons, mishandling by staff, and deviation for prescribed cleaning and sterilization protocols may substantially shorten the life cycle. Contingency protocols should be in place to readily replace a broken spinal endoscope during surgery. More comprehensive implementation of endoscopic spine surgery techniques will hinge on technology advancements to make these hightech surgical instruments more resistant to the stress of daily use and abuse of expanded clinical indications' for surgery. The regulatory burden on endoscope makers is likely to increase, calling for increased reimbursement for facilities to cover the added expense for capital equipment purchase, disposables, and the endoscopic spine surgery program's maintenance. LEVEL OF EVIDENCE: 3. CLINICAL RELEVANCE: End user surgeon survey study.

Multigenerational Toxic Effects on Daphnia magna Induced by Silver Nanoparticles and Glyphosate Mixture.

Multigenerational toxicological effects of a binary mixture of silver nanoparticles (AgNPs) with glyphosate were identified in Daphnia magna using acute and chronic toxicity tests. Acute toxicity interactions were analyzed with the Abbott method. In the chronic tests, the survival, growth, reproduction, and age at first brood were evaluated for the parents and the exposed (F1E) and non-exposed (F1NE) descendants. The scales tested for binary mixture, at the acute level, presented antagonistic and additive interactions, possibly associated with the complexation of the AgNPs by glyphosate. Multigenerational chronic effects related to the parameters, reproduction, and age at first brood were observed in the descendants tested with the individual compounds, with no recovery for F1E and F1NE. In organisms exposed to binary mixture, there was a delay in the age at first brood and also a significant change in the reproduction parameter, with a strong reduction for the parents, F1E, and F1NE, indicating a higher toxicity than the compounds tested individually. Although the results for acute interactions between AgNP and glyphosate did not provide clear evidence, multigenerational chronic binary mixture trials have resulted in unexpected toxicity compared with individual treatments, increasing the concerns associated with this co-exposure in other scenarios. Therefore, the interaction of binary mixture with the organisms merits further investigation and the results reported in the present study will be useful in this regard. Environ Toxicol Chem 2021;40:1123-1131. © 2020 SETAC.

Dural Tears During Lumbar Spinal Endoscopy: Surgeon Skill, Training, Incidence, Risk Factors, and Management.

BACKGROUND: Incidental dural tears during lumbar endoscopy can be challenging to manage. There is limited literature on their appropriate management, risk factors, and the clinical consequences of this typically uncommon complication. MATERIALS AND METHODS: To improve the statistical power of studying durotomy with lumbar endoscopy, we performed a retrospective survey study among endoscopic spine surgeons by email and chat groups on social media networks, including WhatsApp and WeChat. Descriptive and correlative statistics were done on the surgeons' recorded responses to multiple-choice questions. Surgeons were asked about their clinical experience with spinal endoscopy, training background, the types of lumbar endoscopic decompression they perform by approach, the decompression instruments they use, and incidental durotomy incidence with routine lumbar endoscopy. RESULTS: There were 689 dural tears in 64 470 lumbar endoscopies, resulting in an incidental durotomy incidence of 1.07%. Seventy percent of the durotomies were reported by 20.4% of the surgeons. Eliminating these 19 outlier surgeons yielded an adjusted durotomy rate of 0.32. Endoscopic stenosis decompression (54.8%; P < .0001), rather than endoscopic discectomy (44.1%; 41/93), was significantly more associated with durotomy. Medium-sized dural tears (1-10 mm) were the most common (52.2%; 48/93). Small pinhole durotomies (less than 1 mm) were the second most common type (46.7%; 43/93). Rootlet herniations were seen by 46.2% (43/93) of responding surgeons. The posterior dural sac injury during the interlaminar approach (57%; 53/93) occurred more frequently than traversing nerve-root injuries (31.2%) or anterior dural sac (23.7%; 22/93). Exiting nerve-root injuries (10.8%;10/93) were less common. Over half of surgeons did not attempt any repair or closure (52.2%; 47/90). Forty percent (36/90) used sealants. Only 7.8% (7/90) of surgeons attempted an endoscopic repair or sutures (11.1%; 10/90). DuralSeal was the most commonly used brand of commercially available sealant used (42.7%; 35/82). However, other sealants such as Tisseal (15.9%; 13/82), Evicel (2.4%2/82), and additional no-brand sealants (38; 32/82) were also used. Nearly half of the patients (48.3%; 43/89) were treated with 24-48 hours of bed rest. The majority of participating surgeons (64%; 57/89) reported that the long-term outcome was unaffected. Only 18% of surgeons reported having seen the development of a postoperative cerebrospinal fluid (CSF)-fistula (18%;16/89). However, the absolute incidence of CSF fistula was only 0.025% (16/64 470). Severe radiculopathy with dysesthesia; sensory loss; and motor weakness in association with an incidental durotomy were reported by 12.4% (11/89), 3.4% (3/89), and 2.2% (2/89) of surgeons, respectively. CONCLUSIONS: The incidence of dural tears with lumbar endoscopy is about 1%. The incidence of durotomy is higher with the use of power drills and the interlaminar approach. Stenosis decompression that typically requires the more aggressive use of these power instruments has a slightly higher incidence of dural tears than does endoscopic decompression for a herniated disc. Most dural tears are small and can be successfully managed with mechanical compression with Gelfoam and sealants. Two-thirds of patients with incidental dural tears had an entirely uneventful postoperative course. The remaining one-third of patients may develop a persistent CSF leak, radiculopathy with dysesthesia, sensory loss, or motor function loss. Patients should be educated preoperatively and reassured. LEVEL OF EVIDENCE: 3.