Overall Survival and Response with Nivolumab and Relatlimab in Advanced Melanoma.

BACKGROUND: A phase 2/3 trial ­ A Study of Relatlimab Plus Nivolumab Versus Nivolumab Alone in Participants With Advanced Melanoma (RELATIVITY-047) ­ evaluated nivolumab + relatlimab as a fixed-dose combination and found a significant progression-free survival (PFS) benefit over nivolumab monotherapy in previously untreated unresectable or metastatic melanoma. We now report updated PFS and safety data and the first results for overall survival (OS) and objective response rate (ORR). METHODS: Patients were randomly assigned 1:1 to receive nivolumab 480 mg and relatlimab 160 mg fixed-dose combination or nivolumab 480 mg alone, given intravenously every 4 weeks. PFS (primary end point) according to the Response Evaluation Criteria in Solid Tumors, version 1.1, was assessed by blinded independent central review (BICR). Secondary end points, tested hierarchically, were OS and then ORR per Response Evaluation Criteria in Solid Tumors, version 1.1, per BICR. RESULTS: At a median follow-up of 19.3 months, median PFS according to BICR was 10.2 months (95% confidence interval [CI], 6.5 to 14.8) with nivolumab + relatlimab versus 4.6 months (95% CI, 3.5 to 6.4) with nivolumab (hazard ratio, 0.78; 95% CI, 0.64 to 0.94). Median OS was not reached (NR) (95% CI, 34.2 to NR) with nivolumab + relatlimab versus 34.1 months (95% CI, 25.2 to NR) with nivolumab (hazard ratio, 0.80; 95% CI, 0.64 to 1.01; P=0.059) (prespecified value for statistical significance, P≤0.043). ORRs per BICR were 43.1% (95% CI, 37.9 to 48.4) versus 32.6% (95% CI, 27.8 to 37.7), respectively. Grade 3/4 treatment-related adverse events were observed in 21.1% of patients treated with nivolumab + relatlimab versus 11.1% treated with nivolumab. CONCLUSIONS: The fixed-dose combination of nivolumab + relatlimab showed consistent PFS benefit versus nivolumab with approximately 6 months of additional median follow-up. The combination treatment did not reach the preplanned statistical threshold for OS, with a 10.3 percentage-point difference in ORR. Grade 3/4 treatment-related adverse events were more frequent with nivolumab + relatlimab versus nivolumab. (Funded by Bristol Myers Squibb; ClinicalTrials.gov number, NCT03470922.)

Financial Incentives, Not Behavioral Nudges, Led to Optimized HIV Testing among Pregnant Women in a High-Burden Urban Population in Ecuador.

Behavioral economic principles are increasingly being used in the fight against HIV, including improving voluntary testing in sub-Saharan Africa and South America. However, behavioral nudges have not been widely tested as a strategy to optimize HIV testing in pregnant women. Here, we assessed whether behavioral nudges or financial incentives were effective in optimizing HIV testing among pregnant women in a high-HIV burden setting. A randomized clinical trial was conducted between May 21 and Oct 5, 2018, to allocate pregnant women in Ecuador into three study arms: information only, soft commitment (i.e., a behavioral nudge), and financial incentives. All participants received an informational flyer, including the address of a testing location. Participants in the soft-commitment arm signed and kept a form on which they committed to get tested for HIV. Those in the financial incentive arm received a $10 incentive when tested for HIV. A stepwise logistic regression analysis estimated the effect of the study arms on HIV testing rate. Participants in the financial-incentive arm had higher odds of getting an HIV test (adjusted odds ratio 17.06, P < 0.001) as compared with information-only participants. Soft-commitment had the opposite effect (adjusted odds ratio 0.14, P = 0.014). Financial incentives might be useful in improving HIV testing among pregnant women, especially among those who might be at higher risk but who have not completed an HIV test.

Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma.

BACKGROUND: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation. METHODS: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group. CONCLUSIONS: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).

Malocclusion Management Following Mandibular Reconstruction With Free Fibula Flaps.

STUDY DESIGN: Free fibula flaps are nowadays the gold standard for the surgical reconstruction on large mandibular defects. Malocclusion is an important complication of this type of reconstruction and many of these patients end up requiring subsequent orthognathic corrective surgery. This is a descriptive retrospective case series study. OBJECTIVE: To describe the demographic data, operative techniques, corrective methods and postoperative results in the management of malocclusion following mandibular reconstruction with free fibula flap. METHODS: This case series study included patients who underwent free fibula flap mandibular reconstructions and who that subsequently developed malocclusion requiring orthognathic corrective surgery, from June 2010 to December 2019. Panoramic X-rays, cephalometries and/or 3-D facial reconstruction CT scans were used for surgical planning to create surgical cutting guides, templates and occlusal splints in all the patients that underwent corrective orthognathic surgery. RESULTS: There were 46 patients who underwent a free fibula flap mandibular and maxillary reconstruction at San Jose Hospital between June 2010 and December 2019 of these, 5 patients (10.9%) developed postoperative malocclusion. One case from another institution was added to this study for a total of 6 patients with malocclusion following mandibular reconstruction surgery with a fibula free flap. During the orthognathic surgery, vertical osteotomies were performed in 3 patients and bilateral sagittal split osteotomies were necessary in 2 patients and L-shape in 1 patient. Osteogenic distraction was performed in 3 patients as part of their orthognathic treatment. The fixation methods were based in miniplates for 3 of the patients and lag screws for the remaining 3 patients. With this approach, all patients had an adequate occlusion correction with a 100% consolidation at their 6-month follow up. CONCLUSION: Malocclusion is a significant complication following mandibular reconstruction surgery that must be identified and managed. In severe cases, it requires corrective orthognathic surgery in severe cases. We have developed a protocol to avoid pitfalls during the primary reconstruction and in case an orthognathic surgery is required for malocclusion correction, preoperative planning with cutting guides and occlusal splints should be assessed, to guarantee favorable results through a reproducible technique.

Comparison of lithium to second generation antipsychotics for the treatment of bipolar disorder in older veterans.

Approximately 25% of all adults with bipolar disorder are over the age of 65. Literature in older age bipolar disorder is sparse and typically extrapolated from data in younger adults. This retrospective cohort study included patients 65-89 years of age with bipolar I or II disorder who were prescribed lithium or SGA treatment. Primary efficacy outcome was defined as time to discontinuation of treatment and numerous secondary safety outcomes were included such as adverse effects; lab changes; mental health related hospitalizations; and death. No difference was found between the lithium group and the SGA group in days until discontinuation.

Using Incentives and Nudging to Improve Non-Targeted HIV Testing in Ecuador: A Randomized Trial.

Under-detection of HIV/AIDS still burdens many low- and middle-income countries (LMICs). Our randomized trial investigated the effects of financial incentives and a behavioral nudge to induce HIV testing and learning HIV status in Ecuador. In the control group, 12.2% of participants agreed to testing, and 5.3% learned results. A financial incentive paid at testing increased the fraction of participants tested by 50.1 percentage points (95% CI 38.8 to 61.4) and the fraction who learned their status by 8.9 percentage points (95% CI 5.3 to 12.5); the nudge had no effect. The HIV-positive rate was 1.2% in the control group, and incentives prompted a 4.7 percentage point (95% CI 0.5 to 8.9) higher proportion of HIV-positive detection. Incentives also induced earlier testing, suggesting reduced procrastination. This suggests that information with appropriately timed small financial incentives can improve HIV testing and detection of new cases in the general population in LMIC settings.

Exploitation of Agro-Industrial Waste as Potential Source of Bioactive Compounds for Aquaculture.

The agroindustry generates a large amount of waste. In postharvest, food losses can reach up to 50%. This waste represents a source of contamination of soil, air, and bodies of water. This represents a problem for the environment as well as for public health. However, this waste is an important source of bioactive compounds, such as phenolic compounds, terpenes, and ß-glucans, among others. Several biological activities have been attributed to these compounds; for example, antioxidant, antimicrobial, gut microbiota, and immune system modulators. These properties have been associated with improvements in health. Recently, the approach of using these bioactive compounds as food additives for aquaculture have been addressed, where it is sought that organisms, in addition to growing, preserve their health and become disease resistant. The exploitation of agro-industrial waste as a source of bioactive compounds for aquaculture has a triple objective-to provide added value to production chains, reduce pollution, and improve the well-being of organisms through nutrition. However, to make use of the waste, it is necessary to revalue them, mainly by determining their biological effects in aquaculture organisms. The composition of bioactive compounds of agro-industrial wastes, their biological properties, and their application in aquaculture will be addressed here.

Identification of descriptors for structure-activity relationship in ruthenium (II) mixed compounds with antiparasitic activity.

Herein is presented the synthesis, characterization, electrochemical studies, DFT calculations and in vitro evaluation of amoebicidal activity in trophozoites of Entamoeba histolytica of twenty ruthenium (II) mixed compounds with general formulae: [Ru(pdto)(E-E)]Clx (E-E bidentate, either neutral or negatively charged ligands). For compounds under study, O-O, N-O and N-N auxiliary donor ligands demonstrate to have a crucial impact on the electronic properties and that it is possible to modulate the antiparasitic activity. Among analyzed complexes, only four present a better performance compared to typically used metronidazole drug (IC50 < 6.80 µmol/L) to treat amebiasis disease. For studied compounds, structure-activity relationships are strongly determined by either the redox potential (E1/2) of RuII/RuIII and calculated molar volume (V) of the complexes.

Competing actors in the climate change arena in Mexico: A network analysis.

This paper analyzes the actors in the climate change arena and their influence in directing Mexico toward policies that decrease greenhouse gas emissions, such as the carbon tax and climate change law. The network analysis of the agreement of these laws and public policies in Mexico is a lesson for any country that is in the process of designing and adopting environmental laws. The research is performed using a network analysis that is derived from interviews with various main actors and a discourse analysis of the media. Results show that actors do not coordinate their efforts-they meet frequently but in different inter-ministerial commissions-and do not enforce the same policies. The actors in the industry have formed strong coalitions against the carbon tax and the General Law on Climate Change, whereas international institutions have formed coalitions that support these policies and laws.

Avaliação físico-química e sensorial de vinho de jabuticaba submetido a tratamento de radiação gama / Physical-chemical and sensorial evaluation of jaboticaba wine subjected to gamma radiation treatment

A jabuticaba é uma fruta tropical, tipicamente brasileira, sendo originária da região centro-sul. Popularmente apreciada por suas características sensoriais in natura, mas também pela utilização em produtos processados como geleias, licores e bebidas fermentadas (SASSO; CITADIN; DANNER, 2010). Apesar da designação vinho referir- -se segundo a Lei nº 7.678, de 08 de novembro de 1988 (BRASIL, 1988) como "bebida proveniente da fermentação alcoólica de mosto de uva sã, fresca e madura", é permitido pela Portaria Nº 64, de 23 de abril de 2008 a produção de vinhos de outras frutas (BRASIL, 2008), desde que se indique o nome da fruta no rótulo após a palavra vinho, como por exemplo vinho de jabuticaba.(AU)

Effect of exposure to p,p´-DDE during the first half of pregnancy in the maternal thyroid profile of female residents in a Mexican floriculture area.

BACKGROUND: Dichlorodiphenyldichloroethene (p,p´-DDE), the main metabolite of dichlorodiphenyltrichloroethane (DDT), has been associated with changes in human thyroid hormone levels. Maternal thyroid hormones are essential for adequate fetal neurodevelopment during the first half of pregnancy. OBJECTIVE: To evaluate the association between maternal p,p´-DDE concentration and the maternal thyroid profile during the first half of pregnancy. MATERIALS AND METHODS: We analyzed the information of 430 pregnant women from a Mexican floriculture area, with a gestational age ≤16 weeks. By questionnaire, we obtained sociodemographic, reproductive, and life-style, information. Serum concentrations of thyroid stimulating hormone (TSH), and total and free T3 and T4 were determined by means of Enzyme-Linked ImmunoSorbent Assay (ELISA). p,p´-DDE was analyzed by Gas Chromatography. The association between p,p´-DDE and thyroid profile was assessed through linear and logistic regression models. RESULTS: Thirty eight percent of women had p,p´-DDE levels below the Limit of Detection and 12.3% below the Limit of Quantification. Within the quantifiable range, median was 53.03ng/g. TSH >2.5 mIU/L was present in 9.3% of women; 47.7% had isolated hypothyroxinemia; 3.5% had subclinical hypothyroidism, and 5.8% had overt hypothyroidism. We observed a significant positive association between quantifiable p,p´-DDE and total T3 serum levels in comparison with those with concentrations below the Limit of Detection (ß=0.19; 95% CI=0.06, 0.34). There were no significant associations with other hormones of the thyroid profile or with clinical diagnosis. CONCLUSIONS: Our findings suggest that p,p´-DDE exposure, even at low concentrations, could disrupt thyroid homeostasis during pregnancy.

Optimization of Postharvest Conditions To Produce Chocolate Aroma from Jackfruit Seeds.

Jackfruit seeds are an underutilized waste in many tropical countries. This work demonstrates the potential of roasted jackfruit seeds to develop chocolate aroma. Twenty-seven different roasted jackfruit seed flours were produced from local jackfruit by acidifying or fermenting the seeds prior to drying and then roasting under different time/temperature combinations. The chocolate aroma of groups of four flours were ranked by a sensory panel (n = 162), and response surface methodology was used to identify optimum conditions. The results indicated a significant and positive influence of fermentation and acidification on the production of chocolate aroma. SPME/GC-MS of the flours showed that important aroma compounds such as 2,3-diethyl-5-methylpyrazine and 2-phenylethyl acetate were substantially higher in the fermented product and that the more severe roasting conditions produced 2-3 times more 2,3-diethyl-5-methylpyrazine, but less 3-methylbutanal. Moisture, aw, pH, luminosity, and color were also monitored to ensure that these properties were similar to those of cocoa powder or cocoa substitutes.

A comparison of three dispersion media on the physicochemical and toxicological behavior of TiO2 and NiO nanoparticles.

UNLABELLED: Nanomaterials represent a burgeoning field of technological innovation. With the onset of environmental release and commercial product exposure associated with nanomaterial manufacture and proliferation, the concomitant effects on human health remain unknown and demand further investigation. Agglomeration of nanomaterials in biologically relevant media used in in vitro methods further complicates dosing in toxicological study. OBJECTIVE: to compare the effects of in vitro dispersion techniques on the physicochemical and toxicological dosimetry of TiO2 (<50 nm) and NiO (<20 nm) nanoparticles and some resulting toxicological endpoints to test for potential effects. METHODS: three media were prepared for A549 and 16hbe14o cells with varying concentrations of TiO2 and NiO nanoparticles. Physicochemical effects were analyzed with dynamic light scattering, ICP-MS, SEM, and TEM. Toxicological effects were determined after stimulation of cells with nanoparticles for 4 and 24h followed by analysis of inflammatory and oxidative stress markers with ELISA and RT-PCR. Our data show that dispersion media differentially affect physicochemical properties and toxicological endpoints. Therefore, we conclude that in vitro nanotoxicology models that use re-suspension methods of exposure yield inconsistent and misleading biological results due to physicochemical variation of particle characteristics and transport processes.

Composição físico-química e sensorial de nhoque com farinha de soja e farelo de aveia armazenado sob congelamento / Physico-chemical composition and sensorial characteristics of a gnocchi prepared with soy flour and oat bran, stored frozen

The possibility of preventing diseases by means of diet has interested thefood industry to elaborate products with functional foods. Among these,the soybeans contain isofl avones and oat contains soluble fi bers. Both are nutritious foods which can be ingredients to traditional products. The pastas are products of good acceptance and take part in the traditional eating habits of the population. When prepared with mixed fl ours, they need to maintain: acceptable color, good texture, pleasant taste and little loss of solids during cooking. The aim of this study was to prepare gnocchi with soy fl our and oat bran in order to obtain a frozen pre-processed pasta and assess its sensorial, physico-chemical and nutritional characteristics during preparation and storage. To prepare this gnocchi, six formulations with wheat fl our, durum semolina, soy fl our, oat bran or oat fl our were tested. The F6 formulation, which had better acceptance among others with oat bran, was chosen for quality control (pH, acid index, Aw) and sensorial analyses after periods of 0, 30, 60 and 90 days of storage. A little increase in acidity (from 0.31 to 0.46) was observed, whilst no change in pH and Aw was observed during storage. It was also observed that the gnocchi had good acceptance after 90 days of storage when the proportion of potato/ flour blend was 1.6/1. The fl our blend consisted of 10% wheat fl our, 40% durum semolina, 25% soy fl our and 25% oat bran.

La posibilidad de prevenir enfermedades a travésde la dieta dio lugar a la preocupación de laindustria alimenticia en elaborar productos queutilicen alimentos funcionales. Entre estos, lasoya contiene isofl avonas y la avena las fi brassolubles, alimentos nutritivos que pueden seringredientes de productos tradicionales. Lasmasas alimenticias son productos de buenaaceptación que hacen parte del hábito alimentartradicional de la población, y, cuando elaboradascon harina mixta, deben mantener: coloraceptable, buena textura, sabor agradable y bajapérdida de sus sólidos durante el cocimiento. Elobjetivo de este estudio fue elaborar un ñoqui conharina de soya y salvado de avena para obteneruna masa preprocesada congelada y evaluarsus características sensoriales, físico-químicasy nutricionales durante la producción y elalmacenamiento. En la elaboración del ñoquifueron utilizadas seis fórmulas compuestasde harina de trigo, sémola, harina de soyay salvado o harina de avena, en diferentesconcentraciones. La fórmula F6 fue la que tuvomayor aceptación entre las muestras con salvadode avena y fue la escogida para la realizaciónde las análisis de control de calidad (pH, acidezy actividad de agua) y sensorial en los períodosde 0, 30, 60 y 90 días de almacenamiento. Elanálisis de acidez mostró un pequeño aumento,de 0,31 para 0,46. El pH y la Aw no se alterarondurante el almacenamiento, y fue verifi cada unabuena aceptación del ñoqui, en la proporción1,6:1 papas/mezcla de harinas (10%, 40%, 25%y 25%), respectivamente, trigo, sémola, harina desoya y salvado de avena durante 90 días.

A possibilidade de prevenir doenças por meioda dieta tem atraído a atenção das indústriasde alimentos para elaboração de produtos queutilizem alimentos funcionais. Dentre estes,a soja contém isofl avonas e a aveia as fi brassolúveis, alimentos nutritivos que podem seringredientes de produtos tradicionais. As massasalimentícias são produtos de boa aceitação efazem parte do hábito alimentar tradicional dapopulação; e, quando elaboradas com farinhasmistas devem manter: cor aceitável, boa textura,sabor agradável e baixa perda de sólidos duranteo cozimento. O objetivo desse estudo foi elaborarum nhoque com farinha de soja e farelo deaveia, a fi m de obter uma massa pré-processadacongelada e avaliar as características sensoriais,físico-químicas e nutricionais durante aprodução e armazenamento. Para a elaboraçãodesse nhoque foram utilizadas seis formulaçõesà base de farinha de trigo, semolina, farinha desoja, farelo ou farinha de aveia em diferentesconcentrações. A formulação F6, por ter tidomaior aceitação entre as amostras com farelo deaveia, foi escolhida para realização da análisede controle de qualidade (pH, acidez e atividadede água) e análise sensorial nos períodos de 0,30, 60 e 90 dias de armazenamento. Observou-separa a análise de acidez um pequeno aumentode 0,31 para 0,46, já para pH e Aw não ocorreuvariação durante o armazenamento, e foiverifi cada uma boa aceitação do nhoque, naproporção 1,6:1 batata/misturas de farinhas(10% farinha de trigo, 40% semolina, 25%farinha de soja e 25% farelo de aveia) após 90 dias de estocagem.

Desgastes oclusales en dientes ancestrales / Oclusales abrasions in ancients teeth

Se investigó los patrones de abrasiones oclusales en dientes de diez y seis indios Changos que vivieron entre los siglos VII y XII D.C en la costa de norte chileno, cuyos cráneos se rescataron desde sitios arqueológicos en Mejillones y Antofagasta. Se utilizó la escala Molnar para determinar el grado de abrasión oclusal en dientes permanentes Los resultados sugieren que en la alimentación de estos habitantes existió una alta proporción de partículas abrasivas (arena), no registrándose evidencias que estas abrasiones se deban al uso de la dentadura como herramienta. También debió haber ocurrir un cambio en el sistema neuromuscular del sistema estomatognático, generándose una mordida bis a bis, transformado la curva de Spee hasta llegar a desaparecer. En la mayoría de las dentaduras no se observan caries y muestran sus terceros molares erupcionados.

Patterns of occlusional abrasions were studied in teeth from skulls of 16 indigenous inhabitants ("Changos") from northern Chile living in the VIII and the XII centuries AD. The skulls were obtained from archeological sites in Mejillones and Antofagasta (23º5'S). The Molnar scale was used to determine the degree of occlusional abrasion of permanent teeth. The results suggested a high proportion of abrasional material (sand) occurred in the diets of these people, and no evidence was found of abrasion due to using the teeth as tools. Also, there must have been a change in the stomatognathic neuromuscular system, producing a "bis to bis"bite, thus transforming the Spee curve until its nearly complete disappearance. No caries were observed in a majority of the dentitions, and most had the third molar erupted.

Sunflower seed protein concentrates and isolates obtention from ethanol oil extraction meals (Technical note) / Obtención de concentrados y aislados proteicos de harinas de semillas de girasol tratadas con alcohol etílico

The objetive of this work was to study and identify the necessary processing step for obtaining good quality sunflowerseed protein concentrate isolate when the oil is extracted with ethanol. This work is part of a research on using ethanol as renewable solvent for sunflower seed oil recovery and possible further processing of the meal. Both 99ºGL and 90ºGL ethanol were employed in the extractions to produce the concentrate. Isolates were obtained by treating the concentrate with NaOH and HCI solutions and final rinsing with acidified water. Both products were light in color and almost free from chlorogenic acid