First-in-human stage III/IV melanoma​ clinical trial of immune priming agent IFx-Hu2.0.

IFx-Hu2.0 was designed to encode part of the Emm55 protein contained within a plasmid in a formulation intended for transfection into mammalian cells. IFx-Hu2.0 promotes both adaptive and innate immune responses in animal studies. Furthermore, previous studies have demonstrated safety/efficacy in equine, canine, and murine species. We present the first-in-human study of IFx-Hu2.0, administered by intralesional injection into melanoma tumors of seven patients with stage III/IV unresectable melanoma. No dose-limiting toxicities attributable to IFx-Hu2.0 were observed. Grade 1/2 injection site reactions were observed in five of seven patients. IgG and IgM responses were seen in the peripheral blood to Emm55 peptides and known melanoma antigens, suggesting that IFx-Hu2.0 acts as an individualized "in-situ vaccine." Three of four patients previously refractory to anti-PD1 experienced clinical benefit upon subsequent anti-PD1-based treatment. Therefore, this approach is feasible, and clinical/correlative outcomes warrant further investigation for treating metastatic melanoma patients as an immune priming agent.

Diet Digestibility and Partitioning of Nutrients in Adult Male Alpacas Fed a Blend of Oat Hay and Alfalfa Pellets at Two Levels of Intake.

Alpacas are well adapted to consume the poor-quality forages present in the arid conditions of the Andean Altiplano. However, studies focusing on understanding the relationship between diet digestibility and intake are scarce. The aim of this study was to evaluate the effects of two levels of dry matter intake (DMI) on a metabolic body weight (BW0.75) basis. The effects of a maintenance level of intake and an ad libitum level of intake (40 and 50 g of dry matter (DM) per kg of BW0.75, respectively) on the apparent diet digestibility and partitioning of specific nutrients (energy, carbon (C), and nitrogen (N)) of alpacas that were fed a blend of oat hay and alfalfa pellets (70:30 ratio as a percentage on a fed basis) were evaluated. Five adult intact male alpacas (BW = 62.9 ± 8.09 kg at the beginning of the study) were fed with the experimental diet and trained to be allocated in metabolism crates for 30 days. After the completion of this phase, two separate experiments for each level of intake were carried out, each lasting for twenty-six days (with the final five days taken for samples and raw data collection). In both experiments, the animals responded differently in terms of nutrient supply and changes in BW (-140 and 100 g/d for the maintenance and ad libitum levels of intake, respectively). Oat hay consumption was rather similar in both experiments, which may be explained by a reduced ingredient selectivity at the ad libitum level of intake. Diet digestibility was similar in both experiments, despite the greater fecal output of nutrients with the increased level of diet intake. In line with this, diet metabolizability, calculated as the ratio between metabolizable energy (ME) and gross energy (GE) contents, indicated a similar energy utilization of the diet. The apparent digestibility of the organic matter (OMD) ranged from 655 to 669 g/kg DM. Water consumption at the ad libitum level of intake was 21% higher than the observed mean at the maintenance level of intake. Fecal outputs of dietary energy, C, and N accounted for the largest source of excreted nutrients, regardless of the level of intake. The N retention increased from 0.439 at the maintenance level of intake, to 0.473 g of DM/kg BW0.75 when the alpacas were fed ad libitum.

PROTOCOL: In-person interventions to reduce social isolation and loneliness: An evidence and gap map.

This is the protocol for an evidence and gap map. The objectives are as follows: This EGM aims to map available evidence on the effects of in-person interventions to reduce social isolation and/or loneliness across all age groups in all settings.

Readability and Suitability of Spanish-Language Hearing Aid User Guides.

Purpose The purpose of this study was to evaluate the readability and suitability of Spanish-language hearing aid user guides. Method Hearing aid user guides in English and Spanish were downloaded for analysis. Readability for the English guides was calculated using the Flesch Reading Ease Scale and the Flesch-Kincaid Readability Formula, and readability for the Spanish guides was calculated using the Fernandez-Huerta and Spaulding Formula and Fry Graph. The Suitability Assessment of Materials was used to rate the suitability of each Spanish and English pair of hearing aid user guides. Results Of the nine manufacturers that had materials available in English, only five had guides available in Spanish. Although readability for the Spanish and English user guides was similar, both guides were written, on average, at the eighth grade level. Suitability for the analyzed Spanish and English user guides was 78% and 80%, respectively. Conclusions Spanish-language hearing aid user guides were lacking in readability and suitability. Given that patients with limited proficiency in English, including the Hispanic population, are at risk for low health literacy, providers and manufacturers are encouraged to create more Spanish-language materials. User guides in both languages would benefit from revisions to improve readability and suitability. Supplemental Material https://doi.org/10.23641/asha.14569497.

Energy Requirements of Beef Cattle: Current Energy Systems and Factors Influencing Energy Requirements for Maintenance.

The present review compared features of the UK system for predicting energy requirements in beef cattle with a number of feeding systems developed from research institutes consortiums around the world. In addition, energy requirements for maintenance calculated from studies conducted at the Agri-Food and Biosciences Institute (AFBI) in Northern Ireland since the 1990s were compared with compiled data from recent peer-review papers published over the last decade (2009-2020). The mean metabolisable energy requirement for the maintenance (MEm) of growing cattle was 0.672 MJ/kg0.75 according to values obtained from calorimetry studies conducted at AFBI. This value is respectively 8.2 and 19.5% greater than the MEm values obtained by the Agricultural and Food Research Council (AFRC), and the National Academies of Sciences, Engineering and Medicine (NASEM) equations, but it is in close agreement with the Institut National de la Recherche Agronomique (INRA) approach, when assuming a Bos taurus bull (300 kg LW) and an efficiency for converting energy for maintenance (km) of 0.65. Most of the literature data on energy requirements for the maintenance for this animal category were obtained from studies conducted with Bos indicus animals and their crossbreds in Brazilian conditions with this confirming lower requirements of these animals when compared to pure Bos taurus cattle. A simulation of the total ME requirements calculated for an Angus × Friesian steer (LW = 416 kg) offered good quality grass silage, indicated that both AFRC and NASEM systems overestimate (38.5 and 20.5%, respectively) the observed efficiency of converting ME for growth (kg). When the total ME requirements (maintenance + growth) were assessed, both systems underpredicted total ME requirement in 15.8 and 22.1 MJ/d. The mean MEm requirements for suckler cows obtained from the literature (0.596 MJ/kg0.75) is on average 19.1% greater than predictions given by both AFRC and INRA (lactation) equations when considering a 550 kg cow and a km value of 0.72. Although no differences in net energy requirements for maintenance (NEm) were detected between dry and lactating suckler cows, as expected the later displayed greater variation as a result of differences in milk production. On this regard, the INRA model recognise increased NEm requirements for lactating animals compared to dry cows. The re-evaluation of the concept of diet metabolisability and the analysis of existing data on compensatory growth responses are recommended for future updates of the British system (AFRC) having in to account the particularities of grass-based systems in the UK.

In Vitro Incubations Do Not Reflect In Vivo Differences Based on Ranking of Low and High Methane Emitters in Dairy Cows.

This study evaluated if ranking dairy cows as low and high CH4 emitters using the GreenFeed system (GF) can be replicated in in vitro conditions using an automated gas system and its possible implications in terms of fermentation balance. Seven pairs of low and high emitters fed the same diet were selected on the basis of residual CH4 production, and rumen fluid taken from each pair incubated separately in the in vitro gas production system. In total, seven in vitro incubations were performed with inoculums taken from low and high CH4 emitting cows incubated in two substrates differing in forage-to-concentrate proportion, each without or with the addition of cashew nutshell liquid (CNSL) as an inhibitor of CH4 production. Except for the aimed differences in CH4 production, no statistical differences were detected among groups of low and high emitters either in in vivo animal performance or rumen fermentation profile prior to the in vitro incubations. The effect of in vivo ranking was poorly replicated in in vitro conditions after 48 h of anaerobic fermentation. Instead, the effects of diet and CNSL were more consistent. The inclusion of 50% barley in the diet (SB) increased both asymptotic gas production by 17.3% and predicted in vivo CH4 by 26.2%, when compared to 100% grass silage (S) substrate, respectively. The SB diet produced on average more propionate (+28 mmol/mol) and consequently less acetate compared to the S diet. Irrespective of CH4 emitter group, CNSL decreased predicted in vivo CH4 (26.7 vs. 11.1 mL/ g of dry matter; DM) and stoichiometric CH4 (CH4VFA; 304 vs. 235 moles/mol VFA), with these being also reflected in decreased total gas production per unit of volatile fatty acids (VFA). Microbial structure was assessed on rumen fluid sampled prior to in vitro incubation, by sequencing of the V4 region of 16S rRNA gene. Principal coordinate analysis (PCoA) on operational taxonomic unit (OTU) did not show any differences between groups. Some differences appeared of relative abundance between groups in some specific OTUs mainly related to Prevotella. Genus Methanobrevibacter represented 93.7 ± 3.33% of the archaeal sequences. There were no clear differences between groups in relative abundance of Methanobrevibacter.

Revisiting the Relationships between Fat-to-Protein Ratio in Milk and Energy Balance in Dairy Cows of Different Parities, and at Different Stages of Lactation.

A statistical re-assessment of aggregated individual cow data was conducted to examine trends in fat-to-protein ratio in milk (FPR), and relationships between FPR and energy balance (EB, MJ of ME/day) in Holstein-Friesian dairy cows of different parities, and at different stages of lactation. The data were collected from 27 long-term production trials conducted between 1996 and 2016 at the Agri-Food and Biosciences Institute (AFBI) in Hillsborough, Northern Ireland. In total, 1321 lactations (1 to 20 weeks in milk; WIM), derived from 840 individual cows fed mainly grass silage-based diets, were included in the analysis. The energy balance was calculated daily and then averaged weekly for statistical analyses. Data were further split in 4 wk. intervals, namely, 1-4, 5-8, 9-12, 13-16, and 17-20 WIM, and both partial correlations and linear regressions (mixed models) established between the mean FPR and EB during these periods. Three FPR score categories ('Low' FPR, <1.0; 'Normal' FPR, 1.0-1.5; 'High' FPR, >1.5) were adopted and the performance and EB indicators within each category were compared. As expected, multiparous cows experienced a greater negative EB compared to primiparous cows, due to their higher milk production relative to DMI. Relatively minor differences in milk fat and protein content resulted in large differences in FPR curves. Second lactation cows displayed the lowest weekly FPR, and this trend was aligned with smaller BW losses and lower concentrations of non-esterified fatty acids (NEFA) until at least 8 WIM. Partial correlations between FPR and EB were negative, and 'greatest' in early lactation (1-4 WIM; r = -0.38 on average), and gradually decreased as lactation progressed across all parities (17-20 WIM; r = -0.14 on average). With increasing parity, daily EB values tended to become more negative per unit of FPR. In primiparous cows, regression slopes between FPR and EB differed between 1-4 and 5-8 WIM (-54.6 vs. -47.5 MJ of ME/day), while differences in second lactation cows tended towards significance (-57.2 vs. -64.4 MJ of ME/day). Irrespective of the lactation number, after 9-12 WIM, there was a consistent trend for the slope of the linear relationships between FPR and EB to decrease as lactation progressed, with this likely reflecting the decreasing milk nutrient demands of the growing calf. The incidence of 'High' FPR scores was greatest during 1-4 WIM, and decreased as lactation progressed. 'High' FPR scores were associated with increased energy-corrected milk (ECM) yields across all parities and stages of lactation, and with smaller BW gains and increasing concentrations (log transformed) of blood metabolites (non-esterified fatty acid, NEFA; beta-hydroxybutyrate, BHB) until 8 WIM. Results from the present study highlight the strong relationships between FPR in milk, physiological changes, and EB profiles during early lactation. However, while FPR can provide an indication of EB at a herd level, the large cow-to-cow variation indicates that FPR cannot be used as a robust indicator of EB at an individual cow level.

Experimental data on morphological characterization of chars from coal and bagasse blends.

Morphological characterization of chars from coal and bagasse plays an important role in both the burning efficiency and intrinsic reactivity of chars, during a combustion process [1], [2]. In this work, abundant data on the morphology of chars produced from coal and bagasse blends are presented. Char synthesis was performed varying the temperature (900, 1000 and 1100 °C) and bagasse proportion feeding (0, 25, 50, 75 and 100% w/w) in the pyrolysis reaction. Proximate, ultimate, petrographic and vitrinite reflectance of raw coal and bagasse are presented. Char morphology is classified into three groups -- thin walls, thick walls, and solid particles--, and results are exhibited. The data set is a comprehensive source for advancing in a further understanding of char's morphology from coal-bagasse blends.

Effects of source and concentration of neutral detergent fiber from roughage in beef cattle diets: Comparison of methods to measure the effectiveness of fiber.

Methods have been developed to measure the effectiveness of many roughages, but few evaluations have been conducted with tropical feeds. The objectives of this research were to determine the effectiveness of roughage sources based on bioassay and laboratory methods and identify the biological attributes of the diets that correlate with these methods. Six ruminally cannulated Nellore steers (408 ± 12 kg of BW) were randomly assigned to a 6 × 6 Latin square design within six diets: negative control diet (NC) with aNDF as 10% from corn silage (CS); positive control diet (PC) with aNDF as 20% from CS; and four diets containing 10% aNDF from CS and 10% aNDF from each of the following sources: sugarcane (SC), sugarcane bagasse (SCB), soybean hulls (SH), or low oil cottonseed hulls (LOCH). Physical effectiveness factor (pef, related to the physical characteristics of aNDF) and effectiveness factor (ef, related to the ruminal pH) were determined based on a linear model approach that uses a bioassay method in which CS aNDF was assumed to be the standard fiber source. Laboratory methods to estimate pef of roughage sources were based on the proportion of DM of roughage retained on a 1.18-mm sieve pef(>1.18 mm) or retained on the 8.0-mm Penn State Particle Separator screen pef(>8.0 mm). The pef calculated by the bioassay method (total chewing time and ruminal mat resistance) for CS, SCB, and SC were higher values (P < 0.05) compared with SH and LOCH. The pef(rumen mat) of SC and SCB were higher (P < 0.05) than that of CS, SH, and LOCH. The pef(rumen mat) of LOCH was 61% higher than SH. The ef(rumen pH) of SC and LOCH was higher (P < 0.05) than CS and SH. The pef(chewing, min/d), pef(chewing, min/kg of DM), pef(rumen mat), and ef(rumen pH) positively correlated with rumination time, total chewing time, and ruminal mat resistance (values from transit time in seconds). No correlation was observed (P > 0.05) between pef(>8.0 mm) and rumination time, chewing time, and ruminal pH. The pef calculated using the bioassay method as well as pef (>8.0 mm) were negatively correlated with rumen pH (P > 0.05). The values of the effectiveness of fiber sources obtained in this research can be used as a guideline for nutritionists aiming to replace roughage sources from tropical regions in beef cattle finishing diets. Under our conditions, the pef using the bioassay method or laboratory methods were not adequate in predicting ruminal pH.

Effects of source and concentration of neutral detergent fiber from roughage in beef cattle diets on feed intake, ingestive behavior, and ruminal kinetics.

The objectives of this research were to evaluate the effects of source and concentration of α-amylase-treated neutral detergent fiber (aNDF) from roughage on feed intake, ingestive behavior, and ruminal kinetics in beef cattle receiving high-concentrate diets. Six ruminally cannulated Nellore steers (408 ± 12 kg of body weight) were randomly assigned to a 6 × 6 Latin square design with six diets: 10% aNDF from corn silage (10CS); 20% aNDF from corn silage (20CS); or four diets containing 10% aNDF from corn silage and 10% aNDF from one of the following sources: sugarcane (SC), sugarcane bagasse (SCB), soybean hulls (SH), or low oil cottonseed hulls (LOCH). The parameters of passage and degradation kinetics were estimated based on a two-compartmental model with gamma- and exponential-distributed residence times. The nonlinear models were fitted by nonlinear least squares, and a linear mixed-effects model was fitted to all variables measured from the Latin square design that were related to intake, digestibility, digestion kinetic parameters, and residence times. Mean particle size (MPS) between roughage sources (CS, SCB, and SC) and coproducts (SH and LOCH) was affected (P < 0.05). Dry matter intake (DMI) was not affected (P > 0.05) by 20CS, SC, SH, or LOCH. Steers fed 20CS or LOCH diets had 16% and 20% greater DMI, respectively, (P < 0.05) than steers fed 10CS diet. Steers fed SCB consumed the least dry matter (DM). The SH and LOCH diets had lower MPS values (about 8.77 mm) in comparison to 20CS, SCB, and SC diets (about 13.08 mm) and, consequently, affected (P < 0.05) rumen content, ruminal in situ disappearance, nutrient digestibility, and solid fractional passage rate. Chewing time was affected (P < 0.05) by roughage sources and concentration. Lower values of distance travel inside the rumen (min/cm) were observed (P < 0.05) for the SCB and SC diets in comparison with any other diet. Except for SCB, there was no difference (P > 0.05) in rumen fill, among other treatments. Mean daily ruminal pH was not affected (P > 0.05) by 20CS, SCB, SC, and LOCH diets, and it ranged from 6.1 to 6.23. Total short-chain fatty acids concentration was affected (P < 0.05) by roughage source and concentration. Based on our results, we recommend that under Brazilian finishing diets, replacing roughage sources, except for SCB, based on aNDF concentration of the roughage in high-concentrate diets containing finely ground flint corn does not affect DMI.

A heritable subset of the core rumen microbiome dictates dairy cow productivity and emissions.

A 1000-cow study across four European countries was undertaken to understand to what extent ruminant microbiomes can be controlled by the host animal and to identify characteristics of the host rumen microbiome axis that determine productivity and methane emissions. A core rumen microbiome, phylogenetically linked and with a preserved hierarchical structure, was identified. A 39-member subset of the core formed hubs in co-occurrence networks linking microbiome structure to host genetics and phenotype (methane emissions, rumen and blood metabolites, and milk production efficiency). These phenotypes can be predicted from the core microbiome using machine learning algorithms. The heritable core microbes, therefore, present primary targets for rumen manipulation toward sustainable and environmentally friendly agriculture.

Taquicardia ventricular polimórfica tipo torsadess de pointes secundaria a estimulación por marcapasos / Polymorphic ventricular taquicardia "torsades de pointes" associated to abnormal pacemaker stimulation

La taquicardia ventricular polimórfica se origina en los ventrículos, cuyos complejos QRS son de morfología, amplitud y dirección variable, con frecuencias que oscilan entre 200 y 250 lpm, pudiendo ser autolimitadas o degenerar en una fibrilación ventricular. La TdP es un tipo de taquicardia ventricular polimórfica caracterizada por complejos con un eje eléctrico que gira alrededor de la línea isoeléctrica y que está asociada a QT largo. Se presenta el caso de una paciente portadora de marcapaso que presenta episodios de taquicardia ventricular polimórfica, con una morfología típica de TdP, sin documentación de QT prolongado previo ni actual, generada por la estimulación ventricular sobre onda T, de forma accidental por desplazamiento del electrodo auricular a Ventrículo Derecho (VD).

Polymorphic ventricular tachycardia is a tachycardia originating in the ventricles, where the QRS complexes have variable morphology, amplitude, and direction, with frequencies ranging between 200 and 250 bpm; it may be self-limited or degenerate into ventricular fibrillation. Torsades de Pointes (TdP) is a type of polymorphic ventricular tachycardia characterized by complexes with an electrical axis that rotates around the isoelectric line and that is associated with long QT interval. We present the case of a patient with a pacemaker who presents episodes of polymorphic ventricular tachycardia, with a typical morphology of TdP, without documentation of previous or current prolonged QT, generated by ventricular stimulation on the T wave, accidentally due to displacement of the atrial electrode to the Right Ventricle (RV).

In-hospital fellow coverage reduces communication errors in the surgical intensive care unit.

BACKGROUND: Staff coverage strategies of intensive care units (ICUs) impact clinical outcomes. High-intensity staff coverage strategies are associated with lower morbidity and mortality. Accessible clinical expertise, team work, and effective communication have all been attributed to the success of this coverage strategy. We evaluate the impact of in-hospital fellow coverage (IHFC) on improving communication of cardiorespiratory events. METHODS: A prospective observational study performed in an academic tertiary care center with high-intensity staff coverage. The main outcome measure was resident to fellow communication of cardiorespiratory events during IHFC vs home coverage (HC) periods. RESULTS: Three hundred twelve cardiorespiratory events were collected in 114 surgical ICU patients in 134 study days. Complete data were available for 306 events. One hundred three communication errors occurred. IHFC was associated with significantly better communication of events compared to HC (P<.0001). Residents communicated 89% of events during IHFC vs 51% of events during HC (P<.001). Communication patterns of junior and midlevel residents were similar. Midlevel residents communicated 68% of all on-call events (87% IHFC vs 50% HC, P<.001). Junior residents communicated 66% of events (94% IHFC vs 52% HC, P<.001). Communication errors were lower in all ICUs during IHFC (P<.001). CONCLUSIONS: IHFC reduced communication errors.

Student-led courses to teach cone beam CT in the predoctoral dental curriculum.

Cone beam computed tomography (CBCT) provides a new method to evaluate the craniofacial region. The goal of our project was to introduce into the predoctoral dental curriculum a student-initiated, student-led introduction to CBCT and how to use it, with minimal expenditure of financial resources. A third-year student worked with two faculty members to design a course in which a small number of third-year students would lead a small group of second-year students. The first approach involved each small group of second-year dental students discussing one clinical case in which the patient's CBCT record was included. Representatives of each of the ten small groups presented the patient and that patient's clinical problem (e.g., an impacted tooth) to the entire class as well as demonstrating the superiority and limitations of using CBCT in clinical dentistry. The second approach also used small-group meetings led by third-year dental students, but paired two second-year dental students as a team to present the patient's CBCT data in the small-group setting. There were five teams each presenting a different type of patient as assessed only from the CBCT data. The first model focused on the problem (e.g., an impacted tooth), while the second model focused on how to evaluate and use CBCT scans to determine the patient's primary problem. Based on surveys conducted at the end of each course, the majority of students felt they had gained a better understanding of CBCT.

Periocular cutaneous melanoma arising in a radiotherapy field.

A 78-year-old woman had a periocular cutaneous melanoma in the radiation field of a meningioma. A medial canthal melanoma arose 32 years after primary radiation for a sphenoid wing meningioma and 22 years after supplemental radiation for meningioma recurrence. Histologic sections taken from skin surrounding the melanoma showed widespread melanocytic atypia and 2 separate foci of melanoma in situ. Cutaneous melanoma can arise in a radiation field after a long latency period and should be considered an uncommon form of secondary malignancy.

Intoxicación alimentaria masiva en personal militar en la ciudad de Iquitos-Perú, 1985 / Food poisoning mass in military personal at Iquitos, 1985

Se estudió un brote de intoxicación alimentaria en personal militar que afectó al 77 por ciento (75) de una población de reclutas y causó 2 por ciento de muerte. Se catalogó inicialmente como un brote de Botulismo, pero posteriormente se descartó esta etiología, determinándose que se trató de una intoxicación por órgano-fosforados. Se describen algunas manifestaciones clínicas y se proporcionan recomendaciones para el control de este tipo de situaciones