Search

Abstract Background Finding sensitive clinical outcome measures has become crucial in natural history studies and therapeutic trials of neuromuscular disorders. Here, we focus on 1‐year longitudinal data from quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) in a placebo‐controlled study of sirolimus for inclusion body myositis (IBM), also examining their links to functional, strength, and clinical parameters in lower limb muscles. Methods Quantitative MRI and 31P MRS data were collected at 3 T from a single site, involving 44 patients (22 on placebo, 22 on sirolimus) at baseline and year‐1, and 21 healthy controls. Assessments included fat fraction (FF), contractile cross‐sectional area (cCSA), and water T2 in global leg and thigh segments, muscle groups, individual muscles, as well as 31P MRS indices in quadriceps or triceps surae. Analyses covered patient‐control comparisons, annual change assessments via standard t‐tests and linear mixed models, calculation of standardized response means (SRM), and exploration of correlations between MRI, 31P MRS, functional, strength, and clinical parameters. Results The quadriceps and gastrocnemius medialis muscles had the highest FF values, displaying notable heterogeneity and asymmetry, particularly in the quadriceps. In the placebo group, the median 1‐year FF increase in the quadriceps was 3.2% (P

Abstract Background Dysferlinopathy is a phenotypically heterogeneous group of hereditary diseases caused by mutations in the DYSF gene. Early contractures are considered rare, and rigid spine syndrome in dysferlinopathy has been previously reported only once. Case presentation We describe a 23-year-old patient with Miyoshi myopathy with a rigid spine and multiple contractures, a rare phenotypic variant. The disease first manifested when the patient was 13 years old, with fatigue of the gastrocnemius muscles and the development of pronounced contractures of the Achilles tendons, flexors of the fingers, and extensors of the toes, followed by the involvement of large joints and the spine. Magnetic resonance imaging revealed signs of connective tissue and fatty replacement of the posterior muscles of the thighs and lower legs. Edema was noted in the anterior and medial muscle groups of the thighs, lower legs, and the multifidus muscle of the back. Whole genome sequencing revealed previously described mutations in the DYSF gene in exon 39 (c.4282 C > T) and intron 51 (c.5785-824 C > T). An immunohistochemical analysis and Western blot showed the complete absence of dysferlin protein expression in the muscle fibers. Conclusions This case expands the range of clinical and phenotypic correlations of dysferlinopathy and complements the diagnostic search for spine rigidity.

Bemisia tabaci (Gennadius) is as a major pest of vegetable crops in Cameroon. These sap-sucking insects are the main vector of many viruses infecting plants, and several cryptic species have developed resistance against insecticides. Nevertheless, there is very little information about whitefly species on vegetable crops and the endosymbionts that infect them in Cameroon. Here, we investigated the genetic diversity of whiteflies and their frequency of infection by endosymbionts in Cameroon. Ninety-two whitefly samples were collected and characterized using mitochondrial cytochrome oxidase I (mtCOI) markers and Kompetitive Allele Specific PCR (KASP). The analysis of mtCOI sequences of whiteflies indicated the presence of six cryptic species (mitotypes) of Bemisia tabaci, and two distinct clades of Bemisia afer and Trialeurodes vaporariorum. Bemisia tabaci mitotypes identified included: MED on tomato, pepper, okra, and melon; and SSA1-SG1, SSA1-SG2, SSA1-SG5, SSA3, and SSA4 on cassava. The MED mitotype predominated in all regions on the solanaceous crops, suggesting that MED is probably the main phytovirus vector in Cameroonian vegetable cropping systems. The more diverse cassava-colonizing B. tabaci were split into three haplogroups (SNP-based grouping) including SSA-WA, SSA4, and SSA-ECA using KASP genotyping. This is the first time that SSA-ECA has been reported in Cameroon. This haplogroup is predominant in regions currently affected by the severe cassava mosaic virus disease (CMD) and cassava brown streak virus disease (CBSD) pandemics. Three endosymbionts including Arsenophonus, Rickettsia, and Wolbachia were present in female whiteflies tested in this study with varying frequency. Arsenophonus, which has been shown to influence the adaptability of whiteflies, was more frequent in the MED mitotype (75%). Cardinium and Hamiltonella were absent in all whitefly samples. These findings add to the knowledge on the diversity of whiteflies and their associated endosymbionts, which, when combined, influence virus epidemics and responses to whitefly control measures, especially insecticides.

Abstract The ~ 10 km2 strewn field of the Twannberg type IIG iron meteorite is located in the Swiss Jura Mountains, 30 km northwest of Bern. The strewn field has been mapped by a group of citizen scientists since 2006, yielding more than 2000 meteorite fragments with a total mass of 152.7 kg until the end of 2022. With a terrestrial age of 176 ± 19 ka and a minimum pre-atmospheric mass of ~ 250 t, the Twannberg meteorite is a local time marker in an area with a poorly-known paleoenvironmental history. The Twannberg strewn field is located just outside of the maximum extent of ice during the Last Glacial Maximum (LGM). On the Mont Sujet, meteorites are size-sorted in a 6-km long section of the primary strewn field (altitude 945–1370 m a.s.l.), indicating a fall direction from east-northeast to west-southwest (azimuth approximately 250°). On the Twannberg plateau and in the Twannbach gorge, meteorites are not size-sorted and occur in a ~ 5.7-km long area associated with till and recent stream sediments (altitude 430–1075 m a.s.l.). The mass distribution of meteorites on the Twannberg plateau demonstrate that these meteorites were not found where they fell but that they must have been transported up to several km by glacier ice flow after the fall. The distribution of meteorites and of glacially transported Alpine clasts on the Mont Sujet and on the Chasseral chain indicates the presence of local ice caps and of an approximately 200-m higher Alpine ice surface with respect to the LGM at the time of fall. This high ice level during MIS 6 (Marine Isotopic Stage 6, 191–130 ka) indicated by the meteorite distribution is consistent with surface exposure ages of 50–144 ka from nearby resting erratic boulders at altitudes of up to 1290 m a.s.l., including the newly dated Jobert boulder (63 ka). These boulders indicate an ice level ~ 400 m higher than during LGM at a time not later than MIS 6. Post-LGM luminescence ages of loess-containing meteorites on the Mont Sujet and 14C ages of materials associated with meteorite finds indicate relatively young pedoturbation and increased oxidation of meteorites since ~ 7300 cal BP, possibly correlated with deforestation and enhanced erosion resulting from increased human activities since the Neolithic. This study shows that Twannberg meteorites in their palaeoenvironmental context provide valuable information about ice levels and transport directions during MIS 6 and about their interaction with the post-LGM environmental conditions. The unique Twannberg strewn field has the potential to reveal more valuable information.

Abstract The spatial and temporal distribution of Alpine snow is a sensitive gauge of environmental change. While understanding past snow dynamics is essential for reconstructing past climate and forecasting future trends, reliable snowpack data prior to the instrumental record are scarce. We present a novel pairing of cosmogenic paleothermometry and luminescence photochronometry which constrain the temperature and insolation history of bedrock outcrops at the Gotthard Pass, Switzerland, over the last ∼15,000 years. By coupling these results with cosmogenic 14C‐10Be chronology and modern in situ rock thermometry, we infer a ∼70‐day reduction of snowpack at the topographic mid‐slope. Our data indicate stable environmental conditions throughout the Holocene, followed by a 6.6 ± 2.9°C increase of ground surface temperature, coeval with an order‐of‐magnitude or more increase in ground surface insolation. Bracketing the onset of these changes between 1504 and 1807 CE, our findings tie the snowpack decline with the onset of human industrialization.

In the present work, a TiO2/zeolite photocatalyst was synthesized by dispersing TiO2 nanoparticles obtained through the sol-gel method onto the surface of natural zeolite derived from ignimbrite residue. The zeolite was obtained from an ignimbrite rubble treatment collected from a quarry in Arequipa City, Peru. The research focused on the effect of zeolite on the TiO2 nanoparticles. The synthesized photocatalysts were characterized using various techniques, including field-emission scanning electron microscopy (FE-SEM), energy-dispersive X-ray (EDS), X-ray diffraction (XRD), diffuse reflectance spectroscopy (DRS), and Brunauer–Emmett–Teller surface area analysis (BET). The results revealed that the TiO2/zeolite samples displayed high crystallinity, with TiO2 being present in three phases and zeolite being present in the analcime phase. Furthermore, these samples exhibited a band gap of 3.14 eV and a high surface area compared to that of bare TiO2. Finally, the photocatalytic activity of the TiO2/zeolite composite obtained was evaluated toward the decomposition of 10 ppm and 20 ppm of methyl orange (MO) dye. The TiO2/zeolite samples demonstrated improved photocatalytic activity compared to that of pristine TiO2 under the same experimental conditions. This enhancement is primarily attributed to the increased specific surface area of the TiO2/zeolite samples, making them promising materials for future efficient and sustainable photocatalytic applications.

Abstract Background Biomedical technologies have the potential to be advantageous in remote communities. However, information about barriers faced by users of technology in general and in remote Indigenous communities is scarce. The purpose of this study was to characterize the leading challenges faced by researchers who have used biomedical technologies in the Peruvian Amazon. Methods This exploratory, qualitative study with a phenomenological approach depicts the lived experience of participants who were researchers with experience working with biomedical technologies in the Peruvian Amazon in the past five years. Analysis was based on three core themes: design, implementation, and acceptability. Sub-themes included environment, community, and culture. Of the 24 potential participants identified and contacted, 14 agreed to participate, and 13 met inclusion criteria and completed semi-structured interviews. Results were sent to each participant with the opportunity to provide feedback and partake in a 30-minute validation meeting. Five participants consented to a follow-up meeting to validate the results and provide further understanding. Results Participants recognized significant challenges, including technologies designed out-of-context, difficulty transporting the technologies through the Amazon, the impact of the physical environment (e.g., humidity, flooding), and limited existing infrastructure, such as electricity and appropriately trained health personnel. Participants also identified cultural factors, including the need to address past experiences with technology and health interventions, understand and appropriately communicate community benefits, and understand the effect of demographics (e.g., age, education) on the acceptance and uptake of technology. Complementary challenges, such as corruption in authority and waste disposal, and recommendations for technological and health interventions such as co-design were also identified. Conclusions This study proposes that technological and health interventions without efforts to respect local cultures and health priorities, or understand and anticipate contextual challenges, will not meet its goal of improving access to healthcare in remote Amazon communities. Furthermore, the implications of corruption on health services, and improper waste disposal on the environment may lead to more detrimental health inequities.

Abstract Orogens and volcanic arcs at continental plate margins are primary surface expressions of convergent plate tectonics. Although it is established that climate affects the shape, size, and architecture of orogens via orographic erosion gradients, the ascent of magma through the crust and location of volcanoes along magmatic arcs have been considered insensitive to erosion. However, available data reveal westward migration of late-Cenozoic volcanic activity in the Southern Andes and Cascade Range where orography drives an eastward migration of the topographic water divide by increased precipitation and erosion along west-facing slopes. Thermomechanical numerical modeling shows that orographic erosion and the associated leeward topographic migration may entail asymmetric crustal structures that drive the magma ascent toward the region of enhanced erosion. Despite the different tectonic histories of the Southern Andes and the Cascade Range, orographic erosion is a shared causal mechanism that can explain the late-Cenozoic westward migration of the volcanic front along both magmatic arcs.

Abstract Background Water T2 (T2H2O) mapping is increasingly being used in muscular dystrophies to assess active muscle damage. It has been suggested as a surrogate outcome measure for clinical trials. Here, we investigated the prognostic utility of T2H2O to identify changes in muscle function over time in limb girdle muscular dystrophies. Methods Patients with genetically confirmed dysferlinopathy were assessed as part of the Jain Foundation Clinical Outcomes Study in dysferlinopathy. The cohort included 18 patients from two sites, both equipped with 3‐tesla magnetic resonance imaging (MRI) systems from the same vendor. T2H2O value was defined as higher or lower than the median in each muscle bilaterally. The degree of deterioration on four functional tests over 3 years was assessed in a linear model against covariates of high or low T2H2O at baseline, age, disease duration, and baseline function. Results A higher T2H2O at baseline significantly correlated with a greater decline on functional tests in 21 out of 35 muscles and was never associated with slower decline. Higher baseline T2H2O in adductor magnus, vastus intermedius, vastus lateralis, and vastus medialis were the most sensitive, being associated bilaterally with greater decline in multiple timed tests. Patients with a higher than median baseline T2H2O (>40.6 ms) in the right vastus medialis deteriorated 11 points more on the North Star Ambulatory Assessment for Dysferlinopathy and lost an additional 86 m on the 6‐min walk than those with a lower T2H2O (

Optimizing the use of organic and mineral fertilizer in rain-fed maize production is crucial for sustainable food production in sub-Saharan Africa. This study investigates the effect of hill-placement of two nutrient sources (farmyard manure and synthetic fertilizer) on nutrient- and water-use efficiencies of maize crops i.e. recovery efficiency (NUEre), internal utilization efficiency (NUEie) and water use efficiency (WUE). A four-year trial was conducted in the tropical sub-humid zone of the northern Benin with a factorial combination of farmyard manure at three levels (0, 3 and 6 t ha−1, hereafter NM, 3M and 6M, respectively) and three levels of fertilizer [0% (NF), 50% (50F) and 100% (100F) of the recommended rate (76 kg N + 13.1 kg P + 24.9 kg K ha−1) by the national center for agricultural research. The NUEre decreased with increasing rate of manure and/or fertilizer, but the decreasing rate was lower under combined manure and fertilizer application. However, the NUEie increased with the increasing manure and fertilizer amounts. The WUE was significantly higher in 3M and 6M treatments than in NM treatment, and higher in 50F and in 100F than in NF treatments. The combination of 3000 kg ha−1 farmyard manure with half recommended fertilizer rate (100 kg ha−1) could be suggested as an optimal nutrient management practice for maize production in the Northern Benin. Future studies should target the other agro-ecological zones in Benin, and also consider other widely cultivated crops in the study area for reducing yield gaps and promote food security.

Abstract Background Natural history studies in neuromuscular disorders are vital to understand the disease evolution and to find sensitive outcome measures. We performed a longitudinal assessment of quantitative magnetic resonance imaging (MRI) and phosphorus magnetic resonance spectroscopy (31P MRS) outcome measures and evaluated their relationship with function in lower limb skeletal muscle of dysferlinopathy patients. Methods Quantitative MRI/31P MRS data were obtained at 3 T in two different sites in 54 patients and 12 controls, at baseline, and three annual follow‐up visits. Fat fraction (FF), contractile cross‐sectional area (cCSA), and muscle water T2 in both global leg and thigh segments and individual muscles and 31P MRS indices in the anterior leg compartment were assessed. Analysis included comparisons between patients and controls, assessments of annual changes using a linear mixed model, standardized response means (SRM), and correlations between MRI and 31P MRS markers and functional markers. Results Posterior muscles in thigh and leg showed the highest FF values. FF at baseline was highly heterogeneous across patients. In ambulant patients, median annual increases in global thigh and leg segment FF values were 4.1% and 3.0%, respectively (P

Several studies have investigated nutrient-enriched and nutrient poor biochar to improve soil properties, increase nutrient use efficiency and crop productivity. Review articles have presented formulations and production methods of biochar-based fertilizers. They reported nutrient-enriched biochar improves -45ves crop productivity, soil health and preserves the environment. But so far, none of the studies has conceptualized the nutrient-enriched biochar as a biochar-based smart fertilizer or presented the conceptual and intellectual structures and the collaborative networks of authors and countries working on biochar-based smart fertilizers. For the first time, this study has mapped the scientific knowledge generated on the topic and established a solid ground for its innovative progress and research pursuits. A total of 2,779 scientific publications on biochar-based fertilizers were exported from scopus database in August 2022 and were analyzed using bibliometrix software package and the biblioshiny web interface in R version 4.1.3. The results indicated that the papers in our collection cover the period from 2007 to 2022 with a raising number from 2017 to 2021. Almost all documents (99.38%) were co-authored with an average of 6 authors (5.76) per article. The analysis of keywords and the evolution of topics revealed that biochar-based smart fertilizers in relation to organic nutrient sources, soil microbiology and soil sanitation were the most studied topics in the scientific debates. China had more collaboration in the network working on biochar-based fertilizers, while the West African countries belonging to the network have not developed any collaboration so far. This suggests the formulation of research projects that may involve African countries to work with other countries including China, USA, Germany, Australia and Poland. This study is more comprehensive in terms of a global view of the conceptual and intellectual contours and network of actors on biochar-based smart fertilizers. Future research on the topic should be conducted more in the fields under farmers’ conditions and may focus on (i) enrichment of biochar with nutrients from organic sources before its application to the soil, (ii) soil remediation and microbiology in relation to biochar-based fertilizer applications, and (iii) economic profitability of biochar fertilizers for small-scale farmers.

Introduction: Maize-based production systems in Sub-Saharan Africa are largely based on family farming, which is characterized by low-input, nutrient-mining agriculture and practices. These systems usually promote soil degradation through loss of organic matter and erosion. The present study characterizes farms and main soil fertility management options in maize-based farming systems of the northern Benin.Methods: The study was conducted in the municipalities of Malanville, Banikoara and Bembèrèkè. We sampled randomly and interviewed 262 maize farmers, and the statistical analysis (distribution of means and frequencies, chi-square, ANOVA, etc.) was performed.Results and discussion: The results show that maize farming characteristics and socioeconomic conditions (land use and labor, production activities and land allocation, institutional arrangements on land, access to labor and capital, etc.) were diverse across locations and exhibited a wide variation within locations. Several practices were used for the management and sustainable maintenance of soil fertility in maize production systems in northern Benin: maize-legume intercropping, cotton-maize rotation, and mineral and organic fertilizers application. Most of farmers occasionally or regularly used mineral fertilizers (95.4%), followed by legume-cereal rotation/ intercropping (51.9%). Overall, 23.6% and 58.4% of farmers consistently used mineral fertilizer over the last 5 and 10 years, respectively. The amount of applied mineral fertilizer did not significantly vary between locations with an average (applied day after sowing, DAS) of 131.7 ± 13.7 (22 ± 8 DAS), 58.7 ± 9.6 (44 ± 5 DAS) and 164.7 ± 25.4 (38 ± 11 DAS) kg ha−1 for NPK, urea and Mix NPK + urea, respectively applied at, and days after sowing. Most farmers spread the fertilizer around the plants without covering with soil particles. Manure was applied exclusively to food crops through transporting and corralling (28.2%); and most farmers also used manure from their own livestock while few farmers used cattle corralling. Farmyard manure was mainly spread (100% of respondents) on the surface before plowing at the beginning of the rainy season. Maize farmers applied mineral fertilizer based on the level of initial soil fertility (naturally fertile or poor, degree of erosion etc.) and fertilizer purchase costs. Manure was not widely used as an alternative to chemical fertilizers; therefore, farmers need more strengthening and technical assistance on the production of organic fertilizers and manure storage. The findings are useful for policymakers on encouraging the successful implementation of sustainable soil fertility management strategies of maize-based farming systems in northern Benin.

Introdução: a importância das manifestações neuropsicológicas como meio de identificar a presença do HIV-1 no sistema nervoso central. Objetivos: avaliar a possível relação entre o HIV-1 no Sistema Nervoso Central (SNC), mecanismo patológico, proteção do SNC e alterações neu-ropsicológicas cognitivas; Identificar a existência ou falta de sintomas neuropsicológicos e sua importância com a presença do HIV-1 no SNC. Metodos: revisão sistemática de mais de 100 artigos recentemente publicados na literatura médica nacional e internacional via PubMed, referentesaos mecanismos biológicos e patológicos relacionados ao HIV-1 no SNC e as funções neuropsicológicas. Foram estabelecidas correlações entre osaspectos biológicos, patológicos, neuropsicológicos e questões controversas de importância clínica em pacientes infectados pelo HIV-1. Resultados: a maioria dos trabalhos selecionados supõe que o HIV-1 entra precocemente no SNC, que é imunologicamente privilegiado, no curso da infecção eestabelece-se no cérebro ao longo da vida. A via principal de entrada do HIV-1 no cérebro ocorre pelo influxo aumentado de monócitos infectados no SNC. A lesão direta do neurônio cerebral pode ocorrer pela ação de várias proteínas virais como Tat, gp120, Vpr. Em tal situação, a interação diretade proteínas do HIV-1 destrói os neurônios sem qualquer papel intermediário das células gliais. A lesão indireta pode ser a forma mais freqüente emque vários produtos difusíveis dos monócitos ativados, macrófagos, astrócitos e micróglias induzem o processo de morte de neurônios inespecíficos, inocentes e presentes no local. Contrastando com a maioria dos trabalhos publicados, há evidências de que apontam um papel protetor do HIV-1 queativando astrócitos e micróglias preservam a função cognitiva promovendo proteção neuronal. Discussão: os resultados desta revisão sistemáticamostram que o HIV-1 no cérebro pode promover diferentes graus de alterações neuropsicológicas, dependendo da interação do HIV-1 no SNC. No caso de ataque direto do HIV-1 ao neurônio cerebral (neurotoxidade direta), graves alterações neuropsicológicas cognitivas poderiam certamenteocorrer. No caso de neurotoxidade em que monócitos infiltrados, macrófagos, micróglia e astrócitos produzem várias citoquinas, quimiocinas, aminoácidos, proteínas HIV-1 e outros produtos difusíveis, os neurônios podem ser lesados ou morrer dependendo da intensidade da agressão inicial. Asmanifestações cognitivas neuropsicológicas podem ser leves, moderadas ou graves dependendo da intensidade do dano cerebral. No caso de ausênciade sintomas cognitivos na infecção HIV-1 do cérebro, algumas evidências publicadas na literatura mostram um possível papel neuroprotetor de citoquinas, como o TNF produzido pelos monócitos infiltrados e células gliais. Conclusão: os testes neuropsicológicos podem ser importantes para a avaliação prognóstica e o tratamento adequado da infecção HIV-1 do SNC e para a determinação do curso clínico do paciente. Distúrbios neuropsicológicos podem funcionar como marcadores de agressão de proteção para o SNC infectado pelo HIV-1. A atividade viral do HIV-1 no SNC pode serinferida a partir das alterações neuropsicológicas encontradas.

Abstract Background The availability of non‐invasive, accessible, and reliable methods for estimating regional skeletal muscle volume is paramount in conditions involving primary and/or secondary muscle wasting. This work aimed at (i) optimizing serial bioelectrical impedance analysis (SBIA) by computing a conductivity constant based on quantitative magnetic resonance imaging (MRI) data and (ii) investigating the potential of SBIA for estimating lean regional thigh muscle volume in patients with severe muscle disorders. Methods Twenty healthy participants with variable body mass index and 20 patients with idiopathic inflammatory myopathies underwent quantitative MRI. Anatomical images and fat fraction maps were acquired in thighs. After manual muscle segmentation, lean thigh muscle volume (lVMRI) was computed. Subsequently, multifrequency (50 to 350 kHz) serial resistance profiles were acquired between current skin electrodes (i.e. ankle and hand) and voltage electrodes placed on the anterior thigh. In vivo values of the muscle electrical conductivity constant were computed using data from SBIA and MRI gathered in the right thigh of 10 healthy participants. Lean muscle volume (lVBIA) was derived from SBIA measurements using this newly computed constant. Between‐day reproducibility of lVBIA was studied in six healthy participants. Results Electrical conductivity constant values ranged from 0.82 S/m at 50 kHz to 1.16 S/m at 350 kHz. The absolute percentage difference between lVBIA and lVMRI was greater at frequencies >270 kHz (P

Abstract Fibrosis is a key pathological feature in muscle disorders, but its quantification mainly relies on histological and biochemical assays. Muscle fibrosis most frequently is entangled with other pathological processes, as cell membrane lesions, inflammation, necrosis, regeneration, or fatty infiltration, making in vivo assessment difficult. Here, we (1) describe a novel mouse model with variable levels of induced skeletal muscle fibrosis displaying minimal inflammation and no fat infiltration, and (2) report how fibrosis affects non-invasive metrics derived from nuclear magnetic resonance (NMR) and ultrasound shear-wave elastography (SWE) associated with a passive biomechanical assay. Our findings show that collagen fraction correlates with multiple non-invasive metrics. Among them, muscle stiffness as measured by SWE, T2, and extracellular volume (ECV) as measured by NMR have the strongest correlations with histology. We also report that combining metrics in a multi-modality index allowed better discrimination between fibrotic and normal skeletal muscles. This study demonstrates that skeletal muscle fibrosis leads to alterations that can be assessed in vivo with multiple imaging parameters. Furthermore, combining NMR and SWE passive biomechanical assay improves the non-invasive evaluation of skeletal muscle fibrosis and may allow disentangling it from co-occurring pathological alterations in more complex scenarios, such as muscular dystrophies.

Introduction. The paper deals with studying the formation of culture elements during the Cossacks revival process in the late 20th – early 21st centuries. The cultural pattern of a community is always changing. Cultural practices and traditions of the past get integrated into the modern social conditions, while new values and rituals assume the character of traditional ones. The topicality of the subject derives from the fact that the Cossack culture was subject to a dramatic transformation in the 20th century, while many elements of the culture were wiped out. The transmission of the cultural tradition was interrupted. The Cossacks revival in the late 20th century supposed a return to traditional historical forms. However, this task proved difficult because of the break in the transmission of the ethnic culture. The formation of the present-day Cossack cultural system supposed the selection of some elements of culture from the past and their integration into the new conditions as well as the creation of new forms of culture that would contribute to the cultural identification of the Cossacks. Methods and materials. Historiography has predominantly described the traditional forms of the Cossack culture. The issues of cultural construction were touched upon only occasionally. This paper applies the historical and chronological, historicalgenetic methods as well as the conception of socio-cultural construction. Analysis. During the Cossacks revival process its participants demonstrated a sharp increase of interest in the traditional forms of culture. The attempts at their integration into the present-day conditions led to the deformation of cultural forms. They lost their authenticity and transformed themselves into secondary forms of culture, thus cultural patterns of the modern Cossacks got changed. At the same time, new cultural traditions and norms were “invented”. Their function was to fix Cossacks identity and to show that the Cossacks do exist in the social life of the country. The adaptation of the traditions and historical elements of the Cossack socio-cultural system had its peculiarities. The traditions and elements were taken from different epochs and formed an arbitrary composition of different cultural phenomena. Traditions played an important role in the Cossacks revival process because they acted as cultural identification markers for the Cossack community. For that reason even new cultural practices were given the appearance of traditions. Results. In the late 20th – early 21st centuries the restoration of the Cossack culture was actually its construction. A number of trends can be traced in the process. They developed concurrently and contributed to the creation of new cultural milieu.

Inhibiting TGF-β1 to increase immune responses against tumors bears the risk of tumor-promoting toxicity. Here the authors show that selectively blocking TGF-β1 produced by immunosuppressive cells is feasible with anti-GARP:TGF-β1 antibodies and improves the efficacy of PD-1 blockade immunotherapy.

Dysferlinopathy is a muscular dystrophy with a highly variable functional disease progression in which the relationship of function to some patient reported outcome measures (PROMs) has not been previously reported. This analysis aims to identify the suitability of PROMs and their association with motor performance.Two-hundred and four patients with dysferlinopathy were identified in the Jain Foundation's Clinical Outcome Study in Dysferlinopathy from 14 sites in 8 countries. All patients completed the following PROMs: Individualized Neuromuscular Quality of Life Questionnaire (INQoL), International Physical Activity Questionnaire (IPAQ), and activity limitations for patients with upper and/or lower limb impairments (ACTIVLIMs). In addition, nonambulant patients completed the Egen Klassifikation Scale (EK). Assessments were conducted annually at baseline, years 1, 2, 3, and 4. Data were also collected on the North Star Assessment for Limb Girdle Type Muscular Dystrophies (NSAD) and Performance of Upper Limb (PUL) at these time points from year 2. Data were analyzed using descriptive statistics and Rasch analysis was conducted on ACTIVLIM, EK, INQoL. For associations, graphs (NSAD with ACTIVLIM, IPAQ and INQoL and EK with PUL) were generated from generalized estimating equations (GEE). The ACTIVLIM appeared robust psychometrically and was strongly associated with the NSAD total score (Pseudo R2 0.68). The INQoL performed less well and was poorly associated with the NSAD total score (Pseudo R2 0.18). EK scores were strongly associated with PUL (Pseudo R2 0.69). IPAQ was poorly associated with NSAD scores (Pseudo R2 0.09). This study showed that several of the chosen PROMs demonstrated change over time and a good association with functional outcomes. An alternative quality of life measure and method of collecting data on physical activity may need to be selected for assessing dysferlinopathy.

In sub-Saharan Africa, smallholder farming systems continue to record very low yields despite the availability of appropriate crop management technologies. A 2-year field experiment was conducted in 2018 and 2019 at the Agricultural Research Station of Northern Benin to evaluate the growth response, grain yield attributes, and nutrient- and water- use efficiencies of different drought-tolerant (DT) maize varieties (TZEE-W-POP-STR QPM, TZE-Y-POP-STR, 2008Syn-EE-W DT-STR, and 2000Syn-EE-W of 80–90 days cycle), compared to DMR-ESR-W, a drought-susceptible (DS) variety of 90 days cycle, under different fertilizer options [no fertilizer control, microdosing option 1 (MD1, 25 kg N ha−1 + 4 kg P ha−1), option 2 (MD2, 25 kg N ha−1 + 8 kg P ha−1), option 3 (MD3, 35 kg N ha−1 + 8 kg P ha−1), and broadcast fertilizer at recommended rate (RR, 76 kg N ha−1 + 13 kg P ha−1). Generally, combining microdosing with DT varieties showed a very good performance by increasing the leaf area and biomass by 71 and 85%, respectively, at anthesis compared to the conventional practice. Microdosing increases grain and stover yields by 171 and 98%, respectively, compared to an unfertilized control with generally no difference between MD3 and RR treatments. Also, the DT varieties obtained the best yields (+19%), with the highest value observed with the TZE-Y variety. Significant interaction was found between varieties and fertilization for grain and stover yields. During the two cropping seasons, microdose fertilization increases the DT grain yield and gross return by 658 kg ha−1 and 203$USD, respectively, than their application on drought sensitive variety. The results of the current study demonstrated that there is a considerable potential for smallholder farmers of northern Benin to improve the maize productivity by means of DT varieties and of fertilizer microdosing. Using, especially, the MD3 option on the DT variety, TZE-Y, may be the best combination in optimizing the maize production in the sub-humid region of Benin, instead of the climate sensitive variety of the DMR-ESR under the microdosing or a common fertilization practice. However, further testing of the technologies through on-farm experiments are required before a precise advice can be given. Precisely, there is a need to evaluate these management options in farmer's fields, taking into account the climatic, soil, and management conditions to better assess and understand the variation in response and in economic benefits and risk.

The correct distribution of loads on foot, known as plantar pressures, is a relevant parameter for evaluating the evolution of some diseases. Anomalies can lead to pain and discomfort in other body parts. Diabetes changes foot tissues and compromises biomechanics, resulting in ulcers and, eventually, amputation. Customized insoles allow the redistribution of plantar pressures and are a complementary strategy to diabetes management. Nowadays, scanning and 3D printing technology can generate faster and more accurate customized insoles opening new opportunities for local medical device development. This study reports the development of 3D-printed insoles using two polymers, thermoplastic polyether-polyurethane and thermoplastic polyurethane polyester-based polymer, and the evaluation of plantar pressure distribution in walk trials using a clinical protocol and low-cost electronic system. The two 3D-printed insoles performed as well as a standard insole. No significant difference was found in average peak pressure distribution. The digital manufacturing workflow of customized insoles can be implemented in middle-income countries. Three-dimensionally printed insoles have the potential for diabetes management, and further material evaluations are needed before using them in health facilities.

Background: Radium-223 and enzalutamide are approved agents for patients with metastatic castration-resistant prostate cancer (mCRPC). Combining radium-223 and enzalutamide to improve outcomes is of clinical interest due to their differing modes of action and non-overlapping toxicity profiles. Methods: This phase II study enrolled patients with mCRPC and bone metastases. Patients received six cycles of radium-223 in combination with enzalutamide, followed by enzalutamide alone. The primary endpoint was safety for the combination; secondary endpoints included radiographic/clinical progression-free survival (PFS), PSA PFS, overall survival (OS), change in alkaline phosphatase, patient-reported pain outcomes and skeletal related events. Results: Forty-five patients received the combination treatment: 42 patients (93.3%) received all six cycles. Fourteen patients (31.1%) developed grade 3 or 4 toxicities, most commonly fatigue and neutropaenia. Fractures during the combination period occurred in four patients (8.9%). A further 13 patients (28.9%) developed fractures after completing combination treatment, giving a total of 17 patients (37.8%) who developed a fracture at any time on study. The median time to fracture was greater than 17.2 months [95% confidence interval (CI), 17.2–not estimable]. The median time to PSA progression was 18.1 months (95% CI, 12.68–22.60) and the median time to radiological/clinical progression was 28.0 months (95% CI, 22.54–not reached). At the primary analysis, 19 (42.2%) out of 45 patients had died with a median OS not reached (mean 34.8 months, standard error 1.4). Conclusion: In men with progressive mCRPC and bone metastases, the combination of radium-223 and enzalutamide was tolerable with the majority of patients completing the combination treatment. Bone fractures during the combination period were uncommon; however, we did identify a higher incidence of fractures occurring in patients after completing combination treatment. Bone health agents should be administered and bone health should be closely monitored following treatment with radium-223 and enzalutamide.

When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP+ blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.

Abstract Objective Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS‐evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. Methods TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2‐, 4‐, and 6‐hours post drug intake in a double‐blind, placebo‐controlled, randomized, two‐period crossover study of 20 healthy male volunteers. Results Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15–55 msec after TMS) and at late (150–250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time‐dependent increase that correlated with the XEN1101 plasma concentration. Interpretation Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early‐stage clinical trials.

Adsorption of Hg(II) and Zn(II) ions from a binary solution was examined using activated carbons (ACs) prepared from a lowland bioresource waste (Theobroma cacao pod husk). The aim of the study was to determine the potential for utilizing the plant-based ACs as a low-cost adsorbent for removing the metal ions from a binary. Batch adsorption experimentations were conducted to evaluate the initial metal ion concentration and contact time on adsorption. Spectroscopic studies including FTIR, elemental analysis (EA) and SEM were used for its characterization. Equilibrium data was examined using a comparison of linear Langmuir, Freundlich and Temkin isotherm models. The Langmuir and Temkin isotherm model provided the best fit to the experimental data for both metal ions as indicated by the values of the regression coefficient. The kinetic rates were modeled by using the Lagergren-first-order, pseudo-second-order, Elovich and Intraparticle model. The pseudo-first order, pseudo-second order equations and Elovich equation gave the best fit to the experimental data. The presence of intra-particle diffusion mechanism was prominent, although it was not the sole rate-determining step. The results showed that ACs can be effective for removing Hg(II) and Zn(II) ions from solution.

Abstract Objective Limb girdle muscular dystrophy type R9 (LGMD R9) is an autosomal recessive muscle disease for which there is currently no causative treatment. The development of putative therapies requires sensitive outcome measures for clinical trials in this slowly progressing condition. This study extends functional assessments and MRI muscle fat fraction measurements in an LGMD R9 cohort across 6 years. Methods Twenty‐three participants with LGMD R9, previously assessed over a 1‐year period, were re‐enrolled at 6 years. Standardized functional assessments were performed including: myometry, timed tests, and spirometry testing. Quantitative MRI was used to measure fat fraction in lower limb skeletal muscle groups. Results At 6 years, all 14 muscle groups assessed demonstrated significant increases in fat fraction, compared to eight groups in the 1‐year follow‐up study. In direct contrast to the 1‐year follow‐up, the 6‐min walk test, 10‐m walk or run, timed up and go, stair ascend, stair descend and chair rise demonstrated significant decline. Among the functional tests, only FVC significantly declined over both the 1‐ and 6‐year studies. Interpretation These results further support fat fraction measurements as a primary outcome measure alongside functional assessments. The most appropriate individual muscles are the vastus lateralis, gracilis, sartorius, and gastrocnemii. Using composite groups of lower leg muscles, thigh muscles, or triceps surae, yielded high standardized response means (SRMs). Over 6 years, quantitative fat fraction assessment demonstrated higher SRM values than seen in functional tests suggesting greater responsiveness to disease progression.

Abstract Background In uveal melanomas, immune infiltration is a marker of poor prognosis. This work intended to decipher the biological characteristics of intra‐tumor immune population, compare it to other established biomarkers and to patients' outcome. Methods Primary, untreated, and mainly large uveal melanomas with retinal detachment were analyzed using: transcriptomic profiling (n = 15), RT‐qPCR (n = 36), immunohistochemistry (n = 89), Multiplex Ligation‐dependent Probe Amplification (MLPA) for copy number alterations (CNA) analysis (n = 89), array‐CGH (n = 17), and survival statistics (n = 86). Results Gene expression analysis divided uveal melanomas into two groups, according to the IFNγ/STAT1‐IRF1 pathway activation. Tumors with IFNγ‐signature had poorer prognosis and showed increased infiltration of CD8+ T lymphocytes and macrophages. Cox multivariate analyses of immune cell infiltration with MLPA data delineated better prognostic value for three prognostic groups (three‐tier stratification) than two (two‐tier stratification). CNA‐based model comprising monosomy 3, 8q amplification, and LZTS1and NBL1 deletions emerged as the best predictor for disease‐free survival. It outperformed immune cell infiltration in receiver operating characteristic curves. The model that combined CNA and immune infiltration defined risk‐groups according to the number of DNA alterations. Immune cell infiltration was increased in the high‐risk group (73.7%), where it did not correlate with patient survival, while it was associated with poorer outcome in the intermediate risk‐group. Conclusions High degree of immune cell infiltration occurs in a subset of uveal melanomas, is interferon‐gamma‐related, and associated with poor survival. It allows for two‐tier stratification, which is prognostically less efficient than a three‐tier one. The best prognostic stratification is by CNA model with three risk‐groups where immune cell infiltration impacts only some subgroups.

Practice of sports during childhood or adolescence correlates with an earlier onset and more rapidly progressing phenotype in dysferlinopathies. To determine if this correlation relates to greater muscle pathology that persists into adulthood, we investigated the effect of exercise on the degree of muscle fatty replacement measured using muscle MRI. We reviewed pelvic, thigh and leg T1W MRI scans from 160 patients with genetically confirmed dysferlinopathy from the Jain Foundation International clinical outcomes study in dysferlinopathy. Two independent assessors used the Lamminen-Mercuri visual scale to score degree of fat replacement in each muscle. Exercise intensity for each individual was defined as no activity, minimal, moderate, or intensive activity by using metabolic equivalents and patient reported frequency of sports undertaken between the ages of 10 and 18. We used ANCOVA and linear modeling to compare the mean Lamminen-Mercuri score for the pelvis, thigh, and leg between exercise groups, controlling for age at assessment and symptom duration. Intensive exercisers showed greater fatty replacement in the muscles of the pelvis than moderate exercisers, but no significant differences of the thigh or leg. Within the pelvis, Psoas was the muscle most strongly associated with this exercise effect. In patients with a short symptom duration of

The dynamic organization of actin cytoskeleton meshworks relies on multiple actin-binding proteins endowed with distinct actin-remodeling activities. Filamin A is a large multi-domain scaffolding protein that cross-links actin filaments with orthogonal orientation in response to various stimuli. As such it plays key roles in the modulation of cell shape, cell motility, and differentiation throughout development and adult life. The essentiality and complexity of Filamin A is highlighted by mutations that lead to a variety of severe human disorders affecting multiple organs. One of the most conserved activity of Filamin A is to bridge the actin cytoskeleton to integrins, thereby maintaining the later in an inactive state. We here review the numerous mechanisms cells have developed to adjust Filamin A content and activity and focus on the function of Filamin A as a gatekeeper to integrin activation and associated adhesion and motility.

Human movement affects malaria epidemiology at multiple geographical levels; however, few studies measure the role of human movement in the Amazon Region due to the challenging conditions and cost of movement tracking technologies. We developed an open-source low-cost 3D printable GPS-tracker and used this technology in a cohort study to characterize the role of human population movement in malaria epidemiology in a rural riverine village in the Peruvian Amazon. In this pilot study of 20 participants (mean age = 40 years old), 45,980 GPS coordinates were recorded over 1 month. Characteristic movement patterns were observed relative to the infection status and occupation of the participants. Applying two analytical animal movement ecology methods, utilization distributions (UDs) and integrated step selection functions (iSSF), we showed contrasting environmental selection and space use patterns according to infection status. These data suggested an important role of human movement in the epidemiology of malaria in the Peruvian Amazon due to high connectivity between villages of the same riverine network, suggesting limitations of current community-based control strategies. We additionally demonstrate the utility of this low-cost technology with movement ecology analysis to characterize human movement in resource-poor environments.

Summary: Defining the pathways that control cardiac development facilitates understanding the pathogenesis of congenital heart disease. Herein, we identify enrichment of a Cullin5 Ub ligase key subunit, Asb2, in myocardial progenitors and differentiated cardiomyocytes. Using two conditional murine knockouts, Nkx+/Cre.Asb2fl/fl and AHF-Cre.Asb2fl/fl, and tissue clarifying technique, we reveal Asb2 requirement for embryonic survival and complete heart looping. Deletion of Asb2 results in upregulation of its target Filamin A (Flna), and concurrent Flna deletion partially rescues embryonic lethality. Conditional AHF-Cre.Asb2 knockouts harboring one Flna allele have double outlet right ventricle (DORV), which is rescued by biallelic Flna excision. Transcriptomic and immunofluorescence analyses identify Tgfβ/Smad as downstream targets of Asb2/Flna. Finally, using CRISPR/Cas9 genome editing, we demonstrate Asb2 requirement for human cardiomyocyte differentiation suggesting a conserved mechanism between mice and humans. Collectively, our study provides deeper mechanistic understanding of the role of the ubiquitin proteasome system in cardiac development and suggests a previously unidentified murine model for DORV. : Biological Sciences; Molecular Biology; Developmental Biology Subject Areas: Biological Sciences, Molecular Biology, Developmental Biology

The efficacy of immune checkpoint inhibitors has been shown to depend on preexisting antitumor immunity; thus, their combination with cancer vaccines is an attractive therapeutic approach. Plasmacytoid dendritic cells (PDC) are strong inducers of antitumor responses and represent promising vaccine candidates. We developed a cancer vaccine approach based on an allogeneic PDC line that functioned as a very potent antigen-presenting cell in pre-clinical studies. In this phase Ib clinical trial, nine patients with metastatic stage IV melanoma received up to 60 million irradiated PDC line cells loaded with 4 melanoma antigens, injected subcutaneously at weekly intervals. The primary endpoints were safety and tolerability. The vaccine was well tolerated and no serious vaccine-induced side effects were recorded. Strikingly, there was no allogeneic response toward the vaccine, but a significant increase in the frequency of circulating anti-tumor specific T lymphocytes was observed in two patients, accompanied by a switch from a naïve to memory phenotype, thus demonstrating priming of antigen-specific T-cells. Signs of clinical activity were observed, including four stable diseases according to IrRC and vitiligoïd lesions. Four patients were still alive at week 48. We also demonstrate the in vitro enhancement of specific T cell expansion induced by the synergistic combination of peptide-loaded PDC line with anti-PD-1, as compared to peptide-loaded PDC line alone. Taken together, these clinical observations demonstrate the ability of the PDC line based-vaccine to prime and expand antitumor CD8+ responses in cancer patients. Further trials should test the combination of this vaccine with immune checkpoint inhibitors.

Introduction Prevalence and tobacco-related perioperative complications have been largely reported. The impact of vaping (e-cigarette use) on the perioperative period has been rarely evaluated. The purpose of this multicentre cross-sectional survey was to assess the prevalence of vaping and behaviour of patients undergoing elective surgery. Methods After institutional review board committee and patient approvals, patients (aged ≥18 years) scheduled for elective non-cardiac surgery in six French hospitals were assessed preoperatively. Demographic characteristics, and information on vaping, smoking or dual-use status and consumption were reported. Results In six centres, 1712 eligible patients were approached and 1664 patients were included in this study from June 2016 to January 2017. Of these, 62 patients used e-cigarettes in the preoperative period (3%; 95% CI: 2–4), including 24 exclusive e-cigarette users (1%; 95% CI: 1–2), 38 dual-users (2%; 95% CI: 2–3) and 365 smokers (22%; 95% CI: 20–24). Vapers were older than smokers (53 vs 47 years old; p=0.01). During the preoperative period, 12 patients (1%) reported vaping the morning of surgery. Conclusions In the preoperative period, vaping was ten-fold less prevalent than smoking. Although the clinical relevance may be weak, further research is needed to explore the real impact of vaping on patients’ outcomes and to elaborate on clinical recommendations. TRIAL REGISTRATION Clinical Trials.gov: NCT03594643

Fertilizer microdosing is being widely promoted across sub-Saharan Africa, yet all recommendations regarding this technology are derived from short-term studies. Such studies are insufficient to properly assess the production risk caused by climatic variability. To address this issue while avoiding costly long-term experiments, a common and well accepted strategy is to combine results from short-term experiments with validated dynamic crop models. However, there have been few documented attempts so far to model fertilizer microdosing under sub-humid tropical conditions. The objective was therefore to evaluate the potential of the DSSAT model for simulating maize response to fertilizer microdosing, and to use the validated model to assess the effects of inter-annual rainfall variability on maize productivity and economic risk. The model was calibrated and validated against data from a 2-year on-station experiment (2014 and 2015) with 2 levels of hill-placed manure and five mineral fertilization options including broadcast and fertilizer microdosing. Model simulations were in good agreement with the observed grain and biomass yields for conventional broadcast fertilization, with relative RMSE and d-values of 12% and 0.96 for grain and 8% and 0.97 for biomass, respectively. For fertilizer microdosing, the N stress coefficient needed to be adjusted to avoid occurrence of large N stresses during simulation. After optimization, the model adequately reproduced grain yields for fertilizer microdosing, with relative RMSE of 10%. Considering the long-term scenario analysis, the use of the validated model showed that the application of 2 g of NPK15−15−15 fertilizer + 1 g urea per hill (equivalent to 23.8 kg N ha−1, 4.1 kg P ha−1 and 7.8 kg K ha−1) improved both the minimum guaranteed yield and the long-term average without increasing inter-annual variability and the economic risk compared to unfertilized plots. Even though combining microdosing with manure (1–3 t ha−1) was economically slightly riskier than microdosing alone, this risk remained low since a value-cost ratio of 2 could be achieved in almost 100% of the years. Furthermore, combined application consistently reduced the inter-annual yield variability. Considering this as well as the other benefits of manure for soil health, combining microdosing with small quantities of manure would be recommended to increase the sustainability of the system.

BackgroundKetorolac has been associated with a lower risk of recurrence in retrospective studies, especially in patients with positive inflammatory markers. It is still unknown whether a single dose of pre-incisional ketorolac can prolong recurrence-free survival.MethodsThe KBC trial is a multicenter, placebo-controlled, randomized phase III trial in high-risk breast cancer patients powered for 33% reduction in recurrence rate (from 60 to 40%). Patients received one dose of ketorolac tromethamine or a placebo before surgery. Eligible patients were breast cancer patients, planned for curative surgery, and with a Neutrophil-to-Lymphocyte Ratio≥4, node-positive disease or a triple-negative phenotype. The primary endpoint was Disease-Free Survival (DFS) at two years. Secondary endpoints included safety, pain assessment and overall survival.FindingsBetween February 2013 and July 2015, 203 patients were assigned to ketorolac (n = 96) or placebo (n = 107). Baseline characteristics were similar between arms. Patients had a mean age of 55.7 (SD14) years. At two years, 83.1% of the patients were alive and disease free in the ketorolac vs. 89.7% in the placebo arm (HR: 1.23; 95%CI: 0.65-2.31) and, respectively, 96.8% vs. 98.1% were alive (HR: 1.09; 95%CI: 0.34-3.51).ConclusionsA single administration of 30 mg of ketorolac tromethamine before surgery does not increase disease-free survival in high risk breast cancer patients. Overall survival difference between ketorolac tromethamine group and placebo group was not statistically significant. The study was however underpowered because of lower recurrence rates than initially anticipated. No safety concerns were observed.Trial registrationClinicalTrials.gov NCT01806259.

ABSTRACT Phosphate acquisition by fungi is regulated by the phosphate-sensing and acquisition (PHO) signaling pathway. Cryptococcus neoformans disseminates from the lung to the brain and is the commonest cause of fungal meningitis worldwide. To investigate the contribution of PHO signaling to cryptococcal dissemination, we characterized a transcription factor knockout strain (hlh3Δ/pho4Δ) defective in phosphate acquisition. Despite little similarity with other fungal Pho4 proteins, Hlh3/Pho4 functioned like a typical phosphate-responsive transcription factor in phosphate-deprived cryptococci, accumulating in nuclei and triggering expression of genes involved in phosphate acquisition. The pho4Δ mutant strain was susceptible to a number of stresses, the effect of which, except for alkaline pH, was alleviated by phosphate supplementation. Even in the presence of phosphate, the PHO pathway was activated in wild-type cryptococci at or above physiological pH, and under these conditions, the pho4Δ mutant had a growth defect and compromised phosphate uptake. The pho4Δ mutant was hypovirulent in a mouse inhalation model, where dissemination to the brain was reduced dramatically, and markedly hypovirulent in an intravenous dissemination model. The pho4Δ mutant was not detected in blood, nor did it proliferate significantly when cultured with peripheral blood monocytes. In conclusion, dissemination of infection and the pathogenesis of meningitis are dependent on cryptococcal phosphate uptake and stress tolerance at alkaline pH, both of which are Pho4 dependent. IMPORTANCE Cryptococcal meningitis is fatal without treatment and responsible for more than 500,000 deaths annually. To be a successful pathogen, C. neoformans must obtain an adequate supply of essential nutrients, including phosphate, from various host niches. Phosphate acquisition in fungi is regulated by the PHO signaling cascade, which is activated when intracellular phosphate decreases below a critical level. Induction of phosphate acquisition genes leads to the uptake of free phosphate via transporters. By blocking the PHO pathway using a Pho4 transcription factor mutant (pho4Δ mutant), we demonstrate the importance of the pathway for cryptococcal dissemination and the establishment of brain infection in murine models. Specifically, we show that reduced dissemination of the pho4Δ mutant to the brain is due to an alkaline pH tolerance defect, as alkaline pH mimics the conditions of phosphate deprivation. The end result is inhibited proliferation in host tissues, particularly in blood. Podcast: A podcast concerning this article is available.

SUMMARY Although muscular dystrophies are among the most common human genetic disorders, there are few treatment options available. Animal models have become increasingly important for testing new therapies prior to entering human clinical trials. The Dmdmdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD), presenting the same molecular and protein defect as seen in humans with the disease. However, this mouse is not useful for clinical trials because of its very mild phenotype. The mouse model for congenital myodystrophy type 1D, Largemyd, harbors a mutation in the glycosyltransferase Large gene and displays a severe phenotype. To help elucidate the role of the proteins dystrophin and LARGE in the organization of the dystrophin-glycoprotein complex in muscle sarcolemma, we generated double-mutant mice for the dystrophin and LARGE proteins. The new Dmdmdx/Largemyd mouse model is viable and shows a severe phenotype that is associated with the lack of dystrophin in muscle. We tested the usefulness of our new mouse model for cell therapy by systemically injecting them with normal murine mesenchymal adipose stem cells (mASCs). We verified that the mASCs were hosted in the dystrophic muscle. The new mouse model has proven to be very useful for the study of several other therapies, because injected cells can be screened both through DNA and protein analysis. Study of its substantial muscle weakness will also be very informative in the evaluation of functional benefits of these therapies.

The Common Rule is a set of ethical principles that provide guidance on the management of human subjects taking part in biomedical and behavioral research in the United States. The elements of the Common Rule were initially developed in 1981 following a revision of the Declaration of Helsinki in 1975. Most academic facilities follow the Common Rule in the regulation of clinical trials research. Recently, the government has suggested a revision of the Common Rule to include more contemporary and streamlined oversight of clinical research. In this commentary, the leadership of the Society for Immunotherapy of Cancer (SITC) provides their opinion on this plan. While the Society recognizes the considerable contribution of clinical research in supporting progress in tumor immunotherapy and supports the need for revisions to the Common Rule, there is also some concern over certain elements which may restrict access to biospecimens and clinical data at a time when high throughput technologies, computational biology and assay standardization is allowing major advances in understanding cancer biology and providing potential predictive biomarkers of immunotherapy response. The Society values its professional commitment to patients for improving clinical outcomes with tumor immunotherapy and supports continued discussion with all stakeholders before implementing changes to the Common Rule in order to ensure maximal patient protections while promoting continued clinical research at this historic time in cancer research.

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of so-called damage-associated molecular patterns (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical and clinical aspects of ICD, in an attempt to capture the essence of this clinically relevant phenomenon, and identify future challenges for this rapidly expanding field of investigation.

Orientation: Increasing competition has resulted in clothing retailers placing more emphasis on expensive relationship marketing tactics to retain customers. The retailers often use customers’ loyalty programme membership and the duration of their support to identify and target them in relationship-building efforts. Research purpose: This study determines the viability of relationship intention by measuring and categorising clothing customers according to their relationship intentions. The study also explores the duration of customer support for a clothing retailer, membership of their loyalty programme and the relationship thereof with customers’ relationship intentions towards that retailer. Motivation for the study: Relationship building efforts would be better directed at customers with relationship intentions. Research design, approach and method: Quantitative in nature, this study followed a descriptive research design and used an interviewer-administered survey to collect data from 511 clothing retail customers residing in the greater Pretoria metropolitan area. Main findings: Clothing retailers can effectively determine and categorise customers according to their relationship intentions. The duration customers have supported a clothing retailer and its loyalty programme has no relationship with their relationship intentions. Practical/Managerial implications: Clothing retailers should focus their relationship building on customers with relationship intentions, as they are more likely to respond favourably. They are more likely to be retained by the clothing retailer and provide a return on investment. Contribution/value-add: This study gives clothing retailers a reliable and valid measuring instrument that can be used to identify customers with relationship intentions, rather than relying on the duration of the customers’ support and their loyalty programme membership.

Modified Look-Locker Inversion recovery (MOLLI) sequence is increasingly performed for myocardial T1 mapping but is known to underestimate T1 values. The aim of the study was to quantitatively analyze several sources of errors when T1 maps are derived using standard post-processing of the sequence and to propose a reconstruction approach that takes into account inversion efficacy (η), T2 relaxation during balanced steady-state free-precession readouts and B1+ inhomogeneities. Contributions of the different sources of error were analyzed using Bloch equations simulations of MOLLI sequence. Bloch simulations were then combined with the acquisition of fast B1+ and T2 maps to derive more accurate T1 maps. This novel approach was evaluated on phantoms and on five healthy volunteers. Simulations show that T2 variations, B1+ heterogeneities and inversion efficiency represent major confounders for T1 mapping when MOLLI is processed with standard 3-parameters fitting. In vitro data indicate that T1 values are accurately derived with the simulation approach and in vivo data suggest that myocardium T1 are 15% underestimated when processed with the standard 3-parameters fitting. At the cost of additional acquisitions, this method might be suitable in clinical research protocols for precise tissue characterization as it decorrelates T1 and T2 effects on parametric maps provided by MOLLI sequence and avoids inaccuracies when B1+ is not homogenous throughout the myocardium.

Quantitative nuclear magnetic resonance imaging (MRI) has been considered a promising non-invasive tool for monitoring therapeutic essays in small size mouse models of muscular dystrophies. Here, we combined MRI (anatomical images and transverse relaxation time constant-T2-measurements) to texture analyses in the study of four mouse strains covering a wide range of dystrophic phenotypes. Two still unexplored mouse models of muscular dystrophies were analyzed: The severely affected Largemyd mouse and the recently generated and worst double mutant mdx/Largemyd mouse, as compared to the mildly affected mdx and normal mice. The results were compared to histopathological findings. MRI showed increased intermuscular fat and higher muscle T2 in the three dystrophic mouse models when compared to the wild-type mice (T2: mdx/Largemyd: 37.6±2.8 ms; mdx: 35.2±4.5 ms; Largemyd: 36.6±4.0 ms; wild-type: 29.1±1.8 ms, p

We conducted a prospective multinational study of muscle pathology using magnetic resonance imaging (MRI) in patients with limb-girdle muscular dystrophy 2I (LGMD2I). Thirty eight adult ambulant LGMD2I patients (19 male; 19 female) with genetically identical mutations (c.826C>A) in the fukutin-related protein (FKRP) gene were recruited. In each patient, T1-weighted (T1w) imaging was assessed by qualitative grading for 15 individual lower limb muscles and quantitative Dixon imaging was analysed on 14 individual lower limb muscles by region of interest analysis. We described the pattern and appearance of muscle pathology and gender differences, not previously reported for LGMD2I. Diffuse fat infiltration of the gastrocnemii muscles was demonstrated in females, whereas in males fat infiltration was more prominent in the medial than the lateral gastrocnemius (p = 0.05). In the anterior thigh of males, in contrast to females, median fat infiltration in the vastus medialis muscle (45.7%) exceeded that in the vastus lateralis muscle (11.2%) (p

Parotidectomy is a surgical procedure associated to functional (Frey’s syndrome) as well as aesthetic (facial asymmetry) complications that can be very disturbing for the patient. Several procedures have been described to primarily avoid or secondarily reconstruct the facial defect and treat the neurological iatrogenic syndrome. Autologous fat transfer was primarily used in 10 cases to avoid such complications. It is an easy technique widely used in cosmetic and reconstructive surgery. This technique gives very satisfying long-term results on the cosmetic as well as on the physiological point of view.