Explore the vast range of titles available.

Innervation of the shoulder joint is complex and remains poorly understood among regional anesthesiologists and chronic pain specialists. Current literature supports the important contribution of the axillary nerve to the total innervation of the shoulder, as well as its blockade for perioperative pain and denervation for chronic shoulder pain. However, a description of the entire course of the axillary nerve, the corresponding optimal targets, and the sonoanatomy pertinent to pain intervention is lacking. This educational article discusses in detail the functional anatomy and sonographic identification of possible windows for axillary nerve intervention. We discuss the contribution, extent, and type of innervation the axillary nerve provides to the shoulder joint, which is often misunderstood. Ultimately, this article serves to stimulate thoughts and ideas for future research in an area where literature is scarce.

Antimicrobial resistance is a global public health concern, and livestock play a significant role in selecting for resistance and maintaining such reservoirs. Here we study the succession of dairy cattle resistome during early life using metagenomic sequencing, as well as the relationship between resistome, gut microbiota, and diet. In our dataset, the gut of dairy calves serves as a reservoir of 329 antimicrobial resistance genes (ARGs) presumably conferring resistance to 17 classes of antibiotics, and the abundance of ARGs declines gradually during nursing. ARGs appear to co-occur with antibacterial biocide or metal resistance genes. Colostrum is a potential source of ARGs observed in calves at day 2. The dynamic changes in the resistome are likely a result of gut microbiota assembly, which is closely associated with diet transition in dairy calves. Modifications in the resistome may be possible via early-life dietary interventions to reduce overall antimicrobial resistance. Livestock play a role in maintaining antibiotic resistance reservoirs. Here, Liu et al. use metagenomics to study the dynamics of antibiotic resistance genes (ARGs) in the gut of dairy cattle during early life, showing that colostrum is a potential source of ARGs and ARG abundance declines during nursing covarying with dietary transition.

We previously reported that the dismutase SOD1 is overexpressed in breast cancer. However, whether SOD1 plays an active role in tumor formation in vivo has never been demonstrated. Further, as luminal cells of normal breast epithelial cells are enriched in SOD1, whether SOD1 is essential for normal mammary gland development has never been determined. We initiated this study to investigate the role of SOD1 in mammary gland tumorigenesis as well as in normal mammary gland development. We crossed the inducible erbB2 (MMTV-iErbB2) and Wnt (MMTV-Wnt) transgenic mice to the SOD1 heterozygote or knockout mice. Our results show that SOD1 is essential for oncogene-driven proliferation, but not normal proliferation of the mammary gland associated with pregnancy or other normal proliferative tissues such as skin and intestines. We show that activation of the oncogene ErbB2 is associated with increased ROS and that high ROS sub-population of ErbB2 cancer cells show elevated SOD1. In the same cells, decrease in SOD1 is associated with an elevation in both apoptosis as well as oncogene-induced senescence. Based on these results, we suggest that SOD1 carries a housekeeping function that maintains ROS levels below a threshold that supports oncogene-dependent proliferation, while allowing escape from oncogene-induced senescence, independently of the oncogene driving tumor formation. These results identify SOD1 as an ideal target for cancer therapy as SOD1 inhibitors hold the potential to prevent the growth of cancers cells of diverse genotypes, activate multiple modes of cell death therefore making acquired resistance more difficult, while sparing normal tissues.

Reports of long-lasting coronavirus disease 2019 (COVID-19) symptoms, the so-called ‘long COVID’, are rising but little is known about prevalence, risk factors or whether it is possible to predict a protracted course early in the disease. We analyzed data from 4,182 incident cases of COVID-19 in which individuals self-reported their symptoms prospectively in the COVID Symptom Study app 1 . A total of 558 (13.3%) participants reported symptoms lasting ≥28 days, 189 (4.5%) for ≥8 weeks and 95 (2.3%) for ≥12 weeks. Long COVID was characterized by symptoms of fatigue, headache, dyspnea and anosmia and was more likely with increasing age and body mass index and female sex. Experiencing more than five symptoms during the first week of illness was associated with long COVID (odds ratio = 3.53 (2.76–4.50)). A simple model to distinguish between short COVID and long COVID at 7 days (total sample size, n  = 2,149) showed an area under the curve of the receiver operating characteristic curve of 76%, with replication in an independent sample of 2,472 individuals who were positive for severe acute respiratory syndrome coronavirus 2. This model could be used to identify individuals at risk of long COVID for trials of prevention or treatment and to plan education and rehabilitation services. Analysis of data from the COVID Symptom Study app reveals fatigue, headache, dyspnea and anosmia as key attributes of long COVID, with those experiencing five or more symptoms during the first week of being at increased risk of prolonged disease.

A field study was carried out to analyze the short-term impacts of replacing mineral by organic fertilizers on the microbial and biochemical parameters relevant for soil fertility and crop yield. Three types of fertilization regimes were compared: (1) conventional fertilizer regime with inorganic fertilizer, and combined integrated fertilizer regimes in which 25 % of the nutrients were supplied by either (2) rabbit manure or (3) vermicompost. The effects on microbial community structure and function (phospholipid fatty acid [PLFA] profiles, bacterial growth, fungal growth, basal respiration, β-glucosidase, protease and phosphomonoesterase activities), soil biochemical properties (total C, dissolved organic carbon [DOC], N-NH 4 + , N-NO 3 − , PO 4 , total K) and crop yield were investigated in the samples collected from the experimental soil at harvest, 3 months after addition of fertilizer. The integrated fertilizer regimes stimulated microbial growth, altered the structure of soil microbial community and increased enzyme activity relative to inorganic fertilization. Bacterial growth was particularly influenced by the type of fertilizer regime supplied, while fungal growth only responded to the amount of fertilizer provided. The use of manure produced a fast increase in the abundance of PLFA biomarkers for Gram-negative bacteria as compared to inorganic fertilizer. Nutrient supply and crop yield with organic fertilizers were maintained at similar levels to those obtained with inorganic fertilizer. The effects of the organic amendments were observed even when they involved a small portion of the total amount of nutrients supplied; thereby confirming that some of the beneficial effects of integrated fertilizer strategies may occur in the short term.

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.

Aims/hypothesisData analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care.MethodsIn total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2 years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes.ResultsThe five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001).Conclusions/interpretationCluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes.Trial registrationORIGIN trial, ClinicalTrials.gov NCT00069784.

The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 ( SLC13A3 ) and ASBT ( SLC10A2 ). Shared genetic determinants of 7,073 metabolite–disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments. Genome-wide studies of 1,916 plasma and urine metabolites from 5,023 participants of the German Chronic Kidney Disease study provide insights into systemic and kidney-specific enzymatic and transport processes.

Saffron apocarotenoids, including crocins, picrocrocin and safranal, are valuable metabolites with pharmaceutical and cosmetic potential. However, their natural plant sources are difficult to cultivate, which limits large-scale production. The identification of carotenoid cleavage dioxygenases (CCDs), which catalyse the first and most critical step in their biosynthesis, has enabled the production of these apocarotenoids in heterologous plant systems. In this study, we aimed to generate plant cell suspensions expressing Crocus sativus CCD2 and Gardenia jasminoides CCD4a, along with a bacterial phytoene synthase to enhance carotenoid biosynthesis and CsUGT93P1, which improves crocin stability. Transgenic cell suspensions were established from Nicotiana benthamiana plants and Nicotiana tabacum cv. BY-2 cells. In BY-2 cells expressing GjCCD4a, crocin accumulation reached 770 μg/g DW, which further increased upon methyl jasmonate elicitation. Remarkably, the BY-2 transgenic cells exhibited an 18,000-fold increase in β-cyclocitral content compared to wild-type cells. The best-performing N. benthamiana and BY-2 lines were successfully cultivated in wave bioreactors, demonstrating their potential for saffron apocarotenoid production. In the BY-2 bioreactor, apart from saffron apocarotenoids, phytoene and notably high amounts of lycopene were produced, adding value to the platform and indicating a remodelling of the carotenoid pathway. This study establishes the viability and lays the foundation for the scalable production of saffron apocarotenoids and carotenoids in plant cell suspensions.

Objectives. Motor vehicle trauma has been effectively reduced over the past decades; however, it is unclear whether the benefits are equally realized by the vehicle users of either sex. With increases in the number of female drivers involved in fatal crashes and similarity in driving patterns and risk behavior, we sought to evaluate if advances in occupant safety technology provide equal injury protection for drivers of either sex involved in a serious or fatal crash. Methods. We performed a retrospective cohort study with national crash data between 1998 and 2008 to determine the role of driver sex as a predictor of injury outcome when involved in a crash. Results. The odds for a belt-restrained female driver to sustain severe injuries were 47% (95% confidence interval = 28%, 70%) higher than those for a belt-restrained male driver involved in a comparable crash. Conclusions. To address the sex-specific disparity demonstrated in this study, health policies and vehicle regulations must focus on effective safety designs specifically tailored toward the female population for equity in injury reduction.