This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were ...initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL.
Objective: Asthma action plans (AAPs) provide asthma management instructions to families; however, AAPs typically are written at a 7th-9th grade reading level, making them less useful in lower ...literacy families. There is a need to develop simpler AAP formats and content to optimize their utility across all families, including those who are rural and may be at a risk for literacy concerns. Because using pictures can simplify and enhance health education, our study's aim was to develop a pictorial AAP through a series of focus groups with key stakeholders - youth with asthma, caregivers, and physicians. Methods: Fourteen caregiver/youth dyads and four physicians participated in separate focus groups where their preferences for pictorial AAP structure and content were obtained. Focus groups were audio recorded, transcribed, coded with ATLAS.ti, and analyzed for themes. Results: Youth and their caregivers prefer that the AAPs include simple, cartoon-like pictures customized to the patient. Physicians emphasized AAP's capability to display pictures of controller medication given its importance in preventing asthma exacerbations. A stoplight format, currently used in most written AAPs, received positive reviews. Specific suggestions for pictures showing symptoms, medications, and how to take medication were suggested. Words and short phrases accompanying the pictures were thought to add clarity. Conclusions: Key stakeholders viewed pictorial AAPs as positive and potentially effective alternatives to standard written AAPs. It is expected that low literacy youth and caregivers would more easily understand a pictorial AAP presentation, which should facilitate better medication adherence and asthma outcomes in these children.
Investigations were undertaken in the context of the potential environmental impact of carbon capture and storage (CCS) transportation in the form of a hypothetical leak of extreme levels of CO2 into ...the soil environment and subsequent effects on plant physiology. Laboratory studies using purpose built soil chambers, separating and isolating the soil and aerial environments, were used to introduce high levels of CO2 gas exclusively into the rhizosphere. CO2 concentrations greater than 32% in the isolated soil environment revealed a previously unknown whole plant stomatal response. Time course measurements of stomatal conductance (gs), leaf temperature and leaf abscisic acid (ABA) show strong coupling between all three variables over a specific period (3 h following CO2 gassing) occurring as a result of CO2‐specific detection by roots. The coupling of gs and ABA subsequently breaks down resulting in a rapid and complete loss of turgor in the shoot. Root access to water is severely restricted as evidenced by the inability to counter turgor loss, however, the plant regains some turgor over time. Recovery of full turgor is not achieved over the longer term. Results suggest an immediate perception and whole plant response as changes in measured parameters (leaf temperature, gs and ABA) occur in the shoot, but the response is solely due to detection of very high CO2 concentration at the root/soil interface which results in loss of stomatal regulation and disruption to control over water uptake.
Abstract Spasticity is often experienced by individuals with injury or illness of the central nervous system from etiologies such as stroke, spinal cord injury, brain injury, multiple sclerosis, or ...other neurologic conditions. Although spasticity may provide benefits in some patients, it more often leads to complications negatively impacting the patient. Nonpharmacologic treatment options often do not provide long-term reduction of spasticity, and systemic interventions, such as oral medications, can have intolerable side effects. The use of botulinum neurotoxin injections is one option for management of focal spasticity. Several localization techniques are available to physicians that allow for identification of the selected target muscles. These methods include anatomic localization in isolation or in conjunction with electromyography guidance, electrical stimulation guidance, or ultrasound guidance. This article will focus on further description of each of these techniques in relation to the treatment of adult spasticity and will discuss the advantages and disadvantages of each technique, as well as review the literature comparing the techniques.
Mechanical injury to the articular cartilage is a key risk factor in joint damage and predisposition to osteoarthritis. Integrative multi-omics approaches provide a valuable tool to understand tissue ...behavior in response to mechanical injury insult and help to identify key pathways linking injury to tissue damage. Global or untargeted metabolomics provides a comprehensive characterization of the metabolite content of biological samples. In this study, we aimed to identify the metabolic signature of cartilage tissue post injury. We employed an integrative analysis of transcriptomics and global metabolomics of murine epiphyseal hip cartilage before and after injury. Transcriptomics analysis showed a significant enrichment of gene sets involved in regulation of metabolic processes including carbon metabolism, biosynthesis of amino acids, and steroid biosynthesis. Integrative analysis of enriched genes with putatively identified metabolite features post injury showed a significant enrichment for carbohydrate metabolism (glycolysis, galactose, and glycosylate metabolism and pentose phosphate pathway) and amino acid metabolism (arginine biosynthesis and tyrosine, glycine, serine, threonine, and arginine and proline metabolism). We then performed a cross analysis of global metabolomics profiles of murine and porcine
cartilage injury models. The top commonly modulated metabolic pathways post injury included arginine and proline metabolism, arginine biosynthesis, glycolysis/gluconeogenesis, and vitamin B6 metabolic pathways. These results highlight the significant modulation of metabolic responses following mechanical injury to articular cartilage. Further investigation of these pathways would provide new insights into the role of the early metabolic state of articular cartilage post injury in promoting tissue damage and its link to disease progression of osteoarthritis.
Robust systematic approaches for the metabolic engineering of cell factories remain elusive. The available models for predicting phenotypical responses and mechanisms are incomplete, particularly ...within the context of compound toxicity that can be a significant impediment to achieving high yields of a target product. This study describes a Multi-Omic Based Production Strain Improvement (MOBpsi) strategy that is distinguished by integrated time-resolved systems analyses of fed-batch fermentations. As a case study, MOBpsi was applied to improve the performance of an Escherichia coli cell factory producing the commodity chemical styrene. Styrene can be bio-manufactured from phenylalanine via an engineered pathway comprised of the enzymes phenylalanine ammonia lyase and ferulic acid decarboxylase. The toxicity, hydrophobicity, and volatility of styrene combine to make bio-production challenging. Previous attempts to create styrene tolerant E. coli strains by targeted genetic interventions have met with modest success. Application of MOBpsi identified new potential targets for improving performance, resulting in two host strains (E. coli NST74ΔaaeA and NST74ΔaaeA cpxPo) with increased styrene production. The best performing re-engineered chassis, NST74ΔaaeA cpxPo, produced ∼3 × more styrene and exhibited increased viability in fed-batch fermentations. Thus, this case study demonstrates the utility of MOBpsi as a systematic tool for improving the bio-manufacturing of toxic chemicals.
•Product toxicity impairs the performance of cell factories and limits yields.•Systematic approaches to improve strains producing toxic chemicals are few.•MOBpsi integrates time-resolved multi-omic and analytic data from production runs.•The power of MOBpsi was tested with an E. coli cell factory producing styrene.•New genetic interventions were implemented that enhanced styrene production.
Objective: The main objective of this study was to describe the use and limitations of tonsil scrapings (TS), oral fluids (OF), nasal swabs (NS), and environmental swabs (ES) to detect porcine ...reproductive and respiratory syndrome virus (PRRSV). Materials and methods: Two PRRSV-positive growing pig farms using different PRRSV control strategies were enrolled in this study. Sampling began approximately 52- and 21-days post PRRSV exposure for farms 1 and 2, respectively, and occurred once a month for four months using fixed spatial sampling. Samples for OF and ES were collected at the pen level and TS and NS samples were collected at the individual level. All samples were tested using reverse transcriptase-polymerase chain reaction (RT-PCR). Results: A total of 192 samples were collected over the study period: 48 TS, 48 OF, 48 NS, and 48 ES. Overall, 20 TS (41.6%), 0 OF (0.0%), 6 NS (12.5%), and 1 ES (2.1%) tested RT-PCR positive for PRRSV throughout this study. Implications: Tonsil scraping samples yielded more positive PRRSV RT-PCR results for longer time periods when compared to OF, NS, and ES for PRRSV detection in growing pigs. Tonsil scraping samples tested RT-PCR positive for PRRSV up to 168 days post exposure. Oral fluids, NS, and ES sampling methods for PRRSV detection in growing pig populations, particularly months after the initial infection or vaccination, should be used with caution given low RT-PCR positive samples found in this study.
Objective: This qualitative study aimed to explore sun protection barriers and enablers in secondary schools in Victoria.
Methods: Five focus groups were conducted with nominated Health or Physical ...Education (PE) Coordinators (or other staff representatives) from schools in metropolitan and regional Victoria. Discussions were audio-recorded, transcribed and coded thematically.
Results: Participants identified the need for regulatory influences that included minimum standards for sun protection policy, training and shade in the built environment. Participants perceived that sun protection is not always acknowledged to be a duty of care in secondary schools. A crowded health and well-being curriculum, a focus on fostering independence, and challenges overcoming peer norms were perceived to be important contextual influences. At an organisational level, strong leadership and a united approach among staff were identified as critical ingredients for successful policy implementation and organisational change. Several potentially effective strategies were proposed, including increased shade, leveraging from student leaders, normalising sun protection practices and prioritising staff role modelling.
Conclusions: A cultural shift is required for many schools to accept and act on sun protection as a duty of care. A comprehensive approach that includes regulatory action, healthy school policies and leading by example may help protect students and staff from harmful UV exposure during school hours.
In commercial pig farming, sick or injured sows are often treated by producers or hired staff. To date, limited quantitative data exists on treatment compliance and the possible effect on sow ...longevity post-treatment. The objective of the study was to quantify on-farm compliance of treatment selection, frequency, and dosage, as well as to investigate the association between body condition scores (BCS) and other sow-level factors on post-treatment cull risk.
On-farm treatment records, including culling reason or reason of death up to 6 months post-treatment, production records and sow characteristics were obtained for 134 sows over an 8-week period. Treatment compliance was based on the accuracy of recorded treatments compared to the herd veterinarian's established treatment guidelines. Univariable and multivariable logistic regression models including treatment reason, treatment compliance, BCS, parity, production stage and production metrics, were constructed to investigate associations between those variables and sow culling or death. This study found low compliance for on-farm sow treatment protocols, with only 22.4% (30/134) of the sows receiving correct and complete treatment during the duration of the study. No effect of individual treatment components (drug, dosage, or frequency) on sow culling was observed. A trend for an interaction between treatment compliance and BCS was found, and parity and number of piglets born alive were identified as predictors for sow maintenance in the herd.
On-farm sow treatment compliance was low, resulting in that approximately 80% of the enrolled sows were not treated according to existing guidelines. Non-compliance of treatment guidelines did not seem to affect the risk of culling in treated sows but may have prolonged any associated pain, recovery time and negatively impacted the sow welfare during that time period.
Untargeted metabolomics is a powerful tool for measuring and understanding complex biological chemistries. However, employment, bioinformatics and downstream analysis of mass spectrometry (MS) data ...can be daunting for inexperienced users. Numerous open-source and free-to-use data processing and analysis tools exist for various untargeted MS approaches, including liquid chromatography (LC), but choosing the 'correct' pipeline isn't straight-forward. This tutorial, in conjunction with a user-friendly online guide presents a workflow for connecting these tools to process, analyse and annotate various untargeted MS datasets. The workflow is intended to guide exploratory analysis in order to inform decision-making regarding costly and time-consuming downstream targeted MS approaches. We provide practical advice concerning experimental design, organisation of data and downstream analysis, and offer details on sharing and storing valuable MS data for posterity. The workflow is editable and modular, allowing flexibility for updated/changing methodologies and increased clarity and detail as user participation becomes more common. Hence, the authors welcome contributions and improvements to the workflow via the online repository. We believe that this workflow will streamline and condense complex mass-spectrometry approaches into easier, more manageable, analyses thereby generating opportunities for researchers previously discouraged by inaccessible and overly complicated software.
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