3E-5 and 1.3E-6, respectively). The risk scores were positively correlated with each other (rho=0.52, p<0.001). AUCs for the Comorbidity and Text-based scores were high (0.79 and 0.76, respectively). Follow-up manual review of discrepant findings revealed strengths of data-driven methods over manual review, and opportunities for improvement in risk assessment.

Risk scores comprising comorbidities and text offer differing but synergistic insights into characterizing problematic opioid use. This pilot project establishes a foundation for more robust work in the future.

Risk scores comprising comorbidities and text offer differing but synergistic insights into characterizing problematic opioid use. This pilot project establishes a foundation for more robust work in the future.

Studies suggest superior outcomes with use of intravenous (IV) balanced fluids compared to normal saline (NS). However, significant fluid prescribing variability persists, highlighting the knowledge-to-practice gap. We sought to identify contributors to prescribing variation and utilize a clinical decision support system (CDSS) to increase institutional balanced fluid prescribing.

This single-center informatics-enabled quality improvement initiative for patients hospitalized or treated in the emergency department included stepwise interventions of 1) identification of design factors within the computerized provider order entry (CPOE) of our electronic health record (EHR) that contribute to preferential NS ordering, 2) clinician education, 3) fluid stocking modifications, 4) re-design and implementation of a CDSS-integrated IV fluid ordering panel, and 5) comparison of fluid prescribing before and after the intervention. EHR-derived prescribing data was analyzed via single interrupted time series.

Pre-ind increase in balanced fluid prescribing. This impact far exceeded that of clinician education highlighting the importance of CDSS.In this study, we generated the transcriptome of Muraenesox cinereus from four combined tissues (muscle, sexual, liver and heart) using high-seq sequencing technology. De novo assembly was performed using Trinity software and a total of 62,125,296 high-quality clean reads were assembled and clustered into 75,862 unigene with an N50 of 2034 nt. After annotation, 43,157 unigenes had significant hit in Nr database. And then, 24,510 unigenes were annotated into three GO categories biological processes, cellular components, and molecular functions. Moreover, 33,032 unigenes were mapped 25 different clusters of eukaryotic proteins. Furthermore, we predicted the structure of all unigenes using HMMER and MISA software, respectively. The result showed that a total of 33,183 nucleotide sequences of coding regions (direction of the sequences is 5′- > 3′) were confirmed to the protein database and a total of 29,487 simple sequence repeats (SSR) were identified. The whole transcriptome is an important foundation for future genomic research on the M. cinereus, it could provide comprehensively understanding and further characterizations of transcriptomes of non-model organisms.Sugar-based surfactants are involved in skin related allergy cases in the past decade. Skin irritation starts with the interaction of the surfactant with the skin lipids leading to lipid emulsification and eventual barrier damage. Polymers or co-surfactants can be used to mitigate the allergenic effect but the mechanism of formulation mildness on skin remains unclear. We have used the quartz crystal microbalance (QCM) together with dissipative particle dynamics (DPD) simulation, small angle x-ray scattering (SAXS) as well as cell viability tests to decipher the interactions between poloxamers and sucrose monolaurate (SML), and how these interactions could prevent the disruption of a model supported phospholipid bilayer (SLB). Poloxamer addition to the SML solution can delay or totally prevent the disruption of the SLB depending on poloxamer type and concentration. Poloxamer P407 (Pluronic® F127) delays the onset of disruption while poloxamer P188 (Pluronic® F68) does not preserve the bilayer integrity even at high concentration of up to 15% w/w. Preservation of the SLB is likely due to the differences in the aggregates formation between SML-F127 and SML-F68 mixtures with corresponding retarded motion of SML micelles through the SML-F127 polymer matrix that improved cell viability.

Conversion therapy is a promising option for unresectable locally advanced gastric cancer (GC) patients.This study aimed to investigate the feasibility and efficacy of conversion therapy based on S-1, apatinib combined with transarterial chemotherapy and embolization (TACE).

Twenty eligible unresectable locally advanced GC patients were enrolled in this single-arm, single-center, prospective clinical trial. Apatinib was administered orally at 0.5 g once daily and continuously for 58 d, whileS-1 twice daily on d 1-14 was given at a dose calculated according to the body surface area and repeated every 3 wk for three cycles. TACE (oxaliplatin 80 mg/m

and etoposide 80 mg/m

) was performed on d 1 and was repeated on d 31.

Nineteen patients completed conversion therapy and no treatment-related deaths occurred. The objective response rate (ORR) was 94.7% (18/19) and noncurative factors had resolved in 13 patients (68.4%) based on imaging estimation. 18 patients received laparoscopic examination and 12 cases underwent definitive surgery. Based on the intraoperative and postoperative pathological examination, 10 patients received radical resection (R0+D2/D2+). The patients who underwent the conversion surgery had a superior median overall survival (OS) compared with those who did not (P=0.010).

S-1 combined with apatinib and TACE regimen is feasible for preoperative treating initial unresectable locally advanced GC patients with high rates of objective response and radical resection which may provide a survival benefit.

S-1 combined with apatinib and TACE regimen is feasible for preoperative treating initial unresectable locally advanced GC patients with high rates of objective response and radical resection which may provide a survival benefit.When recycling is beneficial for the environment, results from a life cycle assessment (LCA) should give incentives to collection for recycling and also to the use of recycled material in new products. Many approaches for modeling recycling in LCA assign part of the environmental benefits of recycling to the product where the recycled material is used. For example, the Circular Footprint Formula in the framework for Product Environmental Footprints (PEF) assigns less than 45% of the benefits of recycling to a polymer product sent to recycling. Our calculations indicate that this creates an incorrect climate incentive for incineration of renewable LDPE, when the recovered energy substitutes energy sources with 100-300% more climate impact than the Swedish average district heat and electricity. The risk of incorrect incentives can be reduced through allocating part of the net benefits of energy recovery to the life cycle where the energy is used; we propose this part can be 60% for Sweden, but probably less in countries without a district-heating network. Alternatively, the LCA can include the alternative treatment of waste that is displaced at the incinerator by waste from the investigated product. These solutions both make the LCA more balanced and consistent. The allocation factor 0.6 at incineration almost eliminates the risk of incorrect incentives in a PEF of renewable polymers. However, the focus of LCA on one product at a time might still make it insufficient to guide recycling, which requires concerted actions between actors in different life cycles.Argatroban is a direct anti-IIa (thrombin) anticoagulant, administered as a continuous intravenous infusion; it has been approved in many countries for the anticoagulant management of heparin-induced thrombocytopaenia (HIT). Argatroban was recently proposed as the non-heparin anticoagulant of choice for the management of patients diagnosed with Vaccine-induced Immune Thrombotic Thrombocytopaenia (VITT). Immunoglobulins are also promptly intravenously administered in order to rapidly improve platelet count; concomitant therapy with steroids is also often considered. An ad hoc committee of the French Working Group on Haemostasis and Thrombosis members has worked on updated and detailed proposals regarding the management of anticoagulation with argatroban, based on previously released guidance for HIT, and adapted for VITT. In case of VITT, the initial dose to be preferred is 1.0 µg x kg-1 x min-1, with further dose-adjustments based on iterative and frequent clinical and laboratory assessments. It is strongly a and possible causes for alterations of the clotting time must be taken into account. Specifically, in case of VITT, an aPTT ratio (patient’s / mean normal clotting time) between 1.5 and 2.5 is suggested, to be refined according to the sensitivity of the reagent to the effect of a direct thrombin inhibitor. The sole use of aPTT is discouraged one has to resort to a periodical check with an anti-IIa assay at least, with the help of a specialised laboratory if necessary. Dose modifications should proceed in a stepwise manner with 0.1 to 0.2 µg x kg-1 x min-1 up- or downward changes, taking into account the initial dose, laboratory results, and the whole individual setting. Nomograms are available to adjust the infusion rate. Haemoglobin level, platelet count, fibrinogen plasma level and liver tests should be periodically checked, depending on the clinical status, the more so when unstable.A critical question in visual foraging concerns the mechanisms driving the next target selection. Observers first identify a set of candidate targets, and then select the best option among these candidates. Recent evidence suggests that target selection relies on internal biases towards proximity (nearest target from the last selection), priming (target from the same category as the last selection) and value (target associated with high value). Here, we tested the role of eye movements in target selection, and notably whether disabling eye movements during target selection could affect search strategy. We asked observers to perform four foraging tasks differing by selection modality and target value. During gaze foraging, participants had to accurately fixate the targets to select them and could not anticipate the next selection with their eyes, while during mouse foraging they selected the targets with mouse clicks and were free to move their eyes. We moreover manipulated both target value and proximity. Our results revealed notable individual differences in search strategy, confirming the existence of internal biases towards value, proximity and priming. Critically, there were no differences in search strategy between mouse and gaze foraging, suggesting that disabling eye movements during target selection did not affect foraging behaviour. These results importantly suggest that overt orienting is not necessary for target selection. This study provides fundamental information for theoretical conceptions of attentional selection, and emphasizes the importance of covert attention for target selection during visual foraging.Singular causation queries (e.g., „Did Mary’s taking contraceptives cause her thrombosis?”) are ubiquitous in everyday life and crucial in many professional disciplines, such as medicine or law. Knowledge about general causal regularities is necessary but not sufficient for establishing a singular causation relation because it is possible that co-occurrences consistent with known regularities are in an individual case still just coincidental. Thus, further cues are helpful to establish a singular causation relation. In the present research we focus on information about mechanisms as a potent cue. While previous studies have shown that reasoners consider mechanism information as important when it comes to answering singular causation queries, no formal model has been proposed that explains why this is case. We here present a computational model that explains how causal mechanism information affects singular causation judgments. We also use the model to identify conditions that restrict the utility of mechanism information. We report three experiments testing the implications of our formal analysis. In Experiment 1 we found that reasoners systematically use mechanism information, largely in accordance with our formal model, although we also discovered that some people seem to rely on simpler, computationally less demanding reasoning strategies. The results of Experiments 2 and 3 demonstrate that reasoners have a tentative understanding of the conditions that restrict the utility of causal mechanism information.Matrine, an alkaloid derived from traditional Chinese herbs, has been confirmed to regulate immunity and exert anti-inflammatory effects. Matrine injection has been widely used in clinic therapy for anti-tumor and anti-inflammatory diseases. Heart transplantation(HT) is the only solution for the end-stage heart failure, but it is restricted by the cardiac allograft rejection. One of the important pathophysiological processes of post-transplantation rejection is inflammatory cell infiltration. Matrine has been shown to exert a positive protective effect against oxidative stress injury and inflammation, which likely benefits allograft survival. However, it remains unclear whether matrine inhibits alloimmunity or allograft rejection. In this study, we established the heart transplantation model in mouse and extracted bone marrow-derived dendritic cells (BMDCs) to explore the function and mechanism of matrine in heart transplantation. Moreover, combination treatment with matrine and tacrolimus(FK506) had a synergistic effect in preventing acute rejection of heart transplants. Here we found that matrine can prolong the survival of post-transplant and inhibit inflammatory cell infiltration in transplanted hearts of mice. At the same time, matrine increased Treg ratio and decreased CD4+/CD8 + ratio in mice. More importantly, matrine inhibited DCs maturation in mice and reduced oxidative damage and apoptosis in allograft hearts. Furthermore, matrine also downregulated NF-κB pathway and upregulated ERK1/2 signaling pathway. Overall, our study reveals a novel immunosuppressive agent that has the potential to reduce the side effects of existing immunosuppressive agents when used in combination with them.Recently, the medications used for the severe form of the coronavirus disease-19 (COVID-19) therapy are of particular interest. In this sense, it has been supposed that anti-VEGF compounds would be good candidates in the face of „cytokine storm” and intussuscepted angiogenesis due to having an appreciable anti-inflammatory effect. Therefore, they can be subjected to therapeutic protocols to manage acute respiratory distress syndrome (ARDS). Since the compelling evidence emphasized that VEGFs contribute to the inflammatory process and play a mainstay role in disease pathogenesis, in this review, we aimed to highlight the VEGF’s plausible participation in the cytokine storm exacerbation in COVID-19. Next, the recent clinical advances regarding the anti-VEGF medications, including humanized monoclonal antibody, immunosuppressant, a tyrosine kinase inhibitor, and a cytokine inhibitor, have been addressed in the setting of COVID-19 treatment in critically ill patients. Together, retrieving the increased level of VEGF subsets, as well as antagonizing VEGF related receptors, could be helpful for the treatment of COVID-19, especially in those suffering from ARDS.While most patients with coronavirus disease 2019 (COVID-19) present with mild or moderate symptoms, 15% may develop severe pneumonia, 5% develop acute respiratory distress syndrome (ARDS), septic shock, and multiple organ failure. Some patients may also experience arthralgia or arthritis. Cases of reactive arthritis have been reported during or after COVID-19. With the approval of the use of COVID-19 vaccines, the vaccination program was started in our country and is still continuing.Here we present two patients who developed arthritis after COVID-19 vaccination.Acquired resistance to the antitumor activity of antibodies targeting the programmed death 1 (PD-1) programmed death ligand 1 (PD-L1) immune checkpoint in various types of cancers has increasingly been observed during treatment. To gain insight into the molecular mechanism underlying anti-PD-1 therapy resistance, we developed a mouse MC38 colon adenocarcinoma cell line that was made resistant to anti-PD-1 treatment through repeated in vivo selection. We compared the transcriptomic profiles of anti-PD-1 therapy-resistant and -sensitive tumors using RNA sequencing analysis. The immunosuppressive molecule transmembrane glycoprotein NMB (GPNMB) was significantly upregulated in resistant tumor cells, as determined using quantitative real-time polymerase chain reaction and immunofluorescence analyses. Furthermore, deletion of GPNMB in resistant cells successfully restored sensitivity to anti-PD-1 treatment in vivo. Collectively, our results indicate that tumors may develop resistance to anti-PD-1 therapy by upregulating their expression of the immunosuppressive molecule GPNMB. Furthermore, GPNMB is a potential, targetable biomarker for monitoring adaptive resistance to therapeutic PD-1 blockade, and identification of this immunosuppressive molecule may be a breakthrough for new therapies.

M2 macrophages (M2) can affect tumor development by secreting various cytokines, including exosomes (Exo). Herein, we intended to explore how microRNA (miR)-660-5p-modified M2-Exo affected hepatocellular carcinoma (HCC) development through regulating Kruppel-like factor 3 (KLF3).

miR-660-5p and KLF3 levels were first measured in clinical HCC tissues. A miR-targeted relation was explored between miR-660-5p and KLF3. M2-Exo were modified by miR-660-5p-related oligonucleotides and co-cultured with HepG2 cells to determine their effects on cell proliferation, colony formation, invasion, migration, apoptosis and epithelial-mesenchymal transition (EMT). Xenografted tumors were collected from mice to further verify the in vitro results.

Higher miR-660-5p and lower KLF3 levels were examined in HCC. KLF3 was targeted by miR-660-5p. Up-regulated miR-660-5p-modified M2-Exo boosted the grwoth and EMT of HepG2 cells, but this effect was impaired by overexpression of KLF3. miR-660-5p-loaded M2-Exo enhanced tumorigenic ability of HCC cells in mice. On the contrary, down-regulated miR-660-5p reduced M2-Exo-mediated promotion of growth of HCC cells in vitro and in vivo.

Our study summarizes that miR-660-5p-loaded M2-Exo augment HCC development through down-regulating KLF3.

Our study summarizes that miR-660-5p-loaded M2-Exo augment HCC development through down-regulating KLF3.

An increasing amount of evidence indicates that an adverse perinatal environment contributes to a higher risk of metabolic disorders in later life of the offspring. However, the molecular mechanisms are largely unknown. Thus, we investigated the contribution of maternal high-calorie diet and osteocalcin to metabolic homeostasis in the offspring.

Female 8-week-old C57Bl/6N mice were mated with age-matched males and allocated randomly to three groups a normal-diet or a high-fat, high-sucrose diet group, which was administered either saline (control) or GluOC (10 ng/g body mass) from the day of mating to that of delivery, and the dams were fed ND after the delivery. Pups weaned at 24 days after birth were analyzed.

A maternal high-fat, high-sucrose diet during pregnancy causes metabolic disorders in the liver of the offspring via hypermethylation of the Pygl gene, encoding glycogen phosphorylase L, which mediates hepatic glycogenolysis. The lower expression of Pygl induced by the maternal diet causes the hepatic accumulation of glycogen and triglyceride in the offspring, which remains in adulthood. In addition, the administration of uncarboxylated osteocalcin during pregnancy upregulates Pygl expression via both direct CREBH and ATF4 and indirect epigenomic pathways, resulting in the mitigation of the maternal diet-induced obesity and abnormal glucose and lipid metabolism in adulthood.

We propose that maternal energy status is reflected in the hepatic glycogenolysis capacity of the offspring via epigenetic modification of Pygl and uncarboxylated osteocalcin regulates glycogenolysis.

We propose that maternal energy status is reflected in the hepatic glycogenolysis capacity of the offspring via epigenetic modification of Pygl and uncarboxylated osteocalcin regulates glycogenolysis.

Although previous studies found that maternal fish intake is associated with fetal growth, the role of freshwater fish intake remains unknown.

This study aimed to examine the relationships of freshwater fish and n-3 polyunsaturated fatty acids (n-3 PUFAs) intake with the risk of small for gestational age (SGA) in Chinese pregnant women.

Prospective analysis of data from the Tongji Birth cohort (TJBC) in Wuhan, China, from 2018 to 2021.

This study included 1701 pregnant women who had completed a food frequency questionnaire (FFQ) dietary assessment during mid-pregnancy.

Intake of fish was assessed by a semi-quantitative FFQ. Total intake of n-3 PUFAs was the sum of data collected from both dietary and supplemental sources of n-3 PUFAs. Birth information was extracted from medical records.

Multivariate logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs).

The median (IQR) intake of freshwater fish and total n-3 PUFAs was 12.1 (4.3-26.4) g/day andd areas of developing countries.We evaluated the antimicrobial susceptibility of Gram-negative bacteria recovered from ICU patients in US hospitals and compared them to those from non-ICU patients from the same hospitals during the same period. Overall, 4,680 isolates from ICU patients and 16,263 isolates from non-ICU patients were collected from 70 US medical centers in 2018-2020 and susceptibility tested by the broth microdilution method. Ceftazidime-avibactam and ceftolozane-tazobactam were the most active agents against P. aeruginosa and retained activity against multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates. Minocycline and trimethoprim-sulfamethoxazole were very active against S. maltophilia, whereas most antimicrobial agents exhibited low susceptibility to A. baumannii. Ceftazidime-avibactam and meropenem-vaborbactam were the most active agents against Enterobacterales, and retained potent activity against ESBL producers, carbapenem-resistant Enterobacterales (CRE), MDR, and XDR isolates. In summary, antimicrobial susceptibility was generally lower and the occurrence of ESBL, CRE, MDR, and XDR phenotypes were clearly higher among ICU compared to non-ICU isolates.The ability to detect the abstract pattern underlying a temporal sequence of events is crucial to many human activities, including language and mathematics, but its cortical correlates remain poorly understood. It is also unclear whether repeated exposure to the same sequence of sensory stimuli is sufficient to induce the encoding of an abstract amodal representation of the pattern. Using functional MRI, we probed the existence of such abstract codes for sequential patterns, their localization in the human brain, and their relation to existing language and math-responsive networks. We used a passive sequence violation paradigm, in which a given sequence is repeatedly presented before rare deviant sequences are introduced. We presented two binary patterns, AABB and ABAB, in four presentation formats, either visual or auditory, and either cued by the identity of the stimuli or by their spatial location. Regardless of the presentation format, a habituation to the repeated pattern and a response to pattern violations were seen in a set of inferior frontal, intraparietal and temporal areas. Within language areas, such pattern-violation responses were only found in the inferior frontal gyrus (IFG), whereas all math-responsive regions responded to pattern changes. Most of these regions also responded whenever the modality or the cue changed, suggesting a general sensitivity to violation detection. Thus, the representation of sequence patterns appears to be distributed, yet to include a core set of abstract amodal regions, particularly the IFG.Cognitive and behavioural outcomes in stroke reflect the interaction between two complex anatomically-distributed patterns the functional organization of the brain and the structural distribution of ischaemic injury. Conventional outcome models-for individual prediction or population-level inference-commonly ignore this complexity, discarding anatomical variation beyond simple characteristics such as lesion volume. This sets a hard limit on the maximum fidelity such models can achieve. High-dimensional methods can overcome this problem, but only at prohibitively large data scales. Drawing on one of the largest published collections of anatomically-registered imaging of acute stroke-N = 1333-here we use non-linear dimensionality reduction to derive a succinct latent representation of the anatomical patterns of ischaemic injury, agglomerated into 21 distinct intuitive categories. We compare the maximal predictive performance it enables against both simpler low-dimensional and more complex high-dimensional representations, employing multiple empirically-informed ground truth models of distributed structure-outcome relationships. We show our representation sets a substantially higher ceiling on predictive fidelity than conventional low-dimensional approaches, but lower than that achievable within a high-dimensional framework. Where descriptive simplicity is a necessity, such as within clinical care or research trials of modest size, the representation we propose arguably offers a favourable compromise of compactness and fidelity.

There is limited evidence about which composite feature of asthma self-management strategies is the best and should be adopted into practice.

To compare the efficacy of different strategies to support self-management, based on the newly developed framework, in patients with asthma.

We searched PubMed, EMBASE, CENTRAL, CINAHL, and PsycInfo from 1993 to December 2019. We identified randomized controlled trials that explored effects of strategies to support self-management in adult patients with asthma. We conducted network meta-analyses using a random effects model with usual care as the common comparator. Surface under the cumulative ranking curve (SUCRA) methods were used to rank different support strategies.

Thirty-five trials (5,195 patients) were included and classified based on our newly created TIP framework Theme, Intensity, and Provider. We identified six features from the included trials, each represented by one element of the TIPS framework 1) behavioral support >1/month by e-Health (Behav/High/e-Health); 2) behavioral support >1/month by healthcare personnel (Behav/High/HCP); 3) behavioral support <1/month by HCP (Behav/Low/HCP); 4) education support <1/month by e-Health (Ed/Low/e-Health); 5) education support <1/month by HCP (Ed/Low/HCP); and 6) psychosocial support <1/month by HCP (Psychosoc/Low/HCP). Behav/High/e-Health showed significant improvement in asthma control when compared with other two support strategies, which was confirmed by the highest SUCRA of 97.6%. On the other hand, the SUCRA for Behav/Low/HCP suggested that it has the potential to be the best intervention to reduce the risk of hospitalization (89.1%) and ED visit (84.2%).

Different features of asthma self-management support strategies work best on unique outcomes.

Different features of asthma self-management support strategies work best on unique outcomes.

Cold urticaria is a subtype of chronic inducible urticaria (CIndU) associated with significant morbidity and a risk of anaphylaxis. Few studies have assessed the prevalence, management, and prevalence of associated anaphylaxis of cold urticaria.

To evaluate the prevalence of cold urticaria among CIndU and chronic urticaria (CU) cases, to assess the management of cold urticaria and to determine the prevalence of associated anaphylaxis.

PubMed and EMBASE were searched for studies pertaining to cold urticaria and/or CIndU published in the last 10 years. Meta-analyses were conducted to evaluate the prevalence of cold urticaria among CIndU and chronic urticaria (CU) cases, the management of cold urticaria with H1-antihistamines and omalizumab and the prevalence of associated anaphylaxis.

Twenty-two studies were included in the systematic review and 14 in the meta-analysis. The pooled prevalence of cold urticaria among CU and CIndU cases were 7.62% (95%CI 3.45%, 15.99%; I

=98%) and 26.10% (95%CI 14.17%, 43.05%; I

= 97%), respectively. Cold urticaria was managed by H1-antihistamines in 95.67% (95%CI 92.47%, 97.54%; I

=38%) of patients and omalizumab in 5.95% (95%CI 2.55%, 13.27%; I

=83%) of patients. The pooled prevalence of anaphylaxis among cold urticaria cases was 21.49% (95%CI 15.79%, 28.54%; I

=69%).

Cold urticaria constitutes an appreciable proportion of CIndU and CU cases and is predominantly managed with H1-antihistamines, with a minority of patients receiving omalizumab. Anaphylaxis is not rare, and epinephrine auto-injector (EAI) prescription may be considered.

Cold urticaria constitutes an appreciable proportion of CIndU and CU cases and is predominantly managed with H1-antihistamines, with a minority of patients receiving omalizumab. Anaphylaxis is not rare, and epinephrine auto-injector (EAI) prescription may be considered.

Generally, short-acting beta

-agonist (SABA) delivered via metered dose inhaler (MDI) is recommended for quick relief of asthma symptoms. However, in the PeRson EmPowered Asthma RElief (PREPARE) pragmatic trial, 67% reported having used a nebulizer for SABA administration.

To understand preferences, experiences, and decision-making regarding the use of nebulizers in Black and Latinx adults with uncontrolled asthma.

We interviewed 40 of the 1201 PREPARE patients employing a matrix analysis. Those interviewed were Black (n=20) and Latinx (n=20) adults with uncontrolled asthma seeking primary or specialty care in clinics throughout the United States. Data were analyzed used a Rapid Assessment Procedures (RAP) qualitative methodology, informed by grounded theory.

Sub-study participants, on average, reported using a nebulizer 3.5 times/week. Daily use was common, and frequency ranged from less than daily to up to six times daily. Nearly all participants reported a longstanding history of nebulizer use. Participants tended to use their nebulizer at home, and some shared it with others in the home. Many reported preferring a nebulizer over an MDI for relief of severe symptoms and to avoid ER visits or hospitalizations. The extent to which cost affected nebulizer use varied among participants.

Despite asthma guideline recommendations that MDIs be used rather than nebulizers for SABA administration, nebulizer use was common among PREPARE study participants. Clinicians should explore patients’ history and experiences with nebulizer use as part of evaluation of asthma control.

Despite asthma guideline recommendations that MDIs be used rather than nebulizers for SABA administration, nebulizer use was common among PREPARE study participants. Clinicians should explore patients’ history and experiences with nebulizer use as part of evaluation of asthma control.To investigate the role of SUMO modification in the maintenance of pluripotent stem cells we used ML792, a potent and selective inhibitor of SUMO Activating Enzyme. Treatment of human induced pluripotent stem cells with ML792 resulted in the loss of key pluripotency markers. To identify putative effector proteins and establish sites of SUMO modification, cells were engineered to stably express either SUMO1 or SUMO2 with C-terminal TGG to KGG mutations that facilitate GlyGly-K peptide immunoprecipitation and identification. A total of 976 SUMO sites were identified in 427 proteins. STRING enrichment created 3 networks of proteins with functions in regulation of gene expression, ribosome biogenesis and RNA splicing, although the latter two categories represented only 5% of the total GGK peptide intensity. The remainder have roles in transcription and the regulation of chromatin structure. Many of the most heavily SUMOylated proteins form a network of zinc-finger transcription factors centred on TRIM28 and associated with silencing of retroviral elements. At the level of whole proteins there was only limited evidence for SUMO paralogue-specific modification, although at the site level there appears to be a preference for SUMO2 modification over SUMO1 in acidic domains. We show that SUMO influences the pluripotent state in hiPSCs and identify many chromatin-associated proteins as bona fide SUMO substrates in human induced pluripotent stem cells.Targeted proteomics via selected reaction monitoring (SRM) or parallel reaction monitoring (PRM) enables fast and sensitive detection of a preselected set of target peptides. However, the number of peptides that can be monitored in conventional targeting methods is usually rather small. Recently, a series of methods has been described that employ intelligent acquisition strategies to increase the efficiency of mass spectrometers to detect target peptides. These methods are based on one of two strategies. First, retention time adjustment-based methods enable intelligent scheduling of target peptide retention times. These include Picky, iRT, as well as spike-in free real time adjustment methods like MaxQuant.Live. Second, in spike-in triggered acquisition methods like SureQuant, Pseudo-PRM, TOMAHAQ and Scout-MRM, targeted scans are initiated by abundant labeled synthetic peptides added to samples before the run. Both strategies enable the mass spectrometer to better focus data acquisition time on target peptides. This either enables more sensitive detection or a higher number of targets per run. Here, we provide an overview of available advanced targeting methods and highlight their intrinsic strengths and weaknesses and compatibility with specific experimental setups. Our goal is to provide a basic introduction to advanced targeting methods for people starting to work in this field.Helminths are masters at manipulating host’s immune response. Especially parasitic nematodes have evolved strategies that allow them to evade, suppress, or modulate host’s immune response to persist and spread in the host’s organism. While the immunomodulatory effects of nematodes on their hosts are studied with a great commitment, very little is known about nematodes’ own immune system, immune response to their pathogens, and interactions between parasites and bacteria in the host’s organism. To illustrate the response of the parasitic nematode A. simplex s.s. during simulated interaction with Escherichia coli, different concentrations of lipopolysaccharide (LPS) were used, and the proteomic analysis with isobaric mass tags for relative and absolute quantification (TMT-based LC-MS/MS) was performed. In addition, gene expression and biochemical analyzes of selected markers of oxidative stress were determined. The results revealed 1,148 proteins in a group of which 115 were identified as differentially regulated proteins (DRPs), e.g., peroxiredoxin, thioredoxin, macrophage migration inhibitory factor. Gene Ontology annotation and Reactome pathway analysis indicated that metabolic pathways related to catalytic activity, oxidation-reduction processes, antioxidant activity, response to stress and innate immune system were the most common, in which DRPs were involved. Further biochemical analyses let us confirm that the LPS induced the oxidative stress response, which plays a key role in parasitic nematodes innate immunity. Our findings, to our knowledge, indicate for the first time, the complexity of the interaction of parasitic nematode, A. simplex s.s. with bacterial LPS, which mimics the coexistence of helminth and gut bacteria in the host. The simulation of this crosstalk led us to conclude, that the obtained results could be hugely valuable in the integrated systems biology approach to describe a relationship between parasite, host, and its commensal bacteria.Analysis of nucleotide variants is a cornerstone of cancer medicine. Although only 2% of the genomic sequence is protein-coding, mutations occurring in these regions have the potential to influence protein structure or modification status and may have severe impact on disease aetiology. Proteogenomics enables the analysis of sample-specific non-synonymous nucleotide variants with regards to their effect at the proteome and phosphoproteome levels. Here, we developed a proof-of-concept proteogenomics workflow and applied it to the malignant melanoma cell line A375. Initially, we studied the resistance to serine/threonine-protein kinase B-raf (BRAF) inhibitor (BRAFi) vemurafenib in A375 cells. This allowed identification of several oncogenic non-synonymous nucleotide variants, including a gain of function variant on aurora kinase A (AURKA) at F31I. We also detected significant changes in abundance among (phospho)proteins, which led to reactivation of the MAPK signalling pathway in BRAFi-resistant A375 cells. Upon reconstruction of the multi-omic integrated signalling networks, we predicted drug therapies with the potential to disrupt BRAFi resistance mechanism in A375 cells. Notably, we showed that AURKA inhibition is effective and specific against BRAFi-resistant A375 cells. Subsequently, we investigated amino acid variants that interfere with protein post-translational modification (PTM) status and potentially influence A375 cell signalling irrespective of BRAFi resistance. Mass spectrometry (MS) measurements confirmed variant-driven PTM changes in 12 proteins. Among them was the runt-related transcription factor 1 (RUNX1) displaying a variant on a known phosphorylation site S(Ph)276L. We confirmed the loss of phosphorylation site by MS and demonstrated the impact of this variant on RUNX1 interactome.

To assess the repeatability of blood flow velocity index (BFVi) metrics obtained with a recently FDA-cleared laser speckle contrast imaging device, the XyCAM RI, and characterize differences in these metrics between control, glaucoma suspect, and glaucoma subjects.

Prospective observational study PARTICIPANTS 46 subjects (20 control, 16 glaucoma suspect, and 10 glaucoma; one eye per subject) METHODS Key dynamic BFVi metrics-mean, peak, dip, volumetric rise index (VRI), volumetric fall index (VFI), time to rise (TtR), time to fall (TtF), blow out time (BOT), skew, acceleration time index (ATI)-were measured in the optic disc, optic disc vessels, optic disc perfusion region, and macula in four imaging sessions on the same day. Intrasession and intersession variability were calculated using the coefficient of variation (CV) for each metric in each region of interest (ROI). Values for each dynamic BFVi variable were compared between glaucoma subjects, glaucoma suspects, and controls using bivariate and multivnctional glaucoma metrics, and significantly different between glaucoma subjects, glaucoma suspects, and controls. The XyCAM RI may serve as an important tool in glaucoma management in the future.

Dynamic blood flow metrics measured with the XyCAM RI are reliable, associated with structural and functional glaucoma metrics, and significantly different between glaucoma subjects, glaucoma suspects, and controls. The XyCAM RI may serve as an important tool in glaucoma management in the future.Global health electives in neurology residencies provide opportunities for high-income country trainees, but have limited benefits-and may create burdens-for lower-income country hosts. Current suspension of global health electives for U.S. neurology residents due to the COVID-19 pandemic provides an opportunity to reflect on ways to reimagine global health education during this period and beyond. The framework proposed in this article underscores the need for equitable, bidirectional international partnerships and highlights global health educational innovations developed during the pandemic.Trimethylamine-N-oxide (TMAO), a gut microbiota-produced metabolite, is accumulated in chronic kidney disease (CKD) patient. It is well known to contribute to the CKD-related cardiovascular complications. However, the effect of TMAO on peritoneal dialysis (PD)-related peritonitis remains largely unknown. Here, we demonstrate that serum concentrations of TMAO were positively correlated with C-reactive protein (CRP) levels, and the appearance rate of dialysate IL-6 and PAI-1, in PD patients. During the follow-up period of 28.3±8.0 months, patients with higher TMAO levels (≥50 μM) had a higher risk of new onset peritonitis (HR, 3.60; 95%CI, 1.18-10.99; P=0.025) after adjusting for sex, age, diabetes, PD duration, BUN, rGFR, CRP, BMI and β2-M. In CKD rat models, TMAO significantly promoted peritoneal dialysate-induced inflammatory cell infiltration, inflammatory cytokines production in the peritoneum. In vitro study revealed that TMAO directly induced primary peritoneal mesothelial cell necrosis, together with increased production of pro-inflammatory cytokines including CCL2, TNF-α, IL-6 and IL-1β. In addition, TMAO significantly increased TNF-α-induced P-selectin production in mesothelial cells, as well as high glucose-induced TNF-α and CCL2 expression in endothelial cells. In conclusion, our data demonstrates that higher levels of TMAO exacerbate peritoneal inflammation and might be a risk factor of incidence of peritonitis of PD patients.The RegJointTM, a bioabsorbable polylactide scaffold, was introduced in 2011 for scaphometacarpal interposition following trapeziectomy for osteoarthritis. As previous clinical trials provided controversial results, we aimed to prove the non-inferiority of RegJointTM interposition. In this retrospective study, first metacarpal suspension arthroplasty alone (SA) was compared to suspension with RegJointTM interposition (RJ). Thirty-four patients with 37 treated thumbs (SA 14; RJ 23) were assessed clinically and radiologically at a mean follow-up of 5.3 ± 2.6 years (SA 7.96; RJ 3.73). Patient-reported outcomes were measured on three questionnaires (DASH, PRWE and PEM) and a visual analogue pain scale; there were no significant differences between the 2 groups. Clinical assessment comprised range of motion, opposition, pain, first-ray length, hand span, prominence, instability, force and sensitivity to touch. The RJ group showed significantly better palmar abduction (p = 0.026); the other outcome parameters were comparable in the 2 groups. Follow-up radiographs showed osteolysis in 2 SA hands and 3 RJ hands (p = 0.551). First-ray length had decreased by a mean 4.7 ± 2.7 mm at follow-up (SA – 3.8; RJ – 5.2; p = 0.056). No signs of adverse tissue reactions were observed. We conclude that RegJointTM spacers do not produce more complications than suspension alone but provide no added benefit.

To determine safety and efficacy of postoperative spine stereotactic body radiation therapy (SBRT) in the published literature, and to present practice recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS).

A systematic review of the literature was performed, specific to postoperative spine SBRT, using PubMed and Embase databases. A meta-analysis for 1-year local control (LC), overall survival (OS) and vertebral compression fracture (VCF) probability was conducted.

The literature search revealed 251 potentially relevant articles after duplicates were removed. Of these 56 were reviewed in-depth for eligibility and 12 met all the inclusion criteria for analysis. 7 studies were retrospective, 2 prospective observational and 3 were prospective phase I/II clinical trials. Outcomes for a total of 461 patients and 499 spinal segments were reported. 10 studies used an MRI fused to CT-simulation for treatment planning, 2 investigations reported on all patients receiving a CT-myeceptably low toxicity. Patients that may benefit from this include those with oligometastatic disease, radioresistant histology, paraspinal masses and/or those with a history of prior irradiation to the affected spinal segment. The ISRS recommends a minimum interval of 8 to 14 days after invasive surgery prior to simulation for SBRT, with initiation of radiotherapy within 4 weeks of surgery. An MRI fused to the planning CT, and/or the use of a CT-myelogram, are necessary for target and organ-at-risk delineation. A planning organ-at-risk volume (PRV) of 1.5 to 2mm for the spinal cord is advised.Adoptive T cell therapies have shown impressive signals of activity, but their clinical impact could be enhanced by technologies to increase T cell potency and diminish the cost and labor involved in manufacturing these products. Gene editing platforms are under study in this arena to (1) enhance immune cell potency by knocking out molecules that inhibit immune responses; (2) deliver genetic payloads into precise genomic locations and thereby enhance safety and/or improve the gene expression profile by leveraging physiologic promoters, enhancers, and repressors; and (3) enable off-the-shelf therapies by preventing alloreactivity and immune rejection. This review discusses gene editing approaches that have been the best studied in the context of human T cells and adoptive T cell therapies, summarizing their current status and near-term potential for translation.

One in five cancer clinical trials fails with another third failing to meet enrollment goals. Prior efforts to improve enrollment focus on patient facing interventions, but geographic factors such as regional cancer incidence may doom trials before they even begin. For these reasons, we examined associations of regional prostate cancer incidence with trial termination, and identified scientifically-underserved areas where future trials might thrive.

We merged US phase 2-3 prostate cancer clinical trial data from ClinicalTrials.gov with prostate cancer incidence data from statecancerprofiles.cancer.gov. We matched trial information from 293 closed and 560 active trials with incidence data for 2947 counties. Using multivariable logistic regression, we identified associations with trial termination. We identified 'scientifically-underserved’ counties with the highest cancer incidence quintile (>61 annual cases) but lowest active trials quintile (0 or 1 trial).

Of 293 closed trials, one in three was term.Atypical polypoid adenomyoma (APA) is an intrauterine tumor for which hysteroscopic tumor resection allows for fertility preservation. Complete resection is important because of the high recurrence rate of APA, but is difficult due to the lack of characteristic hysteroscopic findings. We previously reported a case in which photodynamic diagnosis (PDD) was useful for detection of APA. Here, we report two additional cases of APA treated by hysteroscopic resection with PDD. The procedure was approved by the ethical committee. Case 1 A 35-year-old female who underwent hysteroscopic surgery for a submucosal tumor suspected to be APA with hypermenorrhea. Case 2 A 37-year-old female in whom hysteroscopic surgery was performed for a residual APA lesion after hormone therapy. In Case 1, PDD identified the tumor borders and this enabled as complete resection as possible. In Case 2, lesions could not be identified clearly under white light, but some areas were PDD-positive and were excised. Among 19 specimens from these two cases and the previously reported case, all PDD-positive specimens were pathologically diagnosed as APA. The sensitivity and specificity of PDD for APA were 76.9% and 100%, respectively. These results suggest that PDD can contribute to identification of APA.

We aimed to investigate the retinal layers and macular capillary structure using optical coherence tomography (OCTA) with acromegaly patients and determine the relationship between OCTA parameters and disease duration, Growth hormone (GH) and Insuline growth factor (IGF – 1) levels.

Twenty-two patients with acromegaly who were followed up in the endocrinology outpatient clinic of Sisli Hamidiye Etfal Health Training and Research Hospital, were recruited into the study. Healthy control group was consisted of 22 age and gender matched subjects. Complete opthalmological examination including best visual acuity (BCVA), axial lenght, intraocular pressure (IOP) measurement, anterior segment and fundus examination, central corneal thickness with pachymetry and OCTA measurement were performed in the patients and healthy control group. Foveal avascular zone (FAZ), foveal vascular density (FVD), parafoveal vascular density (PFVD), choroidal flow (CF), foveal thickness (FT) and choroidal thickness (CT) were compared beetwen groups. Correlation between disease duration, GH and IGF-1 levels and OCTA parameters were evaluated.

There was no statistically significant difference between the groups in terms of BCVA, axial length, IOP, FT, FAZ, FD and PFVD. Choroidal thickness and CF was significantly high in the patients group compared to healthy controls (respectively, p=0.003, p=0.022). The mean follow-up period in patients with acromegaly was 90±50.2 months. There was a significant correlation between GH and subfoveal choroidal thickness in the patient group (p < 0.001, r = 0.52), a significant correlation was determined between disease duration and corneal thickness (p=0.01, r=0.41). In addition, an inverse correlation was detected between the IGF-1 level and the FAZ domain (p=0.022, r= -0.34).

In patients with acromegaly, choroidal vasculature seems to be more affected than the retinal vasculature.

In patients with acromegaly, choroidal vasculature seems to be more affected than the retinal vasculature.

To assess the efficacy of photosensitizers (CP, riboflavin) and gaseous ozone in comparison to the conventional radicular dentin disinfectant (NaOCl) on push-out bond strength (PBS) of PFRC post cemented to radicular dentin MATERIAL AND METHOD Human single-rooted teeth were collected, steriled implanted in polyvinyl pipes up to a cement-o-enamel junction and de coronated. Cleaning and shaping of the canal were performed using the crown down technique followed by obturation of the canal space. Canal space was prepared using peso reamers and samples were divided into four groups based on types of canal disinfectant protocols. Group 1 Riboflavin+ 17%EDTA; group 2 Curcumin Photosensitizer + 17% EDTA; group 3 Gaseous Ozone disinfection (O3) +17% EDTA and group 4 control 2.5% NaOCl +17% EDTA. Within the canal space, fiber post was cemented and cured, and thermocycled. PBS was evaluated using a Universal testing machine (UTM) and failure modes using a stereomicroscope at 40x magnification. One-way analysis of variance (ANOVA) was used to determine the mean and standard deviation of push-out bond strength (PBS).