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Elexacaftor/tezacaftor/ivacaftor (ETI) improves pulmonary disease in people with cystic fibrosis (PwCF), but its effect on gastrointestinal symptoms, which also affect quality of life, is not clear.PROMISE is a 56-center prospective, observational study of ETI in PwCF12 years and at least one F508del allele. Gastrointestinal symptoms, evaluated by validated questionnaires: Patient Assessment of Upper Gastrointestinal Disorders-Symptom (PAGI-SYM), Patient Assessment of Constipation-Symptom (PAC-SYM), Patient Assessment of Constipation-Quality of Life (PAC-QOL)), fecal calprotectin, steatocrit and elastase-1 were measured before and 6 months after ETI initiation. Mean difference and 95% confidence intervals were obtained from linear regression with adjustment for age and sex.438 participants fully completed at least 1 questionnaire. Mean (SD) for baseline PAGI-SYM, PAC-SYM, and PAC-QOL total scores were 0.56 (0.59), 0.47 (0.45), and 0.69 (0.53) out of maximum 5, 4, and 5, respectively (higher score indicates greater severity). Corresponding age- and sex-adjusted 6 months mean changes (95% CI) in total scores were -0.15 (-0.21, -0.09) for PAGI-SYM, -0.14 (-0.19, -0.09) for PAC-SYM, and -0.15 (-0.21, -0.10) for PAC-QOL. While statistically significant, changes were small and unlikely to be of clinical importance. Fecal calprotectin showed a change (95% CI) from baseline of -66.2 µg/g (-86.1, -46.2) at 6 months, while fecal elastase and steatocrit did not meaningfully change.After 6 months of ETI, fecal markers of inflammation decreased. Gastrointestinal symptoms improved, but the effect size was small. Pancreatic insufficiency did not improve.

People with cystic fibrosis (PwCF) suffer from gastrointestinal (GI) symptoms affecting their quality of life (QOL). Despite the relevance of GI symptoms to the overall health of PwCF, a paucity of studies only have comprehensively assessed the prevalence, severity and QOL of GI symptoms in both children and adults with Cystic Fibrosis (CF).Eligible participants ≥2 years of age across 26 US CF centers were followed for 4 weeks. Three validated GI electronic patient-reported outcome measures (ePROMs) with a recall period of 2 weeks and a stool-specific questionnaire were administered weekly over four weeks. Total and domain scores of ePROMs were evaluated overall and in subgroups using linear mixed-effect models.Of 402 enrolled, 58% were ≥ 18 years of age (52% male). The mean (SD) of the total score for PAC-SYM was 0.52 (0.55), for PAGI-SYM was 0.63 (0.67), and for PAC-QOL was 0.67 (0.55). For specific ePROM questions, prevalence of moderate to very severe symptoms were as follows: straining (20.3%), fullness (18.3%), incomplete bowel movements (17.1%), bloating (16.4%), distension (16.4%), abdominal pain (upper-5.1%, lower-7.5%). Comparing participants ≥18 versus18, a higher prevalence of bloating (63.7% versus 27.3%), lower abdominal pain (39.8% vs 26.2%), stomach fullness (75.6% versus 56.2%), and abdominal distension (60.2% versus 34.9%) was found. Both age groups reported high treatment dissatisfaction as measured with PAC-QOL, mean 1.39 (95% CI: 1.30, 1.47).GI symptoms were reported in all age ranges irrespective of gender, with higher prevalence observed amongst older and female subgroups. Dissatisfaction with GI targeted treatments were reported in a large proportion of participants despite therapy, highlighting an unmet need for clinical interventions.GOV: NCT03801993.

The article analyses Vietnam’s commitment to implementing the Trade Facilitation Agreement (TFA) of the World Trade Organization (WTO) from a legal perspective. With the TFA’s importance in terms of trade effects, not to mention its binding scope for all WTO members, Vietnam has reasons to make every effort to complete the TFA’s commitments as soon as possible. Therefore, a review of Vietnamese law to align with the TFA’s obligations and commitments is essential and meaningful. Vietnam’s legal documents reviewed in this study have a direct impact on its foreign trade. Most of the TFA’s duties have already been codified in Vietnamese law, with just a small portion of the remaining specified obligations likely to be incorporated into domestic legal documents in the near future. Full compliance with the TFA, as well as practical implementation, would be a stepping stone toward a variety of benefits for Vietnam’s economic development. Vietnam, TFA, Customs law

This study reports on the synthesis and characterization of ZnO–Ag@AgBr/SBA-15 composites using natural halloysite clay from Yenbai Province, Vietnam, as a silica aluminum source.

OBJECTIVE: The aim of this study was to examine perceptions including knowledge, attitudes, and beliefs about e-cigarettes among ethno-culturally diverse Latino adults living in the US, a rapidly growing minority group for which we know little about their e-cigarette perceptions. DESIGN: A total of 25 focus groups with Latinos (n = 180; ages 18 to 64 years) were conducted in 2014. E-cigarettes users and non-users were recruited via purposive sampling techniques. Participants completed brief questionnaires on sociodemographic factors and tobacco use. Focus group discussions were conducted in English and Spanish, audio-recorded, and transcribed. Data were analyzed using thematic analysis procedures. RESULTS: Participants were of diverse Latino backgrounds. Over one-third (35%) reported current cigarette smoking and 8% reported current e-cigarette or hookah use. Nonsmokers reported experimenting with e-cigarettes and hookah during social occasions. Participants’ perceptions towards e-cigarettes were generally formed in comparison to conventional cigarettes. Perceived benefits of using e-cigarettes included their utility as a smoking cessation aid, higher social acceptability, and lower harm compared to conventional cigarettes. Negative perceptions of e-cigarettes included lower overall satisfaction compared to conventional cigarettes and high content of toxins. Socio-cultural factors (e.g., gender roles, familismo, and simpatía) also influenced perceptions of e-cigarette of study participants. CONCLUSIONS: Overall, Latino adults knew relatively little about the potential health risks associated with e-cigarette use. The limited knowledge about and misinformation of e-cigarettes among this rapidly growing minority group have important public health implications. Findings may inform culturally tailored health communication campaigns, which are much needed among underserved US Latino populations in light of low effectiveness of tobacco control and regulatory efforts.

Ophthalmic neurodegenerative diseases encompass a wide array of molecular pathologies unified by calpain dysregulation. Calpains are calcium-dependent proteases that perpetuate cellular death and inflammation when hyperactivated. Calpain inhibition trials in other organs have faced pharmacological challenges, but the eye offers many advantages for the development and testing of targeted molecular therapeutics, including small molecules, peptides, engineered proteins, drug implants, and gene-based therapies. This review highlights structural mechanisms underlying calpain activation, distinct cellular expression patterns, and in vivo models that link calpain hyperactivity to human retinal and developmental disease. Optimizing therapeutic approaches for calpain-mediated eye diseases can help accelerate clinically feasible strategies for treating calpain dysregulation in other diseased tissues.

BACKGROUND: Whole breast irradiation (WBI) after conservative surgery for ductal carcinoma in situ (DCIS) reduces local recurrence. We investigated whether a tumour bed boost after WBI improved outcomes, and examined radiation dose fractionation sensitivity for non-low-risk DCIS.METHODS: The study was an international, randomised, unmasked, phase 3 trial involving 136 participating centres of six clinical trials organisations in 11 countries (Australia, New Zealand, Singapore, Canada, the Netherlands, Belgium, France, Switzerland, Italy, Ireland, and the UK). Eligible patients were women aged 18 years or older with unilateral, histologically proven, non-low-risk DCIS treated by breast-conserving surgery with at least 1 mm of clear radial resection margins. They were assigned to one of four groups (1:1:1:1) of no tumour bed boost versus boost after conventional versus hypofractionated WBI, or randomly assigned to one of two groups (1:1) of no boost versus boost after each centre prespecified conventional or hypofractionated WBI. The conventional WBI used was 50 Gy in 25 fractions, and hypofractionated WBI was 42·5 Gy in 16 fractions. A boost dose of 16 Gy in eight fractions, if allocated, was delivered after WBI. Patients and clinicians were not masked to treatment allocation. The primary endpoint was time to local recurrence. This trial is registered with ClinicalTrials.gov (NCT00470236).FINDINGS: Between June 25, 2007, and June 30, 2014, 1608 patients were randomly assigned to have no boost (805 patients) or boost (803 patients). Conventional WBI was given to 831 patients, and hypofractionated WBI was given to 777 patients. Median follow-up was 6·6 years. The 5-year free-from-local-recurrence rates were 92·7% (95% CI 90·6-94·4%) in the no-boost group and 97·1% (95·6-98·1%) in the boost group (hazard ratio 0·47; 0·31-0·72; pINTERPRETATION: In patients with resected non-low-risk DCIS, a tumour bed boost after WBI reduced local recurrence with an increase in grade 2 or greater toxicity. The results provide the first randomised trial data to support the use of boost radiation after postoperative WBI in these patients to improve local control. The international scale of the study supports the generalisability of the results.FUNDING: National Health and Medical Research Council of Australia, Susan G Komen for the Cure, Breast Cancer Now, OncoSuisse, Dutch Cancer Society, Canadian Cancer Trials Group.

Otostigmus consonensis sp. nov. was described from Vietnam, and O. sulcipes Verhoeff, 1937 was recorded for the first time in this country. The new species can be recognized by having 18 antennomeres including 2.3–2.5 glabrous basal ones, three coxosternal teeth, tergites 5–20 with complete paramedia sutures, sternites with incomplete paramedian sutures, and the ultimate leg with 11–15 prefemoral spines. The fragment of the COI gene was extracted for each species; thus, a new species and a record of O. sulcipes were supported by the COI genetic distances and the corresponding phylogenetic analysis.

Carbon capture and utilization (CCU) is an emerging technology with commercial potential to convert atmospheric carbon dioxide (CO2) into net zero or negative emission products. In microalgae-based CCU, microalgae utilize CO2 and sunlight to generate biomass for commercial applications. This paper reviews the current state of microalgal culture development for CCU and highlights its potential contribution to addressing climate change challenges. Current microalgal culture systems have not been designed for high throughput biomass growth and carbon capture. Raceways, high-rate algal ponds, and photobioreactors are the most widely used for microalgal cultivation at a large-scale. The limitations of these systems are related to microalgal growth requirements. Ponds are operated at narrow depth to ensure sufficient light distribution and thus need a large land surface. CO2 gas needs to be in a dissolved form for efficient utilization by microalgae. Innovative system designs to achieve optimized distribution of light, nutrient, and CO2 utilization for enhanced biomass production are crucial to achieve large-scale CO2 capture by microalgae. Data corroborated in this review highlights several innovative techniques to deliver CO2 effectively and enhance light illumination to microalgal cells. Submerged and internal illuminations can enhance light distribution without compromising culture volume and land requirements. CO2 delivery technique selections mainly depend on CO2 sources. The carbonation column appears to be the best option regarding efficiency, easy operation, and simple design. The downstream processes of microalgal culture (i.e. harvesting, biomass utilization, and water reuse) are important to make microalgae-based CCU a significant contribution to global carbon mitigation solutions.

Supplementary Figure from Ceramide Kinase Inhibition Drives Ferroptosis and Sensitivity to Cisplatin in Mutant KRAS Lung Cancer by Dysregulating VDAC-Mediated Mitochondria Function

Supplementary Figure from Caspase 9b Drives Cellular Transformation, Lung Inflammation, and Lung Tumorigenesis

Ceramide kinase (CERK) is the mammalian lipid kinase from which the bioactive sphingolipid, ceramide-1-phosphate (C1P), is derived. CERK has been implicated in several promalignant phenotypes with little known as to mechanistic underpinnings. In this study, the mechanism of how CERK inhibition decreases cell survival in mutant (Mut) KRAS non–small cell lung cancer (NSCLC), a major lung cancer subtype, was revealed. Specifically, NSCLC cells possessing a KRAS mutation were more responsive to inhibition, downregulation, and genetic ablation of CERK compared with those with wild-type (WT) KRAS regarding a reduction in cell survival. Inhibition of CERK induced ferroptosis in Mut KRAS NSCLC cells, which required elevating VDAC-regulated mitochondria membrane potential (MMP) and the generation of cellular reactive oxygen species (ROS). Importantly, through modulation of VDAC, CERK inhibition synergized with the first-line NSCLC treatment, cisplatin, in reducing cell survival and in vivo tumor growth. Further mechanistic studies indicated that CERK inhibition affected MMP and cell survival by limiting AKT activation and translocation to mitochondria, and thus, blocking VDAC phosphorylation and tubulin recruitment.Implications:Our findings depict how CERK inhibition may serve as a new key point in combination therapeutic strategy for NSCLC, specifically precision therapeutics targeting NSCLC possessing a KRAS mutation.

Caspase 9 undergoes alternative splicing to produce two opposing isoforms: proapoptotic Caspase 9a and pro-survival Caspase 9b (C9b). Previously, our laboratory reported that C9b is expressed in majority of non–small cell lung cancer tumors and directly activates the NF-κB pathway. In this study, the role of C9b in activation of the NF-κB pathway in vivo, lung inflammation and immune responses, and lung tumorigenesis were examined. Specifically, a transgenic mouse model expressing human C9b in the lung pneumocytes developed inflammatory lung lesions, which correlated with enhanced activation of the NF-κB pathway and increased influx of immunosuppressive myeloid-derived suppressor cells in contrast to wild-type mice. C9b mice presented with facial dermatitis, a thickened and disorganized dermis, enhanced collagen depth, and increased serum levels of IL6. C9b mice also developed spontaneous lung tumors, and C9b cooperated with oncogenic KRAS in lung tumorigenesis. C9b expression also cooperated with oncogenic KRAS and p53 downregulation to drive the full cell transformation of human bronchial epithelial cells (e.g., tumor formation).Implications:Our findings show that C9b can directly activate NF-κB pathway in vivo to modulate lung inflammation, immune cell influx, and peripheral immune responses, which demonstrates that C9b is key factor in driving cell transformation and lung tumorigenesis.

Alternate RNA processing of caspase-9 generates the splice variants caspase 9a (C9a) and caspase 9b (C9b). C9b lacks a domain present in C9a, revealing a tumorigenic function that drives the phenotype of non–small cell lung cancer (NSCLC) cells. In this study, we elucidated the mechanistic underpinnings of the malignant character of this splice isoform. In NSCLC cells, C9b expression correlated with activation of the canonical arm of the NF-κB pathway, a major pathway linked to the NSCLC tumorigenesis. Mechanistic investigations revealed that C9b activates this pathway via direct interaction with cellular inhibitor of apoptosis 1 (cIAP1) and subsequent induction of the E3 ligase activity of this IAP family member. The C9b:cIAP1 interaction occurred via the BIR3 domain of cIAP1 and the IAP-binding motif of C9b, but did not require proteolytic cleavage of C9b. This protein:protein interaction was essential for C9b to promote viability and malignant growth of NSCLC cells in vitro and in vivo, broadly translating to diverse NSCLC oncogenotypes. Overall, our findings identified a novel point for therapeutic invention in NSCLC that may be tractable to small-molecule inhibitors, as a new point to broadly address this widespread deadly disease. Cancer Res; 76(10); 2977–89. ©2016 AACR.

Methods used for Supplemental Data only: WST-1 cell proliferation assay, Ki-67 mmunohistochemical analysis

Supplemental Figure 1: Larger legend table for symbols in fig 1A. Supplemental Figure 2: The expression of BIRC5, CDKN1A, CXCL1 and IER3 correlates with expression of C9b, but not C9a, in human NSCLC tissues. Supplemental Figure 3: Down-regulation of RIP1 abolishes the effect of C9b on IκBα level.. Supplemental Figure 4: The role of C9b in the NF-κB pathway is translational to other cell lines, H838 and HBEpC. Supplemental Figure 5: C9b activates the canonical NF-κB pathway in H838 cells and HBEpCs. Supplemental Figure 6: C9b level inversely correlates with IκBα level in NSCLC cells. Supplemental Figure 7: Down-regulation of cIAP2 has no effect on NF-κB activation and does not inhibit the effect of C9b on the NF-κB pathway. Supplemental Figure 8: Cleavage of C9b is not important for interaction with cIAP1. Supplemental Figure 9: Tumors formed from NSCLC cells stably expressing WT C9b have higher Ki-67 expression (cell proliferation) than tumors formed from control cells or cells expressing IBM-mutated (Mut) C9b. Supplemental Figure 10: The interaction with cIAP1 mediates the enhancing effect of C9b on the cell viability and survival/AIG of NSCLC cells and HBEpCs. Supplemental Figure 11: Suppression of the canonical NF-κB pathway by ectopically expressing the suppressor, IκBα, increases NIK level. Supplemental Figure 12: Down-regulation of NIK does not affect the survival/AIG of NSCLC cells. Supplemental Table 1: qPCR primers for NF-κB target genes utilized in the study Supplemental Table 2: List of NF-κB-related genes that expression was affected by down-regulation of C9b in A549 cells or up-regulation of C9b in HBEpC cells (identified by deep RNA sequencing). Supplemental Table 3: List of NF-κB target genes that expression is contrastingly affected by down-regulation of C9b in A549 cells versus by up-regulation of C9b in HBEpCs. Supplemental Table 4: NSCLC cell lines used in Figure 2D or Supplemental Figure 6. Supplemental Table 5: Sequences of negative control si-RNA and caspase-9a or -9b si-RNA utilized in the study.

Supplementary Methods from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

Supplementary Tables 1-2 from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

Supplementary Figures 1-6 from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

Supplementary Video 1 from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

Supplementary Figure Legends 1-6 from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

Supplementary Video legend from Integrated Microfluidic and Imaging Platform for a Kinase Activity Radioassay to Analyze Minute Patient Cancer Samples

Supplemental Figure Legends for Supplemental Figures 1 through 12.

Oncogenic kinase activity and the resulting aberrant growth and survival signaling are a common driving force of cancer. Accordingly, many successful molecularly targeted anticancer therapeutics are directed at inhibiting kinase activity. To assess kinase activity in minute patient samples, we have developed an immunocapture-based in vitro kinase assay on an integrated polydimethylsiloxane microfluidics platform that can reproducibly measure kinase activity from as few as 3,000 cells. For this platform, we adopted the standard radiometric 32P-ATP–labeled phosphate transfer assay. Implementation on a microfluidic device required us to develop methods for repeated trapping and mixing of solid-phase affinity microbeads. We also developed a solid-state beta-particle camera imbedded directly below the microfluidic device for real-time quantitative detection of the signal from this and other microfluidic radiobioassays. We show that the resulting integrated device can measure ABL kinase activity from BCR-ABL–positive leukemia patient samples. The low sample input requirement of the device creates new potential for direct kinase activity experimentation and diagnostics on patient blood, bone marrow, and needle biopsy samples. Cancer Res; 70(21); 8299–308. ©2010 AACR.

Non-independent and identically distributed (non-IID) data distribution among clients is considered as the key factor that degrades the performance of federated learning (FL). Several approaches to handle non-IID data, such as personalized FL and federated multitask learning (FMTL), are of great interest to research communities. In this work, first, we formulate the FMTL problem using Laplacian regularization to explicitly leverage the relationships among the models of clients for multitask learning. Then, we introduce a new view of the FMTL problem, which, for the first time, shows that the formulated FMTL problem can be used for conventional FL and personalized FL. We also propose two algorithms FedU and decentralized FedU (dFedU) to solve the formulated FMTL problem in communication-centralized and decentralized schemes, respectively. Theoretically, we prove that the convergence rates of both algorithms achieve linear speedup for strongly convex and sublinear speedup of order 1/2 for nonconvex objectives. Experimentally, we show that our algorithms outperform the conventional algorithm FedAvg, FedProx, SCAFFOLD, and AFL in FL settings, MOCHA in FMTL settings, as well as pFedMe and Per-FedAvg in personalized FL settings. Funding Agencies|FMJH Program Gaspard Monge for optimization and operations research

Phase-separated membraneless organelles or biomolecular condensates play diverse functions in cells, however recapturing their characteristics using small organic molecules has been a challenge. In the present study, cell-lysate-based screening of 843 self-assembling small molecules led to the discovery of a simple organic molecule, named huezole, that forms liquid droplets to selectively sequester tubulin. Remarkably, this small molecule enters cultured human cells and prevents cell mitosis by forming tubulin-concentrating condensates in cells. The present study demonstrates the feasibility of producing a synthetic condensate out of non-peptidic small molecules for exogenous control of cellular processes. The modular structure of huezole provides a framework for designing a class of organelle-emulating small molecules.

We describe a strategy to boost the efficiency of gene editing via homology-directed repair (HDR) by covalently modifying the template DNA with interstrand crosslinks. Crosslinked templates (xHDRTs) increase Cas9-mediated editing efficiencies by up to fivefold in K562, HEK293T, U2OS, iPS and primary T cells. Increased editing from xHDRTs is driven by events on the template molecule and requires ataxia telangiectasia and Rad3-related (ATR) kinase and components of the Fanconi anemia pathway.

A Hamiltonian reduction approach is defined, studied, and finally used to derive asymptotic models of internal wave propagation in density stratified fluids in two-dimensional domains. Beginning with the general Hamiltonian formalism of Benjamin [1] for an ideal, stably stratified Euler fluid, the corresponding structure is systematically reduced to the setup of two homogeneous fluids under gravity, separated by an interface and confined between two infinite horizontal plates. A long-wave, small-amplitude asymptotics is then used to obtain a simplified model that encapsulates most of the known properties of the dynamics of such systems, such as bidirectional wave propagation and maximal amplitude travelling waves in the form of fronts. Further reductions, and in particular devising an asymptotic extension of Dirac's theory of Hamiltonian constraints, lead to the completely integrable evolution equations previously considered in the literature for limiting forms of the dynamics of stratified fluids. To assess the performance of the asymptotic models, special solutions are studied and compared with those of the parent equations., Comment: 29 pages, 4 figures

Introduction Clinical outcomes of implantable port catheters (IPCs) placed via alternative veins such as the external jugular and cervical collaterals have not been well established. This investigation evaluates the short- and long-term outcomes of IPCs inserted via alternate cervical veins (ACV) compared to traditionally inserted IPCs via the internal jugular vein (IJV). Materials and Methods A total of 24 patients who received an IPC between 2010 and 2020 via an ACV—defined as the external jugular vein, superficial cervical vein, or unnamed collateral veins—were identified. Based on power analysis, a matched control group of 72 patients who received IPCs via the IJV was identified. Non-inferiority analysis for port complications was performed between the two groups based on the selected non-inferiority margin of 20%. Secondary end points included complication-free survival and comparison of complications by the time at which they occurred. Results ACV access was non-inferior to traditional access for overall complications. Alternate access resulted in fewer complications than traditional access with an estimated reduction of − 7.0% [95% CI − 23.6%, 39.7%]. There was no significant difference in peri-procedural and post-procedural complications between the two groups. Complication-free survival was also equivalent between the two groups. Conclusion IPC placement via ACVs was non-inferior to IPCs placed via traditional access through the IJV. When abnormal pathology obviates the use of IJV access, other cervical veins may be considered prior to seeking alternate locations such as femoral, translumbar, inferior vena cava, and hepatic veins.

SummaryBackgroundNanocovax is a recombinant severe acute respiratory syndrome coronavirus 2 subunit vaccine composed of full-length prefusion stabilized recombinant SARS-CoV-2 spike glycoproteins (S-2P) and aluminum hydroxide adjuvant. In a Phase 1 and 2 studies, (NCT04683484) the vaccine was found to be safe and induce a robust immune response in healthy adult participants.MethodsWe conducted a multicenter, randomized, double-blind, placebo-controlled study to evaluate the safety, immunogenicity, and protective efficacy of the Nanocovax vaccine against Covid-19 in approximately 13,007 volunteers aged 18 years and over. The immunogenicity was assessed based on Anti-S IgG antibody response, surrogate virus neutralization, wild-type SARS-CoV-2 neutralization and the types of helper T-cell response by intracellular staining (ICS) for interferon gamma (IFNg) and interleukin-4 (IL-4). The vaccine efficacy (VE) was calculated basing on serologically confirmed cases of Covid-19.FindingsUp to day 180, incidences of solicited and unsolicited adverse events (AE) were similar between vaccine and placebo groups. 100 serious adverse events (SAE) were observed in both vaccine and placebo groups (out of total 13007 participants). 96 out of these 100 SAEs were determined to be unrelated to the investigational products. 4 SAEs were possibly related, as determined by the Data and Safety Monitoring Board (DSMB) and investigators. Reactogenicity was absent or mild in the majority of participants and of short duration. These findings highlight the excellent safety profile of Nanocovax.Regarding immunogenicity, Nanocovax induced robust IgG and neutralizing antibody responses. Importantly, Anti S-IgG levels and neutralizing antibody titers on day 42 were higher than those of natural infected cases. Nanocovax was found to induce Th2 polarization rather than Th1.Post-hoc analysis showed that the VE against symptomatic disease was 51.5% (95% confidence interval [CI] was [34.4%-64.1%]. VE against severe illness and death were 93.3% [62.2-98.1]. Notably, the dominant strain during the period of this study was Delta variant.InterpretationNanocovax 25 microgram (mcg) was found to be safe with the efficacy against symptomatic infection of Delta variant of 51.5%.FundingResearch was funded by Nanogen Pharmaceutical Biotechnology JSC., and the Ministry of Science and Technology of Vietnam; ClinicalTrials.gov number, NCT04922788.

Teaching to transgress, according to bell hooks, entails educators moving beyond an assembly-line approach to embrace integration of the mind, body, and spirit, and engaging in ways that honor the uniqueness of all students. The purpose of this study was to evaluate our music teacher education program in order to critically analyze how our practices may or may not transgress. In keeping with principles of S-STEP (Self-Study of Teacher Education Practices), we share the provocation for the study and its multiple overlapping stages. We present themes from the S-STEP process resulting from the data, and then reconsider those data using scholarly literature. Findings include the intellectual and spiritual growth of students and educators, and the challenges inherent in teaching to transgress within an online environment.

One of the statements of purpose of the American Recovery and Reinvestment Act (ARRA) was “to assist those most impacted by the recession.” To consider this facet, the grants-in-aid portion of the ARRA is assessed from the perspective of fiscal federalism. We estimate a trend-stationary autoregressive model of county-level wage income dynamics where each county is subject to a common shock (with county-specific factor loading) and an idiosyncratic shock. We then ask if counties that experienced larger negative wage income shocks during the Great Contraction subsequently received more transfers per capita in the form of grants-in-aid. The fact that the negative business cycle shocks pre-date the passage of the ARRA and subsequent disbursements allows identification of the risk-pooling channel of the grants before fiscal multiplier effects confound these two channels. We find statistically significant and economically large risk-pooling effects.

The hippocampus has been a focus of memory research since H.M’s surgery abolished his ability to form new memories, yet its mechanistic role in memory remains debated. Here, we identify a candidate memory mechanism: an anticipatory hippocampal “convergence state”, observed while awaiting valuable information, and which predicts subsequent learning. During fMRI, participants viewed trivia questions eliciting high or low curiosity, followed seconds later by its answer. We reasoned that encoding success requires a confluence of conditions, so that hippocampal states more conducive to memory formation should converge in state space. To operationalize convergence of neural states, we quantified the typicality of multivoxel patterns in the medial temporal lobes during anticipation and encoding of trivia answers. We found that the typicality of anticipatory hippocampal patterns increased during high curiosity. Crucially, anticipatory hippocampal pattern typicality increased with dopaminergic midbrain activation and uniquely accounted for the association between midbrain activation and subsequent recall. We propose that hippocampal convergence states may complete a cascade from motivation and midbrain activation to memory enhancement, and may be a general predictor of memory formation.

Background: The diagnosis and management of chronic cough in primary care is challenging despite it being one of the most common chronic conditions. Objective: Clinical characterization of patients with new-onset chronic cough in the primary care setting. Methods: This was a retrospective study of adult patients (ages ≥ 18 years) with at least three visits with primary care providers (PCP) for new-onset cough, with at least 8 weeks between the first and third visits, within a tertiary-care center and affiliated clinics between January 1, 2010, and January 1, 2019 (N = 174). We calculated the frequency of primary care visits, diagnostic testing, specialist referrals, and prescribed medications up to 18 months after the third visit with a PCP for cough. Results: Of 174 patients who met the criteria of new-onset chronic cough, >50% had four or more primary care visits related to cough. Despite that, 91 (52.3%) did not receive a referral to a specialist, and 41 (23.5%) did not receive an order for a chest radiograph during the evaluation of the chronic cough. Antibiotics and systemic corticosteroids were prescribed to 106 (61%) and 63 (36%) of the patients, respectively, and 20% were prescribed opiates. No patients were prescribed central-neuromodulating agents, and angiotensin-converting enzyme inhibitors were discontinued in 48% of the patients who were taking them (12/25). Conclusion: We found considerable heterogeneity and discrepancies with clinical guideline recommendations in patients who presented with new chronic cough. There is a substantial unmet need to study chronic cough in the primary care setting to inform important stakeholders.