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In this mixed-methods study, we explore themes that emerged from a survey assessing the programmatic experiences of mentors and administrators at institutions in low- and middle-income countries (LMICs) hosting trainees supported by the Fogarty International Center’s Global Health Program for Fellows and Scholars. A total of 89 of 170 potential respondents representing 31 countries completed the survey (response rate, 52.4%). There was agreement among respondents that their institutions received sufficient funds to support trainees and had the capacity to manage operational and financial aspects of the program. A majority also agreed that both LMIC and U.S. trainees were beneficial to the host institutions, and that trainee projects were relevant to the needs of the host country. Respondents felt that program benefits to LMIC trainees could be improved by increasing the research consumables budget, increasing the flexibility of program timelines, and increasing engagement between LMIC and U.S. trainees and institutions. Respondents indicated that both U.S. and LMIC trainees behaved professionally (including demonstrating respectful and ethical behavior) and took appropriate initiative to conduct their research projects. Findings from this study will help inform innovations to similar training initiatives that will enhance sustainability and improve program performance, and will be responsive to local needs.

SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism inWe used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of thisTrp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.

A new glycosyltransferase UGT84A95 was discovered from Penstemon barbatus and exhibited broad substrate specificity toward various phenylethanoid glycosides, flavonoids, terpenoids, stilbene glycosides, coumarins, and simple polyphenols.

This article investigated the effect of Insm1 on RPC differentiation in mice and the underlying mechanism. The retinal tissues of mouse embryo at 12.5 days (E12.5) and postnatal 14 days (P14) were collected, following by the detection of Insm1 and corresponding markers by immunofluorescent staining. RPCs isolated from retinal tissues at P1 were cultured in culture medium for 7 days. The differentiation of photoreceptor and glial cells was assessed after RPCs transferred to the differentiation medium for 20 days. Next, the effect of Insm1 overexpression on the differentiation of RPCs toward rod photoreceptor and glial cells were assessed. Insm1 was highly expressed in RPCs of retinal tissues and decline in photoreceptor cells, while hardly expressed in glial cells. Based on the results of Pax-6 positive immunofluorescent staining and flow cytometry detection, RPCs were successfully isolated from retinal tissues. After the culture in differentiation medium, RPCs showed positive staining of Rhodopsin and glial fibrillary acidic protein (GFAP). Further results showed that overexpression of Insm1 significantly increased the percentage of Rhodopsin positive cells, and up-regulated Sonic Hedgehog (SHH), hairy and enhancer of split homolog-1(Hes1), S-opsin and Rhodopsin levels, while decreased the percentage of Glutamine synthetase positive cells, and reduced Glutamine synthetase and GFAP levels. Whereas, the effect of Insm1 overexpression on these protein levels were partly abolished by the knockdown of SHH or Hes1. We conclude that Insm1 promotes the differentiation of RPCs into photoreceptor cells in the developing retina through up-regulation of SHH.

Background: SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism in SH2B3 (rs3184504) results in substitution of tryptophan (Trp) for arginine (Arg) at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown. Methods: We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of this SH2B3 polymorphism. Mice underwent angiotensin II (Ang II) infusion to evaluate differences in blood pressure (BP) elevation and end-organ damage including albuminuria and renal fibrosis. Cytokine production and Stat4 phosphorylation was also assessed in Arg/Arg and Trp/Trp T cells. Results: Trp/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp/Trp mice compared to Arg/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8 + T cells from Ang II-infused Trp/Trp mice produce significantly more interferon gamma (IFNg) compared to Arg/Arg controls. Interleukin-12 (IL-12)-induced IFNg production is greater in Trp/Trp compared to Arg/Arg CD8 + T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp/Trp compared to Arg/Arg CD8 + T cells, suggesting that Trp-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFNg production. Finally, we demonstrated that a multi-SNP model genetically predicting increased SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans.. Conclusions: Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.

Off-label drug use embodies a thorough clinical diagnosis and evaluation of treatment needs and should not be confused with unreasonable drug use, but it also faces potential risks with drug safety and legal issues.We first established a guideline working group. Following the guideline development process recommended by the World Health Organization Handbook and the Chinese Medical Association, the key questions were determined through literature searches of PubMed, CNKI (Chinese National Knowledge Infrastructure) and other databases. Both the evidence and the clinicians' diagnosis and treatment workload were considered to formulate the initial recommendations. Finally, two rounds of Delphi surveys and one expert seminar were organized to determine the final recommendations of this guideline. Meanwhile, we graded the recommendations based on the body of evidence.We determined nine questions and proposed a total of 23 recommendations regarding the definition of off-label use of drugs, applicable circumstances, classification of evidence, informed consent, legal basis, adverse drug reaction monitoring and evaluation, management procedure, responsibilities and obligations of different stakeholders, medical insurance reimbursement, and the national approval system.This guideline standardized clinical off-label drug use and provided suggestions and references for the management of off-label drug use.

Associations between ulcerative colitis (UC) and ankylosing spondylitis (AS) have been observed in multiple studies, but the common etiology of UC and AS remain unknown. Thus, the current research was conducted to investigate the shared genes and relevant mechanisms in UC and AS. GSE87466 and GSE25101 datasets were used to identify DEGs involved in UC and AS, respectively. The clusterProfiler R package was utilized to detect the biological processes of DEGs in UC and AS. The performance of common DEGs in distinguishing UC or AS samples from control ones were evaluated by ROC curves. The miRWalk, Cistrome and TransmiR database were utilized to construct the network of TF-miRNA-diagnostic biomarker. GSEA method and CTD database were used to investigate the common KEGG pathways shared by UC and AS. In addition, CTD database was also used to detect the interaction score between diagnostic biomarkers and diseases associated with UC or AS. Moreover, prospective diagnostic biomarker-targeting drugs were identified using the DGIdb database. A total of 20 common DEGs were obtained by analyzing data in GSE97466 and GSE25101 datasets. ROC curves revealed that GMFG, GNG11, CLEC4D, CMTM2, VAMP5, S100A8, S100A12 and DGKQ may serve as diagnostic biomarkers for the individuals with AS and UC. A network of TF-miRNA-diagnostic biomarker, composed of 212 nodes and 721 edges, was constructed and visualized by Cytoscape software. Toll-like receptor signaling pathway, antigen processing and presentation, allograft rejection, viral myocarditis, pathways in cancer, graft versus host disease and natural killer cell mediated cytotoxicity were identified as common pathways in UC and AS. For the first time, our study identified 8 common key genes and 7 common pathways in UC and AS. These findings may help to clarify the relationship between UC and AS, and provide guidance in the diagnosis and treatment of UC and AS patients.Author SummaryAnkylosing spondylitis (AS) and Ulcerative colitis (UC) are two types of autoimmune diseases that often co-occur. The simultaneous onset of both diseases often results in severe clinical manifestations and limited therapeutic efficacy. So there is an urgent need to gain a deeper understanding of the causes of UC and AS in order to develop more effective treatment strategies. In this study, we explored the genes and pathways commonly involved in two diseases, constructed a transcriptional network, and further investigated potential drugs. The discoveries could potentially offer insights into the connection between UC and AS, and assist in identifying and managing patients with UC and AS.

Supplemental Methods

Supplemental Figure 1. Representative example from one patient showing the rash that was most frequently observed with ensartinib. The white arrow in the top figure points to the rash that is circled in the bottom figure.

The mean concentration of ensartinib in plasma and skin at multiple time points after a single dose of 50 mg/kg is listed in Supplemental Table 2. At 12 hours post-dose, the concentration of ensartinib was 9.0 higher in the skin than in the plasma.

Ensartinib was tested against wild-type ALK and 17 ALK variants in the Reaction Biology panel. Ensartinib potently inhibited all evaluated ALK variants, with in vitro IC50s

Purpose: BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC.Experimental Design: Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology.Results: Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected.Conclusions: We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general. Clin Cancer Res; 21(11); 2624–34. ©2015 AACR.

Supplementary Methods, Figures 1-2, Tables 1-3. Phylogenetic analysis, novel HPV alignment and NGS gene panel. Figure S1 - β-genus HPV38, HPV17 and HPV111 are most frequently found in BRAFi-cSCC; Figure S2: Protein and nucleic acid sequence alignments of putative novel HPV genotypes; Table S1: HPV L1 sequences were obtained from NCBI for alignment and relatedness analysis; Table S2 Human Papillomavirus Taxonomy; Table S3: Ion Torrent Ampliseq panel targets.

The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.

Supplemental Figure 2. Arithmetic mean concentration-time curves for fasted patients receiving 225 mg of ensartinib on Days 1 and 22 of Cycle 1.

Supplemental Figure 3. Best percentage change from baseline in sum of target lesions is presented for the ALK-positive evaluable patients at 200 mg who had received prior crizotinib and as second-generation ALK TKI. Dashed lines indicate RECIST v1.1 cut-offs for partial response and progressive disease. Of the 16 patients, four had partial responses and four had stable disease. The color scheme represents which second-generation ALK TKI that patient received after crizotinib. Of note, the primary lesion of one of the 16 patients was too small, and thus indeterminate, at the post-baseline assessment, therefore a change in tumor size is not available. This patient had received, in order, prior crizotinib, alectinib, and ceritinib, and developed progression on ensartinib in a non-target brain lesion prior to cycle 3. *Denotes those patients with progressive disease as the best response. >Denotes patients still on study at the time of data cutoff.

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.

Context Individuals with type 1 diabetes (T1D) have a smaller pancreas, but longitudinal changes in pancreas size and shape are unclear. Objective We monitored changes in pancreas size and shape after diagnosis with T1D. Design We conducted a prospective cohort study at an academic medical center between 2014 and 2022. Patients and Healthy Controls Individuals with T1D (n = 91) or controls (n = 90) underwent magnetic resonance imaging (MRI) of the pancreas, including longitudinal MRI in 53 individuals with new-onset T1D. Intervention Interventions included MRI and continuous glucose monitoring (CGM). Main Outcome Measures Pancreas size and shape were measured from MRI. For participants who used CGM, measures of glycemic variability were calculated. Results On longitudinal imaging, pancreas volume and pancreas volume index normalized for body weight declined during the first year after diagnosis. Pancreas volume index continued to decline through the fifth year after diagnosis. A cross-sectional study of individuals with diabetes duration up to 60 years demonstrated that pancreas size in adults negatively correlated with age and disease duration, whereas pancreas volume and pancreas volume index remained stable in controls. Pancreas volume index correlated inversely with low blood glucose index, a measure of risk for hypoglycemia. Pancreas shape was altered in individuals with T1D and further diverged from controls over the first 5 years after diagnosis. Pancreas size and shape are altered in nondiabetic individuals at genetic risk for T1D. Combined pancreas size and shape analysis better distinguished the pancreas of individuals with T1D from controls than size alone. Conclusions Pancreas size declines most rapidly near the clinical diagnosis of T1D and continues to decline throughout adulthood. Declines in pancreas size are accompanied by changes in pancreas shape.

The energy consumption of massive multiple-input multiple-output (MIMO) systems increases with the number of antennas. Optimizing the energy efficiency (EE) of massive MIMO systems is one of the ways to achieve green communication. This paper proposes an EE optimization method that genetic algorithm-based antenna selection and power allocation (GA-AS+PA) for the downlink of a multicell massive MIMO system under the restriction of the users’ sum-rate. First, we use the genetic algorithm to determine the active transmitting antenna of each base station (BS). Then, the transmission power for each user is allocated using the convex optimization method. Finally, the EE of system is optimized under the achieved optimum BS’s transmit power and the number of active antennas. From the simulation results, the GA-AS+PA method can improve the EE of the system while meeting user sum-rate requirements, which achieves better performance compared with random antenna selection+equal power allocation method (RAS+EPA), random antenna selection+power allocation method (RAS+PA), the antenna selection method based on genetic algorithm+equal power allocation method (GA-AS+EPA), and equal power allocation (EPA) these four methods. The EE of the proposed GA-AS+PA method is improved by 33.3% compared to the EPA method.

OBJECTIVE: To explore susceptibility loci associated with uveitis in Behçet's disease (BD).METHODS: We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls. Luciferase reporter analysis and chromatin immunoprecipitation assay were performed to explore the functional role of susceptibility genetic variants near ZMIZ1.RESULTS: Three independent HLA alleles (HLA-B51 [3.75 × 10-190 ], HLA-A26 [1.50 × 10-18 ], and HLA-C0704 [3.44 × 10-16 ]) were identified as having a genome-wide association with BD-related uveitis. In the non-HLA region, in addition to confirming 7 previously reported loci, we identified 22 novel susceptibility variants located in 16 loci. Meta-analysis of the Chinese cohort consisting of 1,931 cases and 6,517 controls and a published Japanese cohort of 611 cases and 737 controls showed genome-wide significant associations with ZMIZ1, RPS6KA4, IL10RA, SIPA1-FIBP-FOSL1, and VAMP1. Functional experiments demonstrated that genetic variants of ZMIZ1 were associated with enhanced transcription activity and increased expression of ZMIZ1.CONCLUSION: This GWAS study identified a novel set of genetic variants that are associated with susceptibility to uveitis in BD. These findings enrich our understanding of the contribution of genetic factors to the disease.

Training the next generation of global health researchers is vital for sustainable research partnerships and global health equity. The Fogarty International Center (National Institutes of Health) supports postdoctoral fellows and professional/graduate students in long-term, hands-on mentored research in low- and middle-income countries (LMICs). We surveyed 627 alumni (58% from the United States, 42% from LMICs) from three sequential Fogarty-sponsored global health research training programs (response rate: N = 257, 41%). Publications in the Index Medicus were used to ascertain scholarly output. Most alumni (63%) reported remaining engaged in LMICs and/or worked in academic/research careers (70%). Since completing their Fogarty fellowship, 144 alumni (56%) had received 438 new grants as principal investigator (PI), co-/multi-PI, or site PI. The 257 responding alumni had 5,318 publications during and since their Fogarty fellowships; 2,083 (39%) listed the Fogarty trainee as the first or senior author. These global health training programs highlight the value of LMIC research experience in nurturing the global health research workforce.

Introduction: Immunosuppressive therapy for uveitis may cause liver damage. Methods: To investigate incidence of liver damage during uveitis treatment, we compared serological Hepatitis B core antibody (HBcAb) status with risk of liver dysfunction in all participants (n = 992), in anterior uveitis (AU) (n = 489), and combined of intermediate, posterior, or panuveitis (IPPU) patients (n = 503). The primary endpoint was incidence of elevated serum alanine aminotransferase level above 2-fold upper limits of normal within 6 months. Results: The incidence rate of primary endpoint for HBcAb-negative and HBcAb-positive patients was 65 and 212 per 1,000 person years, respectively. The absolute rate difference was 147 (95% confidence interval [CI], 80–213) per 1,000 person years. HBcAb positivity was associated with a higher risk for primary endpoint in all participants (adjusted hazard ratio [aHR], 3.53; 95% CI, 1.79–6.99; p value = 2.8 × 10−4) and in IPPU (aHR, 3.80; 95% CI, 1.61–9.01; p value = 0.002). No significant association with primary endpoint was observed for HBcAb positivity in AU (aHR, 3.21; 95% CI, 0.94–10.95; p value = 0.063). AU was mainly treated with topical eye drops (74.0%), whereas IPPU cases received systemic therapy including prednisone (94.0%), cyclosporine (80.9%), or other additionally combined immunomodulatory agents (14.9%). Conclusion: Noninfectious uveitis cases with HBcAb positivity have an increased risk of liver damage. This association was predominantly driven by IPPU but was not significant in AU, suggesting that the association is mediated by systemic therapy.

Intra-abdominal infection is a common cause of sepsis, and intra-abdominal sepsis leads to ∼156 000 U.S. deaths annually. African American/Black adults have higher incidence and mortality rates from sepsis compared to Non-Hispanic White adults. A limited number of studies have traced survival outcomes to molecular changes; however, these studies primarily only included Non-Hispanic White adults. Our goal is to better understand molecular changes that may contribute to differences in sepsis survival in African American/Black and Non-Hispanic White adults with primary intra-abdominal infection. We employed discovery-based plasma proteomics of patient samples from the Protocolized Care for Early Septic Shock (ProCESS) cohort (

ObjectiveEndotoxin-induced uveitis (EIU) is an important tool for human uveitis study. This study was designed to develop a novel EIU model in zebrafish.MethodsAn EIU model in zebrafish was induced by intravitreal lipopolysaccharide (LPS) injection and was assessed dynamically. Optical coherence tomography (OCT) was used to assess infiltrating cells in the vitreous body. The histological changes wereevaluated using HE staining and immune cells were measured by immunofluorescence. The retinal RNA Sequencing (RNA-Seq) was used to explore the transcriptional changes during inflammation. RNA-Seq data were analyzed using time-course sequencing data analysis (TCseq), ClueGO plugin in Cytoscape, and Gene Set Enrichment Analysis (GSEA) software. Flow cytometry and retinal flat mounts were used to dynamically quantify the immune cells.ResultsEIU was successfully induced in zebrafish following intravitreal LPS injection. Inflammation appeared at 4 hours post injection (hpi), reached its peak at 24 hpi, and then resolved at 72 hpi. Immunofluorescence confirmed that massive influx ofneutrophils into the iris and vitreous body, and activation of microglia as evidenced by ameboid-shaped appearance in the retina. Retinal RNA-seq during the EIU course identified four gene clusters with distinct expression characteristics related to Toll-likereceptor signaling pathway, cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and extracellular matrix (ECM)-receptor interaction, respectively. Prednisone immersion inhibited the inflammatory response of EIU in zebrafish, whichwas confirmed by decreased neutrophils detected in flow cytometry and retinal flat mounts.ConclusionsWe developed a novel EIU model in zebrafish, which may be particularly useful for gene-editing and high-throughput screening of new drugs for the prevention and treatment of uveitis.

The aroma characteristics of Pu-erh tea were studied in this work. A total of 117 volatile compounds were identified by HS-SPME combined with GC–TOF/MS, of which 29 active aroma compounds were identified by olfactometry. The active aroma compounds of Pu-erh tea were analyzed by intensity aroma (IA), aroma extraction dilution (AEDA), sensory quantification value (MF), detection frequency (DFA) and odor activity value (OAV). 24, 21 and 23 active aroma components were identified by DFA, AEDA and OAV, while 20 by IA and MF. Recombination of the obtained active aroma components indicated that OAV method was best for determining the active aroma compounds as the aroma profile of OAV recombination model was the most similar to that of Pu-erh tea sample. Omission test of the OAV recombination model furtherly identified 19 characteristic active aroma compounds of Pu-erh tea, and linalool, 1,2,3-trimenthoxybenzebe, 1,2,4-trimethoxybenzene and ɑ-ionone were the key characteristic active aromatic compounds.

Background Assessment and feedback is a common implementation strategy to improve healthcare provider fidelity to clinical guidelines. For immunization guidelines, fidelity is often measured with doses administered during eligible visits. Adding a patient refusal measure captures provider fidelity more completely (i.e., all instances of a provider recommending a vaccine, resulting in vaccination or refusal) and enables providers to track patient vaccine hesitancy patterns. However, many electronic health record (EHR) systems have no structured field to document multiple instances of refusals for specific vaccines, and existing billing codes for refusal are not vaccine specific. This study assessed the feasibility of a novel method for refusal documentation used in a study focused on human papillomavirus (HPV) vaccine. Methods An observational, descriptive-comparative, mixed-methods study design was used to conduct secondary data analysis from an implementation-effectiveness trial. The parent trial compared coach-based versus web-based practice facilitation, including assessment and feedback, to increase HPV vaccination in 21 community-based private pediatric practices. Providers were instructed to document initial HPV vaccine refusals in the EHR's immunization forms and subsequent refusals using dummy procedure codes, for use in assessment and feedback reports. This analysis examined adoption and maintenance of the refusal documentation method during eligible well visits, identified barriers and facilitators to documentation and described demographic patterns in patient refusals. Results Seven practices adopted the refusal documentation method. Among adopter practices, documented refusals started at 2.4% of eligible well visits at baseline, increased to 14.2% at the start of implementation, peaked at 24.0%, then declined to 18.8%. Barriers to refusal documentation included low prioritization, workflow integration and complication of the billing process. Facilitators included high motivation, documentation instructions and coach support. Among adopter practices, odds of refusing HPV vaccine were 25% higher for patients aged 15–17 years versus 11–12 years, and 18% lower for males versus females. Conclusions We demonstrated the value of patient refusal documentation for measuring HPV vaccination guideline fidelity and ways that it can be improved in future research. Creation of vaccine-specific refusal billing codes or EHR adaptations to enable documenting multiple instances of specific vaccine refusals would facilitate consistent refusal documentation. Trial Registration NCT03399396 Registered in ClinicalTrials.gov on 1/16/2018.

Introduction National Comprehensive Cancer Network HCC guidelines recommend Y90 to treat BCLC-C patients only in select cases given the development of systemic regimens. We sought to identify ideal candidates for Y90 by assessing survival and toxicities in this patient group. Materials and methods The Radiation-Emitting Selective Internal radiation spheres in Non-resectable tumor registry is a prospective observational study (NCT: 02,685,631). Patients with advanced HCC were stratified into 3 groups based on tumor location, Eastern Cooperative Oncology Group (ECOG) performance status, and liver function. Group 1: liver isolated HCC, ECOG 0 and Child Pugh (CP) A (n = 12, 16%), Group 2: liver isolated HCC, ECOG ≥ 1 or CP B/C (n = 37, 49%), and Group 3: extrahepatic HCC with any ECOG or CP score (n = 26, 35%). Patients in any group could have macrovascular invasion. Overall survival (OS) and progression-free survival (PFS) with 95% confidence intervals (95% CI) were calculated. Grade 3 + toxicities were tracked using Common Terminology Criteria for Adverse Events v5. Cox proportional hazard model was performed to determine factors affecting OS. Results Seventy-five BCLC-C patients treated between 2015 and 2019 were reviewed. The groups were similar in age, sex, race, and ethnicity (all p > 0.05). Bilobar disease was least common in Group 1 (p p = 0.6). Median PFS for the cohort was 6.3 (4.8–14.7) months. Median PFS for group 1 was not reached. Mean PFS for Group 1 was 17.3 ± 4.8 months. Median PFS for Groups 2 and 3 was 6.8 and 5.9 months (X2 = 1.5, p = 0.5). Twenty-four Grade 3 or greater toxicities developed, most commonly hyperbilirubinemia (8/75, 11%) and thrombocytopenia (2/75, 3%). The incidence of toxicities between groups was similar (all p > 0.05). Cox Proportional Hazard analysis predicted shorter OS with CP class B/C (X2 = 6.7, p = 0.01), while macrovascular invasion (X2 = 0.5, p = 0.5) and ECOG score of ≥ 1 (X2 = 2.1, p = 0.3) was not associated with OS. Conclusions OS of CPA patients with advanced HCC and performance status of 0 was 21.8 months following Y90. CP A cirrhosis is the best predictor of prolonged OS in advanced (BCLC-C) HCC.

Background Disseminated pediatric low-grade gliomas and glioneuronal tumors (dpLGG/GNTs) are associated with a poorer prognosis than nondisseminated pLGG/GNTs. To date there is no comprehensive report characterizing the genome profile of dpLGG/GNTs and their relative survival. This systematic review aims to identify the pattern of genetic alterations and long-term outcomes described for dpLGG/GNT. Methods A systematic review of the literature was performed to identify relevant articles. A quality and risk of bias assessment of articles was done using the GRADE framework and ROBINS-I tool, respectively. Results Fifty studies published from 1994 to 2020 were included in this review with 366 cases reported. There was sporadic reporting of genetic alterations. The most common molecular alterations observed among subjects were 1p deletion (75%) and BRAF-KIAA1549 fusion (55%). BRAF p.V600E mutation was found in 7% of subjects. A higher proportion of subjects demonstrated primary dissemination compared to secondary dissemination (65% vs 25%). First-line chemotherapy consisted of an alkylation-based regimen and vinca alkaloids. Surgical intervention ranged from biopsy alone (59%) to surgical resection (41%) and CSF diversion (28%). Overall, 73% of cases were alive at last follow-up. Survival did not vary by tumor type or timing of dissemination. All studies reviewed either ranked low or moderate for both quality and risk of bias assessments. Conclusions Chromosome 1p deletion and BRAF-KIAA1549 fusion were the most common alterations identified in dpLGG/GNT cases reviewed. The relative molecular heterogeneity between DLGG and DLGNT, however, deserves further exploration and ultimately correlation with their biologic behavior to better understand the pathogenesis of dpLGG/GNT.

Background: To evaluate the additive effects of orthokeratology (OK) lenses and 0.01% atropine on slowing axial elongation in myopic children. Methods: A prospective, randomized, double-blinded, placebo-controlled trial was conducted over a 12-month period. Sixty children aged 8 to 12 years with spherical equivalent refraction from − 1.00 to -4.00 D who had been wearing OK lenses successfully for 2 months (as baseline) were randomly assigned in a 1:1 ratio to combination group (combination of OK lens and 0.01% atropine eye drops) and control group (combination of OK lens and placebo). The primary outcome was change in axial length, along with secondary outcomes including change in pupil diameter (PD) and accommodative amplitude (AMP) at 12 months (measured at 4-month intervals). Results: After 12 months, the overall axial elongation was 0.10 ± 0.14 mm and 0.20 ± 0.15 mm (p = 0.01) in the combination and control groups, respectively. The change in axial length in the two groups showed significant differences only in the first four months (median [Q1, Q3] (95% CI), -0.01 mm [-0.07, 0.05] (-0.06, 0.04) vs. 0.04 mm [0.00, 0.10] (0.02, 0.09); p = 0.04), but no difference thereafter. Multivariate linear regression analysis showed that the axial elongation was significantly slower in the combination group than in the control group (standard β = -0.10, p = 0.02). PD significantly increased by 0.45 mm [0.20, 0.68] at the 4th month visit (p 0.05). Conclusion: The combination therapy was more effective than the OK lens alone in slowing axial elongation after 12 months of treatment, and mainly in the first 4 months. Trial registration: The First Affiliated Hospital of Zhengzhou University, ChiCTR2000033904. Registered 16/06/2020, http://www.chictr.org.cn/login.aspx?referurl=%2flistbycreater.aspx

Aim To explore the association between SNTB1 and ZFHX1B gene polymorphisms with high myopia (HM) in northern Chinese Han population Materials and Methods This study used case- control method and included 457 HM and 860 normal control subjects from northern Chinese Han participants. The four Single nucleotide polymorphisms (SNPs) (rs7839488, rs4395927, rs4455882,and rs6469937) in SNTB1 gene and one SNP in ZFHX1B gene(rs13382811 were chosen with two previous GWAS studies. We compared to assess the association of allelic frequencies and haplotypes between HM with normal controls. The allele and genotype distributions of SNPs in SNTB1 and ZFHX1B gene were compared between two groups by Chi-square test and Fisher exact correction. The pairwise linkage disequilibrium (LD) and haplotype analysis was performed using SHEsis software Results For HM subjects, the mean age was 44.80 ± 17.11 years, and for the control subjects, it was 44.41 ± 14.26 years. There was a linkage disequilibrium (LD) in SNTB1 (rs4395927 and rs4455882). The result showed that C-A haplotype frequency was a little higher in HM subjects than that of the controls (OR = 1.24, 95% CI = 1.01–1.52, P = 0.038). In the meanwhile, the result showed that T-G haplotype frequency was a little lower in HM group (OR = 0.81, 95% CI = 0.66–0.99, P = 0.038). In ZFHX1B gene, the frequency of the minor T allele of rs13382811was significant higher in HM group than in control group (OR = 1.37, 95% CI = 1.41–1.65, P = 0.005) Furthermore, in the CT genotype, there was significant differences in genotype frequency (OR = 1.57, 95% CI = 1.23-2.00, P = 0.001). In dominant model, there was a significant difference (TT + CT vs. CC, OR = 1.55, 95% CI = 1.23–1.95, P = 0.001). Conclusions The SNTB1 and ZFHX1B were both risk genes and increased susceptibility in northern Chinese Han population with high myopia.

Microelectromechanical system (MEMS) devices face unique issues of control and measurement in contrast to conventional devices due to smaller size, lower manufacturing cost, and less power utilization. A MEMS gyroscope multi-agent system is one example of a MEMS device which have many industrial applications. Despite the significant industrial applications of MEMS gyroscope multi-agent systems such as airbag filling systems, stabilization of image, etc., it faces problems of stability and performance due to the existence of external disturbances, noise, and variations in the parameters. So, designing a consensus controller in the presence of uncertainties and disturbances is a challenging task. The basic purpose of this work is to investigate the issues faced by the MEMS gyroscope multi-agent system and propose a non-linear robust tracking and consensus control technique for the drive axis of the multi-agent system MEMS gyroscope. For this purpose, a controller is designed for the robust tracking and consensus control of MEMS gyroscope multi-agent system by the combination of H∞ consensus control and dynamic surface control approaches. The proposed H∞ consensus controller minimizes the external disturbance effects, makes the drive axis achieve resonance, and a tuning method is derived to tune the output response of the drive axis to the desired level. Further, we simulated a closed-loop system to discuss the controller features. In the last part of the paper, simulation examples are presented to verify the effectiveness of the proposed controller in the presence of uncertainties