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In general, the same traffic information is provided to all drivers. This study investigated different responses to traffic information based on vehicle type on a local road. A living lab-based experiment was conducted in Seoul, South Korea. This experiment examined changes in approach speed and braking distances of vehicles in response to safety alerts. Data in the form of video recordings were collected, processed, and statistically analyzed. Two key findings emerged. Firstly, approach speed and braking distances were significantly reduced in both passenger and non-passenger car groups. This suggests that traffic information can effectively manage traffic, even on low-speed local roads, not just on high-speed arterial roads. Secondly, while overall responses were more pronounced in the non-passenger car group, the difference in braking distances between vehicle types was minimal. This indicates that driver responses to the interventions vary depending on the metric employed. These findings were interpreted in the context of safety-enhancing strategies for local roads. Specifically, traffic information should be customized to individual users rather than uniformly provided to all drivers, with tailored practices being essential for effective implementation. Finally, two critical issues—the transferability of results and the need for future research—arising from the living-lab survey environment were discussed.

Colonization with methicillin-resistant Staphylococcus aureus is associated with increased infection risk after hospital discharge. In a multicenter, randomized trial, a program of MRSA decolonization at home led to a significantly lower risk of MRSA infection over a 1-year period than hygiene education alone.

Age-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD. Age-related macular degeneration is characterized by lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE). Here the authors report an in vitro iPSC-RPE model for AMD that recapitulates drusen and RPE atrophy, and identify two drugs that reduce drusen deposits and restore RPE epithelial phenotype.

Ridinilazole, a novel targeted antibacterial being developed for the treatment of C. difficile infection (CDI) and prevention of recurrence, was shown in a recent Phase 2 study to be superior to vancomycin with regard to the primary efficacy measure, sustained clinical response (SCR), with the superiority being driven primarily by marked reductions in the rates of CDI recurrence within 30 days. Tolerability of ridinilazole was comparable to that of vancomycin. The current nested cohort study compared the effects of ridinilazole and vancomycin on fecal microbiota during and after treatment among participants in the Phase 2 study. Changes in the microbiota were assessed using qPCR and high-throughput sequencing on participants' stools collected at multiple time-points (baseline [Day 1], Day 5, end-of-treatment [EOT; Day 10], Day 25, end-of-study [EOS; Day 40], and at CDI recurrence). qPCR analyses showed profound losses of Bacteroides, C. coccoides, C. leptum, and Prevotella groups at EOT with vancomycin treatment, while ridinilazole-treated participants had a modest decrease in C. leptum group levels at EOT, with levels recovering by Day 25. Vancomycin-treated participants had a significant increase in the Enterobacteriaceae group, with this increase persisting beyond EOT. At EOT, alpha diversity decreased with both antibiotics, though to a significantly lesser extent with ridinilazole (p <0.0001). Beta diversity analysis showed a significantly larger weighted Unifrac distance from baseline-to-EOT with vancomycin. Taxonomically, ridinilazole had a markedly narrower impact, with modest reductions in relative abundance in Firmicutes taxa. Microbiota composition returned to baseline sooner with ridinilazole than with vancomycin. Vancomycin treatment resulted in microbiome-wide changes, with significant reductions in relative abundances of Firmicutes, Bacteroidetes, Actinobacteria, and a profound increase in abundance of Proteobacteria. These findings demonstrate that ridinilazole is significantly less disruptive to microbiota than vancomycin, which may contribute to the reduced CDI recurrence observed in the Phase 2 study.

Among resource-rich countries, the United States has the highest rate of child mortality by unintentional firearm use. To test whether children's exposure to violent video games increases dangerous behavior around firearms. This randomized clinical trial was set in a university laboratory and included pairs of children aged 8 to 12 years who knew each other. Of 313 participants who signed up, 250 were tested (2 arrived without partners, 61 did not arrive to participate). Of the 250 children tested, 8 were excluded (2 did not complete the study, 2 had participated in a related study, and 4 were outliers). Each child was paid $25. Data were collected July 1, 2017, to July 31, 2018. In a 3-group randomized design, pairs of children played or watched 1 of 3 versions of the game Minecraft for 20 minutes: (1) violent with guns, (2) violent with swords, or (3) nonviolent. The pairs of children were then placed in a different room and were told they could play with toys and games for 20 minutes. A cabinet in the room contained 2 hidden disabled handguns with counters for trigger pulls. Play sessions were videotaped. Main outcomes were touching a handgun, seconds spent holding a handgun, and number of trigger pulls (including at oneself or the partner). Control variables included sex, age, trait aggressiveness, exposure to violent media, attitudes toward guns, presence of firearms in the home, interest in firearms, and whether the child had taken a firearm safety course. Of 242 participants, 220 children (mean [SD] age, 9.9 [1.4] years; 129 [58.6%] boys) found a gun and were included in analysis. Among the 76 children who played the video game that included gun violence, 47 children (61.8%) touched a handgun. Among the 74 children who played the video game that included sword violence, 42 (56.8%) touched a handgun. Among the 70 children who played the nonviolent video game, 31 (44.3%) touched a handgun. Participants who played a violent version of the game were more likely to shoot at themselves or their partners than those who played a nonviolent game. Other risk factors for dangerous behavior around firearms included self-reported habitual exposure to violent media and trait aggressiveness. Self-reported exposure to violent media was positively associated with total trigger pulls (incidence rate ratio [IRR], 1.40; 95% CI, 1.00-1.98) and trigger pulls at oneself or one's partner (IRR, 1.88; 95% CI, 1.29-2.72). Trait aggression was positively associated with total trigger pulls (IRR, 13.52; 95% CI, 3.14-58.29), trigger pulls at oneself or one's partner (IRR, 25.69; 95% CI, 5.92-111.39), and time spent holding a handgun (IRR, 4.22; 95% CI, 1.62-11.02). One protective factor was having taken a firearm safety training course. Exposure to violent video games increases children's dangerous behavior around firearms. ClinicalTrials.gov identifier NCT03259139.

The transcriptome can reveal insights into precancer biology. We recently conducted RNA-Seq analysis on liver RNA from male rats exposed to the carcinogen, aflatoxin B1 (AFB1), for 90 days prior to liver tumor onset. Among >1,000 differentially expressed transcripts, several novel, unannotated Cufflinks-assembled transcripts, or HAfTs (Hepatic Aflatoxin Transcripts) were found. We hypothesized PCR-cloning and RACE (rapid amplification of cDNA ends) could further HAfT identification. Sanger data was obtained for 6 transcripts by PCR and 16 transcripts by 5'- and 3'-RACE. BLAST alignments showed, with two exceptions, HAfT transcripts were lncRNAs, >200nt without apparent long open reading frames. Six rat HAfT transcripts were classified as 'novel' without RefSeq annotation. Sequence alignment and genomic synteny showed each rat lncRNA had a homologous locus in the mouse genome and over half had homologous loci in the human genome, including at least two loci (and possibly three others) that were previously unannotated. While HAfT functions are not yet clear, coregulatory roles may be possible from their adjacent orientation to known coding genes with altered expression that include 8 HAfT-gene pairs. For example, a unique rat HAfT, homologous to Pvt1, was adjacent to known genes controlling cell proliferation. Additionally, PCR and RACE Sanger sequencing showed many alternative splice variants and refinements of exon sequences compared to Cufflinks assembled transcripts and gene prediction algorithms. Presence of multiple splice variants and short tandem repeats found in some HAfTs may be consequential for secondary structure, transcriptional regulation, and function. In summary, we report novel, differentially expressed lncRNAs after exposure to the genotoxicant, AFB1, prior to neoplastic lesions. Complete cloning and sequencing of such transcripts could pave the way for a new set of sensitive and early prediction markers for chemical hepatocarcinogens.

The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypotheses is the allosteric model. This model posits that binding of pMHC at the extracellular domain triggers a dynamic change in the transmembrane (TM) domain of the TCR subunits, which leads to signaling at the cytoplasmic side. We sought to test this hypothesis by creating a TM ligand for TCR. Previously we described a method to create a soluble peptide capable of inserting into membranes and binding to the TM domain of the receptor tyrosine kinase EphA2 (Alves et al., eLife, 2018). Here, we show that the approach is generalizable to complex membrane receptors, by designing a TM ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit in T cells. As a result, in the presence of this peptide inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened. Co-localization and co-immunoprecipitation in diisobutylene maleic acid (DIBMA) native nanodiscs confirmed that PITCR was able to bind to the TCR. AlphaFold-Multimer predicted that PITCR binds to the TM region of TCR, where it interacts with the two CD3ζ subunits. Our results additionally indicate that PITCR disrupts the allosteric changes in the compactness of the TM bundle that occur upon TCR activation, lending support to the allosteric TCR activation model. The TCR inhibition achieved by PITCR might be useful to treat inflammatory and autoimmune diseases and to prevent organ transplant rejection, as in these conditions aberrant activation of TCR contributes to disease.

Abstract Background Multidrug-resistant organisms (MDROs) spread between hospitals, nursing homes (NHs), and long-term acute care facilities (LTACs) via patient transfers. The Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County is a regional public health collaborative involving decolonization at 38 healthcare facilities selected based on their high degree of patient sharing. We report baseline MDRO prevalence in 21 NHs/LTACs. Methods A random sample of 50 adults for 21 NHs/LTACs (18 NHs, 3 LTACs) were screened for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus spp. (VRE), extended-spectrum β-lactamase–producing organisms (ESBL), and carbapenem-resistant Enterobacteriaceae (CRE) using nares, skin (axilla/groin), and peri-rectal swabs. Facility and resident characteristics associated with MDRO carriage were assessed using multivariable models clustering by person and facility. Results Prevalence of MDROs was 65% in NHs and 80% in LTACs. The most common MDROs in NHs were MRSA (42%) and ESBL (34%); in LTACs they were VRE (55%) and ESBL (38%). CRE prevalence was higher in facilities that manage ventilated LTAC patients and NH residents (8% vs <1%, P < .001). MDRO status was known for 18% of NH residents and 49% of LTAC patients. MDRO-colonized adults commonly harbored additional MDROs (54% MDRO+ NH residents and 62% MDRO+ LTACs patients). History of MRSA (odds ratio [OR] = 1.7; confidence interval [CI]: 1.2, 2.4; P = .004), VRE (OR = 2.1; CI: 1.2, 3.8; P = .01), ESBL (OR = 1.6; CI: 1.1, 2.3; P = .03), and diabetes (OR = 1.3; CI: 1.0, 1.7; P = .03) were associated with any MDRO carriage. Conclusions The majority of NH residents and LTAC patients harbor MDROs. MDRO status is frequently unknown to the facility. The high MDRO prevalence highlights the need for prevention efforts in NHs/LTACs as part of regional efforts to control MDRO spread. Multidrug-resistant organism (MDRO) colonization prevalence was 67% in nursing homes and long-term acute care facilities in a large-scale, randomized point-prevalence study. These data raise questions about allocation of infection control and antimicrobial stewardship resources. The Shared Healthcare Intervention to Eliminate Life-threatening Dissemination of MDROs in Orange County collaborative will measure regional impacts of a coordinated infection prevention initiative on MDRO carriage and infection.

Point-of-care (POC) tests capable of individual health monitoring, transmission reduction, and contact tracing are especially important in a pandemic such as the coronavirus disease 2019 (COVID-19). We develop a disposable POC cartridge that can be mass produced to detect the SARS-CoV-2 N gene through real-time quantitative polymerase chain reaction (qPCR) based on digital microfluidics (DMF). Several critical parameters are studied and improved, including droplet volume consistency, temperature uniformity, and fluorescence intensity linearity on the designed DMF cartridge. The qPCR results showed high accuracy and efficiency for two primer-probe sets of N1 and N2 target regions of the SARS-CoV-2 N gene on the DMF cartridge. Having multiple droplet tracks for qPCR, the presented DMF cartridge can perform multiple tests and controls at once.

Background: Surgical repair of proximal hamstring avulsion injuries can enable the return to preinjury levels of sporting function and minimize the risk of recurrence in both professional and recreational athletes. While venous thromboembolism (VTE) is a recognized complication of surgical repair, the incidence thereof is poorly reported in the literature. Purpose/Hypothesis: To report the incidence of symptomatic VTE after proximal hamstring avulsion repair and assess the efficacy of our thromboprophylaxis protocol. It was hypothesized that the incidence of VTE after proximal hamstring avulsion repair is low and that aspirin is an adequate choice of chemical prophylaxis. Study Design: Cohort study; Level of evidence, 2. Methods: We performed a prospective cohort study of 2 groups of patients who underwent proximal hamstring avulsion (partial and complete) repair between 2000 to 2020 with different thromboprophylaxis protocols. No patients were routinely screened for VTEs, and VTE was investigated only if clinically indicated. Prospectively collected data included demographics, the mechanism and sport that caused injury, use of bracing, and clinical diagnosis of deep vein thrombosis (DVT) or pulmonary embolism (PE). The first cohort (n = 380) was given mechanical prophylaxis in the form of compression stockings for 6 weeks postoperatively. The second cohort (n = 600) was given compression stockings and aspirin 150 mg once daily routinely, or prophylactic low–molecular weight heparin in high-risk individuals, until the 6-week follow-up. Patients in both cohorts underwent early mobilization after surgery; a hinged knee brace locked at 60° to 120° was provided if the tendon repair was under significant tension. The surgical technique and rehabilitation protocol remained consistent throughout the study. Results: The overall incidence of symptomatic VTE was 0.51%. A total of 5 patients developed symptomatic VTEs (3 DVTs, 2 PEs) in the first cohort, and no patients developed symptomatic VTEs in the second cohort (1.32% vs 0%; P = .0048). Conclusion: The incidence of symptomatic VTE after proximal hamstring avulsion repairs was extremely low. A combination of aspirin, early mobilization despite bracing, compression stockings, and good hydration was an effective thromboprophylaxis strategy.