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The increased use of digital devices has implications for health and, particularly, the eyes, due to Computer Vision Syndrome (CVS). Millions of individuals of all ages are at risk of CVS, and its prevalence ranges from 25% to 93%. This trial will evaluate the effectiveness of the Super Enhanced Single Vision Lens 01 (SESL01) versus standard single vision lens in reducing symptoms of CVS assessed by the Computer Vision Syndrome Questionnaire (CVS-Q®) scores. A double-blind, two-arm parallel randomized controlled trial will be conducted at the University of Central Lancashire, Preston (UK), recruiting students and staff with CVS-Q score ≥ 6. A 1:1 randomization and a sample size of 300 participants will be sufficient to detect a 2-point difference in the CVS-Q score between the intervention and control groups with an alpha of 5%, two-sided, allowing for a dropout of 10%. The control group will use standard single vision lenses, and the intervention group SESL01. The primary outcome to week 14 will be the difference in the CVS-Q score between SESL01 and standard single vision lenses. Secondary outcomes include the percentage of participants with CVS-Q score < 6 (no symptoms) and CVS-Q score ≥ 6 (symptoms) in the SESL01 and the standard single vision group at weeks 6, 10 and 14; the percentage of participants in each group with a total CVS-Q score < 6, 6–12, 13–19, and ≥ 20 at weeks 6, 10 and 14. The primary analysis will be the intention to treat. Findings may inform decisions about adopting the SESL01 lenses to reduce CVS. Trial registration: clinicaltrial.gov identifier: NCT05545878. Registered: Sept. 19, 2022. [ABSTRACT FROM AUTHOR]

Little is known about the clinical features, radiology and manometry findings, and treatment outcomes of patients with functional and mechanical esophagogastic junction outflow obstruction (EGJOO). Between November 2011 and February 2015, a total of 1443 high-resolution manometries were reviewed and 49 patients (3.4%) met the manometric criteria for EGJOO. Then, we performed a retrospective chart review, collecting data from manometric studies, timed barium esophagram findings (TBEs), endoscopic reports, and clinical records. Twenty-seven patients had functional EGJOO and 22 patients had an anatomic esophageal obstruction. Common causes of anatomic EGJOO included strictures (36% of patients) and hiatal hernias (31% of patients). There were no differences between groups in manometric or radiographic metrics. Each group had increased basal lower esophageal sphincter and intrabolus pressures, compared with individuals without EGJOO, and most patients had abnormal findings on TBE analysis. Two patients with functional EGJOO progressed to type 3 achalasia. We conclude that patients diagnosed with EGJOO based on manometry findings can have anatomic obstruction or functional EGJOO; high-resolution manometry and TBE do not distinguish between disease causes. [ABSTRACT FROM AUTHOR]

This study examined the influence of tibio-femoral conformity on anteroposterior (AP) knee stability during stair descent, particularly with a dished cruciate sacrificing (CS) design. A joint simulator simulated stair descent of cadaveric knees. Tibio-femoral displacement was measured. Knees were tested in intact, ACL-deficient, and TKA with cruciate-retaining (CR), CS and posterior-stabilizing (PS) inserts. Loading during stair descent simulation caused femur displacement anteriorly prior to quadriceps contraction. Quadriceps contraction reestablished the initial femoral AP position. During simulated stair descent, AP stability was restored using PS, CR or CS inserts with an intact PCL. The CS design without the PCL did not provide AP stability. Increasing quadriceps force to restore AP stability may explain the clinical findings of pain and fatigue experienced by some patients after TKA. [ABSTRACT FROM AUTHOR]

This study compared changes in speech clarity as a function of speaking context. It is well documented that words produced in sentence contexts yield higher intelligibility than words in isolation for speakers with mild to moderate dysarthria. To tease apart the effect of speaker and listener variables, the current study aimed to quantify differences in word intelligibility by speaking task. Eighteen speakers with dysarthria produced a set of 25 words in isolation and within the context of a sentence. Eighteen listeners heard a randomized sample of the isolated productions, single words extracted from the sentences, and the full unaltered sentences. Listeners transcribed what they heard and rated their confidence. Words produced in isolation were just as intelligible as words produced in sentence context, both of which were more intelligible than extracted words. In other words, speakers reduced articulatory clarity in sentence production compared to isolated productions; listeners were able to cope with this reduction in clarity when they had access to contextual information but not when these cues were removed in the extracted condition. These findings are consistent with Lindblom's hypo–hyperarticulation theory in that adults with dysarthria appear to be modulating articulatory precision based on listener/task variables. This work has implications for clinical practice in that isolated word and sentence production tasks yielded equivalent intelligibility findings. Learning outcomes: Readers will recognize that speech intelligibility is influenced by speaker and listener variables and thus the choice of speaking and listening task may yield different results. Commonly held clinical belief is that sentence production tasks yield inflated intelligibility scores but we did not find that in this sample. Findings also indicate that speakers with dysarthria may modulate articulatory clarity in response to listener needs which should be considered in treatment planning. [ABSTRACT FROM AUTHOR]

Abstract: The present study examined articulator movement changes associated with the production of sentential focus in 4, 7 and 11-year-old children and adults. A facial capture system was used to track jaw, lower lip and upper lip movements while words were produced with and without focus in phrase-final and non-final positions. Adults produced focused words with significantly greater movement duration, displacement and velocity than unfocused words. Significant differences in duration, displacement and velocity between focused and unfocused productions were seen in the 7 and 11 year olds, although these results were not as consistent as those seen in the adults. Articulator movement differences between focused and unfocused words were seen in both the phrase-final and non-final positions in adults yet only in the phrase-final position in children. Findings suggest that children begin to modify articulator movement to mark sentential focus between 7 and 11 years of age and are likely to continue to refine movement patterns for this prosodic task throughout adolescence. [ABSTRACT FROM AUTHOR]

Articular chondrocytes have been thought to reside in a homogenous matrix. The physical characteristics of the intercellular matrix of articular cartilage are not well characterized, especially at a nanoscopic scale. The present work tested the hypothesis that the nanomechanical properties of the intercellular matrices of articular cartilage in both the articulating surface and various cellular zones are non-homogeneous. Nanoindentation by atomic force microscopy was applied to the geometric center of the medial, lateral and groove regions of the superficial zone of the rabbit proximal radius cartilage, and then the intercellular matrices of chondrocytes from the superficial to calcifying zones in 40 μm increments. The elastic modulus of the articular surface of the medial condyle (1.46±0.11 MPa) was significantly higher than the lateral condyle (1.18±0.10 MPa), and the groove (0.96±0.07 MPa). There is a significant gradient increase in Young’s moduli from the superficial zone (0.52±0.05 MPa) to calcifying zone (1.69±0.12 MPa). Thus, the nanomechanical properties of the intercellular matrices of the articulating surface are region-specific and likely related to articular function. Heterogeneous biophysical properties of intercellular matrices along the depth from the superficial to calcifying zones suggest that chondrocytes likely reside in a heterogeneous matrix. [Copyright &y& Elsevier]

• Perinatal maternal depression, interpersonal violence, (IPV) substance use and poor sexual health are critical public health concerns with significant negative impacts on child development. • Despite widespread calls for service integration at the systems/organizational level and well-documented benefits to children and families, predictors to service integration by community-based providers (Community Health Workers and Home Visitors) are not well understood. • Our findings elucidate areas for future investment for human services agency administrators and point to future areas of intervention that can bolster integrated service provision, thereby improve efficiency, cost effectiveness, and optimal maternal and child health care outcomes for at-risk populations. Perinatal maternal depression, interpersonal violence, (IPV) substance use and poor sexual health are critical public health concerns with significant negative impacts on child development. Despite widespread calls for service integration at the systems/organizational level and well-documented benefits to children and families, predictors to service integration are not well understood. Using cross-sectional data from 159 community-based providers (CBPs) who identify as community health workers (CHWs) or home visitors (HVs) in New York State, United States, our study aims to examine organizational and individual level predictors to service integration. Service integration in this study is defined as the screening, delivery and referral-making of two or more services over the course of six months. Services of interest in this study include mental health, IPV, sexual health, mental health, and substance abuse services. Descriptive statistics were performed to characterize our sample and show the distribution of service types. Multivariable logistic regression was used to identify salient organizational (job satisfaction: communication, contingent rewards, fringe benefits, operating conditions, and coworker; and training helpfulness) and individual characteristics (self-efficacy) that are associated with service integration, while controlling for demographic characteristics. Forty-four percent of participants (n = 70) integrated all four of the services: mental health, IPV, sexual health and mental health services. Training helpfulness (b = −2.48, p = 0.01), self-efficacy (b = 0.07, p < 0.01), and job satisfaction (b = −0.04, p = 0.01) were significantly associated with provision of integrated services. Specifically, elements of job satisfaction that were associated with integrated service provision included satisfaction with communication (b = −0.28, p < 0.01), coworkers (b = −0.29, p < 0.01), and pay (b = −015, p = 0.02). Findings elucidate areas for future investment for human services agency administrators and point to future areas of intervention that can bolster integrated service provision, thereby improve efficiency, cost effectiveness, and optimal maternal and child health care outcomes for at-risk populations. [ABSTRACT FROM AUTHOR]

Abstract: A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C 12 (PO)/EC50 ratios. [Copyright &y& Elsevier]

Abstract: The discovery of 5,5′- and 6,6′-dialkyl-5,6-dihydro-1H-pyridin-2-ones as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10μM). In vitro DMPK data for selected compounds as well as crystal structures of representative inhibitors complexed with the NS5B protein are also disclosed. [Copyright &y& Elsevier]

Abstract: The synthesis of 4-(1′,1′-dioxo-1′,4′-dihydro-1′λ6-benzo[1′,2′,4′]thiadiazin-3′-yl)-5-hydroxy-2H-pyridazin-3-ones bearing 6-amino substituents as potent inhibitors of the HCV RNA-dependent RNA polymerase (NS5B) is described. Several of these agents also display potent antiviral activity in cell culture experiments (EC50 <0.10μM). In vitro DMPK data (microsome t 1/2, Caco-2 P app) for many of the compounds are also disclosed, and a crystal structure of a representative inhibitor complexed with the NS5B protein is discussed. [Copyright &y& Elsevier]

Abstract: Hexahydro-pyrrolo- and hexahydro-1H-pyrido[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Among these, compound 4c displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b) <10nM; EC50 (1b)=34nM) as well as good stability towards human liver microsomes (HLM t 1/2 =59min). [Copyright &y& Elsevier]

Abstract: 4-(1,1-Dioxo-1,4-dihydro-1λ6-benzo[1,4]thiazin-3-yl)-5-hydroxy-2H-pyridazin-3-one analogs were discovered as a novel class of inhibitors of HCV NS5B polymerase. Structure-based design led to the identification of compound 3a that displayed potent inhibitory activities in biochemical and replicon assays (1b IC50 <10 nM; 1b EC50 =1.1nM) as well as good stability toward human liver microsomes (HLM t 1/2 >60min). [Copyright &y& Elsevier]

Abstract: A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC50 values. The most potent compound exhibited IC50 less than 10nM against the genotype 1b HCV polymerase and EC50 of 70nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated. [Copyright &y& Elsevier]

Abstract: Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3k, which displayed potent inhibitory activities in biochemical and replicon assays (IC50 (1b)<10nM; EC50 (1b)=12nM) as well as good stability towards human liver microsomes (HLM t 1/2 >60min). [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC50 (1b)<10nM; IC50 (1a)=22nM; EC50 (1b)=5nM], good stability toward human liver microsomes (HLM t 1/2 >60min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats. [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as potent inhibitors of genotype 1 HCV NS5B polymerase focusing on the optimization of their drug metabolism and pharmacokinetics (DMPK) profiles. This investigation led to the discovery of potent inhibitors with improved DMPK properties. [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The structure–activity relationship (SAR) associated with variation of the pyridazinone 2- and 6-substituents is discussed. The synthesis and metabolic stability of this new class of compounds are also described. [Copyright &y& Elsevier]

Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. The synthesis, structure–activity relationships (SAR), metabolic stability, and structure-based design approach for this new class of compounds are discussed. [Copyright &y& Elsevier]