Search

This study aimed to assess root canal disinfection through various irrigation protocols, including a novel photothermal system called 'LEAP'. Mandibular premolars were infected with Enterococcus faecalis and divided into five groups for different treatments: Group 1: standard needle irrigation; Group 2: passive ultrasonic irrigation; Group 3: GentleWave; Group 4: LEAP; and Group 5: Group 1 + Group 4. Microbial counts were measured before (S1) and after disinfection (S2) using colony-forming units (CFU) and confocal laser scanning microscopy (CLSM). Results revealed a significant reduction in bacterial counts for all groups (p < 0.05). While the percentage of dead bacteria near the canal wall (0-50 μm) did not differ significantly, at 50-150 μm, LEAP and SNI + LEAP exhibited significantly higher bacterial reduction than other groups (p < 0.05). The findings indicate that LEAP is comparable to existing irrigation devices in the main root canal and notably superior in tubular disinfection., (© 2024 Australian Society of Endodontology Inc.)

Objective: To examine the proportion of healthcare visits are delivered by nurse practitioners and physician assistants versus physicians and how this has changed over time and by clinical setting, diagnosis, and patient demographics., Design: Cross-sectional time series study., Setting: National data from the traditional Medicare insurance program in the USA., Participants: Of people using Medicare (ie, those older than 65 years, permanently disabled, and people with end stage renal disease), a 20% random sample was taken., Main Outcome Measures: The proportion of physician, nurse practitioner, and physician assistant visits in the outpatient and skilled nursing facility settings delivered by physicians, nurse practitioners, and physician assistants, and how this proportion varies by type of visit and diagnosis., Results: From 1 January 2013 to 31 December 2019, 276 million visits were included in the sample. The proportion of all visits delivered by nurse practitioners and physician assistants in a year increased from 14.0% (95% confidence interval 14.0% to 14.0%) to 25.6% (25.6% to 25.6%). In 2019, the proportion of visits delivered by a nurse practitioner or physician assistant varied across conditions, ranging from 13.2% for eye disorders and 20.4% for hypertension to 36.7% for anxiety disorders and 41.5% for respiratory infections. Among all patients with at least one visit in 2019, 41.9% had one or more nurse practitioner or physician assistant visits. Compared with patients who had no visits from a nurse practitioner or physician assistant, the likelihood of receiving any care was greatest among patients who were lower income (2.9% greater), rural residents (19.7%), and disabled (5.6%)., Conclusion: The proportion of visits delivered by nurse practitioners and physician assistants in the USA is increasing rapidly and now accounts for a quarter of all healthcare visits., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Policymakers are increasingly interested in using nurse practitioners to provide health care to rural populations, yet little is known about their characteristics and preparation for independent practice., Methods: We obtained data from the 2018 National Sample Survey of Registered Nurses and compared characteristics of family nurse practitioners (FNPs) employed in rural areas versus those employed in non-rural areas. Regression analysis was used to determine the relationship between the outcome variable of interest, preparation for practice and other covariates., Findings: FNPs practicing in a rural setting felt less prepared for independent practice than their counterparts in non-rural settings except for those prepared with a doctoral degree., Discussion: The majority of FNPs working in rural areas believed they were not as well prepared for independent practice. Because rural FNPs often practice autonomously and without medical back up, nursing educators need to educate FNPs with the skills and knowledge necessary to practice effectively in rural settings., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Conversion of CO 2 into CO with plasma processing is a potential method to transform intermittent sustainable electricity into storable chemical energy. The main challenges for developing this technology are how to get efficient CO 2 conversion with high energy efficiency and how to prove its feasibility on an industrial scale. In this paper we review the mechanisms and performance of different plasma methodologies used in CO 2 conversion. Mindful of the goals of obtaining efficient conversion and high energy efficiency, as well as industrial feasibility in mind, we emphasize a promising new approach of CO 2 conversion by using a thermal plasma in combination with a carbon co-reactant.

Cystobactamids are myxobacteria-derived topoisomerase inhibitors with potent anti-Gram-negative activity. They are formed by a non-ribosomal peptide synthetase (NRPS) and consist of tailored para-aminobenzoic acids, connected by a unique α-methoxy-L-isoasparagine or a β-methoxy-L-asparagine linker moiety. We describe the heterologous expression of the cystobactamid biosynthetic gene cluster (BGC) in Myxococcus xanthus. Targeted gene deletions produce several unnatural cystobactamids. Using in vitro experiments, we reconstitute the key biosynthetic steps of linker formation and shuttling via CysB to the NRPS. The biosynthetic logic involves a previously uncharacterized bifunctional domain found in the stand-alone NRPS module CysH, albicidin biosynthesis and numerous BGCs of unknown natural products. This domain performs either an aminomutase (AM) or an amide dehydratase (DH) type of reaction, depending on the activity of CysJ which hydroxylates CysH-bound L-asparagine. Furthermore, CysQ O-methylates hydroxyl-L-(iso)asparagine only in the presence of the AMDH domain. Taken together, these findings provide direct evidence for unique steps in cystobactamid biosynthesis.

Novel targets are needed for treatment of devastating diseases such as cancer. For decades, natural products have guided innovative therapies by addressing diverse pathways. Inspired by the potent cytotoxic bioactivity of myxobacterial vioprolides A-D, we performed in-depth studies on their mode of action. Based on its prominent potency against human acute lymphoblastic leukemia (ALL) cells, we conducted thermal proteome profiling (TPP) and deciphered the target proteins of the most active derivative vioprolide A (VioA) in Jurkat cells. Nucleolar protein 14 (NOP14), which is essential in ribosome biogenesis, was confirmed as a specific target of VioA by a suite of proteomic and biological follow-up experiments. Given its activity against ALL cells compared to healthy lymphocytes, VioA exhibits unique therapeutic potential for anticancer therapy through a novel mode of action., (© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Social workers (SW) and community health workers (CHW) have emerged as key workforce personnel in efforts to care for elders in the U.S. However, little is known about the presence and roles of SW and CHW in primary care practices. This paper presents findings from a nationally representative survey of geriatrics and primary care practices. Physician and nurse practitioner clinicians were randomly selected within practices, stratifying by practice staffing and presence/absence of geriatric clinicians; our final sample for this analysis included 341 practices. Key findings include: reported challenges in meeting the social service needs of elders, underutilization of SW, and fuller utilization of social work competencies in practices in which both SW and CHW were present. These findings offer a unique perspective of SW on interprofessional teams and have implications for the future of the profession.

Objective: Policies that aim to steer patients from higher to lower cost providers of comparable quality have potential to impact health care cost growth - but their effectiveness depends, in part, on consumer perceptions of value and willingness to make tradeoffs. We sought to understand what was required to shift substantial numbers of consumers to higher-value care settings for several "shoppable" conditions., Methods: A discrete choice experiment (DCE) was conducted to elicit patient preferences for hospital type. We used an Internet panel of 1005 Massachusetts residents to conduct this experiment in 2016. The DCE data were analyzed using alternative-specific conditional logit regression., Results: Consumers reported large influences of out of pocket costs, physician referrals and quality ratings on their choice of hospital. For example, up to a third of consumers would shift from Academic Medical Centers to community hospitals if the latter had higher quality ratings, lower copays or a physician referral. Choice of site for maternity care was most influenced by physician referral; cancer treatment and orthopedic procedures by quality ratings; and MRI by cost, suggesting that patients prioritize quality over cost as perceived risk increases., Conclusions and Implications: Our findings provide guidance for identifying promising policy levers that most influence consumer choice of provider. However, the extent to which potential levers can influence choice is likely to be dependent upon the kind of care being sought., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To describe the study protocol and baseline characteristics of the African Descent and Glaucoma Evaluation Study (ADAGES) III., Design: Cross-sectional, case-control study., Participants: Three thousand two hundred sixty-six glaucoma patients and control participants without glaucoma of African or European descent were recruited from 5 study centers in different regions of the United States., Methods: Individuals of African descent (AD) and European descent (ED) with primary open-angle glaucoma (POAG) and control participants completed a detailed demographic and medical history interview. Standardized height, weight, and blood pressure measurements were obtained. Saliva and blood samples to provide serum, plasma, DNA, and RNA were collected for standardized processing. Visual fields, stereoscopic disc photographs, and details of the ophthalmic examination were obtained and transferred to the University of California, San Diego, Data Coordinating Center for standardized processing and quality review., Main Outcome Measures: Participant gender, age, race, body mass index, blood pressure, history of smoking and alcohol use in POAG patients and control participants were described. Ophthalmic measures included intraocular pressure, visual field mean deviation, central corneal thickness, glaucoma medication use, or past glaucoma surgery. Ocular conditions, including diabetic retinopathy, age-related macular degeneration, and past cataract surgery, were recorded., Results: The 3266 ADAGES III study participants in this report include 2146 AD POAG patients, 695 ED POAG patients, 198 AD control participants, and 227 ED control participants. The AD POAG patients and control participants were significantly younger (both, 67.4 years) than ED POAG patients and control participants (73.4 and 70.2 years, respectively). After adjusting for age, AD POAG patients had different phenotypic characteristics compared with ED POAG patients, including higher intraocular pressure, worse visual acuity and visual field mean deviation, and thinner corneas (all P < 0.001). Family history of glaucoma did not differ between AD and ED POAG patients., Conclusions: With its large sample size, extensive specimen collection, and deep phenotyping of AD and ED glaucoma patients and control participants from different regions in the United States, the ADAGES III genomics study will address gaps in our knowledge of the genetics of POAG in this high-risk population., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Bacteria produce a large number of secondary metabolites with extraordinary chemical structures and bioactivities. Vioprolides are promising anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35, which are initially synthesized as acylated precursors (previoprolides) by nonribosomal peptide synthetases (NRPS). Here, we describe and characterize an unprecedented glycerate esterification process in the biosynthesis of vioprolides. In vitro biochemical investigations revealed that the fatty acyl chain of previoprolides is adenylated by the starting fatty acyl-AMP ligase (FAAL) domain, while the glycerate moiety is incorporated by the FkbH domain. An unusual ester-bond forming condensation domain is shown responsible for the acylation of glycerate. LC-MS analysis and bioactivity assays suggest that the acylation serves for directed membrane transport rather than representing a prodrug mechanism.

Vioprolides are a promising class of anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35. Previously nothing had been reported about their biosynthesis, including the origin of the unusual 4-methylazetidinecarboxylic acid (MAZ) moiety. We describe the vioprolide biosynthetic gene cluster and solve the production obstacle by expression in three heterologous hosts. Starting from unstable production in the wild type at the single-digit mg L -1 scale, we developed a stable host that eventually allowed for yields of up to half a gram per liter in fermenters. Gene inactivations coupled with isotope feeding studies identified an S-adenosylmethionine (SAM)-dependent enzyme and a methyltransferase as being responsible for the generation of the MAZ building block by a proposed mechanism unprecedented in bacteria. Furthermore, nonnatural vioprolide derivatives were generated via rational genetic engineering., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The fascinating ability of myxobacteria to form multicellular spore filled fruiting bodies under starvation conditions was widely studied as a model for cooperative microbial behavior. The potential of a life cycle induced change of secondary metabolism, as a means to discover novel natural products, remains largely underexplored. We therefore studied the model organism Myxococcus xanthus DK1622 under submersed and solid cultivation conditions to find putatively life-cycle related compounds by applying statistical analysis on analytical data. Utilizing the advantageous characteristics of LC-MS, LC-MS/MS, and MALDI-MSI allowed the identification of compounds unambiguously associated with myxobacterial fruiting bodies. Our screening effort resulted in the purification and structure elucidation of a novel compound, the homospermidine lipid, from cultures that had undergone the fruiting process. A combination of molecular networking and targeted LC-MS/MS in conjunction with our in-house metabolomics database subsequently revealed alternative producers of the respective compound as well as a number of compounds belonging to the same structural class. Three further members of this compound class were isolated from an alternative producer and structurally elucidated by NMR. Insights into the biosynthesis of this novel compound class was gained by feeding of isotopically labeled substrates and in silico analysis.

Objectives: Debate continues on whether nurse practitioners (NPs) and physician assistants (PAs) are more likely to order ancillary services, or order more costly services among alternatives, than primary care physicians (PCPs). We compared prescription medication and diagnostic service orders associated with NP/PA versus PCP visits for management of neck or back (N/B) pain or acute respiratory infection (ARI)., Study Design: Retrospective, observational study of visits from January 2006 through March 2008 in the adult primary care practice of Kaiser Permanente in Atlanta, Georgia., Methods: Data were obtained from electronic health records. NP/PA and PCP visits for N/B pain or ARI were propensity score matched on patient age, gender, and comorbidities., Results: On propensity score-matched N/B pain visits (n = 6724), NP/PAs were less likely than PCPs to order a computed tomography (CT)/magnetic resonance image (MRI) scan (2.1% vs 3.3%, respectively) or narcotic analgesic (26.9% vs 28.5%) and more likely to order a nonnarcotic analgesic (13.5% vs 8.5%) or muscle relaxant (45.8% vs 42.5%) (all P ≤.05). On propensity score-matched ARI visits (n = 24,190), NP/PAs were more likely than PCPs to order any antibiotic medication (73.7% vs 65.8%), but less likely to order an x-ray (6.3% vs 8.6%), broad-spectrum antibiotic (41.5% vs 42.5%), or rapid strep test (6.3% vs 9.7%) (all P ≤.05)., Conclusions: In the multidisciplinary primary care practice of this health maintenance organization, NP/PAs attending visits for N/B pain or ARI were less likely than PCPs to order advanced diagnostic radiology imaging services, to prescribe narcotic analgesics, and/or to prescribe broad-spectrum antibiotics.

G-protein-coupled receptors (GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR-mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two-hybrid (MYTH) approach and identified interacting partners for 48 selected full-length human ligand-unoccupied GPCRs in their native membrane environment. The resulting GPCR interactome connects 686 proteins by 987 unique interactions, including 299 membrane proteins involved in a diverse range of cellular functions. To demonstrate the biological relevance of the GPCR interactome, we validated novel interactions of the GPR37, serotonin 5-HT4d, and adenosine ADORA2A receptors. Our data represent the first large-scale interactome mapping for human GPCRs and provide a valuable resource for the analysis of signaling pathways involving this druggable family of integral membrane proteins., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Ripostatin is a promising antibiotic that inhibits RNA polymerase by binding to a novel binding site. In this study, the characterization of the biosynthetic gene cluster of ripostatin, which is a peculiar polyketide synthase (PKS) hybrid cluster encoding cis- and trans-acyltransferase PKS genes, is reported. Moreover, an unprecedented mechanism for phenyl acetic acid formation and loading as a starter unit was discovered. This phenyl-C2 unit is derived from phenylpyruvate (phenyl-C3) and the mechanism described herein explains the mysterious loss of one carbon atom in ripostatin biosynthesis from the phenyl-C3 precursor. Through in vitro reconstitution of the whole loading process, a pyruvate dehydrogenase like protein complex was revealed that performs thiamine pyrophosphate dependent decarboxylation of phenylpyruvate to form a phenylacetyl-S-acyl carrier protein species, which is supplied to the subsequent biosynthetic assembly line for chain extension to finally yield ripostatin., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: There has been concern that greater use of nurse practitioners (NP) and physician assistants (PA) in face-to-face primary care may increase utilization and spending., Objective: To evaluate a natural experiment within Kaiser Permanente in Georgia in the use of NP/PA in primary care., Study Design: From 2006 through early 2008 (the preperiod), each NP or PA was paired with a physician to manage a patient panel. In early 2008, NPs and PAs were removed from all face-to-face primary care. Using the 2006-2010 data, we applied a difference-in-differences analytic approach at the clinic level due to patient triage between a NP/PA and a physician. Clinics were classified into 3 different groups based on the percentage of visits by NP/PA during the preperiod: high (over 20% in-person primary care visits attended by NP/PAs), medium (5%-20%), and low (<5%) NP/PA model clinics., Measures: Referrals to specialist physicians; emergency department visits and inpatient admissions; and advanced diagnostic imaging services., Results: Compared with the low NP/PA model, the high NP/PA model and the medium NP/PA model were associated with 4.9% and 5.1% fewer specialist referrals, respectively (P<0.05 for both estimates); the high NP/PA model and the medium NP/PA model also showed fewer hospitalizations and emergency department visits and fewer advanced diagnostic imaging services, but none of these was statistically significant., Conclusions: We find no evidence to support concerns that under a physician's supervision, NPs and PAs increase utilization and spending.

Myotonic dystrophy type 1 (DM1) is a genetic disorder in which dominant-active DM protein kinase (DMPK) transcripts accumulate in nuclear foci, leading to abnormal regulation of RNA processing. A leading approach to treat DM1 uses DMPK-targeting antisense oligonucleotides (ASOs) to reduce levels of toxic RNA. However, basal levels of DMPK protein are reduced by half in DM1 patients. This raises concern that intolerance for further DMPK loss may limit ASO therapy, especially since mice with Dmpk gene deletion reportedly show cardiac defects and skeletal myopathy. We re-examined cardiac and muscle function in mice with Dmpk gene deletion, and studied post-maturity knockdown using Dmpk-targeting ASOs in mice with heterozygous deletion. Contrary to previous reports, we found no effect of Dmpk gene deletion on cardiac or muscle function, when studied on two genetic backgrounds. In heterozygous knockouts, the administration of ASOs reduced Dmpk expression in cardiac and skeletal muscle by > 90%, yet survival, electrocardiogram intervals, cardiac ejection fraction and muscle strength remained normal. The imposition of cardiac stress by pressure overload, or muscle stress by myotonia, did not unmask a requirement for DMPK. Our results support the feasibility and safety of using ASOs for post-transcriptional silencing of DMPK in muscle and heart., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: The Institute of Medicine has recently argued against a value index as a mechanism to address geographic variation in spending and instead promoted payment reform targeted at individual providers. It is unknown whether such provider-focused payment reform reduces geographic variation in spending., Study Design: We estimated the potential impact of 3 Medicare provider-focused payment policies-pay-for-performance, bundled payment, and accountable care organizations-on geographic variation in Medicare spending across Hospital Referral Regions (HRRs). We compared geographic variation in spending, measured using the coefficient of variation (CV) across HRRs, between the baseline case and a simulation of each of the 3 policies., Methods: Policy simulation based on 2008 national Medicare data combined with other publicly available data., Results: Compared with the baseline (CV, 0.171), neither pay-for-performance nor accountable care organizations would change geographic variation in spending (CV, 0.171), while bundled payment would modestly reduce geographic variation (CV, 0.165)., Conclusions: In our models, the bundled payment for inpatient and post acute care services in Medicare would modestly reduce geographic variation in spending, but neither accountable care organizations nor pay-for-performance appear to have an impact.

Key Points: Na(+) current (INa) results from the integrated function of a molecular aggregate (the voltage-gated Na(+) channel complex) that includes the β subunit family. Mutations or rare variants in Scn1b (encoding the β1 and β1B subunits) have been associated with various inherited arrhythmogenic syndromes, including Brugada syndrome and sudden unexpected death in patients with epilepsy. We used Scn1b null mice to understand better the relation between Scn1b expression, and cardiac electrical function. Loss of Scn1b caused, among other effects, increased amplitude of tetrodotoxin-sensitive INa, delayed after-depolarizations, triggered beats, delayed Ca(2+) transients, frequent spontaneous calcium release events and increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. We propose that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis., Abstract: Na(+) current (INa) is determined not only by the properties of the pore-forming voltage-gated Na(+) channel (VGSC) α subunit, but also by the integrated function of a molecular aggregate (the VGSC complex) that includes the VGSC β subunit family. Mutations or rare variants in Scn1b (encoding the β1 and β1B subunits) have been associated with various inherited arrhythmogenic syndromes, including cases of Brugada syndrome and sudden unexpected death in patients with epilepsy. Here, we have used Scn1b null mouse models to understand better the relation between Scn1b expression, and cardiac electrical function. Using a combination of macropatch and scanning ion conductance microscopy we show that loss of Scn1b in juvenile null animals resulted in increased tetrodotoxin-sensitive INa but only in the cell midsection, even before full T-tubule formation; the latter occurred concurrent with increased message abundance for the neuronal Scn3a mRNA, suggesting increased abundance of tetrodotoxin-sensitive NaV 1.3 protein and yet its exclusion from the region of the intercalated disc. Ventricular myocytes from cardiac-specific adult Scn1b null animals showed increased Scn3a message, prolonged action potential repolarization, presence of delayed after-depolarizations and triggered beats, delayed Ca(2+) transients and frequent spontaneous Ca(2+) release events and at the whole heart level, increased susceptibility to polymorphic ventricular arrhythmias. Most alterations in Ca(2+) homeostasis were prevented by 100 nM tetrodotoxin. Our results suggest that life-threatening arrhythmias in patients with mutations in Scn1b, a gene classically defined as ancillary to the Na(+) channel α subunit, can be partly consequent to disrupted intracellular Ca(2+) homeostasis in ventricular myocytes., (© 2014 The Authors. The Journal of Physiology © 2014 The Physiological Society.)