To describe the efficacy of atropine in controlling salivary flow in patients with sialorrhea or drooling.
We included randomized controlled studies, quasi-randomized trials, case reports, clinical ...trials, systematic reviews, and meta-analyses assessing the use of atropine in patients with sialorrhea or drooling. The endpoints were reduction in salivary flow rate, amount of saliva secreted, reduction in clinical symptoms of sialorrhea, death rattle intensity, or reduction in drooling intensity as measured by an objective scale such as the drooling intensity scale.
A total of 56 studies with 2,378 patients were included in the systematic review. The underlying disease states included brain injury, amyotrophic lateral sclerosis, cerebral palsy, clozapine- and perphenazine-induced sialorrhea, Parkinson's disease, and terminal illness. The routes of atropine administration included sublingual, intravenous, subcutaneous, oral tablet or solution, and direct injection of atropine into parotid glands or at the base of the tongue. The generalized estimated equation regression models showed that sublingual administration is superior to oral and subcutaneous routes.
Atropine is efficacious in managing sialorrhea in most disease states. Sublingual administration of atropine is superior to other routes of administration in reducing salivary flow in patients with sialorrhea.
Clinical algorithms, or "pathways," promote the delivery of medical care that is consistent and equitable. Race, ethnicity, and/or ancestry terms are sometimes included in these types of guidelines, ...but it is unclear if this is appropriate for clinical decision-making. At our institution, we developed and applied a structured framework to determine whether race, ethnicity, or ancestry terms identified in our clinical pathways library should be retained, modified, or removed. First, we reviewed all text and associated reference documents for 132 institutionally-developed clinical pathways and identified 8 pathways that included race, ethnicity, or ancestry terms. Five pathways had clear evidence or a change in institutional policy that supported removal of the term. Multispecialty teams conducted additional in-depth evaluation of the 3 remaining pathways (Acute Viral Illness, Hyperbilirubinemia, and Weight Management) by applying the framework. In total, based on these reviews, race, ethnicity, or ancestry terms were removed (n = 6) or modified (n = 2) in all 8 pathways. Application of the framework established several recommended practices, including: (1) define race, ethnicity, and ancestry rigorously; (2) assess the most likely mechanisms underlying epidemiologic associations; (3) consider whether inclusion of the term is likely to mitigate or exacerbate existing inequities; and (4) exercise caution when applying population-level data to individual patient encounters. This process and framework may be useful to other institutional programs and national organizations in evaluating the inclusion of race, ethnicity, and ancestry in clinical guidelines.
The objective of this study was to determine the association of the use of extracorporeal cardiopulmonary resuscitation (ECPR) with survival to hospital discharge in pediatric patients with a ...noncardiac illness category. A secondary objective was to report on trends in ECPR usage in this population for 20 years.
Retrospective multicenter cohort study.
Hospitals contributing data to the American Heart Association's Get With The Guidelines-Resuscitation registry between 2000 and 2021.
Children (<18 yr) with noncardiac illness category who received greater than or equal to 30 minutes of cardiopulmonary resuscitation (CPR) for in-hospital cardiac arrest.
None.
Propensity score weighting balanced ECPR and conventional CPR (CCPR) groups on hospital and patient characteristics. Multivariable logistic regression incorporating these scores tested the association of ECPR with survival to discharge. A Bayesian logistic regression model estimated the probability of a positive effect from ECPR. A secondary analysis explored temporal trends in ECPR utilization. Of 875 patients, 159 received ECPR and 716 received CCPR. The median age was 1.0 interquartile range: 0.2-7.0 year. Most patients (597/875; 68%) had a primary diagnosis of respiratory insufficiency. Median CPR duration was 45 35-63 minutes. ECPR use increased over time ( p < 0.001). We did not identify differences in survival to discharge between the ECPR group (21.4%) and the CCPR group (16.2%) in univariable analysis ( p = 0.13) or propensity-weighted multivariable logistic regression (adjusted odds ratio 1.42 95% CI, 0.84-2.40; p = 0.19). The Bayesian model estimated an 85.1% posterior probability of a positive effect of ECPR on survival to discharge.
ECPR usage increased substantially for the last 20 years. We failed to identify a significant association between ECPR and survival to hospital discharge, although a post hoc Bayesian analysis suggested a survival benefit (85% posterior probability).
Time-to-event data often violate the proportional hazards assumption inherent in the popular Cox regression model. Such violations are especially common in the sphere of biological and medical data ...where latent heterogeneity due to unmeasured covariates or time varying effects are common. A variety of parametric survival models have been proposed in the literature which make more appropriate assumptions on the hazard function, at least for certain applications. One such model is derived from the First Hitting Time (FHT) paradigm which assumes that a subject’s event time is determined by a latent stochastic process reaching a threshold value. Several random effects specifications of the FHT model have also been proposed which allow for better modeling of data with unmeasured covariates. While often appropriate, these methods often display limited flexibility due to their inability to model a wide range of heterogeneities. To address this issue, we propose a Bayesian model which loosens assumptions on the mixing distribution inherent in the random effects FHT models currently in use. We demonstrate via simulation study that the proposed model greatly improves both survival and parameter estimation in the presence of latent heterogeneity. We also apply the proposed methodology to data from a toxicology/carcinogenicity study which exhibits nonproportional hazards and contrast the results with both the Cox model and two popular FHT models.
Mupirocin is a clinically important antibiotic produced by a trans‐AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens. The major bioactive metabolite, pseudomonic acid A (PA−A), is ...assembled on a tetrasubstituted tetrahydropyran (THP) core incorporating a 6‐hydroxy group proposed to be introduced by α‐hydroxylation of the thioester of the acyl carrier protein (ACP) bound polyketide chain. Herein, we describe an in vitro approach combining purified enzyme components, chemical synthesis, isotopic labelling, mass spectrometry and NMR in conjunction with in vivo studies leading to the first characterisation of the α‐hydroxylation bimodule of the mupirocin biosynthetic pathway. These studies reveal the precise timing of hydroxylation by MupA, substrate specificity and the ACP dependency of the enzyme components that comprise this α‐hydroxylation bimodule. Furthermore, using purified enzyme, it is shown that the MmpA KS0 shows relaxed substrate specificity, suggesting precise spatiotemporal control of in trans MupA recruitment in the context of the PKS. Finally, the detection of multiple intermodular MupA/ACP interactions suggests these bimodules may integrate MupA into their assembly.
Mupirocin is a clinically important polyketide antibiotic bearing a 6‐hydroxy group that is essential for biological activity. NMR spectroscopy, authentic synthetic substrates and mass spectrometry were used to establish the mechanistic steps governing incorporation of this key 6‐hydroxy group by an α‐hydroxylation bimodule that recruits a trans acting monooxygenase, MupA.
IntroductionLyme disease is the most common vectorborne disease in the Northern hemisphere with more than 400 000 new cases in the USA annually. Lyme meningitis is an uncommon but potentially serious ...clinical manifestation of Lyme disease. Intravenous ceftriaxone had been the first-line treatment for Lyme meningitis, but is associated with a high rate of complications. Although efficacy and effectiveness (or real-world evidence) data for oral doxycycline are limited, practice guidelines were recently expanded to recommend either oral doxycycline or ceftriaxone as first-line treatments for Lyme meningitis. Our goal is to compare oral doxycycline with intravenous ceftriaxone for the treatment of Lyme meningitis on short-term recovery and long-term quality of life.Methods and analysisWe are performing a prospective cohort study at 20 US paediatric centres located in diverse geographical range where Lyme disease is endemic. The clinical care team will make all antibiotic treatment decisions for children with Lyme meningitis, as per usual practice. We will follow enrolled children for 6 months to determine time of acute symptom recovery and impact on quality of life.Ethics and disseminationBoston Children’s Hospital, the single Institutional Review Board (sIRB), has approved the study protocol with the other 19 enrolling sites as well as the Utah data coordinating centre relying on the Boston Children’s Hospital sIRB. Once the study is completed, we will publish our findings in a peer-reviewed medical journal.
Huntington's disease is associated with motor, cognitive and behavioral dysfunction. Behavioral symptoms may present before, after, or simultaneously with clinical disease manifestation. The ...relationship between age of onset and behavioral symptom presentation and severity was explored using the Enroll‐HD database. Manifest individuals (n = 4469) were initially divided into three groups for preliminary analysis: early onset (<30 years; n = 479); mid‐adult onset (30‐59 years; n = 3478); and late onset (>59 years; n = 512). Incidence of behavioral symptoms reported at onset was highest in those with early onset symptoms at 26% (n = 126), compared with 19% (n = 678) for mid‐adult onset and 11% (n = 56) for late onset (P < 0.0001). Refined analysis, looking across the continuum of ages rather than between categorical subgroups found that a one‐year increase in age of onset was associated with a 5.6% decrease in the odds of behavioral symptoms being retrospectively reported as the presenting symptom (P < 0.0001). By the time of study enrollment, the odds of reporting severe behavioral symptoms decreased by 5.5% for each one‐year increase in reported age of onset. Exploring environmental, genetic and epigenetic factors that affect age of onset and further characterizing types and severity of behavioral symptoms may improve treatment and understanding of Huntington's disease's impact on affected individuals.
Huntington's disease is a autosomal dominant trinucleotide repeat disorder that results in motor, behavioral and cognitive dysfunction. Onset is usually in midlife but symptoms may start in childhood or late in life. Age of onset in relation to behavioral presentations were explored using a large manifest cohort. An inverse relationship was noted between age of onset and behavioral symptom presentations, highlighting an age associated difference in phenotypic presentations of Huntington's disease.
Total Synthesis of Kalimantacin A Davies, Jonathan A; Bull, Freya M; Walker, Paul D ...
Organic letters,
08/2020, Letnik:
22, Številka:
16
Journal Article
Recenzirano
Odprti dostop
The kalimantacins make up a family of hybrid polyketide-nonribosomal peptide-derived natural products that display potent and selective antibiotic activity against multidrug resistant strains of ...Staphylococcus aureus. Herein, we report the first total synthesis of kalimantacin A, in which three fragments are prepared and then united via Sonogashira and amide couplings. The enantioselective synthetic approach is convergent, unlocking routes to further kalimantacins and analogues for structure–activity relationship studies and clinical evaluation.
Complex polyketides of bacterial origin are biosynthesised by giant assembly-line like megaenzymes of the type 1 modular polyketide synthase (PKS) class. The trans-AT family of modular PKSs, whose ...biosynthetic frameworks diverge significantly from those of the archetypal cis-AT type systems represent a new paradigm in natural product enzymology. One of the most distinctive enzymatic features common to trans-AT PKSs is their ability to introduce methyl groups at positions β to the thiol ester in the growing polyketide chain. This activity is achieved through the action of a five protein HCS cassette, comprising a ketosynthase, a 3-hydroxy-3-methylglutaryl-CoA synthase, a dehydratase, a decarboxylase and a dedicated acyl carrier protein. Here we report a molecular level description, achieved using a combination of X-ray crystallography, in vitro enzyme assays and site-directed mutagenesis, of the bacillaene synthase dehydratase/decarboxylase enzyme couple PksH/PksI, responsible for the final two steps in β-methyl branch installation in this trans-AT PKS. Our work provides detailed mechanistic insight into this biosynthetic peculiarity and establishes a molecular framework for HCS cassette enzyme exploitation and manipulation, which has future potential value in guiding efforts in the targeted synthesis of functionally optimised 'non-natural' natural products.
Spirotetronate and spirotetramate natural products include a multitude of compounds with potent antimicrobial and antitumor activities. Their biosynthesis incorporates many unusual biocatalytic ...steps, including regio‐ and stereo‐specific modifications, cyclizations promoted by Diels–Alderases, and acetylation‐elimination reactions. Here we focus on the acetate elimination catalyzed by AbyA5, implicated in the formation of the key Diels–Alder substrate to give the spirocyclic system of the antibiotic abyssomicin C. Using synthetic substrate analogues, it is shown that AbyA5 catalyzes stereospecific acetate elimination, establishing the (R)‐tetronate acetate as a biosynthetic intermediate. The X‐ray crystal structure of AbyA5, the first of an acetate‐eliminating enzyme, reveals a deviant acetyl esterase fold. Molecular dynamics simulations and enzyme assays show the use of a His‐Ser dyad to catalyze either elimination or hydrolysis, via disparate mechanisms, under substrate control.
To eliminate, or to hydrolyze, that is the question: Structural, mechanistic, and computational studies of the abyssomicin C pathway enzyme AbyA5 establish the molecular origins of enzyme‐catalyzed acetate elimination. The unexpected acetyl‐esterase‐like scaffold of the protein is shown to support both acetate elimination and ester hydrolysis, in a manner dictated by substrate identity.
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