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The Journal of Allergy and Clinical... Mar 2023An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case... (Meta-Analysis)
Meta-Analysis
BACKGROUND
An unmet clinical need exists in the management of treatment-refractory allergic bronchopulmonary aspergillosis (ABPA). Omalizumab has shown promising effects in case series and cohort studies; however, evidence to support its routine clinical use is lacking.
OBJECTIVE
The aim of this systematic review and meta-analysis was to evaluate the clinical effectiveness and safety of omalizumab in patients with ABPA.
METHODS
We conducted a systematic search across standard databases using specific key words until May 13, 2021. We performed a meta-analysis to compare the effectiveness (exacerbations, oral corticosteroid [OCS] use, lung function, and patient-reported asthma control) and safety of pre- and post-omalizumab treatment. Subgroup analyses were performed for treatment duration and underlying disease.
RESULTS
In total, 49 studies (n = 267) were included in the qualitative synthesis and 14 case series (n = 186) in the quantitative meta-analysis. Omalizumab treatment significantly reduced the annualized exacerbation rate compared with pretreatment (mean difference, -2.09 [95% CI, -3.07 to -1.11]; P < .01). There was a reduction in OCS use (risk difference, 0.65 [95% CI, 0.46-0.84]; P < .01), an increase in termination of OCS use (risk difference, 0.53 [95% CI, 0.24-0.82]; P < .01), and a reduction in OCS dose (milligrams per day) (mean difference, -14.62 [95% CI, -19.86 to -9.39]; P < .01) in ABPA patients receiving omalizumab. Omalizumab improved FEV % predicted by 11.9% (95% CI, 8.2-15.6; P < .01) and asthma control, and was well-tolerated.
CONCLUSIONS
Omalizumab treatment reduced exacerbations and OCS use, improved lung function and asthma control in patients with ABPA, and was well-tolerated. The results highlight the potential role of omalizumab in the treatment of ABPA.
Topics: Humans; Omalizumab; Aspergillosis, Allergic Bronchopulmonary; Cystic Fibrosis; Asthma; Adrenal Cortex Hormones
PubMed: 36581073
DOI: 10.1016/j.jaip.2022.12.012 -
Methods in Enzymology 2020Siderophores have important functions for bacteria in iron acquisition and as virulence factors. In this chapter we will discuss the engineering of cyclic hydroxamate...
Siderophores have important functions for bacteria in iron acquisition and as virulence factors. In this chapter we will discuss the engineering of cyclic hydroxamate siderophores by various biochemical approaches based on the example of Shewanella algae. The marine gamma-proteobacterium S. algae produces three different cyclic hydroxamate siderophores as metabolites via a single biosynthetic gene cluster and one of them is an important key player in interspecies competition blocking swarming of Vibrio alginolyticus. AvbD is the key metabolic enzyme assembling the precursors into three different core structures and hence an interesting target for metabolic and biochemical engineering. Synthetic natural and unnatural precursors can be converted in vitro with purified AvbD to generate siderophores with various ring sizes ranging from analytical to milligram scale. These engineered siderophores can be applied, for example, as swarming inhibitors against V. alginolyticus. Here, we describe the synthesis of the natural and unnatural siderophore precursors HS[X]A and provide our detailed protocols for protein expression of AvbD, conversion of HS[X]A with the enzyme to produce ring-size engineered siderophores and secondly for a biosynthetic feeding strategy that allows to extract engineered siderophores in the milligram scale.
Topics: Antibiosis; Bacterial Proteins; Diamines; Escherichia coli; Hydroxamic Acids; Metabolic Engineering; Movement; Peptides, Cyclic; Putrescine; Recombinant Proteins; Shewanella; Siderophores; Succinates; Vibrio alginolyticus
PubMed: 32046852
DOI: 10.1016/bs.mie.2019.10.030 -
Chemistry (Weinheim An Der Bergstrasse,... Mar 2020High-throughput experimentation (HTE) is a growing, enabling technology that allows the execution of large, parallel sets of experiments. Often, automation is required... (Review)
Review
High-throughput experimentation (HTE) is a growing, enabling technology that allows the execution of large, parallel sets of experiments. Often, automation is required to dose compounds on milligram to sub-milligram scale, to run many parallel reactions, and to analyse large datasets. Unique approaches to screen design, implementation, and analysis are required, distinct from traditional synthetic organic chemistry. The discipline also presents a profitable opportunity for individual scientists to learn about and explore fields adjacent to chemistry, including data science, robotics and equipment engineering, and computer programming. This perspective presents the author's viewpoints on the field of HTE, its implementation within a chemistry career, and the automated future of organic chemistry technology.
PubMed: 32125726
DOI: 10.1002/chem.202000656 -
Science Translational Medicine May 2023This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP)...
This first-in-human study evaluated RO7122290, a bispecific fusion protein carrying a split trimeric 4-1BB (CD137) ligand and a fibroblast activation protein α (FAP) binding site that costimulates T cells for improved tumor cell killing in FAP-expressing tumors. Patients with advanced or metastatic solid tumors received escalating weekly intravenous doses of RO7122290 as a single agent ( = 65) or in combination with a 1200-milligram fixed dose of the anti-programmed death-ligand 1 (anti-PD-L1) antibody atezolizumab given every 3 weeks ( = 50), across a tested RO7122290 dose range of 5 to 2000 milligrams and 45 to 2000 milligrams, respectively. Three dose-limiting toxicities were reported, two at different RO7122290 single-agent doses (grade 3 febrile neutropenia and grade 3 cytokine release syndrome) and one for the combination (grade 3 pneumonitis). No maximum tolerated dose was identified. The pharmacokinetic profile of RO7122290 suggested nonlinearity in elimination. The observed changes in peripheral and tissue pharmacodynamic (PD) biomarkers were consistent with the postulated mechanism of action. Treatment-induced PD changes included an increase in proliferating and activated T cells in peripheral blood both in the single-agent and combination arms. Increased infiltration of intratumoral CD8 and Ki67CD8 T cells was observed for both treatment regimens, accompanied by the up-regulation of T cell activation genes and gene signatures. Eleven patients experienced a complete or partial response, six of whom were confirmed to be immune checkpoint inhibitor naive. These results support further evaluation of RO7122290 in combination with atezolizumab or other immune-oncology agents for the treatment of solid tumors.
Topics: Humans; CD8-Positive T-Lymphocytes; Neoplasms; Fibroblasts
PubMed: 37163618
DOI: 10.1126/scitranslmed.abp9229 -
Cornea Apr 2022The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types.
PURPOSE
The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types.
METHODS
This cohort study included patients diagnosed with ulcerative keratitis according to the University of Michigan electronic health record data between September 1, 2014 and December 22, 2020. Ulcerative keratitis was categorized by etiologic type (bacterial, fungal, viral, acanthamoeba, inflammatory, polymicrobial, or unspecified) using rule-based data classification that accounted for billing diagnosis code, antimicrobial or antiinflammatory medications prescribed, laboratory results, and manual chart review. Opioid prescriptions were converted to morphine milligram equivalent and summed over 90 days from diagnosis. Opioid prescription rate and amount were compared between ulcerative keratitis types.
RESULTS
Of 3322 patients with ulcerative keratitis, 173 (5.2%) were prescribed at least 1 opioid for pain management within 90 days of diagnosis. More patients with acanthamoeba (32.4%), fungal (21.1%), and polymicrobial (25.0%) keratitis were treated with opioids compared with bacterial (6.7%), unspecified (2.9%), or viral (1.8%) keratitis (all Bonferroni adjusted P < 0.05). For the 173 patients who were prescribed opioids, a total of 353 prescriptions were given within 90 days of diagnosis, with half given within the first week after diagnosis. The quantity of opioid prescribed within 90 days from diagnosis was not significantly different between ulcerative keratitis types (P = 0.6559). Morphine milligram equivalent units prescribed ranged from 97.5 for acanthamoeba keratitis to 112.5 for fungal keratitis.
CONCLUSIONS
The type of ulcerative keratitis may influence the opioid prescription rate. Providers can better serve patients needing opioids for pain management through improved characterization of pain and development of more tailored pain management regimens.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Child; Child, Preschool; Corneal Ulcer; Drug Prescriptions; Eye Pain; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pain Management; Practice Patterns, Physicians'; Retrospective Studies
PubMed: 34620771
DOI: 10.1097/ICO.0000000000002893 -
Science Advances Oct 2022Homogeneous catalysts have rapid kinetics and keen reaction selectivity. However, their widespread use for industrial catalysis has remained limited because of...
Homogeneous catalysts have rapid kinetics and keen reaction selectivity. However, their widespread use for industrial catalysis has remained limited because of challenges in reusability. Here, we propose a redox-mediated electrochemical approach for catalyst recycling using metallopolymer-functionalized electrodes for binding and release. The redox platform was investigated for the separation of key platinum and palladium homogeneous catalysts used in organic synthesis and industrial chemical manufacturing. Noble metal catalysts for hydrosilylation, silane etherification, Suzuki cross-coupling, and Wacker oxidation were recycled electrochemically. The redox electrodes demonstrated high sorption uptake for platinum-based catalysts ( up to 200 milligrams of platinum per gram of adsorbent) from product mixtures, with up to 99.5% recovery, while retaining full catalytic activity over multiple cycles. The combination of mechanistic studies and electronic structure calculations indicate that selective interactions with anionic intermediates during the catalytic cycle played a key role in the separations. Last, continuous flow cell studies support the scalability and favorable technoeconomics of electrochemical recycling.
PubMed: 36260663
DOI: 10.1126/sciadv.ade3094 -
Chemistry (Weinheim An Der Bergstrasse,... Jul 2021The syntheses, properties and application of the air-stable electron acceptors, diindenopyrazines 4 a-g are reported demonstrating the introduction of functional aryl...
The syntheses, properties and application of the air-stable electron acceptors, diindenopyrazines 4 a-g are reported demonstrating the introduction of functional aryl groups in the 6- and 12-positions. The targets are accessible on the hundred milligram to gram scale. The structure of the aryl groups in 4 a-g modulates their solubility, redox potentials and optical properties. The introduction of electron-poor aryl groups to the electron-poor diindenopyrazine backbone reduces the electron affinity to -4 eV, making the compounds attractive as n-semiconductors. A simple organic field-effect transistor of 4 e -without optimization- shows electron transport with a mobility of up to 0.037 cm V s .
PubMed: 33830516
DOI: 10.1002/chem.202100372 -
Southern Medical Journal Apr 2022Dialysis access creation is a common outpatient procedure that can be completed using general, regional, or local anesthetic techniques. There are few endorsed...
OBJECTIVES
Dialysis access creation is a common outpatient procedure that can be completed using general, regional, or local anesthetic techniques. There are few endorsed guidelines regarding opioid-based pain control following fistula creation. The purpose of this study was to determine whether utilization of regional anesthesia (RA) is associated with the decreased use of narcotics postoperatively.
METHODS
We performed a prospective cohort study including all patients undergoing arteriovenous fistula creation with one vascular surgeon from August 2019 to February 2020. Patients were selected for regional versus general anesthesia. Selection for anesthesia type was determined by the primary anesthesiologist. Patients selected for RA underwent supraclavicular brachial plexus block with 30 cm of 0.5% ropivacaine. Patients were seen in clinic follow-up and completed a questionnaire regarding their postoperative opiate use and pain control.
RESULTS
In the study period, 52 patients underwent arteriovenous fistula creation and completed the follow-up questionnaire. Forty patients received RA. Seventy-five percent of patients sent home with a narcotic prescription filled the prescription. There was a significant difference in postoperative opioid use between the two study groups. Patients who received regional block took on average 3.3 pills totaling 16.5 morphine milligram equivalents, whereas patients who received general anesthesia took on average 6.64 pills totaling 33.2 morphine milligram equivalents ( 0.04).
CONCLUSIONS
Morbidity and mortality related to opiate use continues to be a public health issue in the United States. This study demonstrates that regional anesthetic techniques in comparison to general anesthesia can result in a significant decrease in postoperative opiate consumption.
Topics: Anesthesia, Local; Arteriovenous Shunt, Surgical; Humans; Pain; Prospective Studies; Renal Dialysis; United States
PubMed: 35365842
DOI: 10.14423/SMJ.0000000000001381 -
Nature Reviews. Chemistry Aug 2021In the past decade, the field of organic synthesis has witnessed tremendous advancements in the areas of photoredox catalysis, electrochemistry, C-H activation,... (Review)
Review
In the past decade, the field of organic synthesis has witnessed tremendous advancements in the areas of photoredox catalysis, electrochemistry, C-H activation, reductive coupling and flow chemistry. While these methods and technologies offer many strategic advantages in streamlining syntheses, their application on the process scale is complicated by several factors. In this Review, we discuss the challenges that arise when these reaction classes and/or flow chemistry technology are taken from a research laboratory operating at the milligram scale to a reactor capable of producing kilograms of product. We discuss how these challenges have been overcome through chemical and engineering solutions. Specifically, this Review will highlight key examples that have led to the production of multi-hundred-gram to kilogram quantities of active pharmaceutical ingredients or their intermediates and will provide insight on the scaling-up process to those developing new technologies and reactions.
PubMed: 37117583
DOI: 10.1038/s41570-021-00288-z -
Trends in Biotechnology Nov 2023If biomanufacturing can become a sustainable route for producing chemicals, it will provide a critical step in reducing greenhouse gas emissions to fight climate change.... (Review)
Review
If biomanufacturing can become a sustainable route for producing chemicals, it will provide a critical step in reducing greenhouse gas emissions to fight climate change. However, efforts to industrialize microbial synthesis of chemicals have met with varied success, due, in part, to challenges in translating laboratory successes to industrial scale. With a particular focus on Escherichia coli, this review examines the lessons learned when studying microbial physiology and metabolism under conditions that simulate large-scale bioreactors and methods to minimize cellular waste through reduction of maintenance energy, optimizing the stress response and minimizing culture heterogeneity. With general strategies to overcome these challenges, biomanufacturing process scale-up could be de-risked and the time and cost of bringing promising syntheses to market could be reduced.
Topics: Bioreactors; Industrial Microbiology
PubMed: 37271589
DOI: 10.1016/j.tibtech.2023.05.002