Proteoglycan inhibition of canonical BMP-dependent cartilage maturation delays endochondral ossification.

During endochondral ossification, chondrocytes secrete a proteoglycan (PG)-rich extracellular matrix that can inhibit the process of cartilage maturation, including expression of Ihh and Col10a1. Because bone morphogenetic proteins (BMPs) can promote cartilage maturation, we hypothesized that cartilage PGs normally inhibit BMP signalling. Accordingly, BMP signalling was evaluated in chondrocytes of wild-type and PG mutant (fam20b-/-) zebrafish and inhibited with temporal control using the drug DMH1 or an inducible dominant-negative BMP receptor transgene (dnBMPR). Compared with wild type, phospho-Smad1/5/9, but not phospho-p38, was increased in fam20b-/- chondrocytes, but only after they secreted PGs. Phospho-Smad1/5/9 was decreased in DMH1-treated or dnBMPR-activated wild-type chondrocytes, and DMH1 also decreased phospho-p38 levels. ihha and col10a1a were decreased in DMH1-treated or dnBMPR-activated chondrocytes, and less perichondral bone formed. Finally, early ihha and col10a1a expression and early perichondral bone formation of fam20b mutants were rescued with DMH1 treatment or dnBMPR activation. Therefore, PG inhibition of canonical BMP-dependent cartilage maturation delays endochondral ossification, and these results offer hope for the development of growth factor therapies for skeletal defects of PG diseases.

Comparative genomics reveals electron transfer and syntrophic mechanisms differentiating methanotrophic and methanogenic archaea.

The anaerobic oxidation of methane coupled to sulfate reduction is a microbially mediated process requiring a syntrophic partnership between anaerobic methanotrophic (ANME) archaea and sulfate-reducing bacteria (SRB). Based on genome taxonomy, ANME lineages are polyphyletic within the phylum Halobacterota, none of which have been isolated in pure culture. Here, we reconstruct 28 ANME genomes from environmental metagenomes and flow sorted syntrophic consortia. Together with a reanalysis of previously published datasets, these genomes enable a comparative analysis of all marine ANME clades. We review the genomic features that separate ANME from their methanogenic relatives and identify what differentiates ANME clades. Large multiheme cytochromes and bioenergetic complexes predicted to be involved in novel electron bifurcation reactions are well distributed and conserved in the ANME archaea, while significant variations in the anabolic C1 pathways exists between clades. Our analysis raises the possibility that methylotrophic methanogenesis may have evolved from a methanotrophic ancestor.

GeneticsMakie.jl: a versatile and scalable toolkit for visualizing locus-level genetic and genomic data.

SUMMARY: With the continued deluge of results from genome-wide association and functional genomic studies, it has become increasingly imperative to quickly combine and visualize different layers of genetic and genomic data within a given locus to facilitate exploratory and integrative data analyses. While several tools have been developed to visualize locus-level genetic results, the limited speed, scalability and flexibility of current approaches remain a significant bottleneck. Here, we present a Julia package for high-performance genetics and genomics-related data visualization that enables fast, simultaneous plotting of hundreds of association results along with multiple relevant genomic annotations. Leveraging the powerful plotting and layout utilities from Makie.jl facilitates the customization and extensibility of every component of a plot, enabling generation of publication-ready figures. AVAILABILITY AND IMPLEMENTATION: The GeneticsMakie.jl package is open source and distributed under the MIT license via GitHub (https://github.com/mmkim1210/GeneticsMakie.jl). The GitHub repository contains installation instructions as well as examples and documentation for built-in functions. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Repurposing General Anesthetic Drugs to Treat Depression: A New Frontier for Anesthesiologists in Neuropsychiatric Care.

During the last 100 years, the role of anesthesiologists in psychiatry has focused primarily on facilitating electroconvulsive therapy and mitigating postoperative delirium and other perioperative neurocognitive disorders. The discovery of the rapid and sustained antidepressant properties of ketamine, and early results suggesting that other general anesthetic drugs (including nitrous oxide, propofol, and isoflurane) have antidepressant properties, has positioned anesthesiologists at a new frontier in the treatment of neuropsychiatric disorders. Moreover, shared interest in understanding the biologic underpinnings of anesthetic drugs as psychotropic agents is eroding traditional academic boundaries between anesthesiology and psychiatry. This article presents a brief overview of anesthetic drugs as novel antidepressants and identifies promising future candidates for the treatment of depression. The authors issue a call to action and outline strategies to foster collaborations between anesthesiologists and psychiatrists as they work toward the common goals of repurposing anesthetic drugs as antidepressants and addressing mood disorders in surgical patients.

The heart of anaesthesiology: revitalising humanism in the age of technology.

Technological innovation has greatly aided modern medicine, and anaesthesiology in particular, but also contributes to dehumanising influences that promote physician burnout and dissatisfaction among patients. Here we advocate for a profound reaffirmation of humanistic principles-empathy, compassion, and communication-in perioperative medicine. We propose adaptable strategies to bolster humanism in practice, such as curricular offerings, simulation training, role modelling, and recognition. As perioperative technologies continue to evolve, the threat of depersonalisation in anaesthetic care looms, making commitments to humanism a crucial precondition for healing in the communities in which we work and live.

Short term air pollution exposure during pregnancy and associations with maternal immune markers.

BACKGROUND: Air pollution exposure during pregnancy has been associated with numerous adverse pregnancy, birth, and child health outcomes. One proposed mechanism underlying these associations is maternal immune activation and dysregulation. We examined associations between PM2.5 and NO2 exposure during pregnancy and immune markers within immune function groups (TH1, TH2, TH17, Innate/Early Activation, Regulatory, Homeostatic, and Proinflammatory), and examined whether those associations changed across pregnancy. METHODS: In a pregnancy cohort study (n = 290) in Rochester, New York, we measured immune markers (using Luminex) in maternal plasma up to 3 times during pregnancy. We estimated ambient PM2.5 and NO2 concentrations at participants' home addresses using a spatial-temporal model. Using mixed effects models, we estimated changes in immune marker concentrations associated with interquartile range increases in PM2.5 (2.88 µg/m3) and NO2 (7.82 ppb) 0-6 days before blood collection, and assessed whether associations were different in early, mid, and late pregnancy. RESULTS: Increased NO2 concentrations were associated with higher maternal immune markers, with associations observed across TH1, TH2, TH17, Regulatory, and Homeostatic groups of immune markers. Furthermore, the largest increases in immune markers associated with each 7.82 ppb increase in NO2 concentration were in late pregnancy (e.g., IL-23 = 0.26 pg/ml, 95% CI = 0.07, 0.46) compared to early pregnancy (e.g., IL-23 = 0.08 pg/ml, 95% CI = -0.11, 0.26). CONCLUSIONS: Results were suggestive of NO2-related immune activation. Increases in effect sizes from early to mid to late pregnancy may be due to changes in immune function over the course of pregnancy. These findings provide a basis for immune activation as a mechanism for previously observed associations between air pollution exposure during pregnancy and reduced birthweight, fetal growth restriction, and pregnancy complications.

Vitamin D status in children with congenital melanocytic nevi.

Congenital melanocytic nevi (CMN) are rare, pigmented birthmarks that can predispose patients to melanoma of the central nervous system and skin. Data from non-CMN melanoma cohorts suggest that vitamin D levels may be connected to outcome, prompting this study of 25-hydroxyvitamin D levels in plasma samples from 40 children with CMN. While 27% were insufficient and 13% deficient, this was representative of European populations, and UK supplementation guidelines are already in place. Our data support routine vitamin D supplementation for all CMN patients during winter months, without routine serum measurement.

CHalf: Folding Stability Made Simple.

The structure of a protein defines its function and integrity and correlates with the protein folding stability (PFS). Quantifying PFS allows researchers to assess differential stability of proteins in different disease or ligand binding states, providing insight into protein efficacy and potentially serving as a metric of protein quality. There are a number of mass spectrometry (MS)-based methods to assess PFS, such as Thermal Protein Profiling (TPP), Stability of Proteins from Rates of Oxidation (SPROX), and Iodination Protein Stability Assay (IPSA). Despite the critical value that PFS studies add to the understanding of mechanisms of disease and treatment development, proteomics research is still primarily dominated by concentration-based studies. We found that a major reason for the lack of PFS studies is the lack of a user-friendly data processing tool. Here we present the first user-friendly software, CHalf, with a graphical user interface for calculating PFS. Besides calculating site-specific PFS of a given protein from chemical denature folding stability assays, CHalf is also compatible with thermal denature folding stability assays. CHalf also includes a set of data visualization tools to help identify changes in PFS across protein sequences and in between different treatment conditions. We expect the introduction of CHalf to lower the barrier of entry for researchers to investigate PFS, promoting the usage of PFS in studies. In the long run, we expect this increase in PFS research to accelerate our understanding of the pathogenesis and pathophysiology of disease.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Implementing an electronic sideband offset lock for isotope shift spectroscopy in radium.

We demonstrate laser frequency stabilization with at least 6 GHz of offset tunability using an in-phase/quadrature (IQ) modulator to generate electronic sidebands (ESB) on a titanium sapphire laser at 714 nm and we apply this technique to perform isotope shift spectroscopy of 226Ra and 225Ra. By locking the laser to a single resonance of a high finesse optical cavity and adjusting the lock offset, we determine the frequency difference between the magneto-optical trap (MOT) transitions in the two isotopes to be 2630.0 ± 0.3 MHz, a factor of 29 more precise than the previously available data. Using the known value of the hyperfine splitting of the 3P1 level, we calculate the isotope shift for the 1S0 to 3P1 transition to be 2267.0 ± 2.2 MHz, a factor of 8 more precise than the best available value. Our technique could be applied to countless other atomic systems to provide unprecedented precision in isotope shift spectroscopy and other relative frequency comparisons.

Error Suppression for Arbitrary-Size Black Box Quantum Operations.

Efficient suppression of errors without full error correction is crucial for applications with noisy intermediate-scale quantum devices. Error mitigation allows us to suppress errors in extracting expectation values without the need for any error correction code, but its applications are limited to estimating expectation values, and cannot provide us with high-fidelity quantum operations acting on arbitrary quantum states. To address this challenge, we propose to use error filtration (EF) for gate-based quantum computation, as a practical error suppression scheme without resorting to full quantum error correction. The result is a general-purpose error suppression protocol where the resources required to suppress errors scale independently of the size of the quantum operation, and does not require any logical encoding of the operation. The protocol provides error suppression whenever an error hierarchy is respected-that is, when the ancillary controlled-swap operations are less noisy than the operation to be corrected. We further analyze the application of EF to quantum random access memory, where EF offers hardware-efficient error suppression.

Cognitive deficits after general anaesthesia in animal models: a scoping review.

BACKGROUND: It remains controversial whether general anaesthetic drugs contribute to perioperative neurocognitive disorders in adult patients. Preclinical studies have generated conflicting results, likely because of differing animal models, study protocols, and measured outcomes. This scoping review of preclinical studies addressed the question: 'Do general anaesthetic drugs cause cognitive deficits in adult animals that persist after the drugs have been eliminated from the brain?' METHODS: Reports of preclinical studies in the MEDLINE database published from 1953 to 2021 were examined. A structured review process was used to assess original studies of cognitive behaviours, which were measured after treatment (≥24 h) with commonly used general anaesthetic drugs in adult animals. RESULTS: The initial search yielded 380 articles, of which 106 were fully analysed. The most frequently studied animal model was male (81%; n=86/106) rodents (n=106/106) between 2-3 months or 18-20 months of age. Volatile anaesthetic drugs were more frequently studied than injected drugs, and common outcomes were memory behaviours assessed using the Morris water maze and fear conditioning assays. Cognitive deficits were detected in 77% of studies (n=82/106) and were more frequent in studies of older animals (89%), after inhaled anaesthetics, and longer drug treatments. Limitations of the studies included a lack of physiological monitoring, mortality data, and risk of bias attributable to the absence of randomisation and blinding. CONCLUSIONS: Most studies reported cognitive deficits after general anaesthesia, with age, use of volatile anaesthetic drugs, and duration of anaesthesia as risk factors. Recommendations to improve study design and guide future research are presented.

Steering clear of Akrasia: An integrative review of self-binding Ulysses Contracts in clinical practice.

In many jurisdictions, legal frameworks afford patients the opportunity to make prospective medical decisions or to create directives that contain a special provision forfeiting their own ability to object to those decisions at a future time point, should they lose decision-making capacity. These agreements have been described with widely varying nomenclatures, including Ulysses Contracts, Odysseus Transfers, Psychiatric Advance Directives with Ulysses Clauses, and Powers of Attorney with Special Provisions. As a consequence of this terminological heterogeneity, it is challenging for healthcare providers to understand the terms and uses of these agreements and for ethicists to engage with the nuances of clinical decision-making with such unique provisions surrounding patient autonomy. In theory, prospective self-binding agreements may safeguard patient's "authentic" wishes from future "inauthentic" changes of mind. In practice, it is unclear what may be comprised within these agreements or how-and to what effect-they are used. The primary focus of this integrative review is to curate the existing literature describing Ulysses Contracts (and analogous decisions) used in the clinical arena, in order to empirically synthesize their shared essence and provide insights into the traditional components of these agreements when used in practice, the requirements of their consent processes, and the outcomes of their utilization.

Economic Evaluation Associated With Clinical-Grade Mobile App-Based Digital Therapeutic Interventions: Systematic Review.

BACKGROUND: Digital therapeutics (DTx), a class of software-based clinical interventions, are promising new technologies that can potentially prevent, manage, or treat a spectrum of medical disorders and diseases as well as deliver unprecedented portability for patients and scalability for health care providers. Their adoption and implementation were accelerated by the need for remote care during the COVID-19 pandemic, and awareness about their utility has rapidly grown among providers, payers, and regulators. Despite this, relatively little is known about the capacity of DTx to provide economic value in care. OBJECTIVE: This study aimed to systematically review and summarize the published evidence regarding the cost-effectiveness of clinical-grade mobile app-based DTx and explore the factors affecting such evaluations. METHODS: A systematic review of economic evaluations of clinical-grade mobile app-based DTx was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. Major electronic databases, including PubMed, Cochrane Library, and Web of Science, were searched for eligible studies published from inception to October 28, 2022. Two independent reviewers evaluated the eligibility of all the retrieved articles for inclusion in the review. Methodological quality and risk of bias were assessed for each included study. RESULTS: A total of 18 studies were included in this review. Of the 18 studies, 7 (39%) were nonrandomized study-based economic evaluations, 6 (33%) were model-based evaluations, and 5 (28%) were randomized clinical trial-based evaluations. The DTx intervention subject to assessment was found to be cost-effective in 12 (67%) studies, cost saving in 5 (28%) studies, and cost-effective in 1 (6%) study in only 1 of the 3 countries where it was being deployed in the final study. Qualitative deficiencies in methodology and substantial potential for bias, including risks of performance bias and selection bias in participant recruitment, were identified in several included studies. CONCLUSIONS: This systematic review supports the thesis that DTx interventions offer potential economic benefits. However, DTx economic analyses conducted to date exhibit important methodological shortcomings that must be addressed in future evaluations to reduce the uncertainty surrounding the widespread adoption of DTx interventions. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022358616; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022358616.

Revision total knee arthroplasty for arthrofibrosis improves range of motion.

PURPOSE: Arthrofibrosis after primary total knee arthroplasty (TKA) is a significant contributor to patient dissatisfaction. While treatment algorithms involve early physical therapy and manipulation under anaesthesia (MUA), some patients ultimately require revision TKA. It is unclear whether revision TKA can consistently improve these patient's range of motion (ROM). The purpose of this study was to evaluate ROM when revision TKA was performed for arthrofibrosis. METHODS: A retrospective study of 42 TKA's diagnosed with arthrofibrosis from 2013 to 2019 at a single institution with a minimum 2-year follow-up was performed. The primary outcome was ROM (flexion, extension, and total arc of motion) before and after revision TKA, and secondary outcomes included patient reported outcomes information system (PROMIS) scores. Categorical data were compared using chi-squared analysis, and paired samples t tests were performed to compare ROM at three different times: pre-primary TKA, pre-revision TKA, and post-revision TKA. A multivariable linear regression analysis was performed to assess for effect modification on total ROM. RESULTS: The patient's pre-revision mean flexion was 85.6 degrees, and mean extension was 10.1 degrees. At the time of the revision, the mean age of the cohort was 64.7 years, the average body mass index (BMI) was 29.8, and 62% were female. At a mean follow-up of 4.5 years, revision TKA significantly improved terminal flexion by 18.4 degrees (p < 0.001), terminal extension by 6.8 degrees (p = 0.007), and total arc of motion by 25.2 degrees (p < 0.001). The final ROM after revision TKA was not significantly different from the patient's pre-primary TKA ROM (p = 0.759). PROMIS physical function, depression, and pain interference scores were 39 (SD = 7.72), 49 (SD = 8.39), and 62 (SD = 7.25), respectively. CONCLUSION: Revision TKA for arthrofibrosis significantly improved ROM at a mean follow-up of 4.5 years with over 25 degrees of improvement in the total arc of motion, resulting in final ROM similar to pre-primary TKA ROM. PROMIS physical function and pain scores showed moderate dysfunction, while depression scores were within normal limits. While physical therapy and MUA remain the gold standard for the early treatment of stiffness after TKA, revision TKA can improve ROM. LEVEL OF EVIDENCE: IV.

Impact of 10-Day Fulbright Specialist Program and Project Pink Blue Education Sessions on Medical Oncology Knowledge Among Physicians Who Treat Cancer in Nigeria.

Despite an estimated population of over 201 million and over 115,950 yearly diagnosed new cases of cancer, Nigeria does not have dedicated medical oncologists. Most oncology care is delivered through surgical and clinical oncologists, who are trained in both radiation and medical oncology and they number fewer than 50 in the country. With a limited number of oncology professionals, cancer patients in Nigeria experience poor health outcomes, with an estimated cancer mortality rate of 75,000 deaths per year. Participants from 15 Nigerian states were selected to attend the medical oncology training. Through the support of Fulbright Specialist Program and Project PINK BLUE, two of the authors delivered 10 days of lectures based on ASCO, ESMO, and NCCN guidelines. Mean scores of both the pre- and post-course tests as well as a 1-year follow-up test were compared using GraphPad Prism 7.0a by paired t-tests. Forty-four clinical oncologists were selected for participation. Twenty-five (57%) completed the pre- and post-course tests. Of the 25 that completed both tests, percentage of correct answers increased from 45 to 59% (2-sided p-value < 0.0001). Improvements were seen in attending doctors 45 to 59% (p = 0.0046) and resident doctors 45 to 59% (0.0007). Eleven doctors responded to the 1-year follow-up test. Although not statistically significant, a numerical pattern for the benefits was maintained 1 year after the program (45% pre-course versus 52% post-course correct answers, Fisher's exact, p = 0.4185). In the short term, the training improved medical oncology knowledge in Nigeria, regardless of the participant's carrier stage. Long-term benefits were not sustained in a small sample of participants, and continuing education strategies are necessary. Similar models may be employed across Africa.

Group-Based Medical Mistrust in Adolescents With Poorly Controlled Asthma Living in Rural Areas.

Black youth and rural adolescents are two groups who experience asthma disparities. Racism and discrimination in health care likely lead to group-based (systems-level) medical mistrust for some adolescents. Group-based medical mistrust, one pathway by which racism drives health inequities, is associated with poorer outcomes for patients with chronic conditions. Despite its potential importance in adolescent asthma, previous research has not considered group-based medical mistrust in this population. To fill this gap, we characterize group-based medical mistrust among rural adolescents with poorly controlled asthma, examining demographic differences. We analyzed baseline data from a school-based clinical trial in which 164 adolescents (mean age = 16.3; 76.2% Black) completed the Group-Based Medical Mistrust Scale (GBMMS). Using linear regression, we tested associations with race, gender, and age, controlling for recent medical visits and insurance status. The total GBMMS mean score was 2.3 (SD = 1.22); subscale scores ranged from 2.3 to 2.4. Black adolescents reported significantly higher total GBMMS scores (ß = .45, p = .003) and significantly higher scores on two GBMMS subscales: suspicion of health care providers (ß = .56, p = .007) and lack of support from health care providers (ß = .36, p = .007). Gender and age were not associated with GBMMS scores. Health care providers need to consider medical mistrust and its role in their clinical care. Together with their institutions, health care providers and researchers should work toward changing systems that perpetuate racism to build trust as a means of reducing asthma disparities among adolescents.

Cardiac Investigation Trends Among Primary Care Physicians: A Paradigm Shift.

OBJECTIVE: While numerous recent guidelines support coronary computed tomography angiography (CTA) as a first-line test for stable chest pain, it remains underutilized by primary care physicians (PCPs). We aimed to evaluate cardiac investigation ordering practices following education sessions, as well as the total number of downstream tests and time to diagnosis for patients presenting with stable chest pain. METHODS: A retrospective chart review was completed for eligible patients assessed at the Women's College Hospital Family Practice Health Centre between 2017 and 2019 following the education sessions. The outcome measures were first-choice cardiac investigation, additional downstream testing, time from presentation to first investigation, and time to final diagnosis. RESULTS: 419 patients were included in the final analysis (74.70% female; mean age 61 ± 11 years). Coronary CTA requests by PCPs increased between 2017 and 2019 (18 vs 72 tests; P < .0001). When coronary CTA was the first-line test, patients were less likely to receive additional downstream testing when compared to those receiving other first-line investigations (P < .0001). Coronary CTA was associated with longer time to diagnosis than stress echocardiography (47 ± 45 vs 27 ± 36 days; P = .0068) due to limited availability of coronary CTA appointment times. There was no significant difference in time to final diagnosis among the cardiac imaging modalities observed in the cohort (P = .0623). CONCLUSION: Utilization of coronary CTA as the first-line test for stable chest pain increased following our education sessions targeting PCPs. Coronary CTA was associated with less downstream testing compared to other non-invasive cardiac investigations.

Quantifying In Situ Structural Stabilities of Human Blood Plasma Proteins Using a Novel Iodination Protein Stability Assay.

Many of the diseases that plague society today are driven by a loss of protein quality. One method to quantify protein quality is to measure the protein folding stability (PFS). Here, we present a novel mass spectrometry (MS)-based approach for PFS measurement, iodination protein stability assay (IPSA). IPSA quantifies the PFS by tracking the surface-accessibility differences of tyrosine, histidine, methionine, and cysteine under denaturing conditions. Relative to current methods, IPSA increases protein coverage and granularity to track the PFS changes of a protein along its sequence. To our knowledge, this study is the first time the PFS of human serum proteins has been measured in the context of the blood serum (in situ). We show that IPSA can quantify the PFS differences between different transferrin iron-binding states in near in vivo conditions. We also show that the direction of the denaturation curve reflects the in vivo surface accessibility of the amino acid residue and reproducibly reports a residue-specific PFS. Along with IPSA, we introduce an analysis tool Chalf that provides a simple workflow to calculate the residue-specific PFS. The introduction of IPSA increases the potential to use protein structural stability as a structural quality metric in understanding the etiology and progression of human disease. Data is openly available at Chorusproject.org (project ID 1771).

The Effects of Dexmedetomidine on Perioperative Neurocognitive Outcomes After Cardiac Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

OBJECTIVE: The purpose of this systematic review and meta-analysis is to examine the effect of DEX on delayed dNCR (cognitive dysfunction ≥ 1 week postoperative) after cardiac surgery. BACKGROUND: DEX has salutary effects on cognitive outcomes following cardiac surgery, however, studies are limited by inconsistent assessment tools, timing, and definitions of dysfunction. It is imperative to identify accurate point estimates of effect of DEX on clinically relevant changes in cognitive function. METHODS: Randomized trials of adults undergoing cardiac surgery comparing perioperative DEX to placebo or alternate sedation and assessing cognitive function ≥ 1 week postoperative were included. Data was abstracted by three reviewers independently and in parallel according to PRISMA guidelines. The primary outcome is dNCR. To classify as dNCR, cognitive function must decrease by at least the minimal clinically important difference or accepted alternate measure (eg, Reliable Change Index ≥1.96). Bias was assessed with the Cochrane Collaboration tool. Data was pooled using a random effects model. RESULTS: Nine trials (942 participants) were included in qualitative analysis, of which seven were included in the meta-analysis of dNCR. DEX reduced the incidence of dNCR (OR 0.39, 95% CI 0.25-0.61, P < 0.0001) compared to placebo/no DEX. There was no difference in the incidence of delirium (OR 0.69, 95% CI 0.35-1.34, P = 0.27) or incidence of hemodynamic instability (OR 1.14, 95% CI 0.59-2.18, P = 0.70) associated with perioperative DEX. CONCLUSIONS: DEX reduced the incidence of dNCR 1 week after cardiac surgery. Although this meta-analysis demonstrates short term cognitive outcomes are improved after cardiac surgery with perioperative DEX, future trials examining long term cognitive outcomes, using robust cognitive assessments, and new perioperative neurocognitive disorders nomenclature with objective diagnostic criteria are necessary.