HIV, inflammation, and initiation of methamphetamine use in sexual and gender minorities assigned male at birth.

Methamphetamine use and HIV disproportionately affect sexual and gender minority (SGM) people assigned male at birth. Identifying risk factors for methamphetamine use is crucial to inform preventive interventions. In this cohort study with 1,296 SGM people assigned male at birth, ages 16 to 29, and who resided in Chicago, Poisson regression analyses indicated the prevalence of methamphetamine use increased from 2015 to 2023 [Incidence Rate Ratio (IRR) = 1.07; 95% CI = 1.01 to 1.13; P = 0.02]. This increase was most pronounced among those ages 25 or older at baseline (IRR = 2.20; 95% CI = 1.33 to 3.63; P = 0.002), and 23.9 [Interquartile Range (IQR) = 22.1 to 26.9] was the median age of first-time methamphetamine use. In 826 participants with a prior HIV diagnosis or previous inflammatory measurements, Cox proportional-hazards models examined risk factors for incident, first-time methamphetamine use. Adjusting for other substance use, the rate of incident, first-time methamphetamine use was two-fold greater after HIV diagnosis [adjusted hazard ratio (aHR) = 2.02; 95% CI = 1.27 to 3.23; P = 0.003]. For each SD higher C-reactive protein, the rate of incident, first-time methamphetamine use was 18% greater (aHR = 1.18; 95% CI, 1.05 to 1.34; P = 0.008). HIV seroconversion and inflammation could increase the risk of initiating methamphetamine use in SGM people assigned male at birth.

Global analysis of the RNA-RNA interactome in Acinetobacter baumannii AB5075 uncovers a small regulatory RNA repressing the virulence-related outer membrane protein CarO.

Acinetobacter baumannii is an opportunistic Gram-negative pathogen that infects critically ill patients. The emergence of antimicrobial resistant A. baumannii has exacerbated the need to characterize environmental adaptation, antibiotic resistance and pathogenicity and their genetic regulators to inform intervention strategies. Critical to adaptation to changing environments in bacteria are small regulatory RNAs (sRNAs), however, the role that sRNAs play in the biology of A. baumannii is poorly understood. To assess the regulatory function of sRNAs and to uncover their RNA interaction partners, we employed an RNA proximity ligation and sequencing method (Hi-GRIL-seq) in three different environmental conditions. Forty sRNAs were ligated to sRNA-RNA chimeric sequencing reads, suggesting that sRNA-mediated gene regulation is pervasive in A. baumannii. In-depth characterization uncovered the sRNA Aar to be a post-transcriptional regulator of four mRNA targets including the transcript encoding outer membrane protein CarO. Aar initiates base-pairing with these mRNAs using a conserved seed region of nine nucleotides, sequestering the ribosome binding sites and inhibiting translation. Aar is differentially expressed in multiple stress conditions suggesting a role in fine-tuning translation of the Aar-target molecules. Our study provides mechanistic insights into sRNA-mediated gene regulation in A. baumannii and represents a valuable resource for future RNA-centric research endeavours.

Syphilis Prevalence, Incidence, and Demographic Differences in a Longitudinal Study of Young Sexual and Gender Minority Adults Assigned Male at Birth.

BACKGROUND: Syphilis rates in the United States have increased. Few studies have examined syphilis incidence and prevalence prospectively among young sexual and gender minorities (YSGM). METHODS: This study of YSGM assigned male at birth comes from a Chicago-based prospective cohort at 2 visits 6 months apart (N = 882). Syphilis cases were identified through serologic test results and self-reported history. RESULTS: In this sample, 25.1% had a lifetime prevalence, and 3.3% were incident cases with a crude incidence rate of 6.76 per 100 person-years. CONCLUSIONS: Lifetime syphilis and incidence are high in this sample of YSGM relative to general population samples.

Triangulation of Hard X-Ray Sources in an X-Class Solar Flare with ASO-S/HXI and Solar Orbiter/STIX.

HXI on ASO-S and STIX onboard Solar Orbiter are the first simultaneously operating solar hard X-ray imaging spectrometers. ASO-S's low Earth orbit and Solar Orbiter's periodic displacement from the Sun-Earth line enables multi-viewpoint solar hard X-ray spectroscopic imaging analysis for the first time. Here, we demonstrate the potential of this new capability by reporting the first results of 3D triangulation of hard X-ray sources in the SOL2023-12-31T21:55 X5 flare. HXI and STIX observed the flare near the east limb with an observer separation angle of 18°. We triangulated the brightest regions within each source, which enabled us to characterise the large-scale hard X-ray geometry of the flare. The footpoints were found to be in the chromosphere within uncertainty, as expected, while the thermal looptop source was centred at an altitude of 15.1 ± 1 Mm. Given the footpoint separation, this implies a more elongated magnetic-loop structure than predicted by a semi-circular model. These results show the strong diagnostic power of joint HXI and STIX observations for understanding the 3D geometry of solar flares. We conclude by discussing the next steps required to fully exploit their potential.

Evaluation of the Implementation of Low-Low Hospital Beds With Respect to Fall Frequency and Patient Harms: A Retrospective Analysis.

AIM: To identify whether the introduction of low-low hospital beds resulted in changes in the incidence, associated patient harms and event characteristics of bed-related falls where implemented. DESIGN: This retrospective quality improvement study covered 36 months: 18 months pre-intervention and 18 months post-intervention. METHODS: Our analysis incorporated patient fall data from a hospital in upstate New York. Pre-/post-intervention data covered 18 months on either side of introduction at the units of implementation. Data were sourced from contemporaneously recorded incident reports and the organisation's business intelligence records. Analysis addressed the incidence rate, frequency, patient harm classification and recurrence of bed-related falls, as well as Morse Fall Scale risk classification, patient age, gender and other individualised risk factors. Lastly, we reviewed the presence of individualised interventions, staff assistance during the event, patient census and staffing ratios. Chi-square goodness of fit tests were employed to compare the distribution, and Brunner-Munzel tests the stochastic equality, of the pre- and post-implementation categorical and continuous data. RESULTS: There were no significant differences in the incidence rate of bed-related falls, patient harms or in the need for medical intervention following implementation of the low-low hospital beds. Neither were there any significant differences in the proportion of events resulting in detectable harm or the need for medical intervention post-implementation. The total number of bed-involved falls substantively increased following implementation of the low-low beds, as did the number of events resulting in detectable harms and medical intervention. Among these, substantive increases were noted among events resulting in minor temporary harm and patients referred for diagnostic imaging. The number of events involved patients experiencing recurrent falls of any kind increased significantly post-implementation. CONCLUSION: We found that the introduction of low-low hospital beds preceded no change in the incidence of bed-related falls, associated patient harms or the need for post-event medical intervention where implemented. While data limitations precluded definitive determination with respect to certain event characteristics, several post-implementation changes, including substantive increases in the number of falls occurring during ingress and egress, may suggest a potential for relationship worthy of future study. IMPLICATIONS AND IMPACT: Low-low hospital beds are purported to help reduce the occurrence and severity of bed-related falls, both serious problems in inpatient settings. This study describes null outcomes following an implementation of such beds, with implications for adoption in similar settings. REPORTING METHOD: We adhered to the relevant Enhancing the Quality and Transparency of Health Research guidelines, specifically following the Standards for Quality Improvement Reporting Excellence standards. PATIENT OR PUBLIC CONTRIBUTION: No patient or public involvement in the design or conduct of the study. Nurses and medical staff were involved in intervention implementation, data collection and the conception, design and conduct of the study.

Rapid Multivariate Analysis Approach to Explore Differential Spatial Protein Profiles in Tissue.

Spatially targeted proteomics analyzes the proteome of specific cell types and functional regions within tissue. While spatial context is often essential to understanding biological processes, interpreting sub-region-specific protein profiles can pose a challenge due to the high-dimensional nature of the data. Here, we develop a multivariate approach for rapid exploration of differential protein profiles acquired from distinct tissue regions and apply it to analyze a published spatially targeted proteomics data set collected from Staphylococcus aureus-infected murine kidney, 4 and 10 days postinfection. The data analysis process rapidly filters high-dimensional proteomic data to reveal relevant differentiating species among hundreds to thousands of measured molecules. We employ principal component analysis (PCA) for dimensionality reduction of protein profiles measured by microliquid extraction surface analysis mass spectrometry. Subsequently, k-means clustering of the PCA-processed data groups samples by chemical similarity. Cluster center interpretation revealed a subset of proteins that differentiate between spatial regions of infection over two time points. These proteins appear involved in tricarboxylic acid metabolomic pathways, calcium-dependent processes, and cytoskeletal organization. Gene ontology analysis further uncovered relationships to tissue damage/repair and calcium-related defense mechanisms. Applying our analysis in infectious disease highlighted differential proteomic changes across abscess regions over time, reflecting the dynamic nature of host-pathogen interactions.

Comparative genomics provides structural and functional insights into Bacteroides RNA biology.

Bacteria employ noncoding RNA molecules for a wide range of biological processes, including scaffolding large molecular complexes, catalyzing chemical reactions, defending against phages, and controlling gene expression. Secondary structures, binding partners, and molecular mechanisms have been determined for numerous small noncoding RNAs (sRNAs) in model aerobic bacteria. However, technical hurdles have largely prevented analogous analyses in the anaerobic gut microbiota. While experimental techniques are being developed to investigate the sRNAs of gut commensals, computational tools and comparative genomics can provide immediate functional insight. Here, using Bacteroides thetaiotaomicron as a representative microbiota member, we illustrate how comparative genomics improves our understanding of RNA biology in an understudied gut bacterium. We investigate putative RNA-binding proteins and predict a Bacteroides cold-shock protein homolog to have an RNA-related function. We apply an in silico protocol incorporating both sequence and structural analysis to determine the consensus structures and conservation of nine Bacteroides noncoding RNA families. Using structure probing, we validate and refine these predictions and deposit them in the Rfam database. Through synteny analyses, we illustrate how genomic coconservation can serve as a predictor of sRNA function. Altogether, this work showcases the power of RNA informatics for investigating the RNA biology of anaerobic microbiota members.

Stress and Depression Are Associated with Sexual Function and Satisfaction in Young Men Who Have Sex with Men.

Prior research suggests that better mental health and higher relationship quality are associated with better sexual function and satisfaction. Such insights can inform intervention development for mental, relationship, and sexual health concerns. This study examined the interactions among these variables in a racially and ethnically diverse group of young men who have sex with men (YMSM) in serious relationships (N = 348). Data were drawn from wave 5 of a longitudinal cohort study. We examined cross-sectional associations between depression and stress (predictors) and sexual function, sexual satisfaction, and anal discomfort (outcomes) and to what extent these associations were moderated by relationship quality. Higher endorsement of depression and stress was associated with worse sexual functioning, lower sexual satisfaction, and more anal discomfort. We also found that fewer negative interactions, stronger commitment, and higher relationship satisfaction were associated with better sexual functioning and higher sexual satisfaction. Higher relationship satisfaction and commitment were found to attenuate the association between stress and sexual satisfaction. Contrary to expectations, higher relationship satisfaction also showed a trend toward exacerbating the association between depression and sexual functioning. These results suggest that, for YMSM, high relationship satisfaction and commitment may protect sexual satisfaction from being negatively impacted by high stress. However, YMSM in highly satisfying relationships may experience poor sexual functioning associated with depression as particularly distressing. This study addressed a major gap in the literature by focusing on mental, relationship, and sexual health in a diverse sample. Future research should examine a wider range of sexual functioning outcomes and include minority stress in study design.

An evaluation on the effects of safe person handling program implementation at long term care facilities for persons with complex intellectual, developmental, and medical conditions.

BACKGROUND: This retrospective chart review sought to determine whether the introduction of a safe person handling and mobility (SPHM) program resulted in changes to the frequency, severity, cost, or profile of staff injuries incurred during person handling (PH) tasks at long-term care settings for persons with complex conditions. METHODS: This study analyzed the SPHM program implementation at an organization providing long-term residential, day habilitation, and special education services for persons with complex conditions. Data covered two 4-year periods before and after implementation. Analyses compared the frequency, severity, and cost of staff PH injuries, as well as of the affected body area, staff role, level of treatment, and the incurred costs of Workers' Compensation (WC) claims. RESULTS: There were substantive decreases in the total number of staff PH injuries and WC claims. Staff PH injuries affecting the trunk, the area most associated with PH injuries, decreased the most, followed by the upper extremities. Reductions were concentrated among direct care employees and their supervisors, job titles where PH exposures are most commonly seen. The proportion of staff injuries requiring medical treatment decreased significantly, as did injury severity. The number of lost workdays decreased by 94.6%. Incurred WC costs decreased by 91.1%. The proportion of WC claims associated with lost time decreased significantly. CONCLUSIONS: Substantive reductions in the frequency, severity, and incurred WC cost of staff PH injuries followed implementation of the SPHM program. Likewise, proportional changes were identified among the programs where cases occurred, the need for medical treatment, and WC cost type.

Protein Tyrosine Phosphatase Non-Receptor 11 (PTPN11/Shp2) as a Driver Oncogene and a Novel Therapeutic Target in Non-Small Cell Lung Cancer (NSCLC).

PTPN11 encodes the SHP2 protein tyrosine phosphatase that activates the mitogen-activated protein kinase (MAPK) pathway upstream of KRAS and MEK. PTPN11/Shp2 somatic mutations occur frequently in Juvenile myelomonocytic leukaemia (JMML); however, the role of mutated PTPN11 in lung cancer tumourigenesis and its utility as a therapeutic target has not been fully addressed. We applied mass-spectrometry-based genotyping to DNA extracted from the tumour and matched the normal tissue of 356 NSCLC patients (98 adenocarcinomas (LUAD) and 258 squamous cell carcinomas (LUSC)). Further, PTPN11 mutation cases were identified in additional cohorts, including TCGA, Broad, and MD Anderson datasets and the COSMIC database. PTPN11 constructs harbouring PTPN11 E76A, A72D and C459S mutations were stably expressed in IL-3 dependent BaF3 cells and NSCLC cell lines (NCI-H1703, NCI-H157, NCI-H1299). The MAPK and PI3K pathway activation was evaluated using Western blotting. PTPN11/Shp2 phosphatase activity was measured in whole-cell protein lysates using an Shp2 assay kit. The Shp2 inhibitor (SHPi) was assessed both in vitro and in vivo in a PTPN11-mutated cell line for improved responses to MAPK and PI3K targeting therapies. Somatic PTPN11 hotspot mutations occurred in 4/98 (4.1%) adenocarcinomas and 7/258 (2.7%) squamous cells of 356 NSCLC patients. Additional 26 PTPN11 hotspot mutations occurred in 23 and 3 adenocarcinomas and squamous cell carcinoma, respectively, across the additional cohorts. Mutant PTPN11 significantly increased the IL-3 independent survival of Ba/F3 cells compared to wildtype PTPN11 (p < 0.0001). Ba/F3, NCI-H1703, and NCI-H157 cells expressing mutant PTPN11 exhibited increased PTPN11/Shp2 phosphatase activity and phospho-ERK1/2 levels compared to cells expressing wildtype PTPN11. The transduction of the PTPN11 inactivating mutation C459S into NSCLC cell lines led to decreased phospho-ERK, as well as decreased phospho-AKT in the PTPN11-mutated NCI-H661 cell line. NCI-H661 cells (PTPN11-mutated, KRAS-wild type) were significantly more sensitive to growth inhibition by the PI3K inhibitor copanlisib (IC50: 13.9 ± 4.7 nM) compared to NCI-H1703 (PTPN11/KRAS-wild type) cells (IC50: >10,000 nM). The SHP2 inhibitor, in combination with the PI3K targeting therapy copanlisib, showed no significant difference in tumour development in vivo; however, this significantly prevented MAPK pathway induction in vitro (p < 0.0001). PTPN11/Shp2 demonstrated the in vitro features of a driver oncogene and could potentially sensitize NSCLC cells to PI3K inhibition and inhibit MAPK pathway activation following PI3K pathway targeting.

A Retrospective Analysis of Distal Fibula Fractures Treated With Intramedullary Fibular Nail Fixation.

There is growing literature supporting the use of intramedullary fixation for fracture care because of its smaller incisions, improved biomechanical outcomes, and faster time to weightbearing than traditional internal fixation methods. The aim of this study is to investigate the postoperative outcomes in ankle fractures treated with intramedullary nail fixation in the largest patient cohort to date. From 2015 to 2021, 151 patients were evaluated following surgical treatment of fibular fractures with intramedullary nail fixation. Patients were identified through a medical record database search for appropriate ankle fracture procedure codes. Patient information was reviewed for fracture type, adjunct procedures, time to weightbearing and postoperative complications. Radiographs were assessed for quality and time to radiographic union. The mean time to weightbearing was 4.8 weeks. Minor wound dehiscence was identified in 2 patients (1.3%). Superficial infection was present in 4 patients (2.6%) and a deep infection developed in 2 patients (1.3%). Two patients developed a nonunion (1.5%). There were no DVTs reported, although 1 patient developed a PE postoperatively. Radiographic quality of reduction and time to union is comparable to literature reported plate and screw construct outcomes. Reduction was classified as good in 86.1% of patients and radiographic union was appreciated in 98.5% of patients. This is the largest cohort study evaluating the outcomes of intramedullary nail fixation for ORIF of ankle fractures. These data reinforce that intramedullary nailing provides a minimally invasive approach with accurate anatomic reduction, excellent fracture union rates, low complication rates, and an early return to weightbearing.

Phosphonoacetate Modifications Enhance the Stability and Editing Yields of Guide RNAs for Cas9 Editors.

CRISPR gene editing and control systems continue to emerge and inspire novel research and clinical applications. Advances in CRISPR performance such as optimizing the duration of activity in cells, tissues, and organisms, as well as limiting off-target activities, have been extremely important for expanding the utility of CRISPR-based systems. By investigating the effects of various chemical modifications in guide RNAs (gRNAs) at defined positions and combinations, we find that 2'-O-methyl-3'-phosphonoacetate (MP) modifications can be substantially more effective than 2'-O-methyl-3'-phosphorothioate (MS) modifications at the 3' ends of single-guide RNAs (sgRNAs) to promote high editing yields, in some instances showing an order of magnitude higher editing yield in human cells. MP-modified 3' ends are especially effective at promoting the activity of guide RNAs cotransfected with Cas messenger RNA (mRNA), as the gRNA must persist in cells until the Cas protein is expressed. We demonstrate such an MP enhancement for sgRNAs cotransfected with a BE4 mRNA for cytidine base editing and also demonstrate that MP at the 3' ends of prime editing guide RNAs (pegRNAs) cotransfected with PE2 mRNA can promote maximal prime editing yields. In the presence of serum, sgRNAs with MP-modified 3' ends showed marked improvements in editing efficiency over sgRNAs with MS-modified 3' ends codelivered with Cas9 mRNA and showed more modest improvements at enhancing the activity of transfected ribonucleoprotein (RNP) complexes. Our results suggest that MP should be considered as a performance-enhancing modification for the 3' ends of synthetic gRNAs, especially in situations where the guide RNAs may be susceptible to exonuclease-mediated degradation.

First Hard X-Ray Imaging Results by Solar Orbiter STIX.

The Spectrometer/Telescope for Imaging X-rays (STIX) is one of six remote sensing instruments on-board Solar Orbiter. The telescope applies an indirect imaging technique that uses the measurement of 30 visibilities, i.e., angular Fourier components of the solar flare X-ray source. Hence, the imaging problem for STIX consists of the Fourier inversion of the data measured by the instrument. In this work, we show that the visibility amplitude and phase calibration of 24 out of 30 STIX sub-collimators has reached a satisfactory level for scientific data exploitation and that a set of imaging methods is able to provide the first hard X-ray images of solar flares from Solar Orbiter. Four visibility-based image reconstruction methods and one count-based are applied to calibrated STIX observations of six events with GOES class between C4 and M4 that occurred in May 2021. The resulting reconstructions are compared to those provided by an optimization algorithm used for fitting the amplitudes of STIX visibilities. We show that the five imaging methods produce results morphologically consistent with the ones provided by the Atmospheric Imaging Assembly on board the Solar Dynamic Observatory (SDO/AIA) in UV wavelengths. The χ 2 values and the parameters of the reconstructed sources are comparable between methods, thus confirming their robustness.

COVID-19 mRNA Vaccination Generates Greater Immunoglobulin G Levels in Women Compared to Men.

We investigated whether the antibody response to coronavirus disease 2019 (COVID-19) mRNA vaccination is similar in women and men. In a community cohort without prior COVID-19, first vaccine dose produced higher immunoglobulin G (IgG) levels and percent inhibition of spike-ACE2 receptor binding, a surrogate measure of virus neutralization, in women compared to men (7.0 µg/mL, 51.6% vs 3.3 µg/mL, 36.4%). After 2 doses, IgG levels remained significantly higher for women (30.4 µg/mL) compared to men (20.6 µg/mL), while percent inhibition was similar (98.4% vs 97.7%). Sex-specific antibody response to mRNA vaccination informs future efforts to understand vaccine protection and side effects.

Use of exhaled breath condensate (EBC) in the diagnosis of SARS-COV-2 (COVID-19).

False negatives from nasopharyngeal swabs (NPS) using reverse transcriptase PCR (RT-PCR) in SARS-CoV-2 are high. Exhaled breath condensate (EBC) contains lower respiratory droplets that may improve detection. We performed EBC RT-PCR for SARS-CoV-2 genes (E, S, N, ORF1ab) on NPS-positive (n=16) and NPS-negative/clinically positive COVID-19 patients (n=15) using two commercial assays. EBC detected SARS-CoV-2 in 93.5% (29/31) using the four genes. Pre-SARS-CoV-2 era controls (n=14) were negative. EBC was positive in NPS negative/clinically positive patients in 66.6% (10/15) using the identical E and S (E/S) gene assay used for NPS, 73.3% (11/15) using the N/ORF1ab assay and 14/15 (93.3%) combined.

Molecular screening in a longitudinal cohort of young men who have sex with men and young transgender women: associations with focus on the emerging sexually transmitted pathogen Mycoplasma genitalium.

OBJECTIVES: This investigation sought to characterise risk factors associated with acquisition of traditional and emerging agents of sexually transmitted infection (STI) in a cohort of young men who have sex with men and transgender women. METHODS: 917 participants provided urine and rectal swab submissions assessed by transcription-mediated amplification (TMA)-based assays for Chlamydia trachomatis and Neisseria gonorrhoeae and by off-label TMA-based Trichomonas vaginalis and Mycoplasma genitalium testing. A subset provided specimens at 6-month and 12-month follow-up visits. RESULTS: Prevalence of M. genitalium from rectal and urine specimens (21.7% and 8.9%, respectively) exceeded that of C. trachomatis (8.8% and 1.6%) and other STI agents. Black participants yielded higher prevalence of M. genitalium (30.6%) than non-black participants (17.0%; χ²=22.39; p<0.0001). M. genitalium prevalence from rectal specimens was 41.5% in HIV-positive participants vs 16.3% in HIV-negative participants (χ²=57.72; p<0.0001). Participant age, gender identity, condomless insertive anal/vaginal sexual practice and condomless receptive anal sexual practice were not associated with rectal C. trachomatis (p≥0.10), N. gonorrhoeae (p≥0.29), T. vaginalis (p≥0.18) or M. genitalium (p≥0.20) detection. While prevalence of T. vaginalis was calculated at ≤1.0%, baseline rectal and urine screening status was predictive of detection/non-detection at follow-up. A non-reactive M. genitalium baseline rectal or urine screening result was less predictive of non-reactive follow-up versus C. trachomatis, N. gonorrhoeae and T. vaginalis. CONCLUSIONS: Rectal M. genitalium detection is associated with black race and HIV seropositivity. Baseline M. genitalium infection influences subsequent detection of the organism.

The effect of pyrolysis on the chemical, thermal and rheological properties of pitch.

Pitch-based carbon fibers are of considerable interest as high-performance materials. There are reports over the last several decades detailing (i) methods of improving pitch-based carbon fiber performance, and (ii) reducing the cost of production via novel processing techniques. However, there remain considerable challenges in producing high-performance pitch-based carbon fibers consistently on an industrial scale. This is arguably due to the difficulty of scaling the melt-spinning process to compensate for variability in pitch feedstock quality and a lack of understanding of processing-structure-performance relationships. This work focuses on the early stages of heat treatment (pyrolysis) of isotropic pitch and its effect on the chemical, thermal, and rheological properties of the pitch, which help determine its processability. More specifically, we quantify significant changes in chemical structure, Mw, Tg, Ts, and shear and extensional rheology as a function of pyrolysis time at 400 °C. The extensional rheology, in particular, shows that the 'stretchability' of the pitch samples strongly depends on pyrolysis severity, and is important for characterizing 'drawability'. Using a novel analysis of the uniaxial stretching kinematics, we show an isothermal 'drawability window' that allows for the largest axial and radial Hencky strains at constant rate. We hypothesize that this extensional drawability window could facilitate the successful processing of pitch into high quality fiber, minimizing the trial-and-error approach currently used in the field.

Human iPSC-derived cardiomyocytes and pyridyl-phenyl mexiletine analogs.

In the United States, approximately one million individuals are hospitalized every year for arrhythmias, making arrhythmias one of the top causes of healthcare expenditures. Mexiletine is currently used as an antiarrhythmic drug but has limitations. The purpose of this work was to use normal and Long QT syndrome Type 3 (LQTS3) patient-derived human induced pluripotent stem cell (iPSC)-derived cardiomyocytes to identify an analog of mexiletine with superior drug-like properties. Compared to racemic mexiletine, medicinal chemistry optimization of substituted racemic pyridyl phenyl mexiletine analogs resulted in a more potent sodium channel inhibitor with greater selectivity for the sodium over the potassium channel and for late over peak sodium current.

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood.Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness.Methods: Levels of IL-1ß, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated.Measurements and Main Results: IL-1ß, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1ß, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P < 0.0001). In critically unwell patients with COVID-19, increases in IL-6:AAT predicted prolonged ICU stay and mortality, whereas improvement in IL-6:AAT was associated with clinical resolution (P < 0.0001).Conclusions: The COVID-19 cytokinemia is distinct from that of other types of pneumonia, leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population.

Thoracic epidural-based Enhanced Recovery After Surgery (ERAS) pathway for Nuss repair of pectus excavatum shortened length of stay and decreased rescue intravenous opiate use.

BACKGROUND: PCA- and block-based enhanced recovery after surgery (ERAS) pathways have been shown to decrease hospital length of stay (HLOS) and opiate use following Nuss Repair for Pectus Excavatum (NRPE). No thoracic epidural-based ERAS pathway has demonstrated similar benefits. METHODS: In this pre-post single-center study, data were retrospectively collected for patients ≤ 21 years undergoing NRPE from May 2015 to August 2019. Univariate and multivariate methods were used to evaluate whether implementation of a thoracic epidural-based ERAS in April 2017 was associated with HLOS, opiate use, or pain scores. RESULTS: There were 110 patients: 35 pre- and 75 post-ERAS. HLOS decreased from median 4.8 (1.1) to 3.3 (0.6) days with ERAS (p < 0.001). Use of rescue intravenous opiates decreased from 35.3% pre- to 9.3% with ERAS (p = 0.013). When adjusted for baseline characteristics, ERAS was associated with a 1.3 ± 0.2 day decrease in HLOS and 0.188 times the odds of rescue intravenous opiate use (p = 0.011). CONCLUSIONS: Pain scores, ED visits, and readmissions did not change with ERAS (p > 0.05). Implementation of a thoracic epidural-based ERAS following NRPE was associated with decreased HLOS and need for any rescue intravenous opiates without a change in pain scores, ED visits, or readmission.