Transferrin receptor-based circulating tumor cell enrichment provides a snapshot of the molecular landscape of solid tumors and correlates with clinical outcomes.

Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC. In this study we demonstrate that Transferrin Receptor (TfR) is a selective, efficient biomarker for CTC identification and capture in patients with prostate, pancreatic and NSCLC. TfR identifies significantly higher CTC counts than EpCAM, and TfR + -CTC enumeration correlates with disease progression in metastatic prostate and pancreatic cancers, and overall survival and osimetrinib-resistance in non-small cell lung cancer (NSCLC). Profiling of TfR + -CTCs provides a snapshot of the molecular landscape of each respective tumor type and identifies potential mechanisms underlying treatment response to EGFR TKi and immune checkpoint inhibitors in NSCLC. One sentence summary: Transferrin Receptor identifies circulating tumor cells in solid tumors.

Correction to "ß-Phase Crystallinity, Printability, and Piezoelectric Characteristics of Polyvinylidene Fluoride (PVDF)/Poly(methyl methacrylate) (PMMA)/Cyclopentyl-polyhedral Oligomeric Silsesquioxane (Cp-POSS) Melt-Compounded Blends".

[This corrects the article DOI: 10.1021/acsapm.4c00468.].

Saturation genome editing maps the functional spectrum of pathogenic VHL alleles.

To maximize the impact of precision medicine approaches, it is critical to identify genetic variants underlying disease and to accurately quantify their functional effects. A gene exemplifying the challenge of variant interpretation is the von Hippel-Lindautumor suppressor (VHL). VHL encodes an E3 ubiquitin ligase that regulates the cellular response to hypoxia. Germline pathogenic variants in VHL predispose patients to tumors including clear cell renal cell carcinoma (ccRCC) and pheochromocytoma, and somatic VHL mutations are frequently observed in sporadic renal cancer. Here we optimize and apply saturation genome editing to assay nearly all possible single-nucleotide variants (SNVs) across VHL's coding sequence. To delineate mechanisms, we quantify mRNA dosage effects and compare functional effects in isogenic cell lines. Function scores for 2,268 VHL SNVs identify a core set of pathogenic alleles driving ccRCC with perfect accuracy, inform differential risk across tumor types and reveal new mechanisms by which variants impact function. These results have immediate utility for classifying VHL variants encountered clinically and illustrate how precise functional measurements can resolve pleiotropic and dosage-dependent genotype-phenotype relationships across complete genes.

Network Analysis Reveals Protein Modules Associated with Childhood Respiratory Diseases.

Background: The first year of life is a period of rapid immune development that can impact health trajectories and the risk of developing respiratory-related diseases, such as asthma, recurrent infections, and eczema. However, the biology underlying subsequent disease development remains unknown. Methods: Using weighted gene correlation network analysis (WGCNA), we derived modules of highly correlated immune-related proteins in plasma samples from children at age 1 year (N=294) from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). We applied regression analyses to assess relationships between protein modules and development of childhood respiratory diseases up to age 6 years. We then characterized genomic, environmental, and metabolomic factors associated with modules. Results: WGCNA identified four protein modules at age 1 year associated with incidence of childhood asthma and/or recurrent wheeze (Padj range: 0.02-0.03), respiratory infections (Padj range: 6.3×10-9-2.9×10-6), and eczema (Padj=0.01) by age 6 years; three modules were associated with at least one environmental exposure (Padj range: 2.8×10-10-0.03) and disrupted metabolomic pathway(s) (Padj range: 2.8×10-6-0.04). No genome-wide SNPs were identified as significant genetic risk factors for any protein module. Relationships between protein modules with clinical, environmental, and 'omic factors were temporally sensitive and could not be recapitulated in protein profiles at age 6 years. Conclusion: These findings suggested protein profiles as early as age 1 year predicted development of respiratory-related diseases through age 6 and were associated with changes in pathways related to amino acid and energy metabolism. These may inform new strategies to identify vulnerable individuals based on immune protein profiling.

An in vitro platform for quantifying cell cycle phase lengths in primary human intestinal epithelial cells.

The intestinal epithelium dynamically controls cell cycle, yet no experimental platform exists for directly analyzing cell cycle phases in non-immortalized human intestinal epithelial cells (IECs). Here, we present two reporters and a complete platform for analyzing cell cycle phases in live primary human IECs. We interrogate the transcriptional identity of IECs grown on soft collagen, develop two fluorescent cell cycle reporter IEC lines, design and 3D print a collagen press to make chamber slides for optimal imaging while supporting primary human IEC growth, live image cell cycle dynamics, then assemble a computational pipeline building upon free-to-use programs for semi-automated analysis of cell cycle phases. The PIP-FUCCI construct allows for assigning cell cycle phase from a single image of living cells, and our PIP-H2A construct allows for semi-automated direct quantification of cell cycle phase lengths using our publicly available computational pipeline. Treating PIP-FUCCI IECs with oligomycin demonstrates that inhibiting mitochondrial respiration lengthens G1 phase, and PIP-H2A cells allow us to measure that oligomycin differentially lengthens S and G2/M phases across heterogeneous IECs. These platforms provide opportunities for future studies on pharmaceutical effects on the intestinal epithelium, cell cycle regulation, and more.

Halogenated Phenylpyridines Possessing Chemo-Selectivity for Diverse Molecular Architectures.

Pentafluoropyridine was used as a molecular building block for the installation of aryl bromides, affording a series of multisubstituted halogenated arenes. This operationally simplistic methodology offers precise regioselectivity, ease of scalability, and high purity. 19F Nuclear magnetic resonance (NMR) served as a key diagnostic tool for structural characterization, given the sensitivity with various aryl bromine substitutions on the fluorinated pyridine ring. Furthermore, molecular modeling simulations offered insight into this new class of halogenated phenylpyridines and their unique electronic and reactive properties. This study also demonstrates examples of efficient chemo-selectivity upon either metal-catalyzed aryl-aryl coupling or nucleophilic aromatic substitution of the aryl bromide or fluorinated pyridine scaffold, respectively. A diverse pool of polyarylene structures with high degree of complexity, functionalized linear polymers, and controlled network architectures were achieved from this simple methodology.

Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Results: Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. Conclusions: We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. Key Messages: - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. Capsule summary: This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.

Intensifying Salvage Therapy in Prostate-specific Antigen Recurrent Prostate Cancer After Radical Prostatectomy with Apalutamide, Salvage Radiation, and Docetaxel: The Phase 2 STARTAR Trial.

BACKGROUND AND OBJECTIVE: Androgen deprivation therapy (ADT) with salvage radiation therapy (RT) improves survival for patients with prostate-specific antigen (PSA) recurrence after radical prostatectomy (RP) for prostate cancer (PC), but many patients suffer further relapse. This study aims to determine the benefit of the combination of ADT, apalutamide, salvage RT, and docetaxel for high-risk PSA recurrent PC. METHODS: STARTAR is a multicenter, investigator-initiated phase 2 trial of men with PSA recurrent PC after RP. The key inclusion criteria included M0 by computed tomography/bone scan, Gleason 7 with either T3/positive margin/N1 disease or Gleason 8-10 prostate adenocarcinoma, PSA relapse (0.2-4 ng/ml) <4 yr after RP, and fewer than four positive resected lymph nodes. Patients received ADT with apalutamide for 9 mo, RT starting week 8, and then six cycles of docetaxel. The primary endpoint was 36-mo progression-free survival (PFS) with testosterone recovery and compared against the prior STREAM trial. KEY FINDINGS AND LIMITATIONS: We enrolled 39 men, including those with Gleason 8-10 (46%), pN1 (23%); the median PSA was 0.58 ng/ml. The median follow-up was 37 mo. All patients achieved undetectable PSA nadir. At 24 and 36 mo, PFS rates were 84% and 71%, respectively, which improved significantly over 3-yr 47% historic PFS and 54% enzalutamide/ADT/RT (STREAM) PFS rates (p = 0.004 and p = 0.039, respectively). Common any-grade adverse events included 98% hot flashes, 88% fatigue, 77% alopecia, 53% rash (10% G3), and 5% febrile neutropenia. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this phase 2 trial of ADT, apalutamide, salvage RT, and six cycles of docetaxel for high-risk PSA recurrence, the 3-yr PFS rate improved to 71%, indicating feasible and efficacious treatment intensification, with durable remissions beyond historic data. PATIENT SUMMARY: Prostate cancer recurrence after surgical removal of the tumor occurs often, and current treatment options to limit recurrence after surgery are only partially effective. In this study, we found that the addition of an androgen receptor inhibitor and docetaxel chemotherapy to standard postsurgery radiation therapy and androgen deprivation therapy significantly improved progression-free survival at 3 yr after treatment. These results suggest that intensification of treatment after surgery can provide long-term benefit to a subset of patients with high-risk prostate cancer.

Urinary eicosanoid levels in early life and risk of atopic disease in childhood.

BACKGROUND: Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease. METHODS: This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC2010 (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction. RESULTS: In both cohorts, analyses adjusted for environmental determinants showed that higher TXA2 eicosanoids in early life were associated with increased risk of developing atopic dermatitis (P < FDR5%) and type-2 inflammation (P < .05). In VDAART, lower PGE2 and PGI2 eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (P < FDR5%). For wheeze/asthma, analyses in COPSAC2010 showed that lower isoprostanes and PGF2 eicosanoids and higher PGD2 eicosanoids at age 1 year associated with an increased risk at age 1-10 years (P < .05), whereas analyses in VDAART showed that lower PGE2 and higher TXA2 eicosanoids at age 3 years associated with an increased risk at 6 years (P < FDR5%). CONCLUSIONS: This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.

The impact of time to defibrillation on return of spontaneous circulation in out-of-hospital cardiac arrest patients with recurrent shockable rhythms.

OBJECTIVE: Optimal timing for subsequent defibrillation attempts for Out-of-hospital cardiac arrest (OHCA) patients with recurrent VF/pVT is uncertain. We investigated the relationship between VF/pVT duration and return of spontaneous circulation (ROSC) in OHCA patients with recurrent shockable rhythms. METHODS: We analyzed data from the Salt Lake City Fire Department (SLCFD) spanning from 2012 to 2023. The implementation of rhythm-filtering technology since 2011 enabled real-time rhythm interpretation during CPR, with local protocols allowing early defibrillation for recurrent/refractory VF/pVT cases. We included patients experiencing four or five episodes of VF and pVT rhythms and employed generalized estimating equation (GEE) regression analysis to examine the association between VF/pVT durations preceding recurrent defibrillation and return of spontaneous circulation (ROSC). RESULTS: Analysis of 622 appropriate shocks showed that patients achieving ROSC had significantly shorter median VF/pVT duration than those who did not achieve ROSC (0.83 minutes vs. 1.2 minutes, p = 0.004). Adjusted analysis of those with 4 VF/pVT episodes (N = 142) revealed that longer VF/pVT durations were associated with lower odds of achieving ROSC (odds ratio: 0.81, 95% CI: 0.72-0.93, p = 0.005). Every one-minute delay in intra-arrest defibrillation is predicted to decrease the likelihood of achieving ROSC by 19%. CONCLUSION: Every one-minute increase in intra-arrest VF/pVT duration was associated with a statistically significant 19% decrease in the chance of achieving ROSC. This highlights the importance of reducing time to shock in managing recurrent VF/pVT. The findings suggest reevaluating the current recommendations of two minutes intervals for rhythm check and shock delivery.

Examining the association between ethnicity and out-of-hospital cardiac arrest interventions in Salt Lake City, Utah.

Aims: Previous research has reported racial disparities in out-of-hospital cardiac arrest (OHCA) interventions, including bystander CPR and AED use. However, studies on other prehospital interventions are limited. The primary objective of this study was to investigate race/ethnic disparities in out-of-hospital cardiac arrest (OHCA) interventions: EMS response times, medication administration, and decisions for intra-arrest transport. The secondary objective was to evaluate differences in the provision of Bystander CPR (CPR) and application of AED. Methods: We retrospectively analyzed data from the Salt Lake City Fire Department (2010-2023). We included adults 18 years or older with EMS-treated OHCA. Race/ethnicity was categorized as White people, Asian people, Black people, Hispanic people, and others. We employed multivariable regression analysis to evaluate the association between race/ethnicity and the outcomes of interest. Results: Unadjusted analyses revealed no significant differences across ethnic groups in EMS response, medication administration, bystander CPR, or intra-arrest transport decisions. However, significant ethnic disparities were observed in Automated External Defibrillator (AED) utilization, Black people having the lowest rate (6.5%) and Asian people the highest (21.8%). The adjusted analysis found no significant association between race/ethnicity and all OHCA intervention measures, nor between race/ethnicity and survival outcomes. Conclusions: Our multivariable analysis found no statistically significant association between race/ethnicity and EMS response time, epinephrine administration, antiarrhythmic medication use, bystander CPR, AED intervention, or intra-arrest transport. These results imply regional variations in ethnic disparities in OHCA may not be consistent across all areas, warranting further research into disparities in other regions and additional influential factors like neighborhood conditions and socioeconomic status.

A patient-centered textbook outcome measure effectively discriminates contemporary elective open abdominal aortic aneurysm repair quality.

BACKGROUND: There is persistent controversy surrounding the merit of surgical volume benchmarks being used solely as a sufficient proxy for assessing the quality of open abdominal aortic aneurysm (AAA) repair. Importantly, operative volume quotas may fail to reflect a more nuanced and comprehensive depiction of surgical outcomes most relevant to patients. Accordingly, we herein propose a patient-centered textbook outcome (TO) for AAA repair that is analogous to other large magnitude extirpative operations performed in other surgical specialties, and test its feasibility to discriminate hospital performance using Society for Vascular Surgery (SVS) volume guidelines. METHODS: All elective open infrarenal AAA repairs (OAR) in the SVS-Vascular Quality Initiative were examined (2009-2022). The primary end point was a TO, defined as a composite of no in-hospital complication or reintervention/reoperation, length of stay of ≤10 days, home discharge, and 1-year survival rates. The discriminatory ability of the TO measure was assessed by comparing centers that did or did not meet the SVS annual OAR volume threshold recommendation (high volume ≥10 OARs/year; low volume <10 OARs/year). Logistic regression and multivariable models adjusted for patient and procedure-related differences. RESULTS: A total of 9657 OARs across 198 centers were analyzed (mean age, 69.5 ± 8.4 years; female, 26%; non-White, 12%). A TO was identified in 44% (n = 4293) of the overall cohort. The incidence of individual TO components included no in-hospital complication (61%), no in-hospital reintervention or reoperation (92%), length of stay of ≤10 days (78%), home discharge (76%), and 1-year survival (91%). Median annual center volume was 6 (interquartile range, 3-10) and a majority of centers did not meet the SVS volume suggested threshold (<10 OARs/year, n = 148 [74%]). However, most patients (6265 of 9657 [65%]) underwent OAR in high-volume hospitals. When comparing high- and low-volume centers, a TO was more likely to occur in high-volume institutions: ≥10 OARs/year (46%) vs <10 OARs/year (42%; P = .0006). The association of a protective effect for higher center volume remained after risk adjustment (odds ratio, 1.1; 95% confidence interval, 1.05-1.26; P = .003). CONCLUSIONS: TOs for elective OAR reflect a more nuanced and comprehensive patient centered proxy to measure care delivery, consistent with other surgical specialties. Surprisingly, a TO was achieved in <50% of elective AAA cases nationally. Although the likelihood of a TO seems to correlate with SVS center volume recommendations, it more importantly reflects elements which may be prioritized by patients and thus offers insights into further improving real-world AAA care.

Family history as the strongest predictor of aortic and peripheral aneurysms in patients with intracranial aneurysms.

OBJECTIVE: Intracranial aneurysms (IA) and aortic aneurysms (AA) are both abnormal dilations of arteries with familial predisposition and have been proposed to share co-prevalence and pathophysiology. Associations of IA and non-aortic peripheral aneurysms are less well-studied. The goal of the study was to understand the patterns of aortic and peripheral (extracranial) aneurysms in patients with IA, and risk factors associated with the development of these aneurysms. METHODS: 4701 patients were included in our retrospective analysis of all patients with intracranial aneurysms at our institution over the past 26 years. Patient demographics, comorbidities, and aneurysmal locations were analyzed. Univariate and multivariate analyses were performed to study associations with and without extracranial aneurysms. RESULTS: A total of 3.4% of patients (161 of 4701) with IA had at least one extracranial aneurysm. 2.8% had thoracic or abdominal aortic aneurysms. Age, male sex, hypertension, coronary artery disease, history of ischemic cerebral infarction, connective tissues disease, and family history of extracranial aneurysms in a 1st degree relative were associated with the presence of extracranial aneurysms and a higher number of extracranial aneurysms. In addition, family history of extracranial aneurysms in a second degree relative is associated with the presence of extracranial aneurysms and atrial fibrillation is associated with a higher number of extracranial aneurysms. CONCLUSION: Significant comorbidities are associated with extracranial aneurysms in patients with IA. Family history of extracranial aneurysms has the strongest association and suggests that IA patients with a family history of extracranial aneurysms may benefit from screening.

Using random forest to identify correlates of depression symptoms among adolescents.

PURPOSE: Adolescent depression is a significant public health concern, and studying its multifaceted factors using traditional methods possess challenges. This study employs random forest (RF) algorithms to determine factors predicting adolescent depression scores. METHODS: This study utilized self-reported survey data from 56,008 Canadian students (grades 7-12) attending 182 schools during the 2021/22 academic year. RF algorithms were applied to identify the correlates of (i) depression scores (CESD-R-10) and (ii) presence of clinically relevant depression (CESD-R-10 ≥ 10). RESULTS: RF achieved a 71% explained variance, accurately predicting depression scores within a 3.40 unit margin. The top 10 correlates identified by RF included other measures of mental health (anxiety symptoms, flourishing, emotional dysregulation), home life (excessive parental expectations, happy home life, ability to talk to family), school connectedness, sleep duration, and gender. In predicting clinically relevant depression, the algorithm showed 84% accuracy, 0.89 sensitivity, and 0.79 AUROC, aligning closely with the correlates identified for depression score. CONCLUSION: This study highlights RF's utility in identifying important correlates of adolescent depressive symptoms. RF's natural hierarchy offers an advantage over traditional methods. The findings underscore the importance and additional potential of sleep health promotion and school belonging initiatives in preventing adolescent depression.

Mental Health Trends in Patients With Symptomatic Macromastia After Reduction Mammoplasty.

BACKGROUND: Symptomatic macromastia can significantly affect both physical and mental health. Although previous studies suggested that breast reduction (BR) improves quality of life and mental health conditions, they were limited to smaller sample sizes and largely based on survey feedback. This study aims to further assess the impact of BR on mental health outcomes, specifically looking at prescribing patterns for common antidepressants. METHODS: A national insurance-based database was utilized for data collection. Patients with a diagnosis of macromastia (ICD-10 N62) between the years 2010 and 2021 that either underwent bilateral BR (CPT 19318) or did not undergo BR were included in the study. Demographics and medical comorbidities were compared. Among those who underwent BR, preoperative and postoperative rates of mental health diagnoses and antidepressant use were compared. Logistic regression analysis was performed to determine variables associated with surgery. RESULTS: Patients with a history of macromastia with a history of BR were compared with those with a history of macromastia without BR. A significantly higher percentage of patients in the BR group reported a history of depression (48.5%), obesity (55.7%), and selective serotonin reuptake inhibitor (SSRI)/serotonin-norepinephrine reuptake inhibitor (SNRI) use (55.3%) when compared with that of the no-reduction group (46.3%, 50.8%, and 52.6%). Patients with history of depression and obesity were more likely to undergo BR (odds ratio of 1.11 and 1.31). Patients who underwent BR had significantly reduced rates of mental health outcomes including depression (38.6% to 27.4%), anxiety (4.3% to 3.1%), and SSRI or SNRI prescriptions (46.3% to 29.5%) postoperatively. CONCLUSIONS: Patients who underwent BR for symptomatic macromastia showed significantly reduced rates of depression, anxiety, and most importantly, rates of SSRI/SNRI prescriptions postoperatively when compared to those who did not undergo BR for symptomatic macromastia.

Development of a quantum cascade laser absorption spectrometer for simultaneous measurement of 13C-18O and 18O-18O clumping in CO2.

RATIONALE: Dual clumped isotope paleothermometry determines carbonate formation temperatures by measuring the frequency of 13C-18O (∆638) and 18O-18O (∆828) pairs in carbonates. It resolves isotopic kinetic biases and thus enables more accurate paleotemperature reconstructions. However, high-precision measurements of 18O-18O clumping using current techniques requires large sample sizes and long acquisition times. METHODS: We developed a mid-infrared isotope ratio laser spectrometer (IRLS) for simultaneous measurement of the isotopologue ratios ∆638 and ∆828 in gas-phase carbon dioxide (CO2) at room temperature. Our IRLS uses a single laser scanning from 2290.7 to 2291.1 cm-1 and a 31 m pathlength optical cell, and it simultaneously measures the five isotopologues required for calculating ∆638 and ∆828: 16O12C16O, 16O13C16O, 16O12C18O, 16O13C18O, and 18O12C18O. In addition, our IRLS can measure 16O12C17O, enabling ∆17O analysis. RESULTS: At ~20°C and a CO2 pressure of ~2 Torr, our IRLS system achieved precisions of 0.128‰ and 0.140‰ within 20 s for abundances of the clumped isotopologues 16O13C18O and 18O12C18O, respectively, and precisions of 0.267‰, 0.245‰, and 0.128‰ for 16O12C16O, 16O13C16O, and 16O12C18O. This yielded precisions of 0.348‰ (∆638) and 0.302‰ (∆828) within 25 s. Simulated sample-reference switching highlights the potential of our system and the need for further development. CONCLUSIONS: We demonstrated simultaneous measurements of ∆638 and ∆828 in CO2 to precisions of <0.35‰ within 25 s using a room-temperature, single-laser IRLS. Future developments on better resolving 16O12C16O and 16O13C16O peaks and system temperature control could further improve the measurement precision.

Preventing New Gram-negative Resistance Through Beta-lactam De-escalation in Hospitalized Patients With Sepsis: A Retrospective Cohort Study.

BACKGROUND: Whether antibiotic de-escalation reduces the risk of subsequent antibiotic resistance is uncertain. We sought to determine if beta-lactam (BL) antibiotic de-escalation is associated with decreased incidence of new Gram-negative resistance in hospitalized patients with sepsis. METHODS: In a retrospective cohort study, patients with sepsis who were treated with at least 3 consecutive days of BL antibiotics, the first 2 days of which were with a broad-spectrum BL agent defined as a spectrum score (SS) of ≥7 were enrolled. Patients were grouped into three categories: (1) de-escalation of beta-lactam spectrum score (BLSS), (2) no change in BLSS, or (3) escalation of BLSS. The primary outcome was the isolation of a new drug-resistant Gram-negative bacteria from a clinical culture within 60 days of cohort entry. Fine-Gray proportional hazards regression modeling while accounting for in-hospital death as a competing risk was performed. FINDINGS: Six hundred forty-four patients of 7742 (8.3%) patients developed new gram-negative resistance. The mean time to resistance was 23.7 days yielding an incidence rate of 1.85 (95% confidence interval [CI]: 1.71-2.00) per 1000 patient-days. The lowest incidence rate was observed in the de-escalated group 1.42 (95% CI: 1.16-1.68) per 1000 patient-days. Statistically significant reductions in the development of new gram-negative resistance were associated with BL de-escalation compared to no-change (hazards ratio (HR) 0.59 [95% CI: .48-.73]). CONCLUSIONS: De-escalation was associated with a decreased risk of new resistance development compared to no change. This represents the largest study to date showing the utility of de-escalation in the prevention of antimicrobial resistance.

Employment Outcomes of a Distance Learning System for Formerly Incarcerated Veterans With Mental Illness.

OBJECTIVE: People with previous incarceration and a mental disorder, a substance use disorder, or both are less likely to obtain employment than are those without these characteristics. Distance learning and education (DLE) systems are increasingly being integrated into clinical care and provide a pathway to disseminate vocational services. DLE systems can help reach people with barriers to accessing services, including people without transportation, experiencing homelessness, living in rural areas, or who are homebound. This study evaluated the effectiveness of one DLE system, the COMPASS program, in assisting formerly incarcerated veterans with a mental or substance use disorder to obtain employment. METHODS: The authors used a randomized controlled trial to compare employment outcomes of 39 U.S. veterans receiving the COMPASS intervention with those of 43 veterans receiving a paper self-study vocational manual. All participants had previous legal convictions and had a mental disorder, a substance use disorder, or both. The COMPASS system provided vocational services through asynchronous (online practice assignments, reading, and videos) and synchronous (video and telephone practice interviews and live chats) methods. No in-person vocational services were provided in the COMPASS intervention. RESULTS: At 6 months, participants assigned to receive the COMPASS intervention were more likely to have found employment, defined as 1 day of competitive employment, compared with those assigned to receive the self-study manual (64% vs. 35%, respectively)-and to have found employment faster. CONCLUSIONS: This study's findings provide evidence for the effectiveness of the COMPASS system in providing employment services and suggest that these services may benefit other vulnerable populations.

One-Stage Deep Inferior Epigastric Perforator Flap Salvage of Infected Tissue Expanders.

BACKGROUND: Tissue expander-based breast reconstruction is associated with high rates of infectious complications, often leading to tissue expander explants and delays in receipt of definitive breast reconstruction and adjuvant therapy. In this study, we describe a single-stage technique where deep inferior epigastric artery perforator (DIEP) flaps are used to salvage actively infected tissue expanders among patients originally planning for free flap reconstruction. METHODS: In this technique, patients with tissue expander infections without systemic illness are maintained on oral antibiotics until the day of their DIEP flap surgery, at which time tissue expander explant is performed in conjunction with aggressive attempt at total capsulectomy and immediate DIEP flap reconstruction. Patients are maintained on 1-2 weeks of oral antibiotics tailored to culture data. Patients undergoing this immediate salvage protocol were retrospectively reviewed, and complications and length of stay were assessed. RESULTS: In a retrospective series, a total of six consecutive patients with culture-proven tissue expander infections underwent tissue expander removal and DIEP flap reconstruction in a single stage and were maintained on 7-14 days of oral antibiotics postoperatively. Within this cohort, no surgical site infections, microvascular complications, partial flap losses, reoperations, or returns to the operating room were noted within a 90-day period. CONCLUSIONS: Among a select cohort of patients, actively infected tissue expanders may be salvaged with free flap breast reconstruction in a single surgery with a low incidence of postoperative complications. Prospective studies are needed to evaluate the influence of this treatment strategy on costs, number of surgeries, and dissatisfaction after staged breast reconstruction complicated by tissue expander infections.

Does the Relationship between Affect and Social Interactions among Adults Experiencing Homelessness Differ during Moments when at a Shelter versus Not?

The prevalence of alcohol use disorders is higher amongst adults experiencing homelessness (AEH) compared with domiciled adults. Greater exposure to heavy drinkers increases personal risk for heavy alcohol use. AEH spend substantial periods of time at shelters and report greater pressure to use alcohol when near shelter locations, as well as greater negative affect when near a shelter. It is unclear if the relationship between affect and 1) interacting with people and 2) being near someone AEH drank alcohol with before differs when AEH are at a shelter versus not. AEH reporting alcohol misuse (n = 72, Mage= 47, 85% Male, 68% Non-White) completed five daily smartphone-based ecological momentary assessments (EMAs) over 28 days. Generalized multilevel modeling revealed that when AEH were interacting with someone they drank with before, they had significantly lower positive affect when at a shelter (b = -0.17, p = 0.05), versus when not (b = 0.00, p = 0.99). AEH are likely to interact with previous drinking partners while at shelters. It may be important to deliver real-time treatment messages targeting affect in these moments, as well as deliver alcohol reduction/abstinence messages.