Assessment of a Crisis Standards of Care Scoring System for Resource Prioritization and Estimated Excess Mortality by Race, Ethnicity, and Socially Vulnerable Area During a Regional Surge in COVID-19.

Importance: Crisis standards of care (CSOC) scores designed to allocate scarce resources during the COVID-19 pandemic could exacerbate racial disparities in health care. Objective: To analyze the association of a CSOC scoring system with resource prioritization and estimated excess mortality by race, ethnicity, and residence in a socially vulnerable area. Design, Setting, and Participants: This retrospective cohort analysis included adult patients in the intensive care unit during a regional COVID-19 surge from April 13 to May 22, 2020, at 6 hospitals in a health care network in greater Boston, Massachusetts. Participants were scored by acute severity of illness using the Sequential Organ Failure Assessment score and chronic severity of illness using comorbidity and life expectancy scores, and only participants with complete scores were included. The score was ordinal, with cutoff points suggested by the Massachusetts guidelines. Exposures: Race, ethnicity, Social Vulnerability Index. Main Outcomes and Measures: The primary outcome was proportion of patients in the lowest priority score category stratified by self-reported race. Secondary outcomes were discrimination and calibration of the score overall and by race, ethnicity, and neighborhood Social Vulnerability Index. Projected excess deaths were modeled by race, using the priority scoring system and a random lottery. Results: Of 608 patients in the intensive care unit during the study period, 498 had complete data and were included in the analysis; this population had a median (IQR) age of 67 (56-75) years, 191 (38.4%) female participants, 79 (15.9%) Black participants, and 225 patients (45.7%) with COVID-19. The area under the receiver operating characteristic curve for the priority score was 0.79 and was similar across racial groups. Black patients were more likely than others to be in the lowest priority group (12 [15.2%] vs 34 [8.1%]; P = .046). In an exploratory simulation model using the score for ventilator allocation, with only those in the highest priority group receiving ventilators, there were 43.9% excess deaths among Black patients (18 of 41 patients) and 28.6% (58 of 203 patients among all others (P = .05); when the highest and intermediate priority groups received ventilators, there were 4.9% (2 of 41 patients) excess deaths among Black patients and 3.0% (6 of 203) among all others (P = .53). A random lottery resulted in more excess deaths than the score. Conclusions and Relevance: In this study, a CSOC priority score resulted in lower prioritization of Black patients to receive scarce resources. A model using a random lottery resulted in more estimated excess deaths overall without improving equity by race. CSOC policies must be evaluated for their potential association with racial disparities in health care.

Streamlined Target Deconvolution Approach Utilizing a Single Photoreactive Chloroalkane Capture Tag.

Identification of physiologically relevant targets for lead compounds emerging from drug discovery screens is often the rate-limiting step toward understanding their mechanism of action and potential for undesired off-target effects. To this end, we developed a streamlined chemical proteomic approach utilizing a single, photoreactive cleavable chloroalkane capture tag, which upon attachment to bioactive compounds facilitates selective isolation of their respective cellular targets for subsequent identification by mass spectrometry. When properly positioned, the tag does not significantly affect compound potency and membrane permeability, allowing for binding interactions with the tethered compound (probe) to be established within intact cells under physiological conditions. Subsequent UV-induced covalent photo-cross-linking "freezes" the interactions between the probe and its cellular targets and prevents their dissociation upon cell lysis. Targets cross-linked to the capture tag are then efficiently enriched through covalent capture onto HaloTag coated beads and subsequent selective chemical release from the solid support. The tag's built-in capability for selective enrichment eliminates the need for ligation of a capture tag, thereby simplifying the workflow and reducing variability introduced through additional operational steps. At the same time, the capacity for adequate cross-linking without structural optimization permits modular assembly of photoreactive chloroalkane probes, which reduces the burden of customized chemistry. Using three model compounds, we demonstrate the capability of this approach to identify known and novel cellular targets, including those with low affinity and/or low abundance as well as membrane targets with several transmembrane domains.

ProAlanase is an Effective Alternative to Trypsin for Proteomics Applications and Disulfide Bond Mapping.

Trypsin is the protease of choice in bottom-up proteomics. However, its application can be limited by the amino acid composition of target proteins and the pH of the digestion solution. In this study we characterize ProAlanase, a protease from the fungus Aspergillus niger that cleaves primarily on the C-terminal side of proline and alanine residues. ProAlanase achieves high proteolytic activity and specificity when digestion is carried out at acidic pH (1.5) for relatively short (2 h) time periods. To elucidate the potential of ProAlanase in proteomics applications, we conducted a series of investigations comprising comparative multi-enzymatic profiling of a human cell line proteome, histone PTM analysis, ancient bone protein identification, phosphosite mapping and de novo sequencing of a proline-rich protein and disulfide bond mapping in mAb. The results demonstrate that ProAlanase is highly suitable for proteomics analysis of the arginine- and lysine-rich histones, enabling high sequence coverage of multiple histone family members. It also facilitates an efficient digestion of bone collagen thanks to the cleavage at the C terminus of hydroxyproline which is highly prevalent in collagen. This allows to identify complementary proteins in ProAlanase- and trypsin-digested ancient bone samples, as well as to increase sequence coverage of noncollagenous proteins. Moreover, digestion with ProAlanase improves protein sequence coverage and phosphosite localization for the proline-rich protein Notch3 intracellular domain (N3ICD). Furthermore, we achieve a nearly complete coverage of N3ICD protein by de novo sequencing using the combination of ProAlanase and tryptic peptides. Finally, we demonstrate that ProAlanase is efficient in disulfide bond mapping, showing high coverage of disulfide-containing regions in a nonreduced mAb.

Effect of Chronic Alcoholism on Traumatic Intracranial Hemorrhage.

BACKGROUND: Traumatic intracranial hemorrhage (TICH) is one of the commonest indications for neurosurgical consultation after trauma. Worsening neurologic examination results, size of initial TICH, presence of displaced skull fracture, and concomitant anticoagulant use at the time of injury drive the recommendations for repeat computed tomography of head (RCTH), to assess for stability of intracranial hemorrhage. Chronic alcohol use is not generally considered an indication for repeat head computed tomography (CT). METHODS: A retrospective study of 423 patients with TICH with normal admission platelet (PLT) counts was reviewed for this study, taken as a subset of 1330 patients with TICH admitted to Lahey Hospital and Medical Center over a 3-year period. Of these 423 patients, 330 were classified as nonalcoholics and 93 were classified as alcoholics, based on whether alcohol use disorder was documented in the patient's medical record, present before injury. The normal PLT level was defined as ≥100,000 µ/L. Patients were excluded from review if they had comorbid conditions that could cause PLT dysfunction or coagulopathy. Continuous and categorical variables were compared using independent t test and χ2, respectively. Binary logistic regression was used to predict outcome: stable versus worsening of TICH on RCTH. Statistical analysis was conducted using SPSS version 25. RESULTS: The mean age of the nonalcoholic and alcoholic cohorts were 71.9 years and 54.8 years, respectively. A significantly higher percentage of alcoholics were male. There was a statistically significant difference (χ2 = 8.14; P < 0.004) in radiologic progression of TICH between the 2 groups, with the alcoholics having a worsening RCTH 16.1% of the time compared with only 6.7% in nonalcoholics. Chronic alcohol use was an independent predictor of radiologic progression in patients with normal PLT level (odds ratio, 2.69; confidence interval, 1.34-5.43; P < 0.006). CONCLUSIONS: Chronic alcohol use was an independent predictor of radiologic progression of TICH in the setting of normal PLT level. Modification of this risk of progression with transfusion of fresh PLTs in chronic alcoholic patients with TICH needs to be investigated in a prospective trial.

The effect of anticoagulation on outcomes after liver and spleen injuries: A research consortium of New England centers for trauma (ReCONECT) study.

BACKGROUND: Liver and spleen injuries are the most commonly injured solid organs, the effects of anticoagulation on these injuries has not yet been well characterized. STUDY DESIGN: Multicenter retrospective study. RESULT: During the 4-year study period, 1254 patients, 64 (5%) on anticoagulation (AC), were admitted with liver and/or splenic injury. 58% of patients had a splenic injury, 53% had a liver injury and 11% had both. Patients on AC were older than non-AC patients (mean age 60.9 vs. 38.6 years, p < 0.001). The most common AC drug was warfarin (70%) with atrial fibrillation (47%) the most common indication for AC. There was no significant difference in AAST injury grade between AC and non-AC patients (median grade 2), but AC patients required a blood product transfusion more commonly (58 vs 40%, p = 0.007) particularly FFP (4 vs 19%, p < 0.01). Among those transfused, non-AC patients required slightly more PRBC (5.7 vs 3.8 units, p = 0.018) but similar amount of FFP (3.2 vs 3.1 units, p = 0.92). The two groups had no significant difference in the rates of initial non-operative management (50% (AC) vs 56% (non-AC), p = 0.3)) or failure of non-operative management (7 vs 4%, p = 0.16). AC patients were more likely to be managed initially with angiography (36 vs 20%, p = 0.001) while non-AC patients with surgery (24% vs 13%, p = 0.04). There was no significant difference in LOS and mortality. CONCLUSION: The use of anticoagulation did not result in a difference in outcomes among patients with spleen and/or liver injuries.

Effectiveness of Common Fabrics to Block Aqueous Aerosols of Virus-like Nanoparticles.

Layered systems of commonly available fabric materials can be used by the public and healthcare providers in face masks to reduce the risk of inhaling viruses with protection that is about equivalent to or better than the filtration and adsorption offered by 5-layer N95 respirators. Over 70 different common fabric combinations and masks were evaluated under steady-state, forced convection air flux with pulsed aerosols that simulate forceful respiration. The aerosols contain fluorescent virus-like nanoparticles to track transmission through materials that greatly assist the accuracy of detection, thus avoiding artifacts including pore flooding and the loss of aerosol due to evaporation and droplet breakup. Effective materials comprise both absorbent, hydrophilic layers and barrier, hydrophobic layers. Although the hydrophobic layers can adhere virus-like nanoparticles, they may also repel droplets from adjacent absorbent layers and prevent wicking transport across the fabric system. Effective designs are noted with absorbent layers comprising terry cloth towel, quilting cotton, and flannel. Effective designs are noted with barrier layers comprising nonwoven polypropylene, polyester, and polyaramid.

American Association for the Surgery of Trauma Prevention Committee topical update: Impact of community violence exposure, intimate partner violence, hospital-based violence intervention, building community coalitions and injury prevention program evaluation.

An effective injury prevention program is an important component of a successful trauma system. Maintaining support for a hospital-based injury prevention program is challenging, given competing institutional and trauma program priorities and limited resources. In light of those pressures, the American College of Surgeons Committee on Trauma mandates that trauma centers demonstrate financial support for an injury prevention program as part of the verification process, recognizing that hospital administrators might see such support as discretionary and ripe as a target for expense reduction efforts. This Topical Update from the American Association for the Surgery of Trauma Injury Prevention Committee focuses on strategies to be more effective with the limited resources that are allocated to hospital-based injury prevention programs. First, this review tackles two of the many social determinates of violence, including activities aimed at mitigating the impact of both community violence exposure and intimate partner/domestic violence. Developing or participating in coalitions for injury prevention, both in general with any injury prevention initiative, and specifically while developing a hospital-based violence intervention program, efficiently extends the hospital's efforts by gaining access to expertise, resources, and influence over the target population that the hospital might otherwise have difficulty impacting. Finally, the importance of systematic program evaluation is explored. In an era of dwindling resources for injury prevention, both at the national level and the institutional level, it is important to measure the effectiveness of injury prevention efforts on the target population, and when necessary, make changes to programs to both improve their effectiveness and to assist organizations in making wise choices in the use of their limited resources.

Proceedings of the 2017 Santa Fe Bone Symposium: Insights and Emerging Concepts in the Management of Osteoporosis.

The 18th Annual Santa Fe Bone Symposium was held on August 4-5, 2017, in Santa Fe, New Mexico, USA. The symposium convenes health-care providers and clinical researchers to present and discuss clinical applications of recent advances in research of skeletal diseases. The program includes lectures, oral presentations by endocrinology fellows, case-based panel discussions, and breakout sessions on topics of interest, with emphasis on participation and interaction of all participants. Topics included the evaluation and treatment of adult survivors with pediatric bone diseases, risk assessment and management of atypical femur fractures, nonpharmacologic strategies in the care of osteoporosis, and skeletal effects of parathyroid hormone with opportunities for therapeutic intervention. Management of skeletal complications of rheumatic diseases was discussed. Insights into sequential and combined use of antiresorptive agents were presented. Individualization of patient treatment decisions when clinical practice guidelines may not be applicable was covered. Challenges and opportunities with osteoporosis drug development were discussed. There was an update on progress of Bone Health TeleECHO (Bone Health Extension for Community Healthcare Outcomes), a teleconferencing strategy for sharing knowledge and expanding capacity to deliver best-practice skeletal health care.

Is measurement of renal function necessary for all trauma patients before iodinated contrast administration?

PURPOSE: The purpose of this study was to identify factors at the time of presentation which could quickly exclude or identify renal dysfunction in blunt trauma patients, thus negating serum measurement of renal function prior to contrast-enhanced imaging and expediting care. METHODS: Patients, >18 years old, without renal failure, presenting after blunt trauma, with serum creatinine measured at presentation, were retrospectively studied at a single center. Variables recorded at presentation including vitals, mechanism, and past medical history were analyzed using multivariate regression analysis to identify independent predictors of abnormal renal function. RESULTS: From 2009 to 2015, a total of 1099 patients met the inclusion criteria. Of those, 75 (6.8%) had renal dysfunction at presentation. Patients with renal dysfunction had a mean age of 74.3 (SD 15.5) years old, and 57.3% were male. Multivariate analysis identified independent predictors of renal dysfunction at presentation as age ≥ 61 (p < 0.001), hypotension (p = 0.02), and diabetes (p = 0.02). The presence of a single identified factor had an 85% sensitivity for renal dysfunction and a 98.5% negative predictive value. CONCLUSIONS: Impaired renal function at presentation was infrequent in our trauma cohort. Trauma patients who were normotensive, under the age of 61, and without diabetes were unlikely to have impaired renal function at presentation. In the urgent setting of trauma, patients without these comorbidities are likely safe to forgo screening of renal function prior to contrast-enhanced imaging.

Cervical spine MRI in patients with negative CT: A prospective, multicenter study of the Research Consortium of New England Centers for Trauma (ReCONECT).

BACKGROUND: Although cervical spine CT (CSCT) accurately detects bony injuries, it may not identify all soft tissue injuries. Although some clinicians rely exclusively on a negative CT to remove spine precautions in unevaluable patients or patients with cervicalgia, others use MRI for that purpose. The objective of this study was to determine the rates of abnormal MRI after a negative CSCT. METHODS: Blunt trauma patients who either were unevaluable or had persistent midline cervicalgia and underwent an MRI of the C-spine after a negative CSCT were enrolled prospectively in eight Level I and II New England trauma centers. Demographics, injury patterns, CT and MRI results, and any changes in cervical spine management as a result of MRI imaging were recorded. RESULTS: A total of 767 patients had MRI because of cervicalgia (43.0%), inability to evaluate (44.1%), or both (9.4%). MRI was abnormal in 23.6% of all patients, including ligamentous injury (16.6%), soft tissue swelling (4.3%), vertebral disc injury (1.4%), and dural hematomas (1.3%). Rates of abnormal neurological signs or symptoms were not different among patients with normal versus abnormal MRI. (15.2 vs. 18.8%, p = 0.25). The c-collar was removed in 88.1% of patients with normal MRI and 13.3% of patients with an abnormal MRI. No patient required halo placement, but 11 patients underwent cervical spine surgery after the MRI results. Six of the eleven had neurological signs or symptoms. CONCLUSIONS: In a select population of patients, MRI identified additional injuries in 23.6% of patients despite a normal CSCT. It is uncertain if this is a true limitation of CT technology or represents subtle injuries missed in the interpretation of the scan. The clinical significance of these abnormal MRI findings cannot be determined from this study group. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Reagent for Evaluating Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Performance in Bottom-Up Proteomic Experiments.

We present a novel proteomic standard for assessing liquid chromatography-tandem mass spectrometry (LC-MS/MS) instrument performance, in terms of chromatographic reproducibility and dynamic range within a single LC-MS/MS injection. The peptide mixture standard consists of six peptides that were specifically synthesized to cover a wide range of hydrophobicities (grand average hydropathy (GRAVY) scores of -0.6 to 1.9). A combination of stable isotope labeled amino acids ((13)C and (15)N) were inserted to create five isotopologues. By combining these isotopologues at different ratios, they span four orders of magnitude within each distinct peptide sequence. Each peptide, from lightest to heaviest, increases in abundance by a factor of 10. We evaluate several metrics on our quadrupole orbitrap instrument using the 6 × 5 LC-MS/MS reference mixture spiked into a complex lysate background as a function of dynamic range, including mass measurement accuracy (MMA) and the linear range of quantitation of MS1 and parallel reaction monitoring experiments. Detection and linearity of the instrument routinely spanned three orders of magnitude across the gradient (500 fmol to 0.5 fmol on column) and no systematic trend was observed for MMA of targeted peptides as a function of abundance by analysis of variance analysis (p = 0.17). Detection and linearity of the fifth isotopologue (i.e., 0.05 fmol on column) was dependent on the peptide and instrument scan type (MS1 vs PRM). We foresee that this standard will serve as a powerful method to conduct both intra-instrument performance monitoring/evaluation, technology development, and inter-instrument comparisons.