Search

Hip fractures are a major cause of morbidity and mortality in the elderly, and incur high health and social care costs. Given projected population ageing, the number of incident hip fractures is predicted to increase globally. As fracture classification strongly determines the chosen surgical treatment, differences in fracture classification influence patient outcomes and treatment costs. We aimed to create a machine learning method for identifying and classifying hip fractures, and to compare its performance to experienced human observers. We used 3659 hip radiographs, classified by at least two expert clinicians. The machine learning method was able to classify hip fractures with 19% greater accuracy than humans, achieving overall accuracy of 92%.

The objective of this study was to determine hospital costs and revenue of universal opt-out HIV ED screening. An electronic medical record (EMR)-directed, automated ED screening program was instituted at an academic medical center in San Diego, California. A base model calculated net income in US dollars for the hospital by comparing annual testing costs with reimbursements using payor mixes and cost variables. To account for differences in payor mixes, testing costs, and reimbursement rates across hospitals in the US, we performed a probabilistic sensitivity analysis. The base model included a total of 12,513 annual 4th generation HIV tests with the following payor mix: 18% Medicare, 9% MediCal, 28% commercial and 8% self-payers, with the remainder being capitated contracts. The base model resulted in a net profit for the hospital. In the probabilistic sensitivity analysis, universal 4th generation HIV screening resulted in a net profit for the hospital in 81.9% of simulations. Universal 4th generation opt-out HIV screening in EDs resulted in a net profit to an academic hospital. Sensitivity analysis indicated that ED HIV screening results in a net-profit for the majority of simulations, with higher proportions of self-payers being the major predictor of a net loss.

BackgroundSARS-CoV-2 serologic assays are becoming increasingly available and may serve as a diagnostic aid in a multitude of settings relating to past infection status. However, there is limited literature detailing the longitudinal performance of EUA-cleared serologic assays in US populations, particularly in cohorts with a remote history of PCR-confirmed SARS-CoV-2 infection (e.g., >2 months).MethodsWe evaluated the diagnostic sensitivities and specificities of the Elecsys® Anti-SARS-CoV-2 (anti-N) and Elecsys Anti-SARS-CoV-2 S (anti-S1-RBD) assays, using 174 residual clinical samples up to 267 days post-PCR diagnosis of SARS-CoV-2 infection (n = 154) and a subset of samples obtained prior to the COVID-19 pandemic as negative controls (n = 20).ResultsThe calculated diagnostic sensitivities for the anti-N and anti-S1-RBD assays were 89% and 93%, respectively. Of the 154 samples in the SARS-CoV-2-positive cohort, there were 6 discrepant results between the anti-N and anti-S1-RBD assays, 5 of which were specimens collected ≥200 days post-PCR positivity and only had detectable levels of anti-S1-RBD antibodies. When only considering specimens collected ≥100 days post-PCR positivity (n = 41), the sensitivities for the anti-N and anti-S1-RBD assays were 85% and 98%, respectively.ConclusionsThe anti-S1-RBD assay demonstrated superior sensitivity at time points more remote to the PCR detection date, with 6 more specimens from the SARS-CoV-2-positive cohort detected, 5 of which were collected more than 200 days post-PCR positivity. While analytical differences and reagent lot-to-lot variability are possible, this may indicate that, in some instances, anti-S1-RBD antibodies may persist longer in vivo and may be a better target for detecting remote SARS-CoV-2 infection.

To determine the effect of oat β‑glucan (OBG) on acute glucose and insulin responses and identify significant effect modifiers we searched the MEDLINE, EMBASE, and Cochrane databases through October 27, 2020 for acute, crossover, controlled feeding trials investigating the effect of adding OBG (concentrate or oat-bran) to carbohydrate-containing test-meals compared to comparable or different carbohydrate-matched control-meals in humans regardless of health status. The primary outcome was glucose incremental area-under-the-curve (iAUC). Secondary outcomes were insulin iAUC, and glucose and insulin incremental peak-rise (iPeak). Two reviewers extracted the data and assessed risk-of-bias and certainty-of-evidence (GRADE). Data were pooled using generic inverse-variance with random-effects model and expressed as ratio-of-means with [95% CIs]. We included 103 trial comparisons (N = 538). OBG reduced glucose iAUC and iPeak by 23% (0.77 [0.74, 0.81]) and 28% (0.72 [0.64, 0.76]) and insulin by 22% (0.78 [0.72, 0.85]) and 24% (0.76 [0.65, 0.88]), respectively. Dose, molecular-weight, and comparator were significant effect modifiers of glucose iAUC and iPeak. Significant linear dose-response relationships were observed for all outcomes. OBG molecular-weight >300 kg/mol significantly reduced glucose iAUC and iPeak, whereas molecular-weight p = 0.03) and iPeak (39 vs 25%, p

OBJECTIVES: The efficacy of oat beta-glucan (OBG), a viscous soluble fibre, on postprandial glycemic outcomes may depend on the nature of the control and the dose and molecular weight (MW) utilized. We undertook a systematic review and meta-analysis of acute clinical trials to determine whether these features mediate the glycemic and insulinaemic responses to OBG. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched through October 27, 2020. We included acute, single-meal feeding, controlled trials investigating the effect of OBG (concentrate or oat bran) added to a carbohydrate-containing meal compared to a comparable meal (matched control) or a different carbohydrate-containing meal (unmatched control). Two reviewers extracted the data and assessed the risk of bias and certainty of evidence (GRADE). The primary outcome was incremental area under the curve (iAUC) for blood glucose. Data were pooled using the generic-inverse variance method with random effects model and expressed as ratio of means with [95% Cis]. RESULTS: One hundred and three trial comparisons (N = 538) were included. OBG reduced glucose iAUC and iPeak by 23% (0.77 [0.74, 0.81]) and 28% (0.72 [0.64, 0.76]) and insulin by 22% (0.78 [0.72, 0.85]) and 24% (0.76 [0.65, 0.88]), respectively. Dose, molecular-weight and comparator were significant effect modifiers of glucose iAUC and iPeak. Significant linear dose-response relationships were observed for all outcomes. OBG molecular-weight > 300 kg/mol significantly reduced glucose iAUC and iPeak, whereas, molecular-weight

Background: Intraoperative data may improve models predicting postoperative events. We evaluated the effect of incorporating intraoperative variables to the existing preoperative model on the predictive performance of the model for coronary artery bypass graft. Methods: We analyzed 378 572 isolated coronary artery bypass graft cases performed across 1083 centers, using the national Society of Thoracic Surgeons Adult Cardiac Surgery Database between 2014 and 2016. Outcomes were operative mortality, 5 postoperative complications, and composite representation of all events. We fitted models by logistic regression or extreme gradient boosting (XGBoost). For each modeling approach, we used preoperative only, intraoperative only, or pre+intraoperative variables. We developed 84 models with unique combinations of the 3 variable sets, 2 variable selection methods, 2 modeling approaches, and 7 outcomes. Each model was tested in 20 iterations of 70:30 stratified random splitting into development/testing samples. Model performances were evaluated on the testing dataset using the C statistic, area under the precision-recall curve, and calibration metrics, including the Brier score. Results: The mean patient age was 65.3 years, and 24.7% were women. Operative mortality, excluding intraoperative death, occurred in 1.9%. In all outcomes, models that considered pre+intraoperative variables demonstrated significantly improved Brier score and area under the precision-recall curve compared with models considering pre or intraoperative variables alone. XGBoost without external variable selection had the best C statistics, Brier score, and area under the precision-recall curve values in 4 of the 7 outcomes (mortality, renal failure, prolonged ventilation, and composite) compared with logistic regression models with or without variable selection. Based on the calibration plots, risk restratification for mortality showed that the logistic regression model underestimated the risk in 11 114 patients (9.8%) and overestimated in 12 005 patients (10.6%). In contrast, the XGBoost model underestimated the risk in 7218 patients (6.4%) and overestimated in 0 patients (0%). Conclusions: In isolated coronary artery bypass graft, adding intraoperative variables to preoperative variables resulted in improved predictions of all 7 outcomes. Risk models based on XGBoost may provide a better prediction of adverse events to guide clinical care.

Objectives: Tenofovir alafenamide (TAF) is a preferred nucleotide reverse transcriptase inhibitor used in the treatment of HIV. Co-administration of TAF with rifabutin (RFB) is not recommended due to concerns that RFB decreases TAF gastrointestinal absorption. The objective of this study was to determine the efficacy of antiretroviral therapy regimens that include the co-administration of TAF and RFB. Methods: Persons with HIV (PWH) who received TAF–RFB co-administration for ≥1 month were identified retrospectively. The primary outcome was the maintenance of HIV viral load

Asymmetric hybrid supercapacitors (AHSCs) combine high specific energy and power by merging two electrodes with capacitive and Faradaic charge storage mechanisms. In this study, we introduce AHSC cells that use lithium titanate and activated carbon electrodes in an alkali-ion containing ionic liquid electrolyte. With this cell concept, it is possible to operate the activated carbon electrode in a higher potential window. Consequently, higher cell voltages and a reduced carbon electrode mass can be used, resulting in significantly increased energy compared to aqueous or organic electrolytes. We demonstrate the feasibility of this cell concept for both lithium- and sodium-ion intercalation, underlining the general validity of our approach. Our prototype cells already reach high specific energies of 100 W h/kg, while maintaining a specific power of up to 2 kW/kg and cycling stability of over 1500 cycles. Owing to the IL electrolyte, stable cycling of an AHSC at 80 °C is demonstrated for the first time.

BackgroundClinical babesiosis is diagnosed, and parasite burden is determined, by microscopic inspection of a thick or thin Giemsa-stained peripheral blood smear. However, quantitative analysis by manual microscopy is subject to observer bias, slide distribution errors, statistical sampling error, recording errors, and is inherently burdensome from time management and workflow efficiency standpoints. As such, methods for the automated measurement of percent parasitemia in digital microscopic images of peripheral blood smears could improve clinical accuracy, relative to the predicate method.MethodsIndividual erythrocyte images (shape: 70×70×3) were manually labeled as “parasite” or “normal” and were used to train a model for binary image classification. The best model was then used to calculate percent parasitemia from a clinical validation dataset, and values were compared to a clinical reference value. Lastly, model interpretability was examined using an integrated gradient to identify pixels most likely to influence classification decisions.ResultsThe precision and recall of the model during development testing were 0.92 and 1.00, respectively. In clinical validation, the model returned increasing positive signal with increasing mean reference value. However, there were two highly erroneous false positive values returned by the model. Lastly, the model incorrectly assessed three cases well above the clinical threshold of 10%. The integrated gradient suggested potential sources of false positives including rouleaux formations, cell boundaries, and precipitate as deterministic factors in negative erythrocyte images.ConclusionsWhile the model demonstrated highly accurate single cell classification and correctly assessed most slides, several false positives were highly incorrect. This project highlights the need for integrated testing of ML-based models, even when models in the development phase perform well.

The gold standard for diagnosis of COVID-19 is detection of SARS-CoV-2 RNA by RT-PCR. However, the effect of systematic changes in specimen viral burden on the overall assay performance is not quantitatively described. We observed decreased viral burdens in our testing population as the pandemic progressed, with median sample Ct values increasing from 22.7 to 32.8 from weeks 14 and 20, respectively. We developed a method using computer simulations to quantify the implications of variable SARS-CoV-2 viral burden on observed assay performance. We found that overall decreasing viral burden can have profound effects on assay detection rates. When real-world Ct values were used as source data in a bootstrap resampling simulation, the sensitivity of the same hypothetical assay decreased from 97.59 (95% CI 97.3-97.9) in week 12, to 74.42 (95% CI 73.9-75) in week 20. Furthermore, simulated assays with a 3-fold or 10-fold reduced sensitivity would both appear to be >95% sensitive early in the pandemic, but sensitivity would fall to 85.55 (95% CI 84.9-86.2) and 74.38 (95% CI 73.6-75.1) later in the pandemic, respectively. Our modeling approach can be used to better quantitate the impact that specimen viral burden may have on the clinical application of tests and specimens.

Background Pseudohyponatremia describes an artifactual decrease in plasma sodium result in samples with high proteins and/or lipids when measured by an indirect ion-selective electrode (ISE) method. We suspected that Intralipid®-based lipemia cutoffs are inappropriate for detecting interfering lipids in human samples and a major contributing factor to the existence of pseudohyponatremia. Methods We evaluated 2 approaches to derive a lipemia cutoff for sodium, one in which patient plasma samples were pooled and spiked to simulate hyperlipidemia using Intralipid® (commonly used approach by in-vitro diagnostics manufacturers), and another in which endogenous hyperlipidemic samples (n = 31) were measured by methods not affected by hyperlipidemia (i.e., direct ISE and post-ultracentrifugation indirect ISE). Triglycerides, lipemic index (L-index) and indirect ISE sodium concentrations of samples were measured on Roche Cobas® 8000 and direct ISE on Radiometer® ABL835 Flex analyzers. Endogenous hyperlipidemic samples were also ultracentrifuged on Beckman Coulter® Airfuge to clear excess lipids and re-analyzed for sodium by indirect ISE. Results We discovered that Intralipid® is not an accurate emulation of the lipemic interference seen in pseudohyponatremia because it showed no effect up to the maximum level of lipemia tested (L-index = 2000). By contrast, endogenous hyperlipidemic samples demonstrated significant deviations in sodium concentration (≥4 mmol/l) when L-index approached or exceeded 700, and a strong positive correlation between L-index and the difference between the indirect and direct methods (i.e., extent of pseudohyponatremia). Conclusions Clinical laboratories should lower their tolerance for lipemia from the currently recommended L-index cutoff of 2000 on Roche Cobas 8000®. We recommend reflexing to direct ISE when L-index exceeds 700. Manufacturers and laboratories with other indirect ISE methods should evaluate the effect of lipid interference on their method using hyperlipidemic human samples not Intralipid®.

Background Modern artificial intelligence (AI) and machine learning (ML) methods are now capable of completing tasks with performance characteristics that are comparable to those of expert human operators. As a result, many areas throughout healthcare are incorporating these technologies, including in vitro diagnostics and, more broadly, laboratory medicine. However, there are limited literature reviews of the landscape, likely future, and challenges of the application of AI/ML in laboratory medicine. Content In this review, we begin with a brief introduction to AI and its subfield of ML. The ensuing sections describe ML systems that are currently in clinical laboratory practice or are being proposed for such use in recent literature, ML systems that use laboratory data outside the clinical laboratory, challenges to the adoption of ML, and future opportunities for ML in laboratory medicine. Summary AI and ML have and will continue to influence the practice and scope of laboratory medicine dramatically. This has been made possible by advancements in modern computing and the widespread digitization of health information. These technologies are being rapidly developed and described, but in comparison, their implementation thus far has been modest. To spur the implementation of reliable and sophisticated ML-based technologies, we need to establish best practices further and improve our information system and communication infrastructure. The participation of the clinical laboratory community is essential to ensure that laboratory data are sufficiently available and incorporated conscientiously into robust, safe, and clinically effective ML-supported clinical diagnostics.

We present observations of ASASSN-19dj, a nearby tidal disruption event (TDE) discovered in the post-starburst galaxy KUG 0810+227 by the All-Sky Automated Survey for Supernovae (ASAS-SN) at a distance of d $\simeq98$ Mpc. We observed ASASSN-19dj from $-$21 to 392 d relative to peak ultraviolet (UV)/optical emission using high-cadence, multiwavelength spectroscopy and photometry. From the ASAS-SN $g$-band data, we determine that the TDE began to brighten on 2019 February 6.8 and for the first 16 d the rise was consistent with a flux $\propto t^2$ power-law. ASASSN-19dj peaked in the UV/optical on 2019 March 6.5 (MJD = 58548.5) at a bolometric luminosity of $L = (6.2 \pm 0.2) \times 10^{44} \text{ erg s}^{-1}$. Initially remaining roughly constant in X-rays and slowly fading in the UV/optical, the X-ray flux increased by over an order of magnitude $\sim$225 d after peak, resulting from the expansion of the X-ray emitting region. The late-time X-ray emission is well fitted by a blackbody with an effective radius of $\sim1 \times 10^{12} \text{ cm}$ and a temperature of $\sim6 \times 10^{5} \text{ K}$. The X-ray hardness ratio becomes softer after brightening and then returns to a harder state as the X-rays fade. Analysis of Catalina Real-Time Transient Survey images reveals a nuclear outburst roughly 14.5 yr earlier with a smooth decline and a luminosity of $L_V\geq1.4 \times 10^{43}$ erg s$^{-1}$, although the nature of the flare is unknown. ASASSN-19dj occurred in the most extreme post-starburst galaxy yet to host a TDE, with Lick H$\delta_{A}$ = $7.67\pm0.17$ \AA., Comment: Updated to match accepted MNRAS version

The Centers for Disease Control (CDC) reported that in 2016, 42% of people living with diagnosed HIV were not retained in care (defined as ≥ 2 CD4 or viral load tests ≥ 3 months apart in 2016)3 . Estimates indicate that the 23% of PLWH who have a known HIV status (hereafter, known status) and are not in HIV care account for 43% of all HIV transmissions4 . Thus, retention in HIV care has become a national priority to fight the HIV epidemic.

HIV transmission is increased during acute and early HIV (AEH). Rapid antiretroviral therapy may shorten the duration of infectivity. We show rapid antiretroviral therapy in AEH is acceptable and effective, with 69.0% of participants starting ART within 7 days of HIV diagnosis disclosure, and 88.1% achieving suppression by 48 weeks.

Objective Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2. Design This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository. Setting Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas. Populations The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020. Main outcome and performance measures Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support. Results Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 2152 (99.9%) had a discharge disposition at the end of the study period. Of these, 329 (15.3%) required invasive mechanical ventilation and 305 (14.2%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 80.7 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14–1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50–2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups. Conclusions This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.

Background Coronavirus disease 2019 (COVID-19) was formally characterized as a pandemic on March 11, 2020. Since that time, the COVID-19 pandemic has led to unprecedented demand for healthcare resources. The purpose of this study was to identify changes in laboratory test utilization in the setting of increasing local incidence of COVID-19. Methods We performed a retrospective assessment of laboratory test order and specimen container utilization at a single, urban tertiary care medical center. Data were extracted from the laboratory information system database over a 10-week period, spanning the primordial inflection of COVID-19 incidence in our region. Total testing volumes were calculated during the first 2 and last 2 weeks of the observation period and used as reference points to examine the absolute and relative differences in test order volume between the prepandemic and COVID-19 surge periods. Results Between February 2, 2020, and April 11, 2020, there were 873 397 tests ordered and final verified. The in-house SARS-CoV-2 PCR positivity rate for admitted patients in the last week of the observation period was 30.8%. Significant increases in workload were observed in the send-out laboratory section and for COVID-19 diagnosis (PCR) and management-related testing. Otherwise, there was a net decrease in overall demand across nearly all laboratory sections. Increases in testing were noted for tests related to COVID-19 management. Viral transport media and citrated blue top containers demonstrated increases in utilization. Conclusion Increasing local incidence of COVID-19 had a profound impact on laboratory operations. While volume increases were seen for laboratory tests related to COVID-19 diagnostics and management, including some with limited evidence to support their use, overall testing volumes decreased substantially. During events such as COVID-19, monitoring of such patterns can help inform laboratory management, staffing, and test stewardship recommendations for managing resource and supply availability.

The ongoing coronavirus disease outbreak demonstrates the need for novel applications of real-time data to produce timely information about incident cases. Using health information technology (HIT) and real-world data, we sought to produce an interface that could, in near real time, identify patients presenting with suspected respiratory tract infection and enable monitoring of test results related to specific pathogens, including severe acute respiratory syndrome coronavirus 2. This tool was built upon our computational health platform, which provides access to near real-time data from disparate HIT sources across our health system. This combination of technology allowed us to rapidly prototype, iterate, and deploy a platform to support a cohesive organizational response to a rapidly evolving outbreak. Platforms that allow for agile analytics are needed to keep pace with evolving needs within the health care system.

Background Antibacterial agents are often prescribed for patients with suspected respiratory tract infections even though these are most often caused by viruses. In this study, we sought to evaluate the effect of Respiratory Pathogen Panel (RPP) PCR result availability and antimicrobial stewardship education on antibiotic prescription rates in the adult emergency department (ED). Methods We compared rates of antibacterial and oseltamivir prescriptions between 2 nonconsecutive influenza seasons among ED visits, wherein the latter season followed the implementation of a comprehensive educational stewardship campaign. In addition, we sought to elucidate the effect of RPP-PCR on antibiotic prescriptions, with focus on result availability prior to the conclusion of emergency department encounters. Results Antibiotic prescription rates globally decreased by 17.9% in the FS-17/18 cohort compared to FS-14/15 (P Conclusion This study provides evidence that RPP-PCR results are most helpful if available prior to the end of the provider-patient interaction. Further, these data suggest that detection of influenza remains an influential result in the context of antimicrobial treatment decision making. In addition, these data contribute to the body of literature which supports comprehensive ASP interventions including leadership and patient engagement.

Hepatitis C virus reinfection rates among men who have sex with men are high. Factors associated with infection point to varied sexual and drug-related risks that could be targeted for interventions to prevent infection/reinfection. Modeling indicates that tackling increasing incidence and high reinfection rates requires high levels of hepatitis C virus treatment combined with behavioral interventions. Enhanced testing strategies and prompt retreating of reinfection may be required to promptly diagnosed reinfections. Behavioral interventions studies addressing reinfection are required. Other interventions include traditional harm reduction interventions, adapted behavioral interventions, and interventions to prevent harms related to ChemSex and other risk factors.

Fibrin is a plasma protein with a central role in blood clotting and wound repair.Upon vascular injury, fibrin forms resilient fibrillar networks (clots) via a multi-step self assembly process, from monomers, to double-stranded protofibrils, to a branched network of thick fibers. In vitro, fibrin self-assembly is sensitive to physicochemical conditions like the solution pH and ionic strength, which tune the strength of the non-covalent driving forces. Here we report a surprising finding that the buffer—which is necessary to control the pH and is typically considered to be inert—also significantly influences fibrin self-assembly. We show by confocal microscopy and quantitative light-scattering that various common buffering agents have no effect on the initial assembly of fibrin monomers into protofibrils but strongly hamper the subsequent lateral association of protofibrils into thicker fibers. At 3 mg/ml fibrin, the averagenumber of protofibrils per fiber drops nearly 10-fold, from 180 in the presence of 20 mM HEPES to only 20 in the presence of 200 mM HEPES. By using different enzymes to initiate fibrin self assembly, we reveal that the mechanism of buffer-induced changes in fibrin assembly involves weakening of the interactions between the so-called αC-region, which are long flexible appendages on fibrin that couple adjacent protofibrils. We further find that the structural changes are independent of the molecular structure of the buffering agents and even occur in fibrin networks formed from platelet-poor plasma, suggesting that buffers act by changing the hydrogen bonding network structure of the hydration layer surrounding fibrin. This buffer mediated decrease in protofibril bundling results in a marked reduction in the permeability of fibrin networks. Yet, the buffers only weakly influence the elastic modulus of fibrin networksbecause the effect of higher fiber density is cancelled out by the effect of the smaller stiffness of thinner fibers. Buffers can therefore be used as a tuning parameter to independently control the elastic properties and the permeability of fibrin networks, which is useful in studies of cell adhesion and migration. Our work raises the possibility that fibrin assembly in vivo may be regulated by variations in the acute-phase levels of bicarbonate and phosphate, which act as physiological buffering agents of blood pH. Moreover, our findings add a striking new example of buffer-induced effects on biomolecular self-assembly to recent findings for a range of proteins and lipids.

On the evening of June 23, 2016, a white powder advertised as cocaine was purchased off the streets from multiple sources and used by an unknown number of persons in New Haven, Connecticut. During a period of less than 8 hours, 12 patients were brought to the emergency department (ED) at Yale New Haven Hospital, experiencing signs and symptoms consistent with opioid overdose. The route of intoxication was not known, but presumed to be insufflation ("snorting") in most cases. Some patients required doses of the opioid antidote naloxone exceeding 4 mg (usual initial dose = 0.1-0.2 mg intravenously), and several patients who were alert after receiving naloxone subsequently developed respiratory failure. Nine patients were admitted to the hospital, including four to the intensive care unit (ICU); three required endotracheal intubation, and one required continuous naloxone infusion. Three patients died. The white powder was determined to be fentanyl, a drug 50 times more potent than heroin, and it included trace amounts of cocaine. The episode triggered rapid notification of public health and law enforcement agencies, interviews of patients and their family members to trace and limit further use or distribution of the fentanyl, immediate naloxone resupply and augmentation for emergency medical services (EMS) crews, public health alerts, and plans to accelerate naloxone distribution to opioid users and their friends and families. Effective communication and timely, coordinated, collaborative actions of community partners reduced the harm caused by this event and prevented potential subsequent episodes.

The use of some nucleic acid amplification tests (NAATs) for the diagnosis of group A Streptococcus (GAS) pharyngitis allows laboratories to adopt single-tiered testing without reflex culture. However, centralization may delay the delivery of actionable information to the bedside, particularly in the outpatient setting. We describe two novel workflows at our institution and their effect on in-lab turnaround time (TAT) at a tertiary care microbiology lab. Laboratory records were extracted, and relevant data were analyzed after the implementation of qualitative in vitro diagnostic testing for GAS with the Xpert Xpress Strep A assay, performed using the GeneXpert Infinity-48s. Workflow optimization steps studied included: (i) direct specimen submission to the microbiology laboratory via the pneumatic tube system and (ii) autoverification of GAS NAAT results in the laboratory information system. Between April 2018 and October 2018, 2,595 unique specimens were tested for GAS by PCR. Of these, 2,523 were included in the final analysis. Linear regression established that the total in-lab TAT was significantly reduced by direct specimen submission to the microbiology laboratory, autoverification, and processing during the night shift. We describe two workflow optimization methods that reduced the in-lab TAT for GAS NAAT. Although microbiology labs historically use manual processes, the advent of total laboratory automation and the adoption of on-demand NAATs will allow for more streamlined processing of microbiology specimens. It may be beneficial to consider instrument interfacing and specimen processing optimization during the early phases of implementation planning for NAATs in the microbiology laboratory.

Encephalopathy complicates beta-lactam therapy, particularly with impaired renal function, though no studies have reported ceftaroline-associated encephalopathy. Among 28 patients with estimated glomerular filtration rates

Author(s): Chaillon, Antoine; Sun, Xiaoying; Cachay, Edward R; Looney, David; Wyles, David; Garfein, Richard S; Martin, Thomas CS; Jain, Sonia; Mehta, Sanjay R; Smith, Davey M; Little, Susan J; Martin, Natasha K | Abstract: BackgroundLittle is known about the hepatitis C virus (HCV) epidemic among HIV-infected men who have sex with men (HIV+ MSM) in the United States. In this study, we aimed to determine the incidence of primary HCV infection among HIV+ MSM in San Diego, California.MethodsWe performed a retrospective cohort analysis of HCV infection among HIV+ MSM attending 2 of the largest HIV clinics in San Diego. Incident HCV infection was assessed among HIV+ MSM with a negative anti-HCV test and subsequent HCV test between 2000 and 2017, with data censored to 2015. HCV reinfection was assessed among HIV+ MSM successfully treated for HCV between 2008 and 2015. Infection/reinfection rates were calculated using person-time methods.ResultsAmong 3068 initially HCV-seronegative HIV+ MSM, 178 new infections occurred over 15 796 person-years, giving an incidence of 1.13 per 100 person-years (/100py; 95% confidence interval [CI], 0.97-1.31). Incidence was stable from 2000 to 2014 (0.83/100py; 95% CI, 0.41-1.48), with an increase to 3.01/100py (95% CI, 1.97-4.42) in 2015 (P = .02). Among 43 successfully treated patients, 3 were reinfected.ConclusionsHCV incidence is high among HIV+ MSM in San Diego, with evidence suggesting a recent increase in 2015. Strong HCV testing guidelines and active prevention efforts among HIV+ MSM are urgently needed that include rapid diagnosis, treatment, and risk reduction.

Supernova (SN) 2018oh (ASASSN-18bt) is the first spectroscopically-confirmed type Ia supernova (SN Ia) observed in the $Kepler$ field. The $Kepler$ data revealed an excess emission in its early light curve, allowing to place interesting constraints on its progenitor system (Dimitriadis et al. 2018, Shappee et al. 2018b). Here, we present extensive optical, ultraviolet, and near-infrared photometry, as well as dense sampling of optical spectra, for this object. SN 2018oh is relatively normal in its photometric evolution, with a rise time of 18.3$\pm$0.3 days and $\Delta$m$_{15}(B)=0.96\pm$0.03 mag, but it seems to have bluer $B - V$ colors. We construct the "uvoir" bolometric light curve having peak luminosity as 1.49$\times$10$^{43}$erg s$^{-1}$, from which we derive a nickel mass as 0.55$\pm$0.04M$_{\odot}$ by fitting radiation diffusion models powered by centrally located $^{56}$Ni. Note that the moment when nickel-powered luminosity starts to emerge is +3.85 days after the first light in the Kepler data, suggesting other origins of the early-time emission, e.g., mixing of $^{56}$Ni to outer layers of the ejecta or interaction between the ejecta and nearby circumstellar material or a non-degenerate companion star. The spectral evolution of SN 2018oh is similar to that of a normal SN Ia, but is characterized by prominent and persistent carbon absorption features. The C II features can be detected from the early phases to about 3 weeks after the maximum light, representing the latest detection of carbon ever recorded in a SN Ia. This indicates that a considerable amount of unburned carbon exists in the ejecta of SN 2018oh and may mix into deeper layers., Comment: 48 pages, 23 figures. This paper is part of a coordinated effort between groups. Accepted for publication in ApJ

Polymers of various architectures with zwitterionic functionality have recently been shown to effectively suppress nonspecific fouling of surfaces by proteins and prokaryotic (bacteria) or eukaryotic (mammalian) cells as well as other microorganisms and environmental contaminants. In this work, zwitterionic copolymers were used to make thin coatings on substrates with the layer-by-layer method. Polyelectrolyte multilayers, PEMUs, were built with [poly(allylamine hydrochloride)], PAH, and copolymers of acrylic acid and either the AEDAPS zwitterionic group 3-[2-(acrylamido)-ethyldimethyl ammonio] propane sulfonate (PAA-co-AEDAPS), or benzophenone (PAABp). Benzophenone allowed the PEMU to be toughened by photocrosslinking post-deposition. The attachment of two mammalian cell lines, rat aortic smooth muscle (A7r5) and mouse fibroblasts (3T3), and the biofilm-forming Gram-negative bacteria Escherichia coli was studied on PEMUs terminated with PAA-co-AEDAPS. Consistent with earlier studies, it is shown that PAH/PAA-co-AEDAPS PEMUs resist the adhesion of mammalian cells, but, contrary to our initial hypothesis, are bacterial adhesive and significantly so after maximizing the surface presentation of PAA-co-AEDAPS. This unexpected contrast in the adhesive behavior of prokaryotic and eukaryotic cells is explained by differences in adhesion mechanisms as well as different responses to the topology and morphology of the multilayer surface.

Background There are as many as 300,000 visits to the emergency department in the USA with animal bites every year. The most common infection after cat or dog bite is with Pasteurella Multocida. Many people infected will also have long-term central venous access for dialysis or for other reasons. No prior reports or guidelines exist regarding the management of P. multocida bacteremia due to line infection or bacteremia in the presence of long-term central venous access. We describe the successful treatment of an individual with P. multocida bacteremia secondary to tunnelled line infection managed with line retention. Case presentation A 21 year-old man with a history of granulomatosis with polyangiitis on home hemodialysis presented with fever and hypotension 3 days after dialysis catheter replacement. The patient was found to be bacteremic with Pasteurella Multocida and he subsequently reported a history of cat bite to his dialysis catheter. He declined removal of the tunnelled catheter and was thereafter treated for a total of 2 weeks with intravenous ceftazidime post-dialysis and gentamicin line-locks without recurrence of infection. Conclusions Pasteurella Multocida bacteremia in the presence of a long-term central venous catheter is potentially curable using 2 weeks of intravenous antibiotics and line retention. Further data regarding outcomes of treatment in this setting are required though in select cases clinicians faced with a similar scenario could opt for trial of intravenous therapy and retention of central venous catheter.

Plasmodium vivax remains an important cause of morbidity and mortality across the Americas, Horn of Africa, East and South East Asia. Control of transmission has been hampered by emergence of chloroquine resistance and several intrinsic characteristics of infection including asymptomatic carriage, challenges with diagnosis, difficulty eradicating the carrier state and early gametocyte appearance. Complex human-parasite-vector immunological interactions may facilitate onward infection of mosquitoes. Given these challenges, new therapies are being explored including the development of transmission to mosquito blocking vaccines. Herein, the case supporting the need for transmission-blocking vaccines to augment control of P. vivax parasite transmission and explore factors that are limiting eradication efforts is discussed.

Despite variability in disease surveillance statistics, malaria is widely considered a global public health concern because it causes high rates of morbidity and death, particularly in populations from developing or low- to middle-income countries. In recent years, substantial effort has been made through international collaborations to reduce the global burden and ultimately eradicate the presence of malaria. Optimization of diagnostic assays for malaria remains central to this effort and may help address the need for improved epidemiologic surveillance, population-based screening, and targeted antimalarial treatment campaigns. A recent article published in Science Translational Medicine (1) describes a novel biomarker present in human saliva that detects Plasmodium falciparum gametocytes. The authors report on the discovery of 35 parasite biomarkers by leveraging mass spectrometry and proteomic profiling. Following …

Aim To identify whether patients with congestive cardiac failure have a higher prevalence of inaccurately documented medications on general practice referral letters to emergency departments than other polypharmacy patients. Method A prospective case-control study was undertaken in two urban emergency departments. Patients with a general practitioner referral letter and a history of congestive cardiac failure were recruited as the study group, while patients with a general practitioner referral letter and a history of polypharmacy were recruited as controls. Medications on the referral letter were compared with those dispensed by the patient's usual pharmacist (gold standard) and emergency clinician documentation. Discrepancies were analysed by number, type and potential severity. Results A total of 205 patients were recruited: 69 patients with heart failure in the study group and 136 patients in the control group. The proportion of letters with at least one discrepancy was high in both groups (91 vs 88%, p = 0.57). On average, heart failure patients had more discrepancies per letter (4.8 vs 3.8, p = 0.05). The most common discrepancy in all groups was over-inclusion of medications (68% heart failure and 64% control). Heart failure patients had more discrepancies judged likely to be harmful (24 vs 14%, p < 0.001). Discussion The prevalence of medication discrepancies in referral letters to the emergency department is very high. The overall prevalence of a discrepancy was not higher in heart failure patients compared with other polypharmacy patients, but there were more discrepancies per letter and these discrepancies were potentially more serious. Extra vigilance is required when reconciling medications for patients with heart failure because of higher numbers and greater potential severity of medication discrepancies.

BACKGROUND Morphologic profiling of the erythrocyte population is a widely used and clinically valuable diagnostic modality, but one that relies on a slow manual process associated with significant labor cost and limited reproducibility. Automated profiling of erythrocytes from digital images by capable machine learning approaches would augment the throughput and value of morphologic analysis. To this end, we sought to evaluate the performance of leading implementation strategies for convolutional neural networks (CNNs) when applied to classification of erythrocytes based on morphology. METHODS Erythrocytes were manually classified into 1 of 10 classes using a custom-developed Web application. Using recent literature to guide architectural considerations for neural network design, we implemented a “very deep” CNN, consisting of >150 layers, with dense shortcut connections. RESULTS The final database comprised 3737 labeled cells. Ensemble model predictions on unseen data demonstrated a harmonic mean of recall and precision metrics of 92.70% and 89.39%, respectively. Of the 748 cells in the test set, 23 misclassification errors were made, with a correct classification frequency of 90.60%, represented as a harmonic mean across the 10 morphologic classes. CONCLUSIONS These findings indicate that erythrocyte morphology profiles could be measured with a high degree of accuracy with “very deep” CNNs. Further, these data support future efforts to expand classes and optimize practical performance in a clinical environment as a prelude to full implementation as a clinical tool.

Summary Immunomodulatory drugs including thalidomide, lenalidomide (LEN) and pomalidomide (POM), are effective for treating multiple myeloma (MM). POM has shown enhanced efficacy with dexamethasone (DEX). Pegylated liposomal doxorubicin (PLD) with bortezomib is US Food and Drug Administration-approved for treating MM. PLD with LEN or thalidomide has shown efficacy for MM patients. LEN with DEX, PLD and bortezomib achieves high response rates. We evaluated the combination of POM with DEX 40 mg and PLD 5 mg/m2 with the latter two drugs administered on days 1, 4, 8 and 11 on a 28-day cycle for the treatment of relapsed/refractory MM patients. During Phase 1, the maximum tolerated dose of POM was 4 mg, and was used in Phase 2, which also required patients to be refractory to LEN. However, neutropenia ≥ grade 3 was observed in 10/17 (59%) patients, and the dose was lowered to 3 mg. Median PFS was 5·4 months (range, 0·3–29·0 + months). Overall response rates for patients in Phase 2 were 39% and 31% among subjects receiving POM at 3 mg and 4 mg, respectively, and clinical benefit rates were 51% and 44%, respectively. POM, PLD and DEX is a treatment option for relapsed/refractory MM patients including those who are refractory to LEN.

Background & Aims Moderate cure rates of acute hepatitis C virus (HCV) infections with pegylated interferon and ribavirin have been described in the last decade in men who have sex with men (MSM), who are also coinfected with the human immunodeficiency virus (HIV). However, a subsequent high incidence of HCV reinfections has been reported regionally in men who both clear the infection spontaneously or who respond to treatment. Methods Retrospective analysis of reinfections in HIV infected MSM in eight centers from Austria, France, Germany, and the UK within the NEAT network between May 2002 and June 2014. Results Of 606 individuals who cleared HCV spontaneously or were successfully treated, 149 (24.6%) presented with a subsequent HCV reinfection. Thirty out of 70 (43%) who cleared again or were successfully treated, presented with a second reinfection, 5 with a third, and one with a fourth reinfection. The reinfection incidence was 7.3/100 person-years (95% CI 6.2–8.6). We found a trend for lower incidence among individuals who had spontaneously cleared their incident infection than among individuals who were treated (Hazard ratio 0.62, 95% CI 0.38–1.02, p =0.06). Spontaneous clearance of reinfection was associated with ALT levels >1000IU/ml and spontaneous clearance of a prior infection. Conclusions HCV reinfection is an issue of major concern in HIV-positive MSM. Prevention strategies are needed for high risk groups to reduce morbidity and treatment costs. HIV-positive MSM with a prior HCV infection should be tested every 3 to 6months for reinfection. Those who had achieved a reinfection should be tested every 3months. Lay summary We evaluated the occurrence of HCV reinfection in HIV-positive men who have sex with men. We found an alarming incidence of 7.3/100 person-years. Prevention measures need to address this specific subgroup of patients at high risk for HCV.

For patients who are not suitable candidates for autologous breast reconstruction, the traditional approach has been a staged procedure, by first expanding the skin and chest wall musculature over a period of weeks and then exchanging the expander for a fixed volume implant. While this was conventionally a delayed procedure to be carried out once adjuvant treatments were completed, it is now routinely used in the immediate setting [1].

We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multi-wavelength reverberation mapping campaign. The campaign spanned six months and achieved an almost daily cadence with observations from five ground-based telescopes. The H$\beta$ and He II $\lambda$4686 broad emission-line light curves lag that of the 5100 $\AA$ optical continuum by $4.17^{+0.36}_{-0.36}$ days and $0.79^{+0.35}_{-0.34}$ days, respectively. The H$\beta$ lag relative to the 1158 $\AA$ ultraviolet continuum light curve measured by the Hubble Space Telescope is roughly $\sim$50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is $\sim$50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for H$\beta$ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the H$\beta$ and He II $\lambda$4686 emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C IV, Ly $\alpha$, He II(+O III]), and Si IV(+O IV]) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured H$\beta$ lag is a factor of five shorter than the expected value implied by the $R_\mathrm{BLR} - L_\mathrm{AGN}$ relation based on the past behavior of NGC 5548., Comment: 22 pages, 13 figures, accepted to ApJ

Microenvironment extracellular matrices (ECMs) influence cell adhesion, proliferation and differentiation. The ECMs of different microenvironments have distinctive compositions and architectures. This investigation addresses effects ECMs deposited by a variety of cell types and decellularized with a cold-EDTA protocol have on multipotent human mesenchymal stromal/stem cell (hMSC) behavior and differentiation. The cold-EDTA protocol removes intact cells from ECM, with minimal ECM damage and contamination. The decellularized ECMs deposited by cultured hMSCs, osteogenic hMSCs, and two smooth muscle cell (SMC) lines were tested for distinctive effects on the behavior and differentiation of early passage (‘naive’) hMSC plated and cultured on the decellularized ECMs. Uninduced hMSC decellularized ECM enhanced naive hMSC proliferation and cell motility while maintaining stemness. Decellularized ECM deposited by osteogenic hMSCs early in the differentiation process stimulated naive hMSCs osteogenesis and substrate biomineralization in the absence of added dexamethasone, but this osteogenic induction potential was lower in ECMs decellularized later in the osteogenic hMSC differentiation process. Decellularized ECMs deposited by two smooth muscle cell lines induced naive hMSCs to become smooth muscle cell-like with distinctive phenotypic characteristics of contractile and synthetic smooth muscle cells. This investigation demonstrates a useful approach for obtaining functional cell-deposited ECM and highlights the importance of ECM specificity in influencing stem cell behavior.

We study the sudden optical and ultraviolet (UV) brightening of 1ES 1927+654, which until now was known as a narrow-line active galactic nucleus (AGN). 1ES 1927+654 was part of the small and peculiar class of "true Type-2" AGN, which lack broad emission lines and line-of-sight obscuration. Our high-cadence spectroscopic monitoring captures the appearance of a blue, featureless continuum, followed several weeks later by the appearance of broad Balmer emission lines. This timescale is generally consistent with the expected light travel time between the central engine and the broad-line emission region in (persistent) broad-line AGN. Hubble Space Telescope spectroscopy reveals no evidence for broad UV emission lines (e.g., CIV1549, CIII]1909, MgII2798), probably owing to dust in the broad-line emission region. To the best of our knowledge, this is the first case where the lag between the change in continuum and in broad-line emission of a "changing-look" AGN has been temporally resolved. The nature and timescales of the photometric and spectral evolution disfavor both a change in line-of-sight obscuration and a change of the overall rate of gas inflow as driving the drastic spectral transformations seen in this AGN. Although the peak luminosity and timescales are consistent with those of tidal disruption events seen in inactive galaxies, the spectral properties are not. The X-ray emission displays a markedly different behavior, with frequent flares on timescales of hours to days, and will be presented in a companion publication., accepted for publication in ApJ

Background: circulating measures of inflammatory markers, such as C-reactive protein (CRP) have been associated with an increased risk of future cognitive decline. However, the nature of the relationship among the very old (>75 years) is unclear. Cross-sectional evidence suggests that elevated CRP may even be protective in this age group. This study examines these associations longitudinally. Methods: logistic regression was used to investigate the association between CRP and drop in cognitive performance (≥3 point change on the Mini-Mental State Examination) over a 4-year period in a population of 266 people, mean age 77 years. Results: increased levels of CRP were associated with a decreased risk of a drop in cognitive performance; however, this association was only seen in those without an APOE e4 allele [odds ratio of decline per unit increase in ln(CRP) 0.57, P = 0.04]. The magnitude of the finding remained consistent after adjustment for cardiovascular confounders (smoking, drinking, MI, stroke, diabetes, education, medication and blood pressure). For those with an e4 allele, the relationship with longitudinal cognitive decline was neither statistically significant nor in a consistent direction after controlling for acute inflammation. Conclusions: this study strengthens previous cross-sectional findings and shows elevated levels of CRP to be linked to a decreased risk of longitudinal cognitive decline in the very old. However, as with prior analyses, this was only observed in those not carrying an APOE e4 allele. Future work on larger APOE e4 allele carrying samples is required to determine the nature of the association in this population.