Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease for which few treatment options are available. While most HS is sporadic, some rare kindred show a high-penetrance, autosomal-dominant inheritance. We wanted to identify rare variants that could contribute to HS risk in sporadic cases using candidate gene sequencing. We ultimately identified 21 genes for our capture panel. We included genes of the γ-secretase complex (n = 6) because rare variants in these genes sometimes cause familial HS. We added Notch receptor and ligand genes (n = 13) because γ-secretase is critical for processing Notch receptor signaling. Clinically, some people with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, a rare inflammatory disease, have concurrent HS. Rare variants in PSTPIP1 are known to cause PAPA syndrome, so we included PSTPIP1 and PSTPIP2 in the capture panel. We screened 117 individuals with HS for rare variations and calculated the expected burden using Genome Aggregation Database (gnomAD) allele frequencies. We discovered two pathogenic loss-of-function variants in NCSTN. This class of NCSTN variant can cause familial HS. There was no increased burden of rare variations in any γ-secretase complex gene. We did find that individuals with HS had a significantly increased number of rare missense variants in the SH3 domain of PSTPIP1. This finding, therefore, implicates PSTPIP1 variation in sporadic HS and further supports dysregulated immunity in HS. Our data also suggests that population-scale HS genetic research will yield valuable insights into disease pathology.

Dynamic correlations in lipid bilayer membranes over finite time intervals.

Recent single-molecule measurements [Schoch et al., Proc. Natl. Acad. Sci. U. S. A. 118, e2113202118 (2021)] have observed dynamic lipid-lipid correlations in membranes with submicrometer spatial resolution and submillisecond temporal resolution. While short from an instrumentation standpoint, these length and time scales remain long compared to microscopic molecular motions. Theoretical expressions are derived to infer experimentally measurable correlations from the two-body diffusion matrix appropriate for membrane-bound bodies coupled by hydrodynamic interactions. The temporal (and associated spatial) averaging resulting from finite acquisition times has the effect of washing out correlations as compared to naive predictions (i.e., the bare elements of the diffusion matrix), which would be expected to hold for instantaneous measurements. The theoretical predictions are shown to be in excellent agreement with Brownian dynamics simulations of experimental measurements. Numerical results suggest that the experimental measurement of membrane protein diffusion, in complement to lipid diffusion measurements, might help to resolve the experimental ambiguities encountered for certain black lipid membranes.

Preoperative Assessment of Anxiety and Depression Using Computerized Adaptive Screening Tools: A Pilot Prospective Cohort Study.

BACKGROUND: Serious mental health conditions (eg, anxiety and depression) are common in surgical patients, yet likely underassessed due to the time-consuming and cumbersome traditional screening process. A recently developed computerized adaptive mental health assessment tool (computerized adaptive test-mental health [CAT-MH]) allows rapid, precise, and accurate assessment of numerous mental health disorders, including anxiety and depression, without the need for a trained interviewer. The goal of this investigation was to determine the feasibility of administering CAT-MH for anxiety and depression in the preoperative setting and to obtain preliminary evidence of the prevalence of anxiety and depression in preoperative patients. METHODS: In this prospective cohort study, 100 adult patients scheduled for elective surgery were enrolled and asked to complete the CAT-MH in the preoperative clinic. Urgent and emergency surgeries were excluded as were pregnant patients. Primary feasibility outcomes were completion rate and time to completion. Secondary outcomes were prevalence estimates of anxiety and depression. RESULTS: All 100 enrolled patients completed the study. All patients were able to complete the mental health assessment (mean time: 3.6 ± 1.8 minutes standard deviation). Sixteen patients (16%) screened positive for anxiety (severity: mild, n = 7 [7%]; moderate, n = 7 [7%]); severe, n = 2 [2%]); 12 of 16 (75%) did not have a previous diagnosis of anxiety disorder. Twenty-eight (28%) patients screened positive for depression (severity: mild, n = 26 [26%]; moderate and severe, n = 1 each [1%]); 23 of 28 (82%) had no previous diagnosis of depressive disorder. Nineteen patients (19%) met the screening criteria for major depressive disorder; 14 of 19 (74%) of which had no previous diagnosis of major depressive disorder. CONCLUSIONS: The results of this pilot study support the feasibility of using CAT-MH in a preoperative evaluation and indicate that there is a substantial prevalence of undiagnosed anxiety and depression in surgical patients.

Correlated diffusion in lipid bilayers.

Lipid membranes are complex quasi-two-dimensional fluids, whose importance in biology and unique physical/materials properties have made them a major target for biophysical research. Recent single-molecule tracking experiments in membranes have caused some controversy, calling the venerable Saffman-Delbrück model into question and suggesting that, perhaps, current understanding of membrane hydrodynamics is imperfect. However, single-molecule tracking is not well suited to resolving the details of hydrodynamic flows; observations involving correlations between multiple molecules are superior for this purpose. Here dual-color molecular tracking with submillisecond time resolution and submicron spatial resolution is employed to reveal correlations in the Brownian motion of pairs of fluorescently labeled lipids in membranes. These correlations extend hundreds of nanometers in freely floating bilayers (black lipid membranes) but are severely suppressed in supported lipid bilayers. The measurements are consistent with hydrodynamic predictions based on an extended Saffman-Delbrück theory that explicitly accounts for the two-leaflet bilayer structure of lipid membranes.

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression.

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were -0.75 points on the HDRS-21 at 2 hours (P = 0.73), -1.41 points at 24 hours (P = 0.52), -4.35 points at week 1 (P = 0.05), and -5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were -0.87 points at 2 hours (P = 0.69), -1.93 points at 24 hours (P = 0.37), -2.44 points at week 1 (P = 0.25), and -7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

Characteristics and Risk Factors of Hospitalized and Nonhospitalized COVID-19 Patients, Atlanta, Georgia, USA, March-April 2020.

We compared the characteristics of hospitalized and nonhospitalized patients who had coronavirus disease in Atlanta, Georgia, USA. We found that risk for hospitalization increased with a patient's age and number of concurrent conditions. We also found a potential association between hospitalization and high hemoglobin A1c levels in persons with diabetes.

COVID-19 Clinical Phenotypes: Presentation and Temporal Progression of Disease in a Cohort of Hospitalized Adults in Georgia, United States.

BACKGROUND: The epidemiological features and outcomes of hospitalized adults with coronavirus disease 2019 (COVID-19) have been described; however, the temporal progression and medical complications of disease among hospitalized patients require further study. Detailed descriptions of the natural history of COVID-19 among hospitalized patients are paramount to optimize health care resource utilization, and the detection of different clinical phenotypes may allow tailored clinical management strategies. METHODS: This was a retrospective cohort study of 305 adult patients hospitalized with COVID-19 in 8 academic and community hospitals. Patient characteristics included demographics, comorbidities, medication use, medical complications, intensive care utilization, and longitudinal vital sign and laboratory test values. We examined laboratory and vital sign trends by mortality status and length of stay. To identify clinical phenotypes, we calculated Gower's dissimilarity matrix between each patient's clinical characteristics and clustered similar patients using the partitioning around medoids algorithm. RESULTS: One phenotype of 6 identified was characterized by high mortality (49%), older age, male sex, elevated inflammatory markers, high prevalence of cardiovascular disease, and shock. Patients with this severe phenotype had significantly elevated peak C-reactive protein creatinine, D-dimer, and white blood cell count and lower minimum lymphocyte count compared with other phenotypes (P < .01, all comparisons). CONCLUSIONS: Among a cohort of hospitalized adults, we identified a severe phenotype of COVID-19 based on the characteristics of its clinical course and poor prognosis. These findings need to be validated in other cohorts, as improved understanding of clinical phenotypes and risk factors for their development could help inform prognosis and tailored clinical management for COVID-19.

Predictors at Admission of Mechanical Ventilation and Death in an Observational Cohort of Adults Hospitalized With Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease (COVID-19) can cause severe illness and death. Predictors of poor outcome collected on hospital admission may inform clinical and public health decisions. METHODS: We conducted a retrospective observational cohort investigation of 297 adults admitted to 8 academic and community hospitals in Georgia, United States, during March 2020. Using standardized medical record abstraction, we collected data on predictors including admission demographics, underlying medical conditions, outpatient antihypertensive medications, recorded symptoms, vital signs, radiographic findings, and laboratory values. We used random forest models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for predictors of invasive mechanical ventilation (IMV) and death. RESULTS: Compared with age <45 years, ages 65-74 years and ≥75 years were predictors of IMV (aORs, 3.12 [95% CI, 1.47-6.60] and 2.79 [95% CI, 1.23-6.33], respectively) and the strongest predictors for death (aORs, 12.92 [95% CI, 3.26-51.25] and 18.06 [95% CI, 4.43-73.63], respectively). Comorbidities associated with death (aORs, 2.4-3.8; P < .05) included end-stage renal disease, coronary artery disease, and neurologic disorders, but not pulmonary disease, immunocompromise, or hypertension. Prehospital use vs nonuse of angiotensin receptor blockers (aOR, 2.02 [95% CI, 1.03-3.96]) and dihydropyridine calcium channel blockers (aOR, 1.91 [95% CI, 1.03-3.55]) were associated with death. CONCLUSIONS: After adjustment for patient and clinical characteristics, older age was the strongest predictor of death, exceeding comorbidities, abnormal vital signs, and laboratory test abnormalities. That coronary artery disease, but not chronic lung disease, was associated with death among hospitalized patients warrants further investigation, as do associations between certain antihypertensive medications and death.

Characteristics Associated with Hospitalization Among Patients with COVID-19 - Metropolitan Atlanta, Georgia, March-April 2020.

The first reported U.S. case of coronavirus disease 2019 (COVID-19) was detected in January 2020 (1). As of June 15, 2020, approximately 2 million cases and 115,000 COVID-19-associated deaths have been reported in the United States.* Reports of U.S. patients hospitalized with SARS-CoV-2 infection (the virus that causes COVID-19) describe high proportions of older, male, and black persons (2-4). Similarly, when comparing hospitalized patients with catchment area populations or nonhospitalized COVID-19 patients, high proportions have underlying conditions, including diabetes mellitus, hypertension, obesity, cardiovascular disease, chronic kidney disease, or chronic respiratory disease (3,4). For this report, data were abstracted from the medical records of 220 hospitalized and 311 nonhospitalized patients aged ≥18 years with laboratory-confirmed COVID-19 from six acute care hospitals and associated outpatient clinics in metropolitan Atlanta, Georgia. Multivariable analyses were performed to identify patient characteristics associated with hospitalization. The following characteristics were independently associated with hospitalization: age ≥65 years (adjusted odds ratio [aOR] = 3.4), black race (aOR = 3.2), having diabetes mellitus (aOR = 3.1), lack of insurance (aOR = 2.8), male sex (aOR = 2.4), smoking (aOR = 2.3), and obesity (aOR = 1.9). Infection with SARS-CoV-2 can lead to severe outcomes, including death, and measures to protect persons from infection, such as staying at home, social distancing (5), and awareness and management of underlying conditions should be emphasized for those at highest risk for hospitalization with COVID-19. Measures that prevent the spread of infection to others, such as wearing cloth face coverings (6), should be used whenever possible to protect groups at high risk. Potential barriers to the ability to adhere to these measures need to be addressed.

Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020.

SARS-CoV-2, the novel coronavirus that causes coronavirus disease 2019 (COVID-19), was first detected in the United States during January 2020 (1). Since then, >980,000 cases have been reported in the United States, including >55,000 associated deaths as of April 28, 2020 (2). Detailed data on demographic characteristics, underlying medical conditions, and clinical outcomes for persons hospitalized with COVID-19 are needed to inform prevention strategies and community-specific intervention messages. For this report, CDC, the Georgia Department of Public Health, and eight Georgia hospitals (seven in metropolitan Atlanta and one in southern Georgia) summarized medical record-abstracted data for hospitalized adult patients with laboratory-confirmed* COVID-19 who were admitted during March 2020. Among 305 hospitalized patients with COVID-19, 61.6% were aged <65 years, 50.5% were female, and 83.2% with known race/ethnicity were non-Hispanic black (black). Over a quarter of patients (26.2%) did not have conditions thought to put them at higher risk for severe disease, including being aged ≥65 years. The proportion of hospitalized patients who were black was higher than expected based on overall hospital admissions. In an adjusted time-to-event analysis, black patients were not more likely than were nonblack patients to receive invasive mechanical ventilation† (IMV) or to die during hospitalization (hazard ratio [HR] = 0.63; 95% confidence interval [CI] = 0.35-1.13). Given the overrepresentation of black patients within this hospitalized cohort, it is important for public health officials to ensure that prevention activities prioritize communities and racial/ethnic groups most affected by COVID-19. Clinicians and public officials should be aware that all adults, regardless of underlying conditions or age, are at risk for serious illness from COVID-19.

Motion of objects embedded in lipid bilayer membranes: Advection and effective viscosity.

An interfacial regularized Stokeslet scheme is presented to predict the motion of solid bodies (e.g., proteins or gel-phase domains) embedded within flowing lipid bilayer membranes. The approach provides a numerical route to calculate velocities and angular velocities in complex flow fields that are not amenable to simple Faxén-like approximations. Additionally, when applied to shearing motions, the calculations yield predictions for the effective surface viscosity of dilute rigid-body-laden membranes. In the case of cylindrical proteins, effective viscosity calculations are compared to two prior analytical predictions from the literature. Effective viscosity predictions for a dilute suspension of rod-shaped objects in the membrane are also presented.

Integrated rate laws for processive and distributive enzymatic turnover.

Recently derived steady-state differential rate laws for the catalytic turnover of molecules containing two substrate sites are reformulated as integrated rate laws. The analysis applies to a broad class of Markovian dynamic models, motivated by the varied and often complex mechanisms associated with DNA modifying enzymes. Analysis of experimental data for the methylation kinetics of DNA by Dam (DNA adenine methyltransferase) is drastically improved through the use of integrated rate laws. Data that are too noisy for fitting to differential predictions are reliably interpreted through the integrated rate laws.

Complete permanent mandibular dentition of early Homo from the upper Burgi Member of the Koobi Fora Formation, Ileret, Kenya.

The KNM-ER 64060 dentition derives from a horizon that most likely dates to between 2.02 and 2.03 Ma. A proximate series of postcranial bones (designated KNM-ER 64061) derives from the same siltstone unit and may be associated with the dentition, but their separation on the surface of the site leaves some room for doubt. KNM-ER 64060 is one of fewer than ten hominin specimens from the Early Pleistocene of East Africa that comprises a full or nearly complete mandibular dentition. Its taxonomic attribution is potentially significant, especially if the postcranial elements are related. At least three, and probably four hominin species, including Paranthropus boisei and Homo erectus (= H. ergaster), are known at about this time in East Africa. Other penecontemporaneous fossils have been referred to a single, highly variable species, H. habilis, or two taxa, namely H. habilis and H. rudolfensis. Although the weight of evidence supports the attribution of these specimens to two species, there is notable lack of agreement over the assignation of individual fossils. We take a conservative approach and group all such specimens under the designation "early Homo sp." for comparative purposes. KNM-ER 64060 is clearly attributable to Homo rather than Paranthropus. The preponderance of the evidence suggests that the affinities of KNM-ER 64060 are with fossils assigned to the early Homo sp. category rather than with H. erectus. This is indicated by the overall sizes of the KNM-ER 64060 canine, premolar and molar crowns, the size relationships of the P3 to P4, the relative narrowness of its premolar crowns, the cusp proportions of the M1 and especially those of the M2 and M3, and seemingly the possession of a two-rooted P4. Some of these comparisons suggest further that among the fossils comprising the early Homo sp. sample, the KNM-ER 64060 dentition exhibits greater overall similarity to specimens such as OH 7 and OH 16 that represent Homo habilis sensu stricto.

Copper release and transformation following natural weathering of nano-enabled pressure-treated lumber.

Commercially available lumber, pressure-treated with micronized copper azole (MCA), has largely replaced other inorganic biocides for residential wood treatment in the USA, yet little is known about how different outdoor environmental conditions impact the release of ionic, nano-scale, or larger (micron-scale) copper from this product. Therefore, we weathered pressure treated lumber for 18 months in five different climates across the continental United States. Copper release was quantified every month and local weather conditions were recorded continuously to determine the extent to which local climate regulated the release of copper from this nano-enabled product during its use phase. Two distinct release trends were observed: In cooler, wetter climates release occurred primarily during the first few months of weathering, as the result of copper leaching from surface/near-surface areas. In warmer, drier climates, less copper was initially released due to limited precipitation. However, as the wood dried and cracked, the exposed copper-bearing surface area increased, leading to increased copper release later in the product lifetime. Single-particle-ICP-MS results from laboratory prepared MCA-wood leachate solutions indicated that a) the predominant form of released copper passed through a filter smaller than 0.45 micrometers and b) released particles were largely resistant to dissolution over the course of 6 wks. Toxicity Characteristic Leaching Procedure (TCLP) testing was conducted on nonweathered and weathered MCA-wood samples to simulate landfill conditions during their end-of-life (EoL) phase and revealed that MCA wood released <10% of initially embedded copper. Findings from this study provide data necessary to complete a more comprehensive evaluation of the environmental and human health impacts introduced through release of copper from pressure treated lumber utilizing life cycle assessment (LCA).

High-sensitivity cardiac troponin T increases after stress echocardiography.

INTRODUCTION: Exercise (ESE) and dobutamine stress echocardiography (DSE) have high sensitivity and specificity to detect inducible myocardial ischemia in patients with significant coronary artery disease (CAD). High-sensitivity cardiac troponin (hs-cTn) assays detect troponin concentrations in the ng/L range. The aim of this study was to determine the kinetics of hs-cTnT in patients undergoing ESE and DSE and possible association of hs-cTnT with inducible myocardial ischemia. METHODS: In this prospective study adult patients undergoing ESE/DSE were enrolled. Peripheral blood samples were obtained before, and 30 min, 1, 2, and 4-6 h after completion of ESE/DSE. Hs-cTnT was measured on a Roche Diagnostics Elecsys 2010 analyzer. RESULTS: We enrolled 48 patients (33 ESE and 15 DSE); 11 patients (23%) had elevated baseline hs-cTnT concentrations >14 ng/L (99th percentile URL); 31/48 (65%) developed an hs-cTnT increase after ESE/DSE (peak 4-6 h post stress test), but only three patients (all in ESE group) had a positive stress test. Absolute and relative hs-cTnT increases were higher after DSE (median Δhs-cTnT +9.7 ng/L [IQR 4.5, 27.2]; +123% [IQR 49, 271]) compared to ESE (median Δhs-cTnT +2.3 ng/L [IQR 1, 4.9]; +37% [IQR 9.1, 221]). CONCLUSIONS: One in four patients undergoing ESE/DSE had increased hs-cTnT values prior to stress testing. Hs-cTnT increased above the upper limit of normal occurred commonly after ESE/DSE but was more pronounced after DSE. Increases in hs-cTn did not appear to be associated with inducible myocardial ischemia. These findings may have important implications for the clinical use of hs-cTnT within 6 h after ESE/DSE.

Effect of Nitrous Oxide as a Treatment for Subjective, Idiopathic, Nonpulsatile Bothersome Tinnitus: A Randomized Clinical Trial.

Importance: The tinnitus research literature suggests that N-methyl-d-aspartate (NMDA) receptor antagonists may be useful in reducing tinnitus. Nitrous oxide, a member of the NMDA receptor antagonist class, is a widely used general anesthetic and sedative with a proven safety record. Objective: To investigate whether nitrous oxide can reduce bothersome tinnitus. Design, Setting, and Participants: Randomized, placebo-controlled crossover trial conducted between October 15, 2016, and June 22, 2017. Participants attended 2 interventional sessions separated by at least 14 days and were randomized to receive either placebo first or nitrous oxide first. Participants were followed up through completion of the second arm of the study. The setting was a clinical research unit at an academic medical center. Adults aged 18 to 65 years with subjective, idiopathic, nonpulsatile bothersome tinnitus of 6 months' duration or longer were recruited from 2 clinical research databases. Seventy-one individuals were screened, of whom 40 were enrolled. Of those enrolled, 37 participants completed all components of the study. Interventions: The placebo session consisted of 50% nitrogen and 50% oxygen inhaled for 40 minutes, and the treatment session consisted of 50% nitrous oxide and 50% oxygen inhaled for 40 minutes. Main Outcomes and Measures: Tinnitus was assessed before and after intervention, with the change in the Tinnitus Functional Index (TFI) as the primary outcome measure. Secondary outcome measures included the Patients' Global Impression of Change score and the change in the Global Bothersome Scale score. Results: Among 40 participants in this intent-to-treat randomized clinical trial with 20 participants randomly assigned to each group, the mean (SD) age of participants was 52.9 (11.1) years, with equal numbers of male and female participants. The TFI after intervention was a mean (SD) of 1.8 (8.8) points lower than before intervention in the placebo arm and a mean (SD) of 2.5 (11.0) points lower than before intervention in the nitrous oxide arm. The within-participant mean difference in the change in the TFI of the placebo arm compared with the nitrous oxide arm was -1.1 points (95% CI, -5.6 to 3.4 points). The difference between the placebo and nitrous oxide arms was neither clinically meaningful nor statistically significant. Conclusions and Relevance: Nitrous oxide was no more effective than placebo for the treatment of subjective, idiopathic tinnitus. Trial Registration: ClinicalTrials.gov identifier: NCT03365011.

Lipid diffusion in the distal and proximal leaflets of supported lipid bilayer membranes studied by single particle tracking.

Supported lipid bilayers (SLBs) have been studied extensively as simple but powerful models for cellular membranes. Yet, potential differences in the dynamics of the two leaflets of a SLB remain poorly understood. Here, using single particle tracking, we obtain a detailed picture of bilayer dynamics. We observe two clearly separate diffusing populations, fast and slow, that we associate with motion in the distal and proximal leaflets of the SLB, respectively, based on fluorescence quenching experiments. We estimate diffusion coefficients using standard techniques as well as a new method based on the blur of images due to motion. Fitting the observed diffusion coefficients to a two-leaflet membrane hydrodynamic model allows for the simultaneous determination of the intermonolayer friction coefficient and the substrate-membrane friction coefficient, without any prior assumptions on the strengths of the relevant interactions. Remarkably, our calculations suggest that the viscosity of the interfacial water confined between the membrane and the substrate is elevated by ∼104 as compared to bulk water. Using hidden Markov model analysis, we then obtain insight into the transbilayer movement of lipids. We find that lipid flip-flop dynamics are very fast, with half times in the range of seconds. Importantly, we find little evidence for membrane defect mediated lipid flip-flop for SLBs at temperatures well above the solid-to-liquid transition, though defects seem to be involved when the SLBs are cooled down. Our work thus shows that the combination of single particle tracking and advanced hydrodynamic modeling provides a powerful means to obtain insight into membrane dynamics.

Are high-sensitivity cardiac troponin I values stable between preoperative visit and day of non-cardiac surgery?

BACKGROUND: It is unclear if cardiac troponin values are stable in patients prior to undergoing non-cardiac surgery, or if they tend to rise towards the day of surgery. METHODS: In this small pilot study (n=18) among patients with cardiac risk undergoing non-cardiac surgery, we determined if high-sensitivity cardiac troponin I (hscTnI) changes between the preoperative clinic visit and the day of surgery. HscTnI was measured on an Abbott Architect STAT (Abbott Laboratories, USA) platform. RESULTS: The mean duration between preoperative clinic visit and day of surgery was 8.7±2.8 (SD) days. Median hscTnI was 3.4ng/L [2.0-4.8, IQR] at the preoperative visit and 2.8ng/L [2.3-4.4] on the day of surgery (mean difference-0.24ng/L, 95% CI - 0.73 to 0.24ng/L, p=0.30). Only one patient had a large change (>50%) along with symptoms. DISCUSSION: Evidence from this small study suggests that cardiac troponin values are stable in most high-risk patients, absent clinical events, within 10days prior to non-cardiac surgery.

Specificity versus Processivity in the Sequential Modification of DNA: A Study of DNA Adenine Methyltransferase.

A detailed analysis is carried out on both published experimental results and new experiments for the methylation kinetics of two-site DNA substrates (with site separations between 100 and 800 bp) catalyzed by bacterial DNA adenine methyltransferase (Dam). A previously reported rate enhancement for the second methylation event (relative to that of the first methylation) is shown to result from elevated substrate specificity for singly methylated DNA over that of unmethylated DNA and not processive turnover of both sites by the same copy of Dam. An elementary model is suggested that cleanly fits the experimental data over a broad range of intersite separations. The model hypothesizes a looping mediated interference between competing unmethylated Dam sites on the same DNA strand.