Prebiotic chiral transfer from self-aminoacylating ribozymes may favor either handedness.

Modern life is essentially homochiral, containing D-sugars in nucleic acid backbones and L-amino acids in proteins. Since coded proteins are theorized to have developed from a prebiotic RNA World, the homochirality of L-amino acids observed in all known life presumably resulted from chiral transfer from a homochiral D-RNA World. This transfer would have been mediated by aminoacyl-RNAs defining the genetic code. Previous work on aminoacyl transfer using tRNA mimics has suggested that aminoacylation using D-RNA may be inherently biased toward reactivity with L-amino acids, implying a deterministic path from a D-RNA World to L-proteins. Using a model system of self-aminoacylating D-ribozymes and epimerizable activated amino acid analogs, we test the chiral selectivity of 15 ribozymes derived from an exhaustive search of sequence space. All of the ribozymes exhibit detectable selectivity, and a substantial fraction react preferentially to produce the D-enantiomer of the product. Furthermore, chiral preference is conserved within sequence families. These results are consistent with the transfer of chiral information from RNA to proteins but do not support an intrinsic bias of D-RNA for L-amino acids. Different aminoacylation structures result in different directions of chiral selectivity, such that L-proteins need not emerge from a D-RNA World.

Urbanization and fragmentation have opposing effects on soil nitrogen availability in temperate forest ecosystems.

Nitrogen (N) availability relative to plant demand has been declining in recent years in terrestrial ecosystems throughout the world, a phenomenon known as N oligotrophication. The temperate forests of the northeastern U.S. have experienced a particularly steep decline in bioavailable N, which is expected to be exacerbated by climate change. This region has also experienced rapid urban expansion in recent decades that leads to forest fragmentation, and it is unknown whether and how these changes affect N availability and uptake by forest trees. Many studies have examined the impact of either urbanization or forest fragmentation on nitrogen (N) cycling, but none to our knowledge have focused on the combined effects of these co-occurring environmental changes. We examined the effects of urbanization and fragmentation on oak-dominated (Quercus spp.) forests along an urban to rural gradient from Boston to central Massachusetts (MA). At eight study sites along the urbanization gradient, plant and soil measurements were made along a 90 m transect from a developed edge to an intact forest interior. Rates of net ammonification, net mineralization, and foliar N concentrations were significantly higher in urban than rural sites, while net nitrification and foliar C:N were not different between urban and rural forests. At urban sites, foliar N and net ammonification and mineralization were higher at forest interiors compared to edges, while net nitrification and foliar C:N were higher at rural forest edges than interiors. These results indicate that urban forests in the northeastern U.S. have greater soil N availability and N uptake by trees compared to rural forests, counteracting the trend for widespread N oligotrophication in temperate forests around the globe. Such increases in available N are diminished at forest edges, however, demonstrating that forest fragmentation has the opposite effect of urbanization on coupled N availability and demand by trees.

A Review of Price Transparency Policy and Evaluation of Hospital Compliance in Orthopedic Sports Medicine.

Background: In 2019, the Centers for Medicare and Medicaid Services (CMS) announced that beginning January 1, 2021, hospitals would be required to post pricing information in a usable format for patients via diagnosis-related group (DRG) or charge description master (CDM) sheets. Purpose/Questions: We hypothesized the new price transparency rule would pose challenges for many health care facilities. We therefore sought to find out how much pricing information was available before the rule took effect and how usable it was for patients receiving sports medicine care. Methods: In late 2019, we randomly selected 100 general hospitals (GH) from the CMS hospital list and an additional 21 orthopedic hospitals (OH). The DRG and/or CDM sheets were obtained from hospital websites. Pricing information for 6 sports medicine procedures (rotator cuff repair, shoulder arthroscopy, knee arthroscopy, anterior cruciate ligament reconstruction, meniscal repair, and steroid injection) was evaluated in qualitative and quantitative form. Results: Pricing information was provided by 74% of GH and 86% of OH. The price of steroid injections was frequently reported in usable form, with 80% by GH and 78% by OH. The remaining procedures were reported by less than 27% of GH and 40% of OH. For each procedure, component pricing was provided by at least 60% of GH and 78% of OH. No facility provided a pricing calculator or payer-type specific rates. Conclusions: Prior to the enactment of the new price transparency rule in January 2021, most facilities provided some pricing information to patients. However, reporting rates in sports medicine were low and the available data were of little use to patients.

Intra- and interobserver reliability for predicting hip preservation versus hip arthroplasty utilizing plain radiographs with comparison of surgeon specialization.

Surgeon subspecialty training and practice landscape are formative in diagnostic evaluation and treatment recommendations. Varying recommendations can have substantial impact on patients' care pathways and outcomes. We investigated intra- and interobserver reliability of treatment predictions for total hip arthroplasty (THA) between surgeons performing arthroplasty and/or arthroscopic hip preservation surgery. Anterior-posterior (AP) hip radiographs cropped to include the lateral sourcil, medial sourcil and foveal region of 53 patients with Tönnis Grade 0-3 were evaluated by five surgeons (two performing arthroplasty, two performing arthroscopic hip preservation and one performing both interventions). Surgeons predicted THA versus no THA as the treatment for each image. Predictions were repeated three times with image order randomized, and intra- and interobserver reliability were calculated. Surgeons were blinded to patient characteristics and clinical information. Interobserver reliability was 0.452 whereas intraobserver reliability ranged from 0.270 to 0.690. Arthroscopic hip preservation surgeons were more likely to predict THA (36.9%) than arthroplasty surgeons (32.7%), P = 0.041. Intra- and interobserver reliabilities of surgeons predicting THA versus no THA based on an AP hip radiograph were average at best. Arthroscopic hip preservation surgeons were more likely to predict THA than arthroplasty surgeons. Subjective surgeon interpretation can lead to variability in recommendations to patients; potentially complicating care pathways.

Elevated 1-Year Mortality Rate in Males Sustaining Low-Energy Proximal Femur Fractures and Subgroup Analysis Utilizing Age-Adjusted Charlson Comorbidity Index.

INTRODUCTION: Low-energy proximal femur fractures are common in the aging population and the ability to identify patients at increased mortality risk provides surgeons information to improve informed decision-making with patients and families. We evaluated for gender differences in 1-year mortality after sustaining low-energy proximal femur fractures with subgroup analysis to identify the impact of fracture location, age, and comorbidities on mortality. MATERIALS AND METHODS: Patients ≥40 years of age sustaining a low-energy proximal femur fracture identified at our institution between January 1, 2014, and December 31, 2017. International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes were used to identify comorbidities for calculation of the age-adjusted Charlson comorbidity index (ACCI). The county clerk database was searched to identify mortality within 1 year of injury. One-year mortality rates were calculated and multiple comparisons were made between genders controlling for age, fracture location, and/or ACCI. RESULTS: Women presented with low-energy proximal femur fractures at a rate of almost 3:1 to men at our institution (P = .001). Men demonstrated a significantly increased ACCI at presentation (5.35 ± 2.55 vs 4.86 ± 1.77, P = .03). Men had an increased 1-year mortality rate for all (31.3% vs 21.5%, P = .004) and intertrochanteric (IT) fractures (36.2% vs 22.9%, P = .008). Controlling for ACCI, gender, and fracture location, men demonstrated increased mortality rate with IT fractures (P = .002) and trended toward but did not reach significance with femoral neck fractures (P = .07). DISCUSSION: Men presenting with low-energy femur fractures are at an increased mortality risk compared to women. On average, men present with an overall worse health status as identified by ACCI, which could predispose these patients not only to fractures themselves but also impair their ability to recover from injury. CONCLUSION: Men are at an increased 1-year mortality risk after sustaining proximal femur fractures.

Prescribing and Consumption of Opioids After Primary, Unilateral Total Hip and Knee Arthroplasty in Opioid-Naive Patients.

BACKGROUND: This cohort study was designed to determine the discrepancy between the quantity of opioid prescribed vs that which was consumed after total knee arthroplasty (TKA) and total hip arthroplasty (THA) in opioid-naive patients. METHODS: Seven hundred twenty-three opioid-naive patients (426 TKAs and 297 THAs) from 7 hospitals in Michigan were contacted within 3 months of their surgery. Opioid prescribing and self-reported consumption was calculated in oral morphine equivalents (OMEs). Secondary outcomes included opioid refill in the first 90 days, pain in the first 7 days post-operatively, and satisfaction with pain care. RESULTS: For TKA, the mean prescribing was 632 mg OME (±229), and the mean consumption was 416 mg (±279). For THA, the mean prescribing was 584 mg OME (±335), and the mean consumption was 285 mg (±301). There were no associations between the amount of opioid prescribed and the likelihood of refill, post-operative pain, or satisfaction with pain control. The amount of opioid prescribed was associated with increased consumption, such that each increase of 1 pill was associated with approximately an additional half pill consumed after adjusting for other covariates. Moreover, 48.2% felt that they received "More" or "Much more" opioid than they needed. CONCLUSION: We recommend no more than 50 tablets of 5 mg oxycodone or its equivalent after TKA and 30 tablets after THA. Although dose reductions in other surgeries have not resulted in harm, continued assessment is needed to ensure that there are no unintended effects of opioid reduction, including worsened pain, decreased satisfaction, emergency department visits, or hospital readmissions. LEVEL OF EVIDENCE: Level III; Retrospective, cohort study.

Legal terms of use and public genealogy websites.

Public genealogy websites, to which individuals upload family history, genealogy, and sometimes individual genetic data, have been used in an increasing number of public health, epidemiological, and genetic studies. Yet there is little awareness among researchers of the legal rules that govern the use of these online resources. We analyzed the online Terms of Use (TOU) applicable to 17 popular genealogy websites and found that none of them expressly permit scientific research, while at least 13 contain restrictions that may limit or prohibit scientific research using data obtained from those sites. In order to ensure that researchers who use genealogy and other data from these sites for public health and other scientific research purposes do not inadvertently breach applicable TOUs, we recommend that genealogy website operators consider revising their TOUs to permit this activity.

Repeat cross-sectional data on the progression of the metabolic syndrome in Ossabaw miniature swine.

Ossabaw miniature swine were fed an excess calorie, atherogenic diet for 6, 9, or 12 months. Increased body weight, hypertension, and increased plasma cholesterol and triglycerides are described in Table 1. For more detailed interpretations and conclusions about the data, see our associated research study, "Biphasic alterations in coronary smooth muscle Ca(2+) regulation during coronary artery disease progression in metabolic syndrome" McKenney-Drake, et al. (2016) [1].

Biphasic alterations in coronary smooth muscle Ca(2+) regulation in a repeat cross-sectional study of coronary artery disease severity in metabolic syndrome.

BACKGROUND AND AIMS: Coronary artery disease (CAD) is progressive, classified by stages of severity. Alterations in Ca(2+) regulation within coronary smooth muscle (CSM) cells in metabolic syndrome (MetS) have been observed, but there is a lack of data in relatively early (mild) and late (severe) stages of CAD. The current study examined alterations in CSM Ca(2+) regulation at several time points during CAD progression. METHODS: MetS was induced by feeding an excess calorie atherogenic diet for 6, 9, or 12 months and compared to age-matched lean controls. CAD was measured with intravascular ultrasound (IVUS). Intracellular Ca(2+) was assessed with fura-2. RESULTS: IVUS revealed that the extent of atherosclerotic CAD correlated with the duration on atherogenic diet. Fura-2 imaging of intracellular Ca(2+) in CSM cells revealed heightened Ca(2+) signaling at 9 months on diet, compared to 6 and 12 months, and to age-matched lean controls. Isolated coronary artery rings from swine fed for 9 months followed the same pattern, developing greater tension to depolarization, compared to 6 and 12 months (6 months = 1.8 ± 0.6 g, 9 months = 5.0 ± 1.0 g, 12 months = 0.7 ± 0.1 g). CSM in severe atherosclerotic plaques showed dampened Ca(2+) regulation and decreased proliferation compared to CSM from the wall. CONCLUSIONS: These CSM Ca(2+) regulation data from several time points in CAD progression and severity help to resolve the controversy regarding up-vs. down-regulation of CSM Ca(2+) regulation in previous reports. These data are consistent with the hypothesis that alterations in sarcoplasmic reticulum Ca(2+) contribute to progression of atherosclerotic CAD in MetS.

Metabolic Syndrome Abolishes Glucagon-Like Peptide 1 Receptor Agonist Stimulation of SERCA in Coronary Smooth Muscle.

Metabolic syndrome (MetS) doubles the risk of adverse cardiovascular events. Glucagon-like peptide 1 (GLP-1) receptor agonists induce weight loss, increase insulin secretion, and improve glucose tolerance. Studies in healthy animals suggest cardioprotective properties of GLP-1 receptor agonists, perhaps partially mediated by improved sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) activity. We examined the acute effect of GLP-1 receptor agonists on coronary smooth muscle cells (CSM) enzymatically isolated from lean, healthy Ossabaw miniature swine. Intracellular Ca(2+) handling was interrogated with fura-2. The GLP-1 receptor agonist exenatide activated SERCA but did not alter other Ca(2+) transporters. Further, we tested the hypothesis that chronic, in vivo treatment with GLP-1 receptor agonist AC3174 would attenuate coronary artery disease (CAD) in swine with MetS. MetS was induced in 20 swine by 6 months' feeding of a hypercaloric, atherogenic diet. Swine were then randomized (n = 10/group) into placebo or AC3174 treatment groups and continued the diet for an additional 6 months. AC3174 treatment attenuated weight gain, increased insulin secretion, and improved glucose tolerance. Intravascular ultrasound and histology showed no effect of AC3174 on CAD. MetS abolished SERCA activation by GLP-1 receptor agonists. We conclude that MetS confers vascular resistance to GLP-1 receptor agonists, partially through impaired cellular signaling steps involving SERCA.

Compensatory Enlargement of Ossabaw Miniature Swine Coronary Arteries in Diffuse Atherosclerosis.

Studies in human and non-human primates have confirmed the compensatory enlargement or positive remodeling (Glagov phenomenon) of coronary vessels in the presence of focal stenosis. To our knowledge, this is the first study to document arterial enlargement in a metabolic syndrome animal model with diffuse coronary artery disease (DCAD) in the absence of severe focal stenosis. Two different groups of Ossabaw miniature pigs were fed a high fat atherogenic diet for 4 months (Group I) and 12 months (Group II), respectively. Group I (6 pigs) underwent contrast enhanced computed tomographic angiography (CCTA) and intravascular ultrasound (IVUS) at baseline and after 4 months of high fat diet, whereas Group II (7 pigs) underwent only IVUS at 12 months of high fat diet. IVUS measurements of the left anterior descending (LAD), left circumflex (LCX) and right coronary (RCA) arteries in Group I showed an average increase in their lumen cross-sectional areas (CSA) of 25.8%, 11.4%, and 43.4%, respectively, as compared to baseline. The lumen CSA values of LAD in Group II were found to be between the baseline and 4 months values in Group I. IVUS and CCTA measurements showed a similar trend and positive correlation. Fractional flow reserve (FFR) was 0.91±0.07 at baseline and 0.93±0.05 at 4 months with only 2.2%, 1.6% and 1% stenosis in the LAD, LCX and RCA, respectively. The relation between percent stenosis and lumen CSA shows a classical Glagov phenomenon in this animal model of DCAD.

Epicardial adipose excision slows the progression of porcine coronary atherosclerosis.

BACKGROUND: In humans there is a positive association between epicardial adipose tissue (EAT) volume and coronary atherosclerosis (CAD) burden. We tested the hypothesis that EAT contributes locally to CAD in a pig model. METHODS: Ossabaw miniature swine (n=9) were fed an atherogenic diet for 6 months to produce CAD. A 15 mm length by 3-5 mm width coronary EAT (cEAT) resection was performed over the middle segment of the left anterior descending artery (LAD) 15 mm distal to the left main bifurcation. Pigs recovered for 3 months on atherogenic diet. Intravascular ultrasound (IVUS) was performed in the LAD to quantify atheroma immediately after adipectomy and was repeated after recovery before sacrifice. Coronary wall biopsies were stained immunohistochemically for atherosclerosis markers and cytokines and cEAT was assayed for atherosclerosis-related genes by RT-PCR. Total EAT volume was measured by non-contrast CT before each IVUS. RESULTS: Circumferential plaque length increased (p<0.05) in the proximal and distal LAD segments from baseline until sacrifice whereas plaque length in the middle LAD segment underneath the adipectomy site did not increase. T-cadherin, scavenger receptor A and adiponectin were reduced in the intramural middle LAD. Relative to control pigs without CAD, 11ß-hydroxysteroid dehydrogenase (11ßHSD-1), CCL19, CCL21, prostaglandin D2 synthase, gp91phox [NADPH oxidase], VEGF, VEGFGR1, and angiotensinogen mRNAs were up-regulated in cEAT. EAT volume increased over 3 months. CONCLUSION: In pigs used as their own controls, resection of cEAT decreased the progression of CAD, suggesting that cEAT may exacerbate coronary atherosclerosis.