Optimizing warfarin dosing using deep reinforcement learning.

Warfarin is a widely used anticoagulant, and has a narrow therapeutic range. Dosing of warfarin should be individualized, since slight overdosing or underdosing can have catastrophic or even fatal consequences. Despite much research on warfarin dosing, current dosing protocols do not live up to expectations, especially for patients sensitive to warfarin. We propose a deep reinforcement learning-based dosing model for warfarin. To overcome the issue of relatively small sample sizes in dosing trials, we use a Pharmacokinetic/ Pharmacodynamic (PK/PD) model of warfarin to simulate dose-responses of virtual patients. Applying the proposed algorithm on virtual test patients shows that this model outperforms a set of clinically accepted dosing protocols by a wide margin. We tested the robustness of our dosing protocol on a second PK/PD model and showed that its performance is comparable to the set of baseline protocols.

Peer Recovery Coaches Perceptions of Their Work and Their Implications for Training, Support and Personal Recovery.

The peer recovery workforce, including individuals in sustained recovery from substance use, has grown rapidly in the previous decades. Peer recovery coaches represent a scalable, resource-efficient, and acceptable approach to increasing service delivery, specifically among individuals receiving substance use services in low-resource communities. Despite the potential to improve access to care in traditionally underserved settings, there are a number of barriers to successfully integrating peer recovery coaches in existing recovery services. The current study presents results from two focus groups composed of peer recovery coaches. Findings suggest that peer recovery coaches report discordance between their perceived role and their daily responsibilities and experience both inter- and intrapersonal challenges that impact their own recovery processes. These results point to several promising policy and structural changes that may support and enhance this growing workforce.

Efficacy of Calcium Channel Blockers Versus Other Classes of Antihypertensive Medication in the Treatment of Hypertensive Patients With Previous Stroke and/or Coronary Artery Disease: A Systematic Review and Meta-Analysis.

Hypertensive patients, such as those with established coronary artery disease (CAD) or those who have suffered a stroke, are at increased risk of morbidity and mortality. This systematic literature review and meta-analysis assesses the long-term effects of calcium channel blockers (CCBs) compared with other classes of antihypertensive medications on major cardiovascular (CV) outcomes in these high-risk subgroups of hypertensive patients. Randomized, active controlled parallel group trials were included if they compared CCBs with α-blockers, ß-blockers, angiotensin II receptor blockers, angiotensin-converting enzyme inhibitors, or diuretics, had a follow-up of ≥6 months, and had assessments of blood pressure (BP) and CV events [all-cause death, CV death, major CV events (myocardial infarction, MI; congestive heart failure, CHF; stroke; and CV death), MI, stroke, or CHF] in patients with baseline systolic/diastolic BP ≥140/≥90 mm Hg with either concomitant previous stroke and/or CAD. The final dataset included 19 publications reporting on 7 unique trials. In hypertensive patients with previous stroke, there was no difference between CCBs and comparators for any CV outcome. In those with CAD, there was no difference for all-cause death, CV death, major CV events, and MI for CCBs relative to comparators; however, a reduction in the risk of stroke and an increase in the risk of CHF were seen. For BP lowering, CCBs were at least as efficacious as comparators. The findings of our systematic review and analysis add to the body of evidence for the use of CCBs for the long-term treatment of hypertension in difficult-to-treat high CV risk populations.

Relationship Between Visit-to-Visit Blood Pressure Variability (BPV) and Kidney Function in Patients with Hypertension.

BACKGROUND/AIMS: To investigate the impact of kidney function (using estimated glomerular filtration rate, [eGFR]) on blood pressure variability (BPV) via a retrospective post hoc analysis of patients with hypertension enrolled in two large clinical trials. METHODS: Subject-level data were extracted from ASCOT (N=18,852) and ALLHAT (N=26,441) databases; both were randomized, active controlled studies, with treatment duration for hypertension ≥4 years. Visit-to-visit BPV was assessed using the square root of the coefficient of variation of systolic blood pressure (SBP) across visits from 12 weeks onwards. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease equation, was stratified into ≤60, 61-90, and >90 mL/min/1.73 m2. The relationship between baseline eGFR and systolic BPV was analyzed using an analysis of covariance, with baseline factors considered as covariates. Studies were pooled and analyzed individually. RESULTS: Patient characteristics were largely consistent between studies. In the pooled population (n=38,133) there were 19.1%, 62.9%, and 18.0% patients, with eGFR ≤60, 61-90, and > 90 mL/min/1.73 m2, respectively. Patients with lower baseline eGFR had higher systolic BPV, in the pooled population and the individual analyses. Other baseline predictors of high systolic BPV included high SBP and age, being male, and a smoker. An amlodipine-based regimen was a negative predictor of high systolic BPV, vs. other antihypertensives, regardless of eGFR. CONCLUSIONS: Patients with declining renal function tended to have higher systolic BPV vs. those without, even after adjusting for risk factors. Amlodipine-based therapy reduced BPV more than other antihypertensive agents, regardless of level of eGFR.

Therapeutic Antibody Engineering To Improve Viscosity and Phase Separation Guided by Crystal Structure.

Antibodies at high concentrations often reveal unanticipated biophysical properties suboptimal for therapeutic development. The purpose of this work was to explore the use of point mutations based on crystal structure information to improve antibody physical properties such as viscosity and phase separation (LLPS) at high concentrations. An IgG4 monoclonal antibody (Mab4) that exhibited high viscosity and phase separation at high concentration was used as a model system. Guided by the crystal structure, four CDR point mutants were made to evaluate the role of hydrophobic and charge interactions on solution behavior. Surprisingly and unpredictably, two of the charge mutants, R33G and N35E, showed a reduction in viscosity and a lower propensity to form LLPS at high concentration compared to the wild-type (WT), while a third charge mutant S28K showed an increased propensity to form LLPS compared to the WT. A fourth mutant, F102H, had reduced hydrophobicity, but unchanged viscosity and phase separation behavior. We further evaluated the correlation of various biophysical measurements including second virial coefficient (A2), interaction parameter (kD), weight-average molecular weight (WAMW), and hydrodynamic diameters (DH), at relatively low protein concentration (4 to 15 mg/mL) to physical properties, such as viscosity and liquid-liquid phase separation (LLPS), at high concentration. Surprisingly, kD measured using dynamic light scattering (DLS) at low antibody concentration correlated better with viscosity and phase separation than did A2 for Mab4. Our results suggest that the high viscosity and phase separation observed at high concentration for Mab4 are mainly driven by charge and not hydrophobicity.

A Systematic Review on the Efficacy of Amlodipine in the Treatment of Patients With Hypertension With Concomitant Diabetes Mellitus and/or Renal Dysfunction, When Compared With Other Classes of Antihypertensive Medication.

The long-term cardiovascular (CV) effects of calcium channel blockers, with special focus on amlodipine, were compared with other classes of antihypertensive medications in high-risk hypertensive patient subgroups. A systematic literature review and meta-analysis was undertaken of 38 unique randomized, active-controlled, parallel-group trials comparing amlodipine/calcium channel blockers with diuretics, ß-blockers, α-blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers, with ≥6-month follow-up, and which had included assessment of blood pressure (BP) and CV events [all-cause death, CV death, myocardial infarction (MI), stroke, congestive heart failure (CHF), or major CV events (MACE: MI, CHF, stroke, and CV death)], in hypertensive patients (baseline systolic/diastolic BP ≥140/≥90 mm Hg) with either concomitant diabetes and/or renal dysfunction. In hypertensive patients with diabetes, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, and MI; a decrease in stroke risk, and an increase in CHF risk, was seen. In hypertensive patients with renal dysfunction, no difference was found for amlodipine versus comparators with respect to all-cause death, CV death, MACE, MI, and CHF; a decrease in stroke risk was seen. Amlodipine was found to be at least as efficacious as all the other classes of antihypertensive agents in reducing systolic and diastolic BP. Long-term control of BP is critical for avoiding complications of hypertension in high-risk patients, particularly CV and cerebrovascular events such as stroke. This analysis has provided evidence that amlodipine is an appealing therapeutic option in the long-term management of hypertension in both diabetic and renal dysfunction patients.

Incremental Blood Pressure-Lowering Effect of Titrating Amlodipine for the Treatment of Hypertension in Patients Including Those Aged ≥55 Years.

Small reductions in blood pressure reduce the risk of cardiovascular events. Here, we report 2 post hoc pooled analyses assessing the antihypertensive effect of amlodipine in patients who had not responded to 5 mg and were uptitrated to 10 mg. The first analysis assessed subgroups of patients aged either younger than 55 years or 55 years or older and the second analysis pooled all patients irrespective of age. Of 706 patients in the age-related analysis, a statistically significant decrease in blood pressure from baseline was observed {for younger than 55 years [N = 253]: systolic blood pressure = -12.8 [standard error (SE) = 0.90] mm Hg, diastolic blood pressure = -8.0 [SE = 0.55] mm Hg; for 55 years or older [N = 453]: systolic blood pressure = -12.1 [SE = 0.66] mm Hg, diastolic blood pressure = -6.7 [SE = 0.39] mm Hg; all P < 0.0001}. In total, 45.8% and 39.3% of patients aged younger than 55 and 55 years or older, respectively, achieved their blood pressure goals. Adverse events were experienced by 62 (24.5%) patients aged younger than 55 years and 136 (30.0%) patients aged 55 years or older. Similar efficacy and safety results were seen in the all patient pooled analysis. Titration of amlodipine from 5 mg to 10 mg significantly decreased blood pressure in older hypertensive patients, which is clinically relevant because increased age is associated with hypertension and cardiovascular events.

Efficacy of COX-2 inhibitors in controlling inflammation and capsular opacification after phacoemulsification cataract removal.

OBJECTIVE: To evaluate the efficacy of 0.9% bromfenac (Xibrom™) or a celecoxib-impregnated intraocular lens (celecoxib-IOL) compared with 1% prednisolone acetate (PA) in controlling postoperative inflammation and posterior capsule opacification (PCO). ANIMAL STUDIED: Fifty-nine dogs undergoing cataract extraction by phacoemulsification. PROCEDURE: Bilateral patients received bromfenac or celecoxib-IOL plus PA in one eye, and PA in the contralateral eye. Unilateral patients received bromfenac or PA. Complete ophthalmic examination including tonometry, slit-lamp grading of flare and PCO, and digital image acquisition for masked PCO evaluation was performed within 24 h and 1, 4, 12, 24, and 56 weeks following surgery. RESULTS: Celecoxib-IOL/PA-treated eyes had significantly less flare than PA-treated eyes, which had significantly less flare than bromfenac-treated eyes 24 h postoperatively. There was no significant difference in intraocular pressure (IOP) postoperatively, or at 1, 24, or 56 weeks. Celecoxib-IOL/PA-treated eyes had significantly lower IOP measurements than bromfenac and PA-treated eyes at 4 and 12 weeks. There was no significant difference in PCO level between groups using slit-lamp biomicroscopy at any time point. Masked evaluation of digital images revealed significantly less PCO in celecoxib-IOL/PA- vs. bromfenac-treated eyes at 4 weeks, and in bromfenac- vs. PA-treated eyes at 56 weeks. CONCLUSIONS: Eyes receiving celecoxib-IOL/PA had better initial control of inflammation. Bromfenac was equally effective compared with PA in controlling inflammation. There was no association between COX-2 inhibitor administration and ocular hypertension. Celecoxib-IOL/PA-treated eyes showed better initial control of PCO (up to 12 weeks), while eyes receiving bromfenac had better long-term control of PCO (56 weeks).

The other side of the broken window: a methodology that translates building permits into an ecometric of investment by community members.

Much research has focused on physical disorder in urban neighborhoods as evidence that the community does not maintain local norms and spaces. Little attention has been paid to the opposite: indicators of proactive investment in the neighborhood's upkeep. This manuscript presents a methodology that translates a database of approved building permits into an ecometric of investment by community members, establishing basic content, criteria for reliability, and construct validity. A database from Boston, MA contained 150,493 permits spanning 2.5 years, each record including the property to be modified, permit type, and date issued. Investment was operationalized as the proportion of properties in a census block group that underwent an addition or renovation, excluding larger developments involving the demolition or construction of a building. The reliability analysis found that robust measures could be generated every 6 months, and that longitudinal analysis could differentiate between trajectories across neighborhoods. The validity analysis supported two hypotheses: investment was best predicted by homeownership and median income; and maintained an independent relationship with measures of physical disorder despite controlling for demographics, implying that it captures the other end of a spectrum of neighborhood maintenance. Possible uses for the measure in research and policy are discussed.

Sequential autoencoders for feature engineering and pretraining in major depressive disorder risk prediction.

Objectives: We evaluated autoencoders as a feature engineering and pretraining technique to improve major depressive disorder (MDD) prognostic risk prediction. Autoencoders can represent temporal feature relationships not identified by aggregate features. The predictive performance of autoencoders of multiple sequential structures was evaluated as feature engineering and pretraining strategies on an array of prediction tasks and compared to a restricted Boltzmann machine (RBM) and random forests as a benchmark. Materials and Methods: We study MDD patients from Vanderbilt University Medical Center. Autoencoder models with Attention and long-short-term memory (LSTM) layers were trained to create latent representations of the input data. Predictive performance was evaluated temporally by fitting random forest models to predict future outcomes with engineered features as input and using autoencoder weights to initialize neural network layers. We evaluated area under the precision-recall curve (AUPRC) trends and variation over the study population's treatment course. Results: The pretrained LSTM model improved predictive performance over pretrained Attention models and benchmarks in 3 of 4 outcomes including self-harm/suicide attempt (AUPRCs, LSTM pretrained = 0.012, Attention pretrained = 0.010, RBM = 0.009, random forest = 0.005). The use of autoencoders for feature engineering had varied results, with benchmarks outperforming LSTM and Attention encodings on the self-harm/suicide attempt outcome (AUPRCs, LSTM encodings = 0.003, Attention encodings = 0.004, RBM = 0.009, random forest = 0.005). Discussion: Improvement in prediction resulting from pretraining has the potential for increased clinical impact of MDD risk models. We did not find evidence that the use of temporal feature encodings was additive to predictive performance in the study population. This suggests that predictive information retained by model weights may be lost during encoding. LSTM pretrained model predictive performance is shown to be clinically useful and improves over state-of-the-art predictors in the MDD phenotype. LSTM model performance warrants consideration of use in future related studies. Conclusion: LSTM models with pretrained weights from autoencoders were able to outperform the benchmark and a pretrained Attention model. Future researchers developing risk models in MDD may benefit from the use of LSTM autoencoder pretrained weights.

Movement behavior of swordfish provisions connectivity between the temperate and tropical southwest Pacific Ocean.

Swordfish (Xiphias gladius) are a widely distributed (45°N-45°S) large pelagic fish targeted by fisheries worldwide. Swordfish that occur at high latitudes tend to disproportionately be large adults, so their movements have implications for population dynamics and fisheries management. In the southwest Pacific, little is known about this subset of the stock and existing evidence suggests limited movement from the subtropics into cooler high latitude waters. Here, we capitalize on the recent emergence of a recreational swordfish fishery off temperate southeast Australia to characterize movements of swordfish caught in the fishery with pop-up satellite archival transmitting tags. Data were recovered from tags deployed for 56-250 days on 11 swordfish (50-350 kg) tagged between 38 and 43°S in the western Tasman Sea. Five swordfish entered the Coral Sea (< 30°S), with four reaching north to 11-24°S, up to 3275 km away from location of capture. Behavior modelling suggests these four individuals rapidly transited north until encountering 23-27 °C water, at which point they lingered in the area for several months, consistent with spawning-related partial migration. One migrating swordfish still carrying a tag after the spawning season returned to ~ 120 km of its release location, suggesting site fidelity. Movements toward the central south Pacific were confined to two individuals crossing 165°E. Swordfish predominantly underwent normal diel vertical migration, descending into the mesopelagic zone at dawn (median daytime depth 494.9 m, 95% CI 460.4-529.5 m). Light attenuation predicted daytime depth, with swordfish rising by up to 195 m in turbid water. At night, swordfish were deeper during the full moon, median night-time depth 45.8 m (37.8-55.5) m versus 18.0 m (14.9-21.8) m at new moon. Modelling fine-scale (10 min-1) swordfish depth revealed dynamic effects of moon phase varying predictably across time of night with implications for fisheries interactions. Studying highly migratory fishes near distribution limits allows characterization of the full range of movement phenotypes within a population, a key consideration for important fish stocks in changing oceans.

The utility of molecular diagnostics to predict recurrence of head and neck carcinoma.

BACKGROUND: Locoregional recurrence is the major cause of treatment failure after surgery for oral squamous cell carcinoma. Molecular diagnostics have the potential to improve on clinicopathological parameters to predict this recurrence and plan adjuvant treatment. The test most frequently applied is based on detecting TP53 mutations, but alternative methodology is required for cases that harbour the wild-type gene. METHODS: One hundred and two cases with tumour-adjacent margins, considered to be clear margins by microscopy, were examined using carefully optimised molecular diagnostics based on detection of the TP53 and Ly-6D markers. The markers were also combined to provide a dual approach. RESULTS: The dual molecular diagnostic identified cases with a significant increase in the probablility of developing locoregional recurrence when tumour-adjacent positive and clear margins were compared (P=0.0001). These tests were most useful when the clearance at the resection margins was 5 mm or less. The TP53-based diagnostic was a better predictor of locoregional recurrence than established clinicopathological parameters. CONCLUSION: The optimised TP53-based diagnostic rapidly identifies an important subgroup of cases with close margins that will benefit from new treatment modalities to reduce the risk of recurrence.

Cathelicidin-3 Associated With Serum Extracellular Vesicles Enables Early Diagnosis of a Transmissible Cancer.

The identification of practical early diagnostic biomarkers is a cornerstone of improved prevention and treatment of cancers. Such a case is devil facial tumor disease (DFTD), a highly lethal transmissible cancer afflicting virtually an entire species, the Tasmanian devil (Sarcophilus harrisii). Despite a latent period that can exceed one year, to date DFTD diagnosis requires visual identification of tumor lesions. To enable earlier diagnosis, which is essential for the implementation of effective conservation strategies, we analyzed the extracellular vesicle (EV) proteome of 87 Tasmanian devil serum samples using data-independent acquisition mass spectrometry approaches. The antimicrobial peptide cathelicidin-3 (CATH3), released by innate immune cells, was enriched in serum EV samples of both devils with clinical DFTD (87.9% sensitivity and 94.1% specificity) and devils with latent infection (i.e., collected while overtly healthy, but 3-6 months before subsequent DFTD diagnosis; 93.8% sensitivity and 94.1% specificity). Although high expression of antimicrobial peptides has been mostly related to inflammatory diseases, our results suggest that they can be also used as accurate cancer biomarkers, suggesting a mechanistic role in tumorous processes. This EV-based approach to biomarker discovery is directly applicable to improving understanding and diagnosis of a broad range of diseases in other species, and these findings directly enhance the capacity of conservation strategies to ensure the viability of the imperiled Tasmanian devil population.

A large observational study of cardiovascular outcomes associated with atorvastatin or simvastatin therapy in hypertensive patients without prior cardiovascular disease.

The objective of this study was to examine whether differences in effectiveness exist between statins in hypertensive patients seen in clinical practice. We assessed cardiovascular (CV) outcomes in hypertensive patients without cardiovascular disease who began therapy with atorvastatin (10 or 20 mg/d) or simvastatin (20 or 40 mg/d) between January 1, 2003, and September 30, 2005, using claims data from 92 US managed care plans in the PharMetrics database. A total of 98,471 hypertensive patients were identified, comprising 74,685 atorvastatin users (mean dose 13.6 mg/d) and 23,786 simvastatin users (mean dose 28.6 mg/d), and followed a median 1.5 years for the occurrence of a first CV event. The crude CV event rates were 2.81 and 3.92 per 100 person-years for atorvastatin and simvastatin, respectively [unadjusted hazard ratio (HR): 0.73; 95% confidence interval (CI): 0.68-0.78, P < 0.001]. After adjusting for clinical and demographic confounders, use of atorvastatin was associated with fewer CV events compared with simvastatin (HR: 0.91; 95% CI: 0.84-0.98, P = 0.009). However, the lipid-lowering efficacy of the 2 statins could not be assessed as patient lipid data were unavailable. In conclusion, hypertensive patients without cardiovascular disease who initiated atorvastatin (10 or 20 mg/d) had a significantly lower risk of subsequent CV events compared with those who initiated simvastatin at doses of similar potency (20 or 40 mg/d). As with all observational studies, the study is subject to certain limitations, and the findings should be regarded as hypothesis generating.

Using acoustic telemetry to quantify potential contaminant exposure of Vermilion Rockfish (Sebastes miniatus), Hornyhead Turbot (Pleuronichthys verticalis), and White Croaker (Genyonemus lineatus) at wastewater outfalls in southern California.

Contaminant Exposure Models (CEMs) were developed to predict population-level tissue contaminant concentrations in fishes by pairing sediment-bound contaminant concentrations (DDTs, PCBs) and fine-scale acoustic telemetry data from a habitat-associated species (Vermilion Rockfish, Sebastes miniatus), nomadic flatfish species (Hornyhead Turbot, Pleuronichthys verticalis), and nomadic benthic/midwater schooling species (White Croaker, Genyonemus lineatus) tagged near wastewater outfalls in southern California. Model results were compared to contaminant concentrations in tissue samples. The CEMs developed require further refinement before implementation into management efforts but may act as steppingstones to help shift primary monitoring methods away from the regular field collection of fish for tissue contaminant analyses and towards behavioral modeling and habitat mapping. We also developed Kernel Density Estimates that can be used by managers immediately to identify regions that contribute most to contaminant exposure in species of concern. Prioritizing remediation efforts in these areas are likely to be most effective at improving fish health.

The impact of dental Medicaid reform on dental care provider activity and market penetration of dental support organizations.

BACKGROUND: Medicaid state dental programs have experienced changes related to provider practice settings with the increased growth of dental support organizations (DSOs). The authors conducted this study to assess the impact of state Medicaid reform on the dental practice environment by examining provider activity and practice setting. METHODS: This was a retrospective cohort study of more than 13 million dental claims in the Virginia Medicaid program. It included children and dental care providers in the Virginia dental Medicaid program at some time during a 9-year period (fiscal years 2003-2011). The independent variable was the provider practice setting: private practice, DSO, and safety-net practice. The outcomes included annual measures of claims, patients, and payments per provider. The outcomes were examined over 3 phases of the study period: prereform (2003-2005), implementation phase (2006-2008), and postreform maturation (2009-2011). RESULTS: Provider activity increased after dental program reform, with private-practice providers delivering most of the dental care in the Medicaid program. There was a significant penetration of DSO providers in number of providers, claims per provider, and patients per provider (P < .001). Regression results found that providers in DSO settings had an increased number of patients and claims compared with private-practice providers. CONCLUSIONS: Medicaid reform has resulted in a significant increase in provider participation and growth of DSO-affiliated providers. PRACTICAL IMPLICATIONS: Areas of the state with more dense population had a higher penetrance of dentists practicing in DSO settings providing dental services to children enrolled in Medicaid.

Search for Lorentz invariance and CPT violation with the MINOS far detector.

We searched for a sidereal modulation in the MINOS far detector neutrino rate. Such a signal would be a consequence of Lorentz and CPT violation as described by the standard-model extension framework. It also would be the first detection of a perturbative effect to conventional neutrino mass oscillations. We found no evidence for this sidereal signature, and the upper limits placed on the magnitudes of the Lorentz and CPT violating coefficients describing the theory are an improvement by factors of 20-510 over the current best limits found by using the MINOS near detector.

Estimated effect of US state syringe sale policy on source of last-used injection equipment.

BACKGROUND: Many people who inject drugs (PWID) lack access to a new sterile syringe each time they inject, with increased risk of injection-related harms, including spread of communicable diseases. In the United States (US), restricted access is largely due to state laws and policies regulating syringe access. Our aim in this US-focused study is to estimate variations in syringe acquisition behavior in relation to state-level syringe sale policies, drawing upon self-identified PWID in a nationally representative sample survey. METHODS: Estimates were obtained on the source of the last used syringe from participants of the National Survey on Drug Use and Health (NSDUH) years 2002-2011. States were classified as having restricted syringe policies if they had any restriction on the sale of syringes during the study period (e.g., required a prescription or limited the number being sold). RESULTS: In states with unrestricted syringe sale policies, PWID were more likely to have obtained their most recently used syringe from a safe source (Difference (%) = 9.8, 95% CI: 1.9, 17.7). This difference was largely driven by a larger percent of injectors obtaining syringes from a pharmacy in unrestricted states (Difference = 20.4, 95% CI: 12.2, 28.6) but was partially offset by fewer injectors obtaining syringes from syringe exchange programs (Difference = -10.7, 95% CI: -16.1, -5.3). CONCLUSION: These new findings, taken with other evidence, should help promote removal of policy barriers that now thwart syringe acquisition from a safe source. We hope this additional evidence will provoke policy discussions and may influence regulations that promote public health and reduce the spread of communicable diseases.

In vivo tissue reaction within the outflow conduit in patients supported by HeartWare HVAD.

AIM: The frequency, extent, and nature of tissue ingrowth within the continuous-flow left ventricular assist device (cf-LVAD) outflow conduit has not been systematically assessed. We sought to characterize conduit histopathology at explantation in a cohort of patients with HeartWare ventricular assist device (HVAD) and assess the effect on pump performance. METHODS: Patients undergoing routine histopathological assessment of a HeartWare HVAD removed at transplantation or autopsy were assessed. Outflow conduits were examined macroscopically, and visible tissue was sectioned for microscopic evaluation. In patients who had undergone prior contrast-enhanced computerized tomography (CT) with HVAD in situ, the outflow conduit was measured at the aortic anastomosis and 5 cm proximal to the anastomosis, in the axial and sagittal planes. All patients had their pump flow, flow pulsatility, current, and speed determined from log files examined at 1, 3, 6, 9, and 12 months after LVAD implantation. RESULTS: Twenty-five consecutive patients were assessed (24 LVAD, 1 biventricular assist device (BiVAD)). Of the 26 outflow grafts assessed, there was evidence of tissue ingrowth reaction in 24 (92%) grafts. The most common site was the distal anastomosis (18/24, 75%), with the graft body involved in 14 of 24 (58%) grafts. Microscopic evaluation revealed acute inflammatory infiltrate in 4 of 24 grafts (17%), chronic inflammatory infiltrate in 14 of 24 (58%), neointima formation in 18 of 24 (75%) and fibrosis in 18 of 24 (75%) grafts. The median depth of tissue was 1 mm (range, 0-2 mm). The mean conduit diameter was 9.5 ± 0.6 mm at the aortic anastomosis compared with 11.1 ± 0.5 mm 5 cm proximal to the anastomosis (p < 0.0001). In patients with unchanged pump speed one month after implantation, analysis of log files revealed a significant (5.8 ± 8.6%) decrease in pump flow (4.65 ± 0.86 vs 4.38 ± 0.92 L/min, p = 0.01) and flow pulsatility (5.00 ± 1.10 vs 4.16 ± 1.05 L/min, p = 0.006). CONCLUSIONS: There is evidence of tissue formation within the HVAD outflow conduit in the vast majority of patients, most commonly located at the aortic anastomosis. This is associated with significantly decreased pump flow over time.

Physiological mechanisms linking cold acclimation and the poleward distribution limit of a range-extending marine fish.

Extensions of species' geographical distributions, or range extensions, are among the primary ecological responses to climate change in the oceans. Considerable variation across the rates at which species' ranges change with temperature hinders our ability to forecast range extensions based on climate data alone. To better manage the consequences of ongoing and future range extensions for global marine biodiversity, more information is needed on the biological mechanisms that link temperatures to range limits. This is especially important at understudied, low relative temperatures relevant to poleward range extensions, which appear to outpace warm range edge contractions four times over. Here, we capitalized on the ongoing range extension of a teleost predator, the Australasian snapper Chrysophrys auratus, to examine multiple measures of ecologically relevant physiological performance at the population's poleward range extension front. Swim tunnel respirometry was used to determine how mid-range and poleward range edge winter acclimation temperatures affect metabolic rate, aerobic scope, swimming performance and efficiency and recovery from exercise. Relative to 'optimal' mid-range temperature acclimation, subsequent range edge minimum temperature acclimation resulted in absolute aerobic scope decreasing while factorial aerobic scope increased; efficiency of swimming increased while maximum sustainable swimming speed decreased; and recovery from exercise required a longer duration despite lower oxygen payback. Cold-acclimated swimming faster than 0.9 body lengths sec-1 required a greater proportion of aerobic scope despite decreased cost of transport. Reduced aerobic scope did not account for declines in recovery and lower maximum sustainable swimming speed. These results suggest that while performances decline at range edge minimum temperatures, cold-acclimated snapper are optimized for energy savings and range edge limitation may arise from suboptimal temperature exposure throughout the year rather than acute minimum temperature exposure. We propose incorporating performance data with in situ behaviour and environmental data in bioenergetic models to better understand how thermal tolerance determines range limits.