Resting and exercise haemodynamic characteristics of patients with advanced heart failure and preserved ejection fraction.

AIMS: This study aimed to describe haemodynamic features of patients with advanced heart failure with preserved ejection fraction (HFpEF) as defined by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). METHODS AND RESULTS: We used pooled data from two dedicated HFpEF studies with invasive exercise haemodynamic protocols, the REDUCE LAP-HF (Reduce Elevated Left Atrial Pressure in Patients with Heart Failure) trial and the REDUCE LAP-HF I trial, and categorized patients according to advanced heart failure (AdHF) criteria. The well-characterized HFpEF patients were considered advanced if they had persistent New York Heart Association classification of III-IV and heart failure (HF) hospitalization < 12 months and a 6 min walk test distance < 300 m. Twenty-four (22%) out of 108 patients met the AdHF criteria. On evaluation, clinical characteristics and resting haemodynamics were not different in the two groups. Patients with AdHF had lower work capacity compared with non-advanced patients (35 ± 16 vs. 45 ± 18 W, P = 0.021). Workload-corrected pulmonary capillary wedge pressure normalized to body weight (PCWL) was higher in AdHF patients compared with non-advanced (112 ± 55 vs. 86 ± 49 mmHg/W/kg, P = 0.04). Further, AdHF patients had a smaller increase in cardiac index during exercise (1.1 ± 0.7 vs. 1.6 ± 0.9 L/min/m2 , P = 0.028). CONCLUSIONS: A significantly higher PCWL and lower cardiac index reserve during exercise were observed in AdHF patients compared with non-advanced. These differences were not apparent at rest. Therapies targeting the haemodynamic compromise associated with advanced HFpEF are needed.

Financial analysis of revision knee surgery at a tertiary referral centre as classified according to the Revision Knee Complexity Classification (RKCC).

BACKGROUND: Revision total knee arthroplasty (rTKA) can be complex, with greater costs to the treating hospital than primary TKA. A rTKA regional network has been proposed in England. The aim of this work was to accurately quantify current costs and reimbursement for the rTKA service and to assess whether costs are proportional to case complexity at a tertiary referral centre within the National Health Service (NHS). METHODS: A review of all rTKA performed at our institution over two consecutive financial years (2017-2019) was performed. Cases were classified according to the Revision Knee Complexity Classification (RKCC) and by mode of failure; "infected" and "non-infected". Financial data was acquired through Patient-Level Information and Costing System (PLICS). The primary outcome was the financial difference between tariff and cost per episode. Comparisons between groups were analysed using analysis of variance and two-tailed unpaired t-test as appropriate. RESULTS: 159 patients underwent 188 rTKA procedures. Length of stay and cost significantly increased between complexity groups (p < 0.0001) and for infected revisions (p < 0.0001). All groups sustained a mean deficit but this significantly increased with revision complexity (from £1,903 to £5,269 per case) and for infected revisions. The total deficit to the Trust for the two-year rTKA service was £667,091. CONCLUSIONS: The current level of NHS reimbursement are inadequate for centres that offer rTKA and should be more closely aligned to case complexity. An increase in the most complex rTKA at major revision centres will undoubtedly place an even greater strain on the finances of these units.

Travel time to health facilities in areas of outbreak potential: maps for guiding local preparedness and response.

BACKGROUND: Repeated outbreaks of emerging pathogens underscore the need for preparedness plans to prevent, detect, and respond. As countries develop and improve National Action Plans for Health Security, addressing subnational variation in preparedness is increasingly important. One facet of preparedness and mitigating disease transmission is health facility accessibility, linking infected persons with health systems and vice versa. Where potential patients can access care, local facilities must ensure they can appropriately diagnose, treat, and contain disease spread to prevent secondary transmission; where patients cannot readily access facilities, alternate plans must be developed. Here, we use travel time to link facilities and populations at risk of viral hemorrhagic fevers (VHFs) and identify spatial variation in these respective preparedness demands. METHODS AND FINDINGS: We used geospatial resources of travel friction, pathogen environmental suitability, and health facilities to determine facility accessibility of any at-risk location within a country. We considered in-country and cross-border movements of exposed populations and highlighted vulnerable populations where current facilities are inaccessible and new infrastructure would reduce travel times. We developed profiles for 43 African countries. Resulting maps demonstrate gaps in health facility accessibility and highlight facilities closest to areas at risk for VHF spillover. For instance, in the Central African Republic, we identified travel times of over 24 h to access a health facility. Some countries had more uniformly short travel times, such as Nigeria, although regional disparities exist. For some populations, including many in Botswana, access to areas at risk for VHF nationally was low but proximity to suitable spillover areas in bordering countries was high. Additional analyses provide insights for considering future resource allocation. We provide a contemporary use case for these analyses for the ongoing Ebola outbreak. CONCLUSIONS: These maps demonstrate the use of geospatial analytics for subnational preparedness, identifying facilities close to at-risk populations for prioritizing readiness to detect, treat, and respond to cases and highlighting where gaps in health facility accessibility exist. We identified cross-border threats for VHF exposure and demonstrate an opportunity to improve preparedness activities through the use of precision public health methods and data-driven insights for resource allocation as part of a country's preparedness plans.

Effects of intentional weight loss in patients with obesity and heart failure: a systematic review.

OBJECTIVE: Obesity is an independent risk factor for the development of heart failure, and the two commonly co-exist. The European Society of Cardiology does not provide guidance regarding weight loss strategies in heart failure. The aim of this study was to systematically review the evidence for outcomes following intentional weight loss in patients with heart failure and obesity. METHOD: A systematic review of English articles was undertaken using databases PubMed, Embase and CENTRAL. Randomized controlled trials and observational studies reporting outcomes following intentional weight loss by lifestyle, surgical or pharmacotherapy intervention in patients with obesity and heart failure were included. RESULTS: Four randomized controlled trials and seven observational studies were identified. Two randomized controlled trials used diet and exercise as an intervention, one used diet alone and one used a pharmacological intervention (orlistat). All but one reported significant weight loss. Two reported improvement in exercise capacity and quality of life. One reported improvement in New York Heart Association functional class in heart failure with preserved ejection fraction. The observational studies, five of which reported on outcomes following bariatric surgery, despite being small, heterogeneous and high risk of bias, suggested a trend in improvement of left ventricular function, quality of life and exercise capacity following weight loss. CONCLUSION: Weight loss is achievable with lifestyle intervention in those with heart failure and obesity and may result in improvements in New York Heart Association classification, quality of life and exercise capacity.

A new and reliable classification system for fractures of the navicular and associated injuries to the midfoot.

AIMS: Fractures of the navicular can occur in isolation but, owing to the intimate anatomical and biomechanical relationships, are often associated with other injuries to the neighbouring bones and joints in the foot. As a result, they can lead to long-term morbidity and poor function. Our aim in this study was to identify patterns of injury in a new classification system of traumatic fractures of the navicular, with consideration being given to the commonly associated injuries to the midfoot. PATIENTS AND METHODS: We undertook a retrospective review of 285 consecutive patients presenting over an eight- year period with a fracture of the navicular. Five common patterns of injury were identified and classified according to the radiological features. Type 1 fractures are dorsal avulsion injuries related to the capsule of the talonavicular joint. Type 2 fractures are isolated avulsion injuries to the tuberosity of the navicular. Type 3 fractures are a variant of tarsometatarsal fracture/dislocations creating instability of the medial ray. Type 4 fractures involve the body of the navicular with no associated injury to the lateral column and type 5 fractures occur in conjunction with disruption of the midtarsal joint with crushing of the medial or lateral, or both, columns of the foot. RESULTS: In order to test the reliability and reproducibility of this new classification, a cohort of 30 patients with a fracture of the navicular were classified by six independent assessors at two separate times, six months apart. Interobserver reliability and intraobserver reproducibility both had substantial agreement, with kappa values of 0.80 and 0.72, respectively. CONCLUSION: We propose a logical, all-inclusive, and mutually exclusive classification system for fractures of the navicular that gives associated injuries involving the lateral column due consideration. We have shown that this system is reliable and reproducible and have described the rationale for the subsequent treatment of each type. Cite this article: Bone Joint J 2018;100-B:176-82.

Climate change may restrict dryland forest regeneration in the 21st century.

The persistence and geographic expansion of dryland forests in the 21st century will be influenced by how climate change supports the demographic processes associated with tree regeneration. Yet, the way that climate change may alter regeneration is unclear. We developed a quantitative framework that estimates forest regeneration potential (RP) as a function of key environmental conditions for ponderosa pine, a key dryland forest species. We integrated meteorological data and climate projections for 47 ponderosa pine forest sites across the western United States, and evaluated RP using an ecosystem water balance model. Our primary goal was to contrast conditions supporting regeneration among historical, mid-21st century and late-21st century time frames. Future climatic conditions supported 50% higher RP in 2020-2059 relative to 1910-2014. As temperatures increased more substantially in 2060-2099, seedling survival decreased, RP declined by 50%, and the frequency of years with very low RP increased from 25% to 58%. Thus, climate change may initially support higher RP and increase the likelihood of successful regeneration events, yet will ultimately reduce average RP and the frequency of years with moderate climate support of regeneration. Our results suggest that climate change alone may begin to restrict the persistence and expansion of dryland forests by limiting seedling survival in the late 21st century.

Bone architecture adaptations after spinal cord injury: impact of long-term vibration of a constrained lower limb.

SUMMARY: This study examined the effect of a controlled dose of vibration upon bone density and architecture in people with spinal cord injury (who eventually develop severe osteoporosis). Very sensitive computed tomography (CT) imaging revealed no effect of vibration after 12 months, but other doses of vibration may still be useful to test. INTRODUCTION: The purposes of this report were to determine the effect of a controlled dose of vibratory mechanical input upon individual trabecular bone regions in people with chronic spinal cord injury (SCI) and to examine the longitudinal bone architecture changes in both the acute and chronic state of SCI. METHODS: Participants with SCI received unilateral vibration of the constrained lower limb segment while sitting in a wheelchair (0.6g, 30 Hz, 20 min, three times weekly). The opposite limb served as a control. Bone mineral density (BMD) and trabecular micro-architecture were measured with high-resolution multi-detector CT. For comparison, one participant was studied from the acute (0.14 year) to the chronic state (2.7 years). RESULTS: Twelve months of vibration training did not yield adaptations of BMD or trabecular micro-architecture for the distal tibia or the distal femur. BMD and trabecular network length continued to decline at several distal femur sub-regions, contrary to previous reports suggesting a "steady state" of bone in chronic SCI. In the participant followed from acute to chronic SCI, BMD and architecture decline varied systematically across different anatomical segments of the tibia and femur. CONCLUSIONS: This study supports that vibration training, using this study's dose parameters, is not an effective anti-osteoporosis intervention for people with chronic SCI. Using a high-spatial-resolution CT methodology and segmental analysis, we illustrate novel longitudinal changes in bone that occur after spinal cord injury.

Grassland to shrubland state transitions enhance carbon sequestration in the northern Chihuahuan Desert.

The replacement of native C4 -dominated grassland by C3 -dominated shrubland is considered an ecological state transition where different ecological communities can exist under similar environmental conditions. These state transitions are occurring globally, and may be exacerbated by climate change. One consequence of the global increase in woody vegetation may be enhanced ecosystem carbon sequestration, although the responses of arid and semiarid ecosystems may be highly variable. During a drier than average period from 2007 to 2011 in the northern Chihuahuan Desert, we found established shrubland to sequester 49 g C m(-2) yr(-1) on average, while nearby native C4 grassland was a net source of 31 g C m(-2) yr(-1) over this same period. Differences in C exchange between these ecosystems were pronounced--grassland had similar productivity compared to shrubland but experienced higher C efflux via ecosystem respiration, while shrubland was a consistent C sink because of a longer growing season and lower ecosystem respiration. At daily timescales, rates of carbon exchange were more sensitive to soil moisture variation in grassland than shrubland, such that grassland had a net uptake of C when wet but lost C when dry. Thus, even under unfavorable, drier than average climate conditions, the state transition from grassland to shrubland resulted in a substantial increase in terrestrial C sequestration. These results illustrate the inherent tradeoffs in quantifying ecosystem services that result from ecological state transitions, such as shrub encroachment. In this case, the deleterious changes to ecosystem services often linked to grassland to shrubland state transitions may at least be partially offset by increased ecosystem carbon sequestration.

Effects of HCV seropositive status on buprenorphine pharmacokinetics in opioid-dependent individuals.

BACKGROUND AND OBJECTIVES: The purpose of this study was to examine the effect of hepatitis C virus (HCV) infection on buprenorphine pharmacokinetics in opioid-dependent, buprenorphine/naloxone-maintained adults. METHODS: A retrospective analysis of buprenorphine pharmacokinetics in HCV seropositive and seronegative buprenorphine/naloxone-maintained individuals (N = 49) was undertaken. RESULTS: Relative to HCV seronegative subjects, HCV seropositive subjects had higher buprenorphine exposure, as demonstrated by elevated buprenorphine AUC and Cmax values (p = .03 and .02, respectively) and corresponding elevations in the metabolites, buprenorphine-3-glucuronide AUC values (p = .03) and norbuprenorphine-3-glucuronide AUC and C24 values (p = .05 and .03, respectively). DISCUSSION AND CONCLUSIONS: HCV infection was associated with higher plasma concentrations of buprenorphine and buprenorphine metabolites. SCIENTIFIC SIGNIFICANCE AND FUTURE DIRECTIONS: Findings suggest the potential for opioid toxicity among HCV-infected patients treated with buprenorphine/naloxone, and possible hepatotoxic effects related to increased buprenorphine exposure. HCV-infected patients receiving buprenorphine may need lower doses to maintain therapeutic plasma concentrations.

Interactions between alcohol and the HIV entry inhibitor Maraviroc.

BACKGROUND: Alcohol use is common among people with HIV, and beliefs about alcohol interactions with medications predict decreased medication adherence, risking drug-resistant mutations. Maraviroc is an HIV entry inhibitor approved for treatment of both drug-sensitive and drug-resistant HIV strains. The present study evaluated the effects of alcohol on maraviroc pharmacokinetics and the effects of maraviroc on alcohol pharmacokinetics. METHODS: Ten healthy adults completed alcohol (1 g/kg) and placebo alcohol pharmacokinetics sessions before and after 7 days of maraviroc administration. RESULTS: Alcohol concentrations increased 12% following maraviroc. Maraviroc pharmacokinetics were unaffected by alcohol. CONCLUSIONS: Maraviroc treatment should not be interrupted if alcohol is consumed.

Interactions between alcohol and the antiretroviral medications ritonavir or efavirenz.

OBJECTIVE: Alcohol abuse occurs frequently in those with human immunodeficiency virus (HIV) infection. Alcohol has been linked to poor response to HIV treatment and more rapid progression of HIV. One possible contributor to such observations is drug interactions between alcohol and antiretroviral (ARV) medications. This study examined drug interactions between antiretroviral therapies (ARTs) containing either efavirenz or ritonavir with alcohol. METHODS: Human immunodeficiency virus-infected individuals not currently receiving ARTs participated in a randomized, double-blind, placebo-controlled study in which alcohol (or placebo) was administered and followed by blood sampling for pharmacokinetics, subjective, cardiovascular, and neuropsychological responses obtained at predetermined times. Antiretroviral therapy was then initiated and alcohol (or placebo) sessions were repeated after at least 2 weeks of observed ART. RESULTS: Blood alcohol concentrations (BAC) were lower after ART in a pattern consistent with decreased bioavailability. No effect of alcohol on ritonavir or efavirenz pharmacokinetics was observed. A pharmacodynamic interaction between alcohol and efavirenz was observed as evidenced by no change in intoxication or drowsiness before and after efavirenz ART despite lower BAC. CONCLUSIONS: These results show the effectiveness of implementing ART and its role in diminution of BAC, which could be associated with decreased risk of physiological toxicities related to alcohol consumption relative to those with untreated HIV infection. A potential pharmacodynamic interaction between alcohol and efavirenz was observed as demonstrated by a lack of decline in ratings of intoxication and drowsiness despite decreased BAC. Alcohol consumption did not alter the pharmacokinetics of ritonavir or efavirenz.

Cross-reactivity studies and predictive modeling of "Bath Salts" and other amphetamine-type stimulants with amphetamine screening immunoassays.

INTRODUCTION: The increasing abuse of amphetamine-like compounds presents a challenge for clinicians and clinical laboratories. Although these compounds may be identified by mass spectrometry-based assays, most clinical laboratories use amphetamine immunoassays that have unknown cross-reactivity with novel amphetamine-like drugs. To date, there has been a little systematic study of amphetamine immunoassay cross-reactivity with structurally diverse amphetamine-like drugs or of computational tools to predict cross-reactivity. METHODS: Cross-reactivities of 42 amphetamines and amphetamine-like drugs with three amphetamines screening immunoassays (AxSYM(®) Amphetamine/Methamphetamine II, CEDIA(®) amphetamine/Ecstasy, and EMIT(®) II Plus Amphetamines) were determined. Two- and three-dimensional molecular similarity and modeling approaches were evaluated for the ability to predict cross-reactivity using receiver-operator characteristic curve analysis. RESULTS: Overall, 34%-46% of the drugs tested positive on the immunoassay screens using a concentration of 20,000 ng/mL. The three immunoassays showed differential detection of the various classes of amphetamine-like drugs. Only the CEDIA assay detected piperazines well, while only the EMIT assay cross-reacted with the 2C class. All three immunoassays detected 4-substituted amphetamines. For the AxSYM and EMIT assays, two-dimensional molecular similarity methods that combined similarity to amphetamine/methamphetamine and 3,4-methylenedioxymethampetamine most accurately predicted cross-reactivity. For the CEDIA assay, three-dimensional pharmacophore methods performed best in predicting cross-reactivity. Using the best performing models, cross-reactivities of an additional 261 amphetamine-like compounds were predicted. CONCLUSIONS: Existing amphetamines immunoassays unevenly detect amphetamine-like drugs, particularly in the 2C, piperazine, and ß-keto classes. Computational similarity methods perform well in predicting cross-reactivity and can help prioritize testing of additional compounds in the future.

Untreated HIV infection is associated with higher blood alcohol levels.

BACKGROUND: Alcohol abuse has been associated with HIV/AIDS progression, but the effects of HIV infection and treatment on alcohol exposure have not been explored to date. This pilot study examines the relationship of untreated HIV infection to blood alcohol concentrations (BAC) relative to BAC after initiation of antiretroviral therapy (ART). METHODS: Fifteen volunteers with untreated HIV/AIDS participated in 2 sets of alcohol or alcohol placebo administration studies before and after initiation of ART. Oral alcohol (1 g/kg) or alcohol placebo was administered, participants were followed for pharmacokinetics, subjective responses, and cognitive effects over 8 hours. After initial alcohol studies, the ART regimen selected by participant clinicians was instituted. Observed ART dosing took place for at least 2 weeks. Participants then returned for a second set of alcohol/placebo administration studies while on ART. RESULTS: Participants had significantly higher BAC (P < 0.001) before ART than after ART administration. Alcohol area under the curve was significantly higher in untreated HIV disease (P = 0.011) with significantly higher C(max) (P = 0.015) and C(min) (P = 0.05). The elimination rate was not different between pre-ART and post-ART conditions. Despite declines in BAC after ART initiation, no differences in subjective responses were observed with alcohol administration. CONCLUSIONS: Untreated HIV infection is associated with risk for higher BAC than that observed after ART. These findings indicate that patients with untreated HIV disease who ingest alcohol are at greater risk for alcohol associated adverse events and toxicities and underscores the need for simultaneous treatment of alcohol use disorders and HIV in patients with co-occurring conditions.

Interactions between buprenorphine and the protease inhibitors darunavir-ritonavir and fosamprenavir-ritonavir.

BACKGROUND: This study examined drug interactions between buprenorphine, a partial opioid agonist used for opioid dependence treatment and pain management, and the protease inhibitors (PIs) darunavir-ritonavir and fosamprenavir-ritonavir. METHODS: The pharmacokinetics of buprenorphine and its metabolites and symptoms of opioid withdrawal or excess were compared in opioid-dependent, buprenorphine-naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (11 for darunavir-ritonavir and 10 for fosamprenavir-ritonavir) before and after 15 days of PI administration. PI pharmacokinetics and adverse effects were compared between the buprenorphine-maintained participants and an equal number of sex-, age-, race-, and weight-matched, healthy, non-opioid-dependent volunteers who received darunavir-ritonavir or fosamprenavir-ritonavir but not buprenorphine. RESULTS: There were no significant changes in buprenorphine or PI plasma levels and no significant changes in medication adverse effects or opioid withdrawal. Increased concentrations of the inactive metabolite buprenorphine-3-glucuronide suggested that darunavir-ritonavir and fosamprenavir-ritonavir induced glucuronidation of buprenorphine. CONCLUSIONS: Dose adjustments are not likely to be necessary when buprenorphine and darunavir-ritonavir or fosamprenavir-ritonavir are coadministered for the treatment of opioid dependence and HIV disease.

Use of the BD vacutainer rapid serum tube reduces false-positive results for selected beckman coulter Unicel DxI immunoassays.

We investigated the use of serum samples from BD Vacutainer rapid serum tubes (RSTs; BD, Franklin Lakes, NJ) to reduce undetermined interferences contributing to false-positive immunoassay results in heparin plasma samples. Patients being evaluated for suspected myocardial infarction had specimens drawn into an RST in addition to the standard lithium-heparin plasma separator tube (PST). We measured 28 separate analytes in both specimens using immunoassay, electrochemical, and spectrophotometric methods. Higher results were observed in some PST specimens tested for troponin I, creatine kinase-MB isoenzyme, human chorionic gonadotropin, and thyroid-stimulating hormone. These discrepancies were investigated by repeating analyses after recentrifugation of both specimens. Reanalysis gave results for the PST specimens that were lower and agreed well with initial results from RSTs, suggesting false-positive rates of 10.8% for troponin I and about 2% for each of the other 3 analytes. Overall, specimens collected in RSTs had fewer false-positive immunoassay results than specimens collected in plasma separator tubes.