Population genomic analyses of the chocolate tree, Theobroma cacao L., provide insights into its domestication process.

Domestication has had a strong impact on the development of modern societies. We sequenced 200 genomes of the chocolate plant Theobroma cacao L. to show for the first time to our knowledge that a single population, the Criollo population, underwent strong domestication ~3600 years ago (95% CI: 2481-13,806 years ago). We also show that during the process of domestication, there was strong selection for genes involved in the metabolism of the colored protectants anthocyanins and the stimulant theobromine, as well as disease resistance genes. Our analyses show that domesticated populations of T. cacao (Criollo) maintain a higher proportion of high-frequency deleterious mutations. We also show for the first time the negative consequences of the increased accumulation of deleterious mutations during domestication on the fitness of individuals (significant reduction in kilograms of beans per hectare per year as Criollo ancestry increases, as estimated from a GLM, P = 0.000425).

Integration of Single-Center Data-Driven Vital Sign Parameters into a Modified Pediatric Early Warning System.

OBJECTIVES: Pediatric early warning systems using expert-derived vital sign parameters demonstrate limited sensitivity and specificity in identifying deterioration. We hypothesized that modified tools using data-driven vital sign parameters would improve the performance of a validated tool. DESIGN: Retrospective case control. SETTING: Quaternary-care children's hospital. PATIENTS: Hospitalized, noncritically ill patients less than 18 years old. Cases were defined as patients who experienced an emergent transfer to an ICU or out-of-ICU cardiac arrest. Controls were patients who never required intensive care. Cases and controls were split into training and testing groups. INTERVENTIONS: The Bedside Pediatric Early Warning System was modified by integrating data-driven heart rate and respiratory rate parameters (modified Bedside Pediatric Early Warning System 1 and 2). Modified Bedside Pediatric Early Warning System 1 used the 10th and 90th percentiles as normal parameters, whereas modified Bedside Pediatric Early Warning System 2 used fifth and 95th percentiles. MEASUREMENTS AND MAIN RESULTS: The training set consisted of 358 case events and 1,830 controls; the testing set had 331 case events and 1,215 controls. In the sensitivity analysis, 207 of the 331 testing set cases (62.5%) were predicted by the original tool versus 206 (62.2%; p = 0.54) with modified Bedside Pediatric Early Warning System 1 and 191 (57.7%; p < 0.001) with modified Bedside Pediatric Early Warning System 2. For specificity, 1,005 of the 1,215 testing set control patients (82.7%) were identified by original Bedside Pediatric Early Warning System versus 1,013 (83.1%; p = 0.54) with modified Bedside Pediatric Early Warning System 1 and 1,055 (86.8%; p < 0.001) with modified Bedside Pediatric Early Warning System 2. There was no net gain in sensitivity and specificity using either of the modified Bedside Pediatric Early Warning System tools. CONCLUSIONS: Integration of data-driven vital sign parameters into a validated pediatric early warning system did not significantly impact sensitivity or specificity, and all the tools showed lower than desired sensitivity and specificity at a single cutoff point. Future work is needed to develop an objective tool that can more accurately predict pediatric decompensation.

Cost-Effectiveness of Adding Cardiac Resynchronization Therapy to an Implantable Cardioverter-Defibrillator Among Patients With Mild Heart Failure.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces mortality and heart failure hospitalizations in patients with mild heart failure. OBJECTIVE: To estimate the cost-effectiveness of adding CRT to an implantable cardioverter-defibrillator (CRT-D) compared with implantable cardioverter-defibrillator (ICD) alone among patients with left ventricular systolic dysfunction, prolonged intraventricular conduction, and mild heart failure. DESIGN: Markov decision model. DATA SOURCES: Clinical trials, clinical registries, claims data from Centers for Medicare & Medicaid Services, and Centers for Disease Control and Prevention life tables. TARGET POPULATION: Patients aged 65 years or older with a left ventricular ejection fraction (LVEF) of 30% or less, QRS duration of 120 milliseconds or more, and New York Heart Association (NYHA) class I or II symptoms. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: CRT-D or ICD alone. OUTCOME MEASURES: Life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). RESULTS OF BASE-CASE ANALYSIS: Use of CRT-D increased life expectancy (9.8 years versus 8.8 years), QALYs (8.6 years versus 7.6 years), and costs ($286 500 versus $228 600), yielding a cost per QALY gained of $61 700. RESULTS OF SENSITIVITY ANALYSES: The cost-effectiveness of CRT-D was most dependent on the degree of mortality reduction: When the risk ratio for death was 0.95, the ICER increased to $119 600 per QALY. More expensive CRT-D devices, shorter CRT-D battery life, and older age also made the cost-effectiveness of CRT-D less favorable. LIMITATIONS: The estimated mortality reduction for CRT-D was largely based on a single trial. Data on patients with NYHA class I symptoms were limited. The cost-effectiveness of CRT-D in patients with NYHA class I symptoms remains uncertain. CONCLUSION: In patients with an LVEF of 30% or less, QRS duration of 120 milliseconds or more, and NYHA class II symptoms, CRT-D appears to be economically attractive relative to ICD alone when a reduction in mortality is expected. PRIMARY FUNDING SOURCE: National Institutes of Health, University of Copenhagen, U.S. Department of Veterans Affairs.

Retrospective evaluation of neurotoxic rattlesnake envenomation in dogs and cats: 34 cases (2005-2010).

OBJECTIVE: To describe common physical examination findings, clinicopathologic changes, treatment, and outcome in patients with evidence of neurotoxicity secondary to rattlesnake envenomation. DESIGN: Retrospective multicenter study (2005-2010). SETTING: Three private veterinary referral centers. ANIMALS: Thirty-four client-owned cats and dogs with evidence of neurotoxicity secondary to rattlesnake envenomation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patient signalment, approximate time between envenomation and presentation for veterinary evaluation, physical examination and clinicopathologic findings, treatments, serial neurologic assessment, duration of hospitalization, and outcome were recorded. Signs of neurotoxicity such as ataxia, postural deficits, muscle fasciculations, paresis, paralysis, or seizures were required for inclusion into the study. The incidence of neurotoxicity amongst the general population treated with antivenin for rattlesnake envenomation in this study was 5.4%. Crotalidae Polyvalent Immune Fab(b) and veterinary approved Antivenin (Crotalidae) Polyvalent(a) were both used in this study. There was no statistically significant difference between type of antivenin or number of vials of antivenin administered and neurologic status, length of hospitalization (LOH), or survival. Hypokalemia was a frequently identified complication, but the presence of hypokalemia did not have a statistically significant association with LOH or survival. Four of the 34 patients (11.8%) required positive pressure ventilation for signs consistent with respiratory paralysis; 2 of these patients survived to discharge. Overall mortality rate was 17.6%. Survival was not significantly different between dogs and cats. However, cats had a significantly longer LOH when compared with dogs (median LOH 3.5 d for cats, 2 d for dogs). Cats appear to be overrepresented in the subset of envenomated patients with neurotoxicity. CONCLUSION: Although the incidence of neurotoxicity secondary to rattlesnake envenomation may be relatively low, patients can have rapid progression of their clinical signs and a higher mortality rate, necessitating timely and appropriate treatment. Patients treated for neurotoxicity secondary to envenomation appear to have a fair to good prognosis.

Late positive remodeling and late lumen gain contribute to vascular restoration by a non-drug eluting bioresorbable scaffold: a four-year intravascular ultrasound study in normal porcine coronary arteries.

BACKGROUND: The interplay between mechanical dilatation, resorption, and arterial response following implantation of bioresorbable scaffolds is still poorly understood. METHODS AND RESULTS: Long-term geometric changes in porcine coronary arteries in relation to gradual degradation of bioresorbable scaffolds were assessed in comparison with bare metal stents (BMS). Intravascular ultrasound (IVUS)-derived lumen, outer stent/scaffold, and reference vessel areas were evaluated in 94 polymer scaffolds and 46 BMS at 5 days and 3, 6, 12, 18, 24, and 55 months, in addition to polymer scaffold radial crush strength and molecular weight (M(W)) at 3, 6, and 12 months. BMS outer stent area and lumen area remained constant through 55 months (P=0.05, but within 1 standard deviation of 100%, and P=0.58, respectively), while significant increases were exhibited by polymer-scaffolded vessels with the maximum late lumen gain at 24 months, paralleled by the outer scaffold area increase, and then remaining at that increased level at 55 months (P<0.01). By 12 months polymer scaffolds experienced significant reductions in radial strength and M(W), while the animals underwent the largest weight gain. At 3 months and beyond, the patency ratio (lumen area/reference vessel area) of BMS remained constant (0.71 to 0.85, P=0.49). In contrast, that of polymer scaffolds increased and approached 1 (P=0.13). CONCLUSIONS: Bioresorbable polymer scaffolds allow restoration of the treated segment's ability to remodel outward to achieve level lumen transition between reference vessel and scaffold-treated regions, a process mediated by animal growth and scaffold degradation. This also introduces a challenge to standard analyses of IVUS outcomes relying on constant stent diameters over time.

Neuromuscular junction integrity after chronic nerve compression injury.

Chronic nerve compression injuries (CNC) are progressive demyelinating disorders characterized by a gradual decline of the nerve conduction velocity (NCV) in the affected nerve region. CNC injury induces a robust Schwann cell response with axonal sprouting, but without morphologic evidence of axonal injury. We hypothesize that early CNC injury occurs without damage to neuromuscular junction of motor axons. A well-established animal model was used to assess for damage to motor axons. As sprouting is considered a hallmark of regeneration during and after axonal degeneration and sprouting was confirmed visually at 2 weeks in CNC animals, we assessed for axonal degeneration in motor nerves after CNC by evaluating the integrity of the neuromuscular junction. NCV exhibited a gradual progressive decline consistent with the human condition. Compound motor action potential amplitudes decreased slightly immediately and plateaued, indicating that there was not sustained and increasing axonal loss. Sprouting was confirmed using immunofluorescence and by an increase in number of unmyelinated axons and Remak bundles. Blind analysis of the neuromuscular junction showed no difference between control and CNC images, indicating that there was no evidence for end-unit axonal loss in the soleus muscle. Because the progressive decline in NCV was not paired with a similar progressive decline in amplitude, it is likely that axonal loss is not responsible for slowing of action potentials. Blind analysis of the neuromuscular junction provides further evidence that the axonal sprouting seen early after CNC injury is not a consequence of axonal degeneration in the motor nerves.

The role of neurodiagnostic studies in nerve injuries and other orthopedic disorders.

Neurodiagnostic techniques, such as nerve conduction studies, needle electromyography studies, intraoperative nerve monitoring, and evoked potentials provide useful information for practicing orthopedic surgeons to help localize central from peripheral nervous system lesions. For peripheral nerve lesions, it helps localize the level of the nerve dysfunction (for example, root versus plexus versus peripheral nerve). These techniques are well established and routinely used. Newer techniques have emerged that aim to simplify the technical process of performing these studies and help reduce the discomfort associated with these studies. Many of these newer techniques, however, are in their infancy, and their role in routine use for neurodiagnostic purposes is not clear. This review examines the various types of nerve injuries commonly encountered in orthopedic surgery practice and the role of electrodiagnostic (neurodiagnostic) techniques in diagnosing these conditions.