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Significance To adapt to arboreal lifestyles, treefrogs have evolved a suite of complex traits that support vertical movement and gliding, thus presenting a unique case for studying the genetic basis for traits causally linked to vertical niche expansion. Here, based on two de novo-assembled Asian treefrog genomes, we determined that genes involved in limb development and keratin cytoskeleton likely played a role in the evolution of their climbing systems. Behavioral and morphological evaluation and time-ordered gene coexpression network analysis revealed the developmental patterns and regulatory pathways of the webbed feet used for gliding in Rhacophorus kio .

Purpose The association between clinical and microbiological outcomes and high-dose tigecycline (TGC) was assessed in elderly (≥60 years old) patients with hospital-acquired and ventilator-associated pneumonia due to multidrug-resistant Acinetobacter baumannii(A. baumannii). This study also assessed tigecycline combination with different antibiotics and its influence on the outcome. Patients and methods An observational retrospective cohort study was conducted. Patients over 60 years old were treated with standard-dose (SD) TGC (100-mg intravenous TGC initially, followed by 50-mg doses administered intravenously twice daily) and high-dose (HD) TGC (200-mg intravenous TGC initially, followed by 100-mg doses administered intravenously twice daily) for a microbially confirmed infection. The outcome was 30-day crude mortality, co-administered antimicrobial agent and the microbial eradication percentage in both groups. Results A total of 48 multidrug-resistant A. baumannii respiratory patients were identified. Tigecycline was administered to 85% of ventilation-associated pneumonia (VAP) patients (28/33) in the SD group and 80% of VAP patients (12/15) in the HD group. Combined therapy was the major treatment option in both groups, accounting for 85% and 87%, respectively. Median treatment duration in both groups was 7.36 vs 8.6 days, respectively. Survival days were 13.61 vs 12.4 days (P=0.357), respectively. The 30-day crude mortality was 39.4% (13/33) for the SD group and 14% (2/15) for the HD group (P=0.098). The microbial eradication rate of respiratory specimens in the SD group was higher than that in the HD group (P=0.02). The variables associated with 30-day crude mortality were chronic obstructive pulmonary disease (hazard ratio [HR] 11.63, 95% CI 1.094-123.058; P=0.042), tigecycline treatment duration (HR 0.690, 95% CI 0.515-0.926; P=0.013), and surgery before infection (HR 79.276, 95% CI 6.983-899.979; P=0.000). High-dose tigecycline was not associated with 30-day crude mortality (adjusted HR 0.329, 95% CI 0.074-1.460; P=0.145). Combined antibiotics was also not different between the two groups. Conclusions High-dose tigecycline was not associated with 30-day crude mortality in elderly patients with pneumonia due to multidrug-resistant A. baumannii, although the microbial eradication rate was high.

In this study, we sequenced the complete mitochondrial genome of Thermophis shangrila by using the next-generation sequencing technique. The total length of the mitogenome was 17,407 bp, which was composed of 13 protein coding genes, two rRNA genes (12s and 16s rRNA), 22 tRNA genes, and two control regions (CRI and CRII). The base composition was 32.6% for A, 23.9% for T, 30.0% for C, and 13.5% for G. We added a fragment about 150 bp in length at control region I, which Peng et al. failed to obtain using Sanger dideoxy sequencing.

Currently, the genus Polypedates comprises 26 species distributed in South, Southeast, and East Asia. Because of their relatively low dispersal capability and intolerance to seawater, this genus is ideal for the study of terrestrial range evolution that extends into the island archipelagos of southeastern Asia. In this study, based on data compiled for Polypedatesfrom previous studies and partial mitochondrial and nuclear genes collected in this study, we performed systematic biogeographical analysis. We confirmed a Sundaland origin for the extant genus and showed northward dispersal into mainland Southeast Asia and Asia, which coincided with the timing of paleoclimatic change from the Oligocene to Middle Miocene. Climate fluctuations had a profound impact on species diversification within the genus Polypedates. Furthermore, the Red River did not mediate species exchange between Southeast Asia and mainland Asia until the end of the Miocene, with the sudden onset of northward dispersal in several clades independently at that time. Alternatively, the lineage of widespread insular P. leucomystaxstrongly supports the hypothesis of terrestrial connection between island archipelagos of Southeast Asia during the Mid-Pleistocene paleoclimate fluctuations. Our biogeographical analysis also supports the recent introduction of P. leucomystax to the Philippines and Ryukyus, as previously suggested.

Currently, the genus Polypedates comprises 26 species distributed in South, Southeast, and East Asia. Because of their relatively low dispersal capability and intolerance to seawater, this genus is ideal for the study of terrestrial range evolution that extends into the island archipelagos of southeastern Asia. In this study, based on data compiled for Polypedates from previous studies and partial mitochondrial and nuclear genes collected in this study, we performed systematic biogeographical analysis. We confirmed a Sundaland origin for the extant genus and showed northward dispersal into mainland Southeast Asia and Asia, which coincided with the timing of paleoclimatic change from the Oligocene to Middle Miocene. Climate fluctuations had a profound impact on species diversification within the genus Polypedates. Furthermore, the Red River did not mediate species exchange between Southeast Asia and mainland Asia until the end of the Miocene, with the sudden onset of northward dispersal in several clades independently at that time. Alternatively, the lineage of widespread insular P. leucomystax strongly supports the hypothesis of terrestrial connection between island archipelagos of Southeast Asia during the Mid-Pleistocene paleoclimate fluctuations. Our biogeographical analysis also supports the recent introduction of P. leucomystax to the Philippines and Ryukyus, as previously suggested.

Background: Adverse drug outcomes in the elderly have led to the development of lists of potentially inappropriate medications (PIMs), such as the Beers criteria, and these PIMs have been studied widely; however, it is still unclear whether PIM use is predictive of adverse outcomes in older people. Objective: To qualitatively examine the associations between exposure to PIMs from the general Beers criteria and the Screening Tool of Older Persons’ Prescriptions list and adverse outcomes, such as adverse drug reactions (ADRs)/adverse drug events (ADEs), hospitalization, and mortality. Methods: Specified databases were searched from inception to February 1, 2018. Two reviewers independently selected studies that met the inclusion criteria, assessed study quality, and extracted data. Data were pooled using Stata 12.0. The outcomes were ADRs/ADEs, hospitalization, and mortality. Results: A total of 33 studies met the inclusion criteria. The combined analysis revealed a statistically significant association between ADRs/hospitalizations and PIMs (odds ratio [OR] = 1.44, 95% CI = 1.33-1.56; OR = 1.27, 95% CI = 1.20-1.35), but no statistically significant association was found between mortality and PIMs (OR = 1.04; 95% CI = 0.75-1.45). It is interesting to note that the results changed when different continents/criteria were used for the analysis. Compared with the elderly individuals exposed to 1 PIM, the risk of adverse health outcomes was much higher for those who took ≥2 PIMs. Conclusion and Relevance: We recommend that clinicians avoid prescribing PIMs for older adults whenever feasible. In addition, the observed associations should be generalized to other countries with different PIM criteria with caution.

The broad spectrum antibiotic tigecycline shows promising efficacy against many multiple drug resistant (MDR) pathogens. However, its clinical efficacy in the treatment of hospital-acquired pneumonia (HAP) is unclear. Several studies have reported on the treatment failures of tigecycline monotherapy, suggesting that it may not be sufficient to control severe infections. Combination therapy has become an option to treat MDR bacterial infections. We conducted a literature search using PubMed, Cochrane Library, Embase, Elsevier and the Web of Knowledge databases up to 29 February 2017 to identify relevant published studies. Studies were considered eligible if they were a cohort study that assessed mortality and the safety of tigecycline monotherapy versus combination therapy with other antimicrobial agents for HAP. The primary outcome was treatment mortality rate, while the secondary outcomes were adverse events. Meta-analysis was done using fixed-effects models. Five trials were included. The monotherapy tigecycline had a higher mortality compared to the combination therapy group. There was a significant difference for the treatment of HAP. However, two prospective cohort studies showed that there was no significant difference in mortality rate between the tigecycline monotherapy and the tigecycline combination therapy. Three retrospective cohort studies showed that tigecycline monotherapy had a high mortality rate. Tigecycline combination therapy efficiently treats HAP. There is a great need for well-designed studies to evaluate the effectiveness and safety of combination therapies as they compare to tigecycline monotherapy.

Aim: The aim of the present study is to establish a population pharmacokinetic (PPK) model of valproate (VPA) in Chinese epileptic children to promote the reasonable use of anti-epileptic drugs. Methods: Sparse data of VPA serum concentrations from 417 epileptic children were collected. These patients were divided into 2 groups: the PPK model group ( n =317) and the PPK valid group ( n =100). The PPK parameter values of VPA were calculated by NONMEM software using the data of the PPK model group. A basic model and a final model were set up. To validate the 2 models, the concentrations of PPK valid group were predicted by each model, respectively. The mean prediction error (MPE), mean squared prediction error (MSPE), root mean squared prediction error (RMSPE), weight residues (WRES), and the 95% confidence intervals (95% CI) were also calculated. Then, the values between the 2 models were compared. Results: The PPK of VPA was determined by a 1-compartment model with a first-order absorption process. The basic model was: Ka=3.09 (h -1 ), V/F=20.4 (L), CL/F=0.296 (L/h). The final model was: Ka=0.251+2.24dot(1-HS) (h -1 ), V/F=2.88+0.157dotWT (L), CL/F=0.106 0.98dotCO + 0.0157dotAGE (L/h). For the basic model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -23.53 (-30.36, -16.70), 3728.96 (2872.72, 4585.20), 39.62 (34.34, 44.90), and -0.06 (-0.14, 0.02), respectively. For the final model, the MPE, MSPE, RMSPE, WRES, and the 95% CI were -1.16 (-4.85, 2.53), 1002.83 (1050.64, 1143.61), 23.04 (21.12, 24.96), and 0.08 (-0.04, 0.20), respectively. The final model was more optimal than the basic model. Conclusion: The PPK model of VPA in Chinese epileptic children was successfully established. It will be valuable to facilitate individualized dosage regimens.

Background: Insulin is used to treat patients with both type 1 and type 2 diabetes mellitus. Allergic reac- tions to insulin might be triggered by insulin itself or inactive ingredients in the insulin formulation, includ- ing proteins such as protamine in neutral protamine Hagedorn (NPH) insulin. The use of highly purified animal insulin and human recombinant insulin has reduced the incidence of anaphylactic reactions to insulin from ~30% to Objective: We report a case of fatal allergic shock after the administration of protamine in a patient with a history of allergy to fish and a protamine-containing insulin. Case summary: A 72-year-old Chinese male patient (height, 175 cm; weight, 80 kg) with a history of diabetes and progressive limb weakness was diagnosed with spinal vascular malformations after admission to the Xuan Wu Hospital of Capital Medical University, Beijing, People's Republic of China. He underwent epidural spinal cord arteriovenous fistula embolization with a liquid embolic agent (ethylene vinyl alcohol copolymer) after spinal cord angiography. During the operation, heparin was infused every hour with 6250, 2500, 2500, and 1250 IU, respectively. The last dose of heparin was administered ~10 minutes before the opera- tion was completed. This was followed by the admin-istration of protamine to neutralize the remaining heparin in the patient's body. Blurry vision and dizziness 5 minutes after protamine administration were followed by pruritus and hives over his neck and face. Oxygen was administered and 10 mg of dexamethasone with 2 mg of epinephrine was injected. The patient's heart rate dropped, his blood pressure decreased, and his arterial oxygen saturation (SaO 2 ) declined progressively. About 10 minutes after the administration of protamine sulfate, the patient developed bradycardic arrest. Cardiopulmonary resuscitation efforts were undertaken and the patient was administered epinephrine 2 mg IV, atropine 0.5 mg IV, and subsequently, intravenous dopamine (50 mg/h). Ten minutes later, the patient's heart rate gradually increased, but blood pressure fluctuated, and SaO 2 ranged from 90% to 100%. Despite the initial response, the patient lost consciousness and heart rate declined progressively within 5 hours. Vasoactive agents including dopamine, norepinephrine, and adrenaline were administered. After all these measures proved inef- fectual, the patient died. It was later determined that the patient had a history of allergic reactions to fish as well as to a premixed insulin that contained soluble human insulin 30% and low-protein intensive insulin zinc 70% (NPH). The Naranjo adverse drug reaction probability scale score for the association of protamine with the allergic reaction was 4, suggesting a possible relationship. Conclusion: This case report highlights a preventable fatal allergic reaction possibly associated with protamine administration in a patient with a history of allergy to a protamine-containing insulin.

To evaluate the effects of CYP2C19 and CYP2C9 genotypes on the pharmacokinetic variability of valproic acid (VPA) in epileptic patients using a population pharmacokinetic (PPK) approach. VPA concentrations were measured in 287 epileptic patients, who were genotyped for CYP2C19*2/*3 and CYP2C9*3. Patients who were on monotherapy with VPA were divided into two groups, a PPK-model group (n = 177) and a PPK-valid group (n = 110). The PPK parameter values for VPA were calculated in the PPK-model group by using the NONMEM software. Ultimately, a biological model and a final model were established. Each model was then used to independently predict the concentrations of the PPK-valid group to validate the two models. There was a significant effect of the CYP2C19 and CYP2C9 genotypes on the pharmacokinetic (PK) variability (P

Using sparse data of valproate (VPA) serum concentrations to build a population pharmacokinetic (PPK) model of VPA in Chinese children with epilepsy and to predict serum concentrations for new patients using a Bayesian approach.Two hundred epileptic children, whose VPA serum concentrations were collected, were divided randomly into two groups (A and B, n=100 each). The PPK parameter values of group A were calculated to establish a PPK Model by using the NPEM Program of USC*PACK software. Based on it, VPA serum concentrations of group B were predicted with the Bayesian Fitting Program of the USC*PACK software. To assess the accuracy and precision of prediction, a paired-comparisons t-test was run between predicted and observed concentrations, and then the mean prediction error (MPE), mean square prediction error (MSPE), root mean square prediction error (RMSPE), and coincidence rates for different percentages of prediction error were all calculated.Optimum PPK parameters were: Ka, 2.522+/-2.743 h(-1); Vs, 0.329+/-0.496 L/kg; and Kel, 0.0438+/-0.0384 h(-1). For group B, there was no significant difference between predicted and observed concentrations. MPE was -0.43 mg/L, MSPE was 115.40 (mg/L)2, and RMSPE was 5.47 mg/L. The coincidence rates for percentages of prediction error, which were less than 5 %, 10 %, 15 %, 20 %, 25 %, and 30 %, were 62 %, 74 %, 82 %, 85 %, 89 %, and 93 %, respectively.A PPK model of VPA in epileptic children was successfully established. Based on it, VPA serum concentrations can be predicted accurately with a Bayesian approach.