Interactions and Transport of a Bioconjugated Peptide Targeting the Mitomembrane.

The Szeto-Schiller (SS) peptides are a subclass of cell-penetrating peptides that can specifically target mitochondria and mediate conditions caused by mitochondrial dysfunction. In this work, we constructed an iron-chelating SS peptide and studied its interaction with a mitochondrial-mimicking membrane using atomistic molecular dynamics (MD) simulations. We report that the peptide/membrane interaction is thermodynamically favorable, and the localization of the peptide to the membrane is driven by electrostatic interactions between the cationic residues and the anionic phospholipid headgroups. The insertion of the peptide into the membrane is driven by hydrophobic interactions between the aromatic side chains in the peptide and the lipid acyl tails. We also probed the translocation of the peptide across the membrane by applying nonequilibrium steered MD simulations and resolved the translocation pathway, free energy profile, and metastable states. We explored four distinct orientations of the peptide along the translocation pathway and found that one orientation was energetically more favorable than the other orientations. We tested a significantly slower pulling velocity on the most thermodynamically favorable system and compared metastable states during peptide translocation. We found that the peptide can optimize hydrophobic interactions with the membrane by having aromatic side chains interacting with the lipid acyl tails instead of forming π-π interactions with each other. The mechanistic insights emerging from our work will potentially facilitate improved peptide design with enhanced activity.

Simultaneous real-time PCR detection of nine prevalent sexually transmitted infections using a predesigned double-quenched TaqMan probe panel.

Sexually transmitted diseases are major causes of infertility, ectopic pregnancy, and premature birth. Here, we developed a new multiplex real-time polymerase chain reaction (PCR) assay for the simultaneous detection of nine major sexually transmitted infections (STIs) found in Vietnamese women, including Chlamydia trachomatis, Neisseria gonorrhoeae, Gardnerella vaginalis, Trichomonas vaginalis, Candida albicans, Mycoplasma hominis, Mycoplasma genitalium, and human alphaherpesviruses 1 and 2. A panel containing three tubes × three pathogens/tube was predesigned based on double-quenched TaqMan probes to increase detection sensitivity. There was no cross-reactivity among the nine STIs and other non-targeted microorganisms. Depending on each pathogen, the agreement with commercial kits, sensitivity, specificity, repeatability and reproducibility coefficient of variation (CV), and limit of detection of the developed real-time PCR assay were 99.0%-100%, 92.9%-100%, 100%, <3%, and 8-58 copies/reaction, respectively. One assay cost only 2.34 USD. Application of the assay for the detection of the nine STIs in 535 vaginal swab samples collected from women in Vietnam yielded 532 positive cases (99.44%). Among the positive samples, 37.76% had one pathogen, with G. vaginalis (33.83%) as the most prevalent; 46.36% had two pathogens, with G. vaginalis + C. albicans as the most prevalent combination (38.13%); and 11.78%, 2.99%, and 0.56% had three, four, and five pathogens, respectively. In conclusion, the developed assay represents a sensitive and cost-effective molecular diagnostic tool for the detection of major STIs in Vietnam and is a model for the development of panel detections of common STIs in other countries.

Bicentre, randomized, parallel-arm, sham-controlled trial of transcranial direct-current stimulation (tDCS) in the treatment of palliative care patients with refractory cancer pain.

BACKGROUND: Pain is a common symptom in palliative care cancer patients and is often insufficiently relieved. In recent years, transcranial direct-current stimulation (tDCS) of the motor cortex has been shown to be effective to treat chronic pain, essentially neuropathic pain. We propose to test the efficacy of tDCS in patients experiencing cancer pain in the palliative care setting. METHOD/DESIGN: This article describes the protocol of a bicentre, randomized, parallel-arm, sham-controlled clinical trial evaluating tDCS in the treatment of palliative care patients with refractory cancer pain. Seventy patients between the ages of 18 and 80 years experiencing refractory pain with a pain score of 4/10 on a numerical rating scale (NRS) ranging from 0 to 10 will be enrolled in this trial. The main exclusion criteria are patients unable to fill in the various rating scales and life expectancy less than 3 weeks. Treatment consists of 5 consecutive tDCS sessions targeting the motor cortex (one daily session for 5 days) on the contralateral side to the pain. After randomization (1:1 ratio), 35 patients will receive active stimulation and 35 patients will receive sham stimulation. The primary endpoint is the NRS score and the primary objective is a significant improvement of this score between the baseline score recorded between D-3 and D-1 and the score recorded 4 days after stopping treatment (D8). The secondary objectives are to evaluate whether this improvement is maintained 16 days after stopping treatment (D21) and whether the following scores are improved on D14 and D21: Brief Pain Inventory, Edmonton Symptom Assessment System, Hospital Anxiety and Depression scale, State-Trait Anxiety Inventory and Medication Quantification Scale. DISCUSSION: Positive results of this trial would indicate that tDCS can improve pain and quality of life of cancer patients in the palliative care setting. Reduction of analgesic consumption and improvement of activities of daily living should allow many patients to return home with a decreased workload for caregivers.

Application of Machine Learning in Epileptic Seizure Detection.

Epileptic seizure is a neurological condition caused by short and unexpectedly occurring electrical disruptions in the brain. It is estimated that roughly 60 million individuals worldwide have had an epileptic seizure. Experiencing an epileptic seizure can have serious consequences for the patient. Automatic seizure detection on electroencephalogram (EEG) recordings is essential due to the irregular and unpredictable nature of seizures. By thoroughly analyzing EEG records, neurophysiologists can discover important information and patterns, and proper and timely treatments can be provided for the patients. This research presents a novel machine learning-based approach for detecting epileptic seizures in EEG signals. A public EEG dataset from the University of Bonn was used to validate the approach. Meaningful statistical features were extracted from the original data using discrete wavelet transform analysis, then the relevant features were selected using feature selection based on the binary particle swarm optimizer. This facilitated the reduction of 75% data dimensionality and 47% computational time, which eventually sped up the classification process. After having been selected, relevant features were used to train different machine learning models, then hyperparameter optimization was utilized to further enhance the models' performance. The results achieved up to 98.4% accuracy and showed that the proposed method was very effective and practical in detecting seizure presence in EEG signals. In clinical applications, this method could help relieve the suffering of epilepsy patients and alleviate the workload of neurologists.

Prevalence and genetic basis of first-line drug resistance of Mycobacterium tuberculosis in Ca Mau, Vietnam.

Background and objective: Data on the prevalence of anti-tuberculous drug resistance and its association with genetic mutations in Mycobacterium tuberculosis are limited. Our study explores the genomics of tuberculosis in Ca Mau, Vietnam. Methods: Patients ≥15 years in Ca Mau Province, Vietnam, were screened annually for tuberculosis between 2014 and 2017. Isolates underwent drug susceptibility testing (DST) using the breakpoint method. DNA was extracted and whole genome sequencing (WGS) was performed. Results: We identified 365 positive sputum cultures for M. tuberculosis and processed 237 for DST and 265 for WGS. Resistance to isoniazid was present in 19.8% (95% CI 14.7 to 24.9%), rifampicin in 3.5% (1.1 to 5.7%) and ethambutol in 2.5% (0.9 to 5.4%) of isolates. Relevant mutations in rpoB gene were detected in 3.8% (1.8 to 6.8%). katG, inhA or fabG1 mutations were found in 19.6% (15.0 to 24.9%) with KatG being most common at 12.8% (9.1-17.5%). We found 38.4% of isolates were of Beijing lineage, 49.4% East-African-Indian lineage and 8.4% European-American lineage. There were no associations between resistance profiles and clinical features. Conclusion: The high burden of isoniazid resistance and the katG mutation highlights the challenges facing Vietnam in its efforts to achieve its EndTB goals.

An Analysis of Vocal Features for Parkinson's Disease Classification Using Evolutionary Algorithms.

Parkinson's Disease (PD) is a brain disorder that causes uncontrollable movements. According to estimation, roughly ten million individuals worldwide have had or are developing PD. This disorder can have severe consequences that affect the patient's daily life. Therefore, several previous works have worked on PD detection. Automatic Parkinson's Disease detection in voice recordings can be an innovation compared to other costly methods of ruling out examinations since the nature of this disease is unpredictable and non-curable. Analyzing the collected vocal records will detect essential patterns, and timely recommendations on appropriate treatments will be extremely helpful. This research proposed a machine learning-based approach for classifying healthy people from people with the disease utilizing Grey Wolf Optimization (GWO) for feature selection, along with Light Gradient Boosted Machine (LGBM) to optimize the model performance. The proposed method shows highly competitive results and has the ability to be developed further and implemented in a real-world setting.

Chemical constituents of Aglaia elaeagnoidea and Aglaia odorata and their cytotoxicity.

Two new rocaglamides, 8b-O-5-oxohexylrocaglaol (1) and elaeagnin (2), together with twelve known compounds, were isolated from the bark of Aglaia elaeagnoidea and the whole tree of A. odorata. Their structures were determined using spectroscopic methods, mainly 1D and 2D NMR. Cytotoxic activity against HepG2 human liver cancer cells of the isolated compounds was evaluated in vitro using the SRB assay. Three rocaglamide derivatives, dehydroaglaiastatin (13), 8b-O-5-oxohexylrocaglaol (1) and rocaglaol (5), exhibited significant effects with IC50 values of 0.69, 4.77 and 7.37 µM, respectively.

Establishment and characterisation of cell lines and xenograft mouse models of canine systemic histiocytosis and disseminated histiocytic sarcoma.

Canine histiocytic proliferative disorders include reactive diseases (histiocytosis) and neoplastic diseases (histiocytic sarcoma [HS]), however discrimination is challenging due to their overlapping pathological features. In the present study, novel cell lines and xenograft mouse models of systemic histiocytosis (SyH) and disseminated HS were established, and examined together with cell lines previously established from localized HS and Langerhans cell histiocytosis (LCH). The chromosomal numbers of the SyH and HS cell lines were abnormal, and their population doubling time and morphological features were comparable. Immunophenotypically, SyH and HS cells were CD204+/E-cadherin+ in vitro and in vivo, like their original tissues. Western blot analysis for E-cadherin revealed an immunopositive band of full-length E-cadherin (120 kDa) in cultured cells of localized HS and LCH but not in disseminated HS and SyH; expression level was weaker in localized HS than in LCH. An immunopositive band of fragmented E-cadherin (45 kDa) was detected in cell lines of disseminated HS and SyH. These results suggest that cultured SyH cells have features that are similar to disseminated HS, including chromosomal aberration, high proliferation activity, weak cell adhesion, and expression of fragmented E-cadherin. Fragmentation of the E-cadherin cell adhesion molecule may be associated with the loss of cell adhesion and increased abilities of invasion and migration of neoplastic cells. The established cell lines and xenograft mouse models will aid in understanding the pathogenesis and developing novel treatments of canine histiocytic proliferative disorders.

Antioxidant and Antimicrobial Activities of the Extracts from Different Garcinia Species.

BACKGROUND: Garcinia is a large genus which has promising bioactivities. However, the properties of many Garcinia species have not been investigated thoroughly. AIM: To determine the antioxidant and antimicrobial capabilities of the extracts from different Garcinia species. Methodology. Six Garcinia species, including Garcinia fusca, Garcinia hopii, Garcinia planchonii, Garcinia nigrolineata, Garcinia gaudichaudii, and Garcinia tinctoria were extracted using n-hexane, ethyl acetate, and methanol, producing n-hexane extract (HE), ethyl acetate extract (EAE), and methanol extract (ME). After that, the total polyphenol content was evaluated using Folin-Ciocalteu assay. DPPH, hydroxyl radical scavenging, and total antioxidant capacity assays were performed to test the antioxidant activity. Subsequently, the antimicrobial activities against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) bacterial strains were assessed using Kirby Bauer and the broth microdilution methods. RESULTS: Many Garcinia extracts contained high total polyphenol content consisting of ME of G. hopii ad G. tinctoria, and EAE of G. planchonii and G. tinctoria. The EAE of G. tinctoria showed effective antioxidant capacity (IC50 = 1.5 µg/mL). Additionally, the EAE of G. gaudichaudii was effective against Gram-positive bacteria with minimal inhibition concentration (MIC) of 15.625-25 µg/mL whereas ME of G. planchonii was effective against both Gram-positive bacteria (MIC = 160 µg/mL) and Gram-negative bacteria (MIC = 75 µg/mL). CONCLUSION: Several extracts of Garcinia species demonstrated valuable antioxidant and antimicrobial properties.

Fast and Sensitive Real-Time PCR Detection of Major Antiviral-Drug Resistance Mutations in Chronic Hepatitis B Patients by Use of a Predesigned Panel of Locked-Nucleic-Acid TaqMan Probes.

We developed a novel real-time PCR assay that simultaneously evaluates 11 major nucleos(t)ide antiviral (NA) drug resistance mutations (mt) in chronic hepatitis B patients (CHB), including L180M, M204I/V, and V207M (lamivudine [LMV] resistance), N/H238A/T (adefovir [ADF] resistance), which are circulating in Vietnam; and T184G/L, S202I, and M250V (entecavir [ETV] resistance) and A194T (tenofovir resistance), which have been recently reported in several studies across the globe. We detected drug-resistant mt in hepatitis B virus (HBV) samples using our predesigned panel of allele-specific locked-nucleic acid (LNA) probes. Our assay had a high sensitivity of 5% in a low-HBV DNA population of ≥5 × 103 IU/ml and was validated in a cohort of 130 treatment-naive children and 98 NA-experienced adults with CHB. Single-point mt for LMV and ADF resistance were detected in 57.7% and 54.1% of the child and adult samples, respectively, with rtV207M (children, 42.3%; adults, 36.7%) and rtN238T/A (children, 15.4%; adults, 16.3%) being the most frequent mt in these populations. Multiple-point mt, including rtL180M-rtM204V- rtN238A and rtL180M-rtM204I, were identified in only two children, resulting in LMV-ADF resistance and reduced ETV susceptibility. In conclusion, this assay accurately identified the mt profile of children (98.4%) and adults (91.2%) with CHB, which is comparable to established methods. This fast and sensitive screening method can be used for the detection of major NA-resistant mt circulating in developing countries, as well as providing a model for the development of similar mt-detection assays, especially for use in nonhospitalized patients who need their results within half a day, before starting treatment.

Structures of the alkanesulfonate monooxygenase MsuD provide insight into C-S bond cleavage, substrate scope, and an unexpected role for the tetramer.

Bacterial two-component flavin-dependent monooxygenases cleave the stable C-S bond of environmental and anthropogenic organosulfur compounds. The monooxygenase MsuD converts methanesulfonate (MS-) to sulfite, completing the sulfur assimilation process during sulfate starvation, but the mechanism of this conversion remains unclear. To explore the mechanism of C-S bond cleavage, we report a series of crystal structures of MsuD from Pseudomonas fluorescens in different liganded states. This report provides the first crystal structures of an alkanesulfonate monooxygenase with a bound flavin and alkanesulfonate, elucidating the roles of the active site lid, the protein C terminus, and an active site loop in flavin and/or alkanesulfonate binding. These structures position MS- closest to the flavin N5 position, consistent with an N5-(hydro)peroxyflavin mechanism rather than a classical C4a-(hydro)peroxyflavin mechanism. A fully enclosed active site is observed in the ternary complex, mediated by interchain interaction of the C terminus at the tetramer interface. These structures identify an unexpected function of the protein C terminus in this protein family in stabilizing tetramer formation and the alkanesulfonate-binding site. Spurred by interest from the crystal structures, we conducted biochemical assays and molecular docking that redefine MsuD as a small- to medium-chain alkanesulfonate monooxygenase. Functional mutations verify the sulfonate-binding site and reveal the critical importance of the protein C terminus for monooxygenase function. These findings reveal a deeper understanding of MsuD's functionality at the molecular level and consequently how it operates within its role as part of the sulfur assimilation pathway.

Structure and function of the two-component flavin-dependent methanesulfinate monooxygenase within bacterial sulfur assimilation.

Methyl sulfur compounds are a rich source of environmental sulfur for microorganisms, but their use requires redox systems. The bacterial sfn and msu operons contain two-component flavin-dependent monooxygenases for dimethylsulfone (DMSO2) assimilation: SfnG converts DMSO2 to methanesulfinate (MSI-), and MsuD converts methanesulfonate (MS-) to sulfite. However, the enzymatic oxidation of MSI- to MS- has not been demonstrated, and the function of the last enzyme of the msu operon (MsuC) is unresolved. We employed crystallographic and biochemical studies to identify the function of MsuC from Pseudomonas fluorescens. The crystal structure of MsuC adopts the acyl-CoA dehydrogenase fold with putative binding sites for flavin and MSI-, and functional assays of MsuC in the presence of its oxidoreductase MsuE, FMN, and NADH confirm the enzymatic generation of MS-. These studies reveal that MsuC converts MSI- to MS- in sulfite biosynthesis from DMSO2.

Community-wide Screening for Tuberculosis in a High-Prevalence Setting.

BACKGROUND: The World Health Organization has set ambitious targets for the global elimination of tuberculosis. However, these targets will not be achieved at the current rate of progress. METHODS: We performed a cluster-randomized, controlled trial in Ca Mau Province, Vietnam, to evaluate the effectiveness of active community-wide screening, as compared with standard passive case detection alone, for reducing the prevalence of tuberculosis. Persons 15 years of age or older who resided in 60 intervention clusters (subcommunes) were screened for pulmonary tuberculosis, regardless of symptoms, annually for 3 years, beginning in 2014, by means of rapid nucleic acid amplification testing of spontaneously expectorated sputum samples. Active screening was not performed in the 60 control clusters in the first 3 years. The primary outcome, measured in the fourth year, was the prevalence of microbiologically confirmed pulmonary tuberculosis among persons 15 years of age or older. The secondary outcome was the prevalence of tuberculosis infection, as assessed by an interferon gamma release assay in the fourth year, among children born in 2012. RESULTS: In the fourth-year prevalence survey, we tested 42,150 participants in the intervention group and 41,680 participants in the control group. A total of 53 participants in the intervention group (126 per 100,000 population) and 94 participants in the control group (226 per 100,000) had pulmonary tuberculosis, as confirmed by a positive nucleic acid amplification test for Mycobacterium tuberculosis (prevalence ratio, 0.56; 95% confidence interval [CI], 0.40 to 0.78; P<0.001). The prevalence of tuberculosis infection in children born in 2012 was 3.3% in the intervention group and 2.6% in the control group (prevalence ratio, 1.29; 95% CI, 0.70 to 2.36; P = 0.42). CONCLUSIONS: Three years of community-wide screening in persons 15 years of age or older who resided in Ca Mau Province, Vietnam, resulted in a lower prevalence of pulmonary tuberculosis in the fourth year than standard passive case detection alone. (Funded by the Australian National Health and Medical Research Council; ACT3 Australian New Zealand Clinical Trials Registry number, ACTRN12614000372684.).

Snowpack measurements suggest role for multi-year sea ice regions in Arctic atmospheric bromine and chlorine chemistry.

As sources of reactive halogens, snowpacks in sea ice regions control the oxidative capacity of the Arctic atmosphere. However, measurements of snowpack halide concentrations remain sparse, particularly in the high Arctic, limiting our understanding of and ability to parameterize snowpack participation in tropospheric halogen chemistry. To address this gap, we measured concentrations of chloride, bromide, and sodium in snow samples collected during polar spring above remote multi-year sea ice (MYI) and first-year sea ice (FYI) north of Greenland and Alaska, as well as in the central Arctic, and compared these measurements to a larger dataset collected in the Alaskan coastal Arctic by Krnavek et al. (2012). Regardless of sea ice region, these surface snow samples generally featured lower salinities, compared to coastal snow. Surface snow in FYI regions was typically enriched in bromide and chloride compared to seawater, indicating snowpack deposition of bromine and chlorine-containing trace gases and an ability of the snowpack to participate further in bromine and chlorine activation processes. In contrast, surface snow in MYI regions was more often depleted in bromide, indicating it served as a source of bromine-containing trace gases to the atmosphere prior to sampling. Measurements at various snow depths indicate that the deposition of sea salt aerosols and halogen-containing trace gases to the snowpack surface played a larger role in determining surface snow halide concentrations compared to upward brine migration from sea ice. Calculated enrichment factors for bromide and chloride, relative to sodium, in the MYI snow samples suggests that MYI regions, in addition to FYI regions, have the potential to play an active role in Arctic boundary layer bromine and chlorine chemistry. The ability of MYI regions to participate in springtime atmospheric halogen chemistry should be considered in regional modeling of halogen activation and interpretation of satellite-based tropospheric bromine monoxide column measurements.

Evaluating nighttime lights and population distribution as proxies for mappinganthropogenic CO2 emission in Vietnam, Cambodia and Laos.

Tracking spatiotemporal changes in GHG emissions is key to successful implementation of the United Nations Framework Convention on Climate Change (UNFCCC). And while emission inventories often provide a robust tool to track emission trends at the country level, subnational emission estimates are often not reported or reports vary in robustness as the estimates are often dependent on the spatial modeling approach and ancillary data used to disaggregate the emission inventories. Assessing the errors and uncertainties of the subnational emission estimates is fundamentally challenging due to the lack of physical measurements at the subnational level. To begin addressing the current performance of modeled gridded CO2 emissions, this study compares two common proxies used to disaggregate CO2 emission estimates. We use a known gridded CO2 model based on satellite-observed nighttime light (NTL) data (Open Source Data Inventory for Anthropogenic CO2, ODIAC) and a gridded population dataset driven by a set of ancillary geospatial data. We examine the association at multiple spatial scales of these two datasets for three countries in Southeast Asia: Vietnam, Cambodia and Laos and characterize the spatiotemporal similarities and differences for 2000, 2005, and 2010. We specifically highlight areas of potential uncertainty in the ODIAC model, which relies on the single use of NTL data for disaggregation of the non-point emissions estimates. Results show, over time, how a NTL-based emissions disaggregation tends to concentrate CO2 estimates in different ways than population-based estimates at the subnational level. We discuss important considerations in the disconnect between the two modeled datasets and argue that the spatial differences between data products can be useful to identify areas affected by the errors and uncertainties associated with the NTL-based downscaling in a region with uneven urbanization rates.

Cytotoxic limonoids from the bark of Walsura cochinchinensis.

Three new limonoids, walsucochinones A-C (1-3), along with eight known compounds, were isolated from an ethyl acetate extract of the bark of Walsura cochinchinensis. Their structures were determined using spectroscopic techniques, mainly 1-D and 2-D NMR. The ethyl acetate extract showed cytotoxic activity against MCF-7 human breast cancer cells and cytotoxicity of the isolated compounds were evaluated in vitro using the SRB assay. Walsucochinone C (3) exhibited the most active effect with IC50 value of 16.4 ±â€¯0.2 µM.

Serum 25-hydroxyvitamin D but not dietary vitamin D intake is associated with hemoglobin in women of reproductive age in rural northern Vietnam.

BACKGROUND AND OBJECTIVES: Hypovitaminosis D and anemia are both prevalent in Vietnam, and low vitamin D status may be a risk factor for anemia. This study aimed to 1) describe vitamin D intake and its determinants, and 2) examine the associations of vitamin D intake and serum 25(OH)D concentrations with hemoglobin and anemia. METHODS AND STUDY DESIGN: We used data from the baseline survey of a pre-conceptual micronutrient supplementation trial in women of reproductive age (WRA) in Thai Nguyen, Vietnam (N = 4961). Vitamin D intake was estimated using a semi-quantitative food frequency questionnaire (FFQ). Multivariable regression models were used for the analyses. RESULTS: Median vitamin D intake was 0.2 µg/d (8.0 IU) [IQR: 0.4]. Age, being a farmer, food insecurity, and body mass index (BMI) were inversely associated with vitamin D intake, while socioeconomic status (SES), total energy intake, and education were positively associated with vitamin D intake. Vitamin D intake was not associated with hemoglobin concentration or anemia after adjusting for age, BMI, total energy intake, transferrin receptor, C-reactive protein, α1-acid glycoprotein, SES, occupation, education, ethnicity, and food insecurity (P = 0.56 and P = 0.65 for hemoglobin and anemia, respectively). Controlling for the same covariates, 25(OH)D <50 nmol/L (vs. ≥50 nmol/L) was associated with decreased hemoglobin concentrations (ß = -0.91 (SE:0.42), P = 0.03), but not with anemia (P = 0.11). CONCLUSIONS: Low vitamin D status may be linked to reduced hemoglobin concentrations, but the role of diet in this association was not evident in this population of WRA in Vietnam where dietary vitamin D intake was very low.

2017 update on pain management in patients with chronic kidney disease.

The prevalence of pain has been reported to be >60-70% among patients with advanced and end-stage kidney disease. Although the underlying etiologies of pain may vary, pain per se has been linked to lower quality of life and depression. The latter is of great concern given its known association with reduced survival among patients with end-stage kidney disease. We herein discuss and update the management of pain in patients with chronic kidney disease with and without requirement for renal replacement therapy with the focus on optimizing pain control while minimizing therapy-induced complications.

EMPA-REG OUTCOME: The Cardiologist's Point of View.

Cardiologists could view empagliflozin as a cardiovascular drug that also has a beneficial effect on reducing hyperglycemia in patients with type 2 diabetes mellitus (T2DM). The effects of empagliflozin in lowering the risk of cardiovascular death and hospitalization for heart failure in T2DM patients with high cardiovascular risk during the recent Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME) trial may be explained principally in terms of changes to cardiovascular physiology; namely, by the potential ability of empagliflozin to reduce cardiac workload and myocardial oxygen consumption by lowering blood pressure, improving aortic compliance, and improving ventricular arterial coupling. These concepts and hypotheses are discussed in this report.

Differential cardiovascular profiles of sodium-glucose cotransporter 2 inhibitors: critical evaluation of empagliflozin.

One of the most feared repercussions of type 2 diabetes mellitus is the risk of adverse cardiovascular outcomes. The current antidiabetic agents on the market have had difficulty in showing cardiovascular outcome improvement. The EMPA-REG OUTCOME trial studied the sodium-glucose cotransporter 2 inhibitor empagliflozin in type 2 diabetic patients at high risk of cardiovascular events. The trial results revealed a decrease in the composite primary end points of death from cardiovascular causes, nonfatal myocardial infarction, and nonfatal stroke in those taking empagliflozin vs placebo. Those taking the medication also had a significant decrease in death from any cause, death from cardiovascular cause, and hospitalization for heart failure. The EMPA-REG trial is paradigm shifting because it demonstrates a clear mortality benefit to cardiovascular outcomes with a low side-effect profile, in contrast to prior outcome studies of hypoglycemic agents. Further studies are required to better clarify the long-term safety and efficacy of this promising class of diabetic drugs.