Control of paretic and non-paretic upper extremity during bimanual reaching after stroke.

Most actions of daily life engage the two upper extremities (UEs) in a highly coordinated manner. While it is recognized that bimanual movements are impaired post-stroke, understanding how the paretic and non-paretic UE contributes to this impairment is important for future interventions. We investigated kinetic and kinematics at the shoulder, elbow, and wrist joints in the paretic and non-paretic UE in 8 individuals with chronic stroke and non-dominant UE in 8 healthy controls during unimanual and bimanual tasks. Kinematic analysis revealed little effect of stroke. However, kinetic analysis revealed that during unimanual movements, joint control was impaired during unimanual and bimanual movements in both UEs, although to a lesser extent in the non-paretic than paretic UE. During bimanual movements, joint control did not change in the paretic UE, and it further deteriorated in the non-paretic UE compared with the unimanual movements. Our findings suggest that a single session of bimanual task performance does not improve joint control of the paretic UE and it impairs control of the non-paretic UE, making it more like that of the paretic UE.

Optimization of TAM16, a Benzofuran That Inhibits the Thioesterase Activity of Pks13; Evaluation toward a Preclinical Candidate for a Novel Antituberculosis Clinical Target.

With increasing drug resistance in tuberculosis (TB) patient populations, there is an urgent need for new drugs. Ideally, new agents should work through novel targets so that they are unencumbered by preexisting clinical resistance to current treatments. Benzofuran 1 was identified as a potential lead for TB inhibiting a novel target, the thioesterase domain of Pks13. Although, having promising activity against Mycobacterium tuberculosis, its main liability was inhibition of the hERG cardiac ion channel. This article describes the optimization of the series toward a preclinical candidate. Despite improvements in the hERG liability in vitro, when new compounds were assessed in ex vivo cardiotoxicity models, they still induced cardiac irregularities. Further series development was stopped because of concerns around an insufficient safety window. However, the demonstration of in vivo activity for multiple series members further validates Pks13 as an attractive novel target for antitubercular drugs and supports development of alternative chemotypes.

[Social Determinants of Anemia and Overweight/Obesity among Pregnant Women in Nepal].

OBJECTIVES: To identify the complex factors associated with anemia and overweight/obesity in pregnant Nepali women. METHODS: This study was conducted with 609 pregnant women who visited the Western Regional Hospital in Pokhara, Nepal, for maternal health checkups. We assessed their nutritional status on the basis of their responses to a questionnaire (socio-economic, demographic and health information using the Nepali version of the 14-item Health Literacy Scale), hemoglobin levels and body mass index (BMI). Data were analyzed and adjusted for confounding factors by binomial logistic regression analysis; this aided in identifying factors associated with anemia and overweight/obesity. RESULTS: The significant factor contributing to anemia is a low BMI (p=0.005, aOR=7.930, 95% CI=1.857, 33.870), followed by maternal age in the teens (p=0.000, aOR=3.018, 95% CI=1.852, 4.919). The significant factors contributing to overweight/obesity are household income, excluding the poorest (p=0.004, aOR=2.975, 95% CI=1.404, 6.303), followed by the presence of a nuclear family (p=0.000, aOR =2.156, 95% CI=1.493, 3.112). Functional literacy (p=0.005, aOR=1.045, 95% CI=1.013, 1.077) increases the risk of overweight/obesity, but critical literacy (p=0.009, aOR=0.819, 95% CI=0.705, 0.951) is a factor that buffers its onset. CONCLUSIONS: The association of malnutrition with anemia and overweight/obesity has been confirmed in pregnant Nepali women, indicating the urgent need for new supports and improvements to nutrition. Nutrition education should be designed to take into consideration reproductive generation, as well as families with low health literacy.

Evaluation of an Antimicrobial Stewardship Program for Wound and Burn Care in Three Hospitals in Nepal.

Antimicrobial stewardship (AMS) programs can decrease non-optimal use of antibiotics in hospital settings. There are limited data on AMS programs in burn and chronic wound centers in low- and middle-income countries (LMIC). A post-prescription review and feedback (PPRF) program was implemented in three hospitals in Nepal with a focus on wound and burn care. A total of 241 baseline and 236 post-intervention patient chart data were collected from three hospitals. There was a significant decrease in utilizing days of therapy per 1000 patient days (DOT/1000 PD) of penicillin (p = 0.02), aminoglycoside (p < 0.001), and cephalosporin (p = 0.04). Increases in DOT/1000 PD at post-intervention were significant for metronidazole (p < 0.001), quinolone (p = 0.01), and other antibiotics (p < 0.001). Changes in use of antibiotics varied across hospitals, e.g., cephalosporin use decreased significantly at Kirtipur Hospital (p < 0.001) and Pokhara Academy of Health Sciences (p = 0.02), but not at Kathmandu Model Hospital (p = 0.59). An independent review conducted by infectious disease specialists at the Henry Ford Health System revealed significant changes in antibiotic prescribing practices both overall and by hospital. There was a decrease in mean number of intravenous antibiotic days between baseline (10.1 (SD 8.8)) and post-intervention (8.8 (SD 6.5)) (t = 3.56; p < 0.001), but no difference for oral antibiotics. Compared to baseline, over the 6-month post-intervention period, we found an increase in justified use of antibiotics (p < 0.001), de-escalation (p < 0.001), accurate documentation (p < 0.001), and adherence to the study antibiotic prescribing guidelines at 72 h (p < 0.001) and after diagnoses (p < 0.001). The evaluation data presented provide evidence that PPRF training and program implementation can contribute to hospital-based antibiotic stewardship for wound and burn care in Nepal.

Elesclomol alleviates Menkes pathology and mortality by escorting Cu to cuproenzymes in mice.

Loss-of-function mutations in the copper (Cu) transporter ATP7A cause Menkes disease. Menkes is an infantile, fatal, hereditary copper-deficiency disorder that is characterized by progressive neurological injury culminating in death, typically by 3 years of age. Severe copper deficiency leads to multiple pathologies, including impaired energy generation caused by cytochrome c oxidase dysfunction in the mitochondria. Here we report that the small molecule elesclomol escorted copper to the mitochondria and increased cytochrome c oxidase levels in the brain. Through this mechanism, elesclomol prevented detrimental neurodegenerative changes and improved the survival of the mottled-brindled mouse-a murine model of severe Menkes disease. Thus, elesclomol holds promise for the treatment of Menkes and associated disorders of hereditary copper deficiency.

Predictive multiscale computational model of shoe-floor coefficient of friction.

Understanding the frictional interactions between the shoe and floor during walking is critical to prevention of slips and falls, particularly when contaminants are present. A multiscale finite element model of shoe-floor-contaminant friction was developed that takes into account the surface and material characteristics of the shoe and flooring in microscopic and macroscopic scales. The model calculates shoe-floor coefficient of friction (COF) in boundary lubrication regime where effects of adhesion friction and hydrodynamic pressures are negligible. The validity of model outputs was assessed by comparing model predictions to the experimental results from mechanical COF testing. The multiscale model estimates were linearly related to the experimental results (p < 0.0001). The model predicted 73% of variability in experimentally-measured shoe-floor-contaminant COF. The results demonstrate the potential of multiscale finite element modeling in aiding slip-resistant shoe and flooring design and reducing slip and fall injuries.

Access to 4-Oxazolidinones: A (3 + 2) Cycloaddition Approach.

The novel reactivity of in situ generated aza-oxyallyl cation intermediates with a variety of carbonyl compounds is reported to construct 4-oxazolidinones motifs with good yields and diastereoselectivities. This simple and efficient (3 + 2) cycloaddition method provides direct access to potential bioactive compounds.

Oxidative (3 + 2) Cycloaddition Reactions of Diaza-Oxyallyl Cationic Intermediates and Indoles for the Synthesis of Imidazoloindolines.

An oxidative diaza-(3 + 2) cycloaddition reaction of simple urea derivatives with substituted indoles has been developed. This transformation provides rapid access to highly functionalized imidazoloindolines that are represented in bioactive compounds. The reported method is compatible with a wide variety of functional groups and directly provides unique heterocyclic scaffolds from indoles and a simple urea derivative.

Dearomative Indole Cycloaddition Reactions of Aza-Oxyallyl Cationic Intermediates: Modular Access to Pyrroloindolines.

A regioselective dearomative aza-(3 + 2) cycloaddition reaction of substituted indoles with α-halohydroxamates has been developed. This transformation provides rapid access to highly functionalized pyrroloindolines that are represented in large number of bioactive compounds. The natural product, physostigmine, has been concisely synthesized utilizing this method.