Randomized single oral dose phase 1 study of safety, tolerability, and pharmacokinetics of Iminosugar UV-4 Hydrochloride (UV-4B) in healthy subjects.

BACKGROUND: UV-4 (N-(9'-methoxynonyl)-1-deoxynojirimycin, also called MON-DNJ) is an iminosugar small-molecule oral drug candidate with in vitro antiviral activity against diverse viruses including dengue, influenza, and filoviruses and demonstrated in vivo efficacy against both dengue and influenza viruses. The antiviral mechanism of action of UV-4 is through inhibition of the host endoplasmic reticulum-resident α-glucosidase 1 and α-glucosidase 2 enzymes. This inhibition prevents proper glycan processing and folding of virus glycoproteins, thereby impacting virus assembly, secretion, and the fitness of nascent virions. METHODOLOGY/PRINCIPAL FINDINGS: Here we report a first-in-human, single ascending dose Phase 1a study to evaluate the safety, tolerability, and pharmacokinetics of UV-4 hydrochloride (UV-4B) in healthy subjects (ClinicalTrials.gov Identifier NCT02061358). Sixty-four subjects received single oral doses of UV-4 as the hydrochloride salt equivalent to 3, 10, 30, 90, 180, 360, 720, or 1000 mg of UV-4 (6 subjects per cohort), or placebo (2 subjects per cohort). Single doses of UV-4 hydrochloride were well tolerated with no serious adverse events or dose-dependent increases in adverse events observed. Clinical laboratory results, vital signs, and physical examination data did not reveal any safety signals. Dose-limiting toxicity was not observed; the maximum tolerated dose of UV-4 hydrochloride in humans has not yet been determined (>1000 mg). UV-4 was rapidly absorbed and distributed after dosing with the oral solution formulation used in this study. Median time to reach maximum plasma concentration ranged from 0.5-1 hour and appeared to be independent of dose. Exposure increased approximately in proportion with dose over the 333-fold dose range. UV-4 was quantifiable in pooled urine over the entire collection interval for all doses. CONCLUSIONS/SIGNIFICANCE: UV-4 is a host-targeted broad-spectrum antiviral drug candidate. At doses in humans up to 1000 mg there were no serious adverse events reported and no subjects were withdrawn from the study due to treatment-emergent adverse events. These data suggest that therapeutically relevant drug levels of UV-4 can be safely administered to humans and support further clinical development of UV-4 hydrochloride or other candidate antivirals in the iminosugar class. TRIAL REGISTRATION: ClinicalTrials.gov NCT02061358 https://clinicaltrials.gov/ct2/show/NCT02061358.

Factors influencing environmental sampling recovery of healthcare pathogens from non-porous surfaces with cellulose sponges.

Results from sampling healthcare surfaces for pathogens are difficult to interpret without understanding the factors that influence pathogen detection. We investigated the recovery of four healthcare-associated pathogens from three common surface materials, and how a body fluid simulant (artificial test soil, ATS), deposition method, and contamination levels influence the percent of organisms recovered (%R). Known quantities of carbapenemase-producing KPC+ Klebsiella pneumoniae (KPC), Acinetobacter baumannii, vancomycin-resistant Enterococcus faecalis, and Clostridioides difficile spores (CD) were suspended in Butterfield's buffer or ATS, deposited on 323cm2 steel, plastic, and laminate surfaces, allowed to dry 1h, then sampled with a cellulose sponge wipe. Bacteria were eluted, cultured, CFU counted and %R determined relative to the inoculum. The %R varied by organism, from <1% (KPC) to almost 60% (CD) and was more dependent upon the organism's characteristics and presence of ATS than on surface type. KPC persistence as determined by culture also declined by >1 log10 within the 60 min drying time. For all organisms, the %R was significantly greater if suspended in ATS than if suspended in Butterfield's buffer (p<0.05), and for most organisms the %R was not significantly different when sampled from any of the three surfaces. Organisms deposited in multiple droplets were recovered at equal or higher %R than if spread evenly on the surface. This work assists in interpreting data collected while investigating a healthcare infection outbreak or while conducting infection intervention studies.

Persistence of Bacteriophage Phi 6 on Porous and Nonporous Surfaces and the Potential for Its Use as an Ebola Virus or Coronavirus Surrogate.

The infection of health care workers during the 2013 to 2016 Ebola outbreak raised concerns about fomite transmission. In the wake of the coronavirus disease 2019 (COVID-19) pandemic, investigations are ongoing to determine the role of fomites in coronavirus transmission as well. The bacteriophage phi 6 has a phospholipid envelope and is commonly used in environmental studies as a surrogate for human enveloped viruses. The persistence of phi 6 was evaluated as a surrogate for Ebola virus (EBOV) and coronaviruses on porous and nonporous hospital surfaces. Phi 6 was suspended in a body fluid simulant and inoculated onto 1-cm2 coupons of steel, plastic, and two fabric curtain types. The coupons were placed at two controlled absolute humidity (AH) levels: a low AH of 3.0 g/m3 and a high AH of 14.4 g/m3 Phi 6 declined at a lower rate on all materials under low-AH conditions, with a decay rate of 0.06-log10 PFU/day to 0.11-log10 PFU/day, than under the higher AH conditions, with a decay rate of 0.65-log10 PFU/h to 1.42-log10 PFU/day. There was a significant difference in decay rates between porous and nonporous surfaces at both low AH (P < 0.0001) and high AH (P < 0.0001). Under these laboratory-simulated conditions, phi 6 was found to be a conservative surrogate for EBOV under low-AH conditions in that it persisted longer than Ebola virus in similar AH conditions. Additionally, some coronaviruses persist longer than phi 6 under similar conditions; therefore, phi 6 may not be a suitable surrogate for coronaviruses.IMPORTANCE Understanding the persistence of enveloped viruses helps inform infection control practices and procedures in health care facilities and community settings. These data convey to public health investigators that enveloped viruses can persist and remain infective on surfaces, thus demonstrating a potential risk for transmission. Under these laboratory-simulated Western indoor hospital conditions, we assessed the suitability of phi 6 as a surrogate for environmental persistence research related to enveloped viruses, including EBOV and coronaviruses.

Integrated community case management: planning for sustainability in five African countries.

BACKGROUND: The World Health Organization (WHO) launched an initiative to plan for the sustainability of integrated community case management (iCCM) programmes supported by the Rapid Access Expansion (RAcE) Programme in five African countries in 2016. WHO contracted experts to facilitate sustainability planning among Ministries of Health, WHO, nongovernmental organisation grantees, and other stakeholders. METHODS: We designed an iterative and unique process for each RAcE project area which involved creating a sustainability framework to guide planning; convening meetings to identify and prioritise elements of the framework; forming technical working groups to build country ownership; and, ultimately, creating roadmaps to guide efforts to fully transfer ownership of the iCCM programmes to host countries. For this analysis, we compared priorities identified in roadmaps across RAcE project sites, examined progress against roadmaps via transition plans, and produced recommendations for short-term actions based on roadmap priorities that were unaddressed or needed further attention. RESULTS: This article describes the sustainability planning process, roadmap priorities, progress against roadmaps, and recommendations made for each project area. We found a few patterns among the prioritised roadmap elements. Overall, every project area identified priorities related to policy and coordination of external stakeholders including funders; supply chain management; service delivery and referral system; and communication and social mobilisation, indicating that these factors have persisted despite iCCM programme maturity, and are also of concern to new programmes. We also found that a facilitated process to identify and document programme priorities in roadmaps, along with deliberately planning for transition from an external implementer to a national system could support the sustainability of iCCM programmes by facilitating teams of stakeholders to accomplish explicit tasks related to transitioning the programme. CONCLUSIONS: Certain common elements are of concern for sustaining iCCM programmes across countries, among them political leadership, supply chain management, data processes, human resources, and community engagement. Adapting and using a sustainability planning approach created an inclusive and comprehensive dialogue about systemic factors that influence the sustainability of iCCM services and facilitated changes to health systems in each country.

Taxa de perdas de recém-graduados das instituições de formação em saúde e suas razões no momento da colocação no serviço nacional de saúde em moçambique / Rate of loss of recent graduates from health training institutions and reasons associated to these losses at the time of placement in the national healh srvice

Introdução: Moçambique enfrenta escassez de recursos humanos de saúde para prestar cuidados à população. Este cenário é agravado pelo alastramento do HIV e SIDA que aumenta a demanda pelos serviços de saúde, e pelas possíveis perdas de recém-graduados no momento da colocação no Serviço Nacional de Saúde após a formação, embora não haja dados fiáveis que quantifiquem estas perdas em Moçambique. Métodos: Foi realizado um estudo transversal que envolveu os 2.246 recém-graduados dos anos 2007 e 2008 de 12 Instituições de Formação em Saúde do país, com o propósito de determinar as taxas de perdas de recém-graduados na colocação e identificar razões associadas a essas perdas. Os dados foram obtidos dos livros de registos das Instituições de Formação em Saúde, Departamento dos Recursos Humanos do Ministério da Saúde, Direcções Provinciais de Saúde, listas de pagamento de subsídios de almoço e através de chamadas telefónicas aos recém-graduados considerados como perdidos no Serviço Nacional de Saúde. Os dados foram introduzidos no software ACESS e analisados no SPSS, onde foi feita a análise estatística descritiva e aplicado o teste Qui-Quadrado com o nível de significância de =5%. Resultados: Os registos das Direcções Provinciais de Saúde mostraram uma perda de 688 (30,6%) recém graduados. Ao se consultar as listas de pagamento de subsídio de almoço, estas perdas ficaram reduzidas a 241 (10,7%), ou seja, recuperaram-se 447 recém-graduados dos considerados como perdidos pelos registos das Direcções Provinciais de Saúde. Ainda, recuperaram-se mais 150 recém-graduados através de chamadas telefónicas aos considerados como perdidos pelas listas de pagamento de subsídio de almoço, perfazendo uma perda final de 91 (4,05%) recém-graduados. Estes últimos foram considerados realmente perdidos no Serviço Nacional de Saúde. Destes, 16 % (91) consentiram em ser inquiridos sobre as razões que estive ram na origem das perdas, tendo referido a necessidade de continuação dos estudos (38%), baixos salários (31%) e local de colocação distante do da família (31%). Conclusão: Os resultados revelam a existência de falhas no sistema de registo e seguimento dos recém graduados desde o nível central, provincial, distrital até à unidade sanitária.

Introduction: Mozambique lacks human resources to provide health care services to population. This scenario is exacerbated by the spread of HIV and AIDS which increases the demand for health services as well as by the possible loss of recent graduates at the time of placement in the National Health Service. However, there are no reliable data quantifying these losses in Mozambique. Methods: A cross-sectional study was conducted. This study included all 2.246 recent graduates of 2007 and 2008 of 12 health training institutions. The aim of the study was to determine the rates of loss of recent graduates at the time of placement and to identify reasons for these losses. Data were obtained from record books from health training institutions, the Department of Human Resources of the Ministry of Health, Provincial Health Directorates, lists of lunch subsidy payment and also through telephone calls to recent graduates who were considered lost in the National Health Service. Data were introduced in the ACESS software and were analyzed through SPSS. Descriptive statistical analysis was performed and a chi-square test was used. The level of statistical significance was = 5%. Results: The record books from Provincial Health Directorates revealed that 688 (30%) recent-graduates were lost. However, when the lists of lunch subsidy payments were examined, the number of losses de creased to 241 (10,7%), it means that, 447 recent graduates who had been considered lost were regained. Moreover, more than 150 recent graduated who had been considered lost in the lunch subsidylists, were regained through telephone calls. Thus, the final list of lost graduates totalizes 91 (4,05%) cases. These 91 were really considered lost in the National Health Service. About 16% of these 91 graduated gave us permission to interrogate them about the reasons associated to their loss. They presented the following reasons: need to proceed with their studies (38%), low wages (31%), and placement distant from their families (31%) Conclusion: The results of this study indicate failures in the system of record and monitoring of recent graduates at all levels: central, provincial, district and health center unit.

Serial changes in norepinephrine kinetics associated with feeding dogs a high-fat diet.

The role of increased sympathetic nervous system (SNS) activity in the pathogenesis of obesity hypertension and insulin resistance is controversial. Eight dogs were instrumented and fed a high-fat diet (HFD) for 6 weeks. Dogs were evaluated for changes in weight, blood pressure, insulin resistance, and norepinephrine (NE) kinetics using a two-compartment model. The HFD resulted in weight gain, hypertension, and insulin resistance. During the 6 weeks of the HFD, although plasma NE concentration trended toward increasing (P=.09), SNS, assessed by NE kinetic studies, significantly increased (P=.009). Within 1 week of starting the HFD, NE release into the extravascular compartment (NE(2)) increased from 3.44+/-0.59 microg/mL to 4.87+/-0.80 microg/mL (P<.01) and this increase was maintained over the next 5 weeks of the HFD (NE(2) at week 6 was 4.66+/-0.97 microg/mL). In addition to the increased NE(2) there was also a significant increase in NE clearance (P=.04). There were significant correlations between the increase in NE(2) and both the development of insulin resistance and hypertension. This study supports the hypothesis that activation of the SNS plays a pivotal role in the metabolic and hemodynamic changes that occur with weight gain induced by HFD.

Impaired beta-cell function in human aging: response to nicotinic acid-induced insulin resistance.

CONTEXT: Glucose tolerance declines with age and may involve impaired beta-cell sensitivity to glucose and beta-cell compensation for insulin resistance. OBJECTIVE: We investigated beta-cell sensitivity to glucose and beta-cell compensation for nicotinic acid-induced insulin resistance in young (age <35 yr) people with normal glucose tolerance (NGT) and old (age >60 yr) people with NGT and impaired glucose tolerance (IGT). DESIGN/PATIENTS/SETTING/INTERVENTION: Fifteen young NGT, 16 old NGT, and 14 old IGT were randomized to 2-wk treatment with nicotinic acid or placebo in a double-blind, crossover study in a university medical setting. At the end of each treatment period, participants had a frequently sampled iv glucose tolerance test and ramp clamp, in which insulin secretion rates (ISR) were determined in response to a matched 5-10 mm glucose stimulus. MAIN OUTCOME MEASURES: Insulin sensitivity (S(I)), acute insulin response to iv glucose (AIRg), and disposition index (AIRg x S(I), or beta-cell compensation for insulin resistance) from frequently sampled iv glucose tolerance testing, and ISR area under the curve (or beta-cell sensitivity to glucose) from ramp clamp were determined. RESULTS: Progressive impairments in insulin secretion as assessed by AIRg, disposition index, and ISR area under the curve were identified in older people with NGT, with more marked defects in older people with IGT. Nicotinic acid treatment significantly reduced S(I) in all groups. beta-Cell compensation for nicotinic acid-induced insulin resistance was incomplete in all three groups, with greater defects in the two older groups. CONCLUSIONS: Human aging is associated with impaired beta-cell sensitivity to glucose and impaired beta-cell compensation to insulin resistance.

Limitation of the homeostasis model assessment to predict insulin resistance and beta-cell dysfunction in older people.

CONTEXT: Studies in older people have shown inconsistent agreement between homeostasis model assessment of insulin resistance (HOMA-IR) and dynamic measures of insulin action and have not evaluated HOMA beta-cell. OBJECTIVE: We compared measures of insulin sensitivity and beta-cell function from the frequently sampled iv glucose tolerance test (FSIGT) to HOMA models. DESIGN/PATIENTS/SETTING/INTERVENTION: Two hundred fourteen young and old with normal glucose tolerance (NGT) and old with impaired glucose tolerance (IGT) participated in a retrospective analysis of FSIGT data in a university medical setting. MAIN OUTCOME MEASURE: Sensitivity to insulin (S(I)) and acute insulin response to glucose (AIRg) from FSIGT were compared with HOMA models. RESULTS: S(I) and HOMA-IR measures identified similar patterns of increasing insulin resistance in the two older groups, compared with younger people with NGT, with the greatest degree of insulin resistance in older people with IGT (P < 0.05 vs. young and old NGT for both S(I) and HOMA-IR). Agreement between HOMA-IR and S(I) was moderate (weighted kappa = 0.51). AIRg was similar in young and old NGT but was markedly decreased in old IGT (P < 0.05 vs. young and old NGT). HOMA-beta-cell was similar in the three groups. Agreement between HOMA beta-cell and AIRg was weak (weighted kappa = 0.35). CONCLUSIONS: HOMA-IR may detect age-related insulin resistance when comparing large populations of older people. However, dynamic testing appears to be necessary to quantitate diminished insulin secretion in older people.

Ordinary differential equation PK/PD models using the SAS macro NLINMIX.

We describe some theory and recent enhancements for the SAS macro NLINMIX (Wolfinger, R. D. (1993). Laplace's approximation for nonlinear mixed effects models. Biometrika 80:791-795) that enable model calculation to take place within the interaction matrix language SAS/IML (SAS Institute Inc. (1999a). SAS/IML User's Guide Version 7. Cary, NC: SAS Institute Inc.). They provide greater flexibility and scope for the specification and analysis of complex nonlinear mixed models. For example, using data from a frequently sampled intravenous glucose test, we fit a two-compartment kinetics model that has no closed-form representation. It is derived as the solution of a system of ordinary differential equations and specified as such in SAS/IML. Additional details and example NLINMIX code are available in Appendix A.

Effect of lowering postprandial hyperglycemia on insulin secretion in older people with impaired glucose tolerance.

Glucose tolerance declines with age, resulting in a high prevalence of diabetes and impaired glucose tolerance (IGT) in the older population. Hyperglycemia per se can lead to impaired beta-cell function (glucose toxicity). We tested the role of glucose toxicity in age-related beta-cell dysfunction in older people (65 +/- 8 yr) with IGT treated with the alpha-glucosidase inhibitor acarbose (n = 14) or placebo (n = 13) for 6 wk in a randomized, double-blind study. Baseline and posttreatment studies included 1) an oral glucose tolerance test (OGTT), 2) 1-h postprandial glucose monitoring, 3) a frequently sampled intravenous glucose tolerance test (insulin sensitivity, or S(I)), and 4) glucose ramp clamp (insulin secretion rates, or ISR), in which a variable glucose infusion increases plasma glucose from 5 to 10 mM. The treatment groups had similar baseline body mass index; fasting, 2-h OGTT, and 1-h postprandial glucose levels; and S(I). In these carefully matched older people with IGT, both fasting (5.7 +/- 0.2 vs. 6.3 +/- 0.2 mM, P = 0.002) and 1-h postprandial glucose levels (6.9 +/- 0.3 vs. 8.2 +/- 0.4 mM, P = 0.02) were significantly lower in the acarbose than in the placebo group. Despite this reduction of chronic hyperglycemia in the acarbose vs. placebo group, measures of insulin secretion (ISR area under the curve: 728 +/- 55 vs. 835 +/- 81 pmol/kg, P = 0.9) and acute insulin response to intravenous glucose (329 +/- 67 vs. 301 +/- 54 pM, P = 0.4) remained unchanged and impaired. Thus short-term improvement of chronic hyperglycemia does not reverse beta-cell dysfunction in older people with IGT.

Changes in systemic sympathetic nervous system activity after mitral valve surgery and their relationship to changes in left ventricular size and systolic performance in patients with mitral regurgitation.

BACKGROUND: We have shown that the systemic sympathetic nervous system (SNS) is activated in patients with chronic mitral regurgitation (MR). However, the fate of systemic SNS activity after surgical correction of MR is currently unknown. METHODS: We examined 14 patients with MR who had normal sinus rhythm with an investigational, preoperative cardiac catheterization, including arterial norepinephrine (NE) sampling and [(3)H]-NE infusions and arterial blood sampling to determine NE kinetic parameters using a 2-compartment modeling analysis. The arterial NE and NE kinetic parameters were determined in all patients after mitral valve surgery (MVS) at a mean of 12 months. A 2-dimensional echocardiographic examination was also performed before and after MVS. RESULTS: The average extravascular NE release rates (NE(2)) before and after MVS were 1.89 +/- 0.66 and 2.26 +/- 0.82 microg/min/m(2) (P =.24), respectively. The average left ventricular (LV) end-diastolic dimension, fractional shortening, and ejection fraction decreased, whereas the mean LV end-systolic dimension did not change between the pre- and post-MVS echocardiographic studies. However, these group averages were comprised of patients with MR in whom the NE(2) and echocardiographic values both increased and decreased. This lack of homogeneity was a reflection of our new observation that the pre- to post-MVS changes in NE(2) were directly proportional to the changes in LV end-systolic dimension (r = 0.91, P <.001) and inversely related to the changes in LV fractional shortening (r = -0.82, P <.001) and ejection fraction (r = -0.78, P <.001). CONCLUSIONS: The response in systemic SNS activity in patients with MR after MVS is not homogeneous, and these changes are concordant with the post-MVS changes in LV size and systolic performance. These data further support our earlier observations and extend them to suggest that systemic SNS activation in patients with chronic MR is related to LV remodeling and impaired systolic performance.

Compared with control subjects, the systemic sympathetic nervous system is activated in patients with mitral regurgitation.

BACKGROUND: Whether the systemic sympathetic nervous system is activated as a compensatory mechanism in response to mitral regurgitation (MR) in humans is unknown. We tested the hypotheses that the systemic sympathetic nervous system would be activated in patients with MR in comparison with control subjects and that this activation would occur early in the disease process as a compensatory mechanism for chronic left ventricular (LV) volume overload. METHODS: We studied 37 patients with MR who underwent right heart catheterization and biplane cineventriculography to obtain LV end-diastolic and end-systolic volumes, ejection fractions, and regurgitant volumes. In these 37 patients with MR and in 23 control subjects, an [(3)H]-norepinephrine ([(3)H]-NE) infusion and multiple arterial blood samples provided data for a 2-compartment modeling analysis to calculate extravascular NE release rates (NE(2)). RESULTS: The mean NE(2) (2.05 +/- 0.76 microg/min/m(2)) in the patients with MR was greater than that in the control subjects (1.48 +/- 0.75 microg/min/m(2), P =.007). Furthermore, the mean NE(2) values were also greater in the patients with MR who were in clinical class I (P =.05), with a pulmonary capillary wedge pressure <12 mm Hg (P =.05) or a LV ejection fraction >or=0.60 (P =.06) compared with the control subjects. The mean NE(2) values were increased further in patients with MR who had a LV ejection fraction <0.60 (P =.02). CONCLUSIONS: The systemic sympathetic nervous system is activated in patients with MR in comparison with control subjects, and this activation appears to occur early in the disease process as a compensatory mechanism for LV volume overload.

The GLP-1 derivative NN2211 restores beta-cell sensitivity to glucose in type 2 diabetic patients after a single dose.

Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion in a glucose-dependent manner, but its short half-life limits its therapeutic potential. We tested NN2211, a long-acting GLP-1 derivative, in 10 subjects with type 2 diabetes (means +/- SD: age 63 +/- 8 years, BMI 30.1 +/- 4.2 kg/m(2), HbA(1c) 6.5 +/- 0.8%) in a randomized, double-blind, placebo-controlled, crossover study. A single injection (7.5 micro g/kg) of NN2211 or placebo was administered 9 h before the study. beta-cell sensitivity was assessed by a graded glucose infusion protocol, with glucose levels matched over the 5-12 mmol/l range. Insulin secretion rates (ISRs) were estimated by deconvolution of C-peptide levels. Findings were compared with those in 10 nondiabetic volunteers during the same glucose infusion protocol. In type 2 diabetic subjects, NN2211, in comparison with placebo, increased insulin and C-peptide levels, the ISR area under the curve (AUC) (1,130 +/- 150 vs. 668 +/- 106 pmol/kg; P < 0.001), and the slope of ISR versus plasma glucose (1.26 +/- 0.36 vs. 0.54 +/- 0.18 pmol x l[min(-1) x mmol(-1) x kg(-1)]; P < 0.014), with values similar to those of nondiabetic control subjects (ISR AUC 1,206 +/- 99; slope of ISR versus plasma glucose, 1.44 +/- 0.18). The long-acting GLP-1 derivative, NN2211, restored beta-cell responsiveness to physiological hyperglycemia in type 2 diabetic subjects.