In the present study, the preparation of pharmaceutical mini-tablets was attempted in the framework of Quality by Design (QbD) context, by comparing traditionally used multi-linear regression (MLR), with artificially-intelligence based regression techniques (such as standard artificial neural networks (ANNs), particle swarm optimization (PSO) ANNs and genetic programming (GP)) during Design of Experiment (DoE) implementation. Specifically, the effect of diluent type and particle size fraction for three commonly used direct compression diluents (lactose, pregelatinized starch and dibasic calcium phosphate dihydrate, DCPD) blended with either hydrophilic or hydrophobic flowing aids was evaluated in terms of: a) powder blend properties (such as bulk (Y1) and tapped (Y2) density, Carr's compressibility index (Y3, CCI), Kawakita's compaction fitting parameters a (Y4) and 1/b (Y5)), and b) mini-tablet's properties (such as relative density (Y6), average weight (Y7) and weight variation(Y8)). Results showed better flowing properties for pregelatinized starch and improved packing properties for lactose and DPCD. MLR analysis showed high goodness of fit for the Y1, Y2, Y4, Y6 and Y8 with RMSE values of Y1=0.028, Y2=0.032, Y4=0.019, Y6=0.015 and Y8=0.130; while for rest responses, high correlation was observed from both standard ANNs and GP. PSO-ANNs fitting was the only regression technique that was able to adequately fit all responses simultaneously (RMSE values of Y1=0.026, Y2=0.022, Y3=0.025, Y4=0.010, Y5=0.063, Y6=0.013, Y7=0.064 and Y8=0.104).

A diet of energy-dense food, characterized mainly as a high-fat diet, leads to a persistent excessive consumption defined as overeating. According to the National Institute of Health, more than 2 in 3 adults in the United States are overweight or obese, straining our healthcare system with epidemic proportions. Diets that include abstaining from high-fat foods, ironically, result in an increase in motivation and craving for said high-fat foods, defined as an incubation effect because the behavior aids in developing overeating. Previously, we have shown that modulation of neuromedin U receptor 2 (NMUR2) in the paraventricular nucleus of the hypothalamus (PVN) results in increased food intake and motivation for energy-dense foods. Here, we continue our focus on NMUR2 in the PVN, but in relation to the incubation effect on craving for high-fat food. We employed a model for incubation of craving by having rats abstain from high-fat foods for 30 days before undergoing intake of fatty food on fixed ratio and progressive ratio schedules of reinforcement, and then assess their response to reactivity to cues. Using this model, we compared the feeding behaviors of rats that underwent an mRNA knockdown of the NMUR2 in the PVN to controls after both underwent a 30-day abstinence from high-fat foods. Our results show knockdown of NMUR2 in the PVN blocks the incubation of feeding behavior for food-related cues and high-fat foods.

Methyl donor balance is critical for epigenetic regulation in cells and is maintained by the so-called methionine cycle proteins that regenerate SAM, the universal methyl donor, from homocysteine formed by the activity of methyltransferases. Nnmt is a liver enzyme that methylates nicotinamide but its role in regulating methyl donor balance in the liver is unclear. In this study, we assessed the effect of altered Nnmt expression on various aspects of methyl donor metabolism in the liver. We found that Nnmt overexpression lowered SAM levels and SAM/SAH ratio in both in vivo and in vitro. Nnmt knockdown did not change methyl donor balance in mouse primary hepatocytes but increased SAM levels and SAM/SAH ratio when we kncocked down the expression of Gnmt, the dominantly expressed methyltransferase in liver. Paradoxically, expression of enzymatically-deficient Nnmt increased SAM/SAH ratio suggesting that Nnmt can regulate methyl donor balance independent of its methyltransferase activity. Proteomics analysis of Nnmt-interacting proteins in the liver identified Bhmt, Mat1a and Ahcy, all components of the methionine cycle and functional experiments showed that mutant Nnmt increased remethylation of homocysteine to SAM. In summary, we show that the function of Nnmt in hepatic methyl donor balance is multifactorial. On one hand, Nnmt decreases methyl donor balance, consistent with its activity as a methyltransferase consuming methyl donors. On the other hand, by co-opting the enzymes of the methionine cycle, Nnmt aids the recycling of homocysteine to SAM for another round of methylation.

World leaders gather to consolidate their commitment to ending TB. Vital to the success of renewed efforts is an overdue recognition of the pervasive and pernicious influence of TB stigma. TB stigma is sustained in structures, policies, traditions, and norms. Innovative modifications to infection control, drug dispensing, and surveillance practices are required to increase demand for TB screening and effective therapeutic alliances among those diagnosed. The authors argue that reducing TB stigma requires a scientific and inclusive process, with prominent roles for TB survivors and a willingness to integrate and learn from other stigmatized conditions.

Late presentation to HIV care is common in India despite access to free combination antiretroviral therapy (cART). We assessed risk factors for late presentation among patients with a recent HIV diagnosis in an academic university-based antiretroviral treatment center. This retrospective study included 474 recently diagnosed HIV-infected patients registered for cART between 2012 and 2013. Subjects with CD4+ T-lymphocyte (CD4) count ≤ 350 cells/μL or with an AIDS defining event were defined as late presenters (LP) and patients with CD4 count ≤ 200 cells/μL or with an AIDS defining event were defined as LP with advanced HIV disease (LPAD). Multivariable logistic regression analysis was used to investigate factors associated with late presentation. Of the 474 patients, 356 (75.1%) were LP. Of these, 299 (83.99%) were LPAD and 57 (16.01%) LP were AIDS-free. Median CD4 count among LP was 134 cells/μL (IQR 72.25-219). Mean age of LP was 42.50 ± 8.88 years; 256 (71.9%) were males. Increasing age (> 51 years; Adjusted odds ratio [aOR] 4.19; P = 0.014) and rural residence (aOR 3.19; P = < 0.001) were independently associated with late presentation. HIV-positive housewives (aOR 0.34; P = 0.027), HIV-positive individuals with negative partners (aOR 0.48; P = 0.006), and partners with unknown HIV status (aOR 0.43; P = 0.007) were less likely to present late compared with positive partners of people living with HIV/AIDS (PLWHA). Most patients were LP despite free access to cART. Rural population and older PLHIV should be targeted while implementing HIV care. There is a need to strengthen the HIV care cascade by linking PLWHA to cART immediately after diagnosis.

Travelers to developing regions are at risk for development of influenza-like illness (ILI). Little is known of traveler and trip characteristics associated with the development of ILI. TravMil is a prospective observational study, enrolling subjects presenting to six military travel clinics or predeployment-screening sites. We analyzed pre- and post-travel surveys from travelers visiting regions outside of the continental United States, Western or Northern Europe, Canada, Australia, or New Zealand between January 2010 and March 2016. Influenza-like illness was defined as a self-reported fever associated with either sore throat or cough. Trip and traveler characteristics were analyzed to determine risk factors for the development of ILI. Two thousand nine hundred and thirty-two trips were recorded (55% male, median age 45 years, 69% white, 51% on vacation, median travel duration 17 days). The 2,337 trips included the number of self-reported influenza vaccinations in the preceding 5 years (median 5). Eleven percent of the trips were complicated by an ILI lasting a median of 5 days; 70% and 17% of these reported upper and lower respiratory tract infection, respectively, and 12% reported both. On multivariate analysis, increased risk of ILI was associated with female gender (odds ratio [OR]: 1.60 [confidence interval (CI): 1.25-2.05], P < 0.01), age (years) (OR: 1.01 [CI: 1.01-1.02], P < 0.01); and duration of travel (days) (OR: 1.01 [CI: 1.00-1.01], P < 0.01). Influenza-like illness is common in travelers, regardless of traveler characteristics, purpose of travel, destination, or season of year. Female gender, older age, and longer duration of travel were associated with an increased risk of ILI. Additional tools and strategies are needed to prevent ILI in international travelers.

In 2016 to 2017, we surveyed primary care providers (PCPs) in upper Manhattan and the South Bronx, New York, on their knowledge, attitudes, and practices surrounding preexposure prophylaxis (PrEP) for HIV. Despite efforts to promote survey response, we were only able to obtain a meager response rate, limiting our ability to interpret results. In this short communication, we examine our survey's methodology, as well as the methods used by other similar studies, in order to suggest how certain strategies appear to influence PCP response to PrEP surveys. Administering the survey in a variety of modes, sampling from a professional organization's listserv, promoting the survey topic's relevance to potential participants, and offering monetary incentives to each survey respondent all appear to be promising strategies for increasing response rates in PrEP provider surveys.