Preferential liver gene expression with polypropylenimine dendrimers.

Previously, the lower generation (DAB 8-generation 2 and DAB 16-generation 3) polypropylenimine dendrimers have been shown to be effective gene delivery systems in vitro. In the current work, we sought to: (a) test the effect of the strength of the carrier, DNA electrostatic interaction on gene transfer and (b) to study the in vivo gene transfer activity of these low molecular weight (<1687 Da) non-amphiphilic plain and quaternary ammonium gene carriers. Towards this aim, methyl quaternary ammonium derivatives of DAB 4 (generation 1), DAB 8, DAB 16 and DAB 32 (generation 4) were synthesised to give Q4, Q8, Q16 and Q32, respectively. Quaternisation of DAB 8 proved to be critical in improving DNA binding, as evidenced by data from the ethidium bromide exclusion assay and dendrimer-DNA colloidal stability data. This improved colloidal stability had a major effect on vector tolerability, as Q8-DNA formulations were well tolerated on intravenous injection while a similar DAB 8-DNA dose was lethally toxic by the same route. Quaternisation also improved the in vitro cell biocompatibility of DAB 16-DNA and DAB 32-DNA dendrimer complexes by about 4-fold but not that of the lower generation DAB 4-DNA and DAB 8-DNA formulations. In contrast to previous reports with non-viral gene delivery systems, the intravenous administration of DAB 16-DNA and Q8-DNA formulations resulted in liver targeted gene expression as opposed to the lung targeted gene expression obtained with the control polymer-Exgen 500 [linear poly(ethylenimine)] and a lung avoidance hypothesis is postulated. We conclude that the polypropylenimine dendrimers are promising gene delivery systems which may be used to target the liver and avoid the lung and also that molecular modifications conferring colloidal stability on gene delivery formulations have a profound effect on their tolerability on intravenous administration.     

Profiles of caregiving behaviors among children and adolescents with perinatally acquired HIV

Although parenting behaviors are widely considered an important factor in the adjustment of children and adolescents with chronic physical health needs, few studies have addressed this topic as it pertains to youth with perinatally-acquired human immunodeficiency virus (PHIV). We examined profiles of child-centeredness, control through guilt, consistent discipline, and detachment, and whether these profiles differed in terms of parent- and youth-reported psychiatric disorder symptoms in a cohort of HIV infected youth (N?=?314). Latent profile analyses of caregiving behaviors were conducted separately for children (6–12 years) and adolescents (13–18 years). Two profiles were identified among children: (a) moderate caregiving (87%, n?=?130) and (b) high detachment caregiving (13%, n?=?19), and three profiles were identified among adolescents: (a) moderate caregiving (55%, n?=?88), (b) high detachment caregiving (19%, n?=?30), and (c) high control through guilt caregiving (26%, n?=?42). The high detachment and high control through guilt caregiving profiles displayed higher levels of parent-and youth-reported symptoms than the moderate caregiving profile. These findings suggest that caregiver behaviors of PHIV youth vary as a function of children’s developmental period and differ in terms of youth psychological symptoms.     

Impact of Race and Socioeconomic Status on Outcomes in Patients Hospitalized with COVID-19

BackgroundThe impact of race and socioeconomic status on clinical outcomes has not been quantified in patients hospitalized with coronavirus disease 2019 (COVID-19).ObjectiveTo evaluate the association between patient sociodemographics and neighborhood disadvantage with frequencies of death, invasive mechanical ventilation (IMV), and intensive care unit (ICU) admission in patients hospitalized with COVID-19.DesignRetrospective cohort study.SettingFour hospitals in an integrated health system serving southeast Michigan.ParticipantsAdult patients admitted to the hospital with a COVID-19 diagnosis confirmed by polymerase chain reaction.Main MeasuresPatient sociodemographics, comorbidities, and clinical outcomes were collected. Neighborhood socioeconomic variables were obtained at the census tract level from the 2018 American Community Survey. Relationships between neighborhood median income and clinical outcomes were evaluated using multivariate logistic regression models, controlling for patient age, sex, race, Charlson Comorbidity Index, obesity, smoking status, and living environment.Key ResultsBlack patients lived in significantly poorer neighborhoods than White patients (median income: $34,758 (24,531–56,095) vs. $63,317 (49,850–85,776), p < 0.001) and were more likely to have Medicaid insurance (19.4% vs. 11.2%, p < 0.001). Patients from neighborhoods with lower median income were significantly more likely to require IMV (lowest quartile: 25.4%, highest quartile: 16.0%, p < 0.001) and ICU admission (35.2%, 19.9%, p < 0.001). After adjusting for age, sex, race, and comorbidities, higher neighborhood income ($10,000 increase) remained a significant negative predictor for IMV (OR: 0.95 (95% CI 0.91, 0.99), p = 0.02) and ICU admission (OR: 0.92 (95% CI 0.89, 0.96), p < 0.001).ConclusionsNeighborhood disadvantage, which is closely associated with race, is a predictor of poor clinical outcomes in COVID-19. Measures of neighborhood disadvantage should be used to inform policies that aim to reduce COVID-19 disparities in the Black community.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11606-020-06527-1.KEY WORDS: COVID-19, disparities, disadvantage, socioeconomic status, race     

Identifying and addressing sexual health in serious mental illness: Views of mental health staff working in two National Health Service organizations in England

People with serious mental illness (service users) have needs related to sexual health and sexuality, yet these have been poorly addressed in mental health services. In the present study, we report the current practice of mental health professionals in relation to sexual health. Focus groups conducted in two mental health trusts explored routine practice in relation to discussing, assessing, and planning care in relation to sexual health. A thematic analysis identified seven themes: (i) sexual health provision is a complex issue; (ii) mental health staff are aware of sexual health needs; (iii) current provision regarding sexual health is ‘neglected’; (iv) barriers to sexual health provision; (v) enabling a discussion around sexual health; (vi) sexual health provision is a role for mental health professionals; and (vii) training needs. Mental health staff are aware of complex issues related to sexual health for service users, but this is mainly seen through the lens of risk management and safeguarding. We need to develop the mental health workforce to be able to incorporate sexual health into routine health care.     

Development of an international online learning platform for hepatopancreatobiliary surgical training: a needs assessment

BackgroundThe Americas Hepato-Pancreato-Biliary Association (AHPBA) and the Australian and New Zealand Hepatic, Pancreatic and Biliary Association (ANZHPBA) are developing an online distance learning curriculum to facilitate an interactive didactic experience for hepatopancreatobiliary (HPB) fellows in the operationalization of existing HPB fellow curricula. Two needs assessment surveys were carried out to identify the optimal structure and process for deployment in fellow education.MethodsA 22-question survey querying fellows'' learning styles and current and anticipated use of learning tools was disseminated electronically to 38 North American and Australasian HPB fellows. A follow-up 20-question survey was administered to assess fellows'' feelings regarding online content.ResultsResponse rates were 55% (n = 21) for the first survey and 42% for the second (n = 16). In the first survey, 67% of respondents claimed familiarity with the required HPB curriculum, and 43% indicated dissatisfaction with current personal study strategies. A total of 62% (n = 13) reported studying with focused clinical relevance versus using a prescribed curriculum (n = 1, 5%). Fellows anticipated participating using online tools once (n = 10, 48%) or two or three times (n = 5, 24%) per week. Most respondents (n = 18, 86%) would meaningfully follow one or two discussions per month. The second survey identified themes for improvement such as discussion topics of interest, avoidance of holiday timing and mandatory participation.ConclusionsAn international online distance learning format is an appealing mechanism for improved dissemination and operationalization of the established HPB fellow curricula. Fellows will engage in interactive discussions monthly. Controversial topics or those requiring complex decision making are best suited to this learning format.     

Alvimopan (Adolor/GlaxoSmithKline)

Alvimopan is a potent, peripherally active, mu-opioid receptor antagonist being developed by Adolor and GlaxoSmithKline (GSK) as a potential treatment for post-operative ileus and opioid bowel dysfunction.     

Niosomes and Polymeric Chitosan Based Vesicles Bearing Transferrin and Glucose Ligands for Drug Targeting

Purpose. To prepare polymeric vesicles and niosomes bearing glucose or transferrin ligands for drug targeting. Methods. A glucose-palmitoyl glycol chitosan (PGC) conjugate was synthesised and glucose-PGC polymeric vesicles prepared by sonication of glucose-PGC/ cholesterol. N-palmitoylglucosamine (NPG) was synthesised and NPG niosomes also prepared by sonication of NPG/ sorbitan monostearate/ cholesterol/ cholesteryl poly-24-oxyethylene ether. These 2 glucose vesicles were incubated with colloidal concanavalin A gold (Con-A gold), washed and visualised by transmission electron microscopy (TEM). Transferrin was also conjugated to the surface of PGC vesicles and the uptake of these vesicles investigated in the A431 cell line (over expressing the transferrin receptor) by fluorescent activated cell sorter analysis. Results. TEM imaging confirmed the presence of glucose units on the surface of PGC polymeric vesicles and NPG niosomes. Transferrin was coupled to PGC vesicles at a level of 0.60 ± 0.18 g of transferrin per g polymer. The proportion of FITC-dextran positive A431 cells was 42% (FITC-dextran solution), 74% (plain vesicles) and 90% (transferrin vesicles). Conclusions. Glucose and transferrin bearing chitosan based vesicles and glucose niosomes have been prepared. Glucose bearing vesicles bind Con-A to their surface. Chitosan based vesicles are taken up by A431 cells and transferrin enhances this uptake.