Optimizing drug therapy in patients with advanced dementia: A patient-centered approach

Background: Advanced dementia is a prevalent health problem in geriatric patients. These patients usually suffer from several chronic diseases, frequently leading to an end-of-life situation lasting months or years, generating complex and often inappropriate medication regimens. Objectives: Describe the re-orientation of drug therapy in patients with advanced dementia utilizing a systematic medication review process. Methods: This non-experimental pre-post analysis included all patients with advanced dementia admitted to acute geriatric unit (AGU) over one year. Medications were reviewed by a multidisciplinary team and together with the patient caregivers; new therapeutic objectives based on end-of-life care principles were established. Medications were classified as preventive, therapeutic, or symptomatic. The average number of medications per patient pre- and post-admission was compared. Results: We included 73 patients (mean age 86.1 years, mean Barthel Index: 14.5/100). At admission, patients had a mean of 7.27 drugs compared to 4.82 at discharge (66.85% reduction, P < 0.05). The main drugs withdrawn were cardiovascular and hematological (35.76%). Drugs for prevention decreased by 66.85% (from 1.8 to 0.6, P < 0.05) and those for symptomatic care decreased by 17,52% (from 2.34 to 1.93, P < 0.05). Conclusion: Medication therapy plans in patients with advanced dementia often do not meet their therapeutic goals. The proposed methodology is a useful tool to assess therapeutic appropriateness

Positive interaction between work and home, and psychological availability on women’s work engagemen t: a ‘shortitudinal’ study

Abstract: Orientation: Women’s work engagement is affected by how well they balance their work and personal life, and their level of confidence in their capability at work. Research purpose: Determine whether women’s daily psychological availability mediates daily positive work-home interaction and daily positive home-work interaction on daily work engagement. Motivation for the study: Research into negative work–home and home–work interaction is in abundance. Limited studies focus on the positive effects on women’s experiences at work (i.e. work engagement). Little is known about women’s psychological availability and how it affects their work. Furthermore, little research provides us insights into the day-level experiences of women at work. Research approach/design and method: A quantitative, shortitudinal design was used. Data analyses accounted for multilevel structure in the data (within-person vs. between-person differences). Female employees (n = 60) from various industries in Gauteng, completed electronic diaries in the form of a survey for 10 consecutive working days. Main findings: Daily psychological availability mediates between daily positive work-home interaction and daily work engagement. Daily positive home-work interaction did not predict daily work engagement, but had a significant effect on daily psychological availability. Practical/managerial implications: Examining systems and structures that promote opportunities for women to become more psychologically available at work impacts their sustainable retention. Contribution/value-add: This study found significant relationships between day-level uses of personal resources and spillover effects of home-work and work-home on day-level work engagement. The study further contributes to the literature on positive work–home and home–work interaction

Enhancing well-being and social connectedness for Maori elders through a peer education (Tuakana-Teina) programme: A cross-sectional baseline study

Background: Māori kaumātua (elders) face stark health and social inequities compared to non-Māori New Zealanders. The tuakana-teina (older sibling-younger sibling) peer education programme is a strengths-based approach to enhance well-being and social connectedness. The purpose of this study is to present the baseline data from this programme and identify correlates of well-being outcomes. Method: Participants included 128 kaumātua who completed a self-report survey about health-related quality of life, spirituality, social connection and loneliness, life satisfaction, cultural identity and connection, elder abuse, health service utilisation and demographics. Findings: Multiple regression models illustrated the following correlates of outcomes: (a) self-rated health: needing more help with daily tasks (β = −0.36) and housing problems (β = –0.17); (b) health-related quality of life: needing more help with daily tasks (β = –0.31), housing problems (β = –0.21), and perceived autonomy (β = 0.19); (c) spiritual well-being: understanding of tikanga (cultural protocols) (β = 0.32) and perceived autonomy (β = 0.23); (d) life satisfaction: social support (β = 0.23), sense of purpose (β = 0.23), cultural identity (β = 0.24), trouble paying bills (β = –0.16), and housing problems (β = –0.16); (e) loneliness: elder abuse (β = 0.27), social support (β = –0.21), and missing pleasure of being with whānau (extended family) (β = 0.19). Conclusions: Key correlates for outcomes centred on social support, housing problems, cultural connection and perceived autonomy. These correlates are largely addressed through the programme where tuakana/peer educators provide support and links to social and health services to teina/peer recipients in need. This study illustrates needs and challenges for kaumātua, whilst the larger programme represents a strengths-based and culturally-centred approach to address health issues related to ageing in an Indigenous population

Quantitative profiling of the full APOBEC3 mRNA repertoire in lymphocytes and tissues: implications for HIV-1 restriction

The human APOBEC3 proteins are DNA cytidine deaminases that impede the replication of many different transposons and viruses. The genes that encode APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G and APOBEC3H were generated through relatively recent recombination events. The resulting high degree of inter-relatedness has complicated the development of specific quantitative PCR assays for these genes despite considerable interest in understanding their expression profiles. Here, we describe a set of quantitative PCR assays that specifically measures the mRNA levels of each APOBEC3 gene. The specificity and sensitivity of each assay was validated using a full matrix of APOBEC3 cDNA templates. The assays were used to quantify the APOBEC3 repertoire in multiple human T-cell lines, bulk leukocytes and leukocyte subsets, and 20 different human tissues. The data demonstrate that multiple APOBEC3 genes are expressed constitutively in most types of cells and tissues, and that distinct APOBEC3 genes are induced upon T-cell activation and interferon treatment. These data help define the APOBEC3 repertoire relevant to HIV-1 restriction in T cells, and they suggest a general model in which multiple APOBEC3 proteins function together to provide a constitutive barrier to foreign genetic elements, which can be fortified by transcriptional induction

AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity

Retrotransposons make up over 40% of the mammalian genome. Some copies are still capable of mobilizing and new insertions promote genetic variation. Several members of the APOBEC3 family of DNA cytosine deaminases function to limit the replication of a variety of retroelements, such as the long-terminal repeat (LTR)-containing MusD and Ty1 elements, and that of the non-LTR retrotransposons, L1 and Alu. However, the APOBEC3 genes are limited to mammalian lineages, whereas retrotransposons are far more widespread. This raises the question of what cellular factors control retroelement transposition in species that lack APOBEC3 genes. A strong phylogenetic case can be made that an ancestral activation-induced deaminase (AID)-like gene duplicated and diverged to root the APOBEC3 lineage in mammals. Therefore, we tested the hypothesis that present-day AID proteins possess anti-retroelement activity. We found that AID can inhibit the retrotransposition of L1 through a DNA deamination-independent mechanism. This mechanism may manifest in the cytoplasmic compartment co- or posttranslationally. Together with evidence for AID expression in the ovary, our data combined to suggest that AID has innate immune functions in addition to its integral roles in creating antibody diversity

Expanding ART for Treatment and Prevention of HIV in South Africa: Estimated Cost and Cost-Effectiveness 2011-2050

Background: Antiretroviral Treatment (ART) significantly reduces HIV transmission. We conducted a cost-effectiveness analysis of the impact of expanded ART in South Africa. Methods: We model a best case scenario of 90% annual HIV testing coverage in adults 15-49 years old and four ART eligibility scenarios: CD4 count <200 cells/mm3(current practice), CD4 count <350, CD4 count <500, all CD4 levels. 2011-2050 outcomes include deaths, disability adjusted life years (DALYs), HIV infections, cost, and cost per DALY averted. Service and ART costs reflect South African data and international generic prices. ART reduces transmission by 92%. We conducted sensitivity analyses. Results: Expanding ART to CD4 count <350 cells/mm3prevents an estimated 265,000 (17%) and 1.3 million (15%) new HIV infections over 5 and 40 years, respectively. Cumulative deaths decline 15%, from 12.5 to 10.6 million; DALYs by 14% from 109 to 93 million over 40 years. Costs drop $504 million over 5 years and$3.9 billion over 40 years with breakeven by 2013. Compared with the current scenario, expanding to <500 prevents an additional 585,000 and 3 million new HIV infections over 5 and 40 years, respectively. Expanding to all CD4 levels decreases HIV infections by 3.3 million (45%) and costs by $10 billion over 40 years, with breakeven by 2023. By 2050, using higher ART and monitoring costs, all CD4 levels saves$0.6 billion versus current; other ART scenarios cost $9-194 per DALY averted. If ART reduces transmission by 99$17.5 billion. Sensitivity analyses suggest that poor retention and predominant acute phase transmission reduce DALYs averted by 26% and savings by 7%. Conclusion: Increasing the provision of ART to <350 cells/mm3 may significantly reduce costs while reducing the HIV burden. Feasibility including HIV testing and ART uptake, retention, and adherence should be evaluated

The Restriction of Zoonotic PERV Transmission by Human APOBEC3G

The human APOBEC3G protein is an innate anti-viral factor that can dominantly inhibit the replication of some endogenous and exogenous retroviruses. The prospects of purposefully harnessing such an anti-viral defense are under investigation. Here, long-term co-culture experiments were used to show that porcine endogenous retrovirus (PERV) transmission from pig to human cells is reduced to nearly undetectable levels by expressing human APOBEC3G in virus-producing pig kidney cells. Inhibition occurred by a deamination-independent mechanism, likely after particle production but before the virus could immortalize by integration into human genomic DNA. PERV inhibition did not require the DNA cytosine deaminase activity of APOBEC3G and, correspondingly, APOBEC3G-attributable hypermutations were not detected. In contrast, over-expression of the sole endogenous APOBEC3 protein of pigs failed to interfere significantly with PERV transmission. Together, these data constitute the first proof-of-principle demonstration that APOBEC3 proteins can be used to fortify the innate anti-viral defenses of cells to prevent the zoonotic transmission of an endogenous retrovirus. These studies suggest that human APOBEC3G-transgenic pigs will provide safer, PERV-less xenotransplantation resources and that analogous cross-species APOBEC3-dependent restriction strategies may be useful for thwarting other endogenous as well as exogenous retrovirus infections

Costing Human Rights and Community Support Interventions as a Part of Universal Access to HIV Treatment and Care in a Southern African Setting

Expanding access to antiretroviral therapy (ART) has both individual health benefits and potential to decrease HIV incidence. Ensuring access to HIV services is a significant human rights issue and successful programmes require adequate human rights protections and community support. However, the cost of specific human rights and community support interventions for equitable, sustainable and non-discriminatory access to ART are not well described. Human rights and community support interventions were identified using the literature and through consultations with experts. Specific costs were then determined for these health sector interventions. Population and epidemic data were provided through the Statistics South Africa 2009 national mid-year estimates. Costs of scale up of HIV prevention and treatment were taken from recently published estimates. Interventions addressed access to services, minimising stigma and discrimination against people living with HIV, confidentiality, informed consent and counselling quality. Integrated HIV programme interventions included training for counsellors, ‘Know Your Rights’ information desks, outreach campaigns for most at risk populations, and adherence support. Complementary measures included post-service interviews, human rights abuse monitoring, transportation costs, legal assistance, and funding for human rights and community support organisations. Other essential non-health sector interventions were identified but not included in the costing framework. The annual costs for the human rights and community support interventions are United States (US) $63.8 million (US$1.22 per capita), representing 1.5% of total health sector HIV programme costs. Respect for human rights and community engagement can be understood both as an obligation of expanded ART programmes and as a critically important factor in their success. Basic rights-based and community support interventions constitute only a small percentage of overall programmes costs. ART programs should consider measuring the cost and impact of human rights and community support interventions as key aspects of successful programme expansion

Large-scale Models Reveal the Two-component Mechanics of Striated Muscle

This paper provides a comprehensive explanation of striated muscle mechanics and contraction on the basis of filament rotations. Helical proteins, particularly the coiled-coils of tropomyosin, myosin and α-actinin, shorten their H-bonds cooperatively and produce torque and filament rotations when the Coulombic net-charge repulsion of their highly charged side-chains is diminished by interaction with ions. The classical “two-component model” of active muscle differentiated a “contractile component” which stretches the “series elastic component” during force production. The contractile components are the helically shaped thin filaments of muscle that shorten the sarcomeres by clockwise drilling into the myosin cross-bridges with torque decrease (= force-deficit). Muscle stretch means drawing out the thin filament helices off the cross-bridges under passive counterclockwise rotation with torque increase (= stretch activation). Since each thin filament is anchored by four elastic α-actinin Z-filaments (provided with force-regulating sites for Ca2+ binding), the thin filament rotations change the torsional twist of the four Z-filaments as the “series elastic components”. Large scale models simulate the changes of structure and force in the Z-band by the different Z-filament twisting stages A, B, C, D, E, F and G. Stage D corresponds to the isometric state. The basic phenomena of muscle physiology, i. e. latency relaxation, Fenn-effect, the force-velocity relation, the length-tension relation, unexplained energy, shortening heat, the Huxley-Simmons phases, etc. are explained and interpreted with the help of the model experiments