Predictors of poor adherence among people on antiretroviral treatment in Cape Town,South Africa: a case-control study

A case-control study was conducted to describe the frequency with which structural- and individual-level barriers to adherence are experienced by people receiving antiretroviral (ARV) treatment and to determine predictors of non-adherence. Three hundred adherent and 300 non-adherent patients from 6 clinics in Cape Town completed the LifeWindows Information-Motivation-Behavioral Skills ART Adherence Questionnaire, the Substance Abuse and Mental Illness Symptoms Screener and the Structural Barriers to Clinic Attendance (SBCA) and Medication-taking (SBMT) scales. Overall, information-related barriers were reported most frequently followed by motivation and behaviour skill defects. Structural barriers were reported least frequently. Logistic regression analyses revealed that gender, behaviour skill deficit scores, SBCA scores and SBMT scores predicted non-adherence. Despite the experience of structural barriers being reported least frequently, structural barriers to medication-taking had the greatest impact on adherence (OR: 2.32, 95% CI: 1.73 to 3.12), followed by structural barriers to clinic attendance (OR: 2.06, 95% CI: 1.58 to 2.69) and behaviour skill deficits (OR: 1.34, 95% CI: 1.05 to 1.71). Our data indicate the need for policy directed at the creation of a health-enabling environment that would enhance the likelihood of adherence among antiretroviral therapy users. Specifically, patient empowerment strategies aimed at increasing treatment literacy and management skills should be strengthened. Attempts to reduce structural barriers to antiretroviral treatment adherence should be expanded to include increased access to mental health care services and nutrition support.     

Capillary muscle

The contraction of a muscle generates a force that decreases when increasing the contraction velocity. This “hyperbolic” force–velocity relationship has been known since the seminal work of A. V. Hill in 1938 [Hill AV (1938) Proc R Soc Lond B Biol Sci 126(843):136–195]. Hill’s heuristic equation is still used, and the sliding-filament theory for the sarcomere [Huxley H, Hanson J (1954) Nature 173(4412):973–976; Huxley AF, Niedergerke R (1954) Nature 173(4412):971–973] suggested how its different parameters can be related to the molecular origin of the force generator [Huxley AF (1957) Prog Biophys Biophys Chem 7:255–318; Deshcherevskiĭ VI (1968) Biofizika 13(5):928–935]. Here, we develop a capillary analog of the sarcomere obeying Hill’s equation and discuss its analogy with muscles.From 1487 to 1516, Leonardo da Vinci planned to write a treatise on human anatomy. The book never appeared, but many drawings and writings have been conserved, mainly at the royal collection at Windsor (1):

After a demonstration of all of the parts of the limbs of man and other animals you will represent the proper method of action of these limbs, that is, in rising after lying down, in moving, running and jumping in various attitudes, in lifting and carrying heavy weights, in throwing things to a distance and in swimming and in every act you will show which limbs and which muscles are the causes of the said actions and especially in the play of the arms. (2, 3)

Apart from Leonardo’s attempts, the understanding of muscle contraction has been a long quest since antiquity and the work of Hippocrates of Cos (4). The topological structure of muscles was described in the anatomical studies by Andreas Vesalius in 1543 (5) and the static force generated was quantified in the first biomechanics treatise of Giovanni Borelli in 1680 (Fig. 1A) (6). One realizes the difficulties associated with the understanding of the force generation mechanism by comparing the scale at which the force is used (typically the body scale: 1?m) to the scale at which the force is generated [contraction of the myosin molecule: 10?nm (7)]. Eight orders of magnitude separate the molecular origin of the force from its macroscopic function, namely the motion of organisms. Considering the scales involved, research on muscles has progressed with the development of new techniques, from early microscopy for the micrometer-scale sarcomere (8), to X-ray diffraction (9) and interference microscopy (10) for the actin–myosin sliding structure, and optical tweezers for the study of individual myosin molecules (7).Open in a separate windowFig. 1.(A) Plate of Borelli’s De Motu Animalium. Figure courtesy of ref. 6. (B) Isotonic lever for human subjects [from Wilkie (11)]. A, hand grip attached to cable; B, catch to hold lever up at the end of movement; C, fixed contact; D, lever with moving contact; E, weight. (C) Force–velocity results obtained with two different subjects: red squares, D.W.; black circles, L.M. The solid lines are Eq. 1, with F₀ = 196?N, v_max = b.F₀/a = 7.5?m/s, and F₀/a = 5 for D.W., and F₀ = 200?N, v_max = 7.0?m/s, and F₀/a = 2.1 for L.M. (data from ref. 11).Despite the complexity of the muscular system, the relation between the force F needed to move a given load and the velocity v of the motion is accessible via macroscopic experiments such as the one from Wilkie sketched in Fig. 1B (11). Here, a constant force F = Mg is imposed by the weight E, and one records the maximal speed of contraction, v(F). Decoupling inertial effects from muscle properties, one gets human muscle characteristics as shown in Fig. 1C. The force reaches its maximum F₀ at v = 0, and it vanishes at a maximal speed v = v_max. The evolution between these two limits is captured by an equation proposed by Hill in 1938 (12), (F + a)(v + b) = (F₀ + a)b, which can be written under the hyperbolic form:FF0=1−v/vmax1+(F0/a)v/vmax.[1]This equation is drawn with a solid line in Fig. 1C for two subjects (D.W. and L.M. in ref. 11), using the values F₀ = 196?N, v_max = bF₀/a = 7.5?m/s, and F₀/a = 5 for D.W., and F₀ = 200?N, v_max = 7.0?m/s, and F₀/a = 2.1 for L.M. The isometric tension F₀ defines the force against which the muscle neither shortens nor lengthens, and v_max is the maximal speed reached without load (F = 0). These results illustrate the accuracy of Hill’s equation and the variability of the parameter F₀/a between different subjects. Apart from skeletal human muscles, Hill’s equation (Eq. 1) is found to apply to almost all muscle types and over various species (13).The contractile muscular machinery is made of parallel muscle cells that extend from one tendon to another, which connect to bones. A muscle cell is composed of nuclei and myofibrils, a linear assembly of sarcomeres, the elementary contractile unit. The typical size of sarcomeres is 3 μm, so that their number in myofibril of a 30-cm muscle cell is on the order of 10⁵. A sarcomere itself is made of thin actin filaments connected to thick myosin filaments via myosin heads (Fig. 2 C1 and C2). When a neuron stimulates a muscle cell, an action potential sweeps over the plasma membrane of the muscle cell. The action potential releases internal stores of calcium that flow through the muscle cell and trigger a contraction (C2). Actin and myosin filaments are juxtaposed but cannot interact in the absence of calcium (relaxed-state C1). With calcium, the myosin-binding sites are open on the actin filaments, and ATP makes the myosin motors crawl along the actin, resulting in a contraction of the muscle fiber (C2) (14, 15). The interaction energy increases with the number of cross-bridges, namely with the surface between actin and myosin threads.Open in a separate windowFig. 2.Experimental setup of a capillary muscle and its biological inspiration, the sarcomere. The steel wire is equivalent to the myosin filament that slides in the silicone oil tube, which stands for the actin filament. (A) Position at t = 0, corresponding to relaxed state of the sarcomere (C1). (B) Position at t > 0, corresponding to the contracted state of the sarcomere (C2). (D) Example of capillary contraction obtained with 2r = 1.8?mm, 2R = 5?mm, η = 1 Pa⋅s, γ = 22 mN/m, k = 3.3 μN/m, and x₀ = 7.6?mm.Hill’s equation is a heuristic law and its connection to the sliding-filament model has first been established via adjustable correlations (16) and later via strong theoretical assumptions (17). The purpose of the present article is to build a capillary analog of the sliding-filament model, to record the corresponding force–velocity relationship, and to show how this minimal model system leads to Hill’s equation.     

Determinants of nursing service in urban public hospitals: an economic perspective

The purpose of the present study was to analyze the determinants of nurse staffing in urban public hospitals in Japan. The study sample included 51 public hospitals in 23 urban cities in 1996. Structural equation modeling was performed using the following: nurse-to-inpatient ratio; medical service and hospitalization fees; approved nurse staffing level; outpatient-to-inpatient ratio; subsidy-to-hospital-revenue ratio; and regional variation index of inpatient service expenditures. The nurse-to-inpatient ratio was associated with medical service fees reflecting patients' acuity levels and the subsidy-to-hospital-revenue ratio, but was not associated with the hospital income from hospitalization fees (the largest share of which consists of nursing fees). Public hospitals in areas with limited inpatient care resources had a higher level of approved nurse staffing and a higher subsidy-to-hospital-revenue ratio. A significant determinant of public hospitals' nurse staffing was local government-funded subsidization rather than the balance between nursing service fees and costs.     

Linear mitochondrial genome organization in vivo in the genus Pythium

Pulsed-field gel electrophoresis (PFGE) of isolates of Pythium oligandrum with linear mitochondrial genomes revealed a distinct band in ethidium bromide-stained gels similar in size to values estimated by restriction mapping of mitochondrial DNA (mtDNA). Southern analysis confirmed that these bands were mtDNA and indicated that linear genomes were present in unit-length size as well as multimers. Isolates of this species with circular mtDNA restriction maps also had low levels of linear mono- and multimers. visualized by Southern analysis of PFGE gels. Examination of 17 additional species revealed similar results; three species had distinct linear mtDNA bands in ethidium bromide-stained gels while the remainder had linear mono- and multi-mers in lower amounts detected only by Southern analysis. Sequence analysis of an isolate of P. oligandrum with a primarily circular mitochondrial genomic map and a low amount of linear molecules revealed that the small unique region of the circular map (which corresponded to the terminal region of linear genomes) was flanked by palindromic intrastrand complementary sequences separated by a unique 194-bp sequence. Sequences with similarity to ATPase9 coding regions from other organisms were located adjacent to this region. Sequences with similarity to mitochondrial origins of replication and autonomously replicating sequences were also located in this region: their potential involvement in the generation of linear molecules is discussed.     

Dynamic stabilization of actin filaments

We report here that actin filaments in vitro exist in two populations with significantly different shrinkage rates. Newly polymerized filaments shrink rapidly, primarily from barbed ends, at 1.8/s, but as they age they switch to a stable state that shrinks slowly, primarily from pointed ends, at approximately 0.1/s. This dynamic filament stabilization runs opposite to the classical prediction that actin filaments become more unstable with age as they hydrolyze their bound ATP and release phosphate. Upon cofilin treatment, aged filaments revert to a dynamic state that shows accelerated shrinkage from both ends at a combined rate of 5.9/s. In light of recent electron microscopy studies [Orlova A, et al. (2004) Actin-destabilizing factors disrupt filaments by means of a time reversal of polymerization. Proc Natl Acad Sci USA 101:17664-17668], we propose that dynamic stabilization arises from rearrangement of the filament structure from a relatively disordered state immediately after polymerization to the canonical Holmes helix, a change that is reversed by cofilin binding. Our results suggest that plasticity in the internal structure of the actin filament may play a fundamental role in regulating actin dynamics and may help cells build actin assemblies with vastly different turnover rates.     

Structural basis for activation of the complement system by component C4 cleavage

An essential aspect of innate immunity is recognition of molecular patterns on the surface of pathogens or altered self through the lectin and classical pathways, two of the three well-established activation pathways of the complement system. This recognition causes activation of the MASP-2 or the C1s serine proteases followed by cleavage of the protein C4. Here we present the crystal structures of the 203-kDa human C4 and the 245-kDa C4⋅MASP-2 substrate⋅enzyme complex. When C4 binds to MASP-2, substantial conformational changes in C4 are induced, and its scissile bond region becomes ordered and inserted into the protease catalytic site in a manner canonical to serine proteases. In MASP-2, an exosite located within the CCP domains recognizes the C4 C345C domain 60 Å from the scissile bond. Mutations in C4 and MASP-2 residues at the C345C–CCP interface inhibit the intermolecular interaction and C4 cleavage. The possible assembly of the huge in vivo enzyme–substrate complex consisting of glycan-bound mannan-binding lectin, MASP-2, and C4 is discussed. Our own and prior functional data suggest that C1s in the classical pathway of complement activated by, e.g., antigen–antibody complexes, also recognizes the C4 C345C domain through a CCP exosite. Our results provide a unified structural framework for understanding the early and essential step of C4 cleavage in the elimination of pathogens and altered self through two major pathways of complement activation.     

An MRI based average macaque monkey stereotaxic atlas and space (MNI monkey space)

In studies of the human brain, a standard stereotaxic space such as the Montreal Neurological Institute (MNI space) is widely used to provide a common reference for the three-dimensional localization of functional activation foci and anatomical structures, enabling the comparison of results obtained across different studies. Here we present a standard macaque monkey brain MRI template that offers a common stereotaxic reference frame to localize anatomical and functional information in an organized and reliable way for comparison across individual monkeys and studies. We have used MRI volumes from a group of 25 normal adult macaque monkeys (18 cynomolgus and 7 rhesus) to create a common standard macaque monkey brain as well as atlases for each of these species separately. In addition, the digital macaque monkey volume was subjected to 3D volumetric analysis and comparison of brain structures between the individual brains and the average atlas. Furthermore, we provide a means of transforming any macaque MRI volume into MNI monkey space coordinates in 3D using simple web based tools. Coordinates in MNI monkey space can also be transformed into the coordinate system of a detailed neuroanatomical paper atlas (Paxinos et al., 2008), enabling researchers to identify and delineate cortical and subcortical structures in their individual macaque monkey brains.     

The fitting of scheffé-type models for estimating solubilities of multisolvent systems

In pharmaceutical studies it is often necessary to dissolve a slightly polar drug in a mixture of water and one or more cosolvents, such as ethanol, glycerol, and propylene glycol, to increase the drug's solubility. It is also of interest to knowwhether a maximum in the solubility profile of the drug exists in the mixture of solvents and if so, where.

Scheffé-type models are particular forms of polynomial equations that can be used with variables that are expressed as proportions of the total mixture. These models are simple in form, yet are extremely versatile in terms of modeling the linear and nonlinear blending properties of the constituents in the mixtures. Several data sets are presented to illustratethe fitting of the Scheffé-type models for modeling the solubility of multisolvent systems.     

Stigma-related access barriers and violence against trans women in the Colombian healthcare system

ABSTRACT

Drawing from qualitative research conducted in a participatory action research framework with 28 transgender women in Colombia, this paper presents the stigma-related barriers to healthcare experienced by trans women and their experiences of multi-level violence within the healthcare system. The authors also discuss how advocacy work was conducted as part of the research process and how trans community leaders were involved throughout the project in order to promote policy-relevance and community-based implementation of findings. The paper concludes with a discussion of how the experiences of violence and stigmatisation within the health care system is linked to broader processes of structural stigma reproduced within Colombian society.