Reduction in unplanned hospitalizations associated with a physician focused intervention to reduce potentially inappropriate medication use among older adults: a population-based cohort study.

BACKGROUND: A multimodal general practitioner-focused intervention in the Local Health Authority (LHA) of Parma, Italy, substantially reduced the prevalence of potentially inappropriate medication (PIM) use among older adults. Our objective was to estimate changes in hospitalization rates associated with the Parma LHA quality improvement initiative that reduced PIM use. METHODS: This population-based longitudinal cohort study was conducted among older residents (> 65 years) using the Parma LHA administrative healthcare database. Crude and adjusted unplanned hospitalization rates were estimated in 3 periods (pre-intervention: 2005-2008, intervention: 2009-2010, post-intervention: 2011-2014). Multivariable negative binomial models estimated trends in quarterly hospitalization rates among individuals at risk during each period using a piecewise linear spline for time, adjusted for time-dependent and time-fixed covariates. RESULTS: The pre-intervention, intervention, and post-intervention periods included 117,061, 107,347, and 121,871 older adults and had crude hospitalization rates of 146.2 (95% CI: 142.2-150.3), 146.8 (95% CI: 143.6-150.0), and 140.8 (95% CI: 136.9-144.7) per 1000 persons per year, respectively. The adjusted pre-intervention hospitalization rate was declining by 0.7% per quarter (IRR = 0.993; 95% CI: 0.991-0.995). The hospitalization rate declined more than twice as fast during the intervention period (1.8% per quarter, IRR = 0.982; 95% CI: 0.979-0.985) and was nearly constant post-intervention (IRR: 0.999; 95% CI: 0.997-1.001). Contrasting model predictions for the intervention period (Q1 2009 to Q4 2010), the intervention was associated with 1481 avoided hospitalizations. CONCLUSION: In a large population of older adults, a multimodal general practitioner-focused intervention to decrease PIM use was associated with a decline in the unplanned hospitalization rate. Such interventions to reduce high risk medication use among older adults warrant consideration by health systems seeking to improve health outcomes and reduce high-cost acute care utilization.

Experimental and mathematical analysis of in vitro Pitavastatin hepatic uptake across species.

1. To investigate the non-linear kinetics of in vitro hepatocyte uptake across species, the OATP substrate Pitavastatin was used as a probe. 2. Experiments were conducted at AstraZeneca (Alderley Park, Macclesfield) using freshly isolated rat, dog and human hepatocytes, utilising the "oil spin" methodology described by Hassen et al. (1996). Very few mechanistic models have previously been used to characterise the uptake process. 3. Here two candidate pharmacokinetic non-linear compartmental models are proposed. Both models have been shown to be structurally identifiable and distinghishable previously, which establishes that all unknown parameters could be identified from the experimental observations available and that input/output relationships for both the candidate models were structurally different. 4. A kinetic modelling software package, FACSIMILE (MCPA Software, Faringdon, UK), was used to obtain numerical solutions for the system equations and for parameter estimation. Model fits gave good agreement with the in vitro data and suggest the current widely accepted assumption that the rate of diffusion across the hepatocyte cell membrane is the same at both 4 °C and 37 °C is not valid, at least for Pitavastatin. Although this finding has already been proposed, this is the first time it is comprehensively debunked using statistical testing.

Potential drug-drug interactions among hospitalised TB patients.

BACKGROUND: Hospitalised TB patients are at heightened risk for developing drug-drug interactions (DDIs) due to overlapping CYP450 enzyme and/or drug transporter biotransformation of anti-TB drugs and co-medications given for treating TB-associated comorbidities. We aimed to compare the occurrence, characterisation and determinants of database identified potential DDIs (pDDIs) associated with first-line anti-TB drugs and other co-medications using a subscription and free access drug information database.METHOD: This was a single-centre retrospective study to assess pDDIs between first-line anti-TB drugs and other medications for comorbidities among hospitalised TB patients using IBM Micromedex® and Drugs.com.RESULTS: On multivariate regression analysis, hospitalised TB patients with comorbidities such as diabetes mellitus, HIV infection and hypertension, longer hospitalisation, and patients administered with more than seven drugs during their hospital stay were associated with increased risk for the occurrence of pDDIs. Significant discrepancies were observed in the detection and severity of pDDIs between IBM Micromedex and Drugs.com.CONCLUSION: We recommend using free access drug information database to a subscription drug information database in drug interaction screening protocols in clinics for enhanced identification of pDDIs and reducing monetary burden in resource-limited settings.

Direct and Indirect Effects of Atmospheric Carbon Dioxide Enrichment on Leaf Respiration of Glycine max (L.) Merr.

Long-term and short-term effects of CO2 enrichment on dark respiration were investigated using soybean (Glycine max [L.] Merr.) plants grown at either 35.5 or 71.0 Pa CO2. Indirect effects, or effects of growth in elevated CO2, were examined using a functional model that partitioned respiration into growth and maintenance components. Direct effects, or immediate effects of a short-term change in CO2, were examined by measuring dark respiration, first, at the CO2 partial pressure at which plants were grown, and second, after equilibration in the reciprocal CO2 partial pressure. The functional component model indicated that the maintenance coefficient of respiration increased 34% with elevated CO2, whereas the growth coefficient was not significantly affected. Changes in maintenance respiration were correlated with a 33% increase in leaf total nonstructural carbohydrate concentration, but leaf nitrogen content of soybean leaves was not affected by CO2 enrichment. Thus, increased maintenance respiration may be a consequence of increased nonstructural carbohydrate accumulation. When whole soybean plants were switched from low CO2 to high CO2 for a brief period, leaf respiration was always reduced. However, this direct effect of CO2 partial pressure was approximately 50% less in plants grown in elevated CO2. We conclude from this study that there are potentially important effects of CO2 enrichment on plant respiration but that the effects are different for plants given a short-term increase in CO2 partial pressure versus plants grown in elevated CO2.

Elevated urinary leukotriene E4 excretion in patients with ARDS and severe burns.

Increased synthesis of peptidoleukotrienes may occur in a variety of inflammatory diseases. To test this theory, hospitalized patients with a variety of diseases were studied and urine LTE4 quantitated as an index of total body peptidoleukotriene synthesis. 10 patients with ARDS, 7 of which had additional organ involvement, and 5 patients suffering from severe burn injuries were studied. Patients with uncomplicated ARDS excreted approximately 6-fold higher amounts of LTE4 in urine compared to healthy subjects. When ARDS was complicated by multiple organ failure (MOF), urine LTE4 levels were 2- to 150-fold higher than in healthy volunteers. Patients with severe burn injuries had peak urine LTE4 levels which were approximately 20-fold higher than in healthy volunteers. As additional controls, patients with cardiac arrhythmias (absence of inflammatory disease) and patients with uncomplicated pneumonia (localized inflammation) showed normal or mildly elevated urinary LTE4 levels. The urinary LTE4 levels in ARDS patients did not correlate with serum creatinine, bilirubin, or LDH levels, or with the WBC, nor did renal or liver failure by itself predict extremely elevated urinary LTE4 levels. In conclusion, patients with ARDS or ARDS/MOF and patients with severe injuries and sepsis syndrome excrete higher levels of urinary LTE4 than patients healthy volunteers or patients with limited inflammatory disease. In certain situations, urinary LTE4 levels may be useful as a marker of the degree of inflammation.

Household coping strategies and contradictions in response to seasonal food shortage.

Uncertainty is a primary consideration in adjusting to seasonal environments as attempts are made to synchronize productive inputs with critical periods in the annual cycle. Coping responses of small scale producers therefore rely on the coordination and control of diverse resources, and on flexibility in choosing between multiple options. Generalizations concerning seasonal coping responses to food shortage of households, and of women within households, are reviewed. Particular attention is given to how socio-economic differentiation affects the capacity to use such strategies, and how these differ with regard to the degree of resource commitment and reversibility once initiated. Our primary concern is in exploring the process whereby seasonal strategies become eroded. Thus, as seasonal uncertainties are exacerbated by unpredictable fluctuations in commercial economies, and as productive resources become less accessible to households, adaptive conflicts and contradictions are introduced. Uncertainty is further intensified by illness and unequal access to adaptive options based on class and gender. The increasing inability of small scale producers to cope with seasonal uncertainty emphasizes the need to understand this erosive process.

Photosynthetic responses to CO2 enrichment of four hardwood species in a forest understory.

We compared the CO2- and light-dependence of photosynthesis of four tree species (Acer rubrum, Carya glabra, Cercis canadensis, Liquidambar styraciflua) growing in the understory of a loblolly pine plantation under ambient or ambient plus 200 µl l-1 CO2. Naturally-established saplings were fumigated with a free-air CO2 enrichment system. Light-saturated photosynthetic rates were 159-190% greater for Ce. canadensis saplings grown and measured under elevated CO2. This species had the greatest CO2 stimulation of photosynthesis. Photosynthetic rates were only 59% greater for A. rubrum saplings under CO2 enrichment and Ca. glabra and L. styraciflua had intermediate responses. Elevated CO2 stimulated light-saturated photosynthesis more than the apparent quantum yield. The maximum rate of carboxylation of ribulose-1,5-bisphosphate carboxylase, estimated from gas-exchange measurements, was not consistently affected by growth in elevated CO2. However, the maximum electron transport rate estimated from gas- exchange measurements and from chlorophyll fluorescence, when averaged across species and dates, was approximately 10% higher for saplings in elevated CO2. The proportionately greater stimulation of light-saturated photosynthesis than the apparent quantum yield and elevated rates of maximum electron transport suggests that saplings growing under elevated CO2 make more efficient use of sunflecks. The stimulation of light-saturated photosynthesis by CO2 did not appear to correlate with shade-tolerance ranking of the individual species. However, the species with the greatest enhancement of photosynthesis, Ce. canadensis and L. styraciflua, also invested the greatest proportion of soluble protein in Rubisco. Environmental and endogenous factors affecting N partitioning may partially explain interspecific variation in the photosynthetic response to elevated CO2.

Loblolly pine grown under elevated CO2 affects early instar pine sawfly performance.

Seedlings of loblolly pine Pinus taeda (L.), were grown in open-topped field chambers under three CO2 regimes: ambient, 150 µl l-1 CO2 above ambient, and 300 µl l-1 CO2 above ambient. A fourth, non-chambered ambient treatment was included to assess chamber effects. Needles were used in 96 h feeding trials to determine the performance of young, second instar larvae of loblolly pine's principal leaf herbivore, red-headed pine sawfly, Neodiprion lecontei (Fitch). The relative consumption rate of larvae significantly increased on plants grown under elevated CO2, and needles grown in the highest CO2 regime were consumed 21% more rapidly than needles grown in ambient CO2. Both the significant decline in leaf nitrogen content and the substantial increase in leaf starch content contributed to a significant increase in the starch:nitrogen ratio in plants grown in elevated CO2. Insect consumption rate was negatively related to leaf nitrogen content and positively related to the starch:nitrogen ratio. Of the four volatile leaf monoterpenes measured, only ß-pinene exhibited a significant CO2 effect and declined in plants grown in elevated CO2. Although consumption changed, the relative growth rates of larvae were not different among CO2 treatments. Despite lower nitrogen consumption rates by larvae feeding on the plants grown in elevated CO2, nitrogen accumulation rates were the same for all treatments due to a significant increase in nitrogen utilization efficiency. The ability of this insect to respond at an early, potentially susceptible larval stage to poorer food quality and declining levels of a leaf monoterpene suggest that changes in needle quality within pines in future elevated-CO2 atmospheres may not especially affect young insects and that tree-feeding sawflies may respond in a manner similar to herb-feeding lepidopterans.

Is atmospheric CO2 a selective agent on model C3 annuals?

Atmospheric CO2 partial pressure (pCO2) was as low as 18 Pa during the Pleistocene and is projected to increase from 36 to 70 Pa CO2 before the end of the 21st century. High pCO2 often increases the growth and reproduction of C3 annuals, whereas low pCO2 decreases growth and may reduce or prevent reproduction. Previous predictions regarding the effects of high and low pCO2 on C3 plants have rarely considered the effects of evolution. Knowledge of the potential for evolution of C3 plants in response to CO2 is important for predicting the degree to which plants may sequester atmospheric CO2 in the future, and for understanding how plants may have functioned in response to low pCO2 during the Pleistocene. Therefore, three studies using Arabidopsis thaliana as a model system for C3 annuals were conducted: (1) a selection experiment to measure responses to selection for high seed number (a major component of fitness) at Pleistocene (20 Pa) and future (70 Pa) pCO2 and to determine changes in development rate and biomass production during selection, (2) a growth experiment to determine if the effects of selection on final biomass were evident prior to reproduction, and (3) a reciprocal transplant experiment to test if pCO2 was a selective agent on Arabidopsis. Arabidopsis showed significant positive responses to selection for high seed number at both 20 and 70 Pa CO2 during the selection process. Furthermore, plants selected at 20 Pa CO2 performed better than plants selected at 70 Pa CO2 under low CO2 conditions, indicating that low CO2 acted as a selective agent on these annuals. However, plants selected at 70 Pa CO2 did not have significantly higher seed production than plants selected at 20 Pa CO2 when grown at high pCO2. Nevertheless, there was some evidence that high CO2 may also be a selective agent because changes in development rate and biomass production during selection occurred in opposite directions at low and high pCO2. Plants selected at high pCO2 showed no change or reductions in biomass relative to control plants due to a decrease in the length of the life cycle, as indicated by earlier initiation of flowering and senescence. In contrast, selection at low CO2 resulted in an average 35% increase in biomass production, due to an increase in the length of the life cycle that resulted in a longer period for biomass accumulation before senescence. From the Arabidopsis model system we conclude that some C3 annuals may have produced greater biomass in response to low pCO2 during the Pleistocene relative to what has been predicted from studies exposing a single generation of C3 plants to low pCO2. Furthermore, C3 annuals may exhibit evolutionary responses to high pCO2 in the future that may result in developmental changes, but these are unlikely to increase biomass production. This series of studies shows that CO2 may potentially act as a selective agent on C3 annuals, producing changes in development rate and carbon accumulation that could not have been predicted from single-generation studies.

Nitrogen dynamics and growth of seedlings of an N-fixing tree (Gliricidia sepium (Jacq.) Walp.) exposed to elevated atmospheric carbon dioxide.

Seeds of Gliricidia sepium (Jacq.) Walp., a tree native to seasonal tropical forests of Central America, were inoculated with N-fixing Rhizobium bacteria and grown in growth chambers for 71 days to investigate interactive effects of atmospheric CO2 and plant N status on early seedling growth, nodulation, and N accretion. Seedlings were grown with CO2 partial pressures of 350 and 650 µbar (current ambient and a predicted partial pressure of the mid-21st century) and with plus N or minus N nutrient solutions to control soil N status. Of particular interest was seedling response to CO2 when grown without available soil N, a condition in which seedlings initially experienced severe N deficiency because bacterial N-fixation was the sole source of N. Biomass of leaves, stems, and roots increased significantly with CO2 enrichment (by 32%, 15% and 26%, respectively) provided seedlings were supplied with N fertilizer. Leaf biomass of N-deficient seedlings was increased 50% by CO2 enrichment but there was little indication that photosynthate translocation from leaves to roots or that plant N (fixed by Rhizobium) was altered by elevated CO2. In seedlings supplied with soil N, elevated CO2 increased average nodule weight, total nodule weight per plant, and the amount of leaf nitrogen provided by N-fixation (as indicated by leaf δ15N). While CO2 enrichment reduced the N concentration of some plant tissues, whole plant N accretion increased. Results support the contention that increasing atmospheric CO2 partial pressures will enhance productivity and N-fixing activity of N-fixing tree seedlings, but that the magnitude of early seedling response to CO2 will depend greatly on plant and soil nutrient status.

Effects of low and elevated CO2 on C3 and C4 annuals : I. Growth and biomass allocation.

In order study C3 and C4 plant growth in atmospheric CO2 levels ranging from past through predicted future levels, Abutilon theophrasti (C3) and Amaranthus retroflexus (C4) were grown from seed in growth chambers controlled at CO2 partial pressures of 15 Pa (below Pleistocene minimum), 27 Pa (pre-industrial), 35 Pa (current) and 70 Pa (predicted future). After 35 days of growth, CO2 had no effect on the relative growth rate, total biomass or partitioning of biomass in the C4 species. However, the C3 species had greater biomass accumulation with increasing CO2 partial pressure. C3 plants grown in 15 Pa CO2 for 35 days had only 8% of the total biomass of plants grown in 35 Pa CO2, C3 plants had lower relative growth rates and lower specific leaf mass than plants grown in higher CO2 partial pressures, and aborted reproduction. C3 plants grown in 70 Pa CO2 had greater root mass and root-to-shoot ratios than plants grown in lower CO2 partial pressures. These findings, support other studies that show C3 plant growth is more responsive to CO2 partial pressure than C4 plant growth. Differences in growth responses to CO2 levels of the Pleistocene through the future suggest that competitive interactions of C3 and C4 annuals have changed through geologic time. This study also provided evidence that C3 annuals may be operating near a minimum CO2 partial pressure for growth and reproduction at 15 Pa CO2.

Effects of low and elevated CO2 on C3 and C4 annuals : II. Photosynthesis and leaf biochemistry.

Abutilon theophrasti (C3) and Amaranthus retroflexus (C4), were grown from seed at four partial pressures of CO2: 15 Pa (below Pleistocene minimum), 27 Pa (pre-industrial), 35 Pa (current), and 70 Pa (future) in the Duke Phytotron under high light, high nutrient, and wellwatered conditions to evaluate their photosynthetic response to historic and future levels of CO2. Net photosynthesis at growth CO2 partial pressures increased with increasing CO2 for C3 plants, but not C4 plants. Net photosynthesis of Abutilon at 15 Pa CO2 was 70% less than that of plants grown at 35 Pa CO2, due to greater stomatal and biochemical limitations at 15 Pa CO2. Relative stomatal limitation (RSL) of Abutilon at 15 Pa CO2 was nearly 3 times greater than at 35 Pa CO2. A photosynthesis model was used to estimate ribulose-1,5-bisphosphate carboxylase (rubisco) activity (Vcmax), electron transport mediated RuBP regeneration capacity (J max), and phosphate regeneration capacity (PiRC) in Abutilon from net photosynthesis versus intercellular CO2 (A-C i) curves. All three component processes decreased by approximately 25% in Abutilon grown at 15 Pa compared with 35 Pa CO2. Abutilon grown at 15 Pa CO2 had significant reductions in total rubisco activity (25%), rubisco content (30%), activation state (29%), chlorophyll content (39%), N content (32%), and starch content (68%) compared with plants grown at 35 Pa CO2. Greater allocation to rubisco relative to light reaction components and concomitant decreases in J max and PiRC suggest co-regulation of biochemical processes occurred in Abutilon grown at 15 Pa CO2. There were no significant differences in photosynthesis or leaf properties in Abutilon grown at 27 Pa CO2 compared with 35 Pa CO2, suggesting that the rise in CO2 since the beginning of the industrial age has had little effect on the photosynthetic performance of Abutilon. For Amaranthus, limitations of photosynthesis were balanced between stomatal and biochemical factors such that net photosynthesis was similar in all CO2 treatments. Differences in photosynthetic response to growth over a wide range of CO2 partial pressures suggest changes in the relative performance of C3 and C4 annuals as atmospheric CO2 has fluctuated over geologic time.

Contributions of nutrition versus hypoxia to growth in rural Andean populations.

Previous research on diet and nutrition among peasant agriculturalists in the Andes has produced inconsistent results. As a consequence it has been difficult to determine the extent to which nutritional factors contribute to the slowed, prolonged growth and resultant small adult body size that is characteristic of these highland populations. The study examines patterns of diet and growth in the rural highland community of Nuñoa, Peru (elevation 4,000 m), and compares them to similar data collected on this community during the 1960s. Additional data from other locations in the Andes are then evaluated to discern critical determinants of growth variation. Analyses of the Nuñoan data indicate that nutritional factors have played a significant role in shaping statural growth at this location. Comparisons of other growth surveys indicate that Nuñoans remain among the smallest of all Andean populations. Additionally, urban/rural differences in growth are quite evident in the highlands, with the magnitude of this difference being greater than in other regions (i.e., coastal or jungle). It appears that income level and access to land strongly interact to direct and constrain food consumption patterns. The resulting differences in nutrition, in turn, appear to be strong predictors of growth variation. Consequently, studies that consider 1) dietary intake, 2) level of variability in diet, and 3) relative contributions of purchased and home-produced food to diet should contribute to furthering our understanding of growth variation in the Andes.

Structural identifiability analyses of candidate models for in vitro Pitavastatin hepatic uptake.

In this paper a review of the application of four different techniques (a version of the similarity transformation approach for autonomous uncontrolled systems, a non-differential input/output observable normal form approach, the characteristic set differential algebra and a recent algebraic input/output relationship approach) to determine the structural identifiability of certain in vitro nonlinear pharmacokinetic models is provided. The Organic Anion Transporting Polypeptide (OATP) substrate, Pitavastatin, is used as a probe on freshly isolated animal and human hepatocytes. Candidate pharmacokinetic non-linear compartmental models have been derived to characterise the uptake process of Pitavastatin. As a prerequisite to parameter estimation, structural identifiability analyses are performed to establish that all unknown parameters can be identified from the experimental observations available.

Compartmental modelling of the pharmacokinetics of a breast cancer resistance protein.

A mathematical model for the pharmacokinetics of Hoechst 33342 following administration into a culture medium containing a population of transfected cells (HEK293 hBCRP) with a potent breast cancer resistance protein inhibitor, Fumitremorgin C (FTC), present is described. FTC is reported to almost completely annul resistance mediated by BCRP in vitro. This non-linear compartmental model has seven macroscopic sub-units, with 14 rate parameters. It describes the relationship between the concentration of Hoechst 33342 and FTC, initially spiked in the medium, and the observed change in fluorescence due to Hoechst 33342 binding to DNA. Structural identifiability analysis has been performed using two methods, one based on the similarity transformation/exhaustive modelling approach and the other based on the differential algebra approach. The analyses demonstrated that all models derived are uniquely identifiable for the experiments/observations available. A kinetic modelling software package, namely FACSIMILE (MPCA Software, UK), was used for parameter fitting and to obtain numerical solutions for the system equations. Model fits gave very good agreement with in vitro data provided by AstraZeneca across a variety of experimental scenarios.