The modern quality field in medicine is about one-third of a century old. The purpose of this paper is to summarize what we know about quality of care and indicate what we can do to improve quality ...of care in the next century. We assert that quality can be measured, that quality of care varies enormously, that improving quality of care is difficult, that financial incentives directed at the health system level have little effect on quality, and that we lack a publicly available tool kit to assess quality. To improve quality of care we will need adequate data and that will require patients to provide information about what happened to them and to allow people to abstract their medical records. It also will require that physicians provide patient information when asked. We also need a strategy to measure quality and then report the results and we need to place in the public domain tool kits that can be used by physicians, administrators, and patient groups to assess and improve quality. Each country should have a national quality report, based on standardized comprehensive and scientifically valid measures, which describes the country's progress in improving quality of care. We can act now. For the 70–100 procedures that dominate what physicians do, we should have a computer-based, prospective system to ensure that physicians ask patients the questions required to decide whether to do the procedure. The patient should verify the responses. Answers from patients should be combined with test results and other information obtained from the patient's physician to produce an assessment of the procedure's appropriateness and necessity. Advanced tools to assess quality, based on data from the patient and medical records, are also currently being developed. These tools could be used to comprehensively assess the quality of primary care across multiple conditions at the country, regional, and medical group level.
Hydrologic connectivity between catchment upland and near stream areas is essential for the transmission of water, solutes, and nutrients to streams. However, our current understanding of the role of ...riparian zones in mediating landscape hydrologic connectivity and the catchment scale export of water and solutes is limited. We tested the relationship between the duration of hillslope‐riparian‐stream (HRS) hydrologic connectivity and the rate and degree of riparian shallow groundwater turnover along four HRS well transects within a set of nested mountain catchments (Tenderfoot Creek Experimental Forest, MT). Transect HRS water table connectivity ranged from 9 to 123 days during the annual snowmelt hydrograph. Hillslope water was always characterized by low specific conductance (∼27 μS cm−1). In transects with transient hillslope water tables, riparian groundwater specific conductance was elevated during base flow conditions (∼127 μS cm−1) but shifted toward hillslope signatures once a HRS groundwater connection was established. The degree of riparian groundwater turnover was proportional to the duration of HRS connectivity and inversely related to the riparian: hillslope area ratios (buffer ratio; r2 = 0.95). We applied this relationship to the stream network in seven subcatchments within the Tenderfoot Creek Experimental Forest and compared their turnover distributions to source water contributions measured at each catchment outlet. The amount of riparian groundwater exiting each of the seven catchments was linearly related (r2 = 0.92) to their median riparian turnover time. Our observations suggest that the size and spatial arrangement of hillslope and riparian zones along a stream network and the timing and duration of groundwater connectivity between them is a first‐order control on the magnitude and timing of water and solutes observed at the catchment outlet.
The purpose of the study was to assess the use of curative therapies for hepatocellular carcinoma (HCC) in the population. HCC treatment patterns were examined in Surveillance, Epidemiology, and End ...Results (SEER) 18 registries (28% of U.S.). Joinpoint regression analyses were performed to assess 2000‐2010 incidence trends by tumor size, count, and receipt of potentially curative treatments (transplantation, resection, and ablation). SEER‐Medicare data enabled evaluation of treatment patterns including receipt of sorafenib or transarterial chemoembolization (TACE) by HCC‐associated comorbidities. Diagnoses of tumors ≤5.0 cm in diameter significantly increased during 2000‐2010, surpassing diagnosis of larger tumors. Overall, 23% of cases received potentially curative treatment. Joinpoint models indicated incidence rates of treatment with curative intent increased 17.6% per year during 2000‐2005, then declined by −2.9% per year during 2005‐2010 (P < 0.001). Among HCC cases with a single tumor ≤5.0 cm and no extension beyond the liver, use of ablative therapy significantly increased during 2000‐2010. Use of invasive surgery for single tumors, regardless of size, significantly increased during the initial years of the decade, then plateaued. The group most likely to receive curative treatment in the SEER‐Medicare cases was patients with one, small tumor confined to the liver (657 of 1,597 cases, 41%), with no difference in treatment by hepatic comorbidity status (P = 0.24). A higher proportion of cases with reported liver‐associated comorbidities were, however, diagnosed with tumors ≤5.0 cm in diameter (1,745 0f 2,464, 71%) compared to patients with no reported comorbidities (996 of 2,596, 38%, P < 0.001). Conclusion: Although more HCC patients were diagnosed with early disease over time, the use of curative treatments in this patient group has recently plateaued. Efforts to identify and treat more eligible candidates for curative therapy could be beneficial. (Hepatology 2014;60:1637–1644)
Genome duplication necessarily involves the replication of imperfect DNA templates and, if left to their own devices, replication complexes regularly run into problems. The details of how cells ...overcome these replicative 'hiccups' are beginning to emerge, revealing a complex interplay between DNA replication, recombination and repair that ensures faithful passage of the genetic material from one generation to the next.
Background and Purpose
The 5‐HT receptor subtypes 5‐HT2A and 5‐HT2C are important neurotherapeutic targets, though, obtaining selectivity over 5‐HT2B and H1 receptors is challenging. Here, we ...delineated molecular determinants of selective binding to 5‐HT2A and 5‐HT2C receptors for novel 4‐phenyl‐2‐dimethylaminotetralins (4‐PATs).
Experimental Approach
We synthesized 42 novel 4‐PATs with halogen or aryl moieties at the C(4)‐phenyl meta‐position. Affinity, function, molecular modeling and 5‐HT2A receptor mutagenesis studies were performed to understand structure–activity relationships at 5‐HT2‐type and H1 receptors. Lead 4‐PAT‐type 5‐HT2A/5‐HT2C receptor inverse agonists were compared with pimavanserin, a selective 5‐HT2A/5‐HT2C receptor inverse agonist approved to treat Parkinson's disease‐related psychosis, in the mouse head twitch response and locomotor activity assays, models relevant to antipsychotic drug development.
Key Results
Most 4‐PAT diastereomers in the (2S,4R)‐configuration bound non‐selectively to 5‐HT2A, 5‐HT2C and H1 receptors, with >100‐fold selectivity over 5‐HT2B receptors, whereas diastereomers in the (2R,4R)‐configuration bound preferentially to 5‐HT2A over 5‐HT2C receptors and had >100‐fold selectivity over 5‐HT2B and H1 receptors. Results suggest that G2385.42 and V2355.39 in 5‐HT2A receptors (conserved in 5‐HT2C receptors) are important for high affinity binding, whereas interactions with T1945.42 and W1584.56 determine H1 receptor affinity. The 4‐PAT analog (2S,4R)‐4‐(4'‐(dimethylamino)‐1,1'‐biphenyl‐3‐yl)‐N,N‐dimethyl‐1,2,3,4‐tetrahydronaphthalen‐2‐amine, (2S,4R)‐2k, a potent and selective 5‐HT2A/5‐HT2C receptor inverse agonist, had activity like pimavanserin in the mouse head twitch response assay but was distinct in not suppressing locomotor activity.
Conclusions and Implications
The novel 4‐PAT chemotype can yield selective 5‐HT2A/5‐HT2C receptor inverse agonists for antipsychotic drug development by optimizing ligand–receptor interactions in transmembrane domain 5. Chirality can be exploited to attain selectivity over H1 receptors, which may circumvent sedative effects.
Despite the significant contribution of biogenic volatile
organic compounds (BVOCs) to organic aerosol formation and ozone production
and loss, there are few long-term, year-round, ongoing ...measurements of
their volume mixing ratios and quantification of their impacts on
atmospheric reactivity. To address this gap, we present 1 year of hourly
measurements of chemically resolved BVOCs between 15 September 2019 and
15 September 2020, collected at a research tower in Central Virginia
in a mixed forest representative of ecosystems in the Southeastern US.
Mixing ratios of isoprene, isoprene oxidation products, monoterpenes, and
sesquiterpenes are described and examined for their impact on the hydroxy
radical (OH), ozone, and nitrate reactivity. Mixing ratios of isoprene range
from negligible in the winter to typical summertime 24 h averages of 4–6 ppb, while monoterpenes have more stable mixing ratios in the range of tenths of a part per billion up to ∼2 ppb year-round. Sesquiterpenes are
typically observed at mixing ratios of <10 ppt, but this represents
a lower bound in their abundance. In the growing season, isoprene dominates
OH reactivity but is less important for ozone and nitrate reactivity.
Monoterpenes are the most important BVOCs for ozone and nitrate reactivity
throughout the year and for OH reactivity outside of the growing season. To
better understand the impact of this compound class on OH, ozone, and
nitrate reactivity, the role of individual monoterpenes is examined. Despite
the dominant contribution of α-pinene to total monoterpene mass, the
average reaction rate of the monoterpene mixture with atmospheric oxidants
is between 25 % and 30 % faster than α-pinene due to the
contribution of more reactive but less abundant compounds. A majority of
reactivity comes from α-pinene and limonene (the most significant
low-mixing-ratio, high-reactivity isomer), highlighting the importance of
both mixing ratio and structure in assessing atmospheric impacts of
emissions.
Emissions from natural sources are driven by various external stimuli such as sunlight, temperature, and soil moisture. Once biogenic volatile organic compounds (BVOCs) are emitted into the ...atmosphere, they rapidly react with atmospheric oxidants, which has significant impacts on ozone and aerosol budgets. However, diurnal, seasonal, and interannual variability in these species are poorly captured in emissions models due to a lack of long-term, chemically speciated measurements. Therefore, increasing the monitoring of these emissions will improve the modeling of ozone and secondary organic aerosol concentrations. Using 2 years of speciated hourly BVOC data collected at the Virginia Forest Research Lab (VFRL) in Fluvanna County, Virginia, USA, we examine how minor changes in the composition of monoterpenes between seasons are found to have profound impacts on ozone and OH reactivity. The concentrations of a range of BVOCs in the summer were found to have two different diurnal profiles, which, we demonstrate, appear to be driven by light-dependent versus light-independent emissions. Factor analysis was used to separate the two observed diurnal profiles and determine the contribution from each emission type. Highly reactive BVOCs were found to have a large influence on atmospheric reactivity in the summer, particularly during the daytime. These findings reveal the need to monitor species with high atmospheric reactivity, even though they have low concentrations, to more accurately capture their emission trends in models.
Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used ...to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages.
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