Long-Term Care in the United States: History, Financing, and Directions for Reform

This book is a concise survey of the development of U.S. long-term care and its financing, with comparisons with other rich countries. It also includes a brief comparative account of the impact of the COVID-19 pandemic in the United States and several other countries. The study finds much that is amiss with American long-term care and proposes three sets of progressively more ambitious reforms.https://research.upjohn.org/up_press/1290/thumbnail.jp

An epigenetic breeding system in soybean for increased yield and stability

Epigenetic variation has been associated with a wide range of adaptive phenotypes in plants, but there exist few direct means for exploiting this variation. RNAi suppression of the plant-specific gene, MutS HOMOLOG1 (MSH1), in multiple plant species produces a range of developmental changes accompanied by modulation of defence, phytohormone and abiotic stress response pathways along with methylome repatterning. This msh1-conditioned developmental reprogramming is retained independent of transgene segregation, giving rise to transgene-null ‘memory’ effects. An isogenic memory line crossed to wild type produces progeny families displaying increased variation in adaptive traits that respond to selection. This study investigates amenability of the MSH1 system for inducing agronomically valuable epigenetic variation in soybean. We developed MSH1 epi-populations by crossing with msh1-acquired soybean memory lines. Derived soybean epi-lines showed increase in variance for multiple yield-related traits including pods per plant, seed weight and maturity time in both glasshouse and field trials. Selected epi-F2:4 and epi-F2:5 lines showed an increase in seed yield over wild type. By epi-F2:6, we observed a return of MSH1-derived enhanced growth back to wild-type levels. Epi-populations also showed evidence of reduced epitype-by-environment (e 9 E) interaction, indicating higher yield stability. Transcript profiling of epi-lines identified putative signatures of enhanced growth behaviour across generations. Genes related to cell cycle, abscisic acid biosynthesis and auxin response, particularly SMALL AUXIN UP RNAs (SAURs), were differentially expressed in epi-F2:4 lines that showed increased yield when compared to epi-F2:6. These data support the potential of MSH1-derived epigenetic variation in plant breeding for enhanced yield and yield stability

In utero exposure to cigarette smoke dysregulates human fetal ovarian developmental signalling

STUDY QUESTION How does maternal cigarette smoking disturb development of the human fetal ovary?<p></p> SUMMARY ANSWER Maternal smoking increases fetal estrogen titres and dysregulates several developmental processes in the fetal ovary.<p></p> WHAT IS KNOWN ALREADY Exposure to maternal cigarette smoking during gestation reduces human fetal ovarian cell numbers, germ cell proliferation and subsequent adult fecundity.<p></p> STUDY DESIGN, SIZE, DURATION The effects of maternal cigarette smoking on the second trimester human fetal ovary, fetal endocrine signalling and fetal chemical burden were studied. A total of 105 fetuses were studied, 56 from mothers who smoked during pregnancy and 49 from those who did not.<p></p> PARTICIPANTS/MATERIALS, SETTING METHODS Ovary, liver and plasma samples were collected from electively terminated, normally progressing, second trimester human fetuses. Circulating fetal hormones, levels of 73 fetal ovarian transcripts, protein localization, density of oocytes/primordial follicles and levels of 16 polycyclic aromatic hydrocarbons (PAHs) in the fetal liver were determined.<p></p> MAIN RESULTS AND THE ROLE OF CHANCE Circulating fetal estrogen levels were very high and were increased by maternal smoking (ANOVA, P = 0.055–0.004 versus control). Smoke exposure also dysregulated (two-way ANOVA, smoking versus gestation weeks interaction, P = 0.046–0.023) four fetal ovarian genes (cytochrome P450 scc [CYP11A1], NOBOX oogenesis homeobox [NOBOX], activator of apoptosis harakiri [HRK], nuclear receptor subfamily 2, group E, member 1 [NR2E1]), shifted the ovarian Inhibin βA/inhibin α ratio (NHBA/INHA) transcript ratio in favour of activin (ANOVA, P = 0.049 versus control) and reduced the proportion of dominant-negative estrogen receptor 2 (ERβ: ESR2) isoforms in half the exposed fetuses. PAHs, ligands for the aryl hydrocarbon receptor (AHR), were increased nearly 6-fold by maternal smoking (ANOVA, P = 0.011 versus control). A fifth transcript, COUP transcription factor 1 (nuclear receptor subfamily 2, group F, member 1: NR2F1, which contains multiple AHR-binding sites), was both significantly increased (ANOVA, P = 0.026 versus control) and dysregulated by (two-way ANOVA, smoking versus gestation weeks interaction, P = 0.021) maternal smoking. NR2F1 is associated with repression of FSHR expression and smoke-exposed ovaries failed to show the normal increase in FSHR expression during the second trimester. There was a significantly higher number of DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4) VASA-positive (ANOVA, P = 0.016 versus control), but not POU domain, class 1, transcription factor 1 (POU5F1) OCT3/4-positive, oocytes in smoke-exposed fetuses and this matched with a significantly higher number of primordial follicles (ANOVA, P = 0.024 versus control).<p></p> LIMITATIONS, REASONS FOR CAUTION The effects of maternal smoking on establishment of the maximum fetal primordial follicle pool cannot be reliably studied in our population since the process is not completed until 28 weeks of gestation and normal fetuses older than 21 weeks of gestation are not available for study. Our data suggest that some fetal ovaries are affected by smoke exposure while others are not, indicating that additional studies, with larger numbers, may show more significant effects.<p></p> WIDER IMPLICATIONS OF THE FINDINGS Fetal exposure to chemicals in cigarette smoke is known to lead to reduced fecundity in women. Our study suggests, for the first time, that this occurs via mechanisms involving activation of AHR, disruption of inhibin/activin and estrogen signalling, increased exposure to estrogen and dysregulation of multiple molecular pathways in the exposed human fetal ovary. Our data also suggest that alterations in the ESR2 positive and dominant negative isoforms may be associated with reduced sensitivity of some fetuses to increased estrogens and maternal smoking

Negative Effect of Smoking on the Performance of the QuantiFERON TB Gold in Tube Test.

False negative and indeterminate Interferon Gamma Release Assay (IGRA) results are a well documented problem. Cigarette smoking is known to increase the risk of tuberculosis (TB) and to impair Interferon-gamma (IFN-γ) responses to antigenic challenge, but the impact of smoking on IGRA performance is not known. The aim of this study was to evaluate the effect of smoking on IGRA performance in TB patients in a low and high TB prevalence setting respectively. Patients with confirmed TB from Denmark (DK, n = 34; 20 smokers) and Tanzania (TZ, n = 172; 23 smokers) were tested with the QuantiFERON-TB Gold In tube (QFT). Median IFN-γ level in smokers and non smokers were compared and smoking was analysed as a risk factor for false negative and indeterminate QFT results. Smokers from both DK and TZ had lower IFN-γ antigen responses (median 0.9 vs. 4.2 IU/ml, p = 0.04 and 0.4 vs. 1.6, p < 0.01), less positive (50 vs. 86%, p = 0.03 and 48 vs. 75%, p < 0.01) and more false negative (45 vs. 0%, p < 0.01 and 26 vs. 11%, p = 0.04) QFT results. In Tanzanian patients, logistic regression analysis adjusted for sex, age, HIV and alcohol consumption showed an association of smoking with false negative (OR 17.1, CI: 3.0-99.1, p < 0.01) and indeterminate QFT results (OR 5.1, CI: 1.2-21.3, p = 0.02). Cigarette smoking was associated with false negative and indeterminate IGRA results in both a high and a low TB endemic setting independent of HIV status

Renormalized couplings and scaling correction amplitudes in the N-vector spin models on the sc and the bcc lattices

For the classical N-vector model, with arbitrary N, we have computed through order \beta^{17} the high temperature expansions of the second field derivative of the susceptibility \chi_4(N,\beta) on the simple cubic and on the body centered cubic lattices. (The N-vector model is also known as the O(N) symmetric classical spin Heisenberg model or, in quantum field theory, as the lattice O(N) nonlinear sigma model.) By analyzing the expansion of \chi_4(N,\beta) on the two lattices, and by carefully allowing for the corrections to scaling, we obtain updated estimates of the critical parameters and more accurate tests of the hyperscaling relation d\nu(N) +\gamma(N) -2\Delta_4(N)=0 for a range of values of the spin dimensionality N, including N=0 [the self-avoiding walk model], N=1 [the Ising spin 1/2 model], N=2 [the XY model], N=3 [the classical Heisenberg model]. Using the recently extended series for the susceptibility and for the second correlation moment, we also compute the dimensionless renormalized four point coupling constants and some universal ratios of scaling correction amplitudes in fair agreement with recent renormalization group estimates.Comment: 23 pages, latex, no figure

Cerebrovascular Disease and Perioperative Neurologic Vulnerability: A Prospective Cohort Study

Background: Stroke is a devastating perioperative complication without effective methods for prevention or diagnosis. The objective of this study was to analyze evidence-based strategies for detecting cerebrovascular vulnerability and injury in a high-risk cohort of non-cardiac surgery patients.Methods: This was a single-center, prospective cohort study. Fifty patients undergoing non-cardiac surgery were recruited −25 with known cerebrovascular disease and 25 matched controls. Neurologic vulnerability was measured with intraoperative cerebral oximetry as the primary outcome. Perioperative neurocognitive testing and serum biomarker analysis (S-100β, neuron specific enolase, glial fibrillary acid protein, and matrix metalloproteinase-9) were measured as secondary outcomes.Results: Cerebral desaturation events (an oximetry decrease ≥20% from baseline or &lt;50% absolute value for ≥3 min) occurred in 7/24 (29%) cerebrovascular disease patients and 2/24 (8.3%) controls (relative risk 3.5, 95% CI 0.81–15.2; P = 0.094). Cognitive function trends were similar in both groups, though overall scores (range: 1,500–7,197) were ~1 standard deviation lower in cerebrovascular patients across the entire perioperative period (−1,049 [95% CI −1,662, −436], P &lt; 0.001). No significant serum biomarker differences were found between groups over time. One control patient experienced intraoperative hypoxic-ischemic injury, but no robust biomarker or oximetry changes were observed.Conclusions: Cerebrovascular disease patients did not demonstrate dramatic differences in cerebral oximetry, cognitive trajectory, or molecular biomarkers compared to controls. Moreover, a catastrophic hypoxic-ischemic event was neither predicted nor detected by any strategy tested. These findings support the need for novel research into cerebrovascular risk and vulnerability

Multimodality treatment for esophageal adenocarcinoma: Multi-center propensity-score matched study

Background: The primary aim of this study was to compare survival from neoadjuvant chemoradiotherapy plus surgery (NCRS) versus neoadjuvant chemotherapy plus surgery (NCS) for the treatment of esophageal or junctional adenocarcinoma. The secondary aims were to compare pathological effects, short-term mortality and morbidity, and to evaluate the effect of lymph node harvest upon survival in both treatment groups. Methods: Data were collected from 10 European centers from 2001 to 2012. Six hundred and eight patients with stage II or III oesophageal or oesophago-gastric junctional adenocarcinoma were included; 301 in the NCRS group and 307 in the NCS group. Propensity score matching and Cox regression analyses were used to compensate for

Axial tubule junctions control rapid calcium signaling in atria.

The canonical atrial myocyte (AM) is characterized by sparse transverse tubule (TT) invaginations and slow intracellular Ca2+ propagation but exhibits rapid contractile activation that is susceptible to loss of function during hypertrophic remodeling. Here, we have identified a membrane structure and Ca2+-signaling complex that may enhance the speed of atrial contraction independently of phospholamban regulation. This axial couplon was observed in human and mouse atria and is composed of voluminous axial tubules (ATs) with extensive junctions to the sarcoplasmic reticulum (SR) that include ryanodine receptor 2 (RyR2) clusters. In mouse AM, AT structures triggered Ca2+ release from the SR approximately 2 times faster at the AM center than at the surface. Rapid Ca2+ release correlated with colocalization of highly phosphorylated RyR2 clusters at AT-SR junctions and earlier, more rapid shortening of central sarcomeres. In contrast, mice expressing phosphorylation-incompetent RyR2 displayed depressed AM sarcomere shortening and reduced in vivo atrial contractile function. Moreover, left atrial hypertrophy led to AT proliferation, with a marked increase in the highly phosphorylated RyR2-pS2808 cluster fraction, thereby maintaining cytosolic Ca2+ signaling despite decreases in RyR2 cluster density and RyR2 protein expression. AT couplon "super-hubs" thus underlie faster excitation-contraction coupling in health as well as hypertrophic compensatory adaptation and represent a structural and metabolic mechanism that may contribute to contractile dysfunction and arrhythmias

Murray Valley encephalitis virus surveillance and control initiatives in Australia.

Mechanisms for monitoring Murray Valley encephalitis (MVE) virus activity include surveillance of human cases, surveillance for activity in sentinel animals, monitoring of mosquito vectors and monitoring of weather conditions. The monitoring of human cases is only one possible trigger for public health action and the additional surveillance systems are used in concert to signal the risk of human disease, often before the appearance of human cases. Mosquito vector surveillance includes mosquito trapping for speciation and enumeration of mosquitoes to monitor population sizes and relative composition. Virus isolation from mosquitoes can also be undertaken. Monitoring of weather conditions and vector surveillance determines whether there is a potential for MVE activity to occur. Virus isolation from trapped mosquitoes is necessary to define whether MVE is actually present, but is difficult to deliver in a timely fashion in some jurisdictions. Monitoring of sentinel animals indicates whether MVE transmission to vertebrates is actually occurring. Meteorological surveillance can assist in the prediction of potential MVE virus activity by signalling conditions that have been associated with outbreaks of Murray Valley encephalitis in humans in the past. Predictive models of MVE virus activity for south-eastern Australia have been developed, but due to the infrequency of outbreaks, are yet to be demonstrated as useful for the forecasting of major outbreaks. Surveillance mechanisms vary across the jurisdictions. Surveillance of human disease occurs in all States and Territories by reporting of cases to health authorities. Sentinel flocks of chickens are maintained in 4 jurisdictions (Western Australia, the Northern Territory, Victoria and New South Wales) with collaborations between Western Australia and the Northern Territory. Mosquito monitoring complements the surveillance of sentinel animals in these jurisdictions. In addition, other mosquito monitoring programs exist in other States (including South Australia and Queensland). Public health control measures may include advice to the general public and mosquito management programs to reduce the numbers of both mosquito larvae and adult vectors. Strategic plans for public health action in the event of MVE virus activity are currently developed or being developed in New South Wales, the Northern Territory, South Australia, Western Australia and Victoria. A southern tri-State agreement exists between health departments of New South Wales, Victoria and South Australia and the Commonwealth Department of Health and Aged Care. All partners have agreed to co-operate and provide assistance in predicting and combatting outbreaks of mosquito-borne disease in south-eastern Australia. The newly formed National Arbovirus Advisory Committee is a working party providing advice to the Communicable Diseases Network Australia on arbovirus surveillance and control. Recommendations for further enhancement of national surveillance for Murray Valley encephalitis are described