Capacity planning for waste management systems: an interval fuzzy robust dynamic programming approach.
This study integrates the concepts of interval numbers and fuzzy sets into optimization analysis by dynamic programming as a means of accounting for system uncertainty. The developed interval fuzzy robust dynamic programming (IFRDP) model improves upon previous interval dynamic programming methods. It allows highly uncertain information to be effectively communicated into the optimization process through introducing the concept of fuzzy boundary interval and providing an interval-parameter fuzzy robust programming method for an embedded linear programming problem. Consequently, robustness of the optimization process and solution can be enhanced. The modeling approach is applied to a hypothetical problem for the planning of waste-flow allocation and treatment/disposal facility expansion within a municipal solid waste (MSW) management system. Interval solutions for capacity expansion of waste management facilities and relevant waste-flow allocation are generated and interpreted to provide useful decision alternatives. The results indicate that robust and useful solutions can be obtained, and the proposed IFRDP approach is applicable to practical problems that are associated with highly complex and uncertain information.


Direct and buffering effects of physical activity on stress-related depression in mothers of infants.
This study examined the role of leisure-time physical activity in reducing the impact of high life stress and time pressure on depression, a buffer effect, for mothers of infants. A direct association between leisure-time physical activity and depression, regardless of both sources of stress, was also tested. A sample of approximately 5,000 mothers of infant children completed questionnaires that measured demographic characteristics, frequency of participation in leisure-time physical activity, life stress, time pressure, and depression (depressive symptoms). Hierarchical multiple regression incorporating an interaction component to represent the buffering effect was used to analyze the data. Frequency of leisure-time physical activity was significantly associated with lower levels of depressive symptoms for both types of stress and acted as a buffer of the association between life stress and depressive symptoms, but did not buffer the influence of time pressure on depressive symptoms. These findings indicated that leisure-time physical activity assists in maintaining the mental health of mothers of infants; however, caution is needed when promoting physical activity for mothers who feel under time pressure.


Development of sodium channels during differentiation of chick skeletal muscle in culture. I. Binding studies.
[125I]Scorpion toxin and [3H]saxitoxin, two neurotoxins that bind specifically to different sites on sodium channels, were used to monitor the development of sodium channels during synchronous differentiation of chick skeletal muscle in culture. [3H]Saxitoxin-binding sites are not detectable in myoblasts. They appear only after myoblasts fuse to form myotubes and increase gradually to reach a maximal value of 58 fmol/mg of protein by 8 days in culture. In contrast, [125I]scorpion toxin-binding sites are first detected during the period of cell fusion and increase after fusion to reach a maximum by 4 days in culture, well before either the maximal value of the [3H]saxitoxin binding or the appearance of fully developed sodium action potentials. Neither [3H]saxitoxin binding nor [125I] scorpion toxin binding affinity changes during development; they have values of 1.4 and 62 nM, respectively. These data, and data described in the companion paper (Baumgold, J., J. B. Parent, and I. Spector (1983) J. Neurosci. 3: 1004-1013), suggest that sodium channel development involves two sequential steps: incorporation into the cell membrane of an immature form of the sodium channel capable of binding scorpion toxin alone, followed by the acquisition of the ability to bind saxitoxin and thus to become a mature and functional channel.


Prehospital transportation decisions for patients sustaining major trauma in road traffic crashes in Sweden.
The objective of this study was to evaluate the proportion and characteristics of patients sustaining major trauma in road traffic crashes (RTCs) who could benefit from direct transportation to a trauma center (TC). Currently, there is no national classification of TC in Sweden. In this study, 7 university hospitals (UHs) in Sweden were selected to represent a TC level I or level II. These UHs have similar capabilities as the definition for level I and level II TC in the United States. Major trauma was defined as Injury Severity Score (ISS) > 15. A total of 117,730 patients who were transported by road or air ambulance were selected from the Swedish TRaffic Accident Data Acquisition (STRADA) database between 2007 to 2014. An analysis of the patient characteristics sustaining major trauma in comparison with patients sustaining minor trauma (ISS < 15) was conducted. Major trauma patients transported to a TC versus non-TC were further analysed with respect to injured body region and road user type. Approximately 3% (n = 3, 411) of patients sustained major trauma. Thirty-eight percent of major trauma patients were transported to a TC, and 62% were transported to a non-TC. This results in large proportions of patients with Abbreviated Injury Scale (AIS) 3+ injuries being transported to a non-TC. The number of AIS 3+ head injuries for major trauma patients transported to a TC versus non-TC were similar, whereas a larger number of AIS 3+ thorax injuries were present in the non-TC group. The non-TC major trauma patients had a higher probability of traveling in a car, truck, or bus and to be involved in a crash in a rural location. Our results show that the majority of RTC major trauma patients are transported to a non-TC. This may cause unnecessary morbidity and mortality. These findings can guide the development of improved prehospital treatment guidelines, protocols and decision support systems.


Vitamin D status, body composition, and fitness measures in college-aged students.
Low vitamin D, commonly assessed as serum 25-hydroxyvitamin D (25OHD), is associated with the development of many age-related chronic diseases. A positive relationship exists between elevated 25OHD and muscle synthesis, strength, power, and decreased body fat in elderly individuals. However, these findings have not been consistently reported in younger healthy populations. The purpose of this study was to investigate the relationship between 25OHD and measures of body size, composition, metabolism, and physical fitness in a young physically active population. Thirty-nine subjects (20 men, 19 women; aged 23 ± 0.7 years) reported 6 times for testing. Blood was collected to determine 25OHD. Primary outcomes included the following: body mass index (BMI) and percent body fat (dual x-ray absorptiometry); resting metabolic rate; maximal oxygen uptake (V[Combining Dot Above]O2max); power output (Wingate); and muscular strength (8 repetition maximum for bench press, upright row, and leg extension and flexion exercises). Our analysis included all participants, and subgroup analyses for individuals with suboptimal 25OHD concentration below 35 ng·mL ("low"; n = 20, 25.97 ± 1.97 ng·mL) or equal to and above 35 ng·mL ("high"; n = 19, 44.15 ± 2.17 ng·mL). Twenty subjects in this study had serum levels of 25OHD below 35 ng·mL. There was a significant positive relationship between V[Combining Dot Above]O2max and serum 25OHD and a negative relationship between BMI and serum 25OHD. These data suggest that vitamin D deficiency is prevalent even in a young physically active population in the southern United States and that there was a positive relationship between a measure of cardiovascular fitness and serum 25OHD, and a negative relationship between serum 25OHD and BMI.


Characterizing the Effects of Glutathione as an Immunoadjuvant in the Treatment of Tuberculosis.
Mycobacterium tuberculosis is the etiological agent that is responsible for causing tuberculosis (TB), which continues to affect millions of people worldwide, and the rate of resistance of M. tuberculosis to antibiotics is ever increasing. We tested the synergistic effects of N-acetyl cysteine (NAC; the precursor molecule for the synthesis of glutathione [GSH]) and individual first-line antibiotics typically given for the treatment of TB, such as isoniazid (INH), rifampin (RIF), ethambutol (EMB), and pyrazinamide (PZA), to improve the ability of macrophages to control intracellular M. tuberculosis infection. GSH, a pleiotropic antioxidant molecule, has previously been shown to display both antimycobacterial and immune-enhancing effects. Our results indicate that there was not only an increase in beneficial immunomodulatory effects but also a greater reduction in the intracellular viability of M. tuberculosis when macrophages were treated with the combination of antibiotics (INH, RIF, EMB, or PZA) and NAC.


Active contour based segmentation for insulin granule cores in electron micrographs of beta islet cells.
Transmission electron microscopy images of beta islet cells contain many complex structures, making it difficult to accurately segment insulin granule cores. Quantification of sub cellular structures will allow biologists to better understand cellular mechanics. Two novel, level set active contour models are presented in this paper. The first utilizes a shape regularizer to reduce oversegmentation. The second contribution is a dual active contour, which achieves accurate core segmentations. The segmentation algorithm proceeds through three stages: an initial rough segmentation using the first contribution, cleaning using morphological techniques and a refining step using the proposed dual active contour. Our method is validated on a set of manually defined ground truths.


Sperm migration into and through the oviduct following artificial insemination at different stages of the estrous cycle in the rat.
In order to examine whether sperm migration into and through the oviduct follows an invariable pattern or is subject to regulation, rats in proestrus, estrus, metestrus, or diestrus were inseminated in the upper third of each uterine horn with 10-20 million epididymal spermatozoa. Three or eight hours later, the numbers of spermatozoa free and adhering to the epithelium in the ampullary and isthmic segments were determined. A significantly higher number of spermatozoa were recovered in estrus than in other stages, at 3 h than at 8 h, and at all stages from the isthmus than from the ampulla. Spermatozoa adhering to the epithelium were observed only in proestrus and estrus and in the isthmus. The effect of exogenous estradiol-17beta (E2) and progesterone (P4) on sperm migration was investigated in rats in which the estrous cycle was inhibited pharmacologically. E2 facilitated sperm migration into the oviduct and P4 antagonized this effect, whereas P4 alone had no effect. Concomitant treatment with E2+P4 induced adhesion of spermatozoa to the oviductal epithelium. In conclusion, the pattern of sperm migration into and through the rat oviduct varies with the stage of the cycle, being dependent on E2 and P4. The adhesion of spermatozoa to the rat oviductal epithelium is stage- and segment-specific and requires the combined action of both hormones.


Interventions for preventing influenza: An overview of Cochrane systematic reviews and a Bayesian network meta-analysis.
Influenza places a heavy public health burden in numerous countries every year. In addition to vaccines, there are some interventions that are effective in preventing influenza. This overview of systematic reviews (SRs) aimed to evaluate the efficacy and safety of interventions for influenza prevention. We searched the Cochrane Database of Systematic Reviews, 2020, Issue 1 for relevant Cochrane SRs using the keywords "common cold," "influenza," and "flu." Cochrane SRs that investigated the prevention of influenza were included. Participants included the general population without influenza or influenza-like symptoms, who were treated with preventative interventions and compared to individuals receiving no treatment or placebo. Two reviewers independently screened citations against pre-defined inclusion criteria and extracted data. The methodological quality of these SRs was evaluated using the Assessing the Methodological Quality of Systematic Reviews-II (AMSTAR-II) guidelines. The primary outcome of our analysis was the incidence of influenza, and the secondary outcomes were the incidence of influenza-like illness and hospitalization. In addition to the narrative summary of SR findings, we also pooled data from homogeneous trials among these SRs and produced evidence mapping. We conducted a network meta-analysis to compare the effect across interventions and used the Cochrane approach to grading of recommendations, assessment, development, and evaluation (GRADE) to assess the quality of evidence. Eleven Cochrane SRs were included, covering five medications, eleven vaccinations and four complementary therapies. Among these SRs, 73% scored "high" quality on AMSTAR-II rating. We found that eight interventions, including amantadine, garlic, and six different vaccines, were beneficial for reducing the incidence of influenza compared to placebo, while oseltamivir, zanamivir, Ganmao capsule, Echinacea, and another three types of vaccine were probably beneficial. Ganmao capsule ranked highest for influenza prevention in the network meta-analysis, followed by amantadine, garlic, and vaccines of all types. Monovalent inactivated parenteral vaccine was found to be beneficial in reducing the incidence of influenza-like illness. None of the interventions reduced the hospitalization rate. High-quality evidence showed that garlic or vaccine had advantages in preventing influenza, and that vitamin C is not effective. The effect of other interventions needs to be further verified with high-quality evidence.


Site-Specific Covalent Conjugation of Modified mRNA by tRNA Guanine Transglycosylase.
Modified mRNA (mod-mRNA) has recently been widely studied as the form of RNA useful for therapeutic applications due to its high stability and lowered immune response. Herein, we extend the scope of the recently established RNA-TAG (transglycosylation at guanosine) methodology, a novel approach for genetically encoded site-specific labeling of large mRNA transcripts, by employing mod-mRNA as substrate. As a proof of concept, we covalently attached a fluorescent probe to mCherry encoding mod-mRNA transcripts bearing 5-methylcytidine and/or pseudouridine substitutions with high labeling efficiencies. To provide a versatile labeling methodology with a wide range of possible applications, we employed a two-step strategy for functionalization of the mod-mRNA to highlight the therapeutic potential of this new methodology. We envision that this novel and facile labeling methodology of mod-RNA will have great potential in decorating both coding and noncoding therapeutic RNAs with a variety of diagnostic and functional moieties.


Evaluation of efficacy and sedative profiles of H(1) antihistamines by large-scale surveillance using the visual analogue scale (VAS).
H(1) antihistamines are widely used as therapeutics for allergic diseases. Sedation is a well-known side effect of H(1) antihistamines and sometimes it is life-threatening for patients. Thus it is important to evaluate the sedative properties of H(1) antihistamines to avoid side effects. For this purpose, histamine H(1) receptor (H1R) occupancy and proportional impairment ratios (PIR) are now being used. However, it is not easy to obtain these parameters. Here, we sought to evaluate the sedative properties of H(1) antihistamines by means of a large-scale surveillance at health insurance pharmacies. The survey was conducted at 37 health insurance pharmacies. The therapeutic efficacy and the degree of sleepiness were quantified through a questionnaire using the visual analog scale (VAS) directly from 1742 patients who received H(1) antihistamines. The degree of sleepiness caused by the first-generation antihistamines was significantly higher than that of the second-generation antihistamines. The high VAS score in case of efficacy was found in d-chlorpheniramine, olopatadine, and ebastine. Among the mean values of efficacy, all second-generation antihistamines except for loratadine, bepotastine, and mequitazine were significantly higher than that of clemastine. Regarding the degree of sleepiness, clemastine scored the highest VAS score, and significantly lower scores were obtained in all second-generation antihistamines. The sedative properties of the H(1) antihistamines obtained from VAS analysis were very similar to those of H1R occupancy from positron emission tomography (PET) studies and PIR from meta-analysis. Our results indicate that large-scale surveillance using VAS might be useful to evaluate the profiles of H(1) antihistamines.


Contact Lens Compliance With Ophthalmologists and Other Health Professionals.
To assess the compliance with contact lens (CL) use among ophthalmologists and other health professionals, and to identify the main noncompliant behaviors. A cross-sectional, comparative study was designed for soft CL wearers. Twenty-five ophthalmologists, 24 medical doctors other than ophthalmologists, 20 nurses (health professionals), and 52 lay people (members of the public) subjects were included in the interview. The compliance rate for each behavior were determined and compared. Users were asked to rate their subjective use to calculate self-evaluation scores. The compliance rate was found to be the highest among ophthalmologists; however, the difference was not significant (P=0.083). Although the level of compliance was not associated with the subjects' age, duration of lens wear, or wearing days per week (P>0.05), an association was found with the number of wearing hours per day (P=0.010). Increased wearing hours per day was found to increase the rate of poor compliance (P=0.010). Significant differences were found between the groups in storing lenses in fresh solution, lens wearing time according to the ophthalmologist recommendation, and follow-up visits according to ophthalmologist recommendation (P<0.001, P=0.036, P=0.001, respectively). Self-evaluation scores among ophthalmologists, health professionals, and the lay people were 7.56±0.86, 7.59±1.29, and 7.67±1.60, respectively, and no significant differences existed between the groups (P=0.930). No differences were evident between the groups in terms of good compliance with CL wear and care practices. As this result shows that compliance with CL wear and care practices is not only related to the level of knowledge, different methods should be developed to increase compliance.


An investigation of the centriole cycle using 3T3 and CHO cells.
An investigation of the centriole cycle was based on serial-section electron microscopy of the centrioles of 790 3T3 cells and 40 CHO cells (incomplete sets of sections were excluded from the analysis). Time-course studies indicated that procentrioles first appear 4 h after the start of S-phase; evidence was obtained to suggest that they elongate progressively during the subsequent stages of the cell cycle, and that they start to separate from their parents during mitosis. An association of the structural features of the centriole cycle with the Two-transition Model of the Cell Cycle was ruled out by the finding of two centrioles in most quiescent cells, and the appearance of procentrioles in S-phase in transiently stimulated cells.


Acute mitral regurgitation in suspected acute coronary syndrome: what is the cause?
Patients presenting with acute chest pain and suspected acute coronary syndrome (ACS) who have nonobstructive coronary disease on angiography, but new regional wall motion abnormalities are often diagnosed with takotsubo cardiomyopathy (TTC). The cause of TTC is often physical or emotional stress, and this clinical syndrome occurs more often in women than men. When hemodynamically significant mitral regurgitation (MR) accompanies TTC, the mechanism must be carefully elucidated, as systolic anterior motion (SAM) of the mitral valve can cause significant MR and left ventricular outflow tract (LVOT) obstruction. These patients can be conservatively managed, with SAM-associated MR and LVOT obstruction resolving with medical therapy as TTC-associated left ventricular (LV) dysfunction resolves, as opposed to true ACS where further intervention for MR is often necessary. This case report describes 2 cases of TTC presenting with severe MR, who were initially thought to have ACS-associated MR caused by ischemia, but on further echocardiographic interrogation were found to have SAM-associated MR which resolved along with resolution of LV wall motion abnormalities on medical therapy by follow-up echocardiography.


Application of a remote-sensing three-source energy balance model to improve evapotranspiration partitioning in vineyards.
Improved accuracy of evapotranspiration (ET) estimation, including its partitioning between transpiration (T) and surface evaporation (E), is key to monitor agricultural water use in vineyards, especially to enhance water use efficiency in semi-arid regions such as California, USA. Remote-sensing methods have shown great utility in retrieving ET from surface energy balance models based on thermal infrared data. Notably, the two-source energy balance (TSEB) has been widely and robustly applied in numerous landscapes, including vineyards. However, vineyards add an additional complexity where the landscape is essentially made up of two distinct zones: the grapevine and the interrow, which is often seasonally covered by an herbaceous cover crop. Therefore, it becomes more complex to disentangle the various contributions of the different vegetation elements to total ET, especially through TSEB, which assumes a single vegetation source over a soil layer. As such, a remote-sensing-based three-source energy balance (3SEB) model, which essentially adds a vegetation source to TSEB, was applied in an experimental vineyard located in California's Central Valley to investigate whether it improves the depiction of the grapevine-interrow system. The model was applied in four different blocks in 2019 and 2020, where each block had an eddy-covariance (EC) tower collecting continuous flux, radiometric, and meteorological measurements. 3SEB's latent and sensible heat flux retrievals were accurate with an overall RMSD ~ 50 W/m2 compared to EC measurements. 3SEB improved upon TSEB simulations, with the largest differences being concentrated in the spring season, when there is greater mixing between grapevine foliage and the cover crop. Additionally, 3SEB's modeled ET partitioning (T/ET) compared well against an EC T/ET retrieval method, being only slightly underestimated. Overall, these promising results indicate 3SEB can be of great utility to vineyard irrigation management, especially to improve T/ET estimations and to quantify the contribution of the cover crop to ET. Improved knowledge of T/ET can enhance grapevine water stress detection to support irrigation and water resource management. The online version contains supplementary material available at 10.1007/s00271-022-00787-x.


The genetic signature of conditional expression.
Conditionally expressed genes have the property that every individual in a population carries and transmits the gene, but only a fraction, , expresses the gene and exposes it to natural selection. We show that a consequence of this pattern of inheritance and expression is a weakening of the strength of natural selection, allowing deleterious mutations to accumulate within and between species and inhibiting the spread of beneficial mutations. We extend previous theory to show that conditional expression in space and time have approximately equivalent effects on relaxing the strength of selection and that the effect holds in a spatially heterogeneous environment even with low migration rates among patches. We support our analytical approximations with computer simulations and delineate the parameter range under which the approximations fail. We model the effects of conditional expression on sequence polymorphism at mutation-selection-drift equilibrium, allowing for neutral sites, and show that sequence variation within and between species is inflated by conditional expression, with the effect being strongest in populations with large effective size. As decreases, more sites are recruited into neutrality, leading to pseudogenization and increased drift load. Mutation accumulation diminishes the degree of adaptation of conditionally expressed genes to rare environments, and the mutational cost of phenotypic plasticity, which we quantify as the plasticity load, is greater for more rarely expressed genes. Our theory connects gene-level relative polymorphism and divergence with the spatial and temporal frequency of environments inducing gene expression. Our theory suggests that null hypotheses for levels of standing genetic variation and sequence divergence must be corrected to account for the frequency of expression of the genes under study.


Predicting Diagnosis of Australian Canine and Feline Urinary Bladder Disease Based on Histologic Features.
Anatomic pathology is a vital component of veterinary medicine but as a primarily subjective qualitative or semiquantitative discipline, it is at risk of cognitive biases. Logistic regression is a statistical technique used to explain relationships between data categories and outcomes and is increasingly being applied in medicine for predicting disease probability based on medical and patient variables. Our aims were to evaluate histologic features of canine and feline bladder diseases and explore the utility of logistic regression modeling in identifying associations in veterinary histopathology, then formulate a predictive disease model using urinary bladder as a pilot tissue. The histologic features of 267 canine and 71 feline bladder samples were evaluated, and a logistic regression model was developed to identify associations between the bladder disease diagnosed, and both patient and histologic variables. There were 102 cases of cystitis, 84 neoplasia, 42 urolithiasis and 63 normal bladders. Logistic regression modeling identified six variables that were significantly associated with disease outcome: species, urothelial ulceration, urothelial inflammation, submucosal lymphoid aggregates, neutrophilic submucosal inflammation, and moderate submucosal hemorrhage. This study demonstrated that logistic regression modeling could provide a more objective approach to veterinary histopathology and has opened the door toward predictive disease modeling based on histologic variables.


[Dependences of 137Cs and 90Sr concentration ratios in fish on the potassium and calcium concentrations in the freshwater reservoirs].
Activities of 137Cs and 90Sr, concentrations of the potassium and calcium ions in water and accumulation of the radionuclides in the organisms of various freshwater fish have been measured in the stagnant and semistagnant water reservoirs of Ukraine contaminated as a result of the Chernobyl accident. On the basis of the numerous experimental data for different regions the statistical parameters were derived describing the dependencies of the 137Cs and 90Sr concentration ratios in the muscle tissue of various fish species on the potassium and calcium concentrations in water, respectively.


Systems of care: transition from the bio-psycho-social perspective of the International Classification of Functioning, Disability and Health.
The transition process of vulnerable adolescents, including those with complex health conditions, occurs in all domains of their life. Systems of care are usually designed but also restricted within certain aspects of life, as addressed by health, education and social welfare. The need for a co-ordinated approach to support the transition process has been voiced before, but usually publications focus on one system of care, usually the healthcare system or the education system. Recent moves, especially in the UK, are trying to integrate these different systems allowing for a more integrated transition process. This article illustrates how these developments are represented within the framework of the International Classification of Functioning, Disability and Health (ICF) and provides arguments that favour a greater integration of systems of care. Examples of systems of care from North America and the EU (Germany and the UK) are described. They were selected from a literature search using the terms 'systems of care', 'transition' and 'transitional care' in different combinations. Further supportive information derives from personal experience working in some of these systems in different countries. The systems were analysed according to the components of health they address within the ICF. In order to assist adolescents in transition of services, there is a consensus that the approach should be individualized. The overall goal of any intervention or service should be to achieve optimal functioning of the patients. In the framework of the ICF, this means that biomedical and contextual (psychosocial) issues need to be taken into consideration. This requires an exchange of information between the different systems or the integration of those systems involved with the patient. To facilitate transition, it has been shown that close collaboration between agencies, a transdisciplinary approach of the professionals involved and the use of key workers are helpful.


Evaluation and feedback for effective clinical teaching in postgraduate medical education: validation of an assessment instrument incorporating the CanMEDS roles.
Providing clinical teachers in postgraduate medical education with feedback about their teaching skills is a powerful tool to improve clinical teaching. A systematic review showed that available instruments do not comprehensively cover all domains of clinical teaching. We developed and empirically test a comprehensive instrument for assessing clinical teachers in the setting of workplace learning and linked to the CanMEDS roles. In a Delphi study, the content validity of a preliminary instrument with 88 items was studied, leading to the construction of the EFFECT (evaluation and feedback for effective clinical teaching) instrument. The response process was explored in a pilot test and focus group research with 18 residents of 6 different disciplines. A confirmatory factor analyses (CFA) and reliability analyses were performed on 407 evaluations of 117 supervisors, collected in 3 medical disciplines (paediatrics, pulmonary diseases and surgery) of 6 departments in 4 different hospitals. CFA yielded an 11 factor model with a good to excellent fit and internal consistencies ranged from 0.740 to 0.940 per domain; 7 items could be deleted. The model of workplace learning showed to be a useful framework for developing EFFECT, which incorporates the CanMEDS competencies and proved to be valid and reliable.


Latent Class Analysis of Social Needs in Medicaid Population and Its Impact on Risk Adjustment Models.
A growing number of US states are implementing programs to address the social needs (SNs) of their Medicaid populations through managed care contracts. Incorporating SN might also improve risk adjustment methods used to reimburse Medicaid providers. Identify classes of SN present within the Medicaid population and evaluate the performance improvement in risk adjustment models of health care utilization and cost after incorporating SN classes. A secondary analysis of Medicaid patients during the years 2018 and 2019. Latent class analysis (LCA) was used to identify SN classes. To evaluate the impact of SN classes on measures of hospitalization, emergency (ED) visits, and costs, logistic and linear regression modeling for concurrent and prospective years was used. Model performance was assessed before and after incorporating these SN classes to base models controlling for demographics and comorbidities. 262,325 Medicaid managed care program patients associated with a large urban academic medical center. 7.8% of the study population had at least one SN, with the most prevalent being related to safety (3.9%). Four classes of SN were determined to be optimal based on LCA, including stress-related needs, safety-related needs, access to health care-related needs, and socioeconomic status-related needs. The addition of SN classes improved the performance of concurrent base models' AUC (0.61 vs. 0.58 for predicting ED visits and 0.61 vs. 0.58 for projecting hospitalizations). Incorporating SN clusters significantly improved risk adjustment models of health care utilization and costs in the study population. Further investigation into the predictive value of SN for costs and utilization in different Medicaid populations is merited.


Compliance of Pharmacotherapy with GOLD Guidelines: A Longitudinal Study in Patients with COPD.
To evaluate the clinical implementation of pharmacotherapy recommendations for chronic obstructive pulmonary disease (COPD) based on the Global Initiative for chronic obstructive lung disease (GOLD) guidelines, in a longitudinal setting. This is a sub-analysis of a prospective, non-interventional cohort study including patients with confirmed mild-to-very-severe COPD from seven pulmonary outpatient clinics in Switzerland. Follow-up visits took place annually for up to 7 years, from October 2010 until December 2016. For each visit, we evaluated the compliance of the prescribed pharmacotherapy with the concurrently valid GOLD guideline. We investigated whether step-ups or step-downs in GOLD stage or risk-group were accompanied by concordant changes in prescribed medication. Groups were compared via ANOVA. Data of 305 patients (62±7 years, 66% men) were analysed. In 59.1% of visits, the prescribed medication conformed to the respective valid GOLD-guideline. Patients with very severe COPD were most likely to receive pharmacotherapy in compliance with guidelines. Step-ups and step-downs in risk group, requiring escalation, or de-escalation of pharmacotherapy, were noticed in 24 and 43 follow-up visits, respectively. Step-ups were adequately implemented in 4 (16.7%) and step-downs in six cases (14.0%). The compliance of COPD-pharmacotherapy with GOLD-guidelines is suboptimal, especially in lower risk groups. The high rates of missed out treatment-adjustments suggest that the familiarity of physicians with guidelines leaves room for improvement.


Retroviral expression in mononuclear blood cells isolated from a patient with osteopetrosis (Albers-Schönberg disease).
We report the presence of reverse transcriptase activity in the supernatant of long-term culture of mononuclear blood cells (monocytes and lymphocytes) isolated from a 27-year-old patient suffering from benign osteopetrosis. The enzyme was purified to homogeneity according to the technique of Chandra and Steel, by chromatography, first on DEAE-cellulose (DE 52) and then on phosphocellulose (P11). After purification, the enzyme was characterized biochemically for its template specificity and ionic requirements. The purified enzyme was able to transcribe poly(rA).(dT)12-18 and poly(rC).(dG)12-18 very efficiently and had a marked preference for Mg2+ ions over Mn2+ ions. The pattern of ionic dependency for this enzyme is similar to that of reverse transcriptases purified from human lymphotropic viruses. The patient was tested and found sero-negative for HIV-1, HIV-2, and HTLV-I and seropositive (immunoglobulin G) for cytomegalovirus. Epstein-Barr virus nuclear antigens (EBNA) were detected in the patient's B lymphocytes. Since reverse transcriptase is the hallmark of retroviruses, we suggest that a retrovirus may be involved in the etiology of osteopetrosis.


[The metal tantalum in orthopedic applications].
This paper describes the biological characteristics of the metal tantalum (Ts) and the application status of tantalum in artificial joints, bone necrosis, spine, defects of bone and other aspects of bone. The early clinical application results of tantalum in bone diseases were satisfactory, but it is necessary to do further study of tantalum in a deep going way, and further detailed comparison between the tantalum with other metals as orthopedics implants. The advantage of tantalum materials as orthopedic implants still needs to be verified by a great deal of clinical cases for a long period of time.


Empowering gene delivery with protein engineering platforms.
The repertoire of therapeutic proteins has been substantially augmented by molecular engineering approaches, which have seen remarkable advancement in recent years. In particular, advances in directed evolution technologies have empowered the development of custom-designed proteins with novel and disease-relevant functions. Whereas engineered proteins have typically been administered through systemic injection of the purified molecule, exciting progress in gene delivery affords the opportunity to elicit sustained production of the engineered proteins by targeted cells in the host organism. Combining developments at the leading edge of protein engineering and gene delivery has catapulted a new wave of molecular and cellular therapy approaches, which harbor great promise for personalized and precision medicine. This mini-review outlines currently used display platforms for protein evolution and describes recent examples of how the resulting engineered proteins have been incorporated into DNA- and cell-based therapeutic platforms, both in vitro and in vivo. Collectively, the strategies detailed herein provide a framework for synthesizing molecular engineering workflows with gene therapy systems for a breadth of applications in research and medicine.


Metoclopramide in the diagnosis of pheochromocytoma.
Cardiovascular and plasma catecholamine responses to metoclopramide (MCP), a dopamine antagonist, were examined in 5 patients with pheochromocytoma, 12 patients with essential hypertension (EHT) and 9 normotensive (NT) subjects who displayed symptoms suggestive of pheochromocytoma on a constant daily intake of 100 mEq sodium and 80 mEq potassium. Significant pressor responses to intravenous doses of 5 mg of MCP, which produced no serious pressor episodes and no other undesirable side effects, were found only in the patients with pheochromocytoma, in contrast to the subjects with EHT and NT who tended to display slight depressor responses. After curative surgery for pheochromocytoma, the MCP-induced pressor effects returned to normal. Furthermore, the enhanced pressor effects of MCP in the patients with pheochromocytoma were associated with increased plasma norepinephrine (NE) concentrations. However, the plasma epinephrine (E) concentrations remained unchanged after the MCP injection. Thus, this dose of MCP appears to be a more suitable vasopressor provocative agent in the pharmacological diagnosis of pheochromocytoma compared to currently used agents.


Thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one substituted with ibuprofen: novel non-steroidal anti-inflammatory agents with favorable gastrointestinal tolerance.
In an effort to establish new candidates with improved analgesic and anti-inflammatory activities and lower ulcerogenic risk, a series of thiazolo[3,2-b]-1,2,4-triazole-5(6H)-one derivatives of ibuprofen were synthesized. All compounds were evaluated for their in vivo anti-inflammatory and analgesic activities in mice. Furthermore, the ulcerogenic risks of the compounds were determined. In general, none of the compounds represent a risk for developing stomach injury as much as observed in the reference drugs ibuprofen and indomethacin. The compounds carrying a 3-phenyl-2-propenylidene (1a), (biphenyl-4-yl)methylidene (1f) and (1-methylpyrrol-2-yl)methylidene (1n) at the 6th position of the fused ring have been evaluated as potential analgesic/anti-inflammatory agents without a gastrointestinal side effect. These new compounds, therefore, deserve further attention to develop new lead drugs.


A New Design Strategy for Efficient Thermally Activated Delayed Fluorescence Organic Emitters: From Twisted to Planar Structures.
In the traditional molecular design of thermally activated delayed fluorescence (TADF) emitters composed of electron-donor and electron-acceptor moieties, achieving a small singlet-triplet energy gap (ΔEST ) in strongly twisted structures usually translates into a small fluorescence oscillator strength, which can significantly decrease the emission quantum yield and limit efficiency in organic light-emitting diode devices. Here, based on the results of quantum-chemical calculations on TADF emitters composed of carbazole donor and 2,4,6-triphenyl-1,3,5-triazine acceptor moieties, a new strategy is proposed for the molecular design of efficient TADF emitters that combine a small ΔEST with a large fluorescence oscillator strength. Since this strategy goes beyond the traditional framework of structurally twisted, charge-transfer type emitters, importantly, it opens the way for coplanar molecules to be efficient TADF emitters. Here, a new emitter, composed of azatriangulene and diphenyltriazine moieties, is theoretically designed, which is coplanar due to intramolecular H-bonding interactions. The synthesis of this hexamethylazatriangulene-triazine (HMAT-TRZ) emitter and its preliminary photophysical characterizations point to HMAT-TRZ as a potential efficient TADF emitter.


Physicochemical effects of the lipid phase and protein level on meat emulsion stability, texture, and microstructure.
The effects of beef fat (25%) substitution with rendered beef fat, canola oil, palm oil, or hydrogenated palm oil at varying meat protein levels (8%, 11%, and 14%) were studied in emulsified beef meat batters. There was no significant difference in fat loss among meat batters made with beef fat, rendered beef fat, or palm oil. Hydrogenated palm oil provided the most stable batters at all protein levels. Increasing meat protein to 14% resulted in high fat loss in batters prepared with canola oil, which did not occur in the other formulations. This indicates that the physicochemical characteristics of fat/oil affect emulsion stability. Cooked batter hardness was higher (P < 0.05) when protein level was raised; highest in hydrogenated palm oil batters when compared at similar protein levels. As protein level was raised springiness values were increased in all the meat treatments. Springiness was higher in the canola oil treatments. Light microscopy revealed fat globule coalescence in canola oil meat batters prepared with 14% protein, as well as the development of fat channels and more protein aggregation; both seem to result in lower emulsion stability. Hydrogenated palm oil batters showed fat particles with sharp edges as opposed to the round ones seen in all other treatments.


Diagnosis of MS: a comparison of three different clinical settings.
In order to compare a newly established diagnostic clinic with two existing clinical settings in the management of the diagnostic phase of multiple sclerosis (MS), a retrospective audit was performed over a 12-month period comparing the length of time, adherence to recently published standards and price charged in diagnosing MS in three different clinical diagnostic settings operating within the same hospital: a specifically designed demyelinating disease diagnostic clinic (DDC), a general neurology clinic (GNC) and an inpatient investigation unit (IIU). An audit tool was created to measure the standards advocated by the UK MS Society on management of the diagnostic phase of MS. The costing tool was the price charged to health authorities. A randomized retrospective case note and referral letter review method was used. The entry criterion was a confirmed diagnosis of MS documented in the medical notes following investigation during the period April 1999-April 2001. The time between referral and first appointment favoured the DDC with a mean time of 5.9 weeks, compared to 7.7 weeks for the GNC and 10.0 weeks for the IIU. The mean times between the first appointment and receipt of results were 4.7 weeks (DDC), 18.8 weeks (GNC) and 21.2 weeks (IIU). Prices ranged from pounds sterling 395-pounds sterling 790 (DDC), pounds sterling 95-pounds sterling 380 (GNC) and pounds sterling 1940-pounds sterling 2700 (IIU). This study suggests that the UK MS Society standards are achievable in most areas without excessive additional costs and provides evidence that the DDC offers a better service than other existing models.


Genetically identical twins show comparable tau PET load and spatial distribution.
Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in (i) tau load; and (ii) spatial distribution of tau, measured with 18F-flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6 years), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic 18F-flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial 18F-flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial 18F-flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in 18F-flortaucipir BPND. On visual inspection, Alzheimer's disease-like 18F-flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. 18F-flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; P = 0.01), neocortical (r = 0.59; P < 0.01) and global (r = 0.56; P < 0.01) regions, but not in the temporal region (r = 0.20; P = 0.10). The 18F-flortaucipir distribution pattern was significantly more similar between twins of the same pair [mean r = 0.27; standard deviation (SD) = 0.09] than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (P < 0.01), also after correcting for proxies of off-target binding. Based on the spatial 18F-flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in 18F-flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37 < β < 0.56), physical activity (-0.41 < β < -0.42) and social activity (-0.32 < β < -0.36) (all P < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies.


Imputation of the rare HOXB13 G84E mutation and cancer risk in a large population-based cohort.
An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show that by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from Kaiser specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37–0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4x10-12). The G84E mutation was also associated with an increase in risk for the fourteen other most common cancers considered collectively (p = 5.8x10-4) and more so in cases diagnosed with multiple cancer types, both those including and not including prostate cancer, strongly suggesting pleiotropic effects. [corrected].


The relative reinforcing value of food predicts weight gain in a longitudinal study of 7--10-y-old children.
The relative reinforcing value (RRV) of food, defined as how hard an individual is prepared to work to gain access to food rather than a nonfood alternative, has been shown to be higher in obese adults and children than in their normal-weight counterparts. However, these cross-sectional studies are unable to determine whether a high RRV of food is predictive of adiposity change or whether it is a consequence of being obese. The objective was to examine the association between the RRV of food and 1-y weight gain in children aged 7-10 y. An observational longitudinal study design was used. The RRV of food was determined by using a questionnaire method at baseline when the children (n = 316) were aged 7-9 y. Adiposity [body mass index (BMI), BMI SD score, fat mass index, waist circumference, and waist circumference SD score] was assessed at baseline and after 1 y. Regression analyses indicated that the RRV of food was not associated with any measure of adiposity at baseline or at the 1-y follow-up (all P > 0.58). Changes in BMI (B = 0.06, P < 0.001), BMI SD score (B = 0.03, P = 0.001), and fat mass index (B = 0.09, P = 0.001) after 1 y were significantly predicted by the RRV of food at baseline. The RRV of food predicted the change in adiposity over a relatively short-term period of 1 y and thus may be associated with the development of obesity. The lack of association in cross-sectional analyses indicates that this behavior is a risk factor for weight gain, although weight differences may not emerge until later childhood.


[Construction and expression of anticolonic cancer scFv fragment].
Anticolonic cancer scFv fragment with a VH-linker-VL structure was constructed and expressed in E. coli. SDS-PAGE analysis showed the fragment cloned in pComb3 was not expressed efficiently in JM83, while cloned in pET-22b(+) highly expressed in BL21(DE3) up to 35.5% of the total bacterial protein obtained, if the culture was incubated under 30 degrees C.


Associations between sleep architecture and sleep-disordered breathing and cognition in older community-dwelling men: the Osteoporotic Fractures in Men Sleep Study.
To examine the association between sleep architecture, sleep-disordered breathing, and cognition in older men. Population-based cross-sectional study. Six clinical sites in the United States. Two thousand nine hundred nine community-dwelling men aged 67 and older who were not selected on the basis of sleep problems or cognitive impairment. Predictors were measured using in-home polysomnography: sleep architecture, nocturnal hypoxemia (any sleep time with arterial oxygen saturation <80%), apnea-hypopnea index (AHI), and arousal index. Cognitive outcomes were measured using the modified Mini-Mental State Examination (3MS), Trail-Making Test Part B (TMT-B), and the Digit Vigilance Test (DVT). Analyses adjusted for age, race, education, body mass index, lifestyle, comorbidities, and medication use showed that participants who spent less percentage of time in rapid eye movement (REM) sleep had lower levels of cognition; participants in the lowest quartile (<14.8%) took an average of 5.9 seconds longer on the TMT-B and 20.1 seconds longer on the DVT than those in the highest quartile (≥23.7%). Similarly, greater percentage of time spent in Stage 1 sleep was related to poorer cognitive function. Participants in the highest quartile of Stage 1 sleep (≥8.6%) had worse cognitive scores on average than those in the lowest quartile (<4.0%). Those with nocturnal hypoxemia took an average of 22.3 seconds longer to complete the DVT than those without, but no associations were found with 3MS or the TMT-B. Spending less percentage of time in REM sleep and greater percentage of time in Stage 1 sleep and having higher levels of nocturnal hypoxemia were associated with poorer cognition in older men. Further studies are needed to clarify the direction of these associations and to explore potential mechanisms.


Lipid Hydrolase Enzymes: Pragmatic Prolongevity Targets for Improved Human Healthspan?
Compelling evidence suggests that lipid metabolism, which plays critical roles in fat storage, cell membrane maintenance, and cell signaling, is intricately linked to aging. Lipid hydrolases are important enzymes that catalyze the hydrolysis of more complex lipids into simpler lipids. Diverse interventions targeting lipid hydrolases can prolong or shorten life in model organisms. For example, the genetic removal of or RNAi knockdown against a phospholipase can reduce lifespan in Caenorhabditis elegans, Drosophila melanogaster, and Mus musculus. The removal of lysosomal acid lipase results in premature death in mice, while its overexpression in nematodes generates lean, long-lived individuals. The overexpression or inhibition of diacylglycerol lipase leads to enhanced or reduced longevity, respectively, in both worms and flies. Lifespan can also be extended by knocking down triacylglycerol lipases in yeast, overexpressing fatty acid amide hydrolase in worms, or removing hepatic lipase in a mouse model of coronary disease. Conversely, flies lacking the triacylglycerol lipase Brummer are obese and short lived. Linking sphingolipids and aging, removing the sphingomyelinase inositol phosphosphingolipid phospholipase shortens chronological lifespan in Saccharomyces cerevisiae, while inhibiting an acid sphingomyelinase in worms or inactivating alkaline ceramidase in flies extends lifespan. The clinical potential of manipulating these enzymes is highlighted by the FDA-approved obesity drug orlistat, which is an inhibitor of pancreatic and hepatic lipases that induces weight loss and improves insulin/glucose homeostasis. Additional research is warranted to better understand how these lipid hydrolases impact aging and to determine if clinical interventions targeting them are capable of improving human healthspan.


Immunologic characterization of a rhesus macaque H1N1 challenge model for candidate influenza virus vaccine assessment.
Despite the availability of annually formulated vaccines, influenza virus infection remains a worldwide public health burden. Therefore, it is important to develop preclinical challenge models that enable the evaluation of vaccine candidates while elucidating mechanisms of protection. Here, we report that naive rhesus macaques challenged with 2009 pandemic H1N1 (pH1N1) influenza virus do not develop observable clinical symptoms of disease but develop a subclinical biphasic fever on days 1 and 5 to 6 postchallenge. Whole blood microarray analysis further revealed that interferon activity was associated with fever. We then tested whether type I interferon activity in the blood is a correlate of vaccine efficacy. The animals immunized with candidate vaccines carrying hemagglutinin (HA) or nucleoprotein (NP) exhibited significantly reduced interferon activity on days 5 to 6 postchallenge. Supported by cellular and serological data, we conclude that blood interferon activity is a prominent marker that provides a convenient metric of influenza virus vaccine efficacy in the subclinical rhesus macaque model.


Glycogen phosphorylase, glucose output and vasoconstriction in the perfused rat liver. Concentration-dependence of actions of adrenaline, vasopressin and angiotensin II.
1. Glycogen phosphorylase (a form, in rapidly freeze-clamped samples) and glucose release were measured in the perfused liver, in response to a range of concentrations of adrenaline, [8-arginine]vasopressin (anti-diuretic hormone) and angiotensin II. 2. All three hormones increased phosphorylase a activity by about 10 mumol/min per g of fresh liver, which was more than sufficient to explain concomitant glucose release (1-2mumol/min per g). 3. Minimally effective concentrations which activated phosphorylase were: adrenaline, 10nM (2ng/ml); vasopressin, 40pM (40pg/ml, 15 muunits/ml); angiotensin II, 60pM (60pg/ml). 4. Glycogen synthase activity was inhibited by adrenaline and vasopressin but not significantly by angiotensin II. 5. Vasoconstriction observed with adrenaline and angiotensin II (but not vasopressin) might explain part of the activation of phosphorylase, since equivalent vasoconstriction (in separate perfusions) activated phosphorylase, did not stimulate glucose output or inhibit synthase. 6. The potency of these effects suggests that all three hormones can stimulate hepatic glycogen degradation in vivo (by direct hepatic action). It is proposed that hormones, and ischaemia, stimulate glycogen degradation to provide glucose phosphates for disposal within the liver cell, as well as for release as free gluose.


Construction and characterisation of a series of multi-copy promoter-probe plasmid vectors for Streptomyces using the aminoglycoside phosphotransferase gene from Tn5 as indicator.
Several versatile, multi-copy, promoter-probe plasmid vectors have been constructed that replicate in a wide range of Streptomyces species. Transcriptional activity is detected by the expression of a promoter-less aminoglycoside phosphotransferase gene (neo) derived from the transposon Tn5; expression of this gene confers kanamycin and neomycin resistance on Streptomyces lividans. An efficient transcriptional terminator from E. coli phage fd has been inserted upstream of the neo coding region to prevent significant transcriptional read-through from vector promoters. A translational stop codon situated downstream from the site(s) used for cloning and preceding and in frame with the ATG start codon of the neo gene ensures the detection of transcriptional, rather than translational, fusions. Relative promoter strengths can be determined by gradient plate assays of kanamycin resistance, by measuring the amount of aminoglycoside phosphotransferase produced or by estimating neo mRNA synthesised. The high copy number of the vectors facilitates the rapid isolation and characterisation of promoter-active fragments and convenient restriction sites are available for DNA sequencing and S1 mapping of cloned inserts. Some derivatives contain a polylinker that facilitates the insertion, excision and analysis of cloned fragments and which enhances the use of these plasmids as general cloning vectors.


Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies.
To summarise the evidence regarding the dose-response association between alcohol consumption and risk of rheumatoid arthritis (RA). Studies were identified from search of MEDLINE, Embase and Web of Science databases between 1 January 1946 and 10 April 2013, and from review of the conference abstracts and the reference lists of retrieved articles. Prospective studies that reported relative risks (RRs) with 95% CIs for the association between alcohol consumption and the risk of RA were included. Results from individual studies were pooled using a dose-response meta-analysis. Up to 10 April 2013, 8 prospective studies contained 195 029 participants and 1878 RA cases were included. The results indicated that low to moderate alcohol consumption yielded a preventive effect on RA development (RR: 0.86; 95% CI 0.78 to 0.94), and provided some evidence of a non-linear relationship between alcohol consumption and risk of RA. Dose-response meta-analysis of the study data revealed that compared with that for no alcohol consumption, the adjusted RR was 0.93 (95% CI 0.88 to 0.98) for 3 g/day of alcohol consumption, 0.86 (95% CI 0.76 to 0.97) for 9 g/day, 0.88 (95% CI 0.78 to 0.99) for 12 g/day, 0.91 (95% CI 0.81 to 1.03) for 15 g/day, and 1.28 (95% CI 0.94 to 1.73) for 30 g/day. Subgroup analysis indicated that women who had low to moderate alcohol consumption had a 19% reduction in RA risk. Regardless of sex, a consistent low to moderate alcohol consumption for a period of at least 10 years was found to have a 17% reduction in RA risk. Low to moderate alcohol consumption inversely associated with the development of RA in a manner that appears to be dose-dependent, time-dependent and sex-dependent. Large prospective studies that investigate gene-environment interactions are required to further clarify the aetiology of RA.


What the courts need to know about mental health diagnoses of abused women.
Abused women may appear before the courts because of family or criminal matters. It is not uncommon for an abused woman to be diagnosed as having a mental health condition, including a mental disorder. In this paper, we consider the implications of the use of mental health diagnoses in the court system. We discuss the diagnostic criteria in the DSM-IV and ICD-10 classification systems and examine what other information is needed by the courts to interpret the behaviour and thought processes of abused women. This other information includes: whether the abuse is continuing and the likely impact of its continuance, diagnosis and prognosis, as well as the woman's survival strategies, her coping mechanisms, her support systems, and the severity of the physical and/or psychological abuse. This information needs to be stated within the context of what we currently know about abuse, including up-to-date knowledge about its epidemiology (e.g., prevalence, physical and psychological manifestations, and complex psychological responses). Information about other intervening factors is essential for the courts; and in order to present meaningful testimony on these factors, it is critical for clinicians to have a thorough understanding of the complex dynamics of spousal abuse.


Benign paroxysmal positional vertigo is a common cause of dizziness and unsteadiness in a large population of 75-year-olds.
Studies have shown that 65% of people with dizziness may have a vestibular etiologic diagnosis, possibly benign paroxysmal positional vertigo (BPPV). The diagnosis of BPPV is based on medical history and findings after the Dix-Hallpike test. It is sometimes difficult to perform the Dix-Hallpike test in elderly persons, due to the limited range of motion when extending the neck. In this study, we used a side-lying test to stimulate the posterior semicircular canal, while the head and neck were fully supported on the examination table. The aims of this study were to investigate the prevalence of dizziness and/or impaired balance and BPPV in a population of 75-year-olds by means of a questionnaire and clinical tests, and to compare elderly persons with and without BPPV. A representative population sample of 675 persons completed a questionnaire about dizziness and 571 persons underwent side-lying, static balance and dynamic walking tests. Subjective dizziness and/or impaired balance were found in 36% of subjects, especially when walking outdoors. A significant gender difference was found, with a higher prevalence in women (40%) compared with men (30%) (p<0.01). BPPV was found in 11% and was significantly more common in women (p<0.01). Elderly individuals with BPPV also displayed significantly impaired balance in static and dynamic balance tests compared with persons without BPPV (p<0.01). Persons with BPPV reported significantly more sub- jective problems with dizziness and balance compared with persons without BPPV (p<0.001). Subjective and objective unsteadiness, dizziness and BP- PV are common in the elderly.


Multiomics Sequencing and AlphaFold2 Analysis of the Stereoselective Behavior of Mefentrifluconazole for Bioactivity Improvement and Risk Reduction.
As the first isopropanol chiral triazole fungicide, mefentrifluconazole has broad prospects for application. In this study, the stereoselective stability, bioactivity, fate, and biotoxicity were systematically investigated. Our results indicated that the stability of mefentrifluconazole enantiomers differed between environmental media, and they were stable in water and sediment in the dark. The bactericidal activity of R-mefentrifluconazole against the four target pathogens was 4.6-43 times higher than that of S-mefentrifluconazole. In the water-sediment system, S-mefentrifluconazole dissipated faster than R-mefentrifluconazole in water; however, its accumulation capacity was higher than that of R-mefentrifluconazole in sediment and zebrafish. S-Mefentrifluconazole induced more differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) in zebrafish than did R-mefentrifluconazole. Multiomics sequencing results showed that S-mefentrifluconazole enhanced the antioxidant, detoxification, immune, and metabolic functions of zebrafish by interacting with related proteins. Based on AlphaFold2 modeling and molecular docking, mefentrifluconazole enantiomers had different binding modes with key target proteins in pathogens and zebrafish, which may be the main reason for the stereoselective differences in bioactivity and biotoxicity. Based on its excellent bioactivity and low biotoxicity, the R-enantiomer can be developed to improve the bioactivity and reduce the risk of mefentrifluconazole.


The metabolism of 14C-cibenzoline in dogs and rats.
The disposition of the new antiarrhythmic agent cibenzoline (CBZ) (racemic 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole) in three male dogs was investigated after oral administration of 13.8 mg/kg of 14C-CBZ base. Within 6 days, 60.5 +/- 6.0% of the dose was excreted in urine and 19.2 +/- 4.6% in feces. In 0-24-hr urine, unchanged drug was excreted (41.6% of the dose) as well as the unconjugated 4,5-dehydro metabolite (DHCBZ, 3.7%), conjugated p-hydroxybenzophenone (0.8%, only in one dog), and a phenolic metabolite, p-hydroxycibenzoline (HCBZ) in a rearranged form (RHCBZ) at 5.2% of the dose (free plus conjugated). Studies with synthetic HCBZ indicated that unrearranged HCBZ was excreted and that rearrangement occurred during purification. CBZ from dog urine displayed slight optical activity, based on ORD/CD data, corresponding to an optical purity of 15% of the S-(-)-CBZ, indicating a limited extent of stereoselective metabolism of CBZ in dogs. After an oral 50-mg/kg dose of 14C-CBZ succinate, male rats excreted in 3 days 27.0 +/- 2.8% in urine and 41.5 +/- 2.6% of the dose in feces, and in a repeated experiment 32.1 +/- 1.9% in urine and 54.5 +/- 0.7% in feces. CBZ (7.6%) and DHCBZ (0.2%) were determined in 0-24-hr urine, and CBZ (4.2%) and RHCBZ (4.2% of the dose) were determined in 0-24-hr feces. RHCBZ (3.1%), m-methoxy p-hydroxycibenzoline (8.3%), and p-hydroxybenzophenone (5.3% of the dose) were identified as glucuronide/sulfate conjugates in bile from rats. Evidence that p-hydroxybenzophenone arose from an unstable unidentified metabolite is discussed.


Swimming performance of delta smelt: maximum performance, and behavioral and kinematic limitations on swimming at submaximal velocities.
Swimming performance, measured as critical swimming velocity (Ucrit) and endurance, and swimming behavior and kinematics were measured in delta smelt Hypomesus transpacificus, a threatened estuarine planktivore. Most fish (58 % of the Ucrit test group) were capable of achieving and sustaining moderately high velocities: mean Ucrit was 27.6±5.1 cm s-1 (s.d.). Ucrit was not affected by either acclimation temperature (1221 °C) or fish size (3.26.8 cm standard length) and was generally comparable with values measured for other similarly sized fishes. The remaining 42 % of the fish failed to swim at velocities above 1015 cm s-1. Interestingly, of the fish that provided a Ucrit measurement, 62 % experienced at least one temporary swimming failure between 10 and 20 cm s-1. Endurance was highly variable and, for all velocities, not normally distributed; the only significant decrease, from 6 h to 64 min, occurred between 10 and 15 cm s-1. Kinematic analyses of stroke frequency, stroke amplitude, stride length, glide frequency, glide duration, proportion of time spent stroking and the number of strokes between successive glides showed that delta smelt employed three velocity-dependent swimming gaits: a discontinuous 'stroke-and-glide' swimming behavior below 10 cm s-1; a continuous swimming behavior above 15 cm s-1 and up to Ucrit; and a discontinuous 'burst-and-glide' swimming behavior at velocities above Ucrit. Swimming failure at velocities between 10 and 20 cm s-1 coincided with the transition from 'stroke-and-glide' swimming to continuous swimming; delta smelt were unable or unwilling to swim steadily in the flume within this transition velocity range. These results underscore the importance of monitoring and quantifying behavior in experiments intended as physiological performance tests of whole animals.


Medication assessments by care managers reveal potential safety issues in homebound older adults.
Over-the-counter (OTC) medications, benzodiazepines, and barbiturates are not covered under many Medicare drug benefit plans; hence, their use by homebound older adults is largely unreported. Furthermore, the tiered design of Medicare drug formularies may in fact promote the use of older but potentially inappropriate medications. Little is known about the use of these medications in the homebound older adult population. To determine the prevalence of the use by homebound older adults of OTC drugs, dietary supplements (vitamins, minerals, and herbal products), Part D-excluded medications (benzodiazepines and barbiturates), and potentially inappropriate medications (according to Beers criteria). Patients were enrollees in a home and community-based Medicaid waiver provider. All clients were older than 65 and were dually eligible for Medicare and Medicaid. All clients met Florida Medicaid's medical and financial criteria for nursing home placement. The medication list was obtained by geriatric care managers during a home assessment. A total of 3911 older adults (mean [SD] age 83.6 [8.0] years) were taking an average of 9.9 [4.8] drugs. Of these individuals, 74.5% were using an OTC medication, 41.9% were using a dietary supplement, 29.6% were using a benzodiazepine or barbiturate, and 25.2% were using at least 1 potentially inappropriate medication. Based on data gathered by a geriatric care management assessment, we found that most of the homebound older adults enrolled in our study used medications not included in their Medicare drug benefit. The use of potentially inappropriate medications was also common in this population. Future drug safety initiatives involving the elderly will benefit from engaging care managers in identifying and addressing the potential hazards posed by commonly used prescribed and nonprescribed medications.


New insights into the dihydro-mureidomycin biosynthesis controlled by two unusual proteins in Streptomyces roseosporus.
Uridyl peptide compounds are renowned as a subclass of nucleoside antibiotics for their highly specific antibacterial activity against Gram-negative bacteria and the unique target of action. We previously activated the biosynthetic gene cluster of a uridyl peptide antibiotic, mureidomycin, in Streptomyces roseosporus NRRL 15998 by introducing an exogenous positive regulator gene ssaA, and the generated strain was designated as Sr-hA. This study aims to further explore mureidomycin analogs from Sr-hA as well as the collaborative roles of two wide-spread genes, SSGG-02980 and SSGG-03002 encoding putative nuclease/phosphatase and oxidoreductase respectively, in mureidomycin diversification. In order to understand how SSGG-02980 and SSGG-03002 contribute to mureidomycin biosynthesis, the gene disruption mutants and complementary strains were constructed. Mass spectrometry analyses revealed that two series of pairwise mureidomycin analogs were synthesized in Sr-hA with a two-dalton difference in molecular weight for each pair. By disruption of SSGG-03002, only mureidomycins with lower molecular weight (MRDs, 1-6) could be specifically accumulated in the mutant (∆03002-hA), whereas the other series of products with molecular weight plus 2 Da (rMRDs, 1'-6') became dominant in SSGG-02980 disruption mutant (∆02980-hA). Further comprehensive NMR analyses were performed to elucidate the structures, and three MRDs (3, 4, 5) with unsaturated double bond at C5-C6 of uracil group were characterized from ∆03002-hA. In contrast, the paired rMRDs analogs (3', 4', 5') from ∆SSGG-02980 corresponding to 3, 4 and 5 were shown to contain a single bond at this position. The results verified that SSGG-03002 participates in the reduction of uracil ring, whereas SSGG-02980 antagonizes the effect of SSGG-03002, which has been rarely recognized for a phosphatase. Overall, this study revealed the key roles of two wide-spread families of enzymes in Streptomyces. Of them, oxidoreductase, SSGG-03002, is involved in dihydro-mureidomycin biosynthesis of S. roseosporus, whereas nuclease/phosphatase, SSGG-02980, has an adverse effect on SSGG-03002. This kind of unusual regulation model between nuclease/phosphatase and oxidoreductase is unprecedented, providing new insights into the biosynthesis of mureidomycins in Streptomyces. The findings would be of significance for structural diversification of more uridyl peptide antibiotics against Gram-negative bacteria.


Acceleration and plateau: two patterns and outcomes of isolated severe fetal cerebral ventricular dilation.
We sought to characterize patterns of in utero dilation in isolated severe fetal ventriculomegaly (ISVM) and investigate their value in predicting obstetrical and postnatal outcomes. This is a retrospective cohort study. ISVM was defined as a sonographic cerebral ventricle atrial with width ≥15 mm in the absence of additional cerebral or other anatomic anomalies. The aim of this study was to characterize two ISVM groups using a receiver operator curve to evaluate the rate of ventricular progression versus need for ventriculoperitoneal (VP) shunt postnatally. Outcomes were compared between the groups using Pearson's chi-squared test, Student t-test, and descriptive statistics. Based on the ROC analysis, ventricular growth of ≥3 mm/week versus <3 mm/week distinguished fetuses likely to require a postnatal VP shunt. Fetuses were characterized as accelerators if ventricle growth was ≥3 mm/week at any point and plateaus if <3 mm/week. Accelerators showed a greater average rate of ventricle progression than plateaus (4.1 vs. 1.0 mm/week, respectively, p = .031) and were more likely to be delivered at earlier gestational ages (34.7 vs. 37.1 weeks respectively, p = .02). Ninety percent of accelerators demonstrated a need for shunt placement compared with 18.8% of plateaus (p < .001). Significantly more plateaus (87.5%) underwent a trial of labor while accelerators were more likely to have planned cesareans (70%, p = .009). This study characterizes ISVM into two distinct populations based upon the rate of ventricle expansion, differentiated by the need for postnatal shunting. Once a ventricular growth pattern is determined, these distinctions should prove useful in prenatal management and delivery planning.


Thymic atrophy induced by Plasmodium berghei ANKA and Plasmodium yoelii 17XL infection.
The thymus is the anatomical site where T cells undergo a complex process of differentiation, proliferation, selection, and elimination of autorreactive cells which involves molecular signals in different intrathymic environment. However, the immunological functions of the thymus can be compromised upon exposure to different infections, affecting thymocyte populations. In this work, we investigated the impact of malaria parasites on the thymus by using C57BL/6 mice infected with Plasmodium berghei ANKA and Plasmodium yoelii 17XL; these lethal infection models represent the most severe complications, cerebral malaria, and anemia respectively. Data showed a reduction in the thymic weight and cellularity involving different T cell maturation stages, mainly CD4-CD8- and CD4+CD8+ thymocytes, as well as an increased presence of apoptotic cells, leading to significant thymic cortex reduction. Thymus atrophy showed no association with elevated serum cytokines levels, although increased glucocorticoid levels did. The severity of thymic damage in both models reached the same extend although it occurs at different stages of infection, showing that thymic atrophy does not depend on parasitemia level but on the specific host-parasite interaction.


[Characteristics of microcirculatory changes in various forms of rheumatoid arthritis in children].
Using the method of biomicroscopy of bulbar conjunctiva with application of vessel gaging the authors made observation of 125 patients: 110--with RA and 15--with reactive arthritis. Marked vascular and intravascular changes in combination with dilatation of the capacitive vessels and narrowing of the resistive ones in vasculo-visceral form of RA correlated with the increase of immunological indices of the blood. In patients with vascular form of RA less marked changes of the vessels in dilatation of the capacitive part correlated with immunological indices of the synovial fluid.


Database for exploration of functional context of genes implicated in ovarian cancer.
Ovarian cancer (OC) is becoming the most common gynecological cancer in developed countries and the most lethal gynecological malignancy. It is also the fifth leading cause of all cancer-related deaths in women. The identification of diagnostic biomarkers and development of early detection techniques for OC largely depends on the understanding of the complex functionality and regulation of genes involved in this disease. Unfortunately, information about these OC genes is scattered throughout the literature and various databases making extraction of relevant functional information a complex task. To reduce this problem, we have developed a database dedicated to OC genes to support exploration of functional characterization and analysis of biological processes related to OC. The database contains general information about OC genes, enriched with the results of transcription regulation sequence analysis and with relevant text mining to provide insights into associations of the OC genes with other genes, metabolites, pathways and nuclear proteins. Overall, it enables exploration of relevant information for OC genes from multiple angles, making it a unique resource for OC and will serve as a useful complement to the existing public resources for those interested in OC genetics. Access is free for academic and non-profit users and database can be accessed at http://apps.sanbi.ac.za/ddoc/.


Neonatal examination and screening trial (NEST): a randomised, controlled, switchback trial of alternative policies for low risk infants.
To evaluate the effectiveness of one rather than two hospital neonatal examinations in detection of abnormalities. Randomised controlled switchback trial. Postnatal wards in a teaching hospital in north east Scotland. All infants delivered at the hospital between March 1993 and February 1995. A policy of one neonatal screening examination compared with a policy of two. Congenital conditions diagnosed in hospital; results of community health assessments at 8 weeks and 8 months; outpatient referrals; inpatient admissions; use of general practioner services; focused analysis of outcomes for suspected hip and heart abnormalities. 4835 babies were allocated to receive one screening examination (one screen policy) and 4877 to receive two (two screen policy). More congenital conditions were suspected at discharge among babies examined twice (9.9 v 8.3 diagnoses per 100 babies; 95% confidence interval for difference 0.3 to 2.7). There was no overall significant difference between the groups in use of community, outpatient, or inpatient resources or in health care received. Although more babies who were examined twice attended orthopaedic outpatient clinics (340 (7%) v 289 (6%)), particularly for suspected congenital dislocation of the hip (176 (3.6/100 babies) v 137 (2.8/100 babies); difference -0.8; -1.5 to 0.1), there was no significant difference in the number of babies who required active management (12 (0.2%) v 15 (0.3%)). Despite more suspected abnormalities, there was no evidence of net health gain from a policy of two hospital neonatal examinations. Adoption of a single examination policy would save resources both during the postnatal hospital stay and through fewer outpatient consultations.


Trends in preventive activities for the adult population in family medicine in Croatia: 1995-2012.
A few preventive activities were recorded in Croatian family medicine (FM) from 1995 until 2003, and then in 2004, additional fee-for-service reimbursement for general check-ups for people aged 45 to 65 years was introduced. The aim of this study was to investigate the trends in preventive activities before and after the introduction of those measures by using the Croatian Health Service Yearbooks for 1995-2012 as the main database. Data on the number of preventive, general, and total number of check-ups were collected. The results showed that the total number of check-ups registered in FM was low, suggesting that the additional reimbursement did not bring any improvements. In fact, the trend in the number decreased after 2004. These results are not unexpected because of the ineffectiveness of general check-ups as indicated in the literature. General check-ups should be replaced by targeted preventive interventions with evidence-based effectiveness.


Thiamine deficiency in infancy: long-term follow-up.
In 2003, several hundred Israeli infants risked thiamine deficiency after being fed a soy-based formula deficient in thiamine. Approximately 20 patients were seriously affected, and three of them died. We report the clinical presentation of acute encephalopathy in 11 children and the long-term sequelae of eight children who initially survived. In the acute phase, six had bulbar signs, five had ophthalmologic signs and two had phrenic neuropathy. Three of the five patients with cardiac involvement had cardiomyopathy and died in the acute phase. One patient presented with a complete atrioventricular block. In the long-term, one patient, who was in a chronic vegetative state, died after 6 years. Seven children exhibited mental retardation and motor abnormalities, six developed severe epilepsy, two early kyphoscoliosis, and one patient remained with a complete atrioventricular block. Infants who survive severe infantile thiamine deficiency have serious residual motor and cognitive sequelae as well as epilepsy.


Archaeological soybean (Glycine max) in East Asia: does size matter?
The recently acquired archaeological record for soybean from Japan, China and Korea is shedding light on the context in which this important economic plant became associated with people and was domesticated. This paper examines archaeological (charred) soybean seed size variation to determine what insight can be gained from a comprehensive comparison of 949 specimens from 22 sites. Seed length alone appears to represent seed size change through time, although the length × width × thickness product has the potential to provide better size change resolution. A widespread early association of small seeded soybean is as old as 9000-8600 cal BP in northern China and 7000 cal BP in Japan. Direct AMS radiocarbon dates on charred soybean seeds indicate selection resulted in large seed sizes in Japan by 5000 cal BP (Middle Jomon) and in Korea by 3000 cal BP (Early Mumun). Soybean seeds recovered in China from the Shang through Han periods are similar in length to the large Korean and Japanese specimens, but the overall size of the large Middle and Late Jomon, Early Mumun through Three Kingdom seeds is significantly larger than any of the Chinese specimens. The archaeological record appears to disconfirm the hypothesis of a single domestication of soybean and supports the view informed by recent phyologenetic research that soybean was domesticated in several locations in East Asia.


Ida Mann--her wartime career, 1939-1949.
Ida Mann's wartime accomplishments were most remarkable. Besides her Harley Street practice and her senior appointment at Moorfields (The Royal London Ophthalmic Hospital), she prevented its closure to ophthalmic patients and chaired the Hospital Management Committee; she investigated the pathology of mustard gas keratitis and formed a Chemical Defence Research Team to study ocular effects of warfare chemicals; she was appointed Margaret Ogilvie Reader in Ophthalmology and senior surgeon to the Oxford Eye Hospital; she established the Nuffield Research Laboratory and was awarded a personal professorship, the first in ophthalmology in Britain, the first professorship given to a woman and the only one in ophthalmology by the University of Oxford. Late in the war she married a cancer research pathologist in whose laboratory she cultured a malignant tumour of the lens. Furthermore, she produced a vast number of outstanding research papers, most notably the authoritative monograph on chemical injury to the anterior segment of the eye.


Effects of K(ATP) channel openers, P-1075, pinacidil, and diazoxide, on energetics and contractile function in isolated rat hearts.
We investigated the metabolic effects of a potent opener of ATP-sensitive K(+) (K(ATP)) channels, P-1075, in perfused rat hearts with the help of(31)P NMR spectroscopy. A 20 min infusion of 5 microm P-1075 depleted phosphocreatine and ATP by approximately 40%, concomitantly with a two-fold increase in inorganic phosphate, while oxygen consumption by the hearts increased by 50%. P-1075 induced a cardiac contracture (left ventricular end diastolic pressure increased from 6 to 60 mmHg) and a cardiac arrest after an infusion of approximately 9 min. The effects were fully reversed by glibenclamide (5 microm), but not by sodium 5-hydroxydecanoate (0.4 m m). A P-1075-related K(ATP) opener, pinacidil (0.3 m m), partially reversed the effects of P-1075, but a structurally unrelated opener, diazoxide (0.5 m m), had no effect. Pinacidil and diazoxide alone did not significantly affect PCr and ATP levels. Bioenergetic and functional effects similar to those of P-1075 were induced by infusion of a classic mitochondrial uncoupler, 2,4-dinitrophenol (50 microm); however, they were not abolished by glibenclamide. In addition, it was shown, using(87)Rb NMR, that both agents, P-1075 and 2,4-dinitrophenol, resulted in a stimulation of Rb(+) efflux from the Rb(+) loaded rat hearts by approximately 130 and 65%, respectively, in a glibenclamide-sensitive manner. An inhibitory effect of P-1075 on ATP synthesis cannot be explained by its well-known action on sarcolemmal K(ATP) channels. We concluded that, unlike an uncoupling effect of 2,4-dinitrophenol, an inhibitory effect of P-1075 is produced by uncoupling of oxidative phosphorylation through the activation of mitochondrial K(ATP) channels.


Is a rising cesarean delivery rate inevitable? Trends in industrialized countries, 1987 to 2007.
Cesarean delivery rates have been rising rapidly in many countries in the last decade. The objective of this research is to examine cesarean rates in industrialized countries and assess patterns in the trends toward increasing rates. We examined cesarean delivery rates per 1,000 live births from 1987 to 2007 in 22 industrialized countries. To enhance comparability, the inclusion criteria were at least 50,000 births annually and a per capita gross domestic product of at least U.S.$10,000 in 2007. Poisson regression was selected to model the cesarean delivery rates of countries across time. We examined overall cesarean delivery rates, absolute changes in these rates, and changes in trend lines for cesarean rates for the period from 1987 to 2007. In 2007, 11 of the 21 countries reported overall cesarean rates of more than 25 percent, led by Italy (39%), Portugal (35%), the United States (32%), and Switzerland (32%). Five countries, the Slovak Republic, Czech Republic, Ireland, Austria, and Hungary more than doubled their cesarean delivery rate between 1992 and 2007. Comparing changes in rates across time periods, 14 countries experienced a greater increase in rates in the period between 1998 and 2002 compared with the period between 1993 and 1997. Comparing trends from 2003-2007 to 1998-2002, eighteen countries experienced a slowing down of rate increases across these two periods. Although cesarean delivery rates continue to rise, the rate of increase appears to be slowing down in most industrialized countries.


A New Series of Strigolactone Analogs Derived From Cinnamic Acids as Germination Inducers for Root Parasitic Plants.
Root parasitic plants such as Striga and Orobanche cause significant damage on crop production, particularly in sub-Saharan Africa. Their seeds germinate by sensing host root-derived signaling molecules called strigolactones (SLs). SL mimics can be used as suicidal germination inducers for root parasitic plants. Previous attempts to develop such chemicals have revealed that the methylbutenolide ring (D-ring), a common substructure in all the naturally occurring SLs, is critical for SL agonistic activity, suggesting that it should be possible to generate new SL mimics simply by coupling a D-ring with another molecule. Because structural information regarding SLs and their receptor interaction is still limited, such an approach might be an effective strategy to develop new potent SL agonists. Here, we report development of a series of new SL analogs derived from cinnamic acid (CA), the basis of a class of phenylpropanoid natural products that occur widely in plants. CA has an aromatic ring and a double-bond side-chain structure, which are advantageous for preparing structurally diverse derivatives. We prepared SL analogs from cis and trans configuration CA, and found that all the cis-CA-derived SL analogs had stronger activities as seed germination inducers for the root parasitic plants, Orobanche minor and Striga hermonthica, compared with the corresponding trans-CA-derived analogs. Moreover, introduction of a substitution at the C-4 position increased the germination-stimulating activity. We also found that the SL analogs derived from cis-CA were able to interact directly with SL receptor proteins more effectively than the analogs derived from trans-CA. The cis isomer of CA was previously reported to have a growth promoting effect on non-parasitic plants such as Arabidopsis. We found that SL analogs derived from cis-CA also showed growth promoting activity toward Arabidopsis, suggesting that these new SL agonists might be useful not only as suicidal germination inducers for root parasitic weeds, but also as plant growth promoters for the host plants.


Chromosomal evolution in large pelagic oceanic apex predators, the barracudas (Sphyraenidae, Percomorpha).
Sphyraena (barracudas) represents the only genus of the Sphyraenidae family and includes 27 species distributed into the tropical and subtropical oceanic regions. These pelagic predators can reach large sizes and, thus, attracting significant interest from commercial and sport fishing. Evolutionary data for this fish group, as well its chromosomal patterns, are very incipient. In the present study, the species Sphyraena guachancho, S. barracuda, and S. picudilla were analyzed under conventional (Giemsa staining, C-banding, and Ag-NOR) and molecular (CMA3 banding, and in situ hybridization with 18S rDNA, 5S rDNA, and telomeric probes) cytogenetic methods. The karyotypic patterns contrast with the current phylogenetic relationships proposed for this group, showing by themselves to be distinct among closely related species, and similar among less related ones. This indicates homoplasic characteristics, with similar karyotype patterns originating at least twice, independently. Although still cytogenetically poor investigated, our data were enough to put in evidence a variety of ancient conserved traits and evolutionary novelties for the Sphyraena genus. In this sense, it is fundamental that a larger number of Sphyraenidae species, as well as of other phylogenetically related families, be also investigated. This will solidify the knowledge of their karyotypic patterns, and the evolutionary path followed by the species of this particular fish family.


Writing about life goals: effects on rumination, mood and the cortisol awakening response.
Rumination is a vulnerability factor for the onset and maintenance of emotional distress. This study examined whether writing about life goals is associated with a decrease in ruminative thinking and a reduced cortisol awakening response. 68 healthy participants either wrote about their personal life goals or a control topic. Writing about life goals was associated with a modest decrease in ruminative thinking and a reduced cortisol awakening response at the post-intervention assessment. Results provide initial evidence that writing about life goals can be a helpful aid in decreasing rumination and physiological stress reactivity.


Mexican American Parents' Involvement in Adolescents' Peer Relationships: Exploring the Role of Culture and Adolescents' Peer Experiences.
This study examined the nature and correlates of Mexican American mothers' and fathers' involvement in adolescents' peer relationships along four dimensions: support, restriction, knowledge, and time spent with adolescents and peers. Mexican American adolescents and their parents in 220 families described their family relationships, cultural orientations/values, and experiences with adolescents' peers in home interviews. In addition, time-use data were collected during a series of seven phone calls to measure parents' time spent with adolescents and peers and parents' knowledge of adolescents' daily experiences with peers. Multi-level models revealed connections between parents' involvement in adolescents' peer relationships and both parents' Mexican and Anglo orientations and familism values and adolescents' peer experiences (e.g., deviant peer affiliations, friends' ethnic orientation). Findings further revealed some evidence that parent and adolescent gender moderated the patterns, with mothers' (but not fathers') restrictions on peer relationships being associated with adolescents' deviant peer affiliations and parents placing greater restrictions on daughters' than on sons' peer relationships when they had more frequent deviant peer affiliations.


What have we learned about chronic kidney disease-mineral bone disorder from the EVOLVE and PRIMO trials?
The treatment of chronic kidney disease-mineral bone disorder (CKD-MBD) has traditionally focused on improvement in biochemical parameters of the disease. However, studies evaluating hard clinical end points or surrogate end points are limited. Two randomized controlled trials have recently been published. In the EVOLVE study (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events), cinacalcet was compared with placebo in 3883 haemodialysis patients with secondary hyperparathyroidism. The primary end point (death, myocardial infarction, unstable angina, heart failure or peripheral vascular disease) in an unadjusted intention-to-treat analysis was not significant [hazard ratio 0.93; 95% confidence interval (CI) 0.85-1.02, P=0.11]. However, the pre-specified secondary end points of an adjusted intention-to-treat analysis (hazard ratio 0.88; 95% CI 0.79-0.97, P=0.008) were significant. In the PRIMO (Paricalcitol Capsule Benefits in Renal Failure Induced Cardiac Morbidity) trial, 227 patients with CKD stage 3-4 and left ventricular hypertrophy by echocardiography were randomized to paricalcitol or placebo. The primary end point of change in left ventricular mass index by MRI after 12 months was not different between the two groups, but the prespecified end point of cardiovascular-related hospitalizations was reduced in the paricalcitol-treated group (P=0.04). The results of these two randomized controlled trials have negative primary end points but significant secondary end points and thus require physicians to individualize therapies for the treatment of secondary hyperparathyroidism.