Evaluating the effectiveness of occupational therapy faculty development workshops.
The purpose of this study was to evaluate, from the participants' perspective, the effectiveness over time of 10 occupational therapy faculty development workshops conducted between 1994 and 1998. Surveys were mailed to 179 occupational therapy faculty participants to gather demographic data and perceptions of the following aspects of the workshops: benefits over time of the instructional content, changes made in current teaching practices, progress as a faculty member, and future needs for faculty development. The response rate was 63% (n = 106). The majority (72%) of respondents had less than 5 years of teaching experience. Respondents were women in their early 40s with approximately 12 years of clinical experience and a master's degree. Respondents perceived the most effective aspect of the faculty development workshops as the opportunity to participate in a face-to-face environment in which they observed the skills of a master teacher demonstrating instructional principles. Further, respondents reported that the greatest changes in their current teaching practices occurred in their ability to design, implement, and evaluate a course of instruction, thus increasing their perceptions of progress as a faculty member. The 10 faculty development workshops conducted between 1994 and 1998 were judged effective by occupational therapy faculty members who perceived that their participation resulted in benefits over time to their current teaching practices.


Implementing an mHealth system for substance use disorders in primary care: a mixed methods study of clinicians' initial expectations and first year experiences.
Millions of Americans need but don't receive treatment for substance use, and evidence suggests that addiction-focused interventions on smart phones could support their recovery. There is little research on implementation of addiction-related interventions in primary care, particularly in Federally Qualified Health Centers (FQHCs) that provide primary care to underserved populations. We used mixed methods to examine three FQHCs' implementation of Seva, a smart-phone app that offers patients online support/discussion, health-tracking, and tools for coping with cravings, and offers clinicians information about patients' health tracking and relapses. We examined (a) clinicians' initial perspectives about implementing Seva, and (b) the first year of implementation at Site 1. Prior to staggered implementation at three FQHCs (Midwest city in WI vs. rural town in MT vs. metropolitan NY), interviews, meetings, and focus groups were conducted with 53 clinicians to identify core themes of initial expectations about implementation. One year into implementation at Site 1, clinicians there were re-interviewed. Their reports were supplemented by quantitative data on clinician and patient use of Seva. Clinicians anticipated that Seva could help patients and make behavioral health appointments more efficient, but they were skeptical that physicians would engage with Seva (given high caseloads), and they were uncertain whether patients would use Seva. They were concerned about legal obligations for monitoring patients' interactions online, including possible "cries for help" or inappropriate interactions. One year later at Site 1, behavioral health care providers, rather than physicians, had incorporated Seva into patient care, primarily by discussing it during appointments. Given workflow/load concerns, only a few key clinicians monitored health tracking/relapses and prompted outreach when needed; two researchers monitored the discussion board and alerted the clinic as needed. Clinician turnover/leave complicated this approach. Contrary to clinicians' initial concerns, patients showed sustained, mutually supportive use of Seva, with few instances of misuse. Results suggest the value of (a) focusing implementation on behavioral health care providers rather than physicians, (b) assigning a few individuals (not necessarily clinicians) to monitor health tracking, relapses, and the discussion board, (c) anticipating turnover/leave and having designated replacements. Patients showed sustained, positive use of Seva. ClinicalTrials.gov ( NCT01963234 ).


A double-blind placebo-controlled study to evaluate the effect of progestelle progesterone cream on postmenopausal women.
To evaluate the effect on climacteric symptoms and quality of life, and the safety of four doses of progestelle progesterone cream administered for 24 weeks to postmenopausal women complaining of moderate to severe menopausal symptoms. Design Single-centre, double-blind, randomized, placebo-controlled study. Population Two hundred and twenty-three healthy postmenopausal women, aged between 40 and 60 years and complaining of severe menopausal symptoms were recruited through newspaper advertisements. Women were randomly allocated to progestelle progesterone cream 60, 40, 20, 5 mg or placebo, to be applied daily for six months. Main outcome measures The primary efficacy variable was the psychological, somatic and vasomotor components of the Greene Climacteric Scale after six months. Secondary endpoints were incidence of hot flushes and night sweats, the nine subscales of the Medical Outcome Survey Short Form-36 (SF-36), serum progesterone, endometrial thickness and histology after six months. Adverse events were sought and recorded and followed up to resolution. There were no statistically significant differences between any of the treatment groups and placebo for any of the components of the Greene Score. A statistically significant difference between the 20 mg group and placebo was found for the physical functioning (95% confidence interval [CI] 1.7-12.3; P=0.01) and social functioning (95% CI 1.9-16.7; P=0.01) scales of SF-36 after six months. No other statistically significant differences were found between any treatment group and placebo for any of the other secondary efficacy variables. There appeared to be a higher incidence of headache in the groups treated with progesterone cream. Progesterone cream was no more effective than placebo for relief of menopausal symptoms.


Ethical Discourse of Medical Students on the Phenomenon of Death: A Qualitative Study.
The aim of this study is to discover medical students' ideas on the phenomenon of death; produce information on how these students interpret the value-related problems regarding death that they come across in different units of hospitals; and assess this data in ethical terms. This study included a qualitative research in which 12 focus group interviews were conducted with 92 fifth- and sixth-year medical students. Data obtained from interviews were assessed using a thematic content secondary analysis. The main themes were specified according to the medical students' statements and were reviewed under the contexts of the "dying process"; "effects of death"; "attitude and behavior of health professionals"; "seeing a dead body/looking at a dead body"; "accepting death"; and "forms of expressions of death." Medical students' encounters with death in different units of hospitals leads them to question their values and familiarize themselves with the borders of their areas of profession.


Selection, Analysis and Improvement of Anti-Angiogenesis Compounds Identified by an Anti-HIF-1α Screening and Validation System.
Cancer cells resort to activating hypoxia-inducible factor-1 (HIF-1) as one of several responses to hypoxic conditions. Overexpression of HIF-1, the transcriptional regulator for a group of malignant-pathway related genes including vascular endothelial growth factor (VEGF), is associated with increased tumor growth, vascularization, and metastasis. HIF-1 is composed of an inducible subunit, HIF-1α and a constitutively expressed subunit, HIF-1ß. HIF-1 activity is mainly dependent on the level of HIF-1α protein, the inducible and regulatory subunit of the HIF-1 heterodimer complex; thus, identification of novel anti-HIF-1α agents will lead to effective blockage of the HIF-1 (HIF-1α)-mediated "switch-on" function for those malignant-pathway related genes and suppression of the HIF-1α/VEGF-mediated signaling pathway that promotes cancer progression and metastasis. While there is an extremely large number of small molecule compounds in the database (compound libraries), the currently existing screening system is inefficient and time-consuming; or, at best, the application of the existing screening system is very limited as it is usually not coupled with biological validation processes. The further development of potential drugs is partly hindered due to the cumbersome steps in between the primary screen and consequent validation: the slow, exhausted and sometimes lack of a linked biological validation process contributes to the dismal fate of scant compounds uncovered in the primary screen. To improve upon the status quo, we developed a prototype screening system that is coupled anti-HIF-1α primary screen with secondary anti-VEGF/anti-angiogenesis validation screens. We used breast cancer cells as the model to select potent anti-HIF-1α small-molecule compounds by their abilities to inhibit transactivation of a VEGF promoter fused to a luciferase reporter gene under hypoxia. Positive compounds were then validated by a series of assays that confirm compounds' anti-HIF-1α activities including measurement of their effects on HIF-1α downstream VEGF gene expression and angiogenic ability of breast cancer cells. Moreover, we demonstrated that we could further improve the compound's potency of anti-HIF-1α and anti-angiogenesis by modifying the identified lead to synthesize a superior (novel) drug.


Statistical modelling of transcript profiles of differentially regulated genes.
The vast quantities of gene expression profiling data produced in microarray studies, and the more precise quantitative PCR, are often not statistically analysed to their full potential. Previous studies have summarised gene expression profiles using simple descriptive statistics, basic analysis of variance (ANOVA) and the clustering of genes based on simple models fitted to their expression profiles over time. We report the novel application of statistical non-linear regression modelling techniques to describe the shapes of expression profiles for the fungus Agaricus bisporus, quantified by PCR, and for E. coli and Rattus norvegicus, using microarray technology. The use of parametric non-linear regression models provides a more precise description of expression profiles, reducing the "noise" of the raw data to produce a clear "signal" given by the fitted curve, and describing each profile with a small number of biologically interpretable parameters. This approach then allows the direct comparison and clustering of the shapes of response patterns between genes and potentially enables a greater exploration and interpretation of the biological processes driving gene expression. Quantitative reverse transcriptase PCR-derived time-course data of genes were modelled. "Split-line" or "broken-stick" regression identified the initial time of gene up-regulation, enabling the classification of genes into those with primary and secondary responses. Five-day profiles were modelled using the biologically-oriented, critical exponential curve, y(t) = A + (B + Ct)Rt + epsilon. This non-linear regression approach allowed the expression patterns for different genes to be compared in terms of curve shape, time of maximal transcript level and the decline and asymptotic response levels. Three distinct regulatory patterns were identified for the five genes studied. Applying the regression modelling approach to microarray-derived time course data allowed 11% of the Escherichia coli features to be fitted by an exponential function, and 25% of the Rattus norvegicus features could be described by the critical exponential model, all with statistical significance of p < 0.05. The statistical non-linear regression approaches presented in this study provide detailed biologically oriented descriptions of individual gene expression profiles, using biologically variable data to generate a set of defining parameters. These approaches have application to the modelling and greater interpretation of profiles obtained across a wide range of platforms, such as microarrays. Through careful choice of appropriate model forms, such statistical regression approaches allow an improved comparison of gene expression profiles, and may provide an approach for the greater understanding of common regulatory mechanisms between genes.


The combination of endoscopic sphincterotomy and percutaneous abscess drainage in the management of complicated biliary pancreatitis.
We report four patients with a protracted history of acute pancreatitis complicated by infected pseudocysts or abscesses. Ultrasonography showed that each patient had cholelithiasis. Endoscopic biliary sphincterotomy was performed resulting in the release of stones, gravel, or pus in all four cases. Three of the patients had successful percutaneous abscess drainage, and one patient was drained surgically. The abscesses all resolved, but one patient died suddenly of acute pulmonary embolism. The other three patients are well. We recommend this combined approach to pancreatic abscess drainage because, if there is obstruction to the flow of pancreatic juice at the ampulla of Vater, it is likely that the pancreatitis and abscess will fail to resolve.


Cyclometallation of arylimines and nitrogen-containing heterocycles via room-temperature C-H bond activation with arene ruthenium(II) acetate complexes.
The reaction of [RuCl(2)(p-cymene)](2) with arylimines and 4 equiv. of KOAc in methanol at room temperature produces stable (N^C)-cyclometallated ruthenium(II) complexes via C-H bond activation/deprotonation. This method can be applied also to nitrogen-containing molecules: N-phenylpyrazole, 2-phenyl-2-oxazoline and benzo[h]quinoline. N-Phenyl-pyrazole, [RuCl(2)(p-cymene)](2) and diphenylacetylene directly lead to alkyne insertion into the metallacycle C-Ru bond.


Recognition of decay accelerating factor and alpha(v)beta(3) by inactivated hantaviruses: Toward the development of high-throughput screening flow cytometry assays.
Hantaviruses cause two severe diseases in humans: hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS). The lack of vaccines or specific drugs to prevent or treat HFRS and HCPS and the requirement for conducting experiments in a biosafety level 3 laboratory (BSL-3) limit the ability to probe the mechanism of infection and disease pathogenesis. In this study, we developed a generalizable spectroscopic assay to quantify saturable fluorophore sites solubilized in envelope membranes of Sin Nombre virus (SNV) particles. We then used flow cytometry and live cell confocal fluorescence microscopy imaging to show that ultraviolet (UV)-killed SNV particles bind to the cognate receptors of live virions, namely, decay accelerating factor (DAF/CD55) expressed on Tanoue B cells and alpha(v)beta(3) integrins expressed on Vero E6 cells. SNV binding to DAF is multivalent and of high affinity (K(d) approximately 26pM). Self-exchange competition binding assays between fluorescently labeled SNV and unlabeled SNV are used to evaluate an infectious unit-to-particle ratio of approximately 1:14,000. We configured the assay for measuring the binding of fluorescently labeled SNV to Tanoue B suspension cells using a high-throughput flow cytometer. In this way, we established a proof-of-principle high-throughput screening (HTS) assay for binding inhibition. This is a first step toward developing HTS format assays for small molecule inhibitors of viral-cell interactions as well as dissecting the mechanism of infection in a BSL-2 environment.


Retinol Dehydrogenase-10 Regulates Pancreas Organogenesis and Endocrine Cell Differentiation via Paracrine Retinoic Acid Signaling.
Vitamin A-derived retinoic acid (RA) signals are critical for the development of several organs, including the pancreas. However, the tissue-specific control of RA synthesis in organ and cell lineage development has only poorly been addressed in vivo. Here, we show that retinol dehydrogenase-10 (Rdh10), a key enzyme in embryonic RA production, has important functions in pancreas organogenesis and endocrine cell differentiation. Rdh10 was expressed in the developing pancreas epithelium and surrounding mesenchyme. Rdh10 null mutant mouse embryos exhibited dorsal pancreas agenesis and a hypoplastic ventral pancreas with retarded tubulogenesis and branching. Conditional disruption of Rdh10 from the endoderm caused increased mortality, reduced body weight, and lowered blood glucose levels after birth. Endodermal Rdh10 deficiency led to a smaller dorsal pancreas with a reduced density of early glucagon+ and insulin+ cells. During the secondary transition, the reduction of Neurogenin3+ endocrine progenitors in the mutant dorsal pancreas accounted for fewer α- and β-cells. Changes in the expression of α- and β-cell-specific transcription factors indicated that Rdh10 might also participate in the terminal differentiation of endocrine cells. Together, our results highlight the importance of both mesenchymal and epithelial Rdh10 for pancreogenesis and the first wave of endocrine cell differentiation. We further propose a model in which the Rdh10-expressing exocrine tissue acts as an essential source of RA signals in the second wave of endocrine cell differentiation.


Levodopa/carbidopa microtablets in Parkinson's disease: a study of pharmacokinetics and blinded motor assessment.
Motor function assessments with rating scales in relation to the pharmacokinetics of levodopa may increase the understanding of how to individualize and fine-tune treatments. This study aimed to investigate the pharmacokinetic profiles of levodopa-carbidopa and the motor function following a single-dose microtablet administration in Parkinson's disease. This was a single-center, open-label, single-dose study in 19 patients experiencing motor fluctuations. Patients received 150% of their individual levodopa equivalent morning dose in levodopa-carbidopa microtablets. Blood samples were collected at pre-specified time points. Patients were video recorded and motor function was assessed with six UPDRS part III motor items, dyskinesia score, and the treatment response scale (TRS), rated by three blinded movement disorder specialists. AUC0-4/dose and C max/dose for levodopa was found to be higher in Parkinson's disease patients compared with healthy subjects from a previous study, (p = 0.0008 and p = 0.026, respectively). The mean time to maximum improvement in sum of six UPDRS items score was 78 min (±59) (n = 16), and the mean time to TRS score maximum effect was 54 min (±51) (n = 15). Mean time to onset of dyskinesia was 41 min (±38) (n = 13). In the PD population, following levodopa/carbidopa microtablet administration in fasting state, the Cmax and AUC0-4/dose were found to be higher compared with results from a previous study in young, healthy subjects. A large between subject variability in response and duration of effect was observed, highlighting the importance of a continuous and individual assessment of motor function in order to optimize treatment effect.


Predictors of adherence to diabetes medications: the role of disease and medication beliefs.
Despite the effectiveness of drug therapy in diabetes management high rates of poor adherence persist. The purpose of this study was to identify potentially modifiable patient disease and medication beliefs associated with poor medication adherence among people with diabetes. A cohort of patients with diabetes was recruited from an urban primary-care clinic in New York City. Patients were interviewed in English or Spanish about: disease beliefs, medication beliefs, regimen complexity, diabetes knowledge, depression, self-efficacy, and medication adherence (Morisky scale). Logistic regression was used to identify multivariate predictors of poor medication adherence (Morisky > 1). Patients (n = 151) had diabetes for an average of 13 years with a mean HgA1C of 7.6 (SD 1.7). One-in-four (28%) were poor adherers to their diabetes medicines. In multivariate analyses, predictors of poor medication adherence were: believing you have diabetes only when your sugar is high (OR = 7.4;2-27.2), saying there was no need to take medicine when the glucose was normal (OR = 3.5;0.9-13.7), worrying about side-effects of diabetes medicines (OR = 3.3;1.3-8.7), lack of self-confidence in controlling diabetes (OR = 2.8;1.1-7.1), and feeling medicines are hard to take (OR = 14.0;4.4-44.6). Disease and medication beliefs inconsistent with a chronic disease model of diabetes were significant predictors of poor medication adherence. These suboptimal beliefs are potentially modifiable and are logical targets for educational interventions to improve diabetes self-management.


Enhanced removal of Hg(II) from acidic aqueous solution using thiol-functionalized biomass.
Spent grain, the low-cost and abundant biomass produced in the brewing industry, was functionalized with thiol groups to be used as an adsorbent for Hg(II) removal from acidic aqueous solution. The adsorbents were characterized by the energy-dispersive X-ray analysis (EDAX) and Fourier transform infrared (FTIR) spectroscopy. Optimum pH for Hg(II) adsorption onto the thiol-functionalized spent grain (TFSG) was 2.0. The equilibrium and kinetics of the adsorption of Hg(II) onto TFSG from acidic aqueous solution were investigated. From the Langmuir isotherm model the maximum adsorption capacity of TFSG for Hg(II) was found to be 221.73 mg g(-1), which was higher than that of most various adsorbents reported in literature. Moreover, the adsorption of Hg(II) onto TFSG followed pseudo-second-order kinetic model.


Small molecules and targeted therapies in distant metastatic disease.
Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.


Management of patients at very high risk of osteoporotic fractures through sequential treatments.
Osteoporosis care has evolved markedly over the last 50 years, such that there are now an established clinical definition, validated methods of fracture risk assessment and a range of effective pharmacological agents. Currently, bone-forming (anabolic) agents, in many countries, are used in those patients who have continued to lose bone mineral density (BMD), patients with multiple subsequent fractures or those who have fractured despite treatment with antiresorptive agents. However, head-to-head data suggest that anabolic agents have greater rapidity and efficacy for fracture risk reduction than do antiresorptive therapies. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) convened an expert working group to discuss the tools available to identify patients at high risk of fracture, review the evidence for the use of anabolic agents as the initial intervention in patients at highest risk of fracture and consider the sequence of therapy following their use. This position paper sets out the findings of the group and the consequent recommendations. The key conclusion is that the current evidence base supports an "anabolic first" approach in patients found to be at very high risk of fracture, followed by maintenance therapy using an antiresorptive agent, and with the subsequent need for antiosteoporosis therapy addressed over a lifetime horizon.


REACT study protocol: resilience after the COVID-19 threat (REACT) in adolescents.
COVID-19-related social isolation and stress may have significant mental health effects, including post-traumatic stress, anxiety and depression. These factors are thought to disproportionately affect populations at risk of psychopathology, such as adolescents with a history of childhood adversity (CA). Therefore, examining which factors may buffer the impact of COVID-19-related stress and isolation in vulnerable adolescents is critical. The Resilience After the COVID-19 Threat (REACT) study assesses whether emotion regulation capacity, inflammation and neuroimmune responses to stress induced in the laboratory prior to the pandemic predict responses to COVID-19-related social isolation and stress in adolescents with CA. We aim to elucidate the mechanisms that enable vulnerable adolescents to maintain or regain good mental health when confronted with COVID-19. We recruited 79 adolescents aged 16-26 with CA experiences from the Resilience After Individual Stress Exposure study in which we assessed emotion regulation, neural and immune stress responses to an acute stress task. Our sample completed questionnaires at the start of the UK lockdown ('baseline'; April 2020) and three (July 2020) and 6 months later (October 2020) providing crucial longitudinal information across phases of the pandemic progression and government response. The questionnaires assess (1) mental health, (2) number and severity of life events, (3) physical health, (4) stress perception and (5) loneliness and friendship support. We will use multilevel modelling to examine whether individual differences at baseline are associated with responses to COVID-19-related social isolation and stress. This study has been approved by the Cambridge Psychology Research Ethics Committee (PRE.2020.037). Results of the REACT study will be disseminated in publications in scientific peer-reviewed journals, presentations at scientific conferences and meetings, publications and presentations for the general public, and through social media.


Atlantoaxial transarticular screw fixation: a review of surgical indications, fusion rate, complications, and lessons learned in 67 pediatric patients.
In this, the second of two articles regarding C1-2 transarticular screw fixation, the authors discuss their surgical experience in treating patients 16 years of age and younger, detailing the rate of fusion, complication avoidance, and lessons learned in the pediatric population. The authors retrospectively reviewed 67 consecutive patients (23 girls and 44 boys) younger than 16 years of age in whom at least one C1-2 transarticular screw fixation procedure was performed. A total of 127 transarticular screws were placed in these 67 patients whose mean age at time of surgery was 9 years (range 1.7-16 years). The indications for surgery were trauma in 24 patients, os odontoideum in 22 patients, and congenital anomaly in 17 patients. Forty-four patients underwent atlantoaxial fusion and 23 patients underwent occipitocervical fusion. Two of the 67 patients underwent halo therapy postoperatively. All patients were followed for a minimum of 3 months. In all 67 patients successful fusion was achieved. Complications occurred in seven patients (10.4%), including two vertebral artery injuries. The use of C1-2 transarticular screw fixation, combined with appropriate atlantoaxial and craniovertebral bone/graft constructs, resulted in a 100% fusion rate in a large consecutive series of pediatric patients. The risks of C1-2 transarticular screw fixation can be minimized in this population by undertaking careful patient selection and meticulous preoperative planning.


A tutorial on pilot studies: the what, why and how.
Pilot studies for phase III trials - which are comparative randomized trials designed to provide preliminary evidence on the clinical efficacy of a drug or intervention - are routinely performed in many clinical areas. Also commonly know as "feasibility" or "vanguard" studies, they are designed to assess the safety of treatment or interventions; to assess recruitment potential; to assess the feasibility of international collaboration or coordination for multicentre trials; to increase clinical experience with the study medication or intervention for the phase III trials. They are the best way to assess feasibility of a large, expensive full-scale study, and in fact are an almost essential pre-requisite. Conducting a pilot prior to the main study can enhance the likelihood of success of the main study and potentially help to avoid doomed main studies. The objective of this paper is to provide a detailed examination of the key aspects of pilot studies for phase III trials including: 1) the general reasons for conducting a pilot study; 2) the relationships between pilot studies, proof-of-concept studies, and adaptive designs; 3) the challenges of and misconceptions about pilot studies; 4) the criteria for evaluating the success of a pilot study; 5) frequently asked questions about pilot studies; 7) some ethical aspects related to pilot studies; and 8) some suggestions on how to report the results of pilot investigations using the CONSORT format.


Malaria parasites and red blood cells: from anaemia to transmission.
Malaria parasites, Plasmodium spp., invade and exploit red blood cells during their asexual expansion within the vertebrate host. The parasite has evolved a suite of adaptive mechanisms enabling optimal exploitation of the host blood cell environment, avoiding host destruction, maintaining a parasite reservoir of infection and producing sexual transmission stages to infect mosquitoes. The highly variable nature of the host blood environment, both over the course of an infection and as a result of other parasitic infections, has selected for the evolution of considerable phenotypic plasticity in the parasite's response to its environment, particularly those phenotypes concerning transmission of the parasite to mosquitoes. With the evolution of human society, human malaria disease is becoming an increasingly urban problem. This imposes different selection pressures on the parasite. The extent to which the parasite is truly plastic over the short term rather than adaptive over the long term will determine the urban epidemiology of malaria and is essential for developing appropriate control methods. Understanding the adaptive nature of malaria parasites is thus vital for anticipating the future visage of urban human malaria.


Early childhood undernutrition, preadolescent physical growth, and cognitive achievement in India: A population-based cohort study.
There is a lack of nationally representative estimates for the consequences of early childhood undernutrition on preadolescent outcomes in India. Understanding this relationship is helpful to develop interventions that not only prevent child undernutrition but also mitigate its consequences. In this cohort study, we analyzed prospectively gathered data from 2 waves of the India Human Development Survey (IHDS) to investigate the association of undernutrition during early childhood (0 to 5 years) in 2004 to 2005 with physical and cognitive outcomes during preadolescent (8 to 11 years) years in 2011 to 2012. These surveys interviewed 41,554 households across all 33 states and union territories in India in 2004 to 2005 and reinterviewed 83% of the households in 2011 to 2012. Primary exposure was assessed using the Composite Index of Anthropometric Failure (CIAF) based on 2004 to 2005 survey. Primary outcomes were short stature (height-for-age z-score [HAZ] <-2), thinness (body mass index [BMI] <18.5 kg/m2), reading, and arithmetic skills during preadolescence based on the 2011 to 2012 survey. Survey-weighted generalized linear models were used, and effect modification based on child sex and sociodemographic variables were evaluated using 3-way interaction terms. Of the 7,868 children included in this analysis, 4,334 (57.3%) were undernourished. Being undernourished was associated with increased odds of short stature (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.45 to 2.06) and thinness (OR 1.52, 95% CI 1.33 to 1.73) during the preadolescent period, while it was associated with decreased odds of achieving a higher reading (cumulative odds ratio [cumOR]: 0.76, 0.66 to 0.87) and arithmetic (cumOR: 0.72, 0.63 to 0.82) outcomes. The disparity in outcomes based on CIAF increased with age, especially for female children. Increased level of female education within the household reduced the disadvantages of undernutrition among female children. Study limitations include observational and missing data, which limit our ability to draw strong causal inferences. In this study, we found that early child undernutrition was associated with several adverse preadolescent physical and cognitive outcomes, especially among female children. Improved female education mitigates this association. Female education promotion should assume a central role in Indian public health policy making.


Construction of copper chains with new fluorescent guanidino-functionalized naphthyridine ligands.
The three new blue-fluorescent ligands 2,7-bis(tetramethylguanidino)-1,8-naphthyridine (1), 2,7-bis(N,N'-dimethylethylene-guanidino)-1,8-naphthyridine (2) and 2,7-bis(N,N'-diisopropylguanidino)-1,8-naphthyridine (3) are synthesized, and their optical properties (electronic absorption and emission spectroscopy) studied. Reactions of 1 or 2 with [Cu(CH3CN)4]BF4 yield the Cu4 chain compounds [Cu4(1)2](BF4)4 (that crystallizes as [Cu4(1)2(CH3CN)2](BF4)4·2CH2Cl2) and [Cu4(2)2](BF4)4. The variations of the optical properties upon coordination are evaluated, and the electronic transitions identified by time-dependent DFT (TD-DFT) calculations. Then the redox properties of the new Cu4 chain complexes are studied. In the course of these experiments, the new Cu6 complex [Cu4(1)2(CuCl2)2]2+, in which two CuCl2- units coordinate to the Cu4 chain in [Cu4(1)2]4+, was fully characterized. In addition, the Cu3 chain complexes [Cu3(1)3]3+ and [Cu3(1)2]3+ were isolated as products of redox-induced degradation processes. Finally, we show by quantum chemical calculations that in [M4(1)2]4+ complexes (M = coinage metal), the HOMO changes from a ligand-centered to a metal-centered orbital for replacement of M = Cu by Au.


Agonists of the TRAIL Death Receptor DR5 Sensitize Intestinal Stem Cells to Chemotherapy-Induced Cell Death and Trigger Gastrointestinal Toxicity.
The combination of TRAIL death receptor agonists and radiochemotherapy to treat advanced cancers continues to be investigated in clinical trials. We previously showed that normal cells with a functional DNA damage response (DDR) upregulate the expression of death-inducing receptor DR5/TRAILR2/TNFRSF10B in a p53-dependent manner that sensitizes them to treatment with DR5 agonists. However, it is unclear if targeting DR5 selectively sensitizes cancer cells to agonist treatment following exposure to DNA-damaging chemotherapy, and to what extent normal tissues are targeted. Here, we show that the combined administration of the DR5 agonistic monoclonal antibody (mAb) and chemotherapy to wild-type mice triggered synergistic gastrointestinal toxicities (GIT) that were associated with the death of Lgr5(+) crypt base columnar stem cells in a p53- and DR5-dependent manner. Furthermore, we confirmed that normal human epithelial cells treated with the human DR5-agonistic mAb and chemotherapeutic agents were also greatly sensitized to cell death. Interestingly, our data also indicated that genetic or pharmacologic targeting of Chk2 may counteract GIT without negatively affecting the antitumor responses of combined DR5 agonist/chemotherapy treatment, further linking the DDR to TRAIL death receptor signaling in normal cells. In conclusion, the combination of DR5-targeting agonistic mAbs with DNA damaging chemotherapy may pose a risk of developing toxicity-induced conditions, and the effects of mAb-based strategies on the dose-limiting toxicity of chemotherapy must be considered when establishing new combination therapies.


What proportion of chronic obstructive pulmonary disease outpatients is eligible for inclusion in randomized clinical trials?
We aimed to explore to what extent an unselected population of chronic obstructive pulmonary disease (COPD) outpatients would be eligible for inclusion in randomized clinical trials (RCTs). Retrospective analysis of the clinical records of outpatient subjects with an ascertained diagnosis of COPD. COPD outpatients were assessed against the following inclusion criteria: 40 < age < 80 years, current or former smokers, forced expiratory volume in the first second (FEV1) <70% predicted, no long-term oxygen therapy, no other concomitant lung diseases and absence of major extrapulmonary comorbidities. The study consisted of 2 phases; in phase 1, the criteria for inclusion in RCTs on COPD were selected, and in phase 2, the above criteria were applied to an unselected outpatient COPD population. A total of 578 subjects (83% of the whole group) failed at least one of the inclusion criteria. Lung diseases other than COPD (occurring in 30% of our population, mostly bronchiectasis), long-term oxygen therapy (31%), FEV1 (19%), age (14%) and extrapulmonary comorbidities such as cognitive impairment (14%), arrhythmias (17%) and congestive heart disease (13%) would have been the most frequent causes for exclusion from RCTs. In real-life settings, more than 80% of COPD subjects are currently treated by protocols based on results of RCTs for which they would not have been eligible. We encourage a more extensive use of pragmatic trials in COPD to better modulate the application of results of RCTs to patients encountered in daily practice.


A CK2-dependent mechanism for degradation of the PML tumor suppressor.
The PML tumor suppressor controls key pathways for growth suppression, induction of apoptosis, and cellular senescence. PML loss occurs frequently in human tumors through unknown posttranslational mechanisms. Casein kinase 2 (CK2) is oncogenic and frequently upregulated in human tumors. Here we show that CK2 regulates PML protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at Ser517. Consequently, PML mutants that are resistant to CK2 phosphorylation display increased tumor-suppressive functions. In a faithful mouse model of lung cancer, we demonstrate that Pml inactivation leads to increased tumorigenesis. Furthermore, CK2 pharmacological inhibition enhances the PML tumor-suppressive property in vivo. Importantly, we found an inverse correlation between CK2 kinase activity and PML protein levels in human lung cancer-derived cell lines and primary specimens. These data identify a key posttranslational mechanism that controls PML protein levels and provide therapeutic means toward PML restoration through CK2 inhibition.


Unmet Needs of People With Parkinson's Disease and Their Caregivers During COVID-19-Related Confinement: An Explorative Secondary Data Analysis.
Self-perceived unmet needs in people with typical and atypical parkinsonism (PwP) and their caregivers, support network, personalized ways to address self-perceived unmet needs during confinement, as well as the prevalence of self-reported COVID-19 related symptoms, confirmed SARS-CoV-2 infection, and self-reported COVID-19 related hospitalization in Luxembourg and the Greater Region were assessed. From 18th March to 10th April 2020, 679 PwP were contacted by phone. Data was collected in the form of a semi-structured interview. The thematic synthesis identified 25 themes where PwP need to be supported in order to cope with consequences of the pandemic, and to adapt their daily and health-related activities. The present work highlights that in the context of personalized medicine, depending on the individual needs of support of the patient the identified self-perceived unmet needs were addressed in various ways ranging from one-directed information over interaction up to proactive counseling and monitoring. Family and health professionals, but also other support systems were taking care of the unmet needs of PwP (e.g., shopping, picking-up medication, etc.) during the pandemic. 7/606 PwP (1.15%) reported COVID-19 related symptoms, 4/606 (0.66%) underwent a rRT-PCR-based diagnostic test and 2/606 (0.33%) were confirmed as SARS-CoV-2 positive. None of these PwP reported being hospitalized due to COVID-19. Our results will allow health professionals to expand their services in a meaningful way i.e., personalize their support in the identified themes and thus improve the healthcare of PwP in times of crisis.


Simultaneous Expression of ABCA4 and GPR143 Mutations: A Complex Phenotypic Manifestation.
To describe the complex, overlapping phenotype expressed in a two generation family harboring pathogenic mutations in the ABCA4 and GPR143 genes. Clinical evaluation of a two generation family included quantitative autofluorescence imaging (qAF, 488-nm excitation) using a modified confocal scanning laser ophthalmoscope equipped with an internal fluorescent reference to account for varying laser power detector sensitivity, spectral-domain optical coherence tomography, and full-field ERG testing. Complete sequencing of the ABCA4 and GPR143 genes was carried out in each individual. Affected individuals presented with bull's eye lesions and qAF levels above the 95% confidence interval for healthy eyes; full-field ERG revealed no generalized rod dysfunction but mild implicit time delays in cone responses. Complete sequencing of the ABCA4 gene revealed two disease-causing mutations, p.L541P and p.G1961E; and mutational phase was confirmed in each unaffected parent. Further examination in the affected patients revealed a peripheral "mud-splattered" pattern of hypopigmented RPE after which sequencing of GPR143 revealed a novel missense variant, p.Y157C. The GPR143 variant segregated from the father who did not exhibit any indications of retinal disease with the exception of an abnormal near-infrared autofluorescence (NIR-AF) signal distribution in the macula. An individual carrying both ABCA4 and GPR143 disease-causing mutations can express a complex, overlapping phenotype associated with both Stargardt disease and X-linked ocular albinism (OA1). The absence of OA1-related disease changes (with the exception of NIR-AF changes associated with melanin distribution) in the father may be indicative of mild expressivity or variable gene penetrance.


Ivermectin, antiviral properties and COVID-19: a possible new mechanism of action.
Ivermectin is an antiparasitic drug that has shown also an effective pharmacological activity towards various infective agents, including viruses. This paper proposes an alternative mechanism of action for this drug that makes it capable of having an antiviral action, also against the novel coronavirus, in addition to the processes already reported in literature.


Antagonistic natural and sexual selection on wing shape in a scrambling damselfly.
Wings are a key trait underlying the evolutionary success of birds, bats, and insects. For over a century, researchers have studied the form and function of wings to understand the determinants of flight performance. However, to understand the evolution of flight, we must comprehend not only how morphology affects performance, but also how morphology and performance affect fitness. Natural and sexual selection can either reinforce or oppose each other, but their role in flight evolution remains poorly understood. Here, we show that wing shape is under antagonistic selection with regard to sexual and natural selection in a scrambling damselfly. In a field setting, natural selection (survival) favored individuals with long and slender forewings and short and broad hindwings. In contrast, sexual selection (mating success) favored individuals with short and broad forewings and narrow-based hindwings. Both types of selection favored individuals of intermediate size. These results suggest that individuals face a trade-off between flight energetics and maneuverability and demonstrate how natural and sexual selection can operate in similar directions for some wing traits, that is, wing size, but antagonistically for others, that is, wing shape. Furthermore, they highlight the need to study flight evolution within the context of species' mating systems and mating behaviors.


Drinking Water in the United States: Implications of Water Safety, Access, and Consumption.
Recent water quality crises in the United States, and recognition of the health importance of drinking water in lieu of sugar-sweetened beverages, have raised interest in water safety, access, and consumption. This review uses a socioecological lens to examine these topics across the life course. We review water intakes in the United States relative to requirements, including variation by age and race/ethnicity. We describe US regulations that seek to ensure that drinking water is safe to consume for most Americans and discuss strategies to reduce drinking water exposure to lead, a high-profile regulated drinking water contaminant. We discuss programs, policies, and environmental interventions that foster effective drinking water access, a concept that encompasses key elements needed to improve water intake. We conclude with recommendations for research, policies, regulations, and practices needed to ensure optimal water intake by all in the United States and elsewhere.


Mammary gland density predicts the cancer inhibitory activity of the N-3 to N-6 ratio of dietary fat.
This study investigated the effect of a broad range of dietary ratios of n-3:n-6 fatty acids on mammary gland density and mammary cancer risk. Cancer was induced in female rats by N-methyl-N-nitrosourea. Purified diet that provided 30% of dietary kilocalories from fat was formulated to contain ratios of n-3:n-6 fatty acids from 25:1 to 1:25. Mammary gland density was determined by digital analysis, fatty acids by gas chromatography/flame ionization detection, and other plasma analytes via ELISA. Mammary gland density was reduced dose dependently at n-3:n-6 ratios from 1:1 to 25:1 (r = -0.477, P = 0.038), with a 20.3% decrease of mammary gland density between n-3:n-6 of 1:1 versus 25:1, P < 0.001. Mammary carcinogenesis was inhibited in the absence or presence of tamoxifen (1 mg/kg diet) in a manner predicted by mammary gland density. Plasma n-3 fatty acid concentrations failed to increase above an n-3:n-6 ratio of 5:1, and changes in specific plasma n-3 or n-6 fatty acids were not predictive of mammary gland density or cancer inhibitory activity. A strong reciprocal effect of the n-3:n-6 ratio on plasma leptin (decreased, P = 0.005) and adiponectin (increased, P < 0.001) was observed indicating adipose tissue function was modulated. However, neither cytokine was predictive of mammary gland density. Plasma insulin-like growth factor I (IGF-I) decreased with increasing dietary n-3:n-6 ratio (P = 0.004) and was predictive of the changes in mammary gland density (r = 0.362, P < 0.005). These findings indicate that (i) mammary gland density predicted the carcinogenic response, (ii) the n-3:n-6 ratio exerts effects in the presence or absence of hormonal regulation of carcinogenesis, and (iii) signaling pathways regulated by IGF-I are potential targets for further mechanistic investigation.


Predictions as a window into learning: Anticipatory fixation offsets carry more information about environmental statistics than reactive stimulus-responses.
A core question underlying neurobiological and computational models of behavior is how individuals learn environmental statistics and use them to make predictions. Most investigations of this issue have relied on reactive paradigms, in which inferences about predictive processes are derived by modeling responses to stimuli that vary in likelihood. Here we deployed a novel anticipatory oculomotor metric to determine how input statistics impact anticipatory behavior that is decoupled from target-driven-response. We implemented transition constraints between target locations, so that the probability of a target being presented on the same side as the previous trial was 70% in one condition (pret70) and 30% in the other (pret30). Rather than focus on responses to targets, we studied subtle endogenous anticipatory fixation offsets (AFOs) measured while participants fixated the screen center, awaiting a target. These AFOs were small (<0.4° from center on average), but strongly tracked global-level statistics. Speaking to learning dynamics, trial-by-trial fluctuations in AFO were well-described by a learning model, which identified a lower learning rate in pret70 than pret30, corroborating prior suggestions that pret70 is subjectively treated as more regular. Most importantly, direct comparisons with saccade latencies revealed that AFOs: (a) reflected similar temporal integration windows, (b) carried more information about the statistical context than did saccade latencies, and (c) accounted for most of the information that saccade latencies also contained about inputs statistics. Our work demonstrates how strictly predictive processes reflect learning dynamics, and presents a new direction for studying learning and prediction.


The role of tumor-infiltrating immune cells and chronic inflammation at the tumor site on cancer development, progression, and prognosis: emphasis on non-small cell lung cancer.
In addition to malignant neoplastic cells, cancer tissues also include immune cells, fibroblasts, and endothelial cells, including an abundant collection of growth factors, proangiogenic mediators, cytokines, chemokines, and components of the extracellular matrix. The main physiological function of the immune cells is to monitor tissue homeostasis, to protect against invading pathogens, and to eliminate transformed or damaged cells. Between immune cells and malignant cells in the tumor stroma, there is in fact a complex interaction which has significant prognostic relevance as the immune system has both tumor-promoting and -inhibiting roles. In non-small cell lung cancer (NSCLC), there is a marked infiltration of different types of immune cells, and the distribution, tissue localization, and cell types are significantly associated with progression and survival. Cancer immunotherapy has seen a significant progress during the last decade. An increased understanding of the mechanisms by which lung cancer cells escape the immune system, and the recognition of the key tumor antigens and immune system components in tumor ignorance have led to the development of several lung cancer vaccines. As the NSCLC prognosis in general is dismal, one may hope that future immunotherapy may be an effective adjunct to standard therapy, reversing immunologic tolerance in the tumor microenvironment. This review reports on the tumor stroma and in particular tumor-suppressing and -promoting roles of the immune system. Furthermore, it presents recent literature on relevant immune cell-related research in NSCLC.


Selectivity determinants of GPCR-G-protein binding.
The selective coupling of G-protein-coupled receptors (GPCRs) to specific G proteins is critical to trigger the appropriate physiological response. However, the determinants of selective binding have remained elusive. Here we reveal the existence of a selectivity barcode (that is, patterns of amino acids) on each of the 16 human G proteins that is recognized by distinct regions on the approximately 800 human receptors. Although universally conserved positions in the barcode allow the receptors to bind and activate G proteins in a similar manner, different receptors recognize the unique positions of the G-protein barcode through distinct residues, like multiple keys (receptors) opening the same lock (G protein) using non-identical cuts. Considering the evolutionary history of GPCRs allows the identification of these selectivity-determining residues. These findings lay the foundation for understanding the molecular basis of coupling selectivity within individual receptors and G proteins.


Effect of oral creatine supplementation on respiratory gas exchange and blood lactate accumulation during steady-state incremental treadmill exercise and recovery in man.
1. Oral creatine supplementation has been shown to increase muscle creatine and phosphocreatine concentrations with consequent benefits on performance during short-term maximal exercise. However, recently there have been anecdotal reports that creatine supplementation can also influence the pattern of substrate utilization and improve performance during more prolonged, submaximal exercise, which, based on recent experimental evidence, may have some scientific justification. 2. Eight men performed a continuous incremental exercise test running at 10 km/h on a motorized treadmill at predetermined workloads from 50% to 90% of maximal oxygen uptake, before and after 5 days of creatine supplementation (4 x 5 g daily). Exercise was performed for 6 min at each workload to achieve a steady state, and respiratory gas exchange and blood lactate concentrations were measured during the last 30 s at each workload. Measurements were also made at 5-min intervals for the first 15 min of recovery. 3. The results showed no measurable effect of creatine supplementation on respiratory gas exchange and blood lactate concentrations during either incremental submaximal exercise or recovery. This suggests that creatine supplementation does not influence substrate utilization during and after this type of exercise.


Dissecting the workforce and workplace for clinical endocrinology, and the work of endocrinologists early in their careers.
The United States lacks timely reliable mechanisms for assessing the professional work of subspecialty physicians. The aim was to use early-career members of The Endocrine Society as a model to estimate subspecialty physician involvement in patient care, teaching, research, and administration among clinical, academic, federal, and pharmaceutical/biotech workplaces and to assess the workforce for research within individual workplaces. Physicians joining The Endocrine Society from 1991-2005 and residing in North America were invited to complete a Web-based survey. This report relies on 817 early-career endocrinologists or 29.6% of eligible respondents. Respondents from all types of workplaces engaged in patient care, teaching, research, and administration. The time committed to the four tasks, however, differed significantly among workplaces. Research (basic, translational, disease, patient, population, and prevention) was accomplished within all workplaces, but the scope and scale of investigative work was employer dependent. Recipients of National Institutes of Health K08/23 awards succeeded in receiving federal research project grants (P < 0.001). Respondents associated research with lowered incomes, a perception validated by an estimated drop in annual earnings of 2.8% per half-day spent on research (P < 0.001). Women in academic settings earned less than men (P < 0.01) and were less likely to occupy tenure-eligible positions (P < 0.01). Web-based surveys offer a simple tool for estimating the work of subspecialty physicians and provide a framework for improving biomedical investigation. Several interventions should be considered for endocrinology: recruit physicians from underrepresented demographic groups, increase K08/23 awards, incentivize investigative careers, and improve the national infrastructure for biomedical research.


Ultrastructural and geochemical characterization of Archean-Paleoproterozoic graphite particles: implications for recognizing traces of life in highly metamorphosed rocks.
Abundant graphite particles occur in amphibolite-grade quartzite of the Archean-Paleoproterozoic Wutai Metamorphic Complex in the Wutaishan area of North China. Petrographic thin section observations suggest that the graphite particles occur within and between quartzite clasts and are heterogeneous in origin. Using HF maceration techniques, the Wutai graphite particles were extracted for further investigation. Laser Raman spectroscopic analysis of a population of extracted graphite discs indicated that they experienced a maximum metamorphic temperature of 513 +/- 50 degrees C, which is consistent with the metamorphic grade of the host rock and supports their indigenicity. Scanning and transmission electron microscopy revealed that the particles bear morphological features (such as hexagonal sheets of graphite crystals) related to metamorphism and crystal growth, but a small fraction of them (graphite discs) are characterized by a circular morphology, distinct marginal concentric folds, surficial wrinkles, and complex nanostructures. Ion microprobe analysis of individual graphite discs showed that their carbon isotope compositions range from -7.4 per thousand to -35.9 per thousand V-PDB (Vienna Pee Dee Belemnite), with an average of -20.3 per thousand, which is comparable to bulk analysis of extracted carbonaceous material. The range of their size, ultrastructures, and isotopic signatures suggests that the morphology and geochemistry of the Wutai graphite discs were overprinted by metamorphism and their ultimate carbon source probably had diverse origins that included abiotic processes. We considered both biotic and abiotic origins of the carbon source and graphite disc morphologies and cannot falsify the possibility that some circular graphite discs characterized by marginal folds and surficial wrinkles represent deflated, compressed, and subsequently graphitized organic-walled vesicles. Together with reports by other authors of acanthomorphic acritarchs from greenschist-amphibolite-grade metamorphic rocks, this study suggests that it is worthwhile to examine carbonaceous materials preserved in highly metamorphosed rocks for possible evidence of ancient life.


Nicotine replacement therapy for long-term smoking cessation: a meta-analysis.
To assess if the effect of a single treatment episode with nicotine replacement therapy (NRT) enhances smoking cessation over many years. Meta-analysis of all randomised controlled trials of NRT with final follow-up more than one year after the start of treatment. Twelve eligible trials were identified, all placebo-controlled, having final follow-ups ranging from 2-8 years. All had earlier follow-ups at 12 months. They comprised 2408 active and 2384 placebo treatment participants. The odds ratio (OR) in favour of NRT at final follow-up was 1.99 (95% confidence interval (CI) 1.50 to 2.64). There was no evidence that the effect varied according to length of final follow-up (beta = 0.92, p = 0.28) or duration of initial NRT treatment (beta = 0.99, p > 0.5). The overall relapse rate between the 12 months and final follow-up was 30.0% (95% CI 23.5% to 37.5%). This rate did not differ between NRT and control groups (OR 1.11, 95% CI 0.78 to 1.59), or length of initial NRT treatment. There was also no evidence that it varied according to length of final follow up. Due to relapse, the overall efficacy of NRT treatment in terms of additional ex-smokers declined from 10.7% over and above placebo (6.6% to 14.8%) after one year to 7.2% (3.8% to 11.3%) at an average of 4.3 years follow up. The relative efficacy of a single course of NRT remains constant over many years. The majority of relapse after 12 months occurs within the first or second year and is not detectable thereafter, suggesting that NRT has a permanent effect on smoking cessation. However, initial relapse after one year has the effect of diminishing the number of ex-smokers that can be ultimately attributed to NRT. Results after only 6-12 months of follow-up, as used in existing reviews and treatment guidelines, will overestimate the lifetime benefit and cost-efficacy of NRT by about 30%. Because the long-term benefit of NRT is modest, tobacco dependence treatment might be better viewed as a chronic disorder, requiring repeated episodes of treatment.


Evolution of Deep Convolutional Neural Networks Using Cartesian Genetic Programming.
The convolutional neural network (CNN), one of the deep learning models, has demonstrated outstanding performance in a variety of computer vision tasks. However, as the network architectures become deeper and more complex, designing CNN architectures requires more expert knowledge and trial and error. In this article, we attempt to automatically construct high-performing CNN architectures for a given task. Our method uses Cartesian genetic programming (CGP) to encode the CNN architectures, adopting highly functional modules such as a convolutional block and tensor concatenation, as the node functions in CGP. The CNN structure and connectivity, represented by the CGP, are optimized to maximize accuracy using the evolutionary algorithm. We also introduce simple techniques to accelerate the architecture search: rich initialization and early network training termination. We evaluated our method on the CIFAR-10 and CIFAR-100 datasets, achieving competitive performance with state-of-the-art models. Remarkably, our method can find competitive architectures with a reasonable computational cost compared to other automatic design methods that require considerably more computational time and machine resources.


A low-cost 2D fluorescence detection system for μm sized beads on-chip.
In this paper we describe a compact fluorescence detection system for on-chip analysis of beads, comprising a low-cost optical HD-DVD pickup. The complete system consists of a fluorescence detection unit, a control unit and a microfluidic chip containing microchannels and optical markers. With these markers the laser beam of the optical pickup can be automatically focused at the centre of the microchannel. With the complete system a two-dimensional fluorescent profile across the channel width can be obtained such that there is no need for hydrodynamic or electrokinetic focusing of the particles in a specific part of the channel. Fluorescent μm sized beads suspended in medium have been detected with the system. Since on both sides of the main beam two additional laser beams at a known distance are generated, also the velocity of individual beads has been determined.


Insufficient evidence to determine the effects of routine scale and polish treatments.
The Cochrane Oral Health Group's Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, the metaRegister of Controlled Trials and the US National Institutes of Health Clinical Trials Register. Randomised controlled trials (excluding split mouth) of routine scale and polish treatments with and without OHI in healthy dentate adults without severe periodontitis. Study assessment, data extraction and risk of bias assessment were carried out independently by two reviewers. Mean and standardised mean differences were calculated when different scales were reported. Fixed effects models were used as there were only a small number of studies. Three studies involving a total of 837 patients, and all considered to be at unclear risk of bias were included. No studies reported any adverse effects. Only one trial (conducted in general practice) provided data comparing scale and polish versus no scale and polish. It found no evidence to claim or refute benefit for scale and polish treatments for the outcomes of gingivitis, calculus and plaque. Two studies, both at unclear risk of bias, compared routine scale and polish provided at different time intervals. When comparing six with 12 months there was insufficient evidence to determine a difference for gingivitis at 24 months. There were some statistically significant differences in favour of scaling and polishing provided at more frequent intervals, in particular between three and 12 months for the outcome of gingivitis at 24 months, with OHI, MD -0.14 (95% CI -0.23 to -0.05; P value = 0.003) and without OHI MD -0.21 (95% CI -0.30 to -0.12; P value < 0.001) (mean per patient measured on 0-3 scale), based on one study. There was some evidence of a reduction in calculus. This body of evidence was assessed as of low quality.One study provided data for the comparison of scale and polish treatment with and without OHI. There was a reduction in gingivitis for the 12-month scale and polish treatment when assessed at 24 months MD -0.14 (95% CI -0.22 to -0.06) in favour of including OHI. There were also significant reductions in plaque for both three and 12-month scale and polish treatments when OHI was included. The body of evidence was once again assessed as of low quality. There is insufficient evidence to determine the effects of routine scale and polish treatments. High quality trials conducted in general dental practice settings with sufficiently long follow-up periods (five years or more) are required to address the objectives of this review.


The Effect of Uncoated SPIONs on hiPSC-Differentiated Endothelial Cells.
Endothelial progenitor cells (EPCs) were indicated in vascular repair, angiogenesis of ischemic organs, and inhibition of formation of initial hyperplasia. Differentiation of endothelial cells (ECs) from human induced pluripotent stem cells (hiPSC)-derived endothelial cells (hiPSC-ECs) provides an unlimited supply for clinical application. Furthermore, magnetic cell labelling offers an effective way of targeting and visualization of hiPSC-ECs and is the next step towards in vivo studies. ECs were differentiated from hiPSCs and labelled with uncoated superparamagnetic iron-oxide nanoparticles (uSPIONs). uSPION uptake was compared between hiPSC-ECs and mature ECs isolated from patients by software analysis of microscopy pictures after Prussian blue cell staining. The acute and long-term cytotoxic effects of uSPIONs were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay) and Annexin assay. We showed, for the first time, uptake of uncoated SPIONs (uSPIONs) by hiPSC-ECs. In comparison with mature ECs of identical genetic background hiPSC-ECs showed lower uSPION uptake. However, all the studied endothelial cells were effectively labelled and showed magnetic properties even with low labelling concentration of uSPIONs. uSPIONs prepared by microwave plasma synthesis did not show any cytotoxicity nor impair endothelial properties. We show that hiPSC-ECs labelling with low concentration of uSPIONs is feasible and does not show any toxic effects in vitro, which is an important step towards animal studies.


Differential responses of calcifying and non-calcifying epibionts of a brown macroalga to present-day and future upwelling pCO2.
Seaweeds are key species of the Baltic Sea benthic ecosystems. They are the substratum of numerous fouling epibionts like bryozoans and tubeworms. Several of these epibionts bear calcified structures and could be impacted by the high pCO2 events of the late summer upwellings in the Baltic nearshores. Those events are expected to increase in strength and duration with global change and ocean acidification. If calcifying epibionts are impacted by transient acidification as driven by upwelling events, their increasing prevalence could cause a shift of the fouling communities toward fleshy species. The aim of the present study was to test the sensitivity of selected seaweed macrofoulers to transient elevation of pCO2 in their natural microenvironment, i.e. the boundary layer covering the thallus surface of brown seaweeds. Fragments of the macroalga Fucus serratus bearing an epibiotic community composed of the calcifiers Spirorbis spirorbis (Annelida) and Electra pilosa (Bryozoa) and the non-calcifier Alcyonidium hirsutum (Bryozoa) were maintained for 30 days under three pCO2 conditions: natural 460 ± 59 µatm, present-day upwelling1193 ± 166 µatm and future upwelling 3150 ± 446 µatm. Only the highest pCO2 caused a significant reduction of growth rates and settlement of S. spirorbis individuals. Additionally, S. spirorbis settled juveniles exhibited enhanced calcification of 40% during daylight hours compared to dark hours, possibly reflecting a day-night alternation of an acidification-modulating effect by algal photosynthesis as opposed to an acidification-enhancing effect of algal respiration. E. pilosa colonies showed significantly increased growth rates at intermediate pCO2 (1193 µatm) but no response to higher pCO2. No effect of acidification on A. hirsutum colonies growth rates was observed. The results suggest a remarkable resistance of the algal macro-epibionts to levels of acidification occurring at present day upwellings in the Baltic. Only extreme future upwelling conditions impacted the tubeworm S. spirorbis, but not the bryozoans.


Written Language Acquisition Is Both Shaped by and Has an Impact on Brain Functioning and Cognition.
Spoken language is a distinctive trace of our species and it is naturally acquired during infancy. Written language, in contrast, is artificial, and the correspondences between arbitrary visual symbols and the spoken language for reading and writing should be explicitly learned with external help. In this paper, I present several examples of how written language acquisition is both shaped by and has an impact on brain function and cognition. They show in one hand how our phylogenetic legacy influences education and on the other hand how ontogenetic needs for education can rapidly subdue deeply rooted neurocognitive mechanisms. The understanding of this bidirectional influences provides a more dynamic view of how plasticity interfaces phylogeny and ontogeny in human learning, with implications for both neurosciences and education.


A weak link in metabolism: the metabolic capacity for glycine biosynthesis does not satisfy the need for collagen synthesis.
In a previous paper, we pointed out that the capability to synthesize glycine from serine is constrained by the stoichiometry of the glycine hydroxymethyltransferase reaction, which limits the amount of glycine produced to be no more than equimolar with the amount of C 1 units produced. This constraint predicts a shortage of available glycine if there are no adequate compensating processes. Here, we test this prediction by comparing all reported fl uxes for the production and consumption of glycine in a human adult. Detailed assessment of all possible sources of glycine shows that synthesis from serine accounts for more than 85% of the total, and that the amount of glycine available from synthesis, about 3 g/day, together with that available from the diet, in the range 1.5-3.0 g/day, may fall significantly short of the amount needed for all metabolic uses, including collagen synthesis by about 10 g per day for a 70 kg human. This result supports earlier suggestions in the literature that glycine is a semi-essential amino acid and that it should be taken as a nutritional supplement to guarantee a healthy metabolism.


Focused ion beam for microscopy and in situ sample preparation: application on a crustacean digestive system.
We prove that the focused ion beam (FIB) machine can be used as a microscope and as an in situ cutting device for tissue and cells. For the first time we obtain high-resolution ion images, complemented by electron imaging of different animal tissues both from uncoated and coated samples. In our study, we select the digestive system of Porcellio scaber (isopoda, crustacea) as a test system for FIB microscopy and in situ sample preparation. After the milling operation, some of the ultrastructural elements of hepatopancreatic cells can clearly be recognized. Also, FIB operation reveals significant differences in structural integrity between the apical and basal parts of hepatopancreatic cells, which have not been observed before by classical microscopy techniques. FIB microscopy and in situ sample preparation have advantages over classical microscopy techniques because of: 1. in situ site-specific 2-D sectioning and imaging of subsurface microstructures; 2. no need to embed the sample prior to sectioning; and 3. a wide range of magnifications while imaging the same sample.


Association of hospitalist care with medical utilization after discharge: evidence of cost shift from a cohort study.
Hospitalist care has grown rapidly, in part because it is associated with decreased length of stay and hospital costs. No national studies examining the effect of hospitalist care on hospital costs or on medical utilization and costs after discharge have been done. To assess the relationship of hospitalist care with hospital length of stay, hospital charges, and medical utilization and Medicare costs after discharge. Population-based national cohort study. Hospital care of Medicare patients. A 5% national sample of enrollees in Medicare parts A and B with a primary care physician who were cared for by their primary care physician or a hospitalist during medical hospitalizations from 2001 to 2006. Length of stay, hospital charges, discharge location and physician visits, emergency department visits, rehospitalization, and Medicare spending within 30 days after discharge. In propensity score analysis, hospital length of stay was 0.64 day less among patients receiving hospitalist care. Hospital charges were $282 lower, whereas Medicare costs in the 30 days after discharge were $332 higher (P < 0.001 for both). Patients cared for by hospitalists were less likely to be discharged to home (odds ratio, 0.82 [95% CI, 0.78 to 0.86]) and were more likely to have emergency department visits (odds ratio, 1.18 [CI, 1.12 to 1.24]) and readmissions (odds ratio, 1.08 [CI, 1.02 to 1.14]) after discharge. They also had fewer visits with their primary care physician and more nursing facility visits after discharge. Observational studies are subject to selection bias. Decreased length of stay and hospital costs associated with hospitalist care are offset by higher medical utilization and costs after discharge. National Institute on Aging and National Cancer Institute.


Single molecule correlation spectroscopy in continuous flow mixers with zero-mode waveguides.
Zero-Mode Waveguides were first introduced for Fluorescence Correlation Spectroscopy at micromolar dye concentrations. We show that combining zero-mode waveguides with fluorescence correlation spectroscopy in a continuous flow mixer avoids the compression of the FCS signal due to fluid transport at channel velocities up to approximately 17 mm/s. We derive an analytic scaling relationship [equation: see text] converting this flow velocity insensitivity to improved kinetic rate certainty in time-resolved mixing experiments. Thus zero-mode waveguides make FCS suitable for direct kinetics measurements in rapid continuous flow.


Improving cavity-enhanced spectroscopy of molecular ions in the mid-infrared with up-conversion detection and Brewster-plate spoilers.
The performance of sensitive spectroscopic methods in the mid-IR is often limited by fringing due to parasitic etalons and the background noise in mid-infrared detectors. In particular, the technique Noise Immune Cavity Enhanced Optical Heterodyne Velocity Modulation Spectroscopy (NICE-OHVMS), which is capable of determining the frequencies of strong rovibrational transitions of molecular ions with sub-MHz uncertainty, needs improved sensitivity in order to probe weaker transitions. In this work, we have implemented up-conversion detection with NICE-OHVMS in the 3.2 - 3.9 µm region to enable the use of faster and more sensitive detectors which cover visible wavelengths. The higher bandwidth enabled detection at optimized heterodyne frequencies, which increased the overall signal from the H3+ cation by a factor of three and was able to resolve sub-Doppler features which had previously overlapped. Also, we demonstrate the effectiveness of Brewster-plate spoilers to remove fringes due to parasitic etalons in a cavity enhanced technique. Together, these improvements reduced the instrument's noise equivalent absorption to 5.9×10-11 cm-1 Hz-1/2, which represents a factor of 34 improvement in sensitivity compared to previous implementations of NICE-OHVMS. This work will enable extended high-precision spectroscopic surveys of H3+ and other important molecular ions.


Spontaneous "regression" of enhanced immune function in a photoperiodic rodent Peromyscus maniculatus.
Short days inhibit reproduction and enhance immune function in deer mice (Peromyscus maniculatus). Their reproductive inhibition is sustained by an endogenous timing mechanism: after ca. 20 weeks in short days, reproductive photorefractoriness develops, followed by spontaneous recrudescence of the reproductive system. It is unknown whether analogous seasonal timing mechanisms regulate their immune function or whether enhanced immune function is sustained indefinitely under short days. In order to test this hypothesis, we housed adult male deer mice under long (16 h light day(-1)) or short (8 h light day(-1)) day conditions for 32 weeks or under long day conditions for 20 weeks followed by 12 weeks of short days. Mice under the long day conditions remained photostimulated over the 32 weeks, whereas mice housed under the short day conditions exhibited gonadal regression followed by photorefractoriness and spontaneous recrudescence. Mice transferred to short days at week 20 were reproductively photoregressed at week 32. Total splenocytes, relative splenic mass and mitogen-activated splenocyte proliferation were greater in those mice transferred to short days at week 20 than in those mice housed under either long or short day conditions for 32 consecutive weeks, and immune function in mice exposed to short days for 32 weeks was comparable with that of long day animals. These data suggest that short day enhancement of immune function is not indefinite. With prolonged (< or = 32 weeks) exposure to short days, several measures of immune function exhibit "spontaneous" regression, restoring long day-like immunocompetence. The results suggest that formal similarities and, possibly, common substrates exist among the photoperiodic timekeeping mechanisms that regulate seasonal transitions in reproductive and immune function.


On-chip immunoassay using electrostatic assembly of streptavidin-coated bead micropatterns.
We propose an original concept for a sandwich immunoassay that is completely performed on-chip using streptavidin-coated beads as substrate. The latter are electrostatically self-assembled on aminosilane micropatterns at the bottom of a microfluidic channel. We use mouse IgG diluted in phosphate buffered saline (PBS) with 1% bovine serum albumin (BSA) solution as target antigen. The fluorescent sandwich immunocomplex is formed on the beads during the operation of the chip both in stop-flow and continuous-flow modes. Target mouse IgG antigen is detected down to a concentration of 15 ng/mL in stop-flow mode and 250 pg/mL in continuous-flow mode, using only 1300 nL of sample volume. We also demonstrate the possibility of simultaneous detection of two different antigens in a PBS-BSA solution using a dual microfluidic channel structure.


Combined Oral Medroxyprogesterone/Levonorgestrel-Intrauterine System Treatment for Women With Grade 2 Stage IA Endometrial Cancer.
The aim of this study was to evaluate the oncologic and pregnancy outcomes of combined oral medroxyprogesterone acetate (MPA)/levonorgestrel-intrauterine system (LNG-IUS) treatment in young women with grade 2-differentiated stage IA endometrial adenocarcinoma who wish to preserve fertility. We retrospectively reviewed the medical records of patients with grade 2 stage IA endometrial adenocarcinoma who had received fertility-sparing treatment at CHA Gangnam Medical Center between 2011 and 2015. All of the patients were treated with combined oral MPA (500 mg/d)/LNG-IUS, and follow-up dilatation and curettage were performed every 3 months. A total of 5 patients were included in the study. The mean age was 30.4 ± 5.3 years (range, 25-39 years). After a mean treatment duration of 11.0 ± 6.2 months (range, 6-18 months), complete response (CR) was shown in 3 of the 5 patients, with partial response (PR) in the other 2 patients. One case of recurrence was reported 14 months after achieving CR. This patient was treated again with combined oral MPA/LNG-IUS and achieved CR by 6 months. The average follow-up period was 44.4 ± 26.2 months (range, 12-71 months). There were no cases of progressive disease. No treatment-related complications arose. Combined oral MPA/LNG-IUS treatment is considered to be a reasonably effective fertility-sparing treatment of grade 2 stage IA endometrial cancer. Although our results are encouraging, it is preliminary and should be considered with experienced oncologists in well-defined protocol and with close follow-up.


The Effects of Migration and Assortative Mating on Admixture Linkage Disequilibrium.
Statistical models in medical and population genetics typically assume that individuals assort randomly in a population. While this simplifies model complexity, it contradicts an increasing body of evidence of nonrandom mating in human populations. Specifically, it has been shown that assortative mating is significantly affected by genomic ancestry. In this work, we examine the effects of ancestry-assortative mating on the linkage disequilibrium between local ancestry tracks of individuals in an admixed population. To accomplish this, we develop an extension to the Wright-Fisher model that allows for ancestry-based assortative mating. We show that ancestry-assortment perturbs the distribution of local ancestry linkage disequilibrium (LAD) and the variance of ancestry in a population as a function of the number of generations since admixture. This assortment effect can induce errors in demographic inference of admixed populations when methods assume random mating. We derive closed form formulae for LAD under an assortative-mating model with and without migration. We observe that LAD depends on the correlation of global ancestry of couples in each generation, the migration rate of each of the ancestral populations, the initial proportions of ancestral populations, and the number of generations since admixture. We also present the first direct evidence of ancestry-assortment in African Americans and examine LAD in simulated and real admixed population data of African Americans. We find that demographic inference under the assumption of random mating significantly underestimates the number of generations since admixture, and that accounting for assortative mating using the patterns of LAD results in estimates that more closely agrees with the historical narrative.


Influence of oral contraceptives on anthropomorphometric, endocrine, and metabolic profiles of anovulatory polycystic ovary syndrome patients.
To evaluate the influence of oral contraceptive pills (OCPs) on anthromorphometric, endocrine, and metabolic parameters in women with polycystic ovary syndrome (PCOS). Retrospective cross-sectional cohort study for the period 1993-2011. Tertiary university hospital. PCOS patients, who never, ever, or at time of screening were using OCPs were included. A total of 1,297 patients, of whom 827 were white, were included. All PCOS patients diagnosed according to the Rotterdam 2003 consensus criteria were divided into three groups: current users, (n = 76; 6% of total), ever users (n = 1,018; 78%), and never users (n = 203; 16%). Ever users were subdivided based on the OCP-free interval. None. Anthromorphometric (blood pressure, cycle duration) and ultrasound (follicle count, mean ovarian volume) parameters, endocrine (SHBG, testosterone, free androgen index, antimüllerian hormone [AMH]) and lipid profiles. Current users and ever users were compared with never users. In current users, SHBG was increased and androgen levels decreased. Patients with an OCP-free interval of <1 year had a higher mean follicle count, higher AMH level, and increased serum androgen level compared with never users. SHBG levels remained increased until 5-10 years after cessation of OCP use. OCP use causes a milder phenotypic presentation of PCOS regarding hyperandrogenism. However, it does not alter parameters associated with increased health risks.


Bone healing in the rat and dog with nonglycosylated BMP-2 demonstrating low solubility in fibrin matrices.
A novel form of recombinant human bone morphogenetic protein-2 (BMP-2) was explored for effective incorporation and long-term retention into fibrin ingrowth matrices. The solubility of native BMP-2 is greatly dependent on its glycosylation. To enhance retention of BMP-2 in fibrin matrices, a nonglycosylated form (nglBMP-2), which is less soluble than the native glycosylated protein, was produced recombinantly and evaluated in critical-size defects in the rat calvarium (group n=6). When 1 or 20 microg nglBMP-2 was incorporated by precipitation within the matrix, 74 +/- 4% and 98 +/- 2% healing was observed in the rat calvarium, respectively, as judged radiographically by closure of the defect at 3 weeks. More soluble forms of BMP-2, used as controls, induced less healing, demonstrating a positive correlation between low solubility, retention in vitro, and healing in vivo. Subsequently, the utility of nglBMP-2 was explored in a prospective veterinary clinical trial for inter-carpal fusion in dogs, replacing the standard-of-care, namely autologous cancellous autograft, with nglBMP-2 in fibrin. In a study of 10 sequential canine patients, fibrin with 600 microg/ml nglBMP-2 performed better than autograft in the first weeks of bone healing and comparably thereafter. Furthermore, a greater fraction of animals treated with nglBMP-2 in fibrin demonstrated bone bridging across each of the treated joints at both 12 and 17 weeks than in animals treated with autograft. These results suggest that evaluation in a human clinical setting of nonglycosylated BMP-2 in fibrin matrices might be fruitful.


Ab initio crystal structure prediction by combining symmetry analysis representations and total energy calculations. An insight into the structure of Mg(BH4)2.
In materials science there is an increasing need for developing a robust and reliable first-principle approach capable of predicting crystal structures, by taking only the stoichiometry as an input. We integrate several methodologies to tackle this problem including quantum chemistry cluster calculations, simulated annealing algorithm for structure modelling, density functional theory total energy calculations and symmetry group analysis. A case study is Mg(BH(4))(2) in the aim to find the reasons for discrepancies between theoretically and experimentally proposed structures. In addition to new stable monoclinic, orthorhombic and tetragonal structures, a cubic one is suggested as a possible high energy structure. Moreover, the symmetry group analysis makes possible to link symmetry-related structures via group-subgroup relations, and subsequently identify local minima on the Potential Energy Surface.


Effects of additional blood pressure and lipid measurements on the prediction of cardiovascular risk.
Current guidelines recommend that decisions to start preventative therapy for cardiovascular disease (CVD) should be based on absolute risk; however, current risk equations are based on single measurements of risk factors. We aimed to assess whether two measurements of blood pressure and lipids improves the prediction of cardiovascular risk compared to one measurement. We used sex-specific Cox proportional hazards models to evaluate the risk of first CVD event in 2385 participants of the Framingham Offspring Study attending both the second and third visits. We estimated the effects on risk prediction of using the average of two measurements of blood pressure, total cholesterol, and HDL cholesterol compared to using one measurement of the risk factors. We found that these risk factors were each markedly more predictive of CVD when the average of two measurements was used rather than one measurement and age was less predictive of CVD. There were small improvements in the overall model fit, discrimination, and calibration. Reclassification also showed small improvements across the risk spectrum (net reclassification information, NRI, for women 3.0%, 95% CI -0.9 to 24.8%; NRI for men 4.0%, 95% CI -2.2 to 14.1%) and possibly greater improvements for intermediate-risk individuals (NRI for women 32.3%, 95% CI -21.9 to 46.8%; NRI for men 16.0%, 95% CI -3.3 to 43%). Averaging two measurements of blood pressure and lipids results in marked increases in the predictiveness of these risk factors and smaller improvements in the overall prediction of cardiovascular risk including reclassification.


Detecting elder abuse and neglect: assessment and intervention.
Elder mistreatment includes intentional or neglectful acts by a caregiver or trusted person that harm a vulnerable older person. It can occur in a variety of settings. One out of 10 older adults experiences some form of abuse or neglect by a caregiver each year, and the incidence is expected to increase. Although the U.S. Preventive Services Task Force found insufficient evidence that screening for elder abuse reduces harm, physicians in most states have professional and legal obligations to appropriately diagnose, report, and refer persons who have been abused. Screening or systematic inquiry can detect abuse. A detailed medical evaluation of patients suspected of being abused is necessary because medical and psychiatric conditions can mimic abuse. Signs of abuse may include specific patterns of injury. Interviewing patients and caregivers separately is helpful. Evaluation for possible abuse should include assessment of cognitive function. The Elder Abuse Suspicion Index is validated to screen for abuse in cognitively intact patients. A more detailed two-step process is used to screen patients with cognitive impairment. The National Center on Elder Abuse website provides detailed, state-specific reporting and resource information for family physicians.


Diuretic treatment in decompensated cirrhosis and congestive heart failure: effect of posture.
The diuretic effect of the supine position was evaluated in six patients with cirrhosis and ascites and six with congestive cardiac failure. After fasting overnight in bed the patients received bumetanide 1 mg intravenously and were then immediately randomly assigned to either bed rest in the supine position or normal daily activity in the upright position for the next six hours. Two days later the procedure was repeated, the patients being assigned to the other posture. The diuretic response was similar in patients with heart failure and cirrhosis, and was significantly greater in the supine than in the upright position: mean 1133 v 626 ml/6 h (p less than 0.01). The natriuresis was similarly larger during recumbency: mean sodium 96 v 45 mmol(mEq)/6h (p less than 0.01), and the excreted potassium in six hours was similar in both postures. The glomerular filtration rate was 100 and 66 ml/min (p less than 0.01) and heart rate 76 and 83 beats/min (p less than 0.01) in the supine and upright positions respectively. Plasma concentrations of noradrenaline, renin, and aldosterone were all raised even when the patient adopted the supine position, and a further significant rise was observed during the upright position. The results suggest that the attenuated response to intravenous bumetanide in the upright position and during normal daily activity may be due to the activation of several homeostatic mechanisms that may reduce the excretion of water and salt.


Dentinal shear bond strength, microleakage, and contraction gap of visible light-polymerized liners/bases.
The bond strength and microleakage patterns of three light-curing glass-ionomer cement liners/bases (Vitrebond, XR Ionomer, and Zionomer) were evaluated and compared to a fluoride-releasing resin (TimeLine) designed for the same use. Bond strength tests were performed at 24 hours and 7 days. At 24 hours Vitrebond, Time-Line, and Zionomer had statistically significantly greater bond strengths than XR Ionomer. At 7 days, Vitrebond had a statistically significantly stronger bond than the others. Microleakage was evaluated after 24 hours of thermocycling. Vitrebond and XR Ionomer had statistically significantly less leakage than the others, while TimeLine had significantly more leakage than the others. Polymerization contraction gaps between the liners/bases and dentin were examined with scanning electron microscopy. Contraction gaps were approximately 10 microns with Vitrebond and XR Ionomer and 5 microns with TimeLine. A contraction gap generally was not observed with Zionomer.


Accumulation of saturated intramyocellular lipid is associated with insulin resistance.
Intramyocellular lipid (IMCL) accumulation has been linked to both insulin-resistant and insulin-sensitive (athletes) states. Biochemical analysis of intramuscular triglyceride composition is confounded by extramyocellular triglycerides in biopsy samples, and hence the specific composition of IMCLs is unknown in these states. 1H magnetic resonance spectroscopy (MRS) can be used to overcome this problem. Thus, we used a recently validated 1H MRS method to compare the compositional saturation index (CH2:CH3) and concentration independent of the composition (CH3) of IMCLs in the soleus and tibialis anterior muscles of 16 female insulin-resistant lipodystrophic subjects with that of age- and gender-matched athletes (n = 14) and healthy controls (n = 41). The IMCL CH2:CH3 ratio was significantly higher in both muscles of the lipodystrophic subjects compared with controls but was similar in athletes and controls. IMCL CH2:CH3 was dependent on the IMCL concentration in the controls and, after adjusting the compositional index for quantity (CH2:CH3adj), could distinguish lipodystrophics from athletes. This CH2:CH3adj marker had a stronger relationship with insulin resistance than IMCL concentration alone and was inversely related to VO2max The association of insulin resistance with the accumulation of saturated IMCLs is consistent with a potential pathogenic role for saturated fat and the reported benefits of exercise and diet in insulin-resistant states.


PIF4 Coordinates Thermosensory Growth and Immunity in Arabidopsis.
Temperature is a key seasonal signal that shapes plant growth. Elevated ambient temperature accelerates growth and developmental transitions [1] while compromising plant defenses, leading to increased susceptibility [2, 3]. Suppression of immunity at elevated temperature is at the interface of trade-off between growth and defense [2, 4]. Climate change and the increase in average growth-season temperatures threaten biodiversity and food security [5, 6]. Despite its significance, the molecular mechanisms that link thermosensory growth and defense responses are not known. Here we show that PHYTOCHROME INTERACTING FACTOR 4 (PIF4)-mediated thermosensory growth and architecture adaptations are directly linked to suppression of immunity at elevated temperature. PIF4 positively regulates growth and development and negatively regulates immunity. We also show that natural variation of PIF4-mediated temperature response underlies variation in the balance between growth and defense among Arabidopsis natural strains. Importantly, we find that modulation of PIF4 function alters temperature sensitivity of defense. Perturbation of PIF4-mediated growth has resulted in temperature-resilient disease resistance. This study reveals a molecular link between thermosensory growth and immunity in plants. Elucidation of the molecular mechanisms that define environmental signal integration is key to the development of novel strategies for breeding temperature-resilient disease resistance in crops.


Review article: rifabutin in the treatment of refractory Helicobacter pylori infection.
Even with the current most effective treatment regimens, a relevant proportion of patients will fail to eradicate Helicobacter pylori infection. To evaluate the role of rifabutin in the treatment of H. pylori infection. Bibliographical searches were performed in MEDLINE. Data on the efficacy of rifabutin-containing regimens on H. pylori eradication were combined and meta-analysed using the generic inverse variance method. Rifabutin shows good in vitro activity against H. pylori. Mean H. pylori rifabutin resistance rate (calculated from 11 studies including 2982 patients) was 1.3% (95% confidence interval = 0.9-1.7%). When only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%). On the other hand, higher values of rifabutin resistance were calculated (1.59%) when only post-treatment patients were considered. Overall, mean H. pylori eradication rate (intention-to-treat analysis) with rifabutin-containing regimens (1008 patients) was 73% (67-79%). Respective cure rates for second-line (223 patients), third-line (342 patients) and fourth/fifth-line (95 patients) rifabutin therapies were 79% (67-92%), 66% (55-77%) and 70% (60-79%) respectively. For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day; this dose seems to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10- to 12-day regimens are generally recommended. The mean rate of adverse effects was 22% (19-25%). Myelotoxicity is the most significant, although this complication was rare. Until now, all patients have recovered of leucopenia uneventfully in a few days, and there have been no reports of infection or other adverse outcomes related to it. Rifabutin-containing rescue therapy constitutes an encouraging strategy after multiple (usually three) previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin.