Do older adults become more depressed with age in Taiwan? The role of social position and birth cohort.
Depression is one of the most commonly encountered mental health problems during older adulthood. This study examines differences in depressive symptom trajectories among older Taiwanese adults across two birth cohorts (1920-1924 and 1925-1929), and explores the relationships between socioeconomic position (SEP) variables and symptom trajectories. Data from the Taiwan Longitudinal Study on Aging (TLSA) collected between 1989 and 2003 were analysed. The nationally representative sample is composed of community-living adults (n = 2458) in Taiwan aged 60 years and above. Two distinct domains of depressive symptomatology, negative affect and lack of positive affect, assessed by the short form of the Center of Epidemiological Studies-Depression (CES-D) scale were used for all the analyses. Growth curve models were employed to assess the trajectories of depressive symptoms over time. The relationship between ageing and depressive symptoms appeared linear with a minor curvilinear effect. The depressive symptoms in negative affect increased with age (mean linear growth rate = 0.26, p<0.001) but levelled off (mean quadric growth rate = -0.01, p<0.001), while the symptoms in lack of positive affect displayed an opposite trend. The effects of SEP variables also differed by cohort and outcome domain. Remaining active, living with family and having a high level of education are associated with positive affect later in life, while financial strain and poor health are strongly related to negative affect. These results underline the continued role that SEP plays in psychological adjustment over the course of one's life, independently of ageing.


Equation of motion of a cyclist.
Tractional resistance (RT, N) was determined by towing two cyclists on a racing bike in "fully dropped" posture in calm air on a flat track at constant speed (5--16.5 m/s). RT increased with the air velocity (v, m/s): RT = 3.2 + 0.19 V2. The constant 3.2 N is interpreted as the rolling resistance and the term increasing with v2 as the air resistance. For a given posture this is a function of the body surface (SA, m2), the air temperature (T, degree K), and barometric pressure (PB, Torr). The mechanical power output (W, W) can then be described as a function of the air (v) and ground (s) speed: W = 4.5.10(-2) Ps + 4.1.10(-2) SA (PB/T)v2 s, where P is the overall weight in kg. With a mechanical efficiency of 0.25, the energy expenditure rate (VO2, ml/s) is given by: VO2 = 8.6.10(-3) Ps + 7.8.10(-3) SA (PB/T)v2 s (1 ml O2 = 20.9 J). As the decrease of VO2max with altitude is known from the literature, this last equation allows the calculation of the optimal altitude for top aerobic performance. The prediction derived from this equation is consistent with the present 1-h world record.


Noradrenaline concentration and turnover in different regions of the gastrointestinal tract of the rat: an approach to the evaluation of sympathetic activity in the gut.
The endogenous noradrenaline concentration, fractional turnover, half-life, and turnover rate of tritiated ((3)H) noradrenaline were determined in the oesophagus, non-glandular and glandular portions of the stomach, duodenum, jejunum, ileum, and colon of the rat. The highest concentration of endogenous noradrenaline was present in the duodenum and colon. The (3)H-noradrenaline fractional turnover rates and half-lives were significantly greater in the small and large intestines as compared with the oesophagus and stomach. The noradrenaline turnover rate, which is an estimate of the level of sympathetic activity, was greatest in the colon and duodenum. This method of assessing sympathetic activity in various tissues by direct measurement of the noradrenaline turnover rate may be applied to the study of the adrenergic nervous system in the physiology and pathophysiology of the gastrointestinal tract.


Incorporation of T and B epitopes of the circumsporozoite protein in a chemically defined synthetic vaccine against malaria.
We show here an effective and novel approach to engineer peptide-based vaccines using a chemically defined system, known as multiple peptide antigen systems (MAPs), to protect an inbred mouse strain from infection against rodent malaria. 10 mono- and di-epitope MAP models containing different arrangements and stoichiometry of functional B and/or T helper cell epitopes from the circumsporozoite protein of Plasmodium berghei were used to immunize A/J mice. While these mice did not respond to the mono-epitope MAP bearing only the B or T epitope, very high titers of antibody and protective immunity against sporozoite challenge were elicited by di-epitope MAPs, particularly those with the B and T epitopes in tandem and present in equimolar amounts. These results, obtained in a well-defined rodent malaria model, indicate that MAPs may overcome some of the difficulties in the development of synthetic vaccines, not only for malaria but also for other infectious diseases.


Positive Associations of Dispositional Mindfulness with Cardiovascular Health: the New England Family Study.
Mindfulness (the ability to attend nonjudgmentally to one's own physical and mental processes) is receiving substantial interest as a potential determinant of health. However, little is known whether mindfulness is associated with cardiovascular health. The aim of this study is to evaluate whether dispositional mindfulness is associated with cardiovascular health. Study participants (n = 382) were from the New England Family Study, born in Providence, RI, USA, with mean age 47 years. Dispositional mindfulness was assessed using the Mindful Attention Awareness Scale (MAAS). Cardiovascular health was assessed based on American Heart Association criteria. Cross-sectional multivariable-adjusted log binomial regression analyses were performed. Analyses demonstrated that those with high vs. low MAAS had prevalence ratio (PR) for good cardiovascular health of 1.83 (95 % confidence interval (CI) 1.07, 3.13), adjusted for age, gender, and race/ethnicity. There were significant associations of high vs. low mindfulness with nonsmoking (PR = 1.37, 95 % CI 1.06, 1.76), body mass index <25 kg/m(2) (PR = 2.17, 95 % CI 1.16, 4.07), fasting glucose <100 mg/dL (PR = 1.47, 95 % CI 1.06, 2.04), and high physical activity (PR = 1.56, 95 % CI 1.04, 2.35), but not blood pressure, total cholesterol, or fruit/vegetable consumption. Exploratory mediation analyses suggested that sense of control and depressive symptomatology may be mediators. This study demonstrated preliminary cross-sectional evidence that dispositional mindfulness is positively associated with cardiovascular health, with the associations particularly driven by smoking, body mass index, fasting glucose, and physical activity. If in future research mindfulness-based practices are found to consistently improve cardiovascular disease risk factors, such interventions may have potential to strengthen effects of cardiovascular health promotion programs.


Volumetric imaging of turbulent reactive flows at kHz based on computed tomography.
Diagnostics with three-dimensional (3D) spatial resolution and rapid temporal resolution have been long desired to resolve the complicated turbulence-chemistry interactions. This paper describes a method based on based on tomographic chemiluminescence (TC) to address this diagnostic need. The TC technique used multiple cameras to simultaneously record CH* chemiluminescence emitted by turbulent flames from different view angles. A 3D tomographic algorithm was then applied to reconstruct the instantaneous flame structures volumetrically. Both experimental and computational studies have been conducted to demonstrate and validate the 3D measurements. Experimental results were obtained instantaneously at kHz temporal rate, in a volume of 16 × 16 × 16 cm3, and with a spatial resolution estimated to be 2~3 mm. Computations were conducted to simulate the experimental conditions for comparison and validation.


Psychometric properties and measurement equivalence of the Multidimensional Fatigue Syndrome Inventory- Short Form (MFSI-SF) amongst breast cancer and lymphoma patients in Singapore.
Currently, several fatigue measurement instruments are available to evaluate and measure cancer-related fatigue. Amongst them, Multidimensional Fatigue Syndrome Inventory-Short Form (MFSI-SF) is a self-reported instrument and a multidimensional scale that aims to capture the global, somatic, affective, cognitive and behavioural symptoms of fatigue. This study examines the psychometric properties and measurement equivalence of the English and Chinese versions of MFSI-SF in breast cancer and lymphoma patients in Singapore. Patients were recruited from National Cancer Centre Singapore. Validity, reliability and responsiveness of MFSI-SF were evaluated in this study. Convergent validity was evaluated by correlating total and subscales of MFSI-SF to known related constructs in EORTC QLQ-C30. Known group validity was assessed based on patients' cancer stage, pain, insomnia and depression symptoms. Reliability was evaluated by Cronbach's α. Responsiveness analyses were performed with patients who have undergone at least one cycle of chemotherapy. Multiple regression was used to compare the total and subscale scores of MSFI-SF between the two language versions. Data from 246 (160 English and 86 Chinese version) breast cancer and lymphoma patients were included in the study. Moderate to high correlations were observed between correlated MFSI-SF subscales and EORTC QLQ-C30 domains (|r| = 0.524 to 0.774) except for a poor correlation (r = 0.394) observed between MFSI-SF vigour subscale and EORTC QLQ-C30 role functioning subscale. Total MFSI-SF scores could differentiate between patients with higher depression, pain and insomnia status. Internal consistency of MFSI-SF was also high (α = 0.749 to 0.944). Moderate correlation was observed between change in total MFSI-SF score and change in fatigue symptom scale score and global QoL score on EORTC QLQ-C30 (|r| = 0.478 and 0.404 respectively). Poor correlations were observed between change in scores of hypothesised subscales (|r| = 0.202 to 0.361) except for a moderate correlation between change in MFSI-SF emotional fatigue score and change in EORTC QLQ-C30 emotional functioning domain score. Measurement equivalence was established for all subscales and total MFSI-SF score except for the emotional and vigour subscales. This study supports the use of MFSI-SF as a reasonably valid scale with good internal consistency for measuring fatigue levels in the Singapore cancer population.


Radiocesium in fish from the Savannah River and Steel Creek: potential food chain exposure to the public.
This study examined radiocesium (137Cs) levels in fish from the vicinity of the Department of Energy's Savannah River Site (SRS), a former nuclear weapons production facility in South Carolina. Fish from the Savannah River were sampled above (upstream), along, and below (downstream) the SRS, and from Steel Creek, a tributary that runs through the SRS. There was some off-site contamination of 137Cs in the Savannah River watershed due to low-level releases from past nuclear production on the SRS. The null hypotheses tested were that there would be no differences in 137Cs levels as a function of location along the river, and between species collected from the river and from Steel Creek on the SRS. For six of eight species of fish collected from the Savannah River, there were no differences in 137Cs levels in muscle from fish collected above, along, or below the SRS; exceptions were bowfin and shellcracker. Fish collected from Steel Creek had significantly higher levels (by about an order of magnitude) of 137Cs in muscle tissue than fish collected in the Savannah River. However, no fish from either Steel Creek or the Savannah River had 137Cs levels above the European Economic Community limit for fresh meat of 0.6 Bq/g. Lifetime cancer risk was calculated using the cancer slope factor of 3.2 x 10(-11)/pCi, and various fish consumption scenarios reflecting actual data from Savannah River fishermen. Using mean 137Cs concentrations and median fish consumption for 70 years for Black males-the group with the highest consumption-the excess lifetime risk associated with the eight species of fish in the Savannah River ranged from 9.0 x 10(-7) to 1.0 x 10(-5). The same calculation for fish from Steel Creek gave risk estimates from 1.4 to 8.0 x 10(-5). The 95% level for consumption by Blacks, however, was about 70 kg/year. Black fishermen consuming that amount of bass from Steel Creek would sustain a lifetime risk of 3.1 x 10(-4), whereas the same consumption of Savannah River bass would yield a risk estimate of 1.5 x 10(-5).


Quantitative Proteomic Profiling of Murine Ocular Tissue and the Extracellular Environment.
Mass spectrometry-based proteomics provides a robust and reliable method for detecting and quantifying changes in protein abundance among samples, including cells, tissues, organs, and supernatants. Physical damage or inflammation can compromise the ocular surface permitting colonization by bacterial pathogens, commonly Pseudomonas aeruginosa, and the formation of biofilms. The interplay between P. aeruginosa and the immune system at the site of infection defines the host's ability to defend against bacterial invasion and promote clearance of infection. Profiling of the ocular tissue following infection describes the nature of the host innate immune response and specifically the presence and abundance of neutrophil-associated proteins to neutralize the bacterial biofilm. Moreover, detection of unique proteins produced by P. aeruginosa enable identification of the bacterial species and may serve as a diagnostic approach in a clinical setting. Given the emergence and prevalence of antimicrobial resistant bacterial strains, the ability to rapidly diagnose a bacterial infection promoting quick and accurate treatment will reduce selective pressure towards resistance. Furthermore, the ability to define differences in the host immune response towards bacterial invasion enhances our understanding of innate immune system regulation at the ocular surface. Here, we describe murine ocular infection and sample collection, as well as outline protocols for protein extraction and mass spectrometry profiling from corneal tissue and extracellular environment (eye wash) samples. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Murine model of ocular infection Basic Protocol 2: Murine model sample collection Basic Protocol 3: Protein extraction from eye wash Basic Protocol 4: Protein extraction from corneal tissue Basic Protocol 5: Mass spectrometry-based proteomics and bioinformatics from eye wash and corneal tissue samples.


Addressing challenges faced by insecticide spraying for the control of dengue fever in Bangkok, Thailand: a qualitative approach.
This study focused on evaluating the fumigation scheme and identifying problems encountered during the operation in the Bangkok Metropolitan Administration area. Ten district health officers working in different fumigation teams of the dengue outbreak control programme around Bangkok had participated in an in-depth interview. Five predetermined themes, including (i) dengue surveillance and control strategy, (ii) quality and availability of equipment, (iii) delays, (iv) human resources, and (v) area coverage, and other emerging themes were addressed during the interviews. Although the staff seemed to know the operation protocol of the dengue surveillance and control programmes well, they encountered some difficulties in accessing households for proper spraying, and a lack of human and material resources, especially during an outbreak. Other emerging themes concerned inefficient communications among the sectors from hospital to district offices, leading to inaccurate or missing patient addresses for spraying, and the lack of community networks and public cooperation for the dengue control programmes. The findings suggest that coordination among the relevant health sectors to acquire accurate and timely information about dengue cases is essential. Involving community networks should help to improve public engagement with and participation in the surveillance and outbreak control programmes.


Cell fate in the chick limb bud and relationship to gene expression.
We have produced detailed fate maps for mesenchyme and apical ridge of a stage 20 chick wing bud. The fate maps of the mesenchyme show that most of the wing arises from the posterior half of the bud. Subapical mesenchyme gives rise to digits. Cell populations beneath the ridge in the mid apical region fan out into the anterior tip of the handplate, while posterior cell populations extend right along the posterior margin. Subapical mesenchyme of the leg bud behaves similarly. The absence of anterior bending of posterior cell populations has implications when considering models of vertebrate limb evolution. The fatemaps of the apical ridge show that there is also a marked anterior expansion and cells that were in anterior apical ridge later become incorporated into non-ridge ectoderm along the margin of the bud. Mesenchyme and apical ridge do not expand in concert--the apical ridge extends more anteriorly. We used the fatemaps to investigate the relationship between cell lineage and elaboration of Hoxd-13 and Fgf-4 domains. Hoxd-13 and Fgf-4 are initially expressed posteriorly until about the mid-point of the early wing bud in mesenchyme and apical ridge respectively. Later in development, the genes come to be expressed throughout most of the handplate and apical ridge respectively. We found that at the proximal edge of the Hoxd-13 domain, cell populations stopped expressing the gene as development proceeded and found no evidence that the changes in extent of the domains were due to initiation of gene expression in anterior cells. Instead the changes in extent of expression fit with the fate maps and can be attributed to expansion and fanning out of cell populations initially expressing the genes.


Health burden of skin lesions at low arsenic exposure through groundwater in Pakistan. Is river the source?
A significant proportion of groundwater in south Asia is contaminated with arsenic. Pakistan has low levels of arsenic in groundwater compared with China, Bangladesh and India. A representative multi-stage cluster survey conducted among 3874 persons > or = 15 years of age to determine the prevalence of arsenic skin lesions, its relation with arsenic levels and cumulative arsenic dose in drinking water in a rural district (population: 1.82 million) in Pakistan. Spot-urine arsenic levels were compared among individuals with and without arsenic skin lesions. In addition, the relation of age, body mass index, smoking status with arsenic skin lesions was determined. The geographical distribution of the skin lesions and arsenic-contaminated wells in the district were ascertained using global positioning system. The total arsenic, inorganic and organic forms, in water and spot-urine samples were determined by atomic absorption spectrophotometry. The prevalence of skin lesions of arsenic was estimated for complex survey design, using surveyfreq and surveylogistic options of SAS 9.1 software.The prevalence of definitive cases i.e. hyperkeratosis of both palms and soles, was 3.4 per 1000 and suspected cases i.e. any sign of arsenic skin lesions (melanosis and/or keratosis), were 13.0 per 1000 among > or = 15-year-old persons in the district. Cumulative arsenic exposure (dose) was calculated from levels of arsenic in water and duration of use of current drinking water source. Prevalence of skin lesions increases with cumulative arsenic exposure (dose) in drinking water and arsenic levels in urine. Skin lesions were 2.5-fold among individuals with BMI <18.5 kg/m2. Geographically, more arsenic-contaminated wells and skin lesions were alongside Indus River, suggests a strong link between arsenic contamination of groundwater with proximity to river.This is the first reported epidemiological and clinical evidence of arsenic skin lesions due to groundwater in Pakistan. Further investigations and focal mitigation measures for arsenic may be carried out alongside Indus River.


The influence of multimorbidity on clinical progression of dementia in a population-based cohort.
Co-occurrence with other chronic diseases may influence the progression of dementia, especially in case of multiple chronic diseases. We aimed to verify whether multimorbidity influenced cognitive and daily functioning during nine years after dementia diagnosis compared with the influence in persons without dementia. In the Kungsholmen Project, a population-based cohort study, we followed 310 persons with incident dementia longitudinally. We compared their trajectories with those of 679 persons without dementia. Progression was studied for cognition and activities of daily life (ADLs), measured by MMSE and Katz Index respectively. The effect of multimorbidity and its interaction with dementia status was studied using individual growth models. The mean (SD) follow-up time was 4.7 (2.3) years. As expected, dementia related to both the decline in cognitive and daily functioning. Irrespective of dementia status, persons with more diseases had significantly worse baseline daily functioning. In dementia patients having more diseases also related to a significantly faster decline in daily functioning. Due to the combination of lower functioning in ADLs at baseline and faster decline, dementia patients with multimorbidity were about one to two years ahead of the decline of dementia patients without any co-morbidity. In persons without dementia, no significant decline in ADLs over time was present, nor was multimorbidity related to the decline rate. Cognitive decline measured with MMSE remained unrelated to the number of diseases present at baseline. Multimorbidity was related to baseline daily function in both persons with and without dementia, and with accelerated decline in people with dementia but not in non-demented individuals. No relationship of multimorbidity with cognitive functioning was established. These findings imply a strong interconnection between physical and mental health, where the greatest disablement occurs when both somatic and mental disorders are present.


Expression and functions of FGF-3 in Xenopus development.
We have analyzed the expression pattern of the Xenopus FGF-3 gene during early development and examined its biological activity in three different bioassays using Xenopus embryos. We show that from the early gastrula stage there is a domain of expression around the blastopore which becomes a posterior domain as the blastopore closes. An anterior ectodermal domain becomes detectable from mid-gastrula stages in the prospective hind-brain, and there are several later domains of expression: the midbrain-hindbrain junction, the otocyst, the pharyngeal pouches and the tailbud region. By using double whole-mount in situ hybridizations we show that the XFGF-3 expression in the brain is dynamically regulated both in time and space during development. The anterior domain of early neurula stage embryos corresponds to the prospective rhombomeres 3-5. By the time the neural tube is closed, XFGF-3 expression is restricted to r4 and later a new domain of expression is established at the midbrain/hindbrain junction. In addition, we show that, despite its difference in receptor specificity, XFGF-3 can induce the formation of mesoderm from animal caps similarly to other FGFs. It also displays a posteriorizing activity on whole embryos similar to other FGFs. Although the absence of maternal expression makes it unlikely that XFGF-3 is involved in mesoderm induction in vivo, its posterior domain of expression during gastrulation and its posteriorizing activity suggests that it participates in the maintenance of mesodermal gene expression and in the FGF mediated patterning of the anteroposterior axis during gastrulation.


Impaired functional status and echocardiographic abnormalities signifying global dysfunction enhance the prognostic significance of previously unrecognized myocardial infarction detected by electrocardiography.
The relationship between electrocardiographic unrecognized myocardial infarction (UMI), abnormal functional status, echocardiographic abnormalities, and mortality has not been evaluated. A population-based random sample of 2042 Olmsted County residents, age > or = 45 years, was studied by self-administered questionnaire, chart review, ECG and echocardiogram, and 5 year follow-up for all-cause mortality. UMI (n = 81) was diagnosed if ECG-MI criteria were met without previous documented myocardial infarction. Functional Status was assessed by the Goldman Specific Activity Scale. UMI subjects had an increased prevalence of abnormal functional status compared to no MI controls (22% vs 11%, P < 0.05). This association was independent of sex, obesity, smoking, diabetes, and pulmonary disease. It became insignificant after stratifying for echocardiographic abnormalities. Compared to no MI controls, UMI subjects with impaired functional status had a higher mortality hazard ratio (HR 7.2; P<0.0001) than those without impaired functional status (HR 2.7; P = 0.02). In UMI subjects with impaired functional status and any echocardiographic abnormality signifying global ventricular dysfunction (systolic or diastolic dysfunction, left atrial or left ventricular enlargement), the mortality risk was even higher (HR 9.5; P<0.001) and persisted in multivariate analyses. This increased mortality risk was unaffected by adjustment for regional wall motion abnormalities. The assessment of impaired functional status and echocardiographic abnormalities improves the prognostic significance of UMI. Even in the absence of regional wall motion abnormalities, structural abnormalities of global dysfunction may play a role in mediating the increased mortality associated with UMI.


Circadian clock genes in reproductive tissues and the developing conceptus.
The circadian (near 24-h) clock is involved in the temporal organisation of physiological and biochemical activities of many organisms, including humans. The clock functions through the rhythmic transcription and translation of several genes, forming an oscillatory feedback loop. Genetic analysis has shown that the circadian clock exists in both a central circadian pacemaker (i.e. the suprachiasmatic nucleus of the hypothalamus), as well as in most peripheral tissues. In particular, the circadian clockwork genes are expressed in all female and male reproductive tissues studied so far, as well as in the conceptus itself. The current data clearly show a robust rhythm in female reproductive tissues, but whether rhythmicity also exists in male reproductive tissues remains uncertain. Although the conceptus also expresses most of the canonical circadian genes, the rhythmicity of their expression is still under investigation. Published data indicate that environmental and genetic manipulations influence reproductive function and fecundity, suggesting an important role for the circadian clock in reproduction, and possibly early development.


4D dose simulation in volumetric arc therapy: Accuracy and affecting parameters.
Radiotherapy of lung and liver lesions has changed from normofractioned 3D-CRT to stereotactic treatment in a single or few fractions, often employing volumetric arc therapy (VMAT)-based techniques. Potential unintended interference of respiratory target motion and dynamically changing beam parameters during VMAT dose delivery motivates establishing 4D quality assurance (4D QA) procedures to assess appropriateness of generated VMAT treatment plans when taking into account patient-specific motion characteristics. Current approaches are motion phantom-based 4D QA and image-based 4D VMAT dose simulation. Whereas phantom-based 4D QA is usually restricted to a small number of measurements, the computational approaches allow simulating many motion scenarios. However, 4D VMAT dose simulation depends on various input parameters, influencing estimated doses along with mitigating simulation reliability. Thus, aiming at routine use of simulation-based 4D VMAT QA, the impact of such parameters as well as the overall accuracy of the 4D VMAT dose simulation has to be studied in detail-which is the topic of the present work. In detail, we introduce the principles of 4D VMAT dose simulation, identify influencing parameters and assess their impact on 4D dose simulation accuracy by comparison of simulated motion-affected dose distributions to corresponding dosimetric motion phantom measurements. Exploiting an ITV-based treatment planning approach, VMAT treatment plans were generated for a motion phantom and different motion scenarios (sinusoidal motion of different period/direction; regular/irregular motion). 4D VMAT dose simulation results and dose measurements were compared by local 3% / 3 mm γ-evaluation, with the measured dose distributions serving as ground truth. Overall γ-passing rates of simulations and dynamic measurements ranged from 97% to 100% (mean across all motion scenarios: 98% ± 1%); corresponding values for comparison of different day repeat measurements were between 98% and 100%. Parameters of major influence on 4D VMAT dose simulation accuracy were the degree of temporal discretization of the dose delivery process (the higher, the better) and correct alignment of the assumed breathing phases at the beginning of the dose measurements and simulations. Given the high γ-passing rates between simulated motion-affected doses and dynamic measurements, we consider the simulations to provide a reliable basis for assessment of VMAT motion effects that-in the sense of 4D QA of VMAT treatment plans-allows to verify target coverage in hypofractioned VMAT-based radiotherapy of moving targets. Remaining differences between measurements and simulations motivate, however, further detailed studies.


Toward a Robust Estimation of Respiratory Rate From Pulse Oximeters.
Current methods for estimating respiratory rate (RR) from the photoplethysmogram (PPG) typically fail to distinguish between periods of high- and low-quality input data, and fail to perform well on independent "validation" datasets. The lack of robustness of existing methods directly results in a lack of penetration of such systems into clinical practice. The present work proposes an alternative method to improve the robustness of the estimation of RR from the PPG. The proposed algorithm is based on the use of multiple autoregressive models of different orders for determining the dominant respiratory frequency in the three respiratory-induced variations (frequency, amplitude, and intensity) derived from the PPG. The algorithm was tested on two different datasets comprising 95 eight-minute PPG recordings (in total) acquired from both children and adults in different clinical settings, and its performance using two window sizes (32 and 64 seconds) was compared with that of existing methods in the literature. The proposed method achieved comparable accuracy to existing methods in the literature, with mean absolute errors (median, 25[Formula: see text]-75[Formula: see text] percentiles for a window size of 32 seconds) of 1.5 (0.3-3.3) and 4.0 (1.8-5.5) breaths per minute (for each dataset respectively), whilst providing RR estimates for a greater proportion of windows (over 90% of the input data are kept). Increased robustness of RR estimation by the proposed method was demonstrated. This work demonstrates that the use of large publicly available datasets is essential for improving the robustness of wearable-monitoring algorithms for use in clinical practice.


Recent dynamics and condition of coral reefs in the Colombian Caribbean.
Long-term monitoring data provide a basis to recognize changes in coral reef communities and to implement appropriate management strategies. Unfortunately, coral reef dynamics have been poorly documented at any temporal scale in the Southern Caribbean. Through the "National Monitoring System of Coral Reefs in Colombia" (Spanish acronym: SIMAC), we assessed 32 permanent plots at different depth levels in six reefs areas of the Colombian Caribbean from 1998 to 2004. Temporal trends in coral and algal cover were evaluated by repeated measures ANOVA. The model included the effect of depth levels (a fixed effect), monitoring plots (a random effect) as a nested factor within depths, and time (repeated factor). We found high spatial variability in major benthic components. Overall means indicated that algae were the most abundant biotic component in nearly all areas, ranging from 30.3% at Rosario to 53.3% at San Andrés. Live coral cover varied considerably from 10.1% at Santa Marta up to 43.5% at Urabá. Coral and algae cover per se are not always accurate reef indicators and therefore they need supplementary information. Temporal analyses suggested relative stability of coral and algal cover along the study but the causes for the observed trends were rarely identified. A significant decrease (p = 0.042) in coral cover was only identified for some monitoring plots in Tayrona-time x plot (depth level) interaction, and importantly, few coral species explained this trend. Significant increase (p = 0.005) in algal cover was observed over time for most plots in Rosario. Temporal trajectories in algal cover were influenced by depth-significant time x depth interaction-in San Andrés (increase, p = 0.004) and Urabá (decrease, p = 0.027). Algae trends were mainly explained by changes in algal turfs. Monitoring programs must focus on the mechanisms mediating the changes, in particular those concerning coral recovery and reef resilience in the current context of climate change.


The role of surgeon error in withdrawal of postoperative life support.
Surgeons may be reluctant to withdraw postoperative life support after a poor outcome. A cross-sectional random sample was taken from a US mail survey of 2100 surgeons who routinely perform high-risk operations. We used a hypothetical vignette of a specialty-specific operation complicated by a hemiplegic stroke and respiratory failure. On postoperative day 7, the patient and family requested withdrawal of life-supporting therapy. We experimentally modified the timing and role of surgeon error to assess their influence on surgeons' willingness to withdraw life-supporting care. The adjusted response rate was 56%. Sixty-three percent of respondents would not honor the request to withdraw life-supporting treatment. Willingness to withdraw life-support was significantly lower in the setting of surgeon error (33% vs 41%, P < 0.008) and elective operations rather than in emergency cases (33% vs 41%, P = 0.01). After adjustment for specialty, years of experience, geographic region, and gender, odds of withdrawing life-supporting therapy were significantly greater in cases in which the outcome was not explicitly from error during an emergency operation as compared to iatrogenic injury in elective cases (odds ratio 1.95, 95% confidence intervals 1.26-3.01). Surgeons who did not withdraw life-support were significantly more likely to report the importance of optimism regarding prognosis (79% vs 62%, P < 0.0001) and concern that the patient could not accurately predict future quality of life (80% vs 68%, P < 0.0001). Surgeons are more reluctant to withdraw postoperative life-supporting therapy for patients with complications from surgeon error in the elective setting. This may also be influenced by personal optimism and a belief that patients are unable to predict the value of future health states.


Postidentification feedback affects subsequent eyewitness identification performance.
Eyewitnesses sometimes view more than one lineup during an investigation. We investigated the effects of postidentification feedback following one lineup on responses to a second lineup. Witnesses (N=621) viewed a mock crime and, later, attempted to identify the culprit from an initial (target-absent) lineup and a second (target-present or target-absent) lineup. Prior to viewing the second lineup, some witnesses received accurate feedback stating that the initial lineup did not contain the culprit. A compound-decision, signal detection approach allowed the effects of feedback on identification responses to be described in terms of differences in discriminability and response bias. For witnesses who made an incorrect foil identification from the initial lineup, feedback (vs. no feedback) was associated with poorer discriminability on the second test. For witnesses who correctly rejected the initial lineup, feedback (vs. no feedback) was associated with greater discriminability on the second test. Only witnesses who received feedback after an initial correct rejection performed at a level comparable with a single-lineup control group, suggesting that an initial identification test can impair, but not enhance, performance on a second test involving the same culprit. From a theoretical perspective, the results are consistent with the idea that the way people use memorial information when making memory decisions is flexible. Analyses of preidentification confidence ratings, obtained in a follow-up study (N=133), suggested that the effects of feedback on identification performance may have operated via differences in witnesses' metacognitive beliefs.


Changes in inflammatory biomarkers after renal revascularization in atherosclerotic renal artery stenosis.
Atherosclerotic renal artery stenosis (ARAS) activates oxidative stress and chronic inflammatory injury. Contrast imaging and endovascular stenting pose potential hazards for acute kidney injury, particularly when superimposed upon reduced kidney perfusion. We measured sequential early and long-term changes in circulating inflammatory and injury biomarkers in 12 ARAS subjects subjected to computed tomography imaging and stent revascularization compared with essential hypertensive (EH) subjects of similar age under fixed sodium intake and medication regimens in a clinical research unit. NGAL, TIMP-2, IGFBP7, MCP-1 and TNF-α all were elevated before intervention. Post-stenotic kidney volume, perfusion, blood flow and glomerular filtration rate (GFR) were lower in ARAS than in EH subjects. TIMP-2 and IGFBP7 fell briefly, then rose over 18 h after contrast imaging and stent deployment. Circulating NGAL decreased and remained lower for 27 h. These biomarkers in ARAS returned to baseline after 3 months, while kidney volume, perfusion, blood flow and GFR increased, but remained lower than EH. These divergent patterns of inflammatory signals are consistent with cell cycle arrest (TIMP-2, IGFBP7) and relative protection from acute kidney injury after imaging and stenting. Sustained basal elevation of circulating and renal venous inflammatory biomarkers support ongoing, possibly episodic, renal stress in ARAS that limits toxicity from stent revascularization.


Cyanoacrylate Dermal Closure in Spine Surgery: Systematic Review and Pooled Analysis.
Systematic review. Cyanoacrylate glue closure has been utilized for dermal closure in surgical incisions. Its safety and efficacy in spine surgery are not established. The authors perform a systematic review to determine the rate of surgical site infection (SSI), wound dehiscence, and wound erythema with cyanoacrylate dermal closure in spine surgery. A systematic review adhering to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was performed utilizing the PubMed/MEDLINE, EMBASE, and Cochrane databases on patients undergoing spine surgery with cyanoacrylate dermal closure. Pooled analysis was performed with stratification of patients according to spinal level and the presence/absence of instrumentation. Risk-of-bias and methodological quality was appraised using 17 prespecified criteria. Five articles (1 retrospective cohort study, 4 cases series) with a total of 1282 patients were included. A total of 967 patients, all diagnosed with degenerative spine disease, were suitable for pooled analysis. In 290 patients who underwent anterior cervical discectomy and fusion, and in 23 patients with posterior cervical decompression (without instrumentation), there was 0% rate of SSI, wound dehiscence, and erythema. In 489 patients who underwent lumbar microdiscectomy, there was 0.41% rate of SSI, 0.20% rate of wound dehiscence, and 0.20% rate of wound erythema. In 165 lumbar laminectomy patients, there was a 1.82% rate of SSI, 0.61% rate of wound dehiscence, and 0% rate of wound erythema. Cyanoacrylate dermal closure for the aforementioned procedures is associated with low rates of wound complications (SSI, dehiscence, and erythema). Further studies should be performed, especially in nondegenerative surgery, instrumented thoracic and lumbar spine surgery.


Estrogen adversely affects the prognosis of patients with lung adenocarcinoma.
Estrogen has been postulated to contribute to the development and progression of lung cancer. We examined the epidemiologic evidence, explored the characteristics of estrogen receptors (ER) in lung adenocarcinoma, and investigated the effect of estrogen on lung cancer cell migration, including the signaling pathway involved. For epidemiologic evidence, a total of 1434 consecutive non-small cell lung cancer patients who underwent standardized staging and homogenous treatment were prospectively enrolled from January 2002 to December 2008, and followed until December 2012. The possible prognostic factors to be analyzed included stage, age, gender, menopausal status, smoking history and histology. For laboratory study, lung cancer cell lines A549 and PE089 and malignant pleural effusions from the patients with lung adenocarcinoma were used. We found that the premenopausal patients had more advanced disease and a shorter survival among the never-smoking female patients with lung adenocarcinoma. ERβ was the predominant ER in the lung cancer cell lines. We proposed a different pathway that estrogen upregulated the expression of osteopontin and then promoted cell migration through αvβ3 integrin binding and activated MEK-ERK signaling pathway, which is a common downstream pathway with epidermal growth factor receptor (EGFR) activation. An additive effect of ER antagonists and EGFR antagonists on the inhibition of cell migration was also noted. Our results suggest that estrogen adversely affects the prognosis of patients with lung adenocarcinoma. Osteopontin contributed to the cross-talk between ER and EGFR signaling pathways. Estrogen, with its receptor, has the potential to be a prognosticator and a therapeutic target in lung cancer.


The corticostriatal junction: a crucial region for forebrain development and evolution.
Most parts of the brain are conserved across reptiles and birds (sauropsids) and mammals. Two major qualitative differences occur in the upper part, or pallium, of the telencephalon, the most rostral part of the brain. Mammals have a six-layered neocortex and also exhibit a different morphological organization in the lateral half, or sector, of their pallium than do sauropsids. These differences of lateral pallial construction may derive from small but crucial differences in migration patterns of neuronal precursors generated at or above the corner of the lateral ventricle, the corticostriatal junction (CS). Sauropsids have a large structure, the dorsal ventricular ridge, that is proliferated from this region, and its anterior part (ADVR) receives ascending projections from the dorsal thalamus. Mammals have multiple structures in this same region-the lateral part of neocortex, amygdala, and claustrum-endopiriform formation. We propose here that, as the degree of development of structures that form the deeper tier of the pallium varies across the stages of embryology and across phylogeny, mutations may have occurred during evolution at the origin of mammals that had profound consequences for the fate of neural populations generated in the region of the CS and its neighboring pallial germinal zone.


Effects of forage source and extruded linseed supplementation on methane emissions from growing dairy cattle of differing body weights.
Changes in diet carbohydrate amount and type (i.e., starch vs. fiber) and dietary oil supplements can affect ruminant methane emissions. Our objectives were to measure methane emissions, whole-tract digestibility, and energy and nitrogen utilization from growing dairy cattle at 2 body weight (BW) ranges, fed diets containing either high maize silage (MS) or high grass silage (GS), without or with supplemental oil from extruded linseed (ELS). Four Holstein-Friesian heifers aged 13 mo (BW range from start to finish of 382 to 526 kg) were used in experiment 1, whereas 4 lighter heifers aged 12 mo (BW range from start to finish of 292 to 419 kg) were used in experiment 2. Diets were fed as total mixed rations with forage dry matter (DM) containing high MS or high GS and concentrates in proportions (forage:concentrate, DM basis) of either 75:25 (experiment 1) or 60:40 (experiment 2), respectively. Diets were supplemented without or with ELS (Lintec, BOCM Pauls Ltd., Wherstead, UK; 260 g of oil/kg of DM) at 6% of ration DM. Each experiment was a 4 × 4 Latin square design with 33-d periods, with measurements during d 29 to 33 while animals were housed in respiration chambers. Heifers fed MS at a heavier BW (experiment 1) emitted 20% less methane per unit of DM intake (yield) compared with GS (21.4 vs. 26.6, respectively). However, when repeated with heifers of a lower BW (experiment 2), methane yield did not differ between the 2 diets (26.6g/kg of DM intake). Differences in heifer BW had no overall effect on methane emissions, except when expressed as grams per kilogram of digestible organic matter (OMD) intake (32.4 vs. 36.6, heavy vs. light heifers). Heavier heifers fed MS in experiment 1 had a greater DM intake (9.4kg/d) and lower OMD (755 g/kg), but no difference in N utilization (31% of N intake) compared with heifers fed GS (7.9 kg/d and 799 g/kg, respectively). Tissue energy retention was nearly double for heifers fed MS compared with GS in experiment 1 (15 vs. 8% of energy intake, respectively). Heifers fed MS in experiment 2 had similar DM intake (7.2 kg/d) and retention of energy (5% of intake energy) and N (28% of N intake), compared with GS-fed heifers, but OMD was lower (741 vs. 765 g/kg, respectively). No effect of ELS was noted on any of the variables measured, irrespective of animal BW, and this was likely due to the relatively low amount of supplemental oil provided. Differences in heifer BW did not markedly influence dietary effects on methane emissions. Differences in methane yield were attributable to differences in dietary starch and fiber composition associated with forage type and source.


Cu- and Pd-catalyzed Ullmann reaction on a hexagonal boron nitride layer.
The Ullmann reaction is being widely adopted as a strategy for on-surface organic synthesis. Herein, we investigated the Ullmann reaction on a hexagonal boron nitride (h-BN) layer grown on an Ni(111) substrate using scanning tunneling microscopy (STM). We explored the catalytic activity of Cu and Pd atoms dosed with the molecular precursors. We found that the dispersed atoms of both metals efficiently catalyze the reaction, but lead to different reaction paths.


Gelatin Microgel Incorporated Poly(ethylene glycol)-Based Bioadhesive with Enhanced Adhesive Property and Bioactivity.
Up to 7.5 wt % of chemically cross-linked gelatin microgel was incorporated into dopamine-modified poly(ethylene glycol) (PEGDM) adhesive to simultaneously improve the material property and bioactivity of the PEG-based bioadhesive. Incorporation of gelatin microgel reduced cure time while it increased the elastic modulus and cross-linking density of the adhesive network. Most notably, the loss modulus values for microgel-containing adhesive were an order of magnitude higher when compared to microgel-free control. This drastic increase in the viscous dissipation ability of the adhesive is attributed to the introduction of reversible physical bonds into the adhesive network with the incorporation of the gelatin microgel. Additionally, incorporation of the microgel increased the adhesive properties of PEGDM by 1.5- to 2-fold. From in vitro cell culture studies, the composite adhesive is noncytotoxic and the incorporation of microgels provided binding site for promoting fibroblast attachment and viability. The subcutaneous implantation study indicated that the microgel-containing PEGDM adhesive is biocompatible and the incorporated microgels provided pockets for rapid cellular infiltration. Gelatin microgel incorporation was demonstrated to be a facile method to simultaneously enhance the adhesive property and the bioactivity of PEG-based adhesive.


Modulation of electroosmotic flows in electron-conducting microchannels by coupled quasi-reversible faradaic and adsorption-mediated depolarization.
A theoretical model is proposed for the description of steady electroosmotic flows within a cylindrical electron-conducting microchannel that is depolarized by faradaic and adsorption-mediated processes. The bipolar electron-transfer (e.t.) reactions are examined in the general situation where the electrolyte contains a quasi-reversible redox couple. The rate of the e.t. reactions is governed by transversal convective diffusion of the electroactive species to/from the surface and a position-dependent degree of reversibility. The nonuniform distribution of the electric field in solution, that is intimately coupled to that of the local faradaic current density, alters the double layer composition along the conducting surface via the occurrence of simultaneous electronic and ionic double layer charging processes. This in turn generates a nonlinear distribution of the zeta potential, which affects the electroosmotic flow. The highly coupled spatial profiles for the concentrations of the electroactive species, the faradaic current density, the electrokinetic potential, the electric field and the electroosmotic velocity in/along the metallic channel are solved by consistent numerical analysis of (i) the convective-diffusion equation, (ii) the generalized Butler-Volmer expression that includes mass transport and electron-transfer kinetic contributions, (iii) the continuity and Navier-Stokes equations, and (iv) the Poisson equation for finite currents. The results reported as a function of the surface properties of the channel and the kinetic characteristics of the e.t. reaction illustrate the deviations of the electroosmotic flow profiles as compared to the typical pluglike distribution predicted by Smoluchowski's equation and encountered for homogeneous and dielectric channels. Manipulation of the flow patterns by bipolar electrochemical means is a promising way to control and optimize the local detection and separation of electroactive molecules or molecules dyed with electroactive elements.


Terahertz and far infrared spectroscopy of alanine-rich peptides having variable ellipticity.
Terahertz spectra of four alanine-rich peptides with known secondary structures were studied by terahertz time domain spectroscopy (THz-TDS) and by Fourier transform infrared spectroscopy (FTIR) using a synchrotron light source and a liquid-helium cooled bolometer. At ambient temperatures the usable bandwidth was restricted to 0.2-1.5 THz by the absorbance of water. The existence of a solvation shell around the peptide in solution was observed and its size estimated to be between 11 and 17 Å. By cooling the peptide solution to 80 K in order to reduce the water absorbance the bandwidth was increased to 0.1-3.0 THz for both THz-TDS and FTIR. Spectra were consistent with monotonic absorbance of the peptide and the existence of a solid amorphous low density solvation shell.


A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation.
Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation. Primary human lung fibroblasts, small airway epithelial cells and blood monocytes were treated with IL-1β or cigarette smoke extract in combination with RvD1 in vitro, production of pro-inflammatory mediators was measured. Mice were exposed to dilute mainstream cigarette smoke and treated with RvD1 either concurrently with smoke or after smoking cessation. The effects on lung inflammation and lung macrophage populations were assessed. RvD1 suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. Treatment of mice with RvD1 concurrently with cigarette smoke exposure significantly reduced neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10. RvD1 promoted differentiation of alternatively activated (M2) macrophages and neutrophil efferocytosis. RvD1 also accelerated the resolution of lung inflammation when given after the final smoke exposure. RvD1 has potent anti-inflammatory and pro-resolving effects in cells and mice exposed to cigarette smoke. Resolvins have strong potential as a novel therapeutic approach to resolve lung injury caused by smoke and pulmonary toxicants.


Clinical outcome of sex therapy. Effects of daily v weekly treatment.
The effectiveness of sex therapy has been questioned recently. The present outcome study of 69 lower-middle-class couples, who were not highly selected with respect to severity of personal and marital distress, used standardized instruments to measure change over five time periods: intake, history, posttherapy, three-month, and one-year follow-up. Using an own-control design, a 15-session weekly treatment was compared with a 15-session daily treatment. Overall, treatment was successful in improving sexual and marital satisfaction as well as specific symptom remission; there was little decline at the three-month and one-year follow-ups. The least symptomatic improvement occurred for erectile problems and female secondary inorgasmic dysfunction, and there was some suggestion of a gradual nonsignificant decline of overall sexual and marital satisfaction at follow-up. The outcome of daily v weekly treatment was generally not different, with only some indication of better results for secondary inorgasmia and erectile failure when treated in the weekly mode.


The Fragility Index of Total Hip Arthroplasty Randomized Control Trials: A Systematic Review.
Although randomized controlled trials (RCTs) are considered the benchmark study design, a change of outcomes for a few patients can lead to a reversal of study conclusions. As such, examination of the fragility index (FI) of RCTs has become an increasingly popular method to provide further information regarding the relative robustness of RCT results. The purpose of this study was to systematically characterize and assess the predictors of the FI RCTs in total hip arthroplasty literature. PubMed/MEDLINE, Embase, and Cochrane were systematically searched for all total hip arthroplasty RCTs published between January 2015 and December 2020, which had an equal assignment of participants to a two parallel-arm study design, examined a surgical intervention, and reported on at least one statistically significant dichotomous outcome in the abstract. Potential factors associated with the FI were examined using the Spearman correlation and Mann-Whitney U test. Thirty-four RCTs were selected, with a median number of study participants of 111 (interquartile range [IQR] 72-171] and a median total number of events of 15 (IQR 9.5 to 29). The median FI was 2 (IQR 1 to 6), while six studies had a FI of 0. In 18 cases (52.9%), the number of patients needed to change from no event to event was less than that loss to follow-up. Larger sample size was found to predictive of a higher FI (rs = 0.367, P = 0.033), but the year of publication, journal impact factor, the calculated power analysis size, and loss to follow-up were not associated with FI. The FI serves as a useful addition to other more commonly used approaches of quantitative analyses, such as P values, effect sizes, and confidence intervals, and widespread reporting the FI may provide clinicians with further information about RCT results. Level I, systematic review of Level I studies.


Beat-based and Memory-based Temporal Expectations in Rhythm: Similar Perceptual Effects, Different Underlying Mechanisms.
Predicting the timing of incoming information allows the brain to optimize information processing in dynamic environments. Behaviorally, temporal expectations have been shown to facilitate processing of events at expected time points, such as sounds that coincide with the beat in musical rhythm. Yet, temporal expectations can develop based on different forms of structure in the environment, not just the regularity afforded by a musical beat. Little is still known about how different types of temporal expectations are neurally implemented and affect performance. Here, we orthogonally manipulated the periodicity and predictability of rhythmic sequences to examine the mechanisms underlying beat-based and memory-based temporal expectations, respectively. Behaviorally and using EEG, we looked at the effects of beat-based and memory-based expectations on auditory processing when rhythms were task-relevant or task-irrelevant. At expected time points, both beat-based and memory-based expectations facilitated target detection and led to attenuation of P1 and N1 responses, even when expectations were task-irrelevant (unattended). For beat-based expectations, we additionally found reduced target detection and enhanced N1 responses for events at unexpected time points (e.g., off-beat), regardless of the presence of memory-based expectations or task relevance. This latter finding supports the notion that periodicity selectively induces rhythmic fluctuations in neural excitability and furthermore indicates that, although beat-based and memory-based expectations may similarly affect auditory processing of expected events, their underlying neural mechanisms may be different.


START (screening tool to alert doctors to the right treatment)--an evidence-based screening tool to detect prescribing omissions in elderly patients.
Inappropriate prescribing encompasses acts of commission i.e. giving drugs that are contraindicated or unsuitable, and acts of omission i.e. failure to prescribe drugs when indicated due to ignorance of evidence base or other irrational basis e.g. ageism. There are considerable published data on the prevalence of inappropriate prescribing; however, there are no recent published data on the prevalence of acts of omission. The aim of this study was to calculate the prevalence of acts of prescribing omission in a population of consecutively hospitalised elderly people. A screening tool (screening tool to alert doctors to the right treatment acronym, START), devised from evidence-based prescribing indicators and arranged according to physiological systems was prepared and validated for identifying prescribing omissions in older adults. Data on active medical problems and prescribed medicines were collected in 600 consecutive elderly patients admitted from the community with acute illness to a teaching hospital. On identification of an omitted medication, the patient's medical records were studied to look for a valid reason for the prescribing omission. Using the START list, we found one or more prescribing omissions in 57.9% of patients. In order of prevalence, the most common prescribing omissions were: statins in atherosclerotic disease (26%), warfarin in chronic atrial fibrillation (9.5%), anti-platelet therapy in arterial disease (7.3%) and calcium/vitamin D supplementation in symptomatic osteoporosis (6%). Failure to prescribe appropriate medicines is a highly prevalent problem among older people presenting to hospital with acute illness. A validated screening tool (START) is one method of systematically identifying appropriate omitted medicines in clinical practice.


Drinking Hydrogen-Rich Water Alleviates Chemotherapy-Induced Neuropathic Pain Through the Regulation of Gut Microbiota.
Chemotherapy-induced neuropathic pain (CINP) is one of the most common complications of chemotherapeutic drugs which limits the dose and duration of potentially life-saving anticancer treatment and compromises the quality of life of patients. Our previous studies have reported that molecular hydrogen (H2) can be used to prevent and treat various diseases. But the underlying mechanism remains unclear. The aim of the present study was to explore the effects of hydrogen-rich water on gut microbiota in CINP. All C57BL/6J mice were divided into 4 groups: The group fed with normal drinking water and injected with saline (H2O + Saline), the group fed with normal drinking water and injected with oxaliplatin (H2O + OXA), the group fed with hydrogen-rich water and injected with saline (HW + Saline), and the group fed with hydrogen-rich water and injected with oxaliplatin (HW + OXA). The mechanical paw withdrawal threshold of the mice was tested on days 0, 5, 10, 15 and 20 after hydrogen-rich water treatment. On day 20, feces of mice from different groups were collected for microbial community diversity and structure analysis. The levels of inflammatory cytokines (TNF-α and IL-6), oxidative stress factors (OH- and ONOO-), lipopolysaccharide (LPS) and Toll-like receptor 4 (TLR4) were detected in dorsal root ganglia (DRG), L4-6 spinal cord segments and serum by enzyme-linked immunosorbent assay. The expression of TLR4 in DRG and spinal cords was determined by Western blot. The results illustrated that hydrogen-rich water could alleviate oxaliplatin-induced hyperalgesia, reduce the microbial diversity and alter the structure of gut microbiota, reverse the imbalance of inflammatory cytokines and oxidative stress, and decrease the expression of LPS and TLR4. Hydrogen-rich water may alleviate CINP by affecting the diversity and structure of the gut microbiota, and then the LPS-TLR4 pathway, which provides a direction for further research.


Theoretical, experimental, and optical coherence tomography (OCT) studies of graft apposition and adhesion in Descemets stripping automated endothelial keratoplasty (DSAEK).
To investigate the effects of adhesion promoting surgical adjuncts in Descemets stripping automated endothelial keratoplasty (DSAEK). The effects of air-fill pressure, duration, use of venting incisions and stromal roughening on fluid dispersion, and donor adhesion strength were examined in theoretical, optical coherence tomography (OCT), and strain gauge models of DSAEK. OCT analysis: DSAEK modeled using a microkeratome prepared lenticule inserted under a "recipient" corneo-scleral rim mounted on an artificial anterior chamber. Pressure of 18 mm Hg (n = 6) or 60 mm Hg (n = 6) was applied. The area of interface fluid was measured sequentially. The area of interface fluid before and after opening of venting incisions was measured (n = 6). Adhesion experiments: Direct measurement of adhesion force using a universal testing machine was performed. Peak adhesion after compression at 60 mm Hg/8 minutes, 60 mm Hg/1 minutes, 18 mm Hg/8 minutes, and 18 mm Hg/1 minutes (n = 8 each group) was measured. Subsequently, adhesion after complete removal of interface fluid and after stromal roughening was measured in separate samples (n = 12). Interface fluid diminishes with time during tamponade at both low and high pressures (P < 0.0001). Pressure had no effect on amount or rate of fluid dispersion. Venting incisions eliminated interface fluid in all samples when opened sufficiently. Adhesion is independent of anterior chamber air tamponade pressure (P = 0.38). Complete removal of interface fluid increases average adhesion (16.0 mN vs. 7.8 mN, P = 0.0001). Roughening of the host stroma increased adhesion (13.8 mN vs. 9.8 mN, P = 0.0034). Venting incisions and stromal roughening aid adhesion in DSAEK. Sustained high-pressure anterior chamber air tamponade has no demonstrable effect on measured fluid dispersion or adhesion strength.


Diethyl pyrocarbonate (an imidazole binding substance) inhibits rostral VLM CO2 sensitivity.
Diethyl pyrocarbonate (DEPC) has been useful in vitro as an agent relatively specific for binding to imidazole of histidine. Administered via the cisterna magna DEPC inhibits central chemosensitivity in conscious rabbits, supporting the alphastat hypothesis for central chemoreceptor function. In this study I have applied DEPC via 1 X 3 mm cottonoid pledgets to each of the three ventrolateral medulla (VLM) chemosensitive areas in glomectomized, vagotomized, paralyzed, and servo-ventilated alpha-chloralose-urethan-anesthetized cats. CO2 responses measured by integrated phrenic nerve output were evaluated before and after DEPC application. A dose of 40 mmol/l applied to the rostral chemosensitive area increased the CO2 threshold (5.3%) and significantly decreased (P less than 0.03; Wilcoxon sign rank test) the initial slope (-43%) and the maximum (-41%) of the CO2 response. No significant effects were observed with DEPC application in the intermediate or caudal areas. Treatment with 40 mmol/l hydroxylamine immediately after DEPC in the rostral area prevented the effects supporting the interpretation that imidazole was the reactant with DEPC. The results are consistent with the hypothesis that imidazole-histidine is involved in the mechanism of central chemoreception and indicate that only the rostral area utilizes a DEPC inhibitable mechanism.


Lactobacillus rhamnosus GG modulates innate signaling pathway and cytokine responses to rotavirus vaccine in intestinal mononuclear cells of gnotobiotic pigs transplanted with human gut microbiota.
A better understanding of mechanisms underlying dose-effects of probiotics in their applications as treatments of intestinal infectious or inflammatory diseases and as vaccine adjuvant is needed. In this study, we evaluated the modulatory effects of Lactobacillus rhamnosus GG (LGG) on transplanted human gut microbiota (HGM) and on small intestinal immune cell signaling pathways in gnotobiotic pigs vaccinated with an oral attenuated human rotavirus (AttHRV) vaccine. Neonatal HGM transplanted pigs were given two doses of AttHRV on 5 and 15 days of age and were divided into three groups: none-LGG (AttHRV), 9-doses LGG (AttHRV + LGG9X), and 14-doses LGG (AttHRV + LGG14X) (n = 3-4). At post-AttHRV-inoculation day 28, all pigs were euthanized and intestinal contents and ileal tissue and mononuclear cells (MNC) were collected. AttHRV + LGG14X pigs had significantly increased LGG titers in the large intestinal contents and shifted structure of the microbiota as indicated by the formation of a cluster that is separated from the cluster formed by the AttHRV and AttHRV + LGG9X pigs. The increase in LGG titers concurred with significantly increased ileal HRV-specific IFN-γ producing T cell responses to the AttHRV vaccine reported in our previous publication, suggesting pro-Th1 adjuvant effects of the LGG. Both 9- and 14-doses LGG fed pig groups had significantly higher IkBα level and p-p38/p38 ratio, while significantly lower p-ERK/ERK ratio than the AttHRV pigs, suggesting activation of regulatory signals during immune activation. However, 9-doses, but not 14-doses LGG fed pigs had enhanced IL-6, IL-10, TNF-α, TLR9 mRNA levels, and p38 MAPK and ERK expressions in ileal MNC. Increased TLR9 mRNA was in parallel with higher mRNA levels of cytokines, p-NF-kB and higher p-p38/p38 ratio in MNC of the AttHRV + LGG9X pigs. The relationship between modulation of gut microbiota and regulation of host immunity by different doses of probiotics is complex. LGG exerted divergent dose-dependent effects on the intestinal immune cell signaling pathway responses, with 9-doses LGG being more effective in activating the innate immunostimulating TLR9 signaling pathway than 14-doses in the HGM pigs vaccinated with AttHRV.


Incorporating Genome-Wide Association Mapping Results Into Genomic Prediction Models for Grain Yield and Yield Stability in CIMMYT Spring Bread Wheat.
Untangling the genetic architecture of grain yield (GY) and yield stability is an important determining factor to optimize genomics-assisted selection strategies in wheat. We conducted in-depth investigation on the above using a large set of advanced bread wheat lines (4,302), which were genotyped with genotyping-by-sequencing markers and phenotyped under contrasting (irrigated and stress) environments. Haplotypes-based genome-wide-association study (GWAS) identified 58 associations with GY and 15 with superiority index Pi (measure of stability). Sixteen associations with GY were "environment-specific" with two on chromosomes 3B and 6B with the large effects and 8 associations were consistent across environments and trials. For Pi, 8 associations were from chromosomes 4B and 7B, indicating 'hot spot' regions for stability. Epistatic interactions contributed to an additional 5-9% variation on average. We further explored whether integrating consistent and robust associations identified in GWAS as fixed effects in prediction models improves prediction accuracy. For GY, the model accounting for the haplotype-based GWAS loci as fixed effects led to up to 9-10% increase in prediction accuracy, whereas for Pi this approach did not provide any advantage. This is the first report of integrating genetic architecture of GY and yield stability into prediction models in wheat.


COVID-19-Related Quarantine Effect on Dietary Habits in a Northern Italian Rural Population: Data from the Brisighella Heart Study.
North of Italy was severely hit by the COVID-19 (Coronavirus disease 19) pandemic. This induced the government to adopt severely restrictive measures to reduce the contagion risk, forcing most of the population to stop working and from leisure activities, and to remain at home for several weeks. Our study aimed to evaluate the effect of COVID-related quarantine on smoking and dietary habits of a well-characterized northern Italian rural population. For this purpose, while lockdown restrictions were in place (February-April 2020), 359 subjects from the Brisighella Heart Study cohort underwent a phone interview about their lifestyle habit changes during COVID-19-related quarantine. Quarantine did not significantly modify smoking habit nor body mass index. Subjects significantly increased daily carbohydrates consumption, all fresh vegetables, healthy vegetable oils, milk and yogurt, alcoholic drinks, sugars and sweets, and coffee. The weekly consumption of low-fat meat, cured meat other than ham, cheeses, eggs, nuts and mixed seed oils significantly increased, while the weekly intake of fish, mussels, and legumes significantly decreased during lockdown. The Dietary Quality Index was reduced from 42.4 ± 4.1 to 37.8 ± 4.7 (p < 0.03). In accordance with our findings, COVID-19-related quarantine might worsen the quality of diet, also leading to an increased intake of almost all food categories.


Factors Influencing the Gut Microbiota, Inflammation, and Type 2 Diabetes.
The gut microbiota is a complex community of bacteria residing in the intestine. Animal models have demonstrated that several factors contribute to and can significantly alter the composition of the gut microbiota, including genetics; the mode of delivery at birth; the method of infant feeding; the use of medications, especially antibiotics; and the diet. There may exist a gut microbiota signature that promotes intestinal inflammation and subsequent systemic low-grade inflammation, which in turn promotes the development of type 2 diabetes. There are preliminary studies that suggest that the consumption of probiotic bacteria such as those found in yogurt and other fermented milk products can beneficially alter the composition of the gut microbiome, which in turn changes the host metabolism. Obesity, insulin resistance, fatty liver disease, and low-grade peripheral inflammation are more prevalent in patients with low α diversity in the gut microbiome than they are in patients with high α diversity. Fermented milk products, such as yogurt, deliver a large number of lactic acid bacteria to the gastrointestinal tract. They may modify the intestinal environment, including inhibiting lipopolysaccharide production and increasing the tight junctions of gut epithelia cells.


Lost in translation: the Canadian access to medicines regime from transnational activism to domestic implementation.
Canada was the first country to implement the WTO Decision of August 30, 2003, authorizing the export of generic drugs manufactured under a compulsory license to developing countries in response to a proposal brought forward by non-governmental organizations (NGOs) that now claim dissatisfaction with the Canadian legislation. This empirical case study examines what success means for an NGO campaign. It contrasts interviews, documents, media coverage, and public statements of stakeholders, using quantitative and qualitative analyses. It concludes the NGO network experienced a shift from a mobilizer of public sentiment at the international level to a policy adviser at the domestic level. This shift crystallized a change in leadership toward local, rather than transnational NGOs, and a shift in strategy from being radical to more reformist. While this process of institutionalizing the outcomes of international campaigns is necessary for the implementation of international norms into domestic policy, it required NGOs to compromise their ideal positions, producing some objective successes in legislative reform but subjective dissatisfaction of the NGOs in the failure of Canada's domestic regime to enhance access to medicines on the ground in developing countries.


Classification of positive blood cultures: computer algorithms versus physicians' assessment--development of tools for surveillance of bloodstream infection prognosis using population-based laboratory databases.
Information from blood cultures is utilized for infection control, public health surveillance, and clinical outcome research. This information can be enriched by physicians' assessments of positive blood cultures, which are, however, often available from selected patient groups or pathogens only. The aim of this work was to determine whether patients with positive blood cultures can be classified effectively for outcome research in epidemiological studies by the use of administrative data and computer algorithms, taking physicians' assessments as reference. Physicians' assessments of positive blood cultures were routinely recorded at two Danish hospitals from 2006 through 2008. The physicians' assessments classified positive blood cultures as: a) contamination or bloodstream infection; b) bloodstream infection as mono- or polymicrobial; c) bloodstream infection as community- or hospital-onset; d) community-onset bloodstream infection as healthcare-associated or not. We applied the computer algorithms to data from laboratory databases and the Danish National Patient Registry to classify the same groups and compared these with the physicians' assessments as reference episodes. For each classification, we tabulated episodes derived by the physicians' assessment and the computer algorithm and compared 30-day mortality between concordant and discrepant groups with adjustment for age, gender, and comorbidity. Physicians derived 9,482 reference episodes from 21,705 positive blood cultures. The agreement between computer algorithms and physicians' assessments was high for contamination vs. bloodstream infection (8,966/9,482 reference episodes [96.6%], Kappa = 0.83) and mono- vs. polymicrobial bloodstream infection (6,932/7,288 reference episodes [95.2%], Kappa = 0.76), but lower for community- vs. hospital-onset bloodstream infection (6,056/7,288 reference episodes [83.1%], Kappa = 0.57) and healthcare-association (3,032/4,740 reference episodes [64.0%], Kappa = 0.15). The 30-day mortality in the discrepant groups differed from the concordant groups as regards community- vs. hospital-onset, whereas there were no material differences within the other comparison groups. Using data from health administrative registries, we found high agreement between the computer algorithms and the physicians' assessments as regards contamination vs. bloodstream infection and monomicrobial vs. polymicrobial bloodstream infection, whereas there was only moderate agreement between the computer algorithms and the physicians' assessments concerning the place of onset. These results provide new information on the utility of computer algorithms derived from health administrative registries.


The Effect of Macronutrients on Reproductive Hormones in Overweight and Obese Men: A Pilot Study.
Hypogonadal obese men find it difficult to lose weight. We investigated whether the modification of macronutrient intake can alter testosterone levels independently of the body mass index. Fasted overweight or obese fertile men were asked to consume meals of polyunsaturated fats (PUFA), monounsaturated fats (MUFA), refined carbohydrates (CHO, orange juice, OJ), whey and egg albumin and mixed meals of PUFA and CHO, PUFA and egg albumin, and CHO and egg albumin. Blood was collected at fasting, then hourly for 5 h and analysed to determine the levels of testosterone and other hormones. We found PUFA and MUFA or a mixed meal of PUFA and CHO significantly reduced serum testosterone production to a similar degree over a 5 h period. PUFA decreased serum testosterone levels by 3.2 nmol/L after 1 h compared to baseline (p = 0.023), with this suppression remaining significant up to 5 h postprandially (2.1 nmol/L; p = 0.012). The net overall testosterone levels were reduced by approximately 10 nmol/L × h by PUFA, MUFA and PUFA combined with CHO. CHO alone had little effect on testosterone levels, whereas egg albumin was able to increase them (7.4 cf 2.0 nmol/L × h). Therefore, for men wishing to optimize their testosterone levels, it may be wise to avoid a high fat intake, drink liquids such as water or OJ or even consider fasting. ANZCTR, Australia; ACTRN12617001034325.


Functional rescue of dystrophin-deficient mdx mice by a chimeric peptide-PMO.
Splice modulation using antisense oligonucleotides (AOs) has been shown to yield targeted exon exclusion to restore the open reading frame and generate truncated but partially functional dystrophin protein. This has been successfully demonstrated in dystrophin-deficient mdx mice and in Duchenne muscular dystrophy (DMD) patients. However, DMD is a systemic disease; successful therapeutic exploitation of this approach will therefore depend on effective systemic delivery of AOs to all affected tissues. We have previously shown the potential of a muscle-specific/arginine-rich chimeric peptide-phosphorodiamidate morpholino (PMO) conjugate, but its long-term activity, optimized dosing regimen, capacity for functional correction and safety profile remain to be established. Here, we report the results of this chimeric peptide-PMO conjugate in the mdx mouse using low doses (3 and 6 mg/kg) administered via a 6 biweekly systemic intravenous injection protocol. We show 100% dystrophin-positive fibers and near complete correction of the dystrophin transcript defect in all peripheral muscle groups, with restoration of 50% dystrophin protein over 12 weeks, leading to correction of the DMD pathological phenotype and restoration of muscle function in the absence of detectable toxicity or immune response. Chimeric muscle-specific/cell-penetrating peptides therefore represent highly promising agents for systemic delivery of splice-correcting PMO oligomers for DMD therapy.


Reactive mode composition factor analysis of transition states: the case of coupled electron-proton transfers.
A simple method for the evaluation of the kinetic energy distribution within the reactive mode of a transition state (TS), denoted as the Reactive Mode Composition Factor (RMCF), is presented. It allows one to directly map the barrier properties onto the atomic-motion components of the reaction coordinate at the TS, which has potential to shed light onto some mechanistic features of a chemical process. To demonstrate the applicability of RMCF to reactivity, we link the kinetic energy distribution within a reactive mode with the asynchronicity (η) in C-H bond activation, as they both evolve in a series of coupled proton-electron transfer (CPET) reactions between FeIVO oxidants and 1,4-cyclohexadiene. RMCF shows how the earliness or lateness of a process manifests as a redistribution of kinetic energy in the reactive mode as a function of the free energy of reaction (ΔG0) and η. Finally, the title analysis can be applied to predict H-atom tunneling contributions and kinetic isotope effects in a set of reactions, yielding a transparent rationalization based on the kinetic energy distributions in the reactive mode.


Effectiveness of Interventions for Children With Autism Spectrum Disorder and Their Parents: A Systematic Review of Family Outcomes.
This systematic review examined the literature published from January 2006 to April 2013 related to the effectiveness of occupational therapy interventions for children with autism spectrum disorder (ASD) and their parents to improve parental stress and self-efficacy, coping, and resilience and family participation in daily life and routines. From the 4,457 abstracts, 34 articles were selected that matched the inclusion criteria. The results were mixed and somewhat inconclusive because this body of literature is in its infancy. Studies of children with ASD do not routinely measure parental and family outcomes. Recommendations include an emphasis on family measures other than parental stress and a greater focus on measures of parental and family functioning in all future studies of pediatric interventions to more fully understand the impact of interventions in a wider context.


What is perfect health to an 85-year-old?: evidence for scale recalibration in subjective health ratings.
If an 85-year-old man rates his health as 90 on a scale in which 100 represents "perfect health," would his rating mean the same thing as a 90 rating from a 25-year-old? We conducted a randomized trial of 3 different ways of eliciting subjective health ratings from participants in the Health and Retirement Study to test whether the meaning of perfect health changes as people age, causing people to recalibrate their self-reported health ratings to account for their age. The Health and Retirement Study (HRS) is a nationally representative, prospective study of 22,000 persons born in 1947 or earlier. The data analyzed in this study come from the self-assessed health utilities module administered in 2002 to 1031 randomly selected HRS respondents. Respondents were randomized to receive one of 3 versions of a subjective health rating task. In the perfect health version, they were asked how they would rate their "current health on a scale from 0 to 100, in which 0 represents death and 100 represents perfect health." In the your-age version, the phrase "for someone your age" was added to the end of the question to encourage people to recalibrate their responses based on age, and in the 20-year-old version, the phrase "for a 20-year-old" was added to minimize recalibration. A total of 1015 subjects responded to the rating task (98% response rate). Health ratings varied significantly across versions, with subjects responding to the 20-year-old version reporting lower health (mean rating 66 of 100) than those responding to the your-age version (mean rating of 73, P<0.001) or the perfect health version (mean rating of 73, P<0.001). This result suggests that subjects interpret perfect health to mean "perfect health for someone your age." However, additional analysis showed that the interpretation of the phrase perfect health lies somewhere between the other 2 versions. For example, responses to the perfect health and 20-year-old versions varied significantly by respondent age (both P's<0.075), whereas responses to the your-age scale did not (P=0.8). The phrase "perfect health" is ambiguous, causing some people to recalibrate their responses based on their age. Such ambiguity threatens the validity of common subjective health ratings, thereby reducing the comparability of responses across people of different ages or different circumstances.


Effect of pretransplantation ursodeoxycholic acid therapy on the outcome of liver transplantation in patients with primary biliary cirrhosis.
As ursodeoxycholic acid (UDCA) delays the need for transplantation, this could result in patients with more comorbid disease, therefore more likely to have a worse outcome posttransplantation. The aim of this study is to compare posttransplantation outcome in patients who received UDCA versus placebo who subsequently required a liver transplant. Data on all trial patients referred for transplantation were retrospectively collected from three randomized controlled trials of UDCA in patients with primary biliary cirrhosis (PBC). An intent-to-treat analysis was conducted with patients assigned to their original treatment allocation. UDCA and placebo groups were compared at trial entry, transplant referral, just before transplantation, and 1 month and 1 year posttransplantation. From 1987 to 1996, 37 UDCA-treated and 53 placebo patients were referred for transplantation; their age, sex, and serum bilirubin levels were similar at study entry. Immediately before transplantation, these two groups were again similar with respect to age, bilirubin level, Mayo risk score, and serum creatinine level. Posttransplantation survival rates at 1 month were 93.9% in the UDCA group and 88.4% in the placebo group, and 1 year survival rates were 90.3% and 78.4%, respectively (not significant). Posttransplantation, the two groups had similar rates of infection (53.9% v 58%); however, rejection occurred significantly less often in the UDCA group; 42.9% versus 68. 8% in the placebo group (P =.04). The posttransplantation outcome of UDCA-treated patients with PBC is no different from those who were administered placebo. There is no evidence to suggest the beneficial effect of UDCA in delaying the need for transplantation is associated with a worse outcome once liver transplantation becomes necessary.


An online database for informing ecological network models: http://kelpforest.ucsc.edu.
Ecological network models and analyses are recognized as valuable tools for understanding the dynamics and resiliency of ecosystems, and for informing ecosystem-based approaches to management. However, few databases exist that can provide the life history, demographic and species interaction information necessary to parameterize ecological network models. Faced with the difficulty of synthesizing the information required to construct models for kelp forest ecosystems along the West Coast of North America, we developed an online database (http://kelpforest.ucsc.edu/) to facilitate the collation and dissemination of such information. Many of the database's attributes are novel yet the structure is applicable and adaptable to other ecosystem modeling efforts. Information for each taxonomic unit includes stage-specific life history, demography, and body-size allometries. Species interactions include trophic, competitive, facilitative, and parasitic forms. Each data entry is temporally and spatially explicit. The online data entry interface allows researchers anywhere to contribute and access information. Quality control is facilitated by attributing each entry to unique contributor identities and source citations. The database has proven useful as an archive of species and ecosystem-specific information in the development of several ecological network models, for informing management actions, and for education purposes (e.g., undergraduate and graduate training). To facilitate adaptation of the database by other researches for other ecosystems, the code and technical details on how to customize this database and apply it to other ecosystems are freely available and located at the following link (https://github.com/kelpforest-cameo/databaseui).


Dextran 70 in prophylaxis of thromboembolic disease after surgery: a clinically oriented randomized double-blind trial.
A randomized double-blind trial of prophylaxis of thromboembolism in surgical patients judged by clinical morbidity has been completed. Altogether 831 patients over 40 years of age who underwent elective surgery of the stomach, biliary system, or colon received either dextran 70 or normal saline before the operation. Thirteen of the 435 patients on saline and three of the 396 on dextran developed pulmonary embolism. Eight of these 16 patients died of pulmonary embolism--seven in the saline group and one in the dextran group. As detected either clinically or by 125I-fibrinogen scanning the incidence of deep vein thrombosis was similar in the two groups. There was no increased incidence of excessive bleeding in patients on dextran though clinical impression suggested that some patients on dextran bled excessively. This trial showed that dextran 70 administered by intravenous drip during operation is effective in preventing pulmonary embolism and, in particular, reducing mortality from this cause. It seems to be as effective as subcutaneous heparin but is easier to administer and places less of a burden on nursing services.


Cerebellar Contribution to Preparatory Activity in Motor Neocortex.
In motor neocortex, preparatory activity predictive of specific movements is maintained by a positive feedback loop with the thalamus. Motor thalamus receives excitatory input from the cerebellum, which learns to generate predictive signals for motor control. The contribution of this pathway to neocortical preparatory signals remains poorly understood. Here, we show that, in a virtual reality conditioning task, cerebellar output neurons in the dentate nucleus exhibit preparatory activity similar to that in anterolateral motor cortex prior to reward acquisition. Silencing activity in dentate nucleus by photoactivating inhibitory Purkinje cells in the cerebellar cortex caused robust, short-latency suppression of preparatory activity in anterolateral motor cortex. Our results suggest that preparatory activity is controlled by a learned decrease of Purkinje cell firing in advance of reward under supervision of climbing fiber inputs signaling reward delivery. Thus, cerebellar computations exert a powerful influence on preparatory activity in motor neocortex.


The allelic distribution of a single nucleotide polymorphism in the PDCD5 gene locus of Japanese non-small cell lung cancer patients.
It has been reported that the rs1862214 single nucleotide polymorphism (SNP) in the programmed cell death 5 gene (PDCD5) is associated with smoking-related lung cancer risk and prognosis in a European population with a history of smoking. The aim of this study was to investigate the status and impact of SNPs in the PDCD5 locus of a Japanese population. We developed an assay based on real-time PCR with melting curve analysis for determining the rs1862214 SNP, and examined this SNP in 165 lung cancer patients and 180 healthy volunteers. Of the 165 lung cancer patients (107 smokers), 25 (17), 72 (47) and 68 (43) had the CC, CG and GG genotypes of rs1862214, respectively. Of the 180 volunteers (117 smokers), 31 (24), 81 (52) and 68 (41) had the CC, CG and GG genotypes of rs1862214, respectively. No significant difference in allelic distribution was found between Japanese patients and healthy controls, even among smokers. Based on the published data, the distribution of this SNP appears to be significantly different in Japanese and European populations. No significant difference in prognosis according to the SNP was observed, either in patients with a history of smoking or in the total number of patients. This too differs from the results from a European population. In conclusion, we developed a convenient real-time PCR-based assay for the genotyping of rs1862214 in the PDCD5 locus. The distribution of the rs1862214 SNP in our Japanese population differs from its distribution in a European population, and is not related to the risk of cancer or to poor prognosis in lung cancer. This suggests the presence of an ethnicity-related difference in the role of PDCD5 in the pathogenesis of lung cancer.


Evaluating the evidence for models of life course socioeconomic factors and cardiovascular outcomes: a systematic review.
A relatively consistent body of research supports an inverse graded relationship between socioeconomic status (SES) and cardiovascular disease (CVD). More recently, researchers have proposed various life course SES hypotheses, which posit that the combination, accumulation, and/or interactions of different environments and experiences throughout life can affect adult risk of CVD. Different life course designs have been utilized to examine the impact of SES throughout the life course. This systematic review describes the four most common life course hypotheses, categorizes the studies that have examined the associations between life course SES and CVD according to their life course design, discusses the strengths and weaknesses of the different designs, and summarizes the studies' findings. This research reviewed 49 observational studies in the biomedical literature that included socioeconomic measures at a time other than adulthood as independent variables, and assessed subclinical CHD, incident CVD morbidity and/or mortality, and/or the prevalence of traditional CVD risk factors as their outcomes. Studies were categorized into four groups based upon life course design and analytic approach. The study authors' conclusions and statistical tests were considered in summarizing study results. Study results suggest that low SES throughout the life course modestly impacts CVD risk factors and CVD risk. Specifically, studies reviewed provided moderate support for the role of low early-life SES and elevated levels of CVD risk factors and CVD morbidity and mortality, little support for a unique influence of social mobility on CVD, and consistent support for the detrimental impact of the accumulation of negative SES experiences/conditions across the life course on CVD risk. While the basic life course SES study designs have various methodologic and conceptual limitations, they provide an important approach from which to examine the influence of social factors on CVD development. Some limitations may be addressed through the analysis of study cohorts followed from childhood, the evaluation of CVD risk factors in early and middle adulthood, and the use of multiple SES measures and multiple life course analysis approaches in each life course study.


Killing Mycobacterium tuberculosis In Vitro: What Model Systems Can Teach Us.
Tuberculosis is one of the most successful human diseases in our history due in large part to the multitude of virulence factors exhibited by the causative agent, Mycobacterium tuberculosis. Understanding the pathogenic nuances of this organism in the context of its human host is an ongoing topic of study facilitated by isolating cells from model organisms such as mice and non-human primates. However, M. tuberculosis is an obligate intracellular human pathogen, and disease progression and outcome in these model systems can differ from that of human disease. Current in vitro models of infection include primary macrophages and macrophage-like immortalized cell lines as well as the induced pluripotent stem cell-derived cell types. This article will discuss these in vitro model systems in general, what we have learned so far about utilizing them to answer questions about pathogenesis, the potential role of other cell types in innate control of M. tuberculosis infection, and the development of new coculture systems with multiple cell types. As we continue to expand current in vitro systems and institute new ones, the knowledge gained will improve our understanding of not only tuberculosis but all infectious diseases.


Discriminative stimulus properties of intragastrically administered d-amphetamine and pentobarbital in rhesus monkeys.
Rhesus monkeys were trained to discriminate intragastrically administered d-amphetamine (AMPH) or pentobarbital (PENTO) from saline using a signaled shock-avoidance trail procedure. All monkeys maintained criterion levels (greater than 90% drug-appropriate responding) throughout the duration of the study during training sessions. In the AMPH experiment, the anorectics diethylpropion, mazindol, phendimetrazine, phenmetrazine and phentermine completely substituted for the training dose of AMPH. The atypical antidepressant bupropion and the psychomotor stimulant methylphenidate also completely substituted for AMPH. Other anorectics including benzphetamine, clortermine, fenetylline, mefenorex and the psychomotor stimulant pemoline that share some pharmacological properties with AMPH substituted for AMPH in some, but not all, of the monkeys tested. The anorectics fenfluramine and chlorphentermine failed to substitute for AMPH. Drugs from other pharmacological classes such as morphine, diazepam, nortripyline and PENTO also failed to substitute for AMPH, indicating pharmacological specificity. In the PENTO experiment, the benzodiazepines alprazolam, bromazepam, diazepam, flurazepam, halazepam, lorazepam, midazolam, oxazepam, temazepam and triazolam and the sedatives methaqualone and phenobarbital completely substituted for the training dose of PENTO. The nonbenzodiazepine anxiolytic CL 218,872 only partially substituted for PENTO. In addition, morphine and AMPH failed to substitute for PENTO, indicating pharmacological specificity. In summary, drugs delivered intragastrically functioned as discriminative stimuli in a drug-class specific manner. The ability to use drugs delivered by this route as discriminative stimuli provides a way to compare anorectic drugs to AMPH or sedative drugs to PENTO under conditions that resemble the mode of human consumption to determine whether these drugs are likely to be associated with AMPH-like or PENTO-like drug dependence.