Exploring and Mobilizing the Gene Bank Biodiversity for Wheat Improvement.
Identifying and mobilizing useful genetic variation from germplasm banks to breeding programs is an important strategy for sustaining crop genetic improvement. The molecular diversity of 1,423 spring bread wheat accessions representing major global production environments was investigated using high quality genotyping-by-sequencing (GBS) loci, and gene-based markers for various adaptive and quality traits. Mean diversity index (DI) estimates revealed synthetic hexaploids to be genetically more diverse (DI= 0.284) than elites (DI = 0.267) and landraces (DI = 0.245). GBS markers discovered thousands of new SNP variations in the landraces which were well known to be adapted to drought (1273 novel GBS SNPs) and heat (4473 novel GBS SNPs) stress environments. This may open new avenues for pre-breeding by enriching the elite germplasm with novel alleles for drought and heat tolerance. Furthermore, new allelic variation for vernalization and glutenin genes was also identified from 47 landraces originating from Iraq, Iran, India, Afghanistan, Pakistan, Uzbekistan and Turkmenistan. The information generated in the study has been utilized to select 200 diverse gene bank accessions to harness their potential in pre-breeding and for allele mining of candidate genes for drought and heat stress tolerance, thus channeling novel variation into breeding pipelines. This research is part of CIMMYT's ongoing 'Seeds of Discovery' project visioning towards the development of high yielding wheat varieties that address future challenges from climate change.


Design of interventional studies in thoracic surgery.
Interventional studies differ from observational studies in that one or more specific interventions are evaluated. Randomized controlled trials remain the gold standard for interventional studies and can take different forms. In surgical studies, the three types of randomized controlled trials most commonly encountered are: (I) trials that compare two different medical treatments for patients undergoing surgery; (II) trials that evaluate two different surgical techniques and (III) studies that compare surgery vs. non-operative management. When an intervention is to be evaluated but a randomized controlled trial is not feasible, alternative interventional study designs may be considered.


Restoring healthy developmental trajectories for sexually exploited young runaway girls: fostering protective factors and reducing risk behaviors.
To examine effects of the Runaway Intervention Program (RIP), a strengths-based home visiting, case management, and group support program for sexually assaulted or exploited young runaway girls; staffed by advanced-practice nurses, RIP aims to restore healthy developmental trajectories by reestablishing protective factors, reducing trauma responses, and lowering risk behaviors that are common sequelae of sexual violence. Quasi-experimental study of RIP girls (N = 68) ages 12 to 15 (mean, 13.75 years), assessed at baseline, 6 and 12 months for changes in family and school connectedness, other adult caring, self-esteem, emotional distress, suicidality, recent substance use, plus risky sexual behaviors. Responses at each time were also compared to nonabused and abused urban ninth-grade girls (mean age, 14.64, N = 12,775) from the 2004 Minnesota Student Survey (MSS). Analyses used paired t-tests, McNemars test, Wilcoxon sign-rank, chi-square, and Pearson's correlations. At entry, RIP girls were most like sexually abused MSS peers, with lower levels of protective factors and higher levels of distress and risk behaviors than nonabused MSS girls (p < .05 to p < .01). However, they saw significant improvements by 6 and 12 months, such that all measures of protective factors, positive development, distress, and risk behaviors more closely resembled nonabused MSS girls by 12 months. Of equal note, RIP girls with the greatest emotional distress, the lowest levels of connectedness, and lowest self-esteem at baseline demonstrated the greatest improvement (all p < .001). This appears to be a promising intervention for restoring sexually abused runaway girls to a healthy developmental trajectory.


Efficacy of tablet huperzine-A on memory, cognition, and behavior in Alzheimer's disease.
To evaluate the efficacy and safety of tablet huperzine-A (Hup) in patients with Alzheimer's disease. Using multicenter, prospective, double-blind, parallel, placebo controlled and randomized method, 50 patients were administered orally 0.2 mg (4 tablets) Hup and 53 patients were given po 4 tablets of placebo bid for 8 wk. All patients were evaluated with Wechsler memory scale, Hasegawa dementia scale, mini-mental state examination scale, activity of daily living scale, treatment emergency symptom scale, and measured with BP, HR, ECG, EEG, ALT, AKP, BUN, Cr, Hb, WBC, and urine routine. About 58% (29/50) of patients treated with Hup showed improvements in their memory (P < 0.01), cognitive (P < 0.01), and behavioral (P < 0.01 functions. The efficacy of Hup was better than placebo (36%, 19/53) (P < 0.05). No severe side effect was found. Hup is a promising drug for symptomatic treatment of Alzheimer's disease.


Covid-19, social restrictions, and mental distress among young people: a UK longitudinal, population-based study.
Adolescence is a critical period for social and emotional development. We sought to examine the impacts of Covid-19 and related social restrictions and school closures on adolescent mental health, particularly among disadvantaged, marginalised, and vulnerable groups. We analysed four waves of data - 3 pre-Covid-19 (2016-2019) and 1 mid-Covid-19 (May-Aug 2020; n, 1074; 12-18 years old, >80% minority ethnic groups, 25% free school meals) from REACH (Resilience, Ethnicity, and AdolesCent Mental Health), an adolescent cohort based in inner-London, United Kingdom. Mental health was assessed using validated measures at each time point. We estimated temporal trends in mental distress and examined variations in changes in distress, pre- to mid-Covid-19, by social group, and by pre- and mid-pandemic risks. We found no evidence of an overall increase in mental distress midpandemic (15.9%, 95% CI: 13.0, 19.4) compared with prepandemic (around 18%). However, there were variations in changes in mental distress by subgroups. There were modest variations by social group and by pre-Covid risks (e.g., a small increase in distress among girls (b [unstandardised beta coefficient] 0.42 [-0.19, 1.03]); a small decrease among boys (b - 0.59 [-1.37, 0.19]); p for interaction .007). The most notable variations were by midpandemic risks: that is, broadly, increases in distress among those reporting negative circumstances and impacts (e.g., in finances, housing, social support and relationships, and daily routines) and decreases in distress among those reporting positive impacts. We found strong evidence that mental distress increased among young people who were most negatively impacted by Covid-19 and by related social restrictions during the first lockdown in the United Kingdom.


Molecular architecture of the zebra finch arcopallium.
The arcopallium, a key avian forebrain region, receives inputs from numerous brain areas and is a major source of descending sensory and motor projections. While there is evidence of arcopallial subdivisions, the internal organization or the arcopallium is not well understood. The arcopallium is also considered the avian homologue of mammalian deep cortical layers and/or amygdalar subdivisions, but one-to-one correspondences are controversial. Here we present a molecular characterization of the arcopallium in the zebra finch, a passerine songbird species and a major model organism for vocal learning studies. Based on in situ hybridization for arcopallial-expressed transcripts (AQP1, C1QL3, CBLN2, CNTN4, CYP19A1, ESR1/2, FEZF2, MGP, NECAB2, PCP4, PVALB, SCN3B, SCUBE1, ZBTB20, and others) in comparison with cytoarchitectonic features, we have defined 20 distinct regions that can be grouped into six major domains (anterior, posterior, dorsal, ventral, medial, and intermediate arcopallium, respectively; AA, AP, AD, AV, AM, and AI). The data also help to establish the arcopallium as primarily pallial, support a unique topography of the arcopallium in passerines, highlight similarities between the vocal robust nucleus of the arcopallium (RA) and AI, and provide insights into the similarities and differences of cortical and amygdalar regions between birds and mammals. We also propose the use of AMV (instead of nucleus taenia/TnA), AMD, AD, and AI as initial steps toward a universal arcopallial nomenclature. Besides clarifying the internal organization of the arcopallium, the data provide a coherent basis for further functional and comparative studies of this complex avian brain region.


Inpatient rehabilitation in multiple sclerosis: do the benefits carry over into the community?
To determine the duration and pattern of carry-over of benefits gained after a short period of multidisciplinary inpatient rehabilitation. Few studies have evaluated the outcome of rehabilitation after discharge. Long-term follow-up is required to establish whether gains made during the inpatient stay are sustained over time and in the patient's own environment. Prospective single-group longitudinal study. Fifty consecutive patients with progressive MS undergoing inpatient rehabilitation were followed for 12 months after discharge. Assessments were undertaken on admission (A), at discharge, and subsequently at 3-month intervals for 1 year (1Y) with a battery of measures addressing neurologic status, disability, handicap, quality of life, and emotional well-being. The time taken to return to baseline level was calculated using summary measures, and trends in performance levels were plotted. Twelve-month data were collected for 92% of patients. Although neurologic status declined (median Expanded Disability Status Scale scores: A = 6.8, 1Y = 8.0), improvements were maintained in disability and handicap for 6 months, emotional well-being for 7 months, and health-related quality of life (physical component) for 10 months. The benefits gained from rehabilitation were partly maintained after discharge despite worsening neurologic status. Carry-over of benefits, however, declined over time, reinforcing the need for continuity of care between the inpatient setting and the community.


The Physical Fitness Effects of a Week-Long Specialist Tactical Police Selection Course.
Specialist police tactical teams, like special operations military personnel, are tasked with dangerous, high risk missions which are beyond the scope of general police. Consequently, the selection courses for entry into these teams are physiologically and psychologically demanding. The purpose of this study was to examine the physiological effects of a five-day selection course to aid in candidate preparation and course planning. Measures included body mass, grip strength, sit-and-reach flexibility, and a vertical jump assessment. Eleven candidates finished the selection course with significant decreases in body mass (-2.05 kg, p = 0.006 (95% CI = 3.65-0.45)), grip strength in the right (-14.48 kg, p < 0.001 (95% CI = 21.32-7.64)) and left (-14.27 kg, p < 0.001 (95% CI = 21.89-6.66)) hands and in sit-and-reach flexibility (-6.64 cm, p < 0.001 (95% CI = 9.94-3.33)). No significant decreases in power output or peak jump velocity of 669.77 W (95% CI = 1942.92-603.39) and 0.28 m/s (95% CI = 0.69-0.14) were found and a non-significant, overall increase in vertical jump height of 6.09 cm (95% CI = -6.08 to 18.79) was seen. Decreases in body mass, grip strength and lower limb flexibility are evident in a grueling five-day selection course. Individuals planning on attending these courses should plan for these negative effects and build redundancy into their performance to minimize the effects of fatigue, decrease injury risk and maximize chances of completion.


Local structure of the metal-organic perovskite dimethylammonium manganese(ii) formate.
We report total neutron scattering measurements on the metal-organic perovskite analogue dimethylammonium manganese(ii) formate, (CD3)2ND2[Mn(DCO2)3]. Reverse Monte Carlo modelling shows that, in both the disordered high-temperature and ordered low-temperature phases, the ammonium moiety forms substantially shorter hydrogen bonds (N...O = 2.4 Å and 2.6 Å) than are visible in the average crystal structures. These bonds result from a pincer-like motion of two adjacent formate ions about the dimethylammonium ion in such a way that the framework can adjust independently to the positions of nearest-neighbour dimethylammonium ions. At low temperatures the shortest hydrogen bond is less favourable, apparently because it involves a greater distortion of the framework. Furthermore, in the high-temperature phase, in addition to the three disordered nitrogen positions expected from the average crystal structure, there appear to be also smaller probability maxima between these positions, corresponding to orientations in which the dimethylammonium is hydrogen-bonded to the two oxygen atoms of a single formate ion. The spontaneous strain across the phase transition reveals a contraction of the framework about the dimethylammonium cation, continuing as the material is cooled below the transition temperature. These results provide direct evidence of the local atomic structure of the guest-framework hydrogen bonding, and in particular the distortions of the framework responsible for the phase transition in this system.


Noise, Bifurcations, and Modeling of Interacting Particle Systems.
We consider the stochastic patterns of a system of communicating, or coupled, self-propelled particles in the presence of noise and communication time delay. For sufficiently large environmental noise, there exists a transition between a translating state and a rotating state with stationary center of mass. Time delayed communication creates a bifurcation pattern dependent on the coupling amplitude between particles. Using a mean field model in the large number limit, we show how the complete bifurcation unfolds in the presence of communication delay and coupling amplitude. Relative to the center of mass, the patterns can then be described as transitions between translation, rotation about a stationary point, or a rotating swarm, where the center of mass undergoes a Hopf bifurcation from steady state to a limit cycle. Examples of some of the stochastic patterns will be given for large numbers of particles.


Dynamic coding for cognitive control in prefrontal cortex.
Cognitive flexibility is fundamental to adaptive intelligent behavior. Prefrontal cortex has long been associated with flexible cognitive function, but the neurophysiological principles that enable prefrontal cells to adapt their response properties according to context-dependent rules remain poorly understood. Here, we use time-resolved population-level neural pattern analyses to explore how context is encoded and maintained in primate prefrontal cortex and used in flexible decision making. We show that an instruction cue triggers a rapid series of state transitions before settling into a stable low-activity state. The postcue state is differentially tuned according to the current task-relevant rule. During decision making, the response to a choice stimulus is characterized by an initial stimulus-specific population response but evolves to different final decision-related states depending on the current rule. These results demonstrate how neural tuning profiles in prefrontal cortex adapt to accommodate changes in behavioral context. Highly flexible tuning could be mediated via short-term synaptic plasticity.


Antimicrobial action of calprotectin that does not involve metal withholding.
Calprotectin is a potent antimicrobial that inhibits the growth of pathogens by tightly binding transition metals such as Mn and Zn, thereby preventing their uptake and utilization by invading microbes. At sites of infection, calprotectin is abundantly released from neutrophils, but calprotectin is also present in non-neutrophil cell types that may be relevant to infections. We show here that in patients infected with the Lyme disease pathogen Borreliella (Borrelia) burgdorferi, calprotectin is produced in neutrophil-free regions of the skin, in both epidermal keratinocytes and in immune cells infiltrating the dermis, including CD68 positive macrophages. In culture, B. burgdorferi's growth is inhibited by calprotectin, but surprisingly, the mechanism does not involve the classical withholding of metal nutrients. B. burgdorferi cells exposed to calprotectin cease growth with no reduction in intracellular Mn and no loss in activity of Mn enzymes including the SodA superoxide dismutase. Additionally, there is no obvious loss in intracellular Zn. Rather than metal depletion, we find that calprotectin inhibits B. burgdorferi growth through a mechanism that requires physical association of calprotectin with the bacteria. By comparison, calprotectin inhibited E. coli growth without physically interacting with the microbe, and calprotectin effectively depleted E. coli of intracellular Mn and Zn. Our studies with B. burgdorferi demonstrate that the antimicrobial capacity of calprotectin is complex and extends well beyond simple withholding of metal micronutrients.


A worldwide population study of the Ag-system haplotypes, a genetic polymorphism of human low-density lipoprotein.
The aim of this investigation is to examine the distribution of the Ag immunological polymorphism in human populations on a worldwide scale and to look for possible explanations of this distribution in the field of modern human peopling history and Ag-system evolution. Extensive Ag-antigene typings were carried out on 13 human population samples, including sub-Saharan African, European, west and east Asiatic, Melanesian, Australian aborigine, and Amerindian groups. Complete Ag-haplotype frequencies were estimated by maximum-likelihood-score procedures, and the data were analyzed by genetic distance computations and principal coordinate projections. With the exception of the Amerindian sample, the Ag polymorphism is shown to be highly polymorphic in all the populations tested. Their genetic relationships appear to be closely correlated to their geographical distribution. This suggests that the Ag system has evolved as a neutral or nearly neutral polymorphism and that it is highly informative for modern human peopling history studies. From the worldwide Ag haplotypic distributions, a model for the Ag molecular structure is derived. According to this model and to the most recent results obtained from molecular data, the establishment of the Ag polymorphism could be explained by several mutations and recombination events between the haplotypes most frequently found in human populations today. As a conclusion, genetic and paleontological data suggest that the genetic structure of caucasoid populations (located from North Africa to India) may be the least differentiated from an ancestral genetic stock. Worldwide genetic differentiations are properly explained as the results of westward and eastward human migrations from a Near East-centered but undefined geographical area where modern humans may have originated. The importance of Ag polymorphism analyses for the reconstruction of human settlement history and origins is discussed in the light of the main conclusions of the most recent genetic polymorphism studies.


A yeast homolog of chromatin assembly factor 1 is involved in early ribosome assembly.
Cells have a recurrent need for the correct assembly of protein-nucleic acid complexes. We have studied a yeast homolog of the smallest subunit of chromatin assembly factor 1 (CAF1), encoded by YMR131c and termed "RRB1". Unlike other yeast homologs, Msi1p, and Hat2p, Rrb1p is essential for cell viability. Impairment of Rrb1p function results in decreased levels of free 60S ribosomal subunits and the appearance of half-mer polysomes, suggesting its involvement in ribosome biogenesis. Using tandem affinity purification (TAP ) combined with mass spectrometry, we show that Rrb1p is associated with ribosomal protein L3. A fraction of Rrb1p is also found in a protein-precursor rRNA complex containing at least ten other early-assembling ribosomal proteins. We propose that Rrb1p is required for proper assembly of preribosomal particles during early ribosome biogenesis, presumably by targeting L3 onto the 35S precursor rRNA. This action may resemble the mechanism by which CAF1 assembles histones H3/H4 onto newly replicated DNA.


Diagnostic Accuracy of Microcatheter Derived Fractional Flow Reserve.
Microcatheter derived fractional flow reserve (FFRMC) system has an increased profile compared with pressure-wire derived fractional flow reserve (FFRW). Consequently, the FFRMC system itself may increase the degree of coronary artery stenosis and lower the measured FFR value. This can affect the diagnostic accuracy of the FFRMC system and inadvertently result in erroneous therapy for patients. Our aim was to evaluate the diagnostic accuracy FFRMC measurements and provide a means for clinicians to interpret individual FFRMC results with respect to FFRW. Correlation between FFR measurement techniques was analyzed in this lesion level analysis of 413 patients and 441 lesions from 6 studies. The reference standard to determine physiological significant stenosis was FFRW value ≤0.80. The mean values for FFRMC and FFRW were 0.80 ± 0.11 and 0.83 ± 0.09, respectively. Bland-Altman analysis demonstrated a bias toward overestimation of FFR by FFRMC (bias, -0.03 [0.05]). The overall lesion level diagnostic accuracy of the FFRMC system was 80.4% (95% confidence interval [CI] 76.2% to 84.0%). The diagnostic accuracy for FFRMC values <0.75, 0.75 to 0.85 and >0.85 were 83.7% (95% CI 71.4% to 92.4%), 72.3% (95% CI 59.8% to 75.6%), and 99.2% (95% CI 94.8% to 99.8%), respectively. Using the FFRW threshold of ≤0.80, 16.3% of lesions would have had inappropriate revascularization according to FFRMC measurements. Receiver-operating characteristics suggested the optimal cut-off value of FFRMC to determine ischemia was 0.78. In conclusion, the diagnostic accuracy of FFRMC varies markedly across the spectrum of disease with marked deterioration for values between 0.75 and 0.85. This may result in clinicians to inadvertently revascularize patients with FFR measurements >0.80.


Treatment of pathological gambling.
This paper highlights the development of pharmacological and nonpharmacological treatments for pathological gambling and is based on a review of the literature published in the past 12 months. The efficacy of naltrexone treatment for pathological gambling has been replicated in a double-blind, placebo-controlled, confirmatory study. For mood stabilizers, whereas carbamazepine and topiramate continued to produce positive results, olanzapine failed to show superior outcomes compared with placebo control. Two new pharmacological agents for pathological gambling, N-acetyl cysteine and modafinil, produced significant improvement for pathological gamblers. Several studies examined the outcomes of nonpharmacological treatments. Recent studies showed that cognitive-behavioral therapy failed to produce superior outcomes compared with other less costly methods such as brief interventions. Two new nonpharmacological treatment methods have been reported, including the use of videoconferencing in delivering ongoing supervisions after exposure therapy and the congruence couple therapy, which aims to heal the person as a system whole. Recent treatment outcomes studies address not only the effectiveness, but also the efficacy of different treatment approaches. Results of two meta-analysis studies showed that nonpharmacological treatments have a larger overall effect size than pharmacological treatments; however, owing to the diversity in study designs, it is unclear whether nonpharmacological treatments are more effective than pharmacological treatments at this point.


Disease surveillance among newly arriving refugees and immigrants--Electronic Disease Notification System, United States, 2009.
Approximately 450,000 legal permanent immigrants and 75,000 refugees enter the United States annually after receiving required medical examinations by overseas panel physicians (physicians who follow the CDC medical screening guidelines provided to the U.S. Department of State). CDC has the regulatory responsibility for preventing the introduction, transmission, and spread of communicable diseases into the United States as well as for developing the guidelines, known as technical instructions, for the overseas medical examinations. Other conditions that are not infectious might preclude an immigrant or refugee from entering the United States and also are reported as part of the medical examination. After arrival in the United States, all refugees are recommended to obtain a medical assessment by a health-care provider or a health department within 30 days. In addition, immigrants with certain medical conditions such as noninfectious tuberculosis at the time of the original medical examination are recommended to be evaluated after arrival to ensure that appropriate prevention or treatment measures are instituted. Health departments need timely and accurate notifications of newly arriving immigrants, refugees, and persons with other visa types to facilitate these evaluations. Notifications for all newly arriving refugees (with or without medical conditions) and immigrants with medical conditions are provided by CDC's Electronic Disease Notification (EDN) system. This is the first report describing EDN. This report summarizes notifications by the EDN system during January-December 2009. The EDN system is a centralized electronic reporting system that collects health information on newly arriving refugees and immigrants with Class A and Class B medical conditions. Class A conditions render applicants inadmissible and require a waiver for entry; Class B conditions are admissible but might require treatment or follow-up. Information in the EDN system is used to notify state health departments in all 50 states and the District of Columbia about the arrival of these persons in the United States. In 2009, the EDN system notified U.S. state and local health departments of 104,954 newly arriving refugees and immigrants, of whom 78,899 (75.2%) were refugees (with or without medical conditions), 19,358 (18.4%) were immigrants with medical conditions, and 6,697 (6.4%) were persons with other visa types. Of the 78,899 refugees, 21,319 (27%) had a medical condition. The majority (93.4%) of immigrants with medical conditions had tuberculosis classifications (i.e., either had evidence of latent tuberculosis infection or chest radiograph findings interpreted by the overseas panel physician as consistent with tuberculosis). Of the 41,415 refugees and immigrants with Class A or Class B medical conditions, 405 (1%) had Class A conditions, and 40,994 (99%) had Class B conditions. The majority of refugees and immigrants with suspected Class B tuberculosis were born in the Philippines (41.3%), Mexico (12.1%), Burma (8.7%), Vietnam (7.8%), and the Dominican Republic (5.8%). The majority of refugee notifications were for persons born in Iraq (23.9%), Burma (18.9%), and Bhutan (15.1%). Approximately one third of the tuberculosis notifications were sent to health departments in California (20.5%), Texas (9.8%), and New York (6.3%), and the national reporting rate for tuberculosis follow-up was 75.4% within 30 days of arrival. The findings in this report suggest that 1) overseas medical screening results in a low frequency (0.4%) of inadmissible medical conditions in the United States, 2) the EDN system provides more direct notifications to health departments than the previous paper-based system about newly arriving immigrants and refugees who need medical follow-up, and 3) approximately 75% of follow-up occurs among persons with suspected tuberculosis who are reported to EDN by states receiving newly arriving refugees and immigrants. The data in this report can be used to help state and local health departments provide prompt and effective follow-up, evaluation, and treatment to newly arriving immigrants and refugees. Timely follow-up might prevent additional spread of tuberculosis or other communicable diseases of public health significance into their communities. In addition, information from the EDN system allows health departments to use their resources as effectively as possible by providing clinical information that identifies the refugees and immigrants who should be prioritized for evaluation and treatment.


Switchable broadband terahertz absorber/reflector enabled by hybrid graphene-gold metasurface.
Numerous studies have been made to design switchable terahertz absorber for the application of amplitude modulator. However, it is still a challenge to achieve large modulation range while maintaining broad bandwidth. Here, we propose a switchable broadband absorber/reflector in the low-terahertz regime. By utilizing a hybrid graphene-gold metasurface on SiO2/pSi/PDMS substrate with an aluminum back, an excellent absorption across 0.53-1.05 THz with a wide incident angles for both TE and TM polarizations is achieved. By controlling the voltage across gold electrode and pSi, the chemical potential of graphene can be changed correspondingly. When the chemical potential of graphene varied from 0eV to 0.3eV, the state of the proposed structure can be switched from absorption (>90%) to reflection (>82%) over the whole operation bandwidth. Electric field intensity and surface loss density of the proposed absorber under different chemical potential are given to have a physical insight of the mechanisms. The switchable absorber/reflector can enable a wide application of high performance terahertz devices, such as active camouflage, imaging, modulators and electro-optic switches.


Sub-acute exposure to the herbicide atrazine suppresses cell immune functions in adolescent mice.
Atrazine (ATR), one of the most widely used herbicides worldwide, has caused a series of toxicological and environmental problems. This study sought to investigate the effects of ATR on the immune system of mice. Four-week-old female C57B l/6 mice were treated with 5, 25, and 125 mg/kg ATR for 28 days. On day 29, blood was collected and the spleen was harvested to detect lymphocyte transformation, natural killer (NK) cell activity, cellular phenotypes, and cytokines. Results indicated that the thymus and spleen weights decreased after ATR treatment, and the spleen was found to be more sensitive to ATR than the thymus. Decreases in lymphocyte transformation and NK cell activity were also observed in mice treated with 25 mg/kg ATR and 125 mg/kg ATR compared to the control group. In addition, there were also alterations of lymphocyte phenotypes in the spleen, and the percentages of CD3+ and CD4+ cells decreased in mice treated with 25 mg/kg ATR and 125 mg/kg ATR compared to the control group. Moreover, serum interleukin-4 level decreased significantly after treatment with 25 mg/kg and 125 mg/kg ATR, but ATR did not affect the expression of interleukin-2, interferon-γ, and tumor necrosis factor-α. These results suggest that ATR may have induced damage in spleen cells. As ATR is an environmental contaminant, its immunosuppressive action raises concerns that it may potentiate clinical conditions such as tumors, inflammation, and infections. Thus, it needs to be carefully monitored and studied.


Research review: Polygenic methods and their application to psychiatric traits.
Despite evidence from twin and family studies for an important contribution of genetic factors to both childhood and adult onset psychiatric disorders, identifying robustly associated specific DNA variants has proved challenging. In the pregenomics era the genetic architecture (number, frequency and effect size of risk variants) of complex genetic disorders was unknown. Empirical evidence for the genetic architecture of psychiatric disorders is emerging from the genetic studies of the last 5 years. We review the methods investigating the polygenic nature of complex disorders. We provide mini-guides to genomic profile (or polygenic) risk scoring and to estimation of variance (or heritability) from common SNPs; a glossary of key terms is also provided. We review results of applications of the methods to psychiatric disorders and related traits and consider how these methods inform on missing heritability, hidden heritability and still-missing heritability. Genome-wide genotyping and sequencing studies are providing evidence that psychiatric disorders are truly polygenic, that is they have a genetic architecture of many genetic variants, including risk variants that are both common and rare in the population. Sample sizes published to date are mostly underpowered to detect effect sizes of the magnitude presented by nature, and these effect sizes may be constrained by the biological validity of the diagnostic constructs. Increasing the sample size for genome wide association studies of psychiatric disorders will lead to the identification of more associated genetic variants, as already found for schizophrenia. These loci provide the starting point of functional analyses that might eventually lead to new prevention and treatment options and to improved biological validity of diagnostic constructs. Polygenic analyses will contribute further to our understanding of complex genetic traits as sample sizes increase and as sample resources become richer in phenotypic descriptors, both in terms of clinical symptoms and of nongenetic risk factors.


Constant temperature operation of fiber-optic hot-wire anemometers.
We demonstrate the constant temperature (CT) operation of a fiber-optic anemometer based on a laser-heated silicon Fabry-Perot interferometer (FPI), where the temperature of the FPI is kept constant by adjusting the heating laser power through a feedback control loop and the output signal is the heating laser power. We show that the CT operation can dramatically improve the frequency response over the commonly used constant power (CP) operation, where the laser heating power is kept constant and the output signal is the temperature of the FPI. For demonstration, we used a 100-μm-diameter, 200-μm-thick silicon FPI attached to the tip of a single-mode fiber as the anemometer. The FPI was heated by a 980-nm diode laser, and the temperature was measured using a 1550-nm diode laser. The effect of flow changes was simulated by exposing the silicon FPI to radiation from an external intensity-modulated laser beam. We show that the 10%-90% rise time of the step response in air was reduced from 625 ms for CP operation to 1.8 ms for CT operation, and the 3-dB bandwidth was increased from 0.5 Hz for CP operation to 2 kHz for CT operation. The response of the anemometer also shows good linearity to the radiation power.


Spinal curvature of cultured Japanese mackerel Scomber japonicus associated with a brain myxosporean, Myxobolus acanthogobii.
Skeletal deformities were found in the cultured Japanese mackerel Scomber japonicus. External and radiographical observations showed the deformed fish to exhibit a dorso-ventral spinal curvature (kyphosis) without fracture or dislocation of the vertebrae. Numerous myxosporean cysts, ca. 0.3 to 1.0 mm in diameter, formed in the 4th ventricle, the cavity of the optic tectum, the surface of the olfactory lobe and bulb, the optic lobe and the inferior lobe of the brain. Spore morphology and molecular analysis of the small subunit ribosomal RNA gene sequence identified the myxosporean parasite as Myxobolus acanthogobii, a parasite which also causes scoliosis in yellowtail Seriola quinqeradiata. Histopathological observation showed that the myxosporean cysts were encapsulated within the host's collagenous layer although some had disintegrated to disperse mature spores into the cranial cavity. Occasionally, lymphocytic infiltration and local granulomatous inflammation were found to be associated with spore dispersion.


Sleep discontinuity and impaired sleep continuity affect transition to and from obesity over time: results from the Alameda county study.
To investigate the impact of development in sleep continuity on transition to and from obesity over time. The study used self-reported sleep and body mass index (BMI) measures from the 1965, 1974, 1983, and 1994 waves of the longitudinal Alameda County Study. Sleep continuity was assessed by a question on whether the participants had any troubles falling or staying asleep. Change in sleep and BMI were estimated from the sleep and BMI questions in 1965 and 1994 respectively. Multinomial regression analyses were used to examine the risk/chance for a transition to and from obesity (BMI >or=30 kg/m(2)) due to development in sleep continuity. After adjustment for confounding variables, consistent sleep discontinuity both increases the risk for a transition to obesity and reduces the chance of losing weight, whereas impaired sleep continuity lowers the chance for weight loss. Effects for obesity were non-significant for those with improved sleep continuity. Consistent sleep discontinuity and impaired sleep continuity increases the risk of transition to obesity or of remaining obese.


Amino acid signatures of HLA Class-I and II molecules are strongly associated with SLE susceptibility and autoantibody production in Eastern Asians.
Human leukocyte antigen (HLA) is a key genetic factor conferring risk of systemic lupus erythematosus (SLE), but precise independent localization of HLA effects is extremely challenging. As a result, the contribution of specific HLA alleles and amino-acid residues to the overall risk of SLE and to risk of specific autoantibodies are far from completely understood. Here, we dissected (a) overall SLE association signals across HLA, (b) HLA-peptide interaction, and (c) residue-autoantibody association. Classical alleles, SNPs, and amino-acid residues of eight HLA genes were imputed across 4,915 SLE cases and 13,513 controls from Eastern Asia. We performed association followed by conditional analysis across HLA, assessing both overall SLE risk and risk of autoantibody production. DR15 alleles HLA-DRB1*15:01 (P = 1.4x10-27, odds ratio (OR) = 1.57) and HLA-DQB1*06:02 (P = 7.4x10-23, OR = 1.55) formed the most significant haplotype (OR = 2.33). Conditioned protein-residue signals were stronger than allele signals and mapped predominantly to HLA-DRB1 residue 13 (P = 2.2x10-75) and its proxy position 11 (P = 1.1x10-67), followed by HLA-DRB1-37 (P = 4.5x10-24). After conditioning on HLA-DRB1, novel associations at HLA-A-70 (P = 1.4x10-8), HLA-DPB1-35 (P = 9.0x10-16), HLA-DQB1-37 (P = 2.7x10-14), and HLA-B-9 (P = 6.5x10-15) emerged. Together, these seven residues increased the proportion of explained heritability due to HLA to 2.6%. Risk residues for both overall disease and hallmark autoantibodies (i.e., nRNP: DRB1-11, P = 2.0x10-14; DRB1-13, P = 2.9x10-13; DRB1-30, P = 3.9x10-14) localized to the peptide-binding groove of HLA-DRB1. Enrichment for specific amino-acid characteristics in the peptide-binding groove correlated with overall SLE risk and with autoantibody presence. Risk residues were in primarily negatively charged side-chains, in contrast with rheumatoid arthritis. We identified novel SLE signals in HLA Class I loci (HLA-A, HLA-B), and localized primary Class II signals to five residues in HLA-DRB1, HLA-DPB1, and HLA-DQB1. These findings provide insights about the mechanisms by which the risk residues interact with each other to produce autoantibodies and are involved in SLE pathophysiology.


Antigen discovery: a postgenomic approach to leprosy diagnosis.
Leprosy is an infectious, neurodegenerative disease of humans caused by Mycobacterium leprae. Despite effective control programs, the incidence of leprosy remains stubbornly high, suggesting that transmission may be more common than expected. The rationale of this work was to use bioinformatics and comparative genomics to identify potentially antigenic proteins for diagnostic purposes. This approach defined three classes of proteins: those restricted to M. leprae (class I), those present in M. leprae with orthologues in other organisms besides mycobacteria (class II), and exported or surface-exposed proteins (class III). Twelve genes (two class I, four class II, and six class III proteins) were cloned in Escherichia coli, and their protein products were purified. Six of these proteins were detected in cell extracts of M. leprae by immunoblotting. The immunogenicity of each recombinant protein was then investigated in leprosy patients by measuring the reactivity of circulating antibody and gamma interferon (IFN-gamma) responses in T-cell restimulation assays. Several class II and class III proteins were recognized by circulating antibodies. Importantly, most class II proteins elicited IFN-gamma responses that were significantly stronger than those produced by previously identified antigens. Among them, two class II proteins, ML0308 and ML2498, showed marked humoral and cellular immunogenicity, therefore providing promising candidates for the diagnosis of both tuberculoid and lepromatous forms of leprosy.


Genital chlamydia prevalence in Europe and non-European high income countries: systematic review and meta-analysis.
Accurate information about the prevalence of Chlamydia trachomatis is needed to assess national prevention and control measures. We systematically reviewed population-based cross-sectional studies that estimated chlamydia prevalence in European Union/European Economic Area (EU/EEA) Member States and non-European high income countries from January 1990 to August 2012. We examined results in forest plots, explored heterogeneity using the I² statistic, and conducted random effects meta-analysis if appropriate. Meta-regression was used to examine the relationship between study characteristics and chlamydia prevalence estimates. We included 25 population-based studies from 11 EU/EEA countries and 14 studies from five other high income countries. Four EU/EEA Member States reported on nationally representative surveys of sexually experienced adults aged 18-26 years (response rates 52-71%). In women, chlamydia point prevalence estimates ranged from 3.0-5.3%; the pooled average of these estimates was 3.6% (95% CI 2.4, 4.8, I² 0%). In men, estimates ranged from 2.4-7.3% (pooled average 3.5%; 95% CI 1.9, 5.2, I² 27%). Estimates in EU/EEA Member States were statistically consistent with those in other high income countries (I² 0% for women, 6% for men). There was statistical evidence of an association between survey response rate and estimated chlamydia prevalence; estimates were higher in surveys with lower response rates, (p = 0.003 in women, 0.018 in men). Population-based surveys that estimate chlamydia prevalence are at risk of participation bias owing to low response rates. Estimates obtained in nationally representative samples of the general population of EU/EEA Member States are similar to estimates from other high income countries.


Class prediction and feature selection with linear optimization for metagenomic count data.
The amount of metagenomic data is growing rapidly while the computational methods for metagenome analysis are still in their infancy. It is important to develop novel statistical learning tools for the prediction of associations between bacterial communities and disease phenotypes and for the detection of differentially abundant features. In this study, we presented a novel statistical learning method for simultaneous association prediction and feature selection with metagenomic samples from two or multiple treatment populations on the basis of count data. We developed a linear programming based support vector machine with L(1) and joint L(1,∞) penalties for binary and multiclass classifications with metagenomic count data (metalinprog). We evaluated the performance of our method on several real and simulation datasets. The proposed method can simultaneously identify features and predict classes with the metagenomic count data.


Oscillatory pallidal local field potential activity inversely correlates with limb dyskinesias in Parkinson's disease.
Levodopa induced dyskinesias (LIDs) are poorly understood and yet are a major cause of disability in Parkinson's disease (PD). The activity of neurons in the basal ganglia of patients with PD tends to be strongly synchronized at frequencies under 30 Hz, leading to oscillatory local field potentials (LFPs). As dopaminergic therapy acutely suppresses this synchronization, we investigated whether this suppression may contribute to LIDs. Accordingly, we sought an inverse correlation between oscillatory synchronization and dyskinesia activity across time. To this end, we recorded pallidal LFPs in two Parkinsonian subjects exhibiting LIDs following surgery for deep brain stimulation. We correlated LFP power with simultaneously recorded EMG from the dyskinetic contralateral upper limb. We found highly significant inverse correlations between the oscillatory LFP activity under 30 Hz and dyskinetic EMG (maximum r = -0.65, P < 0.001 and r = -0.33, P < 0.001 for activities over 13-30 Hz in each subject). The inverse relationship between oscillatory pallidal LFP activity and dyskinetic EMG was maintained over time periods of a few seconds and was focal. This observation links the suppression of oscillatory synchronization in the pallidum with dyskinetic muscle activity in PD.


Discovery and safety profiling of a potent preclinical candidate, (4-[4-[[(3R)-3-(hydroxycarbamoyl)-8-azaspiro[4.5]decan-3-yl]sulfonyl]phenoxy]-N-methylbenzamide) (CM-352), for the prevention and treatment of hemorrhage.
Discovery of potent and safe therapeutics that improve upon currently available antifibrinolytics, e.g., tranexamic acid (TXA, 1) and aprotinin, has been challenging. Matrix metalloproteinases (MMPs) participate in thrombus dissolution. Then we designed a novel series of optimized MMP inhibitors that went through phenotypic screening consisting of thromboelastometry and mouse tail bleeding. Our optimized lead compound, CM-352 (2), inhibited fibrinolysis in human whole blood functional assays and was more effective than the current standard of care, 1, in the tail-bleeding model using a 30 000 times lower dose. Moreover, 2 reduced blood loss during liver hepatectomy, while 1 and aprotinin had no effect. Molecule 2 displayed optimal pharmacokinetic and safety profiles with no evidence of thrombosis or coagulation impairment. This novel mechanism of action, targeting MMP, defines a new class of antihemorrhagic agents without interfering with normal hemostatic function. Furthermore, 2 represents a preclinical candidate for the acute treatment of bleeding.


Optic flow induces nonvisual self-motion aftereffects.
There is strong evidence of shared neurophysiological substrates for visual and vestibular processing that likely support our capacity for estimating our own movement through the environment. We examined behavioral consequences of these shared substrates in the form of crossmodal aftereffects. In particular, we examined whether sustained exposure to a visual self-motion stimulus (i.e., optic flow) induces a subsequent bias in nonvisual (i.e., vestibular) self-motion perception in the opposite direction in darkness. Although several previous studies have investigated self-motion aftereffects, none have demonstrated crossmodal transfer, which is the strongest proof that the adapted mechanisms are generalized for self-motion processing. The crossmodal aftereffect was quantified using a motion-nulling procedure in which observers were physically translated on a motion platform to find the movement required to cancel the visually induced aftereffect. Crossmodal transfer was elicited only with the longest-duration visual adaptor (15 s), suggesting that transfer requires sustained vection (i.e., visually induced self-motion perception). Visual-only aftereffects were also measured, but the magnitudes of visual-only and crossmodal aftereffects were not correlated, indicating distinct underlying mechanisms. We propose that crossmodal aftereffects can be understood as an example of contingent or contextual adaptation that arises in response to correlations across signals and functions to reduce these correlations in order to increase coding efficiency. According to this view, crossmodal aftereffects in general (e.g., visual-auditory or visual-tactile) can be explained as accidental manifestations of mechanisms that constantly function to calibrate sensory modalities with each other as well as with the environment.


I suppress, therefore I smoke: effects of thought suppression on smoking behavior.
Thought suppression is a method frequently employed by individuals who are trying to control their thoughts and behaviors. Although this strategy is known to actually increase unwanted thoughts, it is unclear whether thought suppression also results in behavioral rebound. The study presented in this article investigated the effects of suppressing thoughts of smoking in everyday life on the number of cigarettes subsequently smoked. Study participants recorded their daily cigarette intake and stress levels over a 3-week period. In Week 1 and Week 3, participants monitored intake and stress. During Week 2, in addition to monitoring intake and stress, participants in the experimental groups either suppressed or expressed smoking thoughts, whereas the control group continued monitoring. Our results showed a clear behavioral rebound: The suppression group smoked significantly more in Week 3 than the expression or control group did. Moreover, the tendency to suppress thoughts (measured by the White Bear Suppression Inventory) was positively related to the number of attempts to quit smoking. The implications of our findings for smoking cessation are discussed.


Staying put or leaving home: endocrine, neuroendocrine and behavioral consequences in male African striped mice.
Social flexibility occurs when individuals of both sexes can change their social and reproductive tactics, which in turn can influence the social system of an entire population. However, little is known regarding the extent to which individuals of socially flexible species vary in their social behavior and in the underlying physiological mechanisms that support different social tactics. The present study in African striped mice modeled in captivity three male tactics described from the field: (a) philopatric males remaining in the family; (b) solitary roamers; or (c) group-living breeding males. Sixteen pairs and their offspring were kept in captivity, while one male offspring from the family remained as singly housed after he reached 21 days of age. Differences in behavior, morphology, hormone and neuropeptide levels were tested, and physiological measurements were correlated with behavioral measurements. In standardized arena experiments group-living males (philopatrics and breeders) were significantly more aggressive than singly housed males, in agreement with previous data suggesting that group-living, but not roaming males, are territorial. Philopatric males showed signs of reproductive suppression, small testes, lower testosterone and higher corticosterone levels than their singly housed brothers. Higher levels of arginine vasopressin (AVP) were measured in the PVN and BNST of singly housed males compared to group-living males. Based on these findings we hypothesize that roamers are physiologically primed, and capable, if the opportunity to mate arises, to release AVP, form social bonds and become territorial, thus quickly adopting the tactic as breeding male which would yield a higher reproductive success.


A method for correcting breathing-induced field fluctuations in T2*-weighted spinal cord imaging using a respiratory trace.
Spinal cord MRI at ultrahigh field is hampered by time-varying magnetic fields associated with the breathing cycle, giving rise to ghosting artifacts in multi-shot acquisitions. Here, we suggest a correction approach based on linking the signal from a respiratory bellows to field changes inside the spinal cord. The information is used to correct the data at the image reconstruction level. The correction was demonstrated in the context of multi-shot T2*-weighted imaging of the cervical spinal cord at 7T. A respiratory trace was acquired during a high-resolution multi-echo gradient-echo sequence, used for structural imaging and quantitative T2* mapping, and a multi-shot EPI time series, as would be suitable for fMRI. The coupling between the trace and the breathing-induced fields was determined by a short calibration scan in each individual. Images were reconstructed with and without trace-based correction. In the multi-echo acquisition, breathing-induced fields caused severe ghosting in images with long TE, which led to a systematic underestimation of T2* in the spinal cord. The trace-based correction reduced the ghosting and increased the estimated T2* values. Breathing-related ghosting was also observed in the multi-shot EPI images. The correction largely removed the ghosting, thereby improving the temporal signal-to-noise ratio of the time series. Trace-based retrospective correction of breathing-induced field variations can reduce ghosting and improve quantitative metrics in multi-shot structural and functional T2*-weighted imaging of the spinal cord. The method is straightforward to implement and does not rely on sequence modifications or additional hardware beyond a respiratory bellows.


Extensive large colon resection in the pony. I. Surgical procedures and clinical results.
The effect of resection of 75% (length measurement) of the large colon in ponies was studied. Ten ponies in good physical condition were divided into two groups: group I consisted of the six experimental ponies and group II of four control ponies. Preoperatively and postoperatively for five months, ten clinicopathological parameters were determined: body weight, venous blood pH, plasma bicarbonate, total plasma protein concentration, serum electrolyte values (sodium, potassium, chloride), and fecal osmolarity. Subjective assessment of attitude and appetite revealed no difference between the groups or within groups at any time. Resection of a major portion of the large colon did not significantly influence the clinicopathological parameters evaluated. The hematocrit of the ponies in group I did decrease during the first postoperative month and this was attributed to whole blood loss associated with the resection procedures. The results of this investigation indicated that resection of 75% of the large colon in ponies is compatible with life.


Profiles of human serum antibody responses elicited by three leading HIV vaccines focusing on the induction of Env-specific antibodies.
In the current report, we compared the specificities of antibody responses in sera from volunteers enrolled in three US NIH-supported HIV vaccine trials using different immunization regimens. HIV-1 Env-specific binding antibody, neutralizing antibody, antibody-dependent cell-mediated cytotoxicity (ADCC), and profiles of antibody specificity were analyzed for human immune sera collected from vaccinees enrolled in the NIH HIV Vaccine Trial Network (HVTN) Study #041 (recombinant protein alone), HVTN Study #203 (poxviral vector prime-protein boost), and the DP6-001 study (DNA prime-protein boost). Vaccinees from HVTN Study #041 had the highest neutralizing antibody activities against the sensitive virus along with the highest binding antibody responses, particularly those directed toward the V3 loop. DP6-001 sera showed a higher frequency of positive neutralizing antibody activities against more resistant viral isolate with a significantly higher CD4 binding site (CD4bs) antibody response compared to both HVTN studies #041 and #203. No differences were found in CD4-induced (CD4i) antibody responses, ADCC activity, or complement activation by Env-specific antibody among these sera. Given recent renewed interest in realizing the importance of antibody responses for next generation HIV vaccine development, different antibody profiles shown in the current report, based on the analysis of a wide range of antibody parameters, provide critical biomarker information for the selection of HIV vaccines for more advanced human studies and, in particular, those that can elicit antibodies targeting conformational-sensitive and functionally conserved epitopes.


Evaluation of a program for prenatal care case management.
A prenatal care case-management program in Tennessee was evaluated to determine its effectiveness in improving the adequacy of prenatal care reducing the odds of preterm birth (gestation less than 37 weeks) and very low birth weight births (less than 1,500 g). The case-management program, Project HUG, included care provider referrals, visit scheduling, assistance with transportation and nutritional and health education. In a cohort of 66,051 Medicaid women with a birth during the period July 1989 through December 1991, 6% received HUG services. HUG participants had improved utilization of prenatal care, significantly decreased odds of inadequate perinatal care (an odds ratio of 0.71) and significantly increased odds of obtaining prenatal vitamins within 120 days of the last menstrual period (1.79). The apparent benefit of Project HUG was greater among blacks than among whites. However, there was no significant reduction in the incidence of preterm births or very low birth weight births among program participants


A further investigation of "Dialectical thinking as a means of understanding systems-in-development: relevance to Rogers's principles".
Although this critique accepts the assumptions of Wilson and Fitzpatrick concerning a necessary congruence between a science's world view and its method of inquiry, it refutes their argument for Bunge's dialectic as a method appropriate for the study of human phenomena. It is argued that Bunge's dialectic is developed from a dualistic universe and is, therefore, incompatible with Rogers's views on the unitary nature of phenomena. Another, more internally consistent interpretation of the dialectic is introduced for consideration as an alternative.


Cost-effectiveness of simvastatin in the secondary prevention of coronary artery disease in Canada.
To determine the cost-effectiveness of simvastatin in the secondary prevention of coronary artery disease (CAD) in Canada. Cost-effectiveness model based on results from the Scandinavian Simvastatin Survival Study (45 study) and cost and resource utilization data from Canadian sources to simulate the economic impact of long-term simvastatin treatment (15 years). Subjects with mean age of 59.4 years at recruitment into 4S study. Overall death rate and incidence of 5 major nonfatal events associated with CAD: myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, stroke and transient ischemic attack. Direct medical costs associated with CAD were assessed from the perspective of provincial ministries of health (i.e., costs borne by the ministries); the impact of simvastatin treatment on these costs was determined. The 4S study, with a median follow-up of 5.4 years, showed significantly reduced mortality and morbidity among the patients given simvastatin compared with the control subjects. Three premises were designed to predict the consequences of simvastatin treatment of CAD in Canada over 15 years, 10 years beyond the end of the 4S study. The 2 most probable premises, which assumed that the clinical benefits of simvastatin would be cumulative for either the first 10 years or the full 15 years of the model, had incremental costs per year of life gained (cost-effectiveness ratio) of $9867 and $6108 respectively. This model suggests that simvastatin provides a cost-effective approach to the long-term prevention of secondary CAD in Canada.


[Diagnostics and treatment of autism spectrum disorders in older adults: a study by experts].
Empirical research into the diagnostics and treatment of older adults with autism spectrum disorders (ASD) is very limited; so far, only 17 studies have been published. ASD, however, is not confined to child and adult psychiatry. Increasingly, ASD is being identified and treated within the domain of geriatric psychiatry.
 AIM: To investigate diagnostic and therapeutic aspects of ASD in older adults, and to obtain insight into how these aspects are related to ageing.
 METHOD: Delphi techniques were employed via rounds of questionnaires put to experts; consensus was considered to have been achieved when a minimum of two-thirds of the experts 'agreed' or 'fully agreed' to a statement on a five-point scale.
 RESULTS: Consensus was achieved for 10 of the 17 statements. According to the experts, older patients with ASD, form a specific group in psychiatry. With regard to diagnosis, there was a consensus that increased attention needs to be given to age-related aspects by linking symptoms more specifically to the patient's phase of life and to the ageing process. In the treatment of older adults with ASD, adjustments need to be made in relation to ageing.
 CONCLUSION: This study by experts provides additional starting points for more research into specific topics relating to diagnostic and therapeutic aspects of ASD in geriatric psychiatry; these topics include validation of screening and diagnostic instruments, the adjustment of protocols for treatment, psycho-education and the effects of ageing in patients with ASD.


The finger domain of simian virus 40 large T antigen controls DNA-binding specificity.
The specificity and regulation of protein-DNA interactions play a crucial role in all aspects of communication between genotype and phenotype in a cell. The large T antigen of simian virus 40 binds to identical, yet quite differently arranged, pentanucleotide motifs in the simian virus 40 control region, sites I and II. Wild-type T antigen preferentially binds site I. We demonstrate that a bacterial peptide encoding residues 1 to 259 (T260) includes the essential amino acids required for binding to both DNA sites but predominantly binds site II. However, a longer peptide (residues 1 to 369; T370) binds almost exclusively to site I. Thus, the addition of amino acids 260 to 369 to the T260 peptide results in the loss of site II binding. This region includes a single putative metal-binding region, and mutation of T370 at either conserved cysteine of the finger results in equal but inefficient binding to both sites. While no metal binding has been shown to be directly associated with this sequence, these results suggest a novel, perhaps structural, function for such a finger motif, since this domain of T antigen appears to play a crucial role in modulating the DNA-binding behavior of T-antigen peptides.


Reasons why patients choose an ambulance and willingness to consider alternatives.
To test a hypothesis that patients would accept alternatives to transport to an emergency department (ED) by ambulance and to evaluate factors related to patient willingness to consider alternatives. Concerns about resource utilization have prompted emergency medical services (EMS) systems to explore alternatives to ambulance transport to an ED, but studies have evaluated the safety of alternatives, not patient preferences. Trained research assistants surveyed patients transported by ambulance to a university ED. Interfacility transfers, trauma patients, and critically ill patients were excluded. The primary outcome was willingness to accept one of several presented alternatives to ambulance transport to the ED for that visit. Demographic and clinical factors were evaluated for association with willingness to consider alternatives. Relative risks (RR) and 95% confidence intervals (95% CI) were determined by using Mantel-Haenszel stratified methods. Three hundred fifteen subjects completed the survey. Two hundred forty-seven (78.4%) were willing to consider at least one alternative. One hundred ninety-four (61.6%) were willing to consider transportation by car, and 177 (56.2%) were willing to consider transportation by taxi. Factors associated with willingness to consider alternatives included the following: age 18-65 years (RR, 1.25; 95% CI = 1.03 to 1.49), being unemployed (RR, 1.08; 95% CI = 1.08 to 1.33), use of the ED for routine care (RR, 1.25; 95% CI = 1.17 to 1.35), and not being admitted to the hospital (RR, 1.19; 95% CI = 1.04 to 1.40). Race, gender, health insurance status, and EMS interventions en route were not associated with willingness to consider transportation alternatives. Many patients transported by ambulance to an ED would have considered an alternative, if one were offered.


An Unusual Solitary Metatarsal Metastasis from an Endometrioid Endometrial Adenocarcinoma.
Endometrial cancer is the fourth most common tumor in women. Abnormal uterine bleeding is the leading symptom in 90% of cases. The more frequent metastatic sites include lymph nodes, omentum, lungs, and liver. Bone metastasis has been reported to occur in 2-6% of all metastatic endometrial cancers, particularly in high surgical stage and grade, the most common involved site being the spine and hip. We report here the case of a 62-year-old white woman hospitalized for a painful swelling in the left foot, which appeared from January 2014, postmenopausal bleeding, and a progressive weight loss in the last year. An endometrioid, endometrial cancer was diagnosed by hysteroscopy, associated with a solitary bone metastasis of the left metatarsus, histologically confirmed by biopsy. The patient refused any surgical procedure. She received a single-fraction of 800 cGy radiotherapy to the left foot, leading to optimal analgesic control. Subsequently, systemic chemotherapy was started using a carboplatin/paclitaxel-containing regimen with IV zoledronic acid. This treatment is ongoing. There is no standard treatment for endometrial cancer bone metastasis. The prognosis of these patients is poor, with a median survival of about 12-17 months. The treatment is predominantly palliative and relies on several factors, including patient clinical conditions, site and number of bone metastases, and the presence of any additional visceral lesions. An aggressive multimodal treatment should be proposed to very select patients presenting better prognostic factors. In our case, a solitary fifth metatarsal bone metastasis, histologically proved, was shown as initial presentation of an EC. Endometrial cancer can present as initial bone diffusion, even in atypical locations such as acrometastasis and it should be considered when bone metastases are diagnosed.


Temperament and character of patients with alcohol toxicity during COVID - 19 pandemic.
Corona virus epidemic may be acts as a stressor or trauma that affects both physical health and mental health. People exhibited various reactive behaviors to confront with this stressful situation. In Iran, one of the common motives for alcohol consumption is to scape problems and cope with stresses. It has been shown that personality factors influence alcohol consumption, since they are associated with drinking motives. The main purpose of this study was to investigate the correlation between temperament and character and alcohol abuse. This cross-section study was conducted on 135 alcohol intoxicated patients admitted to emergency room in March 2020 and 255 participants who were randomly selected from public in Shiraz. A questionnaire consisted of TCI (Temperament and character inventory) and several questions about COVID-19 pandemic. It was completed by a trained interviewer using the matched answer technique. Demographic factors were self-reported. Among the alcohol intoxicated group, 117 (86.7%) were males and 18(13.3%) were females. The mean age of the participants was 32.43 ± 10.81 years. Among control group, 99 (38.8%) were males and 156 (61.2%) were females. The mean age of control group was 33.12 ± 14.77 years. Alcohol toxicity was mostly observed among the young males (male/female ratio was 6.45). According to temperament and character index, mean scores of novelty seeking, harm avoidant, and self-transcendence were higher in the alcohol toxicity group than normal population (P < 0.01). Mean scores of reward dependent, cooperativeness, and self-directedness were higher in normal population than the alcohol toxicity group (P < 0.001). The mean score of persistence was not significantly different between methanol intoxicated and normal population groups (P = 0.718). Alcohol intoxicated patients had higher scores of novelty-seeking and self-transcendence and lower scores of reward-dependency scores, cooperativeness and self-directedness. These scores are associated with higher likelihood of personality disorders.


Multi-scale modelling to evaluate building energy consumption at the neighbourhood scale.
A new methodology is proposed to couple a meteorological model with a building energy use model. The aim of such a coupling is to improve the boundary conditions of both models with no significant increase in computational time. In the present case, the Canopy Interface Model (CIM) is coupled with CitySim. CitySim provides the geometrical characteristics to CIM, which then calculates a high resolution profile of the meteorological variables. These are in turn used by CitySim to calculate the energy flows in an urban district. We have conducted a series of experiments on the EPFL campus in Lausanne, Switzerland, to show the effectiveness of the coupling strategy. First, measured data from the campus for the year 2015 are used to force CIM and to evaluate its aptitude to reproduce high resolution vertical profiles. Second, we compare the use of local climatic data and data from a meteorological station located outside the urban area, in an evaluation of energy use. In both experiments, we demonstrate the importance of using in building energy software, meteorological variables that account for the urban microclimate. Furthermore, we also show that some building and urban forms are more sensitive to the local environment.


Profiles of Quality in Three Distinct Early Childhood Programs Using the Brief Early Childhood Quality Inventory (BEQI).
Quality early childhood care and education (ECCE) is important for young children's holistic healthy development. As ECCE scales, contextually relevant and feasible measurement is needed to inform policy and programs on strengths and areas for improvement. However, few measures have been designed for use across diverse contexts. Drawing on principles of mixed methods design, this study reports on a new approach to ECCE quality measurement: the Brief Early Childhood Quality Inventory. Using data from the USA, Liberia, and Colombia, results indicate variation in the items perceived as highly relevant to each setting and in the characteristics of classrooms including the degree of child autonomy, the types of activities, and in child/educator interactions and dialogue. However, despite this variation, a small set of items indicate potential functionality as cross-country anchor items. Findings lend support to the idea that quality measures can have some common elements with room for adaptation within and across settings. Future work in this area should address the possibility that the significance of these practices for child development also varies across settings.


Pericardial influences on ventricular filling in the conscious dog. An analysis based on pericardial pressure.
Twenty-five dogs were chronically instrumented to investigate the effects of the normal pericardium on cardiac function. Pulse-transit ultrasonic transducers were implanted to measure multiple ventricular dimensions. The pericardium was incised transversely at the base of the heart and precisely reapproximated, so as to disturb its characteristics minimally. One week later, the dogs were studied in the conscious state, and left ventricular, right ventricular, pericardial, and pleural pressures were measured with matched micromanometers. Data were recorded before and after blood volume expansion. Absolute end-diastolic pericardial pressure varied directly with pleural pressure during the respiratory cycle. Transpericardial pressure (pericardial-pleural pressure) varied little with respiration and was related directly to ventricular diameter during the cardiac cycle with peak transpericardial pressure uniformly occurring at end-diastole. With volume infusion, normalized end-diastolic minor axis diameter and left ventricular transmural pressure (left ventricular-pleural pressure) increased significantly from 0.14 +/- 0.01 and 9.5 mm Hg +/- 1.0 mm Hg, respectively, in the control state to 0.20 +/- 0.01 and 19.3 mm Hg +/- 1.2 mm Hg after volume loading. End-diastolic transpericardial pressure also increased significantly from 2.3 +/- 0.5 mm Hg to 4.1 +/- 0.3 mm Hg, and represented approximately 21% of transmural left ventricular pressure. When measurements were obtained sequentially after implantation, transpericardial pressure was initially high but decreased with time, presumably due to pericardial creep. After volume loading, right ventricular end-diastolic transmural pressure averaged 9.6 mm Hg, and pericardial pressure constituted 42% of right ventricular pressure. Thus, pericardial restraining effects may predominantly influence right ventricular filling and affect the left ventricle through series interaction. In the normal conscious dog, transpericardial pressure remains low over the entire physiological range, and the direct influence of the normal pericardium on diastolic filling of the left ventricle appears to be minimal.


Symptomatic plant viroid infections in phytopathogenic fungi.
Viroids are pathogenic agents that have a small, circular noncoding RNA genome. They have been found only in plant species; therefore, their infectivity and pathogenicity in other organisms remain largely unexplored. In this study, we investigate whether plant viroids can replicate and induce symptoms in filamentous fungi. Seven plant viroids representing viroid groups that replicate in either the nucleus or chloroplast of plant cells were inoculated to three plant pathogenic fungi, Cryphonectria parasitica, Valsa mali, and Fusarium graminearum By transfection of fungal spheroplasts with viroid RNA transcripts, each of the three, hop stunt viroid (HSVd), iresine 1 viroid, and avocado sunblotch viroid, can stably replicate in at least one of those fungi. The viroids are horizontally transmitted through hyphal anastomosis and vertically through conidia. HSVd infection severely debilitates the growth of V. mali but not that of the other two fungi, while in F. graminearum and C. parasitica, with deletion of dicer-like genes, the primary components of the RNA-silencing pathway, HSVd accumulation increases. We further demonstrate that HSVd can be bidirectionally transferred between F. graminearum and plants during infection. The viroids also efficiently infect fungi and induce disease symptoms when the viroid RNAs are exogenously applied to the fungal mycelia. These findings enhance our understanding of viroid replication, host range, and pathogenicity, and of their potential spread to other organisms in nature.


Hospitalizations, costs, and outcomes of severe sepsis in the United States 2003 to 2007.
To assess trends in number of hospitalizations, outcomes, and costs of severe sepsis in the United States. Temporal trends study using the Nationwide Inpatient Sample. Adult patients with severe sepsis (defined as a diagnosis of sepsis and organ dysfunction) diagnosed between 2003 and 2007. We determined the weighted frequency of patients hospitalized with severe sepsis. We calculated age- and sex-adjusted population-based mortality rates for severe sepsis per 100,000 population and also used logistic regression to adjust in-hospital mortality rates for patient characteristics. We calculated inflation-adjusted costs using hospital-specific cost-to-charge ratios. We identified a rapid steady increase in the number of cases of severe sepsis, from 415,280 in 2003 to 711,736 in 2007 (a 71% increase). The total hospital costs for all patients with severe sepsis increased from $15.4 billion in 2003 to $24.3 billion in 2007 (57% increase). The proportion of patients with severe sepsis and only a single organ dysfunction decreased from 51% in 2003 to 45% in 2007 (p < .001), whereas the proportion of patients with three or four or more organ dysfunctions increased 1.19-fold and 1.51-fold, respectively (p < .001). During the same time period, we observed 2% decrease per year in hospital mortality for patients with severe sepsis (p < .001), as well as a slight decrease in the length of stay (9.9 days to 9.2 days; p < .001) and a significant decrease in the geometric mean cost per case of severe sepsis ($20,210 per case in 2003 and $19,330 in 2007; p = .025). The increase in the number of hospitalizations for severe sepsis coupled with declining in-hospital mortality and declining geometric mean cost per case may reflect improvements in care or increases in discharges to skilled nursing facilities; however, these findings more likely represent changes in documentation and hospital coding practices that could bias efforts to conduct national surveillance.


Dietary Supplement of Large Yellow Tea Ameliorates Metabolic Syndrome and Attenuates Hepatic Steatosis in db/db Mice.
Yellow tea has been widely recognized for its health benefits. However, its effects and mechanism are largely unknown. The current study investigated the mechanism of dietary supplements of large yellow tea and its effects on metabolic syndrome and the hepatic steatosis in male db/db mice. Our data showed that dietary supplements of large yellow tea and water extract significantly reduced water intake and food consumption, lowered the serum total and low-density lipoprotein cholesterol and triglyceride levels, and significantly reduced blood glucose level and increased glucose tolerance in db/db mice when compared to untreated db/db mice. In addition, the dietary supplement of large yellow tea prevented the fatty liver formation and restored the normal hepatic structure of db/db mice. Furthermore, the dietary supplement of large yellow tea obviously reduced the lipid synthesis related to gene fatty acid synthase, the sterol regulatory element-binding transcription factor 1 and acetyl-CoA carboxylase α, as well as fatty acid synthase and sterol response element-binding protein 1 expression, while the lipid catabolic genes were not altered in the liver of db/db mice. This study substantiated that the dietary supplement of large yellow tea has potential as a food additive for ameliorating type 2 diabetes-associated symptoms.


The Nef protein of human immunodeficiency virus type 1 enhances serine phosphorylation of the viral matrix.
The human immunodeficiency virus type 1 matrix (MA) protein is phosphorylated during virion maturation on its C-terminal tyrosine and on several serine residues. Whereas MA tyrosine phosphorylation facilitates viral nuclear import, the significance of MA serine phosphorylation remains unclear. Here, we report that MA serine but not tyrosine phosphorylation is strongly enhanced by Nef. Mutations that abrogated the membrane association of Nef and its ability to bind a cellular serine/threonine kinase greatly diminished the extent of virion MA serine phosphorylation. Correspondingly, a protein kinase coimmunoprecipitated with Nef could phosphorylate MA on serine in vitro, producing a phosphopeptide pattern reminiscent of that of virion MA. Recombinant p21-activated kinase hPAK65, a recently proposed relative of the Nef-associated kinase, achieved a comparable result. Taken together, these data suggest that MA is a target of the Nef-associated serine kinase.


Autofluorescence-Directed Confocal Endomicroscopy in Combination With a Three-Biomarker Panel Can Inform Management Decisions in Barrett's Esophagus.
Barrett's esophagus (BE) surveillance with white-light endoscopy and quadrantic biopsies (Seattle protocol) is resource intensive and limited by sampling error. Previous work suggests that autofluorescence imaging (AFI) in combination with a molecular panel might reduce the number of biopsies, but this was not sufficiently sensitive for low-grade dysplasia, now a point for endoscopic intervention. Here we used AFI to direct narrow-field imaging tools for real-time optical assessment of dysplasia and biopsies for a biomarker panel. We compared the new diagnostic algorithm with the current standard. A total of 55 patients with BE were recruited at a single tertiary referral center. Patients underwent high-resolution endoscopy followed by AFI. AFI-targeted areas (n=194) were examined in turn by narrow-band imaging with magnification (NBIz) and probe-based confocal laser endomicroscopy (pCLE). Biopsies were taken from AFI-targeted areas and tested using an established molecular panel comprising aneuploidy plus cyclin A and p53 immunohistochemistry. In the per-patient analysis the overall sensitivity and specificity of AFI-targeted pCLE were 100% and 53.6% for high-grade dysplasia/intramucosal cancer and 96.4% and 74.1% for any grade of dysplasia, respectively. NBIz had equal specificity for dysplasia detection (74.1%), but significantly lower sensitivity (57.1%) than pCLE. The time required to perform AFI-targeted pCLE was shorter that that taken by the Seattle protocol (P=0.0004). We found enrichment of molecular abnormalities in areas with optical dysplasia by pCLE (P<0.001), regardless of histologic dysplasia. The addition of the 3-biomarker panel reduced the false positive rate of pCLE by 50%, leading to sensitivity and specificity for any grade of dysplasia of 89.2% and 88.9%, respectively. The combination of pCLE on AFI-targeted areas and a 3-biomarker panel identifies patients with dysplasia.


The roaming atom pathway in formaldehyde decomposition.
We present a detailed experimental and theoretical investigation of formaldehyde photodissociation to H(2) and CO following excitation to the 2(1)4(1) and 2(1)4(3) transitions in S(1). The CO velocity distributions were obtained using dc slice imaging of single CO rotational states (v=0, j(CO)=5-45). These high-resolution measurements reveal the correlated internal state distribution in the H(2) cofragments. The results show that rotationally hot CO (j(CO) approximately 45) is produced in conjunction with vibrationally "cold" H(2) fragments (v=0-5): these products are formed through the well-known skewed transition state and described in detail in the accompanying paper. After excitation of formaldehyde above the threshold for the radical channel (H(2)CO-->H+HCO) we also find formation of rotationally cold CO (j(CO)=5-28) correlated to highly vibrationally excited H(2) (v=6-8). These products are formed through a novel mechanism that involves near dissociation followed by intramolecular H abstraction [D. Townsend et al., Science 306, 1158 (2004)], and that avoids the region of the transition state entirely. The dynamics of this "roaming" mechanism are the focus of this paper. The correlations between the vibrational states of H(2) and rotational states of CO formed following excitation on the 2(1)4(3) transition allow us to determine the relative contribution to molecular products from the roaming atom channel versus the conventional molecular channel.


Single-Cell Genomic Characterization Reveals the Cellular Reprogramming of the Gastric Tumor Microenvironment.
The tumor microenvironment (TME) consists of a heterogenous cellular milieu that can influence cancer cell behavior. Its characteristics have an impact on treatments such as immunotherapy. These features can be revealed with single-cell RNA sequencing (scRNA-seq). We hypothesized that scRNA-seq analysis of gastric cancer together with paired normal tissue and peripheral blood mononuclear cells (PBMC) would identify critical elements of cellular deregulation not apparent with other approaches. scRNA-seq was conducted on seven patients with gastric cancer and one patient with intestinal metaplasia. We sequenced 56,167 cells comprising gastric cancer (32,407 cells), paired normal tissue (18,657 cells), and PBMCs (5,103 cells). Protein expression was validated by multiplex immunofluorescence. Tumor epithelium had copy number alterations, a distinct gene expression program from normal, with intratumor heterogeneity. Gastric cancer TME was significantly enriched for stromal cells, macrophages, dendritic cells (DC), and Tregs. TME-exclusive stromal cells expressed distinct extracellular matrix components than normal. Macrophages were transcriptionally heterogenous and did not conform to a binary M1/M2 paradigm. Tumor DCs had a unique gene expression program compared to PBMC DCs. TME-specific cytotoxic T cells were exhausted with two heterogenous subsets. Helper, cytotoxic T, Treg, and NK cells expressed multiple immune checkpoint or co-stimulatory molecules. Receptor-ligand analysis revealed TME-exclusive intercellular communication. Single-cell gene expression studies revealed widespread reprogramming across multiple cellular elements in the gastric cancer TME. Cellular remodeling was delineated by changes in cell numbers, transcriptional states, and intercellular interactions. This characterization facilitates understanding of tumor biology and enables identification of novel targets including for immunotherapy.


Predictors of Plasmodium falciparum malaria incidence in Chano Mille, South Ethiopia: a longitudinal study.
We assessed potential effects of local meteorological and environmental conditions, indoor residual spraying with insecticides, insecticide-treated nets (ITNs) use at individual and community levels, and individual factors on Plasmodium falciparum malaria incidence in a village in south Ethiopia. A cohort of 8,121 people was followed for 101 weeks with active and passive surveillance. Among 317 microscopically confirmed P. falciparum malaria episodes, 29.3% occurred among temporary residents. The incidence density was 3.6/10,000 person-weeks of observation. We observed higher malaria incidence among males, children 5-14 years of age, ITNs non-users, the poor, and people who lived closer to vector breeding places. Rainfall increased and indoor residual spraying with Deltamethrin reduced falciparum incidence. Although ITNs prevented falciparum malaria for the users, we did not find that free mass ITNs distribution reduced falciparum malaria on a village level.


Structure-toxicity relationships for the effects to Tetrahymena pyriformis of aliphatic, carbonyl-containing, alpha,beta-unsaturated chemicals.
Toxicity data for 82 aliphatic chemicals with an alpha,beta-unsaturated substructure were compiled. Toxicity was assessed in the 2-day Tetrahymena pyriformis population growth impairment assay. Toxic potency [log(IGC50(-1))] for most of these chemicals was in excess of baseline narcosis as quantified by the 1-octanol/water partition coefficient (log K(ow)). The toxicity of the alpha,beta-unsaturated aldehydes was modeled well by log K(ow) in conjunction with the sum of partial charges on the vinylene carbon atoms (Q(C4) + Q(C3)) and the energy of the lowest unoccupied molecular orbital (E(lumo)). These electronic descriptors were also successful at modeling the toxicity of alpha,beta-unsaturated ketones. The toxicity of a range of acrylates was constant within about 0.2 of a log unit. Conversely, the toxicity of methacrylates and esters containing the vinylene group varied considerably and was explained by their hydrophobicity. The comparison of the quantitative structure-activity relationship (QSAR) for the methacrylates and esters with that for non-polar narcosis showed little significant difference and hence suggested that substitution on the carbon-carbon double bond in the methacrylates and vinylene unsaturated esters does not enhance toxicity over that of baseline. Substitution on the carbon-carbon double bond in the alpha,beta-unsaturated aldehydes resulted in toxicity that was similar to that for saturated derivatives. Although an excellent hydrophobicity-dependent QSAR was developed for the esters containing ethynylene group, these compounds are considered to act as Michael-type acceptors. Attempts to combine different groups of Michael-type acceptors into a single QSAR, based on mechanistically derived descriptors, were unsuccessful. Thus, the modeling of the toxicity of the alpha,beta-unsaturated carbonyl domain is currently limited to models for narrow subdomains.


Safety of the long-term use of proton pump inhibitors.
The proton pump inhibitors (PPIs) as a class are remarkably safe and effective for persons with peptic ulcer disorders. Serious adverse events are extremely rare for PPIs, with case reports of interstitial nephritis with omeprazole, hepatitis with omeprazole and lansoprazole, and disputed visual disturbances with pantoprazole and omeprazole. PPI use is associated with the development of fundic gland polyps (FGP); stopping PPIs is associated with regression of FGP. In the absence of Helicobacter pylori infection, the long-term use of PPIs has not been convincingly proven to cause or be associated with the progression of pre-existing chronic gastritis or gastric atrophy or intestinal metaplasia. Mild/modest hypergastrinemia is a physiological response to the reduction in gastric acid secretion due to any cause. The long-term use of PPIs has not been convincingly proven to cause enterochromaffin-like cell hyperplasia or carcinoid tumors. PPIs increase the risk of community acquired pneumonia, but not of hospital acquired (nosocomial) pneumonia. There is no data to support particular care in prescribing PPI therapy due to concerns about risk of hip fracture with the long-term use of PPIs. Long-term use of PPIs does not lead to vitamin B12 deficiencies, except possibly in the elderly, or in persons with Zollinger-Ellison Syndrome who are on high doses of PPI for prolonged periods of time. There is no convincingly proven data that PPIs increase the risk of Clostridium difficile-associated diarrhea in persons in the community. The discontinuation of PPIs may result in rebound symptoms requiring further and even continuous PPI use for suppression of symptoms. As with all medications, the key is to use PPIs only when clearly indicated, and to reassess continued use so that long-term therapy is used judiciously. Thus, in summary, the PPIs are a safe class of medications to use long-term in persons in whom there is a clear need for the maintenance of extensive acid inhibition.


From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior.
Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.


Clinicopathologic characteristics of mucinous gastric adenocarcinoma.
There has been considerable controversy over the prognosis of mucinous gastric adenocarcinoma (MGC). In this study we analyzed the clinicopathologic differences between MGC and non-mucinous gastric carcinoma (NMGC). In addition, the relationship between mucin content and other clinicopathologic variables, including prognosis in MGC, was also investigated. We reviewed 2118 patients with pathologically-confirmed gastric cancer who underwent gastrectomy at the Department of Surgery, Yonsei University College of Medicine, during the period between Jan. 1987 and Dec. 1993. Among them, 130 patients had gastric carcinoma with extracellular mucin (MGC) and 1988 patients had gastric carcinoma without extracellular mucin (NMGC). We placed the MGC patients into two groups according to mucin content: mucin content involving over 50% of the tumor (dominant type, n = 94) and mucin content involving less than 50% of the tumor area (partial type, n = 36). The results were as follows: MGC was more common in males than NMGC. The size of the tumor in MGC (mean 5.3 cm) was larger than that of NMGC (mean 4.4 cm). The patients with MGC had a higher incidence of Borrmann type IV (MGC: 16.1%, NMGC: 9.9%), more frequent serosal invasion (MGC: 75.4%, NMGC: 48.6%), lymph-node metastasis (MGC: 75.4%, NMGC: 50.7%), and peritoneal metastasis (MGC: 10.0%, NMGC: 3.5%) than patients with NMGC. The patients with MGC were more advanced in stage at the time of diagnosis and had a worse overall 10-year survival rate (44.9%) than patients with NMGC (54.7%). However, the 10-year survival rate according to the stage of MGC was similar to that of NMGC. There were no significant differences between the mucin content and other pathologic variables, including prognosis, i.e. similar biologic behavior between dominant type MGC and partial type MGC. In conclusion, we suggest that MGC was more frequently diagnosed in advanced stage than NMGC with a poorer prognosis and that it is reasonable to consider the carcinoma with mucin content involving more than 30% of the tumor area as MGC.


Pediatric Obesity-Assessment, Treatment, and Prevention: An Endocrine Society Clinical Practice Guideline.
The European Society of Endocrinology and the Pediatric Endocrine Society. This guideline was funded by the Endocrine Society. To formulate clinical practice guidelines for the assessment, treatment, and prevention of pediatric obesity. The participants include an Endocrine Society-appointed Task Force of 6 experts, a methodologist, and a medical writer. This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation approach to describe the strength of recommendations and the quality of evidence. The Task Force commissioned 2 systematic reviews and used the best available evidence from other published systematic reviews and individual studies. One group meeting, several conference calls, and e-mail communications enabled consensus. Endocrine Society committees and members and co-sponsoring organizations reviewed and commented on preliminary drafts of this guideline. Pediatric obesity remains an ongoing serious international health concern affecting ∼17% of US children and adolescents, threatening their adult health and longevity. Pediatric obesity has its basis in genetic susceptibilities influenced by a permissive environment starting in utero and extending through childhood and adolescence. Endocrine etiologies for obesity are rare and usually are accompanied by attenuated growth patterns. Pediatric comorbidities are common and long-term health complications often result; screening for comorbidities of obesity should be applied in a hierarchal, logical manner for early identification before more serious complications result. Genetic screening for rare syndromes is indicated only in the presence of specific historical or physical features. The psychological toll of pediatric obesity on the individual and family necessitates screening for mental health issues and counseling as indicated. The prevention of pediatric obesity by promoting healthful diet, activity, and environment should be a primary goal, as achieving effective, long-lasting results with lifestyle modification once obesity occurs is difficult. Although some behavioral and pharmacotherapy studies report modest success, additional research into accessible and effective methods for preventing and treating pediatric obesity is needed. The use of weight loss medications during childhood and adolescence should be restricted to clinical trials. Increasing evidence demonstrates the effectiveness of bariatric surgery in the most seriously affected mature teenagers who have failed lifestyle modification, but the use of surgery requires experienced teams with resources for long-term follow-up. Adolescents undergoing lifestyle therapy, medication regimens, or bariatric surgery for obesity will need cohesive planning to help them effectively transition to adult care, with continued necessary monitoring, support, and intervention. Transition programs for obesity are an uncharted area requiring further research for efficacy. Despite a significant increase in research on pediatric obesity since the initial publication of these guidelines 8 years ago, further study is needed of the genetic and biological factors that increase the risk of weight gain and influence the response to therapeutic interventions. Also needed are more studies to better understand the genetic and biological factors that cause an obese individual to manifest one comorbidity vs another or to be free of comorbidities. Furthermore, continued investigation into the most effective methods of preventing and treating obesity and into methods for changing environmental and economic factors that will lead to worldwide cultural changes in diet and activity should be priorities. Particular attention to determining ways to effect systemic changes in food environments and total daily mobility, as well as methods for sustaining healthy body mass index changes, is of importance.