Proteomic analysis of irregular, bullet-shaped magnetosomes in the sulphate-reducing magnetotactic bacterium Desulfovibrio magneticus RS-1.
Recent molecular studies on magnetotactic bacteria have identified a number of proteins associated with bacterial magnetites (magnetosomes) and elucidated their importance in magnetite biomineralisation. However, these analyses were limited to magnetotactic bacterial strains belonging to the alpha-subclass of Proteobacteria. We performed a proteomic analysis of magnetosome membrane proteins in Desulfovibrio magneticus strain RS-1, which is phylogenetically classified as a member of the delta-Proteobacteria. In the analysis, the identified proteins were classified based on their putative functions and compared with the proteins from the other magnetotactic bacteria, Magnetospirillum magneticum AMB-1 and M. gryphiswaldense MSR-1. Three magnetosome-specific proteins, MamA (Mms24), MamK, and MamM, were identified in strains RS-1, AMB-1, and MSR-1. Furthermore, genes encoding ten magnetosome membrane proteins, including novel proteins, were assigned to a putative magnetosome island that contains subsets of genes essential for magnetosome formation. The collagen-like protein and putative iron-binding proteins, which are considered to play key roles in magnetite crystal formation, were identified as specific proteins in strain RS-1. Furthermore, genes encoding two homologous proteins of Magnetococcus MC-1 were assigned to a cryptic plasmid of strain RS-1. The newly identified magnetosome membrane proteins might contribute to the formation of the unique irregular, bullet-shaped crystals in this microorganism.


The first nationwide surveillance of antibacterial susceptibility patterns of pathogens isolated from skin and soft-tissue infections in dermatology departments in Japan.
To investigate the trends of antimicrobial resistance in pathogens isolated from skin and soft-tissue infections (SSTI) at dermatology departments in Japan, a Japanese surveillance committee conducted the first nationwide survey in 2013. Three main organisms were collected from SSTI at 30 dermatology departments in medical centers and 10 dermatology clinics. A total of 860 strains - 579 of Staphylococcus aureus, 240 of coagulase-negative Staphylococci, and 41 of Streptococcus pyogenes - were collected and shipped to a central laboratory for antimicrobial susceptibility testing. The patient profiles were also studied. Among all 579 strains of S. aureus, 141 (24.4%) were methicillin-resistant (MRSA). Among 97 Staphylococcus epidermidis strains, 54 (55.7%) were methicillin-resistant (MRSE). MRSA and MRSE were more frequently isolated from inpatients than from outpatients. Furthermore, these methicillin-resistant strains were also isolated more frequently from patients with histories of taking antibiotics within 4 weeks and hospitalization within 1 year compared to those without. However, there were no significant differences in MIC values and susceptibility patterns of the MRSA strains between patients with a history of hospitalization within 1 year and those without. Therefore, most of the isolated MRSA cases at dermatology departments are not healthcare-acquired, but community-acquired MRSA. S. pyogenes strains were susceptible to most antibiotics except macrolides. The information in this study is not only important in terms of local public health but will also contribute to an understanding of epidemic clones of pathogens from SSTI.


Are patients attracted to family physicians by the AAFP's "Competitive Edge" marketing materials?
A prospective study was conducted at a large military family practice clinic to assess the effectiveness of the AAFP's "Competitive Edge" marketing package. Four hundred and sixty-six Army families were randomly assigned to three study groups when they first arrived at Fort Benning, Georgia. One of these groups received two marketing brochures from the "Competitive Edge." The three groups were then followed for two years. There was no significant difference in the rate of enrollment for care in the Family Practice Clinic among the three groups (power = .95). Demographic data suggested that older soldiers who had higher military rank, smaller families, and those who had received care from a family physician in the past were more likely to enroll in family practice. The study demonstrated that the attitudes and knowledge of enrollees and non-enrollees toward the clinical skills of a family physician were similar. A study like this is relatively easy to perform and can be very useful market research for an individual practice.


Long-Term Fine Particulate Matter Exposure and Major Depressive Disorder in a Community-Based Urban Cohort.
Previous studies have associated short-term air pollution exposure with depression. Although an animal study showed an association between long-term exposure to particulate matter ≤ 2.5 μm (PM2.5) and depression, epidemiological studies assessing the long-term association are scarce. We aimed to determine the association between long-term PM2.5 exposure and major depressive disorder (MDD). A total of 27,270 participants 15-79 years of age who maintained an address within the same districts in Seoul, Republic of Korea, throughout the entire study period (between 2002 and 2010) and without a previous MDD diagnosis were analyzed. We used three district-specific exposure indices as measures of long-term PM2.5 exposure. Cox proportional hazards models adjusted for potential confounding factors and measured at district and individual levels were constructed. We further conducted stratified analyses according to underlying chronic diseases such as diabetes mellitus, cardiovascular disease, and chronic obstructive pulmonary disease. The risk of MDD during the follow-up period (2008-2010) increased with an increase of 10 μg/m3 in PM2.5 in 2007 [hazard ratio (HR) = 1.44; 95% CI: 1.17, 1.78], PM2.5 between 2007 and 2010 (HR = 1.59; 95% CI: 1.02, 2.49), and 12-month moving average of PM2.5 until an event or censor (HR = 1.47; 95% CI: 1.14, 1.90). The association between long-term PM2.5 exposure and MDD was greater in participants with underlying chronic diseases than in participants without these diseases. Long-term PM2.5 exposure increased the risk of MDD among the general population. Individuals with underlying chronic diseases are more vulnerable to long-term PM2.5 exposure. Kim KN, Lim YH, Bae HJ, Kim M, Jung K, Hong YC. 2016. Long-term fine particulate matter exposure and major depressive disorder in a community-based urban cohort. Environ Health Perspect 124:1547-1553; http://dx.doi.org/10.1289/EHP192.


DNA vaccination via RALA nanoparticles in a microneedle delivery system induces a potent immune response against the endogenous prostate cancer stem cell antigen.
Castrate resistant prostate cancer (CRPC) remains a major challenge for healthcare professionals. Immunotherapeutic approaches, including DNA vaccination, hold the potential to harness the host's own immune system to mount a cell-mediated, anti-tumour response, capable of clearing disseminated tumour deposits. These anti-cancer vaccines represent a promising strategy for patients with advanced disease, however, to date DNA vaccines have demonstrated limited efficacy in clinical trials, owing to the lack of a suitable DNA delivery system. This study was designed to evaluate the efficacy of a two-tier delivery system incorporating cationic RALA/pDNA nanoparticles (NPs) into a dissolvable microneedle (MN) patch for the purposes of DNA vaccination against prostate cancer. Application of NP-loaded MN patches successfully resulted in endogenous production of the encoded Prostate Stem Cell Antigen (PSCA). Furthermore, immunisation with RALA/pPSCA loaded MNs elicited a tumour-specific immune response against TRAMP-C1 tumours ex vivo. Finally, vaccination with RALA/pPSCA loaded MNs demonstrated anti-tumour activity in both prophylactic and therapeutic prostate cancer models in vivo. This is further evidence that this two-tier MN delivery system is a robust platform for prostate cancer DNA vaccination. STATEMENT OF SIGNIFICANCE: This research describes the development and utilisation of our unique microneedle (MN) DNA delivery system, which enables penetration through the stratum corneum and deposition of the DNA within the highly immunogenic skin layers via a dissolvable MN matrix, and facilitates cellular uptake via complexation of pDNA cargo into nanoparticles (NPs) with the RALA delivery peptide. We report for the first time on using the NP-MN platform to immunise mice with encoded Prostate Stem Cell Antigen (mPSCA) for prostate cancer DNA vaccination. Application of the NP-MN system resulted in local mPSCA expression in vivo. Furthermore, immunisation with the NP-MN system induced a tumour-specific cellular immune response, and inhibited the growth of TRAMP-C1 prostate tumours in both prophylactic and therapeutic challenge models in vivo.


Activating signal cointegrator 2 belongs to a novel steady-state complex that contains a subset of trithorax group proteins.
Many transcription coactivators interact with nuclear receptors in a ligand- and C-terminal transactivation function (AF2)-dependent manner. These include activating signal cointegrator 2 (ASC-2), a recently isolated transcriptional coactivator molecule, which is amplified in human cancers and stimulates transactivation by nuclear receptors and numerous other transcription factors. In this report, we show that ASC-2 belongs to a steady-state complex of approximately 2 MDa (ASC-2 complex [ASCOM]) in HeLa nuclei. ASCOM contains retinoblastoma-binding protein RBQ-3, alpha/beta-tubulins, and trithorax group proteins ALR-1, ALR-2, HALR, and ASH2. In particular, ALR-1/2 and HALR contain a highly conserved 130- to 140-amino-acid motif termed the SET domain, which was recently implicated in histone H3 lysine-specific methylation activities. Indeed, recombinant ALR-1, HALR, and immunopurified ASCOM exhibit very weak but specific H3-lysine 4 methylation activities in vitro, and transactivation by retinoic acid receptor appears to involve ligand-dependent recruitment of ASCOM and subsequent transient H3-lysine 4 methylation of the promoter region in vivo. Thus, ASCOM may represent a distinct coactivator complex of nuclear receptors. Further characterization of ASCOM will lead to a better understanding of how nuclear receptors and other transcription factors mediate transcriptional activation.


Three-dimensional volume off-line analysis as compared to real-time ultrasound for assessing adnexal masses.
To assess the agreement between three-dimensional volume off-line analysis as compared to real-time ultrasound for assessing adnexal masses. Ninety-nine non-consecutive women diagnosed as having an adnexal mass were assessed by transvaginal power Doppler ultrasound. One single examiner performed all ultrasound examinations. Based on the examiner's subjective evaluation using gray scale and Doppler ultrasound findings a presumptive diagnosis (benign or malignant) was provided after real-time ultrasound was performed. Once real-time was done a 3D volume of the adnexal mass was acquired and stored by this examiner. Two examiners, unaware of the real-time ultrasound results, evaluated the 3D volumes using multiplanar display and virtual navigation and also had to provide a presumptive diagnosis (benign or malignant). These two examiners, like the first one, had information about patient's age, menopausal status and complaints. All women underwent surgery or were followed-up until cyst resolution. Histologic diagnosis was used as gold standard. Cysts that resolved spontaneously were considered as benign for analytical purposes. The Kappa index was used to assess the agreement between real time ultrasound and 3D volume analysis. Sensitivity and specificity of both methods were calculated and compared using McNemar test. Forty-one masses were malignant and 58 were benign. Agreement between real-time ultrasound and 3D volume analysis was good for both off-line examiners (Kappa index: 0.82, 95% CI: 0.70-0.93 and 0.78, 95% CI: 0.65-0.90). Sensitivities for real-time ultrasound and 3D volume analyses were 100%, 93% and 90%, respectively (p>0.05). Specificities for real-time ultrasound and 3D volume analyses were 91%, 84% and 86%, respectively (p>0.05). Off-line 3D volume analysis may be a useful method for assessing adnexal masses, showing a good agreement with real-time ultrasound and having a similar diagnostic performance.


Enhanced recovery after elective spinal and peripheral nerve surgery: pilot study from a single institution.
OBJECTIVEEnhanced recovery after surgery (ERAS) protocols address pre-, peri-, and postoperative factors of a patient's surgical journey. The authors sought to assess the effects of a novel ERAS protocol on clinical outcomes for patients undergoing elective spine or peripheral nerve surgery.METHODSThe authors conducted a prospective cohort analysis comparing clinical outcomes of patients undergoing elective spine or peripheral nerve surgery after implementation of the ERAS protocol compared to a historical control cohort in a tertiary care academic medical center. Patients in the historical cohort (September-December 2016) underwent traditional surgical care. Patients in the intervention group (April-June 2017) were enrolled in a unique ERAS protocol created by the Department of Neurosurgery at the University of Pennsylvania. Primary objectives were as follows: opioid and nonopioid pain medication consumption, need for opioid use at 1 month postoperatively, and patient-reported pain scores. Secondary objectives were as follows: mobilization and ambulation status, Foley catheter use, need for straight catheterization, length of stay, need for ICU admission, discharge status, and readmission within 30 days.RESULTSA total of 201 patients underwent surgical care via an ERAS protocol and were compared to a total of 74 patients undergoing traditional perioperative care (control group). The 2 groups were similar in baseline demographics. Intravenous opioid medications postoperatively via patient-controlled analgesia was nearly eliminated in the ERAS group (0.5% vs 54.1%, p < 0.001). This change was not associated with an increase in the average or daily pain scores in the ERAS group. At 1 month following surgery, a smaller proportion of patients in the ERAS group were using opioids (38.8% vs 52.7%, p = 0.041). The ERAS group demonstrated greater mobilization on postoperative day 0 (53.4% vs 17.1%, p < 0.001) and postoperative day 1 (84.1% vs 45.7%, p < 0.001) compared to the control group. Postoperative Foley use was decreased in the ERAS group (20.4% vs 47.3%, p < 0.001) without an increase in the rate of straight catheterization (8.1% vs 11.9%, p = 0.51).CONCLUSIONSImplementation of this novel ERAS pathway safely reduces patients' postoperative opioid requirements during hospitalization and 1 month postoperatively. ERAS results in improved postoperative mobilization and ambulation.


When mirrors lie: "visual capture" of arm position impairs reaching performance.
If we stand at a mirror's edge, we can see one half of our body reflected in the mirror, as if it were the other half of our body, seen "through" the mirror. We used this mirror illusion to examine the effect of conflicts between visually and proprioceptively specified arm positions on subsequent reaching movements made with the unseen right arm. When participants viewed their static left arm in the mirror (i.e., as if it were their right arm), subsequent right-arm reaching movements were affected significantly more when there was conflict between the apparent visual and the proprioceptively specified right-arm positions than when there was no conflict. This result demonstrates that visual capture of arm position can occur when individual body parts are viewed in the mirror and that this capture has a measurable effect on subsequent reaching movements made with an unseen arm. The result has implications for how the brain represents the body across different sensory modalities.


High incidence of acute sub-clinical circumflex artery 'injury' following mitral isthmus ablation.
Mitral isthmus (MI) ablation is technically challenging, requiring long endocardial ablation times and frequently coronary sinus (CS) ablation. The circumflex artery lies in the epicardium in close proximity to the CS and the mitral annulus and may potentially be injured during radiofrequency ablation. Fifty-four patients underwent catheter ablation procedures that included MI ablation for treatment of atrial fibrillation. Irrigated ablation catheters were used with the following settings: endocardial surface (max power: 40/50 W at the annular end; max temperature: 48°C); CS (max power: 25/30 W; max temperature: 48°C). Coronary angiography was performed pre- and post-ablation and analysed by two cardiologists with quantitative coronary angiography. Mitral isthmus block was achieved in 89% of patients (60% required CS ablation). Fifteen patients (28%) had angiographic changes following ablation: eight had mid-circumflex narrowing only, one had circumflex and obtuse marginal (OM) artery narrowing, one had OM narrowing only, and five had distal circumflex occlusion/narrowing. Five patients had significant narrowing (50-84%), which resolved with intracoronary glycerine trinitrate. Fourteen (93%) of the patients with circumflex 'injury' had CS ablation and a longer mean CS ablation time (5.0 ± 3.0 vs. 2.6 ± 3.3 min, P = 0.03). Patients with distal circumflex occlusion had significantly smaller vessel diameter (1.0 ± 0.1 vs. 2.1 ± 0.2 mm, P = 0.03). A shorter distance between the circumflex and the CS was also associated with circumflex 'injury' (3.2 ± 1.9 vs. 5.6 ± 3.2 mm, P = 0.04). There were no electrocardiographic or echocardiographic abnormalities and no angina symptoms during follow-up. Acute sub-clinical circumflex 'injury' following MI ablation is not uncommon. Ablation within the CS, proximity of the circumflex and the CS, and a small distal circumflex were risk factors for 'injury'.


Hierarchical Modular DNA Assembly Using MetClo.
DNA assembly methods are essential for multiple applications including synthetic biology. We recently developed MetClo, a method that uses a single type IIS restriction enzyme for hierarchical modular DNA assembly. This offers great flexibility in the design of the assembly experiment and simplicity of execution. Here we describe a protocol for hierarchical assembly of large DNA constructs from modular DNA parts using the MetClo vector set, a set of assembly vectors designed for the MetClo method.


Making the case for laws that improve health: a framework for public health law research.
Public health law has received considerable attention in recent years and has become an essential field in public health. Public health law research, however, has received less attention. Expert commentary. This article explores public health law research, defined as the scientific study of the relation of law and legal practices to population health. The article offers a logic model of public health law research and a typology of approaches to studying the effects of law on public health. Research on the content and prevalence of public health laws, processes of adopting and implementing laws, and the extent to which and mechanisms through which law affects health outcomes can use methods drawn from epidemiology, economics, sociology, and other disciplines. The maturation of public health law research as a field depends on methodological rigor, adequate research funding, access to appropriate data sources, and policymakers' use of research findings. Public health law research is a young field but holds great promise for supporting evidence-based policy making that will improve population health.


Curability of patients with acute myeloid leukemia who did not undergo transplantation in first remission.
The aims of this study were to quantify the prospects of salvage treatment of patients who did not undergo transplantation in first complete remission (CR1) and to assess the contribution of allograft in second complete remission (CR2) with respect to major risk groups. This evaluation can inform the decision whether to offer a transplant in CR1. Of 8,909 patients who entered the Medical Research Council AML10, AML12, and AML15 trials, 1,271 of 3,919 patients age 16 to 49 years who did not receive a transplant in CR1 relapsed. Of these patients, 19% are alive beyond 5 years compared with 7% of patients who relapsed after an allograft in CR1. Overall survival and the contribution of a transplant in CR2 were assessed overall and by cytogenetic risk group by using Mantel-Byar analysis. Fifty-five percent of patients who relapsed entered CR2. This percentage varied by risk group as follows: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5-year survivals of 32%, 17%, 7%, and 23%, respectively. Sixty-seven percent of remitters received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% v 16%). A more-stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup. Successful salvage treatment of patients who do not undergo transplantation in CR1 and relapse can be achieved in 19% of patients, which is improved by a transplant except in favorable risk disease. This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants.


Adiponectin gene polymorphisms and acute respiratory distress syndrome susceptibility and mortality.
Adiponectin is an anti-inflammatory adipokine that is the most abundant gene product of adipose tissue. Lower levels have been observed in obesity, insulin resistance, and in critical illness. However, elevated levels early in acute respiratory failure have been associated with mortality. Polymorphisms in adiponectin-related genes (ADIPOQ, ADIPOR1, ADIPOR2) have been examined for relationships with obesity, insulin resistance and diabetes, cardiovascular disease, and to circulating adipokine levels, but many gaps in knowledge remain. The current study aims to assess the association between potentially functional polymorphisms in adiponectin-related genes with acute respiratory distress syndrome (ARDS) risk and mortality. Consecutive patients with risk factors for ARDS admitted to the ICU were enrolled and followed prospectively for development of ARDS. ARDS cases were followed through day 60 for all-cause mortality. 2067 patients were successfully genotyped using the Illumina CVD BeadChip high-density platform. Of these, 567 patients developed ARDS. Forty-four single nucleotide polymorphisms (SNPs) on ADIPOQ, ADIPOR1 and ADIPOR2 were successfully genotyped. Of these, 9 SNPs were hypothesized to be functional based on their location (promoter, exon, or 3' untranslated region). These 9 SNPs were analyzed for association with ARDS case status and mortality among ARDS cases. After multivariable analysis and adjustment for multiple comparisons, no SNPs were significantly associated with ARDS case status. Among ARDS cases, homozygotes for the minor allele of rs2082940 (ADIPOQ) had increased mortality (hazard ratio 2.61, 95% confidence interval 1.36-5.00, p = 0.0039) after adjustment for significant covariates. The significance of this association persisted after adjustment for multiple comparisons (FDR_q = 0.029). A common and potentially functional polymorphism in ADIPOQ may impact survival in ARDS. Further studies are required to replicate these results and to correlate genotype with circulating adiponectin levels.


Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis.
Periodontal disease is common among adults in the US and is a potential source of chronic inflammation. Recent data have suggested an important role for chronic inflammation in the development of coronary heart disease (CHD). To aid the United States Preventive Services Task Force (USPSTF) in evaluating whether periodontal disease is an independent novel risk factor for incident CHD. Studies were identified by searching Medline (1966 through March 2008) and reviewing prior systematic reviews, reference lists, and consulting experts. Prospective cohort studies that assessed periodontal disease, Framingham risk factors, and coronary heart disease incidence in the general adult population without known CHD were reviewed and quality rated using criteria developed by the USPSTF. Meta-analysis of good and fair quality studies was conducted to determine summary estimates of the risk of CHD events associated with various categories of periodontal disease. We identified seven articles of good or fair quality from seven cohorts. Several studies found periodontal disease to be independently associated with increased risk of CHD. Summary relative risk estimates for different categories of periodontal disease (including periodontitis, tooth loss, gingivitis, and bone loss) ranged from 1.24 (95% CI 1.01-1.51) to 1.34 (95% CI 1.10-1.63). Risk estimates were similar in subgroup analyses by gender, outcome, study quality, and method of periodontal disease assessment. Periodontal disease is a risk factor or marker for CHD that is independent of traditional CHD risk factors, including socioeconomic status. Further research in this important area of public health is warranted.


Characterizing the Input-Output Function of the Olfactory-Limbic Pathway in the Guinea Pig.
Nowadays the neuroscientific community is taking more and more advantage of the continuous interaction between engineers and computational neuroscientists in order to develop neuroprostheses aimed at replacing damaged brain areas with artificial devices. To this end, a technological effort is required to develop neural network models which can be fed with the recorded electrophysiological patterns to yield the correct brain stimulation to recover the desired functions. In this paper we present a machine learning approach to derive the input-output function of the olfactory-limbic pathway in the in vitro whole brain of guinea pig, less complex and more controllable than an in vivo system. We first experimentally characterized the neuronal pathway by delivering different sets of electrical stimuli from the lateral olfactory tract (LOT) and by recording the corresponding responses in the lateral entorhinal cortex (l-ERC). As a second step, we used information theory to evaluate how much information output features carry about the input. Finally we used the acquired data to learn the LOT-l-ERC "I/O function," by means of the kernel regularized least squares method, able to predict l-ERC responses on the basis of LOT stimulation features. Our modeling approach can be further exploited for brain prostheses applications.


Temporal dynamics of spontaneous default-mode network activity mediate the association between reappraisal and depression.
Cognitive reappraisal is associated with major depressive disorder (MDD), while spontaneous activity patterns of the default mode network (DMN) is implicated in reappraisal and MDD. However, neural mechanisms subserving the close association of spontaneous reappraisal and depression are unclear. Spontaneous reappraisal, depression and resting-state functional magnetic resonance imaging (rsfMRI) were measured from 105 healthy subjects. We assessed the temporal complexity (Hurst exponent), Regional Homogeneity (ReHo) and fractional Amplitude of Low Frequency Fluctuation (fALFF) profiles of DMN, a network involved in both reappraisal and depression. Mediation effects of these standard measures on the relationship between reappraisal and depression, and the contributions of each DMN subregion, were assessed. Results indicated that Hurst exponent (H) of DMN, whether extracted by independent component analysis (ICA) or region of interest (ROI), was significantly associated with reappraisal scores. An individual with a higher reappraisal score has a lower Hurst value of DMN. Mediation analyses suggest that H of DMN partially mediates the association between reappraisal and the degree of depression, and this mediation effect arises from the contribution of medial prefrontal cortex. Neither ReHo nor fALFF showed a similar correlation or mediation effect. These findings suggest that temporal dynamics of DMN play an important role in emotion regulation and its association with depression. H of DMN may serve as a neural marker mediating the association between reappraisal and depression.


Asymmetric right/left encoding of emotions in the human subthalamic nucleus.
Emotional processing is lateralized to the non-dominant brain hemisphere. However, there is no clear spatial model for lateralization of emotional domains in the basal ganglia. The subthalamic nucleus (STN), an input structure in the basal ganglia network, plays a major role in the pathophysiology of Parkinson's disease (PD). This role is probably not limited only to the motor deficits of PD, but may also span the emotional and cognitive deficits commonly observed in PD patients. Beta oscillations (12-30 Hz), the electrophysiological signature of PD, are restricted to the dorsolateral part of the STN that corresponds to the anatomically defined sensorimotor STN. The more medial, more anterior and more ventral parts of the STN are thought to correspond to the anatomically defined limbic and associative territories of the STN. Surprisingly, little is known about the electrophysiological properties of the non-motor domains of the STN, nor about electrophysiological differences between right and left STNs. In this study, microelectrodes were utilized to record the STN spontaneous spiking activity and responses to vocal non-verbal emotional stimuli during deep brain stimulation (DBS) surgeries in human PD patients. The oscillation properties of the STN neurons were used to map the dorsal oscillatory and the ventral non-oscillatory regions of the STN. Emotive auditory stimulation evoked activity in the ventral non-oscillatory region of the right STN. These responses were not observed in the left ventral STN or in the dorsal regions of either the right or left STN. Therefore, our results suggest that the ventral non-oscillatory regions are asymmetrically associated with non-motor functions, with the right ventral STN associated with emotional processing. These results suggest that DBS of the right ventral STN may be associated with beneficial or adverse emotional effects observed in PD patients and may relieve mental symptoms in other neurological and psychiatric diseases.


Superfast multifrequency phase-shifting technique with optimal pulse width modulation.
The technique of generating sinusoidal fringe patterns by defocusing squared binary structured ones has numerous merits for high-speed three-dimensional (3D) shape measurement. However, it is challenging for this method to realize a multifrequency phase-shifting (MFPS) algorithm because it is difficult to simultaneously generate high-quality sinusoidal fringe patterns with different periods. This paper proposes to realize an MFPS algorithm utilizing an optimal pulse width modulation (OPWM) technique that can selectively eliminate high-order harmonics of squared binary patterns. We successfully develop a 556 Hz system utilizing a three-frequency algorithm for simultaneously measuring multiple objects.


p13suc1 of Schizosaccharomyces pombe regulates two distinct forms of the mitotic cdc2 kinase.
suc1 is an essential gene initially identified for its ability to rescue certain temperature-sensitive alleles of cdc2 in Schizosaccharomyces pombe. The role of suc1 in the regulation of the cdc2 kinase is not well understood. In our study, we have characterized the biochemical effect of loss of suc1 function on specific cdc2-cyclin complexes. We show that the cig1 cyclin is associated with cdc2 and that the cdc2-cig1 kinase is activated at mitosis, with kinetics similar to those of the cdc2-cdc13 kinase. We provide evidence that loss of suc1 function affects the kinase activity of the two distinct mitotic forms of the cdc2 kinase. We also show that a dramatic increase in the level of the cdc13 protein is associated with loss of suc1. These results suggest that mitosis cannot be properly completed in the absence of suc1, possibly because of an increase in the level of cdc2-cdc13 complex, and support the idea of a role for suc1 in the regulation of multiple forms of the cdc2 kinase.


Prevalence and associated factors of refractive errors among type 2 diabetics in Kinmen, Taiwan.
A community-based study was conducted to identify the extent of prevalence of refractive errors and their associated factors from among the Chinese type 2 diabetic population in Kinmen. A total of 547 patients (> 40 years old) with type 2 diabetes were examined with a complete eye screening tests including objective autorefraction. Spherical equivalent refractions of right eyes were reported. Data collected include age, gender, general medical information and serum biochemistry. The mean refraction was -0.83 +/- 2.49 D. Prevalence rates were determined for myopia (44.1%), hyperopia (24.1%), high myopia (13.0%), and astigmatism (87.8%). Age is an important factor for all of the refractive errors. After adjustment for age, male gender and > 3 grade nuclear opacity appeared to be statistically significant factors for myopia. For hyperopia, > or =7% HbA1c was a significant associated factor, and for astigmatism, > or =200 mg/dl total cholesterol was the risk factor. Multiple linear regression showed that every increase of one year of age and one percent of HbA1c is associated with 0.04 D (p = 0.003) and 0.13D (p = 0.04) shift in hyperopia, respectively. Nuclear opacity with grade 3-4 and grade 5-6 will shift toward myopia of -0.72D (p = 0.02) and -5.34D (p < 0.0001) after adjustment for other risk factors. This study provides epidemiological data on refractive errors in a Chinese diabetic population in Kinmen, Taiwan. The myopia prevalence is higher than the reported rates in the general population. This survey further confirmed that myopia is more prevalent than hyperopia in the diabetic population. Age and blood sugar shift the refraction toward hyperopia while nuclear cataract reverses it. Correction of refractive errors in the diabetics remained a challenge as not only spectacles but medical intervention is mandatory.


Psychosocial and economic profile of a sample of families with thalassaemic children in Lebanon.
Thalassaemia major is a relatively common disease in Lebanon. This study of 41 families with 54 patients attending the American University of Beirut Medical Center was conducted to define some aspects of the disease in Lebanon and to assess the attitudes of affected families on relevant psychosocial and economic issues. We conclude that because of the high frequency of consanguineous marriage, thalassaemia major is more common in Lebanon than might be expected on the basis of the incidence of the trait. Most patients are diagnosed early in life, but their treatment is generally far from adequate; securing desferrioxamine and paying for follow up visits to the doctor seem to be the most important financial burdens. The general population of the country is not properly informed yet and about 70% of the families had not heard about the disease before having an affected child. The inherited nature of the disease is not clear in the minds of a high percentage of the families, and in about 30% of cases the family had not been told about the advisability of screening to detect heterozygotes. The great majority of families favour a preventive approach to thalassaemia, based on heterozygote screening and the possibility of prenatal diagnosis.


Angiostatic effect of penetrating ocular injury: role of pigment epithelium-derived factor.
To characterize the angiostatic effect of penetrating ocular injury and to begin to explore its mechanism, with an emphasis on the role of pigment epithelium-derived factor (PEDF). Using the rat model of oxygen-induced retinopathy (OIR), single or multiple dry needle injuries were made, penetrating the globe of one eye; the opposite eye served as a control. Eyes were harvested from rats killed 1, 3, and 6 days after injury, and retinas were dissected and processed for assessment of neovascularization and microglial activation or were processed for genetic and proteomic analysis. Temporal and spatial expression patterns of PEDF were analyzed by in situ hybridization. Penetrating ocular injury resulted in a 30% decrease in neovascular area in the retinas of OIR rats. At day 1 after injury, needle insertion caused a 4.1-fold increase in retinal PEDF mRNA and a 1.5-fold increase in retinal PEDF protein. Vitreous PEDF protein increased 3.4-fold in injured eyes compared with noninjured eyes. In situ hybridization showed an increase in PEDF mRNA in areas surrounding the puncture site. Concentrated vitreous protein from injured eyes caused a 60% decrease in retinal neovascularization when injected into the vitreous cavity of OIR rats. Preincubation of vitreous samples with anti-PEDF partially abolished this efficacy. The pattern of angiostasis resulting from penetrating ocular injury is consistent with the release of an endogenous antiangiogenic factor from the wound site. Preliminary studies show a possible role for PEDF in this effect. Further characterization of this role and the identification of other factors may lead to new therapeutic strategies for angiogenic eye conditions.


Educational differences in cancer mortality among women and men: a gender pattern that differs across Europe.
We used longitudinal mortality data sets for the 1990s to compare socioeconomic inequalities in total cancer mortality between women and men aged 30-74 in 12 different European populations (Madrid, Basque region, Barcelona, Slovenia, Turin, Switzerland, France, Belgium, Denmark, Norway, Sweden, Finland) and to investigate which cancer sites explain the differences found. We measured socioeconomic status using educational level and computed relative indices of inequality (RII). We observed large variations within Europe for educational differences in total cancer mortality among men and women. Three patterns were observed: Denmark, Norway and Sweden (significant RII around 1.3-1.4 among both men and women); France, Switzerland, Belgium and Finland (significant RII around 1.7-1.8 among men and around 1.2 among women); Spanish populations, Slovenia and Turin (significant RII from 1.29 to 1.88 among men; no differences among women except in the Basque region, where RII is significantly lower than 1). Lung, upper aerodigestive tract and breast cancers explained most of the variations between gender and populations in the magnitude of inequalities in total cancer mortality. Given time trends in cancer mortality, the gap in the magnitude of socioeconomic inequalities in cancer mortality between gender and between European populations will probably decrease in the future.


Prior herpes simplex virus type 2 infection as a risk factor for HIV infection.
Antibodies to cytomegalovirus (CMV), Epstein-Barr virus (EBV), and herpes simplex viruses types 1 and 2 (HSV-1, HSV-2) in three sequential serum samples from 62 men who did and 61 men who did not develop human immunodeficiency virus (HIV) infection at the time of the final (third) serum specimen were studied. Antibody titers to CMV, EBV, and HSV-1 did not significantly rise in or differ between men who did or did not get HIV infection. However, we found that 32 (68%) of 47 HIV seroconverters had antibodies to HSV-2 at the time the third specimen was drawn, whereas only 26 (46%) of 57 men who remained HIV seronegative had HSV-2 antibody positivity. Seroconversion to HSV-2 between any two serum specimens was found in 11 (42%) of the 26 HIV seroconverters but in only five (14%) of 35 men who remained HIV seronegative. The association between HSV-2 seropositivity (or seroconversion) and subsequent or concurrent HIV seroconversion remained when we controlled for factors known to influence HIV infection, including age, number of sexual partners, and percentage of sexual acts involving receptive anal intercourse. These serologic studies do not support the role of CMV, EBV, or HSV-1 in HIV infection but do suggest that HSV-2 infection is a risk factor for subsequent or concurrent HIV infection.


Effect of induced supraventricular tachycardias on changes in urine output and plasma hormone levels in man.
1. A symptomatic diuresis, polyuria, sometimes accompanies paroxysmal tachycardias in man. A study was undertaken in patients with inducible supraventricular tachycardia, irrespective of the symptom of polyuria, to measure simultaneous changes in urine output and plasma hormone levels during the arrhythmia. 2. During 14 episodes of induced tachycardia in 10 patients, there was a significant increase in mean urine flow, which was independent of the state of patient hydration. During a mean tachycardia duration of 30 +/- 3 min, the mean group urine flow increased from 3.2 +/- 2.3 ml/min to 7.6 +/- 3.7 ml/min (P less than 0.001). This was characterized by a consistent increase in free water excretion and a variable increase in sodium excretion. 3. The plasma atrial natriuretic peptide level (five patients) significantly increased from 7.6 +/- 4.6 pg/ml to 34.6 +/- 21.7 pg/ml (P less than 0.02) during the arrhythmia. There was no significant change in the plasma arginine-vasopressin level and a non-significant reduction in plasma renin activity. 4. This study has shown that induced supraventricular tachycardias in man are accompanied by a significant diuresis. The mechanisms responsible remain unknown, but do not appear to involve the plasma arginine-vasopressin level alone.


Ensemble projections of wildfire activity and carbonaceous aerosol concentrations over the western United States in the mid-21st century.
We estimate future wildfire activity over the western United States during the mid-21st century (2046-2065), based on results from 15 climate models following the A1B scenario. We develop fire prediction models by regressing meteorological variables from the current and previous years together with fire indexes onto observed regional area burned. The regressions explain 0.25-0.60 of the variance in observed annual area burned during 1980-2004, depending on the ecoregion. We also parameterize daily area burned with temperature, precipitation, and relative humidity. This approach explains ~0.5 of the variance in observed area burned over forest ecoregions but shows no predictive capability in the semi-arid regions of Nevada and California. By applying the meteorological fields from 15 climate models to our fire prediction models, we quantify the robustness of our wildfire projections at mid-century. We calculate increases of 24-124% in area burned using regressions and 63-169% with the parameterization. Our projections are most robust in the southwestern desert, where all GCMs predict significant (p<0.05) meteorological changes. For forested ecoregions, more GCMs predict significant increases in future area burned with the parameterization than with the regressions, because the latter approach is sensitive to hydrological variables that show large inter-model variability in the climate projections. The parameterization predicts that the fire season lengthens by 23 days in the warmer and drier climate at mid-century. Using a chemical transport model, we find that wildfire emissions will increase summertime surface organic carbon aerosol over the western United States by 46-70% and black carbon by 20-27% at midcentury, relative to the present day. The pollution is most enhanced during extreme episodes: above the 84th percentile of concentrations, OC increases by ~90% and BC by ~50%, while visibility decreases from 130 km to 100 km in 32 Federal Class 1 areas in Rocky Mountains Forest.


Does the prevalence of latent toxoplasmosis and frequency of Rhesus-negative subjects correlate with the nationwide rate of traffic accidents?
Latent toxoplasmosis is probably the most common protistan parasitic disease with many indirect negative impacts on human health. One of the important impacts is impaired psychomotor function leading to reduced driving efficiency in Toxoplasma-seropositive subjects. Numerous case-control studies have established a positive relation between the seroprevalence of Toxoplasma gondii (Nicolle et Manceaux, 1908) and probability of traffic accidents in study populations. The prevalence of toxoplasmosis varies between populations according to local geographical conditions, hygienic practices and kitchen habits. Similarly, we see a striking variation in the incidence of traffic accidents across countries. Hence, we compiled the largest ever data set on the seroprevalence of toxoplasmosis and tried to understand its role in traffic accident-related deaths and disabilities across 87 countries. Simple non-parametric analysis showed a positive and strong relation of T. gondii seroprevalence and traffic accident related disabilities. Further, we conducted multivariate analysis to control for confounding factors. After controlling for wealth, geographical latitude, health of population, length of roads and number of vehicles, the correlation disappeared. When the frequency of RhD negativity and its interaction with toxoplasmosis were included into the model, the effects of toxoplasmosis seemingly returned. However, the analysed data suffered from the problem of multicollinearity. When a proper method of analysis, ridge regression, was applied, the effects of toxoplasmosis prevalence and RhD negativity frequency disappeared again. The existence of a strong correlation between the prevalence of toxoplasmosis and health of population in particular countries, which was the probable cause of multicollinearity and possible reason for the negative result of the present study, suggests that 'asymptomatic' latent toxoplasmosis could have a large impact on public health.


A novel mechanism for modulating synaptic gene expression: differential localization of alpha-dystrobrevin transcripts in skeletal muscle.
Alpha-dystrobrevin is a dystrophin-related and -associated protein that is involved in synapse maturation and is required for normal muscle function. There are three protein isoforms in skeletal muscle, alpha-dystrobrevin-1, -2, and -3 that are encoded by the single alpha-dystrobrevin gene. To understand the role of these proteins in muscle we have investigated the localisation and transcript distribution of the different alpha-dystrobrevin isoforms. Alpha-dystrobrevin-1 and -2 are concentrated at the neuromuscular junction and are both recruited into agrin-induced acetylcholine receptor clusters in cultured myotubes. We also demonstrate that all alpha-dystrobrevin mRNAs are transcribed from a single promoter in skeletal muscle. However, only transcripts encoding alpha-dystrobrevin-1 are preferentially accumulated at postsynaptic sites. These data suggest that the synaptic accumulation of alpha-dystrobrevin-1 mRNA occurs posttranscriptionally, identifying a novel mechanism for synaptic gene expression. Taken together, these results indicate that different isoforms possess distinct roles in synapse formation and possibly in the pathogenesis of muscular dystrophy.


Forced lipophagy reveals that lipid droplets are required for early embryonic development in mouse.
Although autophagy is classically viewed as a non-selective degradation system, recent studies have revealed that various forms of selective autophagy also play crucial physiological roles. However, the induction of selective autophagy is not well understood. In this study, we established a forced selective autophagy system using a fusion of an autophagy adaptor and a substrate-binding protein. In both mammalian cells and fertilized mouse embryos, efficient forced lipophagy was induced by expression of a fusion of p62 (Sqstm1) and a lipid droplet (LD)-binding domain. In mouse embryos, induction of forced lipophagy caused a reduction in LD size and number, and decreased the triglyceride level throughout embryonic development, resulting in developmental retardation. Furthermore, lipophagy-induced embryos could eliminate excess LDs and were tolerant of lipotoxicity. Thus, by inducing forced lipophagy, expression of the p62 fusion protein generated LD-depleted cells, revealing an unexpected role of LD during preimplantation development.


Age-related differences in formal thought disorder in chronically hospitalized schizophrenic patients: a cross-sectional study across nine decades.
This study used a cross-sectional design to examine the frequency of occurrence and severity of 10 different signs of thought disorder in schizophrenic patients across the lifespan. Schizophrenic patients, who ranged in age from 19 to 96 years (N = 392), were examined with the Scale for Assessment of Thought, Language, and Communication. The cognitive functioning of the geriatric patients (patients over the age of 64, N = 120) was also assessed. Poverty of speech was more common and more severe in geriatric patients, while four different signs of thought disorder that reflect disconnected speech were less common and less severe in geriatric patients. Analysis of covariance found that the lower severity of disconnection thought disorders in the older patients was not attributable to differences in the amount of speech produced. Aspects of disconnected speech were less severe in older patients, while the severity and frequency of poverty of speech were greater. These findings suggest that the two previously identified separate dimensions of communication disorder in schizophrenia vary differently with age and possibly in their cognitive and biological underpinnings.


The sponge effect and carbon emission mitigation potentials of the global cement cycle.
Cement plays a dual role in the global carbon cycle like a sponge: its massive production contributes significantly to present-day global anthropogenic CO2 emissions, yet its hydrated products gradually reabsorb substantial amounts of atmospheric CO2 (carbonation) in the future. The role of this sponge effect along the cement cycle (including production, use, and demolition) in carbon emissions mitigation, however, remains hitherto unexplored. Here, we quantify the effects of demand- and supply-side mitigation measures considering this material-energy-emissions-uptake nexus, finding that climate goals would be imperiled if the growth of cement stocks continues. Future reabsorption of CO2 will be significant (~30% of cumulative CO2 emissions from 2015 to 2100), but climate goal compliant net CO2 emissions reduction along the global cement cycle will require both radical technology advancements (e.g., carbon capture and storage) and widespread deployment of material efficiency measures, which go beyond those envisaged in current technology roadmaps.


Effect of Oral Ranitidine on Urinary Excretion of N-Nitrosodimethylamine (NDMA): A Randomized Clinical Trial.
In 2019, the US Food and Drug Administration (FDA) received a citizen petition indicating that ranitidine contained the probable human carcinogen N-nitrosodimethylamine (NDMA). In addition, the petitioner proposed that ranitidine could convert to NDMA in humans; however, this was primarily based on a small clinical study that detected an increase in urinary excretion of NDMA after oral ranitidine consumption. To evaluate the 24-hour urinary excretion of NDMA after oral administration of ranitidine compared with placebo. Randomized, double-blind, placebo-controlled, crossover clinical trial at a clinical pharmacology unit (West Bend, Wisconsin) conducted in 18 healthy participants. The study began in June 2020, and the end of participant follow-up was July 1, 2020. Participants were randomized to 1 of 4 treatment sequences and over 4 periods received ranitidine (300 mg) and placebo (randomized order) with a noncured-meats diet and then a cured-meats diet. The cured-meats diet was designed to have higher nitrites, nitrates (nitrate-reducing bacteria can convert nitrates to nitrites), and NDMA. Twenty-four-hour urinary excretion of NDMA. Among 18 randomized participants (median age, 33.0 [interquartile range {IQR}, 28.3 to 42.8] years; 9 women [50%]; 7 White [39%], 11 African American [61%]; and 3 Hispanic or Latino ethnicity [17%]), 17 (94%) completed the trial. The median 24-hour NDMA urinary excretion values for ranitidine and placebo were 0.6 ng (IQR, 0 to 29.7) and 10.5 ng (IQR, 0 to 17.8), respectively, with a noncured-meats diet and 11.9 ng (IQR, 5.6 to 48.6) and 23.4 ng (IQR, 8.6 to 36.7), respectively, with a cured-meats diet. There was no statistically significant difference between ranitidine and placebo in 24-hour urinary excretion of NDMA with a noncured-meats diet (median of the paired differences, 0 [IQR, -6.9 to 0] ng; P = .54) or a cured-meats diet (median of the paired differences, -1.1 [IQR, -9.1 to 11.5] ng; P = .71). No drug-related serious adverse events were reported. In this trial that included 18 healthy participants, oral ranitidine (300 mg), compared with placebo, did not significantly increase 24-hour urinary excretion of NDMA when participants consumed noncured-meats or cured-meats diets. The findings do not support that ranitidine is converted to NDMA in a general, healthy population. ClinicalTrials.gov Identifier: NCT04397445.


Plasma rich in growth factors for the treatment of rapidly progressing refractory corneal melting due to erlotinib in nonsmall cell lung cancer.
Erlotinib, an antineoplastic agent, is indicated for the treatment of patients with advanced nonsmall cell lung cancer. Most common adverse events are manageable, although more severe ones require dose reduction or discontinuation of erlotinib treatment. We present a case of severe corneal ulcer treated with autologous plasma rich in growth factors. A 76-year-old woman with stage IVB (cT2a N0 M1c) lung cancer under erlotinib treatment presented with rapidly progressing corneal ulcer. Evolution was torpid and refractory to conventional treatment. Surgical options were dismissed because of the poor performance status of the patient. Despite temporary discontinuation of erlotinib treatment, the corneal ulcer continued to worsen with peripheral corneal neovascularization, stromal thinning, corneal edema, and profuse inflammation of the ocular surface. Treatment with autologous plasma rich in growth factors prevented an imminent corneal perforation and improved the corneal ulcer for over a year of follow-up. Considering the poor results of conventional treatment, both medical and surgical, management of the inflammation of the ocular surface together with the stimulation of the healing processes through regenerative therapy such as PRGF, can be an option worth considering in these cases.


Systematic identification of cancer-specific MHC-binding peptides with RAVEN.
Immunotherapy can revolutionize anti-cancer therapy if specific targets are available. Immunogenic peptides encoded by cancer-specific genes (CSGs) may enable targeted immunotherapy, even of oligo-mutated cancers, which lack neo-antigens generated by protein-coding missense mutations. Here, we describe an algorithm and user-friendly software named RAVEN (Rich Analysis of Variable gene Expressions in Numerous tissues) that automatizes the systematic and fast identification of CSG-encoded peptides highly affine to Major Histocompatibility Complexes (MHC) starting from transcriptome data. We applied RAVEN to a dataset assembled from 2,678 simultaneously normalized gene expression microarrays comprising 50 tumor entities, with a focus on oligo-mutated pediatric cancers, and 71 normal tissue types. RAVEN performed a transcriptome-wide scan in each cancer entity for gender-specific CSGs, and identified several established CSGs, but also many novel candidates potentially suitable for targeting multiple cancer types. The specific expression of the most promising CSGs was validated in cancer cell lines and in a comprehensive tissue-microarray. Subsequently, RAVEN identified likely immunogenic CSG-encoded peptides by predicting their affinity to MHCs and excluded sequence identity to abundantly expressed proteins by interrogating the UniProt protein-database. The predicted affinity of selected peptides was validated in T2-cell peptide-binding assays in which many showed binding-kinetics like a very immunogenic influenza control peptide. Collectively, we provide an exquisitely curated catalogue of cancer-specific and highly MHC-affine peptides across 50 cancer types, and a freely available software (https://github.com/JSGerke/RAVENsoftware) to easily apply our algorithm to any gene expression dataset. We anticipate that our peptide libraries and software constitute a rich resource to advance anti-cancer immunotherapy.


Potent adenosine receptor antagonists that are selective for the A1 receptor subtype.
The xanthines currently represent the most potent class of adenosine receptor antagonists. However, known derivatives of xanthine show little difference in antagonist potency between the two putative adenosine receptor subtypes, A1 and A2. We conducted a systematic study of xanthine structure-activity relationships that compared antagonist potency at the A1 receptor of adipocytes with potency at the A2 receptor of platelets. Since adenosine receptors are coupled to adenylate cyclase in these tissues, inhibition of adenylate cyclase via A1 receptors and stimulation via A2 receptors were used as models of receptor activation. Antagonist potency was quantitated by Schild analysis, which yields an estimate of affinity (Ki) for the drug-receptor interaction. Ki values of a series of xanthine analogues enabled us to identify structural modifications than enhanced antagonist selectivity for one receptor subtype over the other. We found that changes in the substituent at position 8 of the xanthine nucleus influenced antagonist potency at the A1 adenosine receptor more than at the A2 receptor. In particular, an 8-cyclohexyl or 8-cyclopentyl substituent promoted antagonist selectivity for the A1 receptor subtype. Thus, 1,3-dipropyl-8-cyclopentylxanthine had comparatively high affinity (Ki = 0.47 +/- 2 nM) at the A1 receptor, and was roughly 150-fold more potent as an antagonist of the A1- than of the A2-adenosine receptor subtype. In addition, the cycloalkylxanthines were relatively ineffective as inhibitors of cyclic nucleotide phosphodiesterases when used at concentrations that produced marked adenosine receptor antagonism.


Major similarities in the bacterial communities associated with lesioned and healthy Fungiidae corals.
Cultivation-based studies have demonstrated that yellow-band disease (YBD), a lesion-producing ailment affecting diverse species of coral, is caused by a consortium of Vibrio spp. This study takes the first cultivation-independent approach to examine the whole bacterial community associated with YBD-like lesioned corals. Two species of Fungiidae corals, Ctenactis crassa and Herpolitha limax, displaying YBD-like lesions were examined across diverse reefs throughout the Red Sea. Using a pyrosequencing approach targeting the V1-V3 regions of the SSU rRNA gene, no major differences in bacterial community composition or diversity were identified between healthy and lesioned corals of either species. Indicator species analysis did not find Vibrio significantly associated with the lesioned corals. However, operational taxonomic units belonging to the Ruegeria genus of Alphaproteobacteria and NS9 marine group of Flavobacteria were significantly associated with the lesioned corals. The most striking trend of this dataset was that reef location was found to be the most significant influence on the coral-bacterial community. It is possible that more pronounced lesion-specific bacterial signatures might have been concealed by the strong influence of environmental conditions on coral-bacteria. Overall, this study demonstrates inconsistencies between cultivation-independent and cultivation-based studies regarding the role of specific bacteria in coral diseases.


Optimal management of apparatus dead space in the anesthetized infant.
Mechanical ventilation of the anesthetized infant requires careful attention to equipment and ventilator settings to assure optimal gas exchange and minimize the potential for lung injury. Apparatus dead space, defined as dead space resulting from devices placed between the endotracheal tube and the Y-piece of the breathing circuit, is the primary source of dead space controlled by the clinician. Due to the small tidal volumes required by infants and neonates, it is easy to create excessive apparatus dead space resulting in unintended hypercarbia or increased minute ventilation in an effort to achieve a desirable PCO2 . The goal of this review was to evaluate the apparatus that are commonly added to the breathing circuit during anesthesia care, and develop recommendations to guide the clinician in selecting apparatus that are best matched to the clinical goals and the patient's size. We include specific recommendations for apparatus that are best suited for different size pediatric patients, with a particular focus on patients <5 kg.


Assessing Current Local Capacity for Agrifood Production To Meet Household Demand: Analyzing Select Food Commodities across 377 U.S. Metropolitan Areas.
Increasing food production in local urban and peri-urban areas is articulated as a potential way for local governments to achieve multiple sustainability outcomes (environmental, social, and human health). However, scientific judgements on localization are difficult to make because the degree of current food localization has not been systematically measured or defined across large numbers of cities. We develop new methods to quantify current local capacity for food production to meet total household agrifood demand, harmonizing bottom-up and top-down approaches to assess direct-plus-embodied agrifood demand of both fresh and processed foods. We find unique patterns of localization for different agrifoods, with 21% of U.S. metropolitan statistical areas (MSAs) currently capable of local self-sufficiency for eggs and milk equivalents embodied in diet, versus 12% and 16% of MSAs self-sufficient in fruits and vegetables, respectively. Focusing only on the direct fresh food demand, increased current local capacity (e.g., 45% MSAs self-sufficient in direct fluid milk), which also increases with production distances around cities. Overall, significant agricultural production is found to already occur in and around U.S. MSAs for these items. Multivariable analysis finds that state policies that promote urban agriculture may influence greater localization, which, interestingly, is independent of population density. Such spatial demand-production analysis is the first step in informing sustainable city or regional food policies and envisioning spatial food supply chains to urban areas.


Inverse relationship of peripheral thyrotropin-stimulating hormone levels to brain activity in mood disorders.
The author's goal was to investigate relationships between peripheral thyroid hormone levels and cerebral blood flow (CBF) and cerebral glucose metabolism in affectively ill patients. Medication-free inpatients with major depression or bipolar disorder were studied with oxygen-15 water and positron emission tomography (PET) to measure CBF (N = 19) or with [18F] fluorodeoxyglucose and PET to measure cerebral glucose metabolism (N = 29). Linear regression was used to correlate global CBF and cerebral glucose metabolism with serum thyrotropin-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), and free T4 concentrations. Statistical parametric mapping was used to correlate regional CBF and cerebral glucose metabolism with these thyroid indexes. Post hoc t tests were used to further explore the relationships between serum TSH and global CBF and cerebral glucose metabolism. Serum TSH was inversely related to both global and regional CBF and cerebral glucose metabolism. These relationships persisted in the cerebral glucose metabolism analysis and, to a lesser extent, in the CBF analysis after severity of depression had been controlled for. In contrast, no significant relationships were observed between T3, T4, or free T4 and global or regional CBF and cerebral glucose metabolism. These data suggest that peripheral TSH (putatively the best marker of thyroid status) is inversely related to global and regional CBF and cerebral glucose metabolism. These findings indicate relationships between thyroid and cerebral activity that could provide mechanistic hypotheses for thyroid contributions to primary and secondary mood disorders and the psychotropic effects of thyroid axis manipulations.


High-sensitivity time-resolved intracavity laser Fourier transform spectroscopy with vertical-cavity surface-emitting multiple-quantum-well lasers.
Spectra composed of hundreds of time components for absorption path lengths of up to 130 km have been recorded near 1050 nm by combination of two recent techniques, intracavity laser spectroscopy with vertical external cavity surface-emitting multiple-quantum-well lasers and time-resolved Fourier transform spectroscopy. A sensitivity of 1 x 10(-10) cm(-1) Hz(-1/2) is achieved for 10(4) simultaneously acquired spectral elements, 3 orders of magnitude better than the sensitivity obtained in previous similar experiments. Specific advantages of the method, especially for frequency and intensity metrology of weak absorption transitions, are discussed.


Enhancing RGI lyase thermostability by targeted single point mutations.
Rhamnogalacturonan I lyase (RGI lyase) (EC 4.2.2.-) catalyzes the cleavage of rhamnogalacturonan I in pectins by β-elimination. In this study the thermal stability of a RGI lyase (PL 11) originating from Bacillus licheniformis DSM 13/ATCC14580 was increased by a targeted protein engineering approach involving single amino acid substitution. Nine individual amino acids were selected as targets for site-saturated mutagenesis by the use of a predictive consensus approach in combination with prediction of protein mutant stability changes and B-factor iteration testing. After extensive experimental verification of the thermal stability of the designed mutants versus the original wild-type RGI lyase, several promising single point mutations were obtained, particularly in position Glu434 on the surface of the enzyme protein. The best mutant, Glu434Leu, produced a half-life of 31 min at 60 °C, corresponding to a 1.6-fold improvement of the thermal stability compared to the original RGI lyase. Gly55Val was the second best mutation with a thermostability half-life increase of 27 min at 60 °C, and the best mutations following were Glu434Trp, Glu434Phe, and Glu434Tyr, respectively. The data verify the applicability of a combinatorial predictive approach for designing a small site saturation library for improving enzyme thermostability. In addition, new thermostable RGI lyases suitable for enzymatic upgrading of pectinaceous plant biomass materials at elevated temperatures were produced.


Dual kinase-bromodomain inhibitors for rationally designed polypharmacology.
Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multitarget profile has, however, necessitated the application of combination therapies, which can pose major clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as new targets for cancer therapy. Here we report that several clinical kinase inhibitors also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase-bromodomain inhibitors. Nanomolar activity on BRD4 by BI-2536 and TG-101348, which are clinical PLK1 and JAK2-FLT3 kinase inhibitors, respectively, is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a new strategy for rational single-agent polypharmacological targeting. Furthermore, structure-activity relationships and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase-bromodomain inhibitors.


Regulatory principles of developmental signaling.
Signaling between cells is a widely used mechanism by which cell fate and tissue patterning is determined in development. We review the mechanisms by which signaling between cells is regulated so that a cell receives the right amount of signal, at the right time, to achieve its intended developmental fate and position. In nearly all cases, we find that the supply of signal factor (ligand) is the limiting step in initiating a signaling process. Ligand supply is regulated by the transcription and localization of RNA, the spread of ligand from a source, and by inhibitors that operate at several different levels. We emphasize the different regulatory strategies that operate for threshold as opposed to concentration-dependent (morphogen) signaling. Threshold signaling is extensively regulated by feedback mechanisms. Morphogen signaling is regulated quantitatively by receptor loading and transduction flow.


Developing attentional control in naturalistic dynamic road crossing situations.
In the last 20 years, there has been increasing interest in studying visual attentional processes under more natural conditions. In the present study, we propose to determine the critical age at which children show similar to adult performance and attentional control in a visually guided task; in a naturalistic dynamic and socially relevant context: road crossing. We monitored visual exploration and crossing decisions in adults and children aged between 5 and 15 while they watched road traffic videos containing a range of traffic densities with or without pedestrians. 5-10 year old (y/o) children showed less systematic gaze patterns. More specifically, adults and 11-15 y/o children look mainly at the vehicles' appearing point, which is an optimal location to sample diagnostic information for the task. In contrast, 5-10 y/os look more at socially relevant stimuli and attend to moving vehicles further down the trajectory when the traffic density is high. Critically, 5-10 y/o children also make an increased number of crossing decisions compared to 11-15 y/os and adults. Our findings reveal a critical shift around 10 y/o in attentional control and crossing decisions in a road crossing task.


Cisplatin-Based First-Line Treatment of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: Joint Analysis of MILES-3 and MILES-4 Phase III Trials.
Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.


Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus.
Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is considered to be a T cell mediated disease in which TH1 and Tc autoreactive cells attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM, glutamic acid decarboxylase (GAD) 65 appears to play a key role in the development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the experimental model for this disease. It has been shown that shifting the immune response to this antigen from TH1 towards TH2, via the administration of GAD65 peptides to young NOD mice, can suppress the progression to overt T1DM. Accordingly, various protocols of "peptide immunotherapy" of T1DM are under investigation. However, in mice with experimental autoimmune encephalomyelitis (EAE), another autoimmune TH1 mediated disease that mimics human multiple sclerosis, anaphylactic shock can occur when the mice are challenged with certain myelin self peptides that initially were administered with adjuvant to induce the disease. Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM. These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a TH1 to TH2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides.


Characterization of Risk Factors and Timing of Venous Thromboembolism in Patients With Uterine Serous Carcinoma.
To characterize risk factors and timing of venous thromboembolism in women with uterine serous carcinoma. A retrospective cohort study was performed including all women diagnosed with uterine serous carcinoma from 1999 to 2016 at our institution. Clinicopathologic data and information regarding timing of venous thromboembolism were abstracted from the medical record. Logistic regression and Cox proportional hazards modeling were used to examine the association between covariates and risk and timing of venous thromboembolism. Seventy of the 413 included patients (17%) developed venous thromboembolism, with a median time from presentation to venous thromboembolism of 7.2 months (interquartile range 1.0-24.8) and from surgery to venous thromboembolism of 13.2 months (interquartile range 3.5-33.6). Fifty-nine of the 70 patients (84%) who developed venous thromboembolism were diagnosed either before surgery or greater than 6 weeks postoperatively. Twenty-two of the 70 patients (31%) who developed clots were on chemotherapy at the time of diagnosis. Venous thromboembolism was highly associated with cancer stage and presence of hypertension (P<.01). Cox proportional hazards modeling revealed that only cancer stages III and IV (hazard ratio [HR] 3.20, 95% CI 1.54-6.64 and HR 8.68, 95% CI 4.50-16.73, respectively) and hypertensive or cardiovascular diseases (HR 2.29, 95% CI 1.08-4.85 and HR 1.82, 95% CI 1.05-3.13) were associated with time to venous thromboembolism. Patients with uterine serous carcinoma are at high risk of developing venous thromboembolism even many months after their cancer diagnosis. This study generates the hypothesis that venous thromboembolism prophylaxis may be beneficial in patients with uterine serous carcinoma during other time points along the continuum of disease rather than only in the postoperative period, especially for those with advanced cancer.


PKM2 regulates endothelial cell junction dynamics and angiogenesis via ATP production.
Angiogenesis, the formation of new blood vessels from pre-existing ones, occurs in pathophysiological contexts such as wound healing, cancer, and chronic inflammatory disease. During sprouting angiogenesis, endothelial tip and stalk cells coordinately remodel their cell-cell junctions to allow collective migration and extension of the sprout while maintaining barrier integrity. All these processes require energy, and the predominant ATP generation route in endothelial cells is glycolysis. However, it remains unclear how ATP reaches the plasma membrane and intercellular junctions. In this study, we demonstrate that the glycolytic enzyme pyruvate kinase 2 (PKM2) is required for sprouting angiogenesis in vitro and in vivo through the regulation of endothelial cell-junction dynamics and collective migration. We show that PKM2-silencing decreases ATP required for proper VE-cadherin internalization/traffic at endothelial cell-cell junctions. Our study provides fresh insight into the role of ATP subcellular compartmentalization in endothelial cells during angiogenesis. Since manipulation of EC glycolysis constitutes a potential therapeutic intervention route, particularly in tumors and chronic inflammatory disease, these findings may help to refine the targeting of endothelial glycolytic activity in disease.


Patterns of delayed detection and persistence of bovine tuberculosis in confirmed and unconfirmed herd breakdowns in cattle and cattle herds in Great Britain.
Approximately 1500/6000 cattle farms that were depopulated during the foot and mouth epidemic in GB in 2001 had been repopulated and subjected to two unrestricted (herd considered free from bovine tuberculosis (bTB)) herd tests. Factors associated with herd breakdown(s) (HBD) and individual cattle reactor status at the second test were investigated. There were 96 HBD in total, with a 3-fold increased risk of HBD in herds that had had a HBD at the first test after restocking. Two mixed effect models were used to investigate factors associated with 324/246,060 reactor cattle at the second bTB test; 228 reactors were at confirmed HBD and 96 at unconfirmed HBD; 253 (79%) reactors at the second test were present and test negative at the first test. In confirmed HBD, the odds of cattle reacting were higher if the restocked farm had a history of bTB before 2001 and if the source and restocked farms were high frequency tested (HFT) farms (routine bTB tests at ≥1 per 2 years). Reacting cattle were more likely to have been born on the restocked farm before the first test after FMD and less likely to have been purchased from a low frequency tested (LFT) farm (routine bTB tests at 3-4 year intervals) after the first test compared with a baseline of cattle purchased from a LFT farm before the first test. Unconfirmed HBD at the second test was more likely when the first test was a confirmed HBD and when there was a history of bTB in the restocked farm. In contrast to confirmed HBD, cattle purchased from a LFT farm after the first test were at increased risk of reacting at an unconfirmed HBD at the second test. We conclude that a farm history of bTB suggests persistence of bTB on the farm. Confirmed tests indicate exposure to bTB for some time indicated by the increased risk from HFT source and restocked farms and a farm history of bTB. The risks for reactors are related to the farm and herd and duration of exposure to these risks. Therefore, the spread of bTB to naïve herds would be reduced if farmers only introduced cattle known not to have been in herds and on farms exposed to bTB. Management of bTB on farms with bTB is complicated because there is undisclosed infection in cattle and environmental contamination.


The costs and service implications of substituting intermediate care for acute hospital care.
Intermediate care is part of a package of initiatives introduced by the UK Government mainly to relieve pressure on acute hospital beds and reduce delayed discharge (bed blocking). Intermediate care involves caring for patients in a range of settings, such as in the home or community or in nursing and residential homes. This paper considers the scope of intermediate care and its role in relation to acute hospital services. In particular, it develops a framework that can be used to inform decisions about the most cost-effective care pathways for given clinical situations, and also for wider planning purposes. It does this by providing a model for evaluating the costs of intermediate care services provided by different agencies and techniques for calibrating the model locally. It finds that consistent application of the techniques over a period of time, coupled with sound planning and accounting, should result in savings to the health economy.


Atlas-based segmentation for globus pallidus internus targeting on low-resolution MRI.
In this paper we report a method to automatically segment the internal part of globus pallidus (GPi) on the pre-operative low-resolution magnetic resonance images (MRIs) of patients affected by Parkinson's disease. Herein we used an ultra-high resolution human brain dataset as electronic atlas of reference on which we segmented the GPi. First, we registered the ultra-high resolution dataset on the low-resolution dataset using a landmarks-based rigid registration. Then an affine and a non-rigid surface-based registration guided by the structures that surround the target was applied in order to propagate the labels of the GPi on the low-resolution un-segmented dataset and to accurately outline the target. The mapping of the atlas on the low-resolution MRI provided a highly accurate anatomical detail that can be useful for localizing the target.


Factors related to falls, weight-loss and pressure ulcers--more insight in risk assessment among nursing home residents.
To describe how the included items in three different scales, Downton Fall Risk Index, the short form of Mini Nutritional Assessment and the Modified Norton Scale are associated to severe outcomes as falls, weight loss and pressure ulcers. Falls, malnutrition and pressure ulcers are common adverse events among nursing home residents and risk scoring are common preventive activities, mainly focusing on single risks. In Sweden the three scales are routinely used together with the purpose to improve the quality of prevention. Longitudinal quantitative study. Descriptive analyses and Cox regression analyses. Only 4% scored no risk for any of these serious events. Longitudinal risk scoring showed significant impaired mean scores indicating increased risks. This confirms the complexity of this population's status of general condition. There were no statistical significant differences between residents categorised at risk or not regarding events. Physical activity increased falls, but decreased pressure ulcers. For weight loss, cognitive decline and the status of general health were most important. Risk tendencies for falls, malnutrition and pressure ulcers are high in nursing homes, and when measure them at the same time the majority will have several of these risks. Items assessing mobility or items affecting mobility were of most importance. Care processes can always be improved and this study can add to the topic. A more comprehensive view is needed and prevention can not only be based on total scores. Mobility is an important factor for falls and pressure ulcers, both as a risk factor and a protective factor. This involves a challenge for care--to keep the inmates physical active and at the same time prevent falls.


Regulation of gene expression by small molecules in rice.
A system for the regulation of gene expression by small molecules in transgenic rice was developed. This gene switch system consists of two components: (1) a hybrid chemically activated transcription factor, and (2) a synthetic target promoter. The two elements were transformed into rice suspension cells and transgenic plants were regenerated. A luciferase reporter under control of the gene switch system displayed as high as 10,000-fold inducibility following exposure to the small molecule ligand. The dose-response and induction time-course were determined. Regulated luciferase activity in activated plants decreased one day following removal of ligand and could be reactivated multiple times without apparent cosuppression. Analysis of luciferase activity following ligand application to media surrounding the roots suggests that ligand can be absorbed and transported systemically. In contrast, reporter activation was limited to a small area when ligand was applied directly to the leaf surface. The described gene switch system represents an important tool for situations requiring conditional gene expression in a monocot species.


Astrocytic mobilization of glutathione peroxidase-1 contributes to the protective potential against cocaine kindling behaviors in mice via activation of JAK2/STAT3 signaling.
Compelling evidence indicates that oxidative stress contributes to cocaine neurotoxicity. The present study was performed to elucidate the role of the glutathione peroxidase-1 (GPx-1) in cocaine-induced kindling (convulsive) behaviors in mice. Cocaine-induced convulsive behaviors significantly increased GPx-1, p-IkB, and p-JAK2/STAT3 expression, and oxidative burdens in the hippocampus of mice. There was no significant difference in cocaine-induced p-IkB expression between non-transgenic (non-TG) and GPx-1 overexpressing transgenic (GPx-1 TG) mice, but significant differences were observed in cocaine-induced p-JAK2/STAT3 expression and oxidative stress between non-TG and GPx-1 TG mice. Cocaine-induced glial fibrillary acidic protein (GFAP)-labeled astrocytic level was significantly higher in the hippocampus of GPx-1 TG mice. Triple-labeling immunocytochemistry indicated that GPx-1-, p-STAT3-, and GFAP-immunoreactivities were co-localized in the same cells. AG490, a JAK2/STAT3 inhibitor, but not pyrrolidone dithiocarbamate, an NFκB inhibitor, significantly counteracted GPx-1-mediated protective potentials (i.e., anticonvulsant-, antioxidant-, antiapoptotic-effects). Genetic overexpression of GPx-1 significantly attenuated proliferation of Iba-1-labeled microglia induced by cocaine in mice. However, AG490 or astrocytic inhibition (by GFAP antisense oligonucleotide and α-aminoadipate) significantly increased Iba-1-labeled microglial activity and M1 phenotype microglial mRNA levels, reflecting that proinflammatory potentials were mediated by AG490 or astrocytic inhibition. This microglial activation was less pronounced in GPx-1 TG than in non-TG mice. Furthermore, either AG490 or astrocytic inhibition significantly counteracted GPx-1-mediated protective potentials. Therefore, our results suggest that astrocytic modulation between GPx-1 and JAK2/STAT3 might be one of the underlying mechanisms for protecting against convulsive neurotoxicity induced by cocaine.


Phytosanitary Interventions for Safe Global Germplasm Exchange and the Prevention of Transboundary Pest Spread: The Role of CGIAR Germplasm Health Units.
The inherent ability of seeds (orthodox, intermediate, and recalcitrant seeds and vegetative propagules) to serve as carriers of pests and pathogens (hereafter referred to as pests) and the risk of transboundary spread along with the seed movement present a high-risk factor for international germplasm distribution activities. Quarantine and phytosanitary procedures have been established by many countries around the world to minimize seed-borne pest spread by screening export and import consignments of germplasm. The effectiveness of these time-consuming and cost-intensive procedures depends on the knowledge of pest distribution, availability of diagnostic tools for seed health testing, qualified operators, procedures for inspection, and seed phytosanitation. This review describes a unique multidisciplinary approach used by the CGIAR Germplasm Health Units (GHUs) in ensuring phytosanitary protection for the safe conservation and global movement of germplasm from the 11 CGIAR genebanks and breeding programs that acquire and distribute germplasm to and from all parts of the world for agricultural research and food security. We also present the challenges, lessons learned, and recommendations stemming from the experience of GHUs, which collaborate with the national quarantine systems to export and distribute about 100,000 germplasm samples annually to partners located in about 90 to 100 countries. Furthermore, we describe how GHUs adjust their procedures to stay in alignment with evolving phytosanitary regulations and pest risk scenarios. In conclusion, we state the benefits of globally coordinated phytosanitary networks for the prevention of the intercontinental spread of pests that are transmissible through plant propagation materials.


Mechanical power output in rowing should not be determined from oar forces and oar motion alone.
Mechanical power output is a key performance-determining variable in many cyclic sports. In rowing, instantaneous power output is commonly determined as the dot product of handle force moment and oar angular velocity. The aim of this study was to show that this commonly used proxy is theoretically flawed and to provide an indication of the magnitude of the error. To obtain a consistent dataset, simulations were performed using a previously proposed forward dynamical model. Inputs were previously recorded rower kinematics and horizontal oar angle, at 20 and 32 strokes∙min-1. From simulation outputs, true power output and power output according to the common proxy were calculated. The error when using the common proxy was quantified as the difference between the average power output according to the proxy and the true average power output (P̅residual), and as the ratio of this difference to the true average power output (ratiores./rower). At stroke rate 20, P̅residual was 27.4 W and ratiores./rower was 0.143; at stroke rate 32, P̅residual was 44.3 W and ratiores./rower was 0.142. Power output in rowing appears to be underestimated when calculated according to the common proxy. Simulations suggest this error to be at least 10% of the true power output.


Variation in outpatient mental health service utilization under capitation.
To improve the financing of Colorado's public mental health system, the state designed, implemented, and evaluated a pilot program that consisted of three reimbursement models for the provision of outpatient services. Community mental health centers (CMHCs), the primary providers of comprehensive mental health services to Medicaid recipients in Colorado, had to search for innovative ways to provide cost-effective services. This study assessed outpatient service delivery to Medicaid-eligible consumers under this program. This paper is among the first to study variations in the delivery of specific types of outpatient mental health services under capitated financing systems. This study uses claims data (1994-1997) from Colorado's Medicaid and Mental Health Services Agency. The fee-for-service (FFS) model served as the comparison model. Two capitated models under evaluation are: (i) direct capitation (DC), where the state contracts with a non-profit entity to provide both the services and administers the capitated financing, and (ii) managed behavioral health organization (MBHO), which is a joint venture between a for-profit company who manages the capitated financing and a number of non-profit entities who deliver the services. A sample of severely mentally ill patients who reported at least one inpatient visit was included in the analysis. Types of outpatient services of interest are: day-treatment visits, group therapy, individual therapy, medication monitoring, case management, testing, and all other services. Comparisons were set up to examine differences in service utilization and cost between FFS and each of the two capitated models, using a two-part model across three time periods. Results showed differences in service delivery among reimbursement models over time. Capitated providers had higher initial utilization in most outpatient service categories than their FFS counterparts and as a result of capitation, outpatient services delivered under these providers decreased to converge to the FFS pattern. Findings also suggest substitution between group therapy and individual psychotherapy. Overall, more service integration was observed and less complex service packages were provided post capitation. IMPLICATION FOR HEALTH CARE PROVISION AND POLICIES: Financing models and organizational arrangements have an impact on mental health service delivery. Changes in utilization and costs of specific types of outpatient services reflect the effects of capitation. Understanding the mechanism for these changes may lead to more streamlined service delivery allowing extra funding for expanding the range of cost-effective treatment alternatives. These changes pose implications for improving the financing of public mental health systems, coordination of mental health services with other healthcare and human services, and provision of services through a more efficient financing system.


Expertise Shapes Multimodal Imagery for Wine.
Although taste and smell seem hard to imagine, some people nevertheless report vivid imagery in these sensory modalities. We investigate whether experts are better able to imagine smells and tastes because they have learned the ability, or whether they are better imaginers in the first place, and so become experts. To test this, we first compared a group of wine experts to yoked novices using a battery of questionnaires. We show for the first time that experts report greater vividness of wine imagery, with no difference in vividness across sensory modalities. In contrast, novices had more vivid color imagery than taste or odor imagery for wines. Experts and novices did not differ on other vividness of imagery measures, suggesting a domain-specific effect of expertise. Critically, in a second study, we followed a group of students commencing a wine course and a group of matched control participants. Students and controls did not differ before the course, but after the wine course students reported more vivid wine imagery. We provide evidence that expertise improves imagery, exemplifying the extent of plasticity of cognition underlying the chemical senses.


Financial Vulnerability and Worker Well-Being: A Comparison of Long-Term Services and Supports Workers With Other Health Workers.
Over 1.5 million new jobs need to be filled by 2026 for medical assistants, nursing aides, and home care aides, many of which will work in the long-term services and supports (LTSS) sector. Using 16 years of data from the American Time Use Survey, we examined the financial vulnerability of high-skill and low-skill LTSS workers in comparison with other health care workers, while providing insight into their well-being by measuring time spent on work and nonwork activities. We found that, regardless of skill status, working in LTSS was associated with lower wages and an increased likelihood of experiencing poverty compared with other health care workers. Results from time diary data indicated that the LTSS workforce spent a greater share of their time working and commuting to work. Low-skill LTSS workers were hardest hit, spending more time on paid and unpaid activities, such as household and child care responsibilities.


Differential receptor dependencies: expression and significance of muscarinic M1 receptors in the biology of prostate cancer.
Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 µg/ml of dicyclomine. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer.