Subthalamic nucleus deep brain stimulation changes speech respiratory and laryngeal control in Parkinson's disease.
Adequate respiratory and laryngeal motor control are essential for speech, but may be impaired in Parkinson's disease (PD). Bilateral subthalamic nucleus deep brain stimulation (STN DBS) improves limb function in PD, but the effects on respiratory and laryngeal control remain unknown. We tested whether STN DBS would change aerodynamic measures of respiratory and laryngeal control, and whether these changes were correlated with limb function and stimulation parameters. Eighteen PD participants with bilateral STN DBS were tested within a morning session after a minimum of 12 h since their most recent dose of anti-PD medication. Testing occurred when DBS was on, and again 1 h after DBS was turned off, and included aerodynamic measures during syllable production, and standard clinical ratings of limb function. We found that PD participants exhibited changes with DBS, consistent with increased respiratory driving pressure (n = 9) and increased vocal fold closure (n = 9). However, most participants exceeded a typical operating range for these respiratory and laryngeal control variables with DBS. Changes were uncorrelated with limb function, but showed some correlation with stimulation frequency and pulse width, suggesting that speech may benefit more from low-frequency stimulation and shorter pulse width. Therefore, high-frequency STN DBS may be less beneficial for speech-related respiratory and laryngeal control than for limb motor control. It is important to consider these distinctions and their underlying mechanisms when assessing the impact of STN DBS on PD.


Flexibility is important for inhibition of the MDM2/p53 protein-protein interaction by cyclic β-hairpins.
Protein-protein interactions that have large, flat and featureless binding sites are difficult drug targets. In the development of their modulators conventional drug discovery strategies are often unsuccessful. Gaining a detailed understanding of the binding mode of protein-protein interaction inhibitors is therefore of vast importance for their future pharmaceutical use. The MDM2/p53 protein pair is a highly promising target for cancer treatment. Disruption of the protein complex using p53 α-helix mimetics has been shown to be a successful strategy to control p53 activity. To gain further insight into the binding of inhibitors to MDM2, the flexibility of four cyclic β-hairpins that act as α-helical mimetics and potential MDM2/p53 interaction inhibitors was investigated in relation to their inhibitory activity. MDM2-binding of the mimetics was determined using fluorescence polarization and surface plasmon resonance assays, whereas their conformation and dynamics in solution was described by the combined experimental and computational NAMFIS analysis. Molecular flexibility was shown to be important for the activity of the cyclic β-hairpin based MDM2 inhibitors.


The incidence of sarcopenia among hospitalized older patients: results from the Glisten study.
New evidence is emerging on the importance of lean body mass during periods of illness and recovery. The preservation of lean body mass during such periods of intense stress impacts both patient and treatment outcomes. However, data concerning the incidence of sarcopenia among older people during hospitalization are scarce. The objective of this study was to evaluate the development of sarcopenia in a sample of hospitalized older subjects. We used data of 394 participants from the multicentre Italian Study conducted by the Gruppo Lavoro Italiano Sarcopenia-Trattamento e Nutrizione (GLISTEN) in 12 Acute Care Wards (Internal Medicine and Geriatrics) of University Hospitals across Italy. This study was designed to determine the prevalence of sarcopenia at hospital admission and the change in muscle mass and strength during hospitalization. Sarcopenia was defined as low skeletal mass index (kg/m2 ) along with either low handgrip strength or slow walking speed [European Working Groups on Sarcopenia in Older People (EWGSOP) criteria]. Estimation of skeletal muscle mass was performed by bioelectrical impedance analysis (BIA). The mean age of the 394 enrolled patients (including 211 females who accounted for 53% of the sample) was 79.6 ± 6.4 years. Among those without sarcopenia at hospital admission, 14.7% of the study sample met the EWGSOP sarcopenia diagnostic criteria at discharge. The incidence of sarcopenia during hospitalization was significantly associated with the number of days spent in bed but was not correlated with the total length of hospital stay. In particular, patients who developed sarcopenia spent an average of 5.1 days in bed compared with 3.2 days for those with no sarcopenia at discharge (P = 0.02). Patients with sarcopenia showed a significantly lower body mass index compared with non-sarcopenic peers (25.0 ± 3.8 kg/m2 vs. 27.6 ± 4.9 kg/m2 , respectively; P < 0.001). Similarly, the skeletal mass index at admission was significantly lower among patients who developed sarcopenia during hospital stay. Incident sarcopenia during hospital stay is relatively common and is associated with nutritional status and the number of days of bed rest.


Latent structure of intermittent explosive disorder in an epidemiological sample.
Intermittent explosive disorder (IED) is characterized by distinct periods of impulsive aggression marked by assaultive acts or destruction of property. However, impulsive aggression is also a feature of other disorders, all of which are viewed in diagnostic nomenclature as qualitatively distinct from IED. This state of affairs is problematic for categorical models unless it is demonstrated empirically that IED-related impulsive aggression is qualitatively distinct from impulsive aggression observable in other axis I and II disorders. The current study addresses this question using taxometric methods to examine the latent structure of IED. Participants were respondents on the Collaborative Psychiatric Epidemiological Surveys, which obtained data on a range of disorders including intermittent explosive disorder (N=20,013) and a range of psychological variables. Indicator variables used were drawn from the survey items and submitted to select taxometric methods (MAMBAC and MAXEIG) to determine the relative fits of a taxonic versus dimensional model. The results of taxometric analyses provided support for a taxonic, rather than dimensional, structure for IED symptoms in the epidemiological sample. Taxon group membership was associated with treatment seeking, family history of anger attacks, lower age of onset of anger attacks, and male biological sex, providing strong support for the validity of the IED taxon.


Novel CD4+ and CD8+ T-cell determinants within the NS3 protein in subjects with spontaneously resolved HCV infection.
Spontaneous resolution of hepatitis C virus (HCV) infection is a relatively infrequent event, and these individuals provide a unique opportunity to characterize correlates of protective immunity as an important first step in the development of vaccine candidates. The aim of this study was to directly and comprehensively enumerate HCV-nonstructural protein 3 (NS3) specific CD4(+) and CD8(+) T cells ex vivo from HLA diverse individuals who had been successful in spontaneously resolving HCV infection. We measured interferon gamma (IFN-gamma) production with an ELISPOT assay using magnetic bead-separated CD4(+) or CD8(+) T cells in response to autologous DCs that had been pulsed with 15mer per peptides overlapping by 11 amino acids and spanning all of the NS3 protein (150 total peptides). All subjects with spontaneously recovered HCV infection demonstrated vigorous and multispecific CD4(+) T-cell responses to NS3 peptides, and 6 of 10 subjects demonstrated CD8(+) T-cell responses. More importantly, we identified novel, previously unpredicted antigenic regions, which in most cases elicited high frequencies within a given individual. In conclusion, subjects who have spontaneously eradicated HCV infection up to 35 years earlier demonstrate persistent CD4(+) and CD8(+) T-cell responses specific to NS3. By providing a comprehensive screening of all potential T-cell epitopes contained in the NS3 region, our strategy defines the breadth of the T-cell response and identifies novel, unpredicted specificities.


Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors.
The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.


Estimation of neural connections from partially observed neural spikes.
Plasticity is one of the most important properties of the nervous system, which enables animals to adjust their behavior to the ever-changing external environment. Changes in synaptic efficacy between neurons constitute one of the major mechanisms of plasticity. Therefore, estimation of neural connections is crucial for investigating information processing in the brain. Although many analysis methods have been proposed for this purpose, most of them suffer from one or all the following mathematical difficulties: (1) only partially observed neural activity is available; (2) correlations can include both direct and indirect pseudo-interactions; and (3) biological evidence that a neuron typically has only one type of connection (excitatory or inhibitory) should be considered. To overcome these difficulties, a novel probabilistic framework for estimating neural connections from partially observed spikes is proposed in this paper. First, based on the property of a sum of random variables, the proposed method estimates the influence of unobserved neurons on observed neurons and extracts only the correlations among observed neurons. Second, the relationship between pseudo-correlations and target connections is modeled by neural propagation in a multiplicative manner. Third, a novel information-theoretic framework is proposed for estimating neuron types. The proposed method was validated using spike data generated by artificial neural networks. In addition, it was applied to multi-unit data recorded from the CA1 area of a rat's hippocampus. The results confirmed that our estimates are consistent with previous reports. These findings indicate that the proposed method is useful for extracting crucial interactions in neural signals as well as in other multi-probed point process data.


The dual impact of HIV-1 infection and aging on naïve CD4 T-cells: additive and distinct patterns of impairment.
HIV-1-infected adults over the age of 50 years progress to AIDS more rapidly than adults in their twenties or thirties. In addition, HIV-1-infected individuals receiving antiretroviral therapy (ART) present with clinical diseases, such as various cancers and liver disease, more commonly seen in older uninfected adults. These observations suggest that HIV-1 infection in older persons can have detrimental immunological effects that are not completely reversed by ART. As naïve T-cells are critically important in responses to neoantigens, we first analyzed two subsets (CD45RA(+)CD31(+) and CD45RA(+)CD31(-)) within the naïve CD4(+) T-cell compartment in young (20-32 years old) and older (39-58 years old), ART-naïve, HIV-1 seropositive individuals within 1-3 years of infection and in age-matched seronegative controls. HIV-1 infection in the young cohort was associated with lower absolute numbers of, and shorter telomere lengths within, both CD45RA(+)CD31(+)CD4(+) and CD45RA(+)CD31(-)CD4(+) T-cell subsets in comparison to age-matched seronegative controls, changes that resembled seronegative individuals who were decades older. Longitudinal analysis provided evidence of thymic emigration and reconstitution of CD45RA(+)CD31(+)CD4(+) T-cells two years post-ART, but minimal reconstitution of the CD45RA(+)CD31(-)CD4(+) subset, which could impair de novo immune responses. For both ART-naïve and ART-treated HIV-1-infected adults, a renewable pool of thymic emigrants is necessary to maintain CD4(+) T-cell homeostasis. Overall, these results offer a partial explanation both for the faster disease progression of older adults and the observation that viral responders to ART present with clinical diseases associated with older adults.


The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease.
Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.


Comparative study of stock trend prediction using time delay, recurrent and probabilistic neural networks.
Three networks are compared for low false alarm stock trend predictions. Short-term trends, particularly attractive for neural network analysis, can be used profitably in scenarios such as option trading, but only with significant risk. Therefore, we focus on limiting false alarms, which improves the risk/reward ratio by preventing losses. To predict stock trends, we exploit time delay, recurrent, and probabilistic neural networks (TDNN, RNN, and PNN, respectively), utilizing conjugate gradient and multistream extended Kalman filter training for TDNN and RNN. We also discuss different predictability analysis techniques and perform an analysis of predictability based on a history of daily closing price. Our results indicate that all the networks are feasible, the primary preference being one of convenience.


Severe contusion of the femoral vessels in rats alters tissue oxygenation and microvascular blood flow regulation in the skeletal muscles of the limb.
Severe contusion of an artery often presents clinical problems in that it affects flow distal to the injury. However, the effect of a contusion on the microvascular flow regulation in the distal part of the limb is still largely unknown. A multipoint microelectrode technique was used to assess both tissue oxygenation (PtO2) and microflow (hydrogen clearance) on the skeletal muscle surface in a standard contusion injury to the femoral vessels in rats. A significant increase in and an altered distribution of (PtO2) as well as a reduction in and altered distribution of microflow on the muscle surface distal to the injury was found in all animals (n = 27) compared with the uninjured control leg. These findings could not be reproduced experimentally by sympathectomy or when the adjacent skeletal muscle alone was injured. The results suggest that the changes observed distal to the injury are of vascular origin, possibly as a result of endothelial damage at the site of the contusion.


Are high-impact species predictable? An analysis of naturalised grasses in northern Australia.
Predicting which species are likely to cause serious impacts in the future is crucial for targeting management efforts, but the characteristics of such species remain largely unconfirmed. We use data and expert opinion on tropical and subtropical grasses naturalised in Australia since European settlement to identify naturalised and high-impact species and subsequently to test whether high-impact species are predictable. High-impact species for the three main affected sectors (environment, pastoral and agriculture) were determined by assessing evidence against pre-defined criteria. Twenty-one of the 155 naturalised species (14%) were classified as high-impact, including four that affected more than one sector. High-impact species were more likely to have faster spread rates (regions invaded per decade) and to be semi-aquatic. Spread rate was best explained by whether species had been actively spread (as pasture), and time since naturalisation, but may not be explanatory as it was tightly correlated with range size and incidence rate. Giving more weight to minimising the chance of overlooking high-impact species, a priority for biosecurity, meant a wider range of predictors was required to identify high-impact species, and the predictive power of the models was reduced. By-sector analysis of predictors of high impact species was limited by their relative rarity, but showed sector differences, including to the universal predictors (spread rate and habitat) and life history. Furthermore, species causing high impact to agriculture have changed in the past 10 years with changes in farming practice, highlighting the importance of context in determining impact. A rationale for invasion ecology is to improve the prediction and response to future threats. Although our study identifies some universal predictors, it suggests improved prediction will require a far greater emphasis on impact rather than invasiveness, and will need to account for the individual circumstances of affected sectors and the relative rarity of high-impact species.


Fresnel domain nonlinear optical image encryption scheme based on Gerchberg-Saxton phase-retrieval algorithm.
We propose a novel nonlinear image-encryption scheme based on a Gerchberg-Saxton (G-S) phase-retrieval algorithm in the Fresnel transform domain. The decryption process can be performed using conventional double random phase encoding (DRPE) architecture. The encryption is realized by applying G-S phase-retrieval algorithm twice, which generates two asymmetric keys from intermediate phases. The asymmetric keys are generated in such a way that decryption is possible optically with a conventional DRPE method. Due to the asymmetric nature of the keys, the proposed encryption process is nonlinear and offers enhanced security. The cryptanalysis has been carried out, which proves the robustness of proposed scheme against known-plaintext, chosen-plaintext, and special attacks. A simple optical setup for decryption has also been suggested. Results of computer simulation support the idea of the proposed cryptosystem.


Metabolic syndrome and angiographic coronary artery disease prevalence in association with the Framingham risk score.
The association of metabolic syndrome with coronary artery disease (CAD) has been studied extensively. However, little is known about the effect of Framingham risk score (FRS) and metabolic syndrome components on the association of metabolic syndrome with angiographically significant CAD. Our aim was to investigate whether that relationship is influenced by individual's 10-year CAD risk profile as assessed by FRS. Furthermore, we sought to elucidate whether metabolic syndrome is associated with angiographically significant CAD independently of its individual components. We studied a consecutive sample of 150 patients undergoing coronary angiography for the evaluation of chest pain. Metabolic syndrome was defined according to the revised National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, and the 10-year CAD risk was estimated by the FRS. Metabolic syndrome patients had a 2-fold higher CAD prevalence compared to those without metabolic syndrome [odds ratio (OR), 2.004; 95% confidence interval (CI), 1.029-3.905] but this finding was attenuated after adjustment for FRS (OR, 1.770; 95% CI, 0.872-3.594). Stratification of patients into three groups according to FRS revealed that metabolic syndrome predictive ability was confined in those being at <10% 10-year CAD risk. Including metabolic syndrome and its individual components into the same logistic regression model, only the glucose criterion was an independent predictor of angiographically significant CAD (OR, 4.137; 95% CI, 1.477-11.583). Metabolic syndrome is an independent determinant of angiographically significant CAD only among those individuals at low 10-year risk for future coronary events. Individual components of the syndrome, such as impaired fasting glucose, have a stronger association with CAD than the syndrome as a whole.


Treatment options in hepatocellular carcinoma today.
Hepatocellular carcinoma (HCC) is the third most common cause of cancer related death worldwide. As over 90% of HCCs arise in cirrhotic livers preventive methods and surveillance policies have been adopted in most countries with high prevalence of hepatitis B or C infected people. Poor prognosis of HCC has shown some improvement during the last years. Targeted therapy with radiofrequency ablation (RFA), hepatic resection (HR), liver transplantation (LT), and transcatheter arterial chemoembolisation (TACE) seems to have an influence on this development. The heterogeneity of cirrhotic patients with HCC is still a big challenge. A patient with a small tumour in a cirrhotic liver may have a worse prognosis than a patient with a large tumor in a relatively preserved liver after "curative" HR. The choice of the treatment modality depends on the size and the number of tumours, the stage and the cause of cirrhosis and finally on the availability of various modalities in each centre.


Trends of acute poisoning: 22 years experience from a tertiary care hospital in Karachi, Pakistan.
To determine the trends of acute poisoning in terms of frequency, nature of poisoning agent, clinical presentation and its outcome. The retrospective study was conducted at the Aga Khan University Hospital, Karachi, and comprised data of patients who presented with poisoning between January 1989 and December 2010.The patients were randomly selected , and demographic, chemical information, clinical feature, treatment and outcome were analysed using SPSS 16. Of the total hospital admissions during the period, 3,189(0.3%) were cases of poisoning. Of them, medical records of 705(22%) cases were reviewed; 462(65.5%) adult and 243(34.5%) paediatric cases below 16 years of age. The overall median age was 21 years (interquartile range: 4-32 years)Moreover, 544(87%) were critical at the time of presentation. In 647(92%) cases, the poisoning occurred at home. Psychiatric drugs were found involved in 205(29%) cases, followed by prescription drugs 172(24.4%), pesticides 108(15.3%), hydrocarbons 71(10%), analgesics 59(8.7%), household toxins 59(8.7%), alcohol and drug abuse 21(2.97%) and others 47(6.67%). Poisoning was a serious cause of morbidity in children and young adults. Medications were the leading cause and home was the most common place of incident.


Increasing N retention in Coastal Plain agricultural watersheds.
Historically, N availability has limited agricultural production as well as primary production in coastal waters. Prior to the middle of the last century, N available for grain production generally was limited to that supplied by previous legume crops, released from soil organic matter, or returned to the soil in animal wastes. The development of infrastructure to produce relatively low-cost inorganic N fertilizers eliminated the need to focus management of the entire agricultural system on increasing soil N availability. Increased N availability has contributed to dramatic increases in agricultural production but also has led to increased losses of both N and C from agricultural systems. N losses from cropland have been linked to increased algal production in the Chesapeake Bay, with N loss from cropland estimated to be the primary N input to the Bay from Coastal Plain regions of the watershed. The decade-long effort to reduce these losses has focused on reducing agricultural N use, but this strategy has yet to yield apparent reductions in N loadings to Coastal Plain tributaries. Although nitrate leaching losses are often attributed to inefficient use of N inputs, soil nitrate data indicate that both corn and soybeans can utilize nearly all available soil nitrate during periods of active growth. However, both crops tend to stop utilizing nitrate before mineralization has ceased, resulting in a late season buildup of root zone nitrate levels and significant leaching losses even when no N was applied. Reducing nitrate losses due to the inherent N inefficiency of summer annual grain crops will require the addition of winter annual crops to rotations or changes in weed management approaches that result in plant N uptake capacity being more closely matched to soil microbial N processes.


Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia.
Alzheimer's Disease (AD) can be conceptualized as a continuum: patients progress from normal cognition to mild cognitive impairment (MCI) due to AD, followed by increasing severity of AD dementia. Prior research has measured transition probabilities among later stages of AD, but not for the complete spectrum. To estimate annual progression rates across the AD continuum and evaluate the impact of a delay in MCI due to AD on the trajectory of AD dementia and clinical outcomes. Patient-level longitudinal data from the National Alzheimer's Coordinating Center for n=18,103 patients with multiple visits over the age of 65 were used to estimate annual, age-specific transitional probabilities between normal cognition, MCI due to AD, and AD severity states (defined by Clinical Dementia Rating score). Multivariate models predicted the likelihood of death and institutionalization for each health state, conditional on age and time from the previous evaluation. These probabilities were used to populate a transition matrix describing the likelihood of progressing to a particular disease state or death for any given current state and age. Finally, a health state model was developed to estimate the expected effect of a reduction in the risk of transitioning from normal cognition to MCI due to AD on disease progression rates for a cohort of 65-year-old patients over a 35-year time horizon. Annual transition probabilities to more severe states were 8%, 22%, 25%, 36%, and 16% for normal cognition, MCI due to AD, and mild/moderate/severe AD, respectively, at age 65, and increased as a function of age. Progression rates from normal cognition to MCI due to AD ranged from 4% to 10% annually. Severity of cognitive impairment and age both increased the likelihood of institutionalization and death. For a cohort of 100 patients with normal cognition at age 65, a 20% reduction in the annual progression rate to MCI due to AD avoided 5.7 and 5.6 cases of MCI due to AD and AD, respectively. This reduction led to less time spent in severe AD dementia health states and institutionalized, and increased life expectancy. Transition probabilities from normal cognition through AD severity states are important for understanding patient progression across the AD spectrum. These estimates can be used to evaluate the clinical benefits of reducing progression from normal cognition to MCI due to AD on lifetime health outcomes.


A tale of two pili: assembly and function of pili in bacteria.
Bacterial pili have long been recognized as mediators of initial host-pathogen interactions important for the progression of Gram-negative bacterial diseases. An appreciation of the role of pili on virulence in Gram-positive bacteria and the unique properties of their biogenesis is a rapidly emerging area of research. In this review, we focus on recent advances in one of the longest-studied Gram-negative pilus systems, the chaperone/usher assembled pili, along with the newcomer to the field, the sortase-assembled pili of Gram-positive bacteria. In both systems, a wealth of new structural and molecular details has emerged recently. In light of this, we explore similarities between chaperone/usher and sortase-assembled pilus biogenesis and highlight paradigms unique to each, with the goal of using knowledge of each system to raise new questions and inform future studies of the other.


Glucocorticoid treatment of ovariectomized sheep affects mineral density, structure, and mechanical properties of cancellous bone.
Thus far, orthopedic research lacks a suitable animal model of osteoporosis. In OVX sheep, 6 months of steroid exposure reduced bone density and mechanical competence. Bone properties and bone formation did not recover for another 6 months. Therefore, steroid-treated OVX sheep may serve as a large animal model for osteopenic bone. The purpose of this study was to explore the effects of glucocorticoid treatment on cancellous bone density, microarchitecture, biomechanics, and formation of new bone. Sixteen ovariectomized merino sheep received either a 6-month glucocorticoid treatment (GLU; 0.45 mg/kg methylprednisolone) or were left untreated (control). Cancellous bone biopsy specimens from the tibia were harvested 6 months after ovariectomy. After 12 months, the animals were killed, and biopsy specimens were obtained from the contralateral tibia and the lumbar spine. All biopsy specimens were scanned for apparent bone mineral density by peripheral quantitative computed tomography (pQCT) and tested mechanically in uniaxial compression. Three-dimensional bone reconstructions were obtained by microcomputed tomography. Formation of new bone was analyzed using histologies of the femoral condyles. After 6 months, mineral density (-19%) and mechanical competence (-45%) were reduced by glucocorticoid treatment (p < 0.1). BV/TV (-21%; p < 0.01) and trabecular thickness (-20%; p = 0.01) declined, whereas BS/BV increased (24%; p = 0.01). After 12 months, mineral density (-33%) and mechanical properties (-55%) were reduced even more profoundly (p < 0.05). Also, the structural parameters (BS/BV and Tb.Th.) still seemed to be affected by glucocorticoid treatment (p < 0.05). New bone formation, assessed by measurement of osteoid surface, was markedly reduced (-63%, p < 0.1) by glucocorticoid treatment. The differences between groups were generally more pronounced at the tibia and the femur than at the spine. The effects of short-term high-dose steroid administration on bone mineral in this animal model were comparable with those observed in humans after long-term corticoid treatment. Reduction in bone quality and bone formation rate persisted after the cessation of steroid administration. Glucocorticoid treatment of ovariectomized sheep may therefore serve as a large animal model for steroid-induced osteopenia.


Spatial relationship between leukocyte accumulation and microvascular injury during reperfusion following hepatic ischemia.
In order to further elucidate the possible contribution of leukocytes to microvascular injury during reperfusion following total hepatic ischemia, we studied the spatial relationship between areas of white cell accumulation and areas of microvascular damage in the rat liver in vivo. No-flow hepatic ischemia was produced for 90 min in vivo and during the ensuing reperfusion phase (I/R) leukocyte accumulation, absolute number of perfused sinusoids per unit area, and red blood cell velocity were quantitated using in vivo epi-fluorescence video microscopy. The total number of stationary leukocytes in the liver during reperfusion was found to be significantly elevated following ischemia compared to time-matched sham-operated controls. In addition, by 2 hr of reperfusion, approximately 80% of the leukocytes in the I/R group were extravascular compared to only about 50% in the controls. When leukocyte accumulation and microhemodynamics were expressed on the basis of whole liver, the increased accumulation of leukocytes was associated with decreased microvascular perfusion as indicated by decreased number of sinusoids perfused and decreased red blood cell velocity. However, when the data were analyzed on the basis of .05mm2 microscopic fields on the surface of the liver, there was no difference in leukocyte accumulation in areas with sinusoidal blood flow compared to areas that were devoid of perfused sinusoids. Moreover, in a correlation analysis of number of adherent leukocytes/microscopic field vs red blood cell velocity in perfused sinusoids in that field, only a very small negative correlation between leukocytes/field and red blood cell velocity was found (r = -.23, p < .05). These results demonstrate that at the whole organ level leukocyte accumulation appears to correlate well with microvascular damage; however, this increase in whole liver accumulation of leukocytes does not necessarily reflect accumulation at sites of overt microvascular damage. Thus, leukocyte-independent factors are likely to be of considerable quantitative importance in microvascular injury during reperfusion following hepatic ischemia.


The effect of hydrofluoric acid and resin cement formulation on the bond strength to lithium disilicate ceramic.
To investigate how the hydrofluoric acid (HF) concentrations applied to a lithium disilicate glass-ceramic (EMX) affects the surface morphology and microtensile bond strength (μTBS) of ceramics to dentin, using light-cured resin cements with or without UDMA. Sixty-three EMX square ceramic blocks were etched for 20 seconds using different HF concentrations (1%, 5% and 10%) and luted to dentin using two types of resin cement combinations: BisGMA/TEGDMA and BisGMA/TEGDMA/UDMA (n = 10). Each bonded EMX-dentin block was sectioned to obtain 1 mm2 sticks for μTBS evaluation. Half of the sticks were tested after 24 hours and the other half was assessed after 6 months of water storage. Data were statistically assessed using split-plot three-way ANOVA and multiple comparisons were performed using the Tukey's post hoc test (α = 0.05). One EMX sample from each HF concentration was analyzed using field-emission scanning electron microscope (FE-SEM) to characterize the etching pattern. According to the FE-SEM images, increasing the concentration of HF from 1 to 5 and then to 10% led to increased removal of glassy matrix and greater exposure of lithium disilicate crystals. The 10% HF concentration yielded higher μTBS when compared to 1% for BisGMA/TEGDMA formulation (p < 0.05); whereas HF 1% and 5% showed similar μTBS values when compared to 10% HF for BisGMA/TEGDMA/UDMA resin matrix (p > 0.05) at both storage times. Water aging decreased the μTBS values (p < 0.05), except when 10% HF was associated with BisGMA/TEGDMA resin cement. Resin cement formulation and hydrofluoric acid concentrations can interfere with the immediate and long-term glass-ceramic bond strength to dentin.


Cardiovascular disease and impoverishment averted due to a salt reduction policy in South Africa: an extended cost-effectiveness analysis.
The South African Government recently set targets to reduce cardiovascular disease (CVD) by lowering salt consumption. We conducted an extended cost-effectiveness analysis (ECEA) to model the potential health and economic impacts of this salt policy. We used surveys and epidemiologic studies to estimate reductions in CVD resulting from lower salt intake. We calculated the average out-of-pocket (OOP) cost of CVD care, using facility fee schedules and drug prices. We estimated the reduction in OOP expenditures and government subsidies due to the policy. We estimated public and private sector costs of policy implementation. We estimated financial risk protection (FRP) from the policy as (1) cases of catastrophic health expenditure (CHE) averted or (2) cases of poverty averted. We also performed a sensitivity analysis. We found that the salt policy could reduce CVD deaths by 11%, with similar health gains across income quintiles. The policy could save households US$ 4.06 million (2012) in OOP expenditures (US$ 0.29 per capita) and save the government US$ 51.25 million in healthcare subsidies (US$ 2.52 per capita) each year. The cost to the government would be only US$ 0.01 per capita; hence, the policy would be cost saving. If the private sector food reformulation costs were passed on to consumers, food expenditures would increase by <0.2% across all income quintiles. Preventing CVD could avert 2400 cases of CHE or 2000 cases of poverty yearly. Our results were sensitive to baseline CVD mortality rates and the cost of treatment. We conclude that, in addition to health gains, population salt reduction can have positive economic impacts-substantially reducing OOP expenditures and providing FRP, particularly for the middle class. The policy could also provide large government savings on health care.


PTK6/BRK is expressed in the normal mammary gland and activated at the plasma membrane in breast tumors.
Protein Tyrosine kinase 6 (PTK6/BRK) is overexpressed in the majority of human breast tumors and breast tumor cell lines. It is also expressed in normal epithelial linings of the gastrointestinal tract, skin, and prostate. To date, expression of PTK6 has not been extensively examined in the normal human mammary gland. We detected PTK6 mRNA and protein expression in the immortalized normal MCF-10A human mammary gland epithelial cell line, and examined PTK6 expression and activation in a normal human breast tissue microarray, as well as in human breast tumors. Phosphorylation of tyrosine residue 342 in the PTK6 activation loop corresponds with its activation. Similar to findings in the prostate, we detect nuclear and cytoplasmic PTK6 in normal mammary gland epithelial cells, but no phosphorylation of tyrosine residue 342. However, in human breast tumors, striking PTK6 expression and phosphorylation of tyrosine 342 is observed at the plasma membrane. PTK6 is expressed in the normal human mammary gland, but does not appear to be active and may have kinase-independent functions that are distinct from its cancer promoting activities at the membrane. Understanding consequences of PTK6 activation at the plasma membrane may have implications for developing novel targeted therapies against this kinase.


Multiple morbidities assessment.
Essential facts Multimorbidity, in which a person has two or more long-term health conditions, is associated with reduced quality of life, higher mortality, polypharmacy and high treatment burden, higher rates of adverse drug events, and much greater health services usage, including unplanned or emergency care.


Transcutaneous vagus nerve stimulation: retrospective assessment of cardiac safety in a pilot study.
Vagus nerve stimulation has been successfully used as a treatment strategy for epilepsy and affective disorders for years. Transcutaneous vagus nerve stimulation (tVNS) is a new non-invasive method to stimulate the vagus nerve, which has been shown to modulate neuronal activity in distinct brain areas. Here we report effects of tVNS on cardiac function from a pilot study, which was conducted to evaluate the feasibility and safety of tVNS for the treatment of chronic tinnitus. Twenty-four patients with chronic tinnitus underwent treatment with tVNS over 3-10 weeks in an open single-armed pilot study. Safety criteria and practical usability of the neurostimulating device were to investigate by clinical examination and electrocardiography at baseline and at several visits during and after tVNS treatment (week 2, 4, 8, 16, and 24). Two adverse cardiac events (one classified as a severe adverse event) were registered but considered very unlikely to have been caused by the tVNS device. Retrospective analyses of electrocardiographic parameters revealed a trend toward shortening of the QRS complex after tVNS. To our knowledge this is one of the first studies investigating feasibility and safety of tVNS in a clinical sample. In those subjects with no known pre-existing cardiac pathology, preliminary data do not indicate arrhythmic effects of tVNS.


Relation of endometrial cancer risk to past and contemporary body size and body fat distribution.
In a multicenter case-control study that included 403 cases and 297 controls, we examined the relation of past and contemporary body size, including body fat distribution, to the risk of endometrial cancer. The relative contributions of past and contemporary body size were assessed by examining weight and height histories provided by the subjects. Anthropometric indicators thought to reflect early environmental influences (e.g., height and sitting height), current weight, and fat distribution patterns were measured directly. Height was not a risk factor for endometrial cancer, but inexplicably, sitting height was inversely associated with risk. Weight during early adulthood appeared to be directly related to disease risk, but the association was explained by contemporary weight and thus weight gain during adulthood. While contemporary weight was associated with risk of endometrial cancer, the effect was restricted to those in the top quartile. Women whose measured weight at interview exceeded 78 kg had 2.3 times the risk of those weighing less than 58 kg (95% confidence interval, 1.4 to 3.7). Upper-body obesity (waist-to-thigh circumference ratio) was a risk factor independent of body weight. After adjustment for weight, the relative risks of endometrial cancer across increasing quartiles of upper-body obesity were 1.0, 1.5, 1.8, and 2.6 (P for trend < 0.001). These data indicate that both obesity and the distribution of adipose tissue accumulated during adult life increase endometrial cancer risk substantially.


Factors that make it difficult to diagnose cervical tuberculous lymphadenitis.
Cervical tuberculous lymphadenitis is mainly diagnosed by analyzing tissue samples obtained by fine-needle aspiration (FNA). However, some cases remain diagnostic challenges even after polymerase chain reaction analysis of FNA specimens. To delineate differences between cases that are relatively easy to diagnose and those for which diagnosis is difficult, 22 patients with cervical tuberculous lymphadenitis were studied retrospectively. FNA tissues were used to diagnose 14 cases (group A), whereas excisional biopsy was required for accurate diagnosis of 8 cases (group B). These two groups were compared with regard to results of blood examinations, ultrasound appearance, and various other procedures required to reach the final diagnosis. The results indicated that diagnosis of cervical tuberculous lymphadenitis was more difficult for patients with lower white blood cell counts, lower serum C-reactive protein levels, and absence of lymph node fusion or abscess formation on ultrasonography. The possibility of tuberculosis as a cause of cervical lymphadenopathy should always be considered, even when the presenting symptoms are not typical of this disease.


Fate and transport of glyphosate and aminomethylphosphonic acid in surface waters of agricultural basins.
Glyphosate [N-(phosphonomethyl)glycine] is a herbicide used widely throughout the world in the production of many crops and is heavily used on soybeans, corn and cotton. Glyphosate is used in almost all agricultural areas of the United States, and the agricultural use of glyphosate has increased from less than 10 000 Mg in 1992 to more than 80 000 Mg in 2007. The greatest intensity of glyphosate use is in the midwestern United States, where applications are predominantly to genetically modified corn and soybeans. In spite of the increase in usage across the United States, the characterization of the transport of glyphosate and its degradate aminomethylphosphonic acid (AMPA) on a watershed scale is lacking. Glyphosate and AMPA were frequently detected in the surface waters of four agricultural basins. The frequency and magnitude of detections varied across basins, and the load, as a percentage of use, ranged from 0.009 to 0.86% and could be related to three general characteristics: source strength, rainfall runoff and flow route. Glyphosate use in a watershed results in some occurrence in surface water; however, the watersheds most at risk for the offsite transport of glyphosate are those with high application rates, rainfall that results in overland runoff and a flow route that does not include transport through the soil.


[Effects of hyperoxia on the behavior of leukocytes in rat pulmonary microcirculation assessed by confocal laser scanning microscopy].
To study the dynamic interaction between blood cells and endothelial cells in the pulmonary microcirculation, we developed a method for observing leukocytes and erythrocytes in the microcirculation of perfused rat lungs by confocal laser scanning microscopy. We examined the behavior of leukocytes in the microcirculation of rat lungs exposed to hyperoxia, because oxygen toxicity is known to be associated with leukocyte infiltration and endothelial cell damage. Rats were divided into two groups: control (21% O2) and hyperoxia (90% O2 for 48 hours). Lungs were perfused with Krebs-Henseleit solution equilibrated with 21% O2 and 5% CO2 through an artificial lung. Leukocytes stained with carboxyfluorescein diacetate succinimidyl ester and erythrocytes stained with fluorescein isothiocyanate were added to the perfusate, and images of the cells were observed and recorded with a confocal laser scanning microscope and a high-speed video camera. The mean velocities of erythrocytes (Vr) in arterioles, capillaries, and venules of the control group were 1.52, 0.50 and 1.61 mm/sec, respectively. Also in the control group, the velocities of the leukocytes were divided by the mean velocities of the erythrocytes in the same arterioles, capillaries and venules (Vw/Vr) and the results were 0.96, 0.97, and 0.98, respectively. The Vw/Vr values for arterioles in the hyperoxia group were not significantly different from those in the control group, but the Vw/Vr values for capillaries and venules were 27% and 37% lower than their respective control values. Leukocyte sequestration was seen mainly in capillaries in the hyperoxic group. These results suggest that an increase in adhesion in capillaries and venules, such as that caused by adhesion molecules, might play a key role in the behavior of leukocytes in the pulmonary microcirculation during hyperoxia.


The relationships between symptoms, disability, perceived health and quality of life in amyotrophic lateral sclerosis/motor neuron disease.
Objectives: Using the Wilson and Cleary model linking clinical variables to quality of life, we explored the associations between physical and psychological factors, disability, perceived health and quality of life in ALS/MND. Methods: The ongoing UK study of Trajectories of Outcomes in Neurological Conditions (TONiC) recruited participants with ALS/MND to complete a questionnaire pack including demographic factors and several patient reported outcome measures (PROMs); a clinician provided data on disease onset type and duration since diagnosis. All PROMs were transformed from ordinal raw scores to interval-scaled latent estimates via the Rasch measurement model. Results: Data from 636 patients were analyzed; mean age 65.1 years (SD 10.7), 61.3% male. Median duration since diagnosis was 11.2 months (IQR 4.6-29.9; range 0.4-295.9 months); 67.3% had limb and 27.3% bulbar onset disease. Symptoms such as breathlessness and fatigue, along with most domains of activity limitations, were shown to vary by onset type. A series of models illustrated the importance of physical functioning and anxiety upon quality of life, with breathlessness and fatigue having indirect effects. The models were invariant for gender and onset type. Conclusions: This large study highlights the importance of functional status and anxiety as key variables influencing quality of life in ALS/MND. The nature and diversity of factors, both physical and psychological, which have been shown to influence the quality of life of people with ALS/MND provide strong evidence in support of the widespread implementation of multidisciplinary care.


The epidemiology of Theileria parva infections on smallholder dairy farms in Kenya.
The purpose of the study was to characterize the differences in epidemiology (risks of infection, morbidity, mortality) and potential control of East Coast fever (ECF) between the selected strata. Evidence of Theileria parva infection was assessed by increased antibody levels as measured in an indirect ELISA test by the percent positivity (PP) of serum samples relative to a strong positive reference serum. A prospective cohort study was conducted in five purposively sampled agroecological zone (AEZ)-grazing system strata in Murang'a District, Kenya, between March 1995 and June 1996. The study strata were selected to represent the widest range of ECF risks in the district and included, zero-grazing and open-grazing farms in the Upper Midlands (UM) one and four AEZs and zero-grazing farms in the UM2 AEZ. In total, 225 calves from 188 smallholder farms were examined from birth to age six months. Calves were recruited into the study at birth and visited within the first two weeks of life and thereafter at biweekly intervals for up to 14 visits. Important differences were observed between the different AEZ-grazing strata. Seroconversion risks of T. parva were highest in the UM4-open grazing stratum. Antibody prevalence in adult cattle and ECF morbidity and mortality risks were also highest in this stratum. In the open-grazing strata, particularly in the lower elevation AEZ, UM4, there was stronger challenge and a greater impact of ECF. There is likely to be an expansion of smallholder dairy farming into this area so that it is likely to be the most important target production system for ECF control in the central highlands of Kenya.


Grey matter correlates of three language tests in non-demented older adults.
Language has been extensively investigated by functional neuroimaging studies. However, only a limited number of structural neuroimaging studies have examined the relationship between language performance and brain structure in healthy adults, and the number is even less in older adults. The present study sought to investigate correlations between grey matter volumes and three standardized language tests in late life. The participants were 344 non-demented, community-dwelling adults aged 70-90 years, who were drawn from the population-based Sydney Memory and Ageing Study. The three language tests included the Controlled Oral Word Association Task (COWAT), Category Fluency (CF), and Boston Naming Test (BNT). Correlation analyses between voxel-wise GM volumes and language tests showed distinctive GM correlation patterns for each language test. The GM correlates were located in the right frontal and left temporal lobes for COWAT, in the left frontal and temporal lobes for CF, and in bilateral temporal lobes for BNT. Our findings largely corresponded to the neural substrates of language tasks revealed in fMRI studies, and we also observed a less hemispheric asymmetry in the GM correlates of the language tests. Furthermore, we divided the participants into two age groups (70-79 and 80-90 years old), and then examined the correlations between structural laterality indices and language performance for each group. A trend toward significant difference in the correlations was found between the two age groups, with stronger correlations in the group of 70-79 years old than those in the group of 80-90 years old. This difference might suggest a further decline of language lateralization in different stages of late life.


Peptide Sharing Between Viruses and DLX Proteins: A Potential Cross-Reactivity Pathway to Neuropsychiatric Disorders.
The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders-such as rubella, human immunodeficiency virus, and herpesviruses-and human distal-less homeobox (DLX) proteins expressed in developing brain-namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity-that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens.


Evolution of repeated sequence arrays in the D-loop region of bat mitochondrial DNA.
Analysis of mitochondrial DNA control region sequences from 41 species of bats representing 11 families revealed that repeated sequence arrays near the tRNA-Pro gene are present in all vespertilionine bats. Across 18 species tandem repeats varied in size from 78 to 85 bp and contained two to nine repeats. Heteroplasmy ranged from 15% to 63%. Fewer repeats among heteroplasmic than homoplasmic individuals in a species with up to nine repeats indicates selection may act against long arrays. A lower limit of two repeats and more repeats among heteroplasmic than homoplasmic individuals in two species with few repeats suggests length mutations are biased. Significant regressions of heteroplasmy, theta and pi, on repeat number further suggest that repeat duplication rate increases with repeat number. Comparison of vespertilionine bat consensus repeats to mammal control region sequences revealed that tandem repeats of similar size, sequence and number also occur in shrews, cats and bighorn sheep. The presence of two conserved protein-binding sequences in all repeat units indicates that convergent evolution has occurred by duplication of functional units. We speculate that D-loop region tandem repeats may provide signal redundancy and a primitive repair mechanism in the event of somatic mutations to these binding sites.


Exploration of antibiotic resistance risks in a veterinary teaching hospital with Oxford Nanopore long read sequencing.
The Oxford Nanopore MinION DNA sequencing device can produce large amounts of long sequences, typically several kilobases, within a few hours. This long read capacity was exploited to detect antimicrobial resistance genes (ARGs) in a large veterinary teaching hospital environment, and to assess their taxonomic origin, genetic organisation and association with mobilisation markers concurrently. Samples were collected on eight occasions between November 2016 and May 2017 (inclusive) in a longitudinal study. Nanopore sequencing was performed on total DNA extracted from the samples after a minimal enrichment step in broth. Many ARGs present in the veterinary hospital environment could potentially confer resistance to antimicrobials widely used in treating infections of companion animals, including aminoglycosides, extended-spectrum beta-lactams, sulphonamides, macrolides, and tetracyclines. High-risk ARGs, defined here as single or multiple ARGs associated with pathogenic bacterial species or with mobile genetic elements, were shared between the intensive care unit (ICU) patient cages, a dedicated laundry trolley and a floor cleaning mop-bucket. By contrast, a floor surface from an office corridor without animal contact and located outside the veterinary hospital did not contain such high-risk ARGs. Relative abundances of high-risk ARGs and co-localisation of these genes on the same sequence read were higher in the laundry trolley and mop bucket samples, compared to the ICU cages, suggesting that amplification of ARGs is likely to occur in the collection points for hospital waste. These findings have prompted the implementation of targeted intervention measures in the veterinary hospital to mitigate the risks of transferring clinically important ARGs between sites and to improve biosecurity practices in the facility.


The Biological and Hematological Effects of Echinacea purpurea L. Roots Extract in the Immunocompromised Rats with Cyclosporine.
The immune system is the body's defense against foreign organisms and harmful chemicals. Cyclosporine A (CsA) is an immunosuppressant drug widely used. Echinacea purpurea root (EPR) extract is used as an immunostimulant plant. The present study aimed at evaluation of the EPR effects against the CsA immunosuppressive rat model. Thirty-two male Wistar albino rats were randomly divided into control, CsA (immunosuppressive models), CsA + EPR (100 mg/kg/day orally), and CsA + EPR (200 mg/kg/day orally). The biological parameters regarding the food consumption were assessed including feed intake (FI), feed efficiency ratio (FER), and body weights (BW). In addition, the splenic specimens were assessed histopathology. The blood was collected for measuring the blood parameters. All the measured parameters were collected and statistically analyzed. The biological results indicated a significant decrease in BW, FI, and FER in rats treated orally with low and high EPR doses as compared to the control group. The results displayed that the CsA induced a significant decrease in red blood cells (RBCs) and white blood cells (WBCs) count. Histopathologically, CsA induced a marked decrease in the cellularity of the white pulp with congested blood sinusoids of the red pulp together with significant depletion of periarteriolar lymphoid sheath. Both the high and low doses of EPR significantly reversed the altered RBCs and WBCs counts. Histopathologically, both the low and high doses of EPR displayed apparently increase in the periarteriolar area together with the persistence of the congestion of the red pulp blood sinusoids compared to CsA group, indicating partial amelioration of the structural changes. In a nutshell, the current findings revealed that EPR extract ameliorated the hematological changes. However, there was a partial correction of the CsA-induced microscopic changes of the rat spleen.


Human Challenge Studies to Accelerate Coronavirus Vaccine Licensure.
Controlled human challenge trials of SARS-CoV-2 vaccine candidates could accelerate the testing and potential rollout of efficacious vaccines. By replacing conventional phase 3 testing of vaccine candidates, such trials may subtract many months from the licensure process, making efficacious vaccines available more quickly. Obviously, challenging volunteers with this live virus risks inducing severe disease and possibly even death. However, we argue that such studies, by accelerating vaccine evaluation, could reduce the global burden of coronavirus-related mortality and morbidity. Volunteers in such studies could autonomously authorize the risks to themselves, and their net risk could be acceptable if participants comprise healthy young adults, who are at relatively low risk of serious disease following natural infection, if they have a high baseline risk of natural infection, and if during the trial they receive frequent monitoring and, following any infection, the best available care.


Effects of chronic intranasal oxytocin on behavior and cerebral glucose uptake in juvenile titi monkeys.
Intranasal oxytocin (IN OXT) has been proposed as a treatment for autism spectrum disorder (ASD); however, little is known about the effects of long-term exposure. This is the first study in a non-human primate species to examine how developmental exposure to chronic IN OXT affects juvenile's interactions with family members, social preference for parents versus strangers, anxiety-like behavior, and cerebral glucose metabolism. Titi monkeys are socially monogamous and biparental; their family bonds share important characteristics with human family bonds. Fourteen males and 15 females were treated intranasally with saline (n = 14) or 0.8 IU/kg OXT (n = 15), daily from 12 to 18 months of age. Compared to SAL-treated animals, OXT-treated animals of both sexes spent significantly more time grooming other family members (F1 = 8.97, p = 0.006). Overall, OXT-treated subjects were more social (F1 = 8.35, p = 0.005) during preference tests. OXT-treated females displayed an enhanced preference for their parents (t = 2.265, p = 0.026). OXT-treated males had a blunted preference for their parents and an increase in the time spent near unfamiliar pairs (F1 = 10.89, p = 0.001). During anxiety tests, OXT-treated males refused to complete the task more often than SAL-treated males and had longer latencies (p < 0.0001). Neuroimaging studies revealed that OXT-treated animals had higher glucose uptake across the social salience network as a whole after one month of treatment (F1,9 = 1.07, p = 0.042). Our results suggest moderate prosocial effects of chronic IN OXT, that did not depend on anxiolytic properties. We also found important sex differences that should be considered in a translational context.


Influenza vaccination in pregnancy among a group of remote dwelling Aboriginal and Torres Strait Islander mothers in the Northern Territory: The 1+1 Healthy Start to Life study.
Remote-living Aboriginal and Torres Strait Islander women experience a higher burden of influenza infection during pregnancy than any other Australian women. Despite recommendations of inactivated influenza vaccination (IIV) in pregnancy, uptake and safety data are scarce for this population. We examined uptake of IIV in pregnancy and report adverse birth outcomes amongst a predominantly unvaccinated group of remote-living Aboriginal and Torres Strait Islander women from the Northern Territory (NT), using data from the 1+1 Healthy Start to Life study. Data were deterministically linked with the NT Immunisation Register to ascertain IIV exposure in pregnant women during 2003-2006 and 2009-2011 inclusive. Overall, IIV uptake in pregnancy was 3% (n=20/697 pregnancies); 0% (0/414) pre-influenza A(H1N1)pdm09 and 7% (20/293) post-influenza A(H1N1)pdm09 (2009-2011). Vaccine uptake was poor in this cohort and it is unclear at what stage this policy failure occurred. Women with known comorbidities and/or high risk factors were not targeted for vaccination. Much larger study participant numbers are required to validate between group comparisons but there was no clinically nor statistically significant difference in median gestational ages (38 weeks for both groups), mean infant birthweights (3,001 g unvaccinated vs 3,175 g IIV vaccinated), nor birth outcomes between the few women who received IIV in pregnancy and those who did not. There were no stillbirths in women who received an IIV in pregnancy.


Prevalence and impact of childhood adversities and post-traumatic stress disorder in women with fibromyalgia and chronic widespread pain.
This study investigates the prevalence of different types of childhood adversities (CA) and posttraumatic stress disorder (PTSD) in female patients with Fibromyalgia or Chronic Widespread Pain (FM/CWP) compared to patients with Functional Dyspepsia (FD) and achalasia. In FM/CWP, we also investigated the association between CA and PTSD on the one hand and pain severity on the other. Patient samples consisted of 154 female FM/CWP, 83 female FD and 53 female achalasia patients consecutively recruited from a tertiary care hospital. Well-validated self-report questionnaires were used to investigate CA and PTSD. Forty-nine per cent of FM/CWP patients reported at least 1 type of CA, compared to 39.7% of FD patients and 23.4% of achalasia patients (p < 0.01). The prevalence of CA did not differ significantly between FM/CWP and FD, but both groups had a higher prevalence of CA compared to both achalasia and healthy controls (p < 0.01). FM/CWP patients were six times more likely to report PTSD than both FD (p < 0.001) and achalasia (p < 0.001) patients. In FM/CWP, PTSD comorbidity, but not CA, was associated with self-reported pain severity and PTSD severity mediated the relationship between CA and pain severity. In summary, the prevalence of CA is higher in FM/CWP compared to achalasia, but similar to FD. However, PTSD is more prevalent in FM/CWP compared to FD and associated with higher pain intensity in FM/CWP. As expected and has been shown in other functional disorders, we found elevated levels of childhood adversity in FM/CWP patients. Results of this study however suggest that the impact of childhood adversity (i.e. whether such events have led to the development of PTSD symptoms), rather than the mere presence of such adversity, is of crucial importance in FM/CWP patients. Screening for PTSD symptoms should be an essential part of the assessment process in patients suffering from FM/CWP, and both prevention and intervention efforts should take into account PTSD symptoms and their impact on pain severity and general functioning.


Characteristics and outcomes of accidental hypothermia in Japan: the J-Point registry.
Accidental hypothermia (AH) has higher incidence and mortality in geriatric populations. Japan has a rapidly ageing population, and little is known about the epidemiology of hypothermia in this country. We created an AH registry based on retrospective review of patients visiting the ED of 12 institutions with temperature ≤35°C between April 2011 and March 2016. The severity of AH was classified as mild (≤35, ≥32°C), moderate (<32, ≥28°C) or severe (<28°C). The relationship between in-hospital mortality and severity of AH was assessed using a multivariable logistic regression analysis. A total of 572 patients were registered in this registry and 537 patients were eligible for our analysis. The median age was 79 (IQR 66-87) years and the proportion of men was 51.2% (273/537). AH was more likely to occur in elderly patients aged ≥65 years (424/537, 80.0%) and in indoor settings (418/537, 77.8%). The condition most frequently associated with AH, irrespective of severity, was acute medical illness. A lower mean outside temperature was associated with a higher prevalence of AH, and particularly severe AH (p for trend <0.001). The overall proportion of cases resulting in in-hospital death was 24.4% (131/537), with no significant difference between severity levels observed in a multivariable logistic regression analysis (severe group (37/118, 31.4%) vs mild group (42/192, 21.9%), adjusted OR (AOR) 1.01, 95% CI 0.61 to 1.68; and moderate group (52/227, 22.9%) vs mild group, AOR 1.11, 95% CI 0.58 to 2.14). Active prevention and intervention should occur for this important public health issue.


What makes zeolitic imidazolate frameworks hydrophobic or hydrophilic? The impact of geometry and functionalization on water adsorption.
We demonstrate, by means of Grand Canonical Monte Carlo simulation on different members of the ZIF family, how topology, geometry, and linker functionalization drastically affect the water adsorption properties of these materials, tweaking the ZIF materials from hydrophobic to hydrophilic. We show that adequate functionalization of the linkers allows one to tune the host-guest interactions, even featuring dual amphiphilic materials whose pore space features both hydrophobic and hydrophilic regions. Starting from an initially hydrophobic material (ZIF-8), various degrees of hydrophilicity could be obtained, with a gradual evolution from a type V adsorption isotherm in the liquid phase to a type I isotherm in the gas phase. This behavior is similar to what was described earlier in families of hydrophobic all-silica zeolites, with hydrophilic "defects" of various strength, such as silanol nests or the presence of extra-framework cations.


Effect of innate antiviral glycoproteins in breast milk on seroconversion to rotavirus vaccine (Rotarix) in children in Lusaka, Zambia.
Rotavirus vaccines have been introduced into national immunization programmes to mitigate morbidity and mortality associated rotavirus diarrhoea. Lower vaccine effectiveness has however been noted in low-middle income countries, but little is known about the role of maternal components found in breast milk. This study assessed the effect of lactoferrin, lactadherin, and tenascin-c on rotavirus vaccine seroconversion. This was a retrospective cohort study of 128 infants who had been fully immunized with Rotarix™. Serum samples were collected from the infant at baseline and one month after second rotavirus vaccine dose. Breast milk samples were collected from mothers at baseline. Standard ELISA was used to determine titres of rotavirus-specific immunologlobulin G and A in breast milk and serum as well as concentrations of lactoferrin, lactadherin, and tenascin-c. Poisson regression model with robust standard error was used to estimate the effect of breast milk components on seroconversion. The components were modelled on log base 2 so that the effect would be interpreted as a doubling of the concentration. In a multivariable analysis adjusting for maternal age, maternal HIV status, seropositivity at baseline, sex, age of child at vaccination as well as breast milk IgA and IgG, we found evidence of independent effect of LA (Adjusted IRR = 0.95; 95% CI = 0.91-0.99; P = 0.019) on seroconversion while there was no evidence for TNC (Adjusted IRR = 1.00; 95% CI = 0.85-1.17; P = 0.967) and LF (Adjusted RR = 1.01; 95% CI = 0.96-1.05); P = 0.802). We explored the joint effects of the three components but we found no evidence (Adjusted RR = 0.95; 95% CI = 0.81; P = 0.535). High breast milk concentrations of lactadherin might play a role in infant's failure to seroconvert to rotavirus vaccines. Further research to understand this observed association is an important consideration.


Adaptation for protein synthesis efficiency in a naturally occurring self-regulating operon.
The korAB operon in RK2 plasmids is a beautiful natural example of a negatively and cooperatively self-regulating operon. It has been particularly well characterized both experimentally and with mathematical models. We have carried out a detailed investigation of the role of the regulatory mechanism using a biologically grounded mechanistic multi-scale stochastic model that includes plasmid gene regulation and replication in the context of host growth and cell division. We use the model to compare four hypotheses for the action of the regulatory mechanism: increased robustness to extrinsic factors, decreased protein fluctuations, faster response-time of the operon and reduced host burden through improved efficiency of protein production. We find that the strongest impact of all elements of the regulatory architecture is on improving the efficiency of protein synthesis by reduction in the number of mRNA molecules needed to be produced, leading to a greater than ten-fold reduction in host energy required to express these plasmid proteins. A smaller but still significant role is seen for speeding response times, but this is not materially improved by the cooperativity. The self-regulating mechanisms have the least impact on protein fluctuations and robustness. While reduction of host burden is evident in a plasmid context, negative self-regulation is a widely seen motif for chromosomal genes. We propose that an important evolutionary driver for negatively self-regulated genes is to improve the efficiency of protein synthesis.


Inactivation of the lipoxygenase ZmLOX3 increases susceptibility of maize to Aspergillus spp.
Plant and fungal lipoxygenases (LOX) catalyze the oxidation of polyunsaturated fatty acids, creating fatty-acid hydroperoxides (oxylipins). Fungal oxylipins are required for normal fungal development and secondary metabolism, and plant host-derived oxylipins interfere with these processes in fungi, presumably by signal mimicry. The maize LOX gene ZmLOX3 has been implicated previously in seed-Aspergillus interactions, so we tested the interactions of a mutant maize line (lox3-4, in which ZmLOX3 is disrupted) with the mycotoxigenic seed-infecting fungi Aspergillus flavus and Aspergillus nidulans. The lox3-4 mutant was more susceptible than wild-type maize to both Aspergillus species. All strains of A. flavus and A. nidulans produced more conidia and aflatoxin (or the precursor sterigmatocystin) on lox3-4 kernels than on wild-type kernels, in vitro and under field conditions. Although oxylipins did not differ detectably between A. flavus-infected kernels of the lox3-4 and wild-type (WT) maize, oxylipin precursors (free fatty acids) and a downstream metabolite (jasmonic acid) accumulated to greater levels in lox3-4 than in WT kernels. The increased resistance of the lox3-4 mutant to other fungal pathogens (Fusarium, Colletotrichum, Cochliobolus, and Exserohilum spp.) is in sharp contrast to results described herein for Aspergillus spp., suggesting that outcomes of LOX-governed host-pathogen interactions are pathogen-specific.


Descriptive survey and Salmonella surveillance of pastured poultry layer farms in California.
While pasture-raised poultry comprises a small portion of the commercial poultry industry in North America, these alternative rearing systems have become increasingly popular. As such, it is critical to improve our understanding of husbandry practices and prevalence of zoonotic and epizoonotic diseases in these systems. This research reviews the results of a survey sent to 82 commercial pastured poultry farms in California. While the survey response was low (13.4%), it was enhanced by detailed in-person interviews and farm visits. In addition, we conducted drag swabs for Salmonella Enteritidis. On average, farms utilized 12.3% of their total farmland for pastured poultry operations, which often coexisted with other livestock (45%), touch crops (27%), and non-touch crops (45%). While the mean (44.6 sq. ft./hen) and median (22.2 sq. ft./hen) pasture stocking densities were within auditing guidelines, the mean (1.2 sq. ft./hen) and median (0.5 sq. ft./hen) coop stocking densities were below the pending USDA (2016) guidelines recommended in 7 CFR Part 205. Drag swab results showed the presence of Salmonella Enteritidis (SE) in the environment of one of the 11 farms (9.1%). In addition, Salmonella Pullorum (SP) whole blood agglutination tests were used to understand the prevalence of Salmonella spp. in laying hens within the studied farms. Results showed the presence of antibodies in flocks at six of the seven non-SE vaccinated farms, with a mean on-farm prevalence of 25.6% in laying hens. Logistic regression was used to determine risk factors for Group D Salmonella exposure in non-vaccinated flocks, using the SP blood agglutination data as the dependent variable and the survey questions as the independent variables. Statistically significant (P < 0.05) risk factors included exposed wire floors and flock size. These results improve our understanding of Salmonella prevalence and husbandry practices on commercial pastured poultry farms in California.


Finding POEMs in the medical literature.
Articles about primary care topics that measure patient-oriented outcomes (eg, morbidity, mortality, quality of life) should change practice, if the reported results are valid. We call these types of articles POEMs--Patient-Oriented Evidence that Matters. The extent and distribution of POEMs in the medical literature is unknown. We identified 85 medical journals of potential interest to primary care physicians, and counted 8085 original research articles over a 6-month period; 211 of those articles were POEMs (2.6%). Ten journals accounted for 50% of the POEMs identified during the study period: Journal of the American Medical Association, Annals of Internal Medicine, New England Journal of Medicine, Archives of Internal Medicine, Lancet, British Medical Journal, Obstetrics and Gynecology, Arthritis and Rheumatology, American Journal of Obstetrics and Gynecology, and Journal of the American College of Cardiology. Other journals with a high percentage of POEMs were: Journal of Family Practice, Journal of the American Board of Family Practice, and American Journal of Emergency Medicine. Half the journals we surveyed published 0 or 1 POEMs during the study period. Not all clinicians have the time, inclination, or access to review a large number of journals on a regular basis. By focusing on POEMs and the journals that publish them, busy physicians can avoid reading 98% of the original research published each month. This will not only drastically cut physicians' reading time, but also help them obtain the information that is most valuable for their patients.


Identification of mating type genes in the bipolar basidiomycetous yeast Rhodosporidium toruloides: first insight into the MAT locus structure of the Sporidiobolales.
Rhodosporidium toruloides is a heterothallic, bipolar, red yeast that belongs to the Sporidiobolales, an order within a major lineage of basidiomycetes, the Pucciniomycotina. In contrast to other basidiomycetes, considerably less is known about the nature of the mating type (MAT) loci that control sexual reproduction in this lineage. Three genes (RHA1, RHA2, and RHA3) encoding precursors of the MAT A1 pheromone (rhodotorucine A) were previously identified and formed the basis for a genome walking approach that led to the identification of additional MAT genes in complementary mating strains of R. toruloides. Two mating type-specific alleles encoding a p21-activated kinase (PAK; Ste20 homolog) were found between the RHA2 and RHA3 genes, and identification in MAT A2 strains of a gene encoding a presumptive pheromone precursor enabled prediction of the structure of rhodotorucine a. In addition, a putative pheromone receptor gene (STE3 homolog) was identified upstream of RHA1. Analyses of genomic data from two closely related species, Sporobolomyces roseus and Sporidiobolus salmonicolor, identified syntenic regions that contain homologs of all the above-mentioned genes. Notably, six novel pheromone precursor genes were uncovered, which encoded, similarly to the RHA genes, multiple tandem copies of the peptide moiety. This suggests that this structure, which is unique among fungal lipopeptide pheromones, seems to be prevalent in red yeasts. Species comparisons provided evidence for a large, multigenic MAT locus structure in the Sporidiobolales, but no putative homeodomain transcription factor genes (which are present in all basidiomycetous MAT loci characterized thus far) could be found in any of the three species in the vicinity of the MAT genes identified.


Divergent sexual selection enhances reproductive isolation in sticklebacks.
Sexual selection may facilitate speciation because it can cause rapid evolutionary diversification of male mating signals and female preferences. Divergence in these traits can then contribute to reproductive isolation. The sensory drive hypothesis predicts that three mechanisms underlie divergence in sexually selected traits: (1) habitat-specific transmission of male signals; (2) adaptation of female perceptual sensitivity to local ecological conditions; and (3) matching of male signals to female perceptual sensitivity. I test these mechanisms in threespine sticklebacks (Gasterosteus spp.) that live in different light environments. Here I show that female perceptual sensitivity to red light varies with the extent of redshift in the light environment, and contributes to divergent preferences. Male nuptial colour varies with environment and is tuned to female perceptual sensitivity. The extent of divergence among populations in both male signal colour and female preference for red is correlated with the extent of reproductive isolation in these recently diverged species. These results demonstrate that divergent sexual selection generated by sensory drive contributes to speciation.


Decreased microglial Wnt/β-catenin signalling drives microglial pro-inflammatory activation in the developing brain.
Microglia of the developing brain have unique functional properties but how their activation states are regulated is poorly understood. Inflammatory activation of microglia in the still-developing brain of preterm-born infants is associated with permanent neurological sequelae in 9 million infants every year. Investigating the regulators of microglial activation in the developing brain across models of neuroinflammation-mediated injury (mouse, zebrafish) and primary human and mouse microglia we found using analysis of genes and proteins that a reduction in Wnt/β-catenin signalling is necessary and sufficient to drive a microglial phenotype causing hypomyelination. We validated in a cohort of preterm-born infants that genomic variation in the Wnt pathway is associated with the levels of connectivity found in their brains. Using a Wnt agonist delivered by a blood-brain barrier penetrant microglia-specific targeting nanocarrier we prevented in our animal model the pro-inflammatory microglial activation, white matter injury and behavioural deficits. Collectively, these data validate that the Wnt pathway regulates microglial activation, is critical in the evolution of an important form of human brain injury and is a viable therapeutic target.


Changes in Home Parenteral Nutrition Practice Based on the Canadian Home Parenteral Nutrition Patient Registry.
Since 2005, the Canadian home parenteral nutrition (HPN) registry has collected data on patients' demography, outcomes, and HPN clinical practice. At annual meetings, Canadian HPN programs review and discuss results. To evaluate changes over time in patient demography, outcomes, and HPN clinical practice using the registry data. This retrospective study evaluated 369 patients who were prospectively entered in the registry. Two periods were compared for the first data entry: 2005-2008 (n = 182) and 2011-2014 (n = 187). Patient demography, indications for HPN, HPN regimen, nutrition assessment, vascular access, and number of line sepsis per 1000 catheter days were evaluated. For 2011-2014 compared with 2005-2008, indications for HPN changed significantly, with an increased proportion of patients with cancer (37.9% vs 16.7%) and with fewer cases of short bowel syndrome (32% vs 65.5%); line sepsis rate decreased from 1.58 to 0.97 per 1000 catheter days; and the use of tunneled catheters decreased from 64.3% to 38.0% and was no longer the most frequently chosen vascular access method. In contrast, the proportion of peripherally inserted central catheters increased from 21.6% to 52.9%. In addition, there was a reduction in number and days of hospitalizations related to HPN, and favorable changes were noted in the prescription of energy, proteins, and trace elements. The Canadian HPN registry is useful in tracking trends in demography, outcomes, and clinical practice. Results suggest a shift in patient demography and line access with improvement in line sepsis, hospitalizations, and HPN prescriptions.


Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group.
It is increasingly common in oncology practice to perform tumour sequencing using large cancer panels. For pathogenic sequence variants in cancer susceptibility genes identified on tumour-only sequencing, it is often unclear whether they are of somatic or constitutional (germline) origin. There is wide-spread disparity regarding both the extent to which systematic 'germline-focussed analysis' is carried out upon tumour sequencing data and for which variants follow-up analysis of a germline sample is carried out. Here we present analyses of paired sequencing data from 17 152 cancer samples, in which 1494 pathogenic sequence variants were identified across 65 cancer susceptibility genes. From these analyses, the European Society of Medical Oncology Precision Medicine Working Group Germline Subgroup has generated (i) recommendations regarding germline-focussed analyses of tumour-only sequencing data, (ii) indications for germline follow-up testing and (iii) guidance on patient information-giving and consent.


Impact of race on early treatment termination and outcomes in posttraumatic stress disorder treatment.
The present study investigated the influence of race on posttraumatic stress disorder (PTSD) treatment among 94 African American and 214 Caucasian female victims of interpersonal violence participating in 2 studies of cognitive-behavioral treatment for PTSD that were conducted sequentially and continuously. In each study, participants were randomized into 1 of 3 conditions. The first study compared cognitive processing therapy with prolonged exposure and a delayed treatment condition. In the second study, cognitive processing therapy was compared with its constituent components: cognitive therapy only and written accounts. Participants were assessed with the Clinician Administered PTSD Scale and the Structured Clinical Interview for DSM-IV, as well as through self-report measures of PTSD. Analyses revealed that African Americans were significantly less likely to complete treatment compared with Caucasians (45% vs. 73%, respectively, p < .001) and that the differences held even after controlling for education and income. Despite racial differences in treatment completion status, analyses with the intent-to-treat sample indicated no racial differences in outcomes on PTSD measures. The lack of difference in treatment outcomes despite racial differences in dropout may be explained by greater symptom improvement of African Americans who dropped out compared with Caucasians who dropped out. Implications of these findings and practical approaches to addressing sociocultural barriers to care are explored.


Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma.
Glioblastoma multiforme (GBM) is notoriously resistant to therapy, and the development of a durable cure will require the identification of broadly relevant regulators of GBM cell tumorigenicity and survival. Here, we identify Sprouty2 (SPRY2), a known regulator of receptor tyrosine kinases (RTK), as one such regulator. SPRY2 knockdown reduced proliferation and anchorage-independent growth in GBM cells and slowed xenograft tumor growth in mice. SPRY2 knockdown also promoted cell death in response to coinhibition of the epidermal growth factor receptor (EGFR) and the c-MET receptor in GBM cells, an effect that involved regulation of the ability of the p38 mitogen-activated protein kinase (MAPK) to drive cell death in response to inhibitors. Analysis of data from clinical tumor specimens further demonstrated that SPRY2 protein is definitively expressed in GBM tissue, that SPRY2 expression is elevated in GBM tumors expressing EGFR variant III (EGFRvIII), and that elevated SPRY2 mRNA expression portends reduced GBM patient survival. Overall, these results identify SPRY2 and the pathways it regulates as novel candidate biomarkers and therapeutic targets in GBM. SPRY2, counter to its roles in other cancer settings, promotes glioma cell and tumor growth and cellular resistance to targeted inhibitors of oncogenic RTKs, thus making SPRY2 and the cell signaling processes it regulates potential novel therapeutic targets in glioma.


Biomechanical model for muscular dysfunction of the human pharynx using finite element analysis.
The oropharynx functions to transport food from the oral cavity to the esophagus, as well as to maintain an air passage from the nose to the lungs. By combining data from prior material property experimentation, a 3-dimensional finite element method reconstruction of the pharynx, and the utilization of a optimization process based on an inverse dynamic approach, we can estimate the pressures and associated consecutive pressure gradients created internally when the pharynx functions during swallowing. In this study, pharyngeal muscular dysfunction was modeled under 3 scenarios of increasing tissue stiffness. This was done by modifications in the stress-strain relationship material property within the finite element method nodes. This mechanical property was used as a surrogate for clinical changes in muscle function complicating neuromuscular disorders, such as stroke and amyotrophic lateral sclerosis. The pharyngeal tissue and deformation of the cross-sectional area of the pharynx were analyzed while increasing the mechanical stiffness by 25%, 50%, and 75%. Increases in stiffness resulted in modified pressure-area curves predicting diminished movement, primarily in stiffened regions. These simulation results may act as a clinical index illustrating the association between tissue dysfunction and pharyngeal pressure and movement dysfunction. This type of modeling has the potential to act as an investigational tool, as well as a predictive tool, regarding disease progression, cancer treatment, and perhaps even the effects of aging on swallowing function.


Mexican-origin parents' work conditions and adolescents' adjustment.
Mexican-origin parents' work experiences are a distal extrafamilial context for adolescents' adjustment. This 2-wave multiinformant study examined the prospective mechanisms linking parents' work conditions (i.e., self-direction, work pressure, workplace discrimination) to adolescents' adjustment (i.e., educational expectations, depressive symptoms, risky behavior) across the transition to high school drawing on work socialization and spillover models. We examined the indirect effects of parental work conditions on adolescent adjustment through parents' psychological functioning (i.e., depressive symptoms, role overload) and aspects of the parent-adolescent relationship (i.e., parental solicitation, parent-adolescent conflict), as well as moderation by adolescent gender. Participants were 246 predominantly immigrant, Mexican-origin, 2-parent families who participated in home interviews when adolescents were approximately 13 and 15 years of age. Results supported the positive impact of fathers' occupational self-direction on all 3 aspects of adolescents' adjustment through decreased father-adolescent conflict, after controlling for family socioeconomic status and earner status, and underemployment. Parental work pressure and discrimination were indirectly linked to adolescents' adjustment, with different mechanisms emerging for mothers and fathers. Adolescents' gender moderated the associations between fathers' self-direction and girls' depressive symptoms, and fathers' experiences of discrimination and boys' risk behavior. Results suggest that Mexican-origin mothers' and fathers' perceptions of work conditions have important implications for multiple domains of adolescents' adjustment across the transition to high school.


Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment.
There is growing evidence that the interplay of genetic susceptibility and environmental factors leads to primary biliary cirrhosis (PBC). In particular, family members of an infected individual have up to a 100-fold higher risk of developing PBC. Although concordant rates for identical twins in other autoimmune diseases range between 25% and 50%, there are no such data on PBC. Accordingly, we evaluated the concordance of PBC in a genetically defined population of twin sets and evaluated the clinical characteristics between concordant subjects. We identified 16 pairs of twins within a 1400-family cohort followed up by several centers worldwide, evaluated the diagnosis of PBC in all individuals, and determined the zygosity of sets reported as identical by the analysis of 2 highly variable HLA class II regions and 5 short tandem repeats. Eight of 16 sets of twins were monozygotic. In 5 of 8 monozygotic twin sets, both individuals had PBC (pairwise concordance rate, 0.63). Among the dizygotic twins (n = 8), no set was found to be concordant for PBC. Interestingly, the age at onset of disease was similar in 4 of 5 concordant sets of monozygotic pairs; however, there were differences in natural history and disease severity. The concordance rate of PBC in identical twins is among the highest reported in autoimmunity. However, discordant pairs were identified. The data show not only the role of genetics but also emphasize that either epigenetic factors and/or environment play a critical role.


Rare haplotypes in mtDna: applications in the analysis of biosocial aspects of past human populations.
We report on the use of rare mutations to tackle biosocial questions such as kinship and differential burial practices from past human populations. To do this, we have inferred nucleotide position 73 of HVS-II in individuals classified as belonging to haplogroup H from 76 human dental samples from the necropolis of Aldaieta (Basque Country, Spain, 6th-7th century) by means of PCR and restriction enzyme tests. The same analysis has been performed for 146 extant individuals from the northern Iberian peninsula. A combination of haplotype H and 73G in HVS-II, rare in extant populations (0.5-3%), has been found at a frequency of 20% in the ancient population of Aldaieta. These data can be explained in terms of the existence of different burial practices associated with a variety of factors, mainly social status and kinship. This hypothesis is also supported by archeological data. These results indicate that caution should be taken when making phylogenetic inferences from extinct populations, because an uncharacterized kinship can significantly bias allele frequencies.


Cost-effectiveness of tenofovir prophylaxis during pregnancy for the elimination of mother-to-child transmission of the hepatitis B virus: real-world analysis from Thailand.
Despite implementing hepatitis B immunoglobulin (HBIG) and vaccination, data suggest it would not be sufficient to reach the elimination targets. Tenofovir disoproxil fumarate (TDF) has been added to the Thai national standards of care for prevention of transmission of the hepatitis B virus during birth. To optimise national strategies in Thailand, we assessed TDF's effectiveness for prevention of mother-to-child transmission and conducted cost-effectiveness analyses of different TDF-based strategies. We retrospectively reviewed medical records of mother and infant pairs whose mothers were positive for hepatitis B e-antigen (HBeAg) and received TDF to prevent maternal transmission of viral hepatitis B during 2018-2020. Based on the available data on transmission rate, we also applied a decision tree to estimate the cost-effectiveness of different TDF-based strategies to eligible mothers. These included: (1) HBIG for all hepatitis B virus (HBV) exposed infants; (2) HBIG for only infants of HBeAg-positive mothers ('HBIG for e-positive') and (3) without HBIG to infants ('HBIG-free'). The incremental cost-effectiveness ratio between the different strategies and baseline intervention without TDF was calculated. The one-way sensitivity analysis was used to adjust prevalence of HBeAg-positive mothers, cost of HBIG, cost of TDF and transmission rate. Of 223 infants enrolled, 212 (95.0%) received HBIG, while 11 (5.0%) did not. None of the infants had chronic HBV infection. The most cost-saving intervention was 'HBIG-free' followed by 'HBIG for e-positive'. The one-way sensitivity demonstrated that the results were reasonably robust to changes. The cost-saving was greater with a higher hepatitis B virus surface antigen (HBsAg) prevalence. The HBIG-free strategy remained best at 0%-1.4% transmission rates, meeting the additional target for eliminations. The study is the first cost-effectiveness analyses to provide evidence supporting an HBIG-free strategy in an antiviral era. This approach should be considered to prevent mother-to-child transmission in resource-constrained settings, particularly in countries with a high HBsAg prevalence.


Supermatrices, supertrees and serendipitous scaffolding: inferring a well-resolved, genus-level phylogeny of Styphelioideae (Ericaceae) despite missing data.
For the predominantly southern hemisphere plant group Styphelioideae (Ericaceae) published sequence datasets of five markers are now available for all except one of the 38 recognised genera. However, several markers are highly incomplete therefore missing data is problematic for producing a genus level phylogeny. We explore the relative utility of supertree and supermatrix approaches for addressing this challenge, and examine the effects of missing data on tree topology and resolution. Although the supertree approach returned a more conservative hypothesis, overall, both supermatrix and supertree analyses concurred in the topologies they returned. Using multiple genes and a dataset of variably complete taxa we found improved support for the monophyly and position of the tribes and genus level relationships. However, there was mixed support for the Richeeae tribe appearing one node basal to the Cosmelieae tribe or vice versa. It is probable that this will only be resolved through further sequencing. Our study supports previous findings that the amount of data is more critical than the completeness of the dataset in estimating well-resolved trees. Our results suggest that a "serendipitous" scaffolding approach that includes a mixture of well and poorly sequenced taxa can lead to robust phylogenetic hypotheses.