The many-body electronic interactions of Fe(II)-porphyrin.

Fe(II)-porphyrin complexes exhibit a diverse range of electronic interactions between the metal and macrocycle. Herein, the incremental full configuration interaction method is applied to the entire space of valence orbitals of a Fe(II)-porphyrin model using a modest basis set. A novel visualization framework is proposed to analyze individual many-body contributions to the correlation energy, providing detailed maps of this complex's highly correlated electronic structure. This technique is used to parse the numerous interactions of two low-lying triplet states (3A2g and 3Eg) and to show that strong metal d-d and macrocycle π-π orbital interactions preferentially stabilize the 3A2g state. d-π interactions, on the other hand, preferentially stabilize the 3Eg state and primarily appear when correlating six electrons at a time. Ultimately, the Fe(II)-porphyrin model's full set of 88 valence electrons are correlated in 275 orbitals, showing the interactions up to the 4-body level, which covers the great majority of correlations in this system.

Stepwise basis set selection.

The computational cost of quantum chemical methods grows rapidly with increasing level of theory and basis set size. At increasing costs, higher accuracies can be reached, forcing a compromise between cost and accuracy for most molecular systems. Heats of reaction, however, are mostly determined by a subset of atoms that experience significant bonding and/or electronic changes. To exploit this fact, the Stepwise Basis Builder (SBB) algorithm selectively adds basis functions to reactive atoms and maintains small basis sets on spectator atoms. This article introduces the SBB algorithm and how it chooses a basis for each atom, predicts calculation errors, and uses these predicted errors to reach target levels of accuracy. Benchmarks show SBB heats of reaction and activation barriers converge to values consistent with higher-quality calculations using a greatly reduced number of basis functions. © 2018 Wiley Periodicals, Inc.

Oxytocin enhances gaze-following responses to videos of natural social behavior in adult male rhesus monkeys.

Gaze following is a basic building block of social behavior that has been observed in multiple species, including primates. The absence of gaze following is associated with abnormal development of social cognition, such as in autism spectrum disorders (ASD). Some social deficits in ASD, including the failure to look at eyes and the inability to recognize facial expressions, are ameliorated by intranasal administration of oxytocin (IN-OT). Here we tested the hypothesis that IN-OT might enhance social processes that require active engagement with a social partner, such as gaze following. Alternatively, IN-OT may only enhance the perceptual salience of the eyes, and may not modify behavioral responses to social signals. To test this hypothesis, we presented four monkeys with videos of conspecifics displaying natural behaviors. Each video was viewed multiple times before and after the monkeys received intranasally either 50 IU of OT or saline. We found that despite a gradual decrease in attention to the repeated viewing of the same videos (habituation), IN-OT consistently increased the frequency of gaze following saccades. Further analysis confirmed that these behaviors did not occur randomly, but rather predictably in response to the same segments of the videos. These findings suggest that in response to more naturalistic social stimuli IN-OT enhances the propensity to interact with a social partner rather than merely elevating the perceptual salience of the eyes. In light of these findings, gaze following may serve as a metric for pro-social effects of oxytocin that target social action more than social perception.

Association of Toll-like receptor polymorphisms with HIV status in North Americans.

Single-nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes TLR2-4 and TLR7-9, but not in TLR1 and TLR6, have been previously evaluated regarding human immunodeficiency virus (HIV) acquisition and disease progression in various populations, most of which were European. In this study, we examined associations between a total of 41 SNPs in 8 TLR genes (TLR1-4, TLR6-9) and HIV status in North American subjects (total n=276 (Caucasian, n=102; African American, n=150; other, n=24)). Stratification of the data by self-identified race revealed that a total of nine SNPs in TLR1, TLR4, TLR6 and TLR8 in Caucasians, and two other SNPs, one each in TLR4 and TLR8, in African Americans were significantly associated with HIV status at P<0.05. Concordant with the odds ratios of these SNPs, significant differences were observed in the SNP allele frequencies between HIV+ and HIV- subjects. Finally, in Caucasians, certain haplotypes of single (TLR1 and TLR4) and heterodimer (TLR2_TLR6) genes may be inferred as 'susceptible' or 'protective'. Our study provides in-depth insight into the associations between TLR variants, particularly TLR1 and TLR6, and HIV status in North Americans, and suggests that these associations may be race specific.

Variation in human ß-defensin genes: new insights from a multi-population study.

Human ß-defensin 2 (hBD-2) and hBD-3, encoded by DEFB4 and DEFB103A, respectively, have shown anti-HIV activity, and both genes exhibit copy number variation (CNV). Although the role of hBD-1, encoded by DEFB1, in HIV-1 infection is less clear, single nucleotide polymorphisms (SNPs) in DEFB1 may influence viral loads and disease progression. We examined the distribution of DEFB1 SNPs and DEFB4/103A CNV, and the relationship between DEFB1 SNPs and DEFB4/103A CNV using samples from two HIV/AIDS cohorts from the United States (n = 150) and five diverse populations from the Coriell Cell Repositories (n = 46). We determined the frequencies of 10 SNPs in DEFB1 using a post-PCR, oligonucleotide ligation detection reaction-fluorescent microsphere assay, and CNV in DEFB4/103A by real-time quantitative PCR. There were noticeable differences in the frequencies of DEFB1 SNP alleles and haplotypes among various racial/ethnic groups. The DEFB4/103A copy numbers varied from 2 to 8 (median, 4), and there was a significant difference between the copy numbers of self-identified whites and blacks in the US cohorts (Mann-Whitney U-test P = 0.04). A significant difference was observed in the distribution of DEFB4/103A CNV among DEFB1 -52G/A and -390T/A genotypes (Kruskal-Wallis P = 0.017 and 0.026, respectively), while not in the distribution of DEFB4/103A CNV among -52G/A_-44C/G_-20G/A diplotypes. These observations provide additional insights for further investigating the complex interplay between ß-defensin genetic polymorphisms and susceptibility to, or the progression or severity of, HIV infection/disease.

Queensland Lung Cancer Screening Study: rationale, design and methods.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality in Australia. Screening using low-dose computed tomography (LDCT) can reduce lung cancer mortality. The feasibility of screening in Australia is unknown. This paper describes the rationale, design and methods of the Queensland Lung Cancer Screening Study. AIMS: The aim of the study is to describe the methodology for a feasibility study of lung cancer screening by LDCT in Australia. METHODS: The Queensland Lung Cancer Screening Study is an ongoing, prospective observational study of screening by LDCT at a single tertiary institution. Healthy volunteers at high risk of lung cancer (age 60-74 years; smoking history ≥30 pack years, current or quit within 15 years; forced expiratory volume in 1s ≥50% predicted) are recruited from the general public through newspaper advertisement and press release. Participants receive a LDCT scan of the chest at baseline, year 1 and year 2 using a multidetector helical computed tomography scanner and are followed up for a total of 5 years. Feasibility of screening will be assessed by cancer detection rates, lung nodule prevalence, optimal management strategies for lung nodules, economic costs, healthcare utilisation and participant quality of life. CONCLUSIONS: Studying LDCT screening in the Australian setting will help us understand how differences in populations, background diseases and healthcare structures modulate screening effectiveness. This information, together with results from overseas randomised studies, will inform and facilitate local policymaking.

Validation of the Roche AMPLICOR HIV DNA test version 1.5 for early infant diagnosis of HIV in Papua New Guinea.

Human immunodeficiency virus (HIV) is a significant public health issue in Papua New Guinea (PNG). After heterosexual transmission (90%), the second most common route of transmission is vertically from mother to child (3.5%). Before the introduction of molecular methods of HIV testing in PNG, diagnosing exposed infants was problematic because there were no reliable assays available for accurate early infant HIV detection. This study aimed to validate and assess a global gold standard for virological early infant HIV diagnosis in PNG: the AMPLICOR HIV DNA v1.5 assay (Roche) using dried blood spot (DBS) specimens. The assay was validated in three ways: by testing well-characterized DBS and kit controls and by blinded retesting of 42 patient specimens. The assay was further investigated by comparison with a serological assay. The results indicated that the assay was robust and highly reproducible using DBS and kit controls, with 100% sensitivity and specificity. Of the 42 infant DBS specimens that were retested blindly, 100% of the test results were concordant with diagnostic results. Among the 42 infant specimens tested with the Amplicor HIV DNA v1.5 assay we found that 33% of infants (n = 14) were HIV PCR positive and 67% (n = 28) negative. The earliest point of HIV detection established for this study was three months of age. This pilot study indicates that HIV-infected infants in PNG can be effectively diagnosed using virological testing and can thus be started earlier on treatment than was previously possible with serological testing.

Occult cytomegalovirus in vivarium-housed mice may influence transplant allograft acceptance.

We have recently shown that latent murine cytomegalovirus (MCMV) can influence murine transplant allograft acceptance. During these studies we became aware that vivarium-housed control mice can acquire occult MCMV infection. The purpose of this investigation was to confirm occult MCMV transmission and determine the timing, vehicle, and possible consequences of transmission. Mice arriving from a commercial vendor were negative for MCMV both by commercial serologic testing and by our nested PCR. Mice housed in our vivarium became positive for MCMV DNA 30-60 days after arrival, but remained negative for MCMV by commercial serologic testing. To confirm MCMV we sequenced PCR products for several genes and showed >99% homology to MCMV. Further sequence analyses show that the occult MCMV is similar to a laboratory strain of MCMV, but the vehicle of transmission remains unclear. Control tissues from historical experiments with unexplained graft losses were evaluated for occult MCMV, and mice with unexplained allograft losses showed significantly higher incidence of occult MCMV than did allograft acceptors. Deliberate infection with very low titer MCMV confirmed that viral transmission can occur without measurable virus specific antibody or T-cell responses. These data suggest that vivarium-housed mice can develop occult MCMV that is missed by currently available commercial serologic testing, and that these infections may influence transplant allograft acceptance.

Exploratory study of the 'weekend effect' for acute medical admissions to public hospitals in Queensland, Australia.

AIMS: To determine whether in-hospital deaths of patients admitted through emergency departments with acute exacerbations of chronic obstructive pulmonary disease (COPD), acute myocardial infarction, intracerebral haemorrhage and acute hip fracture are increased by weekend versus weekday admission (the 'weekend effect'). METHODS: We performed a retrospective analysis of statewide administrative data from public hospitals in Queensland, Australia, during the 2002/2003-2006/2007 financial years. The primary outcome was 30-day in-hospital mortality. The secondary outcome of 2-day in-hospital mortality helped determine whether increased mortality of weekend admissions was closely linked to weekend medical care. RESULTS: During the study period, there were 30 522 COPD, 17 910 acute myocardial infarction, 4183 acute hip fracture and 1781 intracerebral haemorrhage admissions. There was no significant weekend effect on 30-day in-hospital mortality for COPD (adjusted risk ratio = 0.92, 95% CI: 0.81-1.04, P= 0.222), intracerebral haemorrhage (adjusted risk ratio = 1.01, 95% CI: 0.86-1.16, P= 0.935) or acute hip fracture (adjusted risk ratio = 0.78, 95% CI: 0.54-1.03, P= 0.13). There was a significant weekend effect for acute myocardial infarction (adjusted risk ratio = 1.15, 95% CI: 1.03-1.26, P= 0.007). Two-day in-hospital mortality showed similar results. CONCLUSION: This is the first Australian study on the 'weekend effect' (in a cohort other than neonates), and the first study worldwide to assess specifically the weekend effect among COPD patients. Observed patterns were consistent with overseas research. There was a significant weekend effect for myocardial infarction. Further research is needed to determine whether location (e.g. rural), clinical (e.g. disease severity) and service provision factors (e.g. access to invasive procedures) influence the weekend effect for acute medical conditions in Australia.

Genetic susceptibility to the respiratory effects of air pollution.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

Allogeneic stimulation causes transcriptional reactivation of latent murine cytomegalovirus.

Cytomegalovirus (CMV) reactivation is a well-described complication of transplantation that may be caused by allogeneic stimulation, immunosuppression, or both. These studies were performed to determine if allogeneic stimulation alone is sufficient to reactivate latent CMV. BALB/c mice latently infected with Smith strain murine CMV (MCMV) received allograft (n = 8), allograft plus cortisol (n = 5), or isograft (n = 4) skin. All allograft recipients rejected their grafts within 9 to 12 days of transplantation. Three weeks after grafting, recipients were evaluated for MCMV reactivation, and all allograft recipients (8/8) showed MCMV reactivation, while no isografts had reactivation (0/4). Surprisingly, cortisol therapy blocked MCMV reactivation (0/5). These data suggested that allogeneic stimulation alone can trigger systemic reactivation of latent CMV. Although immunosuppression is thought to contribute to reactivation, certain agents that impair NF-kappaB activation may actually reduce reactivation.

Disruption of murine cardiac allograft acceptance by latent cytomegalovirus.

Cytomegalovirus (CMV) reactivation is a well-described complication of solid organ transplantation. These studies were performed to (1) determine if cardiac allograft transplantation of latently infected recipients results in reactivation of CMV and (2) determine what impact CMV might have on development of graft acceptance/tolerance. BALB/c cardiac allografts were transplanted into C57BL/6 mice with/without latent murine CMV (MCMV). Recipients were treated with gallium nitrate induction and monitored for graft survival, viral immunity and donor reactive DTH responses. Latently infected allograft recipients had approximately 80% graft loss by 100 days after transplant, compared with approximately 8% graft loss in naïve recipients. PCR evaluation demonstrated that MCMV was transmitted to cardiac grafts in all latently infected recipients, and 4/8 allografts had active viral transcription compared to 0/6 isografts. Latently infected allograft recipients showed intragraft IFN-alpha expression consistent with MCMV reactivation, but MCMV did not appear to negatively influence regulatory gene expression. Infected allograft recipients had disruption of splenocyte DTH regulation, but recipient splenocytes remained unresponsive to donor antigen even after allograft losses. These data suggest that transplantation in an environment of latent CMV infection may reactivate virus, and that intragraft responses disrupt development of allograft acceptance.

Genetic susceptibility to the respiratory effects of air pollution.

There is large variation between individuals in their response to air pollutants. This review summarises the existing evidence that genetic factors influence the mechanisms of lung injury caused by air pollutants. Genetic association studies have compared the adverse effects of air pollutants between subjects with specific genotypes in biologically relevant genes. In human studies of ozone exposure, polymorphisms in oxidative stress genes (NQO1, GSTM1, GSTP1) modify respiratory symptoms, lung function, biomarkers and risk of asthma. Inflammatory gene polymorphisms (TNF) influence the lung function response to ozone, and the effect of different levels of ozone on the development of asthma. Polymorphisms in oxidative stress genes (GSTM1, GSTP1) alter the response to combined exposure to ragweed pollen and diesel exhaust particles. Importantly, polymorphisms in an oxidative stress gene (GSTM1) have predicted patients with asthma who benefit from antioxidant supplementation in Mexico City, which has chronically high ozone exposure. Genetic linkage studies of families have not been feasible for studying the effects of air pollution in humans, but some progress has been made with pedigrees of specially bred mice, in identifying chromosomal regions linked to effects of ozone or particles. A high priority now, in addition to avoiding exposure in the most susceptible people, is to clearly identify the most effective and safe chemopreventive agents for individuals who are genetically susceptible to the adverse effects of air pollution (eg, antioxidants to be taken during high ozone levels).

Glycophorin C delta(exon3) is not associated with protection against severe anaemia in Papua New Guinea.

The high frequencies of mutant haemoglobin and erythrocyte surface proteins in malaria-endemic regions have indicated that polymorphisms in human genes have been under selection pressure by severe malarial disease. Glycophorin C (GYPC) is a major surface erythrocyte protein and also a receptor for the Plasmodium falciparum erythrocyte-binding antigen 140 (EBA-140, also known as BAEBL). There is no binding to GYPC in Gerbich-negative (deletion of exon 3 in GYPC gene: GYPCC delta(exon3)) erythrocytes by EBA-140, hence limiting invasion of erythrocytes by certain P. falciparum lines. The GYPCC delta(exon3) allele reaches high frequencies in two areas of Papua New Guinea (PNG) where malaria is highly endemic. There is, however, no indication that Gerbich negativity protects against malaria-related illness. Using archival blood samples collected from children (<6 years of age) in the Wosera District, East Sepik Province, PNG, we investigated GYPC C delta(exon3) as a possible genetic component of protection against severe malarial anaemia (SMA). The frequency of this human genetic polymorphism was found to be in accordance with previous studies. However, our result showed no association between SMA and GYPC C delta(exon3). Until such an association is clearly shown with severe malaria outcomes, these results raise questions regarding the role of malaria as a selective force for Gerbich negativity.

Effects of stocking density, flock size and management on the welfare of laying hens in single-tier aviaries.

Management practices, stocking rate and flock size may affect laying hen welfare but there have been few replicated studies in commercial non-cage systems that investigate this. This study used a broad range of physical and physiological indicators to assess the welfare of hens in 36 commercial flocks. Six laying period treatments were examined with each treatment replicated 6 times. It was not possible to randomly allocate treatments to houses, so treatment and house were largely confounded. Three stocking rates were compared: 7 birds/m(2) (n = 2450), 9 birds/m(2) (n = 3150) and 12 birds/m(2) in either small (n = 2450) or large (n = 4200) flocks. In addition, at 12 birds/m(2), in both small and large flocks, birds were subjected to either standard (SM) or modified (MM) management. MM flocks had nipple drinkers and no nest-box lights. Bone strength, fracture incidence, heterophil:lymphocyte (H:L) ratio, live weight, organ weights, serum creatine, serum osmolality, muscle pH and faecal corticosterone were measured on samples of birds at the end of the rearing period and at the end of lay. During the laying period, mortality, production and integument condition were recorded at regular intervals. Birds housed at 9 birds/m(2) had higher mortality than birds housed at 12 birds/m(2) by the end of lay, but not higher than birds housed at 7 birds/m(2). Birds housed at 7 and 9 birds/m(2) had lower percent liver weight, and worse plumage condition than most of the 12 bird/m(2) treatments. Modified management tended to improve plumage condition. There were no clear effects of flock size on the welfare indicators recorded. At the end of the rearing period fracture incidence was almost negligible and H:L ratio was within a normal range. By the end of lay fracture incidence was 60% and H:L ratio was high, with no treatment effect for either measure. This, together with information on faecal corticosterone, feather loss and mortality, suggests that the welfare of birds in all treatments was relatively poor by the end of lay.

Dynamic regulation of single- and mixed-species malaria infection: insights to specific and non-specific mechanisms of control.

Our increasing appreciation of the high prevalence of mixed-species Plasmodium infection in malaria-endemic regions has resulted in controversy regarding the likely mechanism(s) of regulation for mixed parasite burden within an individual human host. In the present study, we examined dynamic models of Plasmodium spp. regulation by fever and by non-specific (NS) and species-specific (SS) immunity (including the influence of their variable time-delays, duration, and efficacy) in order to assess the likely role of these factors in regulating detectable parasitemia and clinical disease. Our models suggest that in order to observe the irregular waves of fever and parasitemia that are often found in multiply infected subjects, there must be a differential SS immune effect (beyond the regulatory effects of the species-transcendent density-dependent factors previously posited to control mixed-species parasitemia), and time-dependent variation in immunity to the dominant species. By implementation of individual SS immune controls of non-permanent duration, the resulting multi-dimensional model can be viewed as multiple single-species oscillators coupled via a NS species-transcendent controller. This extended model exhibits the essential patterns of long-term mixed infections. Although this 'circuit-immunity' model gives only a qualitative estimate of the complex web of participating agents and reaction pathways, it provides a starting point for future studies of the specific and NS within-host mechanisms that regulate mixed-species malaria infection.

A new method for objective identification and measurement of airway lumen in paediatric flexible videobronchoscopy.

BACKGROUND: Accurate measurements of airway and lesion dimensions are important to the developmental progress of paediatric bronchoscopy. The malacia disorders are an important cause of respiratory morbidity in children, but no methods are currently available to measure these lesions or the airway lumen accurately. A new measurement technique is described here. METHODS: The magnification power of a paediatric videobronchoscope was defined and a simple and user friendly computer based program (Image J) was used to develop an objective technique (colour histogram mode technique, CHMT) for measurement of the airway lumen. RESULTS: In vivo intra-observer and inter-observer repeatability coefficients for repeated area measurements from 28 images using the Bland-Altman method were 0.9 mm2 and 1.6 mm2, respectively. The average intraclass correlation coefficient for repeated measurements of area was 0.93. In vitro validation measurements using a 2 mm diameter tube resolved radii measurements to within 0.1 mm (coefficient of variability 8%). An "acceptable result" was defined in 92% of 734 images completed with the CHMT alone and 8% with its modification. The success rate for two of three images being within 10% of each other's area was 100%. Measurements of cricoid cross sectional areas from 116 patients compared with expected airway areas for age derived from endotracheal tube sizes were comparable. CONCLUSIONS: The CHMT method of identifying and measuring airway dimensions is objective, accurate, and versatile and, as such, is important to the future development of flexible videobronchoscopy.

Cochrane systematic reviews of treatments for lung cancer.

Morbidity and mortality from lung cancer is a major burden to global health. The integration of expert clinical experience, patient preference and high-quality evidence, including Cochrane systematic reviews, can only help improve outcomes from this highly lethal condition.

The effect of delayed visual feedback on telerobotic surgery.

BACKGROUND: Telerobotic surgery is ideally suited for remote applications in which the instrument control console is stationed separately from the end-effectors at the patient's bedside. However, if the distance between the console and the patient is great enough, a lag effect or latency between end-effector manipulation and the depicted image leads to alterations in movement patterns. The purpose of this study was to determine the effect of visual delay on surgical task performance. METHODS: At an endoscopic skill station, an analogue delay device was interposed between the surgical field and monitor to delay the transmission of visual information, thus mimicking the distance effect of data transmission. Three surgeons with similar laparoscopic experience participated in the laparoscopic knot tying portion of the study, and seven residents participated in the accuracy and dexterity tasks. The time to complete a single throw was recorded in seconds after adding consecutively increasingly time delay in 50 ms increments. Similar time delay increments were added for the accuracy and dexterity tasks, which involved passing a needle through two adjacent circles and passing a small cylinder through a larger one to reproduce two-handed coordination and spatial resolution. Data were presented as the median time to complete each task. RESULTS: For all three tasks, an incremental increase in time delay was associated with a significant (p < 0.001) increase in the time to complete the task. For dexterity, a statistically significant (p