Prognostic stratification of HPV-associated oropharyngeal cancer based on CD103+ immune cell abundance in patients treated on TROG 12.01 and De-ESCALaTE randomized trials.

BACKGROUND: High CD103+ intratumoral immune cell (ITIC) abundance is associated with better prognosis in unselected patients with human papilloma virus-associated oropharyngeal squamous cell carcinoma (HPV-associated OPSCC) treated with cisplatin and radiotherapy (CIS/RT). Substituting cetuximab (CETUX) for CIS with RT in HPV-associated OPSCC resulted in inferior efficacy. Our aim was to determine whether quantification of CD103 ITIC could be used to identify a population of HPV-associated OPSCC with superior prognosis. PATIENTS AND METHODS: We pooled data from the TROG 12.01 and De-ESCALaTE randomized trials that compared CETUX/70GyRT with CIS/70GyRT in low-risk HPV-associated OPSCC: American Joint Committee on Cancer 7 stage III (excluding T1-2N1) or stage IV (excluding N2b-c if smoking history >10 pack-years and/or distant metastases), including all patients with available tumor samples. The primary endpoint was failure-free survival (FFS) in patients receiving CETUX/RT comparing CD103+ ITIC high (≥30%) versus low (<30%). High and low CD103 were compared using Cox regression adjusting for age, stage and trial. RESULTS: Tumor samples were available in 159/182 patients on TROG 12.01 and 145/334 on De-ESCALaTE. CD103+ ITIC abundance was high in 27% of patients. The median follow-up was 3.2 years. The 3-year FFS in patients treated with CETUX/RT was 93% [95% confidence interval (CI) 79% to 98%] in high CD103 and 74% (95% CI 63% to 81%) in low CD103 [adjusted hazard ratio = 0.22 (95% CI 0.12-0.41), P < 0.001]. The 3-year overall survival in patients treated with CETUX/RT was 100% in high CD103 and 86% (95% CI 76% to 92%) in low CD103, P < 0.001. In patients treated with CIS/RT, there was no significant difference in FFS. CONCLUSIONS: CD103+ ITIC expression separates CETUX/RT-treated low-risk HPV-associated OPSCC into excellent and poor prognosis subgroups. The high CD103 population is a rational target for de-intensification trials.

Mental health and behavioural problems in adolescents conceived after ART.

STUDY QUESTION: Does mental health and behaviour differ between those conceived with and those conceived without ART? SUMMARY ANSWER: Our study observed less externalizing behaviour (delinquent/aggressive), and more parent-reported internalizing behaviour, as well as more (clinical) depression at age 14 years, in adolescents conceived after ART compared to their non-ART counterparts. WHAT IS KNOWN ALREADY: Health outcomes of ART-conceived offspring may differ from those conceived without ART, and previous studies have reported differences in behaviour and mental health, particularly in childhood. STUDY DESIGN, SIZE, DURATION: The Growing Up Healthy Study (GUHS) is a prospective cohort study, investigating the long-term health of offspring conceived after ART (aged 14, 17 and 20 years), in the two operational fertility clinics in Western Australia 1991-2001 (n = 303). Their long-term health outcomes were compared to those of offspring conceived without ART from the Raine Study Generation 2 (Gen2) born 1989-1991 (n = 2868). Both cohorts are representative of the local adolescent population. PARTICIPANTS/MATERIALS, SETTING, METHODS: Mental health parameters and behaviour were assessed at ages 14 and 17 years, through the parent completed 'Child Behaviour Checklist' (CBCL; ART versus non-ART: age 14 years: N = 150 versus N = 1781, age 17 years: N = 160 versus N = 1351), and the adolescent completed equivalent 'Youth Self-Report' (YSR; age 14 years: by N = 151 versus N = 1557, age 17 years: N = 161 and N = 1232). Both tools generate a T-score (standardized for age and sex) for internalizing (withdrawn, somatic complaints, anxious/depressed), externalizing (delinquent/aggressive behaviour) and total behaviour. Adolescents also completed the 'Beck Depression Inventory for Youth' (BDI-Y; age 14 years: N = 151 versus N = 1563, age 17 years: N = 161 versus N = 1219). Higher scores indicate poorer mental health and behaviour on all the above tools. Parent-reported doctor-diagnosed conditions (anxiety, behavioural problems, attention problems and depression) were also univariately compared between the cohorts. In addition, univariate comparisons were conducted between the GUHS adolescents and Gen2 adolescents born to subfertile parents (time to pregnancy >12 months), as well as between offspring born to subfertile versus fertile parents within the Gen2 cohort. A subgroup analysis excluding offspring born preterm (<37 weeks' gestation) or at low birthweight (<2500 g) was also performed. Generalized estimating equations that account for correlated familial data were adjusted for the following covariates: non-singleton, primiparity, primary caregiver smoking, family financial problems, socio-economic status and both maternal and paternal ages at conception. MAIN RESULTS AND THE ROLE OF CHANCE: At both 14 and 17 years of age, ART versus non-ART-conceived adolescents reported lower mean T-scores for externalizing problems (age 14 years: 49 versus 51, P = 0.045, age 17 years: 49 versus 52, P < 0.001). A similar effect was reported by parents, although not significant (age 14 years: P = 0.293, age 17 years: P = 0.148). Fewer ART-conceived adolescents reported a T-score above the clinical cut-off for externalizing behaviour (≥60; age 14 years: 7.3% versus 16.3%, P = 0.003, age 17 years: 8.1% versus 19.7%, P < 0.001). At both ages, no differences in internalizing behaviour were reported by adolescents (age 14 years: P = 0.218, age 17 years: P = 0.717); however, higher mean scores were reported by parents of the ART-conceived adolescents than by parents of the non-ART conceived adolescents (age 14 years: 51 versus 48, P = 0.027, age 17 years: 50 versus 46, P < 0.001). No differences in internalizing behaviour above the clinical cut-off (T-score ≥ 60) were observed. At age 17 years, parents who conceived through ART reported higher total behaviour scores than those parents who conceived without ART (48 versus 45, P = 0.002). At age 14 years, ART versus non-ART-conceived adolescents reported significantly higher mean scores on the BDI-Y (9 versus 6, P = 0.005); a higher percentage of adolescents with a score indicating clinical depression (≥17; 12.6% versus 8.5%, aOR 2.37 (1.18-4.77), P = 0.016), as well as more moderate/severe depression (≥21; 9.3% versus 4.0%, P = 0.009). At age 17 years, no differences were reported on the BDI-Y. There was also a higher percentage of parent-reported doctor-diagnosed anxiety in the ART cohort (age 14 years: 8.6% versus 3.5%, P = 0.002, at age 17 years: 12.0% versus 4.5%, P < 0.001). Removing adolescents born preterm or at low birthweight did not alter the above results. Comparing outcomes between GUHS adolescents and Gen2 adolescents born to subfertile parents, as well as between those born to subfertile versus fertile parents within Gen2, did not alter results for CBCL and YSR outcomes. Those born to subfertile parents showed higher rates of clinical depression than those born to fertile parents at age 14 years (13.7% versus 6.9%, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is the time difference between the GUHS and Gen2 assessments. Even though we have adjusted for covariates, additional socio-economic and lifestyle factors affecting behaviour and mental well-being could have changed. We were unable to differentiate between different types of ART (e.g. IVF versus ICSI), owing to the low number of ICSI cycles at the time of study. Fertility sub-analyses need to be replicated in larger cohorts to increase power, potentially using siblingship designs. Lastly, selection bias may be present. WIDER IMPLICATIONS OF THE FINDINGS: The reported lower prevalence of externalizing behaviour (delinquent/aggressive), and higher prevalence of internalizing behaviour, as well as more (clinical) depression at age 14 years, in ART versus non-ART-conceived adolescents, is in line with some previous studies, mostly conducted in childhood. It is reassuring that differences in the rates of depression were not observed at age 17 years, however, these findings require replication. As the use of ART is common, and mental health disorders are increasing, knowledge about a potential association is important for parents and healthcare providers alike. STUDY FUNDING/COMPETING INTEREST(S): This project was funded by an NHMRC Grant (Hart et al., ID 1042269). R.J.H. is the Medical Director of Fertility Specialists of Western Australia and a shareholder in Western IVF. He has received educational sponsorship from MSD, Merck-Serono and Ferring Pharmaceuticals. P.B. is the Scientific Director of Concept Fertility Centre, Subiaco, Western Australia. J.L.Y. is the Medical Director of PIVET Medical Centre, Perth, Western Australia. TRIAL REGISTRATION NUMBER: N/A.

Sickle cell bone disease and response to intravenous bisphosphonates in children.

Children with sickle cell disease (SCD) have the potential for extensive and early-onset bone morbidity. This study reports on the diversity of bone morbidity seen in children with SCD followed at three tertiary centers. IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. INTRODUCTION: To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with SCD. METHODS: We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises, or stroke attributed to IV bisphosphonate therapy. CONCLUSION: Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications.

Heterogeneity in the onwards transmission risk between local and imported cases affects practical estimates of the time-dependent reproduction number.

During infectious disease outbreaks, inference of summary statistics characterizing transmission is essential for planning interventions. An important metric is the time-dependent reproduction number (Rt), which represents the expected number of secondary cases generated by each infected individual over the course of their infectious period. The value of Rt varies during an outbreak due to factors such as varying population immunity and changes to interventions, including those that affect individuals' contact networks. While it is possible to estimate a single population-wide Rt, this may belie differences in transmission between subgroups within the population. Here, we explore the effects of this heterogeneity on Rt estimates. Specifically, we consider two groups of infected hosts: those infected outside the local population (imported cases), and those infected locally (local cases). We use a Bayesian approach to estimate Rt, made available for others to use via an online tool, that accounts for differences in the onwards transmission risk from individuals in these groups. Using COVID-19 data from different regions worldwide, we show that different assumptions about the relative transmission risk between imported and local cases affect Rt estimates significantly, with implications for interventions. This highlights the need to collect data during outbreaks describing heterogeneities in transmission between different infected hosts, and to account for these heterogeneities in methods used to estimate Rt. This article is part of the theme issue 'Technical challenges of modelling real-life epidemics and examples of overcoming these'.

Effect of rumen fluke on feed digestibility and methane emissions in sheep.

Thirty-six ewes aged 18 months were assigned to one of three groups (n = 12) on the basis of faecal egg count (FEC) for rumen fluke; C: control (FEC = 0-5 epg), T: affected (FEC ≥ 6 epg) and treated, NT: affected (FEC ≥ 6 epg) and not treated. T ewes were treated with oxyclozanide 14 days prior to the trial commencing. Ewes were fed grass silage ad libitum. Digestibility crates and respiration chambers were used to measure feed digestibility and methane production. Dry matter intake (DMI), feed digestibility and CH4/DMI did not differ (P > 0.05) between treatments. However, CH4/live weight (LW) was significantly greater (P < 0.001) for NT ewes, while that of C and T ewes were similar. This study indicates that a high rumen fluke burden can increase methane emissions but only when expressed on a body weight basis (per kg LW). As the link between rumen fluke infection and methane production has not previously been investigated within the literature, these findings demonstrate the need for further research to better understand these relationships.

How applicable is the TNM 8 staging for human papillomavirus (HPV) related oropharyngeal squamous cell carcinoma (OPSCC) to a UK population of 106 patients? : A cohort comparison of the TNM 7 and TNM8 staging systems for HPV positive oropharyngeal cancer in a UK population.

PURPOSE: TNM8 introduced a new staging system for HPV positive oropharyngeal squamous cell carcinoma (OPSCC). This study aimed to investigate whether the changes made in TNM8 offer the perceived benefit in prognostication when compared to TNM7 in a specific patient population in the North East of England. METHODS: A retrospective cohort comparison study of all patients with HPV positive OPSCC (n = 106) through the Newcastle Head and Neck MDT between January 2012 to December 2014. Overall survival (OS) and Disease specific survival (DSS) data at 3 years was gathered for both TNM7 and TNM8. Log rank test was used to compare survival curves. Harrell's C-index adjusted for age and smoking status was used to assess prognostic ability of the two staging methods. RESULTS: TNM8 downstages disease (TNM7 stage IV patients n = 74, TNM8 stage IV patients n = 2) but gives a more even distribution of patients across disease stages. Survival for TNM8 stage II and III is similar. In our small cohort, the log-rank test detected differences in OS between stages for both scoring methods (TNM7 p = 0.006, TNM8 p < 0.001) and similarly for DSS (TNM7 p = 0.001, TNM8 p < 0.001). Harrell's C-index was similar for both models for OS (TNM7 0.71, TNM8 0.71) and DSS (TNM7 0.74, TNM8 0.70). CONCLUSION: TNM8 downstages disease and prognosticates well for stage I disease but does not differentiate between stage II and III disease when compared to TNM7. Further adaptation is required to address this to make TNM8 a more accurate prognostic tool.

A Narrative Review of Common Uses of Ophthalmic Ultrasound in Emergency Medicine.

BACKGROUND: The timely evaluation of ocular conditions in the emergency department (ED) can be difficult due to a general lack of specialized equipment, trained personnel, and the time-sensitive nature of emergent ocular conditions. Recently, the use of ocular point-of-care ultrasound (POCUS) has been shown to be particularly useful in the ED. POCUS can be used to promptly diagnose various ocular pathologies, which include ocular trauma, vitreous hemorrhage, central retinal artery occlusion, and retinal detachment. OBJECTIVES: This narrative review seeks to inform the reader of current literature regarding the use of POCUS for the assessment of various ocular emergencies in the ED. The goal of this review is to provide the emergency physician with succinct and up-to-date information and instruction regarding the current uses of POCUS for patients presenting with particular ocular emergencies. Ocular pathologies that are common (ocular trauma) or for which ultrasound is particularly useful (such as retinal detachment) are discussed. Other ocular pathologies are also briefly discussed, such as central retinal artery occlusion, which is a promising new application for ultrasound evaluation. DISCUSSION: There have been many studies that provide evidence for the utility of POCUS in the evaluation of trauma and other ocular pathologies, including vitreous hemorrhage, retinal detachment, and central retinal artery occlusion. CONCLUSIONS: Ocular POCUS is a useful modality in the evaluation of acute ocular complaints in the ED. Emergency physicians should be aware of these findings and feel confident in the utility of ocular POCUS in the ED.

Impact of a National Lockdown on Cycling Injuries.

Introduction The Sars-CoV-2 pandemic led to a national lockdown in Ireland from March 12th to June 7th, 2020. The present study aimed to assess the change in the pattern of cycling attendances to an Irish ED during a pandemic. Methods This is a retrospective before-and-after study carried out at a university hospital ED. We compared cycling attendances during Lockdown (LD) (13th March-7th June 2020) with Pre-Lockdown (PLD) (January 1st-March 12th, 2020). Furthermore, we also compared lockdown to an historical control period during the equivalent dates in 2019 (i.e. March 13th-June 7th, 2019) Results There were 151 cycling attendances during LD, 122 in PLD and 164 during the control period. The number of cyclists presenting during "rush hour traffic" in the LD period was 30 (19.9%) versus 42 (34.4%) during PLD (p<0.05) and 51 (31.1%) during the control period (p<0.05). During LD, 8 (5.3%) collisions involved a motor vehicle compared to 26 (21.3%) in PLD (p<0.05) and 43 (26.2%) during the control period (p<0.05). Conclusion Lockdown did not result in increased cycling attendances to this ED. The patients who did sustain a cycling-related injury during lockdown were less likely to have collided with a motor vehicle compared to the control period. The reduction in motor vehicle collisions could be attributed to less traffic congestion and highlights the potential benefits of road-user segregation.

Effect of a New Lithium Preparation on the Behavior of CBA/CaLac Mice in an Experimental Conflict Model.

The use of lithium drugs in clinical practice requires constant monitoring of lithium plasma concentration, because toxicity is sometimes observed at therapeutic concentrations of lithium. This is often associated with fluctuations of plasma concentration of lithium ions after intake of individual doses. Therefore, the use of a porous carrier providing a stable blood level of the drug is extremely promising and important for clinical practice. We studied activity of a new lithium drug (lithium complex) consisting of aluminum-silicon base and lithium citrate immobilized on its surface. Lithium carbonate served as the reference drug. It was shown that lithium carbonate and lithium complex exhibited no anxiolytic activity in the conflict model, but produced an antidepressant effect and improved exploratory behavior of animals.

Using the Retrobulbar Spot Sign to Assist in Diagnosis and Management of Central Retinal Artery Occlusions.

Point-of-care ultrasound has become an integral part of the evaluation of monocular vision loss. Most commonly, it has been used to evaluate retinal detachment, vitreous hemorrhage, and posterior vitreous detachment. Point-of-care ultrasound can also be used to evaluate central retinal arterial occlusion, whereby a retrobulbar spot sign is present. We present a case series of 4 patients presenting with monocular vision loss who were found to have central retinal artery occlusion. We describe what a retrobulbar spot sign is and how its presence or absence can assist in the evaluation and treatment of these patients.

Microbial Source Tracking Using 16S rRNA Amplicon Sequencing Identifies Evidence of Widespread Contamination from Young Children's Feces in an Urban Slum of Nairobi, Kenya.

Child exposure to fecal contamination remains common in low- and middle-income countries after sanitation interventions. Unsafe disposal of children's feces may contribute to this continued exposure, but its relative importance to domestic fecal contamination is not well understood. To address this gap, we interviewed and collected environmental samples (drinking water, caregiver hands, child hands, surfaces, soil, open drainage ditches, standing water, streams) from 40 households in Kibera, an urban slum in Nairobi, Kenya. To track young children's feces (<3 years old) separately from other human-associated fecal sources, we validated distance-based and Bayesian (SourceTracker) microbial source tracking methods using amplicon-based sequencing of the 16S rRNA gene. Contamination by young children's feces could be identified and distinguished separately from older child/adult feces with high sensitivity and specificity in water and soil. Among environmental samples, young children's feces were almost always identified as the dominant source of human fecal contamination inside households (hands, surfaces) whereas older children/adult feces were often identified as the dominant source outside households (standing water, streams, soil). Markers for young children's feces were also detected in standing water and streams, and markers for both fecal sources were equally likely to be dominant in open ditches. These results establish motivation for sanitation interventions that directly address child feces management.

Towards a preventative approach to improving health and reducing health inequalities: a view from Scotland.

Pressures on the health system are intense. Prevention is often seen as a sustainable way to manage these pressures. However, the impact of prevention on the demand for health and social care is not fully understood. It will reflect the balance of opposing forces: reduced needs for health and social care because of improving health and increased needs associated with increasing life expectancy and the diseases of old age, mediated by how the system manages the resulting pressures. This article illustrates how some of these factors are playing out in Scotland. The article also highlights the substantial growth in the evidence base on the economics of prevention and identifies policy developments with the potential to support a shift to prevention that might help move towards more sustainable demands on the health and social care system. These include recognition of the importance of the social determinants of health, the integration of health and social care and 'realistic medicine'. The article suggests that more use needs to be made of available evidence on the economics of prevention and that all stakeholders need to be engaged in tackling the technical and political challenges posed by the shift to prevention.

Embracing polygenicity: a review of methods and tools for psychiatric genetics research.

The availability of genome-wide genetic data on hundreds of thousands of people has led to an equally rapid growth in methodologies available to analyse these data. While the motivation for undertaking genome-wide association studies (GWAS) is identification of genetic markers associated with complex traits, once generated these data can be used for many other analyses. GWAS have demonstrated that complex traits exhibit a highly polygenic genetic architecture, often with shared genetic risk factors across traits. New methods to analyse data from GWAS are increasingly being used to address a diverse set of questions about the aetiology of complex traits and diseases, including psychiatric disorders. Here, we give an overview of some of these methods and present examples of how they have contributed to our understanding of psychiatric disorders. We consider: (i) estimation of the extent of genetic influence on traits, (ii) uncovering of shared genetic control between traits, (iii) predictions of genetic risk for individuals, (iv) uncovering of causal relationships between traits, (v) identifying causal single-nucleotide polymorphisms and genes or (vi) the detection of genetic heterogeneity. This classification helps organise the large number of recently developed methods, although some could be placed in more than one category. While some methods require GWAS data on individual people, others simply use GWAS summary statistics data, allowing novel well-powered analyses to be conducted at a low computational burden.

Pharmacokinetics, disposition, and plasma concentrations of dimethyl sulfoxide (DMSO) in the horse following topical, oral, and intravenous administration.

Compartmental models were used to investigate the pharmacokinetics of intravenous (i.v.), oral (p.o.), and topical (TOP) administration of dimethyl sulfoxide (DMSO). The plasma concentration-time curve following a 15-min i.v. infusion of DMSO was described by a two-compartment model. Median and range of alpha (t1/2α ) and beta (t1/2ß ) half-lives were 0.029 (0.026-0.093) and 14.1 (6.6-16.4) hr, respectively. Plasma concentration-time curves of DMSO following p.o. and TOP administration were best described by one-compartment absorption and elimination models. Following the p.o. administration, median absorption (t1/2ab ) and elimination (t1/2e ) half-lives were 0.15 (0.01-0.77) and 15.5 (8.5-25.2) hr, respectively. The plasma concentrations of DMSO were 47.4-129.9 µg/ml, occurring between 15 min and 4 hr. The fractional absorption (F) during a 24-hr period was 47.4 (22.7-98.1)%. Following TOP administrations, the median t1/2ab and t1/2e were 1.2 (0.49-2.3) and 4.5 (2.1-11.0) hr, respectively. Plasma concentrations were 1.2-8.2 µg/ml occurring at 2-4 hr. Fractional absorption following TOP administration was 0.48 (0.315-4.4)% of the dose administered. Clearance (Cl) of DMSO following the i.v. administration was 3.2 (2.2-6.7) ml hr-1  kg-1 . The corrected clearances (ClF ) for p.o. and TOP administrations were 2.9 (1.1-5.5) and 4.5 (0.52-18.2) ml hr-1  kg-1 .

Method to characterize inorganic particulates in lung tissue biopsies using field emission scanning electron microscopy.

Humans accumulate large numbers of inorganic particles in their lungs over a lifetime. Whether this causes or contributes to debilitating disease over a normal lifespan depends on the type and concentration of the particles. We developed and tested a protocol for in situ characterization of the types and distribution of inorganic particles in biopsied lung tissue from three human groups using field emission scanning electron microscopy (FE-SEM) combined with energy dispersive spectroscopy (EDS). Many distinct particle types were recognized among the 13 000 particles analyzed. Silica, feldspars, clays, titanium dioxides, iron oxides and phosphates were the most common constituents in all samples. Particles were classified into three general groups: endogenous, which form naturally in the body; exogenic particles, natural earth materials; and anthropogenic particles, attributed to industrial sources. These in situ results were compared with those using conventional sodium hypochlorite tissue digestion and particle filtration. With the exception of clays and phosphates, the relative abundances of most common particle types were similar in both approaches. Nonetheless, the digestion/filtration method was determined to alter the texture and relative abundances of some particle types. SEM/EDS analysis of digestion filters could be automated in contrast to the more time intensive in situ analyses.

Effect of Lithium Preparations on Cerebral Electrophysiological Activity in Rats.

The study examined the effects of a novel neurotropic medication based on a lithium complex composed of lithium citrate, polymethylsiloxane, and aluminum oxide on electrophysiological parameters of the rat brain. In contrast to lithium carbonate (the reference drug), the novel preparation resulted in a wave-like dynamics of electrical activity in the visual cortex. Rhythmic photic stimulation of the rats treated with lithium carbonate resulted in appearance of the signs attesting to up-regulation of excitability of cerebral cortex in all examined ranges. In contrast, the complex lithium preparation diminished the delta power spectrum, which was the only affected frequency band. It is hypothesized that the complex lithium medication induces milder activation of the cerebral cortex in comparison with lithium carbonate. The novel medication composed of lithium citrate, aluminum oxide, and polymethylsiloxane, is characterized by greater efficacy and safety than the preparation based on inorganic lithium salt (lithium carbonate).

Major histocompatibility complex-linked social signalling affects female fertility.

Genes of the major histocompatibility complex (MHC) have been shown to influence social signalling and mate preferences in many species, including humans. First observations suggest that MHC signalling may also affect female fertility. To test this hypothesis, we exposed 191 female horses (Equus caballus) to either an MHC-similar or an MHC-dissimilar stimulus male around the time of ovulation and conception. A within-subject experimental design controlled for non-MHC-linked male characteristics, and instrumental insemination with semen of other males (n = 106) controlled for potential confounding effects of semen or embryo characteristics. We found that females were more likely to become pregnant if exposed to an MHC-dissimilar than to an MHC-similar male, while overall genetic distance to the stimulus males (based on microsatellite markers on 20 chromosomes) had no effect. Our results demonstrate that early pregnancy failures can be due to maternal life-history decisions (cryptic female choice) influenced by MHC-linked social signalling.

Pseudo-peptide amyloid-ß blocking inhibitors: molecular dynamics and single molecule force spectroscopy study.

By combining MD simulations and AFS experimental technique, we demonstrated a powerful approach for rational design and single molecule testing of novel inhibitor molecules which can block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. We designed and tested novel pseudo-peptide amyloid-ß (Aß) inhibitors that bind to the Aß peptide and effectively prevent amyloid-amyloid binding. First, molecular dynamics (MD) simulations have provided information on the structures and binding characteristics of the designed pseudo-peptides targeting amyloid fragment Aß (13-23). The binding affinities between the inhibitor and Aß as well as the inhibitor to itself have been estimated using Umbrella Sampling calculations. Atomic Force Spectroscopy (AFS) was used to experimentally test several proposed inhibitors in their ability to block amyloid-amyloid binding - the first step of toxic amyloid oligomer formation. The experimental AFS data are in a good agreement with theoretical MD calculations and demonstrate that three proposed pseudo-peptides bind to amyloid fragment with different affinities and all effectively prevent Aß-Aß binding in similar way. We propose that the designed pseudo-peptides can be used as potential drug candidates to prevent Aß toxicity in Alzheimer's disease.

Childhood atopy and mental health: a prospective, longitudinal investigation.

BACKGROUND: Prior studies have suggested a relationship between atopy and mental health, although methodological barriers have limited the generalizability of these findings. The objective of this study was to investigate the relationship between early-life atopy and vulnerability to mental health problems among youth in the community. METHOD: Data were drawn from the Raine Study (N = 2868), a population-based birth cohort study in Western Australia. Logistic regression and generalized estimating equations were used to examine the relationship between atopy at ages 1-5 years [using parent report and objective biological confirmation (sera IgE)], and the range of internalizing and externalizing mental health problems at ages 5-17 years. RESULTS: Atopy appears to be associated with increased vulnerability to affective and anxiety problems, compared to youth without atopy. These associations remained significant after adjusting for a range of potential confounders. No relationship was evident between atopy and attention deficit hyperactivity disorder or externalizing problems. CONCLUSIONS: Findings are the first linking atopy (measured by both parent report and objective verification) with increased vulnerability to affective and anxiety problems. Therefore, replication is required. If replicated, future research aimed at understanding the possible biological and/or social and environmental pathways underlying these links is needed. Such information could shed light on shared pathways that could lead to more effective treatments for both atopy and internalizing mental health problems.

Land use change impacts on floods at the catchment scale: Challenges and opportunities for future research.

Research gaps in understanding flood changes at the catchment scale caused by changes in forest management, agricultural practices, artificial drainage, and terracing are identified. Potential strategies in addressing these gaps are proposed, such as complex systems approaches to link processes across time scales, long-term experiments on physical-chemical-biological process interactions, and a focus on connectivity and patterns across spatial scales. It is suggested that these strategies will stimulate new research that coherently addresses the issues across hydrology, soil and agricultural sciences, forest engineering, forest ecology, and geomorphology.