Relaxation dynamics in excited helium nanodroplets probed with high resolution, time-resolved photoelectron spectroscopy.

Superfluid helium nanodroplets are often considered as transparent and chemically inert nanometer-sized cryo-matrices for high-resolution or time-resolved spectroscopy of embedded molecules and clusters. On the other hand, when the helium nanodroplets are resonantly excited with XUV radiation, a multitude of ultrafast processes are initiated, such as relaxation into metastable states, formation of nanoscopic bubbles or excimers, and autoionization channels generating low-energy free electrons. Here, we discuss the full spectrum of ultrafast relaxation processes observed when helium nanodroplets are electronically excited. In particular, we perform an in-depth study of the relaxation dynamics occurring in the lowest 1s2s and 1s2p droplet bands using high resolution, time-resolved photoelectron spectroscopy. The simplified excitation scheme and improved resolution allow us to identify the relaxation into metastable triplet and excimer states even when exciting below the droplets' autoionization threshold, unobserved in previous studies.

GenePy - a score for estimating gene pathogenicity in individuals using next-generation sequencing data.

BACKGROUND: Next-generation sequencing is revolutionising diagnosis and treatment of rare diseases, however its application to understanding common disease aetiology is limited. Rare disease applications binarily attribute genetic change(s) at a single locus to a specific phenotype. In common diseases, where multiple genetic variants within and across genes contribute to disease, binary modelling cannot capture the burden of pathogenicity harboured by an individual across a given gene/pathway. We present GenePy, a novel gene-level scoring system for integration and analysis of next-generation sequencing data on a per-individual basis that transforms NGS data interpretation from variant-level to gene-level. This simple and flexible scoring system is intuitive and amenable to integration for machine learning, network and topological approaches, facilitating the investigation of complex phenotypes. RESULTS: Whole-exome sequencing data from 508 individuals were used to generate GenePy scores. For each variant a score is calculated incorporating: i) population allele frequency estimates; ii) individual zygosity, determined through standard variant calling pipelines and; iii) any user defined deleteriousness metric to inform on functional impact. GenePy then combines scores generated for all variants observed into a single gene score for each individual. We generated a matrix of ~ 14,000 GenePy scores for all individuals for each of sixteen popular deleteriousness metrics. All per-gene scores are corrected for gene length. The majority of genes generate GenePy scores < 0.01 although individuals harbouring multiple rare highly deleterious mutations can accumulate extremely high GenePy scores. In the absence of a comparator metric, we examine GenePy performance in discriminating genes known to be associated with three common, complex diseases. A Mann-Whitney U test conducted on GenePy scores for this positive control gene in cases versus controls demonstrates markedly more significant results (p = 1.37 × 10- 4) compared to the most commonly applied association tool that combines common and rare variation (p = 0.003). CONCLUSIONS: Per-gene per-individual GenePy scores are intuitive when assessing genetic variation in individual patients or comparing scores between groups. GenePy outperforms the currently accepted best practice tools for combining common and rare variation. GenePy scores are suitable for downstream data integration with transcriptomic and proteomic data that also report at the gene level.

Serum Beta Hydroxybutyrate Concentrations in Cats with Chronic Kidney Disease, Hyperthyroidism, or Hepatic Lipidosis.

BACKGROUND: Ketones, including beta hydroxybutyrate (BHB), are produced in conditions of negative energy balance and decreased glucose utilization. Serum BHB concentrations in cats are poorly characterized in diseases other than diabetes mellitus. HYPOTHESIS: Serum BHB concentrations will be increased in cats with chronic kidney disease (CKD), hyperthyroidism (HT), or hepatic lipidosis (HL). ANIMALS: Twenty-eight client-owned cats with CKD, 34 cats with HT, and 15 cats with HL; 43 healthy cats. METHODS: Prospective observational study. Serum BHB concentrations were measured at admission in cats with CKD, HT, and HL, for comparison with a reference interval established using healthy cats. Results of dipstick urine ketone measurement, when available, were compared to BHB measurement. RESULTS: Beta hydroxybutyrate was above the reference interval (<0.11 mmol/L) in 6/28 cats (21%) with CKD, 7/34 cats (20%) with HT, and 11/15 cats (73%) with HL, significantly exceeding the expected 2.5% above the reference interval for healthy cats (P < .001 for all groups). Elevations were mild in CKD and HT groups (median BHB 0.1 mmol/L for both groups, 80th percentile 0.12 and 0.11 mmol/L, respectively), but more marked in HL cats (median BHB 0.2 mmol/L, 80th percentile 0.84 mmol/L). None of 11 cats with increased serum BHB concentration having urine dipstick analysis performed within 24 h of sampling for BHB were ketonuric. CONCLUSIONS AND CLINICAL IMPORTANCE: Increases in serum BHB concentrations occur in cats with CKD, HT, and HL, and might provide an useful index of catabolism.

A critical hybrid realist-outcomes systematic review of relationships between medical education programmes and communities: BEME Guide No. 35.

BACKGROUND: The relationships between medical schools and communities have long inspired and troubled medical education programmes. Successive models of community-oriented, community-based and community-engaged medical education have promised much and delivered to varying degrees. A two-armed realist systematic review was undertaken to explore and synthesize the evidence on medical school-community relationships. METHOD: One arm used standard outcomes criteria (Kirkpatrick levels), the other a realist approach seeking out the underlying contexts, mechanisms and outcomes. 38 reviewers completed 489 realist reviews and 271 outcomes reviews; 334 articles were reviewed in the realist arm and 181 in the outcomes arm. Analyses were based on: descriptive statistics on both articles and reviews; the outcomes involved; the quality of the evidence presented; realist contexts, mechanisms, and outcomes; and an analysis of underlying discursive themes. FINDINGS: The literature on medical school-community relationships is heterogeneous and largely idiographic, with no common standards for what a community is, who represents communities, what a relationship is based on, or whose needs are or should be being addressed or considered. CONCLUSIONS: Community relationships can benefit medical education, even if it is not always clear why or how. There is much opportunity to improve the quality and precision of scholarship in this area.

Variance components analyses of multiple asthma traits in a large sample of Australian families ascertained through a twin proband.

BACKGROUND: Intermediate phenotypes are often measured as a proxy for asthma. It is largely unclear to what extent the same set of environmental or genetic factors regulate these traits. OBJECTIVE: Estimate the environmental and genetic correlations between self-reported and clinical asthma traits. METHODS: A total of 3,073 subjects from 802 families were ascertained through a twin proband. Traits measured included self-reported asthma, airway histamine responsiveness (AHR), skin prick response to common allergens including house dust mite (Dermatophagoides pteronyssinus [D. pter]), baseline lung function, total serum immunoglobulin E (IgE) and eosinophilia. Bivariate and multivariate analyses of eight traits were performed with adjustment for ascertainment and significant covariates. RESULTS: Overall 2,716 participants completed an asthma questionnaire and 2,087 were clinically tested, including 1,289 self-reported asthmatics (92% previously diagnosed by a doctor). Asthma, AHR, markers of allergic sensitization and eosinophilia had significant environmental correlations with each other (range: 0.23-0.89). Baseline forced expiratory volume in 1 s (FEV(1)) showed low environmental correlations with most traits. Fewer genetic correlations were significantly different from zero. Phenotypes with greatest genetic similarity were asthma and atopy (0.46), IgE and eosinophilia (0.44), AHR and D. pter (0.43) and AHR and airway obstruction (-0.43). Traits with greatest genetic dissimilarity were FEV(1) and atopy (0.05), airway obstruction and IgE (0.07) and FEV(1) and D. pter (0.11). CONCLUSION: These results suggest that the same set of environmental factors regulates the variation of many asthma traits. In addition, although most traits are regulated to great extent by specific genetic factors, there is still some degree of genetic overlap that could be exploited by multivariate linkage approaches.

Postnatal depression across countries and cultures: a qualitative study.

BACKGROUND: Postnatal depression seems to be a universal condition with similar rates in different countries. However, anthropologists question the cross-cultural equivalence of depression, particularly at a life stage so influenced by cultural factors. AIMS: To develop a qualitative method to explore whether postnatal depression is universally recognised, attributed and described and to enquire into people's perceptions of remedies and services for morbid states of unhappiness within the context of local services. METHOD: The study took place in 15 centres in 11 countries and drew on three groups of informants: focus groups with new mothers, interviews with fathers and grandmothers, and interviews with health professionals. Textual analysis of these three groups was conducted separately in each centre and emergent themes compared across centres. RESULTS: All centres described morbid unhappiness after childbirth comparable to postnatal depression but not all saw this as an illness remediable by health interventions. CONCLUSIONS: Although the findings of this study support the universality of a morbid state of unhappiness following childbirth, they also support concerns about the cross-cultural equivalence of postnatal depression as an illness requiring the intervention of health professionals; this has implications for future research.

Adaptation of the structured clinical interview for DSM-IV disorders for assessing depression in women during pregnancy and post-partum across countries and cultures.

BACKGROUND: To date, no study has used standardised diagnostic assessment procedures to determine whether rates of perinatal depression vary across cultures. AIMS: To adapt the Structured Clinical Interview for DSM-IV Disorders (SCID) for assessing depression and other non-psychotic psychiatric illness perinatally and to pilot the instrument in different centres and cultures. METHOD: Assessments using the adapted SCID and the Edinburgh Postnatal Depression Scale were conducted during the third trimester of pregnancy and at 6 months postpartum with 296 women from ten sites in eight countries. Point prevalence rates during pregnancy and the postnatal period and adjusted 6-month period prevalence rates were computed for caseness, depression and major depression. RESULTS: The third trimester and 6-month point prevalence rates for perinatal depression were 6.9% and 8.0%, respectively. Postnatal 6-month period prevalence rates for perinatal depression ranged from 2.1% to 31.6% across centres and there were significant differences in these rates between centres. CONCLUSIONS: Study findings suggest that the SCID was successfully adapted for this context. Further research on determinants of differences in prevalence of depression across cultures is needed.

Contextual Assessment of the Maternity Experience: development of an instrument for cross-cultural research.

BACKGROUND: There is evidence that stressors may trigger the onset of a depressive episode in vulnerable women. A new UK interview measure, the Contextual Assessment of the Maternity Experience (CAME), was designed to assess major risk factors for emotional disturbances, especially depression, during pregnancy and post-partum. AIMS: With in the context of a cross-cultural study, to establish the usefulness of the CAME, and to test expected associations of the measure with characteristics of the social context and with major or minor depression. METHOD: The CAME was administered antenatally and postnatally in ten study sites, respectively to 296 and 249 women. Affective disorder throughout pregnancy and up to 6 months postnatally was assessed by means of the Structured Clinical Interview for DSM-IVAxis I Disorders. RESULTS: Adversity, poor relationship with either a partner or a confidant, and negative feelings about the pregnancy all predicted onset of depression during the perinatal period. CONCLUSIONS: The CAME was able to assess major domains relevant to the psychosocial context of the maternity experience in different cultures. Overall, the instrument showed acceptable psychometric properties in its first use in different cultural settings.

Maternal attachment style and depression associated with childbirth: preliminary results from a European and US cross-cultural study.

BACKGROUND: Insecure attachment style relates to major depression in women, but its relationship to depression associated with childbirth is largely unknown. A new UK-designed measure, the Attachment Style Interview (ASI), has potential for cross-cultural use as a risk marker for maternal disorder. AIMS: To establish there liability of the ASI across centres, its stability over a 9-month period, and its associations with social context and major or minor depression. METHOD: The ASI was used by nine centres antenatally on 204 women, with 174 followed up 6 months postnatally. Interrater reliability was tested and the ASI was repeated on a subset of 96 women. Affective disorder was assessed by means of the Structured Clinical Interview for DSM-IV. RESULTS: Satisfactory interrater reliability was achieved with relatively high stability rates at follow-up. Insecure attachment related to lower social class position and more negative social context. Specific associations of avoidant attachment style (angry-dismissive or withdrawn) with antenatal disorder, and anxious style (enmeshed or fearful) with postnatal disorder were found. CONCLUSIONS: The ASI can be used reliably in European and US centres as a measure for risk associated with childbirth. Its use will contribute to theoretically under pinned preventive action for disorders associated with childbirth.

The prevention and psychotherapeutic treatment of postpartum depression.

The efficacy of psychotherapeutic interventions for the acute treatment of postpartum depression is strongly supported by empirical data, which suggest that counseling is of benefit as a stand-alone treatment for postpartum depression. Given the paucity of treatment trials using medication for postpartum depression, and the fact that psychotherapeutic interventions do not confer any "exposure" risks to breastfeeding infants, the data also suggest that psychotherapy should be considered a first-line treatment, rather than as an adjunct to medication treatment. There is also some data supporting the use of psychotherapy as a means of preventing postpartum depression, though research is still needed regarding the type of interventions to be used and the types of patients towards whom the interventions should be directed.

Optimizing off-pump coronary artery bypass graft: technical and metabolic aspects.

PURPOSE: Our purpose was to determine if complete revascularization could be successfully performed off bypass in the majority of coronary artery bypass graft (CABG) patients. METHODS: Using a metabolic protocol and the Medtronic Octopus stabilizer device (Medtronic, Inc., Minneapolis, MN), 285 consecutive patients between July 1, 1997 and July 31, 1999 were successfully revascularized off pump via median sternotomy. A relative contraindication for off bypass CABG was cardiogenic shock. The metabolic protocol was designed to enhance systolic and diastolic cardiac function during surgery. RESULTS: Of 298 patients on whom we attempted off-pump revascularizations, 96% (285/298) were successful. The mean number of grafts per case was 3.3. The mean age of patients was 69.5 years, and 38% (109/285) were 75 years of age or older. Perioperative myocardial infarction (MI) occurred in two patients (0.7%) and operative mortality was 2.8% (8/285). Average Parsonnet score was 4.8. Cost savings were realized through minimal blood product utilization (average 1.5 units per case) and decreased cardiopulmonary bypass supplies. CONCLUSION: Complete revascularization can be performed off bypass in the majority of CABG patients. The concomitant use of the Octopus off-bypass technique with aggressive metabolic support ensures manual manipulation of a beating heart and results in a low incidence of postoperative complications and significant cost savings.

6-hydroxydopamine-induced lesions of dopaminergic neurons alter the function of postsynaptic cholinergic neurons without changing cytoskeletal proteins.

The neuropathological hallmarks of many neurodegenerative diseases are intraneuronal inclusions containing cytoskeletal proteins such as neurofilaments in Lewy bodies in Parkinson's disease and tau in neurofibrillary tangles in Alzheimer's disease. Dysfunction in dopaminergic and cholinergic systems also exist in both Alzheimer's disease and Parkinson's disease. Because the primary pathology in Parkinson's disease is localized to the dopaminergic system, we set out to determine if perturbations in cholinergic systems are a consequence of dopaminergic neuron loss. Therefore, following intracerebral microinjections of 6-hydroxydopamine in rats, the activity of cholinergic neurons was measured by hemicholinium binding in cholinergic terminal fields and perturbations in cytoskeletal proteins were examined in dopaminoceptive neurons using immunocytochemistry. The 6-hydroxydopamine injections robustly reduced the number of monoaminergic cell bodies in the lateral midbrain and dramatically decreased dopamine and its major metabolites in dopaminergic projection sites. This treatment increased hemicholinium binding in the prefrontal cortex (200%) and amygdala (284%); however, despite previous reports to the contrary, there were no increases in immunoreactivity for phosphorylated neurofilaments, microtubule-associated protein (MAP) 2, tau or paired helical filament (PHF) tau. This lack of an increase in cytoskeletal proteins was observed following either injections of moderate doses of the toxin directly into the medial forebrain bundle or after high doses were administered intracerebroventricularly. These results suggest that removal of dopaminergic inputs to the forebrain results in hyperactivity of the cholinergic systems but is not sufficient to induce postsynaptic perturbations in cytoskeletal proteins which occur in neurodegenerative diseases.

Directed gene modification via triple helix formation.

The ability to selectively target mammalian genes and disrupt or restore their function would represent an important advance in gene therapy. Mutation of a single nucleotide can often result in a non-functional gene product. Reversion of defective genes to their correct sequences could lead to permanent cures for patients with many genetic diseases. Molecules such as triplex forming oligonucleotides (TFOs) and peptide nucleic acids (PNAs) are currently being employed to bind to double-stranded DNA. Efficient targeting of genomic DNA with these molecules will be the initial step in gene modification.

Efficacy of interpersonal psychotherapy for postpartum depression.

BACKGROUND: Postpartum depression causes women great suffering and has negative consequences for their social relationships and for the development of their infants. Research is needed to evaluate the efficacy of psychotherapy for postpartum depression. METHODS: A total of 120 postpartum women meeting DSM-IV criteria for major depression were recruited from the community and randomly assigned to 12 weeks of interpersonal psychotherapy (IPT) or to a waiting list condition (WLC) control group. Subjects completed interview and self-report assessments of depressive symptoms and social adjustment every 4 weeks. RESULTS: Ninety-nine of the 120 patients completed the protocol. Hamilton Rating Scale for Depression (HRSD) scores of women receiving IPT declined from 19.4 to 8.3, a significantly greater decrease than occurred in the WLC group (19.8 to 16.8). The Beck Depression Inventory (BDI) scores of women who received IPT declined from 23.6 to 10.6 over 12 weeks, a significantly greater decrease than occurred in the WLC group (23.0 to 19.2). A significantly greater proportion of women who received IPT recovered from their depressive episode based on HRSD scores of 6 or lower (37. 5%) and BDI scores of 9 or lower (43.8%) compared with women in the WLC group (13.7% and 13.7%, respectively). Women receiving IPT also had significant improvement on the Postpartum Adjustment Questionnaire and the Social Adjustment Scale-Self-Report relative to women in the WLC group. CONCLUSIONS: These findings suggest that IPT is an efficacious treatment for postpartum depression. Interpersonal psychotherapy reduced depressive symptoms and improved social adjustment, and represents an alternative to pharmacotherapy, particularly for women who are breastfeeding.

Restoration of correct splicing of thalassemic beta-globin pre-mRNA by modified U1 snRNAs.

The T-->G mutation at nucleotide 705 in the second intron of the beta-globin gene creates an aberrant 5' splice site and activates a 3' cryptic splice site upstream from the mutation. As a result, the IVS2-705 pre-mRNA is spliced via the aberrant splice sites leading to a deficiency of beta-globin mRNA and protein and to the genetic blood disorder thalassemia. We have shown previously that in cell culture models of thalassemia, aberrant splicing of beta-thalassemic IVS2-705 pre-mRNA was permanently corrected by a modified murine U7 snRNA that incorporated sequences antisense to the splice sites activated by the mutation. To explore the possibility of using other snRNAs as vectors for antisense sequences, U1 snRNA was modified in a similar manner. Replacement of the U1 9-nucleotide 5' splice site recognition sequence with nucleotides complementary to the aberrant 5' splice site failed to correct splicing of IVS2-705 pre-mRNA. In contrast, U1 snRNA targeted to the cryptic 3' splice site was effective. A hybrid with a modified U7 snRNA gene under the control of the U1 promoter and terminator sequences resulted in the highest levels of correction (up to 70%) in transiently and stably transfected target cells.

Melanocortin-1 receptor polymorphisms and risk of melanoma: is the association explained solely by pigmentation phenotype?

Risk of cutaneous malignant melanoma (CMM) is increased in sun-exposed whites, particularly those with a pale complexion. This study was designed to investigate the relationship of the melanocortin-1 receptor (MC1R) genotype to CMM risk, controlled for pigmentation phenotype. We report the occurrence of five common MC1R variants in an Australian population-based sample of 460 individuals with familial and sporadic CMM and 399 control individuals-and their relationship to such other risk factors as skin, hair, and eye color; freckling; and nevus count. There was a strong relationship between MC1R variants and hair color and skin type. Moreover, MC1R variants were found in 72% of the individuals with CMM, whereas only 56% of the control individuals carried at least one variant (P<.001), a finding independent of strength of family history of melanoma. Three active alleles (Arg151Cys, Arg160Trp, and Asp294His), previously associated with red hair, doubled CMM risk for each additional allele carried (odds ratio 2.0; 95% confidence interval 1. 6-2.6). No such independent association could be demonstrated with the Val60Leu and Asp84Glu variants. Among pale-skinned individuals alone, this association between CMM and MC1R variants was absent, but it persisted among those reporting a medium or olive/dark complexion. We conclude that the effect that MC1R variant alleles have on CMM is partly mediated via determination of pigmentation phenotype and that these alleles may also negate the protection normally afforded by darker skin coloring in some members of this white population.

An outbreak of Serratia marcescens in two neonatal intensive care units.

Outbreaks of infection in neonatal intensive care units (NICUs) due to Serratia marcescens are well recognized. In some outbreaks no point source has been found, whereas in others cross-infection has been associated with contaminated ventilator equipment, disinfectants, hands and breast pumps. We report an outbreak due to S. marcescens that involved two geographically distinct NICUs. The outbreak occurred over a six week period; 17 babies were colonized, 12 at Glasgow Royal Maternity Hospital (GRMH) and five at the Queen Mothers Hospital (QMH). At GRMH three babies developed septicaemia, of whom two died. The outbreak isolates were of the same serotype and phage type and were indistinguishable on the basis of restriction fragment length polymorphism analysis. During the outbreak, two babies shown consistently to be negative on screening, were transferred between the two units. In addition, two members of medical staff attended both units. In QMH no means of cross infection was identified. However, in GRMH the outbreak strain of S. marcescens was isolated from a laryngoscope blade and a sample of expressed breast milk.

Perceptual variation in categorizing individuals according to American College of Rheumatology classification criteria for hand, knee, and hip osteoarthritis (OA): observations based on an Australian Twin Registry study of OA.

OBJECTIVE: The American College of Rheumatology (ACR) classification criteria for osteoarthritis (OA) permit the categorization of individuals for hand, knee, and hip OA and are of defined sensitivity and specificity. They depend on both clinical and radiographic aspects of OA. The clinical diagnosis of OA in the peripheral skeleton is dependent on the skilled examination of several clinical features characteristic of the condition, while the interpretation of radiographs is a perceptual skill based on appreciating specific structural features on plain radiographs. We investigated the interrater reliability of the ACR classification criteria for OA when applied in a community based sample. METHODS: The study was part of a multifaceted diagnostics protocol, evaluating methodologic issues, in the conduct of genetic research in OA. From a cohort of 118 pairs of twins registered with the Australian Twins Registry (ATR), standard clinical examinations of hands, knees, and hips were performed on 74 complete and 11 incomplete pairs of twins over age 50 years. The pairs were selected to represent both twin pairs who had previously self-reported a diagnosis of OA, as well as those who had not. Rheumatologists who performed the assessments were blind to the original self-report. All subjects were examined independently by one of 2 pairs (NB/AK or NB/KM) of consultant rheumatologists, blind to one another's assessments. Each rheumatologist separately assessed the hands, knees, and hips, rating them clinically by ACR criteria for OA. The observations were made without reference to any radiographic or serologic information. RESULTS: Interrater agreement was different for the 3 different anatomic areas and was different for the 2 pairs of rheumatologists. The actual (observed) interrater agreements based on ACR clinical criteria were as follows: hand OA NB/AK = 0.92, NB/KM = 1.00; knee OA NB/AK = 0.94, NB/KM = 0.92; hip OA NB/AK = 0.98, NB/KM = 0.97. Interrater agreement based on ACR clinical criteria, as assessed by the adjusted kappa statistic, was as follows: hand OA NB/AK = 0.84, NB/KM = 1.00; knee OA NB/AK = 0.87, NB/KM = 0.84; hip OA NB/AK = 0.95, NB/KM = 0.93. CONCLUSION: Since clinical agreement was extremely high in all 3 anatomic sites, and for both pairs of assessors, we conclude that for genetic epidemiology purposes, subjects can be examined by a single experienced rheumatologist using the ACR classification criteria.