Diagnostic accuracy and confusability analyses: an application to the Diagnostic Interview for Genetic Studies.
The dominant, contemporary paradigm for developing and refining diagnoses relies heavily on assessing reliability with kappa coefficients and virtually ignores a core component of psychometric practice: the theory of latent structures. This article describes a psychometric approach to psychiatric nosology that emphasizes the diagnostic accuracy and confusability of diagnostic categories. We apply these methods to the Diagnostic Interview for Genetic Studies (DIGS), a structured psychiatric interview designed by the NIMH Genetics Initiative for genetic studies of schizophrenia and bipolar disorder. Our results show that sensitivity and specificity were excellent for both DSM-III-R and RDC diagnoses of major depression, bipolar disorder, and schizophrenia. In contrast, diagnostic accuracy was substantially lower for subtypes of schizoaffective disorder-especially for the DSM-III-R definitions. Both the bipolar and depressed subtypes of DSM-III-R schizoaffective disorder had excellent specificity but poor sensitivity. The RDC definitions also had excellent specificity but were more sensitive than the DSM-III-R schizoaffective diagnoses. The source of low sensitivity for schizoaffective subtypes differed for the two diagnostic systems. For RDC criteria, the schizoaffective subtypes were frequently confused with one another; they were less frequently confused with other diagnoses. In contrast, the DSM-III-R subtypes were often confused with schizophrenia, but not with each other.


Changes in cholesterol metabolism with dietary cholesterol in children with familial hypercholesterolaemia.
1. Possible defects in cholesterol metabolism were sought in children with familial hypercholesterolaemia. 2. In nine affected children (eight heterozygotes and one homozygote) and in five healthy children, cholesterol synthesis and bile acid synthesis were determined from the excretion of steroids in the faeces during a low cholesterol diet. Cholesterol synthesis of 10.1 +/- 4.4 mg day-1 kg-1 in the hypercholesterolaemic children was similar to that in these and other normal children. Mean bile acid synthesis of 4.0 +/- 2.1 mg day-1 kg-1 also resembled normal values though three severely affected heterozygotes excreted substantially less. 3. The response to 4 weeks' additional 450 mg of dietary cholesterol/day led to variable changes in the plasma cholesterol and in the sterol balance. On average the affected children showed a rise in plasma cholesterol which resembled that in healthy subjects. The sterol balance fell in most, suggesting a reduction in cholesterol synthesis, which is the normal response to dietary cholesterol. 4. The response to dietary cholesterol was therefore at least qualitatively similar in the hypercholesterolaemic children to that reported in healthy subjects.


Validity of Teleneuropsychological Assessment in Older Patients with Cognitive Disorders.
The feasibility and reliability of neuropsychological assessment at a distance have been demonstrated, but the validity of this testing medium has not been adequately demonstrated. The purpose of this study was to determine the ability of video teleconferencing administration of neuropsychological measures (teleneuropsychology) in discriminating cognitively impaired from non-impaired groups of older adults. It was predicted that measures administered via video teleconference would distinguish groups and that the magnitude of differences between impaired and non-impaired groups would be similar to group differences achieved in traditional administration. The sample consisted of 197 older subjects, separated into two groups, with and without cognitive impairment. The cognitive impairment group included 78 individuals with clinical diagnoses of mild cognitive impairment or Alzheimer's disease. All participants completed counterbalanced neuropsychological testing using alternate test forms in both a teleneuropsychology and a traditional face-to-face (FTF) administration condition. Tests were selected based upon their common use in dementia evaluations, brevity, and assessment of multiple cognitive domains. Results from FTF and teleneuropsychology test conditions were compared using individual repeated measures ANCOVA, controlling for age, education, gender, and depression scores. All ANCOVA models revealed significant main effects of group and a non-significant interaction between group and administration condition. All ANCOVA models revealed non-significant main effects for administration condition, except category fluency. Results derived from teleneuropsychologically administered tests can distinguish between cognitively impaired and non-impaired individuals similar to traditional FTF assessment. This adds to the growing teleneuropsychology literature by supporting the validity of remote assessments in aging populations.


Crystal structure of post-perovskite-type CaIrO3 reinvestigated: new insights into atomic thermal vibration behaviors.
Single crystals of the title compound, the post-perovskite-type CaIrO3 [calcium iridium(IV) trioxide], have been grown from a CaCl2 flux at atmospheric pressure. The crystal structure consists of an alternate stacking of IrO6 octa-hedral layers and CaO8 hendeca-hedral layers along [010]. Chains formed by edge-sharing of IrO6 octa-hedra (point-group symmetry 2/m..) run along [100] and are inter-connected along [001] by sharing apical O atoms to build up the IrO6 octa-hedral layers. Chains formed by face-sharing of CaO8 hendeca-hedra (point-group symmetry m2m) run along [100] and are inter-connected along [001] by edge-sharing to build up the CaO8 hendeca-hedral layers. The IrO6 octa-hedral layers and CaO8 hendeca-hedral layers are inter-connected by sharing edges. The present structure refinement using a high-power X-ray source confirms the atomic positions determined by Hirai et al. (2009 ▸) [Z. Kristallogr. 224, 345-350], who had revised our previous report [Sugahara et al. (2008 ▸). Am. Mineral. 93, 1148-1152]. However, the displacement ellipsoids of the Ir and Ca atoms based on the present refinement can be approximated as uniaxial ellipsoids elongating along [100], unlike those reported by Hirai et al. (2009 ▸). This suggests that the thermal vibrations of the Ir and Ca atoms are mutually suppressed towards the Ir⋯Ca direction across the shared edge because of the dominant repulsion between the two atoms.


BNT162b2 COVID-19 vaccine and correlates of humoral immune responses and dynamics: a prospective, single-centre, longitudinal cohort study in health-care workers.
Concurrent with the Pfizer-BioNTech BNT162b2 COVID-19 vaccine roll-out in Israel initiated on Dec 19, 2020, we assessed the early antibody responses and antibody kinetics after each vaccine dose in health-care workers of different ages and sexes, and with different comorbidities. We did a prospective, single-centre, longitudinal cohort study at the Sheba Medical Centre (Tel-Hashomer, Israel). Eligible participants were health-care workers at the centre who had a negative anti-SARS-CoV-2 IgG assay before receiving the first dose of the intramuscular vaccine, and at least one serological antibody test after the first dose of the vaccine. Health-care workers with a positive SARS-CoV-2 PCR test before vaccination, a positive anti-SARS-CoV-2 IgG serology test before vaccination, or infection with COVID-19 after vaccination were excluded from the study. Participants were followed up weekly for 5 weeks after the first vaccine dose; a second dose was given at week 3. Serum samples were obtained at baseline and at each weekly follow-up, and antibodies were tested at 1-2 weeks after the first vaccine dose, at week 3 with the administration of the second vaccine dose, and at weeks 4-5 (ie, 1-2 weeks after the second vaccine dose). Participants with comorbidities were approached to participate in an enriched comorbidities subgroup, and at least two neutralising assays were done during the 5 weeks of follow-up in those individuals. IgG assays were done for the entire study population, whereas IgM, IgA, and neutralising antibody assays were done only in the enriched comorbidities subgroup. Concentrations of IgG greater than 0·62 sample-to-cutoff (s/co) ratio and of IgA greater than 1·1 s/co, and titres of neutralising antibodies greater than 10 were considered positive. Scatter plot and correlation analyses, logistic and linear regression analyses, and linear mixed models were used to investigate the longitudinal antibody responses. Between Dec 19, 2020, and Jan 30, 2021, we obtained 4026 serum samples from 2607 eligible, vaccinated participants. 342 individuals were included in the enriched comorbidities subgroup. The first vaccine dose elicited positive IgG and neutralising antibody responses at week 3 in 707 (88·0%) of 803 individuals, and 264 (71·0%) of 372 individuals, respectively, which were rapidly increased at week 4 (ie, 1 week after the second vaccine dose) in 1011 (98·4%) of 1027 and 357 (96·5%) of 370 individuals, respectively. Over 4 weeks of follow-up after vaccination, a high correlation (r=0·92) was detected between IgG against the receptor-binding domain and neutralising antibody titres. First-dose induced IgG response was significantly lower in individuals aged 66 years and older (ratio of means 0·25, 95% CI 0·19-0·31) and immunosuppressed individuals (0·21, 0·14-0·31) compared with individuals aged 18·00-45·99 years and individuals with no immunosuppression, respectively. This disparity was partly abrogated following the second dose. Overall, endpoint regression analysis showed that lower antibody concentrations were consistently associated with male sex (ratio of means 0·84, 95% CI 0·80-0·89), older age (ie, ≥66 years; 0·64, 0·58-0·71), immunosuppression (0·44, 0·33-0·58), and other specific comorbidities: diabetes (0·88, 0·79-0·98), hypertension (0·90, 0·82-0·98), heart disease (0·86, 0·75-1·00), and autoimmune diseases (0·82, 0·73-0·92). BNT162b2 vaccine induces a robust and rapid antibody response. The significant correlation between receptor-binding domain IgG antibodies and neutralisation titres suggests that IgG antibodies might serve as a correlate of neutralisation. The second vaccine dose is particularly important for older and immunosuppressed individuals, highlighting the need for timely second vaccinations and potentially a revaluation of the long gap between doses in some countries. Antibody responses were reduced in susceptible populations and therefore they might be more prone to breakthrough infections. Sheba Medical Center, Israel Ministry of Health.


Novel viral vectors utilizing intron splice-switching to activate genome rescue, expression and replication in targeted cells.
The outcome of virus infection depends from the precise coordination of viral gene expression and genome replication. The ability to control and regulate these processes is therefore important for analysis of infection process. Viruses are also useful tools in bio- and gene technology; they can efficiently kill cancer cells and trigger immune responses to tumors. However, the methods for constructing tissue- or cell-type specific viruses typically suffer from low target-cell specificity and a high risk of reversion. Therefore novel and universal methods of regulation of viral infection are also important for therapeutic application of virus-based systems. Aberrantly spliced introns were introduced into crucial gene-expression units of adenovirus vector and alphavirus DNA/RNA layered vectors and their effects on the viral gene expression, replication and/or the release of infectious genomes were studied in cell culture. Transfection of the cells with splice-switching oligonucleotides was used to correct the introduced functional defect(s). It was demonstrated that viral gene expression, replication and/or the release of infectious genomes can be blocked by the introduction of aberrantly spliced introns. The insertion of such an intron into an adenovirus vector reduced the expression of the targeted gene more than fifty-fold. A similar insertion into an alphavirus DNA/RNA layered vector had a less dramatic effect; here, only the release of the infectious transcript was suppressed but not the subsequent replication and spread of the virus. However the insertion of two aberrantly spliced introns resulted in an over one hundred-fold reduction in the infectivity of the DNA/RNA layered vector. Furthermore, in both systems the observed effects could be reverted by the delivery of splice-switching oligonucleotide(s), which corrected the splicing defects. Splice-switch technology, originally developed for genetic disease therapy, can also be used to control gene expression of viral vectors. This approach represents a novel, universal and powerful method for controlling gene expression, replication, viral spread and, by extension, virus-induced cytotoxic effects and can be used both for basic studies of virus infection and in virus-based gene- and anti-cancer therapy.


ACE and ACE2 activity in diabetic mice.
ACE-related carboxypeptidase (ACE2) may counterbalance the angiotensin (ANG) II-promoting effects of ACE in tissues where both enzymes are found. Alterations in renal ACE and ACE2 expression have been described in experimental models of diabetes, but ACE2 activity was not assessed in previous studies. We developed a microplate-based fluorometric method for the concurrent determination of ACE and ACE2 activity in tissue samples. Enzymatic activity (relative fluorescence unit [RFU] . microg protein(-1) . h(-1)) was examined in ACE and ACE2 knockout mice and in two rodent models of diabetes, the db/db and streptozotocin (STZ)-induced diabetic mice. In kidney cortex, preparations consisting mainly of proximal tubules and cortical collecting tubules, ACE2 activity had a strong positive correlation with ACE2 protein expression (90-kDa band) in both knockout models and their respective wild-type littermates (r = 0.94, P < 0.01). ACE activity, likewise, had a strong positive correlation with renal cortex ACE protein expression (170-kDa band) (r = 0.838, P < 0.005). In renal cortex, ACE2 activity was increased in both models of diabetes (46.7 +/- 4.4 vs. 22.0 +/- 4.7 in db/db and db/m, respectively, P < 0.01, and 22.1 +/- 2.8 vs. 13.1 +/- 1.5 in STZ-induced diabetic versus untreated mice, respectively, P < 0.05). ACE2 mRNA levels in renal cortex from db/db and STZ-induced diabetic mice, by contrast, were not significantly different from their respective controls. In cardiac tissue, ACE2 activity was lower than in renal cortex, and there were no significant differences between diabetic and control mice (db/db 2.03 +/- 0.23 vs. db/m 1.85 +/- 0.10; STZ-induced diabetic 0.42 +/- 0.04 vs. untreated 0.52 +/- 0.07 mice). ACE2 activity in renal cortex correlated positively with ACE2 protein in db/db and db/m mice (r = 0.666, P < 0.005) as well as in STZ-induced diabetic and control mice (r = 0.621, P < 0.05) but not with ACE2 mRNA (r = -0.468 and r = -0.522, respectively). We conclude that in renal cortex from diabetic mice, ACE2 expression is increased at the posttranscriptional level. The availability of an assay for concurrent measurement of ACE and ACE2 activity should be helpful in the evaluation of kidney-specific alterations in the balance of these two carboxypeptidases, which are involved in the control of local ANG II formation and degradation.


Barriers and facilitators to the implementation of brief interventions targeting smoking, nutrition, and physical activity for indigenous populations: a narrative review.
This narrative review aimed to identify and categorize the barriers and facilitators to the provision of brief intervention and behavioral change programs that target several risk behaviors among the Indigenous populations of Australia, Canada, and New Zealand. A systematic database search was conducted of six databases including PubMeD, Embase, CINAHL, HealthStar, PsycINFO, and Web of Science. Thematic analysis was utilized to analyze qualitative data extracted from the included studies, and a narrative approach was employed to synthesize the common themes that emerged. The quality of studies was assessed in accordance with the Joanna Briggs Institute's guidelines and using the software SUMARI - The System for the Unified Management, Assessment and Review of Information. Nine studies were included. The studies were classified at three intervention levels: (1) individual-based brief interventions, (2) family-based interventions, and (3) community-based-interventions. Across the studies, selection of the intervention level was associated with Indigenous priorities and preferences, and approaches with Indigenous collaboration were supported. Barriers and facilitators were grouped under four major categories representing the common themes: (1) characteristics of design, development, and delivery, (2) patient/provider relationship, (3) environmental factors, and (4) organizational capacity and workplace-related factors. Several sub-themes also emerged under the above-mentioned categories including level of intervention, Indigenous leadership and participation, cultural appropriateness, social and economic barriers, and design elements. To improve the effectiveness of multiple health behavior change interventions among Indigenous populations, collaborative approaches that target different intervention levels are beneficial. Further research to bridge the knowledge gap in this topic will help to improve the quality of preventive health strategies to achieve better outcomes at all levels, and will improve intervention implementation from development and delivery fidelity, to acceptability and sustainability.


Study of Tourniquet Use in Simulated First Aid: User Judgment.
The purpose of this study was to survey the judgments of tourniquet users in simulation to discern opportunities for further study. The study design constituted two parts: questions posed to four tourniquet users and then their tourniquet use was surveyed in simulated first aid, where the users had to decide how to perform among five different cases. The questions addressed judged confidence, blood volumes, a reason bleeding resumes, regret of preventable death, hemorrhage assessment, need for side-by-side use of tourniquets, shock severity, predicting reliability, and difference in blood losses. The mechanical performance was tested on a manikin. Case 1 had no bleeding. Case 2 had limb-wound bleeding that indicated tourniquet use in first aid. Case 3 was like case 2, except the patient was a child. Case 4 was like case 2, except caregiving was under gunfire. Case 5 was like case 4, but two tourniquets were to be used side by side. Each user made tests of the five cases to constitute a block. Each user had three blocks. Case order was randomized within blocks. The study had 60 tests. In answering questions relevant to first-aid use of limb tourniquets, judgments were in line with previous studies of judgment science, and thus were plausibly applicable. Mechanical performance results on the manikin were as follows: 38 satisfactory, 10 unsatisfactory (a loose tourniquet and nine incorrect tourniquet placements), and 12 not applicable (case 1 needed no mechanical intervention). For cases 1 to 5, satisfactory results were: 100%, 83%, 100%, 75%, and 58%, respectively. For blocks 1 to 3, satisfactory results were 50%, 83%, and 83%, respectively. For tourniquet use in simulated first aid, the results are plausibly applicable because user judgments were coherent with those in previous studies of judgment science. However, the opportunities for further studies were noted.


Scholarly communication: cultural contexts, evolving models.
Despite predictions that emerging technologies will transform how research is conducted, disseminated, and rewarded, why do we see so little actual shift in how scholars in the most competitive and aspirant institutions actually disseminate their research? I describe research on faculty values and needs in scholarly communication that confirm a number of conservative tendencies in publishing. These tendencies, influenced by tenure and promotion requirements, as well as disciplinary cultures, have both positive and negative consequences. Rigorous research could inform development of good practices and policies in academic publishing, as well as counter rhetoric concerning the future of peer review and scholarly communication.


HPMA copolymers for masking and retargeting of therapeutic viruses.
Hydrophilic polymers are widely used already for steric stabilisation of bioactive proteins, changing their pharmacokinetics and modifying their interactions with the biological environment. Polymers may also be conjugated to biological surfaces, such as viruses, bacteria and mammalian cells, also to endow steric protection and changed properties. Reactive polymers based on N-[2-hydroxypropyl]methacrylamide have shown particular promise for surface coating of viruses, particularly adenovirus, and here we describe the important observations and innovations arising from this combination of chemical and genetic engineering. Adenovirus is a versatile agent that already finds important experimental applications as a recombinant vaccine, and also for cancer therapy, although its activity in both settings is often limited by a potent antibody-neutralising response in humans that is generally not seen in experimental animals. Coating with HPMA copolymers provides protection against neutralisation by antibodies and complement, and covalent linkage of novel ligands to the surface of the polymer can endow new infectious tropisms, mediated through different receptors, that can expand the potential applications of this versatile technology for a range of settings.


Batch-normalization of cerebellar and medulloblastoma gene expression datasets utilizing empirically defined negative control genes.
Medulloblastoma (MB) is a brain cancer predominantly arising in children. Roughly 70% of patients are cured today, but survivors often suffer from severe sequelae. MB has been extensively studied by molecular profiling, but often in small and scattered cohorts. To improve cure rates and reduce treatment side effects, accurate integration of such data to increase analytical power will be important, if not essential. We have integrated 23 transcription datasets, spanning 1350 MB and 291 normal brain samples. To remove batch effects, we combined the Removal of Unwanted Variation (RUV) method with a novel pipeline for determining empirical negative control genes and a panel of metrics to evaluate normalization performance. The documented approach enabled the removal of a majority of batch effects, producing a large-scale, integrative dataset of MB and cerebellar expression data. The proposed strategy will be broadly applicable for accurate integration of data and incorporation of normal reference samples for studies of various diseases. We hope that the integrated dataset will improve current research in the field of MB by allowing more large-scale gene expression analyses. The RUV-normalized expression data is available through the Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geo/) and can be accessed via the GSE series number GSE124814. Supplementary data are available at Bioinformatics online.


Gender, culture, and sex-typed cognitive abilities.
Although gender differences in cognitive abilities are frequently reported, the magnitude of these differences and whether they hold practical significance in the educational outcomes of boys and girls is highly debated. Furthermore, when gender gaps in reading, mathematics and science literacy are reported they are often attributed to innate, biological differences rather than social and cultural factors. Cross-cultural evidence may contribute to this debate, and this study reports national gender differences in reading, mathematics and science literacy from 65 nations participating in the 2009 round of the Programme for International Student Assessment (PISA). Consistently across all nations, girls outperform boys in reading literacy, d = -.44. Boys outperform girls in mathematics in the USA, d = .22 and across OECD nations, d = .13. For science literacy, while the USA showed the largest gender difference across all OECD nations, d = .14, gender differences across OECD nations were non-significant, and a small female advantage was found for non-OECD nations, d = -.09. Across all three domains, these differences were more pronounced at both tails of the distribution for low- and high-achievers. Considerable cross-cultural variability was also observed, and national gender differences were correlated with gender equity measures, economic prosperity, and Hofstede's cultural dimension of power distance. Educational and societal implications of such gender gaps are addressed, as well as the mechanisms by which gender differences in cognitive abilities are culturally mediated.


Molecular dynamics in mouse atrial tumor sarcoplasmic reticulum.
We have determined directly the effects of the inhibitory peptide phospholamban (PLB) on the rotational dynamics of the calcium pump (Ca-ATPase) of cardiac sarcoplasmic reticulum (SR). This was accomplished by comparing mouse ventricular SR, which has PLB levels similar to those found in other mammals, with mouse atrial SR, which is effectively devoid of PLB and thus has much higher (unregulated) calcium pump activity. To obtain sufficient quantities of atrial SR, we isolated the membranes from atrial tumor cells. We used time-resolved phosphorescence anisotropy of an erythrosin isothiocyanate label attached selectively and rigidly to the Ca-ATPase, to detect the microsecond rotational motion of the Ca-ATPase in the two preparations. The time-resolved phosphorescence anisotropy decays of both preparations at 25 degrees C were multi-exponential, because of the presence of different oligomeric species. The rotational correlation times for the different oligomers were similar for the two preparations, but the total decay amplitude was substantially greater for atrial tumor SR, indicating that a smaller fraction of the Ca-ATPase molecules exists as large aggregates. Phosphorylation of PLB in ventricular SR decreased the population of large-scale Ca-ATPase aggregates to a level similar to that of atrial tumor SR. Lipid chain mobility (fluidity), detected by electron paramagnetic resonance of stearic acid spin labels, was very similar in the two preparations, indicating that the higher protein mobility in atrial tumor SR is not due to higher lipid fluidity. We conclude that PLB inhibits by inducing Ca-ATPase lateral aggregation, which can be relieved either by phosphorylating or removing PLB.


Using the Electronic Medical Record to Identify Patients at High Risk for Frequent Emergency Department Visits and High System Costs.
A small proportion of patients account for a high proportion of healthcare use. Accurate preemptive identification may facilitate tailored intervention. We sought to determine whether machine learning techniques using text from a family practice electronic medical record can be used to predict future high emergency department use and total costs by patients who are not yet high emergency department users or high cost to the healthcare system. Text from fields of the cumulative patient profile within an electronic medical record of 43,111 patients was indexed. Separate training and validation cohorts were created. After processing, 11,905 words were used to fit a logistic regression model. The primary outcomes of interest in the 12 months after prediction were 3 or more emergency department visits and being in the top 5% in healthcare expenditures. Outcomes were assessed through linkage to administrative databases housed at the Institute for Clinical Evaluative Sciences. In the model to predict frequent emergency department visits, after excluding patients who were high emergency department users in the previous year, the area under the receiver operating characteristic curve was 0.71. By using the same methodology, the model to predict the top 5% in total system costs had an area under the receiver operating characteristic curve of 0.76. Machine learning techniques can be applied to analyze free text contained in electronic medical records. This dataset is more predictive of patients who will generate future high costs than future emergency department visits. It remains to be seen whether these predictions can be used to reduce costs by early interventions in this cohort of patients.


Strategies adopted by men to deal with uncertainty and anxiety when following an active surveillance/monitoring protocol for localised prostate cancer and implications for care: a longitudinal qualitative study embedded within the ProtecT trial.
Active surveillance (AS) enables men with low risk, localised prostate cancer (PCa) to avoid radical treatment unless progression occurs; lack of reliable AS protocols to determine progression leaves uncertainties for men and clinicians. This study investigated men's strategies for coping with the uncertainties of active monitoring (AM, a surveillance strategy within the Prostate testing for cancer and Treatment, ProtecT trial) over the longer term and implications for optimising supportive care. Longitudinal serial in-depth qualitative interviews every 2-3 years for a median 7 (range 6-14) years following diagnosis. Four centres within the UK Protect trial. Purposive sample of 20 men with localised PCa: median age at diagnosis 64 years (range 52-68); 15 (75%) had low-risk PCa; 12 randomly allocated to, 8 choosing AM. Eleven men continued with AM throughout the study period (median 7 years). Nine received radical treatment after a median 4 years (range 0.8-13.8 years). AM: 3-monthly serum prostate-specific antigen (PSA)-level assessment (year 1), 6-12 monthly thereafter; increase in PSA ≥50% during previous 12 months or patient/clinician concern triggered review. Thematic analysis of 73 interviews identified strategies to accommodate uncertainty and anxiety of living with untreated cancer; implications for patient care. Men sought clarity, control or reassurance, with contextual factors mediating individual responses. Trust in the clinical team was critical for men in balancing anxiety and facilitating successful management change/continued monitoring. Only men from ProtecT were included; men outside ProtecT may have different experiences. Men looked to clinicians for clarity, control and reassurance. Where provided, men felt comfortable continuing AM or having radical treatments when indicated. Clinicians build patient trust by clearly describing uncertainties, allowing patients control wherever possible and being aware of how context influences individual responses. Insights indicate need for supportive services to build trust and patient engagement over the long term. ISRCTN20141297; Pre-results.


Protective antiviral cytotoxic T cell memory is most efficiently maintained by restimulation via dendritic cells.
Dendritic cells (DC) play a key role in the initiation of T cell-mediated immune responses and may therefore be successfully used in antiviral and antitumor vaccination strategies. Because both strength and duration of an immune response determines the outcome of a vaccination protocol, we evaluated the life span of DC-induced antiviral CTL memory against systemic and peripheral challenge infections with lymphocytic choriomeningitis virus (LCMV). We found that expansion and activation of CTL by DC was transient. Protection against systemic LCMV infection after DC immunization was relatively long-lived (>60 days), whereas complete protection against peripheral infection via intracerebral infection or infection into the footpad with LCMV, where rapid recruitment of effector T cells to the site of infection and elimination of viral pathogen plays a major role, was short-lived (<30 days). Protective immunity was most efficiently restored by administration of antigenic peptides via DC, rather than in combination with IFA or in liposomes. These results suggest that Ag presentation by DC may be crucial for both initiation and maintenance of protective CTL-mediated immunity against viruses infecting solid organs or against peripheral mesenchymal or epithelial tumors.


A case of airway obstruction secondary to acute haemorrhage into a benign thyroid cyst.
A 70-year-old female, with a history of progressive dyspnoea, was admitted to the critical care unit after successful resuscitation following a witnessed, out of hospital cardiorespiratory arrest. A presumptive diagnosis of cardiorespiratory arrest secondary to an exacerbation of chronic obstructive pulmonary disease was made. However, on more detailed examination a large anterior, midline neck mass was noted. Following tracheal intubation, a computerised tomography scan of the patient's neck and thorax revealed a seven-centimetre, well-defined, nonenhancing, rounded homogeneous opacity at the thoracic inlet, consistent with a large midline thyroid cyst. Needle aspiration of the cyst was performed and yielded approximately 50 mL of frank blood. After an uncomplicated tracheal extubation and recovery, an elective subtotal thyroidectomy was performed prior to hospital discharge. Histology of the specimen revealed a benign thyroid cyst within a multinodular goitre. Euthyroid multinodular goitres are more likely to be managed conservatively due to an asymptomatic clinical course in most patients. However, the risk of respiratory distress and acute airway obstruction from tracheal compression or acute haemorrhage should be kept in mind. Patients at risk of this life threatening complication should be managed with elective thyroidectomy to reduce morbidity and mortality.


Hepatic metastasis from uveal melanoma: angiographic pattern predictive of survival after hepatic arterial chemoembolization.
To identify clinical features associated with survival after hepatic arterial chemoembolization (HACE) for uveal melanoma metastasis. Retrospective case series including 11 men and 10 women with uveal melanoma metastasis. The hepatic angiographic pattern of metastasis was infiltrative in 12 patients (57%) and nodular in 9 patients (43%). The infiltrative pattern was associated with ciliary body involvement by the primary tumor (Fisher exact test, P = .01) and extrascleral tumor extension (Fisher exact test, P = .01). Mean survival after the first HACE treatment was 7.6 months overall, 3.7 months for the patients with the infiltrative pattern, and 12.7 months for those with the nodular pattern. This difference was highly significant (Kaplan-Meier, P < .001). Chromosome 8p was found to be deleted in 4 patients with the infiltrative pattern and in no patients with the nodular pattern. The hepatic metastasis pattern can be used to predict response to and survival after HACE. Loss of chromosome 8p may be a biomarker for the infiltrative metastasis pattern. Hepatic arterial chemoembolization may play an important role in the treatment of hepatic metastasis from uveal melanoma in patients with the nodular metastatic pattern. Regular screening for hepatic metastasis in patients with uveal melanoma may be beneficial in identifying those who would benefit from HACE.


Unconventional two-dimensional germanium dichalcogenides.
The recently discovered two-dimensional (2D) group IV chalcogenides attract much attention owing to their novel electronic and photonic properties. All the reported materials of this class favor (distorted) octahedral coordination via p bonding; by contrast, in the dichalcogenides where the bonding tendency approaches sp3, no corresponding 2D phase has been realized so far. Here, by engineering the composition of a chalcogenide heterostructure, the hitherto elusive GeTe2 is experimentally observed in a confined 2D environment. Density functional theory simulations predict the existence of a freestanding monolayer of octahedrally coordinated GeTe2 under tensile strain, and the existence of GeSe2 and GeS2 in the same form under equilibrium conditions. These 2D germanium dichalcogenides are either metallic or narrow gap semiconducting, and may lead to new applications in nanoscale electronics.


Sleep or swim? Early-morning training severely restricts the amount of sleep obtained by elite swimmers.
Good sleep is essential for optimal performance, yet few studies have examined the sleep/wake behaviour of elite athletes. The aim of this study was to assess the impact of early-morning training on the amount of sleep obtained by world-class swimmers. A squad of seven swimmers from the Australian Institute of Sport participated in this study during 14 days of high-intensity training in preparation for the 2008 Olympic Games. During these 14 days, participants had 12 training days, each starting with a session at 06:00 h, and 2 rest days. For each day, the amount of sleep obtained by participants was determined using self-report sleep diaries and wrist-worn activity monitors. On nights that preceded training days, participants went to bed at 22:05 h (s=00:52), arose at 05:48 h (s=00:24) and obtained 5.4 h (s=1.3) of sleep. On nights that preceded rest days, participants went to bed at 00:32 h (s=01:29), arose at 09:47 h (s=01:47) and obtained 7.1 h (s=1.2) of sleep. Mixed model analyses revealed that on nights prior to training days, bedtimes and get-up times were significantly earlier (p<0.001), time spent in bed was significantly shorter (p<0.001) and the amount of sleep obtained was significantly less (p<0.001), than on nights prior to rest days. These results indicate that early-morning training sessions severely restrict the amount of sleep obtained by elite athletes. Given that chronic sleep restriction of <6 h per night can impair psychological and physiological functioning, it is possible that early-morning schedules actually limit the effectiveness of training.


Considerations of target surface area and the risk of radiosurgical toxicity.
The goal of this study was to explore conceptual benefits of characterizing delineated target volumes based on surface area and to utilize the concept for assessing risk of therapeutic toxicity in radiosurgery. Four computer-generated targets, a sphere, a cylinder, an ellipsoid and a box, were designed for two distinct scenarios. In the first scenario, all targets had identical volumes, and in the second one, all targets had identical surface areas. High quality stereotactic radiosurgery plans with at least 95% target coverage and selectivity were created for each target in both scenarios. Normal brain volumes V12Gy, V14Gy and V16Gy corresponding to received dose of 12 Gy, 14 Gy and 16 Gy, respectively, were computed and analyzed. Additionally, V12Gy and V14Gy volumes and values for seven prospective toxicity variables were recorded for 100 meningioma patients after Gamma Knife radiosurgery. Multivariable stepwise linear regression and best subset linear regression analyses were performed in two statistical software packages, SAS/STAT and R, respectively. In a phantom study, for the constant volume targets, the volumes of 12 Gy, 14 Gy and 16 Gy isodose clouds were the lowest for the spherical target as an expected corollary of the isoperimetric inequality. For the constant surface area targets, a conventional wisdom is confirmed, as the target volume increases the corresponding volumes V12Gy, V14Gy and V16Gy also increase. In the 100-meningioma patient cohort, the best univariate model featured tumor surface area as the most significantly associated variable with both V12Gy and V14Gy volumes, corresponding to the adjusted R2 values of 0.82 and 0.77, respectively. Two statistical methods converged to matching multivariable models. In a univariate model, target surface area is a better predictor of spilled dose to normal tissue than target largest dimension or target volume itself. In complex multivariate models, target surface area is an independent variable for modeling radiosurgical normal tissue toxicity risk.


The modulated structure of Ba0.39Sr0.61Nb2O6. I. Harmonic solution.
The structure of a crystal of Sr(0.61)Ba(0.39)Nb(2)O(6) has been solved and refined as an incommensurate structure in five-dimensional superspace. The structure is tetragonal, superspace group P4bm(pp1/2,p - p1/2), unit-cell parameters a = 12.4566 (9), c = 7.8698 (6) A, modulation vectors q(1) = 0.3075 (6) (a* + b*), q(2) = 0.3075 (6) (a* - b*). The data collection was performed on a KUMA-CCD diffractometer and allowed the integration of weak first-order satellite reflections. The structure was refined from 2569 reflections to a final value of R = 0.0479. The modulation affects mainly the positions of the O atoms, which are displaced by as much as 0.5 A, and the site 4c that is occupied by Sr and Ba atoms. Only a simplified model, in which this atomic position is occupied by an effective atom Sr/Ba, could be refined from the data set. The modulation of displacement parameters has been used to account for the modulated distribution of Sr and Ba. The whole refinement uses only first-order modulation waves, but there are strong indications that for a complete solution the use of higher-order satellites and a more complicated model is necessary.


Traffic-Related Air Pollution, APOEε4 Status, and Neurodevelopmental Outcomes among School Children Enrolled in the BREATHE Project (Catalonia, Spain).
Traffic-related air pollution is emerging as a risk factor for Alzheimer's disease (AD) and impaired brain development. Individual differences in vulnerability to air pollution may involve the ε4 allele of Apolipoprotein E (APOE) gene, the primary genetic risk factor for AD. We analyzed whether the association between traffic air pollution and neurodevelopmental outcomes is modified by APOEε4 status in children. Data on parent-reported behavior problems (total difficulties scores, Strengths and Difficulties Questionnaire), teacher-reported attention-deficit hyperactivity disorder (ADHD) symptom scores, cognitive performance trajectories (computerized tests of inattentiveness and working memory repeated 2-4 times during January 2012-March 2013), and APOE genotypes were obtained for 1,667 children age 7-11 y attending 39 schools in or near Barcelona. Basal ganglia volume (putamen, caudate, and globus pallidum) was measured in 163 of the children by MRI (October 2012-April 2014.) Average annual outdoor polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and nitrogen dioxide (NO2) concentrations were estimated based on measurements at each school (two 1-wk campaigns conducted 6 months apart in 2012). APOEε4 allele carriers had significantly higher behavior problem scores than noncarriers, and adverse associations with PAHs and NO2 were stronger or limited to ε4 carriers for behavior problem scores (P-interaction 0.03 and 0.04), caudate volume (P-interaction 0.04 and 0.03), and inattentiveness trajectories (P-interaction 0.15 and 0.08, respectively). Patterns of associations with the same outcomes were similar for EC. PAHs, EC, and NO2 were associated with higher behavior problem scores, smaller reductions in inattentiveness over time, and smaller caudate volume in APOEε4 allele carriers in our study population, and corresponding associations were weak or absent among ε4 noncarriers. These findings support a potential role of APOE in biological mechanisms that may contribute to associations between air pollution and neurobehavioral outcomes in children. https://doi.org/10.1289/EHP2246.


Intravenous iron in inflammatory bowel disease.
The prevalence of anemia across studies on patients with inflammatory bowel disease (IBD) is high (30%). Both iron deficiency (ID) and anemia of chronic disease contribute most to the development of anemia in IBD. The prevalence of ID is even higher (45%). Anemia and ID negatively impact the patient's quality of life. Therefore, together with an adequate control of disease activity, iron replacement therapy should start as soon as anemia or ID is detected to attain a normal hemoglobin (Hb) and iron status. Many patients will respond to oral iron, but compliance may be poor, whereas intravenous (i.v.) compounds are safe, provide a faster Hb increase and iron store repletion, and presents a lower rate of treatment discontinuation. Absolute indications for i.v. iron treatment should include severe anemia, intolerance or inappropriate response to oral iron, severe intestinal disease activity, or use of an erythropoietic stimulating agent. Four different products are principally used in clinical practice, which differ in their pharmacokinetic properties and safety profiles: iron gluconate and iron sucrose (lower single doses), and iron dextran and ferric carboxymaltose (higher single doses). After the initial resolution of anemia and the repletion of iron stores, the patient's hematological and iron parameters should be carefully and periodically monitored, and maintenance iron treatment should be provided as required. New i.v. preparations that allow for giving 1000-1500 mg in a single session, thus facilitating patient management, provide an excellent tool to prevent or treat anemia and ID in this patient population, which in turn avoids allogeneic blood transfusion and improves their quality of life.


Acute effects of supramaximal exercise on carotid artery compliance and pulse pressure in young men and women.
The purpose of this study was to determine the cumulative effects of repeated cycling sprints (Wingate tests) on carotid compliance and blood pressure (BP). Fourteen young, healthy men and women completed this study. Vascular and hemodynamic measurements were taken at rest, 5 min following a first Wingate test, 25 min following the first Wingate test, 5 min following a second Wingate test, and 25 min following the second Wingate test. At each time point, the measurements taken included brachial and carotid pulse pressure (PP), heart rate, carotid artery maximum and minimum diameters, and carotid compliance. Carotid BP was obtained with applanation tonometry. Carotid diameters were obtained using ultrasonography and compliance was calculated from carotid diameters and BP. Carotid and brachial PP increased significantly (P < 0.05) 5 min after each Wingate test and returned to near baseline 25 min after each Wingate test. No cumulative PP effects were seen. A cumulative effect was seen for carotid compliance: 5 min following the second sprint, carotid arterial compliance decreased significantly more than 5 min following the first sprint (P < 0.05). A single cycling sprint reduces carotid artery compliance immediately after exercise. Performance of a second identical cycling sprint further compounds this vascular change, reducing carotid artery compliance beyond levels seen following a single cycling sprint.


Wavelength multiplexing encryption using joint transform correlator architecture.
We show that multiple secure data recording under a wavelength multiplexing technique is possible in a joint transform correlator (JTC) arrangement. We evaluate both the performance of the decrypting procedure and the influence of the input image size when decrypting with a wavelength different from that employed in the encryption step. This analysis reveals that the wavelength is a valid parameter to conduct image multiplexing encoding with the JTC architecture. In addition, we study the influence of the minimum wavelength change that prevents decoding cross talk. Computer simulations confirm the performance of the proposed technique.


The outcome of manuscripts submitted to the American Journal of Ophthalmology between 2002 and 2003.
To investigate the outcome of manuscripts submitted to the American Journal of Ophthalmology (AJO) between July 23, 2002 and December 31, 2003. Observational series. Data were collected on all Full-Length Articles and Brief Reports submitted to the AJO. Data were recorded for rejected or withdrawn manuscripts about the date of submission and decision, category of decision, type of article, manuscript region of origin, alternate journal of manuscript, date of publication, and impact factor and immediacy index of the subsequent journal. Corresponding data were collected from the manuscripts accepted over the same period. The Advanced PubMed online database was searched to determine if the rejected or withdrawn manuscripts were published elsewhere. The impact factor and the immediacy index of the journal of the subsequent journal was then recorded and compared with those of the AJO, using the year 2004 for comparison. Of 2,026 manuscripts submitted, 1,444 were rejected by the AJO or withdrawn by the authors and 50% of these were subsequently published elsewhere in a PubMed listed journal. The rejected or withdrawn articles were typically published in lower impact journals, most commonly in general ophthalmology journals in the author's region or in subspecialty journals, although several were published in higher impact journals. The 727 articles were published in 94 different journals and usually with an extended delay. Rejection of a manuscript by the AJO does not preclude publication, but rejected manuscripts are published more often in journals that serve a smaller readership and are cited less frequently, although exceptions exist.


Migraine and retinal microvascular abnormalities: the Atherosclerosis Risk in Communities Study.
This study examined the association between vascular headaches and retinal microvascular disease. We investigated the cross-sectional association between headaches (migraine/other headaches with aura, migraine without aura, other headaches without aura, no headaches) and retinal microvascular signs (retinopathy, focal arteriolar narrowing, arteriovenous nicking; arteriolar and venular calibers) among middle-aged African American and white men and women from the third examination of the Atherosclerosis Risk in Communities Study (1993 through 1995). After controlling for age, gender, race, study center, and cardiovascular risk factors, we determined that persons with headaches were more likely to have retinopathy than those without a history of headaches (odds ratio [OR] = 1.38, 95% CI = 0.96 to 1.99 for migraine/other headaches with aura; OR = 1.49, 95% CI = 1.05 to 2.12 for migraine without aura; and OR = 1.28, 95% CI = 0.99 to 1.65 for other headaches). Associations with migraine were stronger among the subset of participants without a history of diabetes or hypertension (OR = 1.79, 95% CI = 1.09 to 2.95 for migraine/other headaches with aura; and OR = 1.74, 95% CI = 1.11 to 2.71 for migraine without aura). Headaches were not associated with focal arteriolar narrowing or arteriovenous nicking. Persons with headaches tended to have smaller mean arteriolar and venular calibers; however, these associations did not tend to persist among those without hypertension or diabetes. Middle-aged persons with migraine and other headaches were more likely to have retinopathy signs, supporting the hypothesis that neurovascular dysfunction may underlie vascular headaches.


Discordance Between Clinical Assessment and Invasive Hemodynamics in Patients With Advanced Heart Failure.
Historically, invasive hemodynamic guidance was not superior compared to clinical assessment in patients admitted with acute decompensated heart failure (ADHF). This study assessed the accuracy of clinical assessment vs invasive hemodynamics in patients with ADHF. We conducted a prospective cohort study of patients admitted with ADHF. Prior to right-heart catheterization (RHC), physicians categorically predicted right atrial pressure, pulmonary capillary wedge pressure, cardiac index and hemodynamic profile (wet/dry, warm/cold) based on physical examination and clinical data evaluation (warm = cardiac index > 2.2 L/min/m2; wet = pulmonary capillary wedge pressure > 18 mmHg). We collected 218 surveys (of 83 cardiology fellows, 55 attending cardiologists, 45 residents, 35 interns) evaluating 97 patients. Of those patients, 46% were receiving inotropes prior to RHC. The positive and negative predictive values of clinical assessment compared to RHC for the cold and wet subgroups were 74.7% and 50.4%. The accuracy of categorical prediction was 43.6% for right atrial pressure, 34.4% for pulmonary capillary wedge pressure and 49.1% for cardiac index, and accuracy did not differ by clinician (P > 0.05 for all). Interprovider agreement was 44.4%. Therapeutic changes following RHC occurred in 71.1% overall (P < 0.001). Clinical assessment of patients with advanced heart failure presenting with ADHF has low accuracy across all training levels, with exaggerated rates of misrecognition of the most high-risk patients.


Dimensional variation of craniofacial structures in relation to changing masticatory-functional demands.
A reduction in masticatory stress has been an important factor in the evolution of the human skull. Similarly, the recent increase in the occlusal variation has been related to a change in masticatory activity. The present study investigates short-term variation in craniofacial dimensions by examining cephalometrically two Finnish samples, one exposed to a hard and the other to a soft diet. The samples comprised 32 skulls, derived from the 16th and 17th centuries, and 50 living individuals. Out of 18 dimensions measured, 12 showed only non-significant differences between the samples. In the present-day sample, the cranial length and the anterior cranial base were significantly longer, and the upper incisors segment significantly higher. In the skull sample, the posterior facial height, the height of the mandibular ramus, and the antero-posterior width of the pharynx were significantly larger. The results suggest that hard diet, which requires more chewing force and time, promotes vertical growth of the ramus and anterior translocation of the maxilla. The greater posterior face height and greater height of ramus are in accordance with the earlier finding that the mandible shows more anterior growth rotation in an attritive environment. These findings support the hypothesis that the growth of the craniofacial skeleton is regulated by masticatory stress. It is suggested that both the dimensional changes and the lack of dental attrition may have contributed to the higher occlusal variation of modern individuals.


Ischemic preconditioning enhances critical power during a 3 minute all-out cycling test.
This study tested the hypothesis that ischemic preconditioning (IPC) would increase critical power (CP) during a 3 minute all-out cycling test. Twelve males completed two 3 minute all-out cycling tests, in a crossover design, separated by 7 days. These tests were preceded by IPC (4 x 5 minute intervals at 220 mmHg bilateral leg occlusion) or SHAM treatment (4 x 5 minute intervals at 20 mmHg bilateral leg occlusion). CP was calculated as the mean power output during the final 30 s of the 3 minute test with W' taken as the total work done above CP. Muscle oxygenation was measured throughout the exercise period. There was a 15.3 ± 0.3% decrease in muscle oxygenation (TSI; [Tissue saturation index]) during the IPC stimulus, relative to SHAM. CP was significantly increased (241 ± 65 W vs. 234 ± 67 W), whereas W' (18.4 ± 3.8 vs 17.9 ± 3.7 kJ) and total work done (TWD) were not different (61.1 ± 12.7 vs 60.8 ± 12.7 kJ), between the IPC and SHAM trials. IPC enhanced CP during a 3 minute all-out cycling test without impacting W' or TWD. The improved CP after IPC might contribute towards the effect of IPC on endurance performance.


Treatment of decompensated cirrhosis secondary to hepatitis C with antiviral therapy.
To treat decompensated hepatitis C patient with interferon, ribavirin and amantidine to ascertain the sustained viral response. Descriptive study. Shifa International Hospital, Islamabad, from January 2007 to January 2012. HCV PCR patients with decompensated hepatitis C, who had developed a complication like ascites, encephalopathy or variceal bleeding were included in the study. Those with uncontrolled ascites or other complications were excluded. Treatment with standard interferon 3 miU subcutaneously three times a week along with ribavirin 800 mg to 1200 mg and amantidine 100 mg b.i.d. was administered for 12 months. Patients were followed every month with CBC and ALT and HCV PCR was performed after 3 months to document early viral response. They had HCV PCR at the end of the treatment to document end of treatment response. All were further followed for another 6 months at monthly intervals and HCV PCR was performed at the end of this period to document sustained viral response. In all, 165 patients were treated. Treatment had to be discontinued in 42 (26%) patients. Out of these, 16 patients died. Thus, 123 completed treatment. Sustained viral response was documented in 58 out of the 123 (47%) patients. Hepatic encephalopathy, gastrointestinal bleeding, sepsis and development of ascites were the major complications during treatment. Forty seven percent of patients with decompensated hepatitis C cirrhosis were able to achieve sustained viral response after one year treatment with anti-viral therapy. However, complications developed during treatment and, therefore, frequent and close monitoring is necessary in these patients.


Aquaporins in brain: distribution, physiology, and pathophysiology.
Water homeostasis in the brain is of central physiologic and clinical importance. Neuronal activity and ion water homeostasis are inextricably coupled. For example, the clearance of K+ from areas of high neuronal activity is associated with a concomitant water flux. Furthermore, cerebral edema, a final common pathway of numerous neurologic diseases, including stroke, may rapidly become life threatening because of the rigid encasement of the brain. A water channel family, the aquaporins, facilitates water flux through the plasma membrane of many cell types. In rodent brain, several recent studies have demonstrated the presence of different types of aquaporins. Aquaporin 1 (AQP1) was detected on epithelial cells in the choroid plexus whereas AQP4, AQP5 and AQP9 were localized on astrocytes and ependymal cells. In rodent brain, AQP4 is present on astrocytic end-feet in contact with brain vessels, and AQP9 is found on astrocytic processes and cell bodies. In basal physiologic conditions, AQP4 and AQP9 appear to be implicated in brain homeostasis and in central plasma osmolarity regulation. Aquaporin 4 may also play a role in pathophysiologic conditions, as shown by the reduced edema formation observed after water intoxication and focal cerebral ischemia in AQP4-knockout mice. Furthermore, pathophysiologic conditions may modulate AQP4 and AQP9 expression. For example, AQP4 and AQP9 were shown to be upregulated after ischemia or after traumatic injuries. Taken together, these recent reports suggest that water homeostasis in the brain is maintained by regulatory processes that, by control of aquaporin expression and distribution, induce and organize water movements. Facilitation of these movements may contribute to the development of edema formation after acute cerebral insults such as ischemia or traumatic injury.


The lowest spatial frequency channel determines brightness perception.
This study investigates the role played by individual spatial scales in determining the apparent brightness of greyscale patterns. We measured the perceived difference in brightness across an edge in the presence of notch filtering and high-pass filtering for two stimulus configurations, one that elicits the perception of transparency and one that appears opaque. For both stimulus configurations, the apparent brightness of the surfaces delimited by the border decreased monotonically with progressive (ideal) high-pass filtering, with a critical cut-off at 1 c/deg. Using two octave ideal notch filtering, the maximum detrimental effect on apparent brightness was observed at about 1c/deg. Critical frequencies for apparent brightness did not vary with contrast, viewing distance, or surface size, suggesting that apparent brightness is determined by the channel tuned at 1 c/deg. Modelling the data with the local energy model [Morrone, M. C., & Burr, D. C. (1988). Feature detection in human vision: a phase dependent energy model. Proceedings of the Royal Society (London), B235, 221-245] at 1c/deg confirmed the suggestion that this channel mediates apparent brightness for both opaque and transparent borders, with no need for pooling or integration across spatial channels.


Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial.
To compare paroxetine with placebo and imipramine with placebo for the treatment of adolescent depression. After a 7- to 14-day screening period, 275 adolescents with major depression began 8 weeks of double-blind paroxetine (20-40 mg), imipramine (gradual upward titration to 200-300 mg), or placebo. The two primary outcome measures were endpoint response (Hamilton Rating Scale for Depression [HAM-D] score < or = 8 or > or = 50% reduction in baseline HAM-D) and change from baseline HAM-D score. Other depression-related variables were (1) HAM-D depressed mood item; (2) depression item of the Schedule for Affective Disorders and Schizophrenia for Adolescents-Lifetime version (K-SADS-L); (3) Clinical Global Impression (CGI) improvement scores of 1 or 2; (4) nine-item depression subscale of K-SADS-L; and (5) mean CGI improvement scores. Paroxetine demonstrated significantly greater improvement compared with placebo in HAM-D total score < or = 8, HAM-D depressed mood item, K-SADS-L depressed mood item, and CGI score of 1 or 2. The response to imipramine was not significantly different from placebo for any measure. Neither paroxetine nor imipramine differed significantly from placebo on parent- or self-rating measures. Withdrawal rates for adverse effects were 9.7% and 6.9% for paroxetine and placebo, respectively. Of 31.5% of subjects stopping imipramine therapy because of adverse effects, nearly one third did so because of adverse cardiovascular effects. Paroxetine is generally well tolerated and effective for major depression in adolescents.


A syngeneic variance library for functional annotation of human variation: application to BRCA2.
The enormous scope of natural human genetic variation is now becoming defined. To accurately annotate these variants, and to identify those with clinical importance, is often difficult to assess through functional assays. We explored systematic annotation by using homologous recombination to modify a native gene in hemizygous (wt/Deltaexon) human cancer cells, generating a novel syngeneic variance library (SyVaL). We created a SyVaL of BRCA2 variants: nondeleterious, proposed deleterious, deleterious, and of uncertain significance. We found that the null states BRCA2(Deltaex11/Deltaex11) and BRCA2(Deltaex11/Y3308X) were deleterious as assessed by a loss of RAD51 focus formation on genotoxic damage and by acquisition of toxic hypersensitivity to mitomycin C and etoposide, whereas BRCA2(Deltaex11/Y3308Y), BRCA2(Deltaex11/P3292L), and BRCA2(Deltaex11/P3280H) had wild-type function. A proposed phosphorylation site at codon 3291 affecting function was confirmed by substitution of an acidic residue (glutamate, BRCA2(Deltaex11/S3291E)) for the native serine, but in contrast to a prior report, phosphorylation was dispensable (alanine, BRCA2(Deltaex11/S3291A)) for BRCA2-governed cellular phenotypes. These results show that SyVaLs offer a means to comprehensively annotate gene function, facilitating numerical and unambiguous readouts. SyVaLs may be especially useful for genes in which functional assays using exogenous expression are toxic or otherwise unreliable. They also offer a stable, distributable cellular resource for further research.


Medicaid IBCLC Service Coverage following the Affordable Care Act and the Center for Medicare and Medicaid Services Update.
International Board Certified Lactation Consultants (IBCLCs) are associated with increased rates and duration of breastfeeding. Recent US legislation offers opportunities for private and public insurers to include IBCLC services as a covered benefit. To explore US states' Medicaid coverage of IBCLC services following January 2014 legislative expansions of coverage for preventive health services. To assess IBCLC reimbursement practices, 20 states, stratified by Medicaid expansion (yes/no) and 3-month exclusive breastfeeding rates, were selected to participate. An electronic survey was sent to Medicaid and Maternal Health Directors, breastfeeding coordinators, and Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) coordinators between July and December 2014. Email follow-ups clarified missing or ambiguous responses. Of the 15 states responding, 9 had Medicaid expansion. None of the states permitted IBCLCs to bill for services autonomously. In 9 states, IBCLC services were covered with some type of stipulation, for example, billing under a physician. Of the 9 states with IBCLC coverage, 7 had accepted Medicaid expansion. States with higher rates of exclusive breastfeeding were also more likely to provide IBCLC coverage. Recent legislative changes to public and private insurance that could expand coverage of IBCLCs have not yielded appreciable changes, particularly in states without Medicaid expansion. There is a need for research on the effects of adopting expanded coverage for IBCLCs and advocacy to do so.


From thought to action: young parents' reasons for participation in parenting support groups at child welfare centers.
In this article the focus is on young parents' engagement process in relation to participation in parenting support groups carried out at child welfare centers. This qualitative study focuses not only on young parents' reasons for participating or not participating in parenting support groups during different phases in their engagement process, but also on examining the circumstances that may contribute to such changes. The results show that these reasons can be divided into four categories: the staff, other participants, the social network, and practical circumstances. It also appears that these reasons change between different phases of their engagement process. Primarily three different circumstances contributed to variation in parents' reasons: difficulty in predicting the value of participation, increased closeness in relationships with staff and other parents, and the specific life phase in which young parents find themselves. The results have important implications for policy makers and practitioners in their work in formulating and updating parenting support; they also indicate what may be important to focus on in the recruitment of young parents, and also what may be crucial in regard to them completing their engagement in parent support groups.


The role of multimodality imaging in the diagnosis of left ventricular noncompaction.
Left ventricular noncompaction (LVNC) is a heterogeneous entity and, in reality, a likely spectrum of disease which is clinically associated with arrhythmia, thromboembolic complications and sudden cardiac death. With the emergence of cardiac MRI (cMRI), the phenotype is increasingly more prevalent, resulting in clinical uncertainty regarding prognosis and management. The currently accepted hypothesis suggests an early embryonic arrest of the normal, sequential myocardial compaction process. LVNC is observed in isolation or in association with congenital heart disease, neuromuscular disease or a vast array of genetic cardiomyopathies. Definition of the entity varies among international society guidelines with differences both within and between imaging modalities, predominantly echocardiography and cMRI. Long-term prognostic data are emerging but due to the intrinsic variability in reported prevalence, selection bias and lack of pathological to prognostic correlation, there are many uncertainties regarding clinical management. This review seeks to clarify the role of multimodality imaging in diagnosis and management of the disease. We discuss the sensitivity and specificity of the current diagnostic criteria, as well as the nuances in diagnosis using the available imaging modalities.


A transnational perspective on the evolution of the synthetic cannabinoid receptor agonists market: Comparing prison and general populations.
The synthetic cannabinoid receptor agonist (SCRA) market is transnational, and the availability of individual SCRAs changes regularly in response to national and international legislative controls. This generates a cyclic pattern and near constant evolution of SCRA compounds. This study reports toxicology-based and/or seized sample-based prevalence data relating to SCRA use in prisons from Germany, the United Kingdom (UK; Scotland and Wales), and the United States (US), representing 4427 individual test results. The study examines SCRA detections in prisons from July 2018 to September 2020, and where possible, prison-based data are compared with SCRA prevalence data in the wider population. The relative influence of Chinese, other international, and national drug legislation on the prevalence of individual SCRAs in prisons is also considered. tert-Leucinate- and valinate-indole- and indazole-3-carboxamides were the most common SCRA detections, and MDMB-4en-PINACA was one of the most commonly detected SCRAs in all jurisdictions by September 2020. However, despite there being a global production and supply market, there were notable regional differences. Analog controls in German and US legislation may have led to increased compound diversity that is not reflected in the UK which has both analog controls and a blanket ban on psychoactive substances. While there were regional differences, SCRA prevalence in prisons closely aligned with the SCRAs detected on the local market, demonstrating that SCRA (and possibly other NPS) monitoring programs in prisons can act as early warning systems for the wider population in that given jurisdiction.


Cystic fibroepithelioma of Pinkus: two new cases and cystic changes in classical fibroepithelioma of Pinkus.
We report two new cases of cystic fibroepithelioma of Pinkus together with immunohistochemical features and analyze the presence of cystic changes in a series of 16 classical fibroepitheliomas of Pinkus. Our findings show that the formation of cystic spaces is most probably caused by ischemic degeneration of stromal fenestrations, rather than by central tumor cell necrosis. This finding is supported by lack of CD34 positive blood vessels in edematous and hyalinized stromal fenestrations undergoing transformation into cystic spaces, as opposed to the uninvolved stromal fenestrations. Therefore, it is probably more accurate to refer to this process as pseudocystic stromal degeneration rather than true cyst formation. Also, two out of 16 classical Pinkus fibroepitheliomas exhibited focal pseudocystic changes in 50% and 10% of the tumor, respectively, demonstrating that this degenerative process can be found, rarely and focally, in classical cases as well.


Body-mass index, blood pressure, and cause-specific mortality in India: a prospective cohort study of 500 810 adults.
The association between cause-specific mortality and body-mass index (BMI) has been studied mainly in high-income countries. We investigated the relations between BMI, systolic blood pressure, and mortality in India. Men and women aged 35 years or older were recruited into a prospective study from the general population in Chennai, India between Jan 1, 1998, and Dec 31, 2001. Participants were interviewed (data collected included age, sex, education, socioeconomic status, medical history, tobacco smoking, and alcohol intake) and measured (height, weight, and blood pressure). Deaths were identified by linkage to Chennai city mortality records and through active surveillance by household visits from trained graduate non-medical fieldworkers. After the baseline survey, households were visited once in 2002-05, then biennially until 2015. During these repeat visits, structured narratives of any deaths that took place before March 31, 2015, were recorded for physician coding. During 2013-14, a random sample of participants was also resurveyed as per baseline to assess long-term variability in systolic blood pressure and BMI. Cox regression (standardised for tobacco, alcohol, and social factors) was used to relate mortality rate ratios (RRs) at ages 35-69 years to systolic blood pressure, BMI, or BMI adjusted for usual systolic blood pressure. 500 810 participants were recruited. After exclusion of those with chronic disease or incomplete data, 414 746 participants aged 35-69 years (mean 46 [SD 9]; 45% women) remained. At recruitment, mean systolic blood pressure was 127 mm Hg (SD 15), and mean BMI was 23·2 kg/m2 (SD 3·8). Correlations of resurvey and baseline measurements were 0·50 for systolic blood pressure and 0·88 for BMI. Low BMI was strongly associated with poverty, tobacco, and alcohol. Of the 29 519 deaths at ages 35-69 years, the cause was vascular for 14 935 deaths (12 504 cardiac, 1881 stroke, and 550 other). Vascular mortality was strongly associated with systolic blood pressure: RRs per 20 mm Hg increase in usual systolic blood pressure were 2·45 (95% CI 2·16-2·78) for stroke mortality, 1·74 (1·64-1·84) for cardiac mortality, and 1·84 (1·75-1·94) for all vascular mortality. Although BMI strongly affected systolic blood pressure (an increase of about 1 mm Hg per kg/m2) and diabetes prevalence, BMI was little related to cardiac or stroke mortality, with only small excesses even for grade 1 obesity (ie, BMIs of 30·0-35·0 kg/m2). After additional adjustment for usual systolic blood pressure, BMI was inversely related to cardiac and stroke mortality throughout the range 15·0-30·0 kg/m2: when underweight participants (ie, BMI 15·0-18·5 kg/m2) were compared with overweight participants (ie, BMI 25·0-30·0 kg/m2), the blood-pressure-adjusted RR was 1·28 (95% CI 1·20-1·38) for cardiac mortality and 1·46 (1·22-1·73) for stroke mortality. In this South Asian population, BMI was little associated with vascular mortality, even though increased BMI is associated with increased systolic blood pressure, which in turn is associated with increased vascular mortality. Hence, some close correlates of below-average BMI must have important adverse effects, which could be of relevance in all populations. UK Medical Research Council, British Heart Foundation, Cancer Research UK.


Evidence that glutamate acting on presynaptic type-II metabotropic glutamate receptors alone does not fully account for the phenomenon of depolarisation-induced suppression of inhibition in cerebellar Purkinje cells.
Depolarisation-induced suppression of inhibition (DSI) is a form of short-term synaptic plasticity at gamma-aminobutyric-acid-(GABA)ergic synapses between principal neurons and interneurons in both the cerebellum and the hippocampus. The induction of DSI involves an intracellular calcium-dependent release of a retrograde messenger from the postsynaptic principal neuron (Purkinje cell/pyramidal cell in cerebellum/hippocampus) onto presynaptic interneurons, where it is thought to bind to guanine nucleotide-binding protein (G protein)-coupled receptors and subsequently reducing GABA release from these interneurons onto the postsynaptic principal neuron. Pharmacological studies have indicated that glutamate might be a retrograde messenger in both cerebellum and hippocampus, where, in the former at least, it seems to activate type-II metabotropic glutamate receptors (mGluRs). Using LY-341495, a recently described, highly specific and potent antagonist of type-II mGluRs, to block these receptors reduced DSI slightly, but significantly, in spite of the fact that this antagonist completely suppressed the effects of stimulating type-II mGluRs with a specific agonist. Activation of type II mGluRs alone thus cannot account fully for DSI in cerebellum and hence other mechanisms are involved in its induction. Such mechanisms probably involve an additional retrograde signal.


Functional and self-rated health mediate the association between physical indicators of diabetes and depressive symptoms.
Depression is common among persons with diabetes and associated with adverse health outcomes. To date, little is known about the causal mechanisms that lead to depression in diabetes. The aim of the present study was to examine to which extent functional and self-rated health mediate the association between physical health and depressive symptoms in diabetes. Data of n = 3222 individuals with type 2 diabetes were analyzed cross-sectionally and longitudinally at three measurement occasions using path analysis. Indicators of physical health were glycemic control, number of comorbid somatic diseases, BMI, and insulin dependence. Furthermore, functional health, self-rated health and depressive symptoms were assessed. The effects of physical health on depressive symptoms were largely mediated by functional health and self-rated health. There was only a weak indirect effect of physical health on depressive symptoms. In contrast, self-rated health was a strong direct predictor of depressive symptoms. Self-rated health in turn depended strongly on patients' functional health. The way individuals perceive their health appears to have a stronger effect on their depressive symptoms than objective physical indicators of diabetes. Therefore practitioners should be trained to pay more attention to their patients' subjective health perceptions.


The view from two sides: a qualitative study of community and medical perspectives on screening for colorectal cancer using FOBT.
Population-wide screening for people at average risk of colorectal cancer (CRC) by faecal occult blood test (FOBT) is under consideration in Australia. Qualitative methods were used to examine the views of community members who did (n = 18) or did not (n = 12) participate in a pilot program of FOBT screening. In addition, views were obtained from general practitioners (GPs) and specialist gastroenterologists directly involved in the implementation of the program. Two focus group sessions were conducted with screening participants and interviews were conducted with nonparticipants, GPs and gastroenterologists. The findings suggest that CRC screening by FOBT distributed to households by mail was well accepted by the community and by the medical practitioners involved in its implementation. The trial had little negative effect on general practice. Both medical practitioners and consumers raised concerns about the efficacy of FOBT screening. Medical practitioners were also concerned about the potential burden mass screening could place on the public (government-funded) health care sector. It would seem that CRC screening using FOBT will not enjoy unqualified support from the community or from medical practitioners involved in the continuum of screening. Information about the objectives of screening programs, in general, and the efficacy of FOBT screening in particular, needs to be provided to the community to ensure informed individual choice.


Simultaneous recruitment of drug users and men who have sex with men in the United States and Russia using respondent-driven sampling: sampling methods and implications.
The Sexual Acquisition and Transmission of HIV Cooperative Agreement Program (SATHCAP) examined the role of drug use in the sexual transmission of the human immunodeficiency virus (HIV) from traditional high-risk groups, such as men who have sex with men (MSM) and drug users (DU), to lower risk groups in three US cities and in St. Petersburg, Russia. SATHCAP employed respondent-driven sampling (RDS) and a dual high-risk group sampling approach that relied on peer recruitment for a combined, overlapping sample of MSM and DU. The goal of the sampling approach was to recruit an RDS sample of MSM, DU, and individuals who were both MSM and DU (MSM/DU), as well as a sample of sex partners of MSM, DU, and MSM/DU and sex partners of sex partners. The approach efficiently yielded a sample of 8,355 participants, including sex partners, across all four sites. At the US sites-Los Angeles, Chicago, and Raleigh-Durham-the sample consisted of older (mean age = 41 years), primarily black MSM and DU (both injecting and non-injecting); in St. Petersburg, the sample consisted of primarily younger (mean age = 28 years) MSM and DU (injecting). The US sites recruited a large proportion of men who have sex with men and with women, an important group with high potential for establishing a generalized HIV epidemic involving women. The advantage of using the dual high-risk group approach and RDS was, for the most part, the large, efficiently recruited samples of MSM, DU, and MSM/DU. The disadvantages were a recruitment bias by race/ethnicity and income status (at the US sites) and under-enrollment of MSM samples because of short recruitment chains (at the Russian site).


Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression.
MLL (for mixed-lineage leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Its product, a homolog of Drosophila melanogaster trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. Here we report the biochemical purification of MLL and demonstrate that it associates with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including a homolog of Ash2, another Trx-G group protein. Two other members of the novel MLL complex identified here are host cell factor 1 (HCF-1), a transcriptional coregulator, and the related HCF-2, both of which specifically interact with a conserved binding motif in the MLL(N) (p300) subunit of MLL and provide a potential mechanism for regulating its antagonistic transcriptional properties. Menin, a product of the MEN1 tumor suppressor gene, is also a component of the 1-MDa MLL complex. Abrogation of menin expression phenocopies loss of MLL and reveals a critical role for menin in the maintenance of Hox gene expression. Oncogenic mutant forms of MLL retain an ability to interact with menin but not other identified complex components. These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis.


Low glycemic index vegan or low-calorie weight loss diets for women with polycystic ovary syndrome: a randomized controlled feasibility study.
The aim of this randomized pilot was to assess the feasibility of a dietary intervention among women with polycystic ovary syndrome (PCOS) comparing a vegan to a low-calorie (low-cal) diet. Overweight (body mass index, 39.9 ± 6.1 kg/m(2)) women with PCOS (n = 18; age, 27.8 ± 4.5 years; 39% black) who were experiencing infertility were recruited to participate in a 6-month randomized weight loss study delivered through nutrition counseling, e-mail, and Facebook. Body weight and dietary intake were assessed at 0, 3, and 6 months. We hypothesized that weight loss would be greater in the vegan group. Attrition was high at 3 (39%) and 6 months (67%). All analyses were conducted as intention-to-treat and presented as median (interquartile range). Vegan participants lost significantly more weight at 3 months (-1.8% [-5.0%, -0.9%] vegan, 0.0 [-1.2%, 0.3%] low-cal; P = .04), but there was no difference between groups at 6 months (P = .39). Use of Facebook groups was significantly related to percent weight loss at 3 (P < .001) and 6 months (P = .05). Vegan participants had a greater decrease in energy (-265 [-439, 0] kcal/d) and fat intake (-7.4% [-9.2%, 0] energy) at 6 months compared with low-cal participants (0 [0, 112] kcal/d, P = .02; 0 [0, 3.0%] energy, P = .02). These preliminary results suggest that engagement with social media and adoption of a vegan diet may be effective for promoting short-term weight loss among women with PCOS; however, a larger trial that addresses potential high attrition rates is needed to confirm these results.


Survey of bovine mycotic mastitis in different mammary gland statuses in two north-eastern regions of Algeria.
The aim of this study was to evaluate the prevalence of mycotic mastitis in different mammary gland statuses. The study was conducted on 304 dairy cows from ten farms in two north-eastern regions in Algeria; Guelma and Souk Ahras with 922 and 199 samples, respectively, forming thus a total number of 1,121 milk samples. A total of 321 milk samples were collected from clinical mastitis, 544 milk samples from subclinical mastitis and 256 milk samples from healthy mammary glands. Mycological analyses revealed that 10.17% of the treated samples were positive recording 114 species of fungi including 88 yeasts and 26 moulds. The most frequent species was Candida kefyr followed by C. albicans, C. guilliermondii, C. famata, C. tropicalis, C. colliculosa, C. krusei, C. rugosa, C. glabrata, C. parapsilosis, C. inconspicua, Trichosporon sp., Rhodotorula glutinis and Saccharomyces fragilis. Mould species have also been isolated from samples of both healthy milk and clinical mastitis milk. Aspergillus amstelodami (from glaucus group), A. fumigatus and Geotrichum candidum were identified, while the other species including Penicillium sp. and Cladosporium sp. were not identified.


Use of brain natriuretic peptide to detect previously unknown left ventricular dysfunction in patients with acute exacerbation of chronic obstructive pulmonary disease.
Up to 30% of patients with chronic obstructive pulmonary disease (COPD) simultaneously suffer from often-unrecognised chronic heart failure (HF). Their timely identification is challenging as both conditions share similar clinical presentations. To assess the performance of BNP in detecting left ventricular systolic dysfunction in patients with no history of HF admitted for acute exacerbation of COPD in a regional second-care hospital. Retrospective medical records analysis of all patients hospitalised between January 2003 and May 2009 with the final diagnosis of acute exacerbation of COPD, and who had undergone BNP dosage at admission followed by an echocardiography. Among the 57 patients included, 13 had left ventricular systolic dysfunction. There was a statistically significant difference of mean BNP values between patients with or without systolic dysfunction (mean 689 pg/ml vs. 340 pg/ml, p = 0.007). For the detection of systolic dysfunction, a BNP level inferior to 100 pg/ml yielded a sensitivity of 92% and a negative predictive value of 91%, whereas BNP higher than 500 yielded a sensitivity of 80% and a positive predictive value of 47%. In a multivariate logistic regression analysis, a BNP value ≥500 (odds ratio 8.5, 95% confidence interval 1.9 to 38.2, p = 0.005) and history of coronary heart disease (odds ratio 5.9, 95% confidence interval 1.01 to 34.7, p = 0.048) remained as independent and mutually adjusted predictors of left ventricular systolic dysfunction. Our study confirms that BNP can help physicians in identifying heart failure in patients suffering from an acute exacerbation of COPD.


Regulation of the nfsA Gene in Escherichia coli by SoxS.
In Escherichia coli, the response to oxidative stress due to elevated levels of superoxide is mediated, in part, by the soxRS regulon. One member of the soxRS regulon, nfsA, encodes the major oxygen-insensitive nitroreductase in Escherichia coli which catalyzes the reduction of nitroaromatic and nitroheterocyclic compounds by NADPH. In this study we investigate the regulation of nfsA in response to the superoxide generating compound paraquat. The transcription start site (TSS) of nfsA was located upstream of the ybjC gene, a small open reading frame of unknown function located directly upstream of nfsA, suggesting that these two genes form an operon. The activity of the promoter associated with this TSS was confirmed with lacZ fusions and was shown to be inducible by paraquat. Footprinting and band shift analysis showed that purified His-tagged SoxS protein binds to a 20-base sequence 10 bases upstream of the -35 promoter sequence in the forward orientation, suggesting that the ybjC-nfsA promoter is a class I SoxS-dependent promoter.


Animal pee in the sea: consumer-mediated nutrient dynamics in the world's changing oceans.
Humans have drastically altered the abundance of animals in marine ecosystems via exploitation. Reduced abundance can destabilize food webs, leading to cascading indirect effects that dramatically reorganize community structure and shift ecosystem function. However, the additional implications of these top-down changes for biogeochemical cycles via consumer-mediated nutrient dynamics (CND) are often overlooked in marine systems, particularly in coastal areas. Here, we review research that underscores the importance of this bottom-up control at local, regional, and global scales in coastal marine ecosystems, and the potential implications of anthropogenic change to fundamentally alter these processes. We focus attention on the two primary ways consumers affect nutrient dynamics, with emphasis on implications for the nutrient capacity of ecosystems: (1) the storage and retention of nutrients in biomass, and (2) the supply of nutrients via excretion and egestion. Nutrient storage in consumer biomass may be especially important in many marine ecosystems because consumers, as opposed to producers, often dominate organismal biomass. As for nutrient supply, we emphasize how consumers enhance primary production through both press and pulse dynamics. Looking forward, we explore the importance of CDN for improving theory (e.g., ecological stoichiometry, metabolic theory, and biodiversity-ecosystem function relationships), all in the context of global environmental change. Increasing research focus on CND will likely transform our perspectives on how consumers affect the functioning of marine ecosystems.


Peptide libraries define the fine specificity of anti-polysaccharide antibodies to Cryptococcus neoformans.
Cryptococcus neoformans is an encapsulated fungus that causes a life-threatening meningoencephalitis in patients with AIDS. Monoclonal antibodies to the capsular glucuronoxylomannan can modulate the infection in mice, but the epitopes on this complex polysaccharide recognized by protective and non-protective antibodies have not been defined. We have used 2H1, one of our most protective antibodies, to screen phage display peptide libraries for peptide mimotopes that would allow us to explore the fine specificity of anti-cryptococcal polysaccharide antibodies. Hexa- and decapeptides have been identified with sequence homologies that define four motifs: 1, (E)TPXWM/LM/L; 2, W/YXWM/ LYE; 3, DWXDW; and 4, (Ar)WDGQ(Ar). Peptides representing these motifs compete with each other for a shared binding site that overlaps the polysaccharide binding site. Motifs 1 and 2 confer high affinity binding, and PA1, which displays a motif 1 peptide with the sequence LQYTPSWMLV, binds to 2H1 with a Kd of 295 nM. Analysis of the interaction between the 2H1 binding peptides and 24 structurally related anti-polysaccharide antibodies reveals a complex pattern of reactivity that strongly suggests binding to or close to the complementary determining regions. Furthermore, those antibodies that have been shown to have different specificity, and in some cases different protective potential, do not bind any of the peptides selected by the protective 2H1 antibody. This study shows that peptide mimotopes for a complex microbial polysaccharide can be identified by screening phage peptide libraries and demonstrates the usefulness of such peptides in analyzing closely related interactive sites of proteins in general and of antibodies in particular.


Predicting binding to p-glycoprotein by flexible receptor docking.
P-glycoprotein (P-gp) is an ATP-dependent transport protein that is selectively expressed at entry points of xenobiotics where, acting as an efflux pump, it prevents their entering sensitive organs. The protein also plays a key role in the absorption and blood-brain barrier penetration of many drugs, while its overexpression in cancer cells has been linked to multidrug resistance in tumors. The recent publication of the mouse P-gp crystal structure revealed a large and hydrophobic binding cavity with no clearly defined sub-sites that supports an "induced-fit" ligand binding model. We employed flexible receptor docking to develop a new prediction algorithm for P-gp binding specificity. We tested the ability of this method to differentiate between binders and nonbinders of P-gp using consistently measured experimental data from P-gp efflux and calcein-inhibition assays. We also subjected the model to a blind test on a series of peptidic cysteine protease inhibitors, confirming the ability to predict compounds more likely to be P-gp substrates. Finally, we used the method to predict cellular metabolites that may be P-gp substrates. Overall, our results suggest that many P-gp substrates bind deeper in the cavity than the cyclic peptide in the crystal structure and that specificity in P-gp is better understood in terms of physicochemical properties of the ligands (and the binding site), rather than being defined by specific sub-sites.


Infection of mice by Salmonella enterica serovar Enteritidis involves additional genes that are absent in the genome of serovar Typhimurium.
Salmonella enterica serovar Enteritidis causes a systemic, typhoid-like infection in newly hatched poultry and mice. In the present study, a library of 54,000 transposon mutants of S. Enteritidis phage type 4 (PT4) strain P125109 was screened for mutants deficient in the in vivo colonization of the BALB/c mouse model using a microarray-based negative-selection screening. Mutants in genes known to contribute to systemic infection (e.g., Salmonella pathogenicity island 2 [SPI-2], aro, rfa, rfb, phoP, and phoQ) and enteric infection (e.g., SPI-1 and SPI-5) in this and other Salmonella serovars displayed colonization defects in our assay. In addition, a strong attenuation was observed for mutants in genes and genomic islands that are not present in S. Typhimurium or in most other Salmonella serovars. These genes include a type I restriction/modification system (SEN4290 to SEN4292), the peg fimbrial operon (SEN2144A to SEN2145B), a putative pathogenicity island (SEN1970 to SEN1999), and a type VI secretion system remnant SEN1001, encoding a hypothetical protein containing a lysin motif (LysM) domain associated with peptidoglycan binding. Proliferation defects for mutants in these individual genes and in exemplar genes for each of these clusters were confirmed in competitive infections with wild-type S. Enteritidis. A ΔSEN1001 mutant was defective for survival within RAW264.7 murine macrophages in vitro. Complementation assays directly linked the SEN1001 gene to phenotypes observed in vivo and in vitro. The genes identified here may perform novel virulence functions not characterized in previous Salmonella models.


Time-Resolved Resting-State Functional Magnetic Resonance Imaging Analysis: Current Status, Challenges, and New Directions.
Time-resolved analysis of resting-state functional magnetic resonance imaging (rs-fMRI) data allows researchers to extract more information about brain function than traditional functional connectivity analysis, yet a number of challenges in data analysis and interpretation remain. This article briefly summarizes common methods for time-resolved analysis and presents some of the pressing issues and opportunities in the field. From there, the discussion moves to interpretation of the network dynamics observed with rs-fMRI and the role that rs-fMRI can play in elucidating the large-scale organization of brain activity.


How do toddler eating problems relate to their eating behavior, food preferences, and growth?
Eating problems are a common cause of concern for the parents of toddlers, but few studies have examined the correlates of eating problems or the growth patterns associated with them in a large population-based sample. Our goal was to examine the distribution of eating behaviors in a large representative sample of toddlers and their mothers' approach to feeding. In addition, we describe the prevalence of parentally perceived eating problems and how they relate to specific behaviors, food preferences, and growth in the child. We conducted a cross-sectional analysis of data from a United Kingdom population-based birth cohort, the Gateshead Millennium Baby Study, which included 455 questionnaires completed by parents when their children were aged 30 months. Eating was perceived to be a problem by 89 (20%) parents. Eating a limited variety (79 [17%]) and preferring drinks to food (57 [13%]) were the most prevalent problem behaviors. Thirty-seven children (8%) were described by parents as definitely "faddy" (picky), and these children liked fewer foods and had higher eating restriction scores than those described as not faddy. Children who were described as having an eating problem gained less weight over the first 2 years; 11.1% had weight faltering compared with 3.5% in children not described as having an eating problem. Being faddy was only weakly associated with poor growth, and simply eating a limited variety was unrelated to growth. High milk consumption was associated with lower appetite but not with poor growth. Eating problems are common in toddlers and in the majority are associated with normal growth, although weight faltering is more common in such children. Excessive milk-drinking may be a cause of low appetite at meal times.


Railway suicide in England and Wales, 1850-1949.
According to the official statistics of the Registrar General, the first railway suicide occurred in 1852 and more than 10,000 suicides recorded during the period 1852-1949. Throughout this time the number of male cases always exceeded the number of female cases and the railway accounted for a greater proportion of male than female suicides in all but two years. By the early decades of the twentieth century, the railway was used in 5-6% of male suicides and 3-4% of female suicides. The incidence of railway suicide was correlated with the growth of the railway system offering some evidence for the relationship between availability of a lethal means and suicide rates.