Perivascular niche cells sense thrombocytopenia and activate hematopoietic stem cells in an IL-1 dependent manner.
Hematopoietic stem cells (HSCs) residing in specialized niches in the bone marrow are responsible for the balanced output of multiple short-lived blood cell lineages in steady-state and in response to different challenges. However, feedback mechanisms by which HSCs, through their niches, sense acute losses of specific blood cell lineages remain to be established. While all HSCs replenish platelets, previous studies have shown that a large fraction of HSCs are molecularly primed for the megakaryocyte-platelet lineage and are rapidly recruited into proliferation upon platelet depletion. Platelets normally turnover in an activation-dependent manner, herein mimicked by antibodies inducing platelet activation and depletion. Antibody-mediated platelet activation upregulates expression of Interleukin-1 (IL-1) in platelets, and in bone marrow extracellular fluid in vivo. Genetic experiments demonstrate that rather than IL-1 directly activating HSCs, activation of bone marrow Lepr+ perivascular niche cells expressing IL-1 receptor is critical for the optimal activation of quiescent HSCs upon platelet activation and depletion. These findings identify a feedback mechanism by which activation-induced depletion of a mature blood cell lineage leads to a niche-dependent activation of HSCs to reinstate its homeostasis.


Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017.
The Fleischner Society Guidelines for management of solid nodules were published in 2005, and separate guidelines for subsolid nodules were issued in 2013. Since then, new information has become available; therefore, the guidelines have been revised to reflect current thinking on nodule management. The revised guidelines incorporate several substantive changes that reflect current thinking on the management of small nodules. The minimum threshold size for routine follow-up has been increased, and recommended follow-up intervals are now given as a range rather than as a precise time period to give radiologists, clinicians, and patients greater discretion to accommodate individual risk factors and preferences. The guidelines for solid and subsolid nodules have been combined in one simplified table, and specific recommendations have been included for multiple nodules. These guidelines represent the consensus of the Fleischner Society, and as such, they incorporate the opinions of a multidisciplinary international group of thoracic radiologists, pulmonologists, surgeons, pathologists, and other specialists. Changes from the previous guidelines issued by the Fleischner Society are based on new data and accumulated experience. © RSNA, 2017 Online supplemental material is available for this article. An earlier incorrect version of this article appeared online. This article was corrected on March 13, 2017.


Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor-Bearing C57BL/6 Mice.
Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model. A total of 150 C57BL/6 mice were randomized into six treatment groups: control; 8 Gy thoracic radiotherapy (dose schedules 1 and 2); cisplatin 2.5 mg/kg i.p.; cisplatin + radiotherapy (concurrent); and cisplatin + radiotherapy (sequential; n = 25, all groups). At the end of the study (week 41), serum cytokines were assessed by multiplex immunoassay, surface markers of spleen-derived lymphocytes were assessed by immunostaining and flow cytometry, lung tumor expression of programmed death ligands 1 and 2 (PD-L1/2) was evaluated by immunohistochemistry, and miRNA profiling was performed in serum and lymphocytes by quantitative real-time PCR. Lung whole mounts were prepared to assess treatment effects on lung tumor foci formation. The results showed that sequential chemoradiotherapy (two cycles of cisplatin followed by 8 Gy radiotherapy) had equivalent antitumor activity as concurrent therapy. However, sequential cisplatin/radiotherapy resulted in significant differences in several immune response biomarkers, including regulatory T cells, miR-29c, expression of costimulatory molecule CD28, and serum IFNγ. PD-L1 and PD-L2 were strongly expressed in tumor foci, but no trend was seen between groups. These results suggest that monitoring immune status may be necessary when designing treatment regimens combining immunotherapy with chemoradiotherapy.


Difference of cross-spectral densities.
Generally speaking, the difference between two cross-spectral densities (CSDs) does not represent a correlation function. We will furnish a sufficient condition so that such difference be a valid CSD. Using such a condition, we will show through some examples how new classes of CSDs can be generated.


Reduced cerebral blood flow but elevated cerebral glucose metabolic rate in erythropoietin overexpressing transgenic mice with excessive erythrocytosis.
To examine the impact of excessive erythrocytosis on local cerebral blood flow (CBF) and cerebral glucose metabolic rate (CMR(glc)), we made use of our constitutively erythropoietin (Epo)-overexpressing transgenic mouse line (tg-6) that reach a mean hematocrit of 0.87. Compared with wild-type (wt) control siblings, CBF decreased by 44% in tg-6 mice, while upon hemodilution (tg-6-HD) to a physiologic hematocrit (e.g., 0.44) tg-6-HD mice returned the CBF to wt levels. Cerebral blood flow was determined in another transgenic mouse line that overexpresses human Epo in the brain only (tg-21): CBF increased by 17% compared with wt controls. However, oxygen delivery was similar in all four mouse groups tested (wt, tg-6, tg-6-HD and tg-21). Mean CMR(glc) was higher in tg-6 (+72%), tg-6-HD mice (+43%) and tg-21 (+22%) than in wt mice. Local CMR(glc) was higher in all 40 brain regions in tg-6 but only in 15 and 8 regions in tg-6-HD and tg-21 mice. These results show that prolonged increases in hematocrit did not alter cerebral oxygen delivery at a decreased CBF and increased CMR(glc). Hemodilution suggests that high blood viscosity is a cause of the decrease in CBF and partly of the increase in CMR(glc). Cerebral glucose metabolic rate may also be increased by a direct effect of Epo in the brain (tg-21 mice).


Recessive osteogenesis imperfecta: clinical, radiological, and molecular findings.
Osteogenesis imperfecta (OI) or "brittle bone disease" is currently best described as a group of hereditary connective tissue disorders related to primary defects in type I procollagen, and to alterations in type I procollagen biosynthesis, both associated with osteoporosis and increased susceptibility to bone fractures. Initially, the autosomal dominant forms of OI, caused by mutations in either COL1A1 or COL1A2, were described. However, for decades, the molecular defect of a small percentage of patients clinically diagnosed with OI has remained elusive. It has been in the last 6 years that the genetic causes of several forms of OI with autosomal recessive inheritance have been characterized. These comprise defects of collagen chaperones, and proteins involved in type I procollagen assembly, processing and maturation, as well as proteins involved in the formation and homeostasis of bone tissue. This article reviews the recently characterized forms of recessive OI, focusing in particular on their clinical and molecular findings, and on their radiological characterisation. Clinical management and treatment of OI in general will be discussed, too.


Preventing noise induced otoacoustic emission loss by increasing magnesium (Mg2+) intake in guinea-pigs.
This study aimed to explore the effects of increased Mg2+ intake on the activity of the outer hair cells as manifested in Click and Distortion Evoked Otoacoustic Emissions (CEOAEs; DPOAEs) in 25 animals. Thirteen animals were fed with high Mg2+ intake (39 mmol Mg2+/l in drinking water) and 12 without the Mg2+ additive. The OAE amplitudes and frequency ranges as well as the DPOAE thresholds were affected significantly less by noise exposure in the animals fed Mg2+-enriched water. Following the exposure, the auditory recovery was faster in the high than the low Mg2+ animals (controls). In addition, a relationship was found between the Mg2+ level and the emission loss. The post-exposure measures may result from the effect of Mg2+ on cochlear metabolic processes and vascular microcirculation. The results demonstrate that pre-existing low Mg2+ levels will exacerbate noise induced hearing loss (NIHL), and increased Mg2+ intake provides a significant biological cochlear protective effect.


Slice-selective FID acquisition, localized by outer volume suppression (FIDLOVS) for (1)H-MRSI of the human brain at 7 T with minimal signal loss.
In comparison to 1.5 and 3 T, MR spectroscopic imaging at 7 T benefits from signal-to-noise ratio (SNR) gain and increased spectral resolution and should enable mapping of a large number of metabolites at high spatial resolutions. However, to take full advantage of the ultra-high field strength, severe technical challenges, e.g. related to very short T(2) relaxation times and strict limitations on the maximum achievable B(1) field strength, have to be resolved. The latter results in a considerable decrease in bandwidth for conventional amplitude modulated radio frequency pulses (RF-pulses) and thus to an undesirably large chemical-shift displacement artefact. Frequency-modulated RF-pulses can overcome this problem; but to achieve a sufficient bandwidth, long pulse durations are required that lead to undesirably long echo-times in the presence of short T(2) relaxation times. In this work, a new magnetic resonance spectroscopic imaging (MRSI) localization scheme (free induction decay acquisition localized by outer volume suppression, FIDLOVS) is introduced that enables MRSI data acquisition with minimal SNR loss due to T(2) relaxation and thus for the first time mapping of an extended neurochemical profile in the human brain at 7 T. To overcome the contradictory problems of short T(2) relaxation times and long pulse durations, the free induction decay (FID) is directly acquired after slice-selective excitation. Localization in the second and third dimension and skull lipid suppression are based on a T(1)- and B(1)-insensitive outer volume suppression (OVS) sequence. Broadband frequency-modulated excitation and saturation pulses enable a minimization of the chemical-shift displacement artefact in the presence of strict limits on the maximum B(1) field strength. The variable power RF pulses with optimized relaxation delays (VAPOR) water suppression scheme, which is interleaved with OVS pulses, eliminates modulation side bands and strong baseline distortions. Third order shimming is based on the accelerated projection-based automatic shimming routine (FASTERMAP) algorithm. The striking SNR and spectral resolution enable unambiguous quantification and mapping of 12 metabolites including glutamate (Glu), glutamine (Gln), N-acetyl-aspartatyl-glutamate (NAAG), gamma-aminobutyric acid (GABA) and glutathione (GSH). The high SNR is also the basis for highly spatially resolved metabolite mapping.


Postmortem ventilation in cases of penetrating gunshot and stab wounds to the chest.
We sought to determine the effect of postmortem ventilation in combination with a suction pump in cases showing penetrating trauma to the chest with haemo- and/or pneumothorax, for better evaluation of the lungs in postmortem computed tomography (PMCT). The study included 6 subjects (1 female, 5 male; age 32-67years) with a penetrating gunshot or stab wound to the chest and consecutive pneumo- and/or haemothorax. The pneumo- and haemothorax were evacuated by a suction pump, and postmortem ventilation was applied using a home care ventilator. PMCT images with and without postmortem ventilation were compared, as well as the autopsy results. In three cases haemo- and pneumothorax was clearly reduced. Postmortem ventilation led to distinct re-expansion of the lungs in two cases, and to re-expansion of single lung lobes in two cases with shotgun injuries. No visible effect was seen in the remaining two cases, because of extensive destruction of lung tissue and blood aspiration. In two cases the injuries sustained in the individual lung lobes were successfully located during postmortem ventilation. The bullet channel was apparent in one case; in another case, injury of the pericardium became visible by generating pneumopericardium. The present method is capable of improving evaluation of the postmortem lung in the presence of single stab or gunshot wounds and if there is no severe destruction of the respiratory system and aspiration. Forensic autopsy should still be considered as the gold standard, although in some cases the present method might be helpful, especially where no autopsy is required.


Treatment of syphilis: a systematic review.
The incidence of syphilis in the United States is increasing; it is estimated that more than 55,000 new infections will occur in 2014. Treatment regimens are controversial, especially in specific populations, and assessing treatment response based on serology remains a challenge. To review evidence regarding penicillin and nonpenicillin regimens, implications of the "serofast state," and treatment of specific populations including those with neurosyphilis or human immunodeficiency virus (HIV) infection and pregnant women. We searched MEDLINE for English-language human treatment studies dating from January 1965 until July 2014. The American Heart Association classification system was used to rate quality of evidence. We included 102 articles in our review, consisting of randomized trials, meta-analyses, and cohort studies. Case reports and small series were excluded unless they were the only studies providing evidence for a specific treatment strategy. We included 11 randomized trials. Evidence regarding penicillin and nonpenicillin regimens was reviewed from studies involving 11,102 patients. Data on the treatment of early syphilis support the use of a single intramuscular injection of 2.4 million U of benzathine penicillin G, with studies reporting 90% to 100% treatment success rates. The value of multiple-dose treatment of early syphilis is uncertain, especially in HIV-infected individuals. Less evidence is available regarding therapy for late and late latent syphilis. Following treatment, nontreponemal serologic titers should decline in a stable pattern, but a significant proportion of patients may remain seropositive (the "serofast state"). Serologic response to treatment should be evident by 6 months in early syphilis but is generally slower (12-24 months) for latent syphilis. Evidence defining treatment for HIV-infected persons and for pregnant women is limited, but available data support penicillin as first-line therapy. The mainstay of syphilis treatment is parenteral penicillin G despite the relatively modest clinical trial data that support its use.


Adherence of Candida albicans to tissues from mice with drug- or radiation-induced immunodeficiencies.
Host factors that influence binding of Candida albicans to murine spleen, lymph node, and kidney were studied. Organs were harvested from BALB/cByJ and AKR/J mice immunocompromised by irradiation, cyclophosphamide, and cortisone acetate alone or in combination. Tissues from treated mice and untreated littermates were compared for their ability to bind C. albicans in ex vivo assays. Immunosuppressive regimens decreased yeast binding to splenic marginal zones, but when mice recovered for 5 days after treatment, adherence to spleen was similar to adherence in untreated littermates. Adherence to lymph node and kidney in treated mice was not different from binding to these tissues in untreated mice. Total serum immunoglobulin titers correlated with binding of yeast cells to mouse spleen. Blocking studies ruled out a mannosyl-fucosyl receptor-mediated binding. These results suggest that ex vivo adherence of C. albicans represents a host immune defense mechanism by which the immunocompetent host binds blood-borne yeast cells to host immune cells in reticuloendothelial organs to prevent dissemination to other organs.


The burden of chronic mercury intoxication in artisanal small-scale gold mining in Zimbabwe: data availability and preliminary estimates.
Artisanal small-scale gold mining (ASGM) is a poverty-driven activity practiced in over 70 countries worldwide. Zimbabwe is amongst the top ten countries using large quantities of mercury to extract gold from ore. This analysis was performed to check data availability and derive a preliminary estimate of disability-adjusted life years (DALYs) due to mercury use in ASGM in Zimbabwe. Cases of chronic mercury intoxication were identified following an algorithm using mercury-related health effects and mercury in human specimens. The sample prevalence amongst miners and controls (surveyed by the United Nations Industrial Development Organization in 2004 and the University of Munich in 2006) was determined and extrapolated to the entire population of Zimbabwe. Further epidemiological and demographic data were taken from the literature and missing data modeled with DisMod II to quantify DALYs using the methods from the Global Burden of Disease (GBD) 2004 update published by the World Health Organization (WHO). While there was no disability weight (DW) available indicating the relative disease severity of chronic mercury intoxication, the DW of a comparable disease was assigned by following the criteria 1) chronic condition, 2) triggered by a substance, and 3) causing similar health symptoms. Miners showed a sample prevalence of 72% while controls showed no cases of chronic mercury intoxication. Data availability is very limited why it was necessary to model data and make assumptions about the number of exposed population, the definition of chronic mercury intoxication, DW, and epidemiology. If these assumptions hold, the extrapolation would result in around 95,400 DALYs in Zimbabwe's total population in 2004. This analysis provides a preliminary quantification of the mercury-related health burden from ASGM based on the limited data available. If the determined assumptions hold, chronic mercury intoxication is likely to have been one of the top 20 hazards for population health in Zimbabwe in 2004 when comparing with more than 130 categories of diseases and injuries quantified in the WHO's GBD 2004 update. Improving data quality would allow more accurate estimates. However, the results highlight the need to reduce a burden which could be entirely avoided.


The effect of cervical mobility on the natural history of cervical spondylotic myelopathy.
A retrospective study was made of 45 patients who had been treated conservatively for cervical spondylotic myelopathy. A number of aetiological variables were analysed in an attempt to find factors that may be useful in predicting the long term prognosis for this condition. It was found that those who deteriorated were more likely to be female and to have significantly more cervical mobility when compared to those patients whose disability had remained static. It is proposed that measurement of cervical mobility may help to select patients who are more likely to deteriorate and thus more likely to benefit from surgical intervention.


Assessment of publication bias and outcome reporting bias in systematic reviews of health services and delivery research: A meta-epidemiological study.
Strategies to identify and mitigate publication bias and outcome reporting bias are frequently adopted in systematic reviews of clinical interventions but it is not clear how often these are applied in systematic reviews relating to quantitative health services and delivery research (HSDR). We examined whether these biases are mentioned and/or otherwise assessed in HSDR systematic reviews, and evaluated associating factors to inform future practice. We randomly selected 200 quantitative HSDR systematic reviews published in the English language from 2007-2017 from the Health Systems Evidence database (www.healthsystemsevidence.org). We extracted data on factors that may influence whether or not authors mention and/or assess publication bias or outcome reporting bias. We found that 43% (n = 85) of the reviews mentioned publication bias and 10% (n = 19) formally assessed it. Outcome reporting bias was mentioned and assessed in 17% (n = 34) of all the systematic reviews. Insufficient number of studies, heterogeneity and lack of pre-registered protocols were the most commonly reported impediments to assessing the biases. In multivariable logistic regression models, both mentioning and formal assessment of publication bias were associated with: inclusion of a meta-analysis; being a review of intervention rather than association studies; higher journal impact factor, and; reporting the use of systematic review guidelines. Assessment of outcome reporting bias was associated with: being an intervention review; authors reporting the use of Grading of Recommendations, Assessment, Development and Evaluations (GRADE), and; inclusion of only controlled trials. Publication bias and outcome reporting bias are infrequently assessed in HSDR systematic reviews. This may reflect the inherent heterogeneity of HSDR evidence and different methodological approaches to synthesising the evidence, lack of awareness of such biases, limits of current tools and lack of pre-registered study protocols for assessing such biases. Strategies to help raise awareness of the biases, and methods to minimise their occurrence and mitigate their impacts on HSDR systematic reviews, are needed.


Y-27152, a long-acting K+ channel opener with less tachycardia: antihypertensive effects in hypertensive rats and dogs in conscious state.
(+)-(3S,4R)-4-(N-Acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2- dimethyl- 2H-1-benzopyran-3-ol (Y-27152) is a new K+ channel opener with a long duration of action and less tachycardia. In this study, Y-27152 was compared with a K+ channel opener lemakalim and a Ca++ channel blocker nifedipine for antihypertensive activity in conscious spontaneously hypertensive rats (SHR) and two-kidney, one-clip renal hypertensive dogs (RHD). In conscious SHR, Y-27152 (0.1-1 mg/kg, p.o.) produced long-lasting dose-related decreases in systolic blood pressure. At 1 mg/kg, the maximum response occurred 5 to 7 hr after dosing, and 24 hr later, the pressure was still significantly reduced. Heart rate was not changed by these doses of Y-27152, whereas equihypotensive doses of lemakalim or nifedipine were strongly tachycardic. The cardiovascular effects of Y-27152 were antagonized by glibenclamide (20 mg/kg, i.v.). In conscious unrestrained RHD, Y-27152 at doses of 0.01, 0.03 and 0.1 mg/kg lowered blood pressure with a slow onset and long duration of action and had only a minimal effect on heart rate, whereas both lemakalim and nifedipine reduced blood pressure and markedly increased heart rate. No tolerance to the antihypertensive effect of Y-27152 (0.1 mg/kg) occurred during an 8-week repeated daily dosing to RHD and plasma renin activity, and aldosterone levels were not elevated during this period. In rat aortic rings contracted with 20 mM KCl, Y-27152 did not modify the tension; however, its desbenzyl form (Y-26763) produced vasorelaxation, and this effect was antagonized competitively by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)


Agreement and variability in the interpretation of early CT changes in stroke patients qualifying for intravenous rtPA therapy.
Ischemic changes identified on CT scans performed in the first few hours after stroke onset, which are thought to possibly represent early cytotoxic edema and development of irreversible injury, may have important implications for subsequent treatment. However, insecurity and conflicting data exist over the ability of clinicians to correctly recognize and interpret these changes. We performed a detailed review of selected baseline CT scans from the NINDS rt-PA Stroke Trial to test agreement among experienced stroke specialists and other physicians on the presence of early CT ischemic changes. Seventy baseline CT scans from the NINDS Stroke Trial were read and classified for the presence or absence of various early findings of ischemia by 16 individuals, including NINDS trial investigators, other neurologists, other emergency medicine physicians, and radiology or stroke fellows. CT scans included normal scans and scans from patients who later developed symptomatic intracranial hemorrhage, as well as scans on which the NINDS rt-PA Stroke Trial neuroradiologist identified clear-cut early CT changes. For each CT finding, kappa-statistics were used to assess the proportion of agreement beyond chance. kappa-Values (95% confidence interval [CI]) ranged from 0.20 (-0.20, 0.61) (fair agreement) to 0.41 (0.37, 0.45) (moderate agreement) among the 16 viewers, and the kappa-value was only 0.39 (0.29, 0.49) (fair) in answer to the question "do early CT changes involve more than one third of the MCA [middle cerebral artery] territory?" There was substantial variability within each specialty group and between groups. kappa-Values were only fair to moderate even among physicians experienced in selecting and treating acute stroke patients with rtPA. Observed agreement ranged from 68% to 85%. Physicians agreed on the finding of early CT changes involving >33% of the MCA territory 77% of the time, although the kappa-value of 0.39 suggested only moderate agreement beyond chance. There is considerable lack of agreement, even among experienced clinicians, in recognizing and quantifying early CT changes. Improved methods of recognizing and quantifying early ischemic brain damage are needed.


The missing effect of human recombinant Bone Morphogenetic Proteins BMP-2 and BMP-7 in surgical treatment of aseptic forearm nonunion.
In this cohort study, the surgical revision concept of open compression plating and autologous bone grafting with and without additional application of BMP for treatment of aseptic ulna and/or radius shaft nonunion was evaluated. The purpose was to evaluate the clinical and radiological outcome, and to determine any difference in osseous healing, range of time between revision surgery and bone healing, and postoperative complications between the cohort groups. Between 01/2005 and 03/2015, a prospective, randomised, controlled cohort study was performed in a Level I Trauma Centre. Forty-nine patients were treated with the diagnosis of aseptic diaphyseal ulnar and/or radial shaft nonunion using compression plating and autologous bone grafting. Additional biological augmentation using BMP-2 or BMP-7 was performed in 24 patients. Clinical and radiological follow-up was performed six weeks, three and six months after revision surgery in accordance to the system by Anderson. The study group consisted of 38 men and 11 women with a median age of 44 years (range 19-77). Twenty-four out of 49 patients obtained compression plating either with autologous iliac crest bone grafting (11/24 patients) or cancellous bone grafting (13/24 patients) and additional application of BMP-2 (4/24 patients) or BMP-7 (20/24 patients). The remaining 25 patients did not receive any additional application of BMP, but autologous bone grafting. The median follow-up was 15 months (range 6-54 months). Forty-six out of 49 nonunion healed within 12 months after revision surgery with a median time to union of six months. The clinical outcome, as assessed using the system by Anderson, as well as osseous healing, duration of time interval between revision surgery and bone healing, and postoperative complications did not demonstrate significant differences between the cohort groups. Atrophic/oligotrophic forearm nonunion healed irrespective of additional application of BMP combined with autologous bone grafting. For successful treatment, radical resection of fibrous nonunion tissue and internal compression plate fixation is required with the aim of achieving high degree of rigid stability. Also, correction of angular deformities, restoration of length, and precise axial alignment of the distal radio-ulnar joint are mandatory prerequisites to successfully achieve bone healing.


Genetic polymorphisms in metabolism of 2-amino-1-methyl-6-phenylimidazo[4,5-b] pyridine.
Heterocyclic amines (HCAs) are naturally produced during common cooking processes for meats and fish. HCAs are metabolized by various enzymes, including cytochromes P450, N-acetyl transferases, and sulfotransferases, and their bioactivated metabolites are considered to bind to DNA or protein to show carcinogenic effects. More than 20 HCAs have been identified, of which 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is classified as 'reasonably anticipated to be a human carcinogen' to develop cancers in breast, colon and prostate. The purpose of this study was to evaluate human exposure levels of PhIP and to understand the role of genetic polymorphisms of enzymes on PhIP metabolism. Urine samples were collected from subjects (n = 100) before 3-day meat-restricted diets. Subjects consumed grilled chicken, and their blood and urine were collected before and after the administration of the chickens to investigate genetic polymorphisms and PhIP levels. The mean PhIP levels were 4.22 ± 0.12, 0.61 ± 0.19 and 22.64 ± 1.00 pg ml(-1) in urine under normal conditions and before and after chicken administration, respectively. Among 21 Single-nucleotide polymorphisms (SNP) of CYP1A1, CYP1A2, NATs and UGTs investigated in this study, genotypic groups of CYP1A1/T6235C (MSP I) and CYP1A2/-2467delT showed significant differences in PhIP excretion (P < 0.05). These results suggest that genetic polymorphisms might affect PhIP metabolism, which could improve understanding of populations subject to PhIP-derived health risk.


Genetic drift in clines which are maintained by migration and natural selection.
Genetic drift will cause a migration-selection cline to wobble about its expected position. A rough linear approximation is developed, valid when local populations are large. This is used to calculate effects of genetic drift on clines in a stepping-stone model with abrupt and with gradual changes of selection coefficients at a single haploid locus. Among the quantities calculated are measures of slope, standardized variation of gene frequencies around their expected values, and correlation among neighboring populations with respect to deviations from the expected gene frequencies. These quantities appear to be primarily functions of Ns and Nm for a given pattern of selection. Computer simulation gives rough confirmation of these results. Standardized variances of gene frequencies and correlation of neighbors differ along the cline in the case of smooth changes in selection. In no case is pathological behavior of gene frequency deviations found near the boundaries of selective regions. Local behavior of gene frequences of nearby colonies is approximately predicted by a simple adaptation of the stepping-stone theory of Kimura and Weiss. Approximate measures of the lateral variation of the midpoint of a cline and the probability of non-monotonicity are also calculated and discussed.


Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial.
Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia. In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1-3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual. Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] -2·5%, 90% credible interval [CrI] -17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45). Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19. The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.


The Ecology of Microbial Communities Associated with Macrocystis pyrifera.
Kelp forests are characterized by high biodiversity and productivity, and the cycling of kelp-produced carbon is a vital process in this ecosystem. Although bacteria are assumed to play a major role in kelp forest carbon cycling, knowledge of the composition and diversity of these bacterial communities is lacking. Bacterial communities on the surface of Macrocystis pyrifera and adjacent seawater were sampled at the Hopkins Marine Station in Monterey Bay, CA, and further studied using 454-tag pyrosequencing of 16S RNA genes. Our results suggest that M. pyrifera-dominated kelp forests harbor distinct microbial communities that vary temporally. The distribution of sequence tags assigned to Gammaproteobacteria, Alphaproteobacteria and Bacteriodetes differed between the surface of the kelp and the surrounding water. Several abundant Rhodobacteraceae, uncultivated Gammaproteobacteria and Bacteriodetes-associated tags displayed considerable temporal variation, often with similar trends in the seawater and the surface of the kelp. Bacterial community structure and membership correlated with the kelp surface serving as host, and varied over time. Several kelp-specific taxa were highly similar to other bacteria known to either prevent the colonization of eukaryotic larvae or exhibit antibacterial activities. Some of these kelp-specific bacterial associations might play an important role for M. pyrifera. This study provides the first assessment of the diversity and phylogenetic profile of the bacterial communities associated with M. pyrifera.


Evolutionary Strategies for Body Size.
Humans show marked variation in body size around the world, both within and among populations. At present, the tallest people in the world are from the Netherlands and the Balkan countries, while the shortest populations are central African Pygmies. There are genetic, genetic plasticity, developmental, and environmental bases for size variation in Homo sapiens from the recent past and the present. Early populations of Homo species also have shown considerable size variation. Populations from the present and the past are also marked by sexual dimorphism, which, itself, shows group variation. There is abundant evidence for the effects of limited food and disease on human growth and resultant adult body size. This environmental influence has been reflected in "secular trends" (over a span of years) in growth and adult size from socioeconomic prosperity or poverty (availability of resources). Selective and evolutionary advantages of small or large body size also have been documented. Heritability for human height is relatively great with current genome-wide association studies (GWAS) identifying hundreds of genes leading to causes of growth and adult size variation. There are also endocrinological pathways limiting growth. An example is the reduced tissue sensitivity to human growth hormone (HGH) and insulin-like growth factor (IGF-1) in Philippine and African hunter-gatherer populations. In several short-statured hunter-gatherer populations (Asian, African, and South American), it has been hypothesized that short life expectancy has selected for early maturity and truncated growth to enhance fertility. Some island populations of humans and other mammals are thought to have been selected for small size because of limited resources, especially protein. The high-protein content of milk as a staple food may contribute to tall stature in East African pastoral peoples. These and other evolutionary questions linked to life history, male competition, reproduction, and mobility are explored in this paper.


Ileal Tuberculosis Causing Hypercalcemia and Renal Failure.
Hypercalcemia rarely causes acute pancreatitis due to secretory block in the pancreas and damage by accumulated proteases. Hypercalcemia, though described in granulomatous disorders, is uncommon in tuberculosis. Acute kidney injury is known to occur with acute pancreatitis, secondary to sepsis and septic shock; however, acute pancreatitis resulting in acute cortical necrosis is very rare. We report a 22-year-old woman, who presented with pain abdomen and vomiting. She was found to have features of acute pancreatitis, both biochemically and radiologically. She had hypercalcemia on presentation and this was attributed to be the cause for pancreatitis as other causes were ruled out. 1, 25-dihydroxyvitamin D level was high with normal parathyroid hormone level. Whole-body positron emission tomography-computed tomography showed increased fluorodeoxyglucose uptake in the terminal ileum and histology from that area showed noncaseating granuloma with acid-fast bacilli in the tissue. She was treated with antituberculosis therapy; hypercalcemia improved over a period of time and pancreatitis resolved. She developed anuric renal failure, and kidney biopsy showed patchy acute cortical necrosis. She is dialysis dependent at the end of 6 months. To the best of our knowledge, this is the first case report of a patient with ileal tuberculosis presenting with hypercalcemia and acute pancreatitis. This case is reported due to the rarity of extrapulmonary tuberculosis presenting with symptomatic hypercalcemia, acute pancreatitis, and acute renal cortical necrosis.


Multireference Approaches for Excited States of Molecules.
Understanding the properties of electronically excited states is a challenging task that becomes increasingly important for numerous applications in chemistry, molecular physics, molecular biology, and materials science. A substantial impact is exerted by the fascinating progress in time-resolved spectroscopy, which leads to a strongly growing demand for theoretical methods to describe the characteristic features of excited states accurately. Whereas for electronic ground state problems of stable molecules the quantum chemical methodology is now so well developed that informed nonexperts can use it efficiently, the situation is entirely different concerning the investigation of excited states. This review is devoted to a specific class of approaches, usually denoted as multireference (MR) methods, the generality of which is needed for solving many spectroscopic or photodynamical problems. However, the understanding and proper application of these MR methods is often found to be difficult due to their complexity and their computational cost. The purpose of this review is to provide an overview of the most important facts about the different theoretical approaches available and to present by means of a collection of characteristic examples useful information, which can guide the reader in performing their own applications.


Regulation of hepatocyte engraftment and proliferation after cytotoxic drug-induced perturbation of the rat liver.
Perturbations in specific liver cell compartments benefit transplanted cell engraftment and/or proliferation. We analyzed whether cytotoxic drugs interfering with the integrity of genomic DNA or cell division could be useful for liver cell transplantation. We used dipeptidyl peptidase IV deficient (DPPIV-) rats as recipients of syngeneic F344 rat hepatocytes. Rats were pretreated with doxorubicin, irinotecan, or vincristine prior to cell transplantation and synergistic liver perturbations were induced by drug administration followed by partial hepatectomy or carbon tetrachloride treatments. Transplanted cells were identified by DPPIV histochemistry and cell engraftment and proliferation were analyzed morphometrically. Perturbations in endothelial, Kupffer cell, and hepatocyte compartments were analyzed by electron microscopy, carbon incorporation, and blood tests, respectively. Cell engraftment was improved in rats treated with doxorubicin but not with irinotecan or vincristine. Doxorubicin disrupted endothelial cells for up to seven days without causing Kupffer cell or hepatocellular toxicity. Neither doxorubicin nor vincristine induced liver repopulation in animals up to three months, including after partial hepatectomy or carbon tetrachloride-induced additional liver injury. Doxorubicin-induced hepatic endothelial damage enhanced cell engraftment, which should be useful in cell therapy strategies.


Beneficial effects of adrenergic blockade in patients with subarachnoid haemorrhage.
A total of 148 patients presenting within 48 hours of subarachnoid haemorrhage were assigned at random to receive standard management only or standard management and treatment with the adrenergic-blocking agents propranolol and phentolamine (or propranolol alone) for three weeks. One hundred and thirty-four patients completed the study. Assessment at four weeks showed a strong trend for less neurological deficit in the treated group, almost statistically significant (p=0.053) in the women. During the first month the treated group suffered fewer episodes of clinical deterioration consistent with cerebral arterial spasm: thus more treated patients underwent operation and those who did had a better outcome (p=0.030). At one year fewer were dead or disabled (unable to work) in the treated group; a significant difference for women (p=0.030). Possible mechanisms for these actions may include a reduction in pulmonary oedema, prevention of myocardial infarcts, a reduction in plasma renin activity, nd a reduction in cerebral oxygen requirements. It is concluded that early adrenergic blockade benefits patients (particularly women) with subarachnoid haemorrhage for up to one year in terms of lesser neurological deficit. Beta-blocker rather than alpha-blockade appears to be the useful component. A randomised, blind extension of the present study using long-acting propranolol and placebo has shown a significant (p=0.026) decrease in deaths and significantly (p=0.003) fewer poor results in the treatment group.


Development and comparison of a real-time PCR assay for detection of Dichelobacter nodosus with culturing and conventional PCR: harmonisation between three laboratories.
Ovine footrot is a contagious disease with worldwide occurrence in sheep. The main causative agent is the fastidious bacterium Dichelobacter nodosus. In Scandinavia, footrot was first diagnosed in Sweden in 2004 and later also in Norway and Denmark. Clinical examination of sheep feet is fundamental to diagnosis of footrot, but D. nodosus should also be detected to confirm the diagnosis. PCR-based detection using conventional PCR has been used at our institutes, but the method was laborious and there was a need for a faster, easier-to-interpret method. The aim of this study was to develop a TaqMan-based real-time PCR assay for detection of D. nodosus and to compare its performance with culturing and conventional PCR. A D. nodosus-specific TaqMan based real-time PCR assay targeting the 16S rRNA gene was designed. The inclusivity and exclusivity (specificity) of the assay was tested using 55 bacterial and two fungal strains. To evaluate the sensitivity and harmonisation of results between different laboratories, aliquots of a single DNA preparation were analysed at three Scandinavian laboratories. The developed real-time PCR assay was compared to culturing by analysing 126 samples, and to a conventional PCR method by analysing 224 samples. A selection of PCR-products was cloned and sequenced in order to verify that they had been identified correctly. The developed assay had a detection limit of 3.9 fg of D. nodosus genomic DNA. This result was obtained at all three laboratories and corresponds to approximately three copies of the D. nodosus genome per reaction. The assay showed 100% inclusivity and 100% exclusivity for the strains tested. The real-time PCR assay found 54.8% more positive samples than by culturing and 8% more than conventional PCR. The developed real-time PCR assay has good specificity and sensitivity for detection of D. nodosus, and the results are easy to interpret. The method is less time-consuming than either culturing or conventional PCR.


Assessing the representativeness of physician and patient respondents to a primary care survey using administrative data.
QUALICOPC is an international survey of primary care performance. QUALICOPC data have been used in several studies, yet the representativeness of the Canadian QUALICOPC survey is unknown, potentially limiting the generalizability of findings. This study examined the representativeness of QUALICOPC physician and patient respondents in Ontario using health administrative data. This representativeness study linked QUALICOPC physician and patient respondents in Ontario to health administrative databases at the Institute for Clinical Evaluative Sciences. Physician respondents were compared to other physicians in their practice group and all Ontario primary care physicians on demographic and practice characteristics. Patient respondents were compared to other patients rostered to their primary care physicians, patients rostered to their physicians' practice groups, and a random sample of Ontario residents on sociodemographic characteristics, morbidity, and health care utilization. Standardized differences were calculated to compare the distribution of characteristics across cohorts. QUALICOPC physician respondents included a higher proportion of younger, female physicians and Canadian medical graduates compared to other Ontario primary care physicians. A higher proportion of physician respondents practiced in Family Health Team models, compared to the provincial proportion for primary care physicians. QUALICOPC patient respondents were more likely to be older and female, with significantly higher levels of morbidity and health care utilization, compared with the other patient groups examined. However, when looking at the QUALICOPC physicians' whole rosters, rather than just the patient survey respondents, the practice profiles were similar to those of the other physicians in their practice groups and Ontario patients in general. Comparisons revealed some differences in responding physicians' demographic and practice characteristics, as well as differences in responding patients' characteristics compared to the other patient groups tested, which may have resulted from the visit-based sampling strategy. Ontario QUALICOPC physicians had similar practice profiles as compared to non-participating physicians, providing some evidence that the participating practices are representative of other non-participating practices, and patients selected by visit-based sampling may also be representative of visiting patients in other practices. Those using QUALICOPC data should understand this limited representativeness when generalizing results, and consider the potential for bias in their analyses.


The value of real-time three-dimensional transesophageal echocardiography in the assessment of paravalvular leak origin following prosthetic mitral valve replacement.
Two-dimensional (2D) echocardiographic approaches are not sufficient to determine the origin of paravalvular leak (PVL) that occurs after prosthetic mitral valve replacement (MVR). In this study, we investigated the role of real-time three-dimensional transesophageal echocardiography (RT-3D TEE) in detecting the origin and size of PVL occurring after prosthetic MVR. The study included 13 patients (7 females; 6 males; mean age 56+/-10 years; range 37 to 71 years) who developed PVL within a mean of 8.3+/-3.8 years following mechanical prosthetic MVR. Nine patients (69.2%) had atrial fibrillation, and four patients (30.8%) had normal sinus rhythm. Four patients (30.8%) had hemolysis. Paravalvular leak was mild, moderate, and severe in two, six, and five patients, respectively. Real-time 3D TEE was performed using a 3D matrix-array TEE transducer immediately after detection of PVL on 2D TEE examination. Localization of PVL was made using a clock-wise format in relation to the aortic valve and the size of dehiscence was measured. The mean PVL width measured by 2D TEE was 3.00+/-0.92 mm. The mean length of dehiscence was 13.6+/-8.8 mm, and the mean width was 3.88+/-2.04 mm on RT-3D TEE. The PVLs were mainly localized in the posterior and anterior annular positions between 12 to 03 hours (n=7) and 06 to 09 hours (n=3) on RT-3D TEE, respectively, which corresponded to the posteromedial or anterolateral sectors of the posterior annulus. Considering that only the width of the PVL defect can be assessed by 2D TEE, delineation by RT-3D TEE includes the localization of PVL together with the length and width of the defect.


Evaluation of a patient referral contact tracing programme for hepatitis B and C virus infection in drug injectors.
Effective contact tracing for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection could enhance disease control, especially in populations with low HBV vaccination rates and high prevalence of untreated HCV infection. We evaluated a low-cost approach to HBV/HCV contact tracing in injection drug users (IDUs). Index cases (n=26) were IDUs who seroconverted to HBV and/or HCV during a prospective cohort study in Seattle. Interviewers elicited index cases' recent injection partners and administered recall cues and other techniques to boost recall. Index cases received vouchers for free hepatitis testing, which they were to give to locatable partners. Persons redeeming vouchers also received small monetary incentives. Most (26/40) seroconverters participated in the paid contact interviews. Index cases reported many partners (mean=17), and in the aggregate, index cases indicated they could refer more than one third of their elicited partners for testing. Overall, only 17 persons were ultimately referred and just eight of these were confirmed as partners sought for referral. The supplementary elicitation techniques, and especially the recall cues, increased reporting of injection partners substantially. The injection network constructed from reported partnerships was mostly connected and cyclic. Successful contact tracing in IDUs likely requires active involvement by public health staff to locate and notify exposed injection partners.


Peptide Targeting of Fluorescein-Based Sensors to Discrete Intracellular Locales.
Fluorescein-based sensors are the most widely applied class of zinc probes but display adventitious localization in live cells. We present here a peptide-based localization strategy that affords precision in targeting of fluorescein-based zinc sensors. By appending the zinc-selective, reaction-based probe Zinpyr-1 diacetate (DA-ZP1) to the N-terminus of two different targeting peptides we achieve programmable localization and avoid unwanted sequestration within acidic vesicles. Furthermore, this approach can be generalized to other fluorescein-based sensors. When appended to a mitochondrial targeting peptide, the esterase-activated profluorophore 2',7'-dichlorofluorescein diacetate can be used effectively at concentrations four-times lower than previously reported for analogous, non-acetylated derivatives. These results demonstrate on-resin or in-solution esterification of fluorescein to be an effective strategy to facilitate peptide-based targeting in live cells.


Parent-infant interaction: a growth model approach.
The aim of this study is to compare the interaction of fathers and mothers with their 10-12 months old infants (n=97; parental sensitivity and mood, and infant mood) during five structured contiguous play segments, and to examine the utility of individual growth modeling. Conventional comparison of means across play-segments showed that parents were equally responsive, but mothers were happier than fathers, and infants were equally happy during interaction with both parents. Sensitivity and mood were more strongly related for mothers than for fathers. Uni- and multivariate growth models revealed fine-grained patterns not seen in conventional analysis: (a) parental and infant mood decreased across play more for mothers than for fathers, (b) parental sensitivity in one play-segment predicted parental mood and infant mood in the next segment, (c) change in infants' mood was related to change in sensitivity in mothers, and to change in mood in fathers, and (d) mothers' sensitive interaction with the infant was predicted by family socio-demographic background.


Manure history and long-term tillage effects on soil properties and phosphorus losses in runoff.
Manure additions to cropland can reduce total P losses in runoff on well-drained soils due to increased infiltration and reduced soil erosion. Surface residue management in subsequent years may influence the long-term risk of P losses as the manure-supplied organic matter decomposes. The effects of manure history and long-term (8-yr) tillage [chisel plow (CP) and no-till (NT)] on P levels in runoff in continuous corn (Zea mays L.) were investigated on well-drained silt loam soils of southern and southwestern Wisconsin. Soil P levels (0-15 cm) increased with the frequency of manure applications and P stratification was greater near the surface (0-5 cm) in NT than CP. In CP, soil test P level was linearly related to dissolved P (24-105 g ha(-1)) and bioavailable P (64-272 g ha(-1)) loads in runoff, but not total P (653-1893 g ha(-1)). In NT, P loads were reduced by an average of 57% for dissolved P, 70% for bioavailable P, and 91% for total P compared with CP. This reduction was due to lower sediment concentrations and/or lower runoff volumes in NT. There was no relationship between soil test P levels and runoff P concentrations or loads in NT. Long-term manure P applications in excess of P removal by corn in CP systems ultimately increased the potential for greater dissolved and bioavailable P losses in runoff by increasing soil P levels. Maintaining high surface residue cover such as those found in long-term NT corn production systems can mitigate this risk in addition to reducing sediment and particulate P losses.


Feasibility and compliance of automated measurement of quality of life in oncology practice.
Systematic quality-of-life (QOL) assessment may have value in oncology practice by increasing awareness of a wide range of issues, possibly increasing detection of psychologic morbidity, social problems, and changes in physical status, and improving care and its outcomes. However, logistic problems are substantial. Automated systems solve many of these problems. We field-tested the feasibility and compliance that can be achieved using a computer touchscreen system in two consecutive studies. In study 1, a prospective cohort of 272 patients was offered QOL assessment at each clinic appointment for 6 months. In study 2, all patients (N = 1,291) were offered QOL assessment as part of clinic routine during a 12-week period. In study 1, 82% of patients agreed to take part, but over time, compliance was poor (median, 40%; mean, 43%) and deteriorated with longer follow-up. In study 2, the overall compliance was greatly increased (median, 100%; mean, 70%), and compliance was retained over multiple visits. In study 1, compliance was better in younger patients, males, and socially advantaged patients, but was not affected by the presence of depression or anxiety, or QOL. In the second study, building on experience in the first study, data collection and storage in the computer system was excellent, achieving 98% of collected data stored in one center. In general, patients were comfortable with the computers and the approach. Data collection on the wards was more difficult and less complete than in clinics, especially for patients undergoing acute admissions. Feasibility with higher compliance was demonstrated in study 2, in which the data collection was integrated into routine care, and can be improved with further technical initiatives and education of staff.


Altered tetrahydrobiopterin metabolism in patients with phenylalanine hydroxylase deficiency.
The tetrahydrobiopterin (BH4) cofactor is essential for the activity of various enzymes, including phenylalanine (Phe) hydroxylase. In phenylketonuria (PKU) patients, who are chronically exposed to high Phe levels, high urinary excretion of BH4 metabolites neopterin and biopterin is observed. The aim of this longitudinal study was to investigate consistence and variability of the urinary excretion of pterins (neopterin and biopterin) in PKU patients in relation to age and concomitant blood Phe and tyrosine levels. The study was based on the result of 274 pterin examinations (3-13 exams per subject) performed in 47 PKU patients (aged 6 days to 37 years). Multivariate analysis showed that urinary biopterin and neopterin excretion was affected by age and concomitant blood Phe concentration. The influence of blood Phe on both biopterin and neopterin levels was greater in patients younger than 4 months. Later on, interindividual variability was higher than intraindividual variability for both biopterin and neopterin. Common metabolic (blood Phe levels) and individual (age) factors implicated in the assessment of PKU outcome account only marginally and transiently for the variability of neopterin and biopterin excretion in PKU patients. Other unknown homeostatic factors may probably affect the individual response to chronically elevated Phe levels. What is Known: • In PKU patients, a high urinary excretion of biopterin and neopterin is found. • Biopterin and neopterin excretion is influenced by age and phenylalanine levels. W hat is New: • Blood phenylalanine concentration is the major determinant on pterin excretion in PKU patients in the first months of life. • In older PKU patients, the influence of phenylalanine on pterin excretion is less prominent.


The occurrence of nematodes of the genus Trichinella in wolves (Canis lupus) from the Bieszczady Mountains and Augustowska Forest in Poland.
The aim of the present study was to investigate the prevalence of Trichinella infection in wolves (Canis lupus) in two regions in Poland. Muscle samples were collected from 21 wolves between 1999 and 2015 and processed by artificial digestion. In two cases, the muscle larvae (ML) were obtained and stored in alcohol. ML were detected in 12 wolves and genotyped by multiplex PCR. Trichinella britovi was confirmed in 12 wolves (54.5%). The larval burdens in infected animals ranged from 0.009 to 27 larvae per gram. The high prevalence of Trichinella infection in wolves might suggest that this predator is a significant reservoir of Trichinella species in the sylvatic cycle in Poland.


Fractional flow reserve compared with intravascular ultrasound guidance for optimizing stent deployment.
Determination of fractional flow reserve (FFR) has been proposed as a means to assess stent deployment. In this prospective, multicenter trial, we evaluate the use of FFR to optimize stenting by comparing it with standard intravascular ultrasound (IVUS) criteria. Eighty-four stable patients with isolated coronary lesions underwent coronary stent deployment starting at 10 atm and increased serially by 2 atm until the FFR was >/=0.94 or 16 atm was achieved. IVUS was then performed. FFR was measured with a coronary pressure wire with intracoronary adenosine to induce hyperemia. The diagnostic characteristics of an FFR <0.94 to predict suboptimal stent expansion by IVUS, defined in both absolute and relative terms, were calculated. Over a range of IVUS criteria, the highest sensitivity, specificity, and predictive accuracy of FFR were 80%, 30%, and 42%, respectively. Receiver operator characteristic analysis defined an optimal FFR cut point at >/=0.96; at this threshold, the sensitivity, specificity, and predictive accuracy of FFR were 75%, 58%, and 62%, respectively (P=0.03 for comparison of predictive accuracy, P=0.01 for concordance between FFR and IVUS). The negative predictive value was 88%. Significantly better diagnostic performance was achieved in a subgroup that received higher doses (>30 microgram) of intracoronary adenosine during pressure measurements, suggesting that FFR might be overestimated in the other group. A fractional flow reserve <0.96, measured after stent deployment, predicts a suboptimal result based on validated intravascular ultrasound criteria; however, an FFR >/=0.96 does not reliably predict an optimal stent result. Higher doses of intracoronary adenosine than previously used to measure FFR improve these results.


[Impact of vaccination on the infectious diseases epidemiology: example of pertussis].
Several vaccines are now routinely used since fifty years in different developed countries. Their principal impact has been to decrease morbidity and mortality of the infectious diseases they are targeting. One disease, smallpox, is eradicated, poliomyelitis will be soon, diphteria is controlled in several countries but pertussis is still endemic although an efficacious vaccine was used. Why? Pertussis is an example of an infection for which the immunity of the population has changed after the introduction of generalized vaccination with killed whole cell pertussis vaccines, from a natural immunity due to infection to different types of vaccine-induced immunity. These different types of immunity have changed the protection against infection, disease and transmission. The impact of the generalized vaccination in a human population has been an important change in the epidemiology of the disease. In fact, a child-to-child transmission observed before the introduction of vaccination is now replaced by an adolescent-adult to infant transmission. The major consequence is an increase in the mortality and morbidity in non vaccinated infants mostly contaminated by their parents. Researches undertaken on the agent of the disease, the bacterium, Bordetella pertussis, conducted to the development of subunits vaccines, efficacious and better tolerated by infants than whole-cell vaccines. Many developed countries decided to change vaccines but also to add vaccine boosters for adolescents and adults in order to stop the transmission of the disease to infants. However, even after 15 years of studies in many countries, pertussis is still underestimated in adults and generalized adult vaccination remains difficult. The new goal now is to give information to medical students and health care workers in general in order to increase adolescent and adult's vaccination coverage.


Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects.
Smad5 has been implicated as a downstream signal mediator for several bone morphogenetic proteins (BMPs). To understand the in vivo function of Smad5, we generated mice deficient in Smad5 using embryonic stem (ES) cell technology. Homozygous mutant embryos die between E9.5 and E11.5, and display variable phenotypes. Morphological defects are first detected at E8.0 in the developing amnion, gut and heart (the latter defect being similar to BMP-2 knockout mice). At later stages, mutant embryos fail to undergo proper turning, have craniofacial and neural tube abnormalities, and are edematous. In addition, several extraembryonic lesions are observed. After E9.0, the yolk sacs of the mutants contain red blood cells but lack a well-organized vasculature, which is reminiscent of BMP-4, TGF-beta1 and TGF-beta type II receptor knockout mice. In addition, the allantois of many Smad5 mutants is fused to the chorion, but is not well-elongated. A unique feature of the Smad5 mutant embryos is that ectopic vasculogenesis and hematopoiesis is observed in the amnion, likely due to mislocation of allantois tissue. Despite the expression of Smad5 from gastrulation onwards, and in contrast to knockouts of Smad2 and Smad4, Smad5 only becomes essential later in extraembryonic and embryonic development.


Contact with HIV prevention programmes & willingness for new interventions among truckers in India.
Systematic data on existing coverage and willingness for HIV prevention strategies among truckers are not readily available in India. The present study aimed to further the understanding on contact of truckers with existing HIV prevention services and to assess willingness for new HIV prevention strategies. A total of 1,800 truck drivers and helpers aged 16-65 yr passing through Hyderabad were approached to assess contact made with HIV prevention programmes, history of previous HIV testing and their acceptance for circumcision, oral HIV testing, new medications to control HIV (PrEP) and telephonic counselling. Dried blood samples were collected on filter paper and tested for HIV. Multiple logistic regression was performed for analysis of association between contact with HIV prevention programme and socio-demographic, sexual risk behaviour variables and work characteristics. A total of 1,602 (89%) truckers gave interview and provided blood sample. Forty five truckers tested positive for HIV resulting in HIV prevalence of 2.8 per cent (95% CI 2.0-3.6%). Only 126 truckers (7.9%; 95% CI 6.5-9.2%) reported ever being contacted by staff providing HIV prevention interventions. Previous HIV testing was reported by19 per cent (95% CI 17.3-21.2%). Those reporting contact with HIV prevention programmes ever were more likely to have undergone HIV testing (odds ratio 3.6, 95% CI 2.4-5.4). The acceptance for pre-exposure prophylaxis (PrEP) was 87 per cent, oral HIV testing 98 per cent, and telephonic counselling 82 per cent, but was only 9 per cent for circumcision.Truckers who reported having sex with a man and those who halted regularly at dhabas were significantly more willing to undergo circumcision for HIV prevention (odds ratios 2.7, 95% CI 1.4-5.4 and 2.1, 95% CI 1.3-3.2, respectively). Our findings showed that truckers had low contact with HIV prevention programmes, suggesting a need for urgent measures to reach this population more effectively. The willingness for new HIV interventions was high except for circumcision. These findings could be used for further planning of HIV prevention programmes for truckers in India.


The health of students in institutes of higher education: an important and neglected public health problem?
A survey of students in three UK higher education establishments was undertaken to obtain information about students' physical and emotional well-being, their attitudes to, and beliefs about health, and the prevalence of risk factors for future ill health. Health was measured by the prevalence of longstanding illness and by the SF-36 health status measurement tool. Survey results were compared with equivalent data for 18- to 34-year-olds in the local population. The prevalence of long-standing illness was also compared with two national surveys. The survey achieved a 49 per cent response rate. More than one-third of respondents reported a long-standing illness, a higher prevalence than in all comparison surveys. Students scored significantly worse than their peers in the local population on all eight SF-36 dimensions. The greatest difference was for role limitations as a result of emotional problems. The main sources of emotional distress were study or work problems and money. The poor response rate in this survey dictates the need for caution in interpretation of the results. However, they suggest that the health of students is poor relative to that of their peers, and that their emotional health is more of a problem than their physical health. Public health practitioners might want to pay more attention to the health of this important and relatively neglected group. Worries about studies and money appear to be affecting students' academic work, and this should be of concern to higher education establishments.


The role of social capital in explaining mental health inequalities between immigrants and Swedish-born: a population-based cross-sectional study.
Social capital may theoretically explain health inequalities between social groups, but empirical evidence is lacking. Some studies indicate that social capital may be particularly important for immigrant health. Nearly 16% of Sweden's population are foreign-born immigrants and research has shown them to be susceptible to psychological distress, though significant variation has been found between groups. In this study, we investigate the following hypotheses: 1) if non-refugees have better mental health than Swedish-born, and refugees experience worse mental health than Swedish-born; 2) if mental health status converges with that of Swedish-born with longer duration of residence; and 3) if social capital mediates the effect of immigrant status on psychological distress for different immigrant groups as compared to Swedish-born. This cross-sectional study uses baseline data from the Stockholm Public Health Cohort and includes 50,498 randomly-selected individuals from Stockholm County in 2002, 2006, and 2010. Mental health was measured as psychological distress, using the 12-item General Health Questionnaire. Social capital was measured using indicators of bonding, bridging, and linking social capital. Both cognitive and structural aspects were measured for the latter two indicators. Mediation was tested using logistic regression and the Sobel test. The results show that refugees generally had greater odds of psychological distress than non-refugees compared to their respective Swedish-born counterparts. Among immigrant men, both refugees and non-refugees had significantly greater odds of psychological distress than Swedish-born men. Only refugee women in Sweden 10 years or more had significantly greater odds of psychological distress compared to Swedish-born women. The mediation analysis demonstrated that indicators of social capital mediated the association for all immigrant men (except non-refugees in Sweden 3-9 years) and for refugee women in Sweden 10 years or more. While bonding social capital showed the greatest mediatory role among the three social capital types, adding them together had the strongest explanatory effect. Social capital explains differences in mental health for some immigrant groups, highlighting its role as a potentially important post-migration factor. Increased investment from policy-makers regarding how social capital can be promoted among new arrivals may be important for preventing psychological distress.


The value of the Semantic Web in the laboratory.
The Semantic Web is beginning to impact on the wider chemical and physical sciences, beyond the earlier adopted bio-informatics. While useful in large-scale data driven science with automated processing, these technologies can also help integrate the work of smaller scale laboratories producing diverse data. The semantics aid the discovery, reliable re-use of data, provide improved provenance and facilitate automated processing by increased resilience to changes in presentation and reduced ambiguity. The Semantic Web, its tools and collections are not yet competitive with well-established solutions to current problems. It is in the reduced cost of instituting solutions to new problems that the versatility of Semantic Web-enabled data and resources will make their mark once the more general-purpose tools are more available.


Prevalence and factors related to malocclusion, normative and perceived orthodontic treatment need among children and adolescents in Bangladesh.
The purpose of the present study was to assess the prevalence of normative and perceived orthodontic treatment need in schoolchildren and adolescents, related risk factors, and children/parent's aesthetic perception, compared to orthodontist's opinion, in Dhaka city, Bangladesh. A random sample of 800 schoolchildren aging 11-15 years was selected from different schools in the city of Dhaka, Bangladesh. The Dental Health Component (DHC) and Aesthetic Component (AC) of the Index of Orthodontic Treatment Need (IOTN) were assessed as normative treatment need. The Decayed, Missing, Filled Teeth (DMFT) index was used to record caries experience. Children were interviewed on the perception of orthodontic treatment need. Parents also completed a questionnaire on the perception of their child's orthodontic treatment need, assessed by AC/ IOTN. According to the DHC/IOTN, only 24.7% were in the category of definite need (grade 4-5) for orthodontic treatment. A significant difference was found between the clinician/children and clinician/parents perceived AC score of IOTN (p= 0.0001). Multiple logistic regression showed children with a higher DMFT were significantly more likely to need orthodontic treatment, according to the DHC of IOTN. A low proportion of schoolchildren needs normative orthodontic treatment in the city of Dhaka, Bangladesh. Children with a higher DMFT score were significantly more likely to need orthodontic treatment, according to the DHC of IOTN.


Contextual novelty changes reward representations in the striatum.
Reward representation in ventral striatum is boosted by perceptual novelty, although the mechanism of this effect remains elusive. Animal studies indicate a functional loop (Lisman and Grace, 2005) that includes hippocampus, ventral striatum, and midbrain as being important in regulating salience attribution within the context of novel stimuli. According to this model, reward responses in ventral striatum or midbrain should be enhanced in the context of novelty even if reward and novelty constitute unrelated, independent events. Using fMRI, we show that trials with reward-predictive cues and subsequent outcomes elicit higher responses in the striatum if preceded by an unrelated novel picture, indicating that reward representation is enhanced in the context of novelty. Notably, this effect was observed solely when reward occurrence, and hence reward-related salience, was low. These findings support a view that contextual novelty enhances neural responses underlying reward representation in the striatum and concur with the effects of novelty processing as predicted by the model of Lisman and Grace (2005).


Group structure predicts variation in proximity relationships between male-female and male-infant pairs of mountain gorillas (Gorilla beringei beringei).
Relationships between conspecifics are influenced by both ecological factors and the social organization they live in. Systematic variation of both--consistent with predictions derived from socioecology models--is well documented, but there is considerable variation within species and populations that is poorly understood. The mountain gorilla (Gorilla beringei) is unusual because, despite possessing morphology associated with male contest competition (e.g., extreme sexual dimorphism), they are regularly observed in both single-male and multimale groups. Both male-female and male-infant bonds are strong because males provide protection against infanticide and/or predation. Risk of these threats varies with social structure, which may influence the strength of social relationships among group members (including females and offspring, if females with lower infant mortality risk are less protective of infants). Here, we investigate the relationship between group structure and the strength of proximity relationships between males and females, males and infants, and females and offspring. Data come from 10 social groups containing 1-7 adult males, monitored by the Dian Fossey Gorilla Fund's Karisoke Research Center in Volcanoes National Park, Rwanda. After controlling for group size and infant age, association strength was similar for male-female pairs across group types with both dominant and nondominant males, but male-infant relationships were strongest in single-male groups where paternity certainty was high and animals had fewer social partners to choose from. The male:female and male:infant ratios better predicted both male-female and male-infant associations than the absolute number of males, females, or infants did. The fewer the number of males per female or infant, the more both pair types associated. Dominant males in groups containing fewer males had higher eigenvector centrality (a measure of importance in a social network) than dominant males in groups with more males. Results indicate that nondominant males are an important influence on relationships between dominant males and females/infants despite their peripheral social positions, and that relationships between males and infants must be considered an important foundation of gorilla social structure.


Cardiovascular Health in Turner Syndrome: A Scientific Statement From the American Heart Association.
Girls and women with Turner syndrome face a lifelong struggle with both congenital heart disease and acquired cardiovascular conditions. Bicuspid aortic valve is common, and many have left-sided heart obstructive disease of varying severity, from hypoplastic left-sided heart syndrome to minimal aortic stenosis or coarctation of the aorta. Significant enlargement of the thoracic aorta may progress to catastrophic aortic dissection and rupture. It is becoming increasingly apparent that a variety of other cardiovascular conditions, including early-onset hypertension, ischemic heart disease, and stroke, are the major factors reducing the life span of those with Turner syndrome. The presentations and management of cardiovascular conditions in Turner syndrome differ significantly from the general population. Therefore, an international working group reviewed the available evidence regarding the diagnosis and treatment of cardiovascular diseases in Turner syndrome. It is recognized that the suggestions for clinical practice stated here are only the beginning of a process that must also involve the establishment of quality indicators, structures and processes for implementation, and outcome studies.


Controlling Underage Drinking: Fear of Law Enforcement or Internalized Normative Values?
Previous research on alcohol control policies has generally taken a deterrence perspective. Whether internalized normative values, consistent with the changes intended by alcohol policies, were a potential base for securing public compliance with them has received little research attention. To fill this gap, this study examined whether underage young adults' support for underage drinking laws was associated with their alcohol use. National Alcohol Surveys (NAS) data collected in 1995-2005 were used. Multivariate logistic regression analyses were conducted. Covariates included: sex, race, education level, household income, positive alcohol expectancies, the perceived likelihood of law enforcement, and the availability and affordability of alcohol. Controlling for other covariates, support for underage drinking laws was significantly associated with some drinking outcomes. Underage young adults who were not supportive of the minimum legal drinking age law were more likely to engage in frequent binge drinking (OR=3.08) and drinking driving (OR=4.17), and to have initiated drinking at age 16 or younger (OR=2.37). Those who indicated a lower degree of support for the zero-tolerance drunk driving law had higher odds of drinking driving (OR=4.36), as well as higher odds of having ever had alcohol (OR=5.46), current drinking (OR=5.36), and having initiated drinking at the age of 16 or younger (OR=3.09). The perceived likelihood of law enforcement was protective only from frequent binge drinking (OR=0.09). A clear articulation of potential harms associated with underage drinking to help legitimize underage drinking laws, along with their rigorous enforcement, may help reduce underage drinking.


Identification of prostate-specific antigen (PSA) isoforms in complex biological samples utilizing complementary platforms.
Measurements of the prostate-specific antigen (PSA) levels in blood are widely used as diagnostic, predictive and prognostic marker of prostate disease. The selective detection of molecular forms of PSA can contribute clinically to meaningful enhancements of the conventional PSA-test. As it is plausible that an in-depth search for structural variants of PSA gene products may increase our ability to discriminate distinct patho-biological basis and stages of prostate diseases, we have developed a multi-step protocol comprising gel-based methods followed by mass spectrometric identification. Our current aim was to provide a comprehensive identification of PSA variants occurring in seminal fluid. We provide a proof-of-principle for this multiple step analytical approach to identify multiple PSA variants from complex biological samples that revealed distinct molecular characteristics. In addition, sequence-annotated protein bands in SDS-PAGE gels were compared to those detected by Western blots, and by monitoring the enzymatic activity in zymogram gels, using gelatin as a substrate. The high accuracy annotations were obtained by fast turnaround MALDI-Orbitrap analysis from excised and digested gel bands. Multiple PSA forms were identified utilizing a combination of MASCOT and SEQUEST search engines.


Linguistic validation and reliability properties are weak investigated of most dementia-specific quality of life measurements-a systematic review.
For people with dementia, the concept of quality of life (Qol) reflects the disease's impact on the whole person. Thus, Qol is an increasingly used outcome measure in dementia research. This systematic review was performed to identify available dementia-specific Qol measurements and to assess the quality of linguistic validations and reliability studies of these measurements (PROSPERO 2013: CRD42014008725). The MEDLINE, CINAHL, EMBASE, PsycINFO, and Cochrane Methodology Register databases were systematically searched without any date restrictions. Forward and backward citation tracking were performed on the basis of selected articles. A total of 70 articles addressing 19 dementia-specific Qol measurements were identified; nine measurements were adapted to nonorigin countries. The quality of the linguistic validations varied from insufficient to good. Internal consistency was the most frequently tested reliability property. Most of the reliability studies lacked internal validity. Qol measurements for dementia are insufficiently linguistic validated and not well tested for reliability. None of the identified measurements can be recommended without further research. The application of international guidelines and quality criteria is strongly recommended for the performance of linguistic validations and reliability studies of dementia-specific Qol measurements.


Visual outcome of laser treatment in diabetic macular edema: Study from an Urban Diabetes Care Center.
To determine the visual outcome of laser treatment in clinically significant macular edema. This interventional and qausi experimental study was carried out at Diabetic Association of Pakistan (DAP) during January 2011 and December 2012. Approval was taken from Research Ethical Committee of Isra Postgraduate Institute of Ophthalmology. Records of 925 eyes of 464 patients with "Clinical Significant macular edema" (CSME), treated with laser photocoagulation were analyzed. Best-corrected visual acuity (BCVA) at the time of presentation and at the last follow up, minimum of one year and maximum of 45 months was recorded and compared. SPSS version 20.0 was used to analyze the data. Diabetic retinopathy was found in 20.3% (1777) of 8742 diabetic attending DAP Hospital" amongst whom 39.6% (705) had Sight threatening diabetic retinopathy. Laser was advised in 96.4% (680) individuals, accepted by 70.5% (480) individuals. Amongst 960 eyes of 480 patients who accepted laser, 925 eyes had clinically significant macular edema and 35 eyes had PDR who are not included in this study. Amongst 925 eyes with CSME, Grid laser was done in 913 eyes (99%) and focal laser was done in 12 eyes (1%). After a follow up of 12 to 45 months, it was found that best corrected visual acuity had declined in 2.4% (22) eyes, stabilized in 67% (619) eyes and improved in 30.7% (284) eyes. One line improvement on Snellen's chart was fond in 21.3% (197) eyes, 2 lines in 8% (74) eyes, 3 lines in 1.2% (12) eyes and 4 lines in one (0.1%) eye with p-value of 0.000. Laser therapy is an effective treatment in stabilizing/improving the vision in diabetic macular edema particularly at those centers where only Argon Laser is available and OCF, FFA facilities do not exist.


Mammalian exocrine secretions: X. constituents of preorbital secretion of grysbok,Raphicerus melanotis.
Using electron impact and chemical ionization mass spectrometry with methane and nitric oxide as reactant gases in conjunction with mass spectral analysis of the dimethyl disulfide derivatives of unsaturated constituents, 51 compounds have been identified in addition to the compounds previously found in the preorbital secretion of the grysbokRaphicerus melanotis. The compounds identified are saturated, monounsaturated, and diunsaturated alcohols and formates, saturated and monounsaturated aldehydes, saturated carboxylic acids,γ- andδ-lactones, alkyl methyl sulfides, andβ-hydroxyalkyl acetates. All of these compounds have unbranched structures. The constituent previously incorrectly identified as (Z)-5-tetradecen-1-ol, was found to consist of the coeluting (Z)-7- and (Z)-8-tetradecenols.


Hepatitis B virus in patients with chronic hepatitis C treated with direct antiviral agents.
cases of hepatitis B virus (HBV) reactivation have been reported in patients with hepatitis C virus (HCV) treated with direct antiviral agents (DAA). the main objectives of the present study are: a) to determine the prevalence of HBV/HCV coinfection in HCV patients treated with DAAs in the Autonomous Community of Madrid (CM) and also to determine the incidence and clinical relevance of HBV reactivation; and b) to determine the HBV screening rates in HCV patients in our region. For that purpose, 1,337 HCV patients were consecutively treated with DAAs in two hospitals located in South CM between January 2015 and June 2017. nine of the 1,337 (0.67%) participants were HBsAg positive and 356 (26.6%) had previous HBV infection markers. Two of the four (50%) HBsAg positive patients with untreated HBV developed a virological reactivation, but not a biochemical reaction. Of the 356 patients with previous HBV infection markers, all had normal transaminases at the end of treatment and during follow-up. The HBV screening rate amounted to 92.9% of the cohort. the prevalence of HBV (HBsAg positive) infection in patients with chronic hepatitis C in the southern area of the CM is low. HBV reactivation in HBsAg positive patients treated with DAAs is common, although without clinical relevance. In our region, there is a high rate of HBV screening in patients with HCV that are likely treated with DAAs.


Validity of single item responses to short message service texts to monitor depression: an mHealth sub-study of the UK ACUDep trial.
An increasing number of research designs are using text messaging (SMS) as a means of self-reported symptom and outcome monitoring in a variety of long-term health conditions, including severity ratings of depressed mood. The validity of such a single item SMS score to measure latent depression is not currently known and is vital if SMS data are to inform clinical evaluation in the future. A sub-set of depressed participants in the UK ACUDep trial submitted a single SMS text score (R-SMS-DS) between 1 and 9 on how depressed they felt around the same time as completing the PHQ-9 depression questionnaire on paper at 3 months follow-up of the trial. Exploratory categorical data factor analysis (EFA) was used to ascertain the alignment of R-SMS-DS scores with the factor structure of the PHQ-9. Any response bias with regard to age or gender was assessed by differential item functioning (DIF) analysis. Depression scores based on the PHQ-9 and R-SMS-DS at 3 months were available for 337 participants (74 % female; mean age: 42 years, SD = 11.1), 213 of which completed the two outcomes within 6 days of each other. R-SMS-DS scores aligned with the underlying latent depression of the PHQ-9 (factor loading of 0.656) and in particular its affective rather than somatic dimension. The R-SMS-DS score was most strongly correlated with depressed mood (r = 0.607), feeling bad about oneself (r = 0.588) and anhedonia (r = 0.573). R-SMS-DS responses were invariant with respect to gender (p = 0.302). However, there was some evidence for age related response bias (p = 0.031), with older participants being more likely to endorse lower R-SMS-DS scores than younger ones. The R-SMS-DS used in the ACUDep trial was found to be a valid measure of latent affective depression with no gender related response bias. This text message item may therefore represent a useful assessment and monitoring tool meriting evaluation in further research. For future study designs we recommend the collection of outcome data by new health technologies in combination with gold standard instruments to ensure concurrent validity.


Towards an informative mutant phenotype for every bacterial gene.
Mutant phenotypes provide strong clues to the functions of the underlying genes and could allow annotation of the millions of sequenced yet uncharacterized bacterial genes. However, it is not known how many genes have a phenotype under laboratory conditions, how many phenotypes are biologically interpretable for predicting gene function, and what experimental conditions are optimal to maximize the number of genes with a phenotype. To address these issues, we measured the mutant fitness of 1,586 genes of the ethanol-producing bacterium Zymomonas mobilis ZM4 across 492 diverse experiments and found statistically significant phenotypes for 89% of all assayed genes. Thus, in Z. mobilis, most genes have a functional consequence under laboratory conditions. We demonstrate that 41% of Z. mobilis genes have both a strong phenotype and a similar fitness pattern (cofitness) to another gene, and are therefore good candidates for functional annotation using mutant fitness. Among 502 poorly characterized Z. mobilis genes, we identified a significant cofitness relationship for 174. For 57 of these genes without a specific functional annotation, we found additional evidence to support the biological significance of these gene-gene associations, and in 33 instances, we were able to predict specific physiological or biochemical roles for the poorly characterized genes. Last, we identified a set of 79 diverse mutant fitness experiments in Z. mobilis that are nearly as biologically informative as the entire set of 492 experiments. Therefore, our work provides a blueprint for the functional annotation of diverse bacteria using mutant fitness.


Persistence and Prognostic Implications of Orthostatic Hypotension in Older Individuals with Mild-to-Moderate Dementia.
To study the course and prognostic implications of orthostatic hypotension (OH) in older individuals with mild-to-moderate dementia. Referrals to outpatient clinics specialising in old age psychiatry and geriatric medicine in the counties of Rogaland and Hordaland in western Norway with a first-time diagnosis of mild dementia were consecutively asked for inclusion. A total of 211 participants underwent a comprehensive baseline assessment with annual follow-ups. Patients with OH at both baseline and the 1-year follow-up were classified as having persistent OH. Outcome measures were the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating sum of boxes (CDR-SB), and time to death. From baseline to the 4-year follow-up, 30-45% of the participants had OH at each follow-up. In multivariable analysis, persistent OH was not significantly associated with either the longitudinal course of MMSE or CDR-SB scores or survival. OH was moderately prevalent over 4 years in older individuals with mild dementia, and persistent OH did not predict either cognitive or functional decline or survival.


invertFREGENE: software for simulating inversions in population genetic data.
Inversions are a common form of structural variation, which may have a marked effect on the genome and methods to infer quantities of interest such as those relating to population structure and natural selection. However, due to the challenge in detecting inversions, little is presently known about their impact. Software to simulate inversions could be used to provide a better understanding of how to detect and account for them; but while there are several software packages for simulating population genetic data, none incorporate inversion polymorphisms. Here, we describe a software package, modified from the forward-in-time simulator FREGENE, which simulates the evolution of an inversion polymorphism, of specified length, location, frequency and age, in a population of sequences. We describe previously unreported signatures of inversions in SNP data observed in invertFREGENE results and a known inversion in humans. C++ source code and user manual are available for download from http://www.ebi.ac.uk/projects/BARGEN/ under the GPL licence. firstname.lastname@example.com; email@example.com Supplementary data are available at Bioinformatics online.


PubChem3D: Conformer generation.
PubChem, an open archive for the biological activities of small molecules, provides search and analysis tools to assist users in locating desired information. Many of these tools focus on the notion of chemical structure similarity at some level. PubChem3D enables similarity of chemical structure 3-D conformers to augment the existing similarity of 2-D chemical structure graphs. It is also desirable to relate theoretical 3-D descriptions of chemical structures to experimental biological activity. As such, it is important to be assured that the theoretical conformer models can reproduce experimentally determined bioactive conformations. In the present study, we investigate the effects of three primary conformer generation parameters (the fragment sampling rate, the energy window size, and force field variant) upon the accuracy of theoretical conformer models, and determined optimal settings for PubChem3D conformer model generation and conformer sampling. Using the software package OMEGA from OpenEye Scientific Software, Inc., theoretical 3-D conformer models were generated for 25,972 small-molecule ligands, whose 3-D structures were experimentally determined. Different values for primary conformer generation parameters were systematically tested to find optimal settings. Employing a greater fragment sampling rate than the default did not improve the accuracy of the theoretical conformer model ensembles. An ever increasing energy window did increase the overall average accuracy, with rapid convergence observed at 10 kcal/mol and 15 kcal/mol for model building and torsion search, respectively; however, subsequent study showed that an energy threshold of 25 kcal/mol for torsion search resulted in slightly improved results for larger and more flexible structures. Exclusion of coulomb terms from the 94s variant of the Merck molecular force field (MMFF94s) in the torsion search stage gave more accurate conformer models at lower energy windows. Overall average accuracy of reproduction of bioactive conformations was remarkably linear with respect to both non-hydrogen atom count ("size") and effective rotor count ("flexibility"). Using these as independent variables, a regression equation was developed to predict the RMSD accuracy of a theoretical ensemble to reproduce bioactive conformations. The equation was modified to give a minimum RMSD conformer sampling value to help ensure that 90% of the sampled theoretical models should contain at least one conformer within the RMSD sampling value to a "bioactive" conformation. Optimal parameters for conformer generation using OMEGA were explored and determined. An equation was developed that provides an RMSD sampling value to use that is based on the relative accuracy to reproduce bioactive conformations. The optimal conformer generation parameters and RMSD sampling values determined are used by the PubChem3D project to generate theoretical conformer models.