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Classical stewardship efforts have targeted immunocompetent patients; however, appropriate use of antimicrobials in the immunocompromised host has become a target of interest. Cytomegalovirus (CMV) infection is one of the most common and significant complications after solid-organ transplant (SOT). The treatment of CMV requires a dual approach of antiviral drug therapy and reduction of immunosuppression for optimal outcomes. This dual approach to CMV management increases complexity and requires individualization of therapy to balance antiviral efficacy with the risk of allograft rejection. In this review, we focus on the development and implementation of CMV stewardship initiatives, as a component of antimicrobial stewardship in the immunocompromised host, to optimize the management of prevention and treatment of CMV in SOT recipients. These initiatives have the potential not only to improve judicious use of antivirals and prevent resistance but also to improve patient and graft survival given the interconnection between CMV infection and allograft function.
Quetiapine immediate release (quetiapine IR) improves PANSS total, positive, negative and general psychopathology scores in schizophrenia. This study (D1444C00132) evaluated the efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) in patients with acute schizophrenia.
This was a 6-week, double-blind, randomised study (n=588) comparing quetiapine XR (400, 600 or 800 mg/day) and quetiapine IR (400 mg/day) with placebo. Efficacy was assessed using ANCOVA analyses of the change from baseline to study endpoint (Day 42) for: PANSS total score; positive, negative and general psychopathology subscale scores; and aggression and depression cluster scores (modified ITT population, LOCF). Changes in individual PANSS item scores were assessed post hoc.
At Day 42, there were statistically significant reductions (ie two-sided p-value <0.05) versus placebo with all doses of quetiapine XR for the change in PANSS total, positive, general psychopathology and aggression cluster scores. Changes in negative and depression cluster scores were statistically significant versus placebo for quetiapine XR 600 mg/day and 800 mg/day. There was statistically significant separation from placebo with quetiapine XR 600 mg/day and 800 mg/day for the change in 6/7 PANSS positive items, 5/7 negative items, and 12/16 general psychopathology items. For those items with no statistically significant separation from placebo, baseline scores were generally low.
Once-daily quetiapine XR is effective across a broad range of symptoms in acute schizophrenia, including positive and negative symptoms, as well as symptoms of general psychopathology, aggression and depression.
Neuropsychological deficits are considered endophenotypes for schizophrenia, because they are not only found in patients but also in many of their unaffected relatives, albeit in attenuated form. It is not yet clear which of these deficits in relatives are related to genetic or to environmental causes. We tested effects of inferred genetic liability for schizophrenia on neurocognitive variables to address this problem.
Twenty-eight patients with schizophrenia, 129 non-affected biological parents and 143 matched controls were assessed with an extensive neuropsychological test battery including tests of attention, memory, executive functioning and motor soft signs. Twenty-two parents had an ancestral history of schizophrenia and therefore were hypothesized to be more likely than their spouses without such a history (n = 17) to carry a genetic risk for schizophrenia.
Unaffected parents of schizophrenic patients showed significant deficits in a wide array of neuropsychological tasks and task domains. However, comparison of more likely and less likely carriers of illness-related genes showed specifically attentional and executive functioning, but not memory, to vary with degree of inferred genetic loading.
Attentional and executive (frontal) impairments vary with genetic loading for schizophrenia and can be considered true endophenotypes for this disorder. Consequently, these functions are particularly suited to evaluate the functional impact of candidate genes for schizophrenia in future studies.
Prolactin (PRL) data from adolescents treated with olanzapine are presented.
Data from 454 adolescents (13-18, mean=15.9 yrs) with schizophrenia or bipolar mania were pooled from 4 olanzapine (2.5-20.0mg/day) studies (4-32 weeks; 2 double-blind, placebo-controlled studies [combined for acute phase endpoint PRL levels] with open-label extensions; 2 open-label studies). Age- and sex-specific Covance reference ranges defined normal PRL; categorical increases were based on multiples of the upper limit of normal (ULN). Baseline-to-endpoint PRL changes in adolescents were compared with data pooled from 84 olanzapine clinical trials in adults with schizophrenia or bipolar disorder.
Olanzapine-treated adolescents had mean PRL increases at both the acute (11.4μg/L) and open-label endpoints (4.7μg/L). Of those patients with normal PRL levels at baseline (N=311), high PRL occurred in 54.7% at anytime; 32.2% at endpoint. The percentage of patients in which PRL levels shifted from normal-to-abnormal was smaller at endpoint than at anytime during treatment; 26.7% shifted to a higher category. Among patients with normal baseline PRL, 32.7% remained <=1X ULN; 32.3% increased to 1¬<=2X; 6.0%, >2-<=3X; and 1.2%, >3X at anytime; 4.6% had at >=1 potentially PRL-related adverse event. Adolescents had significantly higher mean changes at endpoint (p=.004), and a greater incidence of high PRL levels at anytime during olanzapine treatment (p<.001) versus adults.
Incidence of high PRL was significantly higher, and mean increases in PRL were significantly greater in adolescents versus adults. Mean increases and high PRL incidence were lower at the open-label compared with the acute phase endpoint.
To evaluate efficacy and tolerability of quetiapine sustained release (SR) in a 6-week study (D1444C00132).
588 patients with acute schizophrenia (PANSS total ≥70; CGI-S ≥4) were randomised to fixed-dose quetiapine SR 400, 600 or 800 mg/day (once-daily), quetiapine immediate release (IR) 400 mg/day (200 mg twice-daily; 5-day dose-escalation schedule), or placebo. Quetiapine SR doses: 400, 600 mg reached by Day 2; 800 mg by Day 3. Primary endpoint: change from baseline to Day 42 in PANSS total score (LOCF; ANCOVA). Other assessments: PANSS response rate (% patients with ≥30% reduction in total score from baseline); CGI-I response rate (% patients with rating ≤3); CGI-S; AEs.
446 patients (76%) completed the study (similar across groups). LS mean change from baseline in PANSS total score at Day 42 showed significant improvement versus placebo (-18.8): -24.8 (p=0.03), -30.9 (p<0.001), and -31.3 (p<0.001), quetiapine SR 400, 600, and 800 mg, respectively; -26.6 (p=0.004), quetiapine IR. Statistical separation from placebo at Day 42 for: change from baseline in CGI-S (quetiapine SR 600 and 800 mg; IR); PANSS and CGI-I response rates (all active treatments). Most common AEs with quetiapine: somnolence and dizziness. There were no unexpected AEs with quetiapine SR. Incidence of EPS-related AEs was similar to placebo. Two quetiapine SR and two IR patients discontinued due to AEs in Week 1.
Once-daily quetiapine SR (400-800 mg) was effective versus placebo in patients with acute schizophrenia. Rapid dose escalation was well tolerated, with a therapeutically effective dose reached by Day 2.
The changes in metabolic parameters in olanzapine-treated adolescents were examined.
Data from 454 adolescents (13–18, mean=15.9 years) with schizophrenia or bipolar I disorder were pooled from 4 olanzapine (2.5–20.0mg/day) studies (4–32 weeks). Changes in metabolic parameters in adolescents were compared with those of olanzapine-treated adults (pooled from 84 clinical trials); changes in weight and BMI were compared with US age- and sex-adjusted standardized growth curves.
Olanzapine-treated adolescents had significant increases from baseline-to-endpoint in fasting glucose (p=.021); total cholesterol, LDL, and triglycerides (p<.001); and significant decreases in HDL (p<.001). Significantly more adolescents gained >=7% of their baseline weight versus adults (65.1% vs. 35.6%, p<.001); mean change from baseline-to-endpoint in weight was significantly greater in adolescents (7.0 vs. 3.3kg, p<.001). Adolescents had significantly lower mean changes from baseline-to-endpoint in fasting glucose (0.3 vs. 0.1mmol/L, p=.002) and triglycerides (0.3 vs. 0.2mmol/L, p=.007) versus adults. Significantly more adults experienced treatment-emergent normal-to-high changes at anytime in fasting glucose (4.8% vs. 1.2%, p=.033), total cholesterol (6.9% vs. 1.1%, p=.001), LDL (5.8% vs. 1.5%, p=.014), and triglycerides (25.7% vs. 17.4%, p=.030). Compared with standardized growth curves, olanzapine-treated adolescents had greater increases from baseline-to-endpoint in weight (1.0 vs. 7.1kg, p<.001), height (0.5 vs. 0.7cm, p<.001), and BMI (0.2 vs. 2.2kg/m2, p<.001).
Olanzapine-treated adolescents may gain significantly more weight compared with adults, but may have smaller changes in other metabolic parameters. Clinicians may want to consider both efficacy and changes in metabolic parameters when selecting treatment options for individual adolescent patients.
Neurocognitive and functional neuroimaging studies point to frontal lobe abnormalities in schizophrenia. Molecular and behavioural genetic studies suggest that the frontal lobe is under significant genetic influence. We carried out structural magnetic resonance imaging (MRI) of the frontal lobe in monozygotic (MZ) twins concordant or discordant for schizophrenia and healthy MZ control twins.
The sample comprised 21 concordant pairs, 17 discordant affected and 18 discordant unaffected twins from 19 discordant pairs, and 27 control pairs. Groups were matched on sociodemographic variables. Patient groups (concordant, discordant affected) did not differ on clinical variables. Volumes of superior, middle, inferior and orbital frontal gyri were calculated using the Cavalieri principle on the basis of manual tracing of anatomic boundaries. Group differences were investigated covarying for whole-brain volume, gender and age.
Results for superior frontal gyrus showed that twins with schizophrenia (i.e. concordant twins and discordant affected twins) had reduced volume compared to twins without schizophrenia (i.e. discordant unaffected and control twins), indicating an effect of illness. For middle and orbital frontal gyrus, concordant (but not discordant affected) twins differed from non-schizophrenic twins. There were no group differences in inferior frontal gyrus volume.
These findings suggest that volume reductions in the superior frontal gyrus are associated with a diagnosis of schizophrenia (in the presence or absence of a co-twin with schizophrenia). On the other hand, volume reductions in middle and orbital frontal gyri are seen only in concordant pairs, perhaps reflecting the increased genetic vulnerability in this group.
Affective symptomatology has repeatedly been suggested to confer susceptibility to tardive dyskinesia (TD). In our sample of 174 schizophrenic patients a history of depressive symptoms was not associated with the occurrence of TD, whereas manic symptomatology was significantly associated with the absence of TD. Thus, our data suggest that affective symptomatology cannot unambiguously be considered to predispose to TD.
This study considers the question of whether relapse rates among schizophrenic patients can be reduced by means of relatives' groups. In a randomized, controlled intervention study, two therapeutic strategies (therapeutic relatives' groups, initiated relatives' self-help groups) were compared with each other and with a control group. Interventions were confined to the relatives, with the patients continuing their standard treatment. The study involved 151 relatives of 99 chronic DSMIII schizophrenics. Data were collected before and after a 1-year intervention phase and in a 2-year follow-up. No difference existed between the groups with respect to rehospitalization data. However, numerous differences recorded in the psychopathological findings and in living and working circumstances suggest that therapeutic work with relatives is of clinically significant benefit.
The COVID-19 pandemic has stunned the global community with marked social and psychological ramifications. There are key challenges for psychiatry that require urgent attention to ensure mental health well-being for all – COVID-19-positive patients, healthcare professionals, first responders, people with psychiatric disorders and the general population. This editorial outlines some of these challenges and research questions, and serves as a preliminary framework of what needs to be addressed. Mental healthcare should be an integral component of healthcare policy and practice towards COVID-19. Collaborative efforts from psychiatric organisations and their members are required to maximise appropriate clinical and educational interventions while minimising stigma.
Many factors, including pathogens, environmental change and breeding techniques, affect honeybee immunity/resistance, so substances and natural supplements that enhance it are desired. To eliminate the impact of unknown external factors, in 2016 a cage experiment was conducted under constant laboratory conditions (35 °C, 65% relative humidity). Bees in the control group were fed with sugar dissolved in water at ratio 1:1 ad libitum with no additives, while the other group was fed with sugar syrup (1:1) supplemented with piperine (3 µg/ml) ad libitum. The piperine-treated workers lived 9 days longer compared to the control group. In the piperine-consuming group, protein concentration and the activities of antioxidative enzymes, such as superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) and glutathione S-transferase (GST), were higher than in the control group. The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were also higher in the piperine-treated group. Neutral and acidic proteases inhibitors, as well as neutral protease activities, were higher in the haemolymph of the piperine-treated workers than in untreated bees. Acidic protease activities in the haemolymph were higher in untreated workers only on days 18 and 32. Alkaline protease activities in the control bees were higher from day 10. From 10 days old, the total antioxidant capacity level was significantly higher in the haemolymph of piperine-treated workers. Piperine decreased DNA methylation levels significantly in the older bees. The compound could have the potential to be a natural diet supplement increasing apian resistance to stress factors.
The electrical reliability of multilayer high density interconnection printed circuit boards (HDI-PCBs) is mainly affected by the thermo-mechanical stability of stacked micro via interconnections. Here, a critical failure mode is the stress related crack between the electrolytically filled via and the target pad, commonly known as target pad separation. The junction includes two Cu-Cu-interfaces, one between the target Cu pad and the thin electroless Cu layer and the second between electroless Cu and electrolytic Cu. In this paper we will show that state-of-the-art electroless Cu plating processes are able to provide solid, completely recrystallized and highly reliable stacked via junctions. Defect free interfaces were achieved by using ionic Pd-activators and electroless Cu baths with a cyanide based stabilizer system. Cyanide free electroless Cu baths tend more to the formation of nanometer sized defects, discovered via Transmission Electron Microscopy (TEM). In this case a precise adjustment of single stabilizer components is mandatory to achieve defect free layers. The defects are hollow and were identified as “nano voids”. A critical density of these nano voids weakens the interface, predefines the crack path and reduces the overall reliability of the junction. A precise localization of the nano voids within the junction was enabled by detecting the Ni-containing electroless Cu layer via TEM-Ni mapping. Slower volume exchange of the electroless Cu solution within the blind micro via (BMV) substantially increases the nano void density. The ability of nano voids to migrate and coalesce at elevated temperatures was investigated as well.
Cir X-1 is a young X-ray binary exhibiting X-ray flux changes of four orders of magnitude over several decades. It has been observed many times since the launch of the Chandra X-ray Observatory with high energy transmission grating spectrometer and each time the source gave us a vastly different look. At its very lowest X-ray flux we found a single 1.7 keV blackbody spectrum with an emission radius of 0.5 km. Since the neutron star in Cir X-1 is only few thousand years old we identify this as emission from an accretion column since at this youth the neutron star is assumed to be highly magnetized. At an X-ray flux of 1.8×10−11 erg cm−2 s−1 this implies a moderate magnetic field of a few times of 1011 G. The photoionized X-ray emission line properties at this low flux are consistent with B5-type companion wind. We suggest that Cir X-1 is a very young Be-star binary.
A range of endophenotypes characterise psychosis, however there has been limited work understanding if and how they are inter-related.
This multi-centre study includes 8754 participants: 2212 people with a psychotic disorder, 1487 unaffected relatives of probands, and 5055 healthy controls. We investigated cognition [digit span (N = 3127), block design (N = 5491), and the Rey Auditory Verbal Learning Test (N = 3543)], electrophysiology [P300 amplitude and latency (N = 1102)], and neuroanatomy [lateral ventricular volume (N = 1721)]. We used linear regression to assess the interrelationships between endophenotypes.
The P300 amplitude and latency were not associated (regression coef. −0.06, 95% CI −0.12 to 0.01, p = 0.060), and P300 amplitude was positively associated with block design (coef. 0.19, 95% CI 0.10–0.28, p < 0.001). There was no evidence of associations between lateral ventricular volume and the other measures (all p > 0.38). All the cognitive endophenotypes were associated with each other in the expected directions (all p < 0.001). Lastly, the relationships between pairs of endophenotypes were consistent in all three participant groups, differing for some of the cognitive pairings only in the strengths of the relationships.
The P300 amplitude and latency are independent endophenotypes; the former indexing spatial visualisation and working memory, and the latter is hypothesised to index basic processing speed. Individuals with psychotic illnesses, their unaffected relatives, and healthy controls all show similar patterns of associations between endophenotypes, endorsing the theory of a continuum of psychosis liability across the population.
We present results from a multiwavelength study of the blazar PKS 1954–388 at radio, UV, X-ray, and gamma-ray energies. A RadioAstron observation at 1.66 GHz in June 2012 resulted in the detection of interferometric fringes on baselines of 6.2 Earth-diameters. This suggests a source frame brightness temperature of greater than 2 × 1012 K, well in excess of both equipartition and inverse Compton limits and implying the existence of Doppler boosting in the core. An 8.4-GHz TANAMI VLBI image, made less than a month after the RadioAstron observations, is consistent with a previously reported superluminal motion for a jet component. Flux density monitoring with the Australia Telescope Compact Array confirms previous evidence for long-term variability that increases with observing frequency. A search for more rapid variability revealed no evidence for significant day-scale flux density variation. The ATCA light-curve reveals a strong radio flare beginning in late 2013, which peaks higher, and earlier, at higher frequencies. Comparison with the Fermi gamma-ray light-curve indicates this followed ~ 9 months after the start of a prolonged gamma-ray high-state—a radio lag comparable to that seen in other blazars. The multiwavelength data are combined to derive a Spectral Energy Distribution, which is fitted by a one-zone synchrotron-self-Compton (SSC) model with the addition of external Compton (EC) emission.
A number of laser facilities coming online all over the world promise the capability of high-power laser experiments with shot repetition rates between 1 and 10 Hz. Target availability and technical issues related to the interaction environment could become a bottleneck for the exploitation of such facilities. In this paper, we report on target needs for three different classes of experiments: dynamic compression physics, electron transport and isochoric heating, and laser-driven particle and radiation sources. We also review some of the most challenging issues in target fabrication and high repetition rate operation. Finally, we discuss current target supply strategies and future perspectives to establish a sustainable target provision infrastructure for advanced laser facilities.
In Germany tularemia is a re-emerging zoonotic disease. Therefore, we investigated wild animals and environmental water samples for the presence and phylogenetic diversity of Francisella tularensis in the poorly studied Berlin/Brandenburg region. The phylogenomic analysis of three isolates from wild animals revealed three new subclades within the phylogenetic tree of F. tularensis [B.71 from a raccoon dog (Nyctereutes procyonoides); B.74 from a red fox (Vulpes vulpes), and B.75 from a Eurasian beaver (Castor fiber albicus)]. The results from histological, PCR, and genomic investigations on the dead beaver showed that the animal suffered from a systemic infection. Indications were found that the bacteria were released from the beaver carcass into the surrounding environment. We demonstrated unexpectedly high and novel phylogenetic diversity of F. tularensis in Germany and the fact that the bacteria persist in the environment for at least one climatic season. These findings support a broader host species diversity than previously known regarding Germany. Our data further support the assumption derived from previous serological studies of an underestimated frequency of occurrence of the pathogen in the environment and in wild animals. F. tularensis was isolated from animal species not previously reported as natural hosts in Germany.
This study examines the independent effects of neighbourhood context (i.e. neighbourhood poverty) and exposure to perceived discrimination in shaping risk of obesity over time. Weighted three-level hierarchical linear regression models for a continuous outcome were used to assess the independent effects of neighbourhood poverty and perceived discrimination on obesity over time in a sample of 157 non-Hispanic Black, non-Hispanic White and Hispanic adults in Detroit, USA, in 2002/2003 and 2007/2008. Independent associations were found between neighbourhood poverty and perceived discrimination with central adiposity over time. Residents of neighbourhoods with high concentrations of poverty were more likely to show increases in central adiposity compared with those in neighbourhoods with lower concentrations of poverty. In models adjusted for BMI, neighbourhood poverty at baseline was associated with a greater change in central adiposity among participants who lived in neighbourhoods in the second (B=3.79, p=0.025) and third (B=3.73, p=0.024) poverty quartiles, compared with those in the lowest poverty neighbourhoods. The results from models that included both neighbourhood poverty and perceived discrimination showed that both were associated with increased risk of increased central adiposity over time. Residents of neighbourhoods in the second (B=9.58, p<0.001), third (B=8.25, p=0.004) and fourth (B=7.66, p=0.030) quartiles of poverty were more likely to show greater increases in central adiposity over time, compared with those in the lowest poverty quartile, with mean discrimination at baseline independently and positively associated with increases in central adiposity over time (B=2.36, p=0.020). The results suggest that neighbourhood poverty and perceived discrimination are independently associated with a heightened risk of increase in central adiposity over time. Efforts to address persistent disparities in central adiposity in the USA should include strategies to reduce high concentrations of neighbourhood poverty as well as discrimination.