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Background: Nipocalimab is a human IgG1 monoclonal antibody targeting FcRn that selectively reduces IgG levels without impacting antigen presentation, T- and B-cell functions. This study describes the effect of nipocalimab on vaccine response. Methods: Open-label, parallel, interventional study randomized participants 1:1 to receive intravenous 30mg/kg nipocalimab at Week0 and 15mg/kg at Week2 and Week4 (active) or no drug (control). On Day 3, participants received Tdap and PPSV®23 vaccinations and were followed through Wk16. Results: Twenty-nine participants completed the study and are included (active, n=15; control, n=14). Participants with a positive anti-tetanus IgG response was comparable between groups at Wk2 and Wk16, but lower at Wk4 (nipocalimab 3/15 [20%] vs control 7/14 [50%]; P=0.089). All maintained anti-tetanus IgG above the protective threshold (0.16IU/mL) through Wk16. While anti-pneumococcal-capsular-polysaccharide (PCP) IgG levels were lower during nipocalimab treatment, the percent increase from baseline at Wk2 and Wk16 was comparable between groups. Post-vaccination, anti-PCP IgG remained above 50mg/L and showed a 2-fold increase from baseline throughout the study in both groups. Nipocalimab co-administration with vaccines was safe and well-tolerated. Conclusions: These findings suggest that nipocalimab does not impact the development of an adequate IgG response to T-cell–dependent/independent vaccines and that nipocalimab-treated patients can follow recommended vaccination schedules.
Diagnostic criteria for major depressive disorder allow for heterogeneous symptom profiles but genetic analysis of major depressive symptoms has the potential to identify clinical and etiological subtypes. There are several challenges to integrating symptom data from genetically informative cohorts, such as sample size differences between clinical and community cohorts and various patterns of missing data.
Methods
We conducted genome-wide association studies of major depressive symptoms in three cohorts that were enriched for participants with a diagnosis of depression (Psychiatric Genomics Consortium, Australian Genetics of Depression Study, Generation Scotland) and three community cohorts who were not recruited on the basis of diagnosis (Avon Longitudinal Study of Parents and Children, Estonian Biobank, and UK Biobank). We fit a series of confirmatory factor models with factors that accounted for how symptom data was sampled and then compared alternative models with different symptom factors.
Results
The best fitting model had a distinct factor for Appetite/Weight symptoms and an additional measurement factor that accounted for the skip-structure in community cohorts (use of Depression and Anhedonia as gating symptoms).
Conclusion
The results show the importance of assessing the directionality of symptoms (such as hypersomnia versus insomnia) and of accounting for study and measurement design when meta-analyzing genetic association data.
Although the link between alcohol involvement and behavioral phenotypes (e.g. impulsivity, negative affect, executive function [EF]) is well-established, the directionality of these associations, specificity to stages of alcohol involvement, and extent of shared genetic liability remain unclear. We estimate longitudinal associations between transitions among alcohol milestones, behavioral phenotypes, and indices of genetic risk.
Methods
Data came from the Collaborative Study on the Genetics of Alcoholism (n = 3681; ages 11–36). Alcohol transitions (first: drink, intoxication, alcohol use disorder [AUD] symptom, AUD diagnosis), internalizing, and externalizing phenotypes came from the Semi-Structured Assessment for the Genetics of Alcoholism. EF was measured with the Tower of London and Visual Span Tasks. Polygenic scores (PGS) were computed for alcohol-related and behavioral phenotypes. Cox models estimated associations among PGS, behavior, and alcohol milestones.
Results
Externalizing phenotypes (e.g. conduct disorder symptoms) were associated with future initiation and drinking problems (hazard ratio (HR)⩾1.16). Internalizing (e.g. social anxiety) was associated with hazards for progression from first drink to severe AUD (HR⩾1.55). Initiation and AUD were associated with increased hazards for later depressive symptoms and suicidal ideation (HR⩾1.38), and initiation was associated with increased hazards for future conduct symptoms (HR = 1.60). EF was not associated with alcohol transitions. Drinks per week PGS was linked with increased hazards for alcohol transitions (HR⩾1.06). Problematic alcohol use PGS increased hazards for suicidal ideation (HR = 1.20).
Conclusions
Behavioral markers of addiction vulnerability precede and follow alcohol transitions, highlighting dynamic, bidirectional relationships between behavior and emerging addiction.
In a 2x2 factorial design, (n=6) sheep were either transported by road for 15h or kept in their home pens, and then either starved for 12h with access to water or offered hay ad libitum, with access to water. All groups were offered hay and water 12h after transport. Behavioural observations and measurements of dehydration and feed restriction were made before, during, and for 24h post-transport, to evaluate the implications of these procedures for the welfare of sheep.
After the journey, the immediate priority for the sheep was to eat. Consumption of hay increased water intake and reduced the time spent lying down. The plasma Cortisol concentration was greater in sheep which had been starved during the 12h post-transport period, than in those offered hay during this time; and the plasma free fatty acid concentration was greater in sheep which had been transported than in those which had not. Although transported sheep kept without hay during the first 12h post-transport drank more water than those which had not been transported, the mean time before they drank was greater than 7h. During the transport period, there was less lying behaviour in transported sheep than in non-transported sheep but transported sheep did not lie down more posttransport than non-transported ones. This work suggests that sheep should be offered both feed and water after a 15h journey. However, when feed was not available after a 15h journey, drinking and resting did not appear to be immediate priorities.
When sheep are transported they are potentially exposed to a number of factors, including water and feed deprivation, low space allowance and elevated environmental temperature, that are not related to vehicle motion but could result in animal welfare problems, either on their own or in combination. In a 2x2 factorial experiment, groups of sheep (n = 6) were moved from individual pens where they had access to hay and water to environmental chambers kept at either 14°C or 21°C. Within each chamber, half the sheep had access to water but they were all kept at a space allowance of 041m2 sheep−1 without feed. After 24h they were returned to their individual pens and offered hay and water. Behaviour and a range of biochemical measurements of dehydration and feed restriction were recorded before, during and after the treatment period. During the treatment period there was no evidence of dehydration, and sheep with access to water drank less than they did before the treatment. The plasma concentration of free fatty acids increased during fasting and, post-treatment, the intake of hay was greater than before treatment. The rapid post-treatment intake of dry feed was associated with some evidence of dehydration, as indicated by increased plasma osmolality and plasma vasopressin concentration. This suggests that following provision and consumption of large quantities of feed after a period without access to feed and water during transportation, sheep must be allowed sufficient time to drink before a subsequent journey is undertaken.
The effects of food restriction on the welfare of sheep are as yet unclear. An operant crate and a push-door were used to measure feeding motivation in sheep after Oh, 6h, 12h, 18h and 24h without food. In experiment 1, sheep had to push a panel with their noses to obtain a food reward. In experiment 2, sheep had to run a race and push through a weighted door to reach food; the time taken to reach various points was recorded and the work performed to push through the door was calculated.
In experiment 1, 3 out of 12 sheep became trained to push the panel and there was a difference in the mean number of rewards/session obtained by each animal (P < 0.05). There was no effect of treatment on the number of panel presses performed. In experiment 2, 10 out of 14 sheep were successfully trained. More sheep went through the push-door when deprived of food (P < 0.05), and they were quicker to enter the race, reach the push-door, and reach the food than those which had not been deprived (P < 0.0001). They also spent less time pushing the door than non-deprived sheep (P < 0.0001).
The push-door was a more appropriate method of measuring motivation to feed in sheep, as more sheep learned the task in less time than for the operant crate. As measured by the time taken to enter the race, reach the push-door, push through the door and reach the food there was an increase in feeding motivation after only 6h without food.
The extent of parotidectomy in the management of regional metastatic disease is controversial. This systematic review aimed to appraise data from studies evaluating superficial and total parotidectomy in metastatic cutaneous squamous cell carcinoma and cutaneous malignant melanoma of the head and neck.
Method
A systematic search of PubMed, Embase and Cochrane Library was performed. The protocol was registered with Prospero (CRD42020217962).
Results
A total of five studies evaluated cutaneous malignant melanoma. Only one compared outcomes of superficial and total parotidectomy: they found higher parotid area recurrence following superficial parotidectomy. Seven studies reported outcomes following cutaneous squamous cell carcinoma; some studies found higher regional recurrence and reduced survival in total parotidectomy, but there was likely selection bias in these studies. Others found no difference in survival between superficial and total parotidectomy.
Conclusion
The effect of the extent of parotidectomy on outcomes is unclear in cutaneous malignant melanoma and cutaneous squamous cell carcinoma. This systematic review highlights the need for well-designed studies to direct better care.
We examined whether preadmission history of depression is associated with less delirium/coma-free (DCF) days, worse 1-year depression severity and cognitive impairment.
Design and measurements:
A health proxy reported history of depression. Separate models examined the effect of preadmission history of depression on: (a) intensive care unit (ICU) course, measured as DCF days; (b) depression symptom severity at 3 and 12 months, measured by the Beck Depression Inventory-II (BDI-II); and (c) cognitive performance at 3 and 12 months, measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) global score.
Setting and participants:
Patients admitted to the medical/surgical ICU services were eligible.
Results:
Of 821 subjects eligible at enrollment, 261 (33%) had preadmission history of depression. After adjusting for covariates, preadmission history of depression was not associated with less DCF days (OR 0.78, 95% CI, 0.59–1.03 p = 0.077). A prior history of depression was associated with higher BDI-II scores at 3 and 12 months (3 months OR 2.15, 95% CI, 1.42–3.24 p = <0.001; 12 months OR 1.89, 95% CI, 1.24–2.87 p = 0.003). We did not observe an association between preadmission history of depression and cognitive performance at either 3 or 12 months (3 months beta coefficient −0.04, 95% CI, −2.70–2.62 p = 0.97; 12 months 1.5, 95% CI, −1.26–4.26 p = 0.28).
Conclusion:
Patients with a depression history prior to ICU stay exhibit a greater severity of depressive symptoms in the year after hospitalization.
The GaLactic and Extragalactic All-sky Murchison Widefield Array (GLEAM) is a radio continuum survey at 76–227 MHz of the entire southern sky (Declination $<\!{+}30^{\circ}$) with an angular resolution of ${\approx}2$ arcmin. In this paper, we combine GLEAM data with optical spectroscopy from the 6dF Galaxy Survey to construct a sample of 1 590 local (median $z \approx 0.064$) radio sources with $S_{200\,\mathrm{MHz}} > 55$ mJy across an area of ${\approx}16\,700\,\mathrm{deg}^{2}$. From the optical spectra, we identify the dominant physical process responsible for the radio emission from each galaxy: 73% are fuelled by an active galactic nucleus (AGN) and 27% by star formation. We present the local radio luminosity function for AGN and star-forming (SF) galaxies at 200 MHz and characterise the typical radio spectra of these two populations between 76 MHz and ${\sim}1$ GHz. For the AGN, the median spectral index between 200 MHz and ${\sim}1$ GHz, $\alpha_{\mathrm{high}}$, is $-0.600 \pm 0.010$ (where $S \propto \nu^{\alpha}$) and the median spectral index within the GLEAM band, $\alpha_{\mathrm{low}}$, is $-0.704 \pm 0.011$. For the SF galaxies, the median value of $\alpha_{\mathrm{high}}$ is $-0.650 \pm 0.010$ and the median value of $\alpha_{\mathrm{low}}$ is $-0.596 \pm 0.015$. Among the AGN population, flat-spectrum sources are more common at lower radio luminosity, suggesting the existence of a significant population of weak radio AGN that remain core-dominated even at low frequencies. However, around 4% of local radio AGN have ultra-steep radio spectra at low frequencies ($\alpha_{\mathrm{low}} < -1.2$). These ultra-steep-spectrum sources span a wide range in radio luminosity, and further work is needed to clarify their nature.
Diagnosis of CHD substantially affects parent mental health and family functioning, thereby influencing child neurodevelopmental and psychosocial outcomes. Recognition of the need to proactively support parent mental health and family functioning following cardiac diagnosis to promote psychosocial adaptation has increased substantially over recent years. However, significant gaps in knowledge remain and families continue to report critical unmet psychosocial needs. The Parent Mental Health and Family Functioning Working Group of the Cardiac Neurodevelopmental Outcome Collaborative was formed in 2018 through support from an R13 grant from the National Heart, Lung, and Blood Institute to identify significant knowledge gaps related to parent mental health and family functioning, as well as critical questions that must be answered to further knowledge, policy, care, and outcomes. Conceptually driven investigations are needed to identify parent mental health and family functioning factors with the strongest influence on child outcomes, to obtain a deeper understanding of the biomarkers associated with these factors, and to better understand how parent mental health and family functioning influence child outcomes over time. Investigations are also needed to develop, test, and implement sustainable models of mental health screening and assessment, as well as effective interventions to optimise parent mental health and family functioning to promote psychosocial adaptation. The critical questions and investigations outlined in this paper provide a roadmap for future research to close gaps in knowledge, improve care, and promote positive outcomes for families of children with CHD.
Although mania is the hallmark symptom of bipolar I disorder (BD-I), most patients initially present for treatment with depressive symptoms. Misdiagnosis of BD-I as major depressive disorder (MDD) is common, potentially resulting in poor outcomes and inappropriate antidepressant monotherapy treatment. Screening patients with depressive symptoms is a practical strategy to help healthcare providers (HCPs) identify when additional assessment for BD-I is warranted. The new 6-item Rapid Mood Screener (RMS) is a pragmatic patient-reported BD-I screening tool that relies on easily understood terminology to screen for manic symptoms and other BD-I features in <2 minutes. The RMS was validated in an observational study in patients with clinically confirmed BD-I (n=67) or MDD (n=72). When 4 or more items were endorsed (“yes”), the sensitivity of the RMS for identifying patients with BP-I was 0.88 and specificity was 0.80; positive and negative predictive values were 0.80 and 0.88, respectively. To more thoroughly understand screening tool use among HCPs, a 10-minute survey was conducted.
Methods
A nationwide sample of HCPs (N=200) was selected using multiple HCP panels; HCPs were asked to describe their opinions/current use of screening tools, assess the RMS, and evaluate the RMS versus the widely recognized Mood Disorder Questionnaire (MDQ). Results were reported by grouped specialties (primary care physicians, general nurse practitioners [NPs]/physician assistants [PAs], psychiatrists, and psychiatric NPs/PAs). Included HCPs were in practice <30 years, spent at least 75% of their time in clinical practice, saw at least 10 patients with depression per month, and diagnosed MDD or BD in at least 1 patient per month. Findings were reported using descriptive statistics; statistical significance was reported at the 95% confidence interval.
Results
Among HCPs, 82% used a tool to screen for MDD, while 32% used a tool for BD. Screening tool attributes considered to be of the greatest value included sensitivity (68%), easy to answer questions (66%), specificity (65%), confidence in results (64%), and practicality (62%). Of HCPs familiar with screening tools, 70% thought the RMS was at least somewhat better than other screening tools. Most HCPs were aware of the MDQ (85%), but only 29% reported current use. Most HCPs (81%) preferred the RMS to the MDQ, and the RMS significantly outperformed the MDQ across valued attributes; 76% reported that they were likely to use the RMS to screen new patients with depressive symptoms. A total of 84% said the RMS would have a positive impact on their practice, with 46% saying they would screen more patients for bipolar disorder.
Discussion
The RMS was viewed positively by HCPs who participated in a brief survey. A large percentage of respondents preferred the RMS over the MDQ and indicated that they would use it in their practice. Collectively, responses indicated that the RMS is likely to have a positive impact on screening behavior.
In this paper, we describe the system design and capabilities of the Australian Square Kilometre Array Pathfinder (ASKAP) radio telescope at the conclusion of its construction project and commencement of science operations. ASKAP is one of the first radio telescopes to deploy phased array feed (PAF) technology on a large scale, giving it an instantaneous field of view that covers $31\,\textrm{deg}^{2}$ at $800\,\textrm{MHz}$. As a two-dimensional array of 36$\times$12 m antennas, with baselines ranging from 22 m to 6 km, ASKAP also has excellent snapshot imaging capability and 10 arcsec resolution. This, combined with 288 MHz of instantaneous bandwidth and a unique third axis of rotation on each antenna, gives ASKAP the capability to create high dynamic range images of large sky areas very quickly. It is an excellent telescope for surveys between 700 and $1800\,\textrm{MHz}$ and is expected to facilitate great advances in our understanding of galaxy formation, cosmology, and radio transients while opening new parameter space for discovery of the unknown.
Antisaccade tasks can be used to index cognitive control processes, e.g. attention, behavioral inhibition, working memory, and goal maintenance in people with brain disorders. Though diagnoses of schizophrenia (SZ), schizoaffective (SAD), and bipolar I with psychosis (BDP) are typically considered to be distinct entities, previous work shows patterns of cognitive deficits differing in degree, rather than in kind, across these syndromes.
Methods
Large samples of individuals with psychotic disorders were recruited through the Bipolar-Schizophrenia Network on Intermediate Phenotypes 2 (B-SNIP2) study. Anti- and pro-saccade task performances were evaluated in 189 people with SZ, 185 people with SAD, 96 people with BDP, and 279 healthy comparison participants. Logistic functions were fitted to each group's antisaccade speed-performance tradeoff patterns.
Results
Psychosis groups had higher antisaccade error rates than the healthy group, with SZ and SAD participants committing 2 times as many errors, and BDP participants committing 1.5 times as many errors. Latencies on correctly performed antisaccade trials in SZ and SAD were longer than in healthy participants, although error trial latencies were preserved. Parameters of speed-performance tradeoff functions indicated that compared to the healthy group, SZ and SAD groups had optimal performance characterized by more errors, as well as less benefit from prolonged response latencies. Prosaccade metrics did not differ between groups.
Conclusions
With basic prosaccade mechanisms intact, the higher speed-performance tradeoff cost for antisaccade performance in psychosis cases indicates a deficit that is specific to the higher-order cognitive aspects of saccade generation.
Reconstructs the constitutive role that German actresses played on and off the stage in shaping not only modernist theater aesthetics and performance practices, but also influential strains of modern thought.
ON SEPTEMBER 23, 1904 a new adaptation of Frank Wedekind's Erdgeist premiered at the Neues Theater in Berlin, directed by Max Reinhardt. The production starred Gertrud Eysoldt in the lead as Lulu and, contributing to its novelty, it featured Wedekind himself as the Tierbändiger (animal tamer) in the prologue. At the beginning of the play, Wedekind stepped out from behind the curtain dressed in an iconic ringmaster's costume to deliver the opening lines (figure 3.1):
Walk in! Into the menagerie,
You proud gents, you boisterous women,
With hot desire, and cold dread,
To see the soulless creature,
Tamed by human genius.
The poetic monologue rehearses a well-established opposition between animal and man, who is made master by his intellect and soul. The animal's subjugation on display promises to affirm man's superiority. The Berliner Morgenpost reports that Wedekind “praised the beasts of his circus, all of which he commanded, and introduced a delectable rarity, a poisonous snake: Ms. Eysoldt was carried onto the stage in the pierrot costume of the first act.” The Tierbändiger continues: “She was made to incite calamity / to lure, to seduce, to poison— / to murder without anyone feeling a thing.” To demonstrate his lack of fear and his complete mastery over the deadly creature, he then scratches under her chin like a house pet as he calls her “my sweet beast” (ibid.).
With the overt equation that Wedekind draws between the figure of Lulu and animal predators in the dramatic prologue to Erdgeist it is fitting that reviews of the 1904 stage production also used zoomorphic rhetoric. Critics wrote about “Ms. Eysoldt the all-conquering snake,” or the “snake-woman in the guise of Lulu-Eysoldt.” They praised Eysoldt's performance in the role, to which she brought her “her snake-like grace [Schlangengrazie].” For others, Eysoldt's Lulu was perhaps too convincing and too naturally assimilated. A reviewer for the Volkszeitung comments: “With what uncanny naturalness she plays this snake in human form, this woman, who without conscious reflection coldly steps over the corpses of the men who worship her, and in the end drives the only man who ever loved her to ruin and fires a pistol at him.”