Search

Purpose: To test a theory of immediacy (Christensen) by comparing the effect of 3 different incentives on critical care nurses' survey response rates. Background/Significance: Mailed questionnaire is the most common [...]

Background and Aims: Atherosclerosis and other cardiovascular diseases (CVD) are well established to be both instigated and worsened by inflammation. Indeed, CANTOS formally proved that targeting the inflammatory cytokine IL-1β only could reduce both cardiovascular events and death. However, due to the central role of IL-1β in host defence, blockade increased fatal infections, suggesting targeting key immune mediators over the long natural history of CVD is unsuitable. Thus, discovering alternative mechanisms that generate vascular inflammation may identify more actionable targets., Methods: We used primary human VSMCs and a combination of biochemical, pharmacological and molecular biological techniques to generate the data. Human carotid atherosclerotic plaques were also assessed histologically., Results: We showed that VSMCs expressed and efficiently processed pro-IL-1β to the active form after receiving a single stimulus via IL-1R1 or TLR4. Importantly, pro-IL-1β processing did not utilise inflammasomes or caspases. Unusually, we found that cathepsin C-activated chymase was responsible for cleaving IL-1β in VSMCs, and provided evidence for chymase expression in cultured VSMCs and in the fibrous cap of human plaques. Chymase also efficiently cleaved and activated recombinant pro-IL-1β., Conclusions: Thus, VSMCs are efficient activators of IL-1β that do not use canonical inflammasomes or caspases. Hence, this alternative pathway could be targeted for long-term treatment of CVDs, as it is not central to everyday host defence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Inappropriate immune activity is key in the pathogenesis of multiple diseases, and it is typically driven by excess inflammation and/or autoimmunity. IL-1 is often the effector owing to its powerful role in both innate and adaptive immunity, and, thus, it is tightly controlled at multiple levels. IL-1R2 antagonizes IL-1, but effects of losing this regulation are unknown. We found that IL-1R2 resolves inflammation by rapidly scavenging free IL-1. Specific IL-1R2 loss in germinal center (GC) T follicular regulatory (Tfr) cells increased the GC response after a first, but not booster, immunization, with an increase in T follicular helper (Tfh) cells, GC B cells, and antigen-specific antibodies, which was reversed upon IL-1 blockade. However, IL-1 signaling is not obligate for GC reactions, as WT and Il1r1-/- mice showed equivalent phenotypes, suggesting that GC IL-1 is normally restrained by IL-1R2. Fascinatingly, germline Il1r2-/- mice did not show this phenotype, but conditional Il1r2 deletion in adulthood recapitulated it, implying that compensation during development counteracts IL-1R2 loss. Finally, patients with ulcerative colitis or Crohn's disease had lower serum IL-1R2. All together, we show that IL-1R2 controls important aspects of innate and adaptive immunity and that IL-1R2 level may contribute to human disease propensity and/or progression.

Time attitudes indicate how individuals feel about the past, present, and future. A growing body of research has demonstrated that scores on the Adolescent and Adult Time Inventory-Time Attitudes Scale relate meaningfully to a variety of measures of well-being and psychiatric symptomatology. To date, no study has examined how (if at all) Time Attitudes scores relate to psychiatric disorder. The present study used an existing clinical cohort (N = 68) and assessed the associations among time attitudes, lifetime disorder, and a retrospective measure of childhood trauma. Preliminary analyses revealed that mean scores of the six time attitudes in the present study did not differ substantially from scores reported in a recent meta-analysis. Correlations between time attitude scores and retrospective trauma scores were particularly large for past negative and past positive. Individuals with no past or current disorder reported substantially higher positive attitudes and substantially lower negative attitudes than those without a disorder across all three time periods with interpretable effect sizes. Finally, past negative time attitudes scores were significantly associated with lifetime mood or anxiety disorder, prior to adjustment for scores on self-reported childhood trauma. These results suggest that time attitudes could be a variable of consequence beyond feelings of general well-being and beyond psychiatric symptoms. More studies with larger sample sizes are required in order to examine the relationship between time attitudes and psychiatric disorder., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition., Methods: Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n = 34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n = 50). Gene expression of peripheral blood macrophages was assessed., Results: In the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10 , rs28360457 in P2RX7 , rs1126930 in PRKAG1 and rs80308281 in SLC12A9 . Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10 , P2RX7 , PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls., Conclusion: A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

This study assessed the feasibility of a multi-domain measure of the occurrence, impact, and timing of childhood/adolescent psychological adversity exposure, the Subjective Impact and Timing of Adversity Scale (SITA). Participants were from among those who had previously participated in two waves of data collection when aged approximately 14 and 21 years. Internal consistency estimates at both online and interview stages were acceptable for all SITA domains (with the exception of parental loss). SITA domain scores correlated meaningfully with scores on other scales and psychological measures, supporting convergent validity. Those with lifetime psychiatric diagnoses scored significantly higher on SITA domains than those not meeting diagnostic threshold. There was evidence of the importance of both the subjective impact and timing of adversity with regard to psychiatric diagnoses. The study demonstrates the viability of the SITA; however, further studies are required to substantiate these findings in larger samples.

Four cocrystals containing N'-(butan-2-ylidene)pyridine-4-carbohydrazide (izbt) and one cocrystal containing N'-isopropylideneisonicotinohydrazide (izact) were synthesized by reacting isoniazid with either butan-2-one (for the former) or acetone (for the latter). The coformers used to synthesize the izbt cocrystals were 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2-chloro-4-nitrobenzoic acid and 1-naphthoic acid. 1-Naphthoic acid was also used with izact to form a cocrystal. The 1:1 cocrystals are: N'-(butan-2-ylidene)pyridine-4-carbohydrazide-1-naphthoic acid (izbt-1nta), C 10 H 13 N 3 O·C 11 H 8 O 2 , N'-(butan-2-ylidene)pyridine-4-carbohydrazide-2,4-dihydroxybenzoic acid (izbt-2,4-dhba), C 10 H 13 N 3 O·C 7 H 6 O 4 , N'-(propan-2-ylidene)pyridine-4-carbohydrazide-1-naphthoic acid (izact-1nta), C 9 H 11 N 3 O·C 11 H 8 O 2 , N'-(butan-2-ylidene)pyridine-4-carbohydrazide-2-chloro-4-nitrobenzoic acid (izbt-2c4n), C 10 H 13 N 3 O·C 7 H 4 ClNO 4 , and N'-(butan-2-ylidene)pyridine-4-carbohydrazide-2,5-dihydroxybenzoic acid (izbt-2,5-dhba), C 10 H 13 N 3 O·C 7 H 6 O 4 . The cocrystals containing izbt were compared to those containing the same (or similar) coformers with izact that have been reported either here or in the Cambridge Structural Database (CSD). Most of the cocrystals showed different packing despite having the same hydrogen-bonding motifs. The cocrystals were characterized by single-crystal X-ray diffraction (SC-XRD), powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC)., (open access.)

Interleukin-1 alpha (IL-1α) is a powerful cytokine that drives inflammation and modulates adaptive immunity. Due to these powerful effects, IL-1α is controlled at multiple levels from transcription to cleavage and release from the cell. Genome-wide association studies can identify loci that drive important diseases, although often the functional effect of the variant on phenotype remains unknown or small, with most risk variants in non-coding regions. We find that the common variant rs17561 changes a conserved amino acid in the central region of IL-1α linking the pro piece to the cytokine domain. Using a recall-by-genotype study and whole blood stimulation, we find that minor allele homozygotes release ~50% less IL-1α than the major allele, with IL-1β release equivalent. IL-1α transcript level was identical between groups, implying a post-transcriptional effect, whilst cleavage of recombinant pro-IL-1α by multiple proteases was also equivalent for both forms. Importantly, transfected macrophages also release less minor allele IL-1α upon inflammasome activation, revealing that reduced secretion is directly caused by the missense amino acid substitution and more minor allele IL-1α was retained within the cell. Thus, rs17561 represents a very common hypomorphic mutation in IL-1α. We believe this novel data will be important for determining the potential contribution of IL-1α to disease and/or physiological processes, for example, by Mendelian randomisation, and may aid patient stratification when considering anti-IL-1 therapies., (© 2022 The Authors. Immunology published by John Wiley & Sons Ltd.)

This study aimed to systematically review the evidence for an association between adversity experienced in childhood (≤ 17 years old), and the diagnosis of psychiatric disorder in adulthood. Electronic databases (Scopus, Medline (for Ovid), EMBASE, and PsychINFO) were searched for peer-reviewed, longitudinal cohort studies examining child or adolescent exposure to adversity, and adult-diagnosed depression, anxiety, psychotic disorder, eating disorders, substance abuse disorder, illness anxiety disorder, somatoform disorder, or personality disorder. A total of 39 manuscripts were retained. Results revealed a significant association between the following childhood exposures and adult mental disorder (1.24 ≤ Odds ratios ≤ 2.09): bullying (victimhood, and frequency); emotional abuse; neglect; physical abuse; parental loss; and general maltreatment (unspecified and/or multiple adversity exposure). There were opposing results for being a victim and perpetrator of bullying, and the result for sexual abuse was not statistically significant. There was some evidence of a dose-response relationship with those exposed to multiple forms of maltreatment having more two and a half times odds of developing a mental disorder (Odds ratio = 2.59). The result for sexual abuse is likely an artefact of the prospective assessment of this adversity. In summary, there was strong evidence of an association between childhood adversity and later mental illness, and this supports previously reported meta-analyses. The evidence suggests that childhood and adolescence is an important time for risk for later mental illness, and an important period in which to focus intervention strategies for those known to have been exposed to adversity, particularly multiple adversities., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Borderline Personality Disorder is a severe psychiatric disorder with debilitating consequences. Screening for the disorder is problematic as symptoms overlap with other psychiatric disorders. The McLean Screening Instrument (MSI) assesses endorsement (yes/no) of 10 symptoms, with a cut-off of seven indicating potential caseness. Participants were (N = 68) from an established clinical cohort who completed a structured clinical interview, the MSI, the Childhood Trauma Questionnaire, and the Adolescent and Adult Time Attitudes Scale. A proportion (N = 20) also completed a follow-up interview examining their rationale for endorsing MSI items. Total number of MSI items endorsed was meaningfully related to scores on emotional neglect and negative time attitudes. There was substantive overlap between MSI threshold (≥7 items) and lifetime diagnosis of a mental disorder. The stated rationale for endorsing MSI items, was less indicative of personality trait, and was related more to particular developmental periods, one-off episodes, and life-contexts. Additionally, participants conflated constructs such as emptiness with loneliness, and moodiness with general emotionality. Those meeting MSI threshold recalled more childhood emotional neglect, and were more negative about all time periods. It is apparent that scoring of the MSI is driven by prevailing life circumstances as much as enduring personality traits., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2022. Published by Elsevier B.V.)

Current strategies to predict psychosis identify only a small proportion of individuals at risk. Additional strategies are needed to increase capacity for pre-diction and prevention of serious mental illness, ideally during childhood and adolescence. One possible approach would be to investigate systems in which psychosis risk factors are concentrated during childhood. One notable such system is represented by Child and Adolescent Mental Health Services (CAMHS). Although psychotic disorders are uncommon in CAMHS, many risk factors for psychosis are highly prevalent in young people who enter this system. We hypothesized, therefore, that youth attending CAMHS would be a high-risk group for psychosis if followed into adulthood and, furthermore, that CAMHS systems would capture a substantial proportion of future psychosis cases. We constructed a total population cohort study of all Finns born in 1987 (N=55,875), linking together extensive register data on health care contacts from birth through age 28 years. We identified all individuals diagnosed with a psychotic or bipolar disorder by age 28 (N=1,785). The risk of psychosis/bipolar disorder by age 28 years was 1.8% for individuals who had not attended CAMHS during childhood or adolescence, whereas it was 12.8% for those with a history of any outpatient CAMHS contact (odds ratio, OR=7.9, 95% CI: 7.2-8.7). Furthermore, the risk of psychosis/bipolar disorder by age 28 years was 2.3% for individuals without a history of inpatient CAMHS admission, whereas it was 24.0% for those with a history of inpatient CAMHS admission (OR=13.3, 95% CI: 11.9-14.9), and 36.5% for those with a history of inpatient CAMHS admission in adolescence (age 13-17 years) (OR=24.2, 95% CI: 21.2-27.6). Individuals who attended CAMHS but received no mental disorder diagnosis had an equally high risk of subsequently developing a psychosis/bipolar disorder as individuals who did receive a diagnosis (OR=0.9, 99.5% CI: 0.7-1.1). Compared to other CAMHS attendees, individuals who developed psychosis or bipolar disorder were more likely to have had an initial CAMHS diagnosis of depressive or other mood disorder (OR=2.3, 99.5% CI: 1.6-3.0) and disruptive behaviour disorder (OR=1.7, 99.5% CI: 1.2-2.5). Of all psychosis/bipolar diagnoses by age 28 years, 50.2% occurred in individuals who had, at some point in childhood or adolescence, attended CAMHS, indicating that CAMHS represent not only a high-risk but also a high-capacity system for prediction of psychosis/bipolar disorder. These findings suggest an enormous, untapped potential for large-scale psychosis/bipolar disorder prediction and prevention research within existing specialist CAMHS., (© 2022 World Psychiatric Association.)

Objectives: Hallucinations and delusions that occur in the absence of a psychotic disorder are common in children and adolescents. Longitudinal phenomenological studies exploring these experiences are notably lacking. The objective of the current paper was to explore the phenomenology and characteristics of hallucinations and delusions from early adolescence to early adulthood., Methods: Participants were 17 young people aged 18-21 years from the general population, all of whom had a history of childhood hallucinations and/or delusions. Longitudinal data on the phenomenological characteristics and attributions of reported hallucinatory and delusional phenomena spanning nine years were explored using content analysis., Results: Hallucinatory and delusional phenomena were transient for two-thirds of the sample. The remaining one-third reported reoccurring hallucinatory and delusional phenomena into early adulthood. In those, two typologies were identified: (1) Paranormal typology and (2) Pathological typology. The former was characterised by hallucinatory and delusional phenomena that were exclusively grounded in subcultural paranormal or spiritual belief systems and not a source of distress. The latter was characterised by delusion-like beliefs that were enmeshed with individuals' mood states and a source of distress. The perceived source, the subcultural context and how young people appraised and integrated their experiences differentiated the Paranormal and Pathological typologies., Conclusions: Not all hallucinatory and delusion-like experiences are psychotic-like in nature. To reliably differentiate between pathological and non-pathological hallucinations and delusions, assessments need to explore factors including the phenomenology of individuals' experiences, how people make sense and appraise them, and the subcultural contexts within which they are experienced.

Objective: The "At Risk Mental State" (ARMS) approach to psychosis, also called "Clinical/Ultra High Risk," has had a major impact on psychosis services internationally. Despite well-established developmental differences in the prevalence and expression of psychotic symptoms from childhood into adulthood, there has been no systematic review of psychosis transitions specifically in children and adolescents up to age of 18 years. Evidence for this age group is crucial for developmentally appropriate clinical decisions by child and adolescent psychiatrists., Method: Systematic review and meta-analysis of psychosis risk among children diagnosed with ARMS up to age 18 years, with pooled transition rates after 1-year, 2-year and ≥5-year follow-up., Results: We retrieved 1,107 records and identified 16 articles from 9 studies reporting transition rates on 436 individuals with ARMS aged 9 to 18 years. The pooled transition rate to psychosis at 1 year was 9.5% (95% CI = 5.5%-14.2%, 7 studies included), at 2-years 12.1% (95% CI = 6.7%-18.6%, 4 studies included), and at ≥5 years 16.1% (95% CI = 5.6%-30.0%, 4 studies included). We did not find evidence that the diagnosis of ARMS was associated with increased risk of psychosis once risk-enriching recruitment strategies were taken into account., Conclusion: At 5-year follow-up, 1 in 6 youths diagnosed with an ARMS had transitioned to psychosis, but we did not find evidence that this risk was related to ARMS diagnosis as opposed to sampling/recruitment strategies. Our findings indicate a need for caution in applying ARMS methodology to children and adolescents. and highlight the need for developmentally sensitive approaches when considering psychosis risk., (Copyright © 2021 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: There is evidence that prenatal stress and smoking during pregnancy both independently increase the risk of offspring psychopathology. Here we examine whether increased levels of self-reported stress is associated with increased smoking in a population of pregnant women, and whether prenatal smoking is associated with offspring psychiatric diagnoses independent of prenatal stress exposure., Method: Using a longitudinal birth cohort, we used ordered logistic regressions to examine associations between maternal stress and smoking during pregnancy. We then used logistic regression analyses to examine associations between prenatal smoking and later offspring psychiatric disorders., Results: A dose-response relationship was found between maternally reported stress and smoking during pregnancy. Pregnant women reporting severe stress were more likely to smoke compared to both the moderate stress and no stress groups, and those reporting moderate stress were significantly more likely to smoke compared to the no stress group. Smoking more than 5 cigarettes daily during pregnancy increased the risk of offspring personality disorder (OR 3.08, 95% CI 1.60-5.94) as well as developing any Axis 1 psychiatric disorder, inclusive of mood, anxiety and psychotic disorders (OR 1.45, 95% CI 1.04-2.04). After adjusting for parental psychiatric history and maternal self-reported stress during pregnancy, associations between smoking more than 5 cigarettes daily when pregnancy and offspring personality (OR 2.58 95% CI 1.32-5.06) disorder remained., Conclusion: Exposure to cigarette smoking during gestation could impact a child's mental health. Smoking during pregnancy is a prime target for preventative interventions as unlike most other environmental risk factors, it is very amenable to change., (© 2021. The Author(s).)

Objective: To systematically review evidence for an association between parental death in childhood, and the subsequent development of an anxiety, affective or psychotic disorder., Methods: Electronic databases (Scopus, Medline (for Ovid), EMBASE and PsychINFO) were searched for peer-reviewed, cohort studies in the English language. Meta-analyses were performed for studies reporting hazard ratios, incidence rate ratios and odds ratios. Two studies reported risk ratios, and these were included in an overall pool of odds, risk and incidence rate ratios. Sensitivity analyses were performed (removal of one study at a time) for all meta-analyses, and study quality assessed using the Newcastle-Ottawa Scale., Results: Fifteen studies were retained, and where required, data were averaged in advance of pooling. Significant results were observed in studies reporting hazard ratios (k = 4, 1.48 [95% CI = 1.32-1.66]), incidence rate ratios (k = 3, 1.37 [95% CI = 1.01-1.85]), but not odds ratios (k = 4, 0.87 [95% CI = 0.72, 1.05]). However, the overall pooled effect (using odds, incidence rate and risk ratios) was statistically significant (k = 9, 1.22 [95% CI = 1.03-1.44])., Conclusion: Overall, the evidence suggests that there is a positive association between the death of a parent before age 18, and the subsequent development of an anxiety, affective or psychotic disorder. The lack of a significant pooled effect in studies reporting results as odds ratios is likely an artefact of study design., Limitations: Data were clustered in four countries making generalizability uncertain. Studies adjusted for a variety of possible confounders, and follow-up after death varied considerably., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To systematically review evidence for the association between trauma experienced in childhood or adolescence, and the subsequent experience of affective or psychotic mental disorders in adulthood., Methods: Electronic databases (Scopus, Medline (for Ovid), EMBASE and PsychINFO) were searched for peer-reviewed, longitudinal cohort studies in the English language examining child or adolescent exposure to trauma, and adult-diagnosed depression, anxiety, psychotic disorder or bipolar disorder. A total of 23 manuscripts were retained., Results: Results revealed a significant association between the following childhood exposures and adult mental disorder: bullying (victimhood, perpetration and frequency); emotional abuse; physical neglect; parental loss; and general maltreatment (unspecified and/or multiple trauma exposure). There was some evidence of a dose-response relationship with those exposed to multiple forms of maltreatment having more than three times the odds of developing a mental disorder (Odds ratio = 3.11, 95% CI = 1.36-7.14). There was no significant association found between physical or sexual abuse and adult mental disorder; however, this is likely an artefact of how these adversities were assessed., Conclusion: There is strong evidence of an association between childhood trauma and later mental illness. This association is particularly evident for exposure to bullying, emotional abuse, maltreatment and parental loss. The evidence suggests that childhood and adolescence are an important time for risk for later mental illness, and an important period in which to focus intervention strategies., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mental ill-health is one of the most significant health and social issues affecting young people globally. To address the mental health crisis, a number of cross-sectoral research and action priorities have been identified. These include improving mental health literacy, translating research findings into accessible public health outputs, and the use of digital technologies. There are, however, few examples of public health-oriented knowledge transfer activities involving collaborations between researchers, the Arts, and online platforms in the field of youth mental health., Objective: The primary aim of this project was to translate qualitative research findings into a series of online public mental health animations targeting young people between the ages of 16 and 25 years. A further aim was to track online social media engagement and viewing data for the animations for a period of 12 months., Methods: Qualitative data were collected from a sample of 17 youth in Ireland, aged 18-21 years, as part of the longitudinal population-based Adolescent Brain Development study. Interviews explored the life histories and the emotional and mental health of participants. The narrative analysis revealed 5 thematic findings relating to young people's emotional and mental health. Through a collaboration between research, the Arts, and the online sector, the empirical thematic findings were translated into 5 public health animations. The animations were hosted and promoted on 3 social media platforms of the Irish youth health website called SpunOut. Viewing data, collected over a 12-month period, were analyzed to determine the reach of the animations., Results: Narrative thematic analysis identified anxiety, depression, feeling different, loneliness, and being bullied as common experiences for young people. These thematic findings formed the basis of the animations. During the 12 months following the launch of the animations, they were viewed 15,848 times. A majority of views occurred during the period of the social media ad campaign at a cost of €0.035 (approximately US $0.042) per view. Animations on feeling different and being bullied accounted for the majority of views., Conclusions: This project demonstrates that online animations provide an accessible means of translating empirical research findings into meaningful public health outputs. They offer a cost-effective way to provide targeted online information about mental health, coping, and help-seeking to young people. Cross-sectoral collaboration is required to leverage the knowledge and expertise required to maximize the quality and potential reach of any knowledge transfer activities. A high level of engagement is possible by targeting non-help-seeking young people on their native social media platforms. Paid promotion is, therefore, an important consideration when budgeting for online knowledge translation and dissemination activities in health research., (©Helen Coughlan, David Quin, Kevin O'Brien, Colm Healy, Jack Deacon, Naoise Kavanagh, Niamh Humphries, Mary C Clarke, Mary Cannon. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 09.02.2021.)

Background: Psychotic experiences (PEs) are not uncommon in young people and are associated with both psychopathology and compromised global functioning. Although psychotic experiences are transient (short-lived, self-resolving and non-recurring) for most people who report them, few studies have examined the association between early transient PEs and later functioning in population samples. Additionally, studies using self-report measures of interpersonal and educational/ vocational difficulties are lacking. The aim of this study was to examine the relationship between transient psychotic experiences and self-reported interpersonal and educational/vocational difficulties in adolescence and young adulthood., Methods: Participants were 103 young people from a longitudinal population-based study cohort of mental health in Ireland. They attended for baseline clinical interviews in childhood (age 11-13) and were followed up in young adulthood (age 19-25). Participants who reported psychotic experiences at baseline but not at follow-up were classified as having transient psychotic experiences. Data from both time-points were used to examine the association between transient psychotic experiences and self-reported interpersonal and educational/ vocational difficulties in young adulthood using poisson regression modelling., Results: Young people with a history of transient psychotic experiences reported significantly higher interpersonal (adj IRR: 1.83, 95%ileCI: 1.10-3.02, p = .02) and educational/vocational (adj IRR: 2.28, 95%ileCI: 1.43-3.64, p = .001) difficulties during adolescence. However, no significant differences in interpersonal (adj IRR: 0.49, 95%ileCI: 0.10-2.30, p = .37) or educational/vocational (adj IRR: 0.88, 95%ileCI: 0.37-2.08, p = .77) difficulties were found in young adulthood. Self-reported interpersonal and educational/vocational difficulties in young people both with and without a history of transient psychotic experiences decreased between adolescence and young adulthood., Conclusions: Young people with transient psychotic experiences have increased interpersonal and educational/vocational difficulties in adolescence but these may not persist into the young adult years. This finding indicates that early psychotic experiences may not confer high risk for long-term interpersonal or educational/vocational deficits among young people who experience these phenomena transiently.

Objective: This study aims to examine the associations between prenatal exposure to maternal smoking, birth weight and persistent offspring psychiatric symptoms. Additionally, we aim to examine whether the relationship between prenatal maternal smoking and persistent offspring psychiatric symptoms is mediated by offspring birth weight., Methods: This study used the Growing Up in Ireland (GUI) longitudinal cohort. The GUI is a nationally representative longitudinal study of children which consisted of three data collection waves, at ages 9, 13, and 17 years. Logistic regression analysis was used to examine associations between prenatal tobacco exposure, and offspring psychiatric symptoms. Linear regression was used to examine associations between prenatal tobacco exposure and offspring birth weight. We conducted a mediation analysis examining potential etiological pathways linking maternal smoking during pregnancy, offspring birth weight, and later offspring psychiatric symptoms. All analyses were adjusted for confounders including household income, maternal level of education, and family psychiatric history. Additionally, examination of birth weight and subsequent psychiatric symptoms also was controlled for prematurity., Results: We found that the association between prenatal tobacco exposure and later psychiatric symptoms is mediated by birth weight., Conclusions: This work provides further evidence that maternal smoking during pregnancy is an important modifiable lifestyle factor that has an impact not just on the physical health of offspring but also their mental wellbeing. Supporting women with structured smoking cessation programs at the earliest stages of pregnancy should be a public health priority., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Childhood temperament and its component factors have previously been shown to be associated with depression and anxiety disorders in later life. Studies have also suggested possible links between childhood temperament and later psychosis., Aims: To investigate the association between childhood temperament and its individual component factors, measured at age 5, and later psychiatric disorders., Method: Using a sample from a Finnish birth cohort (N = 1014), we used logistic regression models to examine associations between maternal reported childhood temperament at age 5, and later psychiatric diagnosis, ascertained through linkage with the Finnish Hospital Discharge Register (FHDR)., Results: Individuals with a childhood temperament rated as difficult at age 5 had almost 5-times the odds of developing a psychotic disorder in adulthood compared to those with a temperament rated as average by their mothers (OR = 4.91, 95% CI = 1.51-15.91). The individual temperament factors of approach withdrawal, adaptability and quality of mood were each independently associated with later psychotic disorder while the factors of regularity and threshold were associated with increased risk for mood disorders., Conclusions: This study reports association between early childhood temperament and risk for psychosis and suggests that early childhood temperament may be a good target for early intervention to reduce the risk of psychiatric disorders., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: The diagnosis of cellulitis is made clinically without a gold standard diagnostic test, and cellulitis has many disease mimics. There is currently no consensus for optimal antimicrobial treatment duration or method of antimicrobial delivery., Methods: This was a randomized controlled open-label multicenter trial to determine the safety and efficacy of 24 hours of intravenous (IV) therapy compared with ≥72 hours of IV therapy, both followed by oral therapy to a maximum of 7-10 days' duration for the treatment of lower limb cellulitis., Results: Over 40 months, 80 patients were recruited. Thirty-nine patients were assigned to 24 hours of IV antibiotics and 41 to ≥72 hours of IV antibiotics. The mean duration (range) of IV antibiotics in the 24-hour group was 25.5 (17-40) hours, and in the ≥72-hour group it was 78 (41.5-210) hours. Three patients in the 24-hour arm and 4 patients in the ≥72-hour arm were excluded from the analysis due to withdrawal from the trial. Analysis of the remaining patients revealed that 6 patients (4 in the intervention arm and 2 in the control arm) did not achieve an adequate response to therapy. Only 1 patient experienced self-limiting adverse effects of treatment., Conclusions: The noninferiority of short-course IV therapy cannot be determined from this trial. Challenges included resource limitations for recruitment, misdiagnosis, participant withdrawal, and subjective responses to therapy based on visual assessment by treating clinicians. Further studies are needed to determine if short-course IV therapy is a suitable treatment option., Australia Council of Clinical Trials Registry No: ACTRN12613001366741., (© The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: Exposure to prenatal stress is a ubiquitous and non-specific risk factor for adverse outcomes in adulthood. In this study, we examined associations between exposure to subjective maternal stress during pregnancy and subsequent diagnosis of psychiatric disorders in offspring., Method: This study used the Helsinki Longitudinal Temperament Cohort, a prospective birth cohort of individuals born between 1 July 1975 and 30 June 1976 in Helsinki, Finland. The sample for this study comprised 3626 infants whose mothers had completed health and well-being assessments during pregnancy which included a measure of self-reported stress. We ran logistic regressions to assess potential associations between prenatal stress and offspring psychiatric disorder in adulthood, identified through the Finnish Hospital Discharge Register., Results: Individuals whose mothers reported stress during pregnancy had significantly greater odds of developing a psychiatric disorder (OR = 1.41, 95% CI = 1.10-1.81) particularly a mood disorder (OR = 1.67, 95% CI = 1.10-2.54). These associations remained after adjusting for parental psychiatric history, and other prenatal factors., Conclusions: Individuals exposed to prenatal stress had significantly increased risk of developing psychiatric disorders later in life. This finding highlights the importance of supporting the mental health and emotional well-being of women during pregnancy., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Peristomal skin complications are a common problem for persons with an ileostomy., Purpose: The purpose of this pilot study was to solicit user feedback and perform an initial assessment of the performance of a new barrier seal designed to decrease the risk of chemical-induced dermatitis., Methods: Seven (7) potential participants who were at least 18 years of age, >6 months post surgery, with an end or loop ileostomy and unbroken peristomal skin, and who were capable of changing their appliance themselves or had the availability of care assistance were identified and recruited by the stoma care nurse at the University Hospital, Limerick, Ireland. At the initial visit and after 1 and 2 weeks, participants were asked to rate device comfort, security, and handling; skin condition was assessed by the research nurse using the Ostomy Skin Tool. Descriptive statistics were used to tabulate the results., Results: Five (5) participants completed the study. Discoloration, erosion, and tissue overgrowth scores improved in 3 of 5 patients, and the mean Ostomy Skin Tool score decreased from 5.4 ± 2.19 at the initial assessment to 4 ± 1.87 at the week 2 visit. Comfort, handling, and security ratings increased from a median of 8 at the beginning of the study to 10 at week 2., Conclusion: Initial patient feedback regarding the new product was positive, and skin assessment results suggest the new seal may help improve peristomal skin condition. Larger studies with longer patient follow-up are needed to confirm the results of this pilot evaluation.

Background: Despite the problem of inadequate recruitment to randomised trials, there is little evidence to guide researchers on decisions about how people are effectively recruited to take part in trials. The PRioRiTy study aimed to identify and prioritise important unanswered trial recruitment questions for research. The PRioRiTy study - Priority Setting Partnership (PSP) included members of the public approached to take part in a randomised trial or who have represented participants on randomised trial steering committees, health professionals and research staff with experience of recruiting to randomised trials, people who have designed, conducted, analysed or reported on randomised trials and people with experience of randomised trials methodology., Methods: This partnership was aided by the James Lind Alliance and involved eight stages: (i) identifying a unique, relevant prioritisation area within trial methodology; (ii) establishing a steering group (iii) identifying and engaging with partners and stakeholders; (iv) formulating an initial list of uncertainties; (v) collating the uncertainties into research questions; (vi) confirming that the questions for research are a current recruitment challenge; (vii) shortlisting questions and (viii) final prioritisation through a face-to-face workshop., Results: A total of 790 survey respondents yielded 1693 open-text answers to 6 questions, from which 1880 potential questions for research were identified. After merging duplicates, the number of questions was reduced to 496. Questions were combined further, and those that were submitted by fewer than 15 people and/or fewer than 6 of the 7 stakeholder groups were excluded from the next round of prioritisation resulting in 31 unique questions for research. All 31 questions were confirmed as being unanswered after checking relevant, up-to-date research evidence. The 10 highest priority questions were ranked at a face-to-face workshop. The number 1 ranked question was "How can randomised trials become part of routine care and best utilise current clinical care pathways?" The top 10 research questions can be viewed at www.priorityresearch.ie ., Conclusion: The prioritised questions call for a collective focus on normalising trials as part of clinical care, enhancing communication, addressing barriers, enablers and motivators around participation and exploring greater public involvement in the research process.

A number of bacterial pathogens require the ZnuABC Zinc (Zn 2+ ) transporter and/or a second Zn 2+ transport system to overcome Zn 2+ sequestration by mammalian hosts. Previously we have shown that in addition to ZnuABC, Yersinia pestis possesses a second Zn 2+ transporter that involves components of the yersiniabactin (Ybt), siderophore-dependent iron transport system. Synthesis of the Ybt siderophore and YbtX, a member of the major facilitator superfamily, are both critical components of the second Zn 2+ transport system. Here we demonstrate that a ybtX znu double mutant is essentially avirulent in mouse models of bubonic and pneumonic plague while a ybtX mutant retains high virulence in both plague models. While sequestration of host Zn is a key nutritional immunity factor, excess Zn appears to have a significant antimicrobial role in controlling intracellular bacterial survival. Here, we demonstrate that ZntA, a Zn 2+ exporter, plays a role in resistance to Zn toxicity in vitro, but that a zntA zur double mutant retains high virulence in both pneumonic and bubonic plague models and survival in macrophages. We also confirm that Ybt does not directly bind Zn 2+ in vitro under the conditions tested. However, we detect a significant increase in Zn 2+ -binding ability of filtered supernatants from a Ybt + strain compared to those from a strain unable to produce the siderophore, supporting our previously published data that Ybt biosynthetic genes are involved in the production of a secreted Zn-binding molecule (zincophore). Our data suggest that Ybt or a modified Ybt participate in or promote Zn-binding activity in culture supernatants and is involved in Zn acquisition in Y. pestis.

Portal hypertension is a common clinical syndrome, defined by a pathologic increase in the portal venous pressure. Increased resistance to portal blood flow, the primary factor in the pathophysiology of portal hypertension, is in part due to morphological changes occurring in chronic liver diseases. This results in rerouting of blood flow away from the liver through collateral pathways to low-pressure systemic veins. Through a variety of computed tomographic, sonographic, magnetic resonance imaging and angiographic examples, this article discusses the appearances and prevalence of both common and less common portosystemic collateral channels in the thorax and abdomen. A brief overview of established interventional radiologic techniques for treatment of portal hypertension will also be provided. Awareness of the various imaging manifestations of portal hypertension can be helpful for assessing overall prognosis and planning proper management., Competing Interests: Conflict-of-interest statement: Authors declare no potential conflicts of interests. No financial support.

Objective: The purpose of this study was to evaluate the effectiveness of different reported methods used to teach spinal manipulative therapy to chiropractic students., Methods: For this best-evidence literature synthesis, 5 electronic databases were searched from 1900 to 2015. Eligible studies were critically appraised using the criteria of the Scottish Intercollegiate Guidelines Network. Scientifically admissible studies were synthesized following best-evidence synthesis principles., Results: Twenty articles were critically appraised, including 9 randomized clinical trials, 9 cohort studies, and 2 systematic reviews/meta-analyses. Eleven articles were accepted as scientifically admissible. The type of teaching method aids included a Thrust in Motion cervical manikin, instrumented cardiopulmonary reanimation manikin, padded contact with a load cell, instrumented treatment table with force sensor/transducer, and Dynadjust instrument., Conclusions: Several different methods exist in the literature for teaching spinal manipulative therapy techniques; however, future research in this developing area of chiropractic education is proposed. It is suggested that various teaching methods be included in the regular curricula of chiropractic colleges to aid in developing manipulation skills, efficiency, and knowledge of performance.

A pilot randomized controlled trial that evaluated the effect of remote ischemic preconditioning (RIPC) on clinical outcomes following major vascular surgery was performed. Eligible patients were those scheduled to undergo open abdominal aortic aneurysm repair, endovascular aortic aneurysm repair, carotid endarterectomy, and lower limb revascularization procedures. Patients were randomized to RIPC or to control groups. The primary outcome was a composite clinical end point comprising any of cardiovascular death, myocardial infarction, new-onset arrhythmia, cardiac arrest, congestive cardiac failure, cerebrovascular accident, renal failure requiring renal replacement therapy, mesenteric ischemia, and urgent cardiac revascularization. Secondary outcomes were components of the primary outcome and myocardial injury as assessed by serum troponin values. The primary outcome occurred in 19 (19.2%) of 99 controls and 14 (14.1%) of 99 RIPC group patients (P = .446). There were no significant differences in secondary outcomes. Our trial generated data that will guide future trials. Further trials are urgently needed., (© The Author(s) 2015.)

Inflammation is a key instigator of the immune responses that drive atherosclerosis and allograft rejection. IL-1α, a powerful cytokine that activates both innate and adaptive immunity, induces vessel inflammation after release from necrotic vascular smooth muscle cells (VSMCs). Similarly, IL-1α released from endothelial cells (ECs) damaged during transplant drives allograft rejection. However, IL-1α requires cleavage for full cytokine activity, and what controls cleavage in necrotic ECs is currently unknown. We find that ECs have very low levels of IL-1α activity upon necrosis. However, TNFα or IL-1 induces significant levels of active IL-1α in EC necrotic lysates without alteration in protein levels. Increased activity requires cleavage of IL-1α by calpain to the more active mature form. Immunofluorescence and proximity ligation assays show that IL-1α associates with interleukin-1 receptor-2, and this association is decreased by TNFα or IL-1 and requires caspase activity. Thus, TNFα or IL-1 treatment of ECs leads to caspase proteolytic activity that cleaves interleukin-1 receptor-2, allowing IL-1α dissociation and subsequent processing by calpain. Importantly, ECs could be primed by IL-1α from adjacent damaged VSMCs, and necrotic ECs could activate neighboring normal ECs and VSMCs, causing them to release inflammatory cytokines and up-regulate adhesion molecules, thus amplifying inflammation. These data unravel the molecular mechanisms and interplay between damaged ECs and VSMCs that lead to activation of IL-1α and, thus, initiation of adaptive responses that cause graft rejection., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Objective: Vascular smooth muscle cells (VSMCs) that become senescent are both present within atherosclerotic plaques and thought to be important to the disease process. However, senescent VSMCs are generally considered to only contribute through inaction, with failure to proliferate resulting in VSMC- and collagen-poor unstable fibrous caps. Whether senescent VSMCs can actively contribute to atherogenic processes, such as inflammation, is unknown., Approach and Results: We find that senescent human VSMCs develop a proinflammatory state known as a senescence-associated secretory phenotype. Senescent human VSMCs release high levels of multiple cytokines and chemokines driven by secreted interleukin-1α acting in an autocrine manner. Consequently, the VSMC senescence-associated secretory phenotype promotes chemotaxis of mononuclear cells in vitro and in vivo. In addition, senescent VSMCs release active matrix metalloproteinase-9, secrete less collagen, upregulate multiple inflammasome components, and prime adjacent endothelial cells and VSMCs to a proadhesive and proinflammatory state. Importantly, maintaining the senescence-associated secretory phenotype places a large metabolic burden on senescent VSMCs, such that they can be selectively killed by inhibiting glucose utilization., Conclusions: Senescent VSMCs may actively contribute toward the chronic inflammation associated with atherosclerosis through the interleukin-1α-driven senescence-associated secretory phenotype and the priming of adjacent cells to a proatherosclerotic state. These data also suggest that inhibition of this potentially important source of chronic inflammation in atherosclerosis requires blockade of interleukin-1α and not interleukin-1β., (© 2015 The Authors.)

Importance: Abnormal brain connectivity is thought to have a key role in the pathophysiology of schizophrenia and other psychotic disorders. White matter (WM) abnormalities have been reported in patients with schizophrenia and patients with prodromal syndromes. To our knowledge, no studies have yet reported on WM differences among adolescents who report psychotic experiences, a known vulnerability group for later severe psychopathology, including psychotic illness., Objective: To study WM differences using diffusion-weighted imaging (whole-brain and tractography analyses) in adolescents who report psychotic experiences., Design, Setting, and Participants: A population-based case-control study of 28 adolescents 13 to 16 years old who reported psychotic experiences and a matched sample of 28 adolescents who did not report psychotic experiences drawn from a sample of 212 young people recruited from primary schools in North Dublin and Kildare, Ireland. The study dates were 2008 to 2011., Interventions: High-angular resolution diffusion-weighted imaging data were used to conduct whole-brain WM analysis using tract-based spatial statistics. Based on this exploratory analysis, a tractography-based approach with constrained spherical deconvolution was performed., Results: Compared with control group participants, adolescents who reported psychotic experiences showed WM differences bilaterally in striatal regions in proximity to the putamen (increased fractional anisotropy, P = .01, false discovery rate corrected), and tractography identified significant WM differences bilaterally in the uncinate fasciculus (increased fractional anisotropy in the right [P = .001] and axial diffusivity in the left [P = .01] uncinate fasciculus, respectively). Similar patterns of WM differences between groups survived adjustment for other psychopathology, indicating some specificity for psychotic experiences. Exploratory along-tract analyses showed WM differences between groups in the frontal projections of the right inferior fronto-occipital fasciculus (reduced radial diffusivity in approximately 32% of the tract segment [P ≤ .0001] and increased fractional anisotropy in approximately 16% of the tract segment [P ≤ .0009])., Conclusions and Relevance: In a population-based study of adolescents reporting psychotic experiences, we found a number of WM differences in the region of the putamen located between the inferior fronto-occipital fasciculus and the uncinate fasciculus and in the left parietal regions that include the fiber bundle of the superior longitudinal fasciculus. These findings suggest that subtle structural changes to WM microstructure are not merely a consequence of disorder but may index vulnerability to psychosis even at a very early age.

This unit describes a method for the separation of a mixture of quadruplex conformations formed from the same parent sequence via reversed-phase chromatography (RPC). Polymorphism is inherent to quadruplex formation and even relatively simple quadruplex-forming sequences can fold into a cornucopia of possible conformations and topologies. Isolation of a specific conformation for study can be problematic. This is especially true for conformations of the human telomere sequence d(GGG(TTAGGG)3). High performance liquid chromatography (HPLC), especially reversed-phase chromatography, has been a mainstay of nucleic acid research and purification for many decades. We have successfully applied this method to the problem of separating individual quadruplex species in the ensemble from the same parent sequence., (Copyright © 2013 John Wiley & Sons, Inc. All rights reserved.)

Gold nanoparticles functionalized with biologically compatible layers may achieve stable drug release while avoiding adverse effects in cancer treatment. We study cisplatin and paclitaxel release from gold cores functionalized with hexadecanethiol (TL) and phosphatidylcholine (PC) to form two-layer nanoparticles, or TL, PC, and high density lipoprotein (HDL) to form three-layer nanoparticles. Drug release was monitored for 14 days to assess long term effects of the core surface modifications on release kinetics. Release profiles were fitted to previously developed kinetic models to differentiate possible release mechanisms. The hydrophilic drug (cisplatin) showed an initial (5-h) burst, followed by a steady release over 14 days. The hydrophobic drug (paclitaxel) showed a steady release over the same time period. Two layer nanoparticles released 64.0±2.5% of cisplatin and 22.3±1.5% of paclitaxel, while three layer nanoparticles released the entire encapsulated drug. The Korsmeyer-Peppas model best described each release scenario, while the simplified Higuchi model also adequately described paclitaxel release from the two layer formulation. We conclude that functionalization of gold nanoparticles with a combination of TL and PC may help to modulate both hydrophilic and hydrophobic drug release kinetics, while the addition of HDL may enhance long term release of hydrophobic drug., (Copyright © 2015 Elsevier B.V. All rights reserved.)