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There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls.
Methods
We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS.
Results
We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWE<0.001). In contrast to our hypotheses, siblings with high PRS reported less intense psychotic experiences in response to momentary stress compared to siblings with low PRS. No differences in magnitude of these associations were observed in cases with high v. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS.
Conclusions
This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.
During the first postnatal week in rodents, cholinergic retinal waves initiate in starburst amacrine cells (SACs), propagating to retinal ganglion cells (RGCs) and visual centers, essential for visual circuit refinement. By modulating exocytosis in SACs, dynamic changes in the protein kinase A (PKA) activity can regulate the spatiotemporal patterns of cholinergic waves. Previously, cysteine string protein-α (CSPα) is found to interact with the core exocytotic machinery by PKA-mediated phosphorylation at serine 10 (S10). However, whether PKA-mediated CSPα phosphorylation may regulate cholinergic waves via SACs remains unknown. Here, we examined how CSPα phosphorylation in SACs regulates cholinergic waves. First, we identified that CSPα1 is the major isoform in developing rat SACs and the inner plexiform layer during the first postnatal week. Using SAC-specific expression, we found that the CSPα1-PKA-phosphodeficient mutant (CSP-S10A) decreased wave frequency, but did not alter the wave spatial correlation compared to control, wild-type CSPα1 (CSP-WT), or two PKA-phosphomimetic mutants (CSP-S10D and CSP-S10E). These suggest that CSPα-S10 phosphodeficiency in SACs dampens the frequency of cholinergic waves. Moreover, the level of phospho-PKA substrates was significantly reduced in SACs overexpressing CSP-S10A compared to control or CSP-WT, suggesting that the dampened wave frequency is correlated with the decreased PKA activity. Further, compared to control or CSP-WT, CSP-S10A in SACs reduced the periodicity of wave-associated postsynaptic currents (PSCs) in neighboring RGCs, suggesting that these RGCs received the weakened synaptic inputs from SACs overexpressing CSP-S10A. Finally, CSP-S10A in SACs decreased the PSC amplitude and the slope to peak PSC compared to control or CSP-WT, suggesting that CSPα-S10 phosphodeficiency may dampen the speed of the SAC-RGC transmission. Thus, via PKA-mediated phosphorylation, CSPα in SACs may facilitate the SAC-RGC transmission, contributing to the robust frequency of cholinergic waves.
Changes in children’s attachment security to mother and father were examined for 230 firstborn children (M = 31.17 months), their mothers and fathers participating in a longitudinal investigation starting in the last trimester of the mothers’ pregnancy and 1, 4, 8, and 12 months after the birth of an infant sibling. Both parents completed the Attachment Q-set at prenatal, 4, and 12 months. Growth mixture models revealed four latent classes in which children’s attachments were (a) both secure with a modest decline to both parents (68.3%); (b) more secure with father than mother with a steep decline for both (12.6%); (c) both insecure with no change (10%); and (d) more secure with mother than father with a modest increase for both (9.1%). Multi-group latent growth curve analyses revealed that parenting and coparenting differed across families. Children had lower externalizing behavior problems in families with two secure attachments than in families with one secure attachment, either to mother or to father, who, in turn, had fewer problems than children with two insecure attachments. Findings underscore the strengths of a family systems framework to understand attachment relationships with multiple caregivers and the family risks and protective factors that covary with children’s behavioral adjustment after the birth of a sibling.
While there exist some studies that explored the association between maternal anxiety and depressive symptoms and the risk of attention-deficit/hyperactivity disorder (ADHD) in early and late childhood, studies exploring the risk in late adolescence are however lacking.
Objectives
This is the first study that aimed to investigate the association between maternal anxiety, depressive, as well as comorbid anxiety and depressive symptoms, and the risk of ADHD symptoms in late adolescence.
Methods
We used data from the Raine Study, a birth cohort in Western Australia. The Depression, Anxiety, and Stress Scale (DASS) was used to assess maternal depressive and anxiety symptoms when the child was aged 10. Whereas, the DSM-oriented scales of the child behavior checklist (CBCL) was used to assess ADHD symptoms offspring in adolescents aged 17. Log-binomial regression model was used to explore the associations.
Results
After adjusting for relevant covariates, we found an increased risk of ADHD symptoms in the adolescent children of mothers with anxiety [RR 2.84 (95%CI 1.18-6.83)] as well as comorbid anxiety and depressive symptoms [RR 5.60 (95%CI 3.02-10.37)]. No association was seen with maternal depressive symptoms.
Conclusions
This study suggested that adolescent offspring of mothers with anxiety as well as comorbid anxiety and depressive symptoms had an increased risk of ADHD symptoms. Early detection and management for ADHD symptoms in children of mothers with anxiety and comorbid anxiety and depressive symptoms are needed.
Previous research has suggested that offspring of parents with mental health problems, including depression and anxiety, are at an increased risk of developing anxiety disorders. Few studies have investigated this relationship in young adults.
Objectives
To investigate the risk of anxiety symptoms in young adult offspring of parents with mental health problems
Methods
We used data from the 1989-1991 cohort of the Western Australian Pregnancy (Raine) Study, which is a multi-generational birth cohort study following mothers and their offspring from pregnancy to 28 years of age. The Depression, Anxiety, and Stress Scale (DASS) was used to assess maternal anxiety and depression whereas a self-reported questionnaire was used to assess paternal emotional problems. Anxiety symptoms among offspring at age 20 were measured by using the short form of the Depression, Anxiety, and Stress Scale (DASS 21). A multivariable negative binomial regression model was used to quantify the associations.
Results
After adjustment, maternal anxiety [RR 1.60 (95% CI 1.11-2.32)] and paternal emotional problems [RR 1.32 (95%CI 1.03-1.68)] were associated with an increased risk of anxiety in offspring at age 20 years. Conversely, maternal depressive symptoms [RR 1.04 (95%CI 0.84-1.32)] were not associated with an increased risk of anxiety in offspring.
Conclusions
The present study suggests that maternal anxiety and paternal emotional problems were associated with an increased risk of anxiety in young adult offspring. However, maternal depressive symptoms were not associated with an increased risk of anxiety in the offspring. The findings suggest the potential for targeted screening and intervention of anxiety problems in the offspring.
Alcohol consumption, smoking and mood disorders are leading contributors to the global burden of disease and are highly comorbid. Yet, their interrelationships have remained elusive. The aim of this study was to examine the multi-cross-sectional and longitudinal associations between (change in) smoking and alcohol use and (change in) number of depressive symptoms.
Methods
In this prospective, longitudinal study, 6646 adults from the general population were included with follow-up measurements after 3 and 6 years. Linear mixed-effects models were used to test multi-cross-sectional and longitudinal associations, with smoking behaviour, alcohol use and genetic risk scores for smoking and alcohol use as independent variables and depressive symptoms as dependent variables.
Results
In the multi-cross-sectional analysis, smoking status and number of cigarettes per day were positively associated with depressive symptoms (p < 0.001). Moderate drinking was associated with less symptoms of depression compared to non-use (p = 0.011). Longitudinally, decreases in the numbers of cigarettes per day and alcoholic drinks per week as well as alcohol cessation were associated with a reduction of depressive symptoms (p = 0.001–0.028). Results of genetic risk score analyses aligned with these findings.
Conclusions
While cross-sectionally smoking and moderate alcohol use show opposing associations with depressive symptoms, decreases in smoking behaviour as well as alcohol consumption are associated with improvements in depressive symptoms over time. Although we cannot infer causality, these results open avenues to further investigate interventions targeting smoking and alcohol behaviours in people suffering from depressive symptoms.
Polycystic ovary syndrome (PCOS) is associated with a higher prevalence of sleep disturbances and obesity. Treatment of PCOS includes modifying lifestyle behaviours associated with weight management. However, poor sleep in the non-PCOS population has been associated with poorer lifestyle behaviours. The aim was to investigate whether sleep disturbance confounds or modifies the association between lifestyle factors and PCOS. This was a cross-sectional analysis from the Australian Longitudinal Study on Women’s Health cohort aged 31–36 years in 2009 were analysed (n 6067, 464 PCOS, 5603 non-PCOS). Self-reported data were collected on PCOS, anthropometry, validated modified version of the Active Australia Physical Activity survey, validated FFQ and sleep disturbances through latent class analysis. Women with PCOS had greater adverse sleep symptoms including severe tiredness (P = 0·001), difficulty sleeping (P < 0·001) and restless sleep (P < 0·001), compared with women without PCOS. Women with PCOS also had higher energy consumption (6911 (sd 2453) v. 6654 (sd 2215) kJ, P = 0·017), fibre intake (19·8 (sd 7·8) v. 18·9 (sd 6·9) g, P = 0·012) and diet quality (dietary guidelines index (DGI)) (88·1 (sd 11·6) v. 86·7 (sd 11·1), P = 0·008), lower glycaemic index (50·2 (sd 4·0) v. 50·7 (sd 3·9), P = 0·021) and increased sedentary behaviour (6·3 (sd 2·8) v. 5·9 (sd 2·8) h, P = 0·009). There was a significant interaction between PCOS and sleep disturbances for DGI (P = 0·035), therefore only for women who had adequate sleep was PCOS associated with a higher DGI. For women with poorer sleep, there was no association between PCOS and DGI. The association between PCOS and improved diet quality may only be maintained if women can obtain enough good quality sleep.
Ventilator-capable skilled nursing facilities (vSNFs) are critical to the epidemiology and control of antibiotic-resistant organisms. During an infection prevention intervention to control carbapenem-resistant Enterobacterales (CRE), we conducted a qualitative study to characterize vSNF healthcare personnel beliefs and experiences regarding infection control measures.
Design:
A qualitative study involving semistructured interviews.
Setting:
One vSNF in the Chicago, Illinois, metropolitan region.
Participants:
The study included 17 healthcare personnel representing management, nursing, and nursing assistants.
Methods:
We used face-to-face, semistructured interviews to measure healthcare personnel experiences with infection control measures at the midpoint of a 2-year quality improvement project.
Results:
Healthcare personnel characterized their facility as a home-like environment, yet they recognized that it is a setting where germs were ‘invisible’ and potentially ‘threatening.’ Healthcare personnel described elaborate self-protection measures to avoid acquisition or transfer of germs to their own household. Healthcare personnel were motivated to implement infection control measures to protect residents, but many identified structural barriers such as understaffing and time constraints, and some reported persistent preference for soap and water.
Conclusions:
Healthcare personnel in vSNFs, from management to frontline staff, understood germ theory and the significance of multidrug-resistant organism transmission. However, their ability to implement infection control measures was hampered by resource limitations and mixed beliefs regarding the effectiveness of infection control measures. Self-protection from acquiring multidrug-resistant organisms was a strong motivator for healthcare personnel both outside and inside the workplace, and it could explain variation in adherence to infection control measures such as a higher hand hygiene adherence after resident care than before resident care.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in shortages of personal protective equipment (PPE), underscoring the urgent need for simple, efficient, and inexpensive methods to decontaminate masks and respirators exposed to severe acute respiratory coronavirus virus 2 (SARS-CoV-2). We hypothesized that methylene blue (MB) photochemical treatment, which has various clinical applications, could decontaminate PPE contaminated with coronavirus.
Design:
The 2 arms of the study included (1) PPE inoculation with coronaviruses followed by MB with light (MBL) decontamination treatment and (2) PPE treatment with MBL for 5 cycles of decontamination to determine maintenance of PPE performance.
Methods:
MBL treatment was used to inactivate coronaviruses on 3 N95 filtering facepiece respirator (FFR) and 2 medical mask models. We inoculated FFR and medical mask materials with 3 coronaviruses, including SARS-CoV-2, and we treated them with 10 µM MB and exposed them to 50,000 lux of white light or 12,500 lux of red light for 30 minutes. In parallel, integrity was assessed after 5 cycles of decontamination using multiple US and international test methods, and the process was compared with the FDA-authorized vaporized hydrogen peroxide plus ozone (VHP+O3) decontamination method.
Results:
Overall, MBL robustly and consistently inactivated all 3 coronaviruses with 99.8% to >99.9% virus inactivation across all FFRs and medical masks tested. FFR and medical mask integrity was maintained after 5 cycles of MBL treatment, whereas 1 FFR model failed after 5 cycles of VHP+O3.
Conclusions:
MBL treatment decontaminated respirators and masks by inactivating 3 tested coronaviruses without compromising integrity through 5 cycles of decontamination. MBL decontamination is effective, is low cost, and does not require specialized equipment, making it applicable in low- to high-resource settings.
The schizophrenia polygenic risk score (SCZ-PRS) is an emerging tool in psychiatry.
Aims
We aimed to evaluate the utility of SCZ-PRS in a young, transdiagnostic, clinical cohort.
Method
SCZ-PRSs were calculated for young people who presented to early-intervention youth mental health clinics, including 158 patients of European ancestry, 113 of whom had longitudinal outcome data. We examined associations between SCZ-PRS and diagnosis, clinical stage and functioning at initial assessment, and new-onset psychotic disorder, clinical stage transition and functional course over time in contact with services.
Results
Compared with a control group, patients had elevated PRSs for schizophrenia, bipolar disorder and depression, but not for any non-psychiatric phenotype (for example cardiovascular disease). Higher SCZ-PRSs were elevated in participants with psychotic, bipolar, depressive, anxiety and other disorders. At initial assessment, overall SCZ-PRSs were associated with psychotic disorder (odds ratio (OR) per s.d. increase in SCZ-PRS was 1.68, 95% CI 1.08–2.59, P = 0.020), but not assignment as clinical stage 2+ (i.e. discrete, persistent or recurrent disorder) (OR = 0.90, 95% CI 0.64–1.26, P = 0.53) or functioning (R = 0.03, P = 0.76). Longitudinally, overall SCZ-PRSs were not significantly associated with new-onset psychotic disorder (OR = 0.84, 95% CI 0.34–2.03, P = 0.69), clinical stage transition (OR = 1.02, 95% CI 0.70–1.48, P = 0.92) or persistent functional impairment (OR = 0.84, 95% CI 0.52–1.38, P = 0.50).
Conclusions
In this preliminary study, SCZ-PRSs were associated with psychotic disorder at initial assessment in a young, transdiagnostic, clinical cohort accessing early-intervention services. Larger clinical studies are needed to further evaluate the clinical utility of SCZ-PRSs, especially among individuals with high SCZ-PRS burden.
Gas-fluidized beds of flexible fibres, which have been rarely studied before, are investigated in this work using the coupled approach of the discrete element method and computational fluid dynamics. In the present numerical method, gas–fibre interaction is modelled by calculating the interaction force for each constituent element in the fibre, and the composition of the interaction forces on the constituent elements generates a resultant hydrodynamic force and a resultant hydrodynamic torque on the fibre. Pressure drops and fibre orientation results from the present simulations with various fibre aspect ratios are in good agreement with previous experimental and simulation results. Some novel results are obtained for the effects of fibre flexibility. Larger hydrodynamic forces on fibres (before the bed is fluidized) and smaller minimum fluidization velocities (MFVs) are observed for more flexible fibre beds due to the smaller porosities, while smaller hydrodynamic forces are obtained for the more flexible fibres when the beds are fluidized with significant fibre motion. By scaling the superficial gas velocity using the MFVs, the data of pressure drop can collapse onto the Ergun correlation for stiff fibres of various aspect ratios; however, the pressure drop curves deviate from the Ergun correlation for very flexible fibres, due to the significant fibre bed expansion before the MFV is reached. The fibre aspect ratio and flexibility both have an impact on the solids mixing rate, and it is found that the solids mixing rates are essentially determined by the ratio of the superficial gas velocity to MFV.
Schizophrenia negatively affects quality of life (QoL). A handful of variables from small studies have been reported to influence QoL in patients with schizophrenia, but a study comprehensively dissecting the genetic and non-genetic contributing factors to QoL in these patients is currently lacking.
Aims
We adopted a hypothesis-generating approach to assess the phenotypic and genotypic determinants of QoL in schizophrenia.
Method
The study population comprised 1119 patients with a psychotic disorder, 1979 relatives and 586 healthy controls. Using linear regression, we tested >100 independent demographic, cognitive and clinical phenotypes for their association with QoL in patients. We then performed genome-wide association analyses of QoL and examined the association between polygenic risk scores for schizophrenia, major depressive disorder and subjective well-being and QoL.
Results
We found nine phenotypes to be significantly and independently associated with QoL in patients, the most significant ones being negative (β = −1.17; s.e. 0.05; P = 1 × 10–83; r2 = 38%), depressive (β = −1.07; s.e. 0.05; P = 2 × 10–79; r2 = 36%) and emotional distress (β = −0.09; s.e. 0.01; P = 4 × 10–59, r2 = 25%) symptoms. Schizophrenia and subjective well-being polygenic risk scores, using various P-value thresholds, were significantly and consistently associated with QoL (lowest association P-value = 6.8 × 10–6). Several sensitivity analyses confirmed the results.
Conclusions
Various clinical phenotypes of schizophrenia, as well as schizophrenia and subjective well-being polygenic risk scores, are associated with QoL in patients with schizophrenia and their relatives. These may be targeted by clinicians to more easily identify vulnerable patients with schizophrenia for further social and clinical interventions to improve their QoL.
The SPARC tokamak is a critical next step towards commercial fusion energy. SPARC is designed as a high-field ($B_0 = 12.2$ T), compact ($R_0 = 1.85$ m, $a = 0.57$ m), superconducting, D-T tokamak with the goal of producing fusion gain $Q>2$ from a magnetically confined fusion plasma for the first time. Currently under design, SPARC will continue the high-field path of the Alcator series of tokamaks, utilizing new magnets based on rare earth barium copper oxide high-temperature superconductors to achieve high performance in a compact device. The goal of $Q>2$ is achievable with conservative physics assumptions ($H_{98,y2} = 0.7$) and, with the nominal assumption of $H_{98,y2} = 1$, SPARC is projected to attain $Q \approx 11$ and $P_{\textrm {fusion}} \approx 140$ MW. SPARC will therefore constitute a unique platform for burning plasma physics research with high density ($\langle n_{e} \rangle \approx 3 \times 10^{20}\ \textrm {m}^{-3}$), high temperature ($\langle T_e \rangle \approx 7$ keV) and high power density ($P_{\textrm {fusion}}/V_{\textrm {plasma}} \approx 7\ \textrm {MW}\,\textrm {m}^{-3}$) relevant to fusion power plants. SPARC's place in the path to commercial fusion energy, its parameters and the current status of SPARC design work are presented. This work also describes the basis for global performance projections and summarizes some of the physics analysis that is presented in greater detail in the companion articles of this collection.
OBJECTIVES/GOALS: Nicotinamide adenine dinucleotide (NAD) plays essential roles in energy metabolism and cell signaling pathways. NAD functions as a coenzyme by accepting electrons during glycolysis and the TCA cycle and subsequently donates them to complex I of the electron transport chain providing the driving force for ATP production. NAD also acts as a co-substrate for several classes of enzymes, including sirtuin deacetylases. Both NAD and the enzyme that is rate limiting for synthesis, Nicotinamide phosphoribosyltransferase (Nampt), are depleted in the failing heart, concurrent with hyperacetylation and mitochondrial dysfunction. Moreover, treatment with NAD precursors reduced cardiac injury in several heart failure models. However, NAD precursors may have systemic effects, and it remains unproven whether depletion of myocardial NAD is causative or merely correlative for the onset and progression of heart failure. METHODS/STUDY POPULATION: To test this, we generated a cardiac-specific tamoxifen-inducible (αMHC-MerCreMer) model for deletion of Nampt (Nampt cKO) in cardiomyocytes. Adult mice were administered tamoxifen for 5 days leading to deletion of Nampt, resulting in a 72% reduction in myocardial NAD after two-weeks. RESULTS/ANTICIPATED RESULTS: Echocardiography revealed that Nampt cKO mice displayed a significant reduction in left ventricular (LV) contractility as well as cardiac hypertrophy. Despite the further loss of NAD, the majority of animals survived to 8 weeks of age before experiencing sudden deaths resulting in significant mortality over the next several weeks. Remarkably, we observed only a slight increase in acetylation of mitochondrial proteins, and cardiac mitochondria isolated from Nampt-null mice even at 8 weeks displayed a normal or higher oxygen consumption rate. We found that mitochondrial NAD levels were preferentially maintained and depleted at a slower rate compared to those in bulk tissue. DISCUSSION/SIGNIFICANCE OF IMPACT: While mild depletion of cardiac NAD has been reported in heart failure, our data indicate that the heart can adapt to much more severe loss of NAD prior to the loss of viability.
Although prenatal exposure to high ambient temperatures were reported to be associated with preterm birth, limited research assessed the impact of weather-related extreme heat events (EHE) on birthweight, particularly by trimester. We, therefore, investigated the impact of prenatal EHE on birthweight among term babies (tLBW) by trimester and birthweight percentile. We conducted a population-based case–control study on singleton live births at 38–42 gestational weeks in New York State (NYS) by linking weather data with NYS birth certificates. A total of 22,615 cases were identified as birthweight <2500 gram, and a random sample of 139,168 normal birthweight controls was included. EHE was defined as three consecutive days with the maximum temperatures of ≥32.2 °C/90 °F (EHE90) and two consecutive days of temperatures ≥97th percentile (EHE97) based on the distribution of the maximum temperature for the season and region. We estimated odds ratios (ORs) and 95% confidence intervals (95% CI) with multivariable unconditional logistic regression, controlling for confounders. Overall exposure to EHE97 for 2 d was associated with tLBW (OR 1.05; 95% CI 1.02, 1.09); however, the strongest associations were only observed in the first trimester for both heat indicators, especially when exposure was ≥3 d (ORs ranged: 1.06–1.13). EHE in the first trimester was associated with significant reduction in mean birthweight from 26.78 gram (EHE90) to 36.25 gram (EHE97), which mainly affected the 40th and 60th birthweight percentiles. Findings revealed associations between multiple heat indicators and tLBW, where the impact was consistently strongest in the first trimester.