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There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.
We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.
The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: −0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).
The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
This study attempted to replicate whether a bias in probabilistic reasoning, or ‘jumping to conclusions’(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation.
Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses.
JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46–5.17 for siblings and aRR: 5.07 CI 95% 4.13–6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67–8.51, and in patients: 2.15 CI 95% 0.94–4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences.
These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
Maternal milk consumption can cause changes in the mammary epithelium of the offspring that result in the expression of molecules involved in the induction of differentiation, reducing the risk of developing mammary cancer later in life. We previously showed that animals that maintained a higher intake of maternal milk had a lower incidence of mammary cancer. In the present study, we evaluated one of the possible mechanisms by which the consumption of maternal milk could modify the susceptibility to mammary carcinogenesis. We used Sprague Dawley rats reared in litters of 3 (L3), 8 (L8), or 12 (L12) pups per mother in order to generate a differential consumption of milk. Whole mounts of mammary glands were performed to analyze the changes in morphology. Using real-time polymerase chain reaction (PCR), we analyzed the expression of mammary Pinc, Tbx3, Stat6, and Gata3 genes. We use the real-time methylation-specific polymerase chain reaction method to assess the methylation status of Stat6 and Gata3 CpG sites. Our findings show an increase in the size of the epithelial tree and a smaller number of ducts called terminal end buds in L3 vs. L12. We observed an increased expression of mRNA of Stat6, Gata3, Tbx3, and a lower expression of Pinc in L3 with respect to L12. Stat6 and Gata3 are more methylated in the CpG islands of the promoter analyzed in L12 vs. L3. In conclusion, the increased consumption of maternal milk during the postnatal stage generates epigenetic and morphological changes associated with the differentiation of the mammary gland.
Equity and efficiency are crucial issues behind any tax reform, but they are particularly relevant in countries with high inequality and large shares of poverty. This paper provides a comprehensive socio-economic empirical assessment of Mexico's proposed (and partially implemented) tax reforms in the energy domain, and of a hypothetical partial removal of existing electricity subsidies. Using a rich household income and expenditure survey within the context of a demand system adjustment of non-durable goods, the article provides the public-revenue, environmental and distributional impacts from the simulation of different combinations of energy taxation, subsidy-removal and distributive offsets. The paper also provides detailed ex-ante evidence on the effects of compensatory devices that may contribute to the successful implementation of energy reform packages and significant poverty alleviation in Mexico.
Social and environmental factors such as poverty or violence modulate the risk and course of schizophrenia. However, how they affect the brain in patients with psychosis remains unclear.
We studied how environmental factors are related to brain structure in patients with schizophrenia and controls in Latin America, where these factors are large and unequally distributed.
This is a multicentre study of magnetic resonance imaging in patients with schizophrenia and controls from six Latin American cities. Total and voxel-level grey matter volumes, and their relationship with neighbourhood characteristics such as average income and homicide rates, were analysed with a general linear model.
A total of 334 patients with schizophrenia and 262 controls were included. Income was differentially related to total grey matter volume in both groups (P = 0.006). Controls showed a positive correlation between total grey matter volume and income (R = 0.14, P = 0.02). Surprisingly, this relationship was not present in patients with schizophrenia (R = −0.076, P = 0.17). Voxel-level analysis confirmed that this interaction was widespread across the cortex. After adjusting for global brain changes, income was positively related to prefrontal cortex volumes only in controls. Conversely, the hippocampus in patients with schizophrenia, but not in controls, was relatively larger in affluent environments. There was no significant correlation between environmental violence and brain structure.
Our results highlight the interplay between environment, particularly poverty, and individual characteristics in psychosis. This is particularly important for harsh environments such as low- and middle-income countries, where potentially less brain vulnerability (less grey matter loss) is sufficient to become unwell in adverse (poor) environments.
The dynamics of a stably and thermally stratified fluid-filled cavity harmonically forced in the vertical direction, resulting in a periodic gravity modulation, is studied numerically. Prior simulations in a two-dimensional cavity showed a myriad of complex dynamic behaviours near the onset of instabilities, and here we address the extent to which these persist in three dimensions. Focusing on a parameter regime where the primary subharmonic mode is resonantly driven, we demonstrate comprehensive qualitative agreement between the dynamics in two and three dimensions; the quantitative difference is due to the larger forcing amplitudes needed in three dimensions to overcome the additional viscous damping from the spanwise walls. Using a small detuning of the forcing frequency, together with a relatively large forcing amplitude, leads to a wave-breaking regime where the qualitative agreement between two and three dimensions breaks down.
Previous studies attest that early bilinguals can modify their perceptual identification according to the fine-grained phonetic detail of the language they believe they are hearing. Following Gonzales et al. (2019), we replicate the double phonemic boundary effect in late learners (LBs) using conceptual-based cueing. We administered a forced choice identification task to 169 native English adult learners of Spanish in two sessions. In both sessions, participants identified the same /b/-/p/ voicing continuum, but language context was cued conceptually using the instructions. The data were analyzed using Bayesian multilevel regression. Learners categorized the continuum in a similar manner when they believed they were hearing English. However, when they believed they were hearing Spanish, “voiceless” responses increased as a function of L2 proficiency. This research demonstrates the double phonemic boundary effect can be conceptually cued in LBs and supports accounts positing selective activation of independent perception grammars in L2 learning.
To verify the main advantages and drawbacks of mechanical suturing for pharyngeal closure after total laryngectomy versus a manual suturing technique.
A retrospective review was carried out of 126 total laryngectomies performed between 2008 and 2018. Manual closure was performed in 80 cases (63.5 per cent) and mechanical suturing was performed in 46 cases (36.5 per cent).
Mechanical suturing was used significantly more frequently in patients with: glottic tumours (p = 0.008), less local tumour extension (p = 0.017) and less pre-operative morbidity (p = 0.014). There were no significant differences in the incidence of pharyngocutaneous fistula between the manual suture group (16.3 per cent) and the mechanical suture group (13.0 per cent) (p = 0.628). None of the patients treated with mechanical suturing had positive surgical margins. Cancer-specific survival for the mechanical suture group was higher than that for the manual suture group (p = 0.009).
Mechanical suturing of the pharynx after total laryngectomy is an oncologically safe technique if used in suitable cases.
The majority of available US-published reports present populations with community spread in urban areas. The objective of this report is to describe a rural healthcare system's utilisation of therapeutic options available to treat Coronavirus Disease 2019 (COVID-19) and subsequent patient outcomes. A total of 150 patients were treated for COVID-19 at three hospitals in the Dakotas from 21 March 2020 to 30 April 2020. The most common pharmacological treatment regimens administered were zinc, hydroxychloroquine plus azithromycin and convalescent plasma. Adjunctive treatments included therapeutic anticoagulation, tocilizumab and corticosteroids. As of 1 June 2020, 127 patients have survived to hospital discharge, 12 patients remain hospitalised and 11 patients have expired. The efficacy of hydroxychloroquine and azithromycin use has yet to be determined but was not without risks of corrected QT interval prolongation and arrhythmias in our cohort. We did not appreciate any adverse effects that appeared related to tocilizumab or convalescent plasma administration in those patient subsets. These findings may provide insight into disease severity and treatment options in the rural setting with limited resources to participate in clinical trials and encourage larger comparative studies evaluating treatment efficacy.
The response to librational forcing of a cube in rapid rotation about a diagonal axis is explored. In this orientation, the faces of the cube are all oblique to the rotation axis. The system supports inertial waves, which predominantly comprise beams emitted from the edges and vertices of the cube. Which ones emit and the resulting complicated pattern of three-dimensional reflections and subsequent focusing depend on the libration frequency. Direct numerical simulations of the Navier–Stokes flows with no-slip boundary conditions at low Ekman number (
) and small libration amplitude (
) exhibit complicated spatio-temporal structure that is remarkably well described by considerations of the inviscid reflections of wavebeams over the whole range of libration frequencies from zero to twice the mean rotation rate of the cube.
The following commentary on Jang and Choi’s chapter Issues and New Directions in Personality Disorder (PD) Genetics (This Volume) echoes their call to harness advances in PD assessment rather than rely on politically derived "top down" nosologies. We first discuss how recent work in the joint hierarchical structure of PD traits and psychopathology, as well as, personality dynamics (i.e., how personality manifests in different situations) likely offer fruitful avenues for exploring the more nuanced role of genetics in the development and maintenance of PD. Second, we highlight the need to better understand the role of environment in PD genetics and discuss emerging models (e.g., common pathway model). Third, we stress the need for more research and larger samples in order to arrive at stronger conclusions. Fourth, we consider how advances in gene-environment research can help to determine targets for PD prevention and treatment.
Previous literature supports antipsychotics’ (AP) efficacy in acute first-episode psychosis (FEP) in terms of symptomatology and functioning but also a cognitive detrimental effect. However, regarding functional recovery in stabilised patients, these effects are not clear. Therefore, the main aim of this study is to investigate dopaminergic/anticholinergic burden of (AP) on psychosocial functioning in FEP. We also examined whether cognitive impairment may mediate these effects on functioning.
A total of 157 FEP participants were assessed at study entry, and at 2 months and 2 years after remission of the acute episode. The primary outcomes were social functioning as measured by the functioning assessment short test (FAST). Cognitive domains were assessed as potential mediators. Dopaminergic and anticholinergic AP burden on 2-year psychosocial functioning [measured with chlorpromazine (CPZ) and drug burden index] were independent variables. Secondary outcomes were clinical and socio-demographic variables.
Mediation analysis found a statistical but not meaningful contribution of dopaminergic receptor blockade burden to worse functioning mediated by cognition (for every 600 CPZ equivalent points, 2-year FAST score increased 1.38 points). Regarding verbal memory and attention, there was an indirect effect of CPZ burden on FAST (b = 0.0045, 95% CI 0.0011–0.0091) and (b = 0.0026, 95% CI 0.0001–0.0006) respectively. However, only verbal memory post hoc analyses showed a significant indirect effect (b = 0.009, 95% CI 0.033–0.0151) adding premorbid IQ as covariate. We did not find significant results for anticholinergic burden.
CPZ dose effect over functioning is mediated by verbal memory but this association appears barely relevant.
Until now, no reliable biological markers of risk and relapse in substance-dependent patients have been identified. The yawn-inducing test with apomorphine has been proposed as a marker of the functional status of the dopaminergic system and therefore a predictor of suffering an addiction or predisposition to relapse.
Studying the safety and efficacy of apomorphine test as a predictor of relapse in intranasal cocaine dependent, diagnosed according to DSM-IV-TR.
We performed the test of apomorphine at the beginning (day 1) and end (day 11/12) of a detoxification program in 33 patients (29 men). The majority of patients relapsed after 22 weeks of follow up (87% relapse). The average yawns in the sample were 10.9 ± 9.3 in the initial test (Apo 1) and 10.2 ± 10.2 in the final test (Apo 2). The 42% of patients relapsed early (before 4 weeks) and 45% late (afther 4 weeks). 58% of the sample (N = 19), which did not fall belatedly filled an average of 8.0 yawns in Apo1 and 8.1 on Apo2 and 42% who did so early (N = 14), 14,8 in Apo1 and 14.6 in Apo2. Therefore there are an increased number of yawns in patients with early relapse. No important side effects were reported.
Patients with early relapse have a higher number of yawns that those falling late or abstainers The apomorphine test is a safe test and it is a readily applicable tool in clinical practice and may be a biological marker of risk.
To analyse the consequences of broadening DSM-IV criteria for generalized anxiety disorder (GAD) on the utilization of health care resources and corresponding costs.
Multicentre, prospective and observational study conducted in outpatient psychiatric clinics selected at random and weighted by geographical density of population. Patients with GAD according to DSM-IV criteria and subjects with anxiety symptoms fulfilling broader criteria were compared. Broadening criteria was considered 1-month of excessive or non-excessive worry and only 2 associated symptoms listed on DSM-IV for GAD. Socio-demographic data, medical history and health care resources and corresponding costs were recorded during a 6-month period.
A total of 3,549 patients were systematically recruited; 12.8% excluded because not fulfilling inclusion criteria, 1,815 patients in DSM-IV criteria group (DG) and 1,264 in broad criteria group (BG). Both groups were similar on their sociodemographic characteristics at baseline. Type of treatments prescribed at psychiatric clinics during the study were similar in frequency; anti-depressives (77.0% in DG vs. 75.3% in BG, ns), benzodiazepines (71.5% vs. 67.2% respectively, ns), and anti-convulsants (72.1% vs. 67.0% respectively, ns). Health care resources utilization were statistically reduced to a similar extent in both groups as a consequences of treatments yielding to a cost-of-illness in the 6-month period of 1,196 (1,158) and 1,112 (874), respectively; p=0.304.
In a large sample of subjects, broadening of GAD criteria could lead to earlier diagnosis that would not be associated necessarily to an increase in health care resources utilization or costs to the National Health System.
The European Foundation for Quality Management (EFQM) Excellence Model is a non-prescriptive framework based on nine criteria. The aim of this work is to describe the implementation of the EFQM model as a quality framework for the improvement of an inpatient medium-stay psychiatric unit.
In 2005 a multidisciplinary performance improvement work group was convened to begin a project with these aims:
- The definition of the unit's mission.
- The identification of the unit's main processes.
- The identification of performance and quality results.
- The establishment of an audit period of clinical outcomes.
- The creation of a protocol for admissions.
Between 2005 and 2008 the group designed the following:
- A map showing the medium-stay unit process as well as the main processes.
- The key performance indicators.
- An ECT protocol.
- The Quality Indicators.
- A patient satisfaction survey.
Every year we decide the objectives of each indicator and revise them every month. Efficiency in the use of resources improved, due to an increase in annual admissions (from 190 in 2005 to 213 in 2009) as well as a decrease in length of hospital stays (from 62 days in 2005 to 48 days in 2009).
The management through processes according to the EFQM model is an instrument for the improvement of the quality of assistance. This type of management allows for the definition of the unit's mission, the measure and analysis of results and for the establishment of areas of improvement.
The purpose of this study is to investigate if the MDA plasma concentrations are correlated to negative psychopathology in paranoid schizophrenic inpatients.
The sample was comprised by 38 patients who were admitted in the psychiatric ward of the University Hospital of the Canaries. Thirty eight patients were male and 9 were female with medium average age of 37.41±11.23. Exclusion criteria were psychoactive substance use, presence of acute or chronic organic pathology, treatment with immunosuppressive medication, pregnancy and mental retardation or severe cognitive impairment. There were performed two blood extractions following the circadian rhythm, at 12:00 and at 24:00 hours. One hour before night blood collection, each patient was placed in a reclined position in bed, with the eyes closed, in complete darkness and with eyes covered with a mask. Blood was centrifuged at 3.000 rpm for 10 minutes. Specific biological and psychopathological determinations were performed at admission and at discharge. Psychopathology was assessed with PANSS and by the same psychiatrist. Statistical analyses were carried out with the Social Statistical Package for the Social Sciences (SPSS). MDA was determined spectrophotometrically.
MDA level at night was 1.94±1.54 while MDA level at midday was 2.23±1.36.Mean PANSS negative score was 15.73±6.31.Serum MDA level correlated positively with PANSS negative scores, both at midday and night (midday r=0.39, p< 0.01, midnight r=0.41, p< 0.01).
The total negative subscale score correlated positively with day and night time levels of MDA, therefore we can conclude that MDA may be used as a marker of negative psychopathology.
According to 2008 data, there are 80.000 patients undergoing replacement opiate programs (RMP) in Spain. However, the clinical therapeutic management and the psychiatric and medical comorbidities have not been well described.
To describe the current therapeutic management and psychiatric comorbilities of opiate-dependent patients undergoing a RMP in Spain.
We carried out an observational, cross-sectional, multicenter study from September 2008 to February 2009. Patients > 18 years, with written informed consent, with a opiate-dependence according to DSM-IV-TR criteria and currently scheduled in a RMP in Spain were included.
624 patients (38.89±7.95 y.o.,84% men) were included in the study from 74 centers.
Psychiatric comorbidities were clinically detected in 68% of all valuable patients, most frequently anxiety (53%), mood (48%) and sleep disorders (41%). Patients receiving buprenorphine-naloxone suffered less sleep disorders (19% vs. 43%; p=0.0327) The proportion of patients with at least one psychiatric comorbidity was directly related to methadone dose (p=0.0066).
The most frequent replacement therapy was methadone (94%), usually in ≤ 40 mg/day (38%) and 40-80 mg/day doses (40%); mean follow up period being 45.88±51.86 months. Significant differences were found between methadone doses and retention. Patients with HIV and HCV infection received higher doses of methadone (HIV+ patients (p=0.0024) and HCV+/ HIV+ patients (p=0.0250) due to ARV treatment; and showed less PMM retention.
Patients present high rates of dual diagnosis, and infectious and non-infectious comorbidities, expecting higher doses of methadone than found (54.04±47.26 mg/day) in the study to assure a proper retention in the maintenance programs.
To evaluate the effect of pregabalin as a tapering therapy over the subjective sleep quality of patients who underwent a benzodiazepine withdrawal program.
This was a secondary analysis of a 12-week, prospective, and observational study carried out in patients aged 18 years or over, who met DSM-IV-TR criteria for benzodiazepine dependence without other major psychiatry disorder. Evaluations included the Benzodiazepine Withdrawal Symptom Questionnaire, the Hamilton Anxiety Rating Scale, the Clinical Global Impression scale, and the MOS-Sleep Scale. Changes from baseline to the endpoint in the different scales’ scores as well as correlations of these changes with those of the MOS-Sleep scores were calculated.
282 patients met the criteria for analysis. Mean pregabalin dose was 315 (166) mg/day at end-of-trial. We observed a significant and clinically relevant improvement in sleep outcomes at the study endpoint as measured with the MOS-Sleep Summary Index, that was reduced from 55.8 (18.9) pts at baseline to 25.1 (18.0) pts at week 12 (55% reduction), as well as with the six dimensions of the MOS-Sleep Scale. Moderate correlations were observed between Summary Index and sleep domains with improvements in the anxiety symptoms and in the disease severity as well. Also, sleep ameliorations were observed in the 52% successfully benzodiazepines withdrawals but, although to a lesser extent, in the remaining failures as well.
Pregabalin treatment improves subjective sleep quality in patients who underwent a benzodiazepine withdrawal program and this effect appears partly independent of the improvement of anxiety or withdrawal symptoms.
We present the case of a schizophrenic patient with severe insomnia that had a partial response to high doses of benzodiazepines and sedating antipsychotics. Treatment with agomelatine allowed to suspend benzodiazepine treatment and restore quality of sleep.
Mr. Y is a 36 year old male patient diagnosed with simple schizophrenia that has complained of insomnia since the age of sixteen. During the last three years the treatment that the patient was following was stable and consisted of 100 mg of diazepam, 300 mg of levomepromazine and 120 mg of clotiapine every night. During the last year 60 mg of duloxetine were added to treat a moderate depression. His mood improved with the prescribed treatment, but eleven months later it worsened. In an attempt to simultaneously treat the mood and the sleep disorder, during a period of 4 days, a dosis of 12.5 mg of aglomelatin at dinner was introduced while the morning dose of duloxetine was reduced to 30mg. On the fifth day, agomelatine was increased to 25 mg at dinner while duloxetine was suspended. The antipsychotic treatment was kept stable while the patient was instructed to reduce 10 mg of diazepam every week until next appointment one month later. In the next appointment the patient had completely suspended diazepam one week before the appointment. The patient referred improved sleep quality and no rebound insomnia.
Agomelatine may be a valid treatment of insomnia in schizophrenia.