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The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world’s population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19.
Objectives
The aim of this sudy was to test the potential antiviral and anti-inflammatory activities of fluoxetine against SARS-CoV-2 in a K18-hACE2 mouse model of infection, and against several variants of concern in vitro, and test the hypothesis of the implication of ceramides and/or their derivatives hexosylceramides.
Methods
We evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5.
Results
Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres (Figure 1) and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10) (Figure 2). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects (Figure 3).
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Conclusions
Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.
To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19.
Objectives
The main objective was two-fold: (i) to test the hypothesis that the prevalence of antidepressant use in patients hospitalized with COVID-19 would be lower than in patients with similar characteristics hospitalized without COVID-19, and (ii) to examine, among patients hospitalized with COVID-19, whether antidepressant use is associated with reduced 28-day mortality. Our secondary aim was to examine whether this potential association could only concern specific antidepressant classes or molecules, is dose-dependent, and/or only observed beyond a certain dose threshold.
Methods
We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP–HP (Assistance Publique–Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482) (Figure 1).
Results
Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35–0.41, p < 0.001) (Figure 2). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41–0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents (Figure 3). Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations.
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Conclusions
Antidepressant use is associated with a reduced likelihood of hospitalization in patients infected with SARS-CoV-2 and with a reduced risk of death in patients hospitalized with COVID-19. These associations were stronger for molecules with high FIASMA activity. These findings posit that prospective interventional studies of antidepressants with the highest FIASMA activity may be appropriate to help identify variant-agnostic, affordable, and scalable interventions for outpatient and inpatient therapy of COVID-19.
Autism spectrum disorders (ASD) are associated with high services use, but European data on costs are scarce.
Objectives
Utilisation and annual costs of 385 individuals with ASD (aged 4-67 years; 18.2% females; 37.4% IQ < 85) from German outpatient clinics were assessed.
Methods
Client Service Receipt Inventory
Results
Average annual costs per person were 3287 EUR, with psychiatric inpatient care (19.8%), pharmacotherapy (11.1%), and occupational therapy (11.1%) being the largest cost components. Females incurred higher costs than males (4864 EUR vs. 2936 EUR). In a regression model, female sex (Cost Ratio: 1.65), lower IQ (1.90), and Asperger syndrome (1.54) were associated with higher costs.
Conclusions
In conclusion, ASD-related health costs are comparable to those of schizophrenia, thus underlining its public health relevance. Higher costs in females demand further research.
The influence of pharmaceutical industry (PI) on clinical practice and research in psychiatry has been considered a serious problem. Strict rules and guidelines were developed to regulate the interactions between doctors and PI. However, there is an ongoing debate whether these were thoroughly implemented in practice and internalized by physicians. The objective of our study was to assess the attitudes and behaviors of trainees in psychiatry and child & adolescent psychiatry toward PI across Europe. Methodologically, a validated questionnaire with additional items was administered to1444 trainees in 20 European countries. The minimum response rate was set at 60%. We found a high variation across countries in number of interactions between trainees and PI representatives; Portugal and Turkey had the highest number of interactions. The majority (59.76%) agreed that interactions with PI representatives have an impact on physicians’ prescribing behavior; whereas only 29.26% and 19.79% agreed interactions with PI representatives and gifts from PI have impact on their own prescribing behavior, respectively. Most of the gifts were considered appropriate by the majority, except tickets to vacation spot and social dinner at a restaurant. Of the sample, 70.76% think they have not been given sufficient training regarding how to interact with PI representatives. Only less than 20% indicated they have guidelines at institutional or national level. In conclusion, there is substantial interaction between trainees and PI across countries. The majority feel inadequately trained regarding professional interaction with PI, and believes they are immune to the influence of PI.
Interactions between the pharmaceutical industry (PI) and psychiatrists have been under scrutiny recently, though there is little empirical evidence on the nature of the relationship and its intensity at psychiatry trainee level. We therefore studied the level of PI interactions and the underlying beliefs and attitudes in a large sample of European psychiatric trainees.
Methods:
One thousand four hundred and forty-four psychiatric trainees in 20 European countries were assessed cross-sectionally, with a 62-item questionnaire.
Results:
The total number of PI interactions in the preceding two months varied between countries, with least interactions in The Netherlands (M (Mean) = 0.92, SD = 1.44, range = 0–12) and most in Portugal (M = 19.06, SD = 17.44, range = 0–100). Trainees were more likely to believe that PI interactions have no impact on their own prescribing behaviour than that of other physicians (M = 3.30, SD = 1.26 vs. M = 2.39, SD = 1.06 on a 5-point Likert scale: 1 “completely disagree” to 5 “completely agree”). Assigning an educational role to the pharmaceutical industry was associated with more interactions and higher gift value (IRR (incidence rate ratio) = 1.21, 95%CI = 1.12–1.30 and OR = 1.18, 95%CI = 1.02–1.37).
Conclusions:
There are frequent interactions between European psychiatric trainees and the PI, with significant variation between countries. We identified several factors affecting this interaction, including attribution of an educational role to the PI. Creating alternative educational opportunities and specific training dedicated to PI interactions may therefore help to reduce the impact of the PI on psychiatric training.
The organic personality disorder (OPD) is a multi-faceted group of dia-gnoses in the boarder area of psychiatry and neurology. In the current teaching books OPD is treated rather cursorily. Evidence-based guidelines have not been published. However, OPD is a frequently observed phenomenon both in psychiatry and neurology.
Method
In the present study an overview is given over historic conceptual principles of OPD. Furthermore, we searched MEDLINE for relevant studies regarding psycho-pathology of OPD. Twelve studies were included in the final analysis. Findings regarding etiology, symptomatology and treatment are summarized.
Results
Psychopathology was not specific to type of etiology. Three major groups of symptomatology were identified (enechy-type, apathy and depression-type, impulsiveness and affective lability-type). There are no evidence-based treatement recommendations for OPD, a small number of case reports suggest a possible therapeutic effect of carbamazepine and trazodone.
Conclusion
With regard to psychopathology the traditional classification of Kurt Schneider was affirmed. A multiaxial diagnostic process can integrate a symptomatological and etiological perspective on OPD. Pharmacotherapy should focus on specific syndromes, e.g. hostility. There is a need for further research with the objective of preparing a clinical guideline.
Evidence has suggested that immune imbalance is involved with bipolar disorder (BD); however, its precise mechanism is poorly understood.
Objective
This study investigated whether biochemical changes in the serum from BD patients could modulate the phenotype of macrophages.
Methods
Eighteen subjects with BD and healthy individuals (n = 5) were included in this study. The human monocyte cell line U-937 was activated with PMA (phorbol 12-myristate 13-acetate) and polarization was induced with RPMI-1640 media supplemented with 10% serum from each patient for 24 h. Gene expression of selected M1 and M2 markers was assessed by qPCR.
Results
Macrophages exposed to serum of manic and depressive BD patients displayed an increase of IL-1β (6.40 ± 3.47 and 9.04 ± 5.84 versus 0.23 ± 0.11; P < 0.05) and TNF-α (2.23 ± 0.91 and 2.03 ± 0.45 versus 0.62 ± 0.24; P = 0.002 and P = 0.004, respectively) compared to remitted group. In parallel, U-937 macrophages treated with serum of patients in acute episode displayed a down-regulation of CXCL9 (0.29 ± 0.20 versus 1.86 ± 1.61; P = 0.006) and CXCL10 expression (0.36 ± 0.15 and 0.86 ± 0.24 versus 1.83 ± 0.88; P < 0.000 and P = 0.04) compared to remitters.
Conclusions
Our results are consistent with previous studies showing that changes in peripheral blood markers could modulate M1/M2 polarization in BD. The evidence of macrophages as source of inflammatory cytokines might be helpful to unravel how the mononuclear phagocyte system can be involved in the etiology of BD.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Both blood- and milk-based biomarkers have been analysed for decades in research settings, although often only in one herd, and without focus on the variation in the biomarkers that are specifically related to herd or diet. Biomarkers can be used to detect physiological imbalance and disease risk and may have a role in precision livestock farming (PLF). For use in PLF, it is important to quantify normal variation in specific biomarkers and the source of this variation. The objective of this study was to estimate the between- and within-herd variation in a number of blood metabolites (β-hydroxybutyrate (BHB), non-esterified fatty acids, glucose and serum IGF-1), milk metabolites (free glucose, glucose-6-phosphate, urea, isocitrate, BHB and uric acid), milk enzymes (lactate dehydrogenase and N-acetyl-β-D-glucosaminidase (NAGase)) and composite indicators for metabolic imbalances (Physiological Imbalance-index and energy balance), to help facilitate their adoption within PLF. Blood and milk were sampled from 234 Holstein dairy cows from 6 experimental herds, each in a different European country, and offered a total of 10 different diets. Blood was sampled on 2 occasions at approximately 14 days-in-milk (DIM) and 35 DIM. Milk samples were collected twice weekly (in total 2750 samples) from DIM 1 to 50. Multilevel random regression models were used to estimate the variance components and to calculate the intraclass correlations (ICCs). The ICCs for the milk metabolites, when adjusted for parity and DIM at sampling, demonstrated that between 12% (glucose-6-phosphate) and 46% (urea) of the variation in the metabolites’ levels could be associated with the herd-diet combination. Intraclass Correlations related to the herd-diet combination were generally higher for blood metabolites, from 17% (cholesterol) to approximately 46% (BHB and urea). The high ICCs for urea suggest that this biomarker can be used for monitoring on herd level. The low variance within cow for NAGase indicates that few samples would be needed to describe the status and potentially a general reference value could be used. The low ICC for most of the biomarkers and larger within cow variation emphasises that multiple samples would be needed - most likely on the individual cows - for making the biomarkers useful for monitoring. The majority of biomarkers were influenced by parity and DIM which indicate that these should be accounted for if the biomarker should be used for monitoring.
We studied trends in the incidence of health care-associated infections (HAIs) in LTCFs between 2009 and 2015 and determined the effect of participation in our network. Elder-care physicians reported weekly the number of cases of influenza-like illness, gastroenteritis, (probable) pneumonia, urinary tract infections (UTIs) and all-cause mortality. Trends in the incidence of infection and mortality in relation to LTCF characteristics were calculated using multilevel univariate and multivariate logistic regression. Thirty LTCF participated for 3 years or more, 16 for 2 years and the remaining 12 LTCF for 1 year. During the study period, the median number of beds decreased from 158 to 139, whereas the percentage of residents with private bedrooms increased from 14% to 87%. UTIs were the most frequently reported infections, followed by (probable) pneumonia and gastroenteritis. Adjusted for calendar year and season, we observed a statistically significant decrease in the incidence of influenza-like illness (odds ratio (OR) = 0.8, P < 0.01) and (probable) pneumonia (OR = 0.8, P < 0.01) for each extra year an LTCF participated. Although there are other likely contributors, such as more private rooms and enhanced infection control measures, the decreasing trend of HAI in LTCFs participating in surveillance implies that surveillance is a valuable addition to current strategies to optimise infection control.
Unbalanced metabolic status in the weeks after calving predisposes dairy cows to metabolic and infectious diseases. Blood glucose, IGF-I, non-esterified fatty acids (NEFA) and β-hydroxybutyrate (BHB) are used as indicators of the metabolic status of cows. This work aims to (1) evaluate the potential of milk mid-IR spectra to predict these blood components individually and (2) to evaluate the possibility of predicting the metabolic status of cows based on the clustering of these blood components. Blood samples were collected from 241 Holstein cows on six experimental farms, at days 14 and 35 after calving. Blood samples were analyzed by reference analysis and metabolic status was defined by k-means clustering (k=3) based on the four blood components. Milk mid-IR analyses were undertaken on different instruments and the spectra were harmonized into a common standardized format. Quantitative models predicting blood components were developed using partial least squares regression and discriminant models aiming to differentiate the metabolic status were developed with partial least squares discriminant analysis. Cross-validations were performed for both quantitative and discriminant models using four subsets randomly constituted. Blood glucose, IGF-I, NEFA and BHB were predicted with respective R2 of calibration of 0.55, 0.69, 0.49 and 0.77, and R2 of cross-validation of 0.44, 0.61, 0.39 and 0.70. Although these models were not able to provide precise quantitative values, they allow for screening of individual milk samples for high or low values. The clustering methodology led to the sharing out of the data set into three groups of cows representing healthy, moderately impacted and imbalanced metabolic status. The discriminant models allow to fairly classify the three groups, with a global percentage of correct classification up to 74%. When discriminating the cows with imbalanced metabolic status from cows with healthy and moderately impacted metabolic status, the models were able to distinguish imbalanced group with a global percentage of correct classification up to 92%. The performances were satisfactory considering the variables are not present in milk, and consequently predicted indirectly. This work showed the potential of milk mid-IR analysis to provide new metabolic status indicators based on individual blood components or a combination of these variables into a global status. Models have been developed within a standardized spectral format, and although robustness should preferably be improved with additional data integrating different geographic regions, diets and breeds, they constitute rapid, cost-effective and large-scale tools for management and breeding of dairy cows.
Static lattice energy calculations have been combined with cluster expansion formalism to predict pairwise ordering interactions in the pyrope–grossular solid solution. The ordering interactions, the Js, have been then used to calculate the activity-composition relations over a wide temperature range with the help of the Cluster Variation Method. It is shown that short-range ordering in the system is driven by size mismatch. The prediction of the right signs and magnitudes of the ordering interaction energies requires separation of the mixing enthalpy into the configuration-dependent (chemical) and the configuration-independent (elastic) components. The study predicts the existence of a miscibility gap below 500°C.
Delays in rotavirus vaccine schedule could improve performance in low- and middle-income countries (LMICs). However, delaying the first dose could be detrimental if infants experience severe rotavirus gastroenteritis (RVGE) early in life. Our objective was to describe the timing and predictors of severe RVGE in unvaccinated children in LMICs. We analysed the placebo arms from two clinical trials (cohort 1: NCT00241644; cohort 2: NCT00362648). We estimated the rate, cumulative incidence (per 1000 infants) and age distribution of severe RVGE episodes. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals (CI) for the association between baseline factors and severe RVGE. Cumulative incidence at 6 months of age was 23/1000 (95% CI 15–30) in cohort 1 and 6/1000 (95% CI 3–8) in cohort 2. Early antibiotic use (compared with no use) was associated with 2.03 (95% CI 1.18–3.48) and 1.41 (95% CI 0.80–2.51) times the rate of severe RVGE in cohorts 1 and 2, respectively. The cumulative incidence of severe RVGE was low at 6 months of age, suggesting that a 4-week delay in the vaccination schedule may not result in a large number of severe RVGE episodes prior to vaccine receipt.
Norovirus is detected in one in five diarrhoea episodes in children, yet little is known about environmental risk factors associated with this disease, especially in low-income settings. The objective of this study was to examine environmental risk factors, and spatial and seasonal patterns of norovirus diarrhoea episodes in children in León, Nicaragua. We followed a population-based cohort of children under age 5 years for norovirus diarrhoea over a 1-year period. At baseline, characteristics of each household were recorded. Households were geocoded and spatial locations of garbage dumps, rivers, and markets were collected. In bivariate analysis we observed younger children and those with animals in their households were more likely to have experienced norovirus episodes. In adjusted models, younger children remained at higher risk for norovirus episodes, but only modest associations were observed with family and environmental characteristics. We next identified symptomatic children living in the same household and within 500 m buffer zones around the household of another child infected with the same genotype. Norovirus diarrhoea episodes peaked early in the rainy season. These findings contribute to our understanding of environmental factors and norovirus infection.
A huge gap exists between the production of evidence and its take-up in clinical practice settings. To fill this gap, treatment guidelines, based on explicit assessments of the evidence base, are commonly employed in several fields of medicine, including schizophrenia and related psychotic disorders. It remains unclear, however, whether treatment guidelines have any impact on provider performance and patient outcomes, and how implementation should be conducted to maximise benefit.
For people with schizophrenia, non-adherence to antipsychotic medications may result in high use of health and other services. The objective of our research was to examine the economic consequences of non-adherence in patients with schizophrenia taking antipsychotic medication.
Methods.
Data were taken from QUATRO, a randomized controlled trial that drew a sample of adults with schizophrenia receiving psychiatric services in four European cities: Amsterdam, Leipzig, London and Verona. Trial inclusion criteria were a clinical diagnosis of schizophrenia, requiring on-going antipsychotic medication for at least 1-year following baseline assessment, and exhibiting evidence of clinical instability in the year prior to baseline. The patient-completed Medication Adherence Questionnaire (MAQ) was used to calculate the 5-point Morisky index of adherence. Generalized linear models (GLM) were developed to determine the effect of adherence on (i) health and social care and (ii) societal costs before and after treatment, taking into account other potential cost-influencing factors.
Results.
The effect of non-adherence on costs was mixed. For different groups of services, and according to treatment group assignment, non-adherence was both negatively and positively associated with costs.
Conclusions.
The impact of non-adherence on costs varies across the types of services used by individuals with schizophrenia.
Children with sickle cell anaemia (SCA) might carry hospital-associated bacterial lineages due to frequent hospital stays and antibiotic treatments. In this study we compared Staphylococcus aureus from SCA patients (n = 73) and healthy children (n = 143) in a cross-sectional study in Gabon. S. aureus carriage did not differ between children with SCA (n = 34, 46·6%) and controls matched for age, residence and sex (n = 67, 46·9%). Both groups shared similar S. aureus genotypes. This finding points towards a transmission of S. aureus between both groups in the community. We conclude that resistance rates from population-based studies with healthy participants could therefore also be used to guide treatment and prophylaxis of endogenous infections in children with SCA despite a different selection pressure.
Methicillin-resistant Staphylococcus aureus (MRSA) commonly causes infection in hospitalized patients. Resistance is due to the acquisition of mecA gene located on the chromosomal element SCCmec and to date 12 types have been identified. Specific epidemic clones of MRSA have emerged with enhanced ability to spread within and among hospitals and to cross national boundaries. We studied 30 isolates from patients with MRSA infections at two hospitals in Porto Alegre city from April to December, 2008 and determined their SCCmec type by PCR. Representative strains were typed by PFGE. Eighteen (60%) isolates carried SCCmec type III and had PFGE profiles clonally related to the previously characterized Brazilian epidemic clone, and 11 (36·7%) isolates with pulsotypes closely related to the Cordobes/Chilean clone harboured SCCmec type I. To the best of our knowledge, this is the first report of the appearance of Cordobes/Chilean clone involved in nosocomial infection in Brazil.
Strains of Staphylococcus aureus isolated from shrimp were examined for phage pattern and enterotoxin production; 63% of the strains isolated from North Sea shrimp were typable with the International and additional set of phages, as were 38% of the strains isolated from South-East Asian shrimp. Staphylococcal enterotoxin(s) (SE) were produced by 48% and 35% of strains isolated from North Sea and South-East Asian shrimp respectively. Growth and enterotoxin production by S. aureus in shrimp was examined in storage experiments at 22 °C. S. aureus increased by 1–2 log units in 24 h when the organism was only a minor part of the total microflora of shrimp. When S. aureus was an equivalent part of the total flora its numbers increased by 3–4 log units in 24 h. Enterotoxins A and B became detectable when the number of S. aureus exceeded 107 per g in aseptically peeled shrimp. Results indicate that S. aureus is able to produce enterotoxin in shrimp, but its production depends upon a number of factors, including the relationship between S. aureus and competitive micro-organisms. It is concluded that the presence of S. aureus on commercially produced shrimp represents a potential hazard to health.