One of the frequent questions by users of the mixed model function lmer of the lme4 package has been: How can I get p values for the F and t tests for objects returned by lmer? The lmerTest package ...extends the 'lmerMod' class of the lme4 package, by overloading the anova and summary functions by providing p values for tests for fixed effects. We have implemented the Satterthwaite's method for approximating degrees of freedom for the t and F tests. We have also implemented the construction of Type I - III ANOVA tables. Furthermore, one may also obtain the summary as well as the anova table using the Kenward-Roger approximation for denominator degrees of freedom (based on the KRmodcomp function from the pbkrtest package). Some other convenient mixed model analysis tools such as a step method, that performs backward elimination of nonsignificant effects - both random and fixed, calculation of population means and multiple comparison tests together with plot facilities are provided by the package as well.
Psychiatric outcomes after COVID-19 have been of high concern during the pandemic; however, studies on a nationwide level are lacking.
To estimate the risk of mental disorders and use of psychotropic ...medication among individuals with COVID-19 compared with individuals not tested, individuals with SARS-CoV-2-negative test results, and those hospitalized for non-COVID-19 infections.
This nationwide cohort study used Danish registries to identify all individuals who were alive, 18 years or older, and residing in Denmark between January 1 and March 1, 2020 (N = 4 152 792), excluding individuals with a mental disorder history (n = 616 546), with follow-up until December 31, 2021.
Results of SARS-CoV-2 polymerase chain reaction (PCR) testing (negative, positive, and never tested) and COVID-19 hospitalization.
Risk of new-onset mental disorders (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes F00-F99) and redeemed psychotropic medication (Anatomical Therapeutic Chemical classification codes N05-N06) was estimated through survival analysis using a Cox proportional hazards model, with a hierarchical time-varying exposure, reporting hazard rate ratios (HRR) with 95% CIs. All outcomes were adjusted for age, sex, parental history of mental illness, Charlson Comorbidity Index, educational level, income, and job status.
A total of 526 749 individuals had positive test results for SARS-CoV-2 (50.2% men; mean SD age, 41.18 17.06 years), while 3 124 933 had negative test results (50.6% women; mean SD age, 49.36 19.00 years), and 501 110 had no tests performed (54.6% men; mean SD age, 60.71 19.78 years). Follow-up time was 1.83 years for 93.4% of the population. The risk of mental disorders was increased in individuals with positive (HRR, 1.24 95% CI, 1.17-1.31) and negative (HRR, 1.42 95% CI, 1.38-1.46) test results for SARS-CoV-2 compared with those never tested. Compared with individuals with negative test results, the risk of new-onset mental disorders in SARS-CoV-2-positive individuals was lower in the group aged 18 to 29 years (HRR, 0.75 95% CI, 0.69-0.81), whereas individuals 70 years or older had an increased risk (HRR, 1.25 95% CI, 1.05-1.50). A similar pattern was seen regarding psychotropic medication use, with a decreased risk in the group aged 18 to 29 years (HRR, 0.81 95% CI, 0.76-0.85) and elevated risk in those 70 years or older (HRR, 1.57 95% CI, 1.45-1.70). The risk for new-onset mental disorders was substantially elevated in hospitalized patients with COVID-19 compared with the general population (HRR, 2.54 95% CI, 2.06-3.14); however, no significant difference in risk was seen when compared with hospitalization for non-COVID-19 respiratory tract infections (HRR, 1.03 95% CI, 0.82-1.29).
In this Danish nationwide cohort study, overall risk of new-onset mental disorders in SARS-CoV-2-positive individuals did not exceed the risk among individuals with negative test results (except for those aged ≥70 years). However, when hospitalized, patients with COVID-19 had markedly increased risk compared with the general population, but comparable to risk among patients hospitalized for non-COVID-19 infections. Future studies should include even longer follow-up time and preferentially include immunological biomarkers to further investigate the impact of infection severity on postinfectious mental disorder sequelae.
Hospitalisation with COVID-19 is associated with an increased risk of neurological sequelae; however, representative nationwide studies comparing to other infections with similar severity and also ...including milder SARS-CoV-2 infections have been lacking. Using the nationwide Danish registers including all SARS-CoV-2 PCR test results and hospitalisations between March 1, 2020, and December 31, 2021, we estimate the risk of any first neurological disorder diagnosed in inpatient, outpatient, or emergency room settings. We show that positive tests increase the rate of neurological disorders by a hazard ratio of 1.96 (95% confidence interval: 1.88-2.05) compared to individuals not tested and by a hazard ratio of 1.11 (95% confidence interval: 1.07-1.16) compared to individuals with negative tests only. However, there is no evidence that the risk of neurological disorders is higher for individuals who test positive compared to non-COVID-19 infections treated with anti-infective medication. The risk of neurological disorders is increased after COVID-19-hospitalisation compared to no COVID-19 hospital admission; however, these risks are comparable to hospitalisation with other respiratory infections (P value 0.328). In conclusion, COVID-19 is associated with an increased risk of neurological disorders, but no more than that observed after other infections of similar severity.
A comprehensive meta-analysis on the composition of circulating immune cells from both the myeloid and the lymphoid lines including specialized subsets in blood and cerebrospinal fluid (CSF) of ...patients with psychotic disorders compared with healthy control participants has been lacking.
Multiple databases (PubMed, EMBASE, Cochrane Library, Web of Science, ClinicalTrials.gov, and PsycINFO) were searched for eligible studies up until October 18, 2022. All studies investigating circulating immune cells in the blood and CSF from patients with psychotic disorders (ICD-10: F20 and F22-29) compared with healthy control participants were included.
A total of 86 studies were included in the meta-analysis. In the blood, the following categories of immune cells were elevated: leukocyte count (31 studies, standardized mean difference SMD = 0.35; 95% CI, 0.24 to 0.46), granulocyte count (4 studies, SMD = 0.57; 95% CI, 0.12 to 1.01), neutrophil granulocyte count (21 studies, SMD = 0.32; 95% CI, 0.11 to 0.54), monocyte count (23 studies, SMD = 0.40; 95% CI, 0.23 to 0.56), and B lymphocyte count (10 studies, SMD = 0.26; 95% CI, 0.04 to 0.48). Additionally, the neutrophil/lymphocyte ratio (23 studies, SMD = 0.40; 95% CI, 0.19 to 0.60), the monocyte/lymphocyte ratio (9 studies, SMD = 0.31; 95% CI, 0.04 to 0.57), and the platelet/lymphocyte ratio (10 studies, SMD = 0.23; 95% CI, 0.03 to 0.43) were elevated. The CSF cell count showed a similar tendency but was not significantly elevated (3 studies, SMD = 0.14; 95% CI, −0.04 to 0.32).
The results indicate a broad activation of the immune system in psychotic disorders, with cells from both the myeloid and the lymphoid line being elevated. However, CSF analyses were lacking in most of the studies, and many studies were hampered by insufficient adjustment for confounding factors such as body mass index and smoking.
Prolonged neuropsychiatric and cognitive symptoms are increasingly reported in patients after COVID-19, but studies with well-matched controls are lacking.
To investigate cognitive impairment, ...neuropsychiatric diagnoses, and symptoms in survivors of COVID-19 compared with patients hospitalized for non-COVID-19 illness.
This prospective case-control study from a tertiary referral hospital in Copenhagen, Denmark, conducted between July 2020 and July 2021, followed up hospitalized COVID-19 survivors and control patients hospitalized for non-COVID-19 illness, matched for age, sex, and intensive care unit (ICU) status 6 months after symptom onset.
Hospitalization for COVID-19.
Participants were investigated with the Mini-International Neuropsychiatric Interview, the Montreal Cognitive Assessment (MoCA), neurologic examination, and a semi-structured interview for subjective symptoms. Primary outcomes were total MoCA score and new onset of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) psychiatric diagnoses. Secondary outcomes included specific psychiatric diagnoses, subjective symptoms, and neurologic examination results. All outcomes were adjusted for age, sex, ICU admission, admission length, and days of follow-up. Secondary outcomes were adjusted for multiple testing.
A total of 85 COVID-19 survivors (36 42% women; mean SD age 56.8 14 years) after hospitalization and 61 matched control patients with non-COVID-19 illness (27 44% women, mean age 59.4 years SD, 13) were enrolled. Cognitive status measured by total geometric mean MoCA scores at 6-month follow-up was lower (P = .01) among COVID-19 survivors (26.7; 95% CI, 26.2-27.1) than control patients (27.5; 95% CI, 27.0-27.9). The cognitive status improved substantially (P = .004), from 19.2 (95% CI, 15.2-23.2) at discharge to 26.1 (95% CI, 23.1-29.1) for 15 patients with COVID-19 with MoCA evaluations from hospital discharge. A total of 16 of 85 patients with COVID-19 (19%) and 12 of 61 control patients (20%) had a new-onset psychiatric diagnosis at 6-month follow-up, which was not significantly different (odds ratio, 0.93; 95% CI, 0.39-2.27; P = .87). In fully adjusted models, secondary outcomes were not significantly different, except anosmia, which was more common after COVID-19 (odds ratio, 4.56; 95% CI, 1.52-17.42; P = .006); but no longer when adjusting for multiple testing.
In this prospective case-control study, cognitive status at 6 months was worse among survivors of COVID-19, but the overall burden of neuropsychiatric and neurologic signs and symptoms among survivors of COVID-19 requiring hospitalization was comparable with the burden observed among matched survivors hospitalized for non-COVID-19 causes.
•Anti-inflammatory add-on treatment shows effects for psychotic disorders.•The effect was larger for schizophrenia than other psychotic disorders.•Primarily anti-inflammatory drugs were not superior ...to the other included drugs.•Meta-regression showed decreasing effects with increasing sample sizes.•Future studies should include markers of inflammation to assess drug effects.
Antipsychotic effects of immunomodulating drugs have been suggested; however, a thorough, comprehensive meta-analysis on the effect and safety of anti-inflammatory add-on treatment on psychotic disorders is lacking.
Multiple databases were searched up until February 2020. Only double-blinded, randomized, placebo-controlled clinical trials (RCTs) were included. Primary outcomes were change in total psychopathology and adverse events. Secondary outcomes included, amongst others, positive and negative symptoms, general psychopathology and cognitive domains. We performed random-effects meta-analyses estimating mean differences (MD) and standardized mean differences (SMD) for effect sizes.
Seventy RCTs (N = 4104) were included, investigating either primarily anti-inflammatory drugs, i.e. drugs developed for immunomodulation, such as NSAIDs, minocycline and monoclonal antibodies (k = 15), or drugs with potential anti-inflammatory properties (k = 55), e.g. neurosteroids, N-acetyl cysteine, estrogens, fatty acids, statins, and glitazones. Antipsychotics plus anti-inflammatory treatment, compared to antipsychotics plus placebo, was associated with a PANSS scale MD improvement of -4.57 (95%CI = -5.93 to -3.20) points, corresponding to a SMD effect size of -0.29 (95%CI = -0.40 to -0.19). Trials on schizophrenia (MD = -6.80; 95%CI, -9.08 to -4.52) showed greater improvement (p < 0.01) than trials also including other psychotic disorders. However, primarily anti-inflammatory drugs (MD = 4.00; 95%CI = -7.19 to -0.80) were not superior (p = 0.69) to potential anti-inflammatory drugs (MD = 4.71; 95%CI = -6.26 to -3.17). Furthermore, meta-regression found that smaller studies showed significantly larger effect sizes than the larger studies (p = 0.0085), and only 2 studies had low risk of bias on all domains. Small but significant effects were found on negative symptoms (MD = -1.29), positive symptoms (MD = -0.53), general psychopathology (MD = -1.50) and working memory (SMD = 0.21). No differences were found regarding adverse events, but only 26 studies reported hereon.
Anti-inflammatory add-on treatment to antipsychotics showed improvement of psychotic disorders; however, no superiority was found in primarily anti-inflammatory drugs, raising the question of the mechanism behind the effect, and treatment effect might be overestimated due to the large number of small studies.
Objective
To investigate vagotomy, the severance of the vagus nerve, and its association with mental disorders, as gut‐brain communication partly mediated by the vagus nerve have been suggested as a ...risk factor.
Methods
Nationwide population‐based Danish register study of all individuals alive and living in Denmark during the study period 1977–2016 and who had a hospital contact for ulcer with or without vagotomy. Follow‐up was until any diagnosis of mental disorders requiring hospital contact, emigration, death, or end of follow‐up on December 31, 2016, whichever came first. Data were analyzed using survival analysis and adjusted for sex, age, calendar year, ulcer type, and Charlson comorbidity index score.
Results
During the study period, 113,086 individuals had a hospital contact for ulcer. Of these, 5,408 were exposed to vagotomy where 375 (6.9%) subsequently developed a mental disorder. Vagotomy overall was not associated with mental disorders (HR: 1.10; 95%CI: 0.99–1.23), compared to individuals with ulcer not exposed to vagotomy. However, truncal vagotomy was associated with an increased HR of 1.22 (95%CI: 1.06–1.41) for mental disorders, whereas highly selective vagotomy was not associated with mental disorders (HR: 0.98; 95%CI: 0.84–1.15). Truncal vagotomy was also associated with higher risk of mental disorders when compared to highly selective vagotomy (p = 0.034).
Conclusions
Overall, vagotomy did not increase the risk of mental disorders; however, truncal vagotomy specifically was associated with a small risk increase in mental disorders, whereas no association was found for highly selective vagotomy. Thus, the vagus nerve does not seem to have a major impact on the development of mental disorders.
To develop machine learning models capable of predicting suicide and non-fatal suicide attempt as separate outcomes in the first 30 days after discharge from a psychiatric inpatient stay.
Prospective ...cohort study using nationwide Danish registry data. We included individuals who were 18 years or older, and all discharges from psychiatric hospitalizations in Denmark from 1995 to 2018. We trained predictive models using 10-fold cross validation on 80% of the data and did testing on the remaining 20%.
The best model for predicting non-fatal suicide attempt was an ensemble of predictions from gradient boosting (XGBoost) and categorical boosting (catBoost). The ROC-AUC for predicting suicide attempt was 0.85 (95% CI: 0.84-0.85). At a risk threshold of 4.36%, positive predictive value (PPV) was 11.0% and sensitivity was 47.2%. The best model for predicting suicide was an ensemble of predictions from random forest, XGBoost and catBoost. For suicide, the ROC-AUC was 0.71 (95% CI: 0.70-0.73). At a risk threshold of 0.15%, PPV was 0.34% and sensitivity was 56.0%. The most contributing predictors differed when predicting suicide and suicide attempt, indicating that separate models are needed. The ensemble model was fair across sex and age, and more so than the penalized logistic regression model.
We achieved good performance for predicting suicide attempts and demonstrated a clinical application of ensemble models. Our results indicate a difference in predictive performance for models predicting suicide and suicide attempt, respectively. Thus, we recommend that suicide and suicide attempt are treated as two separate endpoints, in particular for clinical application. We demonstrated that the ensemble model is fairer across sex and age compared with a penalized logistic regression, and therefore we recommend the use of well-tested ensembles despite a more complex explainability.
The impact of product information and repeated exposure of local apple juice on consumer liking, sensory perception and concept associations was studied. Findings showed that consumers had high ...expectations towards the studied local apples juices. Consequently, the liking for the local apple juices was higher when the consumers were informed about the product versus blind tasting. This shift was explained by an assimilation effect i.e. the consumers rated the liking in the informed product condition closer to their expectations. However, the assimilation effect was incomplete as the product information did not fully determine consumer liking. Thus the sensory characteristics were also found to be of importance. Besides liking, the concept associations were also affected by product information. All local apple juices were associated as being more exclusive under informed tasting conditions. No effects were found for liking of the apple juices over repeated exposure. Also, the consumers did not change their sensory perception over repeated consumption. However, the local apple juices were conceptualised as more familiar but remained exclusive after repeated consumption. When local producers have to market their products, they are recommended to focus on product information as a selling point as this information strongly influences liking, concept associations and sensory perception of the product. However, in order to ensure successful products, the sensory characteristics of the product must not be compromised as these influence liking in a manner increasing over repeated consumption.
► Product information generated high expectations towards local apple juices. ► Consumers assimilated towards their expectations resulting in increased liking. ► Local apple juices were associated more exclusively in informed tasting condition. ► Sensory properties should not be compromised as these contributed to liking. ► Local apple juices became familiar but remained exclusive over repeated exposure.
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