Evaluation of a new model for assessment and treatment of uncomplicated ADHD - effect, patient satisfaction and costs.

Aim: Attention-deficit/hyperactivity disorder (ADHD) is the most common diagnosis within child- and adolescent psychiatry. Waiting lists and delayed care are major issues. The aim was to evaluate if standardized care (SC) for assessment and treatment of uncomplicated ADHD would reduce resource utilization and increase satisfaction with preserved improvement within the first year of treatment.Method: Patients 6-12 years with positive screen for uncomplicated ADHD at the brief child and family phone interview (BCFPI), a routine clinical procedure, were triaged to SC. The control group consisted of patients diagnosed with ADHD in 2014 and treated as usual. BCFPI factors at baseline and follow-up after one year and resource utilization were compared.Results: Patients improved in ADHD symptoms (Cohen's d = 0.78, p < 0.001), child function (Cohen's d = 0.80, p < 0.001) and in family situation (Cohen's d = 0.61, p < 0.001) without group differences. Parents of SC patients participated more often in psychoeducational groups (75.5 vs. 49.5%, p < 0.001). SC had shorter time to ADHD diagnosis (8.4 vs. 15.6 weeks, p = 0.01) and to medication (24.6 vs. 32.1 weeks, p = 0.003). SC families were more satisfied with the waiting time (p = 0.01), otherwise there were no differences in satisfaction between the groups. Families of SC patients had fewer visits (4.7 vs. 10.8, p < 0.001) but used the same number of phone calls (6.3 vs. 6.2, p = 0.71). Costs were 55% lower.Conclusions: A SC for ADHD can markedly reduce costs with preserved quality. As resources are limited, child psychiatry would benefit from standardization.

The Validity of the Screen for Child Anxiety Related Emotional Disorders Revised (SCARED-R) Scale and Sub-Scales in Swedish Youth.

We evaluated the clinical utility of the Swedish SCARED-R in child- and adolescent psychiatric outpatients (n = 239) and validated it against Longitudinal Expert All Data (LEAD) DSM IV diagnoses based on the Children's Schedule for Affective Disorders and Schizophrenia (KSADS) and subsequent clinical work-up and treatment outcome. The SCARED-R total score and subscales had acceptable sensitivity/specificity for child and parent reports for cut-offs based on Receiver Operating Characteristics (ROC) curves, with mostly moderate area under the curve. Sensitivity ranged from 75% (parent rated social anxiety) to 79% [child rated Generalized Anxiety Disorder (GAD)]. Specificity, ranged from 60% for child-rated GAD to 88% for parent rated social anxiety. Parent-child agreement was moderate, and each informant provided unique information contributing to most diagnoses. In conclusion, the SCARED-R is useful for screening anxiety symptoms in clinical populations. However, it cannot replace interview based diagnoses, nor is it adequate to use just one informant.

Predictive validity of the K-SADS-PL 2009 version in school-aged and adolescent outpatients.

BACKGROUND: The schedule for affective disorders and schizophrenia for school-age children (K-SADS) is one of the most commonly used standardized diagnostic interviews in child and adolescent psychiatry. Validity studies are scarce, and limited to concurrent validity with other measures and clinical diagnoses. AIMS: To evaluate the K-SADS interview in an outpatient child and adolescent psychiatry (CAP) setting with a Longitudinal Expert All Data (LEAD) procedure. METHODS: CAP residents performed a K-SADS-PL interview with the revised 2009 version containing the new PDD section on 239 clinically referred outpatients of 6-17 years old and their parent(s). A consensus LEAD diagnosis by two senior clinicians 1.2 (SD = 0.6) years later was based on clinical records including the K-SADS and subsequent information from further assessments, information from teachers and other informants, outcome of treatment, and at least three visits after the K-SADS. RESULTS: Predictive validity for K-SADS vs LEAD diagnoses were good-to-excellent for broader categories of anxiety disorders (κ = 0.94), depressive (κ = 0.91), behavioural (κ = 0.91) and tic (κ = 0.81) disorders, good for ADHD (κ = 0.80), and good-to-moderate for autism spectrum disorders (κ = 0.62). Bipolar, psychotic, and eating disorders were too few to be analysed. CONCLUSION: The K-SADS diagnoses elicited from an interview with the child and one from parents on one occasion have an excellent validity for most major child psychiatric disorders. ADHD can be reliably diagnosed at one visit, but clinicians need to stay alert for possible undiagnosed ADHD. Diagnosing autism with K-SADS-PL 2009 version at one visit is not advisable.

Catch-up antibody responses and hybrid immunity in mRNA vaccinated patients at risk of severe COVID-19.

BACKGROUND: The immunogenicity of repeated vaccination and hybrid immunity in vulnerable patients remains unclear. METHODS: We studied the impact of iterative Covid-19 mRNA vaccination and hybrid immunity on antibody levels in immunosuppressed subjects. Patients with liver cirrhosis (n = 38), survivors of allogeneic haematopoietic stem cell transplantation (allo-HSCT) (n = 36) and patients with autoimmune liver disease (n = 14) along with healthy controls (n = 20) were monitored for SARS-CoV-2-S1 IgG after their 1st-3rd vaccine doses, 31 of whom became infected with the Omicron variant after the 2nd dose. Ten uninfected allo-HSCT recipients received an additional 4th vaccine dose. RESULTS: Unexpectedly, immunosuppressed patients achieved antibody levels in parity with controls after the 3rd vaccine dose. In all study cohorts, hybrid immunity (effect of vaccination and natural infection) resulted in approximately 10-fold higher antibody levels than vaccine-induced immunity alone. CONCLUSIONS: Three doses of the Covid-19 mRNA vaccine entailed high antibody concentrations even in immunocompromised individuals, and hybrid-immunity resulted further augmented levels than vaccination alone. Clinical trial registration: EudraCT 2021-000349-42.

The highly expressed calcium-insensitive synaptotagmin-11 and synaptotagmin-13 modulate insulin secretion.

AIM: SYT11 and SYT13, two calcium-insensitive synaptotagmins, are downregulated in islets from type 2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin-secreting cells. METHODS: Correlations between gene expression levels were performed using previously described RNA-seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC-ßH1 and INS-1 832/13 cells. Insulin secretion was measured with ELISA. Patch-clamp was used for single-cell electrophysiology. Confocal microscopy was used to determine intracellular localization. RESULTS: Human islet expression of the transcription factor PDX1 was positively correlated with SYT11 (p = 2.4e-10 ) and SYT13 (p < 2.2e-16 ). Syt11 and Syt13 both co-localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS-1 832/13 cells (siSYT11) resulted in increased basal and glucose-induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K+ . Interestingly, the cAMP-raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage-gated Ca2+ currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells. CONCLUSION: SYT11 and SYT13 have similar localization and transcriptional regulation, but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type-2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.

Diagnostic efficiency and validity of the DSM-oriented Child Behavior Checklist and Youth Self-Report scales in a clinical sample of Swedish youth.

The Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) are widely used measures of psychiatric symptoms and lately also adapted to the DSM. The incremental validity of adding the scales to each other has not been studied. We validated the DSM subscales for affective, anxiety, attention deficit/hyperactivity (ADHD), oppositional defiant (ODD), conduct problems (CD), and obsessive-compulsive disorder (OCD) in consecutively referred child and adolescent psychiatric outpatients (n = 267) against LEAD DSM-IV diagnoses based on the K-SADS-PL and subsequent clinical work-up. Receiver operating characteristic analyses showed that the diagnostic efficiency for most scales were moderate with an area under the curve (AUC) between 0.70 and 0.90 except for CBCL CD, which had high accuracy (AUC>0.90) in line with previous studies showing the acceptable utility of the CBCL DSM scales and the YSR affective, anxiety, and CD scales, while YSR ODD and OCD had low accuracy (AUC<0.70). The findings mostly reveal incremental validity (using logistic regression analyses) for adding the adolescent to the parent version (or vice versa). Youth and parent ratings contributed equally to predict depression and anxiety disorders, while parent ratings were a stronger predictor for ADHD. However, the youth ADHD rating also contributed. Adding young people as informants for ODD and OCD or adding the parent for CD did not improve accuracy. The findings for depression, anxiety disorders, and ADHD support using more than one informant when conducting screening in a clinical context.

Coordination of imidazoles by Cu(II) and Zn(II) as studied by NMR relaxometry, EPR, far-FTIR vibrational spectroscopy and ab initio calculations: effect of methyl substitution.

Synthetic imidazole ligands are typically substituted at the N(1) ((1)-Im) position while natural imidazole ligands are substituted at the C(4) ((4)-Im) position. To outline the difference in coordination properties, the methyl-substituted imidazoles Me(4)-Im and Me(1)-Im were complexed with CuCl(2) and ZnCl(2) and investigated by NMR relaxometry, electron paramagnetic resonance, far-Fourier transform IR vibrational spectroscopy, and ab initio calculations. Me(4)-Im, Me(1)-Im, and Im in excess form the usual tetragonal D(4h) [CuL(4)X(2)] complexes with CuCl(2) whereas the methylated imidazoles form pseudotetrahedral C(2v) complexes instead of the usual octahedral O(h) [ZnIm(6)](2+) complex. All imidazoles display a high degree of covalence in the M-L σ- and π-bonds and the π-interaction strength affects the relative energies of complexation. Opportunities to tailor complexes by the chemical properties of the substituents are envisaged due to the role of the inductive and hyperconjugative effects, rather than position.

Screening efficiency of the Mood and Feelings Questionnaire (MFQ) and Short Mood and Feelings Questionnaire (SMFQ) in Swedish help seeking outpatients.

BACKGROUND: To evaluate screening efficiency and suggest cut-offs for parent and child Mood and Feelings Questionnaire (MFQ) and the short version (SMFQ) in unselected help seeking child- and adolescent psychiatric outpatients for subgroups of 6-12 versus 13-17 year olds and boys versus girls. METHOD: Eligible for inclusion were newly admitted outpatients age 6-17 years (n = 5908) in four Swedish child- and adolescent psychiatry clinics. They were prompted consecutively and n = 307 accepted a specific day for assessment until time slots randomly were filled. We prospectively validated the MFQ (33 items) and SMFQ (13 items) in patients (n = 186) using receiver operating characteristics against a reference test of Longitudinal Expert All Data DSM-IV depression based on a Kiddie-Schedule for Affective Disorders and Schizophrenia and 1.2 (sd .6) years of follow-up. RESULTS: A depressive disorder was confirmed in 59 (31.7%) patients ranging from 14.0% for girls 6-12 years to 53.3% for girls 13-17 years. SMFQ performed roughly equivalent to MFQ. Adolescent score on SMFQ discriminated fairly for boys with Area Under Curve .77 (95% confidence interval .59-.81) and good (.82, .69-.91) for girls and parent ratings for adolescent girls (.85, .73-.93), but not for boys. Depression in children below age 13 could not be discriminated by MFQ or SMFQ whether filled in by child and mostly also when filled in by parent. Favouring maximum kappa value, the optimal cut-off was for MFQ self-report girls ≥32 versus boys ≥11 and for SMFQ self-report girls ≥17 versus boys ≥ 6. Suggested clinical SMFQ cut-offs for girls were ≥12 and for boys ≥ 6. CONCLUSIONS: MFQ and SMFQ can, with gender-based cut-offs, be used for screening in clinical populations of adolescents but not in children. Parent MFQ and SMFQ can be used for adolescent girls but not boys. SMFQ is sufficient for screening.

Validity of the Brief Child and Family Phone Interview by comparison with Longitudinal Expert All Data diagnoses in outpatients.

BACKGROUND: The Brief Child and Family Phone Interview (BCFPI) is a standardized intake and follow-up interview used in child and adolescent mental health services (CAMHS). Although it has shown good validity compared with other measures using parent reports, it has not yet been compared with diagnoses derived from a Longitudinal Expert All Data (LEAD) procedure, which includes information from separate diagnostic interviews with parent(s) and child. The aim was to compare the BCFPI evaluation in an outpatient child and adolescent psychiatry setting with an evaluation derived from a LEAD procedure. METHODS: At four Swedish outpatient CAMHS, 267 patients were interviewed at intake with the BCFPI. Within six weeks, patients and parents were interviewed separately with the 2009 version of the semi-structured Kiddie Schedule for Affective Disorders and Schizophrenia for School-age Children, Present and Lifetime Version (K-SADS-PL) and parents completed the Child Behavior Checklist (CBCL). LEAD diagnoses were subsequently determined by two senior clinicians based on 1.2 years of clinical records including the K-SADS-PL and ensuing information from further assessments, psychological tests, information from teachers and other informants as well as treatment outcome. The Diagnostic and Statistical Manual of Mental Disorders subscales from the CBCL and the subscales from the BCFPI were compared with LEAD diagnoses. These measured symptoms of attention-deficit hyperactivity disorder, oppositional defiant disorder, conduct disorder, separation anxiety disorder, generalized anxiety disorder, and major depressive disorder. RESULTS: The criterion validity for BCFPI versus LEAD diagnoses was fair for oppositional defiant disorder (area under curve, 0.73), generalized anxiety disorder (0.73) and major depressive disorder (0.78), good for attention-deficit hyperactivity disorder (0.81) and conduct disorder (0.83), and excellent for separation anxiety disorder (0.90). The screening properties of BCFPI and CBCL were similar. CONCLUSION: The BCFPI is a concise and valid tool, performed along with the larger and more established CBCL, in screening for major psychiatric disorders. It is well suited as an intake interview in CAMHS.

An Evaluation of Boar Spermatozoa as a Biosensor for the Detection of Sublethal and Lethal Toxicity.

A novel, objective, and rapid computed motility inhibition (CMI) assay was developed to identify and assess sublethal injury in toxin-exposed boar spermatozoa and compared with a subjective visual motility inhibition (VMI) assay. The CMI values were calculated from digital micrographic videos using a custom MATLAB® script by contrasting the motility index values of each experiment with those of the background and control experiments. Following a comparison of the CMI and VMI assays results, it was determined that their agreement depended on the shape of the dose-response curve. Toxins that exhibited a steep slope were indicative of good agreement between the assays. Those depicted by a gentle decline in the slope of the dose-response curve, the CMI assay were shown to be two times more sensitive than the VMI assay. The CMI assay was highly sensitive to the inhibition of mitochondrial function and glucose transport activity by sublethal doses of toxins and to disruption of cellular cation homeostasis by carrier ionophoric toxins, when compared to the cytotoxicity and lethal toxicity assays (i.e., that evaluated the inhibition of cell proliferation in somatic cell lines (FL, PK-15, and MNA cells)) and disruption to spermatozoa membrane integrity. The CMI assay recognized subtle sublethal toxicity changes in metabolism, manifested as a decrease in boar spermatozoa motility. Thus, it was feasible to effectively compare the objectively-measured numerical values for motility inhibition using the CMI assay against those reflecting lethal damage in the spermatozoa cells and somatic cell lines using a cytotoxicity assay.

MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles.

MicroRNAs contribute to the maintenance of optimal cellular functions by fine-tuning protein expression levels. In the pancreatic ß-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates ß-cell dysfunction, and have earlier shown that islets from the diabetic GK-rat model have increased expression of miRNAs, including miR-335-5p (miR-335). Here, we aim to determine the specific role of miR-335 during development of T2D, and the influence of this miRNA on glucose-stimulated insulin secretion and Ca2+-dependent exocytosis. We found that the expression of miR-335 negatively correlated with secretion index in human islets of individuals with prediabetes. Overexpression of miR-335 in human EndoC-ßH1 and in rat INS-1 832/13 cells (OE335) resulted in decreased glucose-stimulated insulin secretion, and OE335 cells showed concomitant reduction in three exocytotic proteins: SNAP25, Syntaxin-binding protein 1 (STXBP1), and synaptotagmin 11 (SYT11). Single-cell capacitance measurements, complemented with TIRF microscopy of the granule marker NPY-mEGFP demonstrated a significant reduction in exocytosis in OE335 cells. The reduction was not associated with defective docking or decreased Ca2+ current. More likely, it is a direct consequence of impaired priming of already docked granules. Earlier reports have proposed reduced granular priming as the cause of reduced first-phase insulin secretion during prediabetes. Here, we show a specific role of miR-335 in regulating insulin secretion during this transition period. Moreover, we can conclude that miR-335 has the capacity to modulate insulin secretion and Ca2+-dependent exocytosis through effects on granular priming.

Bi-layer formation of imidazole-modified ethyl(hydroxyethyl)cellulose at a hydrophobic surface as monitored by QCM-D.

The adsorption behaviour of ethyl(hydroxyethyl)cellulose chemically modified with imidazole (Im-EHEC) at hydrophobic surfaces has been studied with QCM-D. The very slow adsorption isotherm was due to a continuous polymer film reconfiguration and exchange of different sized polymers. The thickness of the film was about 30 nm. The polymers adsorbed Cu(2+) ions into the film from a CuCl(2) solution and a bi-layer was formed when Im-EHEC was added a second time. The second polymer film was only 7 nm thick but highly viscoelastic. After rinsing with water the metal ions was flushed away and the second Im-EHEC layer was released. The imidazole modification of EHEC enables interaction with transition metal ions and opens up for new applications for cellulose based materials.