Validation and verification of the GeneFinder™ COVID-19 Plus RealAmp kit on the ELITe InGenius® instrument.

BACKGROUND: Throughout the SARS-CoV-2 pandemic, a rapid identification of the virus was essential to quickly recognize positive cases and limit further spread by applying appropriate infection prevention. Many diagnostic laboratories use a multiplex Real-Time PCR assay, as they are not only highly sensitive but also specific. Currently, there are several assays and platforms in the market available which target different SARS-CoV-2 genes. The aim of this study was to validate and verify the GeneFinder™ COVID-19 PLUS RealAmp kit on the ELITe InGenius® instrument and compare to the national reference method. METHODS: GeneFinder™ COVID-19 PLUS RealAmp kit was evaluated against the routine WHO in- house Real-Time PCR assay, which is also the national reference method in the Netherlands and used in our laboratory. The sensitivity was tested using the analytical panel from Qnostics (Glasgow, United Kingdom) and the specificity was tested with patient material comprising of other seasonal respiratory viruses. In addition, 96 clinical samples initially analyzed by routine Real-Time PCR were tested using the GeneFinder™ COVID-19 PLUS RealAmp kit on the ELITe InGenius® instrument. RESULTS: The GeneFinder™ COVID-19 PLUS RealAmp kit had a similar performance compared to routine in-house testing, with a limit of detection of 500 dC/mL for the RdRp-gene and E gene. Meanwhile, the N gene showed a limit of detection of 50 dC/mL. The SARS-CoV-2 test was highly specific and detected no other respiratory viruses. The results of the clinical samples were comparable between both assays with similar Ct values observed for the in-house Real-Time-PCR and the GeneFinder™ COVID-19 PLUS RealAmp kit for the N gene. CONCLUSION: The GeneFinder™ COVID-19 PLUS RealAmp kit on the ELITe InGenius® instrument had an appropriate sensitivity and specificity that could be used in small scale laboratories or during night shifts where accurate diagnostics are crucial.

Personalized ESM monitoring and feedback to support psychological treatment for depression: a pragmatic randomized controlled trial (Therap-i).

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent mental disorder with large disease burden, high levels of relapse or persistence, and overall suboptimal outcomes of protocolized pharmacological and psychotherapeutic treatments. There is an urgent need to improve treatment effectiveness, possibly through systematic treatment personalization. In psychotherapeutic treatments this can be achieved by case conceptualization. To support this process, we developed the Therap-i module, which consists of personalized Experienced Sampling Methodology (ESM) and feedback. The Therap-i module is integrated into outpatient psychotherapeutic treatment as usual (TAU) for depression. The study aim is to investigate the efficacy of the Therap-i module in decreasing symptomatology in unresponsive or relapsing patients diagnosed with MDD. We hypothesize that the Therap-i module will contribute to TAU by i) decreasing depressive symptoms, and ii) improving general functioning, therapeutic working alliance, and illness perception. This paper provides details of the study rationale, aims, procedures, and a discussion on potential pitfalls and promises of the module. METHODS: Patients diagnosed with MDD (n = 100) will enrol in a pragmatic two-armed randomized controlled trial. Randomization is stratified according to the patient's treatment resistance level assessed with the Dutch Method for quantification of Treatment Resistance in Depression (DM-TRD). All fill-out the Inventory of Depressive Symptomatology Self Report (IDS-SR), Outcome Questionnaire (OQ-45), Illness Perception Questionnaire Mental Health (IPQ-MH), and Work Alliance Inventory Self Report (WAI-SR). In the intervention arm, through close collaboration between patient, clinician, and researcher, a personalized ESM diary is developed based on the patient's case conceptualization. During the ESM monitoring period (8 weeks, 5 assessments/day), patients receive feedback three times, which is discussed among the abovementioned three parties. Both patients and clinicians will evaluate the Therap-i module. RESULTS: Data collection is ongoing. DISCUSSION: This is the first study in which personalized ESM and feedback is integrated in outpatient psychotherapeutic TAU for depression. The labour intensive procedure and methodological pitfalls are anticipated challenges and were taken into account when designing the study. When hypotheses are confirmed, the Therap-i module may advance treatment for depression by providing insights into personalized patterns driving or perpetuating depressive complaints. TRIAL REGISTRATION: Trial NL7190 (NTR7381) , registered prospectively 03-08-2018.

Meta-analysis of the outcomes of treatment of internal carotid artery near occlusion.

BACKGROUND: Guidelines recommend treating patients with an internal carotid artery near occlusion (ICANO) with best medical therapy (BMT) based on weak evidence. Consequently, patients with ICANO were excluded from randomized trials. The aim of this individual-patient data (IPD) meta-analysis was to determine the optimal treatment approach. METHODS: A systematic search was performed in MEDLINE, EMBASE and the Cochrane Library databases in January 2018. The primary outcome was the occurrence of any stroke or death within the first 30 days of treatment, analysed by multivariable mixed-effect logistic regression. The secondary outcome was the occurrence of any stroke or death beyond 30 days up to 1 year after treatment, evaluated by Kaplan-Meier survival analysis. RESULTS: The search yielded 1526 articles, of which 61 were retrieved for full-text review. Some 32 studies met the inclusion criteria and pooled IPD were available from 11 studies, including some 703 patients with ICANO. Within 30 days, any stroke or death was reported in six patients (1·8 per cent) in the carotid endarterectomy (CEA) group, five (2·2 per cent) in the carotid artery stenting (CAS) group and seven (4·9 per cent) in the BMT group. This resulted in a higher 30-day stroke or death rate after BMT than after CEA (odds ratio 5·63, 95 per cent c.i. 1·30 to 24·45; P = 0·021). No differences were found between CEA and CAS. The 1-year any stroke- or death-free survival rate was 96·1 per cent for CEA, 94·4 per cent for CAS and 81·2 per cent for BMT. CONCLUSION: These data suggest that BMT alone is not superior to CEA or CAS with respect to 30-day or 1-year stroke or death prevention in patients with ICANO. These patients do not appear to constitute a high-risk group for surgery, and consideration should made to including them in future RCTs of internal carotid artery interventions.

Evaluating the social fitness Programme for older people with cognitive problems and their caregivers: lessons learned from a failed trial.

BACKGROUND: This process evaluation article describes the lessons learned from a failed trial which aimed to assess effectiveness of the tailor-made, multidisciplinary Social Fitness Programme to improve social participation of community-dwelling older people with cognitive problems (clients) and their caregivers (couples). METHODS: A process evaluation was performed to get insight in 1) the implementation of the intervention, 2) the context of intervention delivery from professionals' point of view, and 3) the potential impact of intervention delivery from participants' perspectives. Data was gathered using mixed-methods: questionnaires, focus group discussions, interviews, medical records. RESULTS: 1) Implementation. High study decline (65,3%) was mainly caused by a lack of internal motivation to increase social participation expressed by clients. 17 couples participated, however, intervention delivery was insufficient. 2) Context. Barriers during intervention delivery were most often related to client (changing needs), caregiver (increased burden) and health professional factors (delivery of integrated care lacked routine). 3) Impact Qualitative analyses revealed participants to be satisfied with intervention delivery, we were unable to capture these results through our primary outcome measure. CONCLUSIONS: This process evaluation revealed the Social Fitness study did not fit in three ways. First, framing the intervention on social participation promotion was as threatening to clients. The feeling of being unable to adequately contribute to social interactions seemed to be causing embarrassment. Second, the intervention seemed to be too complex to implement in the way it was designed. Third, there is a tension between the offering of a personalised tailor-made intervention and evaluation through a fixed study design. TRIAL REGISTRATION: The trial which is evaluated in this article (the Social Fitness study) is registered with the Dutch Trial Register (NTR), clinical trial number NTR4347 .

Worry and cognitive control predict course trajectories of anxiety in older adults with late-life depression.

BACKGROUND: Many older adults with depressive disorder manifest anxious distress. This longitudinal study examines the predictive value of worry as a maladaptive cognitive emotion regulation strategy, and resources necessary for successful emotion regulation (i.e., cognitive control and resting heart rate variability [HRV]) for the course of anxiety symptoms in depressed older adults. Moreover, it examines whether these emotion regulation variables moderate the impact of negative life events on severity of anxiety symptoms. METHODS: Data of 378 depressed older adults (CIDI) between 60 and 93 years (of whom 144 [41%] had a comorbid anxiety disorder) from the Netherlands Study of Depression in Older Adults (NESDO) were used. Latent Growth Mixture Modeling was used to identify different course trajectories of six-months BAI scores. Univariable and multivariable longitudinal associations of worry, cognitive control and HRV with symptom course trajectories were assessed. RESULTS: We identified a course trajectory with low and improving symptoms (57.9%), a course trajectory with moderate and persistent symptoms (33.5%), and a course trajectory with severe and persistent anxiety symptoms (8.6%). Higher levels of worry and lower levels of cognitive control predicted persistent and severe levels of anxiety symptoms independent of presence of anxiety disorder. However, worry, cognitive control and HRV did not moderate the impact of negative life events on anxiety severity. CONCLUSIONS: Worry may be an important and malleable risk factor for persistence of anxiety symptoms in depressed older adults. Given the high prevalence of anxious depression in older adults, modifying worry may constitute a viable venue for alleviating anxiety levels.

Social participation of people with cognitive problems and their caregivers: a feasibility evaluation of the Social Fitness Programme.

OBJECTIVE: We developed a tailor-made intervention aimed at improving social participation of people with cognitive problems and their caregivers. This programme consists of an integration of healthcare and welfare interventions: occupational therapy, physiotherapy and guidance by a welfare professional. This article describes the feasibility evaluation of this Social Fitness Programme. METHODS: Feasibility in terms of acceptability, demand, implementation, practicability and limited efficacy was evaluated based on experiences from professionals (programme deliverers), people with cognitive problems and their caregivers (programme recipients). We used qualitative research methods (focus group discussions, interviews, collection of treatment records) and applied thematic analyses. RESULTS: The intervention was feasible according to stakeholders, and limited efficacy showed promising results. However, we found feasibility barriers. First, an acceptability barrier: discussing declined social participation was difficult, hindering recruitment. Second, a demand barrier: some people with cognitive problems lacked motivation to improve declined social participation, sometimes in contrast to their caregivers' wishes. Third, implementation and practicability barriers: shared decision-making, focusing the intervention and interdisciplinary collaboration between healthcare and welfare professionals were suboptimal during implementation. DISCUSSION: Although this intervention builds upon scientific evidence, expert opinions and stakeholder needs, implementation was challenging. Healthcare and welfare professionals need to overcome obstacles in their collaboration and focus on integrated intervention delivery. Also, they need to find ways to (empower caregivers to) motivate people with cognitive problems to participate socially. After modifying the intervention and additional training of professionals, a consecutive pilot study to assess feasibility of the research design and outcome measures is justified. Copyright © 2017 John Wiley & Sons, Ltd.

4 × 40-Gb/s TWDM PON downstream transmission over 42 km and 64-way power split using optical duobinary signals and an APD-based receiver.

We demonstrate downstream transmission of a four-channel 40-Gb/s-per-channel time- and wavelength-division-multiplexed PON over a 42-km, 64-split fiber plant using optical duobinary modulation. At 1550 nm, we obtain a reach of 0-26 km or 16-42 km using two dispersion-precompensation values.

Suicide in patients suffering from late-life anxiety disorders; a comparison with younger patients.

BACKGROUND: Anxiety disorders are assumed to increase suicide risk, although confounding by comorbid psychiatric disorders may be one explanation. This study describes the characteristics of older patients with an anxiety disorder who died by suicide in comparison to younger patients. METHOD: A 15-year national clinical survey of all suicides in the UK (n = 25,128). Among the 4,481 older patients who died by suicide (≥ 60 years), 209 (4.7%) suffered from a primary anxiety disorder, and 533 (11.9%) from a comorbid anxiety disorder. Characteristics of older (n = 209) and younger (n = 773) patients with a primary anxiety disorder were compared by logistic regression adjusted for sex and living arrangement. RESULTS: Compared to younger patients, older patients with a primary anxiety disorder were more often males and more often lived alone. Although 60% of older patients had a history of psychiatric admissions and 50% of deliberate self-harm, a history of self-harm, violence, and substance misuse was significantly less frequent compared to younger patients, whereas physical health problems and comorbid depressive illness were more common. Older patients were prescribed significantly more psychotropic drugs and received less psychotherapy compared to younger patients. CONCLUSION: Anxiety disorders are involved in one of every six older patients who died by suicide. Characteristics among patients who died by suicide show severe psychopathology, with a more prominent role for physical decline and social isolation compared to their younger counterparts. Moreover, treatment was less optimal in the elderly, suggesting ageism. These results shed light on the phenomenon of suicide in late-life anxiety disorder and suggest areas where prevention efforts might be focused.

Comorbid anxiety disorders in late-life depression: results of a cohort study.

BACKGROUND: Comorbid anxiety disorders are common in late-life depression and negatively impact treatment outcome. This study aimed to examine personality characteristics as well as early and recent life-events as possible determinants of comorbid anxiety disorders in late-life depression, taking previously examined determinants into account. METHODS: Using the Composite International Diagnostic Interview (CIDI 2.0), we established comorbid anxiety disorders (social phobia (SP), panic disorder (PD), generalized anxiety disorder (GAD), and agoraphobia (AGO)) in 350 patients (aged ≥60 years) suffering from a major depressive disorder according to DSM-IV-TR criteria within the past six months. Adjusted for age, sex, and level of education, we first examined previously identified determinants of anxious depression: depression severity, suicidality, partner status, loneliness, chronic diseases, and gait speed in multiple logistic regression models. Subsequently, associations were explored with the big five personality characteristics as well as early and recent life-events. First, multiple logistic regression analyses were conducted with the presence of any anxiety disorder (yes/no) as dependent variable, where after analyses were repeated for each anxiety disorder, separately. RESULTS: In our sample, the prevalence rate of comorbid anxiety disorders in late-life depression was 38.6%. Determinants of comorbid anxiety disorders were a lower age, female sex, less education, higher depression severity, early traumatization, neuroticism, extraversion, and conscientiousness. Nonetheless, determinants differed across the specific anxiety disorders and lumping all anxiety disorder together masked some determinants (education, personality). CONCLUSIONS: Our findings stress the need to examine determinants of comorbid anxiety disorder for specific anxiety disorders separately, enabling the development of targeted interventions within subgroups of depressed patients.

The effect of different photoperiods in circadian rhythms of per3 knockout mice.

The aim of this study was to analyse the circadian behavioural responses of mice carrying a functional knockout of the Per3 gene (Per3(-/-)) to different light : dark (L : D) cycles. Male adult wild-type (WT) and Per3(-/-) mice were kept under 12-hour light : 12-hour dark conditions (12L : 12D) and then transferred to either a short or long photoperiod and subsequently released into total darkness. All mice were exposed to both conditions, and behavioural activity data were acquired through running wheel activity and analysed for circadian characteristics during these conditions. We observed that, during the transition from 12L : 12D to 16L : 8D, Per3(-/-) mice take approximately one additional day to synchronise to the new L : D cycle compared to WT mice. Under these long photoperiod conditions, Per3(-/-) mice were more active in the light phase. Our results suggest that Per3(-/-) mice are less sensitive to light. The data presented here provides further evidence that Per3 is involved in the suppression of behavioural activity in direct response to light.

EGFR expression is associated with groin node metastases in vulvar cancer, but does not improve their prediction.

OBJECTIVES: High morbidity of elective inguinofemoral lymphadenectomy in early stage vulvar cancer patients urges the need for defining a group of low-risk patients in whom inguinofemoral lymphadenectomy can be safely omitted. Aim of the study was to evaluate whether in addition to 'classic' clinicopathological factors determination of EGFR expression in vulvar cancer can be helpful in defining such a 'low-risk' group. METHODS: Formalin-fixed paraffin-embedded tumor tissue samples of 197 surgically treated T1/2 patients were collected in a Tissue Micro Array (TMA). On this TMA, immunohistochemistry for EGFR was performed. Logistic regression analyses were performed including histopathological characteristics with the presence of nodal metastases as outcome. A predictive model was constructed, and absolute risks were calculated. RESULTS: EGFR expression was present in 68% of the vulvar tumors and related to the presence of lymph node metastases (OR 2.12, 95% CI 1.09-4.10). Our predictive model with only clinicopathological factors was able to define a group of patients with a likelihood of absence of lymph node metastases of 13% (95% CI 5-36), which could be decreased to 6% (95% CI 0-29) after inclusion of EGFR expression (p=0.07). CONCLUSIONS: EGFR expression is present in the majority of vulvar tumors and is associated with groin node metastases in vulvar cancer. Current classic clinicopathological predictive factors for inguinofemoral lymph node metastases with or without EGFR analysis are not strong enough for identification of "sufficiently low" risk T1/2 vulvar cancer patients. Our predictive model approach however is excellent for evaluation of new cell biological parameters, associated with clinical outcome.

Circadian dynamics of vasopressin in mouse selection lines: translation and release in the SCN.

Arg8-vasopressin (AVP), a circadian clock-controlled gene product, is released from the hypothalamic suprachiasmatic nuclei (SCN) in mice in a circadian fashion. Previously reported differences in two mouse lines, initially selected for thermoregulatory nest-building behavior (building small nests (S-mice) or big nests (B-mice)) with different circadian organization of behavior and in number of SCN-AVP immunoreactive neurons, were further investigated. We confirmed and expanded the finding that S-mice exhibited constant high levels of SCN-AVP content with no apparent circadian rhythmicity, whereas B-mice had lower numbers of AVP positive cells which varied with time of day. We found that AVP mRNA expression levels at midnight and midday were similar in both lines, as established by in situ hybridization. When AVP transport and release were blocked by colchicine, SCN-AVP immunoreactivity was similar in both lines. This suggests that differences in SCN-AVP content depend on transport or release. Organotypic SCN cultures of B-mice showed more AVP release per neuron than cultures of S-mice. These results reveal that on a mechanistic level the mouse lines differed in transport and/or release of AVP in the SCN, rather than differential regulation of AVP gene transcription or number of AVP immunoreactive neurons.