A comprehensive comparison between ISAC and ALEX2 multiplex test systems.

OBJECTIVES: Diagnosis of type I hypersensitivity is based on anamnesis, provocation as well as blood- and skin testing. Multiplex specific IgE (sIgE) testing enables determination of sIgE antibodies against multiple recombinant or purified natural allergen components. The aim of this study was to evaluate the performance of the novel ALEX2® (Allergy Explorer, ALEX2 test introduced on the market November 2019) multiplex platform and to compare it with the ImmunoCAP ISAC® test system. METHODS: Serum samples of 49 patients, routinely determined with ISAC, were selected based on positive results covering in total most of the 112 ISAC components. Cohen's kappa, negative percent agreement (NPA), and positive percent agreement (PPA) of ALEX2 data compared to ISAC data (as a non-reference standard) were computed for those allergen components present on both platforms (n=103). Furthermore, in some samples sIgE results against allergen extracts and/or -components tested with either ImmunoCAP® (ThermoFisher) or IMMULITE® (Siemens) were available and compared to ALEX2 results. RESULTS: The overall agreement between ISAC and ALEX2 common allergen components was 94%. NPA and PPA were respectively 95 and 90%. Kappa values differed for specific allergen groups and varied between 0.60 and 0.92 showing moderate to almost perfect agreement. Of the qualitative discrepancies between ALEX2 and ISAC, 59% were related to weak positive results i.e. results under 1 kUA/L or 1 ISU, respectively. CONCLUSIONS: The method comparison between ISAC and ALEX2 multiplex tests showed a high concordance for those allergen components present on both platforms.

Optimal Timing of Prostate Specific Membrane Antigen Positron Emission Tomography/Computerized Tomography for Biochemical Recurrence after Radical Prostatectomy.

PURPOSE: We developed a model predicting the probability of detecting prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography in patients with biochemical recurrence after radical prostatectomy. MATERIALS AND METHODS: We retrospectively included 419 consecutive patients with biochemical recurrence (prostate specific antigen less than 2.0 ng/ml) after radical prostatectomy who underwent 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography to guide salvage therapy. Patients receiving androgen deprivation therapy between radical prostatectomy and prostate specific membrane antigen positron emission tomography/computerized tomography were excluded from the study. We used multivariable logistic regression to assess predictors for the detection of prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography. We minimized overfitting of the model and used decision curve analysis to determine clinical utility. RESULTS: Median prostate specific antigen at scanning was 0.40 ng/ml (IQR 0.30-0.70). Overall 174 (42%) patients had prostate cancer recurrence outside the prostatic fossa. Prostate specific antigen at time of scanning, and grade group, N stage and surgical margin status at radical prostatectomy specimen were significant predictors for detecting prostate cancer recurrence outside the prostatic fossa. The bootstrapped AUC of this model was 0.75 (IQR 0.73-0.77). The decision curve analysis showed a net benefit by a model based probability from 16%. Limitations include the retrospective design and the missing histological correlation of positive lesions. CONCLUSIONS: Next to the prostate specific antigen at time of scanning, grade group, N stage and surgical margin status at radical prostatectomy specimen are significant predictors for detecting prostate cancer recurrence outside the prostatic fossa on prostate specific membrane antigen positron emission tomography/computerized tomography. The presented model is implemented in a dashboard to assist clinicians in determining the optimal time to perform 68Ga-prostate specific membrane antigen-11 positron emission tomography/computerized tomography in patients with biochemical recurrence after radical prostatectomy.

Radiometal-Dependent Biological Profile of the Radiolabeled Gastrin-Releasing Peptide Receptor Antagonist SB3 in Cancer Theranostics: Metabolic and Biodistribution Patterns Defined by Neprilysin.

Recent advances in oncology involve the use of diagnostic/therapeutic radionuclide-carrier pairs that target cancer cells, offering exciting opportunities for personalized patient treatment. Theranostic gastrin-releasing peptide receptor (GRPR)-directed radiopeptides have been proposed for the management of GRPR-expressing prostate and breast cancers. We have recently introduced the PET tracer 68Ga-SB3 (SB3, DOTA- p-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt), a receptor-radioantagonist that enables the visualization of GRPR-positive lesions in humans. Aiming to fully assess the theranostic potential of SB3, we herein report on the impact of switching 68Ga to 111In/177Lu-label on the biological properties of resulting radiopeptides. Notably, the bioavailability of 111In/177Lu-SB3 in mice drastically deteriorated compared with metabolically robust 68Ga-SB3, and as a result led to poorer 111In/177Lu-SB3 uptake in GRPR-positive PC-3 xenografts. The peptide cleavage sites were identified by chromatographic comparison of blood samples from mice intravenously receiving 111In/177Lu-SB3 with each of newly synthesized 111In/177Lu-SB3-fragments. Coinjection of the radioconjugates with the neprilysin (NEP)-inhibitor phosphoramidon led to full stabilization of 111In/177Lu-SB3 in peripheral mouse blood and resulted in markedly enhanced radiolabel uptake in the PC-3 tumors. In conclusion, in situ NEP-inhibition led to indistinguishable 68Ga/111In/177Lu-SB3 profiles in mice emphasizing the theranostic prospects of SB3 for clinical use.

Exome sequencing reveals mutated SLC19A3 in patients with an early-infantile, lethal encephalopathy.

To accomplish a diagnosis in patients with a rare unclassified disorder is difficult. In this study, we used magnetic resonance imaging pattern recognition analysis to identify patients with the same novel heritable disorder. Whole-exome sequencing was performed to discover the mutated gene. We identified seven patients sharing a previously undescribed magnetic resonance imaging pattern, characterized by initial swelling with T2 hyperintensity of the basal nuclei, thalami, cerebral white matter and cortex, pons and midbrain, followed by rarefaction or cystic degeneration of the white matter and, eventually, by progressive cerebral, cerebellar and brainstem atrophy. All patients developed a severe encephalopathy with rapid deterioration of neurological functions a few weeks after birth, followed by respiratory failure and death. Lactate was elevated in body fluids and on magnetic resonance spectroscopy in most patients. Whole-exome sequencing in a single patient revealed two predicted pathogenic, heterozygous missense mutations in the SLC19A3 gene, encoding the second thiamine transporter. Additional predicted pathogenic mutations and deletions were detected by Sanger sequencing in all six other patients. Pathology of brain tissue of two patients demonstrated severe cerebral atrophy and microscopic brain lesions similar to Leigh's syndrome. Although the localization of SLC19A3 expression in brain was similar in the two investigated patients compared to age-matched control subjects, the intensity of the immunoreactivity was increased. Previously published patients with SLC19A3 mutations have a milder clinical phenotype, no laboratory evidence of mitochondrial dysfunction and more limited lesions on magnetic resonance imaging. In some, cerebral atrophy has been reported. The identification of this new, severe, lethal phenotype characterized by subtotal brain degeneration broadens the phenotypic spectrum of SLC19A3 mutations. Recognition of the associated magnetic resonance imaging pattern allows a fast diagnosis in affected infants.

Correction: Wilderink et al. A Theoretical Perspective on Why Socioeconomic Health Inequalities Are Persistent: Building the Case for an Effective Approach. Int. J. Environ. Res. Public Health 2022, 19, 8384.

In the original publication [...].

Urban densification in the Netherlands and its impact on mental health: An expert-based causal loop diagram.

Urban densification is a key strategy to accommodate rapid urban population growth, but emerging evidence suggests serious risks of urban densification for individuals' mental health. To better understand the complex pathways from urban densification to mental health, we integrated interdisciplinary expert knowledge in a causal loop diagram via group model building techniques. Six subsystems were identified: five subsystems describing mechanisms on how changes in the urban system caused by urban densification may impact mental health, and one showing how changes in mental health may alter urban densification. The new insights can help to develop resilient, healthier cities for all.

Mechanisms and contextual factors related to key elements of a successful integrated community-based approach aimed at reducing socioeconomic health inequalities in the Netherlands: A realist evaluation perspective.

BACKGROUND: Reducing health inequalities is a challenge for policymakers and civil society. A multisectoral and multilevel approach is most promising to reduce those inequalities. Previous research showed what key elements of Zwolle Healthy City, an integrated community-based approach aimed at reducing socioeconomic health inequalities, are. To fully understand approaches that are complex and context dependent, questions as 'how does the intervention work' and 'in what context does it work' are just as important as 'what works'. The current study aimed to identify mechanisms and contextual factors associated with the key elements of Zwolle Healthy City, using a realist evaluation perspective. METHODS: Transcripts of semi-structured interviews with a wide range of local professionals were used (n = 29). Following realist evaluation logic in the analysis of this primary data, context-mechanism-outcome configurations were identified and thereafter discussed with experts (n = 5). RESULTS: How mechanisms (M) in certain contexts (C) were of influence on the key elements (O) of the Zwolle Healthy City approach are described. For example, how, in the context of the responsible aldermen embracing the approach (C), regular meetings with the aldermen (M) increased support for the approach among involved professionals (O). Or, how, in the context of available financial resources (C), assigning a program manager (M) contributed positively to coordination and communication (O). All 36 context-mechanism-outcome configurations can be found in the repository. CONCLUSION: This study showed what mechanisms and contextual factors are associated with the key elements of Zwolle Healthy City. By applying realist evaluation logic in the analysis of primary qualitative data we were able to disentangle the complexity of processes of this whole system approach and show this complexity in a structured manner. Also, by describing the context in which the Zwolle Healthy City approach is implemented, we contribute to the transferability of this approach across different contexts.

Drug use and access to drug dependency services for vulnerable migrants who use drugs in the European Union: Consensus statements and recommendations from civil society experts in Europe.

BACKGROUND: The number of migrants in the European Union (EU) has been growing, including migrants at risk of using drugs. Little information is available on the actual drug use among first-generation migrants who use drugs in the EU, nor on their access to drug dependency services. This study aims to reach consensus among experts in the EU on the current situation regarding vulnerable migrants who use drugs in the EU and to develop a set of actionable recommendations. METHODS: Between April and September 2022, a panel of 57 experts on migration and/or drug use, working in 24 countries, participated in a three-stage Delphi study to develop statements and recommendations about drug use and access to healthcare services for migrants who use drugs in the EU. RESULTS: High levels of agreement were reached on the 20 statements (mean=98.0%) and 15 recommendations (mean=99.7%). The recommendations focus on four main topics; 1) increasing data availability and quality, to inform guidelines; 2) increasing the availability of drug dependency services for migrants, including screening for mental health issues and involving migrants who use drugs in the development of services; 3) eliminating country and service level barriers for accessing these services, as well as providing migrants who use drugs with suitable information, and combating stigma and discrimination; 4) the need for increased collaboration among and within EU countries regarding healthcare for migrants who use drugs, at the policy level as well as the service level, including civil society organisations, peer navigation and multilingual cultural mediators. CONCLUSION: Policy action and increased collaboration are required by the EU as a whole and by individual EU member states, in addition to collaboration among healthcare providers and social welfare services, to increase access to healthcare services for migrants who use drugs.

A Theoretical Perspective on Why Socioeconomic Health Inequalities Are Persistent: Building the Case for an Effective Approach.

Despite policy intentions and many interventions aimed at reducing socioeconomic health inequalities in recent decades in the Netherlands and other affluent countries, these inequalities have not been reduced. Based on a narrative literature review, this paper aims to increase insight into why socioeconomic health inequalities are so persistent and build a way forward for improved approaches from a theoretical perspective. Firstly, we present relevant theories focusing on individual determinants of health-related behaviors. Thereafter, we present theories that take into account determinants of the individual level and the environmental level. Lastly, we show the complexity of the system of individual determinants, environmental determinants and behavior change for low socioeconomic position (SEP) groups and describe the next steps in developing and evaluating future effective approaches. These steps include systems thinking, a complex whole-system approach and participation of all stakeholders in system change.

Involving Children in Creating a Healthy Environment in Low Socioeconomic Position (SEP) Neighborhoods in The Netherlands: A Participatory Action Research (PAR) Project.

To ensure that health behavior interventions for children living in low socioeconomic position (SEP) neighborhoods are in line with children's wishes and needs, participation of the children in the development, implementation, and evaluation is crucial. In this paper, we show how children living in three low-SEP neighborhoods in the Netherlands can be involved in Participatory Action Research (PAR) by using the photovoice method, and what influences this research process. Observations, informal chats, semi-structured interviews, and focus group discussions with children and professionals were done to evaluate the research process. The photovoice method provided comprehensive information from the children's perspectives. With the help of the community workers, the children identified feasible actions. We found that it is important to constantly discuss the research process with participants, start with a concrete question or problem, and adapt the project to the local context and skills of participants.

GRPr Antagonist 68Ga-SB3 PET/CT Imaging of Primary Prostate Cancer in Therapy-Naïve Patients.

The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The 68Ga-labeled GRPr antagonist SB3 has shown excellent results in preclinical and clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68Ga-SB3 PET/CT imaging of primary PCa tumors and assess safety. More aims included an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression. Methods: Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before the study were matched. For dosimetry, residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose model, version 2.1. Results: Administration of 68Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 µg) was well tolerated; no significant changes in vital signs or laboratory results were observed. 68Ga-SB3 PET/CT showed lesions in 8 of 10 patients. Pathologic analysis revealed a total of 16 tumor lesions, of which PET/CT showed 14, resulting in a sensitivity of 88%. 68Ga-SB3 PET/CT imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor to PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, the level of GRPr expression showed a significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68Ga-labeled radiopeptides. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys. Conclusion:68Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.

Effectiveness of a school-based physical activity-related injury prevention program on risk behavior and neuromotor fitness a cluster randomized controlled trial.

BACKGROUND: To investigate the effects of a school-based physical activity-related injury prevention program, called 'iPlay', on risk behavior and neuromotor fitness. METHODS: In this cluster randomized controlled trial 40 primary schools throughout the Netherlands were randomly assigned in an intervention (n = 20) or control group (n = 20). The study includes 2,210 children aged 10-12 years.The iPlay-intervention takes one school year and consists of a teacher manual, informative newsletters and posters, a website, and simple exercises to be carried out during physical education classes.Outcomes measures were self-reported injury preventing behavior, self-reported behavioral determinants (knowledge, attitude, social-influence, self-efficacy, and intention), and neuromotor fitness. RESULTS: The iPlay-program was not able to significantly improve injury-preventing behavior. The program did significantly improve knowledge and attitude, two determinants of behavior. The effect of the intervention-program on behavior appeared to be significantly mediated by knowledge and attitude. Improved scores on attitude, social norm, self-efficacy and intention were significantly related to changes in injury preventing behavior. Furthermore, iPlay resulted in small non-significant improvements in neuromotor fitness in favor of the intervention group. CONCLUSION: This cluster randomized controlled trial showed that the iPlay-program did significantly improved behavioral determinants. However, this effect on knowledge and attitude was not strong enough to improve injury preventing behavior. Furthermore, the results confirm the hypothetical model that injury preventing behavior is determined by intention, attitude, social norm and self-efficacy. TRIAL NUMBER: ISRCTN78846684.

Key elements of a successful integrated community-based approach aimed at reducing socioeconomic health inequalities in the Netherlands: A qualitative study.

BACKGROUND: Since 2010, the Zwolle Healthy City approach, an integrated community-based approach, has been implemented in the Dutch municipality of Zwolle. This approach is proven successful in reducing health inequalities. However, the key elements of this approach are not clear. The current study aimed to identify key elements of this successful local community-based approach, according to the perspectives of various stakeholders. METHODS: Semi-structured interviews were carried out with 29 professionals who were involved in the approach in the period 2010-2018 and have occupations at the strategic (n = 4), tactical (n = 17) and operational level (n = 8). Data was analyzed using the thematic analysis approach. RESULTS: We identified nine perceived key elements that contributed to the success of the approach aimed at reducing socioeconomic health inequalities. The respondents indicated the following key elements: (1) collaboration between a variety of local organizations that want to have impact on the health of citizens; (2) support for the approach on the strategic, tactical and operational level of involved organizations; (3) proper communication and coordination, both for the network and within the organizations; (4) embeddedness in organizations' policies and processes and (5) collaboration with private organizations is of added value, although there is no "one size fits all". Other key elements are (6) collaboration with citizens, (7) profiling the approach like a brand and (8) moving along with and taking advantage of opportunities. Finally, (9) continuous monitoring and evaluating goals and processes, and learning from the results, is important. CONCLUSION: Nine key elements were identified that, according to various stakeholders, contributed to the success of the Zwolle Healthy City approach. These insights are important to further strengthen the Zwolle Healthy City approach but may also help and inspire other local integrated community-based approaches aimed at reducing socioeconomic health inequalities, to improve and adapt the approach within their specific local and dynamic context.

Test-retest reliability of the PRIME-MD: limitations in diagnosing mental disorders in primary care.

BACKGROUND: The primary care evaluation of mental disorders (PRIME-MD) can be seen as characteristic for successive refinements of criteria and structured interview techniques for diagnosing psychiatric disorders in primary care. It is one of the most widely used instruments, but there is no evidence to support its test-retest reliability. METHODS: With 1-week intervals between interviews, a test-retest study of the PRIME-MD was conducted in a general practice population of 100 distressed patients (20- to 60-years old) who were on sick leave. RESULTS: Almost everyone (89%) received one or more diagnoses at both measurements, and there was fair total agreement (kappa = 0.27). The best agreement was found for more severe threshold disorders [major depressive disorder (kappa = 0.58), dysthymia (kappa = 0.57), and generalized anxiety disorder (kappa = 0.59)], while we found indefinite results for the sub-threshold disorders [anxiety disorder not otherwise specified (NOS) (kappa =.30), minor depressive disorder (kappa = -0.03), and somatoform disorder NOS (kappa = 0.11)]. CONCLUSION: The PRIME-MD is one of the few instruments in primary care that actually diagnoses specific mental disorders according to the DSM criteria. However, there was a failure to adequately classify sub-threshold disorders. Mental disorders, as seen in primary care, encompass important specific symptoms and clinical syndromes that vary in duration and severity over time, but they also encompass an admixture of somatic and psychological symptoms that do not match current diagnostic systems. This most likely resulted in methodological uncertainty about the level of agreement. Diagnostic criteria in psychiatry need to be operationalized for use in primary care and require further evaluation.

Fetal fraction evaluation in non-invasive prenatal screening (NIPS).

An important factor in quality control of non-invasive prenatal screening (NIPS) or testing (NIPT) is a sufficient percentage of fetal DNA to avoid false-negative results. Here we evaluate 14,379 shallow whole-genome sequenced diagnostic NIPS samples, as well as negative controls, for both technical and biological factors that can influence fetal fraction and its assessment. Technically, bioinformatics analyses can have a profound impact on fetal fraction determination. We found best performance for fetal fraction determination with the Y chromosome based tool DEFRAG for male fetuses and the count based tool SeqFF for female fetuses. Biologically, gestational age of up to 21 weeks and maternal age had no influence on fetal fraction, while an increase in weight and BMI had a negative influence on fetal fraction. While a trend was observed, no statistically significant difference in fetal fraction was found between trisomy and normal samples. Overall, these results confirm the influence of biological factors and give insight into technical factors that can affect fetal fractions in NIPS.

Towards a continuum of care concerning chemsex issues.

In response to the apparent rise in chemsex in the Netherlands Mainline Foundation interviewed 27 MSM about their crystal meth use and/or experience with injecting in a sexual context. These men were interviewed about their motivation for methamphetamine use, their sexual risk-taking behaviour, methods and context of their drug use, and their information- and care needs. In 2015 this resulted in the status report Tina and Slamming: MSM, Crystal Meth Use and Intravenous Drug Use in a Sexual Context. Following the publication of this report Mainline foundation has been offering harm-reduction intervention for MSM and promoting the development of a continuum of care by building networks, training professionals and investing in advocacy. In our view, a continuum of care means the availability of a sufficient level of qualitative and effective preventive interventions, harm reduction services and treatment facilities that are connected, can track and intervene in the 'lifecycle' of individual drug use, and are easily accessible by the target group. This case study describes the various interventions of Mainline foundation, that make up their continuum of care approach concerning chemsex issues.

In Vivo Stabilized SB3, an Attractive GRPR Antagonist, for Pre- and Intra-Operative Imaging for Prostate Cancer.

PURPOSE: The gastrin-releasing peptide receptor (GRPR), overexpressed on various tumor types, is an attractive target for receptor-mediated imaging and therapy. Another interesting approach would be the use of GRPR radioligands for pre-operative imaging and subsequent radio-guided surgery, with the goal to improve surgical outcome. GRPR radioligands were successfully implemented in clinical studies, especially Sarabesin 3 (SB3) is an appealing GRPR antagonist with high receptor affinity. Gallium-68 labeled SB3 has good in vivo stability, after labeling with Indium-111; however, the molecule shows poor in vivo stability, which negatively impacts tumor-targeting capacity. A novel approach to increase in vivo stability of radiopeptides is by co-administration of the neutral endopeptidase (NEP) inhibitor, phosphoramidon (PA). We studied in vivo stability and biodistribution of [111In]SB3 without/with (-/+) PA in mice. Furthermore, SPECT/MRI on a novel, state-of-the-art platform was performed. PROCEDURES: GRPR affinity of SB3 was determined on PC295 xenograft sections using [125I]Tyr4-bombesin with tracer only or with increasing concentrations of SB3. For in vivo stability, mice were injected with 200/2000 pmol [111In]SB3 -/+ 300 µg PA. Blood was collected and analyzed. Biodistribution and SPECT/MRI studies were performed at 1, 4, and 24 h postinjection (p.i.) of 2.5 MBq/200 pmol or 25 MBq/200 pmol [111In]SB3 -/+ 300 µg PA in PC-3-xenografted mice. RESULTS: SB3 showed high affinity for GRPR (IC50 3.5 nM). Co-administration of PA resulted in twice higher intact peptide in vivo vs [111In]SB3 alone. Biodistribution studies at 1, 4, and 24 h p.i. show higher tumor uptake values with PA co-administration (19.7 ± 3.5 vs 10.2 ± 1.5, 17.6 ± 5.1 vs 8.3 ± 1.1, 6.5 ± 3.3 vs 3.1 ± 1.9 % ID/g tissue (P < 0.0001)). Tumor imaging with SPECT/MRI clearly improved after co-injection of PA. CONCLUSIONS: Co-administration of PA increased in vivo tumor targeting capacity of [111In]SB3, making this an attractive combination for GRPR-targeted tumor imaging.