The European Network for Health Technology Assessment (EUnetHTA) Joint Action 3 (JA3) aimed to develop a sustainable European model for scientific and technical collaboration on HTA. It succeeded EUnetHTA JA2, which focused on strengthening practical applications of approaches and tools in the European HTA collaboration. Compared to JA2, several changes in procedures and processes were undertaken throughout JA3 in order to improve the different steps in joint HTA production.

Findings and identified challenges regarding the assessment production processes from JA2 were considered as a basis. In JA3, vast majority of structured and informal feedback was gathered from the assessment teams and project managers via feedback surveys and meetings. Only limited informal feedback from stakeholders (such as patients, health care professionals, and health technology developers) that were involved in EUnetHTA assessments was collected. To this end, experiences were documented and recommendations for a future production process were developed.

During the course of JA3, the joint production resulted in 16 pharmaceutical assessments and 27 assessments of other technologies. The latter included medical devices, diagnostics, interventions, and screening. Due to the different context of pharmaceuticals and other technologies, some technology-specific changes needed to be made in their production process. However, the majority of implemented changes were made for both types of technologies to ensure maximum possible alignment in processes. The implemented changes affected several steps in the production process as well as the involvement of stakeholders in EUnetHTA assessments. The production and related project management of assessments was fine-tuned and resulted in clearer, standardized, and comprehensible processes that facilitated transparency and inclusiveness.

The procedural changes led to further standardization and elaboration of assessment production processes in preparation for a future European HTA system under the EU HTA Regulation. However, some methodological challenges remained to be tackled further in the currently ongoing EUnetHTA 21 service contract.

The objective of the European Network for Health Technology Assessment (EUnetHTA) Joint Action 3 (JA3) was to develop a sustainable European model for future collaboration on HTA, by reducing duplication in HTA production and increasing patient access to health technologies. Compared to the previous JA2, several procedural changes were made aiming to increase usability, transparency, and inclusiveness of relative effectiveness assessments (REAs). This article presents and highlights these changes, explains their rationale as well as their influence on HTA production.

Feedback from REA teams and project managers was collected. At the end of JA3, all lessons learned were mapped, resulting in a set of recommendations for a future REA production process.

In JA3, forty-three EUnetHTA REAs have been produced. Efforts to increase the usability of the REAs were made by focussing on the needs of REA producers and users (HTA agencies) and by increasing stakeholder involvement. Huge steps were taken with regard to transparency, which was achieved through publication of guidances, templates, and up-to-date information on the EUnetHTA website. In an attempt to improve inclusiveness, (stakeholder) interaction and involvement as well as feedback procedures were enhanced and streamlined. The fine-tuned project management brought all aspects together and facilitated a consistent and reliable workflow.

Despite that HTA agencies have different national requirements, the procedural changes made in JA3 proved to counteract some of these challenges. Nevertheless, it is of utmost importance that further perceived methodological differences are being resolved to ensure a strong base for future European collaboration on REA production.

Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population.

Analyses were based on the data of 2956 participants (aged 30–95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models.

Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task.

There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

The European Network for Health Technology Assessment (EUnetHTA) was established in 2006 and comprises over eighty organizations from thirty European countries. In its fifth project phase (Joint Action 3), EUnetHTA set up a quality management system (QMS) to improve the efficiency and standardization of joint work. This article presents EUnetHTA's new QMS and outlines experiences and challenges during its implementation.

Several working groups defined processes and methods to support assessment teams in creating high-quality assessment reports. Existing guidelines, templates, and tools were refined and missing parts were newly created and integrated into the new QMS framework. EUnetHTA has contributed to Health Technology Assessment (HTA) capacity building through training and knowledge sharing. Continuous evaluation helped to identify gaps and shortcomings in processes and structures.

Based on a common quality management concept and defined development and revision procedures, twenty-seven partner organizations jointly developed and maintained around forty standard operating procedures and other components of the QMS. All outputs were incorporated into a web-based platform, the EUnetHTA Companion Guide, which was launched in May 2018. Concerted efforts of working groups were required to ensure consistency and avoid duplication.

With the establishment of a QMS for jointly produced assessment reports, EUnetHTA has taken a significant step toward a sustainable model for scientific and technical collaboration within European HTA. However, the definition of processes and methods meeting the numerous requirements of healthcare systems across Europe remains an ongoing and challenging task.

To estimate dietary fluoride intake (F) over the course of pregnancy and the overall adjusted difference in dietary F intake by pregnancy stages and levels of compliance with dietary recommendations.

Secondary data analysis from a longitudinal pregnancy cohort study in a population exposed to fluoridated salt. Women were followed during the early, middle and late stages of their pregnancy (n 568). The dietary intake of recommended prenatal nutrients according to Mexican dietary guidelines and F intake (mg/d) was estimated with a validated FFQ. Data were summarised with descriptive statistics. Levels of F intake were compared with the USA’s Institute of Medicine adequate intake (AI) of 3 mg/d for pregnancy. Adjusted differences in F intake by pregnancy stages and levels of compliance with recommendations were estimated using random effects models.

Mexico City.

Women participating in the Early Life Exposures in Mexico to ENvironmental Toxicants (ELEMENT) project, from 2001 to 2003.

Median dietary F intake throughout pregnancy ranged from 0·64 (interquartile range (IQR) 0·38) in the early to 0·70 (IQR 0·42) in the middle, and 0·72 (IQR 0·44) mg/d in the late stage (0·01 mg F/kg per d). Corresponding adjusted intakes of F were 0·72 (95 % CI 0·70, 0·74), 0·76 (95 % CI 0·74, 0·77) and 0·80 (95 % CI 0·78, 0·82) mg/d. Women who were moderately and highly compliant with Mexican dietary recommendations ingested, on average, 0·04 and 0·14 mg F/d more than non-compliant women (P < 0·005).

Dietary F intake was below current AI, was greater with the progression of pregnancy and in women who were moderately and highly compliant with dietary recommendations.

Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood.

We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors.

We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy.

This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).

Subclinical psychotic-like experiences (PLE), resembling key symptoms of psychotic disorders, are common throughout the general population and possibly associated with psychosis risk. There is evidence that such symptoms are also associated with structural brain changes.

In 672 healthy individuals, we assessed PLE and associated distress with the symptom-checklist-90R (SCL-90R) scales ‘schizotypal signs’ (STS) and ‘schizophrenia nuclear symptoms’ (SNS) and analysed associations with voxel- and surfaced-based brain structural parameters derived from structural magnetic resonance imaging at 3 T with CAT12.

For SNS, we found a positive correlation with the volume in the left superior parietal lobule and the precuneus, and a negative correlation with the volume in the right inferior temporal gyrus [p < 0.05 cluster-level Family Wise Error (FWE-corrected]. For STS, we found a negative correlation with the volume of the left and right precentral gyrus (p < 0.05 cluster-level FWE-corrected). Surface-based analyses did not detect any significant clusters with the chosen statistical threshold of p < 0.05. However, in exploratory analyses (p < 0.001, uncorrected), we found a positive correlation of SNS with gyrification in the left insula and rostral middle frontal gyrus and of STS with the left precuneus and insula, as well as a negative correlation of STS with gyrification in the left temporal pole.

Our results show that brain structures in areas implicated in schizophrenia are also related to PLE and its associated distress in healthy individuals. This pattern supports a dimensional model of the neural correlates of symptoms of the psychotic spectrum.

Altered neurocognitive function in schizophrenia could reflect both genetic and illness-specific effects.

To use functional magnetic resonance imaging to discriminate between the influences of the genetic risk for schizophrenia and environmental factors on the neural substrate of verbal fluency, a candidate schizophrenia endophenotype using a case control twin design.

We studied 23 monozygotic twin pairs: 13 pairs discordant for schizophrenia and 10 pairs of healthy volunteer twins. Groups were matched for age, gender, handedness, level of education, parental socio-economic status, and ethnicity. Behavioural performance and regional brain activation during a phonological verbal fluency task were assessed.

Relative to healthy control twins, both patients and their non-psychotic co-twins produced fewer correct responses and showed less activation in the medial temporal region and inferior frontal gyrus. Twins with schizophrenia showed greater activation than both their non-psychotic co-twins and controls in right lateral temporal cortex, reflecting reduced deactivation during word generation while their non-psychotic co-twins showed greater activation in the left temporal cortex.

Both genetic vulnerability to schizophrenia and schizophrenia were associated with impaired verbal fluency performance, reduced engagement of the medial temporal region and dorsal inferior frontal gyrus. Schizophrenia was specifically associated with an additional reduction in deactivation in the right temporal cortex.

Alterations in gray matter volume (GMV) are a robust feature of schizophrenia. However, it is not clear to what extent these abnormalities are correlates of the genetic liability to the disorder, as opposed to environmental factors and the disorder itself.

We investigated the influence of genetic risk and illness on GMV in monozygotic (MZ) twin pairs concordant and discordant for schizophrenia.

Total and regional GMVs were measured from magnetic resonance images of 80 twins: 14 MZ pairs concordant for schizophrenia, 9 pairs discordant for schizophrenia, and 17 healthy MZ twin pairs. The three groups were matched for age, gender, handedness, level of education, parental socioeconomic status, and ethnicity.

Total GMV was smaller in twins with schizophrenia (t=-3.17, p= 0.003) and non-psychotic co-twins from discordant pairs (t=-2.66, p= 0.011) than in healthy control twins. Twin pairs concordant for schizophrenia displayed reduced regional GMV in the inferior frontal, medial frontal, and anterior cingulate gyri, the caudate, lingual gyrus and cerebellum relative to healthy twins (p< 0.05, corrected). Within discordant pairs, twins with schizophrenia had less GMV than their non-psychotic co-twins in the insula, superior/medial frontal, pre/postcentral, cingulate and superior temporal gyri, and the paracentral lobule. There were no significant differences in regional GMV between non-psychotic co-twins and healthy controls.

The presence of schizophrenia was specifically related to reduced GMV in frontal, insular, cingulate, medial parietal and temporal cortex, over and above effects of genetic risk for the disorder.