INTRODUCTION:Pharmacological treatment is the mainstay in the acute and long-term management of severe mental disorders such as major depressive disorder, schizophrenia, and bipolar disorder. However, there is large interindividual variability in clinical response, with around one-third of patients presenting treatment-resistance. AREAS COVERED:This review provides a comprehensive overview of genes that modulate the efficacy or safety of antidepressants, antipsychotics, or mood stabilizers based on a high or moderate level of evidence and for which clinical recommendations are available. Next, we highlight novel methodological and analytical approaches such as polygenic scores, pleiotropic analysis and the analysis of multiomic data with machine learning methods that might allow to explain a larger proportion of genetically driven interindividual variability in clinical response to psychotropic medications. EXPERT OPINION:To date, a high level of evidence is only available for metabolizer phenotypes of a limited number of pharmacokinetic genes for antidepressants and antipsychotics (CYP2D6, CYP2C19, and CYP2B6), and selected HLA alleles for the mood stabilizer carbamazepine. However, transdiagnostic polygenic scores as well as machine learning models based on the integration of clinical determinants with multiomic data represent a promising strategy to move us closer to precision psychiatry.

Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group’s (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the guidelines effectively dissuade the use of non-randomized comparisons in rare or rapidly evolving indications and may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies.

This paper summarizes an analysis of the Joint Clinical Assessment (JCA) subgroup’s recommendations for systematic literature reviews (SLRs). While the JCA offers clear guidance on study classification, exclusion criteria reporting, and PRISMA diagram use, several of its recommendations diverge from established best practices in evidence-based medicine (EBM). A comparison with recognized guidelines, such as those from Cochrane and EUnetHTA, reveals that the JCA guidance may lack reliability, comprehensiveness, and reproducibility. Aligning JCA recommendations with gold standards in SLR methodology—would address these shortcomings and enhance methodological rigor.

BACKGROUND:The objective of this work was to support the implementation of the European Health Technology Assessment Regulation (EU HTAR) and optimize performance of the evolving EU HTA system. Therefore, an inclusive multi-stakeholder framework of key performance indicators (KPI) for success measurement was developed. METHODS:A modified Delphi-procedure was applied as follows: (1) development of a generic KPI pool at the Fall Convention 2024 of the European Access Academy (EAA); (2) review of initial pool and identification of additional KPIs; (3) development of prioritized KPIs covering patient, clinician, Health Technology Developer (HTD), and System/Member State (MS) perspectives, and (4) consolidation of the stakeholder-centric KPIs after EAA's Spring Convention 2025. RESULTS:Steps 1 and 2 of the Delphi procedure revealed 14 generic KPI domains. Steps 3 and 4 resulted in four prioritized KPIs for patients (patient input; utilization of patient-centric outcome measures; time to access; equity); six for clinicians (population/intervention/comparator/outcomes (PICO); addressing uncertainty; clinician involvement; transparency; equity and time to access); four for HTDs (PICO; joint scientific consultation (JSC) process; joint clinical assessment (JCA) process; time to national decision making); five from a system/MS perspective (PICO; learning and training the health system; reducing duplication; equity and time to access). The scope of, e.g., the PICO-related KPI, differed between stakeholder groups. Also, several KPIs intentionally reached beyond the remit of EU HTA as they are also dependent on MS-specific factors including national health systems and budgets. DISCUSSION AND CONCLUSIONS:The KPI framework developed here presents a step towards the generation of systematic multi-stakeholder evidence to support a successful implementation of the EU HTAR. The relevance of the identified stakeholder-centric KPIs is confirmed by their alignment with the Health System Goals suggested in the context of "Performance measurement for health improvement" by the World Health Organisation. Implementation of the framework, i.e., measurement of KPIs, is envisioned to provide evidence to inform the 2028 revision of the EU HTAR.

Background: The EU Health Technology Assessment Regulation (EU-HTA R), effective January 2025, mandates Joint Clinical Assessments (JCAs) to harmonize HTA across Member States. However, its implementation raises fundamental questions about methodological coherence, institutional capacity, and epistemological alignment. Objectives: This manuscript (1) systematically assesses whether the stated strategic and operational objectives of the EU-HTA R are achievable under current implementation conditions; (2) examines the implications for EU institutional legitimacy if these objectives are not met; and (3) proposes an epistemological framework as a prerequisite for developing a coherent joint HTA methodology. Methods: We conducted a critical policy analysis of the EU-HTA R, its implementing guidance documents, and published templates, supplemented by a comparative review of Member State HTA methodologies and their underlying philosophical foundations. Results: The analysis reveals that the EU-HTA R is unlikely to achieve its strategic goals under current conditions. Key findings include: guidance documents of substandard methodological quality; a restricted assessment scope that excludes scientific judgement and contextualization; insufficient resources and additional workload for national HTA bodies without reducing existing obligations; unresolved epistemological divergences among Member States spanning Bayesian vs. frequentist approaches, Fisher vs. Neyman-Pearson frameworks, and utilitarian vs. deontological ethical foundations; and procedural shortcomings in stakeholder consultation and expert involvement. These shortcomings risk undermining the epistemic authority and legitimacy of EU institutions. Conclusions: Prior epistemological and normative alignment across Member States is a prerequisite for any robust shared HTA methodology. Revisions to the EU-HTA R and comprehensive updates of guidance documents are necessary, with concrete safeguards-including independent peer review, identified authorship, and adequate resourcing-to ensure substantive rather than merely nominal implementation. A phased roadmap is proposed: establishing clear objectives, aligning epistemological foundations, developing institutional structures, and creating operationally consistent guidance.

Four years after the European Regulation on Health Technology Assessment (EU HTAR) came into force and a little over a year after the implementation phase of the Regulation started, with the publication of the first Joint Clinical Assessment (JCA) report imminent, it is good timing to take a step back and revisit what has been achieved and look at what the main challenges on the way forward are [...]

The practice of Health Technology Assessment (HTA) inherently involves moral, epistemological, and ontological commitments, which shape how assessments are conducted, interpreted, and used for decision-making [...]

Health Technology Assessment (HTA) is shaped by moral (what makes a health technology desirable or acceptable, e.g., beneficence, justice), epistemological (how reliable knowledge is obtained and validated, e.g., evidence standards, uncertainty handling), and ontological (what effects and outcomes are considered real and relevant for assessment) commitments. The EU Joint Clinical Assessment (JCA), intended to harmonize relative effectiveness evaluation, embeds these commitments implicitly rather than explicitly, creating transparency and consistency issues. Critical concerns include: rigid reliance on the PICO framework privileging RCTs and quantifiable outcomes, proliferation of PICOs leading to infeasible evidence requirements, inadequate handling of multiplicity and post-hoc analyses, conflation of certainty and uncertainty, and exclusion of qualitative evidence and stakeholder input. Guidance documents, criticized for methodological weaknesses (e.g., outdated tools, poor external validity assessment, nominal p-values acceptance), further undermine epistemic robustness. These structural flaws risk producing assessments that are non-inclusive, reductionist, and epistemologically inconsistent. Future EU HTA frameworks should explicitly align on foundational commitments and integrate stakeholder perspectives to ensure transparency, scientific credibility, and ethical legitimacy.

Parkinson's disease (PD) is a debilitating neurodegenerative synucleinopathy, characterized by dopaminergic degeneration, pathological deposition of alpha-synuclein (α-Syn), and neuroinflammation in both motor regions of the midbrain and non-motor areas of the cortex. Despite its motor-centric characterization, visual disturbances such as hallucinations, diplopia, altered contrast sensitivity and retinal abnormalities are well-documented non-motor changes of PD. While this evidence points to neuropathological processes in PD that extend beyond the brain, the neuropathological basis of retinal dysfunction and the role of α-Syn remain poorly investigated. Given the central neuropathological role of α-Syn in the PD brain, we assessed whether the retina is affected in a translational rat model of PD based on the intranigral bilateral infusion of toxic oligomers of human α-Synuclein (H-α-SynOs). Rats were stereotaxically injected with H-α-SynOs or PBS (Vehicle) into the substantia nigra pars compacta (SNpc) and sacrificed 3 months post-infusion. Thereafter, several retinal tissue pathological parameters, along with the expression patterns of selected miRNAs and inflammatory markers, were assessed. The retina of rats infused with H-α-SynOs exhibited high levels of phosphorylated-α-Syn (p-α-Syn), along with a significant decrease of tyrosine hydroxylase (TH) expression, reflecting dopaminergic neuron disfunction. Analysis of PD-associated miRNAs in the retina also revealed heightened levels of miR-384-5p, which inversely correlated with the expression of its predicted molecular target, SIRT1, in rats infused with H-α-SynOs. Consistently, H-α-SynOs infusion induced a widespread activation of retinal astrocytes and microglial markers, associated with a heightened proinflammatory cytokine signaling downstream of TLR4/NFκB. Collectively, our data reveal that H-α-SynOs extend their neuropathological effects to retinal damage, reinforcing our rodent model ability to recapitulate PD pathology in both brain and retina. This study underscores the robustness of this preclinical model and its value as translational system for testing proactive interventions targeting PD-related pathology.

Alzheimer’s disease (AD) is the most common cause of dementia worldwide, characterized by accumulation of amyloid-β protein and hyperphosphorylated tau protein in the brain. Neuroinflammation, resulting from chronic activation of brain-resident innate immune cells as well as enhanced peripheral leukocyte access across the blood–brain barrier, crucially affects AD progression. In this context, TNFSF10, a cytokine substantially expressed in the AD brain, has been shown to modulate both the innate and the adaptive branches of the immune response in AD-related neuroinflammation. In this study, we explored whether a TNFSF10-neutralizing treatment could represent a tool to re-balance the overall overshooting inflammatory response in a mouse model of AD. Specifically, 3xTg-AD mice were treated sub-chronically with an anti-TNFSF10 monoclonal antibody for three months, and were then sacrificed at 15 months. TNFSF10 neutralization reduced the expression of the inflammatory marker CD86, inversely related to levels of the anti-inflammatory marker CD206 in the brain of 3xTg-AD mice, suggesting a switch of microglia towards a neuroprotective phenotype. Similar results were observed in the splenic macrophage population. Moreover, flow cytometry revealed a significant decrease of CD4+CD25+FOXP3+ T regulatory cells as well as reduced number of CD11b+LY6Chigh proinflammatory monocytes in both the brain and the spleen of 3xTg-AD mice treated with anti-TNFSF10 monoclonal antibody. Finally, the treatment resulted in lower count of splenic CD4+ and CD8+ T cells expressing PD1. The data suggest that TNFSF10 system-targeted treatment effectively restrain overshooting central and peripheral inflammation by rebalancing the overall immune response, mitigating the progression of AD pathology.

The World Health Organization (WHO) ranks tuberculosis (TB) as one of the top 10 causes of deaths worldwide. Notably, tobacco smoking represents a significant promoting factor in TB progression, being associated with poorer treatment outcomes, delayed conversion to negative smear or culture, and higher dropout rates from treatment plans. Remarkably, high rates of smoking and TB frequently overlaps in the same countries, warranting the need for targeted public health interventions. Prioritising smoking cessation is essential for smokers with TB, as sustained abstinence has been associated with reduced mortality and a more successful cure. This review examines the intricate relationship between cigarette smoking, smoking cessation therapies and anti-TB drugs, focusing on the impact of tobacco smoking compounds on liver detoxifying systems, such as influence of polycyclic aromatic hydrocarbons (PAHs) on hepatic cytochrome P450 (CYP450) enzymes mostly, and on metabolism of antituberculous medications. Integrating smoking cessation and TB treatment programmes must also take into account potential drug-drug interactions between smoking cessation medications and anti-TB drugs, a critical area for patient safety and effective TB management. This review article aims to provide healthcare professionals with the knowledge to better support TB patients who smoke or are intending to quit, to ensure tailored and effective treatment strategies, while highlighting gaps in current research and advocating for further studies to fill these gaps.

Background: We examined four potential challenges for the implementation of the European Union (EU) Regulation 2021/2282 on Health Technology Assessment (EU HTAR): interaction with the European Medicines Agency (EMA), expert input, the interface of European health technology assessment (EU HTA) joint procedures with those within Member States, and the management of conflict of interest. This research aims to explore how to address these challenges in a balanced manner and prioritise key actions for effective collaboration in the context of the EU HTA. Methods: The methodology included a pre-convention survey among relevant stakeholders as well as working groups and the plenary ranking of discussion outcomes at the European Access Academy (EAA) Spring Convention 2024. Results: In the survey, 65.5% of respondents indicated that experts are currently not sufficiently included in the upcoming joint scientific consultations and clinical assessments; only 37.9% suggested that the EU HTA joint procedures would accelerate national appraisal decision-making, and 58.6% believed that the principles of ‘transparency’ and ‘competency’ are balanced in the EU HTA position on conflict of interest. The top priority action points identified in the working groups were the involvement of the best available expertise, the early and inclusive involvement of experts, strengthened early scientific dialogue, and the fostering of the political willingness/financial support of EU Member States to increase capacities. Conclusions: The key topics identified were an approach to conflict of interest that balances transparency obligations and the need for expertise, strengthens the involvement of clinical and patient experts, intensifies early interaction between the EMA and EU HTA, and increases the involvement of the EU Member States.

Background: This work aimed to determine the role and action points for the involvement of medical societies in the European Health Technology Assessment (EU HTA) Methods: An online pre-convention survey was developed addressing four areas related to the EU HTA: (i) medical societies’ role; (ii) role of clinical guidelines; (iii) interface with the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS); and (iv) approaching ‘best-available evidence’ (BAE). A descriptive analysis of questionnaire outcomes was conducted to inform the European Access Academy (EAA) Fall Convention 2023. Within the working groups (WGs), action points were identified and prioritised. Results: A total of 57 experts from 15 countries responded to the survey. The WGs were attended by (i) 11, (ii) 10, (iii) 12, and (iv) 12 experts, respectively, representing a variety of national backgrounds and stakeholder profiles. The most relevant action points identified were as follows: (i) incorporation of clinical context into population, intervention, comparator, outcomes (PICO) schemes, (ii) timely provision of up-to-date therapeutic guidelines, (iii) ensuring the inclusion of MCBS insights into the EU HTA process, and (iv) considering randomized controlled trials (RCTs) as the gold standard and leveraging regulatory insights if development programs only include single-arm trials. Conclusions: The involvement of medical societies is a critical success factor for the EU HTA. The identified key action points foster the involvement of patient associations and medical societies.

Wilson’s disease (WD) is a biallelic disease-causing variant in the ATP7B gene on chromosome 13q14.3 that results in copper accumulation in many organs, particularly the liver and brain. The phenotypic spectrum is wide and symptoms at onset can be heterogeneous. We describe two Sicilian siblings, a young man and his elder sister, both compound heterozygous for the variants c.1286-2A>G and c.2668G>A (p.Val890Met) in the ATB7B gene. The male patient presented with liver cirrhosis, which quickly progressed to end-stage liver disease (Child–Pugh score = C10), while his sister had moderate steatotic liver disease (SLD). Our findings highlight that SLD may not always be related to obesity in overweight patients, especially when there are other potential risk factors such as a family history of chronic liver disease, or the persistence of high transaminase despite the adoption of adequate dietary and pharmacological intervention. Screening for conditions such as WD could identify patients at risk of developing SLD and avoid delays in diagnosis. Phenotypic variability in WD is considerable; therefore, further studies are needed to identify which WD patients have a greater risk of developing SLD and determine factors that can predict the severity of the disease.

Cigarette smoking addiction is a leading cause of morbidity and mortality and presents a challenging interventional target. Interventions for stopping smoking offer trade-offs in ability to displace or blunt the effects of cigarettes, which include positive and negative reinforcement, psychological reward, aversiveness, and sensory enjoyment, and which are mediated through nicotine and non-nicotine elements of smoking. Established therapies, which include nicotine replacement therapies (NRTs), varenicline, and bupropion are being supplemented with a growing evidence base for cytisine and nicotine substitution products, with more rapid acting NRTs on the horizon, all of which are expanding individual choice. An understanding of determinants of efficacy can inform a personalized and adaptive approach to smoking cessation, which presents an opportunity to further improve outcomes. This includes tailoring cessation treatment plans based on initial individual response, preference, and tolerability to first line interventions and considering second-line options (including evidence-based combination therapies) when needed. Video Abstract

BackgroundN-acetyl cysteine (NAC) appears promising as a treatment in patients with substance use disorder (SUD) as it helps rebalance glutamate levels in the central nervous system (CNS). Basal concentrations of glutamate are indeed reduced in SUD patients but increased during craving.Materials and MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether NAC reduce craving rating as compared to a placebo in SUD patients. Secondary outcomes were withdrawal symptoms (WS), side effects (SE) and drop-outs. Estimates are presented as standardized mean differences (SMD) or risk ratio (RR) with 95% confidence interval (CI).ResultsEleven RCTs were included. NAC reduced craving rating (SMD -0.61 (−1.17, −0.06), p = 0.03, I2 = 85%), with no differences in the subgroup analysis according to the drug addiction (alcohol, cocaine, poly-drugs, amphetamine, nicotine) (p = 0.98). Among the secondary outcomes, for WS data showed no significant difference between groups (SMD -0.18 (−0.43, 0.08), p = 0.17); for SE no substantial difference was observed between the two treatment groups (RR = 1.06 (0.89–1.27), p = 0.52, I2 = 0%); for dropouts the results are in favor of the placebo but no statistically significant (RR 1.17 (0.85, 1.61), p = 0.34; I2 = 0%).ConclusionNAC seem to reduce craving rating in SUD patients, but evidence is weak. More studies are needed to confirm this finding.

Alzheimer’s disease (AD), marked by cognitive impairment, predominantly affects the brain regions regulated by cholinergic innervation, such as the cerebral cortex and hippocampus. Cholinergic dysfunction, a key contributor to age-related cognitive decline, has spurred investigations into potential therapeutic interventions. We have previously shown that choline alphoscerate (α-GPC), a cholinergic neurotransmission-enhancing agent, protects from Aβ-mediated neurotoxicity. Herein, we investigated the effects of α-GPC on the microglial phenotype in response to Aβ via modulation of the nicotinic alpha-7 acetylcholine receptor (α7 nAChR). BV2 microglial cells were pre-treated for 1 h with α-GPC and were treated for 24, 48, and 72 h with Aβ1–42 and/or α-BTX, a selective α7nAchR antagonist. Fluorescent immunocytochemistry and Western blot analysis showed that α-GPC was able to antagonize Aβ-induced inflammatory effects. Of note, α-GPC exerted its anti-inflammatory effect by directly activating the α7nAChR receptor, as suggested by the induction of an increase in [Ca2+]i and Ach-like currents. Considering that cholinergic transmission appears crucial in regulating the inflammatory profiles of glial cells, its modulation emerges as a potential pharmaco-therapeutic target to improve outcomes in inflammatory neurodegenerative disorders, such as AD.

Acinetobacter baumannii represents a significant concern in nosocomial settings, particularly in critically ill patients who are forced to remain in hospital for extended periods. The challenge of managing and preventing this organism is further compounded by its increasing ability to develop resistance due to its extraordinary genomic plasticity, particularly in response to adverse environmental conditions. Its recognition as a significant public health risk has provided a significant impetus for the identification of new therapeutic approaches and infection control strategies. Indeed, currently used antimicrobial agents are gradually losing their efficacy, neutralized by newer and newer mechanisms of bacterial resistance, especially to carbapenem antibiotics. A deep understanding of the underlying molecular mechanisms is urgently needed to shed light on the properties that allow A. baumannii enormous resilience against standard therapies. Among the most promising alternatives under investigation are the combination sulbactam/durlobactam, cefepime/zidebactam, imipenem/funobactam, xeruborbactam, and the newest molecules such as novel polymyxins or zosurabalpin. Furthermore, the potential of phage therapy, as well as deep learning and artificial intelligence, offer a complementary approach that could be particularly useful in cases where traditional strategies fail. The fight against A. baumannii is not confined to the microcosm of microbiological research or hospital wards; instead, it is a broader public health dilemma that demands a coordinated, global response.

IntroductionTo summarize insights generated during the preceding four conventions of the European Access Academy (EAA) regarding the interface of patient organizations and medical societies with the evolving European Union (EU) health technology assessment (HTA) process.MethodsIn 2022 and 2023 four EAA conventions were held on the EU HTA regulation, focusing on: (i) its relevance for beating cancer; (ii) stakeholder involvement; (iii) recommended preparatory steps to ensure its successful implementation; and (iv) the role of hematology and oncology as a pacemaker for the EU HTA process. Here we summarize insights generated at the four EAA conventions about the integration of patient and clinician insights in the evolving EU HTA process, including joint scientific consultations (JSC) and joint clinical assessments (JCA).ResultsThroughout the conventions it became clear that the interface of patient associations and clinical societies with the EU HTA process is key for successful implementation of the regulation. All involved stakeholders rely on the principles of evidence-based medicine (EBM), including best internal and external evidence, patient values and expectations, and clinical experience. It was agreed that patient and clinician perspectives on the assessments are needed to balance the technical analysis of best external evidence. While patient input is rather well defined, when and how input from clinical societies is best incorporated during the process remains unclear.ConclusionsAs stipulated by the EBM triad, systematic involvement of patients and clinicians throughout both JSC and JCA is key to ensuring best outcomes for patients and society as a whole, in line with the objectives of the EU HTA regulation.