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The European Joint Programme on Rare Diseases (EJP RD) represents a significant step forward in the rare diseases research ecosystem, integrating over 130 institutions from 35 countries. It focuses on streamlining the process from basic research to clinical application, fostering collaboration at an international scale, and emphasizing patient engagement. The initiative has funded numerous projects across various medical domains, developed the Rare Diseases Virtual Platform, and significantly impacted the rare disease landscape through training, project mentoring, and innovative methodology developments. Expanding beyond, EJP RD collaborates with various initiatives to optimize resource use and is evolving into the European Rare Diseases Research Alliance, aiming to accelerate diagnostics, develop innovative therapies, and assess the rare disease burden to inform policy decisions.

BackgroundTranscranial ultrasound stimulation (TUS) is a non-invasive brain stimulation technique; when skull aberrations are compensated for, this technique allows, with millimetric accuracy, circumvention of the invasive surgical procedure associated with deep brain stimulation (DBS) and the limited spatial specificity of transcranial magnetic stimulation. Objective/hypothesis: We hypothesize that MR-guided low-power TUS can induce a sustained decrease of tremor power in patients suffering from medically refractive essential tremor. MethodsThe dominant hand only was targeted, and two anatomical sites were sonicated in this exploratory study: the ventral intermediate nucleus of the thalamus (VIM) and the dentato-rubro-thalamic tract (DRT). Patients (N = 9) were equipped with MR-compatible accelerometers attached to their hands to monitor their tremor in real-time during TUS. ResultsVIM neurostimulations followed by a low-duty cycle (5 %) DRT stimulation induced a substantial decrease in the tremor power in four patients, with a minimum of 89.9 % reduction when compared with the baseline power a few minutes after the DRT stimulation. The only patient stimulated in the VIM only and with a low duty cycle (5 %) also experienced a sustained reduction of the tremor (up to 93.4 %). Four patients (N = 4) did not respond. The temperature at target was 37.2 ± 1.4 °C compared to 36.8 ± 1.4 °C for a 3 cm away control point. ConclusionsMR-guided low power TUS can induce a substantial and sustained decrease of tremor power. Follow-up studies need to be conducted to reproduce the effect and better to understand the variability of the response amongst patients. MR thermometry during neurostimulations showed no significant thermal rise, supporting a mechanical effect.

BackgroundFew studies include a sufficient number of people to be representative of a general population and to estimate the musculoskeletal pain prevalence.ObjectivesTo estimate the prevalence of musculoskeletal and widespread pain in the French popualtion using a large and representative cohort.MethodsThe Constances cohort is composed of volunteers, aged 18 to 69 years at inclusion. Eligible subjects were selected at random by stratified sampling with unequal probabilities, over-representing individuals with a higher probability of not volunteering (according to their age, sex, socioprofessional category) with adjustment coefficients weight participation bias. Individuals diagnosed with a cancer were excluded. Musculoskeletal pain was assessed by the Nordic Questionnaire. Significant pain lasted at least 30 days during the last 12 months. Widespread pain concerned at least 4 of the 6 areas. Chronic moderate to severe pain reached a pain score ≥ 4/10 in the last 7 days. Data from the entire cohort were described and then the French population prevalence was estimated, based on people included in 2017 with adjustment coefficients.Results193,436 people were included in the cohort. The French population prevalence of each pain location and widespread pain were estimated among the 25,472 people included in 2017.Pain prevalence in the cohort (%)Moderate to severe pain prevalence in the cohort (%)Pain prevalence estimation in the french population (% [SD])Moderate to severe pain prevalence estimation in the french population (% [SD])Back24.616.025.9 [25.4-26.5]17.9 [17.4-18.4]Neck16.610.417.1 [16.7-17.6]11.2 [10.8-11.6]Shoulder16.39.417.0 [16.5-17.5]10.5 [10.1-10.8]Knee18.911.119.8 [19.3-20.2]12.4 [12-12.8]Hand14.07.714.7 [14.2-15.1]8.5 [8.2-8.8]Elbow8.54.39.2 [8.2-9.6]4.9 [4.7-5.2]Widespread pain7.03.8.1 [7.8-8.5]4.2 [4-4.5]ConclusionThe prevalence of musculoskeletal pain in the French population is high, particularly for chronic pain of moderate to severe intensity, which underlines the need to improve their detection, prevention and management.REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

Oligonucleotides are small nucleic acids capable of interacting with DNA or RNA to modulate gene expression. Widely used by researchers as research tools to modulate the expression of the genes they seek to decipher the function, oligonucleotides can also serve as therapeutic agents to regulate targets of interest. After the first marketing authorisation of an oligonucleotide therapeutics in 1998, the field met little clinical success until 2016 when Spinraza® became the first drug authorized for spinal muscular atrophy. This compound became in the following years the first "blockbuster" among this class of molecules, validating the commercial potential of oligonucleotide drugs. Since then, about ten other oligonucleotides hit the market and a broad pipeline is currently in late clinical development. Through our article, we describe therapeutic oligonucleotides, their modes of action and their patentability.

HIV-coinfected patients experience higher incidences of non-liver-related cancers than HCV-monoinfected patients. Chronic inflammation, immunosuppression, but also higher tobacco or alcohol consumption and metabolic dysregulation could explain this higher risk. We aimed to estimate the direct, indirect and total effects of HIV coinfection on the risk of non-liver-related cancers in HCV participants treated with direct-acting antivirals (DAAs). Up to four HCV-monoinfected participants from the ANRS CO22 HEPATHER cohort were matched by age and sex to HIV/HCV-coinfected participants from the ANRS CO13 HEPAVIH cohort. Participants were followed from DAA initiation until the occurrence of a non-liver-related cancer. Counterfactual mediation analysis was carried out to estimate the direct (chronic inflammation and immunosuppression), indirect (tobacco and alcohol consumption and metabolic syndrome) and total effect of HIV coinfection on the risk of non-liver-related cancers. 548 HIV/HCV-coinfected and 2016monoinfected participants were included. Overall, HIV coinfection was associated with a 3.7-fold [95% confidence interval (CI): 1.7-7.0] higher risk of non-liver-related cancers in HCV participants. This increased risk was explained by significant direct effect [hazard ratio (HR) = 3.4, 95% CI: 1.7-6.6] but not indirect effect (HR = 1.1, 95% CI: 0.8-1.5) of HIV coinfection. In HCV participants treated with DAAs, the direct effect of HIV coinfection, reflecting chronic inflammation and immunosuppression, was associated with a 3.7-fold higher risk of non-liver-related cancer. By contrast, the indirect effect of HIV coinfection, reflecting higher tobacco and alcohol consumption and metabolic dysregulation, was not significantly associated with the risk of non-liver-related cancers.

HIV-infected patients have lower bone mineral density and a higher incidence of fractures than the general population of the same age and sex. To assess the impact of antiretroviral (ARV) drugs exposure on the risk of osteoporotic fractures, we conducted a nested case-control study. Cases were individuals enrolled while ARV-naive, with a first prospectively recorded fracture between 2000 and 2010. Controls were randomly selected after matching for sex, age (±3 years), period of HIV diagnosis (<1997/≥1997), and clinical center. The risk of fracture was analyzed with conditional logistic regression models, using different ways to model ARV exposure. All exposure variables and potential confounders were included in multivariable models. Among 861 reviewed cases, 261 fractures were osteoporotic and 254 of cases were matched to at least one control (376 controls). The median year of fracture diagnosis was 2007 (interquartile range 2004-2009): 49% of patients had been exposed to tenofovir disoproxil fumarate (TDF) and 82% to protease inhibitors (PIs). After taking into account the transmission group, AIDS status, geographic origin, body mass index, current smoking status, alcohol consumption, exposure to systemic glucocorticoids, and the period of enrollment, there was no association between the risk of fracture and exposure to TDF [odds ratio for cumulative exposure: 1.04 (0.86-1.27), similar results for ever-exposed subjects], to nucleoside reverse transcriptase inhibitors, or to PIs [odds ratio for cumulative PI exposure: 1.02 (0.92-1.12)]. We found no evidence of an excess risk of fracture after exposure to TDF or PIs. This has important implications for the debate concerning tenofovir alafenamide versus generic TDF.