New Perspectives of Deep Brain Stimulation Indications for Parkinson's Disease: A Critical Review.

Deep Brain Stimulation (DBS) is an effective treatment option for patients with dopaminergic complications of Parkinson's disease (PD) and drug-refractory PD tremor. However, DBS and its indications can be challenging, and they are not often debated in the medical community. Through a critical narrative review, the objective of this paper is to improve the comprehension of DBS indications and help to solve the puzzle that this process can be. Proper patient selection is the first step for a good surgical outcome. In this review, then, relevant considerations are discussed, involving PD genes, PD phenotypes, indications of early stages, non-motor symptoms, neuroimaging predictors, comorbidities, and age. Individualized approaches are encouraged, including clinical and radiological factors. Social support during the whole follow-up and expectations alignment are necessary through this process and are also debated.

Influence of educational level on the prevalence of risk behaviors during the perinatal period. / Influencia del nivel de estudios en la prevalencia de conductas de riesgo durante el periodo perinatal.

The objective of this work was to assess changes during pregnancy and after childbirth in diet, consumption of tobacco, electronic cigarettes, cannabis, alcohol use and exposure to environmental tobacco smoke depending on the mother's educational level.A cross-sectional study was carried out whose target population was 18,822 Galician women aged 18-49 who gave birth between September 2015 and August 2016, and their 19,204 live-born children. A descriptive analysis was performed, and the prevalence of different behaviors was estimated at three time points - pre-pregnancy, pregnancy and after childbirth - depending on the mother's educational level. Percentages of change were calculated.Information was obtained from 6,436 women. Regardless of the educational level, during pregnancy there was an improvement in the different lifestyles. In the first months after childbirth, lifestyles worsened, except for exposure to environmental tobacco smoke and the use of electronic cigarettes. Most of the risk behaviors showed a gradient depending on the educational level; thus, the lower the educational level, the higher the prevalence of risk behaviors.In general, during pregnancy all women adopted healthier lifestyles that they abandoned in the months following childbirth. Women with a lower level of education showed a higher prevalence of risk behaviors, both in the period prior to pregnancy, as well as during pregnancy and after childbirth.

El objetivo de este trabajo fue valorar cambios durante el embarazo y tras el parto en la dieta, consumo de tabaco, cigarrillos electrónicos, alcohol, cannabis y exposición al humo ambiental de tabaco en función del nivel de estudios de la madre. Para ello, se llevó a cabo un estudio transversal cuya población objetivo fueron 18.822 mujeres gallegas de 18-49 años que dieron a luz entre septiembre 2015 y agosto 2016, y sus 19.204 hijos/as nacidos vivos. Se realizó un análisis descriptivo y se estimó la prevalencia de diferentes conductas en tres momentos temporales ­pre-embarazo, embarazo y tras el parto­ en función del nivel de estudios de la madre. Se calcularon los porcentajes de cambio. Se obtuvo información de 6.436 mujeres. Con independencia del nivel de estudios, durante el embarazo se produce una mejora en los diferentes estilos de vida. En los primeros meses tras el parto los estilos de vida empeoran, con excepción de la exposición al humo ambiental de tabaco y el consumo de cigarrillos electrónicos. La mayoría de las conductas de riesgo muestran un gradiente dependiente del nivel educativo; así, a menor nivel educativo, mayor es la prevalencia de conductas de riesgo. En general, durante el embarazo todas las mujeres adoptan estilos de vida más saludables que abandonan en los meses siguientes al parto. Las mujeres con menor nivel de estudios muestran una mayor prevalencia de conductas de riesgo, tanto en el periodo previo al embarazo, como en el embarazo y tras el parto.

Posterior insula repetitive transcranial magnetic stimulation for chronic pain in patients with Parkinson disease - pain type matters: A double-blinded randomized sham-controlled trial.

OBJECTIVES: Altered somatosensory processing in the posterior insula may play a role in chronic pain development and contribute to Parkinson disease (PD)-related pain. Posterior-superior insula (PSI) repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to have analgesic effects among patients with some chronic pain conditions. This study aimed at assessing the efficacy of PSI-rTMS for treating PD-related pain. METHODS: This was a double-blinded, randomized, sham-controlled, parallel-arm trial (NCT03504748). People with PD (PwP)-related chronic pain underwent five daily PSI-rTMS sessions for a week, followed by once weekly maintenance stimulations for seven weeks. rTMS was delivered at 10 Hz and 80% of the resting motor threshold. The primary outcome was a ≥ 30% pain intensity reduction at 8 weeks compared to baseline. Functionality, mood, cognitive, motor status, and somatosensory thresholds were also assessed. RESULTS: Twenty-five patients were enrolled. Mean age was 55.2 ± 9.5 years-old, and 56% were female. Nociceptive pain accounted for 60%, and neuropathic and nociplastic for 20% each. No significant difference was found for 30% pain reduction response rates between active (42.7%) and sham groups (14.6%, p = 0.26). Secondary clinical outcomes and sensory thresholds also did not differ significantly. In a post hoc analysis, PwP with nociceptive pain sub-type experienced more pain relief after active (85.7%) compared to sham PSI-rTMS (25%, p = 0.032). CONCLUSION: Our preliminary results suggest that different types of PD-related pain may respond differently to treatment, and therefore people with PD may benefit from having PD-related pain well characterized in research trials and in clinical practice.

SpadaHC: a database to improve the classification of variants in hereditary cancer genes in the Spanish population.

Accurate classification of genetic variants is crucial for clinical decision-making in hereditary cancer. In Spain, genetic diagnostic laboratories have traditionally approached this task independently due to the lack of a dedicated resource. Here we present SpadaHC, a web-based database for sharing variants in hereditary cancer genes in the Spanish population. SpadaHC is implemented using a three-tier architecture consisting of a relational database, a web tool and a bioinformatics pipeline. Contributing laboratories can share variant classifications and variants from individuals in Variant Calling Format (VCF) format. The platform supports open and restricted access, flexible dataset submissions, automatic pseudo-anonymization, VCF quality control, variant normalization and liftover between genome builds. Users can flexibly explore and search data, receive automatic discrepancy notifications and access SpadaHC population frequencies based on many criteria. In February 2024, SpadaHC included 18 laboratory members, storing 1.17 million variants from 4306 patients and 16 343 laboratory classifications. In the first analysis of the shared data, we identified 84 genetic variants with clinically relevant discrepancies in their classifications and addressed them through a three-phase resolution strategy. This work highlights the importance of data sharing to promote consistency in variant classifications among laboratories, so patients and family members can benefit from more accurate clinical management. Database URL: https://spadahc.ciberisciii.es/.

Geometric deep learning-guided Suzuki reaction conditions assessment for applications in medicinal chemistry.

Suzuki cross-coupling reactions are considered a valuable tool for constructing carbon-carbon bonds in small molecule drug discovery. However, the synthesis of chemical matter often represents a time-consuming and labour-intensive bottleneck. We demonstrate how machine learning methods trained on high-throughput experimentation (HTE) data can be leveraged to enable fast reaction condition selection for novel coupling partners. We show that the trained models support chemists in determining suitable catalyst-solvent-base combinations for individual transformations including an evaluation of the need for HTE screening. We introduce an algorithm for designing 96-well plates optimized towards reaction yields and discuss the model performance of zero- and few-shot machine learning. The best-performing machine learning model achieved a three-category classification accuracy of 76.3% (±0.2%) and an F 1-score for a binary classification of 79.1% (±0.9%). Validation on eight reactions revealed a receiver operating characteristic (ROC) curve (AUC) value of 0.82 (±0.07) for few-shot machine learning. On the other hand, zero-shot machine learning models achieved a mean ROC-AUC value of 0.63 (±0.16). This study positively advocates the application of few-shot machine learning-guided reaction condition selection for HTE campaigns in medicinal chemistry and highlights practical applications as well as challenges associated with zero-shot machine learning.

In Operando Imaging Electrostatic-Driven Disassembly and Reassembly of Collagen Nanostructures.

Collagen is the most abundant protein in tissue scaffolds in live organisms. Collagen can self-assemble in vitro, which has led to a number of biotechnological and biomedical applications. To understand the dominant factors that participate in the formation of collagen nanostructures, here we study in real time and with nanoscale resolution the disassembly and reassembly of collagens. We implement a high-speed force microscope, which provides in situ high spatiotemporal resolution images of collagen nanostructures under changing pH conditions. The disassembly and reassembly are dominated by the electrostatic interactions among amino-acid residues of different molecules. Acidic conditions favor disassembly by neutralizing negatively charged residues. The process sets a net repulsive force between collagen molecules. A neutral pH favors the presence of negative and positively charged residues along the collagen molecules, which promotes their electrostatic attraction. Molecular dynamics simulations reproduce the experimental behavior and validate the electrostatic-based model of the disassembly and reassembly processes.

Epidemiological factors conditioning sarcoptic mange spreading in wild boar (Sus scrofa).

Sarcoptic mange is a widely distributed disease, with numerous potential hosts among domestic and wild animals. Nowadays it is considered a neglected re-emergent infection in humans. As a difference with domestic pigs, and even with several clinical cases reported in some European countries, it seems that Eurasian wild boars (Sus scrofa) have a low susceptibility to clinical mange. However, because of a case of confirmed transmission from Spanish ibex (Capra pyrenaica) to wild boar in the province of Tarragona, we planned a large-scale ELISA survey in the neighboring Valencian Community (SE Spain). We compared 419 wild boar sera from different management systems (fenced vs. open game estates), different ages (piglets, juveniles, and adults), with different behaviour (gregarious females of all ages and male piglets vs. solitary juveniles and adult males), from areas with different wild boar densities, different wild ruminant densities and different sarcoptic mange epidemiologic situations. The whole prevalence of antibodies against sarcoptic mange in the tested wild boars was 10.5%. No significant differences were found when comparing fenced and free ranging wild boars, males and females, gregarious vs. solitary individuals or among different ages. However, wild boar density was a relevant factor. In areas with a hunting bag of <1 wild boar/km2, considered as a low density of suids, the seroprevalence was 2.94%, but rose to 11.52% in high density districts, constituting a significant difference (p = 0.037). Low wild boar populations would act as a protective factor (OR 0.233; p = 0.049) against coming into contact with the mite. The wild ruminant densities or their sarcoptic mange status did not show any effect on wild boars seroprevalence against this disease. These results reinforce the suggested host-taxon Sarcoptes scabiei specificity and the independence of host-species foci.

Indications of Helicobacter pylori Eradication Treatment and Its Influence on Prescriptions and Effectiveness (Hp-EuReg).

BACKGROUND: The influence of indications for Helicobacter pylori investigation on prescriptions and effectiveness is unknown. The aim of the study was to assess the impact of indications for H. pylori investigation on prescriptions, effectiveness, compliance, and tolerance. METHODS: International, prospective, non-interventional registry of the management of H. pylori infection by European gastroenterologists (Hp-EuReg). Treatment-näive patients registered from 2013 to 2023 at e-CRF AEG-REDCap were analyzed. The effectiveness was assessed by modified intention-to-treat analysis. RESULTS: Overall, 53,636 treatment-naïve cases from 34 countries were included. Most frequent indications were: dyspepsia with normal endoscopy (49%), non-investigated dyspepsia (20%), duodenal ulcer (11%), gastric ulcer (7.7%), and gastroesophageal reflux disease (GERD) (2.6%). Therapy effectiveness varied by indication: duodenal ulcer (91%), gastric ulcer (90%), preneoplastic lesions (90%), dyspepsia with normal endoscopy (89%), GERD (88%), and non-investigated dyspepsia (87%). Bismuth-metronidazole-tetracycline and clarithromycin-amoxicillin-bismuth quadruple therapies achieved 90% effectiveness in all indications except GERD. Concomitant clarithromycin-amoxicillin-tinidazole/metronidazole reached 90% cure rates except in patients with non-investigated dyspepsia; whereas sequential clarithromycin-amoxicillin-tinidazole/metronidazole proved optimal (≥90%) in patients with gastric ulcer only. Adverse events were higher in patients treated for dyspepsia with normal endoscopy and duodenal ulcer compared with the remaining indications (23% and 28%, p < 0.001). Therapeutic compliance was higher in patients with duodenal ulcer and preneoplastic lesions (98% and 99%, p < 0.001). CONCLUSION: In Europe, patients with gastric or duodenal ulcers and preneoplastic lesions showed higher H. pylori treatment effectiveness. Bismuth and non-bismuth quadruple therapies achieved optimal results in almost all indications. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02328131.

An international multicentre study of SwiTching from Intravenous to subcutaneous inflixiMab and vEdolizumab in inflammatory bowel diseases: The TIME study.

BACKGROUND AND AIMS: Subcutaneous (SC) formulations of infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel diseases (IBDs). Our aim was to evaluate the effectiveness of switching from intravenous (IV) to SC formulations of IFX and VDZ in IBDs. METHODS: This multicentre, retrospective study collected data of adult patients with Crohn's disease (CD) or ulcerative colitis (UC) switched to SC IFX or VDZ. The primary endpoint was clinical remission at 12 months stratified based on timing of switch. A composite endpoint consisting of therapy discontinuation, reverse-switch, need for steroids, and drug optimization was evaluated. A multivariate analysis investigated the association between patients' characteristics and outcomes. RESULTS: Two hundred and thirty-one patients (59% UC, 53% male, mean age 44 ± 15 years, 68% IFX) from 13 centres were included. The switch occurred at Week 6 in a third of cases (36%). Median time to switch was 13 months. Most patients switched to SC IFX and VDZ were in clinical remission at 3 (87% and 77%), 6 (86% and 83%) and 12 (63% and 60%) months. In the multivariate analysis, there was no difference in clinical remission rate at 12 months; however, patients switched at Week 6 had a higher rate of experiencing any therapeutic changes at 3 (false discovery rate (FDR) = .002), 6 (FDR <1 × 10-10) or 12 months (FDR = .08). Clinical disease activity at baseline (only in UC) (FDR = .07) and previous exposure to biologics (FDR = .001) were risk factors for composite endpoint at 6 and 12 months. CONCLUSION: SC IFX and VDZ are effective in daily clinical practice in IBD patients. Switching patients in remission reduces the risk of negative outcomes.

HIV infection is associated with a less aggressive phenotype of inflammatory bowel disease. A multicenter study of the ENEIDA registry.

BACKGROUND: The coexistence of human immunodeficiency virus (HIV) infection and inflammatory bowel disease (IBD) is uncommon. Data on the impact of HIV on IBD course and its management is scarce. AIM: To describe the IBD phenotype, therapeutic requirements and prevalence of opportunistic infections (OI) in IBD patients with a coexistent HIV infection. METHODS: Case-control, retrospective study including all HIV positive patients diagnosed with IBD in the ENEIDA registry. Patients with positive HIV serology (HIV-IBD) were compared to controls (HIV seronegative), matched 1:3 by year of IBD diagnosis, age, gender and type of IBD. RESULTS: A total of 364 patients (91 HIV-IBD and 273 IBD controls) were included. In the whole cohort, 58% had ulcerative colitis (UC), 35% had Crohn's disease (CD) and 7% were IBD unclassified. The HIV-IBD group presented a significantly higher proportion of proctitis in UC and colonic location in CD but fewer extraintestinal manifestations than controls. Regarding treatments, non-biological therapies (37.4% vs. 57.9%; P=0.001) and biologicals (26.4% vs. 42.1%; P=0.007), were used less frequently among patients in the HIV-IBD group. Conversely, HIV-IBD patients developed more OI than controls regardless of non-biological therapies use. In the multivariate analysis, HIV infection (OR 4.765, 95%CI 2.48-9.14; P<0.001) and having ≥1 comorbidity (OR 2.445, 95%CI 1.23-4.85; P=0.010) were risk factors for developing OI, while CD was protective (OR 0.372, 95%CI 0.18-0.78;P=0.009). CONCLUSIONS: HIV infection appears to be associated with a less aggressive phenotype of IBD and a lesser use of non-biological therapies and biologicals but entails a greater risk of developing OI.

ECCO Guidelines on Therapeutics in Crohn's Disease: Surgical Treatment.

This article is the second in a series of two publications on the European Crohn's and Colitis Organisation [ECCO] evidence-based consensus on the management of Crohn's disease. The first article covers medical management; the present article addresses surgical management, including preoperative aspects and drug management before surgery. It also provides technical advice for a variety of common clinical situations. Both articles together represent the evidence-based recommendations of the ECCO for Crohn's disease and an update of prior ECCO guidelines.

Psoriasis induced by antiTNF therapy in inflammatory bowel disease: Therapeutic management and evolution of both diseases in a nationwide cohort study.

BACKGROUND: some patients with inflammatory bowel disease (IBD) treated with antiTNF develop drug-induced psoriasis (antiTNF-IP). Several therapeutic strategies are possible. AIMS: to assess the management of antiTNF-IP in IBD, and its impact in both diseases. METHODS: patients with antiTNF-IP from ENEIDA registry were included. Therapeutic strategy was classified as continuing the same antiTNF, stopping antiTNF, switch to another antiTNF or swap to a non-antiTNF biologic. IP severity and IBD activity were assessed at baseline and 16, 32 and 54 weeks. RESULTS: 234 patients were included. At baseline, antiTNF-IP was moderate-severe in 60 % of them, and IBD was in remission in 80 %. Therapeutic strategy was associated to antiTNF-IP severity (p < 0.001). AntiTNF-IP improved at week 54 with all strategies, but continuing with the same antiTNF showed the worst results (p = 0.042). Among patients with IBD in remission, relapse was higher in those who stopped antiTNF (p = 0.025). In multivariate analysis, stopping antiTNF, trunk and palms and soles location were associated with antiTNF-IP remission; female sex and previous surgery in Crohn´s disease with IBD relapse. CONCLUSION: skin lesions severity and IBD activity seem to determine antiTNF-IP management. Continuing antiTNF in mild antiTNF-IP, and swap to ustekinumab or switch to another antiTNF in moderate-severe cases, are suitable strategies.

Intraluminal oxygen can keep small bowel mucosa intact in a segmental ischemia model.

Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen leading to structural damage. The application of intraluminal oxygen has been successfully tested in small-animal series during storage and transport of the organ but have been so far clinically unrelatable. In this study, we tested whether a simple and clinically approachable method of intraluminal oxygen application could prevent ischemic damage in a large animal model, during warm ischemia time. We utilised a local no-flow ischemia model of the small intestine in pigs. A low-flow and high-pressure intraluminal oxygen deliverance system was applied in 6 pigs and 6 pigs served as a control group. Mucosal histopathology, hypoxia and barrier markers were evaluated after two hours of no-flow conditions, in both treatment and sham groups, and in healthy tissue. Macro- and microscopically, the luminal oxygen delivered treatment group showed preserved small bowel's appearance, viability, and mucosal integrity. A gradual deterioration of histopathology and barrier markers and increase in hypoxia-inducible factor 1-α expression towards the sites most distant from the oxygen application was observed. Intraluminal low-flow, high oxygen delivery can preserve the intestinal mucosa during total ischemia of the small intestine. This finding can be incorporated in methods to overcome small bowel ischemia and improve intestinal preservation for transplantation.

Stent retriever AssIsted Lysis (SAIL) Technique with Tirofiban: A Potential Bailout Alternative to Angioplasty and Stenting.

BACKGROUND AND PURPOSE: Angioplasty and stenting (A&S) have been described as bailout technique in individuals with failed thrombectomy. We aim to investigate Stent retriever AssIsted Lysis (SAIL) with tirofiban prior to A&S. MATERIALS AND METHODS: Patients from 2 comprehensive stroke centers were reviewed (2020-2023). We included patients with failed thrombectomy and/or underlying intracranial stenosis who received SAIL with tirofiban prior to intended A&S.SAIL consisted in deploying a SR through the occluding lesion to create a by-pass channel and infuse 10ml of tirofiban over 10 minutes either intraarterially (IA) or intravenously (IV). The SR was re-sheathed before retrieval. Primary endpoints were successful reperfusion (eTICI 2b-3) and sICH. Additional endpoints included 90-day mRS 0-2 and mortality. RESULTS: After a median of 3 (IQR 2-4) passes, 44 patients received the SAIL bridging protocol with tirofiban and later they were considered potential candidates for A&S bailout (43.2% IA-SAIL). Post-SAIL successful reperfusion was obtained in 79.5%. A significant residual stenosis (>50%) after successful SAIL was observed in 45.7%.No significant differences were detected according to post-SAIL successful reperfusion (IA-SAIL 80.0% vs IV-SAIL 78.9%; p=0.932), post-SAIL significant stenosis (33.3% vs 55.0%; p=0.203), early symptomatic reocclusion (0% vs 8.0%; p=0.207), or sICH (5.3% vs 8.0%; p=0.721). Rescue A&S was finally performed in 15 (34.1%) patients (IA-SAIL 21.0% vs IV-SAIL 44%; p=0.112).At 90 days, mRS 0-2 (IA-SAIL 50.0% vs IV-SAIL 43.5%; p=0.086) and mortality (26.3% vs 12.0%; p=0.223) were also similar. CONCLUSIONS: In stroke patients in which A&S bailout is considered, SAIL with tirofiban, either intraarterial or intravenous, seems to safely induce sustained recanalization, offering a potential alternative to definitive A&S. ABBREVIATIONS: A&S = Angioplasty and stenting, ICAD = Intracranial Atherosclerotic Disease, ICAS-LVO = Intracranial atherosclerosis related large vessel occlusion, EVT = Endovascular Treatment, LVO = Large Vessel Occlusion; MT = Mechanical Thrombectomy; SR = SR Stent Retriever; SAIL = Stent retriever AssIsted Lysis, sICH = Symptomatic Intracranial Hemorrhage.

Persistence, effectiveness and safety of ustekinumab and vedolizumab therapy for complex perianal fistula in Crohn's disease: The HEAL study from GETECCU.

BACKGROUND: The efficacy of ustekinumab and vedolizumab for treating complex perianal fistula in Crohn's disease has been barely studied. We aimed to assess treatment persistence, clinical remission, and safety of these drugs in this context. METHODS: Crohn's disease patients who had received ustekinumab or vedolizumab for the indication of active complex perianal fistula, were included. Clinical remission was defined according to Fistula Drainage Assessment Index (no drainage through the fistula upon gentle pressure) based on physicians' assessment. RESULTS: Of 155 patients, 136 received ustekinumab, and 35 vedolizumab (16 received both). Median follow-up for ustekinumab was 27 months. Among those on ustekinumab, 54 % achieved remission, and within this group, 27 % relapsed during follow-up. The incidence rate of relapse was 11 % per patient-year. Multivariate analysis found no variables associated with treatment discontinuation or relapse. Median follow-up time for patients receiving vedolizumab was 19 months. Remission was achieved in 46 % of the patients receiving vedolizumab, and among them, 20 % relapsed during follow-up. The incidence rate of relapse was 7 % per patient-year. Adverse events were mild in 6 % on ustekinumab and 8 % on vedolizumab. CONCLUSION: Ustekinumab and vedolizumab appear effective, achieving remission in around half of complex perianal fistula patients, with favorable safety profiles.