Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation.

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5'-phosphate and a 3'-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology.

Assessment of the length of sick leave in patients with inflammatory bowel disease. / Evaluación de la duración de la baja laboral en pacientes con enfermedad inflamatoria intestinal.

INTRODUCTION: Inflammatory bowel disease (IBD) is a chronic disorder that can lead to periods of work-related temporary disability (TD), which may result in the need for permanent disability. The objective was to assess the impact of IBD on patients' temporary disability by analyzing periods, duration, and causes. It also investigates risk factors influencing the severity, frequency, and duration of flare-ups and associated complications in IBD patients. METHOD: The study includes patients aged 18 to 65, with at least 1 day of TD in 2019 (Pre-COVID), referred or not by UMEVI, due to reasons related to IBD. RESULTS: A total of 172 patients were included, and in all cases, TD was associated with IBD. TD was higher in patients over 30 years old, with anxious depressive disorder, who required hospitalization and did not receive prednisone treatment (p<0.05). TD duration was longer in patients belonging to the Special Regime for Self-Employed Workers (RETA): 67 days (IQR: 22-160) versus the General Regime (RG): 33 days (IQR: 8-110), with no statistically significant difference (p=0.120). The mean cost (euro) per worker in this series was euro745.5 (IQR: 231-2608.2). CONCLUSIONS: IBD has a significant impact on patients' temporary work disability. The duration of TD was longer in patients older than 30 years, with anxious-depressive disorder, who required hospital admission and did not receive steroid treatment.

Critical review of the evidence for Vojta Therapy: a systematic review and meta-analysis.

Introduction: It is essential to link the theoretical framework of any neurophysiotherapy approach with a detailed analysis of the central motor control mechanisms that influence motor behavior. Vojta therapy (VT) falls within interventions aiming to modify neuronal activity. Although it is often mistakenly perceived as exclusively pediatric, its utility spans various functional disorders by acting on central pattern modulation. This study aims to review the existing evidence on the effectiveness of VT across a wide range of conditions, both in the adult population and in pediatrics, and analyze common therapeutic mechanisms, focusing on motor control modulation. Aim: The goals of this systematic review are to delineate the existing body of evidence concerning the efficacy of Vojta therapy (VT) in treating a broad range of conditions, as well as understand the common therapeutic mechanisms underlying VT with a specific focus on the neuromodulation of motor control parameters. Methods: PubMed, Cochrane Library, SCOPUS, Web of Science, and Embase databases were searched for eligible studies. The methodological quality of the studies was assessed using the PEDro list and the Risk-Of-Bias Tool to assess the risk of bias in randomized trials. Methodological quality was evaluated using the Risk-Of-Bias Tool for randomized trials. Random-effects meta-analyses with 95% CI were used to quantify the change scores between the VT and control groups. The certainty of our findings (the closeness of the estimated effect to the true effect) was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE). Results: Fifty-five studies were included in the qualitative analysis and 18 in the meta-analysis. Significant differences in cortical activity (p = 0.0001) and muscle activity (p = 0.001) were observed in adults undergoing VT compared to the control, as well as in balance in those living with multiple sclerosis (p < 0.03). Non-significant differences were found in the meta-analysis when evaluating gross motor function, oxygen saturation, respiratory rate, height, and head circumference in pediatrics. Conclusion: Although current evidence supporting VT is limited in quality, there are indications suggesting its potential usefulness for the treatment of respiratory, neurological, and orthopedic pathology. This systematic review and meta-analysis show the robustness of the neurophysiological mechanisms of VT, and that it could be an effective tool for the treatment of balance in adult neurological pathology. Neuromodulation of motor control areas has been confirmed by research focusing on the neurophysiological mechanisms underlying the therapeutic efficacy of VT.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=476848, CRD42023476848.

STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.  Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

Spatially preserved multi-region transcriptomic subtyping and biomarkers of chemoimmunotherapy outcome in extensive-stage small cell lung cancer.

BACKGROUND: Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small-cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. PATIENTS AND METHODS: We analyzed tumor samples from 58 ES-SCLC patients enrolled in two multicenter single-arm phase IIIb studies evaluating front-line chemoimmunotherapy in Spain: n=32 from the IMfirst trial, and n=26 from the CANTABRICO trial. We utilized the GeoMxTM DSP system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). RESULTS: Subtype distribution was similar between both cohorts, except for SCLC-P, not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple co-existing transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity were not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ³12 months) contained an IFNg-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. CONCLUSIONS: This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Pre-existing IFNg-driven immunity and mitochondrial metabolism seem correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

A Patient With Athlete's Heart Syndrome: When the Abnormal Is Normal.

Long-term athletic training can result in structural and conduction changes within the heart, leading to Athlete's heart syndrome (AHS). This syndrome is characterized by increased left ventricle (LV) dimensions, thickness, and mass. Dynamic exercise significantly contributes to these alterations, with sinus bradycardia being a common conduction abnormality, often accompanied by first-degree atrioventricular (AV) block. However, higher degrees of AV conduction abnormalities, such as second- and third-degree blocks, though rare, might occur due to parasympathetic hypertonia. Prompt evaluation is necessary to rule out underlying structural or infiltrative heart diseases. We present the case of a 66-year-old lifelong long-distance runner with marked sinus bradycardia, AV dissociation, and junctional escape rhythm, alongside left ventricular hypertrophy (LVH) and T-wave repolarization abnormalities. Subsequent studies ruled out possible pathologies, and the patient was diagnosed with AHS, characterized by cardiac remodeling and bradycardia due to prolonged cardiac loading. This case underscores the importance of clinical assessment, cardiac imaging, and exclusion of pathologic causes to distinguish normal physiological adaptations from potentially concerning conditions.

Cell-specific Extracellular Vesicles and Their miRNA Cargo Released Into the Organ Preservation Solution During Cold Ischemia Storage as Biomarkers for Liver Transplant Outcomes.

BACKGROUND: Liver transplantation (LT) is crucial for end-stage liver disease patients, but organ shortages persist. Donation after circulatory death (DCD) aims to broaden the donor pool but presents challenges. Complications like acute rejection, hepatic artery thrombosis, and biliary issues still impact posttransplant prognosis. Biomarkers, including extracellular vesicles (EVs) and microRNAs (miRNAs), show promise in understanding and monitoring posttransplant events. This study explores the role of EVs and their miRNA cargo in LT, including their potential as diagnostic tools. METHODS: EVs from intrahepatic end-ischemic organ preservation solution (eiOPS) in 79 donated livers were detected using different techniques (nanosight tracking analysis, transmission electron microscopy, and flow cytometry). EV-derived miRNAs were identified by quantitative real time-polymerase chain reaction. Bioinformatics analysis was performed using the R platform. RESULTS: Different-sized and origin-specific EVs were found in eiOPS, with significantly higher concentrations in DCD compared with donation after brain death organs. Additionally, several EV-associated miRNAs, including let-7d-5p, miR-28-5p, miR-200a-3p, miR-200b-3p, miR-200c-3p, and miR-429, were overexpressed in DCD-derived eiOPS. These miRNAs also exhibited differential expression patterns in liver tissue biopsies. Pathway analysis revealed enrichment in signaling pathways involved in extracellular matrix organization and various cellular processes. Moreover, specific EVs and miRNAs correlated with clinical outcomes, including survival and early allograft dysfunction. A predictive model combining biomarkers and clinical variables showed promise in acute rejection detection after LT. CONCLUSIONS: These findings provide new insights into the use of EVs and miRNAs as biomarkers and their possible influence on posttransplantation outcomes, potentially contributing to improved diagnostic approaches and personalized treatment strategies in LT.

Reliability and Construct Validity of a Mobile Application for the Finger Tapping Test Evaluation in People with Multiple Sclerosis.

The finger tapping test (FTT) is a tool to evaluate the motor performance of the hand and fingers and eye-hand coordination with applicability in people with multiple sclerosis (pwMS). The aim of this study was to evaluate the intra- and inter-rater reliability of the TappingPro® mobile app and the construct validity between this app and validated clinical scales for motor performance in healthy subjects and pwMS. 42 healthy subjects (mean age 25.05) and 13 pwMS (mean age 51.69, EDSS between 3 and 7.5E) participated. FTT was performed with the TappingPro® mobile app. All participants were examined twice, with a one-week interval between the two appointments. For the analysis of construct validity, the Jamar® hydraulic hand dynamometer, Box and Blocks Test (BBT), and Nine Hole Peg Test (NHPT) were used. The intra-rater reliability showed a good correlation (Intraclass Correlation Coefficient, ICC > 0.787) for both upper limbs and both times of FTT for healthy subjects, and an excellent correlation (ICC > 0.956) for upper limbs and both times of FTT for pwMS. The ICC for the inter-rater reliability was good (ICC = 0.869) for the non-dominant upper limb in the FTT 10 s of the healthy subjects, and excellent (ICC > 0.904) for all the other measurements of the healthy subjects and pwMS. However, the Bland-Altman plots showed disagreement between observers and measurements that should be considered in the interpretation of clinical evaluations. The correlation analysis for healthy subjects showed poor associations between all variables, except for the association between hand grip strength and the FTT 60 s in the non-dominant upper limb, which had a moderate coefficient. For pwMS, there were moderate to excellent associations between BBT and the NHPT and FTT for both upper limbs. The correlations between hand grip strength and FFT were poor. This mobile app could be a useful and low-cost assessment tool in pwMS, allowing a simple evaluation and follow-up that has excellent correlation with clinical scales validated in this pathology.

A three-gene expression score for predicting clinical benefit to anti-PD-1 blockade in advanced renal cell carcinoma.

In the advanced renal cell carcinoma (RCC) scenario, there are no consistent biomarkers to predict the clinical benefit patients derived from immune checkpoint blockade (ICB). Taking this into consideration, herein, we conducted a retrospective study in order to develop and validate a gene expression score for predicting clinical benefit to the anti-PD-1 antibody nivolumab in the context of patients diagnosed with advanced clear cell RCC enrolled in the CheckMate-009, CheckMate-010, and CheckMate-025 clinical trials. First, a three-gene expression score (3GES) with prognostic value for overall survival integrating HMGA1, NUP62, and ARHGAP42 transcripts was developed in a cohort of patients treated with nivolumab. Its prognostic value was then validated in the TCGA-KIRC cohort. Second, the predictive value for nivolumab was confirmed in a set of patients from the CheckMate-025 phase 3 clinical trial. Lastly, we explored the correlation of our 3GES with different clinical, molecular, and immune tumor characteristics. If the results of this study are definitively validated in other retrospective and large-scale, prospective studies, the 3GES will represent a valuable tool for guiding the design of ICB-based clinical trials in the aRCC scenario in the near future.

Textbook outcome in patients with biliary duct injury during cholecystectomy.

BACKGROUND: Iatrogenic bile duct injury (BDI) during cholecystectomy is associated with a complex and heterogeneous management owing to the burden of morbidity until their definitive treatment. This study aimed to define the textbook outcomes (TOs) after BDI with the purpose to indicate the ideal treatment and to improve it management. METHODS: We collected data from patients with an BDI between 1990 and 2022 from 27 hospitals. TO was defined as a successful conservative treatment of the iatrogenic BDI or only minor complications after BDI or patients in whom the first repair resolves the iatrogenic BDI without complications or with minor complications. RESULTS: We included 808 patients and a total of 394 patients (46.9%) achieved TO. Overall complications in TO and non-TO groups were 11.9% and 86%, respectively (P < .001). Major complications and mortality in the non-TO group were 57.4% and 9.2%, respectively. The use of end-to-end bile duct anastomosis repair was higher in the non-TO group (23.1 vs 7.8, P < .001). Factors associated with achieving a TO were injury in a specialized center (adjusted odds ratio [aOR], 4.01; 95% CI, 2.68-5.99; P < .001), transfer for a first repair (aOR, 5.72; 95% CI, 3.51-9.34; P < .001), conservative management (aOR, 5.00; 95% CI, 1.63-15.36; P = .005), or surgical management (aOR, 2.45; 95% CI, 1.50-4.00; P < .001). CONCLUSION: TO largely depends on where the BDI is managed and the type of injury. It allows hepatobiliary centers to identify domains of improvement of perioperative management of patients with BDI.

Microwave-assisted hydrodiffusion and gravity extraction: An efficient method to produce pomegranate juice.

Green technologies based on microwaves have been developed by the food industry to produce organoleptically acceptable fruit juices without preliminary processing. Microwave irradiation coupled with hydrodiffusion and gravity (MHG) combines microwave heating with the earth's gravity, allowing the collection of hydrophilic substances released from the irradiated matrix. To the best of our knowledge, MHG extraction has never been experimented to produce pomegranate juice. In this work, we have evaluated it as a potential alternative to the conventional squeezing. A central composite design study (CCD) allowed the selection of the best extractive conditions (irradiation power and extraction time) to obtain a pomegranate juice with higher yield, polyphenol (e.g., catechin and delphinidin-3,5-glucoside) content, and related bioactivities (antioxidant and antidiabetic) than the one obtained by squeezing while maintaining the chemical-physical properties. Thus, this technique appears to be a functional alternative to producing high value pomegranate juice.

Large Right Atrial Myxoma: A Rare Presentation.

We present a case of a 74-year-old female with a large right atrial myxoma who initially presented to her primary care physician with nonspecific constitutional and abdominal symptoms. Her presenting symptoms were initially thought to originate from her gastrointestinal tract, but her workup for a gastrointestinal disorder was nondiagnostic. It was not until this patient developed symptoms of overt right heart failure that a cardiac condition was suspected. Our case highlights the importance of understanding the potential of cardiac myxomas to mimic many diseases, including cardiac, infective, neurologic, immunologic, pulmonary, and malignant diseases. Therefore, clinicians must always maintain a high index of suspicion for cardiac myxomas when evaluating patients with cardiac and non-cardiac-related symptoms that may be due to these tumors.

Successful Rescue Transaortic Valve Replacement Using Edwards Sapien 3 Following Failed Evolut R Implantation in a Degenerated Surgical Bioprosthesis: A Case Report.

This study examines a complex scenario of structural valve degeneration (SVD) in a high surgical-risk patient with a previously implanted 25 mm Carpentier-Edwards (CE) Perimount Magna Ease 3300 (Irvine, CA: Edwards Lifesciences) surgical bioprosthetic valve (SAV), the patient presented with both paravalvular leak (PVL) and central prosthetic valve insufficiency (PVI). The patient was considered for a transaortic valve-in-valve (ViV) intervention with a self-expanding 29 mm Evolut R valve (Minneapolis, MN: Medtronic). The case describes a ViV intervention complicated by the malpositioning of the Evolut R valve secondary to micro-dislodgement into the left ventricular outflow tract (LVOT) after deployment and subsequent migration into the LVOT during an attempted bioprosthetic valve fracture (BVF) of the SAV that aimed to decrease transvalvular gradients. The resulting acute severe PVL resulted in significant hemodynamic deterioration, necessitating emergent intervention by implanting a balloon-expandable 26 mm Edwards SAPIEN 3 valve (Irvine, CA: Edwards Lifesciences), effectively averting the need for a surgical valve explant. This study illuminates the intricacies and emergency management strategies in transcatheter aortic valve replacement (TAVR) procedures, particularly in high-risk patients with SVD, and offers critical insights into the challenges and solutions in ViV implantations.

Effects of the powerball® system on muscle strength, coordination, fatigue, functionality and quality of life in people with multiple sclerosis. A randomized clinical trial.

INTRODUCTION: Although clinical and functional impairments in the lower limbs have been extensively studied in patients with MS, the upper limb (UL) are also frequently affected. Clinical impairment of the UL in patients with MS is very common with muscle strength and hand dexterity as critical factors in maintaining functional activities that are the basis for independence and quality of life in people with MS. OBJECTIVE: To investigate the effects of a training protocol using the Powerball® system in combination with conventional physiotherapy on muscle strength, coordination, fatigue, functionality, and quality of life in persons with MS over an 8-week period. MATERIALS AND METHODS: A double-blind randomized controlled trial was conducted. The control group received conventional treatment, while the experimental group received additional UL training using the Powerball® system. Both groups received the same number of sessions and weeks of intervention. The following outcome measures were used: isometric grip and pinch strength, Box and Block Test (BBT), Nine Hole Peg Test (NHPT), Abilhand scale, Fatigue Severity Scale (FSS), Multiple Sclerosis Impact Scale (MSIS-29), and Likert satisfaction questionnaire for the experimental group. All measures were administered at baseline, after the treatment, and during a 3-week follow-up period. RESULTS: 25 patients completed the study (12 in the experimental and 13 in the control group). The experimental group showed significant improvements in coordination and manual dexterity of the more affected UL as measured by the BBT comparing pre- to post-treatment (p = 0.048) and pre-treatment to follow-up (p = 0.001), and on the less affected UP comparing pre-treatment to follow-up (p < 0.001) and post-treatment to follow-up (p = 0.034). The Likert-type satisfaction questionnaire obtained a mean score of 89.10 (± 8.54) out of 100 points. CONCLUSIONS: Upper limb treatment protocol using the Powerball® system, in combination with conventional physiotherapy for 8 weeks resulted in significant improvements in the intra-group analysis for UL coordination and manual dexterity in favor of the experimental group. The experimental group showed excellent satisfaction to the treatment.

Using online search activity for earlier detection of gynaecological malignancy.

BACKGROUND: Ovarian cancer is the most lethal and endometrial cancer the most common gynaecological cancer in the UK, yet neither have a screening program in place to facilitate early disease detection. The aim is to evaluate whether online search data can be used to differentiate between individuals with malignant and benign gynaecological diagnoses. METHODS: This is a prospective cohort study evaluating online search data in symptomatic individuals (Google user) referred from primary care (GP) with a suspected cancer to a London Hospital (UK) between December 2020 and June 2022. Informed written consent was obtained and online search data was extracted via Google takeout and anonymised. A health filter was applied to extract health-related terms for 24 months prior to GP referral. A predictive model (outcome: malignancy) was developed using (1) search queries (terms model) and (2) categorised search queries (categories model). Area under the ROC curve (AUC) was used to evaluate model performance. 844 women were approached, 652 were eligible to participate and 392 were recruited. Of those recruited, 108 did not complete enrollment, 12 withdrew and 37 were excluded as they did not track Google searches or had an empty search history, leaving a cohort of 235. RESULTS: The cohort had a median age of 53 years old (range 20-81) and a malignancy rate of 26.0%. There was a difference in online search data between those with a benign and malignant diagnosis, noted as early as 360 days in advance of GP referral, when search queries were used directly, but only 60 days in advance, when queries were divided into health categories. A model using online search data from patients (n = 153) who performed health-related search and corrected for sample size, achieved its highest sample-corrected AUC of 0.82, 60 days prior to GP referral. CONCLUSIONS: Online search data appears to be different between individuals with malignant and benign gynaecological conditions, with a signal observed in advance of GP referral date. Online search data needs to be evaluated in a larger dataset to determine its value as an early disease detection tool and whether its use leads to improved clinical outcomes.

Optimizing Valve Selection in Valve-in-Valve Transcatheter Aortic Valve Replacement: A Case Study on Addressing Patient-Prosthesis Mismatch and Early Structural Valve Deterioration in a Morbidly Obese Patient.

Transcatheter aortic valve replacement (TAVR) has increasingly become a fundamental approach for treating aortic valve stenosis (AVS), especially in high surgical risk patients. This case study underscores the criticality of meticulous procedural planning and precise valve selection in patients with severe AVS compounded by obesity. We report a case of a patient who, after receiving a 26 mm Edwards Sapiens 3 valve, presented with worsening exertional dyspnea and a declining indexed effective orifice area (EOAi). This deterioration indicated early structural valve deterioration (SVD), presumably due to patient-prosthesis mismatch (PPM). A subsequent valve-in-valve (ViV) TAVR using a 29 mm Medtronic Evolut Fx valve was successfully executed, leading to a notable improvement in EOAi. This case study emphasizes the complexities inherent in valve choice and sizing in TAVR, particularly highlighting the impact of PPM on obese patients and its potential to precipitate early SVD. The report further explores the emerging strategies in addressing TAVR valve dysfunctions via ViV interventions, shedding light on the nuanced and dynamic nature of TAVR management in obese patients. It advocates for tailored treatment strategies in managing such intricate cases, demonstrating the evolving landscape of TAVR procedures.

Blood gene expression biomarkers of response to anti-TNF drugs in pediatric inflammatory bowel diseases before initiation of treatment.

BACKGROUND/AIMS: Changes in gene expression profiles among individuals with inflammatory bowel diseases (IBDs) could potentially influence the responsiveness to anti-TNF treatment. The aim of this study was to identify genes that could serve as predictors of early response to anti-TNF therapies in pediatric IBD patients prior to the initiation of treatment. METHODS: We conducted a prospective, longitudinal, and multicenter study, enrolling 24 pediatric IBD patients aged less than 18 years who were initiating treatment with either infliximab or adalimumab. RNA-seq from blood samples was analyzed using the DESeq2 library by comparing responders and non-responders to anti-TNF drugs. RESULTS: Bioinformatic analyses unveiled 102 differentially expressed genes, with 99 genes exhibiting higher expression in responders compared to non-responders prior to the initiation of anti-TNF therapy. Functional enrichment analyses highlighted defense response to Gram-negative bacteria (FDR = 2.3 ×10-7) as the most significant biological processes, and hemoglobin binding (FDR = 0.002), as the most significant molecular function. Gene Set Enrichment Analysis (GSEA) revealed notable enrichment in transcriptional misregulation in cancer (FDR = 0.016). Notably, 13 genes (CEACAM8, CEACAM6, CILP2, COL17A1, OLFM4, INHBA, LCN2, LTF, MMP8, DEFA4, PRTN3, AZU1, and ELANE) were selected for validation, and a consistent trend of increased expression in responders prior to drug administration was observed for most of these genes, with findings for 4 of them being statistically significant (CEACAM8, LCN2, LTF2, and PRTN3). CONCLUSIONS: We identified 102 differentially expressed genes involved in the response to anti-TNF drugs in children with IBDs and validated CEACAM8, LCN2, LTF2, and PRTN3. Genes participating in defense response to Gram-negative bacterium, serine-type endopeptidase activity, and transcriptional misregulation in cancer are good candidates for anticipating the response to anti-TNF drugs in children with IBDs.

Intraductal papillary neoplasms of the bile ducts: a comparative study of a rare disease in Europe and Nagoya, Japan.

BACKGROUND: Intraductal papillary neoplasm of the bile ducts (IPNB) is a rare disease in Western countries. The aim of this study was to compare tumor characteristics, management strategies, and outcomes between Western and Eastern patients who underwent surgical resection for IPNB. METHODS: A multi-institutional retrospective series of patients with IPNB undergoing surgery between January 2010 and December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), and at Nagoya University Hospital, Japan. RESULTS: A total of 85 patients (51% male; median age 66 years) from 28 E-AHPBA centers were compared to 91 patients (64% male; median age 71 years) from Nagoya. Patients in Europe had more multiple lesions (23% vs 2%, P < .001), less invasive carcinoma (42% vs 85%, P < .001), and more intrahepatic tumors (52% vs 24%, P < .001) than in Nagoya. Patients in Europe experienced less 90-day grade >3 Clavien-Dindo complications (33% vs 68%, P < .001), but higher 90-day mortality rate (7.0% vs 0%, P = .03). R0 resections (81% vs 82%) were similar. Overall survival, excluding 90-day postoperative deaths, was similar in both regions. DISCUSSION: Despite performing more extensive resections, the low perioperative mortality rate observed in Nagoya was probably influenced by a combination of patient-, tumor-, and surgery-related factors.

Transcranial magnetic stimulation therapy for central post-stroke pain: systematic review and meta-analysis.

Introduction: Although rare, central post-stroke pain remains one of the most refractory forms of neuropathic pain. It has been reported that repetitive transcranial magnetic stimulation (rTMS) may be effective in these cases of pain. Aim: The aim of this study was to investigate the efficacy of rTMS in patients with central post-stroke pain (CPSP). Methods: We included randomized controlled trials or Controlled Trials published until October 3rd, 2022, which studied the effect of rTMS compared to placebo in CPSP. We included studies of adult patients (>18 years) with a clinical diagnosis of stroke, in which the intervention consisted of the application of rTMS to treat CSP. Results: Nine studies were included in the qualitative analysis; 6 studies (4 RCT and 2 non-RCT), with 180 participants, were included in the quantitative analysis. A significant reduction in CPSP was found in favor of rTMS compared with sham, with a large effect size (SMD: -1.45; 95% CI: -1.87; -1.03; p < 0.001; I2: 58%). Conclusion: The findings of the present systematic review with meta-analysis suggest that there is low quality evidence for the effectiveness of rTMS in reducing CPSP. Systematic review registration: Identifier (CRD42022365655).