Application of the new PRINTO classification criteria for juvenile idiopathic arthritis in a sample of Portuguese patients.

BACKGROUND: The International League of Associations for Rheumatology (ILAR) classification system for juvenile idiopathic arthritis (JIA) does not depict homogenous subgroups of disease. As to unify our language with the adult rheumatic diseases, the Pediatric Rheumatology International Trials Organization (PRINTO) is attempting to revise these criteria. OBJECTIVE: To reclassify a JIA sample according to the new provisional PRINTO subsets: systemic JIA (sJIA), RF-positive JIA (RF-JIA), early-onset ANA-positive JIA (eoANA-JIA), enthesitis/spondylitis-related JIA (ESR-JIA), "other JIA" and "unclassified JIA". METHODS: Retrospective study including JIA patients followed in a Pediatric Rheumatology Unit at a university hospital. Medical records were reviewed, and patients were reclassified as per the provisional PRINTO criteria. RESULTS: Of a total of 104 patients, 41 (39.4%) were reclassified as "other JIA", 36 (34.6%) as eoANA-JIA, 15 (14.4%) as ESR-JIA, 8 (7.7%) as sJIA and 4 (3.8%) as RF-JIA. More than 90% of the oligoarticular JIA were reclassified into either eoANA-JIA or "other JIA". Only one negative RF polyarticular JIA converted to RF-JIA due to the presence of a positive anti-citrulinated peptide antibody (ACPA). The psoriatic arthritis (PsA) subgroup disappeared into eoANA-JIA (25%), ESR-JIA (25%) or "other JIA" (50%). There were significant differences in age of onset, but not on the gender ratio or uveitis presence. Antinuclear antibody was more frequent in females (p=0.035) and younger patients (p<0.001). CONCLUSION: The number of affected joints and PsA features elapsed in favour of laboratory RF, ACPA and ANA traits. PsA and oligoarticular JIA were abolished. The "other JIA" entity is heterogenous and prevalent, claiming reformulation.

Single-centre case series report of regional anaesthesia for pain management in vaso-occlusive crisis.

Sickle cell disease is characterised by episodes of vaso-occlusive crisis, a painful complication. Regional anaesthesia has shown promising results in reducing opioid consumption and pain scores. Patients with vaso-occlusive crises who underwent regional anaesthesia in the paediatric intensive care unit were studied. Data regarding pain location, regional analgesia technique, the local anaesthetic used and dose, daily opioid consumption, daily pain scores, use of adjuvants and complications were recorded. The primary outcome was to evaluate the effect of regional anaesthesia on opioid consumption. In this study, we describe 10 cases, referring to six paediatric patients with the vaso-occlusive crisis who underwent regional anaesthesia for severe pain and were unresponsive to increasing doses of opioids. Six cases received epidural analgesia, three continuous peripheral nerve blocks and one received both techniques. Opioid consumption was reduced (58%), and pain scores decreased (72%), both statistically significant reductions.

Regulation of follicular activation signaling pathways by in vitro inhibition of YAP/TAZ activity in mouse ovaries.

The Hippo pathway plays a crucial role in the regulation of follicular activation, which constitutes the first step of the folliculogenesis process. Disruption of this pathway occurs in several non-physiological contexts, after fragmentation for ovarian tissue cryopreservation procedures or chemotherapy exposure, leading to massive follicular growth and depletion. This study aimed to investigate the effect of controlling the Hippo pathway using verteporfin (VERT) during in vitro ovarian culture and to evaluate its potential preventive effects on chemotherapy-induced follicle activation using a mouse model. After exposure of cut ovaries to different concentrations of VERT for 3 h, a dose-dependent effect of VERT was observed that reached significant inhibition of YAP activity at 3 µmol/L. To assess the potential effect of controlling chemotherapy-induced Hippo pathway disruption, whole mouse ovaries were exposed to VERT alone or as a co-treatment with 4-hydroperoxycylophosphamide (4HC). VERT co-treatment prevented chemotherapy-induced YAP activation but had a limited impact on downstream effector gene, Ccn2. Surprisingly, VERT co-treatment also prevented mTOR and survival signaling pathway alterations following chemotherapy exposure. These results suggest an interaction between the two main signaling pathways regulating follicle activation and a protective effect of VERT on 4HC-induced DNA damage.

Neoantigen Targetability in Progressive Advanced Melanoma.

PURPOSE: The availability of (neo)antigens and the infiltration of tumors by (neo)antigen-specific T cells are crucial factors in cancer immunotherapy. In this study, we aimed to investigate the targetability of (neo)antigens in advanced progessive melanoma and explore the potential for continued T-cell-based immunotherapy. EXPERIMENTAL DESIGN: We examined a cohort of eight patients with melanoma who had sequential metastases resected at early and later time points. Antigen-presenting capacity was assessed using IHC and flow cytometry. T-cell infiltration was quantified through multiplex immunofluorescence. Whole-exome and RNA sequencing were conducted to identify neoantigens and assess the expression of neoantigens and tumor-associated antigens. Mass spectrometry was used to evaluate antigen presentation. Tumor recognition by autologous T cells was assessed by coculture assays with cell lines derived from the metastatic lesions. RESULTS: We observed similar T-cell infiltration in paired early and later metastatic (LM) lesions. Although elements of the antigen-presenting machinery were affected in some LM lesions, both the early and later metastasis-derived cell lines were recognized by autologous T cells. At the genomic level, the (neo)antigen landscape was dynamic, but the (neo)antigen load was stable between paired lesions. CONCLUSIONS: Our findings indicate that subsequently isolated tumors from patients with late-stage melanoma retain sufficient antigen-presenting capacity, T-cell infiltration, and a stable (neo)antigen load, allowing recognition of tumor cells by T cells. This indicates a continuous availability of T-cell targets in metastases occurring at different time points and supports further exploration of (neo)antigen-specific T-cell-based therapeutic approaches for advanced melanoma.

Kaposiform Lymphangiomatosis in a Male Adolescent: A Clinical Challenge and the Role of Genetics.

Kaposiform lymphangiomatosis (KLA) is a rare and aggressive generalized lymphatic anomaly (GLA), with distinctive clinical, radiology, morphologic, and genetic features. It does not have a current standard treatment and presents poor overall prognosis. Somatic mutations in the RAS pathway were reported as the likely driver for the majority of patients. We report a case of a 17-year-old male adolescent who was referred to the emergency department due to a severe anemia. Laboratory workup confirmed the anemia and revealed coagulation factor consumption and fibrinolysis. Chest-abdomen-pelvis computed tomography revealed an extensive cervical, mediastinal, abdominal and retroperitoneal "hematoma." During admission, progressive pancytopenia, and disseminated intravascular coagulation were observed, and the hypothesis of a tumor/neoplastic etiology was considered. A thoracoscopy revealed a moderate hemorrhagic pleural effusion and a mediastinal mass resembling a "hemolymphangiomatosis" malformation, which was biopsied. Histology displayed a lymphatic-venous malformation. The patient was presented at the multidisciplinary Vascular Anomalies Center and, due to the complex vascular anomaly diagnosis, oral sirolimus monotherapy was initiated. Four years later, the patient remains clinically stable, with stability of the lesion's dimensions and characteristics. A p.Q61R variant in the NRAS gene [NM_002524.4: c.182A>G, p.(Gln61Arg)], with 5% allelic fraction and 1993x coverage was detected. In conjunction with clinical and pathological findings, it allowed KLA final diagnosis. This case reinforces the importance of a high index of clinical suspicion and highlights the need of referring these cases to referral to Vascular Anomalies Centers.

Successful Treatment of a Child With Epileptic Encephalopathy With Spike-Wave Activation in Sleep and GRIN2A Variant Using Sulthiame.

Epileptic encephalopathy with spike-wave activation in sleep (EE-SWAS) and developmental EE-SWAS (DEE-SWAS) are characterized by variable combinations of cognitive, language, behavioral, and/or motor regression associated with continuous or near-continuous diffuse spike-and-wave complexes during sleep. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) variants have been associated with EE-SWAS. It encodes the most relevant GluN2 subunit of the N-methyl-D-aspartate receptor (NMDAR). Sulthiame reduces NMDAR-mediated neuronal excitability and has been progressively used as monotherapy in self-limited epilepsy with centrotemporal spikes (SeLECTS) or as add-ontherapy in EE-SWAS/DEE-SWAS. A five-year-old female, with family history of epilepsy, was initially diagnosed with SeLECTS and medicated with valproic acid (VPA). One year later, she presented a focal to bilateral tonic-clonic seizure during sleep and learning difficulty. The electroencephalogram revealed continuous spike-and-wave during sleep leading to the diagnosis of EE-SWAS. Prednisolone was effective, but there was repeated recurrence after its discontinuation and associated adverse effects. As an alternative, sulthiame was added to VPA. Four years later, she remains clinically stable. Genetic testing revealed a GRIN2A missense variant, C.3228C>A (p.Asn1076Lys). Sulthiame appeared effective in this recurrent EE-SWAS child, who presented a GRIN2A missense variant with possible NMDAR gain-of-function and adverse effects of corticosteroids. Functional studies​​​​​​​ of GRIN2A variants might become a future tool for individualized therapies.

Gene Expression Analyses in Human Follicles.

The ovary is a heterogeneous organ composed of different cell types. To study the molecular mechanisms occurring during folliculogenesis, the localization of proteins and gene expression can be performed on fixed tissue. However, to properly assess gene expression levels in a human follicle, this complex and delicate structure must be isolated. Hence, an adapted protocol previously described by Woodruff's laboratory has been developed to separate follicles (the oocyte and the granulosa cells) from their surrounding environment. The ovarian cortical tissue is first manually processed to obtain small fragments using two tools: a tissue slicer and a tissue chopper. The tissue is then enzymatically digested with 0.2% collagenase and 0.02% DNase for at least 40 min. This digestion step is performed at 37 °C and 5% CO2 and is accompanied by mechanical pipetting of the medium every 10 min. After incubation, the isolated follicles are collected manually using a calibrated microcapillary pipette under microscope magnification. If follicles are still present in the pieces of tissue, the procedure is completed with manual microdissection. The follicles are collected on ice in a culture medium and are rinsed twice in droplets of phosphate-buffered saline solution. This digestion procedure must be carefully controlled to avoid follicle deterioration. As soon as the structure of the follicles appears to be compromised or after a maximum of 90 min, the reaction is stopped with a 4 °C blocking solution containing 10% fetal bovine serum. A minimum of 20 isolated follicles (sized under 75 µm) should be collected to obtain an adequate amount of total RNA after RNA extraction for real-time quantitative polymerase chain reaction (RT-qPCR). After extraction, the quantification of total RNA from 20 follicles reaches a mean value of 5 ng/µL. The total RNA is then retrotranscribed into cDNA, and the genes of interest are further analyzed using RT-qPCR.

Isotretinoin-Induced Distal Ileitis Mimicking Crohn's Disease.

Terminal ileitis is a common condition defined as inflammation of the terminal portion of the ileum, which is typically associated with inflammatory bowel disease (IBD), classically Crohn's disease (CD). However, it can have other etiologies, including drug-induced ones. Isotretinoin is an effective and commonly used treatment for acne vulgaris, presenting multiple adverse effects. There have been discussions over its association with enteric inflammation, particularly over IBD emergence risk. We report a case of a previously healthy 17-year-old female who presented transitory clinical, laboratory, imaging, and endoscopic evidence of distal ileitis, temporally related to extended isotretinoin treatment and mimicking CD. Repeated clinical, laboratory, imaging, and endoscopic reassessment after isotretinoin discontinuation confirmed an almost complete resolution of the condition, avoiding IBD misdiagnosis and specific medication initiation. Our case highlights the differential diagnosis of ileitis as being of critical importance to avoid further unnecessary diagnostic investigations and inadequate treatment. Serial re-evaluation may be of key importance to reach a final diagnosis. Although recent literature suggests that isotretinoin is not associated with an increased IBD risk, our case highlights the possibility of it inducing small bowel injury and inflammation, similar to what has been reported with other drugs.

Two Siblings With Recurrent Fevers: The Path to Mevalonate Kinase Deficiency Diagnosis.

Systemic autoinflammatory diseases (SAIDs) are a group of disorders that constitute a rare cause of recurrent fevers. Recurrent fevers are defined as periodic febrile episodes lasting from days to weeks, separated by symptom-free intervals of variable duration. They present multiple etiologies, representing a diagnostic challenge. Mevalonate kinase deficiency (MKD) is a genetic SAID, a rare hereditary recurrent fever syndrome (HRF) caused by pathogenic variants in the mevalonate kinase (MVK) gene. It is characterized by the early onset of periodic fever flares, frequently associated with joint, gastrointestinal, skin, and lymph node involvement. Although elevated serum immunoglobulin D (IgD) levels were previously considered an MKD's hallmark, normal values do not exclude it. High serum immunoglobulin A (IgA) is frequent. An acute-phase response and elevated urinary mevalonic acid (UAV) excretion during flares may aid in the diagnosis. Genetic testing is an essential tool to confirm the diagnosis. The authors report two siblings presenting with early infancy onset of recurrent febrile illness and characteristic associated symptoms, one of which was initially misdiagnosed with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. MKD diagnoses were only established at 12 and nine years old, respectively, after the identification of the same two MVKgene variants. The diagnosis in the eldest favored the earlier recognition of MKD in the youngest. Owing to its wide spectrum of manifestations, with many being nonspecific and/or shared with other more frequent entities, a significant proportion of MKD patients present a long delay until its final establishment. These cases illustrate the MKD diagnosis and management's difficulties, reinforcing the importance of a careful clinical history and HRF awareness for its prompt diagnosis and appropriate precocious referral.

Novel Arthrogryposis Multiplex Congenita Presentation in a Newborn With Pierpont Syndrome.

Pierpont syndrome is a rare and recently described multiple congenital anomaly syndrome, classically characterized by global developmental delay, distinctive facial dysmorphic features, and abnormal fat distribution in distal limbs. Only few cases were previously documented. We report a case of a term male neonate admitted to the neonatal intensive care unit because of feeding difficulties. Intrauterine growth restriction, microcephaly, and bilateral equinovarus foot were diagnosed in the second trimester, and prenatal array comparative genomic hybridization showed no abnormality. Physical examination revealed bilateral flexion deformities of wrists, elbows, knees and clubfoot, large hands and feet, deep palmar and plantar grooves, and calcaneo-plantar fat pads. Craniofacial dysmorphism, axial hypotonia, and hypoactivity were also observed. Due to the presence of congenital and non-progressive joint contractures, arthrogryposis multiplex congenita (AMC) was considered. A comprehensive diagnostic workup, including a Next Generation Sequencing target panel, was performed but did not establish a diagnosis. The clinical exome identified an heterozygous pathogenic variant in the TBL1XR1 gene (NM_001321194.1: c.1337A>G, p.[Tyr446Cys]), allowing Pierpont syndrome diagnosis. Our case stands out for reporting the novel AMC presentation in a Pierpont syndrome newborn. The broader and precocious genetic testing proved to be an essential clarifying diagnostic tool. Our patient supports the relation between the p.Tyr446Cys sequence variant in TBL1XR1 gene with this rare syndrome, reinforcing its association with a distinctive and recognizable phenotype, as well as expanding its clinical features to include AMC.

Nickel Allergy After a Negative Test Result Following Nuss Procedure for Pectus Excavatum: a Case Report.

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Early versus late sphenopalatine ganglion block with ropivacaine in postdural puncture headache: an observational study

Abstract Background Postdural puncture headache (PDPH) is a common complication of neuraxial techniques which delays patients' discharge. Sphenopalatine ganglion block (SPGB) is a safe bedside technique with comparable efficacy to Epidural Blood Patch, the gold-standard treatment. There is no evidence on the ideal timing for SPGB performance. We aimed to evaluate the difference between early versus late SPGB concerning efficacy, symptom recurrence and hospital length of stay. Methods We present an observational study with 41 patients diagnosed with PDPH who were submitted to SPGB with ropivacaine 0,75%. The study sample (n = 41) was divided in two groups: an early (less than 24 hours after diagnosis) and a late (more than 24 hours after diagnosis) SPGB group. Pain was evaluated 15 minutes after the block and follow up occurred daily until patients were discharged. Patients' demographic characteristics, neuraxial technique, timing of SPGB, qualitative pain relief and post-SPGB length of stay were registered and analyzed with SPSS statistics (v26) software. Results Early SPGB resulted in a significant reduction in length of stay (p = 0,009) and symptom recurrence (p = 0,036), showing equally effective pain relief, compared to late SPGB. Conclusions SPGB was equally effective in both groups. Data showed that early SPGB reduces length of hospital stay and symptom recurrence, which potentially allows early resumption of daily activities and a reduction in total health costs.

Early versus late sphenopalatine ganglion block with ropivacaine in postdural puncture headache: an observational study.

BACKGROUND: Postdural puncture headache (PDPH) is a common complication of neuraxial techniques which delays patients.ÇÖ discharge. Sphenopalatine ganglion block (SPGB) is a safe bedside technique with comparable efficacy to Epidural Blood Patch, the gold-standard treatment. There is no evidence on the ideal timing for SPGB performance. We aimed to evaluate the difference between early versus late SPGB concerning efficacy, symptom recurrence and hospital length of stay. METHODS: We present an observational study with 41 patients diagnosed with PDPH who were submitted to SPGB with ropivacaine 0,75%. The study sample (n=41) was divided in two groups: an early (less than 24hours after diagnosis) and a late (more than 24hours after diagnosis) SPGB group. Pain was evaluated 15minutes after the block and follow up occurred daily until patients were discharged. PATIENTS: ÇÖ demographic characteristics, neuraxial technique, timing of SPGB, qualitative pain relief and post-SPGB length of stay were registered and analyzed with SPSS statistics (v26) software. RESULTS: Early SPGB resulted in a significant reduction in length of stay (p=0,009) and symptom recurrence (p=0,036), showing equally effective pain relief, compared to late SPGB. CONCLUSIONS: SPGB was equally effective in both groups. Data showed that early SPGB reduces length of hospital stay and symptom recurrence, which potentially allows early resumption of daily activities and a reduction in total health costs.

Preoperative Metal Patch Testing and Titanium Bar Use Criteria in Nuss Procedure: A 56-Patients' Cohort Study.

INTRODUCTION: Nuss procedure is the main reason for metal implants use by pediatric and thoracic surgeons. There is an ongoing debate on how to avoid allergic complications. Herein we describe our 8-year experience with systematic preoperative metal patch testing and our selective titanium bar use in Nuss procedure. MATERIALS AND METHODS: This is a single center retrospective observational cohort study of patients who underwent the Nuss procedure from 2013 to 2020. Preoperative metal patch testing was done in all cases. Criteria for titanium bar utilization were: a positive test for a major component of the stainless-steel bar; or a positive metal patch test and a positive history of atopy, food or metal allergy, or previous allergic reaction to an implant or device. RESULTS: In total, 56 patients were included. Most were male (91.1%) with a median age of 15.0 (13.0-22.0) years old. 19.6% had a positive preoperative metal patch test and 54.5% of these had no personal history of atopy. Stainless-steel bars were used in 27.3% of those patients and titanium bars were used in 72.7%. One patient had a documented minor allergy reaction. None of the 56 patients required early bar removal. CONCLUSION: Our study suggests that routine preoperative allergy testing and a judicious use of titanium bar are safe and avoid metal allergic complications.

Torcular pseudomass is frequently detected on fetal magnetic resonance imaging and reduces with gestational age.

BACKGROUND: The torcular pseudomass is an incidental extra-axial midline mass located between the venous sinuses and the occipital squama in the pediatric population. Although this structure is presumed to be a developmental feature, it has not been characterized on fetal MRI. OBJECTIVE: To determine the frequency, imaging features and longitudinal in utero evolution of torcular pseudomass using fetal MRI. MATERIALS AND METHODS: We present a single-center retrospective study of fetal MRI performed at a tertiary hospital. Two independent reviewers first ordinally scored torcular pseudomass as absent, focal, crescentic or bulky based on morphology. We reviewed available follow-up fetal and postnatal MRI and further classified torcular pseudomass as stable, involuted or progressive. We also collected clinical and demographic data from electronic charts and compared them among categories, corrected for multiple comparisons. RESULTS: This study included a total of 219 fetuses with median gestational age of 28 weeks (interquartile range [IQR]: 23-32 weeks). Torcular pseudomass was absent in 8% (n=17) and present as a focal mass in 15% (n=33), crescentic in 45% (n=98) and bulky in 32% (n=71) of the cases. Median gestational age was statistically different among torcular pseudomass categories and inversely associated with size. Follow-up fetal MRI was available in 9.6% (n=21) of cases (median interval 4 weeks; IQR: 2-9 weeks) and torcular pseudomass in these cases was classified as stable in 67% (n=14), involuted in 29% (n=6) and progressive in 5% (n=1). Postnatal MRI was available in 5% (n=12) of fetuses (median interval 11.5 months, IQR: 3-17 months), and among these cases torcular pseudomass was classified as stable in 33% (n=4) and involuted in 67% (n=8). CONCLUSION: Torcular pseudomass is highly prevalent in the fetal population and shows a natural tendency to involute, even in utero, although it sometimes persists during early infanthood.