Clinical Criteria Research Articles

Epidemiology, clinical spectrum, and outcomes of severe malaria in Eastern Uganda: a prospective study

BackgroundIn sub-Saharan Africa, malaria remains a public health problem despite some reports of declining incidence in the period 2000–2018. Since 2019, there have been some reports of disease epidemics and resurgences in areas that had registered steep declines and unusual clinical presentations. This study aimed to describe the epidemiology, clinical spectrum, and outcomes of severe malaria in children among malaria-endemic Eastern Uganda, a region that has recently experienced disease epidemics.MethodsThis prospective study was conducted at Mbale Regional Referral Hospital, Uganda, from 08th May 2019 to August 15, 2023, as part of the Malaria Epidemiological, Pathophysiological and Intervention studies in Highly Endemic Eastern Uganda (EDCTP–TMA2016SF-1514-MEPIE Study). Children aged 60 days to 12 years who at admission tested positive for malaria and fulfilled the clinical World Health Organization criteria for surveillance of severe malaria were enrolled into the study following appropriate informed consent. Data were collected using a customized proforma on social demographic characteristics, clinical presentation, treatment, and outcomes. Laboratory analyses included complete blood counts, lactate, glucose, blood gases, electrolytes, metabolites, and coagulation markers. In addition, urinalysis using dipsticks was done. Data were analysed using STATA V15. The study had ethical and regulatory approval before data collection commenced.ResultsA total of 1,379 participants were recruited. The median age was 4 years (2 months–12 years). Most children 757/1379 (54.9%) were under 5 years, and 825/1379 (59.8%) were males. The common symptoms were fever 1368 (99.2%), poor appetite 1095 (79.5%), inability to sit upright 1051 (76.2%), vomiting 944 (68.4%) and yellow eyes 833 (60.4%). The common signs included prostration, haemoglobinuria and jaundice. Prolonged hospitalization was found in 284/1339 (21.2%) and was associated with impaired consciousness 116/166 (30.1%), P = 0.003; haemoglobinuria 514/705 (27.1%), P < 0.001 and jaundice 505/690 (26.8%) P < 0.001. The overall mortality was 40/1347 (3.0%). Children who had > 1 severity feature were at a higher risk of mortality.ConclusionIn this prospective study of children with severe malaria in Eastern Uganda, the overall mortality was 3.0% and the more the disease clinical syndromes the higher the risk of death.

Biochemical analysis of miR-217 and miR-532 in patients with fibromyalgia

About 5% of the population suffers from fibromyalgia (FM), a chronic multi-symptom pain illness whose pathophysiology is still unknown. We aimed to be the first to investigate the possible association of sera levels of miR-217 and miR-532 in patients with fibromyalgia and correlate their expression levels to different clinical and biochemical disease criteria. This study included 80 participants who splitted into two groups: 40 fibromyalgia sufferers (12 male and 28 female), and 40 healthy volunteers (10 male and 30 female) who served as the control group. Venous blood samples were collected from all subjects. The miR-217 and miR-532 serum expressions were detected using quantitative real-time PCR (qRT-PCR). According to our data, the fold changes of miR-217 and miR-532 in fibromyalgia patients were significantly lower than in controls, for miR-217 (median = 0.1359, IQR: 0.038–0.287, P < 0.001) and miR-532 [median = 0.2199, IQR: (0.114–0.421), P < 0.001]. In addition, there was a significant negative relationship between Aspartate transaminase (AST) and both miR-217 and miR-532 (r = − 0.480, P = P < 0.001 r = − 0.462, P = P < 0.001), respectively. Serum miR-217 and miR-532 could serve as potential diagnostic biomarkers for fibromyalgia.

Early Detection, Diagnosis, Prevention, and Treatment of Infection to Avoid Sepsis and Septic Shock in Severely Burned Patients: A Narrative Review

The early detection, diagnosis, anticipation, and therapy of infections to prevent sepsis and septic shock remain significant challenges in cases of grave burns. This narrative review explores various tools for early infection detection, including emerging biomarkers, the American Burn Association’s clinical criteria, and traditional blood parameters. A comparative study of the American Burn Association, Mann-Salinas, and Sepsis-3 criteria highlights the superior early detection capabilities of the Sepsis-3 criteria. However, the authors recommend that sepsis should be prospectively evaluated, identified, and classified by the intensive care group, rather than by relying solely on retrospective items, though the latter may still be necessary in certain cases. Advances in biomarker identification, including polymerase chain reaction (PCR) and gene expression (mRNA) profiling, offer diagnostic advantages over current methods, enabling early detection within 4 to 6 h of intensive care unit admission. Mass spectrometry also shows promise for the rapid determination of bacteria, yeast, and fungi based on bacteria protein profiles. Source control remains crucial, and the use of antibacterial topical agents has significantly improved the survival rates of severely burned patients. However, antibiotic selection must be made judiciously to avoid resistance. Despite these advancements, significant progress is still needed to improve the rapid identification, actual presence, prevention, and therapy of infections to reduce the incidence of sepsis and septic shock in this patient subgroup.

Phase I study of efineptakin alfa (NT-I7) for the treatment of Kaposi sarcoma

BackgroundCD4+ T-cell lymphocytopenia and immune dysfunction are factors that drive the onset and persistence of Kaposi sarcoma (KS) in people with (PWH) and without HIV. Standard chemotherapy agents for KS...

Culturally-Relevant Predictors of Thwarted Belongingness Among College Students of Asian Descent

ABSTRACT Suicide is one of the most prevalent causes of death among college students in the United States, and the leading cause of death among Asian American college-aged adults. Given these concerning rates, further investigation is essential to understanding the current levels of suicide risk among this population, including culture-specific risk factors, to influence mental health interventions that support this population. This study aims to explore the impacts of Asian culture-specific factors on thwarted belongingness, a proximal risk factor of suicide desire, among college students of Asian descent guided by the Interpersonal Theory of Suicide. Participants (n = 218) completed a battery of validated measures to assess predictors of thwarted belongingness, which included shame, discrimination, ethnic identity, and perfectionism. Nearly half of participants met clinical cutoff criteria for suicide desire. Further, ethnic identity commitment, perfectionism discrepancy, and external shame were statistically significant predictors of thwarted belongingness among this population. These findings underscore the need for tailored interventions that address these culture-specific factors on college campuses to reduce the risk of suicide among students of Asian descent. Additional implications for college-student serving mental health professionals and future research directions are discussed.

Assessment of Cardiac Sarcoidosis with PET/CT.

18F-FDG PET with CT is an important advanced imaging modality used to assess patients with suspected or known cardiac sarcoidosis (CS). 18F-FDG PET is indicated for CS work-up in patients with extra-CS and abnormal screening results for cardiac involvement, patients under 60 y old presenting with unexplained high-grade atrioventricular heart block, and patients with suspected CS and idiopathic ventricular arrhythmias. In patients with established CS, serial 18F-FDG PET can be used to assess response to immunosuppressive therapy and long-term surveillance for reactivation of myocardial inflammation in patients with low-grade or quiescent disease. Patient preparation before 18F-FDG PET scanning is key in ensuring adequate suppression of physiologic myocardial 18F-FDG uptake, to maximize the power of the test to detect pathology. Inadequate dietary preparation can cause diffuse or focal-on-diffuse 18F-FDG uptake in the absence of active inflammation. It is important to assess resting myocardial perfusion, typically with 82Rb cardiac PET. Several different patterns of abnormalities have been reported in patients with CS, including normal myocardial perfusion with focal or patchy 18F-FDG uptake suggesting myocardial inflammation without scarring; the presence of a myocardial perfusion defect with abnormal 18F-FDG uptake suggesting myocardial scarring with inflammation; and the presence of a myocardial perfusion defect without 18F-FDG uptake indicating myocardial scarring without inflammation. Prognostically, the presence of myocardial perfusion defects and abnormal 18F-FDG uptake has been shown to be an independent predictor of death or ventricular arrythmias. A high myocardial SUVmax in the left and right ventricles has been shown to be an independent predictor of adverse clinical outcomes. Although the diagnostic performance of 18F-FDG PET has been studied, the reference standard for CS tended to rely on clinical criteria, which may be less sensitive than 18F-FDG PET at detecting CS. Therefore, the diagnosis of CS should rely on a multidisciplinary team approach involving multimodality advanced imaging, including echocardiography, cardiovascular MR, and 18F-FDG PET.

Impact of invasive and noninvasive pneumococcal diseases on adult populations: risk factors and vaccination status

BackgroundStreptococcus pneumoniae infections continue to pose significant health risks, particularly in adults with underlying conditions. This study assesses both demographic and clinical profiles of adult patients with invasive and non-invasive pneumococcal diseases, focusing on their vaccination status and outcomes.MethodsWe retrospectively analyzed clinical data from 217 adults diagnosed with pneumococcal infections at Eskişehir Osmangazi University Faculty of Medicine, a tertiary-care university hospital in Eskişehir, Türkiye, from January 2016 to November 2023. Cases meeting specific clinical and microbiological criteria were included. Logistic regression was utilized to identify key predictors of mortality.ResultsOf the 217 patients initially screened, 155 were included in the final analysis, comprising 75 cases of invasive and 80 cases of non-invasive disease. Notably, among those recommended for pneumococcal vaccination, only 20.6% were vaccinated, and strikingly, only 9% were vaccinated before infection. Significant correlations were observed between mortality and various factors, including age, comorbidities, bacteremia, invasive disease, and intensive care unit admissions. Mortality occurred in 39 (25.2%) of the patients, with notably higher risks among those with comorbidities and requiring intensive care.ConclusionPneumococcal infections continue to impose a significant health burden, particularly among older adults and those with pre-existing conditions. Our findings highlight the critical role of comorbidities and intensive care unit admissions in affecting patient outcomes, stressing the importance of timely interventions and enhanced health strategies to improve vaccination rates and overall outcomes in high-risk populations.

Incoherence in the Brain Death Guideline Regarding Brain Blood Flow Testing: Lessons from the Much-Publicized Case of Zack Dunlap.

At age 21, following a severe traumatic brain injury, Zack Dunlap was declared brain-dead according to the American Academy of Neurology guideline (Guideline) when he met the clinical criteria of brain death (minus apnea testing because of bradycardia) with technetium-99m diethylene-triamine-pentaacetate scintigraphy reported as showing no intracranial blood flow. His parents agreed to organ donation. During preparations for organ donation, Zack manifested a purposeful movement in response to a noxious stimulus made by his cousin. Following subsequent neurological recovery, he has returned to a normal life, holding steady employment and raising a family. During an interview, he reported that while in coma, he heard a doctor say that he was brain-dead and felt angry about it. His experience fits the phenomenon of cognitive-motor dissociation. Recently, Zack's medical records were made available to the first author. A critical review of the records uncovered a problem inherent in the logic of the Guideline algorithm regarding brain blood flow scintigraphy. This article discusses the lessons drawn from Zack's case, namely, that both the aforementioned problem and the occurrence of cognitive-motor dissociation in patients deemed to be brain-dead can pose a significant risk of a false-positive declaration of death.

Potentially traumatic childbirth experience, childbirth-related post-traumatic stress disorder symptoms, and the parent-infant relationship in non-birthing parents

BackgroundNon-birthing parents are typically present for the birth of their infants. Evidence suggests that some non-birthing parents may experience witnessing childbirth as traumatic, with some going on to develop childbirth-related post-traumatic stress disorder (CB-PTSD). This study aimed to explore the associations between non-birthing parents’ experiences of childbirth, symptoms of CB-PTSD, and the parent-infant relationship. The COVID-19 pandemic context is considered throughout the study, although it must be noted that most data were not collected during UK lockdown restrictions.MethodsA cross-sectional design was utilised. Participants were non-birthing parents who were present for the birth of their first infant, aged between 6 weeks and 12 months old. Participants were recruited through social media platforms via third-sector organisations, namely Dad Matters; a Home-Start project and The Birth Trauma Association. A total of 312 non-birthing parents provided demographic details and obstetric details of the mother’s birth. They also completed questionnaires about their experiences of the birth they were present for, CB-PTSD symptoms, and levels of warmth and invasion in the parent-infant relationship.ResultsWithin this sample, 49% experienced the birth they were present for as potentially traumatic. Moreover, 10.1% met clinical criteria for CB-PTSD symptoms, and an additional 7% met sub-clinical criteria. Non-birthing parents who experienced birth as potentially traumatic reported significantly higher CB-PTSD symptoms and felt a greater sense of invasion in relation to their infant. However, levels of warmth in the parent-infant relationship were not statistically different between the two groups. CB-PTSD symptoms had significant associations with invasion but not with warmth, and they mediated the relationship between possible birth trauma and invasion in the parent-infant relationship.ConclusionsThis study’s sample revealed a substantial proportion of non-birthing parents experiencing birth as potentially traumatic, with 10.1% meeting CB-PTSD criteria, a higher incidence than previously reported in the literature. This may be attributed the implications of the COVID-19 pandemic. CB-PTSD symptoms were negatively associated with feelings of invasion in the parent-infant relationship, but not with warmth. Future research should aim to replicate this study design with routine samples of non-birthing parents recruited from maternity settings.

Lisfranc Injury: a Comprehensive Analysis of LongTerm Outcomes - the Oswestry Experience.

Lisfranc is a challenging injury both diagnostically and surgically, with sparse long-term literature evidence of surgical practice. We aim to review our long-term specialist orthopaedic institutional experience of Lisfranc injuries and the surgical management of this complex injury, specifically considering surgical outcomes as per radiological and clinical assessment. We present data from a prospectively maintained institutional database, reviewing patients who underwent operative fixation for Lisfranc injury between April 2014 and August 2020. Patients were referred to our institution from hospitals across the country. We included all operatively managed Lisfranc injuries, primary procedures, and patients over the age of 16. Revision procedures, open injuries, polytrauma patients, patients under the age of 16, and those with multiple foot injuries were excluded. We assessed post-operative results as per the Wilpulla radiographic and clinical criteria. We treated 27 patients across the study period, of mean age 37.5 (SD 18.3), 55% male and 45% female. 33.3% of our patients were obese as defined by body mass index >30. As per the Myerson classification, we had 2 category A, 24 category B, and 1 category C injuries. Time to operation was median 14 days (range 0-116), with 2 delayed presentations following failure of conservative treatment. Our median length of stay was 1 day (range 0-16). We had 3 complications: 2 wound infections and 1 re-operation for non-union. Post-operative assessment as per Wilpulla demonstrated 74% of good, 18.5% fair and 7% poor fixation results. In our institutional experience, partial congruity lateral displacement injuries were the majority of surgical referrals. Surgical treatment through open reduction and internal fixation delivers good clinical and radiographically anatomical results. Further to conventional mechanisms of injury, we propose obesity to be an important risk factor for indirect, low-energy injuries that may help identify this injury. Lisfranc injury, long-term, orthopaedic surgery, obesity.

12-Year-Old Girl with Systemic Lupus Erythematosus Complicated by Gangrene and Intermittent Claudication.

Systemic lupus erythematosus (SLE) can present with various symptoms, including rare manifestations such as gangrene. This report describes a 12-year-old girl with SLE who presented with intermittent claudication and gangrene. Although intermittent claudication is rare in paediatric cases, it is essential to consider vascular diseases including those associated with SLE as a potential cause. The patient initially experienced pain, redness, and cold sensations in the right great toe accompanied by intermittent claudication, with symptoms worsening over time. Diagnostic imaging, including contrast-enhanced CT and MRI, revealed occlusion of the right popliteal artery with associated vasculitis and thrombosis. The diagnosis of SLE and antiphospholipid syndrome was confirmed based on clinical criteria. Treatment included prednisone, methylprednisolone pulse therapy, mycophenolate mofetil, hydroxychloroquine, and anticoagulants. The patient showed significant improvement, with resolution of the claudication and effective management of her gangrene through immunosuppressive therapy and careful wound care. This case highlights the importance of considering vascular complications in paediatric SLE and underscores the need for early diagnosis and comprehensive treatment.

Unraveling the heterogeneity of WHO grade 4 gliomas: insights from clinical, imaging, and molecular characterization

PurposeThe 2021 WHO classification of central nervous system tumors introduced molecular criteria to stratify Grade 4 gliomas, which remain heterogeneous. This study aims to elucidate the clinical, radiological, and molecular characteristics of WHO Grade 4 gliomas, focusing on their prognostic implications and the development of a predictive model for astrocytoma IDH-mutant WHO Grade 4 (A4).MethodsA retrospective cohort of 223 patients from Beijing Tiantan Hospital was analyzed. Clinical, radiological, and histopathological data were combined with molecular profiling, focusing on IDH mutations, TERT promoter mutations, and MGMT methylation. A predictive model was developed using LASSO regression to distinguish A4 from glioblastomas and validated with an external dataset from UCSF.ResultsThe cohort included 201 glioblastomas (90.1%) and 22 A4 cases (9.9%). A4 tumors were associated with younger age, higher MGMT promoter methylation, lower rates of TERT mutations, and distinct radiological features, such as cortical non-enhancing tumor infiltration (CnCE). Patients with A4 demonstrated significantly better survival outcomes compared to glioblastoma patients (p < 0.001). The predictive model for A4, incorporating age, tumor margin, and CnCE, achieved an AUC of 0.890 in the training set and 0.951 in the validation set.ConclusionIntegrating molecular and clinical criteria improves prognostication in Grade 4 gliomas. The predictive model developed in this study effectively identifies A4 tumors, facilitating more personalized therapeutic strategies.

HepatoPredict Accurately Selects Hepatocellular Carcinoma Patients for Liver Transplantation Regardless of Tumor Heterogeneity

Background/Objectives: Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths rising worldwide. This is leading to an increased demand for liver transplantation (LT), the most effective treatment for HCC in its initial stages. However, current patient selection criteria are limited in predicting recurrence and raise ethical concerns about equitable access to care. This study aims to enhance patient selection by refining the HepatoPredict (HP) tool, a machine learning-based model that combines molecular and clinical data to forecast LT outcomes. Methods: The updated HP algorithm was trained on a two-center dataset and assessed against standard clinical criteria. Its prognostic performance was evaluated through accuracy metrics, with additional analyses considering tumor heterogeneity and potential sampling bias. Results: HP outperformed all clinical criteria, particularly regarding negative predictive value, addressing critical limitations in existing selection strategies. It also demonstrated improved differentiation of recurrence-free and overall survival outcomes. Importantly, the prognostic accuracy of HP remained largely unaffected by intra-nodule and intra-patient heterogeneity, indicating its robustness even when biopsies were taken from smaller or non-dominant nodules. Conclusions: These findings support the usage of HP as a valuable tool for optimizing LT candidate selection, promoting fair organ allocation and enhancing patient outcomes through integrated analysis of molecular and clinical data.

Integration of molecular testing with clinical criteria and histopathology improves diagnostic precision in immune-mediated liver diseases.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are immune-mediated liver diseases (IMLDs) that are diagnosed by a combination of clinical, serologic, and histologic features. Diagnosis may be challenging, particularly when patients have mixed features of both AIH and PBC, a disease often called overlap syndrome (OS). In addition, many patients have refractory disease. We hypothesized that adding molecular testing to the current diagnostic criteria would provide an additional tool that could assist in correctly classifying patients. RNA was isolated from liver biopsies from patients with AIH (n=16), PBC (n=13), OS (n=8), drug-induced/serology-negative AIH (AIH-DI/Ser-neg, n=6), or controls (n=10). Gene expression was determined using a nCounter Sprint Profiler, and principal component analysis delineated distinct clusters for patients with an inflammatory profile due to AIH, PBC, and AIH-DI/Ser-neg. Two patients with minimal histologic features of PBC clustered with the control group, and two patients with predominantly AIH and minimal PBC features clustered with the PBC group. A patient with OS who received treatment for both conditions showed no disease progression, whereas a patient with OS treated solely for AIH failed to respond. Conversely, one of the gene signatures from a patient diagnosed with PBC fell within the AIH group. This patient did not respond to treatment with ursodiol and ultimately required liver replacement. These findings suggest that the IMLD initially diagnosed in these patients may have been incorrectly classified. As expected, molecular analysis could not identify a distinct cluster for patients diagnosed with OS, and these had variable gene signatures that fell throughout the identified AIH or PBC groups. In summary, gene expression analysis may assist in confirming the type of IMLD, especially when the diagnosis is unclear. Combining molecular testing with existing criteria could provide an additional diagnostic tool, improving patient care and response to treatment.

Pragmatic algorithm for visual assessment of 4-Repeat tauopathies in [18F]PI-2620 PET Scans.

Standardized evaluation of [18F]PI-2620 tau-PET scans in 4R-tauopathies represents an unmet need in clinical practice. This study aims to investigate the effectiveness of visual evaluation of [18F]PI-2620 images for diagnosing 4R-tauopathies and to develop a straight-forward reading algorithm to improve objectivity and data reproducibility. A total of 83 individuals with [18F]PI-2620 PET scans were included. Participants were classified as probable 4R-tauopathies (n = 29), Alzheimer's disease (AD) (n = 20), α-synucleinopathies (n = 15), and healthy controls (n = 19) based on clinical criteria. Visual assessment of tau-PET scans (choice: 4R-tauopathy, AD-tauopathy, no-tauopathy) was conducted using either 20-40-minute or 40-60-minute intervals, with raw (common) and cerebellar grey matter scaled standardized reading settings (intensity-scaled). Two readers evaluated scans independently and blinded, with a third reader providing consensus in case of discrepant primary evaluation. A regional analysis was performed using the cortex, basal ganglia, midbrain, and dentate nucleus. Sensitivity, specificity, and interrater agreement were calculated for all settings and compared against the visual reads of parametric images (0-60-minutes, distribution volume ratios, DVR). Patients with 4R-tauopathies in contrast to non-4R-tauopathies were detected at higher sensitivity in the 20-40-minute frame (common: 79%, scaled: 76%) compared to the 40-60-minute frame (common: 55%, scaled: 62%), albeit with reduced specificity in the common setting (20-40-min: 78%, 40-60-min: 95%), which was ameliorated in the intensity-scaled setting (20-40-min: 91%, 40-60-min: 96%). Combined assessment of multiple brain regions did not significantly improve diagnostic sensitivity, compared to assessing the basal ganglia alone (76% each). Evaluation of intensity-scaled parametric images resulted in higher sensitivity compared to intensity-scaled static scans (86% vs. 76%) at similar specificity (89% vs. 91%). Visual reading of [18F]PI-2620 tau-PET scans demonstrated reliable detection of 4R-tauopathies, particularly when standardized processing methods and early imaging windows were employed. Parametric images should be preferred for visual assessment of 4R-tauopathies.

Assessment and management for latent tuberculosis before advanced therapies for immune-mediated inflammatory diseases: A comprehensive review.

Tuberculosis (TB), caused by Mycobacterium tuberculosis , is the most significant infectious cause of mortality across the globe. While TB disease can prey on immunocompetent individuals, it is more likely to occur in immunocompromised individuals. Immune-mediated inflammatory diseases (IMIDs) are a group of diseases (rheumatoid arthritis, inflammatory bowel disease, ankylosing spondylitis, psoriasis, hidradenitis suppurativa, autoimmune blistering diseases, and others) where there may be a need for systemic immunosuppression to control the disease manifestations, treat symptoms and improve long term outcomes. Immunosuppression may predispose them to active TB either from recent infection or reactivation of Latent TB (LTB). The major determinants of reactivation include the type of therapy (highest risk with TNF inhibitors and JAK inhibitors) and the underlying TB endemicity. The strategy to avoid TB reactivation includes the detection of LTB using tests that detect immunoreactivity to TB antigens (interferon-gamma release assays or tuberculin skin test) and treating LTB before or with initiation of IMID therapies. Available diagnostic tests have deficiencies in diagnostic sensitivity to detect LTB and even worse capability in predicting reactivation of TB. In addition to immunological tests, more stringent testing strategy utilizing one or many LTB equivalents may point towards subclinical TB. LTB equivalents include clinical (past history of TB, recent exposure to TB) and radiological criteria (use of chest roentgenogram, computed tomography, or, sometimes positron emission tomography - computed tomography). The present review summarizes the risk factors for TB reactivation in patients initiated on advanced therapies, geographically appropriate strategies for LTB testing, and treatment of LTB.

Survival improvements in patients with melanoma brain metastases and leptomeningeal disease in the modern era: Insights from a nationwide study (2015-2022).

Advances in modern therapies have improved outcomes for patients with melanoma brain metastases (MBM), though prognosis remains poor. The optimal treatment strategy for patients who do not meet clinical trial inclusion criteria is unclear. This study included all patients with MBM diagnosed in Denmark between 2015 and 2022, identified through the Danish Metastatic Melanoma Database (DAMMED) and local surgical and radiotherapy records. Data were collected from electronic patient records. A total of 838 patients were included, with a median overall survival (OS) of 9.0 months. Of these, 112 (19.4 %) survived beyond 3 years post-diagnosis. Patients treated with immune checkpoint inhibitors (ICI) as first line treatment, specifically ipilimumab + nivolumab, demonstrated an intracranial overall response rate (icORR) of 46 % and a 2-year OS of 49 %. Those treated with BRAF/MEK inhibitors (BRAF/MEKi) had an icORR of 56 % but a 2-year OS of 20 %. Patients with leptomeningeal disease (LMD, n = 67) had a median OS of 8.4 months. Systemic therapy was associated with a superior OS for patients with LMD, though no survival benefit was seen with ICI compared to BRAF/MEKi. Among the 230 patients who underwent surgery, 30 received postoperative stereotactic radiosurgery (SRS); however, there was no difference in OS or intracranial progression-free survival between the groups. A considerable proportion of patients with brain metastases diagnosed after 2015 survived more than 3 years. Patients with LMD appeared to obtain limited benefit of ICI with only few patients alive > 3 years post-diagnosis.

"Psychiatric oblivion": considerations on the hypothesis of a law.

The introduction of a law on psychiatric oblivion, similar to the recent one for oncological oblivion, presents numerous complexities due to the differences between the two areas of illness, especially in terms of recovery and clinical stability. While a definitive cure is often achievable in oncological diseases, in severe mental disorders, such as schizophrenia or bipolar disorder, complete remission in the absence of therapies is rare. Even in cases of effective treatment response, patients may exhibit subclinical symptoms or cognitive and functional deficits, making the concept of psychiatric oblivion particularly problematic. Some diagnostic categories, such as brief psychotic disorder or postpartum depression, could theoretically benefit from oblivion legislation, given the potentially limited course and frequent absence of relapses. However, for the majority of psychiatric conditions the requirement of a long period of remission without therapy appears difficult to achieve. An alternative could be the introduction of criteria based on the stabilization of maintenance therapy, but this would require a more complex and less easily standardized clinical judgment. Other limitations are the residual vulnerability to relapses, the difficulty in determining a precise medical history and the influence of persistent social stigmatization, which could undermine the effects of oblivion. Therefore, the creation of a law on psychiatric oblivion would require a restrictive and selective approach, focused on specific diagnoses and long-term clinical remission criteria, tailored to the clinical and adaptive peculiarities of mental illness.

A phase 1/2 study evaluating the safety and efficacy of autologous TAC T cells in subjects with claudin 18.2+ advanced solid tumors.

828 Background: Claudin18.2 (CLDN18.2) is a tight junction protein found in gastric epithelial cells. It can become abnormally expressed in gastric cancer and other solid tumors, rendering it a candidate for targeted therapy. There are no approved therapeutic agents against CLDN18.2. The T cell antigen coupler (TAC) technology modifies T cells ex vivo , allowing cytotoxicity of tumor cells by co-opting the natural T cell receptor. TAC T cells demonstrate a safer profile than chimeric antigen receptor T cells. TAC01-CLDN18.2 is an autologous T-cell product comprising T cells expressing CLDN18.2 TAC. Methods: In this first-in-human study (NCT05862324), subjects will undergo leukapheresis and may receive bridging anticancer therapy during cell manufacturing. Prior to TAC01-CLDN18.2 infusion, subjects will undergo lymphodepletion chemotherapy. In Phase I, TAC01-CLDN18.2 will be administered at increasing doses (3 cohorts) in adult subjects with ≥2 lines of prior therapy (1 for subjects with pancreatic ductal adenocarcinoma (PDAC)) using the classic 3+3 dose escalation study design. CLDN18.2 expression levels will be determined centrally using a validated clinical trial assay. Dose-limiting toxicities (DLTs) will be assessed up to 28 days after the infusion. A second dose may be administered according to preidentified clinical and safety criteria. In Phase II, dose expansion groups will evaluate the efficacy, safety, and pharmacokinetics of the optimal TAC01-CLDN18.2 dose, with the option of redosing. Indications will include gastric and esophageal adenocarcinoma (group A), PDAC (group B) and ovarian and non-small cell lung cancer (group C) in subjects with &lt;4 lines of prior therapy. Results: The first two dose cohorts of Phase I have been completed, with no reported dose-limiting toxicities (DLT). All of the TAC-related adverse events were low-grade. No cytokine release syndrome was reported. One subject in cohort 2 experienced a grade 1 neurotoxicity, which resolved the same day without intervention. Six subjects reported a total of 6 serious adverse events, none related to TAC01-CLDN18.2. An 83.3% disease control rate was observed at first tumor assessment (Day 29). One subject in cohort 1 with heavily pre-treated PDAC (3 prior lines) with high CLDN18.2 expression has an ongoing, confirmed partial response. The subject received a second dose and is still on treatment (6 months). Conclusions: Treatment with the lower doses of TAC01-CLDN18.2 is safe and shows promising clinical activity in a heavily pre-treated cancer population. Treatment of cohort 3 has begun. Clinical trial information: NCT05862324 .

Friedreich Ataxia: An (Almost) 30-Year History After Gene Discovery.

In the late 1800s, Nikolaus Friedreich first described "degenerative atrophy of the posterior columns of the spinal cord," noting its connection to progressive ataxia, sensory loss, and muscle weakness, now recognized as Friedreich ataxia (FRDA). Renewed interest in the disease in the 1970s and 80s by the Quebec Cooperative Group and by Anita Harding led to the development of clinical diagnostic criteria and insights into associated biochemical abnormalities, although the primary defect remained unknown. In 1988, Susan Chamberlain mapped FRDA's location on chromosome 9. In the early 90s, collaborative research, including work by the author's team, identified a gene, later named FXN, containing an expanded GAA repeat-confirming it as the FRDA mutation. This discovery established a diagnostic foundation for FRDA, advancing genetic testing and opening new research avenues. These new areas of study included the characteristics, origin, and pathogenicity of the GAA repeat expansion; the characterization of frataxin, the encoded protein, including its subcellular localization, structure, and function; the identification of cellular pathways disrupted by frataxin deficiency; and the redefinition of FRDA phenotypes based on genetic testing, along with the study of FRDA's natural history. In addition, efforts focused on the search for biomarkers to reflect diagnosis, disease severity, and progression and, most importantly, the identification and development of therapeutic approaches in both preclinical and clinical settings. The creation of cellular and animal models was crucial to this progress, as was the formation of consortia to collaboratively drive basic and clinical research forward. Now, 28 years after the gene discovery, although much remains to be understood about the disease's mechanisms and the development of effective therapies, the progress is undeniable. A thriving community has emerged, uniting researchers, health care providers, industry professionals, individuals with FRDA, their families, and dedicated volunteers. With this collective effort, a cure is within reach.