T-FINDER: A highly sensitive, pan-HLA platform for functional T cell receptor and ligand discovery.

Effective, unbiased, high-throughput methods to functionally identify both class II and class I HLA-presented T cell epitopes and their cognate T cell receptors (TCRs) are essential for and prerequisite to diagnostic and therapeutic applications, yet remain underdeveloped. Here, we present T-FINDER [T cell Functional Identification and (Neo)-antigen Discovery of Epitopes and Receptors], a system to rapidly deconvolute CD4 and CD8 TCRs and targets physiologically processed and presented by an individual's unmanipulated, complete human leukocyte antigen (HLA) haplotype. Combining a highly sensitive TCR signaling reporter with an antigen processing system to overcome previously undescribed limitations to target expression, T-FINDER both robustly identifies unknown peptide:HLA ligands from antigen libraries and rapidly screens and functionally validates the specificity of large TCR libraries against known or predicted targets. To demonstrate its capabilities, we apply the platform to multiple TCR-based applications, including diffuse midline glioma, celiac disease, and rheumatoid arthritis, providing unique biological insights and showcasing T-FINDER's potency and versatility.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.

Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.

Bispectral index monitoring to detect delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

PURPOSE: Evaluate the bispectral index (BIS) monitoring to detect delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). MATERIALS AND METHODS: A single-center prospective study in patients with aSAH. BIS monitoring was recorded during 25-120 min in two periods, within the initial 72 h (BIS1) and between days 4 and 6 (BIS2) from admission. The median for each exported BIS parameter was analyzed. Transcranial Doppler (TCD) sonography was simultaneously performed with BIS1 (TCD1) and BIS2 (TCD2) monitoring. A multivariate logistic regression model was built to identify the variables associated with DCI. RESULTS: Sixty-four patients were included and 16 (25%) developed DCI. During BIS2 monitoring, significant differences were found in BIS value (left, p = 0.01; right, p = 0.009), 95% spectral edge frequency (left and right, p = 0.04), and total power (left and right, p = 0.04). In multivariable analysis, vasospasm on TCD2 (OR 42.8 [95% CI 3.1-573]; p = 0.005), a median BIS2 value <85 in one or both sides (OR 6.2 [95% CI 1.28-30]; p = 0.023), and age (OR 1.08 [95% CI 1.00-1.17]; p = 0.04) were associated with the development of DCI. CONCLUSIONS: BIS value is the most useful BIS parameter for detecting DCI after aSAH. Pending further validation, BIS monitoring might be even more accurate than TCD.

Typical absence status epilepticus in older people: syndromic delineation.

Objective We describe the clinical, electroencephalograph^ and neuroimaging findings of older patients with typical absence status epilepticus (ASE). Methods This investigation was a retrospective analysis of prospectively collected consecutive patients between January 2011 and October 2021. All patients ≥60 years with impairment of awareness and continuous generalized, rhythmic, synchronous and symmetric epileptiform discharges and normal background on video-electroencephalogram (vEEG) were included. Results Six patients were identified with a diagnosis of typical ASE. The mean age was 67 years. Five could be classified as idiopathic generalized epilepsy (IGE) though two had been erroneously categorized as cryptogenic focal epilepsy (FE). In one, the episode of ASE was thought to represent the beginning of late-onset IGE (de novo late-onset typical ASE). In all cases, ASE was controlled within the first 24 hours. Significance Typical ASE is a rare cause of confusion in the elderly population requiring urgent vEEG evaluation. It most frequently represents reactivation of a previous IGE, in effect related to patients with epilepsy with onset in childhood or adolescence, not previously diagnosed or treated, representing rather the debut of (de novo) late-onset IGE.

A prospective evaluation of phrenic nerve injury after lung transplantation: Incidence, risk factors, and analysis of the surgical procedure.

BACKGROUND: Phrenic nerve injury (PNI) is a complication of lung transplantation related to the surgical procedure and associated with increased morbidity. However, the incidence and risk factors, specifically regarding surgical techniques, have not been adequately studied. METHODS: We conducted a prospective single-center study over 4-years, in recipients of lung transplantation with a normal pretransplant phrenic nerve conduction study (PNCS). Diaphragm ultrasound and PNCS were performed in the first 21 postoperative days and PNI was defined when both tests were abnormal. Patients were followed up until hospital discharge. The association between transplant characteristics and PNI was analyzed by using logistic regression models. RESULTS: Two hundred eleven lung grafts implanted in 127 patients were included in the study. After lung transplantation, PNI was diagnosed in 43.3% of the subjects and 29% of the operated hemithorax. Regression logistic model showed that the variables related to PNI were female gender (p = 0.02), bilateral lung transplantation (BLT) (p = 0.001), right lung graft (p = 0.003), clamshell incision (p = 0.01), mediastinal adhesions (p = 0.002), longer operative time (p = 0.003), intraoperative extracorporeal support (p = 0.02), and blood transfusion (p = 0.003). Conversely, age >61 years (p = 0.008) and higher thoracic diameter (p = 0.04) were protective factors. The use of electrocautery, cardiac mechanical retractors, and diaphragmatic traction was not associated with PNI. Morbidity was increased without any difference in mortality. CONCLUSIONS: PNI is a frequent complication after lung transplantation, associated with higher morbidity. Mainly risk factors were age, BLT, female gender, and variables related to surgical difficulties. Lung graft in the right hemithorax and mediastinal adhesiolysis were the most relevant technical variables.

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection.

BACKGROUND: The role of vitamin D status in COVID-19 patients is a matter of debate. OBJECTIVES: To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity. METHODS: Retrospective case-control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. The association of serum 25OHD levels with COVID-19 severity (admission to the intensive care unit, requirements for mechanical ventilation, or mortality) was also evaluated. RESULTS: Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean ±â€…standard deviation 25OHD levels were 13.8 ±â€…7.2 ng/mL, compared with 20.9 ±â€…7.4 ng/mL in controls (P < .0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001). 25OHD inversely correlates with serum ferritin (P = .013) and D-dimer levels (P = .027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/mL. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components. CONCLUSIONS: 25OHD levels are lower in hospitalized COVID-19 patients than in population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.

Imaging findings of neurologic complications in lung transplantation: Review of a 9-year cohort.

BACKGROUND: Lung transplantation (LT) requires complex multidisciplinary organization and constitutes a therapeutic option and a life-saving procedure. Although the number of lung recipients continues to increase, neurological complications and death rates following lung transplantation are still higher than desirable. PURPOSE: This study aims to analyse the neuroimaging findings in a cohort of adult patients with LT. MATERIAL AND METHODS: A retrospective cohort study of all lung transplant recipients (344 patients: 205 men and 139 women) at a single institution from January 2011 to January 2020. The collected data included demographic features, clinical data and evaluation of the imaging findings. We also recorded the date of neurological complication(s) and the underlying disease motivating lung transplantation. RESULTS: We found an elevated rate of neuroimaging findings in patients following LT with 32.6% of positive studies. In our cohort, the average time after LT to a neurological complication was 4.9 months post-transplant. Encephalopathy, critical illness polyneuropathy and stroke, in that order, were the most frequent neurological complications. Structural abnormalities in brain imaging were more often detected using MRI than CT for indications of encephalopathy and seizures. CONCLUSIONS: LT recipients constitute an especially vulnerable group that needs close surveillance, mainly during the early post-transplant period.

Intracortical focal non-convulsive status epilepticus causing cerebral hypoxia and intracranial hypertension.

We describe the pathophysiological consequences and long-term neurological outcome of a patient with acute brain injury (ABI) in whom intracortical electroencephalography (iEEG) captured an episode of prolonged focal non-convulsive status epilepticus (NCSE) that remained undetectable on scalp electroencephalography. A 53-year-old right-handed woman was admitted to hospital due to a large frontal left intraparenchymal hematoma. Over two and a half days, we captured recurrent non-convulsive electrographic and electroclinical seizures compatible with the diagnosis of intracortical focal NCSE. The patient remained sedated and a burst-suppression pattern was obtained. We also performed invasive brain multimodality monitoring including iEEG and measurements of intracranial pressure (ICP), partial brain tissue oxygenation (PbtO2) and brain temperature. During non-convulsive electrographic and electroclinical seizures, the values of PbtO2 decreased and those of ICP increased. Six months later, brain MRI revealed encephalomalacia localized to the left paramedial fronto-basal region. The neuropsychological assessment carried out one year after the injury showed scores below average in verbal learning memory, motor dexterity and executive functions. In summary, iEEG is a feasible innovative invasive technique that may be used to record non-convulsive electrographic and electroclinical seizures which remain invisible on the surface. Intracortical focal NCSE causes metabolic changes such as reduced brain oxygenation and an increase in ICP that can further damage previously compromised brain tissue.

Vitamin D Status in Hospitalized Patients with SARS-CoV-2 Infection.

BACKGROUND: The role of vitamin D status in COVID-19 patients is a matter of debate. OBJECTIVES: To assess serum 25-hydroxyvitamin D (25OHD) levels in hospitalized patients with COVID-19 and to analyze the possible influence of vitamin D status on disease severity. METHODS: Retrospective case-control study of 216 COVID-19 patients and 197 population-based controls. Serum 25OHD levels were measured in both groups. The association of serum 25OHD levels with COVID-19 severity (admission to the intensive care unit, requirements for mechanical ventilation, or mortality) was also evaluated. RESULTS: Of the 216 patients, 19 were on vitamin D supplements and were analyzed separately. In COVID-19 patients, mean ±â€…standard deviation 25OHD levels were 13.8 ±â€…7.2 ng/mL, compared with 20.9 ±â€…7.4 ng/mL in controls (P < .0001). 25OHD values were lower in men than in women. Vitamin D deficiency was found in 82.2% of COVID-19 cases and 47.2% of population-based controls (P < .0001). 25OHD inversely correlates with serum ferritin (P = .013) and D-dimer levels (P = .027). Vitamin D-deficient COVID-19 patients had a greater prevalence of hypertension and cardiovascular diseases, raised serum ferritin and troponin levels, as well as a longer length of hospital stay than those with serum 25OHD levels ≥20 ng/mL. No causal relationship was found between vitamin D deficiency and COVID-19 severity as a combined endpoint or as its separate components. CONCLUSIONS: 25OHD levels are lower in hospitalized COVID-19 patients than in population-based controls and these patients had a higher prevalence of deficiency. We did not find any relationship between vitamin D concentrations or vitamin deficiency and the severity of the disease.

Lingual epilepsia partialis continua: a detailed video-EEG and neuroimaging study.

Motor epilepsia partialis continua (EPC) is a frequent and widely described variant of simple focal motor status epilepticus. However, lingual EPC is an unusual epileptic condition. We present a case of lingual EPC secondary to low-grade glioma in which the EEG and neuroimaging features were particularly remarkable. The video-EEG showed lateralized periodic discharges with superimposed rhythmic activity and frequent recurrent focal epileptic seizures. Moreover, brain magnetic resonance imaging showed a right temporo-insular cortico-subcortical lesion which was hyperintense on FLAIR, suggestive of low-grade glioma. In addition, diffusion-weighted imaging and arterial spin labelling series showed restricted diffusion in the right temporo-insular and parietal cortex and increased cerebral flow, respectively. All these findings are in keeping with changes related to persistent focal status epilepticus. Finally, we review the literature and discuss the differential diagnosis of this rare epileptic entity. [Published with video sequence].

Epilepsia partialis continua and cortical motor control: insights into physiology.

Motor epilepsia partialis continua is a widely described variant of simple focal motor status epilepticus. However, few studies have addressed associated pathophysiological anomalies that may help us understand the cortical organization, basic functioning and control of voluntary movement. We describe the clinical, video-EEG and neuroimaging findings from two cases of motor epilepsia partialis continua that support the hypothesis of the coexistence of both classic body and complex motor map models in the cortical organization of voluntary movement in humans. [Published with video sequence].

The observation period after clinical brain death diagnosis according to ancillary tests: differences between supratentorial and infratentorial brain injury.

OBJECTIVE: To determine the optimal observation period (OBP) in adults with a clinical diagnosis of brain death (BD) using electroencephalography (EEG) or computerized tomography angiography (CTA). METHODS: We conducted a retrospective observational analysis of adult patients with a diagnosis of BD from January 2000 to February 2017. The optimal OBP was defined as the minimum time interval from the first complete clinical neurological examination (CNE) that ensures that neither a second CNE nor any ancillary test (AT) performed after this period would fail to confirm BD. RESULTS: The study sample included 447 patients. In the supratentorial group, the first AT confirmed BD in 389 cases (98%), but in 8 (2%) cases the complementary test was incongruent. In this group, 8 of 245 patients in whom the first AT was carried out within the first 2 h after a complete CNE had a non-confirmatory test of BD versus none of 152 in whom the first AT was delayed more than 2 h (3.0% vs 0.0%; p = 0.026). In the infratentorial group, we found a higher probability of obtaining a first non-confirmatory AT of BD (34% vs 2%; p = 0.0001) and an OBP greater than 32.5 h was necessary to confirm a BD diagnosis. CONCLUSIONS: We found important differences in the confirmation of BD diagnosis between primary supratentorial and infratentorial lesion, and identified an optimal OBP of 2 h in patients with supratentorial lesions. By contrast, in primary posterior fossa/infratentorial lesions, the determination of an optimal OPB remains less accurate and hence more challenging.

De novo absence status epilepticus of late onset (DNASLO) precipitated by oral treatment with cefuroxime: description of an ambulatory case.

We describe the case of an elderly woman with an episode of ambulatory de novo absence status epilepticus of late onset (DNASLO) after oral treatment with cefuroxime. A high level of suspicion of DNASLO in cases of unexplained confusion in adults or elderly subjects taking cephalosporins is essential to prompt an emergency EEG and, in turn, rapidly achieve an appropriate diagnosis and enable optimal treatment.

Postanoxic alpha, theta or alpha-theta coma: Clinical setting and neurological outcome.

AIM: The aim of this study was to determine the prognosis of 26 consecutive adults with alpha coma (AC), theta coma (TC) or alpha-theta coma (ATC) following CRA and to describe the clinical setting and EEG features of these patients. METHODS: We retrospective analyzed a prospectively collected cohort of adult patients diagnosed as having AC, TC or ATC after CRA between January 2008 and June 2016. None of patients included in this analysis underwent therapeutic hypothermia (TH). Neurological outcome was expressed as the best score 6 months after CRA using the five-point Glasgow-Pisttsburgh Cerebral Performance Categories (CPC) RESULTS: Twenty-six patients were identified with a diagnosis of postanoxic AC, TC or ATC coma. There were 20 (77%) men and 6 (23%) women. The mean age was 63 ±â€¯16 years. The most frequent EEG pattern was TC (21 patients, 80%), followed by AC (3 patients, 12%) and ATC (2 patients, 8%). The cardiac rhythm as primary origin of the CRA was ventricular fibrillation (VF) in 16 patients (61.5%), asystole in 8 patients (34.6%) and ventricular tachycardia (VT) in one patient (3.8%). The presence of EEG reactivity was present in 8 patients (30%). The mortality rate was 85%. Of the 4 surviving patients, two (3.8%) had moderate disability (CPC 2), one (3.8%) had severe disability (CPC 3) and one (3.8%) reached a good recovery. The age was significantly lower in survivors 46.2 ±â€¯10.8 versus nonsurvivors 63.3 ±â€¯15.5 (p = 0.04). There was increased association of EEG reactivity with survival (p = 0.07). CONCLUSION: Hypoxic-ischemic AC, TC and ATC are associated with a poor prognosis and a high rate of mortality. In younger patients with AC, TC and ATC and incomplete forms showing reactivity on the EEG, there is a greater probability of clinical recovery.

Super-refractory nonconvulsive status epilepticus due to self-poisoning with metaldehyde.

INTRODUCTION: Metaldehyde self-poisoning in adults is uncommon and, to the best of our knowledge, an episode of super-refractory nonconvulsive status epilepticus (sr-NCSE) following an suicide attempt has not been previously demonstrated. CASE REPORT: A 68-year-old woman was admitted to our Intensive Care Unit (ICU) in coma. On neurologic examination, the pupils were reactive, brainstem reflexes were present and plantar responses were flexor bilaterally. Routine laboratory tests were unremarkable. Arterial blood gas analysis revealed a mixed acidosis. A computed tomography (CT) scan of the brain and angio-CT were normal. The family confirmed that the patient had had suicidal ideation, and they had discovered a bag of slug killer (metaldehyde 5%) in her room. Two hours after the admission at the ICU, her neurological state remained unchanged. Sedation with intravenous propofol and antiepileptic therapy with levetiracetam (1000 mg/24 h) were started. The next day, propofol infusion was stopped but the level of consciousness of the patient did not improve. A video-electroencephalograhy (v-EEG) showed continuous generalized paroxysms of spike-wave and sharp-slow wave complexes compatible with the diagnosis of generalized NCSE. On day 3, the episode of NCSE was controlled. Finally, 15 days after ICU admission she was discharged with a normal neurological examination. CONCLUSION: This clinical case highlights that in comatose patients as consequence of metaldehyde poisoning, a v-EEG evaluation should be perform in order to rule out the existence of NCSE.

Matriz de densidad espectral de color del BIS bilateral en estado epiléptico / Colour density spectral array of bilateral bispectral index in status epilepticus

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Color density spectral array of bilateral bispectral index system: Electroencephalographic correlate in comatose patients with nonconvulsive status epilepticus.

PURPOSE: to describe the characteristics of the color density spectral array (CDSA) of bilateral bispectral index (b-BIS) monitoring system in patients with comatose nonconvulsive status epilepticus (NCSE). We hypothesized that CDSA could be helpful for monitoring NCSE in critically subjects if continuous EEG (cEEG) is not available. METHODS: we retrospectively analyzed comatose patients admitted to our neurological intensive care unit (NICU) from 2011 to 2014 with a diagnosis of definitive NCSE that underwent b-BIS monitoring for at least 24h to guide anesthetic sedation. Clinical, electroencephalography and neuroimaging findings were analyzed. Moreover, all parameters from the b-BIS data including the CDSA were reviewed during periods of NCSE (NCSE pattern) and profound sedation (sedation pattern). RESULTS: 15 NCSE patients were included. The delay from the diagnosis of NCSE to the onset of b-BIS monitoring was 8 (0.5-31)h and total time of b-BIS monitoring 7.8±6.5 days. CDSA during NCSE pattern was characterized by continuous or intermittent red and dark red tones, spectral edge frequency (SEF) in the delta-theta range, with or without asymmetry and BIS number trend with significant variability. In contrast, CDSA during sedation revealed predominance of orange, yellow, green and occasionally blue tones, SEF in the alpha-beta range, absence of asymmetry and stability of BIS number. CONCLUSIONS: b-BIS monitoring system and, in particular, CDSA used by nonexpert NICU personnel may be helpful to follow-up episodes of NCSE, to detect recurrences of nonconvulsive seizures (NCSzs), and to monitor profound anesthetic therapy in comatose patients when cEEG is not available.