M ycobacterium tuberculosis-specific CD4 T-cell scoring discriminates tuberculosis infection from disease.

BACKGROUND: Rapid and reliable diagnostic work-up of tuberculosis (TB) remains a major healthcare goal. In particular, discrimination of TB infection from TB disease with currently available diagnostic tools is challenging and time consuming. This study aimed at establishing a standardised blood-based assay that rapidly and reliably discriminates TB infection from TB disease based on multiparameter analysis of TB antigen-reactive CD4+ T-cells acting as sensors for TB stage-specific immune status. METHODS: 157 HIV-negative subjects with suspected TB infection or TB disease were recruited from local tertiary care hospitals in Berlin (Germany). Peripheral blood mononuclear cells were analysed for CD4+ T-cells reactive to the Mycobacterium tuberculosis antigens purified protein derivative and early secretory antigenic target 6 kDa/culture filtrate protein 10. The activation state of TB antigen-reactive T-cells, identified by surface expression of CD154, was evaluated according to the expression profile of proliferation marker Ki-67 and activation markers CD38 and HLA-DR. Using data from 81 subjects with clinically confirmed TB infection (n=34) or culture-proven pulmonary or extrapulmonary TB disease (n=47), 12 parameters were derived from the expression profile and integrated into a scoring system. RESULTS: Using the scoring system, our assay (TB-Flow Assay) allowed reliable discrimination of TB infection from both pulmonary and extrapulmonary TB disease with high sensitivity (90.9%) and specificity (93.3%) as was confirmed by Monte-Carlo cross-validation. CONCLUSION: With low time requirement, ease of sample collection, and high sensitivity and specificity both for pulmonary and extrapulmonary TB disease, we believe this novel standardised TB-Flow Assay will improve the work-up of patients with suspected TB disease, supporting rapid TB diagnosis and facilitating treatment decisions.

Emergence of Low-level Delamanid and Bedaquiline Resistance During Extremely Drug-resistant Tuberculosis Treatment.

Two new drugs, delamanid and bedaquiline, have recently been approved for treatment of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis. Here, we report a case of clofazimine, bedaquiline, and low-level delamanid resistances acquired during treatment of a patient with XDR tuberculosis.

Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence.

Probability of event-free survival (pEFS) in pediatric T-cell lymphoblastic lymphoma is about 80%, whereas survival in relapsed patients is very poor. No stratification criteria have been established so far. Recently, activating NOTCH1 mutations were reported to be associated with favorable prognosis, and loss of heterozygosity at chromosome 6q (LOH6q) was reported to be associated with increased relapse risk. The current project was intended to evaluate the prognostic effect of these markers. Mutations in hot spots of NOTCH1 and FBXW7 were analyzed in 116 patients. Concerning LOH6q status, 118 patients were investigated, using microsatellite marker analysis, in addition to an earlier reported cohort of 99 available patients. Ninety-two cases were evaluable for both analyses. All patients were treated with T-cell lymphoblastic lymphoma-Berlin-Frankfurt-Münster group (BFM)-type treatment. LOH6q was observed in 12% of patients (25/217) and associated with unfavorable prognosis (pEFS 27% ± 9% vs 86% ± 3%; P < .0001). In 60% (70/116) of the patients, NOTCH1 mutations were detected and associated with favorable prognosis (pEFS 84% ± 5% vs 66% ± 7%; P = .021). Interestingly, NOTCH1 mutations were rarely observed in patients with LOH in 6q16. Both prognostic markers will be used as stratification criteria in coming Non-Hodgkin Lymphoma-BFM trials.

A Trauma-Informed Approach to the Medical History: Teaching Trauma-Informed Communication Skills to First-Year Medical and Dental Students.

Introduction: Trauma is ubiquitous and associated with negative effects on physical and mental health. Trauma-informed care (TIC) is a framework for mitigating these health effects and improving patients' engagement with medical care. Despite these clinical benefits, TIC is not routinely taught in undergraduate medical education. Methods: We designed a session for first-year medical and dental students to introduce TIC principles and their application in patient care. The session focused on screening for and inquiring about trauma and responding to disclosures of trauma. Using live patient interviews, small-group discussions, and case-based role-plays, the session offered expert instruction and hands-on practice. Students completed pre- and postsession surveys and a 5-month follow-up survey. Students reported their comfort with screening for trauma and responding to disclosures of trauma before and after the session and at 5 months following the session. Results: Of the 164 student participants, 76% completed surveys during the session, and 50% completed the follow-up survey. More than one-third (34%) of respondents reported having received at least one disclosure of trauma from a patient within the first 5 months of medical school. Students' comfort with screening for trauma increased from 30% to 56%, and their comfort with responding to disclosure of trauma increased from 35% to 55%. These improvements persisted on reevaluation at 5 months. Discussion: We present a model for teaching trauma-informed communication skills to first-year medical and dental students. The intervention significantly increased students' comfort level and self-reported clinical skills, and benefits persisted at 5 months.

Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia.

Although deletions of cell cycle regulatory gene loci have long been reported in various malignancies, little is known regarding their relevance in pediatric T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (TALL). The current study focused on loss of heterozygosity (LOH) analyses of the CDKN2A/B (chromosome 9p), ATM (chromosome 11q) and p53 (chromosome 17p) gene loci. Frequencies of LOH were compared in 113 pediatric T-LBL and 125 T-ALL who were treated uniformly according to ALL-BFM strategies. Furthermore, LOH findings were correlated with clinical characteristics and tested for their prognostic relevance. LOH at 9p was detected in 47% of T-LBL and 51% of T-ALL, and was associated with male gender in both. In T-ALL, LOH at 9p was associated with favorable initial treatment response. A tendency for favorable event-free-survival was observed in LOH 9p positive T-LBL. The frequency of LOH at chromosomes 11q and 17p was 5% or less for both diseases.

A Case of Delayed Diagnosis of Moyamoya Disease After Recurrent Strokes.

We present a case of a 58-year-old man with delayed diagnosed moyamoya disease who underwent encephaloduroarteriosynangiosis (EDAS) procedure. This patient with a history of three strokes presented to our facility with new left facial droop. Neurological examination revealed left facial droop and hemiparesis. Brain magnetic resonance imaging (MRI) described right frontal lobe acute ischemia. Head computed tomography (CT) angiography revealed bilateral supraclinoid internal carotid artery (ICA) occlusions. Cerebral angiography demonstrated diffuse intracranial vascular irregularity with stenosis, more above the bilateral supraclinoid ICAs and the right middle cerebral artery (MCA) suggestive of moyamoya disease. Due to the lack of MCA patency, he underwent EDAS. Superficial temporal artery (STA) was dissected inferiorly and the posterior branch was bipolared, then STA was movable. A bur hole made at the superior and inferior portion along the STA. Dura was opened, and STA was brought on top of the pia. His facial droop gradually improved after that. Nine months later, no new strokes reported. Moyamoya disease is a rare neurovascular disorder characterized by narrowing and occlusion of the ICA branches. Its symptoms include recurrent ischemic/hemorrhagic strokes. Incidence in Hispanics has not been studied. The gap between the first manifestations and disease progression is one to eight years. Its diagnosis is often delayed. Our patient had recurrent strokes for five years. Despite therapy with antiplatelets, new ischemic stroke brought him to our institution. Rate of recurrent strokes despite antiplatelets was reported 10.3% per year. Brain CTs and MRIs had failed to detect strokes' etiology. Catheter-directed angiography is the gold standard test for diagnosis of moyamoya disease. Antiplatelet alone is ineffective and surgery is the effective method to prevent further strokes, although there are no studies in adults regarding the efficacy of indirect revascularization. In direct revascularization, usually STA anastomoses to MCA. Indirect method works through the development of leptomeningeal collaterals. Postoperative complications are infarction and hyperperfusion syndrome. Seong-eun et al. proposed that modified EDAS is simpler with less complications in comparison with direct revascularization. Some other studies showed higher chance of stroke in indirect method versus direct technique. In conclusion, it is important to consider moyamoya disease as a differential diagnosis in patients with recurrent strokes.

Neuroleptic drugs in the treatment of tuberculosis: Minimal inhibitory concentrations of different phenothiazines against Mycobacterium tuberculosis.

Due to an increase of drug resistant TB, alternative drugs that are not currently listed in the WHO guidelines on MDR TB treatment are currently being evaluated. Our group tested 100 susceptible, 20 MDR and 2 XDR Mtb strains against the phenothiazine derivatives thioridazine, trifluoperazine and triflupromazine. MIC testing was performed on Middlebrook 7H10 agar and was defined as the lowest drug concentration that inhibits ≥99% of the bacterial population. We confirm very good in vitro activity of phenothiazines against Mycobacterium tuberculosis. In >77% of all strains MICs of ≤10 µg/ml were found.

Cryptococcal ventriculoperitoneal shunt infection.

The standard treatment of hydrocephalus is placement of a ventriculoperitoneal (VP) shunt. While infection is a common complication, rarely are fungal organisms implicated. Cryptococcus neoformans has been reported in only nine cases of shunt infection to our knowledge. The timing from shunt placement to symptom onset varies widely from 10 days to 15 months. We present a patient who developed a cryptococcal infection of his VP shunt more than two decades following shunt placement.

Cell cycle regulatory molecular profiles of pediatric T-cell lymphoblastic leukemia and lymphoma.

Proper regulation of the cell cycle plays a fundamental role in any organism, as it impacts cellular division, differentiation and death. In this intricate process, progression through the phases of the cell cycle relies on various cyclin-cyclin-dependent kinase protein complexes that are regulated by multiple cyclin-dependent kinase inhibitors. Ultimately, the transcription factor E2F is influenced by this cascade and regulates the mRNA levels of proteins needed for cell cycle progression. Thus, disturbance of cell cycle regulation has been shown to be responsible for various types of cancer including adult and pediatric T-cell acute lymphoblastic leukemia and lymphoma (T-ALL and T-LBL, respectively), which are suggested to arise due to developmental arrest of precursor T lymphoblasts at certain early time points in T-cell maturation. Therapy optimization in recent years has resulted in good prognoses for patients of both malignancies. Here, we provide an overview of current knowledge of the cell cycle and its regulators with respect to pediatric T-ALL and T-LBL, both on molecular events underlying the disturbance of cell cycle regulation and on clinical parameters of affected children.