Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling.

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

Rhino-orbito-cerebral mucormycosis: patient characteristics in pre-COVID-19 and COVID-19 period.

BACKGROUND: Rhino-orbito-cerebral-mucormycosis (ROCM), a rare and potentially fatal disease was seen in increasing numbers during the COVID-19 pandemic. This study describes and compares the patient characteristics and outcomes in COVID-19 associated mucormycosis (CAM) and non-COVID-19 mucormycosis (non-CAM). METHODOLOGY: CAM patients (24 cases) were recruited from the COVID-19 period and non-CAM (24 controls) from the pre-COVID-19 period. Clinical data of the CAM group was collected retrospectively with 3 month outcomes prospectively. The non-CAM group data was collected retrospectively. Patient characteristics were compared and risk factors for mortality in ROCM were assessed. RESULTS: Orbital symptoms [altered vision, restricted eye movements, ptosis] and intracranial involvement were higher in CAM patients on presentation. Similarly, the radiological involvement of orbit (orbital apex, superior orbital fissure) and intracranial cavity (intracranial thrombosis, cavernous sinus) was also higher in CAM patients. Newly detected diabetes was found only in CAM patients (29.2%). Although univariate analysis suggested an increased mortality risk in ROCM patients with orbital involvement, the multivariate analysis showed no increased risk with any of the parameters assessed, including COVID-19 positivity. CONCLUSIONS: Compared to the non-CAM, the disease presentation was severe in CAM with higher frequency of orbital and intracranial involvement. However, with early detection and treatment, the short term survival was comparable in both groups.

Health professionals' views about who would benefit from using a closed-loop system: a qualitative study.

AIM: To explore health professionals' views about who would benefit from using a closed-loop system and who should be prioritized for access to the technology in routine clinical care. METHODS: Health professionals (n = 22) delivering the Closed Loop from Onset in type 1 Diabetes (CLOuD) trial were interviewed after they had ≥ 6 months' experience supporting participants using a closed-loop system. Data were analysed thematically. RESULTS: Interviewees described holding strong assumptions about the types of people who would use the technology effectively prior to the trial. Interviewees described changing their views as a result of observing individuals engaging with the closed-loop system in ways they had not anticipated. This included educated, technologically competent individuals who over-interacted with the system in ways which could compromise glycaemic control. Other individuals, who health professionals assumed would struggle to understand and use the technology, were reported to have benefitted from it because they stood back and allowed the system to operate without interference. Interviewees concluded that individual, family and psychological attributes cannot be used as pre-selection criteria and, ideally, all individuals should be given the chance to try the technology. However, it was recognized that clinical guidelines will be needed to inform difficult decisions about treatment allocation (and withdrawal), with young children and infants being considered priority groups. CONCLUSIONS: To ensure fair and equitable access to closed-loop systems, prejudicial assumptions held by health professionals may need to be addressed. To support their decision-making, clinical guidelines need to be made available in a timely manner.

Identifying factors that influence the '6-hour target' in the Emergency Department by applying Regression Analysis.

AIM: To determine factors within the Emergency Department (ED) that have maximum influence on the '6-hour target'. METHODS: Regression Analysis methodology employed to analyse the influence of 9 ED variables on the '6-hour target' compliance. RESULTS: The number of patients waiting to be seen an ED physician at 8pm exerts maximum influence on the '6-hour target' (r = -0.581, p<0.05). CONCLUSION: The '6-hour target' compliance rises with lesser number of patients waiting to be seen by an ED physician at 8pm. Also, the '6-hour target' compliance rises by increasing the number of ED Registrar working hours and the number of ED SHO working hours per day.

Isolation, identification, and screening of biosurfactant-producing and hydrocarbon-degrading bacteria from oil and gas industrial waste.

Qatar is one of the biggest oil and gas producers in the world, coupled with it is challenging environmental conditions (high average temperature: >40 °C, low annual rainfall: 46.71 mm, and high annual evaporation rate: 2200 mm) harbors diverse microbial communities that are novel and robust, with the potential to biodegrade hydrocarbons. In this study, we collected hydrocarbon contaminated sludge, wastewater and soil samples from oil and gas industries in Qatar. Twenty-six bacterial strains were isolated in the laboratory from these samples using high saline conditions and crude oil as the sole carbon source. A total of 15 different bacterial genera were identified in our study that have not been widely reported in the literature or studied for their usage in the biodegradation of hydrocarbons. Interestingly, some of the bacteria that were identified belonged to the same genus however, demonstrated variable growth rates and biosurfactant production. This indicates the possibility of niche specialization and specific evolution to acquire competitive traits for better survival. The most potent strain EXS14, identified as Marinobacter sp., showed the highest growth rate in the oil-containing medium as well as the highest biosurfactant production. When this strain was further tested for biodegradation of hydrocarbons, the results showed that it was able to degrade 90 to 100% of low and medium molecular weight hydrocarbons and 60 to 80% of high molecular weight (C35 to C50) hydrocarbons. This study offers many promising leads for future studies of microbial species and their application for the treatment of hydrocarbon contaminated wastewater and soil in the region and in other areas with similar environmental conditions.

Risk factors and predictors of mortality in acute invasive fungal sinusitis - a single-institution experience.

OBJECTIVE: To determine risk factors affecting mortality in acute invasive fungal sinusitis. METHOD: This observational cohort study was conducted over a five-year period. RESULTS: Of 109 recruited patients, 90 (82.6 per cent) had diabetes mellitus. Predominant fungi were zygomycetes (72.6 per cent) with Rhizopus arrhizus being most common. Of the patients, 12.8 per cent showed a positive biopsy report from radiologically normal sinuses. Factors affecting mortality on multivariate analysis were: female sex (p = 0.022), less than two weeks between symptoms and first intervention (p = 0.01), and intracranial involvement (p = 0.034). Other factors significant on univariate analysis were: peri-orbital swelling (p = 0.016), restricted ocular movements (p = 0.053), intracranial symptoms (p = 0.008), posterior disease (p = 0.058), imaging showing ocular involvement (p = 0.041), fungus being zygomycetes (p = 0.050) and post-operative cavity infection (p = 0.032). Bilateral, palatal and retromaxillary involvement were not associated with poor prognosis. CONCLUSION: Diagnosis of acute invasive fungal sinusitis requires a high index of clinical suspicion. Recognition of factors associated with poor prognosis can help when counselling patients, and can help initiate urgent intervention by debridement and antifungal therapy. Post-operative nasal and sinus cavity care is important to reduce mortality.

Revised workflow practices in the management of acute invasive fungal sinusitis during the coronavirus disease 2019 pandemic.

OBJECTIVE: To document changes in evaluation protocols for acute invasive fungal sinusitis during the coronavirus disease 2019 pandemic, and to analyse concordance between clinical and histopathological diagnoses based on new practice guidelines. METHODS: Protocols for the evaluation of patients with suspected acute invasive fungal sinusitis both prior and during the coronavirus disease 2019 period are described. A retrospective analysis of patients presenting with suspected acute invasive fungal sinusitis from 1 May to 30 June 2021 was conducted, with assessment of the concordance between clinical and final diagnoses. RESULTS: Among 171 patients with high clinical suspicion, 160 (93.6 per cent) had a final histopathological diagnosis of invasive fungal sinusitis, concordant with the clinical diagnosis, with sensitivity of 100 per cent, positive predictive value of 93.6 per cent and negative predictive value of 100 per cent. CONCLUSION: The study highlights a valuable screening tool with good accuracy, involving emphasis on 'red flag' signs in high-risk populations. This could be valuable in situations demanding the avoidance of aerosol-generating procedures and in resource-limited settings facilitating early referral to higher level care centres.

Cost-effectiveness of an Adjuvanted Recombinant Zoster Vaccine in older adults in the United States.

In the United States, herpes zoster (HZ) and related complications are estimated to result in approximately $1.3 billion in medical care costs and $1.7 billion in indirect costs annually. In this study, we compared the cost-effectiveness of a new Adjuvanted Recombinant Zoster Vaccine (RZV), containing recombinant varicella-zoster virus glycoprotein E and the AS01B Adjuvant System, versus No Vaccine, as well as versus the live attenuated HZ vaccine (Zoster Vaccine Live (ZVL)) in subjects aged 60+ years of age (YOA) and other age cohorts aged 50+ YOA. A multi-cohort Markov model was developed which follows 1 million individuals over their remaining lifetimes from the year of vaccination with annual cycle lengths. Second dose compliance for RZV was assumed to be 69%. Efficacy and waning parameters were derived from clinical trials for both vaccines. Epidemiological parameters, costs and utility model inputs were derived from US-specific population-based data. Costs and outcomes were discounted at 3% per year. Deterministic and probabilistic sensitivity analysis, along with scenario and threshold analysis were carried out to explore the overall uncertainty in the model. The model estimated that, compared to No Vaccine against HZ, RZV would prevent 103,603 HZ cases, 11,197 postherpetic neuralgia (PHN) cases, and 14,455 other complications, at an incremental cost of $11,863 per quality-adjusted life-year saved from a societal perspective. Compared to ZVL, the model estimated that, RZV would prevent 71,638 additional HZ cases, 6403 PHN cases, and over 10,582 other complications, resulting in net total societal cost savings of over $96 million. The results were robust to a wide range of sensitivity analyses. Vaccination against HZ with RZV is cost-effective compared to No Vaccine and cost-saving compared to ZVL, in the US population aged 60+ YOA. Clinicaltrial.gov. registered#: NA.

Diadochokinesimetry: a study of patients with Parkinson's disease and manganese exposed workers.

Diadochokinesia, the ability to perform rapid alternating movements is often impaired in patients with extrapyramidal disease. It is a common sign among patients with Parkinsonism or manganism. In the present study we compare patients with Parkinson's disease (n = 11), workers formerly exposed to manganese (n = 10) and control subjects (n = 11) performing rapid alternating hand movements for 5 s under four conditions repeated twice (natural cadence and maximal speed with one or two hands). Data recorded using a diadochokinesimeter built in our laboratory and connected to a 486/33 microcomputer were digitized in real time while subjects rotated back and forth hand held foam spheres connected to flexible rods articulated with optical encoders. Significant differences were found between control subjects and patients with Parkinson's disease, but not with manganese exposed workers, in most variables examined. However, trajectory length (a combination of movement amplitude and velocity) indicated that manganese exposed workers and patients with Parkinson's disease were significantly different from the controls in functional asymmetries between right and left hand. In addition, workers and patients tend to have marked differences between the performance of right and left hands. Improved quantitative measurement of rapid alternating movements may prove to be an important tool in early and differential diagnosis of Parkinson's disease and manganese exposure.

Acute promyelocytic leukemia. New methods in diagnosis and treatment.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by hypergranular leukemic cells, bleeding diathesis and t(15; 17) translocation. The t(15; 17) translocation leads to the production of the PML-RAR alpha fusion protein which plays a vital role in the pathogenesis of APL by arresting normal differentiation of myeloid precursors. However, in the presence of high concentrations of all-trans-retinoic acid (ATRA), the PML-RAR alpha fusion protein serves to stimulate cell differentiation. The diagnosis of APL and the detection of residual disease are based on the t(15; 17) translocation. Treatment with a combination of ATRA and anthracycline-AraC chemotherapy has shown a higher rate of complete remission in APL. We report the case of a 71-year-old male with the rare microgranular variant of APL to illustrate these findings. The patient was treated with a combination of ATRA and Daunorubicin-AraC chemotherapy and achieved complete remission. He developed retinoic acid syndrome as a complication of therapy with ATRA. The methods for diagnosis, the molecular mechanisms in the oncogenesis of APL, rationale of treatment of APL with ATRA, complications of therapy and the new concepts in the treatment of ATRA-resistant APL are discussed.

The efficacy of dynamic slow motion video endoscopy as a test of eustachian tube function.

OBJECTIVE: To assess the efficacy of dynamic slow motion video endoscopy as a test of eustachian tube function based on its correlation with the eustachian tube swallow test. METHOD: The eustachian tube swallow test and dynamic slow motion video endoscopy were performed on 100 clinically normal middle ears of adults undergoing rigid nasal endoscopy for various indications. The dynamic slow motion video endoscopy findings were interpreted by three observers who were blind to the results of the eustachian tube swallow test, and the findings of both techniques were compared. RESULTS: There was a statistically significant correlation between the dynamic slow motion video endoscopy and eustachian tube swallow test results for some of the more lenient criteria. Five of the 100 eustachian tubes had a floppy medial cartilaginous lamina which appeared to contribute to the eustachian tube dysfunction. CONCLUSION: Dynamic slow motion video endoscopy appeared to over-diagnose eustachian tube dysfunction when used as a standalone test of eustachian tube function. However, when used in combination with other tests of eustachian tube function, it can provide valuable information regarding the structural and functional status of the pharyngeal end of the eustachian tube.

Invariant characterization of neural systems.

It is shown that the invariant integral, viz., the Kolmogorov second entropy, is eminently suited to characterize EEG quantitatively. The estimation obtained for a "clinically normal" brain is compared with a previous result obtained from the EEG of a person under epileptic seizure.

Effect of antioxidants on apoptosis and cytokine release in fetal rat Type II pneumocytes exposed to hyperoxia and nitric oxide.

The response of the fetal rat Type II pneumocyte (FTIIP), the stem cell of the alveolar epithelium, to hyperoxia would be helpful to understand the effects of oxygen-induced injury to the developing lung. Our goals were to evaluate the effect of antioxidants (AO) on apoptosis and release of cytokines in freshly isolated FTIIP (day-19) in the presence of 95% O2 and/or nitric oxide (NO). There was increased apoptosis in FTIIP exposed to hyperoxia alone and in combination with NO; this was significantly attenuated (p < 0.01) in the presence of 3 AO, namely grape seed proanthocyanidin extract (GSPE), superoxide dismutase (SOD) and catalase. The anti-inflammatory cytokine IL-10 has been shown to have a role in ameliorating tissue damage owing to persistent inflammation. The release of IL-10 was significantly decreased (p < 0.01) in the presence of GSPE and catalase, compared to control. Addition of SOD led to increased IL-10 compared to GSPE or catalase (p < 0.01) or the combination of GSPE + SOD + catalase (p < or = 0.01). Thus, in our in vitro model of hyperoxic and NO mediated injury to FTIIP, protection from apoptotic cell death with the addition of AO was associated with varying levels of IL-10 release. Our data suggest that the use of SOD and/or IL-10 may decrease hyperoxic lung injury by decreasing apoptosis. Further studies are needed to understand the mode of protection from catalase and GSPE.