Cell-free circulating tumor DNA in patients with high-grade glioma as diagnostic biomarker - A guide to future directive.

BACKGROUND: Owing to the aggressive nature of high-grade gliomas (HGGs), its early diagnosis holds the key to a favorable prognosis. Currently, tissue biopsy is the gold standard to verify HGG's initial diagnosis and can be challenging due to its invasive nature. In this study, our objective was a noninvasive panel for timely detection of HGG and its progression using cell-free circulating tumor DNA (cfTDNA). MATERIALS AND METHODS: Twenty-seven patients with HGG were tested with a 50-gene tumor panel. cfTDNA isolated from serum was checked for single-nucleotide variations (SNVs) or copy number alterations using targeted next-generation sequencing, with further validation of results by checking respective formalin-fixed paraffin-embedded tumor tissues for the same genetic alterations. RESULTS: About 88.8% of the patients were detected with HGG-associated cfTDNA. Around 25% patients were detected with one, 25% patients had three, 25% patients had four, and 12.5% patients each had five and six genetic alterations. About 12 of 50 genes were detected in the serum samples. The SNVs detected included TP53 in 87.5% of patients; PIK3CA and EGFR in 50% of patients; PTEN in 37.5%; KIT and VHL in each 25% of patients; and RB1, NF2, MET, ATRX, CDK2A, and CTNNB1 each in 8.3%-16.6%. On combining EGFR, KIT, PTEN, PIK3CA, TP53, and VHL genes (Govardhan Diagnostic Genetic Module for high-grade glioma), at least one of the genetic alterations was found in 100% of patients. CONCLUSION: These findings illustrate that cfTDNA is easily demonstrable and can be used as a surrogate to tissue biopsy in brain tumor.

Osteosarcoma subtypes: Magnetic resonance and quantitative diffusion weighted imaging criteria.

INTRODUCTION: Osteosarcoma (OS) is a primary bone malignancy, characterized by spindle cells producing osteoid. The objective of this study is to describe the magnetic resonance imaging (MRI) features of different OS subtypes, record their attenuation diffusion coefficient (ADC) values and to point to the relation of their pathologic base and their corresponding ADC value. PATIENTS AND METHODS: We performed a retrospective observational lesion-based analysis for 31 pathologically proven osteosarcoma subtypes: osteoblastic (n = 9), fibroblastic (n = 8), chondroblastic (n = 6), para-osteal (n = 3), periosteal (n = 1), telangiectatic (n = 2), small cell (n = 1) and extra-skeletal (n = 1). On conventional images we recorded: bone of origin, epicenter, intra-articular extension, and invasion of articulating bones, skip lesions, distant metastases, pathological fractures, ossified matrix, hemorrhage and necrosis. We measured the mean ADC value for each lesion. RESULTS: Among the included OS lesions, 51.6% originated at the femur, 29% showed intra-articular extension, 16% invaded neighboring bone, 9% were associated with pathological fracture and 25.8% were associated with distant metastases. On MRI, all lesions showed ossified matrix, 35.5% showed hemorrhage and 58% showed necrosis. The mean ADC values for OS lesions ranged from 0.74 × 10-3 mm2/s (recorded for conventional osteoblastic OS) to 1.50 × 10-3 mm2/s (recorded for telangiectatic OS) with an average value of 1.16 ±â€¯0.18 × 10-3 mm2/s. Conventional chondroblastic OS recorded higher values compared to the other two conventional subtypes. CONCLUSION: Osteosarcoma has different pathologic subtypes which correspondingly vary in their imaging criteria and their ADC values.

The DEK1 Calpain Linker Functions in Three-Dimensional Body Patterning in Physcomitrella patens.

The DEFECTIVE KERNEL1 (DEK1) calpain is a conserved 240-kD key regulator of three-dimensional body patterning in land plants acting via mitotic cell plane positioning. The activity of the cytosolic C-terminal calpain protease is regulated by the membrane-anchored DEK1 MEM, which is connected to the calpain via the 600-amino acid residue Linker. Similar to the calpain and MEM domains, the Linker is highly conserved in the land plant lineage, the similarity dropping sharply compared with orthologous charophyte sequences. Using site-directed mutagenesis, we studied the effect on Physcomitrella patens development by deleting the Linker and two conserved Linker motifs. The results show that removal of the Linker has nearly the same effect as removal of the entire DEK1 gene. In contrast, deletion of the conserved Laminin_G3 (LG3) domain had a milder effect, perturbing leafy gametophore patterning and archegonia development. The LG3 domain from Marchantia polymorpha is fully functional in P. patens, whereas angiosperm sequences are not functional. Deletion of a C-terminal Linker subsegment containing a potential calpain autolytic site severely disturbs gametophore development. Finally, changing one of the three calpain active-site amino acid residues results in the same phenotype as deleting the entire DEK1 gene. Based on the conserved nature of animal and DEK1 calpains, we propose that the DEK1 MEM-Linker complex inactivates the calpain by forcing apart the two calpain subunits carrying the three amino acids of the active site.

Dental Anxiety- Understanding is the Key to Effective Management.

Dental anxiety (DA) is a common problem; the latest Adult Dental Health Survey (UK) reported nearly half of the adult population experienced anxiety when visiting the dentist. Given individual differences in the experience of dental anxiety, it is important for the dentist to understand its development, detection and management. This article aims to provide an overview of the main psychological theories to explain the development of dental anxiety (behavioural, psychoanalytical and cognitive), as well as an overview of anxiety detection and management techniques from a psychological perspective. Clinical relevance: Dental anxiety is a common barrier to oral healthcare, with nearly half of the UK population affected. By understanding its causes, effective management can reduce anxiety, and therefore barriers to achieving high standards of oral health can be overcome.

Short-Term Immunogenicity and Safety of an Accelerated Pre-Exposure Prophylaxis Regimen With Japanese Encephalitis Vaccine in Combination With a Rabies Vaccine: A Phase III, Multicenter, Observer-Blind Study.

BACKGROUND: The current Japanese encephalitis (JE) vaccination regimen requires two doses and 4 weeks to complete, which may not always be feasible for travelers on short notice. One of the primary endpoints of this phase III study was to demonstrate noninferiority of immune responses to a JE vaccine following an accelerated 1-week JE vaccination regimen administered concomitantly with a rabies vaccine as compared to a standard 4-week JE regimen alone. In addition, the immunogenicity of concomitant administration of JE and rabies vaccines following standard regimens was evaluated, as well as the tolerability and safety profile of each regimen under study. METHODS: Healthy adults aged 18 to ≤65 years were randomized to regimens with an accelerated or standard schedule: JE+rabies-standard (n = 167), JE+rabies-accelerated (n = 217) or JE-standard (n = 56). Immunogenicity against JE antigen was assessed by a 50% plaque reduction neutralization test (PRNT50 ) titer of ≥1 : 10, measured 28 days after last active vaccine (LAV) administration. Solicited reactions were collected 7 days after each vaccination; spontaneously reported adverse events (AEs) and serious AEs were monitored up to day 57. This paper reports results until day 57. RESULTS: Noninferiority of immune responses was established for JE+rabies-accelerated compared to the JE-standard regimen 28 days after LAV administration. Overall, 99% and 100% of subjects in the JE+rabies-accelerated and JE-standard groups, respectively, achieved PRNT50 titers of ≥1 : 10 at 28 days after LAV administration. No impact of concomitant rabies vaccination was observed either on immune responses or on the safety profile of the JE vaccine. CONCLUSIONS: This was the first randomized, controlled trial that demonstrated the strong short-term immunogenicity of a new, accelerated, 1-week JE-regimen, which was noninferior to that of the standard regimen, with a satisfactory tolerability and safety profile and no impact of concomitant rabies vaccination. This accelerated regimen, if licensed, could potentially be a valid alternative for individuals requiring a primary series of JE vaccination and rabies pre-exposure prophylaxis on short notice.

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen).

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.

A phase III single arm, multicenter, open-label study to assess the immunogenicity and tolerability of a pentavalent DTwP-HepB-Hib vaccine in indian infants.

Compliance with recommended vaccinations for Indian infants is facilitated by using combination vaccines to minimize the number of required injections. The ready-to-use, preservative free, fully-liquid combination DTwP-HepB-Hib vaccine, Quinvaxem(®), offers convenience of administering five important vaccine antigens to infants in a single injection. This phase III, single-arm, multicenter study was designed to assess immunogenicity and safety of three doses of Quinvaxem(®) to Indian infants administered at 6, 10, and 14 weeks of age. Blood samples were taken prior to the first dose and at one month post last vaccination. Infants were observed clinically for any reaction approximately 30 min following each vaccination, and parents completed subject diaries for solicited local, systemic and any adverse events (AEs) following over a 5 d period. DTwP-HepB-Hib vaccine elicited strong immune responses that exceeded seroprotection/seroconversion thresholds against all vaccine antigens. At one month after third vaccination, percentages of infants achieving predefined protective antibody levels were 99% diphtheria; 100% tetanus; 98% Hepatitis B; 100% Hib short-term (≥ 0.15 µg/mL); 95% Hib long-term (≥ 1.0 µg/mL) protection; and relevant immune response was 99% for pertussis. The vaccine was well tolerated, with no vaccine-related serious AEs. Only one case of high fever (≥ 40 °C) was reported. The most frequently reported reactions were mild to moderate tenderness and erythema. Frequencies of all AEs declined with subsequent vaccinations. This study demonstrated that this convenient, fully-liquid DTwP-HepB-Hib vaccine is highly immunogenic and has a acceptable safety profile for use in Indian infants. ClinicalTrials.gov Identifier: NCT01470287. Clinical Trials Registry of India Number: CTRI/2011/11/002118.

Detection of postoperative sleep-disordered breathing using a portable monitoring device.

PURPOSE: Adverse surgical outcomes may occur more frequently in patients with sleep-disordered breathing (SDB). Despite this concern, there have been no prospective studies using objective measures of postoperative SDB to determine the scope of the problem. We designed a prospective study to determine the feasibility of identifying SDB in elective postoperative patients by the use of a type IV portable monitor (PM). METHODS: Patients >18 years old who presented for elective surgery with at least one postoperative hospital night on a non-monitored unit were enrolled and wore a type IV device that measured nasal flow, heart rate, and oxygen saturation on their first postoperative night. Respiratory disturbance index (RDI) and oxygen desaturation index (ODI) were generated for each patient. RESULTS: Data sufficient for interpretation were collected on 100/116 patients enrolled. SDB (RDI ≥5) was observed in 51% of the study group, and 17% had a RDI >15. An elevated ODI ≥5 was seen in 42%, while 17% had an ODI ≥15. Device malfunction occurred in 16% of the study participants. CONCLUSION: A type IV PM can be employed in the postoperative setting to detect and gauge the severity of SDB.