Cellular and molecular features related to exceptional therapy response and extreme long-term survival in glioblastoma.

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond 2 years despite extensive therapy, which consists of maximal safe surgical resection, radiotherapy, and/or chemotherapy. Recently, it has become clear that GBM is not one homogeneous entity and that both intra-and intertumoral heterogeneity contributes significantly to differences in tumoral behavior which may consequently be responsible for differences in survival. Strikingly and in spite of its dismal prognosis, small fractions of GBM patients seem to display extremely long survival, defined as surviving over 10 years after diagnosis, compared to the large majority of patients. Although the underlying mechanisms for this peculiarity remain largely unknown, emerging data suggest that still poorly characterized both cellular and molecular factors of the tumor microenvironment and their interplay probably play an important role. We hereby give an extensive overview of what is yet known about these cellular and molecular features shaping extreme long survival in GBM.

Use of Multiple Irradiations and Reference Materials as Comparators in Quality Control of Neutron Activation Analysis Data of Biological Samples.

We propose that several different reactor irradiation times followed by assaying of activity for differential counting periods may be employed for quality control (QC) of neutron activation analysis (NAA) data of biological samples. It is also recommended that three to four reference materials (RMs) of similar matrix but from different agencies such as National Institute of Standards and Technology (NIST, USA), International Atomic Energy Agency (IAEA, Vienna), Institute of Nuclear Chemistry and Technology (INCT, Poland), and National Institute of Environmental Studies (NIES, Japan) including a synthetic multielemental primary standard should always be analyzed simultaneously along with the samples. Finally, the mean ± σ values so obtained may be considered as more reliable after statistical analysis. Our analytical data for Na and K in three RMs (SRM 1572, CRM H-9, and Bowen's Kale) using different irradiation periods of 15 m, 2 h, 6 h, and 1 day were comparable with the certified values within error range of + 0.2 to - 2.7%. We report our data for 20 elements in two candidate RMs corn flour (INCT-CF-3) and soya bean flour (INCT-SBF-4) from the INCT, Poland, where Z-score values for most elements are in reasonable range of certified values.

Effect of Twin Block Therapy Versus Fixed Functional Appliances on Pharyngeal Airway Space in Skeletal Class II Patients: A Prospective Cephalometric Study.

Background: Class II malocclusion is one of the most common malocclusion with varied prevalence. Functional therapy with appliances like Twin Block or Fixed functional appliances forms the mainstay of treatment in growing Class II patients. These patients might demonstrate narrow airway due to the retrognathic position of the mandible. This study investigated the effects of twin block and fixed functional appliance therapy (Forsus™ FRD) on the pharyngeal airway space in skeletal Class II patients. Methods: Forty patients with Class II malocclusion were selected and divided into two equal groups of 20 patients each for both Twin block and Forsus group. Lateral cephalograms were obtained before and after the functional appliance therapy. Evaluation was done for changes in hyoid bone position, pharyngeal airway dimensions and tongue position. Results: The variables of the study showed better hyoid position in both the groups. In Twin Block group, an increase in hy-apw2 and hy-PoFH suggested anterior positioning of hyoid and a decrease in H-MP and hy-ML indicated superior positioning. In Forsus group an increase in H-H', hy-FH, hy-ML, hy-NL, hy-NSL and hy-OL suggested inferior positioning of hyoid, while an increase in hy-apw2, hy-CVT, hy-PoFH, hy-RL and hy'-tgo indicated anterior positioning of hyoid bone after functional therapy. Conclusion: Both the twin block and Forsus™ FRD improved the position of the hyoid bone after the functional appliance therapy however the changes were not statistically significant. Twin block and Forsus™ had similar effect on the hyoid bone position, pharyngeal dimensions and the tongue position.

Comparative effect of micro-osteoperforation and Photo-biomodulation on the rate of maxillary canine retraction: A split mouth randomized clinical trial.

INTRODUCTION: The lengthy duration of comprehensive orthodontic treatment has always been a major concern. Various modalities have been proposed to accelerate the orthodontic tooth movement (OTM) with varying degree of success. However, there is limited literature, comparing the efficiency of two commonly used modalities which are relatively simple, safe and comfortable chair-side procedures to accelerate orthodontic tooth movement viz. Photo-biomodulation (PBM) being non-invasive and micro-osteoperforations (MOPs) being minimally invasive. The aim was to evaluate the comparative effect of PBM and MOPs on the rate of orthodontic tooth movement (OTM). METHODS: In this split mouth study, thirty patients requiring ma-xillary first premolar extraction were randomly allocated for Photo-biomodulation (PBM) on one side and for micro-osteoperforations (MOPs) on other side of maxilla. Separate canine retraction was performed and movement was measured over a three month period. RESULTS: Micro-osteoperforations (MOPs) significantly increased the rate of maxillary canine retraction by 1.1 fold when compared to the Photo-biomodulation (PBM).The MOPs can successfully reduce the comprehensive fixed orthodontic treatment time by around 9% as compared to PBM. CONCLUSIONS: Micro-osteoperforation is a more efficient modality of accelerating tooth movement as compared to Photo-biomodulation which can be used in routine orthodontic practice.

Monoclinic-triclinic phase transition induced by pressure in fergusonite-type YbNbO4.

We have carried out a high-pressure study on monoclinic fergusonite-type YbNbO4. Synchrotron powder x-ray diffraction experiments and density-functional theory simulations have been performed. We found a gradual increase of symmetry under compression, with calculations predicting a second-order monoclinic-tetragonal transition at 15 GPa. However, experiments provided evidence of a transition at 11.6 GPa to a triclinic structure, described by space groupP1¯. The appearance of the triclinic phase, which according to calculations is dynamically unstable under hydrostatic conditions, seems to be related to the presence of non-hydrostatic stresses. The triclinic high-pressure phase remains stable up to 31.9 GPa and the phase transition is not reversible. We have determined the pressure dependence of unit-cell parameters of both phases and calculated their room-temperature equation of state. For the fergusonite-phase we have also obtained the isothermal compressibility tensor. In addition to the high-pressure studies, we report ambient-pressure Raman and infrared spectroscopy measurements which have been compared with density-functional theory calculations.

Evaluation of candidate point mutation of Kisspeptin 1 gene associated with litter size in Indian Goat breeds and its effect on transcription factor binding sites.

Kisspeptin gene (Kiss1) has a significant role in reproductive processes in mammals. However, only little information is available about the association of Kiss1 gene with litter size in Indian goat breeds. Thus, blood samples from 285 randomly selected animals were collected for DNA isolation and SNP profiling. The PCR product of 242 bp size harboring g.2540C>T mutation of Kiss1 gene was digested with the restriction enzyme Sac1. Least squares analysis revealed that Barbari goats showed significantly higher average litter size (2.86±0.08) compared to Beetal, Sirohi and Sojat breeds (P < 0.01). SNP locus g.2540C>T of Kiss1 gene also showed significant effect on litter size (P < 0.01). Goats with Genotype CT (2.66 ± 0.07) and TT (2.67 ± 0.26) had significantly higher (P < 0.01) litter size than CC (1.50 ± 0.05). From the transcription factor binding site analysis, it was predicted that due to g.2540C>T SNP, both native and mutant variant forms coded for putative binding sites for different transcription Factor. Allele T had putative binding sites for the androgen receptor which plays a significant role in the signaling pathway involved in increase in ovulation rate; which consequently can have a tremendous effect on average litter size.

Coronavirus disease 2019 associated mucormycosis meandering its way into the orbit: a pictorial review.

BACKGROUND: There has been a recent deluge of coronavirus disease 2019 associated mucormycosis in our country. It affects the paranasal sinuses; however, it has a rapid extrasinus progression (the orbit being most common), which can be fatal if not detected early. It may meander into the orbit through various foramina without frank bone destruction. METHODS: This paper reviews the various gateways of the spread of coronavirus disease 2019 associated mucormycosis to the orbit, even before advent of bone destruction or ocular symptoms. Plausible pathways of invasion and subtle imaging findings are depicted, to enable an early diagnosis. RESULTS: Relevant anatomy and imaging examples have been illustrated to familiarise the surgeons with various routes of coronavirus disease 2019 associated mucormycosis spread to the orbit. Emphasis is laid on searching for subtle imaging findings for the detection of early orbital invasion. CONCLUSION: Early detection and extension of coronavirus disease 2019 associated mucormycosis is facilitated by knowledge of its gateways of spread, which aids the surgeon in prognostication and planning of the surgical approach.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

High dimensional profiling identifies specific immune types along the recovery trajectories of critically ill COVID19 patients.

The COVID-19 pandemic poses a major burden on healthcare and economic systems across the globe. Even though a majority of the population develops only minor symptoms upon SARS-CoV-2 infection, a significant number are hospitalized at intensive care units (ICU) requiring critical care. While insights into the early stages of the disease are rapidly expanding, the dynamic immunological processes occurring in critically ill patients throughout their recovery at ICU are far less understood. Here, we have analysed whole blood samples serially collected from 40 surviving COVID-19 patients throughout their recovery in ICU using high-dimensional cytometry by time-of-flight (CyTOF) and cytokine multiplexing. Based on the neutrophil-to-lymphocyte ratio (NLR), we defined four sequential immunotypes during recovery that correlated to various clinical parameters, including the level of respiratory support at concomitant sampling times. We identified classical monocytes as the first immune cell type to recover by restoration of HLA-DR-positivity and the reduction of immunosuppressive CD163 + monocytes, followed by the recovery of CD8 + and CD4 + T cell and non-classical monocyte populations. The identified immunotypes also correlated to aberrant cytokine and acute-phase reactant levels. Finally, integrative analysis of cytokines and immune cell profiles showed a shift from an initially dysregulated immune response to a more coordinated immunogenic interplay, highlighting the importance of longitudinal sampling to understand the pathophysiology underlying recovery from severe COVID-19.

High-pressure monoclinic-monoclinic transition in fergusonite-type HoNbO4.

In this paper we perform a high-pressure (HP) study of fergusonite-type HoNbO4. Powder x-ray diffraction experiments andab initiodensity-functional theory (DFT) simulations provide evidence of a phase transition at 18.9(1.1) GPa from the monoclinic fergusonite-type structure (space group I2/a) to another monoclinic polymorph described by space group P21/c. The phase transition is reversible and the HP structural behavior is different than the one previously observed in related niobates. The HP phase remains stable up to 29 GPa. The observed transition involves a change in the Nb coordination number from 4 to 6, and it is driven by mechanical instabilities. We have determined the pressure dependence of unit-cell parameters of both phases and calculated their room-temperature equation of state. For the fergusonite-phase we have also obtained the isothermal compressibility tensor. In addition to the HP studies, we report ambient-pressure Raman and infrared (IR) spectroscopy measurements. We have been able to identify all the active modes of fergusonite-type HoNbO4, which have been assigned based upon DFT calculations. These simulations also provide the elastic constants of the different structures and the pressure dependence of the Raman and IR modes of the two phases of HoNbO4. According toab initiocalculations, the reported phase transition is related to a mechanical instability and a phonon softening.

Systemic lupus erythematosus presenting with holocord myelitis.

This is a report of a case of a 25-year-old woman, who presented with a rapidly progressive sensory-motor flaccid quadriparesis which had developed over a few days along with bladder and bowel involvement. She had a past history of photosensitive rash and joint pains along with mild-to-moderate grade fever; for which she had never been evaluated. Serological markers for systemic lupus erythematosus (SLE) were strongly positive and helped in establishing the diagnosis of SLE-related holocord myelitis. High-dose intravenous glucocorticoid followed by intravenous pulse cyclophosphamide was used to treat her and there was a significant improvement. In this case report, the diagnosis of SLE was made for the first time in a patient presenting with holocord myelitis.

Trends in body mass index before and after diagnosis of hidradenitis suppurativa.

BACKGROUND: A temporal relationship between hidradenitis suppurativa (HS) and obesity has not been established. OBJECTIVES: To compare baseline body mass index (BMI) and change in BMI for patients with HS and controls before and after diagnosis. METHODS: We performed a retrospective case-control analysis of 1284 patients with HS and controls matched for age, sex, race and calendar year between 1 January 1999 and 9 September 2019. BMI 7 years prior to first HS diagnosis, and rate of BMI change, were compared for patients with HS and controls using linear mixed effects models. RESULTS: Baseline BMI was higher among patients with HS than controls [mean difference 3·03 kg m-2 , 95% confidence interval (CI) 2·44-3·62; P < 0·001)]. This difference was larger for women [mean difference 3·37 kg m-2 (95% CI 2·73-4·01)] than men [mean difference 1·27 kg m-2 (95% CI - 0·20-2·73; interaction P = 0·01)], and for patients with HS diagnosed before age 40 years [mean difference 4·10 kg m-2 (95% CI 3·15-5·06)] than those diagnosed after age 40 years [mean difference 2·38 kg m-2 (95% CI 1·63-3·12; interaction P < 0·001)]. Prior to diagnosis, average annual increase in BMI among patients with HS was slightly higher than controls. There was no statistically significant change in annual BMI among patients with HS following diagnosis. CONCLUSIONS: Baseline BMI and, to a lesser extent, rate of BMI change appear to be risk factors for developing HS. The influence of BMI may play a larger role among female patients and younger patients.

Validation of global item for assessing impact on quality of life of patients with hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease. The HS core outcome set calls for a patient global assessment (PtGA). OBJECTIVES: To assess the validity, reliability and responsiveness of a candidate single-item PtGA for HS-specific health-related quality of life (HRQoL). METHODS: Cognitive debriefing interviews were conducted with patients with HS in Denmark and the USA. A cross-sectional observational study was done with adults with HS in the USA and Denmark. Candidate PtGA item, demographic items and multiple patient-reported scales - the Hidradenitis Suppurativa Quality of Life (HiSQOL), Dermatology Life Quality Index (DLQI) and numerical rating scale (NRS) for pain - were concurrently administered to evaluate convergent and known-groups validity. Scales with a single-item assessment of change were readministered 24-72 h later, to evaluate reliability and responsiveness. RESULTS: After cognitive debriefing, the candidate PtGA for HS-specific HRQoL was finalized with five response levels. Convergent validity of the PtGA was supported by significant correlations with HiSQOL score [r = 0·79, 95% confidence interval (CI) 0·75-0·82] and DLQI (r = 0·78, 95% CI 0·74-0·82). The PtGA displayed known-groups validity with DLQI score bands based on significance of an anova (P < 0·001). Good test-retest reliability was supported by the intraclass correlation coefficient (0·82, 95% CI 0·78-0·85) for those who reported stable HS. Responsiveness was assessed by differences in PtGA score against a patient-reported assessment of change, which showed significant differences towards improvement. CONCLUSIONS: The single-item PtGA exhibits reliability, validity and responsiveness in assessing HS-specific HRQoL in HS, making it a good provisional tool for HS clinical research.

Computed tomographic analysis of the prevalence of International Frontal Sinus Anatomy Classification cells and their association with frontal sinusitis.

OBJECTIVES: To determine the radiological prevalence of frontal cells according to the International Frontal Sinus Anatomy Classification in patients undergoing computed tomography of the paranasal sinuses for clinical symptoms of chronic rhinosinusitis, and to examine the association between cell classification and frontal sinusitis development. METHODS: A total of 180 (left and right) sides of 90 patients were analysed. The prevalence of each International Frontal Sinus Anatomy Classification cell was assessed. Logistic regression analysis was used to compare the distribution of various cells in patients with and without frontal sinusitis. RESULTS: The agger nasi cell was the most commonly occurring cell, seen in 95.5 per cent of patients. The prevalence rates for supra agger cells, supra agger frontal cells, supra bullar frontal cells, supra bullar cells, supra-orbital ethmoid cells and frontal septal cells were 33.3 per cent, 22.2 per cent, 21.1 per cent, 36.1 per cent, 39.4 per cent and 21.1 per cent, respectively. There was no significant difference in the occurrence of any of the cell types in patients with frontal sinusitis compared to those without (p > 0.05). CONCLUSION: The presence of any of the International Frontal Sinus Anatomy Classification cells was not significantly associated with frontal sinusitis.

Cardiological society of India document on safety measure during echo evaluation of cardiovascular disease in the time of COVID-19.

An echocardiographic investigation is one of the key modalities of diagnosis in cardiology. There has been a rising presence of cardiological comorbidities in patients positive for COVID-19. Hence, it is becoming extremely essential to look into the correct safety precautions, healthcare professionals must take while conducting an echo investigation. The decision matrix formulated for conducting an echocardiographic evaluation is based on presence or absence of cardiological comorbidity vis-à-vis positive, suspected or negative for COVID-19. The safety measures have been constructed keeping in mind the current safety precautions by WHO, CDC and MoHFW, India.

Low-dose ACTH test for evaluation of hypothalamus-pituitary-adrenal axis preoperatively and 3-month follow-up in non-functioning pituitary adenomas.

BACKGROUND: Peri-operative glucocorticoids are routinely administered to patients undergoing trans-sphenoidal surgery for non-functional pituitary adenomas (NFPA) irrespective of hypothalamus-pituitary-adrenal (HPA) axis status. PURPOSE: Evaluation of HPA axis before and 12 weeks after endoscopic trans-sphenoidal adenomectomy (E-TSA) utilizing low-dose (1 µg) ACTH stimulation test (LDACTH) to determine the need for glucocorticoid administration in patients with NFPA. We also determined the factors that can predict occurrence of hypocortisolism at 12 weeks after surgery. METHODS: Sixty-three consecutive patients with NFPA requiring surgical excision were enrolled in this study. Glucocorticoids were administered to patients with demonstrable hypocortisolism [preoperative peak cortisol < 16 µg/dL during LDACTH test, postoperative day 3 (POD-3) 0800 hrs Cortisol < 8 µg/dL or stimulated cortisol (LDACTH) < 16 µg/dL at 12 weeks]. RESULTS: Hypocortisolism was present in 43 patients (68.2%) pre-operatively and persisted in 33 patients (52.4%) on POD-3. Thirty-three patients (52.4%) had hypocortisolism at 12 weeks after surgery. Eleven patients (17.4%) did not require glucocorticoids during the entire study period and 30 patients (47.6%) did not require glucocorticoids after 3 months. None of the patients developed adrenal crisis during the study. Hypocortisolism on the third post-operative day was the single significant predictor of hypocortisolism at 12 weeks after the surgery. There was a significant correlation between POD-3 0800 hrs cortisol ≥ 8µg/dL and stimulated cortisol (LDACTH) ≥16µg/dL at 12 weeks (r = 0.62, p < 0.0001). POD-3 0800 hrs cortisol ≥ 8 µg/dL had 73% sensitivity and 79% specificity in predicting eucortisolism at 12 weeks. CONCLUSIONS: HPA function is preserved in significant proportion of NFPA patients undergoing E-TSA. Perioperative glucocorticoids should be given only in patients with demonstrable preoperative hypocortisolism on 1 µg ACTH test. Postoperative day 3 0800 hrs cortisol is a reasonable predictor of HPA axis status at 12 weeks after surgery.