MMR Data Research Articles

Multi-step synthesis, kinetics and in silico explorations of indole-Phenyl-1,2,4-triazole Bi-heterocyclic hybrids unified with 3-substituted benzamides as elastase inhibitors

In the present research work, a library of unique indole-phenyltriazole hybrids comprising 3-substituted-benzamide moiety was synthesized through convergent multi-step strategy. The structural confirmation of all synthesized molecules was corroborated by IR, 1H NMR, 13C MMR, EI-MS and CHN analysis data. The results of in vitro inhibitory potential of novel benzamides against elastase enzyme revealed that all molecules were potent inhibitors and 10d was most active compound among them having IC50 value of (0.197 ± 0.027 µM), relative to the standard (13.421 ± 0.016 µM). The Kinetics mechanism analyzed by Lineweaver-Burk plots which exposed that 10d inhibited this enzyme competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki determined from Dixon plot for compound 10d was 0.85 µM. Moreover, cytotoxicity of these compounds was also profiled by hemolytic activity and it was observed that almost all these benzamides compounds displayed low cytotoxicity. These molecules also exhibited mild cytotoxicity toward red blood cell membrane. In addition, the in silico computational explorations fully supported the in vitro enzyme inhibitory results. The binding energy ranges from -7.1 to -9.1 kcal/mol, which showed that compound possessed good interaction tendencies to the pancreatic elastase target protein. So, it was anticipated from the experimental results and computational investigations of the current research that these derivatives might lead to further research gateways for obtaining better and safe nontoxic medicinal scaffolds for dealing with the elastase related ailments such as lungs diseases, pruritic skin disease and liver infection.

In-hospital and web-based intervention to counteract vaccine hesitancy in very preterm infants\u2019 families: a NICU experience

BackgroundVaccine hesitancy is a global problem, carrying significant health risks for extremely vulnerable population as that of preterm infants. Social media are emerging as significant tools for public health promotion. Our aim was to evaluate both the coverage and the timeliness of routine immunizations in a cohort of preterm infants (< 33 weeks of gestational age) at 24 months of age whose families have been subjected to in-hospital and web-based interventions to counteract vaccine hesitancy.MethodsFor a period of 2 years parents of preterm infants were instructed during their follow up visits by a member of the NICU team to get correct informations about vaccines from a social network page. Vaccination rates of preterm infants were assessed at 24 months of chronological age with an electronic database and compared to both general population and historical cohort.ResultsCoverage and timeliness of vaccinations at 24 months of age of 170 preterm infants were analyzed in December 2019. Gestational age and birth weight median (IQR) were, respectively, 31.0 (5.0) weeks and 1475.0 (843.8) g. Coverage rates were similar to those of the regional population (p > 0.05), while timeliness of administration was significantly delayed compared to the recommended schedule (p < 0.001). Age of administration was not correlated with either body weight and gestational age at birth (Spearman rank, p > 0.05). DTaP-IPV-HBV-Hib 2nd and 3rd doses, MMR and Varicella vaccines coverage data were higher compared to historical cohort (p < 0.05).ConclusionIncreasing vaccine confidence through web-based interventions could have a positive impact on vaccination acceptance of parents of preterm infants, although timeliness results still delayed. There is a strong need to develop different and effective vaccination strategies to protect this very vulnerable population.

Barriers to Antenatal Care Utilization in Indonesia

MMR data in Indonesia fluctuates according to the data source used. Based on Indonesia Demographicand Health Survey data, MMR in Indonesia in 1990 was 390 per 100,000 live births, in 2004/2007 it was228/100,000 live births, then increased sharply in 2008-2012 by 359/100,000 live births. Whereas based onthe 2015 SUPA data, MMR in Indonesia decreased by 305 per 100,000 per live birth. This study aims toanalyze the barrier to ?4 ANC visits during pregnancy. The analysis uses the 2017 Indonesian Demographicand Health Survey data. Stratification and multistage random sampling method get 15,351 respondents.Barrier determination was done using Binary Logistic Regression. The barriers consisted of the followingvariables: young age, low education, high parity, poverty, not having health insurance, not being able to read,not being exposed to the media, never using the internet, not knowing the danger signs of pregnancy, andbelief in traditional birth attendants

Abstract 3975: Tumor mutation burden and microsatellite instability in colorectal cancer

Abstract Introduction In colorectal cancer (CRC), the use of immunotherapy is currently based on the evaluation of microsatellite instability (MSI) for the identification of patients who may benefit from this treatment. Recently, tumour mutation burden (TMB) has been evaluated as a useful biomarker to predict response to immune checkpoint (IO) therapy. TMB can be measured by means of targeted next generation sequencing with panels covering approximately 1 Mb of the human genome. We performed TMB analysis on tumor cell lines and CRC samples and compared the results with MSI status to explore the relationship between these two biomarkers. Materials and methods MSI status was evaluated by means of routine immunohistochemistry (IHC), the Idylla MSI assay (Biocartis) and with fluorescence capillary electrophoresis-based DNA fragment size analysis of a T17 mononucleotide sequences within intron 8 of heat shock protein 110 kDa HSP110 (17 polythymine, T17). TMB evaluation was performed with the Oncomine Tumor Mutation Load Assay (Thermofisher) on the Ion S5XL platform. Data analysis was carried out using Ion Reporter Software v5.6. TMB was calculated as the total number of somatic single nucleotide variants (SNVs) divided by number of bases with sufficient coverage. Results We first evaluated the TMB in 13 tumor cell lines and correlated the results with massively parallel sequencing data from &amp;gt;1600 genes for the same cell lines available on cBioPortal, demonstrating an high correlation between the Oncomine Tumor Mutation Load Assay and the TMB value obtained by wide genetic profiling (R² = 0.976). We next analyzed a cohort of 23 MMR deficient (MMR-D) and 32 MMR-proficient (MMR-P) formalin fixed paraffin embedded (FFPE) CRC, as classified by IHC. The MMR data were compared to TMB and revealed TMB values not in line with the expected results, since some samples in the MMR-D group had low TMB values (TMB range: 5.5-134.4). We re-evaluated the 23 MMR-D samples by means of the Idylla System. The Idylla MSI assay re-classified 7 samples as microsatellite stable (MSS) and categorized the remaining 16 samples as MSI-High (MSI-H). The results were confirmed by the T17 analysis. In the MSS group (n. 39), the mean and median TMB value were 11.48 and 10.39, with TMB ranging from 4.88 to 33.29. The mean and median TMB for the MSI-H group (n. 16) were 43.89 and 38.63, and the TMB values ranged from 19.63 to 134.4. While the medians of the two groups were significantly different (Mann-Whitney test P&amp;lt;0.0001), these data confirm a high heterogeneity of TMB within MSI-H CRC. One MSS case displayed a TMB close to the median TMB of the MSI-H group (TMB: 33.29). The MSS status of this sample was confirmed by the Idylla System. Conclusions These data suggest that routine IHC methods for MSI evaluation can lead to a wrong classification of CRC. On the other hand, TMB assessment might better identify patients who may benefit from IOs within both the MSI-H and the MSS subgroups. Citation Format: Francesca Fenizia, Raffaella Pasquale, Cristin Roma, Francesca Bergantino, Anna Maria Rachiglio, Nicoletta Chicchinelli, Paolo Graziano, Gerardo Botti, Fabiana Tatangelo, Giosuè Scognamiglio, Christopher Allen, Matilde Lambiase, Alessia Iannaccone, Nicola Normanno. Tumor mutation burden and microsatellite instability in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3975.

Hybrid PET/MR Kernelised Expectation Maximisation Reconstruction for Improved Image-Derived Estimation of the Input Function from the Aorta of Rabbits.

Positron emission tomography (PET) provides simple noninvasive imaging biomarkers for multiple human diseases which can be used to produce quantitative information from single static images or to monitor dynamic processes. Such kinetic studies often require the tracer input function (IF) to be measured but, in contrast to direct blood sampling, the image-derived input function (IDIF) provides a noninvasive alternative technique to estimate the IF. Accurate estimation can, in general, be challenging due to the partial volume effect (PVE), which is particularly important in preclinical work on small animals. The recently proposed hybrid kernelised ordered subsets expectation maximisation (HKEM) method has been shown to improve accuracy and contrast across a range of different datasets and count levels and can be used on PET/MR or PET/CT data. In this work, we apply the method with the purpose of providing accurate estimates of the aorta IDIF for rabbit PET studies. In addition, we proposed a method for the extraction of the aorta region of interest (ROI) using the MR and the HKEM image, to minimise the PVE within the rabbit aortic region—a method which can be directly transferred to the clinical setting. A realistic simulation study was performed with ten independent noise realisations while two, real data, rabbit datasets, acquired with the Biograph Siemens mMR PET/MR scanner, were also considered. For reference and comparison, the data were reconstructed using OSEM, OSEM with Gaussian postfilter and KEM, as well as HKEM. The results across the simulated datasets and different time frames show reduced PVE and accurate IDIF values for the proposed method, with 5% average bias (0.8% minimum and 16% maximum bias). Consistent results were obtained with the real datasets. The results of this study demonstrate that HKEM can be used to accurately estimate the IDIF in preclinical PET/MR studies, such as rabbit mMR data, as well as in clinical human studies. The proposed algorithm is made available as part of an open software library, and it can be used equally successfully on human or animal data acquired from a variety of PET/MR or PET/CT scanners.

Image reconstruction of mMR PET data using the open source software STIR.

Simultaneous PET and MR acquisitions have now become possible with the new hybrid Biograph Molecular MR (mMR) scanner from Siemens. The purpose of this work is to create a platform for mMR 3D and 4D PET image reconstruction which would be freely accessible to the community as well as fully adjustable in order to obtain optimal images for a given research task in PET imaging. The proposed platform is envisaged to prove useful in developing novel and robust image bio-markers which could then be adapted for use on the mMR scanner. STIR (Software for Tomographic Image Reconstruction [1]), an open source C++ library, has been used as a basis for this platform. However, a number of practical issues have to be addressed before useful reconstructed images can be obtained. Many of the practical issues have been addressed and reconstructions of two datasets (phantom and human brain) are demonstrated. The reconstruction pipeline involves the following: Conversion of the Siemens Dicom files to the STIR interfile format. Histogramming the emission data. Component-based normalisation. Estimation and correction for attenuation and scatter using atlas based µ-maps [2]. Correction for randoms. Iterative image reconstruction ([3–5]). Two datasets were used: uniform cylinder phantom and FDG-PET human brain scan. Figure ​Figure11 shows the OSEM reconstruction using the of-line version of the Siemens Healthcare reconstruction software which was made available for this project (top); the STIR reconstruction (middle); and the µ-map including the bed component (bottom). Figure 1 Image reconstruction of the phantom using Siemens proprietary software (top) and STIR (middle). Bottom: the MRI derived µ-map. The reconstruction of the FDG human brain dataset is presented in Figure ​Figure22 using Siemens proprietary software (top) and the proposed STIR pipeline (bottom). Figure 2 Image reconstruction of the human brain FDG-PET dataset using Siemens proprietary software (top) and STIR (bottom). It was demonstrated that STIR image reconstruction of PET mMR data is possible paving the way to more advanced models included in the pipeline of 4D PET reconstruction.

Assay result variability during determination of mismatch repair deficiency status using immunohistochemistry: A transatlantic comparative study.

403 Background: Colorectal cancer patients with deficient mismatch repair (dMMR) have significantly fewer recurrences and may respond less well to chemotherapy. Immunohistochemical (IHC) determination of MMR status is therefore recommended to identify patients in whom adjuvant therapy is not indicated, but little is known regarding the variability of assay results. We aimed to define MMR IHC assay variability in formalin-fixed, paraffin-embedded (FFPE) material from the QUASAR-1 colorectal cancer trial contained within heterogeneity-prone tissue microarrays (TMAs) Methods: TMA sections of FFPE material from the QUASAR-1 trial were distributed to 2 independent laboratories (Leeds, UK and Vitro Molecular Laboratories [VML], FL, USA) for MMR IHC assays. Serial TMA sections were stained with MLH1/MSH2 using techniques blinded to the other laboratory. Each stained section was double-scored independently and results compared to determine inter-assay variability. Results: Matched MMR data were available for 1224 cases of MLH1 and 1223 cases of MSH2. Of these, loss of expression of MMR (dMMR) was reported in 160 cases (13.1%) by VML and 179 cases (14.6%) by Leeds. 140 (11.4%) were dMMR in both labs, 20 cases (1.6%) by VML alone and 39 (3.2%) by Leeds alone. Discordant dMMR status was observed in 56/166 (34%) dMMR cases identified with MLH1 and 10/34 (29%) cases identified with MSH2. Kappa coefficients for inter-assay agreement were 0.798 (95% CI = 0.748 - 0.848) for MMR status overall, 0.778 (95% CI = 0.722 - 0.835) for MLH1 and 0.823 (95% CI = 0.714 - 0.932) for MSH2. 85% (33/39) of discordant Leeds dMMR colon cancers were in the right colon where dMMR is more common, compared to 47% of VML discordant dMMR cases. Conclusions: Independent determination of MMR status by IHC on TMAs is associated with excellent inter-assay agreement. The reasons for MMR case discordance are under further investigation. These results further support routine MMR testing by IHC. No significant financial relationships to disclose.

Estimation of foraging territories of Reticulitermes grassei through mark–release–recapture

AbstractSubterranean termites have highly cryptic life habits and their foraging activities are as a rule confined to below‐ground level gallery systems. Mark–release–recapture (MRR) using fat‐soluble histological dyes is a candidate method for the study of foraging dynamics and territories, but has not hitherto been standardized experimentally. A wide range of dye types and concentrations is reported in the literature. In this study, six potential dyes were evaluated at different concentrations for marking workers of Reticulitermes grassei (Clément) (Isoptera: Rhinotermitidae), under laboratory and simulated field conditions. Neutral red (1% wt/wt) was considered the most effective while showing acceptably low toxicity. In a subsequent field trial using dye impregnated into a wooden bait, the MMR procedure was used to map the foraging territory perimeter of a single colony. Assumptions inherent in the interpretation of MMR data are reviewed. To map the foraging territory perimeter by this method, two theoretical approaches are defined (a conservative and a non‐conservative hypothesis). We show that the approach adopted may affect the estimate obtained by as much as 100%. Results are discussed in the context of the ecology and behaviour of subterranean termite colonies.

P.P.5 11 Autosomal dominant congenital fibre type disproportion. Study of a family

Congenital fibre type disproportion (CFTD) is a rare myopathy, with heterogeneous clinical phenotype and inheritance. Muscle biopsy is characteristic, showing predominance and smallness of type 1 fibres. Few cases were studied by magnetic resonance imaging of muscles (mMR). To present mMR data in three cases of CFTD in two successive generations and to analyse topography of muscle involvement and degree of affection. Patients were studied clinically, by muscle biopsy, CK, mMR and neurophysiological exams. MR was performed in a 2-Tesla system, with two sets of T1-weighted axial slices, 6–8 mm thick, of thighs and legs. Each muscle was scored zero (normal) to four (end stage) blindly of clinical data. For each muscle, on both limbs, scores obtained in the three patients were summated and compared between muscles and compartments. The father was 44 years old and his siblings, a girl of 11 and a boy of 9. They had congenital myopathy with hypotonia and delayed motor milestones. All were thin and hypotonic, with arched palate and normal facial and external eye movements. Axial muscle involvement caused scoliosis, severe in the father, moderate and mild in the children. There was diffuse motor deficit with predominance in lower limbs, especially foot and toe dorsiflexors. CK was normal to mildly increased. The father had typical fibre type disproportion in biceps brachii. Two cases had a myopathic pattern in EMG. Total mMR scores were: extensor hallucis longus (18); extensor digitorum longus (18), tibialis anterior (16,5), sartorius (15), adductor brevis (14), adductor magnus (14), adductor longus (13), vastus medialis (12), soleus (12), tibialis posterior (11), peroneus (10), semitendinosus (10), semimembranosus (10), gracilis ( 9), biceps femoris (8), rectus femoris (8), vastus intermedius (8), vastus lateralis (8), gastrocnemius lateralis (7), gastrocnemius medialis (4) Posterior muscles of thighs were relatively spared compared to anterior and medial compartments. Anterior compartments of legs were most affected, followed by deep posterior, superficial posterior and lateral compartments. Scores had correlation with age and clinical severity of disease.

Research note: Estimating maternal deaths averted: A field-based methodology

Tracking progress in the reduction of maternal deaths in developing countries is of great interest at both the national and international levels (e.g. as one of the Millennium Development Goals). To date there have been two approaches to tracking progress: by measuring or estimating maternal mortality ratios (MMRs an “impact” indicator); and by measuring activities designed to avert maternal deaths (“process” indicators) such as proportion of births attended by a skilled person and the availability and use of emergency obstetric care (EmOC). Both of these approaches have their shortcomings. Maternal mortality ratios generally cannot be used to measure change over short periods of time (e.g. 5 years) and wide confidence intervals may make it impossible to say whether a change has actually occurred. Moreover it is difficult to use MMR data to target activities or to link changes in MMR to program activities. As for process indicators while they are helpful in targeting interventions and can show change in a short period of time they do not satisfy the desire to demonstrate progress in terms of reductions in deaths. (excerpt)

A comparison of receiver technologies in borehole MMR and EM surveys

ABSTRACTA series of downhole magnetometric resistivity (DHMMR) and downhole electromagnetic (DHEM) surveys were conducted near Broken Hill, New South Wales, Australia, and at Zinkgruvan, Sweden, to determine how probe and receiver equipment choices affect the amount of noise visible in borehole MMR and EM data. Noise analyses performed on the data, using the standard deviation to gauge the relative noise levels between different probes and receiver systems, indicate that high noise levels in MMR data result primarily from the use of a three‐component EM probe, which has a reduced effective area and hence a higher noise floor compared with a single‐component EM probe. High noise, attributable to cultural sources such as nearby power lines, in either MMR or EM data can be reduced through the use of full‐waveform, multipurpose receiver systems. These systems allow for the use of tapered stacking, which is a more effective method of eliminating coherent noise associated with power‐line transients than the boxcar‐stacking method used by traditional receiver systems.

Development of a new rapid inversion scheme for Total Field Magnetometric Resistivity (TFMMR) data

A large number of geophysical inversion methods have been published, but there are no published efficient technique applied to either of MMR or TFMMR data. One of the important aspect of inverting TFMMR data is its dependence on all three components of the anomalous magnetic field. In the case of inverting TFMMR data using gradient methods, we propose a preprocessing reduction of data to the pole to overcome the problems of the effect of the geomagnetic field direction and dependency of the TFMMR data on all three components. By doing this, we invert the data only using the sensitivity of the vertical anomalous magnetic field. After formulating the expressions for computing the Frechet derivatives for the anomalous vertical component on a homogeneous half space model, the Marquart-Levenberg method (damped least squares method) incorporating the quasi-Newton approximation for updating the Jacobian matrix in successive iterations is employed. As the most time consuming task in inversion process is to calculate the Frechet derivatives, therefore employing such scheme will considerably reduce the computing time and improve the stability of the inversion. An analytical solution for calculating the Frechet derivatives in wavenumber domain for all mesh nodes component for a homogeneous half space model is developed first. Next for recovering 2-D models, every 4 by 3 element in the x and z directions respectively constitute a resistivity block. This block parametrisation allows for recovering the sharp resistivity contrasts which occur in mineral exploration prospecting or shallow surface experiments. Assuming a linear variation of transformed electric potential and its gradient over the boundary of the elements, we may derive the discretised form of derivative equations. The efficiency and accuracy of the proposed scheme is demonstrated using a set of synthetic data from a double vertical dike model.

Large-scale statistical study of Scanning Multichannel Microwave Radiometer (SMMR) data over Antarctica

AbstractSMMR data over Antarctica have been statistically analysed for four different periods of 1 year (1981) and compared to geophysical data such as surface temperature, snow-accumulation rate and topography. The spatial variations of the microwave signature are stable with time. Although the ten channels are highly correlated, principal-component analysis reveals the importance of polarization and frequency. The difference between brightness temperatures at the two polarizations is found to be dependent on the atmospheric water-vapour fluxes over the ice sheet, which modify the temperature-accumulation ratio and therefore the snow stratification. The brightness-temperature gradient with frequency is related to the topography of the central plateau area. A more important subsidence over diverging areas could explain the different structure of the accumulated snow.

Large-scale statistical study of Scanning Multichannel Microwave Radiometer (SMMR) data over Antarctica

AbstractSMMR data over Antarctica have been statistically analysed for four different periods of 1 year (1981) and compared to geophysical data such as surface temperature, snow-accumulation rate and topography. The spatial variations of the microwave signature are stable with time. Although the ten channels are highly correlated, principal-component analysis reveals the importance of polarization and frequency. The difference between brightness temperatures at the two polarizations is found to be dependent on the atmospheric water-vapour fluxes over the ice sheet, which modify the temperature-accumulation ratio and therefore the snow stratification. The brightness-temperature gradient with frequency is related to the topography of the central plateau area. A more important subsidence over diverging areas could explain the different structure of the accumulated snow.