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High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecologic malignancy in industrialized countries and has limited treatment options. Targeting ataxia-telangiectasia and Rad3-related/cell-cycle checkpoint kinase 1 (CHK1)-mediated S-phase and G2–M-phase cell-cycle checkpoints has been a promising therapeutic strategy in HGSOC. To improve the efficacy of CHK1 inhibitor (CHK1i), we conducted a high-throughput drug combination screening in HGSOC cells. PI3K/mTOR pathway inhibitors (PI3K/mTORi) showed supra-additive cytotoxicity with CHK1i. Combined treatment with CHK1i and PI3K/mTORi significantly attenuated cell viability and increased DNA damage, chromosomal breaks, and mitotic catastrophe compared with monotherapy. PI3K/mTORi decelerated fork speed by promoting new origin firing via increased CDC45, thus potentiating CHK1i-induced replication stress. PI3K/mTORi also augmented CHK1i-induced DNA damage by attenuating DNA homologous recombination repair activity and RAD51 foci formation. High expression of replication stress markers was associated with poor prognosis in patients with HGSOC. Our findings indicate that combined PI3K/mTORi and CHK1i induces greater cell death in HGSOC cells and in vivo models by causing lethal replication stress and DNA damage. This insight can be translated therapeutically by further developing combinations of PI3K and cell-cycle pathway inhibitors in HGSOC.Significance:Dual inhibition of CHK1 and PI3K/mTOR pathways yields potent synthetic lethality by causing lethal replication stress and DNA damage in HGSOC, warranting further clinical development.

Toll-like receptor 4 (TLR4) is an integral factor in the initiation of the innate immune response and plays an important role in cardiovascular diseases such as hypertension and myocardial infarction. Previous studies from our lab demonstrated that central TLR4 blockade reduced cardiac TLR4 expression, attenuated hypertension, and improved cardiac function. However, the contribution of cardiac specific TLR4 to the development of hypertension and cardiac remodeling is unknown. Therefore, we hypothesized that cardiomyocyte specific knockdown of TLR4 would have beneficial effects on hypertension, cardiac hypertrophy, and remodeling. To test this hypothesis, cardiomyocyte-specific TLR4 knockdown (cTLR4KO) mice were generated by crossing floxed TLR4 mice with Myh6-Cre mice, and subjected to angiotensin II (Ang II, 1 µg/kg/min or vehicle for 14 days) hypertension model. Blood pressure measurements using radio telemetry revealed no differences in baseline mean arterial pressure between control littermates and cTLR4KO mice (103 ± 2 vs. 105 ± 3 mmHg, p > 0.05). Ang II-induced hypertension (132 ± 2 vs. 151 ± 3 mmHg, p p

SETTING: The Kerala health system in India has more than 25 years of decentralised implementation experience. Decentralization could assist in addressing health disparities such as gender, disability, and migration. OBJECTIVE: To explore how inequity issues comprising gender, disability and internal migrations were being addressed at present by the decentralised Kerala health system. DESIGN: Our approach was qualitative, using document review, key informant interviews and in-depth interviews with policy makers, health staff and other stakeholders. RESULTS: Gender aspects were incorporated into planning and budgeting, with 10% funds earmarked for women. Projects were gender-specific to women, and within conventional social roles of livelihood, welfare or reproductive health. Recently, transgender focused projects were also initiated. Schemes for people with disabilities remained welfare-centric and driven by top-down policies. The local governments performed beneficiary identification and benefit disbursal. Migrant health aspects were focused on infectious diseases surveillance and later living conditions of migrant workers. CONCLUSION: The importance that health systems place on socioeconomic determinants of health and fundamental human rights is reflected in the health interventions for marginalised communities. In Kerala, there is now a passive application of central rules and a reluctance to utilise local platforms. Changing this is a necessary condition for achieving equal development.

Seizure generation, propagation, and termination occur through spatiotemporal brain networks. In this paper, we demonstrate the significance of large-scale brain interactions in high-frequency (80–200Hz) for the identification of the epileptogenic zone (EZ) and seizure evolution. To incorporate the continuity of neural dynamics, here we have modeled brain connectivity constructed from stereoelectroencephalography (SEEG) data during seizures using multilayer networks. After introducing a new measure of brain connectivity for temporal networks, named multilayer eigenvector centrality (mlEVC), we applied a consensus hierarchical clustering on the developed model to identify the EZ as a cluster of nodes with distinctive brain connectivity in the ictal period. Our algorithm could successfully predict electrodes inside the resected volume as EZ for 88% of participants, who all were seizure-free for at least 12 months after surgery. Our findings illustrated significant and unique desynchronization between EZ and the rest of the brain in the early to mid-seizure. We showed that aging and the duration of epilepsy intensify this desynchronization, which can be the outcome of abnormal neuroplasticity. Additionally, we illustrated that seizures evolve with various network topologies, confirming the existence of different epileptogenic networks in each patient. Our findings suggest not only the importance of early intervention in epilepsy but possible factors that correlate with disease severity. Moreover, by analyzing the propagation patterns of different seizures, we demonstrate the necessity of collecting sufficient data for identifying epileptogenic networks.

With the surge of cases during the third wave of COVID-19, India faced a number of Mucormycosis cases, a rare but potentially fatal fungal infection, caused by the mucormycetes. The increased prevalence of Mucormycosis among COVID-19 patients may be associated with increased use of steroids, or the possible immunocompromised state caused by SARS-CoV2 or coexisting conditions such as diabetes mellitus. Presenting a case of Rhinomaxillary Mucormycosis where patient presented with a complaint of ulcerative lesion on palate. A diagnosis of Mucormycosis was established after Contrast Enhanced Computed Tomography (CECT) and cytology. Management was planned with antifungal therapy and surgical intervention. Due to immunocompromised state patient couldn’t survive

FUS (Fused in sarcoma) is a ubiquitously expressed DNA/RNA binding protein. Mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. While most studies have focused on the role of FUS in motor neuron degeneration, little is known about the effect ofFUSmutations in the whole body, and the impact ofFUSmutations in the correct development of the nervous system. We studied pleiotropic phenotypes in a physiological knock-in mouse model carrying the FUSDelta14 mutation in homozygosity. RNA sequencing was conducting in six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) to identify the genes and pathways altered by the FUSDelta14 mutant protein in the systemic transcriptome. Additionally, brain structural magnetic resonance imaging (MRI) and histological characterisation was conducted in young mice to study the role of FUS mutation in the brain development. FUS mutant protein was upregulated and mislocalised in the cytoplasm in most cells of the tissues analysed. We identified few genes commonly altered in all tissues by this mutation, although most genes and pathways affected were generally tissue-specific. Phenotypic assessment of mice revealed systemic metabolic alterations related to the pathway changes identified. MRI brain scans revealed that homozygous FUSDelta14 brains were smaller and displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with early cognitive impairment and fatal seizures. We demonstrated that the disease aetiology of FUS mutations can include neurodevelopmental and systemic alterations, which should be taken into consideration in the clinic.

Stevens Johnson syndrome (SJS), a life threatening mucocutaneous disease can present with many variations and rapidly worsen in a short period of time. Various etiologies are associated with these conditions, with adverse drug reaction being the most common. While the reaction itself is self-limited, little is known about the frequency and risk factors associated with long term SJS sequelae. Presenting a case of a 40 years old male patient who presented to our dental OPD with the chief complaint of burning sensation in the mouth with complete loss of eyesight, all these resultant due to treatment of Stevens Johnson Syndrome. Therapeutic management was done after proper investigations. This case emphasizes the importance of recognition of long term sequelae of Stevens Johnson syndrome as this is a rare but serious condition that must be diagnosed and treated appropriately. Clinicians should be aware of the potential for long term complications among Stevens Johnson survivors.

Intro: To address gaps in intracerebral hemorrhage (ICH) outcomes, acquisition of long-term data is necessary and resource intensive. We present our experience from follow-up of ICH patients across a 7-hospital certified stroke healthcare system. Methods: From 01/21 to 07/22, follow-up calls were made to adult non-traumatic ICH patients at 30, 90, 180, and 365-day timepoints (TP) post discharge. Consent was obtained at first successful contact, followed by collection of functional, cognitive, and quality of life outcomes. Trained research staff made multiple attempts (calls per patient) to complete assessment at each TP. An attempt was deemed successful if contact was made with a patient/proxy. We report overall and TP-specific rates of successful contact, consent, and completion using logistic regression. We also report the association of individual call success with attempt number and day of week. Results: Overall, 2,214 call attempts were made for 375 patients, of whom 246 (70.7%) were successfully contacted at least once. Of contacted, 173 (70.3%) consented, and 147 consented patients (85.0%) completed all assessments at one or more TPs (Fig A). Proportion of successful contact at 365-day (60.7%) was significantly higher compared to other TPs (Fig B). Consent rate was non-significantly higher for 30 and 90-day TPs (74.4%) compared to 180 and 365-day (68.1%). Conversely, patients were significantly less likely to complete assessments at the first three TPs compared to 365-day. For individual call attempts, first attempts were 1.5-2.4 times more likely to be successful than subsequent attempts, and calls made on Thursdays were 42-52% more likely to be successful. Conclusion: We demonstrate the need to consent patients early in their recovery when they are likely most motivated. As completion rates were lower at early vs. late TPs, we recommend curtailing laborious assessments at early TPs to decrease patient burden and continuing longitudinal follow-up.

Background: Although developments in computational big data methods have enhanced the ability to meaningfully extract information from hospital EMRs, there are inherent gaps in understanding care utilization and long-term patient outcomes outside of in-patient milieu, particularly across hospital systems. Methods: Utilizing registry data from a 7-hospital stroke certified healthcare system serving a large metropolitan, cohorts were identified for Medicare-insured patients with primary discharge diagnoses of acute ischemic stroke (AIS), intracerebral hemorrhage (ICH), or cerebral amyloid angiopathy (CAA). In collaboration with a CMS Qualified Entity which houses health care utilization data for over 80% of the state population (including 100% of Medicare Fee-for-Service), patient records were securely matched and linked. Socio-demographic and enrollment characteristics for matched cohorts are reported. Results: Medical records and claims data were matched for 98.4% of patients (n=6,531) admitted between 05/2016 and 12/2020 (n=5,789 AIS; 696 ICH; 46 CAA). Across all matched patients, the median (IQR) age at hospital admission was 76.0 (69.0-84.0) (54% female; 56% non-Hispanic White; 24% non-Hispanic Black; 13% Hispanic/Latino; median [IQR] Area Deprivation Index: 4 [2-6]). Age-based standard enrollment represented 86% of patients, with the remainder enrolled due to disability or health complications. Median (IQR) number of total years for patients with Part AB and D coverage was 6.9 (5.0-7.0) and 5.4 (2.9-7.0) years, respectively. At the time of reporting, all-cause death rates among Medicare enrollees who sought care are: 33% (AIS), 55% (ICH), and 41% (CAA). Conclusion: In the absence of systematically captured long-term outcomes data, health informatic pipelines that create linkages across multimodal sources provide a valuable framework for enabling longitudinal research on patients throughout and after stroke hospitalizations.

Intro: Incidence of intracerebral hemorrhage (ICH) in the young is increasing but risk factors and outcomes are not well characterized. Methods: Using a stroke-specific bioinformatics pipeline across a 7-hospital certified stroke healthcare system, we identified adult non-traumatic ICH cases between 05/16 and 08/22 and flagged young ICH patients (YIP) aged 18 – 45. We compared sociodemographic, comorbidity, clinical, imaging, and treatment characteristics, and outcomes between YIP and non-YIP using logistic regression. Results: Among 1 869 ICH patients, 187 (10%) were YIP. YIP (vs. Non-YIP) were predominantly privately insured (71.1 % vs. 29.8 %), non-Hispanic Black (33.7% vs. 22.2%), Hispanic (26.7% vs. 21.7%), and single (41.2% vs. 20.5%). A higher proportion of YIP were obese and a lower proportion had pre-existing comorbidities (Figure). A lower proportion of YIP were on statins, antiplatelets, or anticoagulants prior to ICH. A significantly smaller proportion of YIP had large hemorrhage volumes (> 30 ml) and experienced lower rates of in-hospital complications such as delirium and SIRS. A significantly greater proportion of YIP underwent craniotomy and had longer lengths of stay. After adjusting for important clinical and sociodemographic correlates of in-hospital mortality, YIP had a 59% lower likelihood of in-hospital mortality or hospice discharge OR (CI): 0.41 (0.20 – 0.82). Additionally, for outcome assessment, YIP were more likely to be contacted [2.9 (1.26, 8.08)], consented [3.7 (1.8, 7.8)], and complete follow-up survey [1.9 (1.0, 3.8)] than non-YIP. Though 50.5% of YIP had a 90-day mRS >3, there was a 51% lower likelihood of severe disability or death in YIP vs. non-YIP. Conclusion: YIP poses a high morbidity burden and understanding long-term functional and cognitive outcomes is important. High follow-up rates provide an opportunity for engaging this often overlooked and underrepresented cohort of critically ill patients in future research.

Cancers of any type are life-threatening diseases and totally hamper normal body functions. One of the leading causes of death in both adults and children is malignant brain tumors. Asa result, detecting brain tumors in their early stages is critical for accurate diagnosis. Magnetic resonance imaging (MRI) is commonly used to diagnose brain tumors. Brain tumors are complex due to extremely erratic shapes and locations and are challenging to fully understand the nature of the tumor. For MRI analysis, a skilled neurosurgeon is also required. Because there are frequently insufficient highly trained medical experts and a general lack of knowledge about tumors in developing countries, obtaining results from MRIs can be extremely difficult and time-consuming. To overcome this drawback of this, proposed a novel Convolution Neural Network(CNN)with BrainNet for the multiclass classification of tumors. The proposed BrianNet performs better than transfer learning models VGG13, VGG16, VGG19, Squeeznet, and InceptionResV2 which are pre-trained on the Imagenet dataset. The proposed CNN (BrainNet) architecture achieved a training accuracy of 99.96% and test accuracy of 97.71% and an average precision of 94.75%. Medical professionals can classify tumours with the aid of the proposed work.

B-cell acute lymphoblastic leukemia (ALL) is derived from an accumulation of malignant, immature B cells in the bone marrow and blood. Relapse due, in part, to the emergence of tumor cells that are resistant to front line standard chemotherapy is associated with poor patient outcomes. This challenge highlights the need for new treatment strategies to eliminate residual chemoresistant tumor cells. Based on the use of pitavastatin in acute myeloid leukemia (AML), we evaluated its efficacy in an REH ALL cell line derived to be resistant to vincristine. We found that pitavastatin inhibited the proliferation of both parental and vincristine-resistant REH tumor cells at an IC50 of 449 nM and 217 nM, respectively. Mitochondrial bioenergetic assays demonstrated that neither vincristine resistance nor pitavastatin treatment affected cellular oxidative phosphorylation, beta-oxidation, or glycolytic metabolism in ALL cells. In a co-culture model of ALL cells with bone marrow stromal cells, pitavastatin significantly decreased cell viability more robustly in the vincristine-resistant ALL cells compared with their parental controls. Subsequently, NSG mice were used to develop an in vivo model of B-cell ALL using both parental and vincristine-resistant ALL cells. Pitavastatin (10 mg/kg i.p.) significantly reduced the number of human CD45+ REH ALL cells in the bone marrow of mice after 4 weeks of treatment. Mechanistic studies showed that pitavastatin treatment in the vincristine-resistant cells led to apoptosis, with increased levels of cleaved PARP and protein-signaling changes for AMP-activated protein kinase/FoxO3a/Puma. Our data suggest the possible repurposing of pitavastatin as a chemotherapeutic agent in a model of vincristine-resistant B-cell ALL.

Contains fulltext : 291116.pdf (Publisher’s version ) (Open Access) Individuals with intellectual disability (ID) face significant challenges in preventing oral diseases. They also lack access to high-quality oral health care in professional settings. To understand the effects of oral conditions on their lives and health, it is necessary to assess their oral health outcome measures. For those with mild ID, who possess adequate linguistic and cognitive abilities, accessibility features should be incorporated in the dental patient reported outcome (dPRO) measures. But many other individuals often lack the linguistic and cognitive ability to self-report through dPRO measures. While self-reported measures are preferable, requiring dPROs in this population would result in a high amount of missing data and the inability to assess interventions for improving their dental health. Thus, there is a need to use proxy-reported outcome (ProxRO) measures, observer reported outcome (ObsRO) measures, and clinician reported outcome (ClinRO) measures among those with ID. This is also a common approach taken by other specialties that work closely with those with ID, where the measures for activities of daily living and adaptive behavior measures use reporting by caregivers. ProxRO measures in dentistry that were created for infants and young children provide a structure for appropriate adaptations and the creation of relevant outcome measures. Including input from the intensely multidisciplinary teams that provide supports for those with ID is key to creating high-quality measures and oral health interventions for those with ID. 01 januari 2023

Evolution of microbial traits depends on the interaction of a species with its environment as well as with other coinhabiting species. However, our understanding of the evolution of specific microbial traits, such as antibiotic resistance in complex environments is limited. Here, we determine the role of interspecies interactions on the dynamics of nitrofurantoin (NIT) resistance selection among Escherichia coli. We created a synthetic two-species community comprised of two variants of E. coli (NIT susceptible and resistant) and Bacillus subtilis in minimal media with glucose as the sole carbon source. We show that the presence of B. subtilis significantly slows down the selection for the resistant E. coli mutant when NIT is present and that this slowdown is not due to competition for resources. Instead, the dampening of NIT resistance enrichment is largely mediated by extracellular compounds produced by B. subtilis with the peptide YydF playing a significant role. Our results not only demonstrate the impact of interspecies interactions on the evolution of microbial traits but also show the importance of using synthetic microbial systems in unravelling relevant interactions and mechanisms affecting the evolution of antibiotic resistance. This finding implies that interspecies interactions should be considered to better understand and predict resistance evolution in the clinic as well as in nature.

In this paper we consider a generalization of a log-transformed version of the inverse Weibull distribution. Several theoretical properties of the distribution are studied in detail including expressions for its probability density function, reliability function, hazard rate function, quantile function, characteristic function, raw moments, percentile measures, entropy measures, median, mode etc. Certain structural properties of the distribution along with expressions for reliability measures as well as the distribution and moments of order statistics are obtained. Also we discuss the maximum likelihood estimation of the parameters of the proposed distribution and illustrate the usefulness of the model through real life examples. In addition, the asymptotic behaviour of the maximum likelihood estimators are examined with the help of simulated data sets.