A laboratory perspective on accelerating preparatory processes before earthquakes and implications for foreshock detectability.

Dynamic failure in the laboratory is commonly preceded by many foreshocks which accompany premonitory aseismic slip. Aseismic slip is also thought to govern earthquake nucleation in nature, yet, foreshocks are rare. Here, we examine how heterogeneity due to different roughness, damage and pore pressures affects premonitory slip and acoustic emission characteristics. High fluid pressures increase stiffness and reduce heterogeneity which promotes more rapid slip acceleration and shorter precursory periods, similar to the effect of low geometric heterogeneity on smooth faults. The associated acoustic emission activity in low-heterogeneity samples becomes increasingly dominated by earthquake-like double-couple focal mechanisms. The similarity of fluid pressure increase and roughness reduction suggests that increased stress and geometric homogeneity may substantially shorten the duration of foreshock activity. Gradual fault activation and extended foreshock activity is more likely observable on immature faults at shallow depth.

A smartphone-based standalone fluorescence spectroscopy tool for cervical precancer diagnosis in clinical conditions.

Real-time prediction about the severity of noncommunicable diseases like cancers is a boon for early diagnosis and timely cure. Optical techniques due to their minimally invasive nature provide better alternatives in this context than the conventional techniques. The present study talks about a standalone, field portable smartphone-based device which can classify different grades of cervical cancer on the basis of the spectral differences captured in their intrinsic fluorescence spectra with the help of AI/ML technique. In this study, a total number of 75 patients and volunteers, from hospitals at different geographical locations of India, have been tested and classified with this device. A classification approach employing a hybrid mutual information long short-term memory model has been applied to categorize various subject groups, resulting in an average accuracy, specificity, and sensitivity of 96.56%, 96.76%, and 94.37%, respectively using 10-fold cross-validation. This exploratory study demonstrates the potential of combining smartphone-based technology with fluorescence spectroscopy and artificial intelligence as a diagnostic screening approach which could enhance the detection and screening of cervical cancer.

Cervical pre-cancer classification using entropic features and CNN: In vivo validation with a handheld fluorescence probe.

Cervical cancer is one of the most prevalent forms of cancer, with a lengthy latent period and a gradual onset phase. Conventional techniques are found to be severely lacking in real time detection of disease progression which can greatly enhance the cure rate. Due to their high sensitivity and specificity, optical techniques are emerging as reliable tools, particularly in case of cancer. It has been seen that biochemical changes are better highlighted through intrinsic fluorescence devoid of interference from absorption and scattering. Its effectiveness in in-vivo conditions is affected by the fact that the intrinsic spectral signatures vary from patient to patient, as well as in different population groups. Here, we overcome this limitation by collectively enumerating the subtle changes in the spectral profiles and correlations through an information theory based entropic approach, which significantly amplifies the minute spectral variations. In conjunction with artificial intelligence (AI)/machine learning (ML) tools, it yields high specificity and sensitivity with a small dataset from patients in clinical conditions, without artificial augmentation. We have used an in-house developed handheld probe (i-HHP) for extracting intrinsic fluorescence spectra of human cervix from 110 different subjects drawn from diverse population groups. The average classification accuracy of the proposed methodology using 10-fold cross validation is 93.17%. A combination of polarised fluorescence spectra from i-HHP and the proposed classifier is proven to be minimally invasive with the ability to diagnose patients in real time. This paves the way for effective use of relatively smaller sized sensitive fluorescence data with advanced AI/ML tools for early cervical cancer detection in clinics.

Neuronal activity drives IGF2 expression from pericytes to form long-term memory.

Investigations of memory mechanisms have been, thus far, neuron centric, despite the brain comprising diverse cell types. Using rats and mice, we assessed the cell-type-specific contribution of hippocampal insulin-like growth factor 2 (IGF2), a polypeptide regulated by learning and required for long-term memory formation. The highest level of hippocampal IGF2 was detected in pericytes, the multi-functional mural cells of the microvessels that regulate blood flow, vessel formation, the blood-brain barrier, and immune cell entry into the central nervous system. Learning significantly increased pericytic Igf2 expression in the hippocampus, particularly in the highly vascularized stratum lacunosum moleculare and stratum moleculare layers of the dentate gyrus. Igf2 increases required neuronal activity. Regulated hippocampal Igf2 knockout in pericytes, but not in fibroblasts or neurons, impaired long-term memories and blunted the learning-dependent increase of neuronal immediate early genes (IEGs). Thus, neuronal activity-driven signaling from pericytes to neurons via IGF2 is essential for long-term memory.

Smartphone-based fluorescence spectroscopic device for cervical precancer diagnosis: a random forest classification of in vitro data.

Cervical cancer can be treated and cured if diagnosed at an early stage. Optical devices, developed on smartphone-based platforms, are being tested for this purpose as they are cost-effective, robust, and field portable, showing good efficiency compared to the existing commercial devices. This study reports on the applicability of a 3D printed smartphone-based spectroscopic device (3D-SSD) for the early diagnosis of cervical cancer. The proposed device has the ability to evaluate intrinsic fluorescence (IF) from the collected polarized fluorescence (PF) and elastic-scattering (ES) spectra from cervical tissue samples of different grades. IF spectra of 30 cervical tissue samples have been analyzed and classified using a combination of principal component analysis (PCA) and random forest (RF)-based multi-class classification algorithm with an overall accuracy above 90%. The usage of smartphone for image collection, spectral data analysis, and display makes this device a potential contender for use in clinics as a regular screening tool.

Excessive Protein Accumulation and Impaired Autophagy in the Hippocampus of Angelman Syndrome Modeled in Mice.

BACKGROUND: Angelman syndrome (AS), a neurodevelopmental disorder caused by abnormalities of the 15q11.2-q13.1 chromosome region, is characterized by impairment of cognitive and motor functions, sleep problems, and seizures. How the genetic defects of AS produce these neurological symptoms is unclear. Mice modeling AS (AS mice) accumulate activity-regulated cytoskeleton-associated protein (ARC/ARG3.1), a neuronal immediate early gene (IEG) critical for synaptic plasticity. This accumulation suggests an altered protein metabolism. METHODS: Focusing on the dorsal hippocampus (dHC), a brain region critical for memory formation and cognitive functions, we assessed levels and tissue distribution of IEGs, de novo protein synthesis, and markers of protein synthesis, endosomes, autophagy, and synaptic functions in AS mice at baseline and following learning. We also tested autophagic flux and memory retention following autophagy-promoting treatment. RESULTS: AS dHC exhibited accumulation of IEGs ARC, FOS, and EGR1; autophagy proteins MLP3B, SQSTM1, and LAMP1; and reduction of the endosomal protein RAB5A. AS dHC also had increased levels of de novo protein synthesis, impaired autophagic flux with accumulation of autophagosome, and altered synaptic protein levels. Contextual fear conditioning significantly increased levels of IEGs and autophagy proteins, de novo protein synthesis, and autophagic flux in the dHC of normal mice, but not in AS mice. Enhancing autophagy in the dHC alleviated AS-related memory and autophagic flux impairments. CONCLUSIONS: A major biological deficit of AS brain is a defective protein metabolism, particularly that dynamically regulated by learning, resulting in stalled autophagy and accumulation of neuronal proteins. Activating autophagy ameliorates AS cognitive impairments and dHC protein accumulation.

Improving quality of antenatal care services in a high case load tertiary care teaching hospital (Ganesh Shankar Vidyarthi Memorial (GSVM) Medical College) in Kanpur, Uttar Pradesh, India.

In India, half of all pregnant women between the ages of 15 and 49 years are anaemic. In Uttar Pradesh (UP), this figure is slightly higher at 51%. Unfortunately, only 5.4% pregnant women received full antenatal care (ANC) (National Family Health Survey 4, 2015-2016). A formative research conducted in UP in 2016 found that only 9% of pregnant women in UP consume the five recommended food groups, as per global recommendations.Ganesh Shankar Vidyarthi Memorial Medical College Hospital is one of the four high case load tertiary care facilities in Kanpur, UP, with an obstetrics and gynaecology (OBGY) outpatient department (OPD) of 2500-3000 consultations with delivery load of 250-300 deliveries per month and paediatric OPD of approximately 5400-6000 consultations per month. It was identified that pregnant women visiting the OPD for ANC were not receiving maternal nutrition-related services, and anthropometric measurements to assess nutritional status and gestational weight gain were also not done.The department of OBGY decided to apply the four-step Point of Care Quality Improvement (POCQI) approach using Plan-Do-Study-Act cycle for implementation of the maternal nutrition protocol during ANC.In April 2019, with the support of A&T, the hospital team applied the POCQI methodology to improve ANC service provision. By the end of 2019, the measurement and recording of anthropometric parameters increased to 84% and 74% for height and weight, respectively, from the baseline of zero. Hb testing increased from 58% to 84% and blood pressure (BP) monitoring from zero to 84%. Maternal nutrition counselling was delivered to 76% of the pregnant women visiting the OPD, which was a significant achievement for a new practice introduced into the system.The improved practices identified and implemented by the department are being sustained through active engagement of the staff and supportive leadership of the department of OBGY.

Fermatean fuzzy CRITIC-EDAS approach for the selection of sustainable third-party reverse logistics providers using improved generalized score function.

In today's world, the demand for sustainable third-party reverse logistics providers (S3PRLPs) becomes an increasingly considerable issue for industries seeking improved customer service, cost reduction and sustainability perspectives. However, the assessment and selection of right S3PRLP is a complex uncertain decision-making problem due to involvement of numerous conflicting attributes, imprecise human mind and lack of information. Recently, Fermatean fuzzy set (FFS) has been recognized as one of the suitable tools to tackle the uncertain and inaccurate information. In this paper, we introduce a hybrid methodology based on CRITIC and EDAS methods with Fermatean fuzzy sets (FFSs) to solve the S3PRLP selection problem in which the attributes and decision makers' weights are completely unknown. In this framework, CRITIC approach is applied to calculate the attribute weight and EDAS method is used to evaluate the priority order of S3PRLP options. To do this, a new improved generalized score function (IGSF) is developed with its elegant properties. Also, a formula is discussed to calculate the decision makers' weights based on the developed IGSF. Next, developed framework is applied to assess a case study of S3PRLP selection problem with Fermatean fuzzy information, which elucidates the usefulness and practicality of the proposed method. Finally, comparative study is implemented to show the strength of introduced framework with extant approaches. The outcomes of the work confirm that the introduced approach is more feasible and well-consistent with the other extant approaches.

Autophagy-targeted therapy to modulate age-related diseases: Success, pitfalls, and new directions.

Autophagy is a critical metabolic process that supports homeostasis at a basal level and is dynamically regulated in response to various physiological and pathological processes. Autophagy has some etiologic implications that support certain pathological processes due to alterations in the lysosomal-degradative pathway. Some of the conditions related to autophagy play key roles in highly relevant human diseases, e.g., cardiovascular diseases (15.5%), malignant and other neoplasms (9.4%), and neurodegenerative conditions (3.7%). Despite advances in the discovery of new strategies to treat these age-related diseases, autophagy has emerged as a therapeutic option after preclinical and clinical studies. Here, we discuss the pitfalls and success in regulating autophagy initiation and its lysosome-dependent pathway to restore its homeostatic role and mediate therapeutic effects for cancer, neurodegenerative, and cardiac diseases. The main challenge for the development of autophagy regulators for clinical application is the lack of specificity of the repurposed drugs, due to the low pharmacological uniqueness of their target, including those that target the PI3K/AKT/mTOR and AMPK pathway. Then, future efforts must be conducted to deal with this scenery, including the disclosure of key components in the autophagy machinery that may intervene in its therapeutic regulation. Among all efforts, those focusing on the development of novel allosteric inhibitors against autophagy inducers, as well as those targeting autolysosomal function, and their integration into therapeutic regimens should remain a priority for the field.

COVID-19 control strategies and intervention effects in resource limited settings: A modeling study.

INTRODUCTION: Many countries with weaker health systems are struggling to put together a coherent strategy against the COVID-19 epidemic. We explored COVID-19 control strategies that could offer the greatest benefit in resource limited settings. METHODS: Using an age-structured SEIR model, we explored the effects of COVID-19 control interventions-a lockdown, physical distancing measures, and active case finding (testing and isolation, contact tracing and quarantine)-implemented individually and in combination to control a hypothetical COVID-19 epidemic in Kathmandu (population 2.6 million), Nepal. RESULTS: A month-long lockdown will delay peak demand for hospital beds by 36 days, as compared to a base scenario of no intervention (peak demand at 108 days (IQR 97-119); a 2 month long lockdown will delay it by 74 days, without any difference in annual mortality, or healthcare demand volume. Year-long physical distancing measures will reduce peak demand to 36% (IQR 23%-46%) and annual morality to 67% (IQR 48%-77%) of base scenario. Following a month long lockdown with ongoing physical distancing measures and an active case finding intervention that detects 5% of the daily infection burden could reduce projected morality and peak demand by more than 99%. CONCLUSION: Limited resource settings are best served by a combination of early and aggressive case finding with ongoing physical distancing measures to control the COVID-19 epidemic. A lockdown may be helpful until combination interventions can be put in place but is unlikely to reduce annual mortality or healthcare demand.

Autophagy coupled to translation is required for long-term memory.

An increase in protein synthesis following learning is a fundamental and evolutionarily conserved mechanism of long-term memory. To maintain homeostasis, this protein synthesis must be counterbalanced by mechanisms such as protein degradation. Recent studies reported that macroautophagy/autophagy, a major protein degradation mechanism, is required for long-term memory formation. However, how learning regulates autophagy and recruits it into long-term memory formation remains to be established. Here, we show that inhibitory avoidance in rats significantly increases the levels of autophagy and lysosomal degradation proteins, including BECN1/beclin 1, LC3-II, SQSTM1/p62 and LAMP1, as well as autophagic flux in the hippocampus. Moreover, pharmacological inhibition or targeted molecular disruption of the learning-induced autophagy impairs long-term memory, leaving short-term memory intact. The increase in autophagy proteins results from active translation of their mRNA and not from changes in their total mRNA levels. Additionally, the induction of autophagy requires the immediate early gene Arc/Arg3.1. Finally, in contrast to classical regulation of autophagy in other systems, we found that the increase in autophagy upon learning is dispensable for the increase in protein synthesis. We conclude that coupling between learning-induced translation and autophagy, rather than translation per se, is an essential mechanism of long-term memory.Abbreviations: AAV: adeno-associated virus; ARC/ARG3.1: activity regulated cytoskeletal-associated protein; ATG: autophagy related; DG: dentate gyrus; GFP: green fluorescent protein; IA: inhibitory avoidance; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; ODN: oligodeoxynucleotide; qPCR: quantitative polymerase chain reaction; SBI: SBI0206965; SQSTM1/p62: sequestosome 1; SUnSET: surface sensing of translation; TRAP: translating ribosome affinity purification; ULK1: unc-51 like kinase 1.

A role for CIM6P/IGF2 receptor in memory consolidation and enhancement.

Cation-independent mannose-6-phosphate receptor, also called insulin-like growth factor two receptor (CIM6P/IGF2R), plays important roles in growth and development, but is also extensively expressed in the mature nervous system, particularly in the hippocampus, where its functions are largely unknown. One of its major ligands, IGF2, is critical for long-term memory formation and strengthening. Using CIM6P/IGF2R inhibition in rats and neuron-specific knockdown in mice, here we show that hippocampal CIM6P/IGF2R is necessary for hippocampus-dependent memory consolidation, but dispensable for learning, memory retrieval, and reconsolidation. CIM6P/IGF2R controls the training-induced upregulation of de novo protein synthesis, including increase of Arc, Egr1, and c-Fos proteins, without affecting their mRNA induction. Hippocampal or systemic administration of mannose-6-phosphate, like IGF2, significantly enhances memory retention and persistence in a CIM6P/IGF2R-dependent manner. Thus, hippocampal CIM6P/IGF2R plays a critical role in memory consolidation by controlling the rate of training-regulated protein metabolism and is also a target mechanism for memory enhancement.

Activity- and memory training-induced acetylation of α-tubulin in the hippocampus.

Posttranslational modifications play crucial roles in synaptic plasticity and memory formation. The important role of histone acetylation is well established in these processes. However, activity-dependent regulation of acetylation of non-histone proteins is not well understood. We previously showed that α-tubulin is acetylated in an activity-dependent manner. Here, we show that cyclin-dependent kinase 5 (CDK5) plays an important role in α-tubulin acetylation induced by KCl depolarization or N-methyl-D-aspartate stimulation of the hippocampal slices. In addition, KCl depolarization inhibits the activity of SIRT2, an α-tubulin deacetylase. The inhibitory effect of KCl on SIRT2 activity requires CDK5 activity. Furthermore, α-tubulin acetylation is enhanced by memory training in object recognition task. These results suggest that memory formation may involve α-tubulin acetylation.

Significance of Vitamin D on the Susceptibility of Gestational Diabetes Mellitus - A Meta-Analysis.

Vitamin D plays an important role in glucose tolerance by stimulating insulin secretion and evidences suggest a contradictory result on the association between vitamin D status and risk of developing gestational diabetes mellitus (GDM). The present updated meta-analysis has been undertaken to find out the joined effect of vitamin D status on the risk of effect GDM considering previously published articles. Data were collected through literature search using electronic databases to retrieve relevant published research articles using various combinations of the following keywords, "vitamin D," "vitamin D deficiency," "cholecalciferol," "25-hydroxyvitamin D," "25(OH) D," "gestational diabetes mellitus," and "GDM." A total of 36 studies including 7,596 GDM cases and 23,377 non-GDM controls were involved in this study. Overall, pooled meta-analysis showed that pregnant women diagnosed with GDM have 18% higher risk of GDM risk when compared with controls [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.10-1.25; P = 0.00] with high heterogeneity (I2 = 73.29). The mean difference was also significantly different between cases and controls (OR = -0.18, 95% CI - 0.22 to - 0.14; P = 0.00). Subgroup analysis showed significant results with age more than 30 years, Asian and European regions, and case-control, cross-sectional, and nested case-control study design. Low concentration of vitamin D is associated with the development of GDM. Although in future more studies especially systematically designed clinical trials based on vitamin D supplementation with large sample size on different population are needed to elucidate the exact concentration of vitamin D during pregnancy as well as before and after pregnancy.

Nutritional Status among 6-59 Months Children in A Selected Community of A VDC.

INTRODUCTION: Adequate nutrition is essential for proper growth and development of the child. We conducted a cross-sectional descriptive study to find the prevalence of nutritional status of 6-59 month old Tharu children in Duruwa VDC of Dang District. This study also deliberates the socio-economic and demographic character, maternal and child character and child feeding status of the Tharu community children. METHODS: This study is a descriptive cross sectional study and was done between February and March, 2017 in Tharu community of Duruwa, Dang. Total 189 children of age group 6 - 59 months were selected by using systematic random sampling technique; anthropometric measurements were performed to find the nutritional status of children. Pre-coded questionnaire was used to collect information from caretaker. WHO Anthro version 3.2.2 and SPSS version 20 were used to analyze data. RESULTS: Prevalence of wasting, stunting, and underweight were 25 (13.2%), 51 (27%), and 40 (21.2%) respectively. The prevalence of stunting was seen more in females than in males while underweight was higher among males, whereas wasting was very similar in both sexes. CONCLUSIONS: The findings showed that there is still high prevalence of malnutrition in Tharu children of Duruwa so monitoring of nutrition status in Tharu children should be taken seriously and needs to be addressed.

The impact of marital status on health care utilization among Medicare beneficiaries.

To explain prior literature showing that married Medicare beneficiaries achieve better health outcomes at half the per person cost of single beneficiaries, we examined different patterns of healthcare utilization as a potential driver.Using the Medicare Current Beneficiary Survey (MCBS) data, we sought to understand utilization patterns in married versus currently-not-married Medicare beneficiaries. We analyzed the relationship between marital status and healthcare utilization (classified based on setting of care utilization into outpatient, inpatient, and skilled nursing facility (SNF) use) using logistic regression modeling. We specified models to control for possible confounders based on the Andersen model of healthcare utilization.Based on 13,942 respondents in the MCBS dataset, 12,929 had complete data, thus forming the analytic sample, of whom 6473 (50.3%) were married. Of these, 58% (vs. 36% of those currently-not-married) were male, 45% (vs. 47%) were age >75, 24% (vs. 70%) had a household income below $25,000, 18% (vs. 14%) had excellent self-reported general health, and 56% (vs. 36%) had private insurance. Compared to unmarried respondents, married respondents had a trend toward higher odds of having a recent outpatient visit (unadjusted odds ratio (OR) 1.11, 95% confidence interval (CI) 1.04-1.19, adjusted odds ratio (AOR) 1.10, (CI) 0.99-1.22), and lower odds in the year prior to have had an inpatient stay (AOR 0.84, CI 0.72-0.99) or a SNF stay (AOR 0.55, CI 0.40-0.75).Based on MCBS data, odds of self-reported inpatient and SNF use were lower among married respondents, while unadjusted odds of outpatient use were higher, compared to currently-not-married beneficiaries.

Concentration of FAD as a marker for cervical precancer detection.

We report the ex vivo results of an in-house fabricated portable device based on polarized fluorescence measurements in the clinical environment. This device measures the polarized fluorescence and elastic scattering spectra with 405-nm laser and white light sources, respectively. The dominating fluorophore with 405-nm excitation is flavin adenine dinucleotide (FAD) with a fluorescence peak around 510 nm. The measured spectra are highly modulated by the interplay of scattering and absorption effects. Due to this, valuable information gets masked. To reduce these effects, intrinsic fluorescence was extracted by normalizing polarized fluorescence spectra with polarized elastic scattering spectra obtained. A number of fluorophores contribute to the fluorescence spectra and need to be decoupled to understand their roles in the progression of cancer. Nelder-Mead method has been utilized to fit the spectral profile with Gaussian to decouple the different bands of contributing fluorophores (FAD and porphyrin). The change in concentration of FAD during disease progression manifests in the change in ratio of total area to FWHM of its Gaussian profile. Receiver operating characteristic (ROC) curve analysis has been used to discriminate different grades of cervical precancer by using the ratio as input parameter. The sensitivity and specificity for discrimination of normal samples from CIN I (cervical intraepithelial neoplasia) are 75% and 54%, respectively. Further, the normal samples can be discriminated from CIN II samples with 100% and 82% sensitivity and specificity, respectively, and the CIN I from CIN II samples can also be discriminated with 100% sensitivity and 90% specificity, respectively. The results show that the change in the concentration of (FAD) can be used as a marker to discriminate the different grades of the cancer and biochemical changes at an early stage of the cancer can also be monitored with this technique.

From health for all to universal health coverage: Alma Ata is still relevant.

With increasing adoption of universal health coverage (UHC), the health for all agenda is resurgent around the world. However, after a promising start the first time in 1978, the health for all agenda fizzled over the next decade. This commentary discusses the origin of the health for all agenda in the 1970s and the influence of global politico-economic forces in shaping that agenda, its demise and the resurgence in the form of UHC in the twenty-first century. We discuss UHC's focus on finances and the increasing role of market economy in health care, and the opportunities and risks UHC poses. We conclude by saying that UHC's greater focus on finances is prudent, but in order to achieve its promise, UHC needs to regulate the market based provision of healthcare, and incorporate more of the people and community centered ethos of its earlier iteration from 40 years ago.

Reconsidering the roles of endogenous estrogens and xenoestrogens: the membrane estradiol receptor G protein-coupled receptor 30 (GPR30) mediates the effects of various estrogens.

Estrone (E1) and estriol (E3) are considered "weak" estrogens, which exert suppressive effects through estrogen receptors α and ß. However, recent studies have demonstrated that E1 and E3, as well as estradiol (E2), suppress gonadotropin-releasing hormone-induced luteinizing hormone secretion from bovine gonadotrophs via G-protein-coupled receptor 30, which is expressed in various reproductive organs. Currently, there is a lack of fundamental knowledge regarding E1 and E3, including their blood levels. In addition, xenoestrogens may remain in the body over long time periods because of enterohepatic circulation. Therefore, it is time to reconsider the roles of endogenous estrogens and xenoestrogens for reproduction.