Insulin Receptor Associates with Promoters Genome-wide and Regulates Gene Expression.

Insulin receptor (IR) signaling is central to normal metabolic control and dysregulated in prevalent chronic diseases. IR binds insulin at the cell surface and transduces rapid signaling via cytoplasmic kinases. However, mechanisms mediating long-term effects of insulin remain unclear. Here, we show that IR associates with RNA polymerase II in the nucleus, with striking enrichment at promoters genome-wide. The target genes were highly enriched for insulin-related functions including lipid metabolism and protein synthesis and diseases including diabetes, neurodegeneration, and cancer. IR chromatin binding was increased by insulin and impaired in an insulin-resistant disease model. Promoter binding by IR was mediated by coregulator host cell factor-1 (HCF-1) and transcription factors, revealing an HCF-1-dependent pathway for gene regulation by insulin. These results show that IR interacts with transcriptional machinery at promoters and identify a pathway regulating genes linked to insulin's effects in physiology and disease.

Progress in elementary school reading linked to growth of cortical responses to familiar letter combinations within visual word forms.

Learning to read depends on the ability to extract precise details of letter combinations, which convey critical information that distinguishes tens of thousands of visual word forms. To support fluent reading skill, one crucial neural developmental process is one's brain sensitivity to statistical constraints inherent in combining letters into visual word forms. To test this idea in early readers, we tracked the impact of two years of schooling on within-subject longitudinal changes in cortical responses to three different properties of words: coarse tuning for print, and fine tuning to either familiar letter combinations within visual word forms or whole word representations. We then examined how each related to growth in reading skill. Three stimulus contrasts-words versus pseudofonts, words versus pseudowords, pseudowords versus nonwords-were presented while high-density EEG Steady-State Visual Evoked Potentials (SSVEPs, n = 31) were recorded. Internalization of abstract visual word form structures over two years of reading experience resulted in a near doubling of SSVEP amplitude, with increasing left lateralization. Longitudinal changes (decreases) in brain responses to such word form structural information were linked to the growth in reading skills, especially in rapid automatic naming of letters. No such changes were observed for whole word representation processing and coarse tuning for print. Collectively, these findings indicate that sensitivity to visual word form structure develops rapidly through exposure to print and is linked to growth in reading skill. RESEARCH HIGHLIGHTS: Longitudinal changes in cognitive responses to coarse print tuning, visual word from structure, and whole word representation were examined in early readers. Visual word form structure processing demonstrated striking patterns of growth with nearly doubled in EEG amplitude and increased left lateralization. Longitudinal changes (decreases) in brain responses to visual word form structural information were linked to the growth in rapid automatic naming for letters. No longitudinal changes were observed for whole word representation processing and coarse tuning for print.

Nephrotoxicity of Vancomycin in Combination With Beta-Lactam Agents: Ceftolozane-Tazobactam vs Piperacillin-Tazobactam.

BACKGROUND: Vancomycin (VAN)-associated acute kidney injury (AKI) is increased when VAN is combined with certain beta-lactams (BLs) such as piperacillin-tazobactam (TZP) but has not been evaluated with ceftolozane-tazobactam (C/T). Our aim was to investigate the AKI incidence of VAN in combination with C/T (VAN/C/T) compared with VAN in combination to TZP (VAN-TZP). METHODS: We conducted a multicenter, observational, comparative study across the United States. The primary analysis was a composite outcome of AKI and risk, injury, failure, loss, end stage renal disease; Acute Kidney Injury Network; or VAN-induced nephrotoxicity according to the consensus guidelines. Multivariable logistic regression analysis was conducted to adjust for confounding variables and stratified Kaplan-Meir analysis to assess the time to nephrotoxicity between the 2 groups. RESULTS: We included VAN/C/T (n = 90) and VAN-TZP (n = 284) at an enrollment ratio of 3:1. The primary outcome occurred in 12.2% vs 25.0% in the VAN-C/T and VAN-TZP groups, respectively (P = .011). After adjusting for confounding variables, VAN-TZP was associated with increased odds of AKI compared with VAN-C/T; with an adjusted odds ratio of 3.308 (95% confidence interval, 1.560-6.993). Results of the stratified Kaplan-Meir analysis with log-rank time-to-nephrotoxicity analysis indicate that time to AKI was significantly shorter among patients who received VAN-TZP (P = .004). Cox proportional hazards analysis demonstrated that TZP was consistent with the primary analysis (P = .001). CONCLUSIONS: Collectively, our results suggest that the AKI is not likely to be related to tazobactam but rather to piperacillin, which is a component in VAN-TZP but not in VAN-C/T.

Fetal heart rate responses to maternal sleep-disordered breathing.

BACKGROUND: Maternal sleep-disordered breathing is associated with adverse pregnancy outcomes and is considered to be deleterious to the developing fetus. Maternal obesity potentiates sleep-disordered breathing, which, in turn, may contribute to the effect of maternal obesity on adverse fetal outcomes. However, only a few empirical studies have evaluated the contemporaneous effects of maternal sleep-disordered breathing events on fetal well-being. These events include apnea and hypopnea with accompanying desaturations in oxyhemoglobin. OBJECTIVE: This study aimed to reconcile contradictory findings on the associations between maternal apnea or hypopnea events and clinical indicators of fetal compromise. It also sought to broaden the knowledge base by examining the fetal heart rate and heart rate variability before, during, and after episodes of maternal apnea or hypopnea. To accomplish this, we employed overnight polysomnography, the gold standard for ascertaining maternal sleep-disordered breathing, and synchronized it with continuous fetal electrocardiography. STUDY DESIGN: A total of 84 pregnant women with obesity (body mass index >30 kg/m2) participated in laboratory-based polysomnography with digitized fetal electrocardiography recordings during or near 36 weeks of gestation. Sleep was recorded, on average, for 7 hours. Decelerations in fetal heart rate were identified. Fetal heart rate and heart rate variability were quantified before, during, and after each apnea or hypopnea event. Event-level intensity (desaturation magnitude, duration, and nadir O2 saturation level) and person-level characteristics based on the full overnight recording (apnea-hypopnea index, mean O2 saturation, and O2 saturation variability) were analyzed as potential moderators using linear mixed effects models. RESULTS: A total of 2936 sleep-disordered breathing events were identified, distributed among all but 2 participants. On average, participants exhibited 8.7 episodes of apnea or hypopnea per hour (mean desaturation duration, 19.1 seconds; mean O2 saturation nadir, 86.6% per episode); nearly half (n=39) of the participants met the criteria for obstructive sleep apnea. Only 45 of 2936 apnea or hypopnea events were followed by decelerations (1.5%). Conversely, most (n=333, 88%) of the 378 observed decelerations, including the prolonged ones, did not follow an apnea or a hypopnea event. Maternal sleep-disordered breathing burden, body mass index, and fetal sex were unrelated to the number of decelerations. Fetal heart rate variability increased during events of maternal apnea or hypopnea but returned to initial levels soon thereafter. There was a dose-response association between the size of the increase in fetal heart rate variability and the maternal apnea-hypopnea index, event duration, and desaturation depth. Longer desaturations were associated with a decreased likelihood of the variability returning to baseline levels after the event. The mean fetal heart rate did not change during episodes of maternal apnea or hypopnea. CONCLUSION: Episodes of maternal sleep apnea and hypopnea did not evoke decelerations in the fetal heart rate despite the predisposing risk factors that accompany maternal obesity. The significance of the modest transitory increase in fetal heart rate variability in response to apnea and hypopnea episodes is not clear but may reflect compensatory, delimited autonomic responses to momentarily adverse conditions. This study found no evidence that episodes of maternal sleep-disordered breathing pose an immediate threat, as reflected in fetal heart rate responses, to the near-term fetus.

What children do while they wait: The role of self-control strategies in delaying gratification.

Self-control plays an essential role in children's emotional and behavioral adjustment. A central behavioral indicator of self-control is the ability to delay gratification. Few studies have focused on understanding the heterogeneity of self-control behaviors that underlie children's ability to delay gratification. Therefore, we examined the role of spontaneous self-control behaviors (fidgeting, vocalizations, and anticipation/attentional focus toward a reward) in relation to 5-year old children's delay ability using Mischel's delay task (N = 144; Mage = 5.4 years, SD = 0.29). Latent mixture modeling was used to derive three distinct classes of self-control behaviors observed during the delay task: (1) Passive (low fidgeting, low vocalizations, but moderate anticipation), (2) Active (moderate fidgeting, moderate vocalizations, but high anticipation), and (3) Disruptive (high fidgeting, high vocalizations, and high anticipation). Children in the Passive class were more likely to delay the full task time compared with children in the Active class (odds ratio = 1.50, 95 % confidence interval = 1.28-1.81). There were no other differences in delay ability by self-control class. Children whose level of fidgeting and vocalizations matched their level of anticipation (i.e., Passive and Disruptive regulators) were able to delay more successfully than children who were mostly driven by anticipation (Active regulators). Some variation in children's delay ability and use of self-control strategies was explained by sociodemographic differences, specifically maternal age. Findings suggest probing processes underlying children's self-control to identify potential targets for intervention.

Simulating Subject-Specific Aortic Hemodynamic Effects of Valvular Lesions in Rheumatic Heart Disease.

Rheumatic heart disease (RHD) is a neglected tropical disease despite the substantial global health burden. In this study, we aimed to develop a lower cost method of modeling aortic blood flow using subject-specific velocity profiles, aiding our understanding of RHD's consequences on the structure and function of the ascending aorta. Echocardiography and cardiovascular magnetic resonance (CMR) are often used for diagnosis, including valve dysfunction assessments. However, there is a need to further characterize aortic valve lesions to improve treatment options and timing for patients, while using accessible and affordable imaging strategies. Here, we simulated effects of RHD aortic valve lesions on the aorta using computational fluid dynamics (CFD). We hypothesized that inlet velocity distribution and wall shear stress (WSS) will differ between RHD and non-RHD individuals, as well as between subject-specific and standard Womersley velocity profiles. Phase-contrast CMR data from South Africa of six RHD subjects with aortic stenosis and/or regurgitation and six matched controls were used to estimate subject-specific velocity inlet profiles and the mean velocity for Womersley profiles. Our findings were twofold. First, we found WSS in subject-specific RHD was significantly higher (p < 0.05) than control subject simulations, while Womersley simulation groups did not differ. Second, evaluating spatial velocity differences (ΔSV) between simulation types revealed that simulations of RHD had significantly higher ΔSV than non-RHD (p < 0.05), these results highlight the need for implementing subject-specific input into RHD CFD, which we demonstrate how to accomplish through accessible methods.

Using Epigenetic Clocks to Characterize Biological Aging in Studies of Children and Childhood Exposures: a Systematic Review.

Biological age, measured via epigenetic clocks, offers a unique and useful tool for prevention scientists to explore the short- and long-term implications of age deviations for health, development, and behavior. The use of epigenetic clocks in pediatric research is rapidly increasing, and there is a need to review the landscape of this work to understand the utility of these clocks for prevention scientists. We summarize the current state of the literature on the use of specific epigenetic clocks in childhood. Using systematic review methods, we identified studies published through February 2023 that used one of three epigenetic clocks as a measure of biological aging. These epigenetic clocks could either be used as a predictor of health outcomes or as a health outcome of interest. The database search identified 982 records, 908 of which were included in a title and abstract review. After full-text screening, 68 studies were eligible for inclusion. While findings were somewhat mixed, a majority of included studies found significant associations between the epigenetic clock used and the health outcome of interest or between an exposure and the epigenetic clock used. From these results, we propose the use of epigenetic clocks as a tool to understand how exposures impact biologic aging pathways and development in early life, as well as to monitor the effectiveness of preventive interventions that aim to reduce exposure and associated adverse health outcomes.

Chlamydia psittaci -Induced Reactive Infectious Mucocutaneous Eruption With Ocular Involvement.

INTRODUCTION: This report highlights a postinfectious mucocutaneous inflammatory response involving the ocular surface and adnexa after Chlamydophila psittaci exposure. CASE DESCRIPTION: A 35-year-old man presented after a prodrome of upper respiratory symptoms with rash and mucocutaneous blistering involving the ocular and oral mucosa, causing pseudomembranous conjunctivitis and corneal epithelial defects. Extensive inflammatory and infectious workup suggested recent C. psittaci infection. The patient was treated with doxycycline and supportive therapy, whereas the ocular surface was treated with lubrication and prophylactic antibiotics. In follow-up, he has retained excellent visual acuity but required scleral contact lenses to control ocular surface symptoms because of fibrotic changes of the marginal conjunctiva. DISCUSSION: Such blistering inflammation has most commonly been described after pediatric respiratory infections because of Mycoplasma pneumoniae with additional instances related to Chlamydia pneumoniae , Epstein-Barr virus, influenza B, and other stimuli . To the best of our knowledge, this is the first reported case of C. psittaci- induced reactive infectious mucocutaneous eruption (RIME). RIME is a rare parainfectious inflammatory condition with sequelae frequently involving the periocular mucosa. Although systemic and nonocular adverse outcomes in this condition tend to be self-limited, the impact on the ocular surface may be severe, and the consequences to vision may be ongoing, especially if not treated aggressively at the outset.

Solvents and Stabilization in Ionic Liquid Films.

We report the interfacial structures and chemical environments of ionic liquid films as a function of dilution with molecular solvents and over a range of film thicknesses (a few micrometers). Data from spectroscopic ellipsometry and infrared spectroscopy measurements show differences between films comprised of neat ionic liquids, as well as films comprised of ionic liquids diluted with two molecular solvents (water and acetonitrile). While the water-diluted IL films follow thickness trends predicted by the Landau-Levich model, neat IL and IL/MeCN films deviate significantly from predicted behaviors. Specifically, these film thicknesses are far greater than the predicted values, suggesting enhanced intermolecular interactions or other non-Newtonian behaviors not captured by the theory. We correlate film thicknesses with trends in the infrared intensity profiles across film thicknesses and IL-solvent dilution conditions and interpret the changes from expected behaviors as varying amounts of the film volume existing in isotropic (bulk) vs anisotropic (interfacial) states. The hydrogen bonding network of water-diluted ionic liquids is implicated in the agreement of this system with the Landau-Levich model's thickness predictions.

Measuring fetal heart rate and variability: Fetal cardiotocography versus electrocardiography.

Fetal heart rate variability is a key indicator of fetal neurodevelopment and well-being. Most studies have relied on Doppler-based fetal cardiotocography (fCTG) but recent technologies have made fetal electrocardiography (fECG) more widely available. We compared simultaneous recordings of fCTG and fECG in 131 fetuses twice during gestation (28 and 36 weeks) using a commercially available device (Monica AN24). Within-individual correlations for fetal heart rate values, based on averaged data during 50-min recordings, neared 1.0. Continuous and episodic measures of variability were also correlated, particularly at 36 weeks. Data collected during maternal polysomnography at 36 weeks were used to evaluate reliability of variability measures collected during the 50-min recording. Both fCTG- and fECG-derived measures of variability exhibited correspondence with variability during maternal presleep wakefulness and most sleep states. Results did not appreciably differ by data source or method used to calculate variability. fECG monitoring presented challenges, particularly at 28 weeks, when recordings with signal loss of ≤30% were available from only 27% of participants. Success rates improved to 84% at 36 weeks. fCTG was successful in over 90% of participants at each gestational age. Considerations in the selection of fECG versus fCTG in developmental research are discussed.

More than meets the eye: Examining physiological and behavioral regulation during delay of gratification task.

Children continually encounter situations where they must regulate impulsive responses to achieve a goal, requiring both self-control (SC) and delay of gratification. We examined concurrent behavioral SC strategies (fidgeting, vocalizations, anticipation) and physiological regulation (heart rate [HR], respiratory sinus arrhythmia [RSA]) in 126 children (M (SD) = 5.4 (0.29) years) during a standard delay of gratification task. Latent variable models derived latent SC classes and examined the moderating role of HR/RSA on SC and delay ability. Three classes of SC were identified: passive: low fidgeting and vocalizations, moderate anticipation; active: moderate fidgeting, low vocalizations, and high anticipation; and disruptive: moderate fidgeting, high vocalizations, and high anticipation. Children in the active class had the lowest odds of delaying full task time, compared to children in the passive (OR = 0.67, z = -5.25, p < .001) and disruptive classes (OR = 0.76, z = -2.03, p = .04). RSA changes during the task moderated the relationship between SC class and delay ability for children in the active class (aOR = 0.92, z = -3.1, p < .01). Within the group who struggled to delay gratification (active class), a subset exhibiting appropriate autonomic regulation was able to delay. The findings suggest probing congruency of observed behavioral and unobserved physiological regulation.

Fetal heart rate during maternal sleep.

Despite prolonged and cumulative exposure during gestation, little is known about the fetal response to maternal sleep. Eighty-four pregnant women with obesity (based on pre-pregnancy BMI) participated in laboratory-based polysomnography (PSG) with continuous fetal electrocardiogram monitoring at 36 weeks gestation. Multilevel modeling revealed both correspondence and lack of it in maternal and fetal heart rate patterns. Fetal heart rate (fHR) and variability (fHRV), and maternal heart rate (mHR) and variability (mHRV), all declined during the night, with steeper rates of decline prior to 01:00. fHR declined upon maternal sleep onset but was not otherwise associated with maternal sleep stage; fHRV differed during maternal REM and NREM. There was frequent maternal waking after sleep onset (WASO) and fHRV and mHRV were elevated during these episodes. Cross-correlation analyses revealed little temporal coupling between maternal and fetal heart rate, except during WASO, suggesting that any observed associations in maternal and fetal heart rates during sleep are the result of other physiological processes. Implications of the maternal sleep context for the developing fetus are discussed, including the potential consequences of the typical sleep fragmentation that accompanies pregnancy.

To compare the optimal cytoreduction rate in advanced epithelial ovarian cancer stage III/IV after 3 versus 6 cycles of neoadjuvant chemotherapy.

This study aimed to compare the impact of 3 versus 6 cycles of neoadjuvant chemotherapy (NACT) on the optimal cytoreduction in patients of advanced ovarian malignancy during interval debulking surgery (IDS). Thirty patients with advanced-stage IIIc/IV epithelial ovarian cancer, fallopian tube cancer, and primary peritoneal cancer were randomly allocated to receive 6 cycles in the late IDS group versus 3 cycles in early IDS before undergoing interval debulking surgery. A higher percentage of patients achieved optimal cytoreduction in the late IDS group compared to the early IDS group (60 versus 23%) which was statistically significant (p = .010). Giving 6 cycles of NACT before surgery increased the odd of optimal cytoreduction by 10 than giving 3 cycles of NACT which was statistically significant (p = 0.046) Thus, we conclude that administering 6 cycles of neoadjuvant chemotherapy before debulking surgery helps in achieving optimal cytoreduction in a higher number of patients with lesser surgical morbidity.IMPACT STATEMENTWhat is already known on the subject? Currently, there are no established criteria that would help to determine the number of chemotherapy cycles before debulking surgery in patients with advanced ovarian malignancy.What do the results of this study add? Administering 6 cycles of neoadjuvant chemotherapy before debulking surgery helps in achieving optimal cytoreduction in a higher number of patients with lesser surgical morbidity in cases of advanced epithelial ovarian cancer.What are the implications of these findings for clinical practice and/or further research? We conclude that late interval debulking may be used as a treatment option in the advanced stage IIIc/stage IV. However, the findings need to be studied in a larger study group with a longer follow up period.

BRAF V600E mutation in childhood Langerhans cell histiocytosis correlates with multisystem disease and poor survival.

Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia of children with systemic involvement and poor outcome. The altered RAS-RAF-MEK-ERK cell signalling pathway due to somatic mutation of BRAF V600E is the most common genetic abnormality associated with the disease. In the current study, we highlight the frequency of BRAF V600E in our cohort of LCH cases (n = 31) and its relation with clinical outcome. On Real-Time PCR and Sanger sequencing, BRAF V600E was detected in 6/31 (19%) patients. All cases positive for BRAF V600E mutation had multisystem involvement/disseminated disease compared to BRAF mutation negative cases (100% v/s 41%, p = 0.0348). Univariate analysis also revealed significant correlation of mutation positivity with risk category (p = 0.09). The event free survival and overall survival at 36 months for BRAF mutation positive group compared to mutation negative group was 17% v/s 72% (Log rank test p = 0.0110) and 32.5% v/s 82% (p = 0.0330), respectively. In our study, BRAF V600E positivity was low (19%) however, all positive cases had multisystem involvement and a poor three year survival confirming BRAF V600E to be a poor prognostic marker.

Dietary adequacy and nutritional status of Meitei community of Manipur, Northeast India.

Meitei is the main ethnic community that belongs to the north-eastern state of Manipur in India. This community is bestowed with rich biodiverse resources with indigenous foods still form an integral part of their diet. However, limited data on the food and nutrient consumption as well as nutritional status of this community are available. This study was carried out on the children, adolescents and women of reproductive age (WRA) of this community from 12 villages, to determine their food consumption pattern and nutritional status. Basic anthropometry and 24-h dietary intake assessment was conducted. The prevalence of underweight was 27%, stunting was 45% and wasting was 12% in children below 5 years. Stunting was observed among 34% of children 5-17 years of age. About 7% of WRA were undernourished, while 28% were overweight or obese. About 55% of 1-7 year-old children had mean probability adequacy of 12 micronutrients <0.5, and the adequacy of individual micronutrients namely vitamin A, E and calcium were low. Dietary determinants such as low dietary diversity score, dietary species richness and the lowest tertiles of different food groups' intake (except for sugars, fish and sea foods and spices and condiments) predicted micronutrient inadequacy. In addition to a high prevalence of undernutrition in children and adolescents and overnutrition in WRA, the effect of various dietary determinants on micronutrient adequacy in the study group of the Meitei community are reported.

High dietary micronutrient inadequacy in peri-urban school children from a district in South India: Potential for staple food fortification and nutrient supplementation.

Multiple micronutrient deficiencies (MNDs) co-exist, often because of poor intakes and adversely impact health. Habitual diets were assessed in 300 school children (6-17 years old) recruited from two government schools by simple random sampling. Probability of adequacy (PA) for 11 micronutrients and mean probability of adequacy (MPA) was calculated. Haemoglobin, plasma ferritin, folic acid, vitamin B12 and C-reactive protein were estimated. Descriptive statistics and regression analysis were used to estimate magnitude and factors associated with MNDs. The contribution of fortified foods and/or supplements in addressing inadequacies and excessive intakes was modelled. The PA ranged from 0.04 for folate to 0.70 for zinc, and the MPA was 0.27. Prevalence of anaemia (53%), iron deficiency (57%; ID), iron deficiency anaemia (38%; IDA), folate deficiency (24%) and B12 deficiency (43%) was high. Dietary inadequacy of iron, zinc and a low MPA was associated with anaemia and IDA. Inclusion of double fortified salt (DFS), fortified rice (FR) or iron folic acid (IFA) supplements individually in habitual diet reduced probability of iron inadequacy significantly from 82% to ≤13%. Inclusion of DFS and FR simultaneously led to disappearance of iron inadequacy, but risk of excessive intake increased to 16%. Inclusion of DFS, FR and IFA together increased risk of excess iron intake to 40%. Nevertheless, intakes of folate and B12 remained inadequate even with FR and/or IFA. These results indicate a high risk of dietary MNDs in children and suggest need for more systematic intake measurements in representative sample and adjustment of iron dosages to avoid excessive intakes.

Current Status and Recommendations in Multimodal Neuromonitoring.

Every patient in neurocritical care evolves through two phases. Acute pathologies are addressed first. These include trauma, hemorrhagic or ischemic stroke, or neuroinfection. Soon after, the concentration shifts to identifying secondary pathologies like fever, seizures, and ischemia, which may exacerbate the brain injury. Frequent bedside examinations are not sufficient for timely detection and prevention of secondary brain injury (SBI) as per the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care. Multimodality monitoring (MMM) can help in tailoring treatment decisions to prevent such a brain injury. Multimodal neuromonitoring involves data-guided therapeutic interventions by employing various tools and data integration to understand brain physiology. Monitors provide real-time information on cerebral hemodynamics, oxygenation, metabolism, and electrophysiology. The monitors may be invasive/noninvasive and global/regional. We have reviewed such technologies in this write-up. Novel themes like bioinformatics, clinical research, and device development will also be discussed. HOW TO CITE THIS ARTICLE: Ruhatiya RS, Adukia SA, Manjunath RB, Maheshwarappa HM. Current Status and Recommendations in Multimodal Neuromonitoring. Indian J Crit Care Med 2020;24(5):353-360.

Extrapulmonary Features of COVID-19: A Concise Review.

Typical manifestations of coronavirus disease (COVID-19) involve the upper and lower respiratory tract. But as the pandemic surges, we are encountering numerous case reports and series of extrapulmonary presentations of COVID-19 in the outpatient department. Abundant retrospective data have also cited various extrapulmonary complications in the hospitalized COVID-19 patients. This knowledge needs to be condensed and disseminated in order to improve COVID-19 surveillance and to reduce the accidental exposure of healthcare workers. Our review suggests that gastrointestinal tract, cardiovascular system, nervous system, renal system, and manifestations due to hematological abnormalities are common masqueraders to watch out for. HOW TO CITE THIS ARTICLE: Adukia SA, Ruhatiya RS, Maheshwarappa HM, Manjunath RB, Jain GN. Extrapulmonary Features of COVID-19: A Concise Review. Indian J Crit Care Med 2020;24(7):575-580.

Implicit and explicit spatial-numerical representations diverge in number-form synesthetes.

In number-form (NF) synesthesia-a condition in which people report vivid, automatic and consistent mental layouts for numerical sequences-numbers and space are closely linked. These explicit associations are similar to the implicit associations demonstrated by the Spatial-Numerical Association of Response Codes (SNARC) effect. Thus, NF synesthesia offers a unique opportunity to investigate spatial-numerical associations. We tested implicit and explicit representations in NF synesthetes using a multiple case-study design. Over two sessions, synesthetes participated in a semi-structured interview focusing on the nature of their associations, as well as SNARC and number line estimation tasks. Contrary to our hypotheses, only one synesthete demonstrated SNARC effects congruent with her reported form, whereas two others exhibited SNARC effects that were the opposite of their explicit NFs. While this inconsistency between implicit and explicit representations may indicate separate underlying cognitive mechanisms, factors such as task-specific constraints and strategic variability must also be considered.

An in-silico study examining the induction of apoptosis by Cryptotanshinone in metastatic melanoma cell lines.

BACKGROUND: Metastatic melanoma is an aggressive form of skin cancer that evades various anti-cancer treatments including surgery, radio-,immuno- and chemo-therapy. TRAIL-induced apoptosis is a desirable method to treat melanoma since, unlike other treatments, it does not harm non-cancerous cells. The pro-inflammatory response to melanoma by nF κB and STAT3 pathways makes the cancer cells resist TRAIL-induced apoptosis. We show that due to to its dual action on DR5, a death receptor for TRAIL and on STAT3, Cryptotanshinone can be used to increase sensitivity to TRAIL. METHODS: The development of chemoresistance and invasive properties in melanoma cells involves several biological pathways. The key components of these pathways are represented as a Boolean network with multiple inputs and multiple outputs. RESULTS: The possible mutations in genes that can lead to cancer are captured by faults in the combinatorial circuit and the model is used to theoretically predict the effectiveness of Cryptotanshinone for inducing apoptosis in melanoma cell lines. This prediction is experimentally validated by showing that Cryptotanshinone can cause enhanced cell death in A375 melanoma cells. CONCLUSION: The results presented in this paper facilitate a better understanding of melanoma drug resistance. Furthermore, this framework can be used to detect additional drug intervention points in the pathway that could amplify the action of Cryptotanshinone.