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Climate change is one of the greatest threats to human health in the 21st century. Climate directly impacts health through climatic extremes, air quality, sea-level rise, food production systems and water resources. Climate also affects infectious diseases, which have played a significant role in human history, impacting the rise and fall of civilizations. The world is witnessing Climate change. Vector-borne diseases account for over 17% of all infectious diseases. There is increasing evidence about the impact of climate change on Vector Borne Diseases. In this paper, I have collected secondary data from published articles, journals, reports, and books on this major issue to discuss the effects of climate change on VBDs in India through this article. This paper will briefly review the changing epidemiology of the most important vector-borne diseases in India.

Galectin-3 (Gal-3), a member of the β-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.

Drug-delivery technologies for modified drug release have been in existence for decades, but their utilization has been largely limited to post-launch efforts improving therapeutic outcomes. Recently, they have gained renewed importance because the pharmaceutical industry is steadily shifting to a more integrated discovery-development approach. In discovery, modulating target engagement via drug-delivery technologies can enable crucial pharmacological studies for building well-defined criteria for molecular design. In development, earlier implementation of delivery technologies can enhance the value of drug products through reduced dosing frequency and improved tolerability and/or safety profile, thereby leading to better adherence and therapeutic effectiveness.

Education is one of the most important means of upward mobility for the tribals. This is a research narrative on how an NGO, named TUDI (Tribal Unity for Development Initiative) achieved phenomenal results in a period of two decades among the group of tribals called the Paniyars in the Wayanad district of Kerala, India. The systematic and consistent efforts of TUDI at the integral development of the tribals, with great emphasis on empowering them through education, have born rich dividends. This study explores how TUDI was instrumental in bringing out many graduates, post graduates and government and other employees in just 20 years from a community whose children hardly progressed beyond the primary school level two decades ago.

Obesity is significantly associated with uncontrolled blood pressure and resistant hypertension (RH). There are limited studies on the prevalence and determinants of RH in patients with higher body mass index (BMI) values. Since the hypertension guidelines changed in 2017, the prevalence of RH has become unknown and now is subject to be estimated by further studies. We conducted a cross-sectional study in an urban Federally Qualified Health Center in New York City aiming to estimate the prevalence of RH in high-risk overweight and obese patients based on the new hypertension definition, BP threshold ≥130/80 mm Hg, and also to describe the associated comorbid conditions in these patients. We identified 761 eligible high-risk overweight and obese subjects with hypertension between October 2017 and October 2018. Apparent treatment-RH was found in 13.6% among the entire study population. This represented 15.4% of those treated with BP-lowering agents. True RH confirmed with out-of-office elevated BP was found in 6.7% of the study population and 7.4% among patients treated with BP-lowering agents. Prevalence was higher with higher BMI values. Those with true RH were more likely to be black, to have diabetes mellitus requiring insulin, chronic kidney disease stage 3 or above and diastolic heart failure. In conclusion, obesity is significantly associated with RH and other significant metabolic comorbid conditions.

Peripartum cardiomyopathy is a relatively rare condition, that usually presents with features of heart failure in the peripartum period. The ongoing pandemic caused by coronavirus disease 2019 (COVID-19) has been reported to be associated with myocarditis, with progression to dilated cardiomyopathy and heart failure. Dilated cardiomyopathy in a peripartum patient with COVID-19 infection may present a diagnostic dilemma. We report a case of dilated cardiomyopathy in a peripartum patient with COVID-19 infection. She presented with shortness of breath in the peripartum period. Chest X-ray showed a grossly enlarged heart with bilateral pulmonary infiltrates consistent with congestive heart failure or viral pneumonia. Echocardiography revealed dilated chambers with 22% left ventricular ejection fraction (LVEF) and global hypokinesis. Despite completing 5 days of remdesivir and dexamethasone, she had worsening dyspnea on postpartum day 10, a repeat echocardiogram showed further reduction in LVEF to 10-15% and was discharged with a life-vest after acute management. She had multiple hospital admissions for decompensated heart failure. Myocardial core biopsy showed marked acute inflammation and necrosis. She had an intra-aortic balloon pump, left ventricular and right ventricular assist devices placed on account of persistent hemodynamic instability, and is now scheduled to have a cardiac transplant.

Galectin-3 is a member of a family of β-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.

Background/Introduction: The COVID 19 pandemic has highlighted the racial and ethnic disparities that plague our healthcare system. These studies also highlight that in people with poorly controlled chronic health conditions such as hypertension, diabetes and obesity, the severity of the COVID 19 infection is greater. With this study, we focus on the impact of the pandemic on an existing chronic condition, diabetes. The pandemic resulted in redeployment of our resident providers to the inpatient setting, resulting in disruption of the patient-physician relationship at Ryan Adair. The patients and the providers had to quickly adapt to a telehealth platform which was a novel challenge to both. We sought to define the use and impact of telemedicine for a low-income, urban population during the COVID-19 pandemic. Objectives: To examine the use of tele visits among an urban, racially diverse, low-income population during the COVID-19 pandemic. To assess the impact of tele visits on chronic disease outcomes for this population. Methods: This project is conducted at Ryan Adair Health Center, a Federally Qualified Health Center (FQHC) located in the Central Harlem neighborhood of Manhattan that serves as a primary care training site for our Internal Medicine residents. To understand the impact of telehealth access, we focused on a single cohort that included all diabetic patients seen by resident providers within 3 months prior to the pandemic surge. We examined data for these patients over three discrete time periods: “prepandemic” (12/15/2019–3/15/2020), “pandemic surge” (3/16/2020–5/31/2020) and “post-surge” (6/1/2020–8/15/2020). This data will be tracked every three months to understand use and impact over the course of the pandemic. The variables measured included HbA1c and the number and type of visits. We compared pre-pandemic HbA1c values with post-surge values. We stratified tele visits into telephone versus tele video visits. A non-interventional retrospective chart review study design was used. Results: Among our pre-pandemic cohort of diabetic patients (n = 225), 35.1% (n = 79) engaged in tele visits during the pandemic surge, 6.66% engaged in onsite visits, and 56% had no engagement (Figure 1). For patients who engaged in tele visits during the surge, the average HbA1c improved by 0.172%. For patients without tele visits during the surge, the average HbA1c worsened by 0.42%. Among the subgroup of high -risk diabetics during the pre-pandemic period (HbA1c >9), those with improved HbA1c had more tele visits during both the surge and the post-surge periods compared to those whose HbA1c worsened (improvement of 1.73 vs. worsening of 1.9%) (Figure 2). Among those who accessed tele visits during the surge period, 79.74% were phone-only (n = 63), 7.59% (n = 6) were tele video-only while 12.6% (n = 10) were both (Figure 3). Conclusion: Our data suggest that telemedicine access improved average HbA1c outcomes among a low-income urban diabetic population. During the surge, HbA1c decreased or remained unchanged with telemedicine encounters, while patients without engagement in tele visits showed worsening HbA1c levels. A surprising result was that 79% of tele visits were conducted via phone-only, suggesting a benefit for use of this modality toward improving diabetes control for our population. Most patients in our cohort had no engagement in care during the surge period, highlighting the need to explore barriers to telehealth access. The true impact of HbA1c reduction through tele visits may represent an underestimation, since resident providers were redeployed to the inpatient setting during the surge, thus patients were seen by providers unknown to them. Exploration of data over the coming months will help elucidate the impact of provider continuity during tele visits on HbA1c outcome.

Introduction With growing health care costs, high-value care is an increasingly important subject for medical training. Many resident and medical student curricula have incorporated lectures-based material about this topic. However, practical-type experiences are needed to refine critical-thinking skills essential for high-value care. Methods To provide such practical experiences, we developed an instructional game for resident-level education that incorporated cost-constraint-based approaches in the workup of anemia. To play the game, teams of learners were given patients with anemia of unknown cause. To pay for their diagnostic tests of choice, teams earned money by correctly answering internal medicine resident-level anemia questions. The first team to successfully work up and diagnose three patients won. Results Resident learners had very positive reviews of our game. As a team, groups of residents across all levels were able to develop cost-effective strategies for diagnosis. Our game also served as a resource for anemia education. Residents on average felt the game enhanced their ability to apply medical knowledge and clinical reasoning (M = 4.7 out of 5, where 5 = strongly agree), as well as high-value care (4.6), and should remain in the program for the high-value care curriculum (4.9). Discussion Game-based learning provides a fun, orthogonal approach to learning critical-thinking skills used during anemia diagnostic patient workups. Although we did not quantify change in diagnostic test ordering, according to resident-learners, our high-value care game improved their ability to integrate cost-effective strategies into their practice of medicine.

Background: The estimates of 10-year risk for atherosclerotic disease (ASCVD-10) is applicable for individuals who are 40 to 79 years old without prior cardiovascular disease. While multiple components of the risk estimator are shared risk factors for many cardiovascular diseases, the ASCVD-10 does not consider the BMI value and limited studies examined the relationship between the ASCVD-10 risk score and resistant hypertension (RH). Methods: This is a cross-sectional study based on an out-patient primary care practice conducted between Oct 2017 to Oct 2018. Subjects with hypertension with either high-risk overweight (BMI ≥27 & ≤29.9 kg/m2 plus ≥1 obesity-related comorbid conditions) and subjects with obesity (BMI ≥30 kg/m2) were included. Subjects with prior ASCVD were excluded. Apparent treatment-resistant hypertension (ATRH) detected with an average of two blood pressure (BP) readings at the office was confirmed with home BP measurement to exclude pseudoresistance and verify true resistant hypertension (TRH). BP cutoff of >130/80 mmHg was used. Multivariate logistic regression adjusted for significantly different baseline variables among subjects with TRH vs non-TRH was used to examine the performance of ASCVD-10 in predicting TRH. Variables that are part of the ASCVD-10 score were excluded from the adjustment. Results: We identified 595 eligible subjects. Mean age was 60.4 years and 381 (64.1%) were females. ATRH was detected in 69 subjects but only 35 subjects had TRH after home BP measurement confirmation. Subjects with TRH compared to non-TRH were more likely to be of black race (51.4% vs 33.1%, p=0.022), to have chronic kidney disease (34.2% vs 11.3%, p Conclusion: The ASCVD-10 risk score can possibly be used as a predictor for the risk of having or developing RH in subjects with obesity or high-risk overweight.

In March 2020, the COVID-19 pandemic became an increasingly urgent issue of public health concern in the United States. Patients on dialysis are considered to be at increased risk for infection due to their medical comorbidities and need for continued face-to-face encounters in dialysis units. In our outpatient dialysis practice, 42 out of 269 patients (15.6%) were infected with COVID-19 during the first wave of the pandemic. In this retrospective report, we review issues of infection control, access to interventional procedures, and communication encountered in our practice. We discuss lessons learned in patient outcomes and the importance of transitioning patients to home modalities. Further planning for a potential second wave of COVID-19 may help ensure improved quality of care for patients in the dialysis program.

Needs and Objectives: Poorly-controlled hypertension is associated with increased risk of adverse cardiovascular outcomes and thus is an important healthcare quality metric for primary care practices. Yet achieving blood pressure goals among socially-complex, economically-disadvantaged patient populations can be challenging due to cost-related non-adherence, poor health literacy and other social determinant barriers. Indeed, by early 2019, only 59% of hypertensive patients at our inner-city community health clinic had a blood pressure less than 140/90. The goal of this resident-driven quality improvement (QI) project was to increase blood pressure control among our hypertensive patients to a network target of 75% over 6 months. Setting and Participants: Our project was implemented at the Ryan Adair Center, a Federally Qualified Health Center located in Central Harlem that serves as a primary care practice site for Internal Medicine residents. The patient population consists predominantly of Black and Latino patients, most of whom are on Medicaid and live well below the federal poverty line. Our target population was hypertensive patients. Intervention: We used the Plan-Do-Study-Act method to carry out our clinic-based project. PGY1’s at the site served as the QI project leaders with faculty oversight. Cycle 1 focused on nurse education regarding proper blood pressure measurement. Cycle 2 focused on home blood pressure monitoring including patient education on proper technique and the importance of maintaining a daily log. Cycle 3 focused on assessment of health literacy via a patient questionnaire. Cycle 4 focused on provider education by ensuring that our patients were prescribed an appropriate medication regimen based on ACC/AHA Guidelines. Cycle 5 focused on referring patients with continued poor control to community health coaches to identify barriers like nutrition, medication access, and health literacy. Evaluation: Using our clinic’s online hypertensive registry (DRVS), we tracked on a monthly basis the percentage of hypertensive patients who had controlled blood pressure ( Discussion/lessons learned: Through this project, we demonstrated a meaningful improvement in hypertensive control among an economically-disadvantaged, racially diverse urban patient population. Accurate nurse measurements, engagement of patients in self-management, and resident education on evidence-based medication standards have all contributed to this success. Future directions will explore the impact of community health coaches in hypertension control and use of standard questionnaire to assess health literacy.

Background: For several decades, aspirin (ASA) has been used as primary prevention against ASCVD in adults. In 2018, three major trials (ASPREE, ARRIVE, and ASCEND) redefined our understanding of ASA and showed a net harm rather than benefit when ASA is used for primary prevention of ASCVD. These trials greatly impacted the current 2019 ACC/AHA Primary Prevention Guidelines, which now recommend the following: (a) Low-dose ASA might be considered for primary prevention of ASCVD in select higher ASCVD adults aged 40-70 years who are not at increased bleeding risk and (b) Low-dose ASA should not be administered for primary prevention of ASCVD among adults over the age of 70. The objective of the project was to re-evaluate the use and indications of ASA in our patient population and appropriately remove ASA when no longer indicated. With proper resident education and intervention, we hypothesized that we could reduce the number of inappropriate ASA prescriptions by 10%. Methods/Results: During a 6-month observational period, 254 patients at Ryan Health/Adair (a federally qualified health center which also serves as a primary care site for an internal medicine residency clinic) were found to be taking ASA, and of those 140 patients were found to be on ASA for primary ASCVD prevention. The interventions included implementation of an algorithm that reflected the most up to date guidelines. The intervention lasted 3 months. Any patient that was found to be on ASA inappropriately was discontinued. During this period ASA was successfully removed from 25 patients’ medication list, with an overall reduction by 17.9%. Of the 25 patients, 20% were over the age of 70, 80% were between the ages of 40-70, and 48% were male. In the remaining 115 patients in which ASA was continued, 27.8% were over the age of 70, 69.6% were between the ages of 40-70, 2.6% were under the age of 40, and 49.6% were male. The successful ASA removal group comprised of 44% Hispanic/Latino, 44% African American, 4% White, and 8% Unidentified. The ASA non-removal group comprised of 34.8% Hispanic/Latino, 44.3% African American, 5.2% White, and 15.7% Unidentified. Additionally, 80% of the patient taken off ASA spoke English, while only 69.6% of patient in the ASA non-removal group spoke English. Conclusions: Several differences were found between the two groups. Some key limitations between the two groups included (a) unclear past medical history leading to physicians being uncomfortable with removing ASA, (b) inability to speak in patient’s native language to facilitate proper discussion about ASA removal, and (c) patient refusal to stop ASA. Next steps include further cardiac testing (CT coronaries, stress test) to better characterize the risk of patients with unclear history. However, overall, there is likely a net benefit in prioritizing ASA removal in the primary care setting now that it is no longer recommended in key populations.

Aims: Multi-species Allometric Scaling (MSS) from at least three species have been used traditionally to predict human CL and Vss. Single-species Scaling (SSS) can be applied to predict these parameters from a single species using a fixed body weight exponent. SSS is less time- and resource-intense compared to MSS and thus appears to be a very promising method to implement in a screening strategy during the drug discovery phase. Study Design: To evaluate SSS predictivity compared to MSS, six discovery compounds were evaluated in pharmacokinetic studies with the intravenous administration to rat, rabbit, dog, and/or cynomolgus monkey. Human CL and Vss were predicted by MSS and SSS, applying protein binding correction. Relative fold difference between these two methods was calculated to define success rate as a percent of the predictions of SSS within two- to four-fold of MSS predictions. Results: SSS showed a high success rate for human CL prediction with 67% within 2-fold and 94% within 4-fold of MSS. The success rate of human Vss prediction by SSS was also good with 61% within 2-fold and 89% within 4-fold of MSS. Conclusion: These data demonstrate the potential application of SSS to streamline the screening strategy of drug discovery programs.

Background Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α). In addition, the PGC-1α promoter has binding sites for early growth response 3 (Egr3), which plays a dynamic role in cocaine action in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor D 1 (D1-MSN) versus D 2 (D2-MSN). However, the role of PGC-1α in NAc in cocaine action is unknown. Methods PGC-1α messenger RNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1α promoter was examined in NAc using chromatin immunoprecipitation after repeated cocaine. PGC-1α ribosome-associated messenger RNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1α was expressed in NAc D1-MSNs versus D2-MSNs using a Cre-inducible adeno-associated virus and Cre lines during cocaine conditioned place preference and cocaine-induced locomotion. Results Repeated cocaine increased PGC-1α levels and increased Egr3 binding and H3K4me3 at the PGC-1α promoter in NAc. Increased PGC-1α occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral-mediated expression of PGC-1α in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors. Conclusions We demonstrate a novel role for PGC-1α in NAc in cocaine action. PGC-1α is enhanced in NAc D1-MSNs, specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1α promoter. Finally, we demonstrate a bidirectional role for PGC-1α in mediating behavioral plasticity to cocaine through D1-MSNs versus D2-MSNs.

Most of practical combustion occurs in turbulent flows which involve strong coupling between turbulence and chemical processes. The heat release from combustion alters the fluid properties such as density and viscosity and in turns affects the turbulence. Direct numerical simulations (DNS) provides a tool for obtaining both temporally and spatially resolved data in three dimension (3D). This chapter presents a brief overview of importance of DNS in turbulent combustion, the role of turbulence and identifies different combustion modes. The mathematical formulation and numerical implementation for DNS are introduced. The second half of this chapter presents DNS results for ignition in both homogeneous and stratified mixtures. It has been found that minimum ignition energy is required to obtain successful ignition in different turbulence regimes. An increase in turbulent velocity fluctuation may leads to a misfire. Additionally the difference between growing flames and those which are quenched by turbulence have been discussed with the help of the reaction–diffusion balance analysis. Furthermore, the turbulence intensity and length scale of the mixture inhomogeneity have important influences on achieving self-sustained combustion following successful ignition events.

The druggability and developability space is rapidly evolving in the post-genomic era. In the past, Lipinski’s rule-of-five (Ro5) emerged and served as a guide for drug-like molecule design for oral delivery in the traditional druggable target space. In contrast, in this new era, a transition is occurring in drug discovery towards novel approaches to bind and modulate challenging biological targets that have led to transformative treatments for patients. Consequently, drugging novel targets using a variety of emerging molecular modalities, namely beyond the Ro5 (bRo5) small molecules (such as protein-protein interaction modulators, protein-targeted chimeras, or PROTACs), peptide/peptidomimetics, and nucleic acid-based modalities, have become a key focus in drug discovery. Herein, the emerging druggability and developability space is discussed side by side to build a general understanding of the potential development challenges of these novel modalities. An overview is provided on the evolving novel targets and molecular modalities, followed by a detailed analysis of the druggability aspects as well as the strategies used to progress drug candidate, and the trending chemistry and formulation strategies used to assess developability.

The application and impact of human dose projection (HDP) has been well recognized in the late drug development phase, with increasing appreciation earlier during discovery and early development. This commentary describes the perspective of pharmaceutical scientists on the evolving application and impact of HDP at various phases from discovery to early development, including lead generation, lead optimization, lead up to candidate nomination, and early drug development. The underlying fundamental concepts and key input parameters for HDP are briefly discussed. A broad overview of phase-specific tools and approaches commonly utilized for human dose projection in the pharmaceutical industry is provided. A discussion of phase-appropriate implementation strategies, associated limitations/assumptions and continuous refinement for HDP from discovery to early development is presented. The authors describe the phase-specific applications of human dose projection to facilitate key assessments and relative impact on decision points.

Background: Hypertension (HTN) management has been updated in the 2017 ACC/AHA guidelines. The guidelines continued emphasizing on the use of diuretics, especially Chlorthalidone, as an essential component of first line therapy and as a preferred agent when 3 or more agents are required. Methods: This is a retrospective cross-sectional study evaluating the efficacy of diuretics when 3 or more agents are required in obese (BMI >=30) and high-risk overweight pts (BMI >=27 & Results: Of the 760 pts, 157 (55.4% females, 7.1% white, 37.5% black, 55.4% hispanic) had 3 or 4 BP lowering agents prescribed. Mean age was 65y and mean BMI was 34.8, 144 (92%) reported compliance, 97 (61.7%) had DM, 19 (12%) were smokers and 59 (37.5%) had CKD stage 3 or above. Among the 144 compliant pt, 117 (81.2%) were on a diuretic, Chlorthalidone in 31 (26.5%) of them, 93 (64.5%) were on 3 BP lowering agents with one agent being a diuretic in 68 (73%) of them, and 55 (38.1%) were on 4 agents with one agent being a diuretic in 51 (92.7%) of them. Two or more agents were on maximum dose in 20 (29.4%) of those on 3 BP agents including a diuretic, in 7 (28%) of those on 3 BP agents without a diuretic and in 32 (58.1%) of those on 4 BP agents including a diuretic. Results were calculated in compliant pts only. Pts who were on a diuretic vs without were less likely to have BP >130/80 (34% [40 of 117] vs 63% [17 of 27], p130/80 and 122 vs 131 mmHg for mean SBP, p Conclusion: Adherence to the guidelines in prescribing a diuretic when multiple BP lowering agents are required results in significantly lower SBP and better HTN control. We hope providers identify high risk pts early and institute a more evidence and guideline based anti-hypertensive regimen.

The influences of initial mixture distribution on localized forced ignition of globally stoichiometric stratified mixtures have been analyzed using three-dimensional compressible direct numerical simulations. The globally stoichiometric mixtures (i.e., ) for different root-mean-square (rms) values of equivalence ratio (i.e., = 0.2, 0.4, and 0.6) and the Taylor micro-scale of equivalence ratio variation (i.e., 2.1, 5.5, and 8.3 with being the Zel’dovich flame thickness of stoichiometric mixture) have been analyzed for different initial rms values of turbulent velocity . The equivalence ratio variation is initialized following both Gaussian and bi-modal distributions for a given set of values of and in order to analyze the effects of mixture distribution. The localized forced ignition is accounted for by considering a source term in the energy conservation equation that deposits energy for a stipulated time interval. It has been demonstrated that the initial equivalence ratio distribution has signif...

Rosuvastatin is a widely prescribed antihyperlipidemic which undergoes limited metabolism, but is an in vitro substrate of multiple transporters [organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, OATP1A2, OATP2B1, sodium-taurocholate cotransporting polypeptide, breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), MRP4, organic anion transporter 3]. It is therefore frequently used as a probe substrate in clinical drug-drug interaction (DDI) studies to investigate transporter inhibition. Although each of these transporters is believed to play a role in rosuvastatin disposition, multiple pharmacogenetic studies confirm that OATP1B1 and BCRP play an important role in vivo. Ronacaleret, a drug-development candidate for treatment of osteoporosis (now terminated), was shown to inhibit OATP1B1 in vitro (IC50 = 11 µM), whereas it did not inhibit BCRP. Since a DDI risk through inhibition of OATP1B1 could not be discharged, a clinical DDI study was performed with rosuvastatin before initiation of phase II trials. Unexpectedly, coadministration with ronacaleret decreased rosuvastatin exposure by approximately 50%, whereas time of maximal plasma concentration and terminal half-life remained unchanged, suggesting decreased absorption and/or enhanced first-pass elimination of rosuvastatin. Of the potential in vivo rosuvastatin transporter pathways, two might explain the observed results: intestinal OATP2B1 and hepatic MRP4. Further investigations revealed that ronacaleret inhibited OATP2B1 (in vitro IC50 = 12 µM), indicating a DDI risk through inhibition of absorption. Ronacaleret did not inhibit MRP4, discharging the possibility of enhanced first-pass elimination of rosuvastatin (reduced basolateral secretion from hepatocytes into blood). Therefore, a likely mechanism of the observed DDI is inhibition of intestinal OATP2B1, demonstrating the in vivo importance of this transporter in rosuvastatin absorption in humans.

The influences of fuel Lewis number LeF (ranging from 0.8 to 1.2) on localised forced ignition and early stages of combustion of stoichiometric and fuel-lean homogeneous mixtures have been analysed using simple chemistry three-dimensional compressible direct numerical simulations for different values of root-mean-square velocity fluctuation and the energy deposition characteristics (i.e. characteristic width and the duration of energy deposition by the ignitor). The localised forced ignition is modelled using a source term in the energy transport equation, which deposits energy in a Gaussian manner from the centre of the ignitor over a stipulated period of time. The fuel Lewis number LeF has been found to have significant influences on the extent of burning of stoichiometric and fuel-lean homogeneous mixtures. It has been shown that the width of ignition energy deposition and the duration over which the ignition energy is deposited have significant influences on the success of ignition and subsequent flame propagation. An increase in the width of ignition energy deposition and the duration of energy deposition for a given amount of ignition energy have been found to have detrimental effects on the ignition event, which may ultimately lead to misfire. For a given value of [Formula: see text] ( LeF), the rate of heat transfer from the hot gas kernel increases with increasing LeF[Formula: see text], which in turn leads to a reduction in the extent of overall burning for both stoichiometric and fuel-lean homogeneous mixtures but the detrimental effects of high values of [Formula: see text] on localised forced ignition are particularly prevalent for fuel-lean mixtures. Detailed physical explanations have been provided for the observed [Formula: see text] and energy deposition characteristics effects.

While considerable research has targeted physical performance in older adults, less is known about the ability to rise from the floor among community-dwelling elders. The purposes of the study were to (1) examine physical performance correlates of timed supine to stand performance and (2) identify the predominant motor pattern used to complete floor rise. Fifty-three community-dwelling adults over the age of 60 (x = 78.5 ± 8.5; 36 [68%] females) performed a timed supine to stand test and physical performance assessments. Forty-eight subjects (90.6%) demonstrated an initial roll with asymmetrical squat sequence when rising to stand. Supine to stand performance time was significantly correlated with all physical performance tests, including gait speed (r = −.61; p < .001), grip strength (r = −.30; p < .05), and Timed Up and Go (TUG) performance (r = .71; p < .001). Forty-eight percent of the variance in rise time (p < .001) was attributed to TUG velocity. Findings serve to enhance both functional performance assessment and floor rise interventions.

Background: Adolescence is a period of turmoil, leading to several mental health challenges including anxiety and/or depression. Anxiety and depressive disorders affects 10-15% of adolescents. Anxiety and depression are associated with substantial negative effects on adolescent’s social, emotional and academic success. This leads to poor social and coping skills, low self-esteem, perceptions of social rejection, and difficulty forming friendships. This study was carried out with an objective to study prevalence and risk factors for anxiety and depression among adolescents.Methods: A cross sectional study conducted from April 2014 to December 2015 among 1026 school going adolescents from 4 schools of Rajkot, Gujarat, India. Anxiety and depression were measured using Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) respectively. Chi-square test was applied as test of significance.Results: Majority of the students (58.1%) was belonged to early adolescent age group. Two third were males. Maximum adolescents (42.5%) were coming from class III. Prevalence of moderate-severe anxiety and depression was 9.9% and 18.5%. Anxiety was not significantly associated with age, gender and socio economic class. Prevalence of depression was significantly higher in boys (20.5%) as compared to girls (14.5%, p=0.02). Moderate to severe depression was gradually increased with increasing in age. Adolescent from upper socio economic class (I, II, III- 19.1%) were severely depressed than adolescent from lower socio economic class (IV, V- 4.1%).Conclusions: Anxiety and depression was significantly present in adolescent age group. Depression was commonly observed in boys and gradually increased with increasing in age. There is need of strengthening school health services with screening and cost effective interventions to minimize the risk of drug abuse, suicide and violence.

Background: Proper good nutrition are essential for mental development, physical growth, health and wellbeing and survival of adolescents. School based data of India shows a prevalence of obesity is 5.6% to 24.0% among children and adolescents. Psychosocial complications associated with obesity include poor self-image, depression, and difficulties in both social environment and home. This study was carried out with an objective to find out prevalence of malnutrition and associated factors.Methods: A cross sectional study conducted among 1026 school going adolescents from 4 schools of Rajkot, Gujarat, India. Depression and anxiety were measured using Beck Depression Inventory and Beck Anxiety Inventory. Chi-square test was applied as test of significance.Results: Majority of the students (58.1%) were belonged to early adolescent age group. About 67.1% were males. About 16.6% were underweight and 1.2% were obese. Overweight was more prevalent in girls (5.6%) as compared to boys (1.2%). Prevalence of anxiety and depression was 9.9% and 18.5% respectively. Anxiety was frequently found in overweight and obese adolescents (82.0%) as compared to only underweight and normal adolescents (7.1%, p

Localised forced ignition of mono-disperse pulverised coal particle-laden mixtures has been analysed based on three-dimensional Direct Numerical Simulations for the carrier phase with simplified chemistry for the combustion of volatile gases. The coal particles are treated as point sources and tracked in a Lagrangian manner. The coupling between Eulerian gaseous and Lagrangian particulate phases has been achieved by appropriate source terms in the mass, momentum, energy and species conservation equations. A detailed parametric analysis has been carried out to analyse the effects of particle equivalence ratio Φ p (which is defined based on the total available primary volatile fuel in the particulate phase), root-mean-square of turbulent velocity u ′ and particle diameter d p on the early stages of combustion. Both non-premixed and premixed modes of combustion have been observed in the reaction zone for the flames resulting from localised ignition. An increase in Φ p is found to be detrimental for sustaining combustion, whereas a reduction in particle size may adversely affect the extent of burning. It has been found that an increase in u ′ increases the rate of mixing of devolatilised fuel with the surrounding air, which, though beneficial for sustaining combustion, increases the heat transfer rate from the hot gas kernel, thus leading to flame extinction for high values of u ′. Detailed physical explanations have been provided to explain the observed effects of Φ p , root-mean-square turbulent velocity fluctuation u ′ and particle diameter d p on combustion of coal particle-laden mixtures following successful localised forced ignition.

Therapeutic plasma exchange (TPE) has long been utilized to manage a variety of immune-mediated diseases. The basic principle relies on removal of circulating pathogenic substances from the bloodstream. Methods of plasma separation include centrifuge (cTPE) and membrane (mTPE). Although mTPE has existed for a few decades, recent advances in developing highly permeable filters that are compatible with currently existing dialysis machines has opened a new frontier. Published data in the area of technical and clinical experience with mTPE is lacking. We report our single center experience of 998 inpatient mTPE treatments performed in 237 patients at a large tertiary care academic center. The most common treatment indication was neurologic. We found a very low incidence of patient-reported complications. Filter clotting without the use of anticoagulation occurred in 7.7% of treatments. Laboratory parameters that significantly changed during the course of therapy included serum potassium, platelet count, and partial thromboplastin time. We found that mTPE can be safely and efficiently performed as an alternative to cTPE, and suggest an individualized approach when prescribing this therapy.

Localised forced ignition of globally stoichiometric stratified mixtures (i.e. =1.0) has been analysed here based on direct numerical simulations for different initial values of velocity and equivalence ratio fluctuations (i.e. u′ and φ′), and the Taylor micro-scale lφ of equivalence ratio φ variation. The localised ignition is accounted for by a source term in the energy transport equation which deposits energy over a stipulated time interval. It has been found that combustion takes place predominantly under premixed mode in the case of successful ignition. The initial values of φ′ and lφ have been found to have significant effects on the extent of burning of stratified mixtures following localised ignition. It has been found that an increase in u′(φ′) has adverse effects on the burned gas mass, whereas the effects of lφ on the extent of burning are non-monotonic and dependent on φ′. Detailed physical explanations have been provided for the observed u′, φ′ and lφ dependences on the extent of burnin...

The objective of study was to evaluate and correlate the pathological characteristics of breast cancer patients with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (Her2/neu) detected by immunohistochemistry and/or fluorescent in situ hybridization method. We have conducted 2 year study of 204 cases of breast cancer at HCG-Medisurge Hospitals, Ahmedabad from 2009 to 2011. Significant correlation was found in ER and PR expression whereas no correlation was found in hormonal receptors and Her2/neu expression. ER and PR positivity increased with advancing age in breast carcinoma patients while not affecting Her2/neu expression. The expression of hormone receptors were higher in infiltrating lobular carcinoma and infiltrating duct carcinoma subtypes of breast carcinoma as compared to other subtypes such medullary and in situ carcinoma. High-grade carcinoma patients were predominantly ER/PR negative and Her2/neu positive as compared to lower grade breast carcinoma whereas high-stage carcinoma patients were ER/PR positive and Her2/neu positive as compared to lower stage breast carcinoma.

With the constant media attention that cultism receives today, people want to know “to what extent do destructive cults’ leaders employ mind control techniques to recruit members in order to achieve their aims?” The research question was developed and inspired by several books and television shows focused on cults. This research question was then investigated by evaluating numerous researches found in online libraries, journals, podcasts, and books. The researches were then compiled and important notes were marked. All the key definitions are mentioned as well as limitations of the research methods used in order to assess cults. In order to holistically address the question all the three levels of analysis were used: biological, cognitive, and sociocultural. The concepts are further clarified with explaining two major exemplar cults: Peoples Temple and Heaven’s Gate. The essay concludes that though there are some possibilities where mind control may be employed with admirable intentions, most of the evidence suggests otherwise. Moreover, individuals lose their identity in the cults. They are trained and conditioned and degraded from humans to mere pets. Cult leaders rob their members of the one thing that makes them human by entirely controlling them: higher cognitive thinking. All of them share one major trait: their need to control anything and everything. In terms of dependency, it is a two-way relationship since the members are dependent on the leader and the leader is dependent on the members as his/her power stems from the members’ vulnerability. Finally, to answer the research question it could be said that to a large extent destructive cults’ leaders employ mind control techniques to recruit members in order to achieve their aims.

The aim of this experiment was to investigate the impact of levels of processing (Independent Variable) on our memory (Dependent Variable). We hypothesized to find that a deeper level of processing lead to a better memory and in turn, greater recall. The experiment controlled variables such as environmental conditions, age of the target population and educational background of the participants. The experiment uses the Independent Measures design and the participants are a convenience sample of teenagers. We reduced Practice Effect and Fatigue Effect by using the Single-Blind Technique. The results proved the hypothesis: Semantic encoding lead to greater retention and a deeper trace of memory whereas Structural encoding lead to a shallow processing of memory. These results are replicated in Craik and Lockhart‟s (1972), Levels of Processing model. The researches done by Hyde and Jenkins (1973) and Craik and Tulving (1975) also prove the same results: deeper levels of processing lead to better recall. The Mann-Whitney U test also made a clear distinction in the number of words recalled due to deep and shallow processing. The study also raised some limitations such as generalizations, rehearsal, ecological validity and others. In totality, the experiment effectively manipulated variables and reproduced accurate results.

Nausea and vomiting are some of the major side effects caused by certain drug therapies, e.g. chemotherapy, radiotherapy and general anesthesia. Because of the nature of the symptoms, oral delivery is inappropriate, while intravenous administration may be unpractical. The aim of the present study was to develop a transdermal gel (2% Klucel®) for ondansetron, a first line 5-HT3-receptor-antagonist antiemetic. The effects of the penetration enhancer camphor and isopropyl-myristate (IPM) were first investigated in-vitro using modified Franz diffusion-cells and then tested in-vivo in a rabbit model by measuring skin and plasma concentrations. Since a disadvantage of transdermal delivery is a prolonged lag-time, the effect of skin treatment with a micro-needle roller was tested. The in-vitro permeation studies through excised porcine ear skin showed that the presence of 2.5% camphor or IPM increased steady state flux by 1.2- and 2.5-fold, respectively, compared to the control gel. Ondansetron was not detectable in either skin or plasma following in-vivo application of the base-gel, whereas the camphor gel and IPM gel delivered 20 and 81 µg/cm(2) of ondansetron, respectively. Microporation led to an increase in plasma Cmax and AUC by 10.47 ± 1.68-fold and 9.31 ± 4.91-fold, respectively, for the camphor gel, and by 2.31 ± 0.53-fold and 1.59 ± 0.38-fold, respectively for the IPM gel. In conclusion, the 2.5% IPM gel demonstrated optimal in-vivo transdermal flux. Skin pretreatment with a micro-needle roller slightly improved the delivery of the IPM gel, whereas dramatically increased the transdermal delivery of the camphor gel.