Conservative kidney management and kidney supportive care: core components of integrated care for people with kidney failure.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

Deciphering molecular regulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) signalling networks in Oryza genus amid environmental stress.

The Oryza genus, containing Oryza sativa L., is quintessential to sustain global food security. This genus has a lot of sophisticated molecular mechanisms to cope with environmental stress, particularly during vulnerable stages like flowering. Recent studies have found key involvements and genetic modifications that increase resilience to stress, including exogenous application of melatonin, allantoin, and trehalose as well as OsSAPK3 and OsAAI1 in the genetic realm. Due to climate change and anthropogenic reasons, there is a rise in sea level which raises a concern of salinity stress. It is tackled through osmotic adjustment and ion homeostasis, mediated by genes like P5CS, P5CR, GSH1, GSH2, and SPS, and ion transporters like NHX, NKT, and SKC, respectively. Oxidative damage is reduced by a complex action of antioxidants, scavenging RONS. A complex action of genes mediates cold stress with studies highlighting the roles of OsWRKY71, microRNA2871b, OsDOF1, and OsICE1. There is a need to research the mechanism of action of proteins like OsRbohA in ROS control and the action of regulatory genes in stress response. This is highly relevant due to the changing climate which will raise a lot of environmental changes that will adversely affect production and global food security if certain countermeasures are not taken. Overall, this study aims to unravel the molecular intricacies of ROS and RNS signaling networks in Oryza plants under stress conditions, with the ultimate goal of informing strategies for enhancing stress tolerance and crop performance in this important agricultural genus.

Development of a rapid and validated stability-indicating UPLC-PDA method for concurrent quantification of impurity profiling and an assay of ipratropium bromide and salbutamol sulfate in inhalation dosage form.

The objective of the proposed work was to develop a rapid and new reverse phase ultra-performance liquid chromatographic (RP-UPLC) method for the simultaneous quantification of related impurities of ipratropium bromide and salbutamol sulfate in the combined inhalation dosage form. Herein, the chromatographic separation was achieved on Acquity BEH C18 (100mm×2.1mm, 1.7µm) column by following gradient elution of solvent A as 2mM potassium dihydrogen phosphate with 0.025% of 1-pentane sulphonic acid sodium salt (pH 3.0 buffer) and solvent B as pH 3.0 buffer, acetonitrile and methanol in the ratio of (32:50:18, v/v/v) at a flow rate of 0.3mL/min. The samples were detected and quantified at 220nm. To prove the stability-indicating potential of the method, forced degradation studies were performed using acidic, basic, oxidative, thermal, and photolytic conditions. After sufficient exposure, the resultant solutions were injected and found that all degradants and impurities formed during stress studies were well separated from each other and from the main peak compounds. The performance of the method was validated according to the present ICH Q2 (R1) guidelines. The method has good linearity (r≥0.999) and consistent recoveries were obtained with a range of 91.3-108.8% for all compounds. The % RSD obtained for the precision experiments was less than 5% and also there is a good sensitivity (LOQ≤0.5µg/mL) for all compounds. The intended method proved its applicability and that it can be beneficial to pharmaceutical industries for quick quantification of related impurities and assay in quality control department for analysis of ipratropium bromide and salbutamol sulfate inhalation dosage form.

Centrifugal Assembly of Helical Bijel Fibers for pH Responsive Composite Hydrogels.

In microfluidics, centrifugal forces are important for centrifugal microfluidic chips and curved microchannels. Here, an unrecognized use of the centrifugal effect in microfluidics is introduced. The assembly of helical soft matter fibers in a rotating microcapillary is investigated. During assembly, the fibers undergo phase separation, generating particle stabilized bicontinuous interfacially jammed emulsions gels. This process is accompanied by a transition of the fiber density over time. As a result, the direction of the centrifugal force in the rotating microcapillary changes. The authors analyze this effect systematically with high-speed video microscopy and complementary computer simulations. The resulting understanding enables the control of the helical fiber assembly into microropes. These microropes can be converted into pH responsive hydrogels that swell and shrink with potential applications in tissue engineering, soft robotics, controlled release, and sensing. More generally, the knowledge gained from this work shows that centrifugal forces potentially enable directed self-assembly or separation of colloids, biological cells, and emulsions in microfluidics.

Disposition of Nirmatrelvir, an Orally Bioavailable Inhibitor of SARS-CoV-2 3C-Like Protease, across Animals and Humans.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of coronavirus disease 2019 (COVID-19) in adults and pediatric patients. Disposition studies on nirmatrelvir in animals and in human reagents, which were used to support clinical studies, are described herein. Plasma clearance was moderate in rats (27.2 ml/min per kg) and monkeys (17.1 ml/min per kg), resulting in half-lives of 5.1 and 0.8 hours, respectively. The corresponding oral bioavailability was moderate in rats (34%-50%) and low in monkeys (8.5%), primarily due to oxidative metabolism along the gastrointestinal tract in this species. Nirmatrelvir demonstrated moderate plasma protein binding in rats, monkeys, and humans with mean unbound fractions ranging from 0.310 to 0.478. The metabolism of nirmatrelvir was qualitatively similar in liver microsomes and hepatocytes from rats, monkeys, and humans; prominent metabolites arose via cytochrome P450 (CYP450)-mediated oxidations on the P1 pyrrolidinone ring, P2 6,6-dimethyl-3-azabicyclo[3.1.0]hexane, and the tertiary-butyl group at the P3 position. Reaction phenotyping studies in human liver microsomes revealed that CYP3A4 was primarily responsible (fraction metabolized = 0.99) for the oxidative metabolism of nirmatrelvir. Minor clearance mechanisms involving renal and biliary excretion of unchanged nirmatrelvir were also noted in animals and in sandwich-cultured human hepatocytes. Nirmatrelvir was a reversible and time-dependent inhibitor as well as inducer of CYP3A activity in vitro. First-in-human pharmacokinetic studies have demonstrated a considerable boost in the oral systemic exposure of nirmatrelvir upon coadministration with the CYP3A4 inhibitor ritonavir, consistent with the predominant role of CYP3A4 in nirmatrelvir metabolism. SIGNIFICANCE STATEMENT: The manuscript describes the preclinical disposition, metabolism, and drug-drug interaction potential of PF-07321332 (nirmatrelvir), an orally active peptidomimetic-based inhibitor of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CL protease, which has been granted emergency use authorization by multiple regulatory agencies around the globe for the treatment of coronavirus disease 2019 (COVID-19) in COVID-19-positive adults and pediatric patients who are at high risk for progression to severe COVID-19, including hospitalization or death.

Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study.

BACKGROUND: Psoriasis treatments lack durable efficacy and have inconvenient administration, highlighting the need for new therapies. OBJECTIVE: To evaluate the efficacy and safety of tyrosine kinase 2 inhibitor, PF-06826647, in moderate-to-severe plaque psoriasis. METHODS: This phase 2b, double-blind study randomized participants to oral, once-daily PF-06826647 (1:1:2:2:2) 50:100:200:400 mg:placebo (16 weeks), then 200 or 400 mg (24 weeks) (NCT03895372). The primary end point was a proportion of participants achieving psoriasis area severity index (PASI) 90 at week 16. Secondary end points (PASI50/75/90/100; Physician's Global Assessment) and safety were assessed to week 40. RESULTS: Overall, 178 participants were treated. A significantly greater proportion of participants (risk difference % [90% CI]) achieved PASI90 in the 200-mg (33.0 [18.0, 47.1], P = .0004) and 400-mg (46.5 [30.6, 60.6], P < .0001; week 16) groups versus placebo. Significant increases from placebo were observed for all secondary end points (200 and 400 mg; weeks 6-16; P < .05); increases were evident to week 40 (categorical data). PF-06826647 was well tolerated and most treatment-emergent adverse events were mild/moderate. Eighteen participants discontinued due to treatment-emergent adverse events (14 arising from laboratory abnormalities). LIMITATIONS: Limitations included the large proportion of White males and non-placebo-controlled extension. CONCLUSION: PF-06826647 200 and 400 mg once daily showed significant efficacy versus placebo at week 16 and was well tolerated over 40 weeks.

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors.

Meningiomas account for one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system there remains considerable uncertainty in predicting tumor behavior. Here, we analyzed 160 tumors from all 3 World Health Organization (WHO) grades (I through III) using clinical, gene expression, and sequencing data. Unsupervised clustering analysis identified 3 molecular types (A, B, and C) that reliably predicted recurrence. These groups did not directly correlate with the WHO grading system, which classifies more than half of the tumors in the most aggressive molecular type as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, which results in cell-cycle activation; only tumors in this category tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

A Point Prevalence Study of the Use of Antibiotics in Six Tertiary Care Hospitals in the Kathmandu Valley, Nepal.

Background Point prevalence survey (PPS) on antibiotic use developed by the WHO has already been used in many hospitals globally. Objective To obtain information on antibiotic prescribtion using point prevalence survey methodology in six private hospitals in the Kathmandu valley. Method This descriptive cross-sectional study was completed during 20th July to 28th July 2021 using point prevalence survey methodology. The study was conducted among inpatients admitted at or before 8:00 AM on the day of survey in various wards. Data was presented as frequencies and percentages. Result Maximum number of patients were above 60 years [34 (18.7%)]. Number of male and female participants were equal [91 (50%)]. Only one antibiotic was used in 81 patients (44.5%) followed by two antibiotics in 71 (39%) patients. Duration of prophylactic antibiotic use was one day in 66 (63.7%) patients. Blood, urine, sputum, and wound swabs were the common samples for culture. Cultures were positive for 17 (24.7%) samples. The common organisms isolated were E. Coli, Pseudomonas aeruginosa and Klebsiella pneumoniae. Ceftriaxone was the most used antibiotic. Drug and therapeutics, infection control committee and pharmacovigilance activities were present in 3/6 (50%) study sites. Antimicrobial stewardship was present in 3/6 (50%) and microbiological services was present in all hospitals. Antibiotic formulary and antibiotic guideline were present in 4/6 sites and facilities to audit or review surgical antibiotic prophylaxis choice in 2/6 (33.3%) sites, facility to monitor antibiotic use in 4/6 (66.6%) and cumulative antibiotic susceptibility reports in 2/6 (33.3%) study sites. Conclusion Ceftriaxone was the most used antibiotic. E. Coli, Pseudomonas aeruginosa and Klebsiella pneumonia were the commonly isolated organisms. Not all parameters for infrastructure, policy and practice and monitoring and feedback were present at the study sites. KEY WORDS.

King or royal family? Testing for species boundaries in the King Cobra, Ophiophagus hannah (Cantor, 1836), using morphology and multilocus DNA analyses.

In widespread species, the diverse ecological conditions in which the populations occur, and the presence of many potential geographical barriers through their range are expected to have created ample opportunities for the evolution of distinct, often cryptic lineages. In this work, we tested for species boundaries in one such widespread species, the king cobra, Ophiophagus hannah (Cantor, 1836), a largely tropical elapid snake distributed across the Oriental realm. Based on extensive geographical sampling across most of the range of the species, we initially tested for candidate species (CS) using Maximum-Likelihood analysis of mitochondrial genes. We then tested the resulting CS using both morphological data and sequences of three single-copy nuclear genes. We used snapclust to determine the optimal number of clusters in the nuclear dataset, and Bayesian Phylogenetics and Phylogeography (BPP) to test for likely species status. We used non-metric multidimensional scaling (nMDS) analysis for discerning morphological separation. We recovered four independently evolving, geographically separated lineages that we consider Confirmed Candidate Species: (1) Western Ghats lineage; (2) Indo-Chinese lineage (3) Indo-Malayan lineage; (4) Luzon Island lineage, in the Philippine Archipelago. We discuss patterns of lineage divergence, particularly in the context of low morphological divergence, and the conservation implications of recognizing several endemic king cobra lineages.

Localization, Disorder, and Entropy in a Coarse-Grained Model of the Amorphous Solid.

We study the role of disorder in producing the metastable states in which the extent of mass localization is intermediate between that of a liquid and a crystal with long-range order. We estimate the corresponding entropy with the coarse-grained description of a many-particle system used in the classical density functional model. We demonstrate that intermediate localization of the particles results in a change of the entropy from what is obtained from a microscopic approach using for sharply localized vibrational modes following a Debye distribution. An additional contribution is included in the density of vibrational states g(ω) to account for this excess entropy. A corresponding peak in g(ω)/ω2 vs. frequency ω matches the characteristic boson peak seen in amorphous solids. In the present work, we also compare the shear modulus for the inhomogeneous solid having localized density profiles with the corresponding elastic response for the uniform liquid in the limit of high frequencies.

A 2D Advancing-Front Delaunay Mesh Refinement Algorithm.

I present a generalization of Chew's first algorithm for Delaunay mesh refinement. I split the line segments of an input planar straight line graph (PSLG) such that the lengths of split segments are asymptotically proportional to the local feature size at their endpoints. By employing prior algorithms, I then refine the truly or constrained Delaunay triangulation of the PSLG by inserting off-center Steiner vertices of "skinny" triangles while prioritizing triangles with shortest edges first. This technique inserts Steiner vertices in an advancing front manner such that we obtain a size-optimal, truly or constrained Delaunay mesh if the desired minimum angle is less than 30° (in the absence of small input angles). This is an improvement over prior algorithms that produce size-optimal meshes with minimum angles of about 26.4°and 28.6°for truly and constrained Delaunay meshes, respectively. Even in the presence of small input angles, the upper bound on the maximum angle is an angle strictly greater than 120° (an improvement from about 137°). The lower bound on the minimum angle in the presence of small angles is identical to prior bounds.

Health-care Professionals' Knowledge and Perception of Adverse Drug Reaction Reporting and Pharmacovigilance in a Tertiary Care Teaching Hospital of Nepal.

Background: Underreporting of adverse drug reactions (ADRs) is common globally, and Nepal is not an exception to this. Health-care professionals (HCPs) play a vital role in reporting ADR during routine practice. Lack of knowledge and awareness about pharmacovigilance and reporting ADRs among HCPs may contribute to underreporting. Objective: The objective of this study was to evaluate the knowledge and perception of HCPs regarding ADR reporting and pharmacovigilance in a tertiary care teaching hospital in, Nepal. Methods: A descriptive cross-sectional study was conducted. A questionnaire was distributed to 215 HCPs (medical doctors, nurses, and pharmacists) between March and September 2018. Knowledge and perception regarding ADR reporting and pharmacovigilance were studied. Data were analyzed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp, Armonk, New York). Results: The HCPs included 75 medical doctors, 126 nurses, and 14 pharmacists. Majority of the participants were female (67%), and the majority of participants were not aware of pharmacovigilance. Among the participants, pharmacists were found to have better knowledge regarding pharmacovigilance. However, other HCPs (doctors and nurses) strongly agreed about the necessity of having adequate knowledge about pharmacovigilance. Out of 215, 57.7% agreed that the important benefit of reporting ADR was to identify safe drugs and improve patient safety. The main reasons for not reporting were - ADR reporting was not widely promoted by relevant authorities (47%), followed by not knowing where and how to report ADR (34.9%). However, other HCPs (doctors and nurses) strongly agreed about the necessity of having adequate knowledge about pharmacovigilance. Conclusions: The knowledge of HCPs on ADR reporting and pharmacovigilance was poor. Despite a low knowledge of ADR reporting and pharmacovigilance among HCPs, there was a positive perception that ADR reporting is necessary and ADR monitoring system should be established in the hospital. This study also highlights a need for future intervention studies focusing on educating HCPs about ADR and pharmacovigilance.

Tuning of electron tunneling: a case study using BODIPY molecular layers.

Redox active π-conjugated organic molecules have shown the potential to be used as electronic components such as diode and memory elements. Here, we demonstrate that using simple surface chemistry, rectification characteristics can be tuned to reproducible negative differential resistance (NDR) with a very high peak-to-valley ratio (PVR) up to 1000 in 2,6-diethyl-4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indecene (BODIPY) grafted on Si. The change in properties is related to oxidation and reduction of BODIPY, which results in the change in resonant to non-resonant tunneling of electrons under bias. This has been explained by the ab initio molecular-orbital theoretical calculations.

An insight into the pharmaceutical sector in Yemen during conflict: challenges and recommendations.

In our world today, we need to understand, measure, and respond to inequality. The conflict and siege in Yemen have caused serious repercussions and consequences for the pharmaceutical sector and health of the people. Hospital, health centres and facilities, medicines warehouses and pharmaceutical factories have been destroyed. Further, the conflict has aggravated the health situation with shortages of medicines, an increase in chronic illnesses, and multiple epidemics and casualties. This article aims to highlight the challenges faced by the pharmaceutical sector in Yemen. It will address the overall state of health of the Yemeni people, as well as focus on the past, current status and future development of the pharmaceutical sector. Further, it will focus on possible remedial actions to solve some of these problems. These problems can be tackled if the responsible parties have the political will to do so. Acknowledging the different classes of problems is undeniably very important to provide clarity on the future of Yemen's supposedly promising pharmaceutical landscape.

Attitudes and practices of community pharmacists and barriers to their participation in public health activities in Yemen: mind the gap.

BACKGROUND: Patients in Yemen commonly visit community pharmacies to obtain consultation or treatment for common ailments. Community pharmacists have an opportunity to optimize medication use and improve patient outcomes. This study aimed to evaluate the attitudes and practices of community pharmacists regarding their participation in public health activities and barriers to their participation in these activities. METHODS: This cross-sectional study was carried out among community pharmacists working in pharmacies located in urban areas of the Aden governorate of Yemen from March to June 2017 using a self-administered questionnaire. We selected pharmacies from a line list using proportional sampling according to the number of pharmacies in the urban areas of each district. The questionnaire contained four sections: demographic characteristics, attitudes, practices, and barriers encountered. Data were analyzed descriptively, and the Chi-square test was used for analyzing the association of variables (alpha = 0.05). RESULTS: The questionnaire was distributed to 200 community pharmacists working in community pharmacies. Of the 200 respondents, 62% (n = 124) were male. Overall, the mean age (sd) was 30.0 years (8.6) with the number of years of work experience between 2 and 9.9 years (n = 158, 79%). On average, 62.3% of the pharmacists had a positive attitude toward participation in public health activities. Providing education to stop tobacco chewing, smoking, alcohol drinking and improve oral hygiene was an important activity of the community pharmacists. Blood pressure measurements (86%, n = 172) and glucose tests (45%, n = 90) were commonly conducted for clients. Lack of time (71%, n = 142) and lack of teamwork (70%, n = 140) were mentioned as common barriers to participation in public health activities. CONCLUSIONS: Community pharmacists had a positive attitude toward public health activities. Health education and routine health tests were important practices of the community pharmacists. Barriers need to be overcome to enable more active participation by community pharmacists in public health activities by consulting with all stakeholders, assessing the situation, considering alternatives and taking action.

Sleep Apnea-Predictor of Functional Outcome in Acute Ischemic Stroke.

BACKGROUND: Sleep apnea is increasingly being recognized as 1 of the important, modifiable risk factors of stroke and cardiovascular diseases. Sleep apnea is thought to impair the functional recovery following stroke. Hence, we evaluated the patients with acute ischemic stroke for prevalence of sleep apnea and compared the functional outcomes of patients with and without sleep apnea, at 3rd month of acute ischemic stroke. METHOD: This study was conducted in Kasturba Medical College (KMC) hospital, Manipal, India, between May 2015 and August 2016. We included 102 consecutive patients of acute ischemic stroke with hemiplegic upper limb power of Medical Research Council (MRC) 3 or less. Sleep apnea was diagnosed in these patients using the sleep disordered Questionnaire, Berlin Questionnaire, and Epworth sleepiness scale. Functional outcome was measured using Barthel score on day 7 and at 3rd month following the onset of stroke. RESULT: Out of 102 patients, sleep apnea was present in 31 (30.6%) patients, more in males (67.7%) and elderly. Hypertension was present in 66.6% of patients with sleep apnea. NIHSS score at admission did not differ between the 2 groups. At 3rd month, the Barthel score calculated was better among patient with no apnea, but this was not statistically significant (P = .119). When mean Barthel score at baseline and 3rd month was calculated using repeated measure Analysis of Variance (ANOVA) between the 2 groups, gain in functional independence in no apnea group was statistically significant (P < .001). CONCLUSION: Sleep-disordered breathing is an independent risk factor for stroke, and sleep apnea is also associated with other known stroke risk factors like hypertension. In acute ischemic stroke, sleep apnea has a negative impact on functional recovery. Sleep apnea is amenable to treatment and should be considered in patients with acute ischemic stroke to improve the chance of recovery, and to reduce the risk of recurrence.

The Unmet Need for Pharmacists as Important Members of the Emergency Department Team in Resource-Limited Settings: A Case of Nepal.

Background: The role of pharmacists in many developed countries has evolved from the traditional practice of dispensing medicines to contributing directly or indirectly to improve patient health outcomes. They are providing hospital services and patient care including services in the emergency department (ED). However, there is limited evidence for pharmacist involvement in the ED from resource-limited countries such as Nepal. Objective: The aim of this study is to discuss the role of pharmacists and highlight the unmet need of pharmacists in ED in Nepal. Methods: A narrative review of existing literature was conducted. Results: The status of ED services in Nepalese hospitals is not yet at a desirable level, and there is limited information about the role of pharmacists in EDs. Evidence obtained from developed nations on the role of pharmacists in EDs suggests that they help in improving patient outcomes by minimizing medication errors, adverse drug reactions, and enhance patient care. Conclusion: The study highlights the need for pharmacists in EDs in resource-limited settings. There is limited evidence of pharmacists' role in EDs from Nepal. Therefore, this study suggests a need for further studies on the possible contribution of pharmacists to ED services in Nepal.

Perception about Medicines among the General Public in the Semi-rural Areas of Nepal.

Background Patients' perceptions and beliefs about medicine are affected by their culture, tradition, socioeconomic status, peer influence, educational level, advertisements among other factors. Objective To explore the perception about medicines among the general public in different semi-rural areas of Nepal. Method Cross-sectional study was conducted at different locations within Kathmandu valley from July 2015 to December 2016; 385 individuals were approached using simple random sampling but only 260, aged 18 years and above, who were taking medicines for their health problems, completed the interviewer-administered survey. Their perceptions about medicines were studied using a structured questionnaire based on the WHO booklet "How to investigate the use of medicines by consumers" and analysed using SPSS version 22. Association between respondents' age, gender, education level and perception were statistically analysed using χ2 test and/or Fisher's exact test and multivariate analysis of variance. Result Sixty-one respondents (23.5%) were in age group 56-65 years. Patients' perceptions of medicine safety based on colour, shape, name of medicine, method of administration, compatibility, etc. was statistically different among respondents with regard to their level of education (p = 0.022). More individuals with lower education believed that expensive medicines were more effective (p < 0.001). Increased level of education made them more aware of negative consequences of reusing previous prescriptions (p=0.039). Conclusion Problems with knowledge about medicines were noted among lesser educated individuals. Based on findings, policy makers may develop educational strategies to increase awareness about medicines.

Replication timing is regulated by the number of MCMs loaded at origins.

Replication timing is a crucial aspect of genome regulation that is strongly correlated with chromatin structure, gene expression, DNA repair, and genome evolution. Replication timing is determined by the timing of replication origin firing, which involves activation of MCM helicase complexes loaded at replication origins. Nonetheless, how the timing of such origin firing is regulated remains mysterious. Here, we show that the number of MCMs loaded at origins regulates replication timing. We show for the first time in vivo that multiple MCMs are loaded at origins. Because early origins have more MCMs loaded, they are, on average, more likely to fire early in S phase. Our results provide a mechanistic explanation for the observed heterogeneity in origin firing and help to explain how defined replication timing profiles emerge from stochastic origin firing. These results establish a framework in which further mechanistic studies on replication timing, such as the strong effect of heterochromatin, can be pursued.

How and why multiple MCMs are loaded at origins of DNA replication.

Recent work suggests that DNA replication origins are regulated by the number of multiple mini-chromosome maintenance (MCM) complexes loaded. Origins are defined by the loading of MCM - the replicative helicase which initiates DNA replication and replication kinetics determined by origin's location and firing times. However, activation of MCM is heterogeneous; different origins firing at different times in different cells. Also, more MCMs are loaded in G1 than are used in S phase. These aspects of MCM biology are explained by the observation that multiple MCMs are loaded at origins. Having more MCMs at early origins makes them more likely to fire, effecting differences in origin efficiency that define replication timing. Nonetheless, multiple MCM loading raises new questions, such as how they are loaded, where these MCMs reside at origins, and how their presence affects replication timing. In this review, we address these questions and discuss future avenues of research.