Quantum Mechanical Study of Weak Molecular Interactions

Noncovalent interactions have a long history and have received huge attention since their discovery almost a century ago. The prevalence of noncovalent interactions can be seen in the formation of simple dimers to structural and functional modification of large biomolecules. Even though plenty of experimental and theoretical studies are performed to understand various noncovalent interactions, the nature and variety of those interactions are still subject of study. And still they are receiving tremendous attention due to their significant role in the stability and conformation of biomolecules, catalysis of organic and inorganic reactions, crystal packing and material design. This dissertation explores various new sorts of noncovalent interactions, compares them with existing ones, and extensively studies the relevance of noncovalent interactions to various biological systems of interest by applying quantum mechanical tools. A new sort of noncovalent interaction has been identified where two electronegative atoms interact directly with each other with no intervening hydrogen or halogen atoms. These interactions are found to be surprisingly strong, even stronger than regular OH···O and NH···O hydrogen bonds in some cases, and are stabilized by the charge transfer from electron donor to electron acceptor. The major portion of this dissertation deals with the rigorous investigation of new sorts of interactions like P···N, S···N, Cl···N and several other charge transfer types of interactions with side by side comparison with hydrogen and halogen bonds. Similarly, a new carbonyl-carbonyl stacking geometry in peptide-peptide interactions is explored. These stacking geometries are energetically close to stronger NH···O hydrogen bonds, and get some assistance from CH···O hydrogen bonds. Carbon is considered one of the potent H-bond donors, albeit weaker, due to its ubiquitous presence in biomolecules. So, another portion of this dissertation is focused on the study of neutral and charged CH hydrogen bonds simulating various interpeptide interactions and enzyme catalysis. And the last part of this dissertation deals with the putative H-bonds that might be present in tip functionalized carbon nanotubes

Measurement of Fertility Benefits with Low Dose Thyroxine in Sub-fertile women

Introduction: High prevalence rate of thyroid dysfunction associated infertility is identified by a number of studies in Nepal. Thyroid dysfunction not only affects fertility but is also associated with miscarriage and fetal death. The objective of this study was to measure the fertility rate after low dose Thyroxine, 12.5 microgram, in women with subfertility. Methods: This was a descriptive and observational study done among women visiting infertility and in-vitro fertilization (IVF) center at Nepalgunj Medical College, Nepal. After undergoing baseline investigations for infertility, all women diagnosed with primary or secondary infertility were enrolled in the study. Male factor and tubal factor infertility was excluded. All 136 women who were enrolled in the study received 12.5 microgram of thyroxine supplementation for a period of three months and subsequently followed up until the same time period. Results: Out of 136 women, 83 (61.02%) women achieved pregnancy within three months of supplementation with low dose thyroxine. Among them, 34 (40.9%) women with primary infertility achieved pregnancy within three months. Similarly 14 (16.8%) women with previous miscarriage, 20 (24.09%) women with previous caesarean section within past five years back, and 15 (18.07%) with previous IUFD achieved pregnancy within three months. Conclusion: Low dose thyroxine supplementation would be beneficial and recommended to subfertile women of reproductive age group in the endemic regions of hypothyroidism. Dose adjustment would give extended benefits as soon as pregnancy is achieved

Biofilm and MBL production among imipenem resistant Pseudomonas aeruginosa and Acinetobacter species

Pseudomonas aeruginosa and Acinetobacter species are the primary cause of nosocomial infections. The advent of Metallo-beta-lactamase (MBL) and biofilm-producing bacterial strains poses a serious threat to reserve drugs such as carbapenem. The objective of this study was to determine the rate of MBL and biofilm production among imipenem resistant P. aeruginosa (IRPA) and imipenem resistant Acinetobacter spp. (IRAS) isolates. A total of 79 P. aeruginosa and 117 Acinetobacter spp. were isolated from various clinical specimens of patients from July 2016 to January 2017 at Manipal Teaching Hospital, Pokhara. MBL in IRPA and IRAS isolates were detected by Combined disc test and E-test. Biofilm production in imipenem resistant isolates was carried out by Microtitre plate assay. Fifteen (19%) P. aeruginosa and 57 (48.7%) Acinetobacter spp. were imipenem resistant isolates. MBL producers were found among 53.3% of IRPA and 38.6% of IRAS, whereas 100% of IRPA and 82.5% of IRAS were biofilm producers. All the biofilm producer IRPA isolates were Extensively Drug-Resistant (XDR), and a larger proportion of XDR IRAS strains were of high biofilm-producing phenotype. However, the majority of imipenem resistant (80% of IRPA and 49.1% of IRAS) and MBL producing (63%) isolates were weak biofilm formers. The study demonstrated the high capability of IRPA and IRAS to form a biofilm, which was strongly related to higher drug resistance. Nonetheless, imipenem resistant and MBL producer isolates showed an analogous association with the degree of biofilm formation. These MBL cum biofilm producer isolates were better susceptible to polymyxin B and ampicillin-sulbactam. DOI: http://dx.doi.org/10.5281/zenodo.419547

Use of antimicrobials during the COVID-19 pandemic: a qualitative study among stakeholders in Nepal

The COVID-19 pandemic was a major public health threat and the pressure to find curative therapies was tremendous. Particularly in the early critical phase of the pandemic, a lot of empirical treatments, including antimicrobials, were recommended. Drawing on interviews with patients, clinicians and drug dispensers, this article explores the use of antimicrobials for the management of COVID-19 in Nepal. A total of 30 stakeholders (10 clinicians, 10 dispensers and 10 COVID-19 patients) were identified purposively and were approached for an interview. Clinicians and dispensers in three tertiary hospitals in Kathmandu assisted in the recruitment of COVID-19 patients who were undergoing follow-up at an out-patient department. Interviews were audio recorded, translated and transcribed into English, and were analyzed thematically. The respondents report that over-the-counter (OTC) use of antibiotics was widespread during the COVID-19 pandemic in Nepal. This was mostly rooted in patients' attempts to mitigate the potential severity of respiratory illnesses, and the fear of the stigmatization and social isolation linked to being identified as a COVID-19 patient. Patients who visited drug shops and physicians reportedly requested specific medicines including antibiotics. Clinicians reported uncertainty when treating COVID-19 cases that added pressure to prescribe antimicrobials. Respondents from all stakeholder groups recognized the dangers of excessive use of antimicrobials, with some referring to the development of resistance. The COVID-19 pandemic added pressure to prescribe, dispense and overuse antimicrobials, accentuating the pre-existing OTC use of antimicrobials. Infectious disease outbreaks and epidemics warrant special caution regarding the use of antimicrobials and specific policy response

Solvation Enhances the Distinction Between Carboxylated Armchair and Zigzag Single-Wall Carbon Nanotubes (SWNT-COOH)

The effect of various solvents on the structures and properties of carboxylated SWNTs has been explored using the Same Level Different Basis Set approach (SLDB), where B3LYP functional of density functional theory (DFT) was applied. Armchair (4,4) and zigzag (8,0) and (9,0) tubes were considered as the test bed. In order to simulate varying concentration of –COOH groups, one to five acids groups were placed at one end of these tubes. These samples were placed in different solvents (namely, CS2, THF and water) with varying polarity and results were compared with gas-phase properties. Similar to the gas-phase, zigzag tubes also exhibit both regular (r-COOH, v(C=O) above 1700 cm-1) and low-frequency (lf-COOH, v(C=O) below 1700 cm-1) acid groups. Characteristics of r-COOH group are not affected much in solvents, but lf-COOH of the zigzag tube is the one that makes these tubes distinguishable from its armchair cousin. Stability and charge distribution of SWNT-COOH strongly depend on the number of acid groups in different solvents which may help controlling further functionalization. Vibrational analyses reveal certain features in the 1400-1600 cm-1 range that are characteristic of lf-COOH in different solvents, which may help in the assignment of experimental spectra of oxidized SWNT in solvents

The durability of long-lasting insecticidal nets distributed to the households between 2009 and 2013 in Nepal

Background: Understanding and improving the durability of long-lasting insecticidal nets (LLINs) in the field are critical for planning future implementation strategies including behavioral change for care and maintenance. LLIN distribution at high coverage is considered to be one of the adjunctive transmission reduction strategies in Nepal’s Malaria Strategic Plan 2014–2025. The main objective of this study was to assess the durability through assessment of community usage, physical integrity, residual bio-efficacy, and chemical retention in LLINs: Interceptor®, Yorkool®, and PermaNet ®2.0 which were used in Nepal during 2009 through 2013. Methods: Assessments were conducted on random samples (n = 440) of LLINs from the eleven districts representing four ecological zones: Terai plain region (Kailali and Kanchanpur districts), outer Terai fluvial ecosystem (Surkhet, Dang, and Rupandhei districts), inner Terai forest ecosystem (Mahhothari, Dhanusa, and Illam districts), and Hills and river valley (Kavrepalanchock and Sindhupalchok districts). For each LLIN, fabric integrity in terms of proportionate hole index (pHI) and residual bio-efficacy were assessed. However, for chemical retention, a representative sample of 44 nets (15 Yorkool®, 10 Permanet®2.0, and 19 Interceptor®) was evaluated. Data were analyzed using descriptive statistics stratified by LLINs brand, districts, and duration of exposure. Results: On average, duration of use of LLINs was shortest for the Yorkool® samples, followed by PermaNet® 2.0 and Interceptor® with median ages of 8.9 (IQR = 0.4), 23.8 (IQR = 3.2), and 50.1 (IQR = 3.2) months, respectively. Over 80% of field distributed Yorkool® and PermaNet® 2.0 nets were in good condition (pHI< 25) compared to Interceptor® (66%). Bio-efficacy analysis showed that average mortality rates of Interceptor and Yorkool were below World Health Organization (WHO) optimal effectiveness of ≥ 80% compared to 2-year-old PermaNet 2.0 which attained 80%. Chemical retention analysis was consistent with bio-efficacy results. Conclusion: This study shows that distribution of LLINs is effective for malaria control; however, serviceable life of LLINs should be considered in terms of waning residual bio-efficacy that warrants replacement. As an adjunctive malaria control tool, National Malaria Control Program of Nepal can benefit by renewing the distribution of LLINs in an appropriate time frame in addition to utilizing durable and effective LLINs

Effects of Charge and Substituent on the S∙∙∙N Chalcogen Bond

Neutral complexes containing a S···N chalcogen bond are compared with similar systems in which a positive charge has been added to the S-containing electron acceptor, using high-level ab initio calculations. The effects on both XS···N and XS+···N bonds are evaluated for a range of different substituents X = CH3, CF3, NH2, NO2, OH, Cl, and F, using NH3 as the common electron donor. The binding energy of XMeS···NH3 varies between 2.3 and 4.3 kcal/mol, with the strongest interaction occurring for X = F. The binding is strengthened by a factor of 2–10 in charged XH2S+···NH3 complexes, reaching a maximum of 37 kcal/mol for X = F. The binding is weakened to some degree when the H atoms are replaced by methyl groups in XMe2S+···NH3. The source of the interaction in the charged systems, like their neutral counterparts, is derived from a charge transfer from the N lone pair into the σ*(SX) antibonding orbital, supplemented by a strong electrostatic and smaller dispersion component. The binding is also derived from small contributions from a CH···N H-bond involving the methyl groups, which is most notable in the weaker complexes

The Magnitude and Mechanism of Charge Enhancement of CH∙∙O H-bonds

Quantum calculations find that neutral methylamines and thioethers form complexes, with N-methylacetamide (NMA) as proton acceptor, with binding energies of 2–5 kcal/mol. This interaction is magnified by a factor of 4–9, bringing the binding energy up to as much as 20 kcal/mol, when a CH3+ group is added to the proton donor. Complexes prefer trifurcated arrangements, wherein three separate methyl groups donate a proton to the O acceptor. Binding energies lessen when the systems are immersed in solvents of increasing polarity, but the ionic complexes retain their favored status even in water. The binding energy is reduced when the methyl groups are replaced by longer alkyl chains. The proton acceptor prefers to associate with those CH groups that are as close as possible to the S/N center of the formal positive charge. A single linear CH··O hydrogen bond (H-bond) is less favorable than is trifurcation with three separate methyl groups. A trifurcated arrangement with three H atoms of the same methyl group is even less favorable. Various means of analysis, including NBO, SAPT, NMR, and electron density shifts, all identify the +CH··O interaction as a true H-bond

Alcohol use and burden for 195 countries and territories, 1990-2016 : a systematic analysis for the Global Burden of Disease Study 2016

Background Alcohol use is a leading risk factor for death and disability, but its overall association with health remains complex given the possible protective effects of moderate alcohol consumption on some conditions. With our comprehensive approach to health accounting within the Global Burden of Diseases, Injuries, and Risk Factors Study 2016, we generated improved estimates of alcohol use and alcohol-attributable deaths and disability-adjusted life-years (DALYs) for 195 locations from 1990 to 2016, for both sexes and for 5-year age groups between the ages of 15 years and 95 years and older. Methods Using 694 data sources of individual and population-level alcohol consumption, along with 592 prospective and retrospective studies on the risk of alcohol use, we produced estimates of the prevalence of current drinking, abstention, the distribution of alcohol consumption among current drinkers in standard drinks daily (defined as 10 g of pure ethyl alcohol), and alcohol-attributable deaths and DALYs. We made several methodological improvements compared with previous estimates: first, we adjusted alcohol sales estimates to take into account tourist and unrecorded consumption; second, we did a new meta-analysis of relative risks for 23 health outcomes associated with alcohol use; and third, we developed a new method to quantify the level of alcohol consumption that minimises the overall risk to individual health. Findings Globally, alcohol use was the seventh leading risk factor for both deaths and DALYs in 2016, accounting for 2.2% (95% uncertainty interval [UI] 1.5-3.0) of age-standardised female deaths and 6.8% (5.8-8.0) of age-standardised male deaths. Among the population aged 15-49 years, alcohol use was the leading risk factor globally in 2016, with 3.8% (95% UI 3.2-4-3) of female deaths and 12.2% (10.8-13-6) of male deaths attributable to alcohol use. For the population aged 15-49 years, female attributable DALYs were 2.3% (95% UI 2.0-2.6) and male attributable DALYs were 8.9% (7.8-9.9). The three leading causes of attributable deaths in this age group were tuberculosis (1.4% [95% UI 1. 0-1. 7] of total deaths), road injuries (1.2% [0.7-1.9]), and self-harm (1.1% [0.6-1.5]). For populations aged 50 years and older, cancers accounted for a large proportion of total alcohol-attributable deaths in 2016, constituting 27.1% (95% UI 21.2-33.3) of total alcohol-attributable female deaths and 18.9% (15.3-22.6) of male deaths. The level of alcohol consumption that minimised harm across health outcomes was zero (95% UI 0.0-0.8) standard drinks per week. Interpretation Alcohol use is a leading risk factor for global disease burden and causes substantial health loss. We found that the risk of all-cause mortality, and of cancers specifically, rises with increasing levels of consumption, and the level of consumption that minimises health loss is zero. These results suggest that alcohol control policies might need to be revised worldwide, refocusing on efforts to lower overall population-level consumption.Peer reviewe

Measuring performance on the Healthcare Access and Quality Index for 195 countries and territories and selected subnational locations: A systematic analysis from the Global Burden of Disease Study 2016

Background: A key component of achieving universal health coverage is ensuring that all populations have access to quality health care. Examining where gains have occurred or progress has faltered across and within countries is crucial to guiding decisions and strategies for future improvement. We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2016 (GBD 2016) to assess personal health-care access and quality with the Healthcare Access and Quality (HAQ) Index for 195 countries and territories, as well as subnational locations in seven countries, from 1990 to 2016. Methods Drawing from established methods and updated estimates from GBD 2016, we used 32 causes from which death should not occur in the presence of effective care to approximate personal health-care access and quality by location and over time. To better isolate potential effects of personal health-care access and quality from underlying risk factor patterns, we risk-standardised cause-specific deaths due to non-cancers by location-year, replacing the local joint exposure of environmental and behavioural risks with the global level of exposure. Supported by the expansion of cancer registry data in GBD 2016, we used mortality-to-incidence ratios for cancers instead of risk-standardised death rates to provide a stronger signal of the effects of personal health care and access on cancer survival. We transformed each cause to a scale of 0-100, with 0 as the first percentile (worst) observed between 1990 and 2016, and 100 as the 99th percentile (best); we set these thresholds at the country level, and then applied them to subnational locations. We applied a principal components analysis to construct the HAQ Index using all scaled cause values, providing an overall score of 0-100 of personal health-care access and quality by location over time. We then compared HAQ Index levels and trends by quintiles on the Socio-demographic Index (SDI), a summary measure of overall development. As derived from the broader GBD study and other data sources, we examined relationships between national HAQ Index scores and potential correlates of performance, such as total health spending per capita. Findings In 2016, HAQ Index performance spanned from a high of 97\ub71 (95% UI 95\ub78-98\ub71) in Iceland, followed by 96\ub76 (94\ub79-97\ub79) in Norway and 96\ub71 (94\ub75-97\ub73) in the Netherlands, to values as low as 18\ub76 (13\ub71-24\ub74) in the Central African Republic, 19\ub70 (14\ub73-23\ub77) in Somalia, and 23\ub74 (20\ub72-26\ub78) in Guinea-Bissau. The pace of progress achieved between 1990 and 2016 varied, with markedly faster improvements occurring between 2000 and 2016 for many countries in sub-Saharan Africa and southeast Asia, whereas several countries in Latin America and elsewhere saw progress stagnate after experiencing considerable advances in the HAQ Index between 1990 and 2000. Striking subnational disparities emerged in personal health-care access and quality, with China and India having particularly large gaps between locations with the highest and lowest scores in 2016. In China, performance ranged from 91\ub75 (89\ub71-93\ub76) in Beijing to 48\ub70 (43\ub74-53\ub72) in Tibet (a 43\ub75-point difference), while India saw a 30\ub78-point disparity, from 64\ub78 (59\ub76-68\ub78) in Goa to 34\ub70 (30\ub73-38\ub71) in Assam. Japan recorded the smallest range in subnational HAQ performance in 2016 (a 4\ub78-point difference), whereas differences between subnational locations with the highest and lowest HAQ Index values were more than two times as high for the USA and three times as high for England. State-level gaps in the HAQ Index in Mexico somewhat narrowed from 1990 to 2016 (from a 20\ub79-point to 17\ub70-point difference), whereas in Brazil, disparities slightly increased across states during this time (a 17\ub72-point to 20\ub74-point difference). Performance on the HAQ Index showed strong linkages to overall development, with high and high-middle SDI countries generally having higher scores and faster gains for non-communicable diseases. Nonetheless, countries across the development spectrum saw substantial gains in some key health service areas from 2000 to 2016, most notably vaccine-preventable diseases. Overall, national performance on the HAQ Index was positively associated with higher levels of total health spending per capita, as well as health systems inputs, but these relationships were quite heterogeneous, particularly among low-to-middle SDI countries. Interpretation GBD 2016 provides a more detailed understanding of past success and current challenges in improving personal health-care access and quality worldwide. Despite substantial gains since 2000, many low-SDI and middle- SDI countries face considerable challenges unless heightened policy action and investments focus on advancing access to and quality of health care across key health services, especially non-communicable diseases. Stagnating or minimal improvements experienced by several low-middle to high-middle SDI countries could reflect the complexities of re-orienting both primary and secondary health-care services beyond the more limited foci of the Millennium Development Goals. Alongside initiatives to strengthen public health programmes, the pursuit of universal health coverage hinges upon improving both access and quality worldwide, and thus requires adopting a more comprehensive view-and subsequent provision-of quality health care for all populations