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

Laser Spectroscopy of Atomic Gadolinium

We investigated the hyperfine structure and isotope shift measurements on the spin-forbidden transitions of atomic gadolinium (Gd) at 726 nm and 743 nm in a hollow cathode glow discharge. The spectroscopic study of this sample will help to develop better isotope separation techniques. This also aids in narrowband laser cooling of Gd for novel dipolar physics investigations, and advances new technology in high precision devices. This was accomplished by performing optogalvanic spectroscopy inside an atomic vapor source. As a source, we have used a Gd hollow cathode discharge lamp with neon as a low-pressure buffer gas. Resonant absorption of a Ti:Sapphire laser beam lead to a change in the steady-state population. This sensitive technique proves useful for achieving good signal-to-noise ratio in our investigations of the relatively weak intercombination lines at 726 nm and 743 nm. In addition to this, we have performed a King Plot analysis on the above mentioned lines. This analysis is performed to evaluate the specific mass shift and the ratio of field-shift parameters. From this study, Gd shows the King Plot non-linearity in the 743 nm line, which could be a vital finding to aid in searches for hypothetical new light bosons. In addition, we believe that this result will help to add spectroscopic information to the NIST database with respect to Gd

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

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

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

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

Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk outcome pairs, and new data on risk exposure levels and risk outcome associations. Methods: We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017. Findings: In 2017,34.1 million (95% uncertainty interval [UI] 33.3-35.0) deaths and 121 billion (144-1.28) DALYs were attributable to GBD risk factors. Globally, 61.0% (59.6-62.4) of deaths and 48.3% (46.3-50.2) of DALYs were attributed to the GBD 2017 risk factors. When ranked by risk-attributable DALYs, high systolic blood pressure (SBP) was the leading risk factor, accounting for 10.4 million (9.39-11.5) deaths and 218 million (198-237) DALYs, followed by smoking (7.10 million [6.83-7.37] deaths and 182 million [173-193] DALYs), high fasting plasma glucose (6.53 million [5.23-8.23] deaths and 171 million [144-201] DALYs), high body-mass index (BMI; 4.72 million [2.99-6.70] deaths and 148 million [98.6-202] DALYs), and short gestation for birthweight (1.43 million [1.36-1.51] deaths and 139 million [131-147] DALYs). In total, risk-attributable DALYs declined by 4.9% (3.3-6.5) between 2007 and 2017. In the absence of demographic changes (ie, population growth and ageing), changes in risk exposure and risk-deleted DALYs would have led to a 23.5% decline in DALYs during that period. Conversely, in the absence of changes in risk exposure and risk-deleted DALYs, demographic changes would have led to an 18.6% increase in DALYs during that period. The ratios of observed risk exposure levels to exposure levels expected based on SDI (O/E ratios) increased globally for unsafe drinking water and household air pollution between 1990 and 2017. This result suggests that development is occurring more rapidly than are changes in the underlying risk structure in a population. Conversely, nearly universal declines in O/E ratios for smoking and alcohol use indicate that, for a given SDI, exposure to these risks is declining. In 2017, the leading Level 4 risk factor for age-standardised DALY rates was high SBP in four super-regions: central Europe, eastern Europe, and central Asia; north Africa and Middle East; south Asia; and southeast Asia, east Asia, and Oceania. The leading risk factor in the high-income super-region was smoking, in Latin America and Caribbean was high BMI, and in sub-Saharan Africa was unsafe sex. O/E ratios for unsafe sex in sub-Saharan Africa were notably high, and those for alcohol use in north Africa and the Middle East were notably low. Interpretation: By quantifying levels and trends in exposures to risk factors and the resulting disease burden, this assessment offers insight into where past policy and programme efforts might have been successful and highlights current priorities for public health action. Decreases in behavioural, environmental, and occupational risks have largely offset the effects of population growth and ageing, in relation to trends in absolute burden. Conversely, the combination of increasing metabolic risks and population ageing will probably continue to drive the increasing trends in non-communicable diseases at the global level, which presents both a public health challenge and opportunity. We see considerable spatiotemporal heterogeneity in levels of risk exposure and risk-attributable burden. Although levels of development underlie some of this heterogeneity, O/E ratios show risks for which countries are overperforming or underperforming relative to their level of development. As such, these ratios provide a benchmarking tool to help to focus local decision making. Our findings reinforce the importance of both risk exposure monitoring and epidemiological research to assess causal connections between risks and health outcomes, and they highlight the usefulness of the GBD study in synthesising data to draw comprehensive and robust conclusions that help to inform good policy and strategic health planning

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