DEVELOPMENT OF COPPER-CATALYZED SUZUKI-MIYAURA COUPLING USING ALKYLBORON REAGENTS AND NICKEL-CATALYZED ALKENE DICARBOFUNCTIONALIZATION REACTIONS

This thesis is divided into two parts. The first part deals with the development of copper-catalyzed Suzuki-Miyaura coupling of alkylboron reagents for the first time. In the second part, we will discuss the development of novel nickel-catalyzed alkene dicarbofunctionalization reactions. Part I. Cross-coupling reactions are versatile tools to form new carbon-carbon bonds and are widely used in the synthesis of various drug molecules, natural products and materials. However, these reactions are typically catalyzed by palladium, an expensive and rare metal which makes the reaction unsustainable in long-terms. Additionally, palladium-catalyzed cross-coupling reactions with alkylorganometallic reagents suffer from side reactions due to complications by β-hydride elimination and protodemetalation. The reactions also less tolerate to heteroarenes as these substrates generally deactivate the catalysts. These problems are largely addressed by using sterically hindered, expensive and difficult-to-make ligands. Recently, copper, a cheap and highly abundant metal, has emerged as an alternative catalyst, and has been utilized increasingly in cross-coupling reactions. The rising use of copper in cross-coupling can be attributed to lower tendency of alkylcopper intermediates for β-hydride elimination than those of analogous alkylpalladium species. Additionally, copper catalysts are also known to tolerate heteroarenes much better than palladium catalysts. In this thesis, we present our results on the development of a copper-catalyzed Suzuki-Miyaura cross-coupling reaction of alkylboron reagents with aryl and heteroaryl iodides. This novel reaction works well with alkylboron reagents without any complication form β-hydride elimination and tolerates heteroarenes without requiring sterically hindered and expensive ligands. We also conducted mechanistic studies of this reaction through independent synthesis of pertinent reaction intermediates such as anionic dialkylborate complexes, radical clock experiment and a Hammett plot. The experimental results with discrete alkylboron intermediates indicate that anionic alkyl(alkoxy)borate complexes, which are generally accepted as active transmetalating species, undergo disproportionation into anionic dialkylborate intermediates prior to transmetalation to copper catalyst. Radical clock experiment and the Hammett plot indicate that the reaction proceeds through non-radical pathway. Part II. In this part, we discuss the development of nickel-catalyzed regioselective alkene dicarbofunctionalization reactions by using the imines as a coordination group. These reactions that simultaneously form two carbon-carbon bonds across alkenes will offer a highly effective strategy for providing modular, convergent, and expedient routes to generate complex bioactive molecules. However, the development of regioselective three-component dicarbofunctionalization of unactivated alkenes has remained a formidable challenge for more than three decades. These reactions are limited to difunctionalizing geometrically constrained norbornenes. Recent use of coordination approach brought some success in dicarbofunctionalization of unactivated alkenes. However, the current state of the coordination approach is also seriously limited as only alkenes proceeding via five-membered metallacycles or via stable and mostly planar six-membered metallacycles with vinylarenes can be utilized as substrates. Aliphatic γ, δ-alkenyl carbonyl compounds, which generate more challenging and less stable six-membered metallacycles, cannot be used as substrates. The use of these alkenes suffers from two key limitations: (1) formation of cross-coupling products caused by slow migratory insertion of alkenes due to weak binding, and (2) formation of Heck products caused by faster β-H elimination from metallacycles than competing transmetalation with organometallic reagents. These side reactions have seriously limited the generality of the coordination approach and the scope of alkene dicarbofunctionalization reactions. In this thesis, we will implement two novel strategies to difunctionalize unactivated alkenes regioselectively using organic halides and organometallic reagents. First, we will introduce a strategy of cationic catalysis, where cationic Ni(II) catalysts are generated in situ to address the key issues identified above. This process will enable us to perform regioselective γ, δ-difunctionalization of unactivated alkenes located at the γ, δ-position of carbonyl compounds. It is our observation that cationic Ni(II) promotes transmetalation faster than β-H elimination. This is unprecedented and will be of paramount fundamental significance in catalysis. Since this new cationic catalysis concept addresses two major issues that are common in alkene difunctionalization, we also anticipate that this discovery will be widely applicable for a general class of alkene substrates. In our second strategy, we introduce a novel concept of metallacycle contraction process, a reaction that harnesses the potential of alkylmetal intermediates to undergo β-H elimination to contract a six-membered metallacycle to a five-membered metallacycle, and difunctionalizes unactivated alkenes at the unusual 1,3-position rather than the usual 1,2-position of alkenes. This unprecedented reaction allows us to create two new carbon-carbon bonds at the β- and δ-positions of carbonyl compounds containing γ, δ-alkenes

Effect of integrated nutrient management on growth and yield of radish

Integrated Nutrient Management (INM) is necessary to enhance sustainable yield in an eco-friendly way. A field experiment was conducted in the research field of Midwest Academy and Research Institute College of Live Sciences, Tulsipur, Dang from November 2018 to January 2019 to investigate the effect of integrated nutrient management on growth and yield of radish. Mino Early variety was used in the experiment. The experiment was laid out on Randomized Complete Block Design with four replications and 5 treatments. Nitrogen (N) was supplied through different sources. The treatment combinations were: control (T1), 100% recommended N through chemical fertilizer (T2), 50% recommended N through chemical fertilizer + 50% N through farmyard manure (FYM) (T3), 50% recommended N through chemical fertilizer + 50% N through poultry manure (T4) and 50% recommended N through chemical fertilizer + 50% vermicompost (T5). Significant effect was noted on leaf numbers, root length, root diameter and yield per ha but no significant effect was noted on the germination percentage and plant height. The highest germination percentage  (77.00 %), plant height (13.27 cm), root length (16.94 cm), root diameter (3.01 cm), and yield per ha (16.55 t/ha) was recorded at T4 (50% recommended N through chemical fertilizer + 50% N through poultry manure). T5 (50% recommended N through chemical fertilizer + 50% vermicompost) recorded the highest leaf numbers (10.40). In our experiment, T4 (50% recommended N through chemical fertilizer + 50% N through poultry manure) was found to be superior, so in inner terai places like Tulsipur, Dang it is suggested to apply 50% recommended N through chemical fertilizer + 50% N through poultry manure to obtain a high yield of radish

Acute Lower Respiratory Infection in Childhood and Household Fuel Use in Bhaktapur, Nepal

Background: Globally, solid fuels are used by about 3 billion people for cooking. These fuels have been associated with many health effects, including acute lower respiratory infection (ALRI) in young children. Nepal has a high prevalence of use of biomass for cooking and heating. Objective: This case–control study was conducted among a population in the Bhaktapur municipality, Nepal, to investigate the relationship of cookfuel type to ALRI in young children. Methods: Cases with ALRI and age-matched controls were enrolled from an open cohort of children 2–35 months old, under active monthly surveillance for ALRI. A questionnaire was used to obtain information on family characteristics, including household cooking and heating appliances and fuels. The main analysis was carried out using conditional logistic regression. Population-attributable fractions (PAF) for stove types were calculated. Results: A total of 917 children (452 cases and 465 controls) were recruited into the study. Relative to use of electricity for cooking, ALRI was increased in association with any use of biomass stoves [odds ratio (OR) = 1.93; 95% CI: 1.24, 2.98], kerosene stoves (OR = 1.87; 95% CI: 1.24, 2.83), and gas stoves (OR = 1.62; 95% CI: 1.05, 2.50). Use of wood, kerosene, or coal heating was also associated with ALRI (OR = 1.45; 95% CI: 0.97, 2.14), compared with no heating or electricity or gas heating. PAFs for ALRI were 18.0% (95% CI: 8.1, 26.9%) and 18.7% (95% CI: 8.4%–27.8%), for biomass and kerosene stoves, respectively. Conclusions: The study supports previous reports indicating that use of biomass as a household fuel is a risk factor for ALRI, and provides new evidence that use of kerosene for cooking may also be a risk factor for ALRI in young children

Prevalence of chronic obstructive pulmonary disease (COPD) among rheumatoid arthritis: results from national inpatient database.

Rheumatoid arthritis (RA) is being increasingly recognized as an important contributor to chronic obstructive pulmonary disease (COPD). Although smoking is a major risk factor, other factors may play a role. We used National Inpatient Sample (NIS) from 2013 to explore this relationship. We used propensity matching with a 1:3 nearest-neighbor-matching algorithm to match 1 RA hospitalization to 3 age- and-sex-matched comparators. In the age- and-sex-matched population, RA had a higher odds of COPD (OR 1.20, 95% CI: 1.17-1.22

Ulnar Compression Neuropathy Secondary to Ganglion Cyst at the Elbow Joint: A Case Report

Ulnar neuropathy is a common peripheral neuropathy, with cubital tunnel compression being the second most frequent upper extremity compression syndrome. Ganglion cysts, though rare, can contribute to ulnar nerve compression in the cubital tunnel. Here, we present a case of a 62-year-old farmer with longstanding diabetes and dyslipidemia who experienced progressive pain and numbness in his medial fingers, exacerbated by elbow flexion. Initially misdiagnosed and treated for Hansen’s disease. Clinico-radiological evaluation revealed a multiloculated cystic lesion in the posteromedial aspect of his left elbow, compressing the ulnar nerve. Surgical excision of the ganglion cyst alleviated symptoms, though residual motor deficits persisted postoperatively. This case underscores the importance of considering ganglion cysts in the differential diagnosis of cubital tunnel syndrome, highlighting the diagnostic challenges and therapeutic considerations in managing this rare etiology

Butorphanol in Labour Analgesia

Introduction: Labour is the process where uterine contractions lead to expulsion of product of conception through the vagina into the outer world. Labour pain is one of the most severe pains which has ever been evaluated and its fear is one of the reasons women wouldn’t go for natural delivery. Delivery is a painful experience for all of the women except a few of them. The labor pain results from some physiological-psychological causes. Different pharmacological and non-pharmacological methods have been tried for pain relief in labour. The objective of this study is to see the effect of butorphanol injection in labour pain. Methods: It is a descriptive cross-sectional study conducted in B.P. Koirala institute of health sciences. We observed 200 pregnant women meeting the inclusion criteria and giving the informed consent who were on 1 mg butorphanol i.m. at the onset of active stage of labour every 4 hourly and on demand. Pain assessment was done by Numerical Pain analogue scale measured from 1 to 10. Fetal heart rate monitoring was done according to the hospital protocol. Caesarean section was performed for obstetrical indication. Neonatal outcome was evaluated by on duty pediatrician and APGAR score were noted at 1 and 5 min. Results: The pain scores in first, second, third, fourth hour were (8.83±0.773), (9.84±0.544), (9.94±0.338), (9.6±0.298) respectively, where 1st and 2nd hour is statistically significant. Conclusions: Butorphanol is an effective labour analgesia without significant adverse effects on women and the neonatal outcome

Stone Clearance by Computed Tomography after Percutaneous Nephrolithotomy: A Descriptive Cross-sectional Study

Introduction: Percutaneous nephrolithotomy has the highest stone free rate among other procedures with relatively higher complication rate. Post-operative imaging after stone surgeries has not been uniform. This study was done to study about the stone clearance by computed tomography after percutaneous nephrolithotomy. Methods: The descriptive cross-sectional study was conducted in the Department of Urology, Bir Hospital for six months duration. The patients undergoing percutaneous nephrolithotomy and those with intra-operative fluoroscopic clearance were evaluated with a low dose computed tomography after 48 hours to assess residual fragments its size and location. Patient’s demographics, stone characteristics and complications were compared between the stone free and with residual stone patients. Results: Out of 72 percutaneous nephrolithotomy performed, 40 patients were included in the study. Low dose computed tomography kidney, ureter and bladder after 48 hours of surgery detected residual fragments in 11 (27.5%) patients. The RFs size of 4mm were found in 4 (36.36%). The stone size was 352.47 ± 97.47 mm2 and 254.79 ± 172.68mm2 in group with residual fragments and stone free group respectively. Conclusions: Low dose computed tomography kidney, ureter and bladder done for assessment of stone clearance after 48 hours of percutaneous nephrolithomy detected residual in around one fourth of patients, however majority of them had residual fragments 4mm size

Predicting the potential distribution and habitat variables associated with pangolins in Nepal

Pangolins are highly-threatened due to illegal hunting and poaching, and by the loss, degradation, and fragmentation of their habitats. In Nepal, effective conservation actions for pangolins are scarce due to limited information on the distribution of pangolins in many areas of the country. To identify the nationwide distribution of pangolins in Nepal, and assess the environmental variables associated with their habitat, we conducted an extensive literature review to collate data from previous studies, canvassed information from key informant interviews and expert opinion, and conducted transect surveys and sign surveys. The occurrence of pangolins was recorded based on sightings and indirect signs (such as burrows, digs, tracks, and scats) along 115 belt transects of 500-m length with a fixed width of 50-m, and habitat parameters were surveyed using 347 quadrats of 10 m*10 m. Pangolin presence was confirmed from 61 out of 75 districts from the eastern to the far western parts of the country. The highest frequency of burrows (74%) was observed in the forested habitat constituting brown soil with medium texture (0.02–2 mm) within an elevation range of 500–1500 m above sea level. Logistic regression suggested that the occurrence of pangolin was highly influenced by ground cover and canopy cover of 50–75%, litter depth, and the distance to termite mounds and roads. We used 4136 occurrence GPS points of pangolin burrows that were compiled and collected from the literature review and field surveys in order to predict the potential habitat distribution of pangolin using maximum entropy algorithm (MaxEnt 3.4.1). The model predicted 15.2% (22,393 km2) of the total land of Nepal as potentially suitable habitat for pangolin, with 38.3% (8574 km2) of potential habitat in the eastern region, followed by 37.6% (8432 km2) in the central and 24.1% (5,387 km2) in the western regions. The results of this study present a national baseline for pangolin distribution and serve as an important document for developing and executing conservation actions and management plans for the long-term conservation of pangolins in Nepal

Development and validation of a novel clinical risk score to predict hypoxaemia in children with pneumonia using the WHO PREPARE dataset

Background: Hypoxaemia predicts mortality at all levels of care, and appropriate management can reduce preventable deaths. However, pulse oximetry and oxygen therapy remain inaccessible in many primary care health facilities. We aimed to develop and validate a simple risk score comprising commonly evaluated clinical features to predict hypoxaemia in 2–59-month-old children with pneumonia. Methods: Data from seven studies conducted in five countries from the Pneumonia Research Partnership to Assess WHO Recommendations (PREPARE) dataset were included. Readily available clinical features and demographic variables were used to develop a multivariable logistic regression model to predict hypoxemia (oxygen saturation <90%) at presentation to care. The adjusted log coefficients were transformed to derive the PREPARE hypoxemia risk score and its diagnostic value was assessed in a held-out, temporal validation dataset. The model and risk score were analysed by evaluating the area under the receiver operating characteristic curve (AUC), sensitivity and specificity. Results: We included 14 509 children in the analysis; 9.8% (n=2515) were hypoxemic at presentation. The multivariable regression model to predict hypoxemia included age, sex, respiratory distress (nasal flaring, grunting and/or head nodding), lower chest indrawing, respiratory rate, body temperature and weight-for-age z-score. The model showed fair discrimination (AUC 0.70, 95% CI 0.67 to 0.73) and calibration in the validation dataset. The simplified PREPARE hypoxaemia risk score includes five variables: age, respiratory distress, lower chest indrawing, respiratory rate and weight-for-age z-score. Conclusion: The PREPARE hypoxemia risk score, comprising five easily available characteristics, has the potential to be used to identify hypoxemia in children with pneumonia with a fair degree of certainty for use in health facilities without pulse oximetry. Its implementation would require careful consideration to limit the burden of inappropriate referrals on patients and the health system. Further external validation in community settings in low- and middle-income countries is required