(Fe-Co-Ni-Zn)-Based Metal-Organic Framework-Derived Electrocatalyst for Zinc-Air Batteries.

Zinc-air batteries (ZABs) have garnered significant interest as a viable substitute for lithium-ion batteries (LIBs), primarily due to their impressive energy density and low cost. However, the efficacy of zinc-air batteries is heavily dependent on electrocatalysts, which play a vital role in enhancing reaction efficiency and stability. This scholarly review article highlights the crucial significance of electrocatalysts in zinc-air batteries and explores the rationale behind employing Fe-Co-Ni-Zn-based metal-organic framework (MOF)-derived hybrid materials as potential electrocatalysts. These MOF-derived electrocatalysts offer advantages such as abundancy, high catalytic activity, tunability, and structural stability. Various synthesis methods and characterization techniques are employed to optimize the properties of MOF-derived electrocatalysts. Such electrocatalysts exhibit excellent catalytic activity, stability, and selectivity, making them suitable for applications in ZABs. Furthermore, they demonstrate notable capabilities in the realm of ZABs, encompassing elevated energy density, efficacy, and prolonged longevity. It is imperative to continue extensively researching and developing this area to propel the advancement of ZAB technology forward and pave the way for its practical implementation across diverse fields.

Biocatalytic role of cytochrome P450s to produce antibiotics: A review.

Cytochrome P450s belong to a family of heme-binding monooxygenases, which catalyze regio- and stereospecific functionalisation of C-H, C-C, and C-N bonds, including heteroatom oxidation, oxidative C-C bond cleavages, and nitrene transfer. P450s are considered useful biocatalysts for the production of pharmaceutical products, fine chemicals, and bioremediating agents. Despite having tremendous biotechnological potential, being heme-monooxygenases, P450s require either autologous or heterologous redox partner(s) to perform chemical transformations. Randomly distributed P450s throughout a bacterial genome and devoid of particular redox partners in natural products biosynthetic gene clusters (BGCs) showed an extra challenge to reveal their pharmaceutical potential. However, continuous efforts have been made to understand their involvement in antibiotic biosynthesis and their modification, and this review focused on such BGCs. Here, particularly, we have discussed the role of P450s involved in the production of macrolides and aminocoumarin antibiotics, nonribosomal peptide (NRPSs) antibiotics, ribosomally synthesized and post-translationally modified peptide (RiPPs) antibiotics, and others. Several reactions catalyzed by P450s, as well as the role of their redox partners involved in the BGCs of various antibiotics and their derivatives, have been primarily addressed in this review, which would be useful in further exploration of P450s for the biosynthesis of new therapeutics.

Public engagement during a typhoid conjugate vaccine trial in Lalitpur, Nepal- experience, challenges and lessons learnt.

Typhoid is a public health problem in Nepal. To generate evidence on the impact of Typhoid Conjugate Vaccine (TCV), a phase 3, double-blind, randomized controlled trial was conducted in Lalitpur, Nepal. 20,000 children aged between 9 months and ≤16 years were vaccinated with a new TCV, or control vaccine. Participants were actively followed for safety and efficacy over 2 years through passive surveillance (PS) clinics. Several challenges were encountered during vaccination and PS stemming from misinformation, misconception, and fear around clinical trials in the community. Public engagement (PE) activities were conducted across various tiers moving from decision makers in the first tier; to elected local representatives in the second tier; ending with interaction in community with parents/guardians of the targeted population. Prior and during vaccination, engagement was conducted to inform about the study and discuss the importance of vaccination. Post-vaccination, engagement was conducted to inform about PS clinics, alleviate study concerns and share study updates. Direct and continuous interaction with community stakeholders, including parents/guardians of the targeted population contributed to build trust around the study and community willingness to be involved. It helped to raise awareness, drive away misconceptions, and allowed adaptation according to feedback from community members.

Efficacy of typhoid conjugate vaccine in Nepal: final results of a phase 3, randomised, controlled trial.

BACKGROUND: Typhoid fever is a major public health problem in low-resource settings. Vaccination can help curb the disease and might reduce transmission. We have previously reported an interim analysis of the efficacy of typhoid conjugate vaccine (TCV) in Nepali children. Here we report the final results after 2 years of follow-up. METHODS: We did a participant-masked and observer-masked individually randomised trial in Lalitpur, Nepal, in which 20 019 children aged 9 months to younger than 16 years were randomly assigned in a 1:1 ratio to receive a single dose of TCV (Typbar TCV, Bharat Biotech International, India) or capsular group A meningococcal conjugate vaccine (MenA). Participants were followed up until April 9, 2020. The primary outcome was blood culture-confirmed typhoid fever. Cases were captured via passive surveillance and active telephone surveillance followed by medical record review. The trial is registered at ISRCTN registry, ISRCTN43385161 and is ongoing. FINDINGS: From Nov 20, 2017, to April 9, 2018, of 20 119 children screened, 20 019 participants were randomly assigned to receive TCV or MenA vaccine. There were 75 cases of blood culture-confirmed typhoid fever included in the analysis (13 in the TCV group and 62 in the MenA group) over the 2-year period. The protective efficacy of TCV against blood culture-confirmed typhoid fever at 2 years was 79·0% (95% CI 61·9-88·5; p<0·0001). The incidence of typhoid fever was 72 (95% CI 38-123) cases per 100 000 person-years in the TCV group and 342 (95% CI 262-438) cases per 100 000 person-years in the MenA group. Adverse events occurring within the first 7 days post-vaccination were reported previously. INTERPRETATION: The final results of this randomised, controlled trial are in keeping with the results of our published interim analysis. There is no evidence of waning protection over a 2-year period. These findings add further support for the WHO recommendations on control of enteric fever. FUNDING: Bill & Melinda Gates Foundation.

Reprogramming natural proteins using unnatural amino acids.

Unnatural amino acids have gained significant attention in protein engineering and drug discovery as they allow the evolution of proteins with enhanced stability and activity. The incorporation of unnatural amino acids into proteins offers a rational approach to engineer enzymes for designing efficient biocatalysts that exhibit versatile physicochemical properties and biological functions. This review highlights the biological and synthetic routes of unnatural amino acids to yield a modified protein with altered functionality and their incorporation methods. Unnatural amino acids offer a wide array of applications such as antibody-drug conjugates, probes for change in protein conformation and structure-activity relationships, peptide-based imaging, antimicrobial activities, etc. Besides their emerging applications in fundamental and applied science, systemic research is necessary to explore unnatural amino acids with novel side chains that can address the limitations of natural amino acids.

Process evaluation of a district mental healthcare plan in Nepal: a mixed-methods case study.

BACKGROUND: The PRogramme for Improving Mental Health carE (PRIME) evaluated the process and outcomes of the implementation of a mental healthcare plan (MHCP) in Chitwan, Nepal. AIMS: To describe the process of implementation, the barriers and facilitating factors, and to evaluate the process indicators of the MHCP. METHOD: A case study design that combined qualitative and quantitative methods based on a programme theory of change (ToC) was used and included: (a) district-, community- and health-facility profiles; (b) monthly implementation logs; (c) pre- and post-training evaluation; (d) out-patient clinical data and (e) qualitative interviews with patients and caregivers. RESULTS: The MHCP was able to achieve most of the indicators outlined by the ToC. Of the total 32 indicators, 21 (66%) were fully achieved, 10 (31%) partially achieved and 1 (3%) were not achieved at all. The proportion of primary care patients that received mental health services increased by 1200% over the 3-year implementation period. Major barriers included frequent transfer of trained health workers, lack of confidential space for consultation, no mental health supervision in the existing system, and stigma. Involvement of Ministry of Health, procurement of new psychotropic medicines through PRIME, motivation of health workers and the development of a new supervision system were key facilitating factors. CONCLUSIONS: Effective implementation of mental health services in primary care settings require interventions to increase demand for services and to ensure there is clinical supervision for health workers, private rooms for consultations, a separate cadre of psychosocial workers and a regular supply of psychotropic medicines.

Phase 3 Efficacy Analysis of a Typhoid Conjugate Vaccine Trial in Nepal.

BACKGROUND: Salmonella Typhi is a major cause of fever in children in low- and middle-income countries. A typhoid conjugate vaccine (TCV) that was recently prequalified by the World Health Organization was shown to be efficacious in a human challenge model, but data from efficacy trials in areas where typhoid is endemic are lacking. METHODS: In this phase 3, randomized, controlled trial in Lalitpur, Nepal, in which both the participants and observers were unaware of the trial-group assignments, we randomly assigned children who were between 9 months and 16 years of age, in a 1:1 ratio, to receive either a TCV or a capsular group A meningococcal conjugate vaccine (MenA) as a control. The primary outcome was typhoid fever confirmed by blood culture. We present the prespecified analysis of the primary and main secondary outcomes (including an immunogenicity subgroup); the 2-year trial follow-up is ongoing. RESULTS: A total of 10,005 participants received the TCV and 10,014 received the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 7 participants who received TCV (79 cases per 100,000 person-years) and in 38 who received MenA vaccine (428 cases per 100,000 person-years) (vaccine efficacy, 81.6%; 95% confidence interval, 58.8 to 91.8; P<0.001). A total of 132 serious adverse events (61 in the TCV group and 71 in the MenA vaccine group) occurred in the first 6 months, and 1 event (pyrexia) was identified as being vaccine-related; the participant remained unaware of the trial-group assignment. Similar rates of adverse events were noted in the two trial groups; fever developed in 5.0% of participants in the TCV group and 5.4% in the MenA vaccine group in the first week after vaccination. In the immunogenicity subgroup, seroconversion (a Vi IgG level that at least quadrupled 28 days after vaccination) was 99% in the TCV group (677 of 683 participants) and 2% in the MenA vaccine group (8 of 380 participants). CONCLUSIONS: A single dose of TCV was immunogenic and effective in reducing S. Typhi bacteremia in children 9 months to 16 years of age. (Funded by the Bill and Melinda Gates Foundation; Current Controlled Trials number, ISRCTN43385161.).

Functionalization of Pentaphosphorus Cations by Complexation.

The chemistry of polyphosphorus cations has rapidly developed in recent years, but their coordination behavior has remained mostly unexplored. Herein, we describe the reactivity of [P5 R2 ]+ cations with cyclopentadienyl metal complexes. The reaction of [CpAr Fe(µ-Br)]2 (CpAr =C5 (C6 H4 -4-Et)5 ) with [P5 R2 ][GaCl4 ] (R=iPr and 2,4,6-Me3 C6 H2 (Mes)) afforded bicyclo[1.1.0]pentaphosphanes (1-R, R=iPr and Mes), showing an unsymmetric "butterfly" structure. The same products 1-R were formed from K[CpAr ] and [P5 R2 ][GaCl4 ]. The cationic complexes [CpAr Co(η4 -P5 R2 )][GaCl4 ] (2-R[GaCl4 ], R=iPr and Cy) and [(CpAr Ni)2 (η3:3 -P5 R2 )][GaCl4 ] (3-R[GaCl4 ]) were obtained from [P5 R2 ][GaCl4 ] and [CpAr M(µ-Br)]2 (M=Co and Ni) as well as by using low-valent "CpAr MI " sources. Anion metathesis of 2-R[GaCl4 ] and 3-R[GaCl4 ] was achieved with Na[BArF24 ]. The P5 framework of the resulting salts 2-R[BArF24 ] can be further functionalized with nucleophiles. Thus reactions with [Et4 N]X (X=CN and Cl) give unprecedented cyano- and chloro-functionalized complexes, while organo-functionalization was achieved with CyMgCl.

Logistics of Implementing a Large-scale Typhoid Vaccine Trial in Kathmandu, Nepal.

Typhoid fever is estimated to affect over 20 million people per year worldwide, with infants, children, and adolescents in south-central and southeast Asia experiencing the greatest burden of disease. The Typhoid Vaccine Acceleration Consortium (TyVAC) aims to support the introduction of typhoid conjugate vaccines into Gavi-eligible countries in an effort to reduce morbidity and mortality from typhoid. TyVAC-Nepal is a large-scale, participant- and observer-blind, individually randomized, controlled trial evaluating the efficacy of a newly developed typhoid conjugate vaccine in an urban setting in Nepal. In order to effectively deliver the trial, a number of key elements required meticulous planning. Public engagement strategies were considered early, and involved the implementation of a tiered approach. Approximately 300 staff were employed and trained in order to achieve the mass vaccination of 20 000 children aged 9 months to ≤16 years old over a 4-month period. There were 19 vaccination clinics established across the Lalitpur metropolitan city in the Kathmandu valley. Participants will be followed for 2 years post-vaccination to measure the rate reduction of blood culture-confirmed typhoid fever in the vaccination arm as compared to the control arm. The experience of conducting this large-scale vaccine trial suggests that comprehensive planning, continuous monitoring, and an ability to adapt plans in response to feedback are key.

Versatile Coordination Modes of Triphospha-1,4-pentadiene-2,4-diamine.

1,3,5-Triphospha-1,4-pentadiene-2,4-diamine reacts with [M(CO)4L] (M = Mo, L = nbd (norbornadiene); M = W, L = 2 CH3CN) to give the chelate complexes [M(CO)4(PMes{C(NHCy)PMes}2-κ P1 ,P3)]. In contrast, an unusual intramolecular rearrangement occurred with [Cu(CH3CN)4]PF6 leading to the dimeric copper(I) complex [Cu(CNCy){PHMesPMesC(NHCy)PMes-κ P1 ,P3}]2(PF6)2. The mechanism of the rearrangement was supported by quantum-mechanical calculations. The transition-metal complexes were characterized by multinuclear NMR spectroscopy, mass spectrometry, infrared spectroscopy, and X-ray crystallography.

A Sixteen-Membered Au8 P8 Macrocycle Based on Gold(I) and Diphospha(III)guanidine.

The reaction of cyclo-P4 Mes4 C(NCy) (1) with two equivalents of [AuCl(tht)] (tht=tetrahydrothiophene) resulted in the formation of unusual sixteen-membered Au-P macrocycle 2. This macrocycle contains diphospha(III)guanidinate as a coordinating ligand, which is formed by P-P bond cleavage of 1. Macrocycle 2 was characterized by multinuclear NMR spectroscopy, mass spectrometry and X-ray crystallography.

Unusual Reactivity of Sodium Tetramesityltetraphosphanediide towards Cyclohexyl Isocyanide.

The reaction of [Na2 (thf)4 (P4 Mes4 )] (Mes=2,4,6-Me3 C6 H2 ) with cyclohexyl isocyanide (2:5) resulted in the formation of the heterocyclic N-(tetramesityltetraphosphacyclopentylidene)cyclohexylamine [cyclo-{P4 Mes4 C(NCy)}] (2) (30-35 %), the unusual 1,3,5-triphospha-1,4-pentadiene (3) (40-45 %), and small amounts of the dimeric iminomethylidenephosphane cyclo-{PMesC(NCy)}2 (4). With catalytic amounts of AgBF4 , 2 was the major product. The reaction of 2 with [CuBr(SMe2 )] (1:1) produced bromido-bridged dimeric CuI complex 5. Molecular structures of compounds 3, 4, and 5 were obtained.

Mental health care in Nepal: current situation and challenges for development of a district mental health care plan.

BACKGROUND: Globally mental health problems are a serious public health concern. Currently four out of five people with severe mental illness in Low and Middle Income Countries (LMIC) receive no effective treatment. There is an urgent need to address this enormous treatment gap. Changing the focus of specialist mental health workers (psychiatrists and psychologists) from only service delivery to also designing and managing mental health services; building clinical capacity of the primary health care (PHC) workers, and providing supervision and quality assurance of mental health services may help in scaling up mental health services in LMICs. Little is known however, about the mental health policy and services context for these strategies in fragile-state settings, such as Nepal. METHOD: A standard situation analysis tool was developed by the PRogramme for Improving Mental health carE (PRIME) consortium to systematically analyze and describe the current gaps in mental health care in Nepal, in order to inform the development of a district level mental health care plan (MHCP). It comprised six sections; general information (e.g. population, socio-economic conditions); mental health policies and plans; mental health treatment coverage; district health services; and community services. Data was obtained from secondary sources, including scientific publications, reports, project documents and hospital records. RESULTS: Mental health policy exists in Nepal, having been adopted in 1997, but implementation of the policy framework has yet to begin. In common with other LMICs, the budget allocated for mental health is minimal. Mental health services are concentrated in the big cities, with 0.22 psychiatrists and 0.06 psychologists per 100,000 population. The key challenges experienced in developing a district level MHCP included, overburdened health workers, lack of psychotropic medicines in the PHC, lack of mental health supervision in the existing system, and lack of a coordinating body in the Ministry of Health and Population (MoHP). Strategies to overcome these challenges included involvement of MoHP in the process, especially by providing psychotropic medicines and appointing a senior level officer to facilitate project activities, and collaboration with National Health Training Centers (NHTC) in training programs. CONCLUSIONS: This study describes many challenges facing mental health care in Nepal. Most of these challenges are not new, yet this study contributes to our understanding of these difficulties by outlining the national and district level factors that have a direct influence on the development of a district level mental health care plan.

Prevalence of cardiovascular health risk behaviors in a remote rural community of Sindhuli district, Nepal.

BACKGROUND: Cardiovascular disease (CVD) is emerging as a public health menace among low and middle income countries. It has particularly affected the poorest. However, there is paucity of information about CVD risk factors profile among Nepalese rural communities where the majority of people live in poverty. Therefore, this study aimed to identify the prevalence of cardiovascular health risk behaviors in an outback community of Nepal. METHODS: We conducted a descriptive cross-sectional study in Tinkanya Village Development Committee (VDC), Sindhuli between January and March, 2014. Total 406 participants of age 20 to 50 years were selected randomly. Data were collected using WHO-NCD STEPwise approach questionnaires and analyzed with SPSS V.16.0 and R i386 2.15.3 software. RESULT: The mean age of participants was 36.2 ± 9 years. Majority of participants (76.3%) were from lower socio-economic class, Adibasi/Janajati (63.1%), and without formal schooling (46.3%). Smoking was present in 28.6%, alcohol consumption in 47.8%, insufficient fruits and vegetables intake in 96.6%, insufficient physical activity in 48.8%; 25.6% had high waist circumference, 37.4% had overweight and obesity. Average daily salt intake per capita was 14.4 grams ±4.89 grams. Hypertension was detected in 12.3%. It had an inverse relationship with education and socio-economic status. In binary logistic regression analysis, age, smoking, body mass index (BMI) and daily salt intake were identified as significant predictors of hypertension. CONCLUSION: Present study showed high prevalence of smoking, alcohol consumption, insufficient fruit and vegetable intake, daily salt intake, overweight and obesity and hypertension among remote rural population suggesting higher risk for developing CVD in future. Nepalese rural communities, therefore, are in need of population-wide comprehensive intervention approaches for reducing CVD health risk behaviors.

Electrophile-induced nucleophilic substitution of the nido-dicarbaundecaborate anion nido-7,8-C2B9H12- by conjugated heterodienes.

Substitution of the dicarbaundecaborate anion nido-7,8-C2B9H12(-) (1) by precise hydride abstraction followed by nucleophilic attack usually leads to symmetric products 10-R-nido-7,8-C2B9H11. However, thioacetamide (MeC(S)NH2) as nucleophile and acetone/AlCl3 as hydride abstractor gave asymmetric 9-[MeC(NHiPr)S]-nido-7,8-C2B9H11 (2), whereas N,N-dimethylthioacetamide (MeC(S)NMe2) gave the expected symmetric 10-[MeC(NMe2)S]-nido-7,8-C2B9H11 (4). For the formation of 2, acetone and thioacetamide are assumed to give the intermediate MeC(S)N(CMe2) (3), which then attacks 1 with formation of 2. Similarly, reaction of acetyliminium chloride [MeC(O)NH(CPh2)]Cl (5) with 1 in THF gave a mixture of 9- and 10-substituted [MeC(NHCHPh2)O]-nido-7,8-C2B9H11 (6 and 7, respectively). These reactions are the first examples in which compounds (here heterodienes) that unite the functionalities of both hydride acceptor and nucleophilic site react with 1 in a bimolecular fashion. Furthermore, the analogous reaction of 1 and 5 (in an equilibrium mixture with acetyl chloride and benzophenone imine) in MeCN afforded 10-[MeC(NCPh2)NH]-nido-7,8-C2B9H11 (8) and MeC(O)NHCHPh2 (9).