Modular synthesis of functional libraries by accelerated SuFEx click chemistry.

Accelerated SuFEx Click Chemistry (ASCC) is a powerful method for coupling aryl and alkyl alcohols with SuFEx-compatible functional groups. With its hallmark favorable kinetics and exceptional product yields, ASCC streamlines the synthetic workflow, simplifies the purification process, and is ideally suited for discovering functional molecules. We showcase the versatility and practicality of the ASCC reaction as a tool for the late-stage derivatization of bioactive molecules and in the array synthesis of sulfonate-linked, high-potency, microtubule targeting agents (MTAs) that exhibit nanomolar anticancer activity against multidrug-resistant cancer cell lines. These findings underscore ASCC's promise as a robust platform for drug discovery.

Apparatus to measure density and viscosity of high-pressure carbon dioxide-alcohol mixtures.

Thermophysical properties of (single phase) binary CO2-alcohol mixtures under high pressure and moderate temperature conditions are important in supercritical fluid processes. An apparatus to measure mixture density as a function of temperature (up to 80 °C) and pressure (up to 15.9 MPa) over the full range of CO2 mass fractions was designed and commissioned. The fluid delivery system enables precise control and rapid variation of the CO2 mass fraction to within 0.2% of the desired value. Our apparatus advances the state-of-the-art by assuring a uniform mixture and assuring accuracy through redundant measurements, i.e., a variable-volume method with an uncertainty of 1% of reading and a Coriolis density meter with an uncertainty of 7 kg/m3. The results for a representative CO2-ethanol mixture are provided. Moreover, a third independent "bomb" experiment was used to measure density under selected conditions to further verify our measurements and, when present, discrepancies between them and the published data for the representative system. It is shown that, when the discrepancies were present, it was due to insufficient mixing in the other apparatus. Our apparatus also measures the viscosities of the mixtures using a viscometer accurate to 0.02 cP.

Protocol for producing phosphoramidate using phosphorus fluoride exchange click chemistry.

Phosphorus fluoride exchange (PFEx) is a catalytic click reaction that involves exchanging high oxidation state P-F bonds with alcohol and amine nucleophiles, reliably yielding P-O- and P-N-linked compounds. Here, we describe steps for preparing a phosphoramidic difluoride and performing two sequential PFEx reactions to yield a phosphoramidate through careful catalyst selection. We then detail procedures for handling and quenching potentially toxic P-F-containing compounds to ensure user safety when conducting PFEx reactions. For complete details on the use and execution of this protocol, please refer to Sun et al.1.

Effects of temperature on the life history traits of intermediate host snails of fascioliasis: A systematic review.

BACKGROUND: The impact of climate change has led to variations in various biological processes, leading to altered transmission dynamics of infectious diseases, including snail-borne diseases (SBDs). Fascioliasis is one of the neglected zoonotic tropical snail-borne diseases caused by the trematode of the genus Fasciola. This review focused on laboratory experimental and model studies that evaluate the potential effect of temperature change on the ecology and biology of the intermediate host snails (IHS) of Fasciola. METHODS: A literature search was conducted on Google Scholar, EBSCOhost, and PubMed databases using predefined medical subject heading terms, Boolean operators, and truncation symbols in combination with direct keywords: Fasciolosis AND Temperature, Lymnaea OR Austropeplea OR Radix OR Galba OR Fossaria OR Pseudosuccinea AND growth, fecundity, AND survival at the global scale. Other search terms used were (Fascioliasis AND Temperature), (Lymnaea AND Temperature), (Austropeplea AND Temperature), (Fossaria AND Temperature), (Galba AND Temperature), (Pseudosuccinea AND Temperature), and (Radix AND Temperature). RESULTS: The final synthesis included thirty-five published articles. The studies reviewed indicated that temperature rise may alter the distribution, and optimal conditions for breeding, growth, and survival of IHS, ultimately resulting in changing the transmission dynamics of fascioliasis. The literature also confirmed that the life history traits of IHS and their interaction with the liver fluke parasites are driven by temperature, and hence climate change may have profound outcomes on the population size of snails, parasite density, and disease epidemiology. CONCLUSION: We concluded that understanding the impact of temperature on the growth, fecundity, and survival of IHS may broaden our knowledge of the possible effects of climate change and hence inform fascioliasis control programs.

Barriers and Facilitators of Adherence to Oral Anticancer Medications Among Women with Breast Cancer: A Qualitative Study.

Purpose: Despite the life-saving benefits of oral anticancer medications (OAMs) to women with breast cancer (BC), adherence remains suboptimal and, in many cases, not well documented. The study examined barriers and facilitators of adherence to OAMs among women receiving BC treatment in Nigeria. Patients and Methods: The study was framed within the World Health Organization (WHO) Multidimensional Model of Adherence. We conducted qualitative in-depth interviews of 16 purposively sampled women in two tertiary hospitals in Southern Nigeria. The interviews were audio-recorded and transcribed verbatim. The interview data were analyzed using the Framework Method. Results: The key barriers to OAM adherence mentioned were socioeconomic factors (high cost of medication) and therapy-related factors (medication side effects). The key facilitating mechanisms for adherence to OAMs mentioned included; (i) patient-related psychosocial factors such as self-encouragement and self-discipline in sticking to the prescription, taking the medication at a particular time each day, receiving practical support from family members; and (ii) healthcare team/system factors such as obtaining an adequate supply of the medication at the pharmacy. Conclusion: Barriers and facilitators to OAM adherence are multidimensional. The study findings highlight the potential benefit of a multifaceted intervention (such as patient education and monitoring or strategies promoting cost-containment and side effects management) to optimize adherence. Therefore, our findings may inform the designing and evaluating of context-specific adherence measures and multifaceted intervention strategies targeting key barriers and approaches that enable adherence to enhance patient outcomes.

Infection Rates of Fasciola Intermediate Host Snail Species and Their Distribution in Africa: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to collate the infection rates of Fasciola spp. in intermediate host snails and their distribution in Africa. The overall infectivity prevalences of Galba truncatula, Radix natalensis, and Pseudosuccinea columella are 52%, 8%, and 3%, respectively. The intermediate host snails native to Africa (R. natalensis and G. truncatula) have been examined more than the invasive P. columella. The studies included in the review ranged from 1999 to 2022. North Africa has the highest prevalence of G. truncatula, with an infection rate of 52%. The review reveals that naturally infected intermediate host snails (G. truncatula, R. natalensis, and P. columella) are found in various regions of Africa. G. truncatula accounts for 22% (from three countries) of the studies included in the review and it was only found in the North African region with the highest overall infection rate of 52%. More studies on infection rate and distribution are needed to effectively control and prevent future transmissions.

Factors influencing the utilization of doctoral research findings at a university in KwaZulu-Natal, South Africa: Views of academic leaders.

BACKGROUND: Translation of health research findings into policy remains a challenge in sub-Saharan Africa. Factors influencing health research utilization are poorly described in literature. Therefore, identifying factors that influence the utilization of research findings for policy formulation is essential to facilitate implementation of evidence-based interventions. The purpose of this study was to explore the views of academic leaders as to why doctoral research is not adequately used in policymaking. METHODS: In-depth interviews were held with purposively selected key informants from the College of Health Sciences. An open-ended interview guide aimed at exploring college leadership views on factors influencing utilization of PhD generated knowledge into policy was used. Data was analysed thematically using NVivo 12 software. Thematic analysis was used to generate themes around the factors influencing utilization of doctoral research into policy. RESULTS: Factors such as inaccessibility of research results, lack of funding, poor quality of research, lack of continuity in translating research into policy, lack of timeliness of research results and lack of collaboration between researchers and policymakers hindered the utilization of PhD generated knowledge. Participants recommended engagement with the Department of Health/policymakers, collaboration with Department of Health/policymakers, increasing enrolment of South African citizens into PhD program, making final research products available to Department of Health/policymakers, and provision of funding for dissemination of research results. CONCLUSION: The study demonstrated that final doctoral research results are mainly disseminated through journal articles and theses. Participants cited inaccessibility of research findings, lack of funding and poor-quality research as the most common factors hindering utilization of doctoral research findings. The study also recommended availing adequate funding for dissemination of research results, collaboration between researchers and policymakers, facilitation of policymaker-researcher engagement to find best ways of using research findings to influence policy and making final research products accessible to policymakers. Further research to gain the perspective of policymakers as to why doctoral research is not adequately used in policy formulation is recommended.

Spatial and seasonal distribution of human schistosomiasis intermediate host snails and their interactions with other freshwater snails in 7 districts of KwaZulu-Natal province, South Africa.

The spatial and seasonal distribution, abundance, and infection rates of human schistosomiasis intermediate host snails and interactions with other freshwater snails, water physicochemical parameters, and climatic factors was determined in this study. A longitudinal malacology survey was conducted at seventy-nine sites in seven districts in KwaZulu-Natal province between September 2020 and August 2021. Snail sampling was done simultaneously by two trained personnel for fifteen minutes, once in three months. A total of 15,756 snails were collected during the study period. Eight freshwater snails were found: Bulinus globosus (n = 1396), Biomphalaria pfeifferi (n = 1130), Lymnaea natalensis (n = 1195), Bulinus tropicus (n = 1722), Bulinus forskalii (n = 195), Tarebia granifera (n = 8078), Physa acuta (n = 1579), and Bivalves (n = 461). The infection rates of B. globosus and B. pfeifferi are 3.5% and 0.9%, respectively. In our study, rainfall, pH, type of habitats, other freshwater snails and seasons influenced the distribution, abundance, and infection rates of human schistosomiasis intermediate host snails (p-value < 0.05). Our findings provide useful information which can be adopted in designing and implementing snail control strategies as part of schistosomiasis control in the study area.

Ethene-1,1-disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1-Bissulfonylfluoride Substituted Cyclobutene Hubs.

We present the synthesis of 1,1-bis(fluorosulfonyl)-2-(pyridin-1-ium-1-yl)ethan-1-ide, a bench-stable precursor to ethene-1,1-disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1-bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4-membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase diversification of the novel cyclobutene cores through selective Cs2 CO3 -activated SuFEx click chemistry between a single S-F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.

Inhibition of mitochondrial metabolism by (-)-jerantinine A: synthesis and biological studies in triple-negative breast cancer cells.

A concise semi-synthesis of the Aspidosperma alkaloids, (-)-jerantinine A and (-)-melodinine P, and derivatives thereof, is reported. The novel compounds were shown to have potent activity against MDA-MB-231 triple-negative breast cancer cells. Furthermore, unbiased metabolomics and live cell reporter assays reveal (-)-jerantinine A alters cellular redox metabolism and induces oxidative stress that coincides with cell cycle arrest.

Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria.

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.

Spatial distribution, abundance, and infection rates of human schistosome-transmitting snails and related physicochemical parameters in KwaZulu-Natal (KZN) province, South Africa.

This study investigated the spatial distribution, abundance, and infection rates of human schistosome-transmitting snails and related physicochemical parameters and environmental factors in 11 districts in KwaZulu-Natal (KZN) province, South Africa, from December 2020-February 2021. Snail sampling was carried out in 128 sites by two people for 15 min using scooping and handpicking methods. Geographical information system (GIS) was used to map surveyed sites. In situ measurements of physicochemical parameters were recorded, while remote sensing was used to obtain measurements for climatic factors required to achieve the study's objective. Cercarial shedding and snail-crushing methods were used to detect snail infections. Kruskal-Wallis test was used to test the differences in snail abundance among snail species, districts, and habitat types. A negative binomial generalized linear mixed model was used to identify the physicochemical parameters and environmental factors influencing the abundance of snail species. A total of 734 human schistosome-transmitting snails were collected. Bu. globosus were significantly more abundant (n = 488) and widely distributed (found in 27 sites) compared to B. pfeifferi (n = 246) found in 8 sites. Bu. globosus and B. pfeifferi had infection rates of 3.89% and 2.44%, respectively. Dissolved oxygen and normalized difference vegetation index showed a statistically positive relationship, while normalized difference wetness index showed a statistically negative relationship with the abundance of Bu. globosus. However, there was no statistically significant relationship between B. pfeifferi abundance, physicochemical parameters, and climatic factors. Our study described the current distribution, abundance, and infection status of human schistosome-transmitting snails in KZN province, which will contribute to informing control measure policies for schistosomiasis.

Digital Mental Health Interventions for Young People in Rural South Africa: Prospects and Challenges for Implementation.

Globally, most young people living with mental health conditions lack access to mental health care but have access to a mobile device. The growing access to mobile devices in South Africa has the potential to increase access to mental health care services through digital platforms. However, uptake of digital mental health interventions may be hampered by several factors, such as privacy, confidentiality, informed consent, and affordability. This study identified the prospects and challenges of implementing a mobile phone-based mental health intervention for young people in Ingwavuma area. Data were collected from 93 young people in three villages purposefully selected in Ingwavuma area. Participants included in the study were aged 16-24. Data were collected through a questionnaire. Thematic and descriptive analysis was performed on the qualitative and quantitative data, respectively. Mental health education was low, with only 22% of participants having received prior education on mental health. About 50% of the participants had come across a mental health app, but none of them had used any of these apps; 87% of participants had Internet access; 60% preferred to use social media to contact a health worker; and 92% suggested that use of digital apps would improve mental health literacy among young people. Barriers to access of digital mental health interventions were identified as the high cost of data, restrictive religious beliefs, limited privacy, lack of native languages on most digital platforms, low digital literacy, and complicated user interface. In uMkhanyakude, uptake of digital mental health apps among the young people was low. We recommend that, developers create context-specific digital applications catered for young people from different cultural backgrounds. Socio-economic issues such as affordability also need to be addressed in developing these tools.

Plain Language Summary of Publication of the safety and efficacy of ARRY-371797 in people with dilated cardiomyopathy and a faulty LMNA gene.

WHAT IS THIS PLAIN LANGUAGE SUMMARY ABOUT?: This plain language summary describes the results of a study looking at the effects of a medicine called ARRY-371797 (also known as PF-07265803) in people with dilated cardiomyopathy (DCM for short) caused by a faulty LMNA gene. This condition is called LMNA-related DCM. DCM happens when the heart becomes bigger and weaker than normal, impacting functional capacity and leading to symptoms of heart failure. This means the heart is not able to pump blood around the body as easily, and people are unable to do as much in their daily lives (like getting dressed and going shopping). People may inherit a faulty LMNA gene from one of their parents, or a faulty LMNA gene may develop when mistakes happen during cell growth and replication. ARRY-371797 targets a specific mechanism in the body that can lead to heart problems in people with a faulty LMNA gene. As ARRY-371797 is not currently approved for use outside of clinical trials, it doesn't currently have an easily recognizable trade name. WHAT WERE THE RESULTS?: 12 American people (average age 50 years) with LMNA-related DCM took part in the study and received 400 mg or 100 mg of ARRY-371797 twice daily for 48 weeks. People knew which dose of ARRY-371797 they were taking. People were checked after 4, 12, 24, 36 and 48 weeks of taking ARRY-371797 to see how far they could walk in the 6-minute walk test (6MWT for short). The level of NT-proBNP in their blood was also measured. NT-proBNP is a biomarker used to measure the severity of heart failure. A biomarker is something found in the body that can be measured to indicate the extent of a disease. -After taking ARRY-371797 for 12 weeks, people were able to walk further in the 6MWT and had lower levels of NT-proBNP in their blood. This suggests improvement in functional capacity (exercise tolerance) and heart function. Researchers also asked people about their quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ for short), and looked for any side effects. -Researchers saw some improvement in KCCQ scores. -Researchers saw no major side effects that they considered to be related to ARRY-371797 treatment. A side effect is something that people feel was caused by a medicine or treatment. Overall, this study showed that people with LMNA-related DCM who took ARRY-371797 had improved functional capacity (exercise tolerance), improved heart function, and improved quality of life. Phase 2 study (NCT02057341) Phase 2 long-term extension study (NCT02351856) Phase 3 REALM-DCM study (NCT03439514).

Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study.

BACKGROUND: Lamin A/C gene (LMNA)-related dilated cardiomyopathy is a serious and life-threatening condition with a high unmet medical need. This phase 2 study assessed the effects of the oral selective p38 mitogen-activated protein kinase inhibitor ARRY-371797 on functional capacity and cardiac function in patients with LMNA-related dilated cardiomyopathy. METHODS: Patients with LMNA-related dilated cardiomyopathy in New York Heart Association class II-IIIA, on background heart failure treatment, received ARRY-371797 100 or 400 mg twice daily for 48 weeks. The primary end point was change from baseline in the 6-minute walk test distance at 12 weeks. Secondary end points included changes over time in 6-minute walk test distance, NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration, left ventricular ejection fraction, and quality-of-life scores on the Kansas City Cardiomyopathy Questionnaire. Data from the 2 dose groups were combined. RESULTS: Twelve patients were enrolled; median (minimum, maximum) 6-minute walk test distance at baseline was 314 (246, 412) m. At week 12, the mean (80% CI) increase from baseline in 6-minute walk test distance was 69 (39, 100) m (median, 47 m). Median NT-proBNP concentration declined from 1409 pg/mL at baseline to 848 pg/mL at week 12. Mean left ventricular ejection fraction was stable at week 12. There was a trend toward improvement in Kansas City Cardiomyopathy Questionnaire Overall and Clinical Summary scores at week 12. No clinically significant drug-related safety concerns were identified. CONCLUSIONS: ARRY-371797 was well tolerated and resulted in potential increases in functional capacity and lower concentrations of cardiac biomarker NT-proBNP in patients with LMNA-related dilated cardiomyopathy. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02057341.