Optimization of salbutamol sulfate dissolution from sustained release matrix formulations using an artificial neural network

An artificial neural network was used to optimize the release of salbutamol sulfate from hydrophilic matrix formulations. Model formulations to be used for training, testing and validating the neural network were manufactured with the aid of a central composite design with varying the levels of Methocel® K100M, xanthan gum, Carbopol® 974P and Surelease® as the input factors. In vitro dissolution time profiles at six different sampling times were used as target data in training the neural network for formulation optimization. A multi layer perceptron with one hidden layer was constructed using Matlab®, and the number of nodes in the hidden layer was optimized by trial and error to develop a model with the best predictive ability. The results revealed that a neural network with nine nodes was optimal for developing and optimizing formulations. Simulations undertaken with the training data revealed that the constructed model was useable. The optimized neural network was used for optimization of formulation with desirable release characteristics and the results indicated that there was agreement between the predicted formulation and the manufactured formulation. This work illustrates the possible utility of artificial neural networks for the optimization of pharmaceutical formulations with desirable performance characteristics

Huntingtin disrupts lipid bilayers in a polyQ-length dependent manner

AbstractHuntington's Disease (HD) is a neurodegenerative disorder that is defined by the accumulation of nanoscale aggregates comprised of the huntingtin (htt) protein. Aggregation is directly caused by an expanded polyglutamine (polyQ) domain in htt, leading to a diverse population of aggregate species, such as oligomers, fibrils, and annular aggregates. Furthermore, the length of this polyQ domain is directly related to onset and severity of disease. The first 17 N-terminal amino acids of htt have been shown to further modulate aggregation. Additionally, these 17 amino acids appear to have lipid binding properties as htt interacts with a variety of membrane-containing structures present in cells, such as organelles, and interactions with these membrane surfaces may further modulate htt aggregation. To investigate the interaction between htt exon1 and lipid bilayers, in situ atomic force microscopy (AFM) was used to directly monitor the aggregation of htt exon1 constructs with varying Q-lengths (35Q, 46Q, 51Q, and myc-53Q) on supported lipid membranes comprised of total brain lipid extract. The exon1 fragments accumulated on the lipid membranes, causing disruption of the membrane, in a polyQ dependent manner. Furthermore, the addition of an N-terminal myc-tag to the htt exon1 fragments impeded the interaction of htt with the bilayer

Swelling, erosion and drug release characteristics of salbutamol sulfate from hydroxypropyl methylcellulose-based matrix tablets

Background: Hydrophilic matrix formulations are important and simple technologies that are used to manufacture sustained release dosage forms. Method: Hydroxypropyl methylcellulose-based matrix tablets, with and without additives, were manufactured to investigate the rate of hydration, rate of erosion, and rate and mechanism of drug release. Scanning electron microscopy was used to assess changes in the microstructure of the tablets during drug release testing and whether these changes could be related to the rate of drug release from the formulations. Results: The results revealed that the rate of hydration and erosion was dependent on the polymer combination(s) used, which in turn affected the rate and mechanism of drug release from these formulations. It was also apparent that changes in the microstructure of matrix tablets could be related to the different rates of drug release that were observed from the test formulations. Conclusion: The use of scanning electron microscopy provides useful information to further understand drug release mechanisms from matrix tablets

Adolescence As Risk Factor for Adverse Pregnancy Outcome in Central Africa – A Cross-Sectional Study

BACKGROUND: Sub-Saharan Africa has the highest rates of maternal and neonatal mortality worldwide. Young maternal age at delivery has been proposed as risk factor for adverse pregnancy outcome, yet there is insufficient data from Sub-Saharan Africa. The present study aimed to investigate the influence of maternal adolescence on pregnancy outcomes in the Central African country Gabon. METHODOLOGY AND PRINCIPAL FINDINGS: Data on maternal age, parity, birth weight, gestational age, maternal Plasmodium falciparum infection, use of bednets, and intake of intermittent preventive treatment of malaria in pregnancy were collected in a cross-sectional survey in 775 women giving birth in three mother-child health centers in Gabon. Adolescent women (≤16 years of age) had a significantly increased risk to deliver a baby with low birth weight in univariable analysis (22.8%, 13/57, vs. 9.3%, 67/718, OR: 2.9, 95% CI: 1.5-5.6) and young maternal age showed a statistically significant association with the risk for low birth weight in multivariable regression analysis after correction for established risk factors (OR: 2.7; 95% CI: 1.1-6.5). In further analysis adolescent women were shown to attend significantly less antenatal care visits than adult mothers (3.3±1.9 versus 4.4±1.9 mean visits, p<0.01, n = 356) and this difference accounted at least for part of the excess risk for low birth weight in adolescents. CONCLUSION: Our data demonstrate the importance of adolescent age as risk factor for adverse pregnancy outcome. Antenatal care programs specifically tailored for the needs of adolescents may be necessary to improve the frequency of antenatal care visits and pregnancy outcomes in this risk group in Central Africa

Towards Heat-stable Oxytocin Formulations: Analysis of Degradation Kinetics and Identification of Degradation Products

Purpose. To investigate degradation kinetics of oxytocin as a function of temperature and pH, and identify the degradation products. Materials and Methods. Accelerated degradation of oxytocin formulated at pH 2.0, 4.5, 7.0 and 9.0 was performed at 40, 55, 70 and 80°C. Degradation rate constants were determined from RP-HPLC data. Formulations were characterized by HP-SEC, UV absorption and fluorescence spectroscopy. Degradation products were identified by ESI-MS/MS. Results. The loss of intact oxytocin in RP-HPLC was pH- and temperature-dependent and followed (pseudo) first order kinetics. Degradation was fastest at pH 9.0, followed by pH 7.0, pH 2.0 and pH 4.5. The Arrhenius equation proved suitable to describe the kinetics, with the highest activation energy (116.3 kJ/mol) being found for pH 4.5 formulations. At pH 2.0 deamidation of Gln 4, Asn 5, and Gly 9-NH2, as well as combinations thereof were found. At pH 4.5, 7.0 and 9.0, the formation of tri- and tetrasulfidecontaining oxytocin as well as different types of disulfide and dityrosine-linked dimers were found to occur. Beta-elimination and larger aggregates were also observed. At pH 9.0, mono-deamidation of Gln 4, Asn 5, and Gly 9-NH2 additionally occurred. Conclusions. Multiple degradation products of oxytocin have been identified unequivocally, including various deamidated species, intramolecular oligosulfides and covalent aggregates. The strongly pH dependent degradation can be described by the Arrhenius equation. KEY WORDS: aggregation; Arrhenius kinetics; degradation; mass spectrometry; oxytocin

Population structure of Salmonella enterica Typhi in Harare, Zimbabwe (2012–19) before typhoid conjugate vaccine roll-out: A genomic epidemiology study

Background: The continued emergence of Salmonella enterica serovar Typhi, with ever increasing antimicrobial resistance, necessitates the use of vaccines in endemic countries. A typhoid fever outbreak in Harare, Zimbabwe, in 2018 from a multidrug resistant S Typhi with additional resistance to ciprofloxacin was the catalyst for the introduction of a typhoid conjugate vaccine programme. We aimed to investigate the emergence and evolution of antimicrobial resistance of endemic S Typhi in Zimbabwe and to determine the population structure, gene flux, and sequence polymorphisms of strains isolated before a typhoid conjugate vaccine programme to provide a baseline for future evaluation of the effect of the vaccination programme. Methods: In this genomic epidemiology study, we used short-read whole-genome sequencing of S Typhi isolated from clinical cases of typhoid fever in Harare, Zimbabwe, between Jan 1, 2012, and Feb 9, 2019, to determine the S Typhi population structure, gene flux, and sequence polymorphisms and reconstructed the evolution of antimicrobial resistance. Maximum likelihood time-scaled phylogenetic trees of Zimbabwe isolates in the context of global isolates obtained from the National Center for Biotechnology Information were constructed to infer spread and emergence of antimicrobial resistance. Findings: The population structure of S Typhi in Harare, Zimbabwe, from 2012 to 2019 was dominated by multidrug resistant genotype 4.3.1.1.EA1 (H58) that spread to Zimbabwe from neighbouring countries in around 2009 (95% credible interval 2008·5–2010·0). Acquisition of an IncN plasmid carrying antimicrobial resistance genes including a qnrS gene and a mutation in the quinolone resistance determining region of gyrA gene contributed to non-susceptibility and resistance to quinolone antibiotics. A minority population of antimicrobial susceptible S Typhi genotype 3.3.1 strains were present throughout. Interpretation: The currently dominant S Typhi population is genotype 4.3.1.1 that spread to Zimbabwe and acquired additional antimicrobial resistance though acquisition of a plasmid and mutation in the gyrA gene. This study provides a baseline population structure for future evaluation of the effect of the typhoid conjugate vaccine programme in Harare

Predictors of nurses’ and midwives’ intentions to provide maternal and child healthcare services to adolescents in South Africa

BACKGROUND: Adolescent mothers are at a much higher risk for maternal mortality compared to mothers aged 20 years and above. Newborns born to adolescent mothers are also more likely to have low birth weight, with the risk of long-term effects such as early onset of adult diabetes than newborns of older mothers. Few studies have investigated the determinants of adequate quality maternal and child healthcare services to pregnant adolescents. This study was conducted to gain an understanding of nurses’ and midwives’ intentions to provide maternal and child healthcare and family planning services to adolescents in South Africa. METHODS: A total of 190 nurses and midwives completed a cross-sectional survey. The survey included components on demographics, knowledge of maternal and child healthcare (MCH) and family planning (FP) services, attitude towards family planning services, subjective norms regarding maternal and child healthcare and family planning services, self-efficacy with maternal and child healthcare and family planning services, and intentions to provide maternal and child healthcare and family planning services to adolescents. Pearson’s correlation analysis was conducted to determine the association between knowledge, attitude, subjective norms, self-efficacy, and intention variables for FP and MCH services. A 2-step linear regression analysis was then conducted for both FP and MCH services to predict the intentions to provide FP and MCH services to adolescents. RESULTS: Self-efficacy to conduct MCH services (β = 0.55, p < 0.01) and years of experience as a nurse- midwife (β = 0.14, p < 0.05) were associated with stronger intentions to provide the services. Self-efficacy to provide FP services (β = 0.30, p < 0.01) was associated with stronger intentions to provide FP services. CONCLUSIONS: Self-efficacy has a strong and positive association with the intentions to provide both MCH and FP services, while there is a moderate association with attitude and norms. There is a need to improve and strengthen nurses’ and midwives’ self-efficacy in conducting both MCH and FP services in order to improve the quality and utilization of the services by adolescents in South Africa.IS

SWOT analysis of the use of digital health technologies in primary health care in the Sub-Saharan African Region: a qualitative study

Background: In many health systems globally, digital health technologies (DHT) have become increasingly commonplace as a means of delivering primary care. COVID-19 has further increased the pace of this trend. While DHTs have been postulated to reduce inequalities, increase access, and strengthen health systems, how DHT implementation has been realised in the sub-Saharan Africa (SSA) healthcare environment remains to be further explored. Objective: To capture the multidisciplinary experiences of SSA experts and primary care healthcare providers using DHTs to explore the strengths and weaknesses, as well as opportunities and threats regarding the implementation and use of DHTs in SSA primary care settings. Methods: A combination of qualitative approaches was adopted (i.e., online focus groups and semi-structured interviews), using an online platform. Participants were recruited through AfroPHC and researchers contact networks, using convenience sampling, and included if having experience with digital technologies in primary health care in SSA. Focus and interviews were conducted, respectively, in November 2021 and January-March 2022. Topic guides were used to cover relevant topics in the interviews and focus groups, using the Strengths, Weaknesses, Opportunities and Threats (SWOT) framework. Transcripts were compiled verbatim and systematically reviewed by two independent reviewers using thematic analysis to identify emerging themes. The Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist was used to ensure the study meets the recommended standards of qualitative data reporting. Results: Strengths of DHT use ranged from improving access to care, supporting the continuity of care, and increasing care satisfaction and trust, to greater collaboration, enabling safer decision-making, and hastening progress towards universal health coverage. Weaknesses included poor digital literacy, health inequalities, lack of human resources, inadequate training, lack of basic infrastructure and equipment, and poor coordination when implementing DHTs. DHTs were perceived as an opportunity to improve patient digital literacy, increase equity, promote more patient-centric design in upcoming DHTs, streamline healthcare resource expenditure, and provide a means to learn international best practices. Major threats identified include the lack of buy-in from both patients and providers, insufficient human resources and local capacity, inadequate governmental support, overly restrictive regulations, and a lack of focus on cybersecurity and means for patient data protection. Conclusions: The research highlights the complex challenges of implementing DHTs in the SSA context, as a fast-moving health delivery modality, as well as the need for multi-stakeholder involvement. Future research should explore the nuances of these findings across different technologies and settings in the SSA region, and its implications on health and health care equity, capitalising on mixed-methods research, including the use of real-world quantitative data to understand patient health needs. The promise of digital health will only be realised when informed by studies that incorporate patient perspective at every stage of the research cycle

Response to the Novel Corona Virus (COVID-19) Pandemic Across Africa: Successes, Challenges, and Implications for the Future

Background: The COVID-19 pandemic has already claimed considerable lives. There are major concerns in Africa due to existing high prevalence rates for both infectious and non-infectious diseases and limited resources in terms of personnel, beds and equipment. Alongside this, concerns that lockdown and other measures will have on prevention and management of other infectious diseases and non-communicable diseases (NCDs). NCDs are an increasing issue with rising morbidity and mortality rates. The World Health Organization (WHO) warns that a lack of nets and treatment could result in up to 18 million additional cases of malaria and up to 30,000 additional deaths in sub-Saharan Africa. Objective: Document current prevalence and mortality rates from COVID-19 alongside economic and other measures to reduce its spread and impact across Africa. In addition, suggested ways forward among all key stakeholder groups. Our Approach: Contextualise the findings from a wide range of publications including internet-based publications coupled with input from senior-level personnel. Ongoing Activities: Prevalence and mortality rates are currently lower in Africa than among several Western countries and the USA. This could be due to a number of factors including early instigation of lockdown and border closures, the younger age of the population, lack of robust reporting systems and as yet unidentified genetic and other factors. Innovation is accelerating to address concerns with available equipment. There are ongoing steps to address the level of misinformation and its consequences including fines. There are also ongoing initiatives across Africa to start addressing the unintended consequences of COVID-19 activities including lockdown measures and their impact on NCDs including the likely rise in mental health disorders, exacerbated by increasing stigma associated with COVID-19. Strategies include extending prescription lengths, telemedicine and encouraging vaccination. However, these need to be accelerated to prevent increased morbidity and mortality. Conclusion: There are multiple activities across Africa to reduce the spread of COVID-19 and address misinformation, which can have catastrophic consequences, assisted by the WHO and others, which appear to be working in a number of countries. Research is ongoing to clarify the unintended consequences given ongoing concerns to guide future activities. Countries are learning from each other