Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis

Treatment of multidrug-resistant tuberculosis (MDR-TB) is extremely challenging due to the virulence of the etiologic strains of Mycobacterium tuberculosis (M. tb), the aberrant host immune responses and the diminishing treatment options with TB drugs. New treatment regimens incorporating therapeutics targeting both M. tb and host factors are urgently needed to improve the clinical management outcomes of MDR-TB. Host-directed therapies (HDT) could avert destructive tuberculous lung pathology, facilitate eradication of M. tb, improve survival and prevent long-term functional disability. In this review we (1) discuss the use of HDT for cancer and other infections, drawing parallels and the precedent they set for MDR-TB treatment, (2) highlight preclinical studies of pharmacological agents commonly used in clinical practice which have HDT potential, and (3) outline developments in cellular therapy to promote clinically beneficial immunomodulation to improve treatment outcomes in patients with pulmonary MDR-TB. The use of HDTs as adjuncts to MDR-TB therapy requires urgent evaluation

Mycobacterium tuberculosis proteins involved in cell wall lipid biosynthesis improve BCG vaccine efficacy in a murine TB model

OBJECTIVES: Advances in tuberculosis (TB) vaccine development are urgently required to enhance global disease management. We evaluated the potential of Mycobacterium tuberculosis (M. tb)-derived protein antigens Rv0447c, Rv2957 and Rv2958c to boost BCG vaccine efficacy in the presence or absence of glucopyranosyl lipid adjuvant formulated in a stable emulsion (GLA-SE) adjuvant. METHODS: Mice received the BCG vaccine, followed by Rv0447c, Rv2957 and Rv2958c protein boosting with or without GLA-SE adjuvant 3 and 6 weeks later. Immune responses were examined at given time points. 9 weeks post vaccination, mice were aerosol-challenged with M. tb, and sacrificed at 6 and 12 weeks to assess bacterial burden. RESULTS: Vaccination of mice with BCG and M. tb proteins in the presence of GLA-SE adjuvant triggered strong IFN-γ and IL-2 production by splenocytes; more TNF-α was produced without GLA-SE addition. Antibody responses to all three antigens did not differ, with or without GLA-SE adjuvant. Protein boosting without GLA-SE adjuvant resulted in vaccinated animals having better control of pulmonary M. tb load at 6 and 12 weeks post aerosol infection, while animals receiving the protein boost with GLA-SE adjuvant exhibited more bacteria in the lungs. CONCLUSIONS: Our data provides evidence for developing Rv2958c, Rv2957 and Rv0447c in a heterologous prime-boost vaccination strategy with BCG

Community perceptions of a malaria vaccine in the Kintampo districts of Ghana.

BACKGROUND: Malaria remains the leading cause of morbidity and mortality in sub-Saharan Africa despite tools currently available for its control. Making malaria vaccine available for routine use will be a major hallmark, but its acceptance by community members and health professionals within the health system could pose considerable challenge as has been found with the introduction of polio vaccinations in parts of West Africa. Some of these challenges may not be expected since decisions people make are many a time driven by a complex myriad of perceptions. This paper reports knowledge and perceptions of community members in the Kintampo area of Ghana where malaria vaccine trials have been ongoing as part of the drive for the first-ever licensed malaria vaccine in the near future. METHODS: Both qualitative and quantitative methods were used in the data collection processes. Women and men whose children were or were not involved in the malaria vaccine trial were invited to participate in focus group discussions (FGDs). Respondents, made up of heads of religious groupings in the study area, health care providers, traditional healers and traditional birth attendants, were also invited to participate in in-depth interviews (IDIs). A cross-sectional survey was conducted in communities where the malaria vaccine trial (Mal 047RTS,S) was carried out. In total, 12 FGDs, 15 IDIs and 466 household head interviews were conducted. RESULTS: Knowledge about vaccines was widespread among participants. Respondents would like their children to be vaccinated against all childhood illnesses including malaria. Knowledge of the long existing routine vaccines was relatively high among respondents compared to hepatitis B and Haemophilus influenza type B vaccines that were introduced more recently in 2002. There was no clear religious belief or sociocultural practice that will serve as a possible barrier to the acceptance of a malaria vaccine. CONCLUSION: With the assumption that a malaria vaccine will be as efficacious as other EPI vaccines, community members in Central Ghana will accept and prefer malaria vaccine to malaria drugs as a malaria control tool. Beliefs and cultural practices as barriers to the acceptance of malaria vaccine were virtually unknown in the communities surveyed

Inkjet-printed graphene electrodes for dye-sensitized solar cells

We present a stable inkjet printable graphene ink, formulated in isopropyl alcohol via liquid phase exfoliation of chemically pristine graphite with a polymer stabilizer. The rheology and low deposition temperature of the ink allow uniform printing. We use the graphene ink to fabricate counter electrodes (CE) for natural and ruthenium-based dye-sensitized solar cells (DSSCs). The repeatability of the printing process for the CEs is demonstrated through an array of inkjet-printed graphene electrodes, with ∼5% standard deviation in the sheet resistance. As photosensitizers, we investigate natural tropical dye extracts from Pennisetum glaucum, Hibiscus sabdariffa and Caesalpinia pulcherrima. Among the three natural dyes, we find extracts from C. pulcherrima exhibit the best performance, with ∼0.9% conversion efficiency using a printed graphene CE and a comparable ∼1.1% efficiency using a platinum (Pt) CE. When used with N719 dye, the inkjet-printed graphene CE shows a ∼3.0% conversion efficiency, compared to ∼4.4% obtained using Pt CEs. Our results show that inkjet printable graphene inks, without any chemical functionalization, offers a flexible and scalable fabrication route, with a material cost of only ∼2.7% of the equivalent solution processed Pt-based electrodes.Authors acknowledge support from CAPREX, Cambridge Africa Alborada Fund, Carnegie-University of Ghana Next Generation of Africa Academics programme and the Royal Academy of Engineering (RAEng) through a research fellowship (Graphlex)

Shaping and transporting diamagnetic sessile drops

Electromagnetic fields are commonly used to control small quantities of fluids in microfluidics and digital microfluidics. Magnetic control techniques are less well studied than their electric counterparts, with only a few investigations into liquid diamagnetism. The ratio of magnetic to surface energy (magnetic Bond number B m) is an order of magnitude smaller for diamagnetic drops (B m ≈-0.3 at 1.2 T applied field) than for paramagnetic drops (B m ≈ 9.0 at 1.2 T applied field). This weaker interaction between the magnetic field and the diamagnetic drop has led to the phenomenon being overlooked in digital microfluidics. Here, we investigate shaping and transport of diamagnetic drops using magnetostatic fields. Our findings highlight how diamagnetic fluids can be used as a novel tool in the toolbox of microfluidics and digital microfluidics

Field-induced shaping of sessile paramagnetic drops

We use the electromagnetic stress tensor to describe the elongation of paramagnetic drops in uniform magnetic fields. This approach implies a linear relationship between the shape of the drops and the square of the applied field, which we confirm experimentally. We show that this effect scales with the volume and susceptibility of the drops. By using this unified electromagnetic approach, we highlight the potential applications of combining electric and magnetic techniques for controlled shaping of drops in liquid displays, liquid lenses, and chemical mixing of drops in microfluidics

Predictors of Antibiotics Co-prescription with Antimalarials for Patients Presenting with Fever in Rural Tanzania.

Successful implementation of malaria treatment policy depends on the prescription practices for patients with malaria. This paper describes prescription patterns and assesses factors associated with co-prescription of antibiotics and artemether-lumefantrine (AL) for patients presenting with fever in rural Tanzania. From June 2009 to September 2011, a cohort event monitoring program was conducted among all patients treated at 8 selected health facilities in Ifakara and Rufiji Health and Demographic Surveillance System (HDSS).It included all patients presenting with fever and prescribed with AL. Logistic regression was used to model the predictors on the outcome variable which is co-prescription of AL and antibiotics on a single clinical visit. A cohort of 11,648 was recruited and followed up with 92% presenting with fever. Presumptive treatment was used in 56% of patients treated with AL. On average 2.4 (1 -- 7) drugs was prescribed per encounter, indicating co-prescription of AL with other drugs. Children under five had higher odds of AL and antibiotics co-prescription (OR = 0.63, 95% CI: 0.46 -- 0.85) than those aged more than five years. Patients testing negative had higher odds (OR = 2.22, 95%CI: 1.65 -- 2.97) of AL and antibiotics co-prescription. Patients receiving treatment from dispensaries had higher odds (OR = 1.45, 95% CI: 0.84 -- 2.30) of AL and antibiotics co-prescription than those from served in health centres even though the deference was not statistically significant. Regardless the fact that Malaria is declining but due to lack of laboratories and mRDT in most health facilities in the rural areas, clinicians are still treating malaria presumptively. This leads them to prescribe more drugs to treat all possibilities

Correct Dosing of Artemether-Lumefantrine for Management of Uncomplicated Malaria in Rural Tanzania: Do facility and Patient Characteristics Matter?

Use of artemisinin-based combination therapy (ACT), such as artemether-lumefantrine (AL), requires a strict dosing schedule that follows the drugs' pharmacokinetic properties. The quality of malaria case management was assessed in two areas in rural Tanzania, to ascertain patient characteristics and facility-specific factors that influence correct dosing of AL for management of uncomplicated malaria. Exit interviews were conducted with patients attending health facilities for initial illness consultation. Information about health workers' training and supervision visits was collected. Health facilities were inventoried for capacity and availability of medical products related to care of malaria patients. The outcome was correct dosing of AL based on age and weight. Logistic regression was used to assess health facility factors and patient characteristics associated with correct dosing of AL by age and weight. A total of 1,531 patients were interviewed, but 60 pregnant women were excluded from the analysis. Only 503 (34.2%) patients who received AL were assessed for correct dosing. Most patients who received AL (85.3%) were seen in public health facilities, 75.7% in a dispensary and 91.1% in a facility that had AL in stock on the survey day. Overall, 92.1% (463) of AL prescriptions were correct by age or weight; but 85.7% of patients received correct dosing by weight alone and 78.5% received correct dosing by age alone. In multivariate analysis, patients in the middle dosing bands in terms of age or weight, had statistically significant lower odds of correct AL dosing (p < 0.05) compared to those in the lowest age or weight group. Other factors such as health worker supervision and training on ACT did not improve the odds of correct AL dosing. Although malaria treatment guidelines indicate AL dosing can be prescribed based on age or weight of the patient, findings from this study show that patients within the middle age and weight dosing bands were least likely to receive a correct dose by either measure. Clinicians should be made aware of AL dosing errors for patients aged three to 12 years and advised to use weight-based prescriptions whenever possible

Adverse childhood experiences increase HIV risk factors in Agbogbloshie, Ghana

Adverse Childhood Experiences (ACEs) have been associated with increased risk factors for HIV transmission, but the causal pathway is uncertain. This study documents the prevalence of ACEs by gender and their association with HIV risk factors and assesses depressive symptoms as mediating this relationship. A cross-sectional survey was conducted in 2019 among a representative sample of men and women, aged 18–24 years, living in an informal settlement in Accra, Ghana. Data on sociodemographic characteristics, ACEs, ten HIV risk factors (five sexual behaviors, HIV/AIDS knowledge, sexual assault, three substance use behaviors), and depressive symptoms were collected. Multiple logistic regression models were estimated to assess the independent association between four or more ACEs and each of the ten HIV risk factors. Structural equation models examined depressive symptoms as a mediator in these associations. A third (34.6%) of participants reported four or more ACEs, and among those who experienced four or more ACEs 60% were men and 40% were women. Gender did not modify the effect of the association between four or more ACEs and HIV factors and therefore the multiple regression analysis was not stratified by gender. After controlling for sociodemographic covariates and depressive symptoms, having experienced four or more ACEs was associated with alcohol use (OR = 3.88; 95% CI: 1.34, 11.21), injection drug use (OR = 2.78; 95% CI: 1.15, 6.73), low knowledge of HIV (OR = 3.59; 95% CI: 1.43, 9.00), sexually transmitted infection (OR = 3.70; 95% CI: 1.15, 11.96), and sexual assault (OR = 3.58; 95% CI: 1.07, 12.05). There was some evidence that depressive symptoms could be mediating the association between reporting four or more ACEs and ever having a sexually transmitted infection. The mitigation of ACEs and depressive symptoms has the potential to decrease HIV risk factors and thus reduce the risk for HIV transmission among youth living in informal settlements