A Crosslinked Calcium-Alginate-Pectinate-Cellulose Acetophthalate Gelisphere System for Linear Drug Release

This study proposes a novel binary crosslinked ternary multiple-unit system, collectively referred to as calcium-alginate-pectinate-cellulose acetophthalate gelispheres (CAPCA), for the purpose of obtaining linear, controlled drug release. This polymeric system, composed of sodium alginate, pectin, and cellulose acetophthalate, was developed through a binary crosslinking reaction in a composite aqueous system consisting of calcium and acetate ions. The crosslinking reaction was optimized in terms of maximizing drug release suppression and could be obtained by exposing the gelispheres for 24 hours to a combined aqueous solution of 15% w/v acetic acid and 2% w/v calcium chloride. The highly acidic nature of this solution (pH 1.9) was desirable for enhancing the drug entrapment efficiency of the gelispheres. Synchronization of matrix swelling and erosion appeared to be responsible for the attainment of zero-order drug release. However, such perfect synchronization was only achievable through application of the ternary polymeric combination presented in this work. The main advantages of the ternary system shown in this study over the previously presented binary calcium-alginate-pectinate system (CAP) proposed by Pillay and Fassihi (1999a, 1999b), was provision of extended drug release over 18 hours, minimization of late-phase drug release tapering, and provision of superior linearity in drug release profiles. Kinetic modeling of dissolution data using various power law equations highlighted the significance of matrix relaxation and erosion in modulation of drug release rate. In all cases of model fitting excellent correlation (r 2 > 0.98) was obtained between observed and predicted data. Textural profiling of crosslinked gelispheres reflected a significantly lower reduction in matrix resilience as the concentration of cellulose acetophthalate was increased in the gelisphere formulation. This may be attributed to the concentration-dependent matrix plastic-transforming property of cellulose acetophthalate.     

Eliminating mother-to-child HIV transmission in South Africa

Problem

The World Health Organization has produced clear guidelines for the prevention of mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV). However, ensuring that all PMTCT programme components are implemented to a high quality in all facilities presents challenges.

Approach

Although South Africa initiated its PMTCT programme in 2002, later than most other countries, political support has increased since 2008. Operational research has received more attention and objective data have been used more effectively.

Local setting

In 2010, around 30% of all pregnant women in South Africa were HIV-positive and half of all deaths in children younger than 5 years were associated with the virus.

Relevant changes

Between 2008 and 2011, the estimated proportion of HIV-exposed infants younger than 2 months who underwent routine polymerase chain reaction (PCR) tests to detect early HIV transmission increased from 36.6% to 70.4%. The estimated HIV transmission rate decreased from 9.6% to 2.8%. Population-based surveys in 2010 and 2011 reported transmission rates of 3.5% and 2.7%, respectively.

Lessons learnt

Critical actions for improving programme outcomes included: ensuring rapid implementation of changes in PMTCT policy at the field level through training and guideline dissemination; ensuring good coordination with technical partners, such as international health agencies and international and local nongovernmental organizations; and making use of data and indicators on all aspects of the PMTCT programme. Enabling health-care staff at primary care facilities to initiate antiretroviral therapy and expanding laboratory services for measuring CD4+ T-cell counts and for PCR testing were also helpful.     

Patients with treated indolent lymphomas immunized with BNT162b2 have reduced anti-spike neutralizing IgG to SARS-CoV-2 variants,but preserved antigen-specific T cell responses

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN (N = 9), ICT (N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti-spike immunoglobulin G (IgG) was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti-spike IgG correlated with lymphocyte count (r = .63; p = .002), and time from treatment (r = .56; p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis (p = .03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC (p < .0001). Anti-spike IgG correlated with neutralization of the delta variant (r = .62, p < .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p < .0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant.     

The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates

Background: In sub-Saharan Africa, rates of sustained HIV virologic suppression remain below international goals. HIV resistance testing, while common in resource-rich settings, has not gained traction due to concerns about cost and sustainability.

Objective: We designed a randomized clinical trial to determine the feasibility, effectiveness, and cost-effectiveness of routine HIV resistance testing in sub-Saharan Africa.

Approach: We describe challenges common to intervention studies in resource-limited settings, and strategies used to address them, including: (1) optimizing generalizability and cost-effectiveness estimates to promote transition from study results to policy; (2) minimizing bias due to patient attrition; and (3) addressing ethical issues related to enrollment of pregnant women.

Methods: The study randomizes people in Uganda and South Africa with virologic failure on first-line therapy to standard of care virologic monitoring or immediate resistance testing. To strengthen external validity, study procedures are conducted within publicly supported laboratory and clinical facilities using local staff. To optimize cost estimates, we collect primary data on quality of life and medical resource utilization. To minimize losses from observation, we collect locally relevant contact information, including Whatsapp account details, for field-based tracking of missing participants. Finally, pregnant women are followed with an adapted protocol which includes an increased visit frequency to minimize risk to them and their fetuses.

Conclusions: REVAMP is a pragammatic randomized clinical trial designed to test the effectiveness and cost-effectiveness of HIV resistance testing versus standard of care in sub-Saharan Africa. We anticipate the results will directly inform HIV policy in sub-Saharan Africa to optimize care for HIV-infected patients.     

The amygdaloid body of two carnivore species: The feliform banded mongoose and the caniform domestic ferret

The current study provides an analysis of the cytoarchitecture, myeloarchitecture, and chemoarchitecture of the amygdaloid body of the banded mongoose (Mungos mungo) and domestic ferret (Mustela putorius furo). Using architectural and immunohistochemical stains, we observe that the organization of the nuclear and cortical portions of the amygdaloid complex is very similar in both species. The one major difference is the presence of a cortex‐amygdala transition zone observed in the domestic ferret that is absent in the banded mongoose. In addition, the chemoarchitecture is, for the most part, quite similar in the two species, but several variances, such as differing densities of neurons expressing the calcium‐binding proteins in specific nuclei are noted. Despite this, certain aspects of the chemoarchitecture, such as the cholinergic innervation of the magnocellular division of the basal nuclear cluster and the presence of doublecortin expressing neurons in the shell division of the accessory basal nuclear cluster, appear to be consistent features of the Eutherian mammal amygdala. The domestic ferret presented with an overall lower myelin density throughout the amygdaloid body than the banded mongoose, a feature that may reflect artificial selection in the process of domestication for increased juvenile‐like behavior in the adult domestic ferret, such as a muted fear response. The shared, but temporally distant, ancestry of the banded mongoose and domestic ferret allows us to generate observations relevant to understanding the relative influence that phylogenetic constraints, adaptive evolutionary plasticity, and the domestication process may play in the organization and chemoarchitecture of the amygdaloid body.