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A retrospective study was conducted to assess glycaemic control in relation to pregnancy outcomes in pre-existing and gestational diabetics. Computerised blood glucose records from 47 pre-existing diabetic patients and 33 gestational diabetics were collected prospectively and then analysed retrospectively in relation to pregnancy outcomes. There were two spontaneous miscarriages from the pre-existing diabetic cohort. A total of 44 279 individual blood glucose estimations were made. The mean fasting glucose for pre-existing diabetic patients fell significantly throughout pregnancy, being 7·7±2·1, 7·2±3·1 and 6·5±2·4 mmol/l, respectively, for trimesters 1,2 and 3 (P<0·01). The mean post-prandial glucose for each trimester were 8·9±2·0, 8·6±1·6 and 8·2±1·2 mmol/l (P<0·01). The HbAlc for pre-existing diabetic patients for each trimester was 7·5±1·4%, 6·1±1·0% and 5·9±0·7%, respectively. Gestational diabetic patients had a mean fasting glucose of 5·6±1·5 mmol/l and a mean post-prandial glucose of 8·0±2·1 mmol/l during trimester 3. Home glucose monitoring correlated reasonably well with first trimester HbA1c (r[sup 2]=0·43, P<0·001), but this relationship became less valid as pregnancy progressed. The mean gestation at delivery was 37 weeks, although 30% of women were delivered between 34 and 37 weeks and 8% delivered before 34 weeks. Labour was induced in 49% of patients and the overall caesarean section rate was 58%. The mean birth weight for pre-existing diabetic patients was 3479 g (1410-5000 g) and for women with gestational diabetes was 3605 g (1890-5920 g). For pre-existing diabetic patients HbA1c did not correlate with birth weight; however, home blood glucose data from trimester 2 did correlate (r[sup 2]=0·15, P<0·005) and there appeared to be stronger relationship with trimester 3 data (r[sup 2]=0·24, P<0·005). There was no association between trimester 3 glucose data and birth weight in the gestational cohort. The babies born to pre-existing diabetic mothers had a high incidence of admission to a neonatal unit and over 50% of the babies had proven hypoglycaemia. Our present computerised system for home blood glucose monitoring has shown that for pre-existing diabetes patients but not gestational diabetic patients, glycaemic control in the second and third trimester influences birth weight. The current degree of glycaemic control in the mothers did not prevent a high rate of neonatal hypoglycaemia. [ABSTRACT FROM AUTHOR]

Introduction: The World Health Organization (WHO) advocates the use of reliance practices to enable national regulatory authorities (NRAs) to improve patients' access to medicines. This study considered whether reliance review translates into swifter medicine authorization., Methods: Abridged review outcomes were examined for New Chemical Entity (NCE) and generic applications to the South African Health Products Regulatory Authority (SAHPRA) in Chemistry, Manufacturing and Controls (CMC) and clinical/bioequivalence (BE), as well as overall NCE authorization times., Results: SAHPRA NCE CMC review time was 91 days (abridged) vs. 179 days (full), applicant response time was 34 vs. 105 days, respectively, and there was a >2-fold time reduction for abridged vs. full CMC review (125 vs. 284 days). There was a 99-day decrease in clinical approval time through an abridged review (230 vs. 329 days) and a decrease in marketing authorization time for NCE abridged assessment (446 vs. 619 days). SAHPRA review time for generic applications was 97 days (abridged) vs. 191 days (full); applicant response time was 26 days (abridged) vs. 81 days (full) and there was a >2-fold time reduction for CMC and BE abridged vs. full review (122 vs. 272 days)., Conclusion: These results clearly support World Health Organization recommendations for the use of reliance-based regulatory review to expedite the worldwide availability of safe, effective and needed medications., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Danks, Semete-Makokotlela, Otwombe, Parag, Walker and Salek.)

Introduction: Regulatory reliance, harmonization and work sharing have grown over the last few years, resulting in greater sharing of work and information among regulators, enabling efficient use of limited resources and preventing duplication of work. Various initiatives on the African continent include ZaZiBoNa, the Southern African Development Community (SADC) collaborative medicines registration initiative. ZaZiBoNa has resulted in great savings in time and resources; however, identified challenges include lack of clear information regarding the participating countries registration processes and requirements as well as lengthy registration times. The aim of this study, therefore, was to compare the data requirements and review models employed in the assessment of applications for registration, the target timelines for key milestones and the metrics of applications received and approved in 2019 and 2020 by Mozambique, Namibia, South Africa, Tanzania, Zambia, and Zimbabwe. Methods: A senior member of the division responsible for issuing marketing authorisations completed an established and validated questionnaire, which standardizes the review process, allowing key milestones, activities and practices of the six regulatory authorities to be identified and compared. The completed questionnaires were validated by the heads of the respective agencies. Results: The majority of applications received and approved by all six agencies in 2019 and 2020 were for generics. The mean approval times for generics varied across the countries, with ranges of 218-890 calendar days in 2019 and 158-696 calendar days in 2020. All three types of scientific assessment review models were used by the six agencies and data requirements and extent of scientific assessment were similar for five countries, while one conducted full reviews for new active substances. A large variation was observed in the targets set by the six agencies for the different milestones as well as overall approval times. Conclusions: The study identified the strengths of the countries as well as opportunities for improvement and alignment. Implementation of the recommendations made as in this study will enhance the countries' individual systems, enabling them to efficiently support the ZaZiBoNa initiative., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sithole, Mahlangu, Capote, Sitoie, Shifotoka, Gaeseb, Danks, Nkambule, Juma, Fimbo, Munkombwe, Mwale, Salek and Walker.)

Background: The aims of this study were to compare the overall regulatory review timelines achieved by the South African Health Products Regulatory Authority (SAHPRA) in 2020 to the timelines historically achieved by the Medicines Control Council (MCC). This study also aimed to evaluate the regulatory review processes and the good review practices that have been implemented by SAHPRA to support the assessment of new chemical entities and generic product applications for market authorization in the business-as-usual and backlog process streams. Methods: A questionnaire was completed and verified by SAHPRA to describe the structure of the organization, the resources available, the process for regulatory review of new chemical entities and generic products and the level of implementation of good review practices and regulatory decision-making practices for market authorization. Data were collected and analyzed on the overall approval timelines for new chemical entities and generic products registered by SAHPRA in 2020 in the business-as-usual and backlog process streams. Results: A full, independent scientific review was conducted for all new chemical entities and generic product applications in the business-as-usual stream. Facilitated regulatory pathways were introduced for the review of new chemical entities and generic products in the backlog stream. As a result, the timelines for approval of applications in the backlog stream were 68% quicker for both new chemical entities and generics, using facilitated regulatory pathways, such as abridged and verification review models. Conclusion: The comparisons made through this study provided insight into the improvements that have been made through the establishment of SAHPRA and the transition in 2018 from the MCC. The re-engineered processes that have been developed and implemented by SAHPRA to address the backlog in the review of the applications for market authorization have demonstrated a decrease in the overall median approval times. The expansion of these processes into the routine review of medical products will contribute to the enhanced regulatory performance of SAHPRA and patients' access to new medicines., Competing Interests: LD, PN and BS-M were employed by the South African Health Products Regulatory Authority (SAHPRA). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Keyter, Salek, Danks, Nkambule, Semete-Makokotlela and Walker.)

Tumour necrosis factor (TNF) is produced by primary human macrophages in response to stimulation by exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs) via Toll-like receptor (TLR) signalling. However, uncontrolled TNF production can be deleterious and hence it is tightly controlled at multiple stages. We have previously shown that Bruton's tyrosine kinase (Btk) regulates TLR4-induced TNF production via p38 MAP Kinase by stabilising TNF messenger RNA. Using both gene over-expression and siRNA-mediated knockdown we have examined the role of Btk in TLR7/8 mediated TNF production. Our data shows that Btk acts in the TLR7/8 pathway and mediates Ser-536 phosphorylation of p65 RelA and subsequent nuclear entry in primary human macrophages. These data show an important role for Btk in TLR7/8 mediated TNF production and reveal distinct differences for Btk in TLR4 versus TLR7/8 signalling., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: RANKL is mainly expressed by synovial fibroblasts and T cells within the joints of rheumatoid arthritis patients. The relative importance of RANKL expression by these cell types for the formation of bone erosions is unclear. We therefore aimed to quantify the contribution of RANKL by each cell type to osteoclast differentiation and bone destruction during inflammatory arthritis., Methods: RANKL was specifically deleted in T cells (Tnfsf11(flox/Δ) Lck-Cre), in collagen VI expressing cells including synovial fibroblasts (Tnfsf11(flox/Δ) Col6a1-Cre) and in collagen II expressing cells including articular chondrocytes (Tnfsf11(flox/Δ) Col2a1-Cre). Erosive disease was induced using the collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA) models. Osteoclasts and cartilage degradation were assessed by histology and bone erosions were assessed by micro-CT., Results: The inflammatory joint score during CAIA was equivalent in all mice regardless of cell-targeted deletion of RANKL. Significant increases in osteoclast numbers and bone erosions were observed in both the Tnfsf11(flox/Δ) and the Tnfsf11(flox/Δ) Lck-Cre groups during CAIA; however, the Tnfsf11(flox/Δ) Col6a1-Cre mice showed significant protection against osteoclast formation and bone erosions. Similar results on osteoclast formation and bone erosions were obtained in CIA mice. The deletion of RANKL on any cell type did not prevent articular cartilage loss in either model of arthritis used., Conclusions: The expression of RANKL on synovial fibroblasts rather than T cells is predominantly responsible for the formation of osteoclasts and erosions during inflammatory arthritis. Synovial fibroblasts would be the best direct target in RANKL inhibition therapies., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The central nervous system (CNS) is an immunologically privileged site protected from uncontrolled access of T cells by the blood-brain barrier (BBB), which is breached upon autoimmune inflammation. Here we have shown that receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) on T cells regulates C-C type chemokine ligand 20 (CCL20) production by astrocytes and T cell localization in the CNS. Importantly, mice specifically lacking RANKL in T cells were resistant to experimental autoimmune encephalomyelitis (EAE) due to altered T cell trafficking. Pharmacological inhibition of RANKL prevented the development of EAE without affecting the peripheral immune response, indicating that RANKL is a potential therapeutic target for treating autoimmune diseases in the CNS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Self-tolerance to immune reactions is established via promiscuous expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs), leading to the elimination of T cells that respond to self-antigens. The transcriptional regulator Aire has been thought to be sufficient for the induction of TRAs, despite some indications that other factors may promote TRA expression in the thymus. Here, we show that the transcription factor Fezf2 directly regulates various TRA genes in mTECs independently of Aire. Mice lacking Fezf2 in mTECs displayed severe autoimmune symptoms, including the production of autoantibodies and inflammatory cell infiltration targeted to peripheral organs. These responses differed from those detected in Aire-deficient mice. Furthermore, Fezf2 expression and Aire expression are regulated by distinct signaling pathways and promote the expression of different classes of proteins. Thus, two independent factors, Fezf2 and Aire, permit the expression of TRAs in the thymus to ensure immune tolerance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM.