Importation and distribution of unregistered medicines in the public sector: similarities, differences and shared challenges among Southern African Development Community (SADC) countries

BackgroundThe purpose of the study was to assess the requirements for approval of the importation of unregistered medicines for use in the public sector in the Southern African Development Community (SADC) countries.MethodsThe study reviewed the legal provisions and requirements to be fulfilled when importing unregistered medicines for the public sector in SADC countries relative to two comparators drawn from countries with stringent regulatory systems through extant document analysis. The relative implementation index score was calculated and used to measure the level of implementing legal provisions and requirements to be fulfilled. Analysis was performed using the STATA software package. ResultsApproximately 13 out of 16 SADC countries had a relative implementation index below 50%. The aggregated implementation index across all SADC countries was 44%, ranging from 4% to 54%, while the two comparators had a relative implementation index of 81% and 85%, respectively.ConclusionImplementing the minimum requirements for importing unregistered medicines for the public sector was deficient compared to the jurisdictions with stringent regulatory systems, and wide implementation gaps also existed within the SADC region.

Trustworthy Augmented Intelligence in Health Care

Augmented Intelligence (AI) systems have the power to transform health care and bring us closer to the quadruple aim: enhancing patient experience, improving population health, reducing costs, and improving the work life of health care providers. Earning physicians' trust is critical for accelerating adoption of AI into patient care. As technology evolves, the medical community will need to develop standards for these innovative technologies and re-visit current regulatory systems that physicians and patients rely on to ensure that health care AI is responsible, evidence-based, free from bias, and designed and deployed to promote equity. To develop actionable guidance for trustworthy AI in health care, the AMA reviewed literature on the challenges health care AI poses and reflected on existing guidance as a starting point for addressing those challenges (including models for regulating the introduction of innovative technologies into clinical care).

Lysine Acetylation, Cancer Hallmarks and Emerging Onco-Therapeutic Opportunities

Acetylation, a reversible epigenetic process, is implicated in many critical cellular regulatory systems including transcriptional regulation, protein structure, activity, stability, and localization. Lysine acetylation is the most prevalent and intensively investigated among the diverse acetylation forms. Owing to the intrinsic connections of acetylation with cell metabolism, acetylation has been associated with metabolic disorders including cancers. Yet, relatively little has been reported on the features of acetylation against the cancer hallmarks, even though this knowledge may help identify appropriate therapeutic strategies or combinatorial modalities for the effective treatment and resolution of malignancies. By examining the available data related to the efficacy of lysine acetylation against tumor cells and elaborating the primary cancer hallmarks and the associated mechanisms to target the specific hallmarks, this review identifies the intrinsic connections between lysine acetylation and cancer hallmarks and proposes novel modalities that can be combined with HDAC inhibitors for cancer treatment with higher efficacy and minimum adverse effects.

Reconciling fragmented sectors of health research regulation: toward an ecosystem of processual regulation

The delivery of good outcomes from human health research is entirely dependent on the proper functioning of the attendant regulatory systems. This article focuses on the processes of regulation themselves, and how these might be better understood, so that regulators and other stakeholders have a strong normative basis upon which to pursue the regulatory objective of achieving outcomes with maximum social value. The argument is made that the concept of ‘processual regulation’—which promotes a whole systems approach to regulation—can assist greatly in the design, implementation, and review of human health research. This moves beyond the current often-fragmented approach to regulation towards a joined-up, reflective, and responsive system that has fitness-for-purpose at its core.

The features of changes in adrenal hormones content in mariners during a voyage to different climatic and geographical areas

The hard-working conditions of mariners require a high degree of adaptation of the regulatory systems of the organism. In ensuring adaptation, one of the leading ones is the endocrine system (especially the pituitary-adrenal axis.The aim of the study is to investigate changes in hormonal parameters in mariners during a voyage to various climatic and geographical regions.Materials and methods: Russian seamen were examined during the dynamics of the voyage to various climatogeographic regions. They have determined the levels of adrenocorticotropic hormone (ACTH) and cortisol four times (before the voyage, at the beginning, in the middle and at the end).The results of the study and their discussion: at the beginning of the voyage, the level of ACTH and cortisol were increased; by the middle of the voyage, ACTH decreased but cortisol remained at the same values; by the end of the voyage, the levels of both hormones decreased and reached values much lower than before the voyage. Considering the dynamics of hormonal levels, the normal course of the general adaptation process occurs in the first half of the voyage. A significant decrease in ACTH and cortisol levels in the second half of the voyage may be a sign of breakdown of adaptive capacity.

Intron Retention Coupled with Nonsense-Mediated Decay is Involved in Cellulase Biosynthesis in Cellulolytic Fungi

Background Knowledge on regulatory networks associated with cellulase biosynthesis is prerequisite for exploitation of such regulatory systems in ehancing cellulase production with low cost. The biological functions of intron retention (IR) and nonsense-mediated mRNA decay (NMD) in filamentous fungi is lack of study, let alone their roles in cellulase biosynthesis. Result We found that major cellulase genes (cel7a, cel7b, and cel3a) exhibited concomitant decrease in IR rates and increase in their gene expression in T. reesei under cellulase-producing condition (cellulose and lactose) that was accompanied with a more active NMD pathway, as compared to non cellulase-producing condition (glucose). In the presence of the NMD pathway inhibitor that successfully repressed the NMD pathway, the mRNA levels of cellulase genes were sharply down-regulated, but the rates of IR in these genes were significantly up-regulated. Consistently, the cellulase activities were severely inhibited. In addition, the NMD pathway inhibitor caused the downregulated mRNA levels of two important genes of the target of rapamycin (TOR) pathway, trfkbp12 and trTOR1. The absence of gene trfkbp12 made the cellulase production in T. reesei more sensitive to the NMD pathway inhibitor. Conclusion All these findings suggest that the IR of cellulase genes regulates their own gene expression by coupling with the NMD pathway, which might involve the TOR pathway. Our results provide better understanding on intron retention, the NMD pathway, and cellulase production mechanism in filamentous fungi.

Alcohol Use in China: Unrecorded and Recorded Bai Jiu in Three Rural Regions

In China, approximately 70% of beverage alcohol is consumed in the form of spirits. An estimated 25% of all alcohol consumed is unrecorded, mostly spirits (bai jiu), produced outside regulatory systems in small neighborhood distilleries, mostly in rural areas. Unrecorded bai jiu drinkers are generally older, male, prefer higher-strength bai jiu, and drink daily and mostly at home. To explore possible regional differences, researchers used interview data from 2919 bai jiu drinkers in rural areas in Hebei, Anhui, and Hubei provinces in China. Results confirmed that patterns varied by province. The sample in Hubei preferred unrecorded bai jiu with a more stable preference to alcohol type, tended to drink less frequently, and reported experiencing less drinking pressure, suggesting lower-risk drinking patterns in this region. The Hebei and Anhui sample reported higher frequency and greater amount of alcohol consumption, were more likely to experience drinking pressure, indicating higher-risk patterns in alcohol use in these two regions. The results provide needed details about regional differences in unrecorded bai jiu drinking patterns that are not evident in aggregated data and suggest variations in drinking patterns that may reflect local geography, local values, traditions, and ethnic differences.

Oxidative Stress and X-ray Exposure Levels-Dependent Survival and Metabolic Changes in Murine HSPCs

Haematopoietic bone marrow cells are amongst the most sensitive to ionizing radiation (IR), initially resulting in cell death or genotoxicity that may later lead to leukaemia development, most frequently Acute Myeloid Leukaemia (AML). The target cells for radiation-induced Acute Myeloid Leukaemia (rAML) are believed to lie in the haematopoietic stem and progenitor cell (HSPC) compartment. Using the inbred strain CBA/Ca as a murine model of rAML, progress has been made in understanding the underlying mechanisms, characterisation of target cell population and responses to IR. Complex regulatory systems maintain haematopoietic homeostasis which may act to modulate the risk of rAML. However, little is currently known about the role of metabolic factors and diet in these regulatory systems and modification of the risk of AML development. This study characterises cellular proliferative and clonogenic potential as well as metabolic changes within murine HSPCs under oxidative stress and X-ray exposure. Ambient oxygen (normoxia; 20.8% O2) levels were found to increase irradiated HSPC-stress, stimulating proliferative activity compared to low oxygen (3% O2) levels. IR exposure has a negative influence on the proliferative capability of HSPCs in a dose-dependent manner (0–2 Gy) and this is more pronounced under a normoxic state. One Gy x-irradiated HSPCs cultured under normoxic conditions displayed a significant increase in oxygen consumption compared to those cultured under low O2 conditions and to unirradiated HSPCs. Furthermore, mitochondrial analyses revealed a significant increase in mitochondrial DNA (mtDNA) content, mitochondrial mass and membrane potential in a dose-dependent manner under normoxic conditions. Our results demonstrate that both IR and normoxia act as stressors for HSPCs, leading to significant metabolic deregulation and mitochondrial dysfunctionality which may affect long term risks such as leukaemia.

Negative autoregulation mitigates collateral RNase activity of repeat-targeting CRISPR-Cas13d in mammalian cells

Cas13 is a unique family of CRISPR endonucleases exhibiting programmable binding and cleavage of RNAs and is a strong candidate for eukaryotic RNA knockdown in the laboratory and the clinic. However, sequence-specific binding of Cas13 to the target RNA unleashes non-specific bystander RNA cleavage, or collateral activity, which may confound knockdown experiments and raises concerns for therapeutic applications. Although conserved across orthologs and robust in cell-free and bacterial environments, the extent of collateral activity in mammalian cells remains disputed. Here, we investigate Cas13d collateral activity in the context of an RNA-targeting therapy for myotonic dystrophy type 1, a disease caused by a transcribed long CTG repeat expansion. We find that when targeting CUGn RNA in HeLa and other cell lines, Cas13d depletes endogenous and transgenic RNAs, interferes with critical cellular processes, and activates stress response and apoptosis pathways. We also observe collateral effects when targeting other repetitive and unique transgenic sequences, and we provide evidence for collateral activity when targeting highly expressed endogenous transcripts. To minimize collateral activity for repeat-targeting Cas13d therapeutics, we introduce gRNA excision for negative-autoregulatory optimization (GENO), a simple strategy that leverages crRNA processing to control Cas13d expression and is easily integrated into an AAV gene therapy. We argue that thorough assessment of collateral activity is necessary when applying Cas13d in mammalian cells and that implementation of GENO illustrates the advantages of compact and universally robust regulatory systems for Cas-based gene therapies.

Heart rate variability in persons of Tajik nationality during adaptation

Relevance . Maintaining the health of migrants while adapting to the new climatic and geographical conditions of residence is an urgent task. The impact of non-specific factors on the body of migrants in new climatogeographic conditions leads to the strain of regulatory and adaptive mechanisms, and in extreme cases to their failure. Objective - to determine the features of heart rate variability in young Tajiks, depending on the type of temperament living in Krasnoyarsk for more than a year. Materials and Methods: A study of heart rate variability in 63 Tajiks aged 18-40 years with different types of temperament, living in Krasnoyarsk for more than a year, was conducted. The types of temperament were determined by indices in accordance with the method of identifying VP-types of temperament according to E.Yu. Petrosyan, Yu. I. Savchenkov. The following indicators of heart rate variability (HRV) were evaluated: heart rate, the power of the high-frequency, low-frequency and very low-frequency spectrum (BV, MV-2, MV-1) of the HRV component, the voltage index of regulatory systems (IN), the centralization index (CI) and the activity index of regulatory systems. To assess the statistical significance of the differences between the samples, the Students criteria were used. Results and Discussion. It was revealed that migrants with an intense type of temperament after moving to a new place of residence increased the indicators of heart rate, BV and IN. At the same time, in the studied groups with a calm and adequate type of temperament, the power of BV was significantly reduced, with an increase in heart rate and CI. The conclusion is made about the influence of typological features of temperament on HRV indicators, when adapting to new climatogeographic living conditions. Individuals with an adequate type of temperament demonstrate the normal functioning of the adaptive capabilities of the body. In individuals with the calm type, an increase in the tension of the regulatory mechanisms was revealed. Conclusion . Significant changes in HRV are demonstrated by migrants with an intense type of temperament, in particular, they are characterized by a high voltage of regulatory mechanisms.