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Abstract Objectives To determine if HIV modifies the association between hyperglycaemia and active tuberculosis in Lusaka, Zambia. Methods A case–control study among newly—diagnosed adult tuberculosis cases and population controls in three areas of Lusaka. Hyperglycaemia is determined by random blood glucose (RBG) concentration measured at the time of recruitment; active tuberculosis disease by clinical diagnosis, and HIV status by serological result. Multivariable logistic regression is used to explore the primary association and effect modification by HIV. Results The prevalence of RBG concentration ≥ 11.1 mmol/L among 3843 tuberculosis cases was 1.4% and among 6977 controls was 1.5%. Overall, the adjusted odds ratio of active tuberculosis was 1.60 (95% CI 0.91–2.82) comparing those with RBG concentration ≥ 11.1–

Abstract Efimov trimers are exotic three-body quantum states that emerge from the different types of three-body continua in the vicinity of two-atom Feshbach resonances. In particular, as the strength of the interaction is decreased to a critical point, an Efimov state merges into the atom-dimer threshold and eventually dissociates into an unbound atom-dimer pair. Here we explore the Efimov state in the vicinity of this critical point using coherent few-body spectroscopy in 7Li atoms using a narrow two-body Feshbach resonance. Contrary to the expectation, we find that the 7Li Efimov trimer does not immediately dissociate when passing the threshold, and survives as a metastable state embedded in the atom-dimer continuum. We identify this behavior with a universal phenomenon related to the emergence of a repulsive interaction in the atom-dimer channel which reshapes the three-body interactions in any system characterized by a narrow Feshbach resonance. Specifically, our results shed light on the nature of 7Li Efimov states and provide a path to understand various puzzling phenomena associated with them.

We sought to assess the effectiveness and cost-effectiveness of potential new public health and healthcare NCD risk reduction efforts among Palestinians in Gaza. We created a microsimulation model using: (i) a cross-sectional household survey of NCD risk factors among 4,576 Palestinian adults aged ≥40 years old in Gaza; (ii) a modified Delphi process among local public health experts to identify potentially feasible new interventions; and (iii) reviews of intervention cost and effectiveness, modified to the Gazan and refugee contexts. The survey revealed 28.6% tobacco smoking, a 40.4% prevalence of hypertension diagnosis (with a 95.6% medication treatment rate), a 25.6% prevalence of diabetes diagnosis (with 95.3% on treatment), a 21.9% prevalence of dyslipidemia (with 79.6% on a statin), and a 9.8% prevalence of asthma or chronic obstructive pulmonary disease (without known treatment). A calibrated model estimated a loss of 9,516 DALYs per 10,000 population over the 10-year policy horizon. The interventions having an incremental cost-effectiveness ratio (ICER) less than three times the GDP per capita of Palestine per DALY averted (

Abstract Background Since the early 1990s there has been a burgeoning interest in global health teaching in undergraduate medical curricula. In this article we trace the evolution of this teaching and present recommendations for how the discipline might develop in future years. Discussion Undergraduate global health teaching has seen a marked growth over the past ten years, partly as a response to student demand and partly due to increasing globalization, cross-border movement of pathogens and international migration of health care workers. This teaching has many different strands and types in terms of topic focus, disciplinary background, the point in medical studies in which it is taught and whether it is compulsory or optional. We carried out a survey of medical schools across the world in an effort to analyse their teaching of global health. Results indicate that this teaching is rising in prominence, particularly through global health elective/exchange programmes and increasing teaching of subjects such as globalization and health and international comparison of health systems. Our findings indicate that global health teaching is moving away from its previous focus on tropical medicine towards issues of more global relevance. We suggest that there are three types of doctor who may wish to work in global health – the ‘globalised doctor’, ‘humanitarian doctor’ and ‘policy doctor’ – and that each of these three types will require different teaching in order to meet the required competencies. This teaching needs to be inserted into medical curricula in different ways, notably into core curricula, a special overseas doctor track, optional student selected components, elective programmes, optional intercalated degrees and postgraduate study. Summary We argue that teaching of global health in undergraduate medical curricula must respond to changing understandings of the term global health. In particular it must be taught from the perspective of more disciplines than just biomedicine, in order to reflect the social, political and economic causes of ill health. In this way global health can provide valuable training for all doctors, whether they choose to remain in their countries of origin or work abroad.

Abstract Background There has long been debate around the definition of the field of education, research and practice known as global health. In this article we step back from attempts at definition and instead ask what current definitions tell us about the evolution of the field, identifying gaps and points of debate and using these to inform discussions of how global health might be taught. Discussion What we now know as global health has its roots in the late 19th century, in the largely colonial, biomedical pursuit of ‘international health’. The twentieth century saw a change in emphasis of the field towards a much broader conceptualisation of global health, encompassing broader social determinants of health and a truly global focus. The disciplinary focus has broadened greatly to include economics, anthropology and political science, among others. There have been a number of attempts to define the new field of global health. We suggest there are three central areas of contention: what the object of knowledge of global health is, the types of knowledge to be used and around the purpose of knowledge in the field of global health. We draw a number of conclusions from this discussion. First, that definitions should pay attention to differences as well as commonalities in different parts of the world, and that the definitions of global health themselves depend to some extent on the position of the definer. Second, global health’s core strength lies in its interdisciplinary character, in particular the incorporation of approaches from outside biomedicine. This approach recognises that political, social and economic factors are central causes of ill health. Last, we argue that definition should avoid inclusion of values. In particular we argue that equity, a key element of many definitions of global health, is a value-laden concept and carries with it significant ideological baggage. As such, its widespread inclusion in the definitions of global health is inappropriate as it suggests that only people sharing these values may be seen as ‘doing’ global health. Nevertheless, discussion of values should be a key part of global health education. Summary Our discussions lead us to emphasise the importance of an approach to teaching global health that is flexible, interdisciplinary and acknowledges the different interpretations and values of those practising and teaching the field.

Abstract Background Individuals who had normoglycemia but whose 2-hour plasma glucose (2hPG) concentrations did not return to the fasting plasma glucose (FPG) levels during an oral glucose tolerance test (OGTT) have been shown to have increased cardiovascular mortality. This is further investigated regarding to the first events of coronary heart disease (CHD) and ischemic stroke (IS). Method Data from 9 Finnish and Swedish cohorts comprising 3743 men and 3916 women aged 25 to 90 years who had FPG FPG (Group II) compared with those having 2hPG ≤ FPG (Group I). Results A total of 466 (115) CHD and 235 (106) IS events occurred in men (women) during a median follow-up of 16.4 years. Individuals in Group II were older and had greater body mass index, blood pressure, 2hPG and fasting insulin than those in Group I in both sexes. Multivariate adjusted HRs (95% confidence intervals) for incidence of CHD, IS, and composite CVD events (CHD + IS) in men were 1.13 (0.93-1.37), 1.40 (1.06-1.85) and 1.20 (1.01-1.42) in the Group II as compared with those in the Group I. The corresponding HRs in women were 1.33 (0.83-2.13), 0.94 (0.59-1.51) and 1.11 (0.79-1.54), respectively. Conclusion Within normoglycemic range individuals whose 2hPG did not return to their FPG levels during an OGTT had increased risk of CHD and IS.

Background: One of the mechanisms regulating the biological activity of tumor necrosis factor (TNF) in cells is the co-expression of TNFR1/TNFR2 receptors. A model with a differential level of receptor expression is required to evaluate the contribution of these mechanisms. Aim: The development of a cellular model to compare the effects of TNF on cells depending on the presence of both receptors and TNFR2 alone. Methods: TNFR1 absence modifications of ZR-75/1 and K-562 cell lines were obtained by TNFR1 knockout. The presence of deletions was confirmed by Sanger sequencing, and the absence of cell membrane receptor expression was confirmed by flow cytometry. The dose-dependent effect of TNF on intact and knockout cells was comparatively evaluated by the effect on the cell cycle, the type of cell death, and the profile of expressed genes. Results: Knockout of TNFR1 resulted in a redistribution of TNFR2 receptors with an increased proportion of TNFR2+ cells in both lines and a multidirectional change in the density of expression in the lines (increased in K562 and decreased in ZR75/1). The presence of a large number of cells with high TNFR2 density in the absence of TNFR1 in the K562 cells was associated with greater sensitivity to TNF-stimulating doses and increased proliferation but did not result in a significant change in cell death parameters. A twofold increase in TNFR2+ cell distribution in this cell line at a reduced expression density in ZR75/1 cells was associated with a change in sensitivity to low cytokine concentrations in terms of proliferation; an overall increase in cell death, most pronounced at standard stimulating concentrations; and increased expression of the lymphocyte-activation gene groups, host–pathogen interaction, and innate immunity. Conclusions: The absence of TNFR1 leads to different variants of compensatory redistribution of TNFR2 in cellular models, which affects the type of cell response and the threshold level of sensitivity. The directionality of cytokine action modulation and sensitivity to TNF levels depends not only on the fraction of cells expressing TNFR2 but also on the density of expression.

Abstract Background In order to improve the health of people with Type 1 diabetes in developing countries, a clear analysis of the constraints to insulin access and diabetes care is needed. We developed a Rapid Assessment Protocol for Insulin Access, comprising a series of questionnaires as well as a protocol for the gathering of other data through site visits, discussions, and document reviews. Methods The Rapid Assessment Protocol for Insulin Access draws on the principles of Rapid Assessment Protocols which have been developed and implemented in several different areas. This protocol was adapted through a thorough literature review on diabetes, chronic condition management and medicine supply in developing countries. A visit to three countries in sub-Saharan Africa and meetings with different experts in the field of diabetes helped refine the questionnaires. Following the development of the questionnaires these were tested with various people familiar with diabetes and/or healthcare in developing countries. The Protocol was piloted in Mozambique then refined and had two further iterations in Zambia and Mali. Translations of questionnaires were made into local languages when necessary, with back translation to ensure precision. Results In each country the protocol was implemented in 3 areas – the capital city, a large urban centre and a predominantly rural area and their respective surroundings. Interviews were carried out by local teams trained on how to use the tool. Data was then collected and entered into a database for analysis. Conclusion The Rapid Assessment Protocol for Insulin Access was developed to provide a situational analysis of Type 1 diabetes, in order to make recommendations to the national Ministries of Health and Diabetes Associations. It provided valuable information on patients' access to insulin, syringes, monitoring and care. It was thus able to sketch a picture of the health care system with regards to its ability to care for people with diabetes. In all countries where this tool was used the involvement of local stakeholders resulted in the process acting as a catalyst in bringing diabetes to the attention of the health authorities.

Ludwig van Beethoven. Symphonien V, Nr. 9 d-Moll Opus 125: mit SchlussChor iiber Schillers Ode 'An die Freude' fur grosses Orchester, 4 Solo- und ChorStimmen. Herausgegeben von Beate Angelika Kraus [...]

Tumor necrosis factor alpha (TNF-α) is a cytokine that is responsible for many processes associated with immune response and inflammation. It is involved in the development of an antiviral response to many virus infections. This factor was shown to be activated in influenza A virus infection, which enhances production of other cytokines. The overexpression of these cytokines can lead to a cytokine storm. To study the role of TNF-α in the development of pathologies associated with viral infection, we generated a Tnfa knockout mouse strain. We demonstrated that these mice were characterized by a significant increase in the number of viral genomes compared to that in the parental strain, but the amount of live virus did not differ. A histopathology of the lungs in the genetically modified animals was significantly lower in terms of interalveolar septal infiltration. The generated model may be used to further study pathological processes in viral infections.

The human immunodeficiency virus (HIV) epidemic is a global issue. The estimated number of people with HIV is 39,000,000 to date. Antiviral therapy is the primary approach to treat the infection. However, it does not allow for a complete elimination of the pathogen. The advances in modern gene therapy methods open up new possibilities of effective therapy. One of these areas of possibility is the development of technologies to prevent virus penetration into the cell. Currently, a number of technologies aimed at either the prevention of virus binding to the CCR5 coreceptor or its knockout are undergoing various stages of clinical trials. Since HIV can also utilize the CXCR4 coreceptor, technologies to modify this receptor are also required. Standard knockout of CXCR4 is impossible due to its physiological significance. This review presents an analysis of interactions between individual amino acids in CXCR4 and physiological ligands and HIV gp120. It also discusses potential targets for gene therapy approaches aimed at modifying the coreceptor.

Mass gatherings may elicit experiences of profound personal change. Here the authors show across six field sites that reporting of transformative experiences at mass gatherings are common, increase over time, and predict lasting increases in participants’ circle of moral regard.

Recombinant adeno-associated virus (rAAV) is the leading platform for delivering genetic constructs in vivo. To date, three AAV-based gene therapeutic agents have been approved by the FDA and are used in clinical practice. Despite the distinct advantages of gene therapy development, it is clear that AAV vectors need to be improved. Enhancements in viral vectors are mainly associated with capsid protein modifications. However, there are other structures that significantly affect the AAV life cycle and transduction. The Rep proteins, in combination with inverted terminal repeats (ITRs), determine viral genome replication, encapsidation, etc. Moreover, transgene cassette expression in recombinant variants is directly related to AAV production and transduction efficiency. This review discusses the ways to improve AAV vectors by modifying ITRs, a transgene cassette, and the Rep proteins.

Abstract Background There are many reports on rearrangements occurring separately in the regions of chromosomes 9p and 15q affected in the case under study. 15q duplication syndrome is caused by the presence of at least one extra maternally derived copy of the Prader–Willi/Angelman critical region. Trisomy 9p is the fourth most frequent chromosome anomaly with a clinically recognizable syndrome often accompanied by intellectual disability. Here we report a new case of a patient with maternally derived unique complex sSMC resulting in partial trisomy of both chromosomes 9 and 15 associated with intellectual disability. Case presentation We characterise a supernumerary derivative chromosome 15: 47,XY,+der(15)t(9;15)(p21.2;q13.2), likely resulting from 3:1 malsegregation during maternal gametogenesis. Chromosomal analysis showed that a phenotypically normal mother is a carrier of balanced translocation t(9;15)(p21.1;q13.2). Her 7-year-old son showed signs of intellectual disability and a number of physical abnormalities including bilateral cryptorchidism and congenital megaureter. The child’s magnetic resonance imaging showed changes in brain volume and in structural and functional connectivity revealing phenotypic changes caused by the presence of the extra chromosome material, whereas the mother’s brain MRI was normal. Sequence analyses of the microdissected der(15) chromosome detected two breakpoint regions: HSA9:25,928,021-26,157,441 (9p21.2 band) and HSA15:30,552,104-30,765,905 (15q13.2 band). The breakpoint region on chromosome HSA9 is poor in genetic features with several areas of high homology with the breakpoint region on chromosome 15. The breakpoint region on HSA15 is located in the area of a large segmental duplication. Conclusions We discuss the case of these phenotypic and brain MRI features in light of reported signatures for 9p partial trisomy and 15 duplication syndromes and analyze how the genomic characteristics of the found breakpoint regions have contributed to the origin of the derivative chromosome. We recommend MRI for all patients with a developmental delay, especially in cases with identified rearrangements, to accumulate more information on brain phenotypes related to chromosomal syndromes.

Abstract Background The presence of small supernumerary marker chromosomes (sSMCs) in a karyotype leads to diagnostic questions because the resulting extra material may cause abnormal development depending on the origin of the duplication/triplication. Because SMCs are so small, their origin cannot be determined by conventional cytogenetic techniques, and new molecular cytogenetic methods are necessary. Here, we applied a target approach to chromosome rearrangement analysis by isolating a chromosome of interest via microdissection and using it in fluorescence in situ hybridization (FISH) as a probe in combination with whole-chromosome painting probes. This approach allows to identify origins of both the euchromatin and repeat-rich regions of a marker. Case presentation We report a case of an adult male with congenital atresia of the rectum and anus, anotia, and atresia of the external auditory canal along with hearing loss. Karyotyping and FISH analysis with whole-chromosome painting probes of acrocentric chromosomes and the constructed microdissection library of the marker chromosome reliably identified an additional chromosome in some metaphases: mos 47,XY,+idic(22)(q11.2)[14]/46,XY [23]. Conclusion We propose to use whole-chromosome libraries and microdissected chromosomes in FISH to identify SMCs enriched with repeated sequences. We show that the methodology is successful in identifying the composition of a satellited marker chromosome.

FRAXopathies are caused by the expansion of the CGG repeat in the 5′UTR of the FMR1 gene, which encodes the protein responsible for the synthesis of FMRP. This mutation leads to dramatic changes in FMRP expression at both the mRNA and protein levels. Evidence is emerging that changes in FMR1 mRNA expression can lead to the dysregulation of the miRNAs that target its 3′UTR. In the present work, B-lymphocyte cell lines obtained from patients with FRAXopathies were used, and a wide variety of FMR1 gene activities were observed, allowing the identification of the relationships between FMR1 dysregulation and miRNA activity. We studied the expression levels of eight miRNAs that target the FMR1 gene. To prove the interaction of the studied miRNAs with FMR1, a plasmid was constructed that possesses three primary structures: the miRNA gene, with expression driven by an inducible promoter; a constitutively expressed FusionRed reporter; and an eGFP reporter followed by the 3′UTR of the FMR1 gene. We evaluated changes in miRNA expression in response to alterations in FMR1 gene activity in a model cell line as well as interactions with some miRNAs with the FMR1 3′UTR.

There are more than 30 inherited human disorders connected with repeat expansion (myotonic dystrophy type I, Huntington’s disease, Fragile X syndrome). Fragile X syndrome is the most common reason for inherited intellectual disability in the human population. The ways of the expansion development remain unclear. An important feature of expanded repeats is the ability to form stable alternative DNA secondary structures. There are hypotheses about the nature of repeat instability. It is proposed that these DNA secondary structures can block various stages of DNA metabolism processes, such as replication, repair and recombination and it is considered as the source of repeat instability. However, none of the hypotheses is fully conf irmed or is the only valid one. Here, an experimental system for studying (CGG)n repeat expansion associated with transcription and TCR­-NER is proposed. It is noteworthy that the aberrations of transcription are a poorly studied mechanism of (CGG)n instability. However, the proposed systems take into account the contribution of other processes of DNA metabolism and, therefore, the developed systems are universal and applicable for various studies. Transgenic cell lines carrying a repeat of normal or premutant length under the control of an inducible promoter were established and a method for repeat instability quantif ication was developed. One type of the cell lines contains an exogenous repeat integrated into the genome by the Sleeping Beauty transposon; in another cell line, the vector is maintained as an episome due to the SV40 origin of replication. These experimental systems can serve for f inding the causes of instability and the development of therapeutic agents. In addition, a criterion was developed for the quantif ication of exogenous (CGG)n repeat instability in the transgenic cell lines’ genome.

Tobacco smoking, a significant public health concern globally, is associated with a rise in noncommunicable diseases (NCDs) and preventable deaths, with pronounced impacts in conflict zones like Gaza. A cross-sectional study, conducted in 2020, in Gaza focused on individuals over 40 years of age, aiming to identify predictors of tobacco use and its links to diseases like coronary artery disease (CAD), chronic lung disease (CLD), and stroke using regression analysis. The research, based on the Gaza NCD study data with 4576 participants and a 96.6% response rate, found an overall tobacco smoking prevalence of 19.4%, with higher rates among men. After adjusting for various factors, the study identified significant associations between cigarette smoking in men and adverse health outcomes, such as CAD and CLD, with adjusted odds ratios (OR) of 1.67, 95% CI (1.22–2.29) and 1.68, 95% CI (1.21–2.33) respectively. However, after adjusting for independent variables, shisha smoking in men showed no association with these health outcomes. The findings of this study could assist other researchers in designing interventions aimed at reducing smoking prevalence by utilizing the associated factors identified in our analysis, such as age, education level, physical activity, and body mass index among men in Gaza. [ABSTRACT FROM AUTHOR]

Background: One of the mechanisms regulating the biological activity of tumor necrosis factor (TNF) in cells is the co-expression of TNFR1/TNFR2 receptors. A model with a differential level of receptor expression is required to evaluate the contribution of these mechanisms. Aim: The development of a cellular model to compare the effects of TNF on cells depending on the presence of both receptors and TNFR2 alone. Methods: TNFR1 absence modifications of ZR-75/1 and K-562 cell lines were obtained by TNFR1 knockout. The presence of deletions was confirmed by Sanger sequencing, and the absence of cell membrane receptor expression was confirmed by flow cytometry. The dose-dependent effect of TNF on intact and knockout cells was comparatively evaluated by the effect on the cell cycle, the type of cell death, and the profile of expressed genes. Results: Knockout of TNFR1 resulted in a redistribution of TNFR2 receptors with an increased proportion of TNFR2+ cells in both lines and a multidirectional change in the density of expression in the lines (increased in K562 and decreased in ZR75/1). The presence of a large number of cells with high TNFR2 density in the absence of TNFR1 in the K562 cells was associated with greater sensitivity to TNF-stimulating doses and increased proliferation but did not result in a significant change in cell death parameters. A twofold increase in TNFR2+ cell distribution in this cell line at a reduced expression density in ZR75/1 cells was associated with a change in sensitivity to low cytokine concentrations in terms of proliferation; an overall increase in cell death, most pronounced at standard stimulating concentrations; and increased expression of the lymphocyte-activation gene groups, host–pathogen interaction, and innate immunity. Conclusions: The absence of TNFR1 leads to different variants of compensatory redistribution of TNFR2 in cellular models, which affects the type of cell response and the threshold level of sensitivity. The directionality of cytokine action modulation and sensitivity to TNF levels depends not only on the fraction of cells expressing TNFR2 but also on the density of expression. [ABSTRACT FROM AUTHOR]

Gene therapy is widely used to treat incurable disorders and has become a routine procedure in clinical practice. Since viruses can exhibit specific tropisms, effectively penetrate the cell, and are easy to use, most gene therapy approaches are based on viral delivery of genetic material. However, viral vectors have some disadvantages, such as immune response and cytotoxicity induced by a disturbance of cell metabolism, including miRNA pathways that are an important part of transcription regulation. Therefore, any viral-based gene therapy approach involves the evaluation of side effects and safety. It is possible for such effects to be caused either by the viral vectors themselves or by the delivered genetic material. Many gene therapy techniques use non-coding RNA delivery as an effective agent for gene expression regulation, with the risk of cellular miRNA pathways being affected due to the nature of the non-coding RNAs. This review describes the effect of viral vector entry and non-coding RNA delivery by these vectors on miRNA signaling pathways.

Expansion over 200 CGG repeats in FMR1 gene causes inherited intellectual disability or autism spectrum disorder named as fragile X syndrome. Despite the known cause fragile X syndrome pathogenesis has not been specified yet. The ICGi026-A iPSCs line was obtained by the reprogramming of the peripheral blood mononuclear cells from a 9-year-old boy with fragile X syndrome. The ICGi026-A iPSCs expressed pluripotency markers, had a normal male karyotype (46, XY) and had the capacity to in vivo differentiate into the cells of three germ layers.

SARS-CoV-2, which emerged in Wuhan (China), has become a great worldwide problem in 2020 and has led to more than 1,000,000 deaths worldwide. Many laboratories are searching for ways to fight this pandemic. We studied the action of the cellular antiviral protein tetherin, which is encoded by the BST2 gene. We deleted the transmembrane domain-encoding part of the gene in the Vero cell line. The transmembrane domain is a target for virus-antagonizing proteins. We showed a decrease in SARS-CoV-2 in cells with deleted transmembrane BST2 domains compared to the initial Vero cell line. Similar results were obtained for SARS-CoV and avian influenza virus. This finding may help the development of antiviral therapies competitively targeting the transmembrane domain of tetherin with viral-antagonizing proteins.