The pharmacological treatment of granulomatosis with polyangiitis: a review of clinical trials registered in clinicaltrials.gov and the International Clinical Trials Registry Platform.

To date, there is no published overview of the drug pipeline in granulomatosis with polyangiitis (GPA), a rare disease. The aim of this study was to identify clinical trials from two study repositories. A review of clinical trials was conducted using publicly available data. Clinicaltrials.gov and International Clinical Trials Registry Platform were searched from inception until 25 September 2022. Only GPA-specific studies were included; these were described in detail. A total of 137 studies were identified in the trial repositories, of which 108 (79%) studies were found to concern GPA. Of these 108 studies, 67 enrolled GPA patients to investigate pharmacotherapy in this disease (62%). Most studies included all severity types (n = 51; 76%); the scope of almost half of the studies was remission induction (n = 33; 49%). The drug class which was by the most widely investigated in trials was the non-corticosteroid immunosuppressant drug class (46; 68.7%), monoclonal antibodies (32; 47.8%), and corticosteroids (31; 46.3%). There is a need for more GPA trials to generate evidence on effectiveness in terms of severity-specificity and maintenance of remission.

The pharmacological treatment of granulomatosis with polyangiitis: a review of clinical trials To date, there is no published overview of the drug pipeline in granulomatosis with polyangiitis (referred to in this paper as GPA), a rare disease. The aim of this study was to identify such studies from two study archives. Clinicaltrials.gov and International Clinical Trials Registry Platform (ICTRP) were searched from inception until 25th September 2022. Studies recruiting GPA patients were included; these were described in detail. A total of 137 studies were identified in the trial repositories, of which 108 were found to concern GPA. Of these 108 studies, 67 enrolled GPA patients to investigate the treatment of this disease through the administration of drugs. Most studies included all severity types (n = 51); the scope of almost half of the studies was to induce remission (n = 33). The drug classes which were the most widely investigated in trials were non-corticosteroid immunosuppressant drugs (n = 46), monoclonal antibodies (n = 32), and corticosteroids (n = 31). There is a need for more GPA clinical trials to generate evidence on effectiveness of drugs in terms of severity-specificity and maintenance of remission.

Viral activation and ecological restructuring characterize a microbiome axis of spaceflight-associated immune activation.

Maintenance of astronaut health during spaceflight will require monitoring and potentially modulating their microbiomes, which play a role in some space-derived health disorders. However, documenting the response of microbiota to spaceflight has been difficult thus far due to mission constraints that lead to limited sampling. Here, we executed a six-month longitudinal study centered on a three-day flight to quantify the high-resolution microbiome response to spaceflight. Via paired metagenomics and metatranscriptomics alongside single immune profiling, we resolved a microbiome "architecture" of spaceflight characterized by time-dependent and taxonomically divergent microbiome alterations across 750 samples and ten body sites. We observed pan-phyletic viral activation and signs of persistent changes that, in the oral microbiome, yielded plaque-associated pathobionts with strong associations to immune cell gene expression. Further, we found enrichments of microbial genes associated with antibiotic production, toxin-antitoxin systems, and stress response enriched universally across the body sites. We also used strain-level tracking to measure the potential propagation of microbial species from the crew members to each other and the environment, identifying microbes that were prone to seed the capsule surface and move between the crew. Finally, we identified associations between microbiome and host immune cell shifts, proposing both a microbiome axis of immune changes during flight as well as the sources of some of those changes. In summary, these datasets and methods reveal connections between crew immunology, the microbiome, and their likely drivers and lay the groundwork for future microbiome studies of spaceflight.

Evolutionary and spatiotemporal analyses reveal multiple introductions and cryptic transmission of SARS-CoV-2 VOC/VOI in Malta.

IMPORTANCE: Our study provides insights into the evolution of the coronavirus disease 2019 (COVID-19) pandemic in Malta, a highly connected and understudied country. We combined epidemiological and phylodynamic analyses to analyze trends in the number of new cases, deaths, tests, positivity rates, and evolutionary and dispersal patterns from August 2020 to January 2022. Our reconstructions inferred 173 independent severe acute respiratory syndrome coronavirus 2 introductions into Malta from various global regions. Our study demonstrates that characterizing epidemiological trends coupled with phylodynamic modeling can inform the implementation of public health interventions to help control COVID-19 transmission in the community.

Enhancing European capabilities for application of multi-omics studies in biology and biomedicine space research.

Following on from the NASA twins' study, there has been a tremendous interest in the use of omics techniques in spaceflight. Individual space agencies, NASA's GeneLab, JAXA's ibSLS, and the ESA-funded Space Omics Topical Team and the International Standards for Space Omics Processing (ISSOP) groups have established several initiatives to support this growth. Here, we present recommendations from the Space Omics Topical Team to promote standard application of space omics in Europe. We focus on four main themes: i) continued participation in and coordination with international omics endeavors, ii) strengthening of the European space omics infrastructure including workforce and facilities, iii) capitalizing on the emerging opportunities in the commercial space sector, and iv) capitalizing on the emerging opportunities in human subjects research.

Challenges and considerations for single-cell and spatially resolved transcriptomics sample collection during spaceflight.

Single-cell RNA sequencing (scRNA-seq) and spatially resolved transcriptomics (SRT) have experienced rapid development in recent years. The findings of spaceflight-based scRNA-seq and SRT investigations are likely to improve our understanding of life in space and our comprehension of gene expression in various cell systems and tissue dynamics. However, compared to their Earth-based counterparts, gene expression experiments conducted in spaceflight have not experienced the same pace of development. Out of the hundreds of spaceflight gene expression datasets available, only a few used scRNA-seq and SRT. In this perspective piece, we explore the growing importance of scRNA-seq and SRT in space biology and discuss the challenges and considerations relevant to robust experimental design to enable growth of these methods in the field.

The Maleth program: Malta's first space mission discoveries on the microbiome of diabetic foot ulcers.

The purpose of the Maleth Program, also known as Project Maleth, is Malta's first space program to evaluate human skin tissue microbiome changes in type 2 diabetes mellitus (T2DM) patients afflicted with diabetic foot ulcers (DFU). This was carried out in both ground-based models and spaceflight. The first mission (Maleth I) under this program was carried out to uncover the effects of spaceflight, microgravity and radiation on human skin tissue microbiome samples from six T2DM patients recruited into the study. Each patient human skin tissue sample was split in three, with one section processed immediately for genomic profiling by 16S typing and the rest were processed for longer term ground-control and spaceflight experiments. Ground-control and spaceflight human skin tissue samples were also processed for genomic profiling upon mission re-entry and completion. Maleth I's overall objective was achieved, as human skin tissue samples with their microbiomes travelled to space and back yielding positive results by both standard microbiology techniques and genetic typing using 16S rRNA amplicon sequencing. Preliminary findings of this mission are discussed in light of its innovative approach at DFU microbiome research, and the clinical implications that may emerge from this and other future similar studies.

Identifying and categorizing compounds that reduce corneal transforming growth factor beta induced protein levels: a scoping review.

INTRODUCTION: Transforming growth factor beta induced (TGFBI) gene mutations have been reported as the cause of a group of genetically inherited, visually debilitating, corneal dystrophies (CD). A scoping literature review to identify and categorize compounds that inhibit corneal TGFBI expression and/or promote TGFBIp degradation was performed. Emphasis was given to their potential to be used as a cost-effective approach via drug repurposing. AREAS COVERED: We performed a thorough search of original peer-reviewed literature using electronic bibliographic databases and selected articles according to a set of criteria. The total number of articles retrieved from the search terms applied to the databases was 2344. The number of relevant full-text articles included added up to 19. We identified 16 compounds that can theoretically reduce the levels of mutant TGFBIp in human corneal cells. EXPERT OPINION: Currently, the only temporary treatments available for this condition are lubricant drops and surgery. Here, we explored the crosstalk between cascades that regulate TGFBI expression and identified compounds that target these pathways. Compounds that inhibit DNA synthesis and function, increase elimination of TGFBIp or bind to mutant TGFBIp were also explored with the aim of highlighting promising compounds that can be used in future cost-effective drug-repurposing studies.

Routine omics collection is a golden opportunity for European human research in space and analog environments.

Widespread generation and analysis of omics data have revolutionized molecular medicine on Earth, yet its power to yield new mechanistic insights and improve occupational health during spaceflight is still to be fully realized in humans. Nevertheless, rapid technological advancements and ever-regular spaceflight programs mean that longitudinal, standardized, and cost-effective collection of human space omics data are firmly within reach. Here, we consider the practicality and scientific return of different sampling methods and omic types in the context of human spaceflight. We also appraise ethical and legal considerations pertinent to omics data derived from European astronauts and spaceflight participants (SFPs). Ultimately, we propose that a routine omics collection program in spaceflight and analog environments presents a golden opportunity. Unlocking this bright future of artificial intelligence (AI)-driven analyses and personalized medicine approaches will require further investigation into best practices, including policy design and standardization of omics data, metadata, and sampling methods.

Extraterrestrial Gynecology: Could Spaceflight Increase the Risk of Developing Cancer in Female Astronauts? An Updated Review.

Outer space is an extremely hostile environment for human life, with ionizing radiation from galactic cosmic rays and microgravity posing the most significant hazards to the health of astronauts. Spaceflight has also been shown to have an impact on established cancer hallmarks, possibly increasing carcinogenic risk. Terrestrially, women have a higher incidence of radiation-induced cancers, largely driven by lung, thyroid, breast, and ovarian cancers, and therefore, historically, they have been permitted to spend significantly less time in space than men. In the present review, we focus on the effects of microgravity and radiation on the female reproductive system, particularly gynecological cancer. The aim is to provide a summary of the research that has been carried out related to the risk of gynecological cancer, highlighting what further studies are needed to pave the way for safer exploration class missions, as well as postflight screening and management of women astronauts following long-duration spaceflight.

Maltese Allelic Variants in Corneal Dystrophy Genes in a Worldwide Setting.

INTRODUCTION: This study aimed to establish which worldwide population cohorts have a genetic make-up closest to that of a large sample of the Maltese population with regard to corneal dystrophy (CD) genes. METHODS: Single nucleotide polymorphisms (SNPs) in the Maltese cohort were compared with worldwide cohorts. Fixation index (FST) values were calculated to evaluate population differentiation. The genetic prevalence of CD subtypes in worldwide and Maltese cohorts were calculated, and single nucleotide missense mutations present in the Maltese cohort were evaluated for potential pathogenicity. RESULTS: FST values showed that CD-related genes differ substantially among the studied cohorts. FST values for each SNP showed greatest differentiation between the Maltese and African cohorts and least differentiation with the Puerto Rican, Mexican, and Colombian cohorts. One TGFBI casual CD mutation, 502V, which causes a Bowman's layer CD/atypical Thiel-Behnke CD was identified in the Maltese cohort. The KRT3 NC_000012.11:g.53186088G>C mutation was potentially deleterious. CONCLUSION: Identifying populations with least genetic differentiation can facilitate and help guide future diagnostic and treatment strategies for Maltese individuals with CDs in the absence of comparable Maltese data. Analysing the previously unknown CD genetic pool present in a large Maltese cohort adds to the global genetic bank that researchers rely on for medical progress.

Epigenomic analysis of KLF1 haploinsufficiency in primary human erythroblasts.

Haploinsufficiency for the erythroid-specific transcription factor KLF1 is associated with hereditary persistence of fetal hemoglobin (HPFH). Increased HbF ameliorates the symptoms of ß-hemoglobinopathies and downregulation of KLF1 activity has been proposed as a potential therapeutic strategy. However, the feasibility of this approach has been challenged by the observation that KLF1 haploinsufficient individuals with the same KLF1 variant, within the same family, display a wide range of HbF levels. This phenotypic variability is not readily explained by co-inheritance of known HbF-modulating variants in the HBB, HBS1L-MYB and/or BCL11A loci. We studied cultured erythroid progenitors obtained from Maltese individuals in which KLF1 p.K288X carriers display HbF levels ranging between 1.3 and 12.3% of total Hb. Using a combination of gene expression analysis, chromatin accessibility assays and promoter activity tests we find that variation in expression of the wildtype KLF1 allele may explain a significant part of the variability in HbF levels observed in KLF1 haploinsufficiency. Our results have general bearing on the variable penetrance of haploinsufficiency phenotypes and on conflicting interpretations of pathogenicity of variants in other transcriptional regulators such as EP300, GATA2 and RUNX1.

Back pain: An aftermath of Covid-19 pandemic? A Malta perspective.

BACKGROUND: Back pain is the commonest musculoskeletal complaint across the world. The Covid-19 pandemic led to mitigating measures including remote working that enhanced a sedentary lifestyle. The aim of this study was to investigate whether back pain complaints have increased from pre-Covid-19 to during the Covid-19 period among the adult population of Malta, while exploring the possible contributing factors. METHODS: An online survey was distributed through social media targeting the adult population of Malta. Questions on sociodemographic data, occurrence of back pain pre-Covid-19 and since the onset of Covid-19 was gathered, along with changes in behavioural attitudes, daily routine and physical activity. Descriptive and multiple logistic regression analyses were performed. RESULTS: Out of the 388 responders, 30% experienced chronic back pain pre-Covid-19, 49% experienced back pain since Covid-19, with the majority of the latter claiming that they never experienced back pain before Covid-19. Significant changes were present in daily routine and physical activity (PA) patterns. Indeed, continuously sitting down (OR: 15.53; p ≤ 0.01), no PA (OR: 4.22; p ≤ <0.01), once a week PA (OR: 5.74; p ≤ <0.01), two to three times PA a week (OR: 2.58; p = 0.05) and four to five PA a week (OR: 3.46; p = 0.02) were associated with experiencing new onset back pain since the onset of Covid-19, when adjusted for sex, age, education and employment status. CONCLUSION: The pandemic has changed population behaviour resulting in an enhanced back pain occurrence. This is anticipated to impact the individual's disability adjusted life years as well as increase the burden on the economy and healthcare services. A designated multidisciplinary action plan is recommended to reduce back pain impact.

Novel therapies in ß-thalassaemia.

Beta-thalassaemia is one of the most significant haemoglobinopathies worldwide resulting in the synthesis of little or no ß-globin chains. Without treatment, ß-thalassaemia major is lethal within the first decade of life due to the complex pathophysiology, which leads to wide clinical manifestations. Current clinical management for these patients depends on repeated transfusions followed by iron-chelating therapy. Several novel approaches to correct the resulting α/ß-globin chain imbalance, treat ineffective erythropoiesis and improve iron overload are currently being developed. Up to now, the only curative treatment for ß-thalassemia is haematopoietic stem-cell transplantation, but this is a risky and costly procedure. Gene therapy, gene editing and base editing are emerging as a powerful approach to treat this disease. In ß-thalassaemia, gene therapy involves the insertion of a vector containing the normal ß-globin or γ-globin gene into haematopoietic stem cells to permanently produce normal red blood cells. Gene editing and base editing involves the use of zinc finger nucleases, transcription activator-like nucleases and clustered regularly interspaced short palindromic repeats/Cas9 to either correct the causative mutation or else insert a single nucleotide variant that will increase foetal haemoglobin. In this review, we will examine the current management strategies used to treat ß-thalassaemia and focus on the novel therapies targeting ineffective erythropoiesis, improving iron overload and correction of the globin chain imbalance.

Novel leukocyte-depleted platelet-rich plasma-based skin equivalent as an in vitro model of chronic wounds: a preliminary study.

BACKGROUND: Chronic leg ulcerations are associated with Haemoglobin disorders, Type2 Diabetes Mellitus, and long-term venous insufficiency, where poor perfusion and altered metabolism develop into a chronic inflammation that impairs wound closure. Skin equivalent organotypic cultures can be engineered in vitro to study skin biology and wound closure by modelling the specific cellular components of the skin. This study aimed to develop a novel bioactive platelet-rich plasma (PRP) leukocyte depleted scaffold to facilitate the study of common clinical skin wounds in patients with poor chronic skin perfusion and low leukocyte infiltration. A scratch assay was performed on the skin model to mimic two skin wound conditions, an untreated condition and a condition treated with recombinant tumour necrotic factor (rTNF) to imitate the stimulation of an inflammatory state. Gene expression of IL8 and TGFA was analysed in both conditions. Statistical analysis was done through ANOVA and paired student t-test. P < 0.05 was considered significant. RESULTS: A skin model that consisted of a leukocyte-depleted, platelet-rich plasma scaffold was setup with embedded fibroblasts as dermal equivalents and seeded keratinocytes as multi-layered epidermis. Gene expression levels of IL8 and TGFA were significantly different between the control and scratched conditions (p < 0.001 and p < 0.01 respectively), as well as between the control and treated conditions (p < 0.01 and p < 0.001 respectively). The scratch assay induced IL8 upregulation after 3 h (p < 0.05) which continued to increase up to day 1 (p < 0.05). On the other hand, the administration of TNF led to the downregulation of IL8 (p < 0.01), followed by an upregulation on day 2. IL8 gene expression decreased in the scratched condition after day 1 as the natural healing process took place and was lower than in the treated condition on day 8 (p < 0.05). Both untreated and treated conditions showed a downregulation of TGFA 3 h after scratch when compared with the control condition (p < 0.01). Administration of rTNF showed significant downregulation of TGFA after 24 h when compared with the control (p < 0.01) and treated conditions (p < 0.05). CONCLUSION: This study suggests that a leukocyte-depleted PRP-based skin equivalent can be a useful model for the in vitro study of chronic skin wounds related to poor skin perfusion.

Drug safety in thalassemia: lessons from the present and directions for the future.

Introduction: Beta-thalassemia is an autosomal recessive hereditary anemia characterized by reduced or absent ß-globin chain synthesis, affecting about 60,000 people peryear. Management for ß-thalassemia major includes regular blood transfusions followed by iron chelating therapy and drug targeting ineffective erythropoiesis.Areas covered: The safety of licensed drugs for the management of ß-thalassemia is reviewed, using evidence from clinical trials and observational research. Such drugs include the iron chelators and the erythrocyte maturation agent luspatercept. The safety of emerging treatment, such as hydroxyurea and thalidomide is also reviewed.Expert opinion: Beta-thalassemia is arare disease, and is not surprising that there are limited studies investigating the safety of drugs used in this disease. Indeed, although observational studies are the main source of drug safety information in areal-world setting, only eleven studies were identified for iron-chelators and none of these estimated the risk of agiven safety outcome. Future work should aim to better leverage existing sources of real-world datato investigate drug safety in thalassemia.

Overview of microRNAs as liquid biopsy biomarkers for colorectal cancer sub-type profiling and chemoresistance.

Colorectal cancer (CRC) is the third most common cancer worldwide. It has also been demonstrated that over the last ten years the incidence of CRC among younger people below the age of 50 is also increasing. Screening for colorectal cancer is of utmost importance; the rationale behind screening is to target the malignancy and reduce the incidence and mortality of the disease. Diagnostic methods to screen for incidence or relapse are therefore a requisite to detect cancer as early as possible. Scientific findings demonstrate that many deaths are due to lack of screening and therefore early identification will lead to greater survivability. In colorectal cancer, diagnostic tests include liquid biopsy biomarkers. Since the discovery of microRNAs (miRNAs), many studies have demonstrated the relationship between miRNAs and the various sub-types of CRC. Several miRNAs have been identified after analysing serum or plasma samples in patients, and such miRNAs were found to be significantly dysregulated. Such findings place the possibility of miRNAs to be at the epicentre of novel diagnostic techniques for CRC identification and sub-type stratification, including other characteristics associated with CRC development such as patient prognosis. The following review serves to underline the latest findings for miRNAs with such potential for routine diagnostic employment in CRC diagnostics and treatments.

Possible Role of Circulating Bone Marrow Mesenchymal Progenitors in Modulating Inflammation and Promoting Wound Repair.

Circulating bone marrow mesenchymal progenitors (BMMPs) are known to be potent antigen-presenting cells that migrate to damaged tissue to secrete cytokines and growth factors. An altered or dysregulated inflammatory cascade leads to a poor healing outcome. A skin model developed in our previous study was used to observe the immuno-modulatory properties of circulating BMMP cells in inflammatory chronic wounds in a scenario of low skin perfusion. BMMPs were analysed exclusively and in conjunction with recombinant tumour necrosis factor alpha (TNFα) and recombinant hepatocyte growth factor (HGF) supplementation. We analysed the expression levels of interleukin-8 (IL-8) and ecto-5'-nucleotidase (CD73), together with protein levels for IL-8, stem cell factor (SCF), and fibroblast growth factor 1 (FGF-1). The successfully isolated BMMPs were positive for both hemopoietic and mesenchymal markers and showed the ability to differentiate into adipocytes, chondrocytes, and osteocytes. Significant differences were found in IL-8 and CD73 expressions and IL-8 and SCF concentrations, for all conditions studied over the three time points taken into consideration. Our data suggests that BMMPs may modulate the inflammatory response by regulating IL-8 and CD73 and influencing IL-8 and SCF protein secretions. In conclusion, we suggest that BMMPs play a role in wound repair and that their induced application might be suitable for scenarios with a low skin perfusion.

Colour and chemical stability of bismuth oxide in dental materials with solutions used in routine clinical practice.

Bismuth(III) oxide is included as a radio-opacifier in dental materials, including hydraulic silicate cements, the material of choice for several endodontic procedures. It has been implicated in tooth discoloration after contact with endodontic irrigants, in particular NaOCl solution, To date, there has been no work on the chemistry: all reports have been of clinical findings only. The purpose now was to report the reactions leading to colour change from Bi2O3 in contact with solutions used in routine endodontic practice. Ten-gram portions of Bi2O3 were immersed in either water, NaOH, NaCl, NaOCl or HCl solution, either in the dark or exposed to visible light, and samples retrieved at 1, 4, 12 and 24 weeks. After washing, these were exposed to either added CO2 or not, for 1 week while drying, and under the same dark or light conditions. Changes in appearance were monitored by photography and colour measurement, and chemically by X-ray diffraction and Fourier-transform infrared spectroscopy. 24-week material was studied using electron paramagnetic resonance and Raman spectroscopy; NaOCl-treated material was also examined by scanning electron microscopy. With water, NaCl and NaOH, bismuth subcarbonate was formed. With or without added carbon dioxide, discoloration occurred from pale yellow to light brown when exposed to light, and to a lesser extent in the dark, intensifying with time. In contrast, exposure to NaOCl rapidly formed a dark brown-black sodium bismuthate. With HCl, white BiOCl was formed. Bi2O3 is not at all inert in this context as is commonly believed, denying its principle of use. Previously unreported solution-mediated reaction occurs readily even in water and NaCl solution, forming new compounds that discolour. In contact with NaOCl sodium bismuthate is formed; severe darkening occurs rapidly. The reactivity is such that Bi2O3 is not indicated for dental materials and should be withdrawn from use.

Overview of current microRNA biomarker signatures as potential diagnostic tools for leukaemic conditions.

Haematological malignancies encompass all variations of leukaemia at both the chronic and acute level, together with the specific cell type induced into tumourigenesis. Current diagnostic protocols for leukaemic conditions rely heavily on cytomorphology and other histological examinations from bone marrow aspirates, with the latter being a highly invasive surgical procedure for the patient. The discovery of microRNAs as one of the key gene regulatory networks in the past two decades has enabled researchers to investigate the possibility of exploiting the identification of dysregulated expression profiles for specific microRNAs present in the leukaemic patient's bloodstream as novel liquid biopsy diagnostic tools. This review article serves to consolidate recent global research efforts aiming to achieve such scopes.