Age-related immune cell dynamics influence outcomes after allogeneic haematopoietic cell transplantation.

An efficient immunological reconstitution construes the pillar for the success of allogeneic haematopoietic cell transplantation (HCT) in haematological disorders. Factors influencing post-transplant immune recovery have been largely investigated across multiple cohorts issuing heterogeneous results. Differences in outcomes in adult and paediatric populations suggest an age-related contribution to post-transplant immune reconstitution; however, it is unclear how recipient and donor age may affect the dynamics of single immune cells. Here, we retrospectively collected and analysed immunological data of 174 patients (58 children and 116 adults) consecutively transplanted for haematological disorders in our centre. We show that trajectories of specific immune cells were strictly dependent on recipient age and pretransplant virus exposure, with the strongest effect seen on T CD4+ and B-cell counterparts, while donor age and transplant platforms had a minimal impact. This mirrored different kinetics of immune reconstitution in adult and paediatric patients, with major divergences in immune cell composition in late post-transplant phases, featuring better survival, relapse-free survival and cumulative incidence of pathogen-specific infections in younger patients. Altogether, these findings underpin the importance of recipient age on post-transplant immune cell recovery and define the basic dynamics of the immune reconstitution in paediatric and adult populations as a benchmark for future studies.

Systemic complement activation influences outcomes after allogeneic hematopoietic cell transplantation: A prospective French multicenter trial.

Complement activation has shown a role in murine models of graft-versus-host disease (GVHD) and in endothelial complications after allogeneic hematopoietic cell transplantation (allo-HSCT). However, its impact on post-transplant outcomes has not been so far fully elucidated. Here, we conducted a prospective multicentric trial (NCT01520623) performing serial measurements of complement proteins, regulators, and CH50 activity for 12 weeks after allo-HSCT in 85 patients receiving a myeloablative conditioning (MAC) regimen for various hematological malignancies. Twenty-six out of 85 patients showed an "activated" complement profile through the classical/lectin pathway, defined as a post-transplant decline of C3/C4 and CH50 activity. Time-dependent Cox regression models demonstrated that complement activation within the first weeks after allo-HSCT was associated with increased non-relapse mortality (hazard ratio [HR]: 3.69, 95% confident interval [CI]: 1.55-8.78, p = .003) and poorer overall survival (HR: 2.72, 95% CI: 1.37-5.39, p = .004) due to increased incidence of grade II-IV acute GVHD and in particular gastrointestinal (GI) GVHD (HR: 36.8, 95% CI: 12.4-109.1, p < .001), higher incidences of thrombotic microangiopathy (HR: 8.58, 95% CI: 2.16-34.08, p = .0022), capillary leak syndrome (HR: 7.36, 95% CI: 2.51-21.66, p = .00028), post-engraftment bacterial infections (HR: 2.37, 95% CI: 1.22-4.63, p = .0108), and EBV reactivation (HR: 3.33, 95% CI: 1.31-8.45, p = .0112). Through specific immune staining, we showed the correlation of deposition of C1q, C3d, C4d, and of C5b9 components on endothelial cells in GI GVHD lesions with the histological grade of GVHD. Altogether these findings define the epidemiology and the clinical impact of complement classical/lectin pathway activation after MAC regimens and provide a rational for the use of complement inhibitory therapeutics in a post-allo-HSCT setting.

[Improvement of the cognitive-behavioral pathway by setting up a multidisciplinary city-hospital staff]. / Amélioration du parcours cognitivo-comportemental par la mise en place d'un staff pluridisciplinaire ville-hôpital.

In order to improve the cognitive-behavioral pathway, and based on a well-established history of city-hospital collaboration, a monthly staff meeting bringing together hospital and out-of-hospital professionals and a users' association makes it possible to analyze and respond in a coordinated and graduated manner to complex situations. After nine months of operation, the story of three complex situations illustrates the benefits and limits of such a system.

Wharton's jelly-derived stromal cells and their cell therapy applications in allogeneic haematopoietic stem cell transplantation.

For decades, mesenchymal stromal cells (MSCs) have been of great interest in the fields of regenerative medicine, tissue engineering and immunomodulation. Their tremendous potential makes it desirable to cryopreserve and bank MSCs to increase their accessibility and availability. Postnatally derived MSCs seem to be of particular interest because they are harvested after delivery without ethical controversy, they have the capacity to expand at a higher rate than adult-derived MSCs, in which expansion decreases with ageing, and they have demonstrated immunological and haematological supportive properties similar to those of adult-derived MSCs. In this review, we focus on MSCs obtained from Wharton's jelly (the mucous connective tissue of the umbilical cord between the amniotic epithelium and the umbilical vessels). Wharton's jelly MSCs (WJ-MSCs) are a good candidate for cellular therapy in haematology, with accumulating data supporting their potential to sustain haematopoietic stem cell engraftment and to modulate alloreactivity such as Graft Versus Host Disease (GVHD). We first present an overview of their in-vitro properties and the results of preclinical murine models confirming the suitability of WJ-MSCs for cellular therapy in haematology. Next, we focus on clinical trials and discuss tolerance, efficacy and infusion protocols reported in haematology for GVHD and engraftment.

Diabetes and severe COVID-19 infection: Connecting the dots.

Diabetes is a significant risk factor for coronavirus disease 2019 (COVID-19) severity, poor prognosis, and mortality. Uncontrolled hyperglycaemia is associated with impaired innate and adaptive immunity predisposing to severe infection. In addition, there are other mechanisms linked to diabetes such as the upregulation of angiotensin-converting enzyme-2 receptor that might aid in viral entry and spread. The chronic low-grade inflammation and endothelial dysfunction might provide the backdrop to the development of cytokine storm and thromboembolic complications. Understanding the pathophysiology behind severe COVID-19 in diabetes will help to optimise management.

Killing from the inside: Intracellular role of T3SS in the fate of Pseudomonas aeruginosa within macrophages revealed by mgtC and oprF mutants.

While considered solely an extracellular pathogen, increasing evidence indicates that Pseudomonas aeruginosa encounters intracellular environment in diverse mammalian cell types, including macrophages. In the present study, we have deciphered the intramacrophage fate of wild-type P. aeruginosa PAO1 strain by live and electron microscopy. P. aeruginosa first resided in phagosomal vacuoles and subsequently could be detected in the cytoplasm, indicating phagosomal escape of the pathogen, a finding also supported by vacuolar rupture assay. The intracellular bacteria could eventually induce cell lysis, both in a macrophage cell line and primary human macrophages. Two bacterial factors, MgtC and OprF, recently identified to be important for survival of P. aeruginosa in macrophages, were found to be involved in bacterial escape from the phagosome as well as in cell lysis caused by intracellular bacteria. Strikingly, type III secretion system (T3SS) genes of P. aeruginosa were down-regulated within macrophages in both mgtC and oprF mutants. Concordantly, cyclic di-GMP (c-di-GMP) level was increased in both mutants, providing a clue for negative regulation of T3SS inside macrophages. Consistent with the phenotypes and gene expression pattern of mgtC and oprF mutants, a T3SS mutant (ΔpscN) exhibited defect in phagosomal escape and macrophage lysis driven by internalized bacteria. Importantly, these effects appeared to be largely dependent on the ExoS effector, in contrast with the known T3SS-dependent, but ExoS independent, cytotoxicity caused by extracellular P. aeruginosa towards macrophages. Moreover, this macrophage damage caused by intracellular P. aeruginosa was found to be dependent on GTPase Activating Protein (GAP) domain of ExoS. Hence, our work highlights T3SS and ExoS, whose expression is modulated by MgtC and OprF, as key players in the intramacrophage life of P. aeruginosa which allow internalized bacteria to lyse macrophages.

PtpA, a secreted tyrosine phosphatase from Staphylococcus aureus, contributes to virulence and interacts with coronin-1A during infection.

Secretion of bacterial signaling proteins and adaptation to the host, especially during infection, are processes that are often linked in pathogenic bacteria. The human pathogen Staphylococcus aureus is equipped with a large arsenal of immune-modulating factors, allowing it to either subvert the host immune response or to create permissive niches for its survival. Recently, we showed that one of the low-molecular-weight protein tyrosine phosphatases produced by S. aureus, PtpA, is secreted during growth. Here, we report that deletion of ptpA in S. aureus affects intramacrophage survival and infectivity. We also observed that PtpA is secreted during macrophage infection. Immunoprecipitation assays identified several host proteins as putative intracellular binding partners for PtpA, including coronin-1A, a cytoskeleton-associated protein that is implicated in a variety of cellular processes. Of note, we demonstrated that coronin-1A is phosphorylated on tyrosine residues upon S. aureus infection and that its phosphorylation profile is linked to PtpA expression. Our results confirm that PtpA has a critical role during infection as a bacterial effector protein that counteracts host defenses.

Population-specific dynamics and selection patterns of transposable element insertions in European natural populations.

Transposable elements (TEs) are ubiquitous sequences in genomes of virtually all species. While TEs have been investigated for several decades, only recently we have the opportunity to study their genome-wide population dynamics. Most of the studies so far have been restricted either to the analysis of the insertions annotated in the reference genome or to the analysis of a limited number of populations. Taking advantage of the European Drosophila population genomics consortium (DrosEU) sequencing data set, we have identified and measured the dynamics of TEs in a large sample of European Drosophila melanogaster natural populations. We showed that the mobilome landscape is population-specific and highly diverse depending on the TE family. In contrast with previous studies based on SNP variants, no geographical structure was observed for TE abundance or TE divergence in European populations. We further identified de novo individual insertions using two available programs and, as expected, most of the insertions were present at low frequencies. Nevertheless, we identified a subset of TEs present at high frequencies and located in genomic regions with a high recombination rate. These TEs are candidates for being the target of positive selection, although neutral processes should be discarded before reaching any conclusion on the type of selection acting on them. Finally, parallel patterns of association between the frequency of TE insertions and several geographical and temporal variables were found between European and North American populations, suggesting that TEs can be potentially implicated in the adaptation of populations across continents.

A narrative synthesis of research evidence for tinnitus-related complaints as reported by patients and their significant others.

BACKGROUND: There are a large number of assessment tools for tinnitus, with little consensus on what it is important to measure and no preference for a minimum reporting standard. The item content of tinnitus assessment tools should seek to capture relevant impacts of tinnitus on everyday life, but no-one has yet synthesised information about the range of tinnitus complaints. This review is thus the first comprehensive and authoritative collection and synthesis of what adults with tinnitus and their significant others report as problems in their everyday lives caused by tinnitus. METHODS: Electronic searches were conducted in PubMed, Embase, CINAHL, as well as grey literature sources to identify publications from January 1980 to June 2015 in which participants were enrolled because tinnitus was their primary complaint. A manual search of seven relevant journals updated the search to December 2017. Of the 3699 titles identified overall, 84 records (reporting 86 studies) met our inclusion criteria and were taken through to data collection. Coders collated generic and tinnitus-specific complaints reported by people with tinnitus. All relevant data items were then analyzed using an iterative approach to narrative synthesis to form domain groupings representing complaints of tinnitus, which were compared patients and significant others. RESULTS: From the 86 studies analyzed using data collected from 16,381 patients, 42 discrete complaints were identified spanning physical and psychological health, quality of life and negative attributes of the tinnitus sound. This diversity was not captured by any individual study alone. There was good convergence between complaints collected using open- and closed-format questions, with the exception of general moods and perceptual attributes of tinnitus (location, loudness, pitch and unpleasantness); reported only using closed questions. Just two studies addressed data from the perspective of significant others (n = 79), but there was substantial correspondence with the patient framework, especially regarding relationships and social life. CONCLUSIONS: Our findings contribute fundamental new knowledge and a unique resource that enables investigators to appreciate the broad impacts of tinnitus on an individual. Our findings can also be used to guide questions during diagnostic assessment, to evaluate existing tinnitus-specific HR-QoL questionnaires and develop new ones, where necessary. TRIAL REGISTRATION: PROSPERO registration number: CRD42015020629 . Protocol published in BMJ Open. 2016;6e009171.

A Macrophage Subversion Factor Is Shared by Intracellular and Extracellular Pathogens.

Pathogenic bacteria have developed strategies to adapt to host environment and resist host immune response. Several intracellular bacterial pathogens, including Salmonella enterica and Mycobacterium tuberculosis, share the horizontally-acquired MgtC virulence factor that is important for multiplication inside macrophages. MgtC is also found in pathogenic Pseudomonas species. Here we investigate for the first time the role of MgtC in the virulence of an extracellular pathogen, Pseudomonas aeruginosa. A P. aeruginosa mgtC mutant is attenuated in the systemic infection model of zebrafish embryos, and strikingly, the attenuated phenotype is dependent on the presence of macrophages. In ex vivo experiments, the P. aeruginosa mgtC mutant is more sensitive to macrophage killing than the wild-type strain. However, wild-type and mutant strains behave similarly toward macrophage killing when macrophages are treated with an inhibitor of the vacuolar proton ATPase. Importantly, P. aeruginosa mgtC gene expression is strongly induced within macrophages and phagosome acidification contributes to an optimal expression of the gene. Thus, our results support the implication of a macrophage intracellular stage during P. aeruginosa acute infection and suggest that Pseudomonas MgtC requires phagosome acidification to play its intracellular role. Moreover, we demonstrate that P. aeruginosa MgtC is required for optimal growth in Mg2+ deprived medium, a property shared by MgtC factors from intracellular pathogens and, under Mg2+ limitation, P. aeruginosa MgtC prevents biofilm formation. We propose that MgtC shares a similar function in intracellular and extracellular pathogens, which contributes to macrophage resistance and fine-tune adaptation to host immune response in relation to the different bacterial lifestyles. In addition, the phenotypes observed with the mgtC mutant in infection models can be mimicked in wild-type P. aeruginosa strain by producing a MgtC antagonistic peptide, thus highlighting MgtC as a promising new target for anti-virulence strategies.

MgtC as a Host-Induced Factor and Vaccine Candidate against Mycobacterium abscessus Infection.

Mycobacterium abscessus is an emerging pathogenic mycobacterium involved in pulmonary and mucocutaneous infections, presenting a serious threat for patients with cystic fibrosis (CF). The lack of an efficient treatment regimen and the emergence of multidrug resistance in clinical isolates require the development of new therapeutic strategies against this pathogen. Reverse genetics has revealed genes that are present in M. abscessus but absent from saprophytic mycobacteria and that are potentially involved in pathogenicity. Among them, MAB_3593 encodes MgtC, a known virulence factor involved in intramacrophage survival and adaptation to Mg(2+) deprivation in several major bacterial pathogens. Here, we demonstrated a strong induction of M. abscessus MgtC at both the transcriptional and translational levels when bacteria reside inside macrophages or upon Mg(2+) deprivation. Moreover, we showed that M. abscessus MgtC was recognized by sera from M. abscessus-infected CF patients. The intramacrophage growth (J774 or THP1 cells) of a M. abscessus knockout mgtC mutant was, however, not significantly impeded. Importantly, our results indicated that inhibition of MgtC in vivo through immunization with M. abscessus mgtC DNA, formulated with a tetrafunctional amphiphilic block copolymer, exerted a protective effect against an aerosolized M. abscessus challenge in CF (ΔF508 FVB) mice. The formulated DNA immunization was likely associated with the production of specific MgtC antibodies, which may stimulate a protective effect by counteracting MgtC activity during M. abscessus infection. These results emphasize the importance of M. abscessus MgtC in vivo and provide a basis for the development of novel therapeutic tools against pulmonary M. abscessus infections in CF patients.

46,XX disorder of sex development associated with skin abnormalities due to homozygous R-Spondin 1 loss of function mutation.

A child, who was reared as male, presented in his early childhood to the endocrine clinic with penoscrotal hypospadias which was noticed at birth. On examination, he had both gonads in the scrotal sacs with complete scrotal fusion, rugosities and chordee with a single opening. He had increased palmoplantar skin desquamation. As an initial part of the workup, karyotyping was done, which was 46,XX. To rule out the most common cause of 46,XX disorder of sex development (DSD) in phenotypical males (SRY - Sex Determining Region Y gene - translocation), fluorescent in situ hybridisation for SRY was done, which was negative. Whole exome sequencing revealed a homozygous loss of function mutation in the R-Spondin1 gene. Here we report a rare case of 46,XX DSD with loss of function mutation in the R-Spondin1 gene associated with skin abnormalities.

Orforglipron, a novel non-peptide oral daily glucagon-like peptide-1 receptor agonist as an anti-obesity medicine: A systematic review and meta-analysis.

Background: Orforglipron is a novel once-daily oral non-peptide glucagon-like peptide-1 receptor agonist with several recently published randomized controlled trials (RCTs) evaluating its role in diabetes and obesity. No meta-analysis has analyzed the efficacy and safety of orforglipron; this meta-analysis aimed to address this knowledge gap. Methods: A systematic search was conducted in electronic databases to identify RCTs that included individuals with obesity who were administered orforglipron and compared to either a placebo or an active comparator. The primary outcome of interest was the percent change in body weight. Results: From 12 initially screened articles, data from three RCTs involving 774 people were analyzed with a follow-up duration of up to 36 weeks. Compared to placebo, patients receiving orforglipron 12 mg/day (mean difference (MD), MD -5.48%, 95% CI [-7.64, -3.33], p < 0.01), 24 mg/day (MD -8.51%, 95% confidence interval (CI) [-9.88, -7.14], p < 0.01), 36 mg/day (MD -8.84%, 95% CI [-11.68, -6.00], p < 0.01) and 45 mg/day (MD -8.24%, 95% CI [-12.84, -3.63], p < 0.01) had a significantly greater percent reduction in body weight. The percentage of patients being able to achieve >15% weight loss from baseline was significantly higher with orforglipron 24 mg/day [Odds ratio (OR) 21.90 (95% CI [4.06, 118.15], p = 0.0003), 36 mg/day (OR 17.43, 95% CI [3.18, 95.66], p = 0.001) and 45 mg/day (OR 23.17, 95% CI [4.37, 123.03], p = 0.0002). Total but not severe adverse events were significantly higher with all the doses of orforglipron compared to placebo, with the hazard ratios being higher with higher doses. Gastrointestinal side-effects were predominant side effects, being dose-dependent, with nausea, vomiting, constipation, and gastroesophageal reflux being the predominant ones. Conclusion: Orforglipron at 24-45 mg/day doses is an effective weight loss medication. The efficacy versus side effect profile suggests that 24-36 mg/day is the most optimal dose for orforglipron as an anti-obesity medicine.

Contribution of intramacrophage stages to Pseudomonas aeruginosa infection outcome in zebrafish embryos: insights from mgtC and oprF mutants.

Pseudomonas aeruginosa often colonizes immunocompromised patients, causing acute and chronic infections. This bacterium can reside transiently inside cultured macrophages, but the contribution of the intramacrophic stage during infection remains unclear. MgtC and OprF have been identified as important bacterial factors when P. aeruginosa resides inside cultured macrophages. In this study, we showed that P. aeruginosa mgtC and oprF mutants, particular the latter one, had attenuated virulence in both mouse and zebrafish animal models of acute infection. To further investigate P. aeruginosa pathogenesis in zebrafish at a stage different from acute infection, we monitored bacterial load and visualized fluorescent bacteria in live larvae up to 4 days after infection. Whereas the attenuated phenotype of the oprF mutant was associated with a rapid elimination of bacteria, the mgtC mutant was able to persist at low level, a feature also observed with the wild-type strain in surviving larvae. Interestingly, these persistent bacteria can be visualized in macrophages of zebrafish. In a short-time infection model using a macrophage cell line, electron microscopy revealed that internalized P. aeruginosa wild-type bacteria were either released after macrophage lysis or remained intracellularly, where they were localized in vacuoles or in the cytoplasm. The mgtC mutant could also be detected inside macrophages, but without causing cell damage, whereas the oprF mutant was almost completely eliminated after phagocytosis, or localized in phagolysosomes. Taken together, our results show that the main role of OprF for intramacrophage survival impacts both acute and persistent infection by this bacterium. On the other hand, MgtC plays a clear role in acute infection but is not essential for bacterial persistence, in relation with the finding that the mgtC mutant is not completely eliminated by macrophages.

Global Warming and Endocrinology: The Hyderabad Declaration of the South Asian Federation of Endocrine Societies.

Global warming and endocrine disorders are intertwined issues posing significant challenges. Greenhouse gases emanating from human activities drive global warming, leading to temperature rise and altered weather patterns. South Asia has experienced a noticeable temperature surge over the past century. The sizable population residing in the region heightens the susceptibility to the impact of global warming. In addition to affecting agriculture, water resources, and livelihood, environmental changes interfere with endocrine functioning. Resulting lifestyle changes increase the risk of metabolic and endocrine disorders. Individuals with diabetes face heightened vulnerability to extreme weather due to impaired thermoregulation. A high ambient temperature predisposes to heat-related illnesses, infertility, and nephropathy. Additionally, essential endocrine drugs and medical devices are susceptible to temperature fluctuations. The South Asian Federation of Endocrine Societies (SAFES) calls for collaboration among stakeholders to combat climate change and promote healthy living. Comprehensive approaches, including the establishment of sustainable food systems, promotion of physical activity, and raising awareness about environmental impacts, are imperative. SAFES recommends strategies such as prioritizing plant-based diets, reducing meat consumption, optimizing medical device usage, and enhancing accessibility to endocrine care. Raising awareness and educating caregivers and people living with diabetes on necessary precautions during extreme weather conditions are paramount. The heat sensitivity of insulin, blood glucose monitoring devices, and insulin pumps necessitates proper storage and consideration of environmental conditions for optimal efficacy. The inter-connectedness of global warming and endocrine disorders underscores the necessity of international collaboration guided by national endocrine societies. SAFES urges all stakeholders to actively implement sustainable practices to improve endocrine health in the face of climate change.

Highly immunosuppressive myeloid cells correlate with early relapse after allogeneic stem cell transplantation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for myeloid malignancies such as some acute myeloid leukemias (AML) and high-risk myelodysplastic syndromes (MDS). It aims to eradicate the malignant clone using immunocompetent donor cells (graft-versus-leukemia effect, GVL). Unfortunately, relapse is the primary cause of transplant failure mainly related on HLA loss or downregulation and upregulation of inhibitory ligands on blasts which result in donor immune effector dysfunctions. METHODS: Between 2018 and 2021, we conducted a monocentric prospective study including 61 consecutive patients transplanted for AML or high-risk MDS. We longitudinally investigated immune cells at days + 30, + 90 and + 180 post-transplant from bone marrow and peripheral blood. We assessed the dynamics between myeloid derived suppressor cells (MDSCs) and T-cells. RESULTS: Among the 61 patients, 45 did not relapse over the first 12 months while 16 relapsed during the first year post-transplant. Through months 1 to 6, comparison with healthy donors revealed an heterogenous increase in MDSC frequency. In all recipients, the predominant MDSC subset was granulocytic with no specific phenotypic relapse signature. However, in relapsed patients, in vitro and in vivo functional analyses revealed that MDSCs from peripheral blood were highly immunosuppressive from day + 30 onwards, with an activated NLRP3 inflammasome signature. Only circulating immunosuppressive MDSCs were statistically correlated to circulating double-positive Tim3+LAG3+ exhausted T cells. CONCLUSION: Our simple in vitro functional assay defining MDSC immunosuppressive properties might serve as an early biomarker of relapse and raise the question of new preventive treatments targeting MDSCs in the future. Trial registration NCT03357172.

Insights for integrated conservation from attitudes of people toward protected areas near Hwange National Park, Zimbabwe.

Increase in human settlements at the edge of protected areas (PAs) is perceived as a major threat to conservation of biodiversity. Although it is crucial to integrate the interests of surrounding communities into PA management, key drivers of changes in local populations and the effects of conservation on local livelihoods and perceptions remain poorly understood. We assessed population changes from 1990 to 2010 in 9 villages located between 2 PAs with different management policies (access to natural resources or not). We conducted semi-directive interviews at the household level (n =217) to document reasons for settlement in the area and villager's attitudes toward the PAs. We examined drivers of these attitudes relative to household typology, feelings about conservation, and concerns for the future with mixed linear models. Population increased by 61% from 2000 to 2010, a period of political and economic crisis in Zimbabwe. Forty-seven percent of immigrants were attracted by the area; others had been resettled from other villages or were returning to family lands. Attitudes toward PAs were generally positive, but immigrants attracted by the area and who used resources within the PA with fewer restrictions expressed more negative attitudes toward PAs. Household location, losses due to wild animals, and restrictions on access to natural resources were the main drivers of this negative attitude. Profit-seeking migrants did not expect these constraints and were particularly concerned with local overpopulation and access to natural resources. To avoid socio-ecological traps near PAs (i.e., unforeseen reduced adaptive capacity) integrated conservation should address mismatches between management policy and local expectations. This requires accounting for endogenous processes, for example, local socio-ecological dynamics and values that shape the coexistence between humans and wildlife.

A study to evaluate the knowledge, vaccination status and acceptance of adult vaccinations against respiratory infections in patients with type 2 diabetes in South India.

Introduction: Respiratory infections like influenza and pneumococcus increase mortality, morbidity, hospitalisation risks and healthcare costs in people with type 2 diabetes which can be prevented by vaccinations. However, there is not much data regarding how many people with type 2 diabetes in India receive pneumococcal and influenza vaccinations. Methods: This is a cross-sectional study conducted between March 2022 to May 2022 at a tertiary care centre in South India. Patients were interviewed through face to face questionnaire regarding awareness, knowledge of influenza and pneumococcal infections, availability and need of vaccines, vaccination status and the possible reasons for not receiving vaccines. Results: A total of 388 patients were recruited in the study. Knowledge about influenza and pneumococcal infections were present only in 4.8% and 4.1% respectively. And 98.7% of patients had no awareness about the availability and need for vaccines. Only 0.5% and 0.7% of patients received influenza and pneumococcal vaccinations respectively. After counselling and spreading awareness, 76.2% of patients said that they would receive vaccination in the next visit. Also, 23.19% of the patients refused to take any vaccinations even after counselling. And 23.7% of patients feared complications after vaccinations. Conclusion: Pneumococcal and Influenza vaccination uptake rates are extremely low in people with type 2 diabetes in India. Urgent measures are required to increase the awareness in patients and healthcare workers about the availability, need for vaccinations and effectiveness of vaccines which would lead to improvement in vaccination rates.

Role of novel sodium glucose co-transporter-2 inhibitor enavogliflozin in type-2 diabetes: A systematic review and meta-analysis.

BACKGROUND: Enavogliflozin is a novel sodium glucose co-transporter-2 inhibitor (SGLT2i) developed in South Korea. This meta-analysis was done as no meta-analysis has analysed the efficacy and safety of enavogliflozin in type-2 diabetes (T2DM). METHODS: Electronic databases were systematically reviewed for randomized controlled trials having patients with T2DM receiving enavogliflozin in treatment-arm, and placebo/any other medicine in control-arm. Primary outcome was to evaluate changes in glycosylated haemoglobin (HbA1C). Secondary outcomes were to evaluate alterations in fasting glucose (FPG), 2-h post prandial glucose (2-h PPG), blood pressure (BP), weight, lipids, and adverse events. RESULTS: Data from 4 trials (684 patients) was analysed for clinical outcomes over 12-24 weeks clinical use. Compared to placebo, patients receiving enavogliflozin had significantly lower HbA1c [MD -0.76%(95% CI: 0.93 to -0.60); P < 0.00001; I2 = 97%], FPG [MD -2.12 mmol/l(95%CI: 2.47 to -1.77); P < 0.00001; I2 = 91%], body-weight [MD-1.37 kgs (95% CI: 1.73-1.00); P < 0.00001; I2 = 89%], systolic BP [MD-4.99 mm Hg (95%CI: 7.83 to -2.16); P = 0.0006; I2 = 47%], diastolic BP [MD-3.09 mm Hg(95%CI: 3.38 to -2.81); P < 0.00001; I2 = 0%]. Treatment emergent adverse-events [OR1.16(95%CI:0.64-2.09); P = 0.63; I2 = 0%], serious adverse events [OR1.81(95%CI:0.37-8.83); P = 0.46; I2 = 0%], urinary infections [OR1.37(95%CI:0.09-20.61); P = 0.82; I2 = 33%] and genital infections [OR 3.07(95%CI:0.31-29.88); P = 0.33; I2 = 0%] were comparable. Compared to dapagliflozin, patients receiving enavogliflozin had significantly lower HbA1c [MD-0.06%(95%CI: 0.07-0.05); P < 0.00001; I2 = 0%], FPG [MD-0.19 mmol/l(95%CI: 0.21 to -0.17); P < 0.00001; I2 = 0%], body-weight [MD-0.20 kgs(95%CI: 0.24 to -0.15); P < 0.00001; I2 = 0%], diastolic BP [MD -0.92 mm Hg (95%CI: 1.36 to -0.48); P < 0.0001; I2 = 91%] and significantly higher urine glucose creatinine ratio [MD 16.69 g/g (95%CI:16.11-17.26); P < 0.00001; I2 = 0%]. CONCLUSION: Enavogliflozin is a well tolerated and effective SGLT2i for T2DM and may be superior to dapagliflozin with regard to certain clinical aspects over 6 months clinical use.

Structure-based design, synthesis and biological evaluation of a NAD+ analogue targeting Pseudomonas aeruginosa NAD kinase.

Multidrug resistance is a major public health problem that requires the urgent development of new antibiotics and therefore the identification of novel bacterial targets. The activity of nicotinamide adenine dinucleotide kinase, NADK, is essential in all bacteria tested so far, including many human pathogens that display antibiotic resistance leading to the failure of current treatments. Inhibiting NADK is therefore a promising and innovative antibacterial strategy since there is currently no drug on the market targeting this enzyme. Through a fragment-based drug design approach, we have recently developed a NAD+ -competitive inhibitor of NADKs, which displayed in vivo activity against Staphylococcus aureus. Here, we show that this compound, a di-adenosine derivative, is inactive against the NADK enzyme from the Gram-negative bacteria Pseudomonas aeruginosa (PaNADK). This lack of activity can be explained by the crystal structure of PaNADK, which was determined in complex with NADP+ in this study. Structural analysis led us to design and synthesize a benzamide adenine dinucleoside analogue, active against PaNADK. This novel compound efficiently inhibited PaNADK enzymatic activity in vitro with a Ki of 4.6 µm. Moreover, this compound reduced P. aeruginosa infection in vivo in a zebrafish model.