Integrated miRNA-mRNA Analysis Reveals Critical miRNAs and Targets in Diet-Induced Obesity-Related Glomerulopathy.

This study aimed to investigate obesity-related glomerulopathy (ORG) at cellular, structural, and transcriptomic levels. Thirty Wistar rats were randomized into two groups: 15 rats were fed with a standard diet (SD-rats), and 15 rats were fed with a high-fat diet (HFD-rats). After 10 weeks, the weight, kidney function, histological features, and transcriptomic changes were assessed. HFD-rats gained significantly more weight (55.8% vs. 29.2%; p < 0.001) and albuminuria (10,384.04 ng/mL vs. 5845.45 ng/mL; p < 0.001) compared to SD-rats. HFD-rats exhibited early stages of ORG, with predominant mesangial matrix increase and podocyte hypertrophy (PH). These lesions correlated with differentially expressed (DE) genes and miRNAs. Functional analysis showed that miR-205, which was DE in both the kidneys and urine of HFD-rats, negatively regulated the PTEN gene, promoting lipid endocytosis in podocytes. The downregulation of PTEN was proved through a higher PTEN/nephrin ratio in the SD-rats and the presence of lipid vacuoles in HFD-podocytes. This study has found a specific targetome of miRNAs and gene expression in early stages of ORG. Also, it emphasizes the potential value of miR-205 as a urinary biomarker for detecting podocyte injury in ORG, offering a tool for early diagnosis, and opening new avenues for future therapeutic research of obesity-related glomerulopathy.

[Prevalence of physical inactivity and risk of sarcopenia in primary care. Cross-sectional study]. / Prevalencia de inactividad física y riesgo de sarcopenia en atención primaria. Estudio transversal.

OBJECTIVES: Assess the prevalence of physical inactivity and risk of sarcopenia in primary care patients and their companions. DESIGN: Cross-sectional study. We carried out an anonymous survey of primary care users (patients and companions) in primary care consultations and stands coinciding with a community health activity for World Physical Activity Day. SITE: Five primary care centers (CAPs) of the South Metropolitan health region: in Cornellà de Llobregat (CAP Jaume Soler), in l'Hospitalet de Llobregat (CAP Florida Nord, CAP Florida Sud and CAP Bellvitge) and in Viladecans (CAP Maria Bernades) between 27 March to April 6, 2023 (coinciding with World Physical Activity Day). PARTICIPANTS: Primary care population consists of patients and their companions over 18 years of age. INTERVENTIONS: The health workers administered questionnaires to users and companions. MAIN MEASUREMENTS: We evaluated physical inactivity with the BPAAT questionnaire, risk of sarcopenia with SARC-F screening test, sex and age range. We performed an univariate descriptive analysis to report prevalence. RESULTS: Nine hundred ninety-eight participants were surveyed. Physical inactivity was present in 38.9% of the participants. Among those over 50 years (665 participants), 15.4% were at risk of sarcopenia (9.58% men, 19.2% women). CONCLUSIONS: The prevalence of physical inactivity and risk of sarcopenia (in individuals over 50 years old) in the studied population is high. Women have greater physical inactivity and a greater risk of sarcopenia than men.

The relationship between nanoscale genome organization and gene expression in mouse embryonic stem cells during pluripotency transition.

During early development, gene expression is tightly regulated. However, how genome organization controls gene expression during the transition from naïve embryonic stem cells to epiblast stem cells is still poorly understood. Using single-molecule microscopy approaches to reach nanoscale resolution, we show that genome remodeling affects gene transcription during pluripotency transition. Specifically, after exit from the naïve pluripotency state, chromatin becomes less compacted, and the OCT4 transcription factor has lower mobility and is more bound to its cognate sites. In epiblast cells, the active transcription hallmark, H3K9ac, decreases within the Oct4 locus, correlating with reduced accessibility of OCT4 and, in turn, with reduced expression of Oct4 nascent RNAs. Despite the high variability in the distances between active pluripotency genes, distances between Nodal and Oct4 decrease during epiblast specification. In particular, highly expressed Oct4 alleles are closer to nuclear speckles during all stages of the pluripotency transition, while only a distinct group of highly expressed Nodal alleles are in close proximity to Oct4 when associated with a nuclear speckle in epiblast cells. Overall, our results provide new insights into the role of the spatiotemporal genome remodeling during mouse pluripotency transition and its correlation with the expression of key pluripotency genes.

Immortalized human myotonic dystrophy type 1 muscle cell lines to address patient heterogeneity.

Historically, cellular models have been used as a tool to study myotonic dystrophy type 1 (DM1) and the validation of therapies in said pathology. However, there is a need for in vitro models that represent the clinical heterogeneity observed in patients with DM1 that is lacking in classical models. In this study, we immortalized three DM1 muscle lines derived from patients with different DM1 subtypes and clinical backgrounds and characterized them at the genetic, epigenetic, and molecular levels. All three cell lines display DM1 hallmarks, such as the accumulation of RNA foci, MBNL1 sequestration, splicing alterations, and reduced fusion. In addition, alterations in early myogenic markers, myotube diameter and CTCF1 DNA methylation were also found in DM1 cells. Notably, the new lines show a high level of heterogeneity in both the size of the CTG expansion and the aforementioned molecular alterations. Importantly, these immortalized cells also responded to previously tested therapeutics. Altogether, our results show that these three human DM1 cellular models are suitable to study the pathophysiological heterogeneity of DM1 and to test future therapeutic options.

INF2 formin variants linked to human inherited kidney disease reprogram the transcriptome, causing mitotic chaos and cell death.

Mutations in the human INF2 gene cause autosomal dominant focal segmental glomerulosclerosis (FSGS)-a condition characterized by podocyte loss, scarring, and subsequent kidney degeneration. To understand INF2-linked pathogenicity, we examined the effect of pathogenic INF2 on renal epithelial cell lines and human primary podocytes. Our study revealed an increased incidence of mitotic cells with surplus microtubule-organizing centers fostering multipolar spindle assembly, leading to nuclear abnormalities, particularly multi-micronucleation. The levels of expression of exogenous pathogenic INF2 were similar to those of endogenous INF2. The aberrant nuclear phenotypes were observed regardless of the expression method used (retrovirus infection or plasmid transfection) or the promoter (LTR or CMV) used, and were absent with exogenous wild type INF2 expression. This indicates that the effect of pathogenic INF2 is not due to overexpression or experimental cell manipulation, but instead to the intrinsic properties of pathogenic INF2. Inactivation of the INF2 catalytic domain prevented aberrant nuclei formation. Pathogenic INF2 triggered the translocation of the transcriptional cofactor MRTF into the nucleus. RNA sequencing revealed a profound alteration in the transcriptome that could be primarily attributed to the sustained activation of the MRTF-SRF transcriptional complex. Cells eventually underwent mitotic catastrophe and death. Reducing MRTF-SRF activation mitigated multi-micronucleation, reducing the extent of cell death. Our results, if validated in animal models, could provide insights into the mechanism driving glomerular degeneration in INF2-linked FSGS and may suggest potential therapeutic strategies for impeding FSGS progression.

Taste of common prebiotic oligosaccharides: Impact of molecular structure.

Prebiotic oligosaccharides are naturally occurring non-digestible carbohydrates with demonstrated health benefits. They are also a chemically diverse class of nutrients, offering an opportunity to investigate the impact of molecular structure on oligosaccharide taste perception. Accordingly, a relevant question is whether these compounds are detected by the human gustatory system, and if so, whether they elicit sweet or 'starchy' taste. Here, in three psychophysical experiments, we investigated the taste perception of three commercially popular prebiotics [fructooligosaccharides (FOS), galactooligosaccharides (GOS), xylooligosaccharides (XOS)] in highly pure form. Each of these classes of prebiotics differs in the type of glycosyl residue, and position and type of bond between those residues. In experiments I and II, participants were asked to discriminate a total of 9 stimuli [FOS, GOS, XOS; degree of polymerization (DP) of 2, 3, 4] prepared at 75 mM in the presence and absence of lactisole, a sweet receptor antagonist. We found that all nine compounds were detectable (p<0.05). We also found that GOS and XOS DP 4 were discriminable even with lactisole, suggesting that their detection is not via the canonical sweet receptor. Accordingly, in experiment III, the taste of GOS and XOS DP 4 were directly compared with that of MOS (maltooligosaccharides) DP 4-6, which has been reported to elicit 'starchy' taste. We found that GOS and MOS were perceived similarly although narrowly discriminable, while XOS was easily discriminable from both GOS or MOS. The current findings suggest that molecular structure of oligosaccharides impacts their taste perception in human.

Modeling of Intracellular Taurine Levels Associated with Ovarian Cancer Reveals Activation of p53, ERK, mTOR and DNA-Damage-Sensing-Dependent Cell Protection.

Taurine, a non-proteogenic amino acid and commonly used nutritional supplement, can protect various tissues from degeneration associated with the action of the DNA-damaging chemotherapeutic agent cisplatin. Whether and how taurine protects human ovarian cancer (OC) cells from DNA damage caused by cisplatin is not well understood. We found that OC ascites-derived cells contained significantly more intracellular taurine than cell culture-modeled OC. In culture, elevation of intracellular taurine concentration to OC ascites-cell-associated levels suppressed proliferation of various OC cell lines and patient-derived organoids, reduced glycolysis, and induced cell protection from cisplatin. Taurine cell protection was associated with decreased DNA damage in response to cisplatin. A combination of RNA sequencing, reverse-phase protein arrays, live-cell microscopy, flow cytometry, and biochemical validation experiments provided evidence for taurine-mediated induction of mutant or wild-type p53 binding to DNA, activation of p53 effectors involved in negative regulation of the cell cycle (p21), and glycolysis (TIGAR). Paradoxically, taurine's suppression of cell proliferation was associated with activation of pro-mitogenic signal transduction including ERK, mTOR, and increased mRNA expression of major DNA damage-sensing molecules such as DNAPK, ATM and ATR. While inhibition of ERK or p53 did not interfere with taurine's ability to protect cells from cisplatin, suppression of mTOR with Torin2, a clinically relevant inhibitor that also targets DNAPK and ATM/ATR, broke taurine's cell protection. Our studies implicate that elevation of intracellular taurine could suppress cell growth and metabolism, and activate cell protective mechanisms involving mTOR and DNA damage-sensing signal transducti.

Multi-toric optical element to compensate ocular astigmatism with increased tolerance under rotation.

A new, to the best of our knowledge, optical element designed to compensate regular astigmatism while exhibiting increased tolerance to rotational misalignment is introduced. The element incorporates an optical design based on concentric annular regions with slightly different cylindrical axis angular positions. To assess visual quality performance as a function of rotation, retinal image simulation and clinical assessments with an adaptive optics visual simulator were carried out. The results demonstrate the superior performance of the newly proposed element in the presence of rotational errors when compared to traditional solutions.

Measured and Estimated Glomerular Filtration Rate to Evaluate Rapid Progression and Changes over Time in Autosomal Polycystic Kidney Disease: Potential Impact on Therapeutic Decision-Making.

Autosomal polycystic kidney disease (ADPKD) is the most common genetic form of kidney failure, reflecting unmet needs in management. Prescription of the only approved treatment (tolvaptan) is limited to persons with rapidly progressing ADPKD. Rapid progression may be diagnosed by assessing glomerular filtration rate (GFR) decline, usually estimated (eGFR) from equations based on serum creatinine (eGFRcr) or cystatin-C (eGFRcys). We have assessed the concordance between eGFR decline and identification of rapid progression (rapid eGFR loss), and measured GFR (mGFR) declines (rapid mGFR loss) using iohexol clearance in 140 adults with ADPKD with ≥3 mGFR and eGFRcr assessments, of which 97 also had eGFRcys assessments. The agreement between mGFR and eGFR decline was poor: mean concordance correlation coefficients (CCCs) between the method declines were low (0.661, range 0.628 to 0.713), and Bland and Altman limits of agreement between eGFR and mGFR declines were wide. CCC was lower for eGFRcys. From a practical point of view, creatinine-based formulas failed to detect rapid mGFR loss (-3 mL/min/y or faster) in around 37% of the cases. Moreover, formulas falsely indicated around 40% of the cases with moderate or stable decline as rapid progressors. The reliability of formulas in detecting real mGFR decline was lower in the non-rapid-progressors group with respect to that in rapid-progressor patients. The performance of eGFRcys and eGFRcr-cys equations was even worse. In conclusion, eGFR decline may misrepresent mGFR decline in ADPKD in a significant percentage of patients, potentially misclassifying them as progressors or non-progressors and impacting decisions of initiation of tolvaptan therapy.

Unveiling the role of novel carbohydrate-binding modules in laminarin interaction of multimodular proteins from marine Bacteroidota during phytoplankton blooms.

Laminarin, a ß(1,3)-glucan, serves as a storage polysaccharide in marine microalgae such as diatoms. Its abundance, water solubility and simple structure make it an appealing substrate for marine bacteria. Consequently, many marine bacteria have evolved strategies to scavenge and decompose laminarin, employing carbohydrate-binding modules (CBMs) as crucial components. In this study, we characterized two previously unassigned domains as laminarin-binding CBMs in multimodular proteins from the marine bacterium Christiangramia forsetii KT0803T, thereby introducing the new laminarin-binding CBM families CBM102 and CBM103. We identified four CBM102s in a surface glycan-binding protein (SGBP) and a single CBM103 linked to a glycoside hydrolase module from family 16 (GH16_3). Our analysis revealed that both modular proteins have an elongated shape, with GH16_3 exhibiting greater flexibility than SGBP. This flexibility may aid in the recognition and/or degradation of laminarin, while the constraints in SGBP could facilitate the docking of laminarin onto the bacterial surface. Exploration of bacterial metagenome-assembled genomes (MAGs) from phytoplankton blooms in the North Sea showed that both laminarin-binding CBM families are widespread among marine Bacteroidota. The high protein abundance of CBM102- and CBM103-containing proteins during phytoplankton blooms further emphasizes their significance in marine laminarin utilization.

Alpha-glucans from bacterial necromass indicate an intra-population loop within the marine carbon cycle.

Phytoplankton blooms provoke bacterioplankton blooms, from which bacterial biomass (necromass) is released via increased zooplankton grazing and viral lysis. While bacterial consumption of algal biomass during blooms is well-studied, little is known about the concurrent recycling of these substantial amounts of bacterial necromass. We demonstrate that bacterial biomass, such as bacterial alpha-glucan storage polysaccharides, generated from the consumption of algal organic matter, is reused and thus itself a major bacterial carbon source in vitro and during a diatom-dominated bloom. We highlight conserved enzymes and binding proteins of dominant bloom-responder clades that are presumably involved in the recycling of bacterial alpha-glucan by members of the bacterial community. We furthermore demonstrate that the corresponding protein machineries can be specifically induced by extracted alpha-glucan-rich bacterial polysaccharide extracts. This recycling of bacterial necromass likely constitutes a large-scale intra-population energy conservation mechanism that keeps substantial amounts of carbon in a dedicated part of the microbial loop.

Clinician Prediction of Survival vs Calculated Prediction Scores in Patients Requiring Extracorporeal Membrane Oxygenation.

BACKGROUND: Determining appropriate extracorporeal membrane oxygenation (ECMO) candidacy ensures appropriate utilization of this costly resource. The current ECMO survival prediction scores do not consider clinician assessment of patient viability. This study compared clinician prediction of survival to hospital discharge versus prediction scores. OBJECTIVES: The aim of this study was to compare clinician prediction of patients' survival to hospital discharge versus prognostic prediction scores (Respiratory ECMO Survival Prediction [RESP] or Survival After Veno-Arterial ECMO [SAVE] score) to actual survival. METHODS: This was an observational descriptive study from January 2020 to November 2021 conducted with interviews of nurses, perfusionists, and physicians who were involved during the initiation of ECMO within the first 24 hours of cannulation. Data were retrieved from the medical record to determine prediction scores and survival outcomes at hospital discharge. Accuracy of clinician prediction of survival was compared to the RESP or SAVE prediction scores and actual survival to hospital discharge. RESULTS: Accurate prediction of survival to hospital discharge for veno-venous ECMO by nurses was 47%, 64% by perfusionists, 45% by physicians, and 45% by the RESP score. Accurate predictions of patients on veno-arterial ECMO were correct in 54% of nurses, 77% of physicians, and 14% by the SAVE score. Physicians were more accurate than the SAVE score, P = .021, and perfusionists were significantly more accurate than the RESP score, P = .044. There was no relationship between ECMO specialists' years of experience and accuracy of predications. CONCLUSION: Extracorporeal membrane oxygenation clinicians may have better predictions of survival to hospital discharge than the prediction scores. Further research is needed to develop accurate prediction tools to help determine ECMO eligibility.

Phthalates and substitute plasticizers: Main achievements from the European human biomonitoring initiative HBM4EU.

Phthalates and the substitute plasticizer DINCH belong to the first group of priority substances investigated by the European Human Biomonitoring Initiative (HBM4EU) to answer policy-relevant questions and safeguard an efficient science-to-policy transfer of results. Human internal exposure levels were assessed using two data sets from all European regions and Israel. The first collated existing human biomonitoring (HBM) data (2005-2019). The second consisted of new data generated in the harmonized "HBM4EU Aligned Studies" (2014-2021) on children and teenagers for the ten most relevant phthalates and DINCH, accompanied by a quality assurance/quality control (QA/QC) program for 17 urinary exposure biomarkers. Exposures differed between countries, European regions, age groups and educational levels. Toxicologically derived Human biomonitoring guidance values (HBM-GVs) were exceeded in up to 5% of the participants of the HBM4EU Aligned Studies. A mixture risk assessment (MRA) including five reprotoxic phthalates (DEHP, DnBP, DiBP, BBzP, DiNP) revealed that for about 17% of the children and teenagers, health risks cannot be excluded. Concern about male reproductive health emphasized the need to include other anti-androgenic substances for MRA. Contaminated food and the use of personal care products were identified as relevant exposure determinants paving the way for new regulatory measures. Time trend analyses verified the efficacy of regulations: especially for the highly regulated phthalates exposure dropped significantly, while levels of the substitutes DINCH and DEHTP increased. The HBM4EU e-waste study, however, suggests that workers involved in e-waste management may be exposed to higher levels of restricted phthalates. Exposure-effect association studies indicated the relevance of a range of endpoints. A set of HBM indicators was derived to facilitate and accelerate science-to-policy transfer. Result indicators allow different groups and regions to be easily compared. Impact indicators allow health risks to be directly interpreted. The presented results enable successful science-to-policy transfer and support timely and targeted policy measures.

Delayed subaponeurotic fluid collection (DSFC): systematic review and case report.

PURPOSE: DSFC (delayed subaponeurotic fluid collection) is a benign pathology associated with the first weeks of life and scarcely described in the literature. Normally characterized by a lack of trauma and/or cranial fracture, it is associated with a history of instrumental delivery and the use of fetal electrodes. Taking it in consideration in the differential diagnosis of neonatal scalp swelling becomes important. The objective of this work is to expand knowledge on this entity: history, clinical characteristics, diagnosis, and treatment. METHODS: This article describes a new clinical case and conducts a systematic review according to the PRISMA criteria. RESULTS: Sixty-seven cases are included, they are summarized in a table. CONCLUSIONS: DSFC appears generally 15-16 weeks after birth. The diagnosis is mainly clinical, based on a history of instrumental birth, labor dystocia, or trauma, and with compatible symptoms and evolution. It may be supported by complementary tests such as ultrasound and or CT of the skull in doubtful cases. The treatment of choice is only conservative, and all cases resolve spontaneously and completely after an average of 4 weeks.

Intensive Calcium Monitoring Following Parathyroidectomy: Prevention of Hungry Bone Syndrome in Children.

Cite this article as: García Díaz FJ, Martin LB, Gómez Gila AL, Navarro Moreno C. Intensive calcium monitoring following parathyroidectomy: Prevention of hungry bone syndrome in children. Turk Arch Pediatr. 2024;59(1):109-111.

Reshaping Smart Cities through NGSI-LD Enrichment.

The vast amount of information stemming from the deployment of the Internet of Things and open data portals is poised to provide significant benefits for both the private and public sectors, such as the development of value-added services or an increase in the efficiency of public services. This is further enhanced due to the potential of semantic information models such as NGSI-LD, which enable the enrichment and linkage of semantic data, strengthened by the contextual information present by definition. In this scenario, advanced data processing techniques need to be defined and developed for the processing of harmonised datasets and data streams. Our work is based on a structured approach that leverages the principles of linked-data modelling and semantics, as well as a data enrichment toolchain framework developed around NGSI-LD. Within this framework, we reveal the potential for enrichment and linkage techniques to reshape how data are exploited in smart cities, with a particular focus on citizen-centred initiatives. Moreover, we showcase the effectiveness of these data processing techniques through specific examples of entity transformations. The findings, which focus on improving data comprehension and bolstering smart city advancements, set the stage for the future exploration and refinement of the symbiosis between semantic data and smart city ecosystems.

The error of estimated GFR in predialysis care.

The error of estimated glomerular filtration rate (eGFR) and its consequences in predialysis are unknown. In this prospective multicentre study, 315 predialysis patients underwent measured GFR (mGFR) by the clearance of iohexol and eGFR by 52 formulas. Agreement between eGFR and mGFR was evaluated by concordance correlation coefficient (CCC), total deviation index (TDI) and coverage probability (CP). In a sub-analysis we assessed the impact of eGFR error on decision-making as (i) initiating dialysis, (ii) preparation for renal replacement therapy (RRT) and (iii) continuing clinical follow-up. For this sub-analysis, patients who started RRT due to clinical indications (uremia, fluid overload, etc.) were excluded. eGFR had scarce precision and accuracy in reflecting mGFR (average CCC 0.6, TDI 70% and cp 22%) both in creatinine- and cystatin-based formulas. Variations -larger than 10 ml/min- between mGFR and eGFR were frequent. The error of formulas would have suggested (a) premature preparation for RTT in 14% of stable patients evaluated by mGFR; (b) to continue clinical follow-up in 59% of subjects with indication for RTT preparation due to low GFRm and (c) to delay dialysis in all asymptomatic patients (n = 6) in whom RRT was indicated based on very low mGFR. The error of formulas in predialysis was frequent and large and may have consequences in clinical care.

The dynamic buffering of social support on depressive symptoms and cancer worries in patients seeking cancer genetic counseling.

PURPOSE: Social support is a crucial protective factor against psychological concerns in patients with cancer. However, there is limited knowledge regarding the differential impacts of social support on cancer worries and depressive symptoms in patients undergoing genetic counseling for hereditary cancer. The current study utilized a high-volume database from a multi-site cancer genetics clinic to assess the impact of perceived social support on depressive symptoms and cancer worries among patients of different age groups (young versus older patients) and diagnosis status (diagnosed survivors versus undiagnosed). METHODS: 6,666 patients completed brief assessments of depressive symptoms, cancer worries, social support, and demographic questionnaires as part of routine clinical care between October 2016 and October 2020. Logistics and moderated regression were used to analyze the relationships between social support, depressive symptoms, and cancer worries. RESULTS: Increased social support was associated with fewer depressive symptoms and fewer cancer worries across all patients. Social support mitigated depressive symptoms most significantly for young adult patients with and without cancer. Social support mitigated cancer worries most significantly for young adults with cancer and older adults without cancer. CONCLUSIONS: While results were mixed, general findings upheld original hypotheses. Social support buffered depressive symptoms and cancer worries differentially for patients of different ages and different disease status. IMPLICATIONS FOR CANCER SURVIVORS: Social support groups are beneficial for all patients and should be emphasized by cancer clinics. However, increasing patient-tailored and age-appropriate support networks will be crucial for managing depression and cancer worries for high-risk survivors: young adults with cancer.

A Connector for Integrating NGSI-LD Data into Open Data Portals.

Nowadays, there are plenty of data sources generating massive amounts of information that, combined with novel data analytics frameworks, are meant to support optimisation in many application domains. Nonetheless, there are still shortcomings in terms of data discoverability, accessibility and interoperability. Open Data portals have emerged as a shift towards openness and discoverability. However, they do not impose any condition to the data itself, just stipulate how datasets have to be described. Alternatively, the NGSI-LD standard pursues harmonisation in terms of data modelling and accessibility. This paper presents a solution that bridges these two domains (i.e., Open Data portals and NGSI-LD-based data) in order to keep benefiting from the structured description of datasets offered by Open Data portals, while ensuring the interoperability provided by the NGSI-LD standard. Our solution aggregates the data into coherent datasets and generate high-quality descriptions, ensuring comprehensiveness, interoperability and accessibility. The proposed solution has been validated through a real-world implementation that exposes IoT data in NGSI-LD format through the European Data Portal (EDP). Moreover, the results from the Metadata Quality Assessment that the EDP implements, show that the datasets' descriptions generated achieve excellent ranking in terms of the Findability, Accessibility, Interoperability and Reusability (FAIR) data principles.

Putative correlates of protection against shigellosis assessing immunomarkers across responses to S. sonnei investigational vaccine.

Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4ß7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.