Massive Bone Marrow Infiltration by Disseminated Alveolar Rhabdomyosarcoma Mimicking Acute Leukemia.

RMS is a malignant tumor of soft tissues affecting primarily children and adolescents. Around 6% to 23% RMS patients present bone marrow infiltration but leukemia-like involvement is very rare; in these patients cytomorphology on bone marrow smears can lead to misdiagnosis. Differential diagnosis with alveolar RMS should be kept in mind in every pediatric patient presenting with a marked bone marrow involvement in the absence of typical lymphoproliferative findings.

A Novel NUTM1-NSMCE2 Fusion Gene in a Pediatric Chest NUT Carcinoma.

Nuclear protein of the testis carcinoma is an exceedingly rare and poorly differentiated carcinoma characterized by BDR4::NUTM1 gene translocation. Typically, the tumor affects young adults, and no standardized recommendations for therapeutic management have been available since 2022; the clinical course remains mostly dismal. We report the successful multimodal treatment of a 13-year-old boy affected by a primary chest NUT-carcinoma with a novel NUTM1 rearrangement that remains in complete continuous remission at 30 months from diagnosis.

Real-world experience with filgotinib for rheumatoid arthritis in Germany : A retrospective chart review.

BACKGROUND: Real-world data for filgotinib, a Janus kinase (JAK)1 inhibitor, are limited in patients with rheumatoid arthritis (RA). OBJECTIVES: To explore real-world filgotinib use in patients with RA in Germany. MATERIALS AND METHODS: This retrospective chart review included patients aged ≥ 18 years with confirmed moderate to severe RA who initiated filgotinib before December 1, 2021, with ≥ 6 months of medical records available prior to filgotinib initiation or after initial diagnosis. Patient characteristics, prior treatments, reasons for initiating/discontinuing filgotinib, disease activity, dose adjustments and concomitant treatments were recorded. RESULTS: In total, 301 patients from 20 German rheumatology outpatient units were included. One-third were aged ≥ 65 years and almost half had ≥ 1 cardiovascular (CV) risk factor. Most patients initiated filgotinib as monotherapy (83.7%; 12.7% of whom with glucocorticoids) and at the 200 mg dose (84.7%); higher proportions of those initiating the 100 versus 200 mg dose were aged ≥ 65 years and had renal impairment or ≥ 1 CV risk factor. Oral administration (78.4%), fast onset of action (66.8%) and administration as monotherapy (65.4%) were the most common reasons for initiating filgotinib. At 12 months, 41 (18.4%) patients had discontinued filgotinib, most commonly due to lack of effectiveness. After 6­months of follow-up, 36.8% of patients had achieved Clinical Disease Activity Index (CDAI) remission and 45.6% had achieved CDAI low disease activity. CONCLUSIONS: In clinical practice in Germany, reasons for initiating filgotinib in patients with RA were related to dosing flexibility and general JAK inhibitor attributes. Filgotinib was used predominantly as monotherapy and was effective and generally well tolerated; however, longer-term data in larger, prospective cohorts are needed.

Pannonibacter anstelovis sp. nov. Isolated from Two Cases of Bloodstream Infections in Paediatric Patients.

This study describes two cases of bacteraemia sustained by a new putative Pannonibacter species isolated at the U.O.C. of Microbiology and Virology of the Policlinico of Bari (Bari, Italy) from the blood cultures of two patients admitted to the Paediatric Oncohaematology Unit. Pannonibacter spp. is an environmental Gram-negative bacterium not commonly associated with nosocomial infections. Species identification was performed using Sanger sequencing of the 16S rRNA gene and Whole-Genome Sequencing (WGS) for both strains. Genomic analyses for the two isolates, BLAST similarity search, and phylogeny for the 16S rDNA sequences lead to an assignment to the species Pannonibacter phragmitetus. However, by performing ANIb, ANIm, tetranucleotide correlation, and DNA-DNA digital hybridization, analyses of the two draft genomes showed that they were very different from those of the species P. phragmitetus. MALDI-TOF analysis, assessment of antimicrobial susceptibility by E-test method, and Analytical Profile Index (API) tests were also performed. This result highlights how environmental bacterial species can easily adapt to the human host and, especially in nosocomial environments, also gain pathogenic potential through antimicrobial resistance.

Dissipative coupling in a Bragg-grating-coupled single resonator with Fano resonance for anti-PT-symmetric gyroscopes.

Anti-parity-time-symmetric Hamiltonians show an enhanced sensitivity to external perturbations that can be used for high-performance angular velocity sensing. Dissipative coupling is a valuable way for realizing anti-PT-symmetric Hamiltonians with optical resonators and is usually obtained by means of auxiliary waveguides. Here, we model and experimentally show the dissipative coupling between two counterpropagating modes of a single resonator, by means of a Bragg-grating placed in the feeding bus. The proposed solution enables the possibility of accurately designing the dissipative coupling strength in integrated non-Hermitian gyroscopes, thus providing high flexibility in the design of the proposed sensor. Moreover, we theoretically and experimentally demonstrate that the dissipative coupling between two counterpropagating modes of the same resonant cavity can give rise to an asymmetric Fano resonance.

From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models.

BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent. METHODS: Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models. RESULTS: Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as "very high priority", that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient's tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors. CONCLUSIONS: PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.

Human mitochondrial uncoupling protein 3 functions as a metabolite transporter.

Since its discovery, a major debate about mitochondrial uncoupling protein 3 (UCP3) has been whether its metabolic actions result primarily from mitochondrial inner membrane proton transport, a process that decreases respiratory efficiency and ATP synthesis. However, UCP3 expression and activity are induced by conditions that would seem at odds with inefficient 'uncoupled' respiration, including fasting and exercise. Here, we demonstrate that the bacterially expressed human UCP3, reconstituted into liposomes, catalyses a strict exchange of aspartate, malate, sulphate and phosphate. The R282Q mutation abolishes the transport activity of the protein. Although the substrate specificity and inhibitor sensitivity of UCP3 display similarity with that of its close homolog UCP2, the two proteins significantly differ in their transport mode and kinetic constants.

In Vitro Effects of Low-energy Ultrasound Treatment on Healthy CD3/CD8+ Lymphocytes, Red blood cells, Acute Myeloid leukemia cells, and Jurkat cell line.

The study of the biological effects of low-energy ultrasound and its applications is a rapidly expanding research area. Low-energy ultrasound could be used as anti-tumoral therapy with or without the pharmacological combination even if the second situation has been scarcely investigated up to now. Very little information is available about the ultrasound effects on healthy red blood cells, CD3, and mainly CD8 subset lymphocytes which is the main subset cell having cytotoxic function towards cancer cells. In this study, we investigated in vitro the bioeffects of low energy ultrasound on red blood cells and PBMCs isolated from healthy donors as well as on two myeloid leukemia cell lines (OCI- AML-3 MOLM-13) and lymphoblastic Jurkat cell line. Using low-energy ultrasound (US), a study was conducted to determine how it affects CD3/CD8 lymphocytes and leukemia cells, as well as its potential role in treating blood cancers, by analyzing changes in mitochondrial membrane potential, phosphatidylserine asymmetry, morphological changes for myeloid AML cell lines, proliferation and cytotoxic activation of healthy lymphocytes, and apoptosis for RBCs after US exposure. Overall, we demonstrated that CD3/CD8 lymphocytes proliferation/activation and cytotoxic functions are fully preserved after ultrasound treatments, whereas leukemia cell lines undergo apoptosis and stop proliferating suggesting a potential method of treating blood cancer.

Natural Bioactive Compounds against Oxidative Stress: Dietary Polyphenols Strike Back.

Oxidative stress is a major cellular and metabolic burden that can really alter cell life and become the base for disease onset and development. Many widespread pathologies can develop from an unresolved oxidative stress situation; thus, addressing this state is paramount for human health. Our antioxidant enzymes sometimes are not just enough. Fortifying our defense and the antioxidant and anti-inflammatory system can make a difference in our health: if this is attainable with our dietary habits, it could be a dream come true. Polyphenols are a fantastic tool indeed in the fight against oxidative stress: they are easy to obtain, with little cost, no side effects, and have a multitude of metabolic actions. This perspective review would shed light on polyphenol's metabolic and molecular action regarding oxidative stress to help preserve our health.

High-Performance Pockels Effect Modulation and Switching in Silicon-Based GaP/Si, AlP/Si, ZnS/Si, AlN/3C-SiC, GaAs/Ge, ZnSe/GaAs, and ZnSe/Ge Superlattice-On-Insulator Integrated Circuits.

We propose new a Si-based waveguided Superlattice-on-Insulator (SLOI) platforms for high-performance electro-optical (EO) 2 × 2 and N × M switching and 1 × 1 modulation, including broad spectrum and resonant. We present a theoretical investigation based on the tight-binding Hamiltonian of the Pockels EO effect in the lattice-matched undoped (GaP)N/(Si2)M, (AlP)N/(Si2)M, (ZnS)N/(Si2)M, (AlN)N/(3C-SiC)M, (GaAs)N/(Ge2)M, (ZnSe)N/(GaAs)M, and (ZnSe)N/(Ge2)M wafer-scale short-period superlattices that are etched into waveguided networks of small-footprint Mach-Zehnder interferometers and micro-ring resonators to yield opto-electronic chips. The spectra of the Pockels r33 coefficient have been simulated as a function of the number of the atomic monolayers for "non-relaxed" heterointerfaces. The large obtained r33 values enable the SLOI circuit platforms to offer a very favorable combination of monolithic construction, cost-effective manufacturability, high modulation/switching speed, high information bandwidth, tiny footprint, low energy per bit, low switching voltage, near-IR-and-telecom wavelength coverage, and push-pull operation. By optimizing waveguide, clad, and electrode dimensions, we obtained very desirable values of the VπL performance metric, in the range of 0.062 to 0.275 V·cm, portending a bright future for a variety of applications, such as sensor networks or Internet of Things (IoT).

Non-Hermitian Sensing in Photonics and Electronics: A Review.

Recently, non-Hermitian Hamiltonians have gained a lot of interest, especially in optics and electronics. In particular, the existence of real eigenvalues of non-Hermitian systems has opened a wide set of possibilities, especially, but not only, for sensing applications, exploiting the physics of exceptional points. In particular, the square root dependence of the eigenvalue splitting on different design parameters, exhibited by 2 × 2 non-Hermitian Hamiltonian matrices at the exceptional point, paved the way to the integration of high-performance sensors. The square root dependence of the eigenfrequencies on the design parameters is the reason for a theoretically infinite sensitivity in the proximity of the exceptional point. Recently, higher-order exceptional points have demonstrated the possibility of achieving the nth root dependence of the eigenfrequency splitting on perturbations. However, the exceptional sensitivity to external parameters is, at the same time, the major drawback of non-Hermitian configurations, leading to the high influence of noise. In this review, the basic principles of PT-symmetric and anti-PT-symmetric Hamiltonians will be shown, both in photonics and in electronics. The influence of noise on non-Hermitian configurations will be investigated and the newest solutions to overcome these problems will be illustrated. Finally, an overview of the newest outstanding results in sensing applications of non-Hermitian photonics and electronics will be provided.

Covid-19 and absence of music therapy: Impact on mother-child dyad during invasive procedures in pediatric oncology.

During COVID-19 pandemic, Italian pediatric oncology departments were obliged to adopt restrictive measures to minimize the risk of in-hospital infections in frail patients and staff members. Access to the wards was significantly reduced and music therapy (MT) activities were suspended. The aim of this study was to compare the level of anxiety and sedation in pediatric patients undergoing invasive procedure before (T1), during(T2) and after(T3) the pandemic, with and without the presence of MT. From January to September 2020, all children aged 2-15 with oncological and hematological diseases undergoing to invasive procedure were enrolled. During T1 and T3 children received preoperative preparation with MT by a certified music-therapist. In T2 they received music or video by clinical staff. Preoperative anxiety scores were measured with the m- YPAS scale. Interviews with mothers were performed. The average consumption of drugs used was analyzed. Significant differences in preoperative anxiety levels between scores in T1, T2 (p.value = 0,0000014) and in T2, T3 (p.value = 0,0000031) were observed. No difference between T1-T3 (p.value = 0,96). Higher dosage of midazolam in T2 (1,14 mg 0,189) compared to T1 (0, 71 mg 0,399) and T2 (1,14 mg 0,189) were observed. Mothers also recorded higher scores on anxiety and stress without music therapy.

Role of centers with different patient volumes in the management of rhabdomyosarcoma. An analysis by the Italian Pediatric Soft Tissue Sarcoma Committee.

PROCEDURE: The survival of children with rhabdomyosarcoma (RMS) has gradually improved as a result of the adoption of multidisciplinary treatments. Dedicated skills and facilities are indispensable and more readily available at reference centers. In this study, we examined the role of centers' experience (based on the number of patients treated) in their management of patients with RMS. METHODS: We analyzed 342 patients with localized RMS enrolled in the European RMS 2005 protocol from October 2005 to December 2016 at 31 Italian centers that are part of the Soft Tissue Sarcoma Committee (STSC). We grouped the centers by the number of patients each one enrolled (Group 1: >40; Group 2: <40 and >10; and Group 3: <10), and compared a number of indicators to assess the appropriateness of patients' diagnostic workup and treatment and their survival. RESULTS: Overall, 74.6% of patients were treated at 10 centers, and only three of them classifiable as high-volume centers. Only minor differences emerged between the three patient groups in terms of diagnostic investigations and treatment modalities. Survival was similar in the three groups. Approximately, one in four children treated at the centers in Groups 2 and 3 traveled to another center for surgery or radiotherapy. CONCLUSION: Patients treated at STSC centers with different amounts of experience had similar results in terms of survival. This is attributable to all centers in the network adhering to protocol recommendations and receiving the STSC's support on diagnostics and multidisciplinary treatments for RMS.

Front-Line Window Therapy with Temozolomide and Irinotecan in Patients with Primary Disseminated Multifocal Ewing Sarcoma: Results of the ISG/AIEOP EW-2 Study.

PURPOSE: The main objective was to evaluate the activity and tolerability of TEMIRI as a front-line treatment in primary disseminated Ewing sarcoma (PDMES) using the RECIST 1.1 criteria. The secondary objectives included the assessment of toxicity and the performance status/symptom changes. METHODS: Between 2012 and 2018, patients with PDMES received two courses of temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every 3 weeks as an amendment to the Italian Sarcoma Group/Associazione Italiana EmatoIogia ed Oncologia Pediatrica (ISG/AIEOP) EW-2 protocol (EUDRACT#2009-012353-37, Vers. 1.02). RESULTS: Thirty-four patients were enrolled. The median age at diagnosis was 19 years (range 3-55). After TEMIRI, the RECIST response was as follows: a partial response in 20 (59%) patients, stable disease in 11 (32%), and disease progression in 3 (9%). The ECOG/Lansky score was improved in 25/34 (73.5%) cases, and a reduction or disappearance of pain was observed in 31/34 patients (91%). The incidence of grade 3-4 toxicity was 3%. The 3-year event-free survival (EFS) and overall survival (OS) were 21% (95% CI 6-35%) and 36% (95% CI: 18-54%), respectively. CONCLUSION: the smooth handling and encouraging activity demonstrated by up-front TEMIRI did not change the EFS in PDMES, so this result suggests the need for the further evaluation of the efficacy of TEMIRI in combination with conventional treatments in non-metastatic patients.

Cell surface Nucleolin represents a novel cellular target for neuroblastoma therapy.

BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Nucleolin (NCL) is a protein overexpressed and partially localized on the cell surface of tumor cells of adult cancers. Little is known about NCL and pediatric tumors and nothing is reported about cell surface NCL and NB. METHODS: NB cell lines, Schwannian stroma-poor NB tumors and bone marrow (BM)-infiltrating NB cells were evaluated for the expression of cell surface NCL by Flow Cytometry, Imaging Flow Cytometry and Immunohistochemistry analyses. The cytotoxic activity of doxorubicin (DXR)-loaded nanocarriers decorated with the NCL-recognizing F3 peptide (T-DXR) was evaluated in terms of inhibition of NB cell proliferation and induction of cell death in vitro, whereas metastatic and orthotopic animal models of NB were used to examine their in vivo anti-tumor potential. RESULTS: NB cell lines, NB tumor cells (including patient-derived and Patient-Derived Xenografts-PDX) and 70% of BM-infiltrating NB cells show cell surface NCL expression. NCL staining was evident on both tumor and endothelial tumor cells in NB xenografts. F3 peptide-targeted nanoparticles, co-localizing with cell surface NCL, strongly associates with NB cells showing selective tumor cell internalization. T-DXR result significantly more effective, in terms of inhibition of cell proliferation and reduction of cell viability in vitro, and in terms of delay of tumor growth in all NB animal model tested, when compared to both control mice and those treated with the untargeted formulation. CONCLUSIONS: Our findings demonstrate that NCL could represent an innovative therapeutic cellular target for NB.

A novel BRD4-LEUTX fusion in a pediatric sarcoma with epithelioid morphology and diffuse S100 expression.

Malignant epithelioid soft tissue tumors encompass a wide spectrum of lesions. Among them, Epithelioid Malignant Peripheral Nerve Sheath Tumors (MPNST) constitute a distinct subgroup, accounting for <5% of all MPNST. Epithelioid MPNST are infrequently associated with neurofibromatosis type 1, occasionally arise in a schwannoma and show diffuse S100 and CD34 expression, often combined with INI-1 loss. However, the molecular mechanisms underlying the tumorigenesis of epithelioid MPNST remain largely unknown. We describe a case of a 10-year-old girl with an epithelioid malignancy of the orbit. The tumor proved positive for S100, CD34 and SOX10, and, although INI-1 expression was maintained, the overall features suggested the possibility of an epithelioid MPNST, arising in an unusual location. NGS analysis revealed a novel in-frame BRD4-LEUTX fusion gene. LEUTX plays an important role in embryonal genome activation and its expression is mostly suppressed postnatally. We were able to detect increased levels of LEUTX transcript in the tumor, indicating that BRD4-LEUTX fusion leads to LEUTX re-activation. To our knowledge, this fusion has never been reported previously. Whether the current case represents an example of epithelioid MPNST or a distinct tumor entity remains to be determined.

A Unique Case of Bilateral Thalamic High-Grade Glioma in a Pediatric Patient with LI-Fraumeni Syndrome: Case Presentation and Review of the Literature.

Li-Fraumeni syndrome (LFS) is a rare high-penetrance and autosomal-dominant pathological condition caused by the germline mutation of the TP53 gene, predisposing to the development of tumors from pediatric age. We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/Pubmed and MeSH Database using the terms "Li-Fraumeni" AND "pediatric high-grade glioma (HGG)", identifying six cases of HGGs in pediatric patients with LFS. We added a further case with peculiar features such as no familiar history of LFS, association of embryonal rhabdomyosarcoma and bithalamic HGG, whose immunohistochemical profile was accurately defined by Next Generation Sequencing. Knowledge synthesis and case analysis grounded the discussion about challenges in the management of this pathology in pediatric age.

Compact resonant 2 × 2 crossbar switch using three coupled waveguides with a central nanobeam.

This theoretical simulation paper presents designs and projected performance of ∼1550-nm silicon-on-insulator (SOI) and ∼2000-nm Ge-on-Si-on-nitride and Ge-on-nitride 2×2 optical crossbar switches based upon a three-waveguide coupler in which the central waveguide is a nanobeam actuated by the thermo-optical (TO) effect. A TO heater stripe is located atop the central nanobeam. To implement accurate and realistic designs, the 3D finite difference time domain approach was employed. The metrics of crossbar switching, insertion loss (IL) and crosstalk (CT) were evaluated for choices of 3-waveguide structure parameters and TO-induced index changes. The predicted ILs and CTs were excellent, enabling the designed devices to be considered as fundamental building blocks in wavelength-division-multiplexed cross-connect (WXC) applications. Proposed here are compact, nonblocking space-and-wavelength routing switches to be constructed in a monolithic, industry-standard SOI chip (and in Ge-on-SON and GON chips). Specifics are given for realizing 16 × 16 × Mλ WXCs as well as reconfigurable, multi-resonant, programmable hexagonal and diamond meshes.

The mitochondrial aspartate/glutamate carrier (AGC or Aralar1) isoforms in D. melanogaster: biochemical characterization, gene structure, and evolutionary analysis.

BACKGROUND: In man two mitochondrial aspartate/glutamate carrier (AGC) isoforms, known as aralar and citrin, are required to accomplish several metabolic pathways. In order to fill the existing gap of knowledge in Drosophila melanogaster, we have studied aralar1 gene, orthologue of human AGC-encoding genes in this organism. METHODS: The blastp algorithm and the "reciprocal best hit" approach have been used to identify the human orthologue of AGCs in Drosophilidae and non-Drosophilidae. Aralar1 proteins have been overexpressed in Escherichia coli and functionally reconstituted into liposomes for transport assays. RESULTS: The transcriptional organization of aralar1 comprises six isoforms, three constitutively expressed (aralar1-RA, RD and RF), and the remaining three distributed during the development or in different tissues (aralar1-RB, RC and RE). Aralar1-PA and Aralar1-PE, representative of all isoforms, have been biochemically characterized. Recombinant Aralar1-PA and Aralar1-PE proteins share similar efficiency to exchange glutamate against aspartate, and same substrate affinities than the human isoforms. Interestingly, although Aralar1-PA and Aralar1-PE diverge only in their EF-hand 8, they greatly differ in their specific activities and substrate specificity. CONCLUSIONS: The tight regulation of aralar1 transcripts expression and the high request of aspartate and glutamate during early embryogenesis suggest a crucial role of Aralar1 in this Drosophila developmental stage. Furthermore, biochemical characterization and calcium sensitivity have identified Aralar1-PA and Aralar1-PE as the human aralar and citrin counterparts, respectively. GENERAL SIGNIFICANCE: The functional characterization of the fruit fly mitochondrial AGC transporter represents a crucial step toward a complete understanding of the metabolic events acting during early embryogenesis.

Evaluation of a Nutraceutical Product with Probiotics, Vitamin D, Plus Banaba Leaf Extracts (Lagerstroemia speciosa) in Glycemic Control.

BACKGROUND: Dysbiosis is related to changes in the composition and behaviour of intestinal microbiota, which may contribute to an age-related decline in metabolic and immune system functioning (immune-senescence). OBJECTIVE: The microbiota-targeted dietary and probiotic interventions have been shown to favorably affect the host health by an enhancement of antioxidant activity, improving immune homeostasis, suppression of chronic inflammation, regulation of metabolism and prevention of insulin resistance. RESULTS: In our study, the use of specific probiotics strains improved the serum concentration of glycemic markers, thereby promoting better overall health. CONCLUSION: Probiotics may help correct defects in the gut microbial environment improving metabolic parameters, such as blood sugar levels, glycosylated hemoglobin and a decrease in body weight.