Dynamic PET Reveals Compartmentalized Brain and Lung Tissue Antibiotic Exposures.

Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we performed first-in-human dynamic 18F-pretomanid positron emission tomography (PET) studies in eight human subjects for three-dimensional, multi-compartmental in situ visualization of antibiotic concentration-time exposures (area under the curve - AUC), demonstrating preferential brain (AUCtissue/plasma 2.25) versus lung (AUCtissue/plasma 0.97) tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of antibiotics active against MDR strains were confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicted human dosing necessary to attain therapeutic brain exposures in human subjects. These data were used to design optimized, pretomanid-based regimens which were evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrated discordant activities in brain and lung tissues in the same animal, correlating with the compartmentalized tissue exposures of the component antibiotics. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for the development of antimicrobial regimens for meningitis and other infections in compartments with unique antibiotic penetration.

Validation of conventional non-invasive fibrosis scoring systems in patients with metabolic associated fatty liver disease.

BACKGROUND: Non-invasive fibrosis scores are not yet validated in the newly defined metabolic associated fatty liver disease (MAFLD). AIM: To evaluate the diagnostic performance of four non-invasive scores including aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index (FIB-4), body mass index, aspartate aminotransferase/alanine aminotransferase ratio, diabetes score (BARD), and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with MAFLD. METHODS: Consecutive patients with histologically confirmed MAFLD were included. The discrimination ability of different non-invasive scores was compared. RESULTS: A total of 417 patients were included; 156 (37.4%) of them had advanced fibrosis (Metavir ≥ F3). The area under receiver operating characteristic curve of FIB-4, NFS, APRI, and BARD for predicting advanced fibrosis was 0.736, 0.724, 0.671, and 0.609, respectively. The area under receiver operating characteristic curve of FIB-4 and NFS was similar (P = 0.523), while the difference between FIB-4 and APRI (P = 0.001) and FIB-4 and BARD (P < 0.001) was statistically significant. The best thresholds of FIB-4, NFS, APRI, and BARD for diagnosis of advanced fibrosis in MAFLD were 1.05, -2.1, 0.42, and 2. A subgroup analysis showed that FIB-4, APRI, and NFS performed worse in the pure MAFLD group than in the hepatitis B virus-MAFLD group. CONCLUSION: APRI and BARD scores do not perform well in MAFLD. The FIB-4 and NFS could be more useful, but a new threshold is needed. Novel non-invasive scoring systems for fibrosis are required for MAFLD.

MAFLD Criteria May Overlook a Subtype of Patient with Steatohepatitis and Significant Fibrosis.

INTRODUCTION: Metabolic associated fatty liver disease (MAFLD) is a novel concept for fatty liver disease. Different from non-alcoholic fatty liver disease (NAFLD), the diagnosis of MAFLD requires the presence of metabolic risks. This study aimed to characterize patients with liver steatosis but without metabolic risks (non-MR-steatosis) which may not be diagnosed by MAFLD criteria. METHODS: Consecutive patients who underwent biopsy were included in this study. The clinic-pathological characteristics of non-MR-steatosis, NAFLD and MAFLD were compared. RESULTS: A total of 1217 cases were included. There were 426 (35.00%) cases with MAFLD, 585 (48.07%) with NAFLD and 168 (13.80%) with non-MR-steatosis. The majority of the cases were infected with HBV (93.26%). The age and metabolic profiles were highest in MAFLD and lowest in non-MR-steatosis. The body mass index (BMI) level was also lowest in non-MR-steatosis (20.78 ± 1.54 kg/m2). The ALT and AST levels of the non-MR-steatosis group were not statistically different from those of MAFLD or NAFLD groups (p > 0.05). Histologically, there was no significant difference in the degrees of inflammation and fibrosis among the three groups. The severity of steatosis in non-MR-steatosis group was lower than MAFLD or NAFLD groups (p < 0.05). These results were consistent in both HBV and non-HBV subgroups. CONCLUSION: MAFLD criteria may overlook some steatotic patients without metabolic risks, who may also have steatohepatitis and significant fibrosis.

Circadian Misalignment Rather Than Sleep Duration is Associated with MAFLD: A Population-Based Propensity Score-Matched Study.

BACKGROUND AND AIMS: Circadian misalignment (CM) leads to metabolic disorder. Metabolic (dysfunction) associated fatty liver disease (MAFLD) is a novel definition for fatty liver disease that requires the presence of metabolic dysfunction. As the association between CM and MAFLD remains unclear, this study is designed to explore whether there is an association between CM and MAFLD. METHODS: NHANES 2017-2018 database was used in this study. Liver steatosis and fibrosis were diagnosed by Fibroscan®. CM was defined by the presence of mistimed sleep, late sleep or irregular chronotype. Propensity score matching (PSM) was used to match subjects for their age and gender. RESULTS: A total of 4552 participants were included in the study, with 2089 (45.89%) identified as MAFLD and 894 (19.64%) as CM. Participants with CM were significantly younger than those without (46.06 ± 18.06 vs 50.93 ± 17.78, p<0.001). PSM for age and gender resulted in 894 participants with CM and 892 with non-CM. CM group had higher body mass index, liver enzymes, glucose and lipid levels. The prevalence of MAFLD was higher in the CM group than the non-CM group (45.41% vs 28.48%, p<0.001). The presence of CM increased the risk of MAFLD by more than twofold. Short sleep duration (<6 hours) was not independently associated with MAFLD or fibrosis if additionally adjusting for CM. CONCLUSION: CM is independently associated with MAFLD, while short sleep duration (<6 hours) is not an independent risk factor for MAFLD or liver fibrosis after adjusting for CM.

MAFLD Criteria Guide the Subtyping of Patients with Fatty Liver Disease.

BACKGROUND AND AIMS: Metabolic associated fatty liver disease (MAFLD) is diagnosed in patients with hepatic steatosis when they have the following three metabolic conditions: obesity/overweight, diabetes and metabolic dysregulation, either alone or in combination. There is no clarity whether subtypes of MAFLD diagnosed by different metabolic conditions carry different levels of risk for intra- and extra-hepatic organs. This study aims to depict the characteristics of these subtypes in a large population. METHODS: The data were retrieved from the third National Health and Nutrition Examination Surveys of the United States. The clinical and biochemical features in different MAFLD subtypes were compared. The outcome of interest was significant and advanced fibrosis. RESULTS: Out of 4,087 (31.24%) participants with MAFLD, 1,165 (28.51%) were diagnosed by single metabolic condition, 2,053 (50.23%) by two conditions, and 869 (21.26%) by all three metabolic conditions. With increasing numbers of metabolic conditions, participants tended to be older, were more likely to be female, and had more severe renal impairment and liver fibrosis (P<0.05). MAFLD patients with a lower number of metabolic conditions were more likely to have excessive alcohol consumption. Among MAFLD with single metabolic condition, those diagnosed by diabetes alone had the highest proportion of advanced fibrosis identified by non-invasive fibrosis models (P<0.05). CONCLUSION: More metabolic conditions upon the diagnosis of MALFD indicate higher risk of fibrosis. Patients with MAFLD diagnosed by diabetes alone are more likely to have advanced hepatic fibrosis than those with other metabolic conditions alone. Individualized management is required for MAFLD with different subtypes.

Immunogenicity of late stage specific peptide antigens of Mycobacterium tuberculosis.

Global burden of latent TB infection comprises one-third of the world population. Identifying potential Mycobacterium tuberculosis (Mtb) latency associated antigens that can generate protective immunity against the pathogen is crucial for designing an effective TB vaccine. Usually the immune system responds to a small number of amino acids as MHC Class I or Class II peptides. The precision to trigger epitope specific protective T-cell immune response could therefore be achieved with synthetic peptide-based subunit vaccine. In the present study we have considered an immunoinformatic approach using available softwares (ProPred, IEDB, NETMHC, BIMAS, Vaxijen2.0) and docking and visualizing softwares (CABSDOCK, HEX, Pymol, Discovery Studio) to select 10 peptides as latency antigens from 4 proteins (Rv2626, Rv2627, Rv2628, and Rv2032) of DosR regulon of Mtb. As Intracellular IFN-γ secreted by T cells is the most essential cytokine in Th1 mediated protective immunity, these peptides were verified as potential immunogenic epitopes in Peripheral Blood Mononuclear Cells (PBMCs) of 10 healthy contacts of TB patients (HTB) and 10 Category I Pulmonary TB patients (PTB).The antigen-specific CD4 and CD8 T cells expressing intracellular IFN-γ were analyzed using monoclonal antibodies in all subjects by multi-parameter flow cytometry. Both, PTB and HTB individuals responded to DosR peptides by showing increased frequency of IFN-γ+CD4 and IFN-γ+CD8 T cells. The T-cell responses were significantly higher in PTB patients in comparision to the HTB individuals. Additionally, our synthetic peptides and pools showed higher frequencies of IFN-γ+CD4 and IFN-γ+CD8 T cells than the peptides of Ag85B. This pilot study can be taken up further in larger sample size which may support the untapped opportunity of designing Mtb DosR inclusive peptide based post-exposure subunit vaccine.

Dual Role of GM-CSF as a Pro-Inflammatory and a Regulatory Cytokine: Implications for Immune Therapy.

Granulocyte macrophage colony stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine. Its inflammatory activity is primarily due its role as a growth and differentiation factor for granulocyte and macrophage populations. In this capacity, among other clinical applications, it has been used to bolster anti-tumor immune responses. GM-CSF-mediated inflammation has also been implicated in certain types of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Thus, agents that can block GM-CSF or its receptor have been used as anti-inflammatory therapies. However, a review of literature reveals that in many situations GM-CSF can act as an anti-inflammatory/regulatory cytokine. We and others have shown that GM-CSF can modulate dendritic cell differentiation to render them "tolerogenic," which, in turn, can increase regulatory T-cell numbers and function. Therefore, the pro-inflammatory and regulatory effects of GM-CSF appear to depend on the dose and the presence of other relevant cytokines in the context of an immune response. A thorough understanding of the various immunomodulatory effects of GM-CSF will facilitate more appropriate use and thus further enhance its clinical utility.

Effect of sialagogue on bleeding on probing in Sjögren's syndrome.

BACKGROUND: Bleeding on probing (BOP) is a frequent observation in patients with Sjögren's syndrome and a sialagogue is routinely prescribed for these patients. OBJECTIVE: The objective of this study was to evaluate the effect of sialagogue (muscarinic cholinergic agonists) on BOP in patients with Sjögren's syndrome. MATERIALS AND METHODS: This observational study included 57 subjects. Study population was divided into two groups: Subjects on sialagogue (n = 32) and subjects not on sialagogue due to their side-effects (non-sialagogue, n = 25). The number of sites with BOP was recorded on all teeth. RESULTS: The subjects on sialagogue had a significantly lower mean (standard error) number of sites with BOP 22.97 (2.65) as compared with the non-sialagogue group 46.59 (6.20), P < 0.001. After adjusting for the use of remineralizing rinse the subjects on sialagogue had a significantly lower number of sites with BOP (P < 0.001). CONCLUSION: In this observational study treatment with sialagogue may prevent BOP in patients with Sjögren's syndrome.

Effect of misfit of cement-retained implant single crowns on crestal bone changes.

The purpose of this clinical study was to compare peri-implant crestal bone levels between misfitting (overhanging/open margin) cement-retained implant single crowns (SCs) vs accurately fitted implant SCs. Seventeen subjects were divided into two groups: test group (misfitting crowns, n = 10) and control group (accurately fitted crowns, n = 7). Crestal bone level changes were assessed using digital software. The average differences in mean bone loss within and between the two groups were statistically significant. Cement-retained implant SCs with marginal misfit resulted in more crestal bone loss than accurately fitted crowns after a mean of 3 years in function.

Trap door: an alternative procedure to the triangular distal wedge for the elimination of distal periodontal pockets adjacent to edentulous areas.

The study compared a novel trap door (TD) technique with the triangular distal wedge (TW) procedure for the elimination of distal periodontal pockets adjacent to edentulous areas. Thirteen patients with suprabony pockets ≥ 5 mm at the distal surface of terminal molars bilaterally were included in this prospective, single-blinded, randomized clinical trial using a split-mouth design. The authors demonstrated the efficacy of an alternative TD technique in the elimination of the distal pockets adjacent to the terminal molars.

The pregnant dental patient.

When dealing with a pregnant patient, the dental practitioner should keep in mind the various physiological changes that occur in the pregnant female and the potential effects on the fetus in using various types of local anesthesia. This article reviews the current considerations in the use of local anesthesia in the pregnant dental patient, and the safety of local anesthetics, their dosage, and any adverse effect on mother and fetus. It also discusses various dental procedures and the trimester during which they can be performed. Lastly, this article talks about the complications that can occur with a pregnant dental patient in the dental chair.

Dietary considerations for patients with dry mouth.

Dental caries is seen frequently in patients diagnosed with dry mouth. Nutritional counseling is important for the effective management of dry mouth and to arrest dental caries. With early intervention and proper individualized care, patients with dry mouth should be able to lead full, comfortable lives.

Diagnosis and treatment of dry mouth.

For effective management of dry mouth, early diagnosis and aggressive, symptom-based treatment are necessary to help alleviate much of the discomfort and to retard progression of the disorder. Many effective strategies are available to help patients manage their symptoms. Routine follow-up care with physicians and dentists is essential. With early intervention and proper individualized care, people with dry mouth should be able to lead full and comfortable lives.

Effect of omega-3 and vitamin E supplementation on dry mouth in patients with Sjögren's syndrome.

To determine whether omega-3 (n-3) increases saliva production in patients with Sjögren's syndrome, 61 patients with Sjögren's received either wheat germ oil (n = 23) or n-3 supplement (TheraTears Nutrition®) (n = 38) in a prospective, randomized, double-masked trial. The outcomes assessed were salivary secretion and markers for oral inflammation. The differences between the n-3 group and wheat germ oil group were not statistically significant for either unstimulated (US) or stimulated (SS) salivary secretion (p= 0.38 and p= 0.346, respectively) nor for the number of sites with probing depth (PD) ≥ 4 mm (p= 0.834). In this pilot study, supplementation with n-3 was not found to be significantly better than wheat germ oil in stimulating saliva production in patients with Sjögren's syndrome.

The effect of a selective cyclooxygenase-2 inhibitor (celecoxib) on chronic periodontitis.

BACKGROUND: Non-steroidal anti-inflammatory agents inhibit the production of cyclooxygenase (COX) products and can attenuate bone loss. In this double-masked, placebo-controlled, randomized clinical trial, the efficacy of celecoxib (COX-2 inhibitor) was evaluated in conjunction with scaling and root planing (SRP) in subjects with chronic periodontitis (CP). METHODS: A total of 131 subjects were randomized to receive SRP and either celecoxib (200 mg) or placebo every day for 6 months. Clinical outcomes were assessed every 3 months for 12 months as mean changes from baseline. Primary efficacy parameters included clinical attachment level (CAL) and probing depth (PD). Secondary outcomes included percentages of tooth sites with CAL loss or gain > or =2 mm, changes in bleeding on probing (BOP), plaque index, and mobility. Prior to analysis, tooth sites were grouped based on baseline PD as shallow (1 to 3 mm), moderate (4 to 6 mm), or deep (> or =7 mm). RESULTS: Mean PD reduction and CAL gain were greater in the celecoxib group, primarily in moderate and deep sites, throughout the study (PD: 3.84 mm versus 2.06 mm, P <0.001; CAL: 3.74 mm versus 1.43 mm, P <0.0001 for deep sites at 12 months). The celecoxib group also exhibited a greater percentage of sites with > or =2 mm CAL gain and fewer sites with > or =2 mm CAL loss. Both groups showed improved plaque control and BOP scores. Demographic, social, and behavioral factors did not affect treatment outcomes. CONCLUSIONS: Celecoxib can be an effective adjunctive treatment to SRP to reduce progressive attachment loss in subjects with CP. Its beneficiary effect persisted even at 6 months postadministration. However, given the increased cardiovascular risks associated with the use of this drug, close patient supervision and strict adherence to dosage and administration guidelines established by the Unites States Food and Drug Administration are of paramount importance.