Adult Subjects Research Articles

CD22 CAR T Cell-Related IEC-HS Is Associated with an IFN-γ Cytokine Signature

Introduction Chimeric antigen receptor T-cell therapy targeting CD22 (CAR22) shows promise for patients with relapsed / refractory B-cell acute lymphoblastic leukemia (ALL) and large B cell lymphoma (LBCL) (Fry et al. Nat Med 2018; Baird et al. Blood 2020). The overall response rate for CAR22 in adults who received prior CD19 CAR therapy is 100% and 68% in ALL and LBCL respectively (Tandem 2023) (NCT04088890). However, 33% of pediatric ALL patients who received CAR22 developed immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) (Shah et al. JCO 2020). IEC-HS is characterized by hyperferritinemia, cytopenias, coagulopathy and end organ damage. Pediatric ALL data suggest many cytokines including IFN-γ, IL-1β, IL-18 and TNF-α are upregulated in IEC-HS (Ishii et al. JCI 2020, Lichtenstein et al. Blood 2021). Here, we report the clinical features and cytokines associated with IEC-HS after CAR22 infusion in predominantly adult subjects with ALL and LBCL. Methods Plasma was collected weekly from Day 0 to 28 for 54 patients (ALL: n = 16, LBCL: n = 38; adult: n = 51, pediatrics: n = 3) who were treated with CAR22 manufactured using an automated, closed-system Miltenyi CliniMACS Prodigy device. Three dose levels were tested (ALL: 3 x 10 5 cells/kg, LBCL dose level 1 (DL1): 1 x 10 6 cells/kg, LBCL dose level 2 (DL2): 3 x 10 6 cells/kg). Clinical characteristics associated with IEC-HS were retrospectively collected and graded according to consensus criteria (Hines et al. TCT 2023). Eighty cytokines were quantified in batch via multiplexed fluorescence immunoassay (Luminex) to generate mean fluorescent indices (MFIs). Unsupervised hierarchical clustering using Euclidean distance and ward.D2 linkage were employed to analyze cytokine dynamics. Statistical analyses were performed using R (v 4.2.2). Results 8 of 54 (15%) patients developed IEC-HS, all were ≥18 years old. 5 patients had LBCL, 3 had ALL. 5 cases were grade 2, 3 were grade 4. Median onset was D+12 (range 8 - 21). All patients had prior CRS with median onset at D+1 (range 0 - 9). The 3 ALL patients had ongoing CRS and spectral overlap with IEC-HS at time of diagnosis whereas LBCL patients' CRS resolved prior to IEC-HS onset. IEC-HS patients had significant increases in inflammatory markers (ferritin, CRP, LDH, triglycerides), coagulation markers (INR, PTT), cytopenias (hemoglobin, platelets) and transaminases (Table 1). Patients most commonly received high-dose glucocorticoids, tocilizumab and anakinra. Additional agents for grade 4 IEC-HS included anti-thymoglobulin, dasatanib and emapalumab. 5 of 8 patients developed serious infections requiring IV antimicrobials including bacteremia, invasive fungal infections and viral reactivation. 5 patients with IEC-HS died after achieving complete response: 3 due to IEC-HS and concomitant infection, 1 from t-AML and 1 lost to follow up. IEC-HS occurred more frequently at higher doses in LBCL where multiple doses were tested (DL2: 33% vs DL1: 7%, p = 0.08). Peak serum CAR22 concentration was markedly elevated in patients who developed IEC-HS compared to those who did not (median 648 vs 42 cells/µL, p<0.001). Unsupervised hierarchical clustering performed on serial cytokine measurements identified a signature of IFN-γ-related cytokines including CXCL9, CXCL10, TNFα, FasL, IL6 and IL18 as being closely related in IEC-HS (Figure 1). Most cytokines in the signature peaked at D+14, consistent with onset of clinical IEC-HS. Peak levels of nearly all cytokines in the interferon-γ cluster were significantly elevated in IEC-HS patients compared to patients who did not develop IEC-HS, and this cluster contained most cytokines with significant increases in peak levels (Figure 1). Conclusions IEC-HS is a potentially life-threatening toxicity associated with CAR22 across age and underlying malignancy. The high rates of non-relapse mortality and severe infections in this study highlight the importance of understanding the immune dysregulation underlying IEC-HS. Higher CAR22 dose and expansion were associated with IEC-HS, indicating optimal dosing as a potential preventive strategy. The observed IFN-γ cytokine signature is consistent with myeloid cell activation and Th1 T-cell skewing that likely contributes to IEC-HS pathogenesis. These cytokines may be amenable to therapeutic intervention and further study of approaches targeting JAK/STAT and IFN-γ are warranted.

Maintenance Ruxolitinib Is Associated with Low Rates of Chronic Gvhd Requiring Systemic Treatment in Older Adults with AML/MDS Undergoing Allogeneic HCT: Results of a Phase II Multicenter Trial

Introduction: Despite recent advances in graft-versus-host disease (GVHD) prophylaxis, novel approaches to effective prevention of chronic GVHD remain of utmost importance. This is particularly true for older transplant recipients,for whom high-dose cyclophosphamide or prolonged treatment with corticosteroids is challenging. Ruxolitinib, an oral selective inhibitor of JAK1/2, is FDA-approved for the treatment of refractory acute and chronic GVHD. However, the clinical efficacy of JAK inhibition in preventing severe chronic GVHD is not well characterized. Methods: In this prospective, multicenter phase II trial (NCT03286530), older adult subjects (age 60-80) with AML in CR1 or MDS undergoing RIC allogeneic HCT were enrolled. Transplants could be conducted from HLA-matched related donors or 7/8 or 8/8 HLA-matched unrelated donors. Transplants were required to use busulfan- or melphalan-based reduced intensity conditioning and peripheral blood stem cells. Standard GVHD prophylaxis consisted of tacrolimus and methotrexate (5-10 mg/m 2 on Days +1, +3, and +6 ± +11). Subjects were enrolled prior to transplant. Ruxolitinib therapy could begin between Day +30 and Day +100, after meeting pre-treatment criteria, which included: donor engraftment, ongoing remission confirmed by biopsy, adequate hematopoietic recovery (Hgb ≥8 g/dL, PLT ≥50K/uL), and the absence of progressive acute GVHD. Ruxolitinib was administered at 10 mg BID continuously in 28-day cycles (allowing for dose reductions due to drug interactions or cytopenias), for up to 24 cycles. The primary objective was to evaluate the GRFS at 1-year after HCT. Key secondary objectives included the cumulative incidence of chronic GVHD, acute GVHD, and relapse, as well as overall survival. Results: Seventy-eight subjects were enrolled, and 63 subjects received ruxolitinib on trial. The reasons for not initiating ruxolitinib were acute GVHD (n=4), physician discretion (n=3), disease relapse (n=2), low chimerism (n=2), death (n=2), primary graft failure (n=1), and subject withdrawal (n=1). In the treated subjects, the median age was 68 years (range, 61-79). Fifty-five (87.3%) subjects had AML and 8 (12.7%) had MDS. Transplants were performed from HLA-matched related (n=16, 25.4%) or unrelated (n=47, 74.6%) donors with either Fludarabine/Melphalan (n=34, 54%) or Fludarabine/Busulfan (n=29, 46%). The median start date of ruxolitinib after HCT was day 45 (range, 32-93). The median follow-up of survivors was 19 months (range, 3-64) at last cutoff (2/14/23). At the time of analysis, the median number of cycles on treatment is 14 (range, 1-24). 17 subjects remain on therapy; the reasons for discontinuation include completed treatment (n=21), disease relapse (n=13), adverse events (n=7), and physician discretion (n=5). The most common (severe grade ≥3) adverse events experienced while on ruxolitinib were neutropenia (n=18, 29% of subjects), thrombocytopenia (n=17, 27% of subjects), and anemia (n=16, 25% of subjects). Seven subjects experienced grade ≥3 infectious events; no fungal infections have occurred. In subjects receiving ruxolitinib, the 6-month cumulative incidence of Grade II-IV acute GVHD was 14% (95%CI, 7-24) and Grade III-IV acute GVHD was 4.8% (95%CI, 1.3-12), with three cases of grade II-IV GVHD occurring prior to initiation of ruxolitinib. While the 12-month incidence of all cases of chronic GVHD is 27% (95%CI, 17-39), the 12-month incidence of chronic GVHD requiring systemic therapy is 8.4% (95%CI, 3.1-17). The 18-month cumulative incidence of NRM is 5.6% (95%CI, 1.4-14); with only one death attributed to GVHD and one death due to infection (COVID-19), thus far. The 18-month cumulative incidence of disease relapse is 27% (95%CI, 16-39). The 12-month GRFS (primary endpoint) is 70% (95%CI, 56-80). The 18-month OS, PFS, and CRFS are 78% (95%CI, 64-88), 68% (95%CI, 53-78) and 64% (95%CI, 50-76), respectively ( Figure 1). Conclusion: Prolonged administration of ruxolitinib following allogeneic HCT is associated with low rates of chronic GVHD requiring systemic treatment. The incidence of relapse is comparable to historical rates, suggesting no compromise of GVL effect. Despite the anticipated cytopenias with therapy, most subjects were able to remain on treatment. The incorporation of JAK inhibition into GVHD prevention approaches warrants further investigation.

Evaluation of Red Cell Deformability in Sickle Cell Disease Patients, Sickle Cell Carriers, and Healthy Controls Using Lorrca-Derived Parameters

BACKGROUND Red blood cell (RBC) deformability plays a critical role in RBC elongation and viscosity, and when reduced, perfusion of peripheral tissues and oxygen delivery are impaired. Intracellular ATP maintains water and ion homeostasis in RBCs; reduced ATP leads to water and ion loss, dehydration and loss of RBC elasticity. RBC dehydration increases mean corpuscular hemoglobin concentration (MCHC) and also affects distribution of RBC width (RDW). Patients with sickle cell disease (SCD) have reduced RBC ATP, and markedly reduced RBC deformability when compared to healthy individuals. Here, we employed Laser-Optical Rotational Red Cell Analyzer (LORRCA, RR Mechatronics) to evaluate deformability in RBCs from patients with SCD (HbSS) compared to RBCs from sickle cell carriers (HbAS) and ethnic-matched healthy controls (HbAA). We further analyzed how these LORRCA-derived parameters correlate with ATP, MCHC, and RDW. METHODS We enrolled adult subjects (age ≥ 18 years) of African-descent, and not recently transfused (within 8 weeks) under protocol NCT03685721 approved by the NHLBI Institutional Review Board. Fresh whole blood in EDTA was processed on the same day of collection. Cells were counted and diluted in polyvinylpyrrolidone (PVP) solution before undergoing LORRCA assays including deformability, osmoscan, and oxygenscan (HbSS subjects). The deformability assay uses the elongation Index (EI) to measure the cells' ability to undergo deformation with increasing shear stress at 0.95, 3, and 30 Pascals (Pa). The osmoscan assay measures the deformability under continuous osmotic changes (0-600mOsm/kg) and has several parameters: O min (RBC fragility); El max (maximum deformability and membrane flexibility); O max (osmolality where EI max is achieved) and O hyper (intracellular viscosity and maximum deformability in the hypertonic region). The oxygenscan assay measures the oxygen pressure at the time when RBCs start to become rigid (point of sickling). Whole blood levels of ATP were measured using LC-MS/MS with LLOQ at 50.0 μg/mL and converted to intracellular concentrations by dividing by the hematocrit (as a fraction). Descriptive statistics and correlation (Spearman) of ATP, RDW, and MCHC with each LORRCA parameter were performed using R (v4.2.3) and Prism(v9). RESULTS We studied 156 subjects which comprised of 63 HbSS (33 males), 61 HbAS (23 males) and 32 HbAA (8 males) genotypes. The average age in years (range) in HbSS was 32 (18-58); in HbAS, 43 (18-70), and in HbAA, 38 (19-72). As shear stress and osmotic pressure increased, the mean EI and osmolality were significantly (p<0.001, unpaired two-sample t-test) lower in the HbSS cohort compared to HbAS and HbAA (Figure 1). There was no significant difference in the mean EI and osmolality between HbAA and HbAS with increasing shear stresses and osmotic pressures. As shear stress increased, the correlation of deformability with reduced ATP got significantly stronger in the HbSS cohort (r= -0.351 at 0.95 Pa to r=-0.401 at 30 Pa) but the trend was reversed for the HbAS and HbAA cohort (Table 1). Under increasing osmotic pressure, a significant correlation was found between reduced ATP and maximal deformability (EI Max) in HbSS (p=0.008) compared to HbAS (p=0.896) and HbAA (p=0.114). MCHC was significantly correlated with RBC hydration state (O Hyper) in all 3 genotypic groups (HbSS, HbAS and HbAA). Similarly, RDW correlated with maximal deformability (EI Max) under increasing osmotic pressure in all 3 cohorts. In the HbSS subjects, there was a significant positive correlation of ATP and RDW with point of sickling (oxygenscan); MCHC was negatively correlated but was not significant. CONCLUSION RBC deformability was reduced in HbSS patients compared to HbAS and HbAA under increasing shear stress and osmotic pressure. ATP levels showed significant correlation with RBC deformability as measured by LORRCA, particularly in patients with SCD, suggesting increasing ATP levels as an important therapeutic strategy in patients with SCD. In keeping with published data, our analyses showed that RBC volume and size as well as intracellular hemoglobin concentration can affect deformability.

2144. A Phase 1, Multicenter, Open-Label, Parallel-Group Study to Assess the Safety and Pharmacokinetics (PK) of Oral Epetraborole Tablets in Adult Subjects with Varying Degrees of Renal Function

Abstract Background Epetraborole (EBO), an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria, is in clinical development for treatment-refractory MAC lung disease. The objective of the study was to evaluate EBO PK in adult subjects with varying degrees of renal impairment (RI) including end stage renal disease (ESRD) with intermittent hemodialysis (IHD). Methods Open-label, single-dose EBO 500 mg PO was given to subjects in 5 cohorts: normal renal function, mild, moderate, and severe RI, and ESRD-IHD (Table); ESRD subjects received a second 500 mg dose on Day 5 approximately 1 hour before receiving IHD. EBO and its inactive major metabolite (M3) concentrations in plasma, urine and dialysate were measured by validated LC-MS/MS methods. Plasma PK parameters were determined using non-compartmental methods and compared among cohorts using analysis of variance (ANOVA). Standard clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Results 40 subjects were enrolled (8/cohort). Subjects with RI did not exhibit quantitatively distinct EBO plasma PK profiles compared to those with normal renal function; AUC mean ratios were 110-140% in subjects with RI, and the mean ratios of maximum observed concentration (Cmax ) values did not exceed 116% (Table). The elimination half-life (t1/2) increased slightly from 9.3 to 11.0 h in ESRD subjects, and clearance decreased by about 30%. Renal elimination was not a major route of excretion (∼15% of dose over 72 h) for EBO, with mean renal clearance ranging from 4.24 L/h to 1.04 L/h. Metabolite M3 AUC increased 4-fold in subjects with severe RI, and t1/2 increased from 20 to 32 h. EBO was well tolerated; 7 subjects (17.5%) experienced at least 1 TEAE (11 events), all mild in severity except 1 moderately-severe TEAE of worsening anemia. There were no severe or serious TEAEs. Conclusion Minimal increases in plasma EBO exposures and similar t1/2 values were observed in subjects with varying degrees of RI, including ESRD-IHD. Single 500 mg doses of EBO were well tolerated in each RI cohort. Overall, these data suggest that no dose adjustment of EBO is needed in subjects with any degree of RI. Disclosures All Authors: No reported disclosures

2556. A Phase 1, Open-Label, Single Dose Study to Evaluate the Pharmacokinetics (PK), Safety, and Tolerability of Epetraborole Tablets and the Impact of Alcohol Dehydrogenase (ADH) Genotype on the PK of Epetraborole and Metabolite M3 in Healthy Japanese Adult Subjects

Abstract Background Epetraborole (EBO), an orally available bacterial leucyl transfer RNA synthetase inhibitor with potent activity against nontuberculous mycobacteria, is under clinical development for treatment-refractory MAC lung disease. Nonclinical studies suggest that metabolism of EBO to metabolite M3 may involve oxidation by ADH. The goal of this study was to evaluate the impact of ADH genotype on the PK of EBO and M3 in healthy Japanese subjects. Methods In this open-label trial, a single 500 mg EBO dose was administered to subjects in 3 cohorts defined by ADH1B genotype (*1/*1, *1/*2, or *2/*2). EBO and M3 plasma concentrations were measured by a validated LC-MS/MS method, and plasma EBO and M3 PK were determined using non-compartmental methods. Standard clinical and laboratory evaluations and treatment-emergent adverse events (TEAEs) were assessed. Results 18 subjects were enrolled (6/cohort). EBO was rapidly absorbed, with M3 subsequently appearing in plasma. After reaching Cmax, EBO and M3 concentrations declined with a geometric mean t1/2 of 10.7 to 11.4 h and 26.7 to 33.1 h, respectively. EBO exposures (Cmax and AUC) were similar between Cohort 1 and Cohort 2, while exposures were 1.2- to 1.4-fold higher in Cohort 3 (Table); however, exposure of M3 was similar across all cohorts. Compared to Cohort 1, M3:EBO ratios for Cohort 3 were generally similar for Cmax and were approximately 26% lower for AUC. No apparent differences in t1/2 were observed across cohorts for either EBO or M3. No TEAEs or clinically significant changes in clinical laboratory parameters, vital signs, physical examinations, or ECGs were reported in this study. Conclusion Administration of EBO in Japanese subjects with varying ADH1B genotypes had no meaningful effect on EBO or M3 plasma exposure. The slightly increased EBO exposures associated with the 500 mg dosage in subjects with ADH1B *2/*2 genotype were within the range of tolerable exposures. Oral EBO was well tolerated in this study; no TEAEs were reported. This Phase 1 study did not identify any risk that would preclude evaluation of oral EBO administered 500 mg daily in patients with different ADH1B genotypes, including Japanese patients. Disclosures All Authors: No reported disclosures

1379. Evaluation of Cardiovascular Disease Risk among People Living with HIV in Lebanon

Abstract Background Since the introduction of antiretroviral therapy (ART), People Living with HIV (PLHIV) have become more prone to developing chronic illnesses, such as cardiovascular diseases (CVD), than to suffer from AIDS related conditions. The global burden of CVD associated with HIV has tripled over the last two decades, especially in low/middle income countries. Scarce data exist on the prevalence of CVD and CVD risk factors among PLHIV in the Middle East and North Africa (MENA) region. Therefore, we aim to examine the prevalence of CVD risk factors and calculate the CV risk in a cohort of PLHIV in Lebanon. Methods This is a retrospective chart review conducted between 2018 and 2023 at an HIV clinic in a tertiary care center in Lebanon. The study population includes adult subjects receiving ART and with at least 6 months of undetectable viral loads. Data included demographics, laboratory values, HIV-specific data, and review of traditional CVD risk factors. Atherosclerotic Cardiovascular Disease (ASCVD) risk score was calculated using the American College of Cardiology Risk Estimator Plus, to estimate patients’ 10-year risk for developing ASCVD. Descriptive statistics were implemented to summarize the cohort’s characteristics and the prevalence of CVD risk factors. Results A total of 85 HIV-infected subjects were included in the analysis. Subjects’ characteristics are summarized in table 1. The majority were males (89.4%), and the mean age was 43.31±12.28 years. The prevalence of smoking, alcohol consumption, and illicit drug use was 70.6%, 54.1%, and 20%, respectively. The mean BMI was 26.1±5 kg/m². Additionally, 20.2 % of subjects had dyslipidemia, 6% had diabetes, and 15.5% had hypertension. The mean current CD4 cell count was 687.83 ±356 cells/ml. The cohort had a mean ASCVD risk score of 8.8%, higher than that of age-matched population (mean ASCVD risk score of US firefighters aged 40-44 years is 1.8%). Conclusion This study shows the prevalence of traditional CVD risk factors among PLHIV receiving effective ART in Lebanon. The cohort mean ASCVD risk score indicates an intermediate risk for developing CVD over the next decade. in the MENA region, we need larger studies to inform on the prevalence of CVD among PLHIV, and to develop guidelines to mitigate the risk. Disclosures All Authors: No reported disclosures

Remimazolam Pilot for Office-Based Dental Sedation: Adverse Events, Awareness and Outcomes

In recent years, remimazolam has gained approval for use in adult procedural sedation in both the United Kingdom and the United States, potentially offering an alternative to conventional sedatives like propofol and midazolam for procedural sedation. However, there is a limited body of literature that systematically reviews the outcomes of a remimazolam-alfentanil combination protocol for routine office-based dental procedures. The primary objective of this pilot study was to assess the occurrence of significant adverse events associated with the use of a remimazolam-alfentanil sedation protocol for adult dental procedures. Secondary outcomes included evaluating physiological responses, sedation effectiveness, patient and clinician satisfaction and the incidence of intraprocedural awareness. Notably, no significant adverse events were reported among the 25 adult subjects who received remimazolam and alfentanil, and all dental procedures were successfully completed. Patients and clinicians expressed high levels of satisfaction, and patients did not report any distressing memories associated with the dental procedure. These findings suggest that in a limited cohort, the remimazolam-alfentanil regimen appears to be well tolerated and effective for office-based dental procedures in adult patients, with a low risk of adverse events, acceptable hemodynamic effects, rapid onset and recovery and minimal intraoperative awareness. This study provides valuable insights into the potential use of the remimazolam-alfentanil combination in dental sedation practice.

ADA_ETA_BIO2021: real-world evaluation of adherence, persistence, and cost-effectiveness of originator and biosimilar biologic drugs in the treatment of rheumatoid arthritis: a multicenter study in Italy

Objectives The objective was to assess the adherence, persistence, and costs of bDMARDs through a multicentre study of nine Italian hospital pharmacies. Methods The drugs analysed were Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab and Tocilizumab. Adult subjects with Rheumatoid Arthritis were considered in the analysis. In this study, we calculated the following metrics: Adherence to treatment was evaluated as dose-intensity, which is the ratio between the amount of medication received and probably taken by the patient at home (Received Daily Dose, RDD) and the amount prescribed by the clinician (Prescribed Daily Dose, PDD). Persistence was calculated as the number of days between the first and last dispensing of the same drug. Lastly, costs were assessed based on persistence to treatment and normalized for adherence. Results Adherence to treatment was found to be above 0.8 for all drugs studied. The median persistence for a 5-year treatment period was 1.4 years for Abatacept, 1.7 years for Adalimumab, 1.8 years for Certolizumab, 1.4 years for Etanercept, 1.3 years for Golimumab, and 1.6 years for Tocilizumab. Conclusions This multicentre retrospective observational study of bDMARDs used in the treatment of RA showed that, for all the drugs studied, there was no problem with adherence to treatment but rather a difficulty in maintaining treatment with the same drug over time.

The reduction of the left ventricular long-axis early diastolic peak velocity (e') evident by early-middle age occurs in the absence of aging-related slowing of active relaxation.

A decrease in the left ventricular (LV) long-axis early diastolic peak velocity (e') is evident by early-middle age, but it is unknown to what extent this decrease is due to slowing of the speed of active relaxation versus a reduction in LV long-axis excursion during early diastole (EDExc). Pulsed-wave tissue Doppler imaging (TDI) signals were acquired from the septal and lateral borders of the mitral annulus in 62 healthy adult subjects of age 18-45years. EDExc and LV systolic excursion (SExc) were measured as the integrals of the respective TDI signals. The speed of active relaxation was indirectly assessed using time interval measurements related to the TDI early diastolic signal, including the isovolumic relaxation time (IVRT'), the acceleration time (EDAT), and the duration (EDDur). Multiple linear regression analyses were performed to identify the relationships between e', age, EDExc, SExc, and time intervals. The findings were similar for both LV walls. Age was negatively correlated with e' and EDExc, but was not correlated with SExc, IVRT', EDAT, or EDDur. The closest correlate of EDExc was SExc, and EDExc was independently correlated with both SExc and age. e' was also positively correlated with SExc, but the closest correlate of e' was EDExc, and when combined with EDExc, EDDur became an independent predictor of e'. The aging-related decrease in e' evident by early-middle age occurs in the absence of aging-related slowing of active relaxation and therefore can be largely attributed to the accompanying reduction in EDExc.

Oral Bacteria, Virus and Fungi in Saliva and Tissue Samples from Adult Subjects with Oral Squamous Cell Carcinoma: An Umbrella Review

Oral squamous cell carcinoma (OSCC) is the most common oral cavity malignancy associated with multiple risk factors. In the last 14 years, oral dysbiosis has attracted the scientific community’s attention as a potential oncogenic factor, in parallel with the development of omics technologies that have revolutionized microbiological research. The present umbrella review aimed to investigate the oral microbiological content (bacilli, viruses, and fungi) of tissue and saliva samples from adult (>18 years) patients with OSCC. The secondary objective was to compare the oral microbiome of OSCC subjects with non-OSCC subjects. The study protocol was under the PRISMA statement and registered on PROSPERO (CRD42023448153). Data from 32 systematic reviews were extracted, qualitatively summarized, and analyzed using AMSTAR-2. An increase in oral bacteria of the phylum Fusobacteria, Proteobacteria, and Bacteroidetes and a decrease in Firmicutes and Actinobacteria were observed in OSCC patients. The increased bacterial genera were periodontopathogens. The most common viruses were EBV and HPV, especially the high-risk genotypes. Candida was the most studied oral fungus and was always increased in OSCC subjects. Further studies should investigate the possible carcinogenic mechanisms of oral microorganisms found increased in tissue samples and saliva from adult subjects with OSCC.

Analysis of the Effect of Different Physical Exercise Protocols on Depression in Adults: Systematic Review and Meta-analysis of Randomized Controlled Trials.

Physical exercise (PE) is an effective treatment for depression, alone or as an adjunct. There is a lack of indicators regarding the frequency, intensity, duration, and type of physical exercise (PE). This study aims to synthesize and analyze the dose-effect of different PE protocols in adult subjects in the treatment of depression, based on the analysis of randomized controlled trials (RCTs). The search was conducted using Web of Science, PubMed, and Cochrane Library electronic databases. Studies with an exercise-based intervention published by December 31, 2021 were identified. RCTs and meta-analyses involving adults with depression were also included; 10 studies were selected, including a total of 956 subjects. Systematic review and meta-analysis. Level 1. Effect sizes were summarized using standardized mean differences (95% confidence interval) by effected randomized models. The results reinforce that exercise appears to be beneficial in improving depression among adults aged 18 to 65 years. Interventions lasting above 150 minutes per week of moderate intensity and group interventions seem to have a more significant effect on reducing depression. Studies have revealed that aerobic exercise, compared with resistance or flexibility, has a more positive effect on depression. PE can be a way to reduce depression and can be used as a possible adjunctive tool for pharmacological and/or alternative treatments. Considering the findings of this study, it is important that health professionals (eg, exercise physiologists, physicians, nurses, psychologists) promote the practice of PE as a complementary alternative and act early to prevent the worsening of depression. CRD42020188909.

The Interrelation Between Obesity and Gingivitis in Adults

Background: Fat deposition in excess is known as obesity. It is a risk factor for many systemic diseases including cardiovascular and atherosclerotic diseases. It is also a risk factor for periodontal disease. This study was undertaken to evaluate association between obesity and gingivitis. Methods: 50 adult subjects participated in this study. Waist circumference (WC) and Body mass index (BMI) was measured. Visceral fat (VF) was measured with Bioelectrical impedance analyzer (BIA). For gingivitis, gingival index (GI) and Plaque index (PI) was measured. Statistical analysis was done using Multinomial logistic regression and Chi-square test. Results: There was significant correlation between BMI and gingivitis (P˂0.05), whereas no relationship was found between gingivitis, visceral fat and waist circumference (P˃0.05). Conclusion: Only relationship was found between BMI and gingivitis. Obese subjects may have a risk of gingivitis.

OGC P33 Comparison of the post-operative outcomes of surgical and chemical interventions on the gastric pylorus during oesophagectomy: A systematic review and meta-analysis

Abstract Background Oesophagectomy can lead to gastric dysmotility and pyloric dysfunction, causing delayed gastric emptying (DGE). DGE is associated with significant postoperative morbidity, namely aspiration pneumonia and anastomotic leak. Surgical drainage and botox injections (BI) on pylorus were described to combat DGE. Pyloric interventions however can increase risk of bile reflux, oesophagitis, dumping syndrome and pyloric leaks. Current literature showed equivocal short- and long-term outcomes of pyloric drainage procedures, with no consensus on the necessity of such procedures. We aim to evaluate the latest literature, comparing effects of different pylorus surgical drainage methods, BI and watch-and-wait approach on the pylorus during oesophagectomy Methods The OVID database was searched systematically. Articles were screened with the Rayyan software. Inclusion Criteria of articles are as follows: • RCT and comparative cohort studies (retrospective and prospective) which included any drainage methods, performed at the same time as oesophagectomy • Oesophagectomy for benign or malignant conditions • Studies of adult human subjects ≥ age of 18 years old • Studies published in English language • Studies published within the last 25 years Primary outcomes evaluated were DGE and pulmonary complication rates. A traditional pairwise meta-analysis was performed with Revman 5.4, utilizing a random effects model for analysis of the pooled outcome measures. Results Data of 3925 patients from 27 publications evaluating up to ten pyloric interventions were analyzed. Most studies were retrospective in nature (24 studies). Due to heterogeneity of reported outcomes, pooled meta-analyses were only performed on limited studies. Pooled analyses showed pyloric interventions reduced DGE rates in 19 studies and pulmonary complications in 11 studies. Relative risks (95% CI; p value) were 0.95 (0.7,1.29; p=0.74) and 0.88 (0.72,1.08; p=0.22), respectively.Figure 1:Forrest plot comparing DGE rates of Pyloric Interventions vs No Intervention Figure 2:Forrest plot comparing rates of Pulmonary Morbidity of Pyloric Interventions vs No Intervention Conclusions Our systematic review and meta-analysis did not observe statistically significant and conclusive evidence favouring pyloric drainage procedures to none. High quality comparative studies and inconsistent scrutinization of post operative outcomes were lacking. Prospectively designed RCT or propensity matched cohort studies comparing surgical pyloric drainage, BI and no intervention should be conducted to produce standardized comparison. We suggest analyzing post operative outcomes by measuring data which could be objectively recorded (DGE utilizing the latest definition, pulmonary morbidity, anastomotic leak, biliary reflux rates, radiographic or endoscopic findings etc.) combined with subjective measurement of patient symptoms, where a patient-centred questionnaire could be performed.

Twenty-four-month interim results from a prospective, single-arm clinical trial evaluating the performance and safety of cellular bone allograft in patients undergoing lumbar spinal fusion

BackgroundAutologous bone grafts are the gold standard for spinal fusion; however, harvesting autologous bone can result in donor site infection, hematomas, increased operative time, and prolonged pain. Cellular bone allografts (CBAs) are a viable alternative that avoids the need for bone harvesting and may increase fusion success alone or when used as an adjunct material. The present study examined the efficacy and safety of CBA when used as an adjunct graft material to lumbar arthrodesis.MethodsA prospective, single-arm, multicenter clinical trial (NCT 02969616) was conducted in adult subjects (> 18 years of age) undergoing lumbar spinal fusion with CBA graft (CBA used as primary (≥ 50% by volume), with augmentation up to 50%). Radiographic fusion status was assessed by an independent review of dynamic radiographs and CT scans. Clinical outcomes were assessed with the Oswestry Disability Index (ODI), and Visual Analog Scales (VAS) score for back and leg pain. Adverse events were assessed through the 24-month follow-up period. The presented data represents an analysis of available subjects (n = 86) who completed 24 months of postoperative follow-up at the time the data was locked for analysis.ResultsPostoperative 24-month fusion success was achieved in 95.3% of subjects (n = 82/86) undergoing lumbar spinal surgery. Clinical outcomes showed statistically significant improvements in ODI (46.3% improvement), VAS-Back pain (75.5% improvement), and VAS-Leg pain (85.5% improvement) (p < 0.01) scores at Month 24. No subject characteristics or surgical factors were associated with pseudoarthrosis. A favorable safety profile with a limited number of adverse events was observed.ConclusionsThe use of CBA as an adjunct graft material showed high rates of successful lumbar arthrodesis and significant improvements in pain and disability scores. CBA provides an alternative to autograft with comparable fusion success rates and clinical benefits.Trial registrationNCT 02969616.

Bioequivalence assessment of two formulations of empagliflozin in healthy adult subjects

Objective: The objective of the study was to evaluate the bioequivalence (BE) between Izaban® (test) and Jardiance® (reference) empagliflozin 25 mg, oral tablets, in healthy adult subjects. Materials and Methods: A randomized, open-label, two-sequence, and two-period crossover comparative oral bioavailability study was conducted on healthy adult subjects. It was tested BE in vivo using a comparative pharmacokinetic (PK) evaluation. Serial blood samples were collected up to 72 h following oral administration of the study drugs, plasma concentrations of empagliflozin were using liquid chromatography mass spectrometry (LC-MS-MS) method. Results: The test and reference drug products were considered bioequivalent when the geometric means of the test (T)/reference (R) ratios and 90% confidence intervals (CIs) fall within the range of 80.00–125.00%. For PK parameters, % T/R ratios and 90% CIs were Cmax: 105.11% (100.28–110.18%), area under curve (AUC0-t): 103.25% (99.62–107.00%), and AUC0-∞ 102.71% (99.26–106.28%). Conclusion: Our study demonstrated in vivo BE between the two empagliflozin formulations tested in healthy subjects under fasting conditions.

Added γ-oryzanol boosted anti-inflammatory effects of canola oil in adult subjects with type 2 diabetes: a randomized controlled clinical trial.

This study was conducted to examine the effects of daily intake of γ-oryzanol (ORZ)-fortified canola oil, as compared with plain canola and sunflower oils, on certain inflammatory and oxidative stress biomarkers in adult subjects with Type 2 Diabetes (T2D). We randomly allocated 92 adult subjects with T2D from both sexes to one of the following groups to receive: (a) ORZ-fortified canola oil (ORZO; n1 = 30); (b) unfortified canola oil (CANO; n2 = 32); or (c) sunflower oil (SUFO; n3 = 30) for 12weeks. Dietary and laboratory evaluations were performed initially and finally. Serum hs-CRP concentrations significantly decreased in ORZO group (from 3.1 ± 0.2 to 1.2 ± 0.2 mg/L), as compared with CANO (p = 0.003) and SUFO (p < 0.001) groups. Serum IL-6 significantly decreased just in ORZO (-22.8%, p = 0.042) and CANO groups (-19.8%, p = 0.038). However, the between-group differences were not significant. Serum IL-1β slightly decreased in ORZO (-28.1%, p = 0.11) and increased in SUFO (+ 20.6%, p = 0.079) but between-group difference was statistically significant (p = 0.017). Serum IFN-γ concentrations decreased significantly only in ORZO (from 3.3 ± 0.08 to 2.9 ± 0.21 IU/mL, p = 0.044). Salivary IgA concentrations increased significantly in all three intervention groups. Notwithstanding, only the difference between ORZO and CANO groups was statistically significant (p = 0.042). Similarly, circulating malondialdehyde concentrations significantly decreased in all three groups but with no between-group significant difference. Daily consumption of ORZ-fortified canola oil, compared with unfortified canola and sunflower oils, for 12 weeks resulted in boosting of certain anti-inflammatory effects of canola oil. These findings may have preventive implications for both clinicians and policy makers. This clinical trial was registered at clinicaltrials.gov (03.08.2022; NCT05271045).

Category Learning Selectively Enhances Representations of Boundary-Adjacent Exemplars in Early Visual Cortex.

Category learning and visual perception are fundamentally interactive processes, such that successful categorization often depends on the ability to make fine visual discriminations between stimuli that vary on continuously valued dimensions. Research suggests that category learning can improve perceptual discrimination along the stimulus dimensions that predict category membership and that these perceptual enhancements are a byproduct of functional plasticity in the visual system. However, the precise mechanisms underlying learning-dependent sensory modulation in categorization are not well understood. We hypothesized that category learning leads to a representational sharpening of underlying sensory populations tuned to values at or near the category boundary. Furthermore, such sharpening should occur largely during active learning of new categories. These hypotheses were tested using fMRI and a theoretically constrained model of vision to quantify changes in the shape of orientation representations while human adult subjects learned to categorize physically identical stimuli based on either an orientation rule (N = 12) or an orthogonal spatial frequency rule (N = 13). Consistent with our predictions, modeling results revealed relatively enhanced reconstructed representations of stimulus orientation in visual cortex (V1-V3) only for orientation rule learners. Moreover, these reconstructed representations varied as a function of distance from the category boundary, such that representations for challenging stimuli near the boundary were significantly sharper than those for stimuli at the category centers. These results support an efficient model of plasticity wherein only the sensory populations tuned to the most behaviorally relevant regions of feature space are enhanced during category learning.

12-Month Efficacy of Advanced Hybrid Closed-Loop System in Adult Type 1 Diabetes Patients.

Automated insulin delivery (AID) systems have improved glycemic control in individuals with type 1 diabetes (T1D). The "advanced hybrid closed loop" (AHCL) stands out as the most recent development in AID systems for T1D management. In a real-world clinical environment, we retrospectively evaluated the AHCL MiniMed™ 780G system's effectiveness to achieve and sustain glycemic control over a 12-month period in 22 adult T1D subjects. Within just 14 days of activating the automatic mode, the AHCL MiniMed 780G system showed rapid improvement in glycemic control, which persisted for 12 months. These findings underscore the effectiveness of AHCL systems in achieving and preserving optimal glycemic control in adults with T1D over a very long follow-up.

Dysregulated monocyte-derived macrophage response to Group B Streptococcus in newborns.

Streptococcus agalactiae (Group B Streptococcus, GBS) is a leading pathogen of neonatal sepsis. The host-pathogen interactions underlying the progression to life-threatening infection in newborns are incompletely understood. Macrophages are first line in host defenses against GBS, contributing to the initiation, amplification, and termination of immune responses. The goal of this study was to compare the response of newborn and adult monocyte-derived macrophages (MDMs) to GBS. Monocytes from umbilical cord blood of healthy term newborns and from peripheral blood of healthy adult subjects were cultured with M-CSF to induce MDMs. M-CSF-MDMs, GM-CSF- and IFNγ-activated MDMs were exposed to GBS COH1, a reference strain for neonatal sepsis. GBS induced a greater release of IL-1β, IL-6, IL-10, IL-12p70 and IL-23 in newborn compared to adult MDMs, while IL-18, IL-21, IL-22, TNF, RANTES/CCL5, MCP-1/CCL2 and IL-8/CXCL8 were released at similar levels. MDM responses to GBS were strongly influenced by conditions of activation and were distinct from those to synthetic bacterial lipopeptides and lipopolysaccharides. Under similar conditions of opsonization, newborn MDMs phagocytosed and killed GBS as efficiently as adult MDMs. Altogether, the production of excessive levels of Th1- (IL-12p70), Th17-related (IL-1β, IL-6, IL-23) and anti-inflammatory (IL-10) cytokines is consistent with a dysregulated response to GBS in newborns. The high responsiveness of newborn MDMs may play a role in the progression of GBS infection in newborns, possibly contributing to the development of life-threatening organ dysfunction.

Epidemiology of Tracheostomized Adult Patients Admitted to Specialized Weaning Centers After Acute COVID-19.

Epidemiological data on patients with COVID-19 referred to specialized weaning centers (SWCs) are sparse, particularly in low- and middle-income countries. Our aim was to describe clinical features, epidemiology, and outcomes of subjects admitted to SWCs in Argentina. We conducted a prospective, multi-center, observational study between July 2020-December 2021 in 12 SWCs. We collected demographic characteristics, laboratory results, pulmonary function, and dependence on mechanical ventilation at admission, decannulation, weaning from mechanical ventilation, and status at discharge. A multiple logistic model was built to predict home discharge. We enrolled 568 tracheostomized adult subjects after the acute COVID-19 phase who were transferred to SWCs. Age was 62 [52-71], males 70%, Charlson comorbidity index was 2 [0-3], and length of stay in ICU was 42 [32-56] d. Of the 315 ventilator-dependent subjects, 72.4% were weaned, 427 (75.2%) were decannulated, and 366 subjects (64.5%) were discharged home. The mortality rate was 6.0%. In multivariate analysis, age (odds ratio 0.30 [95% CI 0.16-0.56], P < .001), Charlson comorbidity index (odds ratio 0.43 [95% CI 0.22-0.84], P < .01), mechanical ventilation duration in ICU (odds ratio 0.80 [95% CI 0.72-0.89], P < .001), renal failure (odds ratio 0.40 [95% CI 0.22-0.73], P = .003), and expiratory muscle weakness (odds ratio 0.35 [95% CI 0.19-0.62], P < .001) were independently associated with home discharge. Most subjects with COVID-19 transferred to SWCs were weaned, achieved decannulation, and were discharged to home. Age, high-comorbidity burden, prolonged mechanical ventilation in ICU, renal failure at admission, and expiratory muscle weakness were inversely associated with home discharge.