Kilogram Of Body Weight Research Articles

Effects of Gadolinium Deposition in the Brain on Motor or Behavioral Function: A Mouse Model.

Background Recent studies showing gadolinium deposition in multiple organs have raised concerns about the safety of gadolinium-based contrast agents (GBCAs). Purpose To explore whether gadolinium deposition in brain structures will cause any motor or behavioral alterations. Materials and Methods This study was performed from July 2019 to December 2020. Groups of 17 female BALB/c mice were each repeatedly injected with phosphate-buffered saline (control group, group A), a macrocyclic GBCA (group B), or a linear GBCA (group C) for 8 weeks (5 mmol per kilogram of bodyweight per week for GBCAs). Brain MRI studies were performed every other week to observe the signal intensity change caused by the gadolinium deposition. After the injection period, rotarod performance test, open field test, elevated plus-maze test, light-dark anxiety test, locomotor activity assessment test, passive avoidance memory test, Y-maze test, and forced swimming test were performed to assess the locomotor abilities, anxiety level, and memory. Among-group differences were compared by using one-way or two-way factorial analysis of variance with Tukey post hoc testing or Dunnett post hoc testing. Results Gadolinium deposition in the bilateral deep cerebellar nuclei was confirmed with MRI only in mice injected with a linear GBCA. At 8 weeks, contrast ratio of group C (0.11; 95% CI: 0.10, 0.12) was higher than that of group A (-2.1 × 10-3; 95% CI: -0.011, 7.5 × 10-3; P < .001) and group B (2.7 × 10-4; 95% CI: -8.2 × 10-3, 8.7 × 10-3; P < .001). Behavioral analyses showed that locomotor abilities, anxiety level, and long-term or short-term memory were not different in mice injected with linear or macrocyclic GBCAs. Conclusion No motor or behavioral alterations were observed in mice with brain gadolinium deposition. Also, the findings support the safety of macrocyclic gadolinium-based contrast agents. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Chen in this issue.

A Monoclonal Antibody for Malaria Prevention

BackgroundAdditional interventions are needed to reduce the morbidity and mortality caused by malaria.MethodsWe conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS.ResultsA total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 μg per milliliter at the time of controlled human malaria infection.ConclusionsAmong adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.)

Comparison of Different Herbal Additives on Immune Response and Growth Performance of Broiler Chickens

This experiment was conducted to compare the effects of four commercial herbal additives (Noviherb®, Bioessence®, Biostrong®, and Novigrow®), and a commercial antibiotic (virginiamycin) on growth performance, carcass yield, visceral organs weight, thyroid hormones, and humoral immune responses of broiler chickens. Nine hundred day-old Ross 308 male broiler chicks were reared in litter-covered floor cages and distributed into five experimental groups with six replicates of 30 birds. Five dietary treatments tested were diets supplemented with Noviherb®, Bioessence®, Biostrong® (each of them 100g/ton of diet), Novigrow® (1000g/ton of diet), and virginiamycin (100g/ton of diet) as a positive control. Feed intake, body weight, mortality, feed conversion ratio, European broiler index, and feed cost per kilogram of body weight were measured during the experiment. Antibody titers against sheep red blood cells (SRBC), immunoglobulin G, immunoglobulin M, and plasma concentrations of thyroxine (T4) and triiodothyronine (T3) were evaluated at the age of 42 days. Then, four birds per replicate were killed to determine the relative weight of carcass and organs. The GLM procedures of SAS software and Duncan’s multiple range test were applied to analyze data in a completely randomized design with five treatments and six replicates of 30 birds per each. The effects of herbal additives on productive traits feed cost per kilogram of body weight and relative weight of organs were not significant in comparison with antibiotic treatment. Dietary inclusion of Noviherb®, Biostrong®, and Novigrow® significantly decreased feed cost per kilogram of carcass compared with Bioessence® or antibiotic treatments (p&lt;0.05). The titers of IgG in Noviherb® and virginiamycin were significantly higher (p&lt;0.05) than in Biostrong® and Novigrow® fed groups. The plasma concentration of triiodothyronine was significantly decreased (p&lt;0.05) by dietary inclusion of Noviherb® and Novigrow® compared to the antibiotic. In conclusion, all the evaluated herbal additives could act as a substitute for the growth-promoting antibiotic.

Knee Extensor Muscle Strength And The Depressive Status Among Older Japanese Women: A Cross-sectional Study

Depression is commonly regarded as a crucial public health issue because of its detrimental effect on increased mortality and its huge economic burden. Although physical function is generally related depression symptoms, it remains controversial whether lower-extremity muscle strength is a risk factor for geriatric depression symptoms among older women. PURPOSE: To investigate the cross-sectional association between knee extensor muscle strength and geriatric depressive status. METHODS: A cross-sectional study was conducted on 1258 older Japanese women (mean age 71.8 years [standard deviation: 4.3]) who lived in the metropolitan area of Tokyo and were recruited from the basic resident register. They completed an isometric knee extensor muscle strength measurement (newton per kilogram of body weight) and responded to an interview-based questionnaire on their smoking and alcohol consumption habits, history of lifestyle-related diseases (hypertension, stroke, heart disease, diabetes, dyslipidemia, osteoporosis, and cancer), working conditions, hobbies or lessons, participation in volunteer work, living alone status, sleep time, and dietary pattern. Depressive symptoms were defined as a 15-item Geriatric Depression Scale (GDS) score ≥ 6 points. Multivariable odds ratios (OR) and 95 percent confidence intervals (CI) for the presence of depressive symptoms were obtained using a logistic regression model after adjusting for age, body mass index, and the above-mentioned confounding factors. RESULTS: A total of 112 women (8.9%) had geriatric depressive symptoms. After adjusting for various covariates, OR (95% CI) of the depressive symptoms was 1.11 (0.66, 1.89) for the second quartile of knee extensor muscle strength per body weight, 0.38 (0.18, 0.73) for the third quartile and 0.70 (0.38, 1.29) for the fourth quartile, using the first quartile as a reference category (p for trend = 0.04). CONCLUSIONS: Our findings suggest that low muscle strength is associated with geriatric depressive symptoms in older Japanese women. We need to further explore its longitudinal association in the future.

Total water intake by kilogram of body weight: Analysis of the Australian 2011 to 2013 National Nutrition and Physical Activity Survey.

Water is critical for human survival, yet water intake equations may not reflect contemporary populations. This research aims to determine the total water intake of a representative Australian population, per kilogram of body weight (mL/kg) and stratified by age and sex. A secondary analysis of the 2011 to 2013 National Nutrition and Physical Activity Survey (n=10 146) was conducted. Dietary intake from food and beverages was assessed by a 24-hour recall, with respondent's weight objectively measured. Data were descriptively analysed, with multiple linear regressions used to identify the impact of demographic and physiologic factors on total water intake (mL/kg). The median (interquartile range) daily total water intake per kilogram of body weight for children (2-8 years), adolescents (9-18 years) and adults (19+ years) were 77.1 (57.4-100)mL/kg, 40.4 (29.3-53.4)mL/kg and 35.5mL/kg (26.1-47.8), respectively. Increasing height and waist circumference were associated with reduced total water intake, with a change of -1.03 mL/kg (-1.43, -0.618) [coefficient (95% confidence interval)] in children for height and -0.448 mL/kg (-0.484, -0.412) in adults for waist circumference. Similarly, seasonality decreased intake, with greatest reductions in winter [adolescents: -4.11 mL/kg (-6.83, -1.40)]. In comparison, being male, living in rural areas and having a physical occupation were associated with greater intake, by 1.73 mL/kg (0.347, 3.10), 4.74 mL/kg (3.47, 6.00) and 2.82 (trade workers: 1.08, 4.59) in adults, respectively. Total water intake (mL/kg) decreased with age in both sexes. The results highlight possibilities to incorporate other factors into water intake equations to improve their accuracy.

A Trial of Hyperimmune Globulin to Prevent Congenital Cytomegalovirus Infection

BackgroundPrimary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection.MethodsIn this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks’ gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed.ResultsFrom 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P=0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo.ConclusionsAmong pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks’ gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.)

Long-term activity of tandem CD19/CD20 CAR therapy in refractory/relapsed B-cell lymphoma: a single-arm, phase 1\u20132 trial

Increasing the remission rate and reducing the recurrence rate can improve the clinical efficacy of chimeric antigen receptor (CAR) T cell therapy in recurrent/refractory non-Hodgkin lymphoma (r/rNHL). In this open-label, single-arm phase I/II trial, 87 patients with r/rNHL, including 58 patients with aggressive diffuse large B-cell lymphoma and 24 with high tumour burden, received an infusion at doses of 0.5 × 106–8 × 106 TanCAR7 T cells per kilogram of body weight after conditioning chemotherapy. The best overall response rate was 78% (95% confidence interval [CI], 68–86); response rates were consistent across prognostic subgroups. The median follow-up was 27.7 months. The median progression-free survival was 27.6 months (95% CI, 11 to not reached). Cytokine release syndrome (CRS) occurred in 61 patients (70%) with 60% of cases being grade 1 or 2 and 10% being grade 3 or greater. Grade 3 CAR T cell-related encephalopathy syndrome (CRES) occurred in 2 patients (2%). Two patients died from treatment-associated severe pulmonary infection, and one died from CRS-related pulmonary injury between 1 and 3 months post infusion. Long-term remissions were observed following the use of TanCAR7 T cells in r/rNHL with a safety profile that included CRS but few cases of CRES.

Myocardial fibrosis quantification methods by cardiovascular magnetic resonance imaging with contrast-enhancement in patients with Fabry disease

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): National Agency for Academic Exchange (NAWA). Background. Presence and extent of late gadolinium enhancement (LGE) in patients with Fabry disease (FD) is a predictor of adverse cardiac events. However there is no gold standard method to quantify the amount of myocardial fibrosis in cardiac magnetic resonance imaging (CMR). Purpose. The aim of this study was to establish the most reliable and reproducible technique for quantifying LGE in patients with FD. Methods. 68 patients with FD (40% male, 40 ± 16 years old) treated in our outpatient clinic, who underwent CMR with administration of 0.2 mmol of gadobutrol per kilogram of body weight between December 2012 and March 2019 were enrolled into the study. Presence of LGE was described in 25 patients (37%). Twenty patients underwent CMR with the same LGE sequence (Philips 1.5 Tesla, two-dimensional multi-breath-hold inversion recovery sequence) and were enrolled into further analysis. LGE quantifications were performed using gray-scale thresholds with 2, 3, 4, 5 and 6 standard deviations (SD) above the mean signal intensity for the remote myocardial tissue, full width at half maximum method (FWHM), visual assessment with threshold (VAT) and fully manual method (MM; Philips IntelliSpace Portal 10). LGE quantifications were done twice by the same observer in different time periods and once by another observer. Intraclass correlation coefficient (ICC), Bland- Altman analysis and coefficient of variation (CV) were used to assess intra- and interobserver reliability and reproducibility. Results. The mean quantity of fibrosis mass (in gram) in all studied patients was: 35.5 ± 18.7 at 2SD, 21.0 ± 12.8 at 3SD, 12.7 ± 8.5 at 4SD, 8.0 ± 5.7 at 5SD, 5.3 ± 4.1 at 6SD, 1.9 ± 1.8 at FWHM, 8.6 ± 7.4 at VAT and 9.1 ± 6.1 at MM. Intra-observer reliability of almost all studied LGE quantification methods was excellent, with a range of ICCs from 0.90 for 6SD to 0.95 for VAT, with one exception for FWHM, which had good intraobserver reliability (ICC 0.84; all P &amp;lt; 0.05). Interobserver reliability was excellent for VAT (ICC 0.94) and good for all other LGE quantifications methods (range of ICCs from 0.76 for MM to 0.87 for 5SD, all P &amp;lt; 0.05). 5SD had the lowest CV (6%) for intraobserver reproducibility and 2SD and VAT for interobserver reproducibility (35% and 38%). FWHM had the highest CV for both intra- and interobserver reproducibility (63% and 94%, accordingly). Conclusions 1. All studied methods of LGE quantification in patients with FD and presence of myocardial fibrosis have good to excellent intra- and interobserver reliability. 2. The total amount of LGE differs in studied LGE quantifications methods. Therefore in clinical practice it is important to report which technique of LGE quantification was used and choose the same for CMR-follow up. 3. FWHM might be avoided for LGE quantification in patients with FD due to the highest intra- and interobserver variability in comparison to other available techniques.

Reawakening of Human Fetal Hemoglobin and an Epigenetic Path to the Clinic for Sickle Cell Disease and Beta-Thalassemia: Identification of an Orally-Available, Potent, and Selective Euchromatic Histone Lysine Methyltransferase 1 and 2 (EHMT1/2) Inhibitor

Expression of genes in the β-globin locus switch via epigenetic control at key stages of early gestational development from an embryonic (HbE, α2ε2) to fetal form (HbF, α2γ2) and again around birth to the adult form (HbA, α2β2). Sickle cell disease (SCD) is a multi-organ genetic disorder caused by a point mutation in the adult β-globin gene producing sickled hemoglobin (HbS, α2βs2). It is well-established that SCD patients carrying genetic variations in HbF-regulatory loci have a concomitant increase in blood levels of HbF (ranging from 5-25% of total Hb). These individuals exhibit fewer major crises or no clinical symptoms, suggesting that re-expression of the γ-gene and increasing HbF is a potential disease modifying treatment approach for SCD patients. Hydroxyurea (HU) and L-glutamine are currently the only FDA-approved drugs for the treatment of SCD, with HU working in-part, through the re-induction of HbF. Safety and efficacy responses to HU vary widely, and there remains a strong need for more robust HbF induction strategies with improved safety profiles.Previous groups have shown that inhibitors to various epigenetic modifiers are able to overcome γ-gene silencing and induce HbF; however, associated defects in hematopoiesis have been reported. Recently, histone methytransferase enzymes EHMT1 and EHMT2, responsible for the repressive chromatin mark dimethyl-lysine 9 on histone H3 (H3K9me2), have been shown to be essential for robust repression of γ-globin expression. To-date, an in vitro tool compound UNC0638 has demonstrated activation of γ-globin expression in human adult erythroid progenitor cells but no evaluation of in vivo efficacy of EHMT1/2 inhibition on HbF induction has been possible due to a lack of drug-like properties.Here we describe the generation and characterization of a potent, selective, and orally available small molecule inhibitor of EHMT1/2, EPZ035544. EHMT2 enzymatic activity in a biochemical assay, as measured by the half-maximal inhibitory concentration (IC50) is 10nM and cellular inhibition of H3K9me2 correlated well with an IC50 of 55nM. Treatment of EPZ035544 in primary human CD34+ progenitor cells led to dose-dependent decreases in H3K9me2 with concomitant induction of γ-globin relative to β-globin expression of 10-30% as measured by mass spectrometry and qPCR leading to 100% of F-positive cells. Chromatin immunoprecipitation and sequencing studies performed on EPZ035544-treated CD34+ cells demonstrated that H3K9me2 was reduced throughout the genome with an associated increase in H3K9Ac. The γ-globin gene locus displayed a reduction of H3K9me2 and an increase of H3K9Ac and RNA Polymerase II occupancy leading to significantly increased γ-globin gene expression upon EPZ035544 treatment.The drug-like properties of EPZ035544 enabled the first prolonged in vivo investigation of an EHMT1/2 inhibitor by continuous oral dosing over 90 days in C57BL/6 mice. As mice do not have HbF, we measured the levels of embryonic hemoglobin (Hbb-εy) which is normally repressed after birth. We performed twice-daily (BID) oral dosing in two dose groups: 25 and 50 mg per kilogram of body weight (mg/kg) and once-daily (QD) oral dosing in a single dose group of 75 mg/kg. Dose-dependent increases in the absolute levels of Hbb-εy mRNA in peripheral blood mononuclear cells (PBMCs) were observed with maximal induction of ~ 100 fold achieved at the 50 mg/kg BID and 75 mg/kg QD doses. Using quantitative mass spectrometry, we also observed drug-induced increases in Hbb-εy at the protein level. A corresponding reduction in H3K9me2 levels in PBMCs and bone marrow, as measured by flow cytometry and ELISA, strongly suggests that these effects were a direct consequence of EHMT1/2 inhibition. EPZ035544 was well tolerated throughout the study with no significant changes observed in body weights, spleen weights, or complete blood cell counts. In summary, we have developed an orally bioavailable EHMT1/2 inhibitor with demonstrated on-target in vivo induction of mouse Hbb-εy expression with up to 90 days of continuous dosing. To our knowledge this is the first study to test the in vivo effects of an EHMT1/2 inhibitor on hemoglobin induction. We believe this approach holds promise as a novel treatment option for β-globinopathies, and we continue to advance our program towards the clinic. DisclosuresChan-Penebre:Epizyme Inc.: Employment, Equity Ownership. Gibaja:Epizyme Inc.: Employment, Equity Ownership. Campbell:Epizyme Inc.: Employment, Equity Ownership. Olu:Epizyme Inc.: Employment, Equity Ownership. Admirand:Epizyme Inc.: Employment, Equity Ownership. Brach:Epizyme Inc.: Employment, Equity Ownership. Tang:Epizyme Inc.: Employment, Equity Ownership. Raimondi:Epizyme Inc.: Employment, Equity Ownership. Hood:Epizyme Inc.: Employment, Equity Ownership. Cocozaki:Epizyme Inc.: Employment, Equity Ownership. Karaman:Epizyme Inc.: Employment, Equity Ownership. Stickland:Epizyme Inc.: Employment, Equity Ownership. Munchhof:Michael J. Munchhof LLC: Consultancy. Armstrong:Epizyme Inc.: Employment, Equity Ownership. Riera:Epizyme Inc.: Employment, Equity Ownership. Orkin:Bioverativ: Consultancy; Epizyme Inc.: Consultancy. Boriack-Sjodin:Epizyme Inc.: Employment, Equity Ownership. Janzen:Epizyme Inc.: Employment, Equity Ownership. Blakemore:Epizyme Inc.: Employment, Equity Ownership. Ribich:Epizyme Inc.: Employment, Equity Ownership. Chesworth:Epizyme Inc.: Employment, Equity Ownership. Smith:Epizyme Inc.: Employment, Equity Ownership. Duncan:Epizyme Inc.: Employment, Equity Ownership.

Feline comorbidities: Pathophysiology and management of the obese diabetic cat.

Up to 40% of the domestic feline population is overweight or obese. Obesity in cats leads to insulin resistance via multiple mechanisms, with each excess kilogram of body weight resulting in a 30% decline in insulin sensitivity. Obese, insulin-resistant cats with concurrent beta-cell dysfunction are at risk of progression to overt diabetes mellitus. In cats that develop diabetes, appropriate treatment includes dietary modification to achieve ideal body condition (for reduction of insulin resistance), and optimization of diet composition and insulin therapy (for glycemic control and the chance of diabetic remission). Initially, as many obese cats that become diabetic will have lost a significant amount of weight and muscle mass by the time of presentation, some degree of diabetic control should be attempted with insulin before initiating any caloric restriction. Once body weight has stabilized, if further weight loss is needed, a diet with ≤ 12-15% carbohydrate metabolizable energy (ME) and >40% protein ME should be fed at 80% of resting energy requirement for ideal weight, with the goal of 0.5-1% weight loss per week. Other approaches may be necessary in some cats that need either substantial caloric restriction or do not find low carbohydrate diets palatable. Long-acting insulins are preferred as initial choices and oral antidiabetic drugs can be used in combination with diet if owners are unable or unwilling to give insulin injections. Glucagon-like peptide-1 (GLP-1) agonists have recently been investigated for use as adjunctive treatment in diabetic cats and sodium-glucose cotransporter-2 (SGLT2) inhibitors are currently being evaluated in clinical trials. The information in this review is drawn from: epidemiological studies on obesity prevalence; prospective longitudinal studies of development of insulin resistance with obesity; randomized controlled studies; and expert opinion regarding the effect of diet on diabetes management in cats.

Effective Treatment of Relapsed/Refractory Multiple Myeloma Including Extramedullary Involvement By BCMA-Specific Chimeric Antigen Receptor-Modified T Cells

Relapsed and refractory (R/R) multiple myeloma patients have very poor prognosis, especially when they present extramedullary lesions. Currently, chimeric antigen receptor-modified T cells (CAR-T) for lymphoproliferative diseases such as B-precursor acute lymphoblastic leukemia and B-cell lymphoma have yielded encouraging therapeutic effects. However, clinical study on the efficacy of CAR-T in multiple myeloma is just at beginning. B cell maturation antigen (BCMA) displays restricted expression on plasma cells and is regarded as a potential therapeutic target in myeloma patients. In this one arm trial approved by the IRBs of the participating hospitals, bi-epitope targeting CAR-T with specificity against BCMA (LCAR-B38M) was used to treat R/R multiple myeloma. As of 2017-7-31, 5 patients (RJ01-03, CZ01-02, including 2 females and 3 males; average age: 51 years) were enrolled in the study. Their Ig subtypes were: IgG lamda in 2 cases, IgG kappa in 2 cases and IgD lamda in one case. Relapse occurred in all patients after treatment with classical chemotherapy, immunomodulatory drugs and proteosome inhibitors, 3 of them had also received autologous hematopoietic stem cell transplantation. Plasma cells accounted for 3% in one case (RJ03) and 22 to 69% in 4 cases among BM cells. BCMA was positive on plasma cells in all cases. Plasma M-proteins were at abnormally high levels (11.52-64.53g/L) in all these cases, and free light chains were positive in 4 cases but negative in the case RJ03. Of note, two patients exhibited extramedullary lesions. One bore plasmacytoma on the forehead and the other presented extramedullary involvement in the lower jaw, chest skin and liver. Interphase fluorescence in situ hybridization (FISH) detected high risk chromosome abnormalities in 3 cases, including one with 1q21 amplification, one with TP53 deletion, and one carried both of these two abnormalities. Split FISH signal of IGH was detected in 2 cases, though not juxtaposing to the common known high risk partner genes.Patients underwent leukopheresis to collect T-cells for the preparation of BCMA-specific CAR-T. Pre-CAR-T treatment was performed with fludarabine (25mg/m2) and cyclophosphamide (250mg/m2) daily for 3 days (d-5~d-3). A dose of 0.17 or 1.05×106 (median=0.62) CAR-T cells per kilogram of body weight was intravenously infused on three days (d0, d2, and d6). At one month after CAR-T treatment, all 5 patients achieved an objective response, 1 achieving immunophenotypic complete remission, 1 reaching very good partial remission and 3 obtaining partial remission. Figure 1 shows the return to negativity of BM minimal residual disease and serum M protein in the case RJ01 at two months post CAR-T. Notably, large subcutaneous masses seen in two patients (RJ02, RJ03) were significantly reduced after treatment (Figure 2a and 2b). Peripheral blood CAR-Ts were consistently detected after infusion (Figure 3). The most common adverse effects were the high fever and hypotension attributable to cytokine release syndrome (CRS) and were manageable with nonsteroidal anti-inflammatory drugs (NSAIDs) or tocilizumab. The fluid was supplemented to maintain the blood pressure in case of need. No dose-limiting toxicities or treatment-related deaths were observed. Therefore, BCMA-specific CAR-T represents a promising safe therapeutic approach for R/R multiple myeloma, including cases with severe extramedullary invasions.Figure 1. Minimal residual disease (MRD) and serum M protein in patient RJ01. (a) Flow cytometry detection of bone marrow MRD (CD138+CD38+CD56+CD19-) before and two months after CAR-T therapy. (b) The change of plasma M protein concentration after CAR-T infusion. The final assessment was on day 65 post CAR-T.Figure 2. Subcutaneous masses reduction in patients with extramedullary plasmacytoma. (a) A large number of immature plasma cells are seen on the smears obtained from the mass on the forehead of the case RJ02 (black arrows). On day 20 post CAR-T infusion, the plasmacytoma on the forehead was remarkably reduced. Scale bar=10µm. (b) The histopathology reveals that the mass of the lower jaw in the case RJ03 was a plasmacytoma, which was largely reduced on day 23 post CAR-T. Scale bar=100µm.Figure 3. CAR-T cells in peripheral blood of the patient RJ02. Flow cytometry shows the percentage of BCMA specific CAR-T cells in CD3 positive peripheral T cells. The time course is indicated as days (d) after CAR-T infusion. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Home-Delivered Meals: Characterization of Food Intake in Elderly Beneficiaries.

Objective. In this study, we focus on elderly people (≥70 years old) benefiting from a home delivery meal service as part of a social welfare program. We aimed to: (i) assess the gap between the recommended and actual nutritional intake in this population and (ii) study the relationship between the intake of nutrients and the variables characterizing the participants’ health and nutritional status. Design. A dietary survey (24-hour record) was conducted during a home interview, with 64 people receiving a home delivery meal service (75% women; 70–97 years old). At the same time, the participants answered questionnaires assessing their nutritional and health status. Results. Our data showed that the consumption of 70 to 80% participants was not sufficient for reaching the nutritional recommendations for energy and macronutrients. Additionally, the data showed that the lower the energy and protein intakes, the higher the risk of malnutrition. In addition, one third of the participants were both overweight or obese and at risk of undernutrition or undernourished. Our study demonstrated that the heavier the person, the more difficult it was for them to meet the nutritional recommendations based on kilograms of body weight. Finally, individuals receiving two to three delivered meals per day had higher energy and protein intakes than those receiving a single meal. Conclusion. These results suggest that it is important that home meal delivery companies improve the quality of their meals and service so that their recipients can better meet nutritional recommendations.

New volumetric capnography-derived parameter: a potentially valuable tool for detecting hyperventilation during cardiopulmonary resuscitation in a porcine model.

BackgroundVolumetric capnography is increasingly being applied in cardiopulmonary resuscitation. However, during cardiopulmonary resuscitation, the abnormal ventilation state affects the monitoring effect of the most commonly used capnography-derived parameter, the partial carbon dioxide end-tidal pressure (PetCO2). In this study, we evaluated the ability of a new volumetric capnography-derived parameter, the ratio between the PetCO2 and the volume of carbon dioxide (CO2) eliminated per min and per kilogram of body weight, for detecting hyperventilation during cardiopulmonary resuscitation.MethodsWe used 12 porcine models of primary ventricular fibrillation-induced cardiac arrest. Ventricular fibrillation was induced and left untreated for 4 min. Standardized chest compressions were performed throughout the experiment using mechanical cardiopulmonary resuscitation. Following 5 min of normal ventilation as a washout period, each animal underwent 4 types of ventilation. The main outcome measures were the PetCO2, the ratio between the PetCO2 and the volume of CO2 eliminated per min and per kilogram of body weight with each ventilation type.ResultsDifferent ventilation types had a significant effect on the volumetric capnography-derived parameters. The PetCO2 and ratio between the PetCO2 and the volume of CO2 eliminated per min and per kilogram of body weight values during cardiopulmonary resuscitation was significantly higher in non-hyperventilating than in hyperventilating animals. The ratio reflected hyperventilation accurately and immediately, with an area under the curve (AUC) of 0.98. The optimal cut-off point of the ratio for discriminating hyperventilation from non-hyperventilation was 6.36, with a sensitivity and specificity of 0.99 and 0.89, respectively.ConclusionsThe ratio between the PetCO2 and the volume of CO2 eliminated per min and per kilogram of body weight showed good performance in discriminating hyperventilation from non-hyperventilation and was sensitive to changes in ventilation status. This ratio may be a valuable clinical indicator for monitoring the ventilation status during cardiopulmonary resuscitation.

Nutritional Intake by Meal Time Zone in Geriatric Patients Is Related to Nutritional Assessment Index.

BackgroundThe blood metabolome profiles depend on the meal intake time zone regardless of having the same meal. The serum albumin (Alb) level, which is important in managing geriatric patients with chronic diseases, is included in the metabolome analysis. In this study, we aimed to examine the relationship between Alb and the nutritional value of hospital meals consumed at breakfast, lunch, and dinner among geriatric patients. Chrononutrition was considered while drawing inferences.MethodsWe retrospectively surveyed 52 geriatric patients with chronic diseases (aged 79.7 ± 8.7 years) admitted at a small-scale hospital providing combined healthcare measures and oral nutritional support. The dietary intake per kilogram of body weight of nutritional components for breakfast, lunch, and dinner was individually expressed as the ratio to the whole daily food intake. The dietary pattern was determined by principal component analysis. We also conducted linear regression analysis, with Alb as the dependent variable, and age, sex, and grade assigned in this study as well as the first, second, and third principal components of the dietary patterns as the independent variables.ResultsThree principal components with an eigenvalue of > 1 were extracted. The second principal component was a significantly negative determinant factor for Alb (B = -0.108, P = 0.016). In patients with high Alb levels, the energy, protein, and fat ratios at lunch were positively correlated, while the energy and carbohydrate ratios at dinner were negatively correlated. Mealtimes were fixed.ConclusionsThe results of this study showed that the dietary pattern predominantly observed in patients with high Alb levels may be positively associated with Alb synthesis.

Case 294.

History A 50-year-old woman presented to the emergency department of our hospital with a 2-day history of lower limb pain associated with unusual asthenia and diffuse arthralgia over the past 3 weeks. She was a native of Guinea and had lived in France for most of her life, working as a personal care assistant. Her only medical history of note was an occurrence of fetal death at 12 weeks gestation when she was 35 years old. She had bilateral lower limb swelling, without changes in skin temperature or color. All proximal and distal arterial pulses were felt. General physical examination findings were otherwise unremarkable. Her laboratory tests showed a decreased hemoglobin concentration of 8.9 g/dL (normal range, 12-16 g/dL), a decreased platelet count of 45 × 109/L (normal range, 150-400 × 109/L), a C-reactive protein level of 158 mg/L (normal range, <5 mg/L) and a d-dimer level of 2000 mg/L (normal range, <500 mg/L). Compression US of the lower limbs revealed bilateral calf vein thrombosis involving the fibular and posterior tibial veins. Curative anticoagulation using low-molecular-weight heparin (enoxaparin, subcutaneous injection of 100 units per kilogram of body weight twice a day) was started. The day after the start of anticoagulation therapy, the patient reported dyspnea and acute chest and abdominal pain. Her vital signs were assessed, and she had elevated blood pressure and increased heart rate and respiratory rate, but she remained afebrile. Her cardiac auscultation was unremarkable, besides tachycardia. Skin examination revealed small areas of necrosis on the fingertips of her right hand. Laboratory studies were repeated and showed an increase in serum creatinine level from a baseline value of 0.49 mg/dL to a new value of 1.01 mg/dL (normal range, 0.6-1.1 mg/dL), an apparition of low-grade proteinuria of 0.43 g per day (normal range, <0.3 g/day), and a high serum troponin level of 1066 ng/L (normal range, <14 ng/L), whereas electrocardiography showed no ST segment modification and echocardiography revealed a moderately altered left ventricular ejection fraction (45%). There was no coronary occlusion seen at emergency coronarography. Contrast-enhanced CT of the chest, abdomen, and pelvis was performed (Figs 1, 2) together with cardiac MRI (Figs 3, 4).

The effect of intense physical activity session with glutamine supplementation on selected factors of wrestlers' immune system

Athletes with heavy training loads are prone to infectious diseases. It has been shown that these exercises may suppress immune function. The aim of this study was to investigate the effect of one session of intense physical activity with glutamine supplementation on selected factors of wrestlers' immune system. For this purpose, 20 wrestlers were selected and randomly divided into two groups of supplement and placebo. The first blood sample was taken from the subjects. Then they did the Bruce test. Immediately after the end of the test, blood samples were taken from the subjects for the second time and then to the supplement group. The glutamine supplement was given the same amount of maltodextrin per kilogram of body weight and the placebo group. Blood samples were taken from the subjects for the third and fourth time 1 and 2.5 hours after taking the supplement or placebo. After measuring blood factors, the findings were statistically analyzed (ANOVA) at a significance level of p &lt;0.05. The results showed that the percentage of neutrophils in the supplement group increased significantly 2.5 hours after supplementation compared to immediately after exercise and 1 hour after supplementation. This increase was less in the supplement group than in the placebo group. The percentage of lymphocytes in the supplement group decreased significantly 2.5 hours after supplementation compared to the pre-test, immediately after exercise and 1 hour after supplementation, which was less in the supplement group than the placebo group. The percentage of monocytes in the supplement group increased significantly 2.5 hours after supplementation compared to immediately after exercise. This increase was less in the supplement group than in the placebo group. The results of this study showed that glutamine supplementation during strenuous exercise has beneficial effects on the immune system of athletes.

Donor-derived CD7 CAR T cells for T-cell acute lymphoblastic leukemia.

10001 Background: Despite the success of chimeric antigen receptor T cell therapy in B cell malignances, there is currently no proved CAR T treatment for T cell neoplasms. We provide first evidence support the use of donor derived CAR T cells in T cell leukemia. Methods: In this phase 1 trial, CD7 CAR T cells were manufactured with T cells from prior SCT prior to a single infusion at doses of 5 × 105 or 1 × 106 (± 30%) cells per kilogram of body weight. donors, or from new donors who were HLA-matched or haploidentical, via leukopheresis and transduced with a lentiviral vector which carries a CD7 CAR construct. The primary endpoint was safety. Short-term efficacy was also assessed. Results: Results of 20 enrolled patients who received infusion are reported. Of 20 patients, 12 received previous HSCT-donor derived CAR T cells and 8 received fresh haplo-identical donor derived CAR T cells and plan to received transplantation as consolidation after remission.Adverse events included grade 3-4 hematologic toxicity in all (100%), grade 3-4 and grade 1-2 cytokine release syndrome in 2 (10%) and in 18 (90%), grade 1 neurotoxicity in 3 (15%), grade 1-2 graft-versus-host disease in 12 (60%), and grade 1 viral activation in 3 (15%) patients. Nineteen (95%) patients had a response, including 18 (90%) with complete remission and 1 (5%) with partial remission. Of 19 responders, 7 were bridged to SCT and remained minimal residual disease (MRD)-negative until last visit; 12 were followed up at a medium of 4.4 months, among whom 9 remained MRD-negative, 1 had a relapse, 1 discontinued for other treatment, and 1 died of pulmonary fungal infection at 5.5 months. CAR cells mostly persisted beyond 3 months. Patient CD7-positive healthy T cells were depleted, while CD7-negative T cells increased. Conclusions: We report the initial toxicity profile and anti-leukemia activity of a donor-derived CD7-targeted cellular immunotherapy for patients with relapsed or refractory T-ALL. (Funded by the National Key R&amp;D program; ChiCTR.org number, ChiCTR2000034762). Clinical trial information: ChiCTR2000034762. [Table: see text]

New PFAS health risk levels cement gap between US agencies

A division of the US Department of Health and Human Services has finalized health risk levels for four per- and polyfluoroalkyl substances (PFAS). PFAS are valuable as manufacturing aids and in consumer products for properties such as resistance to heat, stains, and water. But those properties also mean that they are environmentally persistent, and several have been linked to cancer and other health problems. The Agency for Toxic Substances and Disease Registry (ATSDR) says the minimal risk level for perfluorooctanoic acid (PFOA) is 3 × 10 –6 mg per kilogram of body weight per day, while the level for perfluorooctanesulfonic acid (PFOS) is 2 × 10 –6 mg per kilogram of body weight per day. Those levels are an order of magnitude lower than the Environmental Protection Agency’s advisory safe daily dose levels. For two other substances evaluated by the ATSDR, perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA), the EPA

The effects of intravenous infusion of autologous mesenchymal stromal cells in patients with subacute middle cerebral artery infarct: a phase 2 randomized controlled trial on safety, tolerability and efficacy

Background aimsMesenchymal stromal cells (MSCs) are characterized by paracrine and immunomodulatory functions capable of changing the microenvironment of damaged brain tissue toward a more regenerative and less inflammatory milieu. The authors conducted a phase 2, single-center, assessor-blinded randomized controlled trial to investigate the safety and efficacy of intravenous autologous bone marrow-derived MSCs (BMMSCs) in patients with subacute middle cerebral artery (MCA) infarct. MethodsPatients aged 30–75 years who had severe ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 10–35) involving the MCA territory were recruited within 2 months of stroke onset. Using permuted block randomization, patients were assigned to receive 2 million BMMSCs per kilogram of body weight (treatment group) or standard medical care (control group). The primary outcomes were the NIHSS, modified Rankin Scale (mRS), Barthel Index (BI) and total infarct volume on brain magnetic resonance imaging (MRI) at 12 months. All outcome assessments were performed by blinded assessors. Per protocol, analyses were performed for between-group comparisons. ResultsSeventeen patients were recruited. Nine were assigned to the treatment group, and eight were controls. All patients were severely disabled following their MCA infarct (median mRS = 4.0 [4.0–5.0], BI = 5.0 [5.0–25.0], NIHSS = 16.0 [11.5–21.0]). The baseline infarct volume on the MRI was larger in the treatment group (median, 71.7 [30.5–101.7] mL versus 26.7 [12.9–75.3] mL, P = 0.10). There were no between-group differences in median NIHSS score (7.0 versus 6.0, P = 0.96), mRS (2.0 versus 3.0, P = 0.38) or BI (95.0 versus 67.5, P = 0.33) at 12 months. At 12 months, there was significant improvement in absolute change in median infarct volume, but not in total infarct volume, from baseline in the treatment group (P = 0.027). No treatment-related adverse effects occurred in the BMMSC group. ConclusionsIntravenous infusion of BMMSCs in patients with subacute MCA infarct was safe and well tolerated. Although there was no neurological recovery or functional outcome improvement at 12 months, there was improvement in absolute change in median infarct volume in the treatment group. Larger, well-designed studies are warranted to confirm this and the efficacy of BMMSCs in ischemic stroke.

Therapeutic Efficacy of Aerobic Exercise Training along with Oak Husk Hydroalcoholic Extract for Amelioration of Inflammation in Obese Elderly Male Mice.

Background Fibrinogen and interleukin-1β as a proinflammatory cytokine and interleukin-10 and nesfatin-1 as an anti-inflammatory cytokine have an important role in the development and prevention of systemic inflammation and incidence of obesity-induced diseases. Thus, this study is aimed at the interaction effects of aerobic training and oak husk hydroalcoholic extract consumption on plasma levels of fibrinogen, interleukin-1β, nesfatin-1, and interleukin-10 in obese elderly male mice. Materials and Methods In this experimental study, 40 fat male mice were fed a high-fat diet for 4 weeks to induce obesity, and subsequently, they were divided randomly into four groups: control, supplement, exercise-placebo, and exercise-supplement. The training groups performed aerobic exercise 5 days a week for 6 weeks (approximately 80-75% VOmax2). The supplement groups received a solution of oak husk hydroalcoholic extract at a dose of 20 milligram per kilogram of body weight for 6 weeks. Blood samples were taken 48 h after the last training session, and the levels of IL-10, fibrinogen, IL-1β, and nesfatin-1 were measured. Data were analyzed using one-way ANOVA and LSD post hoc tests. Results The results showed that six-week training and oak husk hydroalcoholic extract consumption significantly increased the levels of IL-10 and nesfatin-1 in experimental groups (P < 0.001). Also, the levels of fibrinogen and IL-1β decreased significantly in training groups. Averages between group variations of all indicators were statistically significant, and they were more meaningfully pronounced in the exercise-supplement group than other groups (P ≤ 0.05). Conclusions Considering the results of the present study, the use of moderate aerobic exercise and oak husk hydroalcoholic extract is recommended to reduce the risk of obesity; it may also have a positive effect on inflammatory factors.