Kilogram Of Body Weight Research Articles

Associations between dietary pesticide residue mixture exposure and mortality in a population-based prospective cohort of men and women

BackgroundThere is a concern that pesticide residues, regularly detected in foods, might pose a health risk to the consumer, but epidemiological evidence is limited. We assessed the associations between dietary exposure to a mixture of pesticide residues and mortality. MethodsFood consumption was assessed in 68,844 participants from the Swedish Mammography Cohort and the Cohort of Swedish Men, 45–83 years at baseline (1997). Concentrations of pesticide residues detected in foods on the Swedish market (1996–1998), mainly fruits and vegetables, were obtained via monitoring programs. To assess mixture effects, we summed per food item the ratios of each single pesticide mean residue concentration divided by its acceptable daily intake to create for each participant a Dietary Pesticide Hazard Index (adjusted for energy intake and expressed per kilogram of body weight). Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95 % confidence intervals (95 %CI). ResultsDuring 15 years of follow-up (1998–2014), a total of 16,527 deaths occurred, of which 6,238 were caused by cardiovascular disease (CVD) and 5,364 by cancer. Comparing extreme quintiles of Dietary Pesticide Hazard Index, the highest category was inversely associated with CVD mortality HR, 0.82 (95 % CI, 0.75–0.90) and with cancer mortality HR 0.82 (95 % CI 0.75–0.91). In analyses stratified by high/low Dietary Pesticide Hazard Index, similar inverse associations were observed by increasing fruit and vegetable consumption. ConclusionsWe observed no indications that dietary exposure to pesticide residue mixtures was associated with increased mortality, nor any clear indications that the benefits of fruit and vegetable consumption on mortality was compromised. Yet, our results need to be interpreted with caution.

How Do Older Patients with End-Stage Osteoarthritis of the Hip Eat Prior to Hip Replacement? A Preliminary Snapshot That Highlights a Poor Diet

Diet quantity and quality in older adults is critical for the proper functioning of the musculoskeletal system. In view of hip surgery, old patients should consume 1.2–1.5 g of proteins and 27–30 kcal per kilo of body weight daily, and adhere to healthy eating habits. In this analytical study, we studied diet quantity and quality in relation to the clinical chemistry and functional status of 57 older adults undergoing elective hip replacement. Nine in ten patients did not meet suggested protein and energy intakes and only one in ten patients exhibited high adherence to the Mediterranean diet. Legume consumption adjusted for sex, age, body mass index, and health status successfully forecasted haemoglobin levels (p < 0.05), and patients regularly consuming olive oil reported minor hip disability compared to those using it less frequently (p < 0.05). Patients who reported daily ingestion of <1 serving of meat versus those consuming >1.5 servings had greater cumulative comorbidity (p < 0.05), with meat consumption independently predicting walking ability, mobility, and balance in the fully adjusted model (p < 0.01). In conclusion, our patients seem to eat poorly. There is room for improvement in pre-operative pathways to make older adults eat better, but there is a need to plan an interventional study to fully understand the cause–effect of a dietary pattern or specific food in enhancing recovery after surgery.

Associations between High Protein Intake, Linear Growth, and Stunting in Children and Adolescents: A Cross-Sectional Study.

Childhood and adolescence are critical periods for linear growth and preventing stunting. Current evidence indicates that dietary protein intake in children and adolescents is often two to three times higher than the recommendations in many regions worldwide. However, few studies have focused on the association between high protein intake and linear growth and stunting in this population. We aim to investigate this association in children and adolescents aged 6 to 18 years in a population with relatively high protein consumption. We conducted a large cross-sectional study involving 3299 participants from Shenzhen, a modern metropolis of China. Protein intake, including total protein, animal protein, and plant protein, was evaluated by a food-frequency questionnaire and expressed as grams per kilogram of body weight per day (g·kg-1·d-1) and as a percentage of total energy intake (%E). The primary outcomes were body height and height-for-age Z score (HAZ). Generalized linear models and logistic regression analyses were employed to examine the associations between protein intake and outcomes. We also conducted stratified analyses across different genders and pubertal stages in the aforementioned associations. The mean protein intake was 1.81 g·kg-1·d-1 (17% E). After adjusting for serum calcium, zinc, vitamin D3, vitamin A levels, birth outcomes, lifestyle, and parental characteristics, each standard deviation increase of 1 in protein intake (0.64 kg-1·d-1) is found to be associated with a -5.78 cm change in body height (95% CI: -6.12, -5.45) and a -0.79 change in HAZ (95% CI: -0.84, -0.74). Consistent results were observed when protein intake was expressed as %E or specifically as animal or plant protein. Moreover, the relationship between protein intake and linear growth remained consistent across genders in different pubertal stages, similar to that of the overall participants. Our findings highlight the potential hazards of high protein intake on linear growth in children and adolescents. Caution should be exercised when promoting increased protein consumption in children and adolescents who already have a high intake of protein.

Dietary L-Tryptophan consumption determines the number of colonic regulatory T cells and susceptibility to colitis via GPR15

Environmental factors are the major contributor to the onset of immunological disorders such as ulcerative colitis. However, their identities remain unclear. Here, we discover that the amount of consumed L-Tryptophan (L-Trp), a ubiquitous dietary component, determines the transcription level of the colonic T cell homing receptor, GPR15, hence affecting the number of colonic FOXP3+ regulatory T (Treg) cells and local immune homeostasis. Ingested L-Trp is converted by host IDO1/2 enzymes, but not by gut microbiota, to compounds that induce GPR15 transcription preferentially in Treg cells via the aryl hydrocarbon receptor. Consequently, two weeks of dietary L-Trp supplementation nearly double the colonic GPR15+ Treg cells via GPR15-mediated homing and substantially reduce the future risk of colitis. In addition, humans consume 3–4 times less L-Trp per kilogram of body weight and have fewer colonic GPR15+ Treg cells than mice. Thus, we uncover a microbiota-independent mechanism linking dietary L-Trp and colonic Treg cells, that may have therapeutic potential.

Changes in Skeletal Muscle Protein Metabolism Signaling Induced by Glutamine Supplementation and Exercise.

To evaluate the effects of resistance exercise training (RET) and/or glutamine supplementation (GS) on signaling protein synthesis in adult rat skeletal muscles. The following groups were studied: (1) control, no exercise (C); (2) exercise, hypertrophy resistance exercise training protocol (T); (3) no exercise, supplemented with glutamine (G); and (4) exercise and supplemented with glutamine (GT). The rats performed hypertrophic training, climbing a vertical ladder with a height of 1.1 m at an 80° incline relative to the horizontal with extra weights tied to their tails. The RET was performed three days a week for five weeks. Each training session consisted of six ladder climbs. The extra weight load was progressively increased for each animal during each training session. The G groups received daily L-glutamine by gavage (one g per kilogram of body weight per day) for five weeks. The C group received the same volume of water during the same period. The rats were euthanized, and the extensor digitorum longus (EDL) muscles from both hind limbs were removed and immediately weighed. Glutamine and glutamate concentrations were measured, and histological, signaling protein contents, and mRNA expression analyses were performed. Supplementation with free L-glutamine increased the glutamine concentration in the EDL muscle in the C group. The glutamate concentration was augmented in the EDL muscles from T rats. The EDL muscle mass did not change, but a significant rise was reported in the cross-sectional area (CSA) of the fibers in the three experimental groups. The levels of the phosphorylated proteins (pAkt/Akt, pp70S6K/p70S6K, p4E-BP1/4E-BP1, and pS6/S6 ratios) were significantly increased in EDL muscles of G rats, and the activation of p4E-BP1 was present in T rats. The fiber CSAs of the EDL muscles in T, G, and GT rats were increased compared to the C group. These changes were accompanied by a reduction in the 26 proteasome activity of EDL muscles from T rats. Five weeks of GS and/or RET induced muscle hypertrophy, as indicated by the increased CSAs of the EDL muscle fibers. The increase in CSA was mediated via the upregulated phosphorylation of Akt, 4E-BP1, p70S6k, and S6 in G animals and 4E-BP1 in T animals. In the EDL muscles from T animals, a decrease in proteasome activity, favoring a further increase in the CSA of the muscle fibers, was reported.

Ethnopharmacological Study on Nigella Sativa Seeds Extracts: Pharmacognostical Screening, Abortifacient Potential and its Evolution Parameters

Current research investigates the abortifacient properties of Nigella sativa, a natural alternative to pharmaceutical abortifacients such as mifepristone. Abortion induced by mifepristone is often accompanied by distressing side effects, prompting the exploration of safer alternatives. Nigella sativa seeds were processed into coarse powder through grinding and subjected to ethanolic and aqueous extractions. Pregnant mice were administered extracts at 400 milligrams per kilogram of body weight, with a comparison group receiving 2.85 mg/kg p.o. of mifepristone. The study showed a significant decrease in fetal survival rates with nigella sativa extract treatment with the untreated control group exhibiting a 100% survival rate and the 400 mg/kg p.o. Dose groups showed rates of 26.66% for aqueous extract and 33.33% for ethanolic extract. Importantly, none of the fetuses in the mifeprin-treated group survived. The results indicate a promising 70% abortion rate with well-tolerated doses of Nigella sativa extracts, highlighting the potential for natural alternatives to mitigate the side effects associated with mifepristone administration. This research underscores the importance of exploring botanical sources for safer and more tolerable options in induced abortion.

CD19/BCMA CAR-T Cell Therapy for Refractory Systemic Lupus Erythematosus - Safety and Preliminary Efficacy Data from a Phase I Clinical Study

Background: Despite significant advances in the treatment of systemic lupus erythematosus (SLE), a subset of patients continue to experience severe progression of their disease despite multiple immunosuppressive and targeted therapies. Furthermore, to date, drug-free remission and seroconversion have been difficult to achieve in SLE. CD19 single-targeted chimeric antigen receptor (CAR) T-cell therapies have shown promising efficacy in SLE but have been unable to attack CD19-negative, long-lived plasma cells, which produce numerous antibodies.This trial aims to study the safety, tolerability and preliminary efficacy of deep B-cell clearance in patients with refractory SLE using autologous anti-CD19 and BCMA CAR-T cells. Method: The CAR product was manufactured by Shanghai YaKe Biotechnology Ltd. The clinical study was conducted in a dose-escalation format. T cells were enriched from patient's peripheral blood, transfected with lentiviral vectors and expanded. After lymphodepleting chemotherapy with cyclophosphamide/fludarabine (D-4 to D-2), patients receive a single infusion of 1-2x106 CD19 CAR-T cells and BCMA CAR-T cells per kilogram of body weight at D0. On the first day of chemotherapy initiation , all SLE-related immunosuppressants, biologics, etc. were discontinued except for a few patients who were maintained on low-dose prednisolone. Tolerability was assessed by monitoring cytokine release syndrome (CRS), immune-related effector cell neurotoxicity syndrome (ICANS), and infections. Initial efficacy was assessed by attainment of lupus low disease activity state (LLDAS), dsDNA antibody and ANA seroconversion, and discontinuation of all SLE-specific therapies. Results: As of July 31, 2023, 12 patients with refractory SLE were treated with CD19/BCMA CAR-T cells with a median follow-up of 118.5 (45-524) days. All patients had active severe SLE and had received glucocorticoids, hydroxychloroquine, tacrolimus, total glucosides of paeony, merti-macrolide, leflunomide, azathioprine, methotrexate, cyclophosphamide, immunoglobulin, rituximab, belimumab, and Tetracycline before treatment with CAR-T cells, which were standard treatments that were either ineffective or difficult to withdraw.3 patients received 1x10^6/kg of each of CD19 CAR-T cells and BCMA CAR-T cells, and 9 patients received 2x10^6/kg of each of CD19 CAR-T cells and BCMA CAR-T cells 2x10^6/kg. CAR-T cells were prepared successfully in all patients. BCMA CAR-T achieved expansion in all patients, while CD19 CAR-T did not expand in 1 patient, and expansion of CAR T cells preceded depletion of circulating B cells. All patients developed grade 1 CRS, which manifested as controllable fever, and no ICANS occurred. 11 patients (91.7%) developed grade 4 hematologic toxicity, and 1 patient (8.3%) developed grade 3 hematologic toxicity. Within 6 months of CAR-T treatment, 2 patients were infected with neocoronavirus, 1 patient developed gastrointestinal tract infection, and 1 patient developed pulmonary infection , and all of them recovered after treatment. The SLEDAI-2K score decreased in all patients, from a mean of 18.3 to 1.5. Low-level proteinuria persisted in some patients, possibly due to previously accumulated glomerular filtration impairment. All patients met LLDAS criteria and were able to successfully discontinue all SLE-related medications, including glucocorticoids. peripheral blood B cells recovered at approximately 3 months after CAR-T therapy. To date, no SLE flares have occurred. Conclusions: These data suggest that CD19/BCMA CAR-T cell therapy is well tolerated and can induce rapid and durable remission in severe refractory SLE.

Study on the Impact of G-CSF Mobilization on the Level of MDSCs in Donor Peripheral Blood and Its Correlation with Patient Prognosis

Introduction:MDSCs are a newly discovered and heterogeneous population of immature bone marrow cells with immunosuppressive characteristics, capable of inhibiting innate and adaptive immune responses. Granulocyte colony-stimulating factor (G-CSF) is a member of the hematopoietic growth factor cytokine family responsible for the proliferation, maturation, differentiation, and survival of neutrophil lineage. In many hospitals in China, allo-HSCT procedures often involve administering G-CSF continuously for 5 days to healthy donors before collecting the graft, to mobilize white blood cells. This study discusses the impact of G-CSF mobilization on the absolute values and functions of total immunosuppressive myeloid-derived suppressor cells (MDSCs) and their subsets, M-MDSCs and P-MDSCs, in the peripheral blood of healthy donors. Furthermore, it explores the effects of transferring MDSCs from the graft to the patient's body on their prognosis and immune reconstitution. Method：From August 2022 to December 2022, a total of 72 donors and 72 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) were selected as the subjects at Lu Daopei Hospital in Beijing. Among the donors, there were 47 males and 25 females, with a median age of 34 years (19, 48). Among the patients, there were 33 males and 39 females, with a median age of 34 years (23, 45). The patients were diagnosed as acute leukemia or MDS in CR status and further categorized into infection group, graft-versus-host disease (GVHD) group, and no-event group based on post-transplantation outcomes. Peripheral blood samples were collected from the donors before and on the 5th day after mobilization, as well as from the graft and the patients. Flow cytometry was employed to determine the absolute counts of MDSCs and their subsets. Result 1. The absolute count of total MDSCs in the donor's peripheral blood before mobilization was 3/μl (2, 8), accounting for 0.1% (0.0, 0.2) of PBMCs, significantly lower than the absolute count of total MDSCs in the donor's peripheral blood after G-CSF mobilization, which was 2283/μl (1091, 5288), accounting for 6.4% (3.2, 9.5) of PBMCs, P<0.01. In the infection group, the absolute count and percentage of total MDSCs, P-MDSCs, and LOX1+P-MDSCs in the donor's peripheral blood after mobilization were higher than those in the donor's peripheral blood corresponding to the no-event group, and significantly higher than those in the donor's peripheral blood corresponding to the GVHD group. P<0.05. Similarly, the absolute count and percentage of total MDSCs, P-MDSCs, and LOX1+P-MDSCs in the correspondingdonor's peripheral blood inthe infection group after mobilization were higher than those in the donor's peripheral blood corresponding to the no-event group, and significantly higher than those in the donor's peripheral blood corresponding to the GVHD group., P<0.05. The absolute count and percentage of M-MDSCs in the infection group were higher than the no-event group and GVHD group, but the differences among the three did not reach statistical significance. Patients who developed infections after transplantation received a higher absolute count of total MDSCs from the graft compared to the no-event group, and significantly higher than the GVHD group, P<0.05. The mortality rate in the infection group was 30% (8/26), in the GVHD group was 14% (3/21), and in the no-event group was 0% (0/25). The ROC curve area under the curve (AUC) for the absolute count of total MDSCs per kilogram of body weight from the donor in the GVHD group was 0.669, with a cutoff of 1.7×107/kg, while in the infection group, the AUC was 0.661, with a cutoff of 4.3×107/kg. Conclusion: G-CSF can induce an increase in the content and enhancement of function of MDSCs in the donor's peripheral blood Maintaining a balance of MDSCs helps ensure immune homeostasis after transplantation.

Efficacy and Safety of TLR2 Co-Stimulated CAR T Cells in CD19-Positive Lymphoid Malignancies with Central Nervous System Involvement

Background CD19 chimeric antigen receptor (CAR) T cell therapy showed remarkable remission rates in patients with refractory or relapsed (R/R) non-Hodgkin's lymphoma (NHL) and acute lymphoblastic leukemia (ALL). However, data on outcomes of CAR T cell therapy for patients with central nervous system (CNS) involvement are limited, as most of them have been excluded from most pivotal CAR-T studies because of concerns about treatment-related neurotoxicity. Here, we show results of a third generation of CD19 CAR T cells for patients with R/R B cell cancers with CNS involvement in a single-center cohort study. Methods A total of 21 patients with R/R B cell malignancies (including ALL and NHL) with CNS involvement were included in this study. Patients derived peripheral lymphocytes were collected through apheresis and lentivirally transduced with a 3 rd generation CAR containing CD28 and TLR2 co-stimulatory domains. The cells were expanded ex vivo and administered in a single infusion (1×10 6 or 2×10 6 CAR T cells per kilogram of body weight) after a conditioning regimen of cyclophosphamide and fludarabine. Results Of the 21 patients with CNS involvement, 11 patients with ALL and 10 with NHL were included in this study, with a data cutoff of July 2023. All 11 patients with ALL had both bone marrow (BM) and cerebrospinal fluid (CSF) involvement. Of the 10 patients with NHL, 5 of the 10 lymphoma patients had parenchyma involvement, 6 patients (6/10) had CSF infiltration and 1 had oculus sinister involvement; the majority of patients (8/10) were diagnosed with secondary CNS lymphoma, whereas 2 patient was primary CNS lymphoma. Of the 21 patients who were treated, the overall response rate (ORR) was 71% (15/21), with 73% (8/11) in ALL and 70% (7/10) in NHL. 67% of patients with ALL (7/11) had a complete remission in both BM and CSF, while 40% of NHL patients (4/10) had a complete response and 30% (3/10) received a partial response. The median overall survival (OS) of ALL was 14.3 months, with a median follow-up of 20.3 months, while the median OS of NHL was not reached with a median follow-up of 14.2 months. Median progression-free survival (PFS) of ALL and NHL were 11.1 months (95% CI, 0.7-29.9 months) and 4.8 months (95% CI, 1.0-15.3 months), respectively (P = 0.84). In the total CNS cohort, cytokine release syndrome (CRS) of any grade was seen in 20 patients (95%), grade 3 in 3 patients (14%). ICANS occurred in 9 patients (42.8%, including 5 ALL and 4 NHL patients), grade 3 in 5 patients (23.8%), and there was no grade 4 event. Median time to ICANS was 5 days (range, 2-10 days) after CAR-T infusion. All the CRS or ICANS were manageable. No significant difference in occurrence of and time to ICANS was seen between ALL and NHL patients (P = 0.22 and 0.96). CAR T cells were identified in CSF of patients following infusion, and the median time to peak CAR T cells in CSF of ALL and NHL were 6.5 days and 10 days post-infusion, respectively (P = 0.141). Median time to last documented follow-up of all patients (alive or dead) was 18.1 months (range 1.0-31.2 months). At the end point of observation, 5 of the 11 ALL patients and 5 of 10 NHL patients were still alive with sustained CR of CNS disease and systemic disease (Figure 1). Conclusion TLR2-costimulated CAR T cell therapy for patients with R/R B cell malignancies with CNS involvement is safe, feasible, and results in high response rates and durable remission in both ALL and NHL patients with CNS disease. The clinical trial was registered at www.clinicaltrials.gov as # NCT04605666.

A Phase 1 Study of RJMty19: Anti-CD19 Humanized CAR-Engineered Allogeneic Double Negative T Cells in Adults with B-Cell Non-Hodgkin's Lymphoma

Introduction: Autologous CAR-T cell therapies has been shown to benefit patients with relapsed/refractory B-cell non-Hodgkin's lymphoma (B-NHL). However, the intrinsic characteristics of autologous CAR-T cell products such as preparation failure, high cost, long production cycle, and bridging therapy required for some patients make it less accessible for a wide range of patients. RJMty19 is a first-in-class humanized anti-CD19 CAR-engineered allogeneic double negative T cells (DNTs). RJMty19 exhibits the advantages of both adaptive and natural immunity and has a high proportion of stem cell-like memory T cells (Tscm). Furthermore, RJMty19 fulfills the requirements of an off-the-shelf cellular immunotherapy, including not causing graft-versus-host disease (GvHD), resistance to host-versus-graft (HvG) rejection, scalability, and storability (WYZE 2022). Preclinical studies had shown that CD19-CAR-DNT has a better safety profile compared to conventional CD19-CAR-T (Zhang 2022). Hence, the first-in-human clinical evaluation of RJMty19 is being undertaken in this Phase 1 study in patients with B-NHL. Methods: This is a first-in-class, open-label, single-dose, phase 1 study of CD19-CAR-DNT cells. The study is designed to evaluate five dose levels (DL) of RJMty19 in a 3+3 dose-escalation scheme: 1×10 6, 3×10 6, 9×10 6, 2×10 7 and 3×10 7 viable CAR + DNT cells per kilogram of body weight. Eligibility criteria included the presence of measurable lesions, at least 2 lines of prior therapy, ECOG score of 0 to 1. All patients received lymphodepleting chemotherapy with fludarabine and cyclophosphamide. The primary endpoint is dose-limiting toxicities, incidence of adverse events and clinically significant laboratory abnormalities. Secondary endpoints include evaluation of standard cellular PK parameters, PD, immunogenicity, objective response rates (ORR) and disease control rate (DCR) per Lugano 2014 Criteria. This phase 1 study is registered on clinicaltrials.gov (NCT05453669). Results ： As of July 31 2023, 15 patients with B-NHL were enrolled and 12 patients were evaluable (including one subject finished infusion for just 10 days). Of the 11 patients who had completed DLT evaluations at Day 28, five (45.5%) were male, and the average age was 59.7 years (range 45-74). At baseline, 73% of patients with IPI score ≥ 3 (range 0-4); the median volume of target lesion was 169,000 (4520-513,688) mm 3. The median number of prior therapies was three (range2-9). Furthermore, five patients had prior BTKi therapy and four patients had prior lenalidomide/venetoclax therapy before recruiting into the trial. No patients had been treated with autologous CD19-CART products. Following single RJMty19 infusion, there was no cases of GvHD, ICANS and SAEs. Only one patient developed a grade 2 CRS which was resolved within 24 hours. Except for fever, all of ≥grade 3 adverse events were hematologic disorders including leukopenia, lymphocytopenia, neutropenia, reduced platelet count and anemia (Table 1). Among patients who received ≥ 9×10 6 CAR-DNT cells/kg (DL ≥3; N=5), best DCR and ORR were 100% (5/5) and 40% (2/5) respectively at Day 28 with B-ultrasound imaging. One of patients in DL4 achieved 87% reduction of tumor lesions (SPD) at Day 31 and Day 61. CD19-CAR-DNT cell kinetics improved in a dose-dependent manner with peak cell expansion occurring between Day 5 and 7 at DL4 based on flow cytometry. Additionally, the mean of C max in DL4 is 384 CAR + DNT cells per microliter (μl) blood (N=3), and the highest peak value of 936 CAR + DNT cells/μl was detected in the recent enrolled patient.

Safe and Effective Blood Preservation Through Acute Normovolemic Hemodilution and Low-Dose Tranexamic Acid in Open Partial Hepatectomy.

In this study, we evaluated the efficacy of tranexamic acid (TXA) and acute normovolemic hemodilution (ANH) with 6% hydroxyethyl starch (130/0.4) in minimizing blood loss during open partial liver resection. Coagulation function was assessed using thromboelastography (TEG) and hemostasis tests, while renal function changes were tracked through serum creatinine values post-surgery. Thirty patients undergoing open partial liver resection were allocated to two groups: Group T received TXA + ANH, and Group A received ANH alone. Blood was drawn from the radial artery under general anesthesia. Both groups received peripheral vein injections of 6% hydroxyethyl starch 130/0.4. Group T additionally received intravenous TXA. Primary outcomes included blood loss and allogeneic blood transfusions. TEG assessed coagulation status and renal function was monitored. Group T demonstrated superior outcomes compared to Group A. Group T had significantly lower intraoperative blood loss (700 mL vs 1200 mL) and a lower bleeding rate per kilogram of body weight (13.3 mL/kg vs 20.4 mL/kg). Coagulation parameters favored Group T, with higher TEG maximum amplitude (55.91 mm vs 45.88 mm) and lower activated partial thromboplastin time (38.04 seconds vs 41.49 seconds). Neither group experienced acute renal injury or kidney function deficiency during hospitalization. TXA and ANH in a small dose during liver resection stabilize clotting, reduce blood loss by 6% compared to hydroxyethyl starch 130/0.4, and do not affect renal function.

Intraperitoneal Injection of MCC950 Inhibits the Progression of Myopia in Form-Deprivation Myopic Mice.

Myopia, one of the most prevalent ocular diseases worldwide, is projected to affect nearly half of the global population by 2050. The main cause of myopia in most patients is axial myopia, which primarily occurs due to the elongation of the eyeball, driven by changes in the extracellular matrix (ECM) of scleral cells. Previous studies have shown that NLRP3, an important inflammatory mediator, plays a critical role in regulating the expression of MMP-2 in the sclera. This, in turn, leads to a decrease in the expression of Collagen-1, a major component of the scleral ECM, triggering the remodeling of the scleral ECM. This study aimed to investigate the effect of MCC950, an inhibitor of NLRP3, on the progression of myopia using a mouse form-deprivation myopia (FDM) model. The FDM mouse model was constructed by subjecting three-week-old C57BL/6J mice to form-deprivation. The mice were divided into experimental (n = 10/group; FDM2M, FDM4M, FDM2W, and FDM4W) and control groups (n = 5/group). The experimental groups were further categorized based on the duration of form deprivation (2 and 4 weeks, labeled as 2 and 4, respectively) and the type of injection received (MCC950 or saline, labeled as M and W, respectively). MCC950 was injected at a concentration of 50 mg/mL, with a dose of 10 mg per kilogram of body weight. Meanwhile, the saline group received the same volume of saline. Refraction and axial length measurements were performed for each eye. The expression levels of NLRP3, caspase-1, IL-1β, IL-18, MMP-2, and Collagen-1 in the sclera were assessed using immunohistochemistry and Western blotting. The intraperitoneal injection of MCC950 did not significantly affect refraction or axial length in normal mice (p > 0.05). However, in FDM mice, MCC950 attenuated the elongation of the axial length and resulted in a smaller shift towards myopia compared to the saline group (FDM4M vs. FDM4W, p = 0.03 and p < 0.05, respectively). MCC950 decreased MMP-2 expression (p < 0.05) but increased Collagen-1 expression (p < 0.05) in the experimental eyes when compared to the saline group. Within the MCC950 group, the expression of MMP-2 was increased in the experimental eyes at 4 weeks (p < 0.05), while that of Collagen-1 was decreased (p < 0.05), which is consistent with changes in refractive error. Immunohistochemical analysis yielded similar results (p < 0.05). MCC950 also reduced the expression levels of NLRP3 (p = 0.03), caspase-1 (p < 0.05), IL-1β (p < 0.05), and IL-18 (p < 0.05) in the experimental eyes compared to the saline group. Within the MCC950 group, the expression levels of NLRP3 and caspase-1 were comparable between the experimental and control eyes (p > 0.05), whereas IL-18 expression was higher in experimental eyes (p < 0.05). IL-1β expression was higher in the experimental eyes only at week 4 (p < 0.05). The intraperitoneal injection of MCC950 can inhibit the progression of myopia in FDM mice, possibly by regulating collagen remodeling in the sclera through the NLRP3-MMP-2 signaling pathway. Therefore, MCC950 holds promise as a potential therapeutic agent for controlling the progression of myopia.

Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis

BackgroundTransthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.MethodsIn this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.ResultsA total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges–Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P=0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P=0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.ConclusionsIn this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.)

Umbilical cord mesenchymal stem cell; a potential therapy on reducing intimal hyperplasia in rabbit arteriovenous fistula (AVF) model, analysis the expression of HIF-1a, eNOS, and MMP-2

Introduction: AVF is the best option for hemodialysis access, but its patency rate drops after one year. UC-MSCs were used to reduce inflammation and promote vascular tissue repair in AVF rabbit models. Methods: In this study, 28 male domestic rabbits (Lepus Domestica) were divided into four groups: KN as a negative control, KP as a positive control with placebo therapy, P1 as the treatment group with in situ UC-MSCs, and P2 as the treatment group with intravenous UC-MSCs. The UC-MSCs dose administered was 1,000,000 cells per kilogram of body weight. After 28 days, all groups of rabbit models with AVF were sacrificed. HIF-1α, eNOS, and MMP-2 levels were measured using ELISA Sandwich methods and analyzed using a one-way ANOVA test followed by post hoc Duncan test. Results: The study found significant differences in HIF-1α, eNOS, and MMP-2 levels among the treatment groups. P3 and P4 treatments did not significantly differ in HIF-1α levels, but P3 had a lower average HIF-1α level than P4. The KP group had the highest concentration of eNOS, significantly higher than P1, P2, and KN. ENOs concentration decreased in P1 and P2 and was significantly lower than KP. The level of MMP-2 in AVF rabbits that received intravenous UC-MSCs was significantly higher than that of healthy rabbits (KN), but significantly lower than the AVF rabbit group that received a placebo. The MMP-2 level in AVF rabbits receiving in situ UC-MSCs was significantly lower than in the placebo and intravenous UC-MSC groups. Conclusion. This study suggests that local delivery of in situ UC-MSCs targeting HIF-1α, eNOS, and MMP-2 levels can effectively reduce intimal hyperplasia (IH) in rabbit models of AVF, potentially preventing early AVF failure and serving as a promising therapy to prevent and reduce IH in AVF.

Effects of 4weeks of whole-body vibration training on energy expenditure during deep squats of male well-trained students.

From the perspective of energy expenditure, this study investigated the effects of whole-body vibration training on the energy metabolism of deep squats with different weights. Twenty-two healthy male college students with sports experiences were selected and randomly assigned to perform resistance exercise vibration (REV) or resistance exercise (RE) with varying loads two times per week for 4weeks. Oxygen uptake and heart rate were measured before, during, and after exercises using a gas analyzer, and energy expenditure was calculated. The results showed the following: 1) the oxygen uptake and energy expenditure of the REV group were significantly higher than those of the RE group during and 30min after exercise (p < 0.01), respectively, and the excess post-exercise oxygen consumption (EPOC) was also significantly higher than that of the RE group (p < 0.01). 2) Changes in the oxygen uptake and energy expenditure were stable with increasing exercise in both vibration and non-vibration conditions. There was no difference in energy expenditure per unit of body mass versus additional energy per kilogram of body weight (p > 0.05). 3) No significant differences in changing exercise intensity were observed in the REV group compared to those in the RE group during the adjacent incremental load phases of △ (40%-0%) and △ (80%-40%) of load during and 30min after exercise (p > 0.05). Our results suggest that 1) vibration training can increase energy expenditure during low-intensity training and excess post-exercise oxygen consumption, and improve the exercise intensity. 2) The effects on energy expenditure were the same for both weight-bearing and non-weight-bearing deep squats, up to 40% of body mass.

Factors Involved in the Evolution of the Basal Metabolic Rate over 30 Months After Roux-en-Y Gastric Bypass.

After Roux-en-Y gastric bypass (RYGB), the basal metabolic rate (BMR) falls. However, it is important to know how BMR per kilogram of body weight (BMR/kg) varies in the postoperative period. The present study evaluated the changes in the BMR/kg and its correlates over 30 months after RYGB. Eighty adult patients of both genders who underwent RYGB agreed to participate in the study. The following evaluations were performed before surgery (n=48) and 6 (n=27), 12 (n=28), 24 (n=40), and 30 months (n=29) after surgery: anthropometry, body composition (bioelectrical impedance), metabolic analysis (indirect calorimetry), and diet (food recall). Statistical analysis was performed (p = 0.05). Although BMR decreased after surgery, BMR/kg increased significantly as compared to baseline from 12 months onward, peaking at 24 months and not significantly dipping at 30 months, suggesting stabilization of BMR/kg 2 years after surgery (pre, 10.68 ± 2.33 kcal/kg; 12 months, 12.46 ± 2.85 kcal/kg; 24 months, 18.78 ± 4.81 kcal/kg; 30 months, 18.12 ± 3.69 kcal/kg; p <0.001). Regarding the variables that influenced the BMR/kg, at 12 months, they were %LBM and intake of calcium-source foods (34%); at 24 months, it was protein intake (16%); and at 30 months, it was the intake of calcium-source foods (26.7%). RYGB is associated with a significant increase in BMR when it is adjusted to body weight from 12 to 24 months postoperatively. Among the factors involved in the increase in BMR/kg are body composition and intake of protein-rich foods.

Establishment and effectiveness evaluation of pre-test probability model of coronary heart disease combined with cardiopulmonary exercise test indexes

To establish a pre-test probability model of coronary heart disease (CHD) combined with cardiopulmonary exercise test (CPET) indexes and to compare the clinical effectiveness with Duke clinical score (DCS) and updated Diamond-Forrester model (UDFM), thus further explore the predictive value. 342 cases were used to establish the prediction model equation and another 80 cases were used to verify the effectiveness. The patients were divided into CHD group (n = 157) and non-CHD group (n = 185) according to coronary artery stenosis degree >50% or not. Combining DCS and UDFM as reference models with CPET indexes, a multivariate logistic regression model was established. The area under the ROC curve of the three models were calculated to compare the predictive effectiveness. There were significant differences in gender, chest pain type, myocardial infarction history, hypertension history, smoking, pathological Q wave and ST-T change between two groups (P < 0.01), as well as age, LVEF, heart rate at anaerobic domain, peak oxygen uptake in kilograms of body weight, percentage of peak oxygen uptake to the predicted value, the oxygen uptake efficiency slope and carbon dioxide ventilation equivalent slope (P < 0.05). Multivariate analysis showed gender, age, chest pain type, myocardial infarction history, hypertension history, smoking, pathological Q wave, ST-T change, and peak oxygen pulse were independent risk factors of CHD. The pre-test probability model of CHD combined with CPET indexes has good distinguish and calibrate ability, its prediction accuracy is slightly better than DCS and UDFM, which still needs to be verified externally in more samples.

Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy

SummaryWe treated a 27-year-old patient with Duchenne’s muscular dystrophy (DMD) with recombinant adeno-associated virus (rAAV) serotype 9 containing dSaCas9 (i.e., “dead” Staphylococcus aureus Cas9, in which the Cas9 nuclease activity has been inactivated) fused to VP64; this transgene was designed to up-regulate cortical dystrophin as a custom CRISPR–transactivator therapy. The dose of rAAV used was 1×1014 vector genomes per kilogram of body weight. Mild cardiac dysfunction and pericardial effusion developed, followed by acute respiratory distress syndrome (ARDS) and cardiac arrest 6 days after transgene treatment; the patient died 2 days later. A postmortem examination showed severe diffuse alveolar damage. Expression of transgene in the liver was minimal, and there was no evidence of AAV serotype 9 antibodies or effector T-cell reactivity in the organs. These findings indicate that an innate immune reaction caused ARDS in a patient with advanced DMD treated with high-dose rAAV gene therapy. (Funded by Cure Rare Disease.)

Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia

BackgroundCeftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus.MethodsIn this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia–related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed.ResultsOf 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], −7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, −6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, −2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole.ConclusionsCeftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.)

PET imaging of microglia using PBR28suv determines therapeutic efficacy of autologous bone marrow mononuclear cells therapy in traumatic brain injury

Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of rats: Sham, CCI-alone and CCI-BMMNCs (AUTO). One hundred twenty days after injury, rodents were imaged with PBR28 and their cognitive behavior assessed utilizing the Morris Water Maze. Subsequent ex vivo analysis included brain volume and immunohistochemistry. BMMNCs therapy attenuated PBR28suv in comparison to CCI alone and it improved spatial learning as measured by the Morris Water Maze. Ex vivo analysis demonstrated preservation of brain volume, a decrease in amoeboid-shaped microglia in the dentate gyrus and an increase in the ratio of ramified to amoeboid microglia in the thalamus. PBR28suv is a viable option to measure efficacy of BMMNCs therapy after TBI.