Low-dose Regimen Research Articles

Efficacy and safety of the ultraslow low-dose thrombolytic regimen for mechanical prosthetic valve thrombosis: a prospective cohort study

Abstract Background Mechanical prosthetic valve thrombosis (MPVT) remains a significant and life-threatening complication. While surgery is here considered the gold standard therapy, it has a high perioperative risk in the acute setting. Preliminary evidence suggests that an ultraslow low-dose thrombolytic regimen may offer a safer and equally effective alternative compared to both conventional fast-infusion thrombolytic approaches or surgical options. Purpose We aimed at evaluating efficacy and safety of a previously described ultraslow low-dose thrombolytic regimen for treating acute MPVT in hospitalized adult patients. Methods This prospective single-center cohort study included all consecutive adult patients with acute MPVT treated with our ultraslow low-dose thrombolytic regimen. Patients with contraindication to thrombolytic therapy or left-sided MPVT with a minimum thrombus size of 0.8 cm2 or severe dyspnea with NYHA FC IV were excluded, and considered candidate to surgery. The regimen here used consisted of 25 mg rtPA infused over 25 hours. If initially failed, a repeat 6-hour infusion of 25 mg rtPA was administered up to a maximum total cumulative dose of 150 mg or until an adverse event occurred. The primary objective was the rate of complete MPVT resolution, defined as >75% reduction in the obstructive gradient by transthoracic echocardiography, less than 10 degrees residual constraint in opening and closing valve motion angles as quantified by fluoroscopy, and alleviation of patients’ thrombosis-associated symptoms or signs. Results From April 2018 to November 2023, 135 infusions of thrombolytic therapy were administered in 118 patients (median age: 35 years (IQR, 25-49); 59 [50%] women) (Table 1). 12 patients had more than one episode of MPVT during the study period. Obstructive prosthetic valve thrombosis occurred in 89.6% (121/135) of cases. Pulmonary valves were most frequently affected (n = 84, 62.2%), followed by tricuspid (n = 34, 25.2%), mitral (n = 10, 7.4%), and aortic (n = 7, 5.2%) valves. A complete thrombolysis success was achieved in 119/135 episodes of thrombolytic therapy (88.1%); of these, 47/119 patients (39.5%) responded after the first thrombolytic dose. The median total dose administered was 50 mg (IQR, 25-75) over a median infusion duration of 30 hours (IQR, 25-36). Four patients responded partially to the regimen, six patients were candidates for bailout surgery, and only one fatal intracranial bleeding occurred. No other thromboembolic or bleeding adverse events were observed. Conclusion This is the largest prospective evaluation on the safety and efficacy of the ultraslow low-dose thrombolytic regimen, which proved highly effective - in this prospective cohort - in achieving prosthetic valve thrombosis resolution with minimal complications. Further larger clinical trials are warranted.Table 1- baseline CharacteristicsStudy Outcomes

A low-dose pemetrexed-cisplatin combination regimen induces significant nephrotoxicity in mice

BackgroundPemetrexed is combined with cisplatin to treat cancer. Whether pemetrexed-cisplatin combination chemotherapy exacerbates cisplatin nephrotoxicity is unclear. Here, we investigated kidney injury in mice administered a non-lethal low-dose regimen of pemetrexed or cisplatin alone and compared it with a pemetrexed-cisplatin combination.MethodsMice were randomly divided into four groups and administered intraperitoneally the experimental drugs solubilized in captisol (sulfobutylether β-cyclodextrin). Group 1 received captisol, Group 2 pemetrexed (10 mg/kg), Group 3 cisplatin (1 mg/kg), and Group 4 pemetrexed (10 mg/kg) plus cisplatin (1 mg/kg). The mice were treated every other day for two weeks, three times per week. Glomerular filtration rate (GFR) was determined on the third day after the last treatment, followed by a necropsy.ResultsWhereas the relative kidney weight was comparable in the control vs. pemetrexed or cisplatin alone group, it was significantly increased in the combination group. Mice treated with cisplatin and pemetrexed-cisplatin combination exhibited reduced GFR. The pemetrexed-cisplatin combination caused significant increases in the plasma or urinary levels of kidney injury biomarkers, renal lipid peroxidation, and nitrosative stress compared with pemetrexed or cisplatin alone. Histopathology revealed that pemetrexed or cisplatin alone had minimal effects on the kidneys. By contrast, the pemetrexed-cisplatin combination caused tubular degeneration, dilatation, and granular casts. Live-cell imaging showed that the pemetrexed-cisplatin combination caused more severe apoptosis of primary renal epithelial cells than individual concentrations.ConclusionsThese findings suggest that combining pemetrexed and cisplatin causes oxidative kidney damage at individual doses that do not cause significant nephrotoxicity. Hence, the renal function of patients undergoing treatment with the pemetrexed-cisplatin combination needs extensive monitoring.

High-Dose TXA Is Associated with Less Blood Loss Than Low-Dose TXA without Increased Complications in Patients with Complex Adult Spinal Deformity.

Tranexamic acid (TXA) is commonly utilized to reduce blood loss in adult spinal deformity (ASD) surgery. Despite its widespread use, there is a lack of consensus regarding the optimal dosing regimen. The aim of this study was to assess differences in blood loss and complications between high, medium, and low-dose TXA regimens among patients undergoing surgery for complex ASD. A multicenter database was retrospectively analyzed to identify 265 patients with complex ASD. Patients were separated into 3 groups by TXA regimen: (1) low dose (<20-mg/kg loading dose with ≤2-mg/kg/hr maintenance dose), (2) medium dose (20 to 50-mg/kg loading dose with 2 to 5-mg/kg/hr maintenance dose), and (3) high dose (>50-mg/kg loading dose with ≥5-mg/kg/hr maintenance dose). The measured outcomes included blood loss, complications, and red blood cell (RBC) units transfused intraoperatively and perioperatively. The multivariable analysis controlled for TXA dosing regimen, levels fused, operating room time, preoperative hemoglobin, 3-column osteotomy, and posterior interbody fusion. The cohort was predominantly White (91.3%) and female (69.1%) and had a mean age of 61.6 years. Of the 265 patients, 54 (20.4%) received low-dose, 131 (49.4%) received medium-dose, and 80 (30.2%) received high-dose TXA. The median blood loss was 1,200 mL (interquartile range [IQR], 750 to 2,000). The median RBC units transfused intraoperatively was 1.0 (IQR, 0.0 to 2.0), and the median RBC units transfused perioperatively was 2.0 (IQR, 1.0 to 4.0). Compared with the high-dose group, the low-dose group had increased blood loss (by 513.0 mL; p = 0.022) as well as increased RBC units transfused intraoperatively (by 0.6 units; p < 0.001) and perioperatively (by 0.3 units; p = 0.024). The medium-dose group had increased blood loss (by 491.8 mL; p = 0.006) as well as increased RBC units transfused intraoperatively (by 0.7 units; p < 0.001) and perioperatively (by 0.5 units; p < 0.001) compared with the high-dose group. Patients with ASD who received high-dose intraoperative TXA had fewer RBC transfusions intraoperatively, fewer RBC transfusions perioperatively, and less blood loss than those who received low or medium-dose TXA, with no differences in the rates of seizure or thromboembolic complications. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Efficacy and safety of a low-dose sulfamethoxazole/trimethoprim regimen in preventing pneumocystis pneumonia: A retrospective study using a large-scale electronic medical record database

IntroductionSulfamethoxazole/trimethoprim (ST) is a first-line drug for preventing pneumocystis pneumonia (PCP). Several small-scale studies have suggested the usefulness of the low-dose regimen of ST (200/40 mg/day) over the standard-dose one (400/80 mg/day). Thus, this study aimed to investigate the efficacy and safety of low-dose and standard-dose regimens of ST in preventing PCP in patients with non human immunodeficiency virus infection using a large-scale electronic medical record database. MethodsThis retrospective study included patients who received ST prophylaxis for PCP registered in the RWD database between June 2007 and February 2023. Patients received either standard-dose (400/80 mg/day) or low-dose (200/40 mg/day) regimen groups. The incidence of cases initiated PCP therapeutic dose (ci-PCPTD) (ST ≥ 3600/720 mg/day) and adverse events (AEs) was evaluated, and risk factors for ci-PCPTD were investigated. ResultsA total of 11,384 patients received the standard-dose, whereas 7973 received the low-dose regimen groups. No significant difference in the cumulative incidence of ci-PCPTD was observed between the standard-dose (0.67%) and low-dose regimen group (0.47%). Lung disease was a significant risk factor for ci-PCPTD. The cumulative incidence of ci-PCPTD in patients with acute exacerbation of interstitial pneumonia was 1.3% in both groups, and no significant difference was observed between the two groups. The low-dose regimen group had a lower incidence of all AEs than the standard-dose regimen group. ConclusionThese results based on a large-scale electronic medical record database provide important evidence supporting the clinical significance of low-dose regimen of ST.

Superior survival after unrelated allogeneic stem cell transplantation with low-dose ATG compared to low-dose TBI in myeloablative fludarabine/busulfan-based regimen for MDS on behalf of the adult MDS Working Group of the JSTCT

The fludarabine/intravenous busulfan 12.8 mg/kg (FB4) regimen is an effective conditioning regimen in allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome (MDS); however, limited data is available on the prognostic impact of FB4 with low-dose anti-thymoglobulin (ATG ≤ 5 mg/kg) or low-dose total body irradiation (TBI ≤ 4 Gy). Therefore, we retrospectively evaluated the outcomes in 280 adults with de novo MDS who underwent their first transplantation from an unrelated donor between 2009 and 2018. Median age was 61 years (range, 16 to 70 years). In the FB4 alone (FB4), FB4 plus ATG (FB4-ATG), and FB4 plus TBI (FB4-TBI) groups, 3-year overall survival (OS) rates were 39.9, 64.8, and 43.7 %; 3-year non-relapse mortality (NRM) were 32.1, 22.1, and 27.1%; and 3-year relapse incidences were 34.7, 21.2, and 28.9%, respectively. The multivariate analyses showed that FB4-ATG group significantly correlated with better OS (hazard Ratio [HR], 0.51; 95% confidence interval [CI], 0.27-0.95; P=0.032) than FB4 group. FB4-ATG group tended to correlate with lower NRM (HR, 0.36;95% CI, 0.13-1.06; P=0.063) than FB4 group. In comparison with FB4-TBI group, FB4-ATG group showed better OS (HR 0.52, 95% CI 0.27-0.99, P=0.049) and NRM (HR 0.034, 95% CI 0.11-0.92, P=0.034). No significant differences were observed in OS and NRM between the FB4-TBI and FB4 groups. The present study demonstrated that the FB4 plus low-dose ATG regimen improved OS and NRM, but FB4 plus low-dose TBI regimen had no clear benefit over FB4 alone, in MDS patients who used unrelated donors.

A weekly low-dose regimen of decitabine and venetoclax is efficacious and less myelotoxic in a racially diverse cohort

AbstractA metronomic, low-dose schedule of decitabine and venetoclax was safe and effective in myeloid malignancies with few dose reductions or interruptions in an older diverse population. Median overall survival for patients with acute myeloid leukemia and a TP53-mutation was 16.1 and 11.3 months, respectively. This trial was registered at www.clinicaltrials.gov as #NCT05184842.

Low-dose pro-resolving mediators temporally reset the resolution response to microbial inflammation

BackgroundSpecialized pro-resolving mediators (SPMs) promote resolution of inflammation, clear infections and stimulate tissue regeneration. These include resolvins, protectins, and maresins. During self-resolving acute inflammation, SPMs are produced and have key functions activating endogenous resolution response for returning to homeostasis. Herein, we addressed whether infections initiated with ongoing inflammation alter resolution programs, and if low-dose repetitive SPM regimen re-programs the resolution response.MethodsInflammation was initiated with zymosan (1 mg/mouse) followed by E. coli (105 CFU/mouse) infections carried out in murine peritonitis, and exudates collected at 4-72 h. Leukocytes were enumerated using light microscopy, percentages of PMN, monocytes and macrophages were determined using flow cytometry, and resolution indices calculated. Lipid mediators and SPM profiles were established using mass spectrometry-based metabololipidomics. Repetitive dosing with a SPM panel consisting of RvD1, RvD2, RvD5, MaR1 and RvE2 (0.1 ng/mouse each, i.p.) was given to mice, followed by zymosan challenge. Leukocyte composition, resolution indices and RNA-sequencing were carried out for the repetitive SPM treatments.ResultsE. coli infections initiated acute inflammation-resolution programs with temporal SPM production in the infectious exudates. Zymosan-induced inflammation prior to E. coli peritonitis shifted exudate resolution indices and delayed E. coli clearance. Lipid mediator metabololipidomics demonstrated that E. coli infection with ongoing zymosan-induced inflammation shifted the time course of exudate SPMs, activating a SPM cluster that included RvD1, RvD5 and MaR1 during the initiation phase of infectious inflammation (0-4 h); RvD5 and MaR1 were present also in the resolution phase (24-48 h). To emulate daily SPM regimens used in humans, a repetitive subthreshold dosing of the SPM panel RvD1, RvD2, RvD5, MaR1 and RvE2 each at 0.1 ng per mouse was administered. This low-dose SPM regimen accelerated exudate PMN clearance following zymosan-induced inflammation, and shortened the resolution interval by > 70%. These low-dose SPMs regulated genes and pathways related to immune response, chemokine clearance and tissue repair, as demonstrated by using RNA-sequencing.ConclusionsInfections encountered during ongoing inflammation in mice reset the resolution mechanisms of inflammation via SPM clusters. Low-dose SPMs activate innate immune responses and pathways towards the resolution response that can be reprogrammed.

Oxytocin regimen used for induction of labor and pregnancy outcomes

BackgroundFollowing the results of the ARRIVE trial, which demonstrated a reduction in cesarean delivery with no increase in adverse perinatal outcomes after elective induction of labor (IOL) in low-risk nulliparous patients at 39 weeks’ gestation compared with expectant management, the use of induction has increased. Current evidence is insufficient to recommend mid-high-dose over low-dose regimens for routine IOL. Objective(s)We sought to evaluate the association of oxytocin regimen with cesarean delivery and an adverse perinatal composite outcome in low-risk nulliparous patients undergoing IOL at 39 weeks of gestation or greater. Study DesignThis is a secondary analysis of the NICHD Maternal-Fetal Medicine Units Network ARRIVE randomized trial. Patients induced with a mid-to high-dose oxytocin regimen (MHD; starting or incremental increase >2 mU/min) were compared with those receiving a low-dose oxytocin regimen (LD; starting and incremental increase ≤2 mU/min). The co-primary outcomes for this secondary analysis were 1) cesarean delivery and 2) composite of perinatal death or severe neonatal complications. Multivariable Poisson regression was used to estimate adjusted relative risks (aRR) and 97.5% confidence intervals (CI) for the co-primary endpoints, 95% CI for binomial outcomes and multinomial logistic regression was used to estimate adjusted odds ratios (aOR) and 95% CIs for multinomial outcomes. ResultsOf 6,106 participants enrolled in the primary trial, 2,933 underwent induction with oxytocin: 861 in the MHD group and 2,072 in the LD group. The lower frequency of cesarean delivery in the MHD group compared with the LD group (20.3% vs. 25.2%, RR 0.81, 95%CI (0.69-0.94)) was not significant after adjustment (aRR 0.90, 97.5%CI (0.76-1.07)). The composite of perinatal death or severe neonatal complications was more frequent in the MHD group compared with the LD group (6.7% vs. 4.3%, RR 1.55, 95%CI (1.13-2.14)) and remained significant after adjustment (aRR 1.61, 97.5%CI (1.11-2.35)). The majority of the cases in the composite were from the respiratory support (5.2% vs. 3.1%) component with an increase in transient tachypnea of the newborn (3.8% vs. 2.5%, aRR 1.63, 95% CI (1.04-2.54)). The duration of neonatal respiratory support for one day was significantly higher in the MHD group compared with the LD group (3.5% vs. 1.4%, aRR 2.59, 95%CI (1.52-4.39)); however, support beyond one day was not different between the two groups. The MHD group, when compared with the LD group had a higher operative vaginal delivery rate (10.0% vs. 7.0%, aRR 1.54, 95%CI (1.18-2.00)) and shorter duration of time from start of oxytocin to delivery [crude median (interquartile range) 12 (8-17) vs. 13 (9-19) hours, adjusted median difference -2 (-2 to -1), p<0.001], respectively. Conclusion(s)Mid-high-dose oxytocin regimen use for IOL in nulliparas at ≥ 39 weeks’ gestation was not associated with improved maternal or neonatal outcomes compared with low-dose regimens. Although mid-high-dose oxytocin regimen use was associated with a shorter duration of labor, there was an increase in self-limited neonatal respiratory support and no difference in cesarean rates. More evidence is needed to define the magnitude of potential maternal and neonatal benefits and risks associated with oxytocin regimens.

Combination Therapy With Rituximab and Low-Dose Cyclophosphamide and Prednisone in Membranous Nephropathy

IntroductionStandard treatment with cyclophosphamide or rituximab is suboptimal. We adapted and used the low dose regimen used in vasculitis (rituximab 2*1000mg; cyclophosphamide 1.5mg/kg/day * 8weeks and prednisone (iv 2* 1gr + 3 weeks oral starting at 1mg/kg). MethodsHigh-risk, anti-PLA2R antibodies (PLA2Rab) positive MN patients were included in this single-arm prospective cohort study. PLA2Rab levels were regularly measured. We report PLA2Rab kinetics and overall immunological and clinical remission (CR) rate. ResultsWe analyzed 26 patients (15 males, age 57 ± 14 years, PLA2Rab titer 176 RU/ml [115-460], Screatinine 128 μmol/l [102-136], Salbumin 18 g/l [14-21] and uPCR 7.1 gram/10 mmol [5.7-10]). Within 8 weeks IR (ELISA < 14RU/ml) was 88 %. Proteinuria remission after initial therapy developed in 21 patients. Seven patients received renewed therapy, which resulted in proteinuria remission in all. IR and CR were associated with baseline PLA2Rab tertile. Five of 7 patients in need of additional therapy were identified at 4 weeks after start of therapy by PLA2Rab T ½> 7 days. Serious adverse events occurred in four patients. Adverse events were mild, leukopenia was most frequent. ConclusionLow-dose triple therapy induced a rapid IR and CR in the majority of patients. Patients with insufficient clinical response were characterized by high baseline PLA2Rab levels and longer PLA2Rab T ½. Assessment of PLA2Rab levels within 2-4 weeks after start of therapy may enable to identify patients who need more intensive therapy.

442.8: Selective BCL-2 inhibition to promote hematopoietic mixed chimerism and renal allograft tolerance in low-dose cyclophosphamide-based conditioning regimen without myelosuppression.

442.8: Selective BCL-2 inhibition to promote hematopoietic mixed chimerism and renal allograft tolerance in low-dose cyclophosphamide-based conditioning regimen without myelosuppression.

Ultraslow low-dose thrombolytic therapy in patients with acute mechanical prosthetic heart valve thrombosis – A prospective cohort study

BackgroundWhile surgery still remains the gold standard treatment for mechanical prosthetic valve thrombosis (MPVT) by many guidelines, the ultraslow low-dose thrombolytic regimen has been reported as a promising alternative. MethodsIn this prospective single-center cohort, patients with acute MPVT were treated with an ultraslow low-dose thrombolytic regimen consisting of 25 mg infusion of recombinant tissue-type plasminogen activator (rtPA) over 25 h. The regimen could be repeated in case of failure until resolution/occurrence of adverse events or a maximum cumulative dose of 150 mg. The primary outcome was the complete MPVT resolution rate; other outcomes included first-dose success rate, major bleeding, thromboembolic events, mortality, and total thrombolytic dose/duration. ResultsBetween April 2018 to January 2024, 135 episodes of acute MPVT were treated with an ultraslow low-dose thrombolytic regimen in 118 patients. In 118/135 (87.4 %) episodes, right-sided prosthetic valve was involved. Complete success was achieved in 88.1 % of cases, with 39.5 % responding after the first dose. The median total dose was 50 mg over a median of 30 h. Only one fatal intracranial hemorrhage occurred (0.7 %), with no other bleeding or thromboembolic complications. ConclusionThe ultraslow low-dose thrombolytic regimen appears to exhibit high efficacy and acceptable safety in treating acute MPVT. Further large clinical trials are essential for validating these preliminary findings.

Effectiveness and safety of low dose Rituximab as remission-maintenance treatment for patients with refractory idiopathic inflammatory myopathies: results of a retrospective study from a monocentric cohort

ObjectiveOur aim was to assess efficacy and safety of Rituximab (RTX) in patients with refractory Idiopathic inflammatory myopathies (IIM) from a monocentric cohort. Thereafter, we evaluated the efficacy of a low-dose RTX regimen as a remission-maintenance therapy.MethodsWe retrospectively evaluated a cohort of patients affected with IIM treated with RTX. All patients were refractory to glucocorticoids (GC) and at least one immunosuppressant. Two infusions of 1 g two weeks apart were considered as standard cycle of RTX, a single dose of 1 g every six months was deemed as a low-dose RTX regimen. Complete and partial response were defined according to physician’s judgment, laboratory and radiological features.ResultsThirty-six patients affected with IIM were enrolled. Eighteen patients (50%) required the use of RTX for muscular involvement, 6 (16.7%) for interstitial lung disease (ILD), 12 (33.3%) for both myositis and ILD. We observed complete response to RTX in 25 patients (69.4%), partial response in 7 (19.4%) and no response in 4 (11.1%), with an overall response of 88.8% (partial and complete response). From the subgroup of twenty-five patients that achieved a complete response, six were treated with a low dose maintenance therapy maintaining a complete response to RTX. Twenty-six patients who achieved a complete or partial response were able to decrease the mean daily GC dose. Infections were the major adverse events detected in our study.ConclusionsRTX shows favorable outcomes in refractory patients with IIM. A low-dose regimen of RTX appears to be effective in maintaining remission after induction with standard dose.Key Points• The precise pathogenic mechanism of idiopathic inflammatory myopathies (IIM) remains elusive; however, a growing body of data support the autoimmune hypothesis. In this context, rituximab, a B cell-depleting agent, has emerged as a second-line therapeutic option in IIM.• Several studies have assessed It its effectiveness in refractory IIM patients.• Limited information exists on the use of Rituximab as maintenance therapy in patients who have achieved remission following induction therapy with Rituximab.

Feature-agnostic metabolomics for determining effective subcytotoxic doses of common pesticides in human cells.

Although classical molecular biology assays can provide a measure of cellular response to chemical challenges, they rely on a single biological phenomenon to infer a broader measure of cellular metabolic response. These methods do not always afford the necessary sensitivity to answer questions of subcytotoxic effects, nor do they work for all cell types. Likewise, boutique assays such as cardiomyocyte beat rate may indirectly measure cellular metabolic response, but they too, are limited to measuring a specific biological phenomenon and are often limited to a single cell type. For these reasons, toxicological researchers need new approaches to determine metabolic changes across various doses in differing cell types, especially within the low-dose regime. The data collected herein demonstrate that LC-MS/MS-based untargeted metabolomics with a feature-agnostic view of the data, combined with a suite of statistical methods including an adapted environmental threshold analysis, provides a versatile, robust, and holistic approach to directly monitoring the overall cellular metabolomic response to pesticides. When employing this method in investigating two different cell types, human cardiomyocytes and neurons, this approach revealed separate subcytotoxic metabolomic responses at doses of 0.1 and 1 µM of chlorpyrifos and carbaryl. These findings suggest that this agnostic approach to untargeted metabolomics can provide a new tool for determining effective dose by metabolomics of chemical challenges, such as pesticides, in a direct measurement of metabolomic response that is not cell type-specific or observable using traditional assays.

Society of Critical Care Medicine and American Society of Health-System Pharmacists Guideline for the Prevention of Stress-Related Gastrointestinal Bleeding in Critically Ill Adults.

Critically ill adults can develop stress-related mucosal damage from gastrointestinal hypoperfusion and reperfusion injury, predisposing them to clinically important stress-related upper gastrointestinal bleeding (UGIB). The objective of this guideline was to develop evidence-based recommendations for the prevention of UGIB in adults in the ICU. A multiprofessional panel of 18 international experts from dietetics, critical care medicine, nursing, and pharmacy, and two methodologists developed evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guideline development including task force selection and voting. The panel members identified and formulated 13 Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and then assessed the certainty of the evidence using the GRADE approach. We used the evidence-to-decision framework to formulate the recommendations. Good practice statements were included to provide additional guidance. The panel generated nine conditional recommendations and made four good practice statements. Factors that likely increase the risk for clinically important stress-related UGIB in critically ill adults include coagulopathy, shock, and chronic liver disease. There is no firm evidence for mechanical ventilation alone being a risk factor. Enteral nutrition probably reduces UGIB risk. All critically ill adults with factors that likely increase the risk for stress-related UGIB should receive either proton pump inhibitors or histamine-2 receptor antagonists, at low dosage regimens, to prevent UGIB. Prophylaxis should be discontinued when critical illness is no longer evident or the risk factor(s) is no longer present despite ongoing critical illness. Discontinuation of stress ulcer prophylaxis before transfer out of the ICU is necessary to prevent inappropriate prescribing. The guideline panel achieved consensus regarding the recommendations for the prevention of stress-related UGIB. These recommendations are intended for consideration along with the patient's existing clinical status.

Meta-analysis of the effect of curcumin supplementation on skeletal muscle damage status.

Meta-analysis was conducted to examine the effect of supplemental curcumin intake on skeletal muscle injury status and to propose an optimal intervention program. In accordance with the procedures specified in the PRISMA statement for systematic reviews and meta-analyses of randomized controlled trials, the Review Manager 5.3 was used to analyze the results of creatine kinase (CK), muscle soreness, interleukin-6 (IL-6), and range of motion (ROM) as outcome indicators in the 349 subjects included in the 14 articles. The effect size of curcumin supplementation on muscle soreness, mean difference (MD) = -0.61; the relationship between curcumin supplementation and muscle soreness for time of measurement (I2 = 83.6%)、the relationship between curcumin supplementation and muscle soreness for period of intervention (I2 = 26.2%)、the relationship between whether one had been trained (I2 = 0%) and supplementation dose (I2 = 0%) were not heterogeneous for the relationship between curcumin supplementation and muscle soreness; The effect size on CK, MD = -137.32; the relationship between curcumin supplementation and CK (I2 = 79.7%)、intervention period (I2 = 91.9%)、whether or not trained (I2 = 90.7%)、and no heterogeneity in the relationship between curcumin supplementation and CK for the time of measurement (I2 = 0%); The effect size MD = 4.10 for the effect on ROM; The effect size for IL-6 was MD = -0.33. This meta-analysis highlights that curcumin supplementation significantly mitigates skeletal muscle damage, with notable improvements in CK levels, muscle soreness, IL-6 levels, and ROM. The results highlight the importance of curcumin dosage and timing, revealing that prolonged supplementation yields the best results, especially for untrained individuals or those less exposed to muscle-damaging exercise. For muscle soreness and ROM enhancement, a pre-emptive, low-dose regimen is beneficial, while immediate post-exercise supplementation is most effective at reducing CK and IL-6 levels.

Low-dose anti-thymocyte globulin plus low-dose posttransplant cyclophosphamide-based regimen for prevention of graft-versus-host disease in haploidentical peripheral blood stem cell transplantation for pediatric patients with hematologic malignancies.

The low-dose anti-thymocyte globulin (ATG) plus low-dose post transplantation cyclophosphamide (PTCy) -based (low-dose ATG/PTCy-based) regimen had a promising activity in preventing of graft-versus-host disease (GVHD) in adult patients. However, its efficacy in pediatric patients remain to be defined. Here, we presented the findings from 35 pediatric patients undergoing haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with the new regimen for GVHD prophylaxis. The cumulative incidences (CIs) of grades II-III and III-IV acute GVHD (aGVHD) were 34% (95% CI, 17-48%) and 11% (95% CI, 0-21%) within 180 days post-transplantation, respectively. The CIs of chronic GVHD (cGVHD) and moderate-to-severe cGVHD within 2 years were 26% (95% CI, 7-41%) and 12% (95% CI, 0-25%), respectively. The 2-year probabilities of overall survival, relapse-free survival, and graft-versus-host disease and relapse-free survival were 89% (95% CI, 78-100%), 82% (95% CI, 68-98%) and 59% (95% CI, 43-80%), respectively. The CIs of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) reactivation by day 180 were 37% (95% CI, 19-51%) and 20% (95% CI, 6-32%) respectively. These results strongly advocate for the efficacy of the low-dose ATG/PTCy-based regimen as a robust strategy for GVHD prevention in haplo-PBSCT for pediatric patients.

High-Dose versus Low-Dose Oxytocin for Labor Augmentation: A Meta-Analysis of Randomized Controlled Trials.

Background/Objectives: Although oxytocin administration is recommended for delayed labor progress, there is no consensus over the preferred optimal dose of oxytocin. We aimed to perform a meta-analysis of pregnancy outcomes comparing high-dose versus low-dose oxytocin regimens for augmentation of delayed labor. Methods: PubMed, Embase, and Cochrane databases were systematically searched for studies comparing high-dose with low-dose oxytocin for labor augmentation from inception up to May 2023. The outcomes assessed were cesarean rate, instrumental delivery rate, postpartum hemorrhage, neonatal death, and uterine tachysystole. Subgroup analysis was performed with randomized controlled trials (RCTs) and propensity-matched studies. Statistical analysis was performed using Rstudio. Heterogeneity was assessed with I2 statistics, and a random-risk effect was used if I2 > 50%. Results: Twenty-one studies met inclusion criteria, and eighteen were RCTs. A total of 14.834 patients were included, of whom 7.921 (53.3%) received high-dose and 6.913 (46.6%) received low-dose oxytocin during labor augmentation. No statistical differences were found in cesarean delivery, neonatal mortality, postpartum hemorrhage and vaginal instrumentation rate. However, uterine tachysystole incidence was significantly higher with high-dose oxytocin (95% Cl, 1.30-1.94, p = 0.3; 0.6; I2 = 9%). Conclusions: Labor augmentation with a low-dose oxytocin regimen is effective as with a high-dose regimen, but with significantly less uterine tachysystole events, which can lead to intrauterine and neonatal complications. Our findings suggest that a low-dose regimen may be safe and effective for labor augmentation in medical practice.

Hemostatic radiotherapy: a narrative review of the literature.

In locally advanced cancer, bleeding is a common clinical presentation and radiotherapy (RT) provides a noninvasive, well-tolerated, cost-effective treatment. However, the choice for fractionation dose and schedule seem to merely depend on physician's preference rather than specific guidelines. We reviewed the available literature on palliative hemostatic RT for response rate (RR) and bleeding duration in relation with the given dose. The PubMed database was used to search for articles, which were assessed by predetermined inclusion and exclusion criteria. A total of 54 articles, published over the last 20 years until December 2023 were analyzed for dose and/or fractionation regimen and their relation to the RR. A variety of fractionation schedules are used for palliative symptom control, including hemostasis. Research focusing on hemostatic irradiation specifically and prospective studies are rare. Moreover, to our knowledge, there are no specific (prospective) studies ongoing. Both external beam radiotherapy (EBRT) and brachytherapy lead to bleeding control and daily or weekly hypofractionated irradiation is safe and effective for both high and low biological equivalent dose (BED) regimens. If feasible, based on patient condition, some studies favor higher BED regimens to obtain more durable tumor/higher bleeding response. Higher radiation dose for thoracic irradiation may be indicative for simultaneous presentation of obstruction and/or dysphagia. Brachytherapy may be used solely or in combination with EBRT or in the setting of re-irradiation. Short-course regimens are preferred in patients in with low performance index scores. For future studies, multivariate analysis, including BED, can be important to assess efficacy of different fractionation schedules for a variety of tumor etiologies. Hemostatic RT, both by EBRT and brachytherapy, appears to be a safe and effective palliative treatment that clinically and statistically significantly reduces bleeding in cancer patients. The available literature is limited regarding prospective and uniform evaluation of hemostatic RT, including fractionation schedules. BED seems to be indicative for a better RR for specific indications. Current evidence suggests that treatment decisions should be tailored according to the patients' condition, tumor etiology and other clinical symptoms. More (prospective) research focusing on hemostasis is necessary to develop clear guidelines.

Low-dose pegylated recombinant human granulocyte-colony stimulating factor as hematopoietic support for adjuvant chemotherapy in Chinese patients with breast cancer: An open-label, randomized, non-inferiority trial.

The recommended dosage of pegylated recombinant human granulocyte-colony stimulating factor (PEG-rhG-CSF) for Western chemotherapy patients is 6mg per cycle. However, for Eastern Asians, the optimal dose remains unknown. This open-label, randomized, non-inferiority trial (NCT05283616) enrolled Chinese female breast cancer patients receiving adjuvant chemotherapy. Participants were randomized to receive either 3 or 6mg of PEG-rhG-CSF per cycle, stratified by body weight (BW; ≤60 kg vs. >60 kg). The primary endpoint was timely absolute neutrophil count (ANC) recovery before the second cycle of chemotherapy. A total of 122 patients were randomized and 116 were included for efficacy analyses. The timely ANC recovery rate in the 3mg arm was 89.8%, compared to 93.0% in the 6mg arm (one-sided 95% confidence interval [CI] lower limit for difference: -11.7%), meeting the prespecified non-inferiority margin of 15%. The rate was 93.3% with PEG-rhG-CSF 3mg and 96.6% with 6mg in patients with BW ≤ 60 kg, and 86.2% and 89.3%, respectively, in those with BW > 60 kg. Although the incidence of severe neutropenia was similar across arms, the occurrence of excessively high ANC and white blood cell counts was higher in the 6mg arm. No grade ≥3 adverse events related to PEG-rhG-CSF occurred. Three milligrams of PEG-rhG-CSF per cycle provided non-inferior neutrophil protection and attenuated neutrophil overshoot compared to 6mg doses. This low-dose regimen could be a new supportive care option for Chinese breast cancer patients receiving anthracycline-based adjuvant chemotherapy.

Optimizing Cefiderocol Dosing Through Population Pharmacokinetic/Pharmacodynamic Simulation: An Assessment of Drug Cost Reductions.

Cefiderocol is a siderophore cephalosporin antibiotic with bactericidal activity against carbapenem-resistant Enterobacterales. However, an efficient dosing strategy is yet to be developed. This study aimed to evaluate efficient lower-dose regimens and estimate potential drug cost reductions. This simulation study used a virtual population of 10,000 resampled individuals based on a reported population pharmacokinetic model. The target index for maximal bactericidal activity was the time for the unbound cefiderocol concentration to be above the minimum inhibitory concentration (TAM_unbound) of 100%, which was determined using a minimum inhibitory concentration distribution or specific value. The probability of achieving 100% TAM_unbound with the standard, low- (reduced by 1 g or one dose), and extended low- (reduced by 2 g or 2 doses) dose regimens was nearly 100%. The lowest probability of achieving 100% TAM_unbound with the extended low-dose regimen at a creatinine clearance range of 90-120 mL/min was 86.4%. The probability of achieving TAM_unbound of 100% was more than 90% for MIC of ≤0.5 mcg/mL with the extended low-dosing regimen. Furthermore, using an efficient dosing regimen reduced the medical costs over a 10-day treatment period for 10 patients, from $122,826.50 to $62,665.69 $ and ¥12,598,187 $ to ¥5,451,173 in the United States and Japan, respectively. A lower dosing regimen for cefiderocol could result in substantial reductions in drug costs while still achieving 100% TAM_unbound.