Standard-dose Group Research Articles

Real-world oral anticoagulants for Asian patients with non-valvular atrial fibrillation: A PRISMA-compliant article.

Background and Purpose:This study aimed to evaluate the comparative efficacy and safety of 4 non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in Asians with non-valvular atrial fibrillation in real-world practice through a network meta-analysis of observational studies.Methods:We searched multiple comprehensive databases (PubMed, Embase, and Cochrane library) for studies published until August 2020. Hazard ratios and 95% confidence intervals were used for the pooled estimates. Efficacy outcomes included ischemic stroke (IS), stroke/systemic embolism (SSE), myocardial infarction (MI), and all-cause mortality, and safety outcomes included major bleeding, gastrointestinal (GI) bleeding, and intracerebral hemorrhage (ICH). The P score was calculated for ranking probabilities. Subgroup analyses were separately performed in accordance with the dosage range of NOACs (“standard-” and “low-dose”).Results:A total of 11, 6, and 8 studies were allocated to the total population, standard-dose group, and low-dose group, respectively. In the total study population, edoxaban ranked the best in terms of IS and ICH prevention and apixaban ranked the best for SSE, major bleeding, and GI bleeding. In the standard-dose regimen, apixaban ranked the best in terms of IS and SSE prevention. For major bleeding, GI bleeding, and ICH, edoxaban ranked the best. In the low-dose regimen, edoxaban ranked the best for IS, SSE, GI bleeding, and ICH prevention. For major bleeding prevention, apixaban ranked best.Conclusions:All 4 NOACs had different efficacy and safety outcomes according to their type and dosage. Apixaban and edoxaban might be relatively better and more well-balanced treatment for Asian patients with non-valvular atrial fibrillation.

Effectiveness and safety of infliximab dose escalation in patients with refractory Takayasu arteritis: A real-life experience from a monocentric cohort.

To evaluate effectiveness and safety of infliximab dose escalation in Takayasu arteritis (TAK) patients. To identify factors associated with refractoriness to standard-dose infliximab. Medical records of infliximab-treated TAK patients from a large single-centre observational cohort were reviewed. Infliximab therapy duration, concomitant therapies, and reasons for dose escalation and therapy suspension were evaluated. Occurrence of adverse events was recorded. A comparison between patients who maintained infliximab standard-dose and those who needed dose-escalation was performed. Factors associated with refractoriness to standard dose were analysed. Forty-one patients were included. Starting infliximab dose was 5 mg/kg 6-weekly and 28 patients (68%) needed dose escalation. Persistence/recurrence of clinical symptoms was the most frequent reason for escalation. Median therapy duration was 39 (IQR, 26-61) months in the standard-dose group and 68 (38-87) months in the intensified-dose group. In the intensified-dose-group, infliximab was suspended in eight patients (29%) after a median of 38 (31-71) months, due to loss of response (n = 7) or patient's request (n = 1). Patients in the intensified-dose group had a higher number of relapses (3.4 vs 0.8 events/patient) and received a higher cumulative steroid dose (1.7 [1.6-2.3] vs 1.3 [1-1.6] g/month of prednisone). Three patients from the intensified-dose group had serious infections; one patient from the standard-dose group developed paradoxical psoriasis. At univariate analysis, age at diagnosis and age at infliximab start were associated with infliximab escalation. In TAK, dose escalation is safe and allows to optimise infliximab durability in refractory patients. Younger patients seem to be more refractory to standard dosages.

Clinical evidence of initiating a very low dose of sacubitril/valsartan: a prospective observational analysis

Sacubitril/valsartan is superior to enalapril in reducing the risks of cardiovascular death and preventing hospitalization in patients with heart failure and reduced ejection fraction (HFrEF). However, patients often do not receive sacubitril/valsartan because of concerns about hypotension. We examined the feasibility of initiating sacubitril/valsartan at a very low dose (VLD) in potentially intolerant patients with HFrEF and subsequent dose up-titration, treatment persistence and outcomes. We analyzed 206 patients with HFrEF grouped according to starting sacubitril/valsartan dose. The VLD group (n = 106) commenced 25 mg twice daily, and the standard-dose (SD) group (n = 100) started on ≥ 50 mg twice daily. Baseline systolic blood pressure was 103 ± 12 mmHg vs. 119 ± 14 mmHg in the SD group (P < 0.001). The maximal target dose achievement rate was higher in the SD group (27.0% vs 9.4%, p = 0.001) and the VLD group experienced more dose up-titrations and fewer down-titrations than the SD group. The VLD group had a decrease in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) similar to the SD group and a similar increase in left ventricular ejection fraction. There were no significant differences in symptomatic hypotension, worsening renal function, hyperkalemia, cardiovascular mortality, and rehospitalization due to HF between the two groups during follow-up period. In patients considered by the treating physician likely to be intolerant of sacubitril/valsartan, initiation with 25 mg twice daily was generally possible and patients remained in therapy, with similar decreases in NT-proBNP and increases in left ventricular ejection fraction to those observed in patients receiving SD sacubitril/valsartan.

Efficacy of Different Doses of Daunorubicin Induced Chemotherapy in Patients with Newly Diagnosed Primary Acute Myeloid Leukemia Under 65 Years Old

To compare the efficacy and safety of different doses of daunorubicin combined with a standard dose of cytarabine as induction chemotherapy in newly diagnosed primary acute myeloid leukemia (AML) patients. The clinical data and outcome were retrospectively analyzed in 86 newly diagnosed primary AML patients who were under 65 years old and treated with daunorubicin combined with cytarabine (DA regimen) at West China Hospital of Sichuan University from January 2017 to June 2019. Patients were divided into 2 groups based on the dose of daunorubicin they received, 35 cases in the escalated-dose group ［75 mg/(m2·d)］ and 51 cases in the standard-dose group ［60 mg/(m2·d)］. And then the effects of different doses of daunorubicin on complete remission (CR) rate, minimal residual disease (MRD)-negative CR rate, relapse-free survival (RFS), overall survival (OS), and adverse events were analyzed. Median follow-up time of all the patients was 15 months. The CR rate and MRD- CR rate of the escalated-dose group was 88.5% and 71.4%, respectively, which were higher than 64.7% and 41.2% of the standard-dose group (P=0.029, P=0.008). The estimated 2-year RFS of the escalated-dose group was 68.4%, which was higher than 38.5% of the standard-dose group (P=0.015), but estimated 2-year OS showed no statistically significant difference (77.1% vs 66.7%, P=0.059), as well as grade 3－4 adverse events. The escalated dose of daunorubicin had prolonged RFS (13 months vs not reached, P=0.022) and OS (23 months vs not reached, P=0.029) in the FLT3-ITD－ AML patients. The escalated dose of daunorubicin can induce higher complete remission rate, deeper remission and longer duration of remission without increasing adverse events in newly diagnosed primary AML patients.

Efficacy of lower dose pirfenidone for idiopathic pulmonary fibrosis in real practice: a retrospective cohort study.

Background/AimsPirfenidone slows the progression of idiopathic pulmonary fibrosis (IPF). We investigated its efficacy and safety in terms of dose and disease severity in real-world patients with IPF.MethodsThis multicenter retrospective cohort study investigated 338 patients treated with pirfenidone between July 2012 and March 2018. Demographics, pulmonary function, mortality, and pirfenidone-related adverse events were also investigated. Efficacy was analyzed according to pirfenidone dose and disease severity using linear mixed-effects models to assess the annual decline rate of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO).ResultsThe mean %FVCpredicted and %DLCOpredicted values were 72.6% ± 13.1% and 61.4% ± 17.9%, respectively. The mean duration of pirfenidone treatment was 16.1 ± 9.0 months. In the standard dose (1,800 mg/day) group, the mean %FVCpredicted was −6.56% (95% confidence interval [CI], −9.26 to −3.87) per year before, but −4.43% (95% CI, −5.87 to −3.00) per year after treatment with pirfenidone. In the non-standard lower dose group, the mean %FVCpredicted was −4.96% (95% CI, −6.82 to −3.09) per year before, but −1.79% (95% CI, −2.75 to −0.83) per year after treatment with pirfenidone. The FVC decline rate was significantly reduced, regardless of the Gender-Age-Physiology (GAP) stage. Adverse events and mortality were similar across dose groups; however, they were more frequent in GAP stages II–III than in the stage I group.ConclusionsThe effect of pirfenidone on reducing disease progression of IPF persisted even with a consistently lower dose of pirfenidone.

Safety and efficacy evaluation of low-dose trimethoprim-sulfamethoxazole for prophylaxis of Pneumocystis pneumonia in HIV uninfected patients undergoing hemodialysis: a retrospective observational study

BackgroundPneumocystis pneumonia (PCP) is a potentially life-threatening infection. Trimethoprim-sulfamethoxazole (TMP-SMX) is considered as the first regimen for PCP prophylaxis according to several guidelines. The recommended prophylactic dose of TMP-SMX has been determined based on patients with normal renal function, but the appropriate dosage for patients undergoing hemodialysis is unknown. The aim of this study was to investigate the efficacy and safety of low-dose TMP-SMX in patients undergoing hemodialysis.MethodsHIV-uninfected adult patients who were undergoing hemodialysis and administered TMP-SMX for PCP prophylaxis, were included, and divided into standard-dose (≥6 single strength (SS, TMP-SMX 80 mg/400 mg tablets/week) and low-dose groups (< 6 SS tablets/week). The endpoints were cumulative incidence of PCP and cumulative discontinuation rate of TMP-SMX due to adverse events. For comparison of the groups, we employed the chi-squared test for categorical variables and the Mann-Whitney U test for continuous variables. Risk factors for the endpoints were evaluated using the Cox Fine and Gray method.ResultsThe median age of the 81 patients included in the study was 67 years (IQR: 60–76 years), and 52 patients (64.2%) were men. No patients in either group developed PCP during the observation period. The yearly cumulative incidence of discontinuation was 12.1% (95% confidence interval [CI]: 0.027–0.29) in the low-dose group and 35.6% (95% CI: 0.20–0.52) in the standard-dose group (P = 0.019). The adjusted hazard ratio of the low-dose group compared to standard-dose group was 0.18 (95% CI: 0.04–0.86, P = 0.032).ConclusionsNone of the study patients developed PCP, and the cumulative discontinuation rate of TMP-SMX due to adverse events was significantly lower in the low-dose group compared to that in the standard-dose group (P = 0.032). These results indicate that low-dose TMP-SMX is an appropriate regimen to maintain a balance between PCP prophylaxis and prevention of adverse events due to TMP-SMX administration. These findings can guide health care professionals to determine TMP-SMX dosage when considering PCP prophylaxis for patients undergoing hemodialysis.

Clinical Evaluation of the Efficacy and Safety of Co-Administration of Wuzhi Capsule and Tacrolimus in Adult Chinese Patients with Myasthenia Gravis.

BackgroundTacrolimus has been recommended as an effective immunosuppressant for patients with myasthenia gravis (MG), while the high price, variable bioavailability, and narrow therapeutic window restrict its clinical application. Wuzhi capsule (WZC) could improve tacrolimus blood concentration by inhibiting the metabolism of cytochrome P450 3A (CYP3A) and P-glycoprotein (P-gp). There are few studies focused on the coadministration of WZC and tacrolimus in autoimmune diseases. This study was aimed at quantifying the efficacy and safety of coadministration of WZC and tacrolimus in adult Chinese patients with MG.MethodsIn this retrospective study, 122 patients with MG on tacrolimus were enrolled. The initial tacrolimus dose was 2 mg/d. Patients with standard initial tacrolimus concentration were classified into group A (standard-dose group). Those failed to reach target concentration were divided into group B (high-dose group) and group C (co-administering WZC group), according to treatment adjustment of increasing tacrolimus dose and co-administration of WZC, respectively. A logistic analysis was used to identify factors associated with clinical outcome. Adverse drug reactions (ADRs) were recorded for safety analysis.ResultsThe tacrolimus concentration after coadministration of WZC was remarkably increased. It was higher compared with simply increasing the tacrolimus dose (p<0.001). The multivariate logistic analysis indicated that the baseline quantitative MG score was a predictive factor for clinical outcomes (OR=0.189; 95% CI 0.082–0.436; p<0.001). Fourteen patients (11.5%) reported ADRs after tacrolimus therapy. ADRs incidence was not related to WZC coadministration.ConclusionThe coadministration of WZC and tacrolimus can substantially elevate the tacrolimus concentration. It is a safe and economic treatment for adult Chinese patients with MG. Patients with a worse disease condition tend to present a better clinical outcome after tacrolimus therapy.

Efficacy of Low Dose Generic Antithymocyte Globulin and Cyclosporine in Idiopathic Aplastic Anemia

Background: In transplant ineligible idiopathic aplastic anemia (IAA) patients, immunosuppressant therapy (IST) with equine Anti-thymocyte globulin (eATG) and cyclosporine is a standard treatment option. In resource constraint settings, where cost is an indisputable determinant of care, haematologists perennially face challenges to come forward with economical yet effective treatment strategies to ensure wider affordability. To explore cost-effective therapeutic options for this under addressed patient population, we studied the efficacy of a lower dose of generic eATG.Methods: Transplant ineligible AA patients (age > 12 years) treated with generic eATG (Thymogam) and cyclosporine from January 2010 to December 2016 were retrospectively analysed. Efficacy of low dose generic eATG (25 mg/kg/d for 4 days) was analysed and compared with standard dose of generic eATG (40 mg/kg/d for 4 days). The choice of eATG dose was based on affordability of the patient. The patients who had completed eATG therapy and followed up at 3 months and 6 months were included in efficacy analysis. Overall response rate (ORR) [including complete response (CR) and partial response (PR)] at 3 months and 6 months were analysed.Results: Thirty-four AA patients treated with generic eATG and cyclosporine were analysed. Mean age was 23.74 years (range 13-45 years); 22 (64.7%) were males. PNH clone was present in 13 (38.2%) patients. Median duration of follow up was 21.1 months (range 3-42 months). Out of 34 patients included in the study, one patient died on day 15 of therapy due to febrile neutropenia, 32 followed up at 3 months and 30 completed 6 months follow up. ORR in the study population was 48.8% at 3 months and 60.6% at 6 months. Difference between ORR at 3 months with low dose (42.9%, CR 0, PR 6) and standard dose eATG (47.3%, CR 0, PR 9) was not significantly significant (p = 0.8). Similarly, difference in ORR at 6 months was not statistically significant between low dose (53.8%, CR 0, PR 7) and standard dose (61.1%, CR 1, PR 10) eATG (p = 0.537). Serious adverse events were observed in three patients in low dose group [non-fatal febrile neutropenia 1; seizure 1; acute kidney injury (AKI) 1] and 7 patients in standard dose group [death due to febrile neutropenia 1; non-fatal febrile neutropenia 2; intracranial bleed 1; AKI 2; flash pulmonary edema 1]. On multivariate analysis for ORR at 6 months, none of the expected variables (age, absolute neutrophil count, absolute lymphocyte count, interval between onset of symptoms to initiation of therapy) could reach statistical significance. Two patients relapsed (after 30 months and 36 months, respectively) after receiving low dose ATG and three patients relapsed after receiving standard dose ATG (after 18 months, 26 months and 38 months, respectively).Conclusion: We found that efficacy of low dose generic eATG was similar to the standard dose generic eATG. We conclude that IST with low dose generic eATG and cyclosporine is an efficacious and economical approach that can potentially enhance treatment affordability in IAA patients. However, prospective studies with larger number of patients are needed to further validate these results. DisclosuresNo relevant conflicts of interest to declare.

Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study

Biologic treatment options are limited for children with ulcerative colitis. The aim of this study was to assess the safety and efficacy of adalimumab in children with moderate-to-severe ulcerative colitis. The double-blind ENVISION I study was done at 24 hospitals in ten countries. Children (4-17 years) with moderate-to-severe ulcerative colitis despite stable doses of concurrent treatment with oral corticosteroids or immunosuppressants were enrolled. Per the original study design, patients were randomly assigned with an Interactive Voice Response System (IVRS) to receive either high-dose induction adalimumab (2·4 mg/kg [maximum 160 mg] at weeks 0 and 1) or standard-dose induction adalimumab (2·4 mg/kg at week 0 and placebo at week 1); both groups received 1·2 mg/kg (maximum 80 mg) at week 2 and 0·6 mg/kg (maximum 40 mg) at weeks 4 and 6. Patients with partial Mayo score (PMS) response at week 8 (defined as a decrease of two or more points and a decrease of ≥30% from baseline in PMS) were randomly assigned (2:2:1)-using IVRS-to receive either high-dose maintenance adalimumab (0·6 mg/kg weekly), standard-dose maintenance adalimumab (0·6 mg/kg every other week), or placebo up to week 52 (random assignment to the placebo group was ceased mid-trial, as was randomisation in the induction phase with all subsequent patients receiving open-label high-dose induction adalimumab). Coprimary endpoints were the proportion of patients with PMS remission at week 8 (intent-to-treat [ITT]-E population, not including those patients who were not randomised in the induction phase) and full Mayo score (FMS) remission at week 52 in week 8 PMS responders (maintenance ITT-E [mITT-E] population), for which the pooled adalimumab group (patients who received high-dose or standard-dose adalimumab) and the individual dose groups were compared against external adult placebo rates. We report results of the final confirmatory analysis. This trial is registered with ClinicalTrials.gov, NCT02065557. 93 children were recruited between Oct 13, 2014, and Sept 5, 2018, to the main study (77 [83%] were randomly assigned [double-blind] to receive high-dose or standard-dose induction adalimumab; 16 [17%] received open-label high-dose induction adalimumab after study design change). At week 8, 74 (80%) children who were PMS responders continued to the maintenance period. 62 (84%) patients were randomly assigned to receive high-dose or standard-dose maintenance adalimumab treatment; 12 (16%) patients received placebo. In patients in the ITT-E population who were randomly assigned to receive high-dose induction adalimumab, a significantly higher proportion of patients were in PMS remission at week 8 (28 [60%] of 47) compared with external placebo (19·8%; p=0·0001). 13 (43%) of 30 patients in the standard-dose induction adalimumab group were in PMS remission at week 8 versus an external placebo rate of 19·8%, but this difference was not significant (p=0·38). Similarly, FMS remission at week 52 in children who were week 8 PMS responders was reported in a significantly higher proportion of patients in mITT-E population who received high-dose maintenance adalimumab (14 [45%] of 31 patients) versus external placebo at week 52 (18·4%; p=0·0001). Nine (29%) of 31 patients in the standard-dose maintenance adalimumab group were in FMS remission at week 52 versus an external placebo rate of 18·4%, but this difference was not significant (p=0·38). Remission rates in the pooled adalimumab groups were significantly better compared with external placebo (PMS remission at week 8: 41 [53%] of 77 patients; p<0·0001; FMS remission at week 52: 23 [37%] of 62 patients; p=0·0001). 21 (23%) of 93 patients in the main study had one or more treatment-emergent serious adverse events during any adalimumab exposure. The most common adverse events were headache, anaemia, and ulcerative colitis flare during the induction period and ulcerative colitis flare, headache, and nasopharyngitis during the maintenance period. Clinically meaningful rates of remission and response were reported in children who received adalimumab in this study. No new safety signals were observed, suggesting that adalimumab is an efficacious and safe treatment option for children with moderate-to-severe ulcerative colitis. AbbVie.

Impact of Vitamin D and Calcium Supplementation on Bone Mineral Density and Bone Metabolism Among Thai Adolescents With Perinatally Acquired Human Immunodeficiency Virus (HIV) Infection: A Randomized Clinical Trial.

To evaluate the impact of vitamin D and calcium supplementation (VitD/Ca) on lumbar spine bone mineral density (LSBMD) and bone metabolism among Thai adolescents with perinatally acquired HIV (PHIVA). A multicenter, randomized, active-control, open-labeled trial was conducted. PHIVA (aged 10-20 years) who were on stable cART were enrolled. Baseline LSBMD status was defined as low (z-score ≤ -2) and normal (> -2). Eligible PHIVA were randomly assigned to receive standard-dose (400 IU/1200 mg/day) or high-dose (400 IU/1200 mg/day plus ergocalciferol 20 000 IU/week) VitD/Ca supplementation for 48 weeks (ratio 1:1, stratified by baseline LSBMD). Study outcomes were changes in LSBMD, LSBMD z-scores, and bone metabolism-related biomarkers (25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone [iPTH], C-terminal telopeptide [CTX], procollagen type I amino-terminal propeptide [PINP]) from baseline to week 48. Among 200 enrolled PHIVA, median age was 16 (IQR:14-18) years; 61% were on NNRTI-based cART. Median 25(OH)D level was 25.5 (IQR: 20.8-33.0) ng/mL. After 48-week VitD/Ca supplementation, LSBMD significantly increased in both treatment groups (high-dose: median: +0.07 [IQR: +0.04 to +0.11] g/cm2; P < .001; standard-dose: +0.09 [+0.03 to +0.13] g/cm2; P < .001). Notably, the change in LSBMD z-scores was significantly greater in high-dose versus standard-dose groups (median: +0.4 [IQR: -0.1 to +0.9] vs +0.1 [-0.4 to +0.7]; P = .02). Levels of 25(OH)D increased, whereas iPTH, CTX, and PINP declined significantly in both groups (P < .05), but no between-group differences were demonstrated. Over 48-week VitD/Ca supplementation, significant increases in LSBMD, and significant decreases in bone metabolism-related markers were observed among our Thai PHIVA in both treatment groups. The improvement in LSBMD z-score was more enhanced with high-dose VitD/Ca supplementation than standard-dose. High-dose VitD/Ca supplementation might be considered to promote bone health in this population. NCT02426840.

Intermediate-Dose versus Standard-Dose Prophylactic Anticoagulation in Patients with COVID-19 Admitted to the Intensive Care Unit: 90-Day Results from the INSPIRATION Randomized Trial.

Thrombotic complications are considered among the main extrapulmonary manifestations of coronavirus disease 2019 (COVID-19). The optimal type and duration of prophylactic antithrombotic therapy in these patients remain unknown. This article reports the final (90-day) results of the Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) study. Patients with COVID-19 admitted to intensive care were randomized to intermediate-dose versus standard-dose prophylactic anticoagulation for 30 days, irrespective of hospital discharge status. The primary efficacy outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause death. The main safety outcome was major bleeding. Of 600 randomized patients, 562 entered the modified intention-to-treat analysis (median age [Q1, Q3]: 62 [50, 71] years; 237 [42.2%] women), of whom 336 (59.8%) survived to hospital discharge. The primary outcome occurred in 132 (47.8%) of patients assigned to intermediate dose and 130 (45.4%) patients assigned to standard-dose prophylactic anticoagulation (hazard ratio [HR]: 1.21, 95% confidence interval [CI]: 0.95-1.55, p = 0.11). Findings were similar for other efficacy outcomes, and in the landmark analysis from days 31 to 90 (HR: 1.59, 95% CI: 0.45-5.06). There were 7 (2.5%) major bleeding events in the intermediate-dose group (including 3 fatal events) and 4 (1.4%) major bleeding events in the standard-dose group (none fatal) (HR: 1.82, 95% CI: 0.53-6.24). Intermediate-dose compared with standard-dose prophylactic anticoagulation did not reduce a composite of death, treatment with ECMO, or venous or arterial thrombosis at 90-day follow-up.

Inflammation Associated Gene Expression in the Mammary Gland of Lactating Mothers Who Delivered Preterm and Were Randomly Assigned to a Standard vs Increased DHA Supplement

ObjectivesOur objective was to characterize the mRNA-seq transcriptome of the mammary gland of lactating mothers who delivered preterm and were enrolled in a randomized control trial (RCT) of standard versus increased DHA supplementation. We hypothesized that inflammation associated gene expression would be attenuated in the increased DHA group versus the standard dose group. MethodsThe RCT was completed by 8 participants randomized to standard of care DHA supplements (200 mg/day, STD group) and 10 randomized to increased DHA supplements (1000 mg/day, EXP group). High quality extracellular mammary epithelial cell mRNA was isolated from fresh milk fat and submitted to RNA-sequencing in n = 4 STD and n = 6 EXP DHA samples. Aligned and quantified reads were examined for differentially expressed genes using t-tests (DEG, p < 0.05 after false discovery rate adjustment). The resulting DEG list was intersected with the Broad Institute list of hallmark inflammation genes. Ontological analysis of DEGs was performed with Toppcluster. ResultsThere were 409 DEGs overall, including 9 hallmark inflammation genes. In the EXP group, up-regulation of inflammation-inhibiting genes included NFKBIA (FC = 4.0) and IL18BP (FC = 3.6); and down-regulation of pro-inflammatory genes included IL7R (FC = –3.6) and IL1RL1 (FC = –3.9). Ontological analysis revealed 5 clusters of up-regulated gene sets in the EXP group, including immune regulation and management of oxidative stress associated clusters. Strong up-regulation was also seen in the major milk proteins LALBA (3.8-fold increase) and CSN2 (3.4-fold increase). ConclusionsThese findings reveal that increased DHA supplementation during lactation can modulate the expression of inflammation-associated genes within the mammary gland and support improved mammary gland function. These effects may have important clinical implications towards producing milk with a more optimal inflammasome profile and improving overall mammary gland health and function in lactating mothers who deliver preterm, with an overall benefit of reducing inflammation-driven morbidity in their premature infants. Future research with a larger RCT and greater interrogation of milk composition and volume is warranted. Funding SourcesNIH, Mead Johnson Nutrition.

Comparative effectiveness of higher adalimumab maintenance therapy versus standard dose in anti-tumor necrosis factor experienced Crohn's disease patients: A propensity-score matched cohort analysis.

Crohn's disease (CD) patients who previously failed anti-tumor necrosis factor (TNF) therapy are at higher risk of treatment failure with subsequent biologics. This study aims to determine the effectiveness and safety of higher maintenance dose regimens of adalimumab compared with standard doses in CD patients who failed anti-TNF. In this retrospective observational study, CD patients who failed anti-TNF and received adalimumab were categorized according to their post-induction maintenance regimen; 40mg subcutaneous (sc) weekly or 80mg sc every other week were defined as a high-dose (HD) maintenance regimen, and 40mg sc every other week was defined as a standard-dose (SD) maintenance regimen. The primary outcome was time to treatment failure. Cox proportional hazards regression was used to adjust for confounders. Sensitivity analysis was conducted using propensity scores to create a cohort of matched participants with similar distribution of baseline covariates. Forty patients started on HD regimens following induction, and 77 patients received the SD regimen. The median time to failure in the HD group was 6.6years (interquartile range [IQR] 4.0-9.6) and 3.0years (IQR 0.9-9.4) in the SD group (log-rank test P=0.006). Patients on HD adalimumab had a lower hazard rate of treatment failure (hazard ratio: 0.27; 95% confidence interval [0.12, 0.62]; P=0.002) compared with SD patients. No difference in adverse events was identified between groups (30% vs 31.2%, P=1.0). Results were similar in the propensity score-matched cohort. High-dose maintenance regimens were associated with longer time-to-failure as compared with SD regimens in CD patient who failed anti-TNF.

Spironolactone Improves the All-Cause Mortality and Re-Hospitalization Rates in Acute Myocardial Infarction with Chronic Kidney Disease Patients.

Background: Mineralocorticoid receptor antagonists (MRA) improve outcomes in chronic kidney disease (CKD) and acute myocardial infarction (AMI) patients. However, the lack of evidence regarding long-term clinical outcomes in the use of MRA, including spironolactone, in patients with AMI combined with CKD. Objectives: This study aimed to investigate whether spironolactone could significantly reduce the risk of all-cause mortality and re-admission in patients with AMI and CKD. Methods: In this single center, observational, retrospective, registry based clinical study, a total of 2,465 AMI patients were initially screened; after excluding patients with estimated glomerular filtration rate more than 60 ml/min/1.73 m2, 360 patients in the standard treatment group and 200 patients in the spironolactone group met the criteria. All enrolled patients follow-up for 30 months. The primary outcomes were all-cause mortality and re-admission. The key safety outcome was hyperkalemia rates during the 30 months follow-up period. Results: 160 (44.4%) and 41 (20.5%) patients in the standard treatment and spironolactone groups died, respectively [hazard ratio (HR): 0.389; 95% confidence interval (CI): 0.276–0.548; p < 0.001]. Re-admission occurred in 217 (60.3%) and 95 (47.5%) patients in the standard treatment and spironolactone groups, respectively (HR: 0.664; 95% CI: 0.522–0.846; p = 0.004). The spironolactone group was divided into two based on the daily dose, low dose group (no more than 40 mg) and high dose group (more than 40 mg); the differences in the mortality rate between low dose group (16.7%) and the standard treatment group (44.4%) (HR: 0.309; 95% CI: 0.228–0.418; p < 0.001) and high dose group (34.1%) (HR: 0.429; 95% CI: 0.199–0.925; p = 0.007) were significant. The differences in re-hospitalization rate between low dose group (43.6%) and the standard treatment group (60.3%) (HR: 0.583; 95% CI: 0.457–0.744; p < 0.001) and high dose group (61.4%) (HR: 0.551; 95% CI: 0.326–0.930; p = 0.007) was significant. Hyperkalemia occurred in 18 (9.0%) and 18 (5.0%) patients in the spironolactone group and standard treatment group, respectively (HR: 1.879; 95% CI: 0.954–3.700; p = 0.068). Whereas, Hyperkalemia occurred in high dose group (20.5%) significantly more often than in the standard treatment group (p < 0.001) and low dose group (5.8%) (p = 0.003). Conclusion: Using MRA, such as spironolactone, may substantially reduce the risk of both all-cause mortality and re-admission in patients with AMI and CKD; the use of low-dose spironolactone has the best efficacy and safety. However, this was a relatively small sample size, single center, observational, retrospective, registry based clinical study and further prospective evaluation in adequately powered randomized trials were needed before further use of spironolactone in AMI with CKD population.

Comparison of the efficacy of hematopoietic stem cell mobilization regimens: a systematic review and network meta-analysis of preclinical studies

BackgroundMobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies.MethodsWe searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin− Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200–250 μg/kg/day) group and the LD (low dose, 100–150 μg/kg/day) group based on doses, and were classified into the short-term (2–3 days) group and the long-term (4–5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen.ResultsWe included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0−2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0–2733.0).ConclusionsConsidering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.

Corticosteroids for hospitalized patients with mild to critically-ill COVID-19: a multicenter, retrospective, propensity score-matched study

Corticosteroids use in coronavirus disease 2019 (COVID-19) is controversial, especially in mild to severe patients who do not require invasive/noninvasive ventilation. Moreover, many factors remain unclear regarding the appropriate use of corticosteroids for COVID-19. In this context, this multicenter, retrospective, propensity score–matched study was launched to evaluate the efficacy of systemic corticosteroid administration for hospitalized patients with COVID-19 ranging in the degree of severity from mild to critically-ill disease. This multicenter, retrospective study enrolled consecutive hospitalized COVID-19 patients diagnosed January–April 2020 across 30 institutions in Japan. Clinical outcomes were compared for COVID-19 patients who received or did not receive corticosteroids, after adjusting for propensity scores. The primary endpoint was the odds ratio (OR) for improvement on a 7-point ordinal score on Day 15. Of 1092 COVID-19 patients analyzed, 118 patients were assigned to either the corticosteroid and non-corticosteroid group, after propensity score matching. At baseline, most patients did not require invasive/noninvasive ventilation (85.6% corticosteroid group vs. 89.8% non-corticosteroid group). The odds of improvement in a 7-point ordinal score on Day 15 was significantly lower for the corticosteroid versus non-corticosteroid group (OR, 0.611; 95% confidence interval [CI], 0.388–0.962; p = 0.034). The time to improvement in radiological findings was significantly shorter in the corticosteroid versus non-corticosteroid group (hazard ratio [HR], 1.758; 95% CI, 1.323–2.337; p < 0.001), regardless of baseline clinical status. The duration of invasive mechanical ventilation was shorter in corticosteroid versus non-corticosteroid group (HR, 1.466; 95% CI, 0.841–2.554; p = 0.177). Of the 106 patients who received methylprednisolone, the duration of invasive mechanical ventilation was significantly shorter in the pulse/semi-pulse versus standard dose group (HR, 2.831; 95% CI, 1.347–5.950; p = 0.006). In conclusion, corticosteroids for hospitalized patients with COVID-19 did not improve clinical status on Day 15, but reduced the time to improvement in radiological findings for all patients regardless of disease severity and also reduced the duration of invasive mechanical ventilation in patients who required intubation.Trial registration: This study was registered in the University hospital Medical Information Network Clinical Trials Registry on April 21, 2020 (ID: UMIN000040211).

Low-dose versus standard-dose four-factor prothrombin complex concentrate for factor-Xa inhibitor reversal in spontaneous and traumatic intracranial hemorrhage.

Current neurocritical care guidelines recommend 50IU/kg four-factor prothrombin complex concentrate (4PCC) for factor Xa inhibitor (FXaI) reversal in intracranial hemorrhage (ICH) based on few clinical studies conducted among non-ICH subjects. Two recent studies suggest that low-dose (25IU/kg) 4PCC may be similar to 50IU/kg in reversal of FXaI in ICH, and both 25 and 50IU/kg doses are used in clinical practice for this indication. To our knowledge, no studies have directly compared 25IU/kg versus 50IU/kg 4PCC for FXaI reversal in ICH. The purpose of this study is to determine whether there is a difference in hemostatic efficacy between 25IU/kg versus 50IU/kg 4PCC for FXaI reversal in ICH. This multicenter, retrospective cohort study was performed in five hospitals in central Texas from November 2013 to December 2019. Patients were identified with a medication use report of 4PCC and were classified in the low- or standard-dose group based on whether the 25IU/kg or 50IU/kg dose was received, respectively. A total of 93 patients were included (25IU/kg, n=62; 50IU/kg, n=31). There was no difference in hemostatic efficacy between groups (82.3% low dose vs. 83.9% standard dose, p=0.846). No differences were identified in-hospital mortality, length of stay, thrombotic events, or the need for surgery or additional blood products between groups. For the reversal of FXaI in ICH, a 25IU/kg dose may be an effective alternative to 50IU/kg 4PCC dosing.

Safety and efficacy of low-dose ticagrelor in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention

It remains unclear whether low-dose ticagrelor offers better safety and similar efficacy for Asian patients with acute coronary syndromes (ACS). We aimed to compare the safety and effectiveness of low-dose ticagrelor vs standard-dose ticagrelor in Chinese patients with ACS undergoing percutaneous coronary intervention (PCI). In this observational cohort study, a total of 2110 ACS patients who were event-free at 3 months after the index PCI were divided into standard-dose ticagrelor (90 mg twice daily) (n = 1830) or low-dose ticagrelor (45 mg twice daily) (n = 280) on a background of aspirin 100 mg once daily for at least another 9 months. The primary end point was type 2, 3, or 5 bleeding according to the Bleeding Academic Research Consortium (BARC) criteria over a 1-year follow-up period post-PCI. Predictors of the primary end point were identified. Both Cox regression and propensity score matching analyses were used. The cumulative incidence of BARC type 2, 3, or 5 bleeding was lower in the low-dose ticagrelor group vs the standard-dose group either before (adjusted HR 0.24; 95% CI 0.07–0.77; p = .016) or after matching (HR 0.25; 95% CI 0.08–0.85; p = .026). A composite of cardiac death, myocardial infarction, or stroke was not significantly different between the two groups (0.4% vs 0.9%, respectively). By multivariate analysis, only low-dose ticagrelor was a protected predictor of BARC type 2, 3, or 5 bleeding either before (HR 0.28, 95% CI 0.09–0.89) or after matching (HR 0.24, 95% CI 0.07–0.82). A low-dose regimen of ticagrelor might provide better safety than standard-dose ticagrelor in Chinese patients with ACS undergoing PCI.

Initially Reduced Linezolid Dosing Regimen to Prevent Thrombocytopenia in Hemodialysis Patients.

This retrospective cohort study investigated the effects of an initially reduced linezolid dosing regimen in hemodialysis patients through therapeutic drug monitoring (TDM). Patients were divided into two groups depending on their initial dose of linezolid (standard dose of 600 mg every 12 h or initially reduced dose of 300 mg every 12 h/600 mg every 24 h). The cumulative incidence rates of thrombocytopenia and severe thrombocytopenia were compared between both groups using the Kaplan–Meier method and log-rank test. Eleven episodes of 8 chronic hemodialysis patients were included; 5 were in the initially reduced-dose group. Thrombocytopenia developed in 81.8% of patients. The cumulative incidence rates of thrombocytopenia and severe thrombocytopenia in the initially reduced-dose group were significantly lower than in the standard-dose group (p < 0.05). At the standard dose, the median linezolid trough concentration (Cmin) just before hemodialysis was 49.5 mg/L, and Cmin at the reduced doses of 300 mg every 12 h and 600 mg every 24 h were 20.6 mg/L and 6.0 mg/L, respectively. All five episodes underwent TDM in the standard-dose group required dose reduction to 600 mg per day. Our findings indicate that initial dose reduction should be implemented to reduce the risk of linezolid-induced thrombocytopenia among hemodialysis patients.

Regional Gene Therapy with Transduced Human Cells: The Influence of “Cell Dose” on Bone Repair

Regional gene therapy using a lentiviral vector containing the BMP-2 complementary DNA (cDNA) has been shown to heal critical-sized bone defects in rodent models. An appropriate "cellular dose" needs to be defined for eventual translation into human trials. The purpose of this study was to evaluate bone defect healing potential and quality using three different doses of transduced human bone marrow cells (HBMCs). HBMCs were transduced with a lentiviral vector containing either BMP-2 or green fluorescent protein (GFP). All cells were loaded onto compression-resistant matrices and implanted in the bone defect of athymic rats. Treatment groups included femoral defects that were treated with a low-dose (1 × 106 cells), standard-dose (5 × 106 cells), and high-dose (1.5 × 107 cells) HBMCs transduced with lentiviral vector containing BMP-2 cDNA. The three control groups were bone defects treated with HBMCs that were either nontransduced or transduced with vector containing GFP. All animals were sacrificed at 12 weeks. The bone formed in each defect was evaluated with plain radiographs, microcomputed tomography (microCT), histomorphometric analysis, and biomechanical testing. Bone defects treated with higher doses of BMP-2-producing cells were more likely to have healed (6/14 of the low-dose group; 12/14 of the standard-dose group; 14/14 of the high-dose group; χ2(2) = 15.501, p < 0.001). None of the bone defects in the control groups had healed. Bone defects treated with high dose and standard dose of BMP-2-producing cells consistently outperformed those treated with a low dose in terms of bone formation, as assessed by microCT and histomorphometry, and biomechanical parameters. However, statistical significance was only seen between defects treated with high dose and low dose. Larger doses of BMP-2-producing cells were associated with a higher likelihood of forming heterotopic ossification. Femurs treated with a standard- and high-dose BMP-2-producing cells demonstrated similar healing and biomechanical properties. Increased doses of BMP-2 delivered through higher cell doses have the potential to heal large bone defects. Adapting regional gene therapy for use in humans will require a balance between promoting bone repair and limiting heterotopic ossification. Impact statement Critical bone loss may result from complex traumatic bone injury (i.e., open fracture or blast injury), revision total joint arthroplasty, and spine pseudoarthrosis. This is a challenging clinical problem to treat and regional gene therapy is an innovative means of addressing it. This study provides information regarding the quantity of cells or "cell dose" of transduced cells needed to treat a critical-sized bone defect in a rat model. This information may be extrapolated for use in humans in future trials.