OBJECTIVE: This study aims to evaluate the effectiveness and safety of administering double-dose tamsulosin (0.8 mg) for treating patients with benign prostatic hyperplasia (BPH) who have not responded to the standard single dose of tamsulosin (0.4 mg) and are deemed unsuitable for transurethral resection (TUR) intervention.
METHODS: Between November 2022 and July 2023, we prospectively analyzed 111 patients who were experiencing severe BPH symptoms. These patients received a double dose of tamsulosin for one month. We collected baseline characteristics such as age, body mass index, and underlying medical conditions. Various parameters including the International Prostate Symptom Score (IPSS), prostate-specific antigen (PSA) levels, prostate volume, peak urinary flow rate (Qmax), voided volume, and post-void residual volume were evaluated before and after treatment.
RESULTS: All 111 patients completed the study. The mean age, PSA level, and prostate volume were 63.12 ± 4.83 years, 3.42 ± 0.93 ng/ml, and 50.37 ± 19.23 ml, respectively. Of these patients, 93 showed improvement in Qmax, post-void residual volume, and IPSS score (p-value = 0.001). The total IPSS score and total Qmax improved from 24.03 ± 2.49 and 7.72 ± 1.64 ml/sec to 16.41 ± 3.84 and 12.08 ± 2.37 ml/sec, respectively.
CONCLUSIONS: Double-dose 0.8mg tamsulosin as an alpha-blocker therapy appears to be a viable temporary management option for BPH patients who have not responded to the standard single dose 0.4mg tamsulosin and are not suitable candidates for TUR intervention.

OBJECTIVE: With the increasing prevalence of osteoarthritis of the hip and knee, total joint replacement, the end-stage treatment, provides pain relief and restoration of function, but is often associated with massive blood loss. Tranexamic acid (TXA) has been reported to reduce perioperative blood loss in hip or knee arthroplasty. However, the optimal dose of TXA administration remains controversial. Therefore, we performed a meta-analysis combining data from 5 trials comparing the efficacy and safety of one fixed dose of 1 g intravenously administered TXA with two doses of 1 g each administered intravenously for hip or knee arthroplasty.
METHODS: PubMed, Medline, Embase, Web of Science, and The Cochrane Library were searched from January 2000 to February 2023. Our meta-analysis included randomized controlled trials and cohort studies comparing the efficacy and safety of different doses of intravenous TXA (IV-TXA) for THA or TKA. The observation endpoints included total blood loss, postoperative hemoglobin drop, blood transfusion rate, length of hospital stay, incidence of deep venous thrombosis (DVT), and incidence of pulmonary embolism (PE). Meta-analysis was performed according to Cochrane\'s guidelines and PRISMA statement. The Danish RevMan5.3 software was used for data merging.
RESULTS: Five cohort studies involving 5542 patients met the inclusion criteria. Our meta-analysis showed that the two groups were significantly higher in total blood loss (mean difference (MD) = - 65.60, 95% confidence interval (CI) [- 131.46, 0.26], P = 0.05); blood transfusion rate (risk difference (RD) = 0.00, 95% CI [- 0.01, 0.02], P = 0.55); postoperative hemoglobin (MD = 0.02, 95% CI [- 0.09, 0.13], P = 0.31); postoperative hospital stay days (MD = - 0.13), 95% CI [- 0.35, 0.09], P = 0.25); DVT (RD = 0.00, 95% CI [- 0.00, 0.01], P = 0.67); PE (RD = 0.00, 95% CI [- 0.01, 0.00], P = 0.79). There was some inherent heterogeneity due to variance in sample size across each major study.
CONCLUSIONS: 1 dose of 1 g and 2 doses of 1 g IV-TXA each time have similar effects on reducing blood loss, blood transfusion rate, postoperative hemoglobin level, and postoperative hospital stay after TKA or THA, without increasing the risk of postoperative complications risk. For patients at high risk of thromboembolic events, one dose of 1 g TXA throughout surgery may be preferred. However, higher-quality RCT is needed to explore the optimal protocol dose to recommend the widespread use of TXA in total joint arthroplasty. Trial registration We conducted literature selection, eligibility criteria evaluation, data extraction and analysis on the research program registered in Prospero (CRD42023405387) on March 16, 2023.

OBJECTIVE: To compare the outcomes of single versus double doses of tocilizumab in patients with severe COVID-19, especially on different types of oxygenation requirements.
METHODS: This cross-sectional study was carried out from January 2020 to March 2020. Patients diagnosed with COVID-19, who received at least one dose of tocilizumab, were included. The dependent variable was tocilizumab dose (single versus double). The primary outcome variable was oxygen demand on the first and last day of hospitalization. A series of comparisons between patients administered one dose of tocilizumab versus 2 doses were conducted.
RESULTS: Herein, 80 patients with severe COVID-19 infection were included, of whom 68.8% received one dose of tocilizumab, while 31.3% received a double dose. Two-thirds of the patients were male, with an overall average age of 58 years. In patients receiving 2 doses, oxygen demand tended to worsen by the seventh day, while in those who received one dose. The group that received 2 doses had a longer length of hospital stay.
CONCLUSIONS: This study could not capture the additional value of the second dose for different health outcomes. However, the results can inform clinician from experience when facing uncertainty due to new virus or variant.

UNASSIGNED: Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) inevitably occurs in non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations. There are approximately half of the patients who developed resistance to EGFR-TKIs treatment, the mechanism of which remains undiscovered. We occasionally found that double-dose icotinib as further-line salvage treatment may induce the emerging mutation of EGFR exon 20 T790M in NSCLC patients. The present study, therefore, was conducted to explore the probability of the emerging T790M mutation after exposure to double-dose icotinib in metastatic NSCLC patients.
UNASSIGNED: Metastatic NSCLC patients who received double-dose icotinib as salvage treatment after progression on first-generation TKIs and systematic chemotherapy were screened. Thereafter, patients who received a repeated next-generation sequencing (NGS) test with tumor sample were further enrolled. The procedure of NGS was performed with the standard criteria. Finally, the clinical characteristics, treatment procedures, and outcomes of eligible patients were reviewed and presented.
UNASSIGNED: Three patients have been detected with the emerging T790M mutation after double-dose icotinib exposure, with a mutation frequency of 19.6%, 8.2%, and 87.5%. During the treatment of targetable TKIs including almonertinib or osimertinib, partial response was observed in two patients, and stable disease was observed in the other. The progression-free survival by targetable TKIs for the patients was 3.7+ months (still in extension), 4.9+ months (still in extension), and 6.3 months. Manageable adverse events were observed during the treatment of TKIs.
UNASSIGNED: The results of the present study revealed that the emerging EGFR exon 20 T790M mutation might be induced by double-dose icotinib exposure in further-line treatment. Patients with the emerging T790M mutation responded well to the treatment of targetable TKIs including almonertinib or osimertinib.

Background: Colorectal cancer (CRC) is the third most common cancer in Europe, with an annual increase in incidence ranging between 0.4 and 3.6% in various countries. Although the development of CRC was extensively studied, limited number of new therapies were developed in the last few years. Bevacizumab is frequently used as first- and second-line therapy for management of metastatic CRC (mCRC). The aim of this study is to present our experience with using bevacizumab beyond disease progression at different dosage levels in mCRC patients, in terms of overall survival, progression-free survival, time to treatment failure, and toxicities. Methods: We performed a consecutive retrospective analysis of patients with confirmed mCRC who were treated with bevacizumab at \"Prof Dr. Ion Chiricuta\" Institute of Oncology, Cluj-Napoca, Romania. We included patients who had received bevacizumab as first- or second-line therapy and further stratified them according to the dose administered as a second-line (either standard dose of 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks, or double dose of 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks-depending on the classical chemotherapy partner). All patients had received bevacizumab beyond progression (BYP) which is defined as continuing bevacizumab administration through second-line treatment despite disease progression. In each group, we evaluated the prognostic factors that influenced survival and treatment outcome. Results: One hundred and fifty-one (151) patients were included in the study. Themedian age of patients receiving double dose bevacizumab (DDB) and standard dose bevacizumab (SDB) was 58 years (range 41-71) and 57 years (range 19-75), respectively. The median overall survival in the DDB group was 41 months (range 27-49) compared to 25 months (range 23-29) in the SDB group (p = 0.01 log-rank test). First-line oxaliplatin-based treatment was used more frequently regardless of group, while irinotecan-based more frequently used as a second-line treatment (p = 0.014). Both oxaliplatin- and irinotecan-based regimens were found to be suitable partners for BYP. Statistical analysis revealed that dose intensity, primary tumor location, and cumulative exposure to BYP had significant influence on survival. Conclusion: Doubling the dose of bevacizumab after first progression may improve survival in mCRC patients. Increasing bevacizumab dose intensity could override the prognostic impact of primary tumor location in patients receiving double the dose of bevacizumab after first disease progression.

OBJECTIVE: The effect of double-dose oseltamivir on mortality in patients with influenza remains controversial. We systematically reviewed the literature to investigate whether double-dose oseltamivir influences mortality in patients with influenza.
METHODS: PubMed, Excerpta Medica Database (Embase) and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for randomized controlled trials (RCTs) and observational studies regarding the effect of double-dose oseltamivir on mortality in patients with influenza. The primary outcome was all-cause mortality. The Mantel-Haenszel method with random effects model was used to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs).
CONCLUSIONS: Ten studies (four RCTs and six observational studies), involving 20 947 patients, were included. Pooled analysis suggested that double-dose oseltamivir was not associated with decreased mortality in patients with influenza, both in RCTs (OR, 1.29; 95% CI, 0.52-3.15; P = .58) and observational studies (OR, 1.59; 95% CI, 0.79-3.19; P = .20; I2  = 51%). Double-dose oseltamivir did not show statistical benefit on the virologic clearance rate (OR, 1.26; 95% CI, 0.85-1.88; P = .25; I2  = 0%) or the incidence of adverse events (AEs) (OR, 1.52; 95% CI, 0.85-2.72; P = .15; I2  = 59%).
CONCLUSIONS: Current evidence indicates that double-dose oseltamivir does not decrease mortality or have advantages on the outcome of virologic clearance rate and incidence of AEs. However, the finding largely relied on the data from observational studies, which may potentially have led to selection bias. Therefore, high-quality and adequately powered RCTs are warranted.

OBJECTIVE: The risk factors and the impact of NAI treatments in patients with severe influenza A-associated pneumonia remain unclear.
METHODS: A multicenter, retrospective, observational study was conducted in Zhejiang, China during a severe influenza epidemic in August 2017-May 2018. Clinical records of patients (>14 y) hospitalized with laboratory-confirmed influenza A virus infection and who developed severe pneumonia were compared to those with mild-to-moderate pneumonia. Risk factors related to pneumonia severity and effects of NAI treatments (monotherapy and combination of peramivir and oseltamivir) were analyzed.
RESULTS: 202 patients with influenza A-associated severe pneumonia were enrolled, of whom 84 (41.6%) had died. Male gender (OR = 1.782; 95% CI: 1.089-2.917; P = 0.022), chronic pulmonary disease (OR = 2.581; 95% CI: 1.447-4.603; P = 0.001) and diabetes mellitus (OR = 2.042; 95% CI: 1.135-3.673; P = 0.017) were risk factors related to influenza A pneumonia severity. In cox proportional hazards model, severe pneumonia patients treated with double dose oseltamivir (300mg/d) had a better survival rate compared to those receiving a single dose (150 mg/d) (HR = 0.475; 95%CI: 0.254-0.887; P = 0.019). However, different doses of peramivir (300 mg/d vs. 600 mg/d) and combination therapy (oseltamivir-peramivir vs. monotherapy) showed no differences in 60-day mortality (P = 0.392 and P = 0.658, respectively).
CONCLUSIONS: Patients with male gender, chronic pulmonary disease, or diabetes mellitus were at high risk of developing severe pneumonia after influenza A infection. Double dose oseltamivir might be considered in treating influenza A-associated severe pneumonia.

BACKGROUND: The aim of this study was to compare and summarize the lipid-altering effects of combination therapy with ezetimibe and statins (E/S) and a double dose of statin (D/S) monotherapy on patients with hypercholesterolemia.
METHODS: We conducted search on 2 medical databases, PubMed and EMBASE to identify all relevant studies. A meta-analysis was performed to clarify the efficacy in the two groups. Only double-blind Randomized controlled study (RCTs) of efficacy evaluation in the two groups with ezetimibe and statins and a double dose of statin in participants with hypercholesterolemia that examined low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC) and high-density lipoprotein (HDL) were included. Two reviewers extracted data from all primary studies independently. The primary data were the level of LDL-C, TC and HDL-C concentrations at the end point and are expressed as mean and standard deviation (SD).
RESULTS: A total of 11 double-blind, active or placebo-controlled studies with 1926 hypercholesterolemia adults randomized to ezetimibe 10 mg added to ongoing statins (N = 994) or statin titration (doubling) (N = 932) were pooled for the global meta-analysis. The effect size between treatment groups within individual studies was assessed by weighted mean difference (MD) using a random- or fixed-effect model. The result showed that the participants in E/S group get obvious lower LDL-C [MD = -13.14 mg/dL, 95%CI (-16.83, -9.44), p = 0.00001] and TC concentration [MD = -23.79 mg/dL, 95%CI (-38.65, -8.93), p = 0.002] from baseline to follow-up, comparing to the D/S group. Besides, no significant between-group differences were observed for concentrations of HDL-C [MD = 0.46 mg/dL, 95%CI (- 1.14, 2.06), p = 0.57]. According to subgroup analysis, the combination of ezetimibe and atorvastatin (10 mg) [MD = -16.98 mg/dL, p < 0 .0001] or simvastatin (20 mg) [MD = -17.35 mg/dL, p < 0 .0001] showed stronger ability of reducing LDL-C than combination of ezetimibe and rosuvastatin (10 mg) [MD = -9.29 mg/dL, p = 0.05]. The efficacy of short-term (endpoint time between 6 to 16 week) and long-term (52 week) treatment in the LDL-C between two groups did not show significant differences. Besides, only participants from Asia treated with combination therapy were associated with a significant lower LDL-C concentration [MD = -14.7 mg/dL, p < 0 .0001].
CONCLUSIONS: The addition of ezetimibe to statin appears to be more effective on reducing LDL-C and TC concentrations than doubling the statin dose. Moreover, the ability to reduce cholesterol levels of combinations therapy with ezetimibe and different statins or to participants from different geographic location may vary, based on this meta-analysis, while more samples are needed to verify.

The study compared immunogenicity and safety between alternative higher-dose and standard-dose trivalent vaccines in immunocompromised individuals. A literature search was performed using the PubMed, Embase, and Cochrane databases from inception until March 2019 to identify studies comparing the immunogenicity of alternative higher-dose (including high-dose, double-dose, and booster-dose vaccines) and standard-dose trivalent influenza vaccines in patients who underwent transplantation or chemotherapy. Effect estimates from the individual studies were derived and calculated using the DerSimonian and Laird random-effect model. The protocol for this systematic review is registered with PROSPERO (number CRD42019129220). Eight relevant studies involving 1020 patients were included in the systematic review and meta-analysis. The meta-analysis demonstrated that the higher-dose strategy provided had significantly superior seroconversion and seroprotection for A/H1N1 strains than the standard dose. Regarding H3N2 and B strains, no differences in immunogenicity responses were noted. No differences in safety were observed between the vaccination strategies. Alternative higher-dose vaccination strategies appear to associate with superior immunogenicity responses for A/H1N1 strains, and the strategies were generally well tolerated in immunocompromised populations. Future studies should clarify the optimal timing, frequency and dose of vaccination and assess whether these strategies improve vaccine immunogenicity and clinical outcomes.

The use of vaccines with higher doses of antigen is an attractive strategy to improve the immunogenicity of influenza vaccination in transplant recipients. However, the effect of vaccination with a double-dose (DD) containing 30 µg of antigen in this population remains unknown.
We performed a randomized controlled trial to compare the immunogenicity and safety of DD (30 µg) vs. standard dose (SD, 15 µg) of a trivalent inactivated influenza vaccine in kidney and liver transplant recipients. Immunogenicity was assessed by hemagglutination-inhibition assay. Vaccine response was defined as seroconversion to at least one viral strain 2 weeks after vaccination and seroprotection as a titer ≥40.
Sixty-three kidney and 16 liver transplant recipients were enrolled. Forty patients received the DD and 39 the SD vaccine. Overall, 40% of patients in the DD compared to 26% in the SD group (P = 0.174) responded to vaccine. In the DD arm, more patients were seroprotected to all viral strains after vaccination (88% vs 69%, P = 0.048). Post vaccination geometric mean titers of antibodies were 131.9 vs. 89.7 (P = 0.187) for H1N1, 185.4 vs. 138.7 (P = 0.182) for H3N2, and 96.6 vs. 68.8 (P = 0.081) for influenza B with the DD vs. SD. In both groups, most of the adverse events were mild and no vaccine-related severe adverse events were observed.
Double-dose influenza vaccine is safe and may increase antibody response in transplant recipients. In this population, DD vaccination could be an alternative when high-dose vaccine is not available. NCT02746783.