Single Regimen Research Articles

Scp776, A Novel IGF-1 Fusion Protein for Acute Therapy to Promote Escape From Apoptosis in Tissues Affected by Ischemic Injury: 2 Randomized Placebo-Controlled Phase 1 Studies in Healthy Adults.

Apoptosis is a major driver of cell loss and infarct expansion in ischemic injuries such as acute ischemic stroke (AIS) and acute myocardial infarction (AMI). Insulin-like growth factor-1 (IGF-1) can mitigate cell death and potentiate recovery following acute ischemic injury, but short half-life and nonspecificity limit its therapeutic potential. Scp776 is an IGF-1 fusion protein designed to target damaged tissue and promote apoptosis escape and is in clinical development as an acute therapy for AIS and AMI. Two phase 1 placebo-controlled studies in healthy volunteers evaluated safety, tolerability, pharmacokinetic profile, and pharmacodynamics under single (1, 2, or 4mg/kg) or multiple (6, 6.2, or 7.25mg/kg total doses) dosing regimens. In addition, a blood glucose management plan was developed and implemented to mitigate hypoglycemia that may develop following scp776 injection. Scp776 was well tolerated in healthy volunteers (n=51) without serious adverse events. Exposure increased in a near dose-proportional manner with a mean half-life across all doses of 8hours. Adaptive dextrose infusions maintained normal blood glucose levels with occasional mild hypoglycemic events. These results informed scp776 dose selection and the design of blood glucose monitoring protocols for phase 2 studies.

Healthcare resource utilization and costs among treatment-naïve people with HIV in state Medicaids: analysis of multi-tablet vs. single-tablet antiretroviral regimen initiators with and without concurrent mental health disorders

BACKGROUND Research is needed to understand the impact of mental health disorders (MHD) on healthcare resource utilization (HCRU) and costs among people with human immunodeficiency virus (PWH). OBJECTIVES Examine the HCRU and cost burden among treatment-naïve PWH with and without MHD initiating single tablet antiretroviral regimens (STRs) and multi-tablet regimens (MTRs). METHODS A retrospective database analysis of US Medicaid population from Anlitiks’ All Payor Claims database between 01/01/16 to 06/30/23 was conducted. Treatment-naïve MTR-initiators vs STR-initiators (the index was the first prescription fill claim date) with ≥ 12-months pre- and post-index continuous enrollment and no pre-index HIV-2 diagnosis among PWH/MHD and PWH/no-MHD during 01/01/17-06/30/22 were selected. Demographics, clinical characteristics, HCRU and costs between MTR-initiators vs STR-initiators among PWH/MHD and PWH/no-MHD were described using Chi-square tests and Wilcoxon rank-sum or t-tests for categorical and continuous variables, as appropriate. HCRU and costs were examined using multivariable logistic and gamma-log link regression models, controlling for potential confounders. RESULTS MTR-initiators (PWH/MHD: n = 7,874, PWH/no-MHD: n = 3,612) vs. STR-initiators (PWH/MHD: 46,024, PWH/no-MHD: 23,452) were significantly younger (PWH/MHD: 43.6 vs. 47.2 years; PWH/no-MHD: 39.2 vs. 43.3 years) and more likely to be female (PWH/MHD: 46.4% vs. 35.7%; PWH/no-MHD: 42.3% vs 29.7%) in both groups (all p-values < 0.05). MTR-initiators vs. STR-initiators had significantly higher rates of inpatient (IP) hospitalizations (PWH/MHD: 28.9% vs. 27.1%; PWH/no-MHD:13.9% vs. 11.9%) and emergency department (ED) visits (PWH/MHD: 53.3% vs. 49.2%; PWH/no-MHD: 35.2% vs. 31.8%) among both those with and without MHD (all p-values < 0.05). MTR-initiators vs. STR-initiators also had significantly higher adjusted all-cause medical costs (PWH/MHD: $60,228 vs $40,634; PWH/no-MHD: $33,623 vs. $17,996) (all p-values < 0.05). CONCLUSIONS Among PWH/MHD and PWH/no-MHD, MTR-initiators experienced significantly higher HCRU, and 1.5 times greater costs compared to STR-initiators. In both MTR and STR-initiator groups, PWH/MHD cohort consistently demonstrated a greater HCRU and cost burden than PWH/no-MHD.

Linaclotide as a Single Agent Bowel Preparation Regimen Before Colonoscopy.

Linaclotide as a Single Agent Bowel Preparation Regimen Before Colonoscopy.

Optimal hyperthermic intraperitoneal chemotherapy regimen for advanced and peritoneal metastatic gastric cancer: a systematic review and Bayesian network meta-analysis.

Peritoneal metastasis is one of the most common modes of spread of gastric cancer. Currently, surgical treatment combined with hyperthermic intraperitoneal chemotherapy (HIPEC) and systemic chemotherapy has demonstrated promising outcomes in both the treatment and prevention of peritoneal metastasis in gastric cancer. However, various HIPEC drug regimens are in clinical use, and their efficacy remains unclear. This study aims to evaluate the effectiveness of different HIPEC drug regimens in patients with advanced gastric cancer to determine the optimal therapeutic approach. This study conducted a systematic review and Bayesian network meta-analysis. Patients in the experimental group underwent surgery combined with HIPEC and chemotherapy. The search period covered literature from database inception to June 1, 2024. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate overall survival (OS) as the primary outcome. Odds ratios (ORs) with 95% CIs were used to assess overall disease recurrence, peritoneal recurrence, and postoperative morbidity as secondary outcomes. To ensure scientific rigor and transparency, this study has been registered with PROSPERO (CRD42024533948). A total of 11 randomized controlled trials (RCTs) involving 1092 patients were included. Compared to surgery combined with chemotherapy, the regimens of cisplatin (HRs = 0.52, 95% CI: 0.38-0.73), mitomycin C (HRs = 0.99, 95% CI: 0.55-1.79), cisplatin plus fluorouracil (HRs = 0.60, 95% CI: 0.38-0.95), and oxaliplatin plus 5-fluorouracil (HRs = 0.53, 95% CI: 0.36-0.78) all demonstrated benefits in OS. The cisplatin (ORs = 0.16, 95% CI: 0.03-0.60) and mitomycin C (ORs = 0.03, 95% CI: 0-0.71) regimens also showed advantages in reducing peritoneal recurrence, with no impact on postoperative morbidity. Importantly, the cisplatin regimen was superior to other regimens in terms of OS and overall disease recurrence, achieving a balance between efficacy and safety. Compared to chemotherapy alone, HIPEC treatment shows significant benefits in OS without a notable disadvantage in postoperative morbidity. Although no single HIPEC regimen demonstrated clear benefits across all outcomes, the cisplatin regimen performed well in multiple aspects, indicating its potential for further research and clinical application. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=533948, identifier CRD42024533948.

Reverse Selection Designs for Accommodating Multiple Control Arms.

Evaluating a novel treatment in a randomized controlled trial requires comparison against existing therapies. If several existing therapies of similar benefit exist, the identification of a single control regimen may be difficult. For this situation, we propose a reverse selection design which, in its simplest form, includes a single experimental treatment arm and two control arms. Rather than carrying both control arms through the entire trial, the control arms are compared at an early interim analysis, ideally while accrual is ongoing. At this time, the worst-performing control arm is dropped and randomization continues to the remaining arms. At the end of the study, we compare the treatment to the remaining control arm. When no head-to-head comparison of the extant therapies is available or feasible, this design requires a smaller sample size than a traditional three-arm design or two sequential trials in which the extant therapies are compared and the better treatment is used in a subsequent trial as the control arm. This is because the final comparison is only between two arms and because the early interim analysis occurs prior to the end of accrual - yet with enough information such that any substantially better control arm will be selected. We evaluate the operating characteristics of a reverse selection design via simulation and show that it reduces the required sample size needed to compare the treatment against the best control, controls type I error, and likely selects the right control arm to use in the final analysis.

Actinomycin-D vs Methotrexate in Low-Risk Gestational Tropoblastic Neoplasia: Which is the better option?

Background Low-Risk Gestational Trophoblastic Neoplasia (LRGTN) is a malignant trophoblastic disease that can be cured with the proper management. Actinomycin-D (ACT) and Methotrexate (MTX) have been used as a single drug regimen for LRGTN. Therefore, this study aims to compare the efficacy and safety of ACT-based regimen and MTX-based regimen for LRGTN treatment. Methods Electronic databases were systematically searched for Randomized Controlled Trials (RCTs) and High-Quality Non-Randomized Controlled Trials (Non-RCTs) comparing ACT with MTX for patients with LRGTN. Studies were fully screened, extracted, and assessed. Studies without Complete Remission (CR) were excluded. The meta-analysis was carried out to quantify the efficacy and safety of each ACT and MTX regimens based on odds ratios (ORs) and 95% confidence intervals (95% CIs). Results: In total, 8 RCTs and 14 non-RCTs were included (2203 patients). Our study concludes that ACT has a higher CR than MTX (79.4% [716/902] vs 66.9%[871/1301]; OR 2.13; 95% CI 1.46-3.10, in the random-effects model). Furthermore, ACT is better in terms of efficacy compared to MTX in both the RCTs [81.2% (259/319) vs 66.1% (199/301); OR 2.17; 95% CI 1.49-3.16, in the fixed-effects model] and non-RCTs group [457/583 (78.4%) vs 672/1000(67.2%); OR 2.10; 95% CI 1.28-3.45, in the random-effects model]. Safety wise, the use of ACT has a higher incidence of alopecia (OR 3.52, 95% CI: 1.27-9.75, in the random-effects model) compared to MTX while MTX has a higher risk of developing liver toxicity (OR 0.54, 95% CI: 0.32-0.91, in the fixed-effects model) compared to ACT. Other side effects are not significantly different between the two groups. Conclusion: Our meta-analysis concluded that ACT has a better efficacy compared to MTX for LRGTN patients. In terms of safety, ACT-based regimens have a higher chance of suffering from alopecia and a lower chance of suffering from liver toxicity. Future clinical studies on single-drug regimens for LRGTN should be conducted in order to produce higher-quality data. Keywords: Methotrexate, MTX, Dactinomycin, Actinomycin-D, ACT, Low-Risk Gestational Trophoblastic Neoplasia, LRGTN

Antibiotics for surgical site infections in patients undergoing orthognathic surgery.

PubMed, Embase, Web of Science and Scopus. Randomized Controlled Trials (RCTs) for patients undergoing orthognathic surgery of any type, which evaluated surgical site infections (SSI) in either: long-term (at least 2 days) post-surgical antibiotic dosing versus short term (one day) post-surgical dosing for the same drug; or Orthognathic surgery patients administered a post-surgical single-day antibiotic versus a singular pre-operative dosing of any antibiotic in the post-surgical phase. Singe-arm studies, retrospective studies, unpublished data, studies which were not peer-reviewed, editorials and trials not dealing with patients undergoing orthognathic surgery specifically were not included. Data for the publication year, primary author name, location of the study, antibiotic type, antibiotic protocol with its type, dosing and timing, sample size, protocol of the control group, male gender, age, diagnosis and rates of SSIs were extracted from the included studies. Pooled rates of SSIs were utilized to produce risk ratio (RR). A total of eleven RCTs met the inclusion criteria. As per the meta-analysis, post-orthognathic surgery SSI risk was reduced significantly as a result of long-term prophylactic antibiotic usage when compared to short-term utilization. Further, the meta-analysis demonstrated that there was a significant reduction of SSI risk in patients on a single day prophylactic antibiotic regimen in comparison to those on a single preoperative antibiotic dose. The study observed that long-term (2-7 days) prophylactic antibiotics reduce SSI risk when compared to antibiotic administration over a single day. In turn, it was also found that the latter was of greater benefit over a pre-operative single antibiotic dosage.

Harnessing Variability Signatures and Biological Noise May Enhance Immunotherapies' Efficacy and Act as Novel Biomarkers for Diagnosing and Monitoring Immune-Associated Disorders.

Lack of response to immunotherapies poses a significant challenge in treating immune-mediated disorders and cancers. While the mechanisms associated with poor responsiveness are not well defined and change between and among subjects, the current methods for overcoming the loss of response are insufficient. The Constrained Disorder Principle (CDP) explains biological systems based on their inherent variability, bounded by dynamic boundaries that change in response to internal and external perturbations. Inter and intra-subject variability characterize the immune system, making it difficult to provide a single therapeutic regimen to all patients and even the same patients over time. The dynamicity of the immune variability is also a significant challenge for personalizing immunotherapies. The CDP-based second-generation artificial intelligence system is an outcome-based dynamic platform that incorporates personalized variability signatures into the therapeutic regimen and may provide methods for improving the response and overcoming the loss of response to treatments. The signatures of immune variability may also offer a method for identifying new biomarkers for early diagnosis, monitoring immune-related disorders, and evaluating the response to treatments.

Comparative Efficacy of Single-Dose versus Multiple-Dose Antibiotic Prophylaxis in Reducing Postoperative Infections in Elective Cesarean Deliveries

Cesarean Sections (CS) were common surgeries that may lead to complications like endometritis and Surgical Site Infections (SSIs). While prophylactic antibiotics reduce these risks, the ideal dosing regimen remains debated. Objective: To evaluates whether a single or multiple-dose antibiotic regimen offers better protection against infections in patients undergoing planned cesarean sections. Methods: A six-month quasi-experimental study was conducted from October 1, 2020, to March 30, 2021, at Lady Reading Hospital in Peshawar. Eighty-two women scheduled for elective CS were assigned into two groups: one received a single 1g dose of intravenous cefazolin before surgery, and the other received the same initial dose followed by two additional doses every eight hours. Primary outcomes assessed were the incidence of endometritis and SSIs within 30 days post-surgery. Results: Postpartum infections were significantly lower in the multiple-dose group (4.9%) compared to the single-dose group (19.5%, p = 0.039). The multiple-dose group also had fewer SSIs (4.9% vs. 14.6%, p = 0.140) and no cases of endometritis (0% vs. 4.9%, p = 0.154), though these differences were not statistically significant. There were no significant differences in adverse drug reactions, hospital stay duration, or antibiotic resistance development between the groups. Conclusions: Multiple-dose antibiotic regimens may reduce infection rates in planned CS without increasing adverse effects or antibiotic resistance. Further studies were needed to confirm these findings and optimize prophylactic strategies.

Ternary inulin hydrogel with long-term intestinal retention for simultaneously reversing IBD and its fibrotic complication.

Excessive accumulation of reactive oxygen and nitrogen species (RONS) and dysbiosis of intestinal microbiota are pivotal symptoms for inflammatory bowel disease (IBD) and its associated complications, such as intestinal fibrosis. This research introduces a probiotic inulin hydrogel loaded with polypyrrole (PPy) nanozymes and antifibrotic drug pirfenidone (PFD) (PPy/PFD@Inulin gel) designed for the concurrent amelioration of IBD and its fibrotic complication. Upon oral administration, the inulin gel matrix could extend the gastrointestinal residence time of PPy nanozymes and PFD, facilitating the efficient reduction of pro-inflammatory cytokine levels and enhancement of the intestinal epithelial barrier repair as well as the suppression of intestinal fibrosis through sustained RONS scavenging, modulation of gut microbiota and attenuation of the TGF-β/Smad signaling pathway to inhibit fibroblast proliferation. Notably, the PPy/PFD@Inulin gel demonstrated significant prophylactic and therapeutic efficacy in acute and chronic colitis as well as intestinal fibrosis induced by dextran sodium sulfate (DSS) in mouse models. Thus, the engineered ternary PPy/PFD@Inulin gel offered a pioneered paradigm for simultaneous reversal of IBD and its associated complications, such as intestinal fibrosis, in a single therapeutic regimen.

Efficacy of PARP inhibitor therapy after targeted BRAF/MEK failure in advanced melanoma

Modern advancements in targeted therapy and immunotherapy have significantly improved survival outcomes for advanced melanoma; however, there remains a need for novel approaches to overcome disease progression and treatment resistance. In recent years, PARPi therapy has shown great promise both as a single regimen and in combination with other therapeutics in melanoma. Here, we describe three unique cases of advanced BRAF V600 mutated melanoma that progressed on targeted BRAF/MEK agents that subsequently exhibited partial to near-complete responses to combinatory PARPi and BRAF/MEK inhibitors. This highlights both a potential synergy underlying this combinatory approach and its efficacy as a treatment option for patients with advanced melanoma refractory to targeted and/or immunotherapies. Prospective clinical trials are needed to explore this synergic effect in larger melanoma cohorts to investigate this combination for treating refractory advanced melanoma.

Association between intra-articular hyaluronic acid injections in delaying total knee arthroplasty and safety evaluation in primary knee osteoarthritis: analysis based on Health Insurance Review and Assessment Service (HIRA) claim database in Republic of Korea

BackgroundThe prevalence of knee osteoarthritis (KOA), a progressive degenerative disease, is gradually increasing, and it is a progressive degenerative disease. In patients with mild-to-moderate KOA, intra-articular hyaluronic acid (IA-HA) has been shown to be an effective non-operative treatment option that can provide significant pain relief and symptom improvement by increasing intra-articular viscoelasticity. This study aimed to evaluate the efficacy of IA-HA injections in delaying total knee arthroplasty (TKA) and the safety of IA-HA according to IA-HA type and combination with intra-articular corticosteroid (IA-CS) using a large health insurance claim database.MethodsFor this retrospective cohort study, the study population included patients aged ≥ 50 years with a first diagnosis of KOA between 2009 and 2014, who underwent TKA by 2020, using the Health Insurance Review and Assessment Service claim database in Republic of Korea. IA-HA injections were categorized as single or multiple injection regimen agents. Cox proportional hazard models estimated hazard ratios (HR) for TKA risk, adjusted for covariates. Logistic regression assessed the occurrence of adverse events after IA-HA administration.ResultsIn all, 36,983 patients were included. Patients who received IA-HA injections had a significantly longer time to TKA compared to those who did not (mean delay of approximately 1 year). The IA-HA group had a significantly lower risk of TKA (HR: 0.61, 95% CI: 0.60–0.62) than non-IA-HA group after adjusting for covariates, which included age, sex, medical history, number of hospital beds, and CS injection. Single injection IA-HA regimen agents showed the longest time to TKA and lowest risk (HR: 0.56, 95% CI: 0.53–0.59). TKA risk decreased with the number of IA-HA cycles. Adverse events occurred in 6.7% of IA-HA cases without CS, with very low incidence of infection. Multiple injection regimen agents (multiple injection regimen 7.0% vs. single injection regimen 3.6%) and concurrent IA-CS use (concurrent IA-CS use 13.9% vs. IA-HA only 6.7%) were associated with higher infection risk.ConclusionIA-HA injections were associated with a significant delay in TKA among patients with KOA. Single-injection regimen agents had the lowest TKA risk. Infection risk increased with multiple injections and concurrent IA-CS use. These findings could suggest the use of IA-HA as an effective non-operative intervention option for managing KOA and delaying TKA. Careful selection of IA-HA type and consideration of concurrent IA-CS use could play a role in delaying the time to TKA and reducing complications.

Repeated versus single praziquantel dosing regimen in treatment of female genital schistosomiasis: a phase 2 randomised controlled trial showing no difference in efficacy

Repeated versus single praziquantel dosing regimen in treatment of female genital schistosomiasis: a phase 2 randomised controlled trial showing no difference in efficacy

Effect of different single and combined antihypertensive drug regimens on the mortality of critical care patients.

To investigate the effect of different single and combined pre-admission antihypertensive drug regimens on the prognosis of critically ill patients. We performed a retrospective cohort study using data from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database. All initial ICU admission records of patients with hypertension and previous antihypertensive exposure before ICU admission were included. Our primary outcome was 90-day mortality. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were used to balance the distribution of baseline characteristics. Logistic regression analysis and subgroup analysis were performed to determine the independent effect of different single and combined antihypertensive drug regimens on 90-day mortality. A total of 13,142 patients were included in the final analysis. The 90-day mortality rate in the combined groups is lower than that in the single therapy group (10.94% vs 11.12%), but no statistical significance was found in the original cohort (p = 0.742). After adjustment for potential confounders, the significantly decreased 90-day mortality rate was found in the combined groups (10.78% vs 12.65%, p = 0.004 in PSM; 10.34% vs 11.90%, p = 0.007). Patients who were exposed to either ACEIs or ARBs had a better prognosis than those not exposed (7.19% vs 17.08%, p < 0.001 in single antihypertensive groups; 8.14% vs18.91%, p < 0.001 in combined antihypertensive groups). The results keep robustness in the PSM and IPTW cohorts. In the logistic regression model analysis, combined therapy was associated with a 12%-20% reduced risk of 90-day death after adjusting potential confounders (OR 0.80-0.88, all p < 0.05), while exposure to ACEIs or ARBs was associated with the decreased risk of 90-day death by 52%-62% (OR 0.38-0.48, all p < 0.001) and 40%-62% (OR 0.38-0.60, all p < 0.001) in the single and combined therapy groups, respectively. The results were still robust to subgroup analysis. Pre-admission combined antihypertensive therapy is associated with a significantly lower risk of death than exposure to single antihypertensives in critically ill patients. Meanwhile, either ACEIs or ARBs seem to be the optimal candidates for both single and combined therapy. Further high-quality trials are needed to confirm our findings.

Discovery of Novel, Potent and Orally Bioavailable SMARCA2 PROTACs with Synergistic Anti-tumor Activity in Combination with KRAS G12C Inhibitors.

Cancer genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. We and others have identified SMARCA2 to be synthetic lethal to SMARCA4, indicating SMARCA2 is a high value therapeutic target. Here, we disclose the discovery and characterization of potent, selective and orally bioavailable Cereblon-based SMARCA2 PROTACs. Biochemically, YDR1 and YD54 are potent SMARCA2 degraders with an average DC 50 of 7.7nM and 3.5nM respectively in SMARCA4 mutant lung cancer cells. Phenotypically, both YDR1 and YD54 selectively inhibited growth of SMARCA4 mutant cancer cells. Further, we showed anti-tumor growth inhibitory activity of YDR1 and YD54 in SMARCA4 mutant xenograft models of lung cancer. Finally, we show that YDR1 and YD54 synergize with the KRAS G12C inhibitor sotorasib to inhibit growth of SMARCA4 and KRAS G12C co-mutant lung cancer cells. These findings provide additional evidence for the utility of single agent or combination regimens containing SMARCA2 PROTACs as synthetic lethal therapeutics against SMARCA4 mutant cancers.

Upholding or Breaking the Law of Superposition in Pharmacokinetics.

The law of superposition underpins first-order linear pharmacokinetic relationships. Most drugs, therefore, after a single dose can be described by first-order or linear processes, which can be superposed to understand multiple-dose regimen behavior. However, there are a number of situations where drugs could display behaviors after multiple dosing that leads to capacity-limited or saturation non-linear kinetics and the law of superposition is overruled. This review presents a practical guide to understand the equations and calculations for single and multiple-dosing regimens after intravenous and oral administration. It also provides the pharmaceutical basis for saturation in ADME processes and the consequent changes in the area under the concentration-time curve, which represents drug exposure that can lead to the modulation of efficacy and/or toxic effects. The pharmacokineticist must implicitly understand the principles of superposition, which are a central tenet of drug behavior and disposition during drug development.

Efficacy of Antibiotic Regimens for Sepsis or Possible Serious Bacterial Infection in Young Infants Aged 0 to 59 Days: A Systematic Review and Meta-analysis.

Sepsis is a leading cause of young infant mortality. To evaluate the efficacy of different antibiotic regimens to treat young infant sepsis or possible serious bacterial infection (PSBI) on clinical outcomes. MEDLINE, Embase, CINAHL, World Health Organization Global Index Medicus, Cochrane Central Registry of Trials. We included randomized controlled trials (RCTs) of young infants 0 to 59 days with sepsis or PBSI (population) comparing the efficacy of antibiotic regimens (intervention) with alternate regimens or management (control) on clinical outcomes. We extracted data and assessed risk of bias in duplicate. We performed random-effects meta-analysis, and used Grading of Recommendations, Assessment, Development, and Evaluation to assess certainty of evidence. Of 2390 publications, we included 41 RCTs (n = 18 054). Thirty-five trials were hospital-based and 6 were nonhospital-based. Meta-analysis of 4 trials demonstrated similar rates of treatment success with intramuscular/intravenous third generation cephalosporins versus intramuscular/intravenous penicillin or ampicillin + gentamicin (RR 1.03, 95% CI 0.93-1.13]; n = 1083; moderate certainty of evidence). Meta-analysis of 3 trials demonstrated similar rates of treatment failure with oral amoxicillin + intramuscular gentamicin versus intramuscular penicillin + gentamicin for nonhospital treatment of clinical severe illness (RR 0.86, 95% CI 0.72-1.02]; n = 5054; low certainty of evidence). Other studies were heterogeneous. RCTs evaluated heterogeneous regimens, limiting our ability to pool data. We found limited evidence to support any single antibiotic regimen as superior to alternate regimens to treat young infant sepsis or PSBI.

Outcomes After Multimodality Treatment of Pancreatic Cancer in an Unselected Single-Center Cohort.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal and rarely resectable malignancy. Here we explore the outcomes of surgery, as compared to definitive radiotherapy (dRT) or systemic therapy only in PDAC. Pancreatic surgery and radiotherapy in Southwest Finland have been centralized to Turku University Hospital. Previously validated population-based electronic health records database was searched for all unselected PDAC patients from the years 2009-2019. Main outcome was median overall survival (mOS). Demographics, pathology, surgery, and oncological treatment data were collected. We identified 1006 patients with PDAC, 49% male, median age 71 years and 77% presenting with metastatic disease. In total, 405 patients were treated; 92 resected, 26 dRT without resection and 287 systemic therapy only. mOS was 34.6 months for resected, 26.7 months for dRT, and 7.5 months for systemic therapy patients. Among the 88 patients with locally advanced inoperable PDAC, dRT was independently associated with longer mOS (26.7 months) as compared to systemic therapy only (mOS 10.6 months). Among the 287 patients treated with systemic therapy only, combination chemotherapy was independently associated with longer mOS (11.6 months) as compared to gemcitabine-monotherapy (6.8 months). In patients progressing to second-line systemic treatment after gemcitabine failure, mOS was the same (5.0 months) with single or combination regimens. Surgery remains the only curative approach for PDAC. In locally advanced PDAC, dRT was associated with longer survival as compared to systemic therapy only. Concerning first-line systemic therapy, our results support the use of combination chemotherapy over single-agent therapy.

Efficacy of Antibiotic Regimens for Pneumonia in Young Infants Aged 0-59 Days: A Systematic Review.

Pneumonia is a leading cause of death in young infants. To evaluate the efficacy of different antibiotic regimens to treat young infant pneumonia on critical clinical outcomes. MEDLINE, Embase, CINAHL, World Health Organization (WHO) Global Index Medicus, Cochrane Central Registry of Trials. We included randomized controlled trials of young infants aged 0 to 59 days with pneumonia (population) comparing the efficacy of antibiotic regimens (intervention) with alternate regimens or management (control) on clinical outcomes. We extracted data and assessed risk of bias in duplicate. We used Grading of Recommendations, Assessment, Development, and Evaluation to assess certainty of evidence. Trials were heterogeneous, which precluded data pooling. Of 2601 publications screened, 10 randomized controlled trials were included. Seven trials were hospital-based (n = 869) and 3 were nonhospital-based (n = 4329). No hospital-based trials evaluated WHO-recommended first-choice regimens. One trial found the WHO-recommended second-choice antibiotic, cefotaxime, to have similar rates of treatment success as non-WHO-recommended regimens of either amoxicillin-clavulanate (RR 0.99, 95% confidence interval 0.82-1.10) or amoxicillin-clavulanate/cefotaxime (RR 1.02, 95% confidence interval 0.86-1.12). Among 3 nonhospital-based trials comparing oral amoxicillin to alternate regimens to treat isolated tachypnea among infants aged 7-59 days, there were no differences in treatment failure between amoxicillin and alternate regimens. Certainty of evidence was low or very low for all primary outcomes. We found limited evidence to support the superiority of any single antibiotic regimen over alternate regimens to treat young infant pneumonia.

Treatment of infections caused by carbapenem-resistant Acinetobacter baumannii.

Patients with severe carbapenem-resistant Acinetobacter baumannii (CRAB) infections currently face significant treatment challenges. When patients display signs of infection and the clinical suspicion of CRAB infections is high, appropriate treatment should be immediately provided. However, current treatment plans and clinical data for CRAB are limited. Inherent and acquired resistance mechanisms, as well as host factors, significantly restrict options for empirical medication. Moreover, inappropriate drug coverage can have detrimental effects on patients. Most existing studies have limitations, such as a restricted sample size, and are predominantly observational or non-randomized, which report significant variability in patient infection severity and comorbidities. Therefore, a gold-standard therapy remains lacking. Current and future treatment options of infections due to CRAB were described in this review. The dose and considerable side effects restrict treatment options for polymyxins, and high doses of ampicillin-sulbactam or tigecycline appear to be the best option at the time of initial treatment. Moreover, new drugs such as durlobactam and cefiderocol have substantial therapeutic capabilities and may be effective salvage treatments. Bacteriophages and antimicrobial peptides may serve as alternative treatment options in the near future. The advantages of a combination antimicrobial regimen appear to predominate those of a single regimen. Despite its significant nephrotoxicity, colistin is considered a primary treatment and is often used in combination with antimicrobials, such as tigecycline, ampicillin-sulbactam, meropenem, or fosfomycin. The Infectious Diseases Society of America (IDSA) has deemed high-dose ampicillin-sulbactam, which is typically combined with high-dose tigecycline, polymyxin, and other antibacterial agents, the best option for treating serious CRAB infections. A rational combination of drug use and the exploration of new therapeutic drugs can alleviate or prevent the effects of CRAB infections, shorten hospital stays, and reduce patient mortality.