A Novel Mechanistic Model for Future Research in the Elements of the ERAS Program in Patients With Sickle Cell Disease.

Enhanced recovery after surgery (ERAS) is a patient-centered, evidence-based, multidisciplinary team-developed approach to a surgical stress response that is implemented to optimize physiological function and facilitate recovery for the best possible outcomes from surgery. Although there are currently well-known published guidelines for the perioperative management of patients with sickle cell disease, there are currently no specific and evidencebased ERAS protocols that address the needs of these patients. A novel mechanistic model has recently been found that could change ERAS protocols for patients with sickle cell disease with regard to a current preoperative carbohydrate loading drink recommendation, nutrition and intravenous fluid management. ERAS has great benefits for most patient populations, but emerging research suggests that patients with sickle cell disease may process and respond differently to varying concentrations of serum glucose and serum cations (hyperglycemia and hypertonic states). This adverse response involves actin, a cytoskeletal protein, in the red blood cell and how increased hemoglobin glycosylation may lead to a malfunction in this protein and a transition to vaso-occlusive crises in patients with sickle cell disease. Further research is warranted with this new mechanistic model to develop more meticulous and customized perioperative management plans to address risk mitigation in patients with sickle cell disease.

The efficacy and safety of different does of intravenous tranexamic acid on blood loss in fresh foot and ankle fractures: a prospective, randomized controlled study.

BACKGROUND: There are a few studies on the effectiveness and safety of intravenous administration of tranexamic acid(TXA) in patients who underwent foot and ankle surgery, especially for preoperative hidden blood loss in patients with freshfoot and ankle fractures. Thus, the aim of this study was to investigate whether intravenous administration of different doses of TXA can effectively reduce perioperative blood loss and blood loss before surgery and to determine its safety. METHODS: A total of 150 patients with fresh closed foot and ankle fractures from July 2021 to July 2023 were randomly divided into a control group (placebo controlled [PC]), standard-dose group (low-dose group [LD], 1 g/24 h; medium-dose group [MD], 2 g/24 h), and high-dose group (HD, 3 g/24 h; ultrahigh-dose group [UD], 4 g/24 h). After admission, all patients completed hematological examinations as soon as possible and at multiple other time points postsurgery. RESULTS: There was a significant difference in the incidence of hidden blood loss before the operation between the TXA group and the control group, and the effect was greater in the overdose groups than in the standard-dose groups. There were significant differences in surgical blood loss (intraoperative and postoperative), postoperative HGB changes, and hidden blood loss among the groups. The TXA groups showed a significant decrease in blood loss compared to that of the control group, and the overdose groups had a more significant effect than the standard-dose groups. A total of 9 patients in the control group had early wound infection or poor healing, while only 1 patient in the other groups had this complication, and the difference among the groups was significant. No patients in any group suffered from late deep wound infection, cardiovascular or cerebrovascular events or symptomatic VTE. CONCLUSION: This is the first study on whether TXA can reduce preoperative hidden blood loss in patients with freshfoot and ankle fractures. In our study, on the one hand, intravenous application of TXA after foot and ankle fractures as soon as possible can reduce preoperative blood loss and postoperative blood loss. On the other hand, TXA can also lower wound complications, and over-doses of TXA are more effective than standard doses. Moreover, overdoses of TXA do not increase the incidence of DVT.

Effectiveness of hospital-based oral dextrose gel in prevention and treatment of asymptomatic newborns at risk of hypoglycemia.

OBJECTIVE: To evaluate the effectiveness of using hospital-based 40% dextrose gel (DG) in preventing and treating asymptomatic hypoglycemia in infants of diabetic mothers (IDM), large for gestational age (LGA), and macrosomic neonates. METHODS: A medical chart review was conducted to compare data between before (April 2018 to March 2019, epoch 1) and after (September 2020 to November 2021, epoch 2) 40% DG implementation. DG, prepared by the hospital pharmaceutical unit, was applied within 30-45 min after birth, and three additional doses could be repeated during the first 6 h of life in combination with early feeding. The primary outcome was the rate of intravenous dextrose administration. Secondary outcomes were the incidence of hypoglycemia, first capillary blood glucose concentrations, and the length of hospital stay. RESULTS: Six hundred forty-three at-risk newborns were included (320 before and 323 after implementation of DG). Maternal and neonatal baseline characteristics were not different between the two epochs. The incidence of hypoglycemia was not different (17.8% in before versus 14.6% in after implementation, p = 0.26). The rate of intravenous dextrose administration after DG implementation was significantly lower than that before DG implementation (3.4% versus 10.3%, p < 0.001, risk reduction ratio = 0.33, 95% CI = 0.17-0.64). The length of hospital stay was not different between the two epochs. CONCLUSIONS: Implementing a protocol for administration of hospital-based 40% DG can reduce the need of intravenous dextrose administration among IDM, LGA and macrosomic neonates.

Denosumab and sclerotherapy for recurrent spinal aneurysmal bone cyst in a child.

Aneurysmal bone cyst (ABC) is a non-malignant, locally destructive, blood-filled lesion in the bone that tends to grow aggressively. A young girl presented with a rapid recurrence after aggressive surgery of a large symptomatic sacral-spinal ABC. After a multidisciplinary tumour board, she was successfully treated with sclerotherapy and monthly intravenous denosumab. The patient has maintained asymptomatic for over 36 months now and has returned to full activity and strength. She never required surgery and has had radiologic resolution of the lesions. Treatment of recurrent ABC requires a multidisciplinary team approach. We believe this to be the first report to use this combined therapy to provide an alternative to morbid surgery for children with ABCs.

Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

Transient Acute Diplopia as a Rare Side Effect of Hydromorphone: A Case Report.

Diplopia, or double vision, has been listed as a rare adverse effect of intravenous hydromorphone, although there are no case studies or literature documenting this. We detail a case of acute transient diplopia correlated with the use of intraoperative hydromorphone and postoperative hydromorphone patient-controlled analgesia. Although the mechanism for this adverse effect is unknown, there may be risk factors that predispose patients to the potential toxic metabolic effects of hydromorphone. We share the first published case of diplopia as a clinically relevant adverse effect of hydromorphone and propose a potential reason behind this association.

Letter to editor: Serum concentration-guided intravenous magnesium sulfate administration for neuroprotection in patients with aneurysmal subarachnoid hemorrhage: A retrospective evaluation of a 12-year single-center experience.

This critique examines a 12-year retrospective study on serum magnesium concentration-guided administration of magnesium sulfate in 548 patients with aneurysmal subarachnoid hemorrhage (aSAH). The study reported that maintaining serum magnesium levels between 2 and 2.5 mmol/L reduced rates of delayed cerebral infarction and improved clinical outcomes. However, limitations due to its retrospective nature, single-center design, and unequal treatment group sizes may affect generalizability. Future multicentric randomized controlled trials are recommended to validate these findings and refine magnesium dosing strategies for aSAH treatment.

Using a LOng peripheral intraVEnous catheter with retractable guidewire to optimize first-insertion success for patients with Difficult IntraVenous Access in the emergency department (LOVE-DIVA): a study protocol for a randomized controlled trial.

INTRODUCTION: First-insertion success rates for peripheral vascular access devices (PVADs) in patients with difficult venous access (DIVA) are low, which negatively affects staff workload, patient experience, and organizational cost. There is mixed evidence regarding the impact of a peripheral vascular access device with retractable coiled tip guidewire (GW; AccuCath™, BD) on the first-insertion success rate. The aim of this study is to investigate whether the use of long GW-PVADs, compared with standard PVADs, reduces the risk of first-time insertion failure, in patients admitted to emergency departments (EDs). METHODS AND ANALYSIS: A parallel-group, two-arm, randomized controlled trial will be carried out in two Australian EDs to compare long GW-PVADs (5.8 cm length) against standard care PVADs (short or long). Patients ≥18 years of age meeting DIVA criteria will be eligible for the trial. The sample size is 203 participants for each arm. Web-based central randomization will be used to ensure allocation concealment. Neither clinicians nor patients can be blinded to treatment allocation. Primary outcome is the first-insertion success rate. Secondary outcomes include the number of insertion attempts, time to insert PVAD, all-cause failure, dwell-time, patient-reported pain, serious adverse events, complications, subsequent vascular access devices required, patient satisfaction, staff satisfaction, and healthcare costs. Differences between the two groups will be analyzed using Cox proportional hazards regression. Cost-effectiveness analysis will also be conducted. Intention-to-treat analysis will be used. ETHICS AND DISSEMINATION: The study is approved by Metro South Ethics Committee (HREC/2022/QMS/82264) and Griffith University (2022/077). The findings will be published in a peer-reviewed journal. TRIAL REGISTRATION: ACTRN12622000299707.

How the Food and Drug Administration Drug Approval Process Relates to the Potential Approval of Intravenous Racemic Ketamine for Treatment-resistant Major Depression.

This column focuses on the status of intravenous racemic ketamine for the treatment of patients suffering from a form of major depressive disorder that does not respond to trials of currently available biogenic amine antidepressants. To provide context, the column reviews the 3 pivotal elements of the usual Food and Drug Administration (FDA) drug approval process: (1) the unmet medical need (ie, the indication) for which the drug is being developed, (2) the efficacy of the drug for that condition, and (3) the safety/tolerability of the drug. This column is based on the author's 45-year history of drug development work and is not a statement of the FDA. There are typically 3 phases in the drug development process: (1) studies done in normal volunteers, (2) typically small-scale proof of concept studies, and (3) large-scale registration trials. This third phase is critical in determining the efficacy, safety, and tolerability of the drug in a manner that most closely follows the clinical use of the drug. This column focuses specifically on whether generally small-scale studies done in academic centers are sufficient for drug approval, and it briefly reviews lithium and clozapine as examples of psychiatric medications that had such academic research in the literature, as well as clinical use in other countries. Those data supported the unique value of these medications in patients with bipolar disorder and treatment-resistant schizophrenia (ie, the unmet medical need), respectively, and the findings led American psychiatrists to advocate for FDA approval of these medications. Their efforts led to the needed registration trials for FDA approval of these medications. This column reviews the key features of registration trials and the reason that they are critical for FDA approval, and it discusses 2 special considerations related to the intravenous administration of racemic ketamine. First, racemic ketamine is not esketamine but, instead, it contains R-ketamine in addition to S-ketamine (ie, esketamine). The second consideration is that differences between intravenous and intranasal administration may affect the safety of the drug. While safety concerns were specifically addressed in the registration trials for esketamine, comparable research remains to be done for intravenous racemic ketamine. Understanding how the FDA's drug approval process works is important for prescribers, their patients, and the public.

Intravenous administration of IL-12 encoding self-replicating RNA-lipid nanoparticle complex leads to safe and effective antitumor responses.

Interleukin 12 (IL-12) is a potent immunostimulatory cytokine mainly produced by antigen-presenting cells (e.g., dendritic cells, macrophages) and plays an important role in innate and adaptive immunity against cancers. Therapies that can synergistically modulate innate immunity and stimulate adaptive anti-tumor responses are of great interest for cancer immunotherapy. Here we investigated the lipid nanoparticle-encapsulated self-replicating RNA (srRNA) encoding IL-12 (referred to as JCXH-211) for the treatment of cancers. Both local (intratumoral) and systemic (intravenous) administration of JCXH-211 in tumor-bearing mice induced a high-level expression of IL-12 in tumor tissues, leading to modulation of tumor microenvironment and systemic activation of antitumor immunity. Particularly, JCXH-211 can inhibit the tumor-infiltration of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). When combined with anti-PD1 antibody, it was able to enhance the recruitment of T cells and NK cells into tumors. In multiple mouse solid tumor models, intravenous injection of JCXH-211 not only eradicated large preestablished tumors, but also induced protective immune memory that prevented the growth of rechallenged tumors. Finally, intravenous injection of JCXH-211 did not cause noticeable systemic toxicity in tumor-bearing mice and non-human primates. Thus, our study demonstrated the feasibility of intravenous administration of JCXH-211 for the treatment of advanced cancers.

Intravenous metoclopramide for increasing endoscopic mucosal visualization in patients with acute upper gastrointestinal bleeding: a multicenter, randomized, double-blind, controlled trial.

Acute upper gastrointestinal hemorrhage (UGIH) is the most common emergency condition that requires rapid endoscopic treatment. This study aimed to evaluate the effects of pre-endoscopic intravenous metoclopramide on endoscopic mucosal visualization (EMV) in patients with acute UGIH. This was a multicenter, randomized, double-blind controlled trial of participants diagnosed with acute UGIH. All participants underwent esophagogastroduodenoscopy within 24 h. Participants were assigned to either the metoclopramide or placebo group. Modified Avgerinos scores were evaluated during endoscopy. In total, 284 out of 300 patients completed the per-protocol procedure. The mean age was 62.8 ± 14.3 years, and 67.6% were men. Metoclopramide group achieved a higher total EMV and gastric body EMV score than the other group (7.34 ± 1.1 vs 6.94 ± 1.6; P = 0.017 and 1.80 ± 0.4 vs 1.64 ± 0.6; P = 0.006, respectively). Success in identifying lesions was not different between the groups (96.5% in metoclopramide and 93.6% in placebo group; P = 0.26). In the metoclopramide group, those with active variceal bleeding compared with the control group demonstrated substantial improvements in gastric EMV (1.83 ± 0.4 vs 1.28 ± 0.8, P = 0.004), antral EMV (1.96 ± 0.2 vs 1.56 ± 0.6, P = 0.003), and total EMV score (7.48 ± 1.1 vs 6.2 ± 2.3, P = 0.02). Pre-endoscopic intravenous metoclopramide improved the quality of EMV in variceal etiologies of UGIH, which was especially prominent in those who had signs of active bleeding based on nasogastric tube assessment.Trial Registration: Trial was registered in Clinical Trials: TCTR 20210708004 (08/07/2021).