Rejected

Pelvic pain, either related or unrelated to menstruation, is especially common in women of reproductive age. Thirty-nine per cent of all women suffer from chronic pelvic pain at some point in their lives, and pelvic venous congestion syndrome (PVCS) is the cause of this pain in 30% of cases. The aim of this study was to determine factors affecting the success of endovascular venous embolization used in the treatment of PVCS, and to present the long-term treatment results.

RRx-001 is a small molecule NLRP3 inflammasome inhibitor with anti-CD47 and antiangiogenic/vascular normalization properties in a Phase 3 clinical trial that has been designated as a drug-device combination by the FDA. In the Phase 1 first-in-man dose escalation clinical trial, where RRx-001 was given by direct intravenous (IV) infusion, the main adverse event was a sterile painful infusion phlebitis (IP). Less pain was experienced when RRx-001 was infused at a slower rate over multiple hours which was impractical on an outpatient basis. In Phase 2, for reasons of convenience and safety, RRx-001 was co-administered with an aliquot of autologous blood from an device called the eLOOP on the premise that RRx-001 binds to hemoglobin on red blood cells (RBCs), making it unavailable to directly interact with venous nociceptors. Phlebitis has the potential to progress to deep venous thrombosis or septic thrombophlebitis or post-thrombotic syndrome in hypercoagulable and immunosuppressed cancer patients. In this 13-week toxicology study of once weekly IV RRx-001 administration to Wistar Han rats followed by a recovery period of 28 days. The main observed toxicity was a significant inflammatory response in the vein wall, consistent with superficial venous thrombosis observed in man. Due to this development, direct IV infusion of RRx-001 is relatively contraindicated in favor of co-administration with autologous blood.

The objective of this study is to investigate the effect of dexmedetomidine on postoperative pain and recovery time in obese patients.

In this study, Plasmodium falciparum was detected in patients that were declared negative for malaria microscopy and rapid diagnostic test kit (mRDT), using Plasmodium 18s rRNA loop-mediated isothermal amplification (LAMP) technique. The main aim of this study was to assess the usefulness of LAMP assay for detecting pre-clinical malaria, when microscopy and mRDT were less sensitive. DNA was obtained from 100 μL of whole blood using the boil and spin method. Subsequently, the Plasmodium 18s rRNA LAMP assay was performed to amplify the specific Plasmodium 18s rRNA gene. Microscopy and mRDT negative samples [697/2223 (31.2%)] were used for this study. Compared to frequencies obtained for the other demographic variables, most of the patients were < 6 years (37.7%), females (59.0%), peri-urban dwellers (39.0%) and patients that sought outpatient department services (39.3%). Overall, the prevalence of Plasmodium 18s rRNA was 17.5%. when stratified by study variables, Plasmodium 18s rRNA LAMP positivity was higher in patients over 30 years [58/122 (54.2%)], males [69/122 (56.5%)], rural dwellers [69/122 (56.5%)] and patients that sought OPD services [68/122 (55.7%)]. The risk of being infected with Plasmodium when routine tests were negative was higher in 15-30-year group (OR = 3.03, 95% CI: 1.6-5.8, p = 0.0007), patients > 30 years (OR = 15.2, 95% CI: 8.3-27.7, p<0.001), males (OR = 2.1, 95% CI: 1.4-3.2, p = 0.0002) and rural dwellers (OR = 2.2, 95% CI:1.4-3.6, p = 0.0009). However, risk was lower in post-natal children (OR = 0.3, 95% CI: 0.18-0.51, p<0.001). Majority (81.5%) of the infected patients presented with headache, herpes labialis, diarrhea and vomiting. We demonstrated the lack of sensitivities of microscopy and mRDT for one-time diagnosis of malaria. Therefore, it is essential to utilize a sensitive technique such as Plasmodium 18s rRNA LAMP to increase the detection rate of Plasmodium infection.

Propofol is the most widely administered intravenous anesthetic to induce deep sedation for gastroscopy procedures. Coadministration of nalbuphine can provide analgesia and sedation to patients experiencing visceral pain, thereby decreasing the amount of propofol needed and reducing the risk of propofol-induced adverse events. We carried out this study to determine the median effective dose (ED50) of propofol in combination with different dosages of nalbuphine and the optimal dosage of nalbuphine during painless gastroscopy. We recruited sixty-five patients aged 18-60 years who underwent elective painless gastroscopy. A total of sixty-one patients were allocated randomly to the N1 group (nalbuphine 0.1 mg/kg) or N2 group (nalbuphine 0.15 mg/kg). Three minutes after administration of nalbuphine, patients received a preset dose of propofol at 2.0 mg/kg with a dose gradient of 0.2 mg/kg according to Dixon's "up-and-down" method. The primary outcome was the ED50 of propofol in combination with nalbuphine. Hemodynamic parameters, recovery time, pain score, and adverse events were recorded as secondary outcomes. The ED50 of propofol in the N2 group was significantly lower than that observed in the N1 group ( < 0.01). Using probit analysis, the ED50 and ED95 of propofol were 1.632 mg/kg and 2.759 mg/kg in the N1 group and 1.111 mg/kg and 2.243 mg/kg in the N2 group, respectively. The incidence of hypotension in the N2 group was lower than that in the N1 group ( < 0.05), and the recovery time was shorter than that of the N1 group ( < 0.05). In adult patients, 0.15 mg/kg nalbuphine led to a significant reduction in the ED50 and ED95 of propofol during gastroscopy. This dose of nalbuphine also reduced the incidence of hypotension and shortened the recovery time. Therefore, nalbuphine (0.15 mg/kg) combined with propofol is a safe option for enhancing recovery after painless gastroscopy in adult patients. : [https://www.chictr.org.cn/edit.aspx?pid=126699&htm=4], identifier [ChiCTR2100053204].

The association between inflammation and major depressive disorder (MDD) remains poorly understood, given the heterogeneity of patients with MDD.

Comprehensive methods for evaluating safety are needed to objectively assess the full risk profile of a medication. The confidence of the prescribing provider in the safety and effectiveness of pharmaceuticals is extremely important. Pharmacovigilance is a key component of drug safety regulatory processes and is paramount for ensuring the safety profile of medications used to treat patients. All participants in the healthcare system, including healthcare providers and consumers, should understand and meaningfully engage in the pharmacovigilance process; healthcare providers should integrate pharmacovigilance into everyday practice, inviting feedback from patients. This narrative review aims to give an overview of the main topics underlying pharmacovigilance and drug safety in pharmaceutical research phase after the authorization of a drug in the United States. The US Food and Drug Administration guidance and post-approval regulatory actions are considered from an industry perspective.

This patient and public-involved systematic review originally focused on arachnoiditis, a supposedly rare "iatrogenic chronic meningitis" causing permanent neurologic damage and intractable pain. We sought to prove disease existence, causation, symptoms, and inform future directions. After 63 terms for the same pathology were found, the study was renamed Diseases of the Leptomeninges (DLMs). We present results that nullify traditional clinical thinking about DLMs, answer study questions, and create a unified path forward.

Genetic and preclinical studies have implicated adenylyl cyclase 1 (AC1) as a potential target for the treatment of chronic inflammatory pain. AC1 activity is increased following inflammatory pain stimuli and AC1 knockout mice show a marked reduction in responses to inflammatory pain. Previous drug discovery efforts have centered around the inhibition of AC1 activity in cell-based assays. In the present study, we used an approach focused on inhibition of the protein-protein interaction (PPI) between Ca/calmodulin (CaM) and AC1, an interaction that is required for activation of AC1. We developed a novel fluorescence polarization (FP) assay focused on the PPI between an AC1 peptide and CaM and used this assay to screen over 23,000 compounds for inhibitors of the AC1-CaM PPI. Next, we used a cellular NanoBiT assay to validate 21 FP hits for inhibition of the AC1-CaM PPI in a cellular context with full-length proteins. Based on efficacy, potency, and selectivity for AC1, hits , , , , , and were prioritized. We then tested these compounds for inhibition of AC1 activity in cyclic AMP (cAMP) accumulation assays, using HEK293 cells stably expressing AC1. Hit contained a dithiophene scaffold and was of particular interest because it shared structural similarities with our recently reported benzamide series of AC1 inhibitors. We next tested a small set of 13 compounds containing the dithiophene scaffold for structure-activity relationship studies. Although many compounds were non-selective, we observed trends for tuning AC1/AC8 selectivity based on heterocycle type and substituents. Having an ethyl on the central thiophene caused the scaffold to be more selective for AC8. Cyclization of the alkyl substituent fused to the thiophene significantly reduced activity and also shifted selectivity toward AC8. Notably, combining the fused cyclohexane-thiophene ring system with a morpholine heterocycle significantly increased potency at both AC1 and AC8. Through designing a novel FP screen and NanoBiT assay, and evaluating hits in cAMP accumulation assays, we have discovered a novel, potent, dithiophene scaffold for inhibition of the AC1- and AC8-CaM PPI. We also report the most potent fully efficacious inhibitor of AC8 activity known to-date.

Chronic low back pain (CLBP) after percutaneous endoscopic transforaminal discectomy (PTED) surgery may be caused by preoperative lumbar microinstability (MI). However, there is a paucity of research on the relationship between lumbar microinstability and chronic low back pain. The purpose of this article is to assess the preoperative radiographic characteristics of patients and evaluate the effects of lumbar microinstability on patient-reported outcomes among single-level lumbar disc herniation (LDH) patients who underwent PTED.