Rejected

Older adults and patients with chronic disease presenting with muscle weakness or musculoskeletal disorders may benefit from low-load resistance exercise (LLRE) with blood flow restriction (BFR). LLRE-BFR has been shown to increase muscle size, strength, and endurance comparable to traditional resistance exercise but without the use of heavy loads. However, potential negative effects from LLRE-BFR present as a barrier to participation and limit its wider use. This study examined the perceptual, affective, and cardiovascular responses to a bout of LLRE-BFR and compared the responses to LLRE and moderate-load resistance exercise (MLRE). Twenty older adults (64.3 ± 4.2 years) performed LLRE-BFR, LLRE and MLRE consisting of 4 sets of leg press and knee extension, in a randomised crossover design. LLRE-BFR was more demanding than LLRE and MLRE through increased pain ( ≤ 0.024, = 0.8-1.4) and reduced affect ( ≤ 0.048, = -0.5–0.9). Despite this, LLRE-BFR was enjoyed and promoted a positive affective response ( ≤ 0.035, = 0.5-0.9) following exercise comparable to MLRE. This study supports the use of LLRE-BFR for older adults and encourages future research to examine the safety, acceptability, and efficacy of LLRE-BFR in patients with chronic disease.

Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 µg ethinylestradiol (EE)) was investigated. A randomized, double-blind, parallel-group study was performed in 24 healthy male and female subjects. A single oral dose of COC was administered alone and after 35 days of once daily (o.d.) administration of cenerimod 0.5 (n = 10) or 4 (n = 14) mg. Exposure to EE alone or in combination with cenerimod was comparable as reflected by the geometric mean ratios and the respective 90% confidence intervals, while a slight increase in exposure (approximately 10-25%) to levonorgestrel was observed at clinically relevant concentrations of cenerimod. Overall, COC alone or in combination with cenerimod was safe and well tolerated. Two subjects reported one adverse event each (one headache after COC alone, and gastroenteritis in combination with cenerimod 4 mg). In conclusion, cenerimod does not affect the PK of levonorgestrel or EE to a clinically relevant extent. Therefore, COC can be selected as method of contraception during and after cenerimod therapy without the risk of interaction.

Thoracic epidural analgesia (TEA) and transversus abdominis plane (TAP) block are used for pain control after abdominal surgery. Although there have been several meta-analyses comparing these two techniques, the conclusion was limited by a small number of studies and heterogeneity among studies. Our meta-analysis used the Medline, EMBASE, and Cochrane central library databases from their inception through September 2022. Randomized controlled trials (RCTs) comparing TEA and TAP block were included. The pre-specified primary outcome was the pain score at rest at 12 h postoperatively. Twenty-two RCTs involving 1975 patients were included. Pooled analyses showed the pain score at rest at 12 h postoperatively was significantly different between groups favoring TEA group (Mean difference [MD] 0.58, 95% confidence interval CI – 0.01, 1.15, P = 0.04, I = 94%). TEA group significantly reduced the pain score at 48 h at rest (MD 0.59, 95% CI 0.15, 1.03, P = 0.009, I = 86%) and at 48 h at movement (MD 0.53, 95% CI 0.07, 0.99, P = 0.03, I = 76%). However, there was no significant difference at other time points. Time to ambulation was shorter in TAP block but the incidence of hypotension at 24 h and 72 h was significantly lower in TAP block compared to TEA. Trial sequential analysis showed that the required information size has not yet been reached. Our meta-analysis demonstrated there was no significant or clinically meaningful difference in the postoperative pain scores between TEA and TAP block group. Given the insufficient information size revealed by TSA, the high risk of bias of our included studies, and the significant heterogeneity of our meta-analysis results, our results should be interpreted carefully but it is not likely that the addition of further studies could prove any clinically meaningful difference in pain score between these two techniques.

Nociceptive afferent signaling evoked by inflammation and nerve injury is mediated by the opening of ligand-gated and voltage-gated receptors or channels localized to cholesterol-rich lipid raft membrane domains. Dorsal root ganglion (DRG) nociceptors express high levels of toll-like receptor 4 (TLR4), which also localize to lipid rafts. Genetic deletion or pharmacologic blocking of TLR4 diminishes pain associated with chemotherapy-induced peripheral neuropathy (CIPN). In DRGs of mice with paclitaxel-induced CIPN, we analyzed DRG neuronal lipid rafts, expression of TLR4, activation of transient receptor potential cation channel subfamily V member 1 (TRPV1), and TLR4-TRPV1 interaction. Using proximity ligation assay, flow cytometry, and whole-mount DRG microscopy, we found that CIPN increased DRG neuronal lipid rafts and TLR4 expression. These effects were reversed by intrathecal injection of apolipoprotein A-I binding protein (AIBP), a protein that binds to TLR4 and specifically targets cholesterol depletion from TLR4-expressing cells. Chemotherapy-induced peripheral neuropathy increased TRPV1 phosphorylation, localization to neuronal lipid rafts, and proximity to TLR4. These effects were also reversed by AIBP treatment. Regulation of TRPV1-TLR4 interactions and their associated lipid rafts by AIBP covaried with the enduring reversal of mechanical allodynia otherwise observed in CIPN. In addition, AIBP reduced intracellular calcium in response to the TRPV1 agonist capsaicin, which was increased in DRG neurons from paclitaxel-treated mice and in the naïve mouse DRG neurons incubated in vitro with paclitaxel. Together, these results suggest that the assembly of nociceptive and inflammatory receptors in the environment of lipid rafts regulates nociceptive signaling in DRG neurons and that AIBP can control lipid raft-associated nociceptive processing.

Fibrinolysis is a natural process that ensures blood fluidity through the removal of fibrin deposits. However, excessive fibrinolytic activity can lead to complications in different circumstances, such as general surgery or severe trauma. The current antifibrinolytic drugs in the market, aminocaproic acid (EACA) and tranexamic acid (TXA), require high doses repetitively to maintain their therapeutic effect. These high doses are related to a number of side effects such as headaches, nasal symptoms, or gastrointestinal discomfort and severely limit their use in patients with renal impairment. Therefore, the discovery of novel antifibrinolytics with a higher specificity and lower dosage could vastly improve the applicability of these drugs. Herein, we synthesized a total of ten compounds consisting of a combination of three key moieties: an oxadiazolone, a triazole, and a terminal amine. The IC of each compound was calculated in our clot lysis assays, and the best candidate () provided approximately a 2.5-fold improvement over the current gold standard, TXA. Molecular docking and molecular dynamics were used to perform a structure-activity relationship (SAR) analysis with the lysine binding site in the Kringle 1 domain of plasminogen. This analysis revealed that 1,2,3-triazole was crucial for the activity, enhancing the binding affinity through pi-pi stacking and polar interactions with Tyr72. The results presented in this work open the door to further investigate this new family as potential antifibrinolytic drugs.

In recent years, our group and others have reported multiple cases of consistent neurological recovery in people with spinal cord injury (SCI) following a protocol that integrates locomotion training with brain machine interfaces (BMI). The primary objective of this pilot study was to compare the neurological outcomes (motor, tactile, nociception, proprioception, and vibration) in both an intensive assisted locomotion training (LOC) and a neurorehabilitation protocol integrating assisted locomotion with a noninvasive brain-machine interface (L + BMI), virtual reality, and tactile feedback. We also investigated whether individuals with chronic-complete SCI could learn to perform leg motor imagery. We ran a parallel two-arm randomized pilot study; the experiments took place in São Paulo, Brazil. Eight adults sensorimotor-complete (AIS A) (all male) with chronic (> 6 months) traumatic spinal SCI participated in the protocol that was organized in two blocks of 14 weeks of training and an 8-week follow-up. The participants were allocated to either the LOC group (n = 4) or L + BMI group (n = 4) using block randomization (blinded outcome assessment). We show three important results: (i) locomotion training alone can induce some level of neurological recovery in sensorimotor-complete SCI, and (ii) the recovery rate is enhanced when such locomotion training is associated with BMI and tactile feedback (∆Mean Lower Extremity Motor score improvement for LOC =  + 2.5, L + B =  + 3.5; ∆Pinprick score: LOC =  + 3.75, L + B =  + 4.75 and ∆Tactile score LOC =  + 4.75, L + B =  + 9.5). (iii) Furthermore, we report that the BMI classifier accuracy was significantly above the chance level for all participants in L + B group. Our study shows potential for sensory and motor improvement in individuals with chronic complete SCI following a protocol with BMIs and locomotion therapy. We report no dropouts nor adverse events in both subgroups participating in the study, opening the possibility for a more definitive clinical trial with a larger cohort of people with SCI.Trial registration: http://www.ensaiosclinicos.gov.br/ identifier RBR-2pb8gq.

Mesh repair has been demonstrated to be superior to suture alone in ventral hernia repair. In a previous short-term pilot study, we found lower postoperative narcotic requirements with self-adhering mesh. The aim of this study is to follow-up on that pilot study, using long term data.

Corneal wounds resulting from injury, surgeries, or other intrusions not only cause pain, but also can predispose an individual to infection. While some inflammation may be beneficial to protect against microbial infection of wounds, the inflammatory process, if excessive, may delay corneal wound healing. An examination of the literature on the effect of inflammation on corneal wound healing suggests that manipulations that result in reductions in severe or chronic inflammation lead to better outcomes in terms of corneal clarity, thickness, and healing. However, some acute inflammation is necessary to allow efficient bacterial and fungal clearance and prevent corneal infection. This inflammation can be triggered by microbial components that activate the innate immune system through toll-like receptor (TLR) pathways. In particular, TLR2 and TLR4 activation leads to pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) activation. Similarly, endogenous molecules released from disrupted cells, known as damage-associated molecular patterns (DAMPs), can also activate TLR2, TLR4 and NFκB, with the resultant inflammation worsening the outcome of corneal wound healing. In sterile keratitis without infection, inflammation can occur though TLRs to impact corneal wound healing and reduce corneal transparency. This review demonstrates the need for acute inflammation to prevent pathogenic infiltration, while supporting the idea that a reduction in chronic and/or excessive inflammation will allow for improved wound healing.

Acute kidney injury (AKI) is a common complication after cardiac surgery and is associated with increased morbidity and mortality. However, no specific treatment options are available, emphasizing the need for preventive measures. The aim of this study was to clarify the effect of glutamine on [TIMP2]*[IGFBP7] levels at the end of the intervention period.