The effect of perioperative of dexamethasone on postoperative complications after pancreaticoduodenectomy (PANDEX): a study protocol for a pragmatic multicenter randomized controlled trial.

BACKGROUND: Pancreaticoduodenectomy (PD) nowadays serves as a standard treatment for patients with disorders of the pancreas, intestine, and bile duct. Although the mortality rate of patients undergoing PD has decreased significantly, postoperative complication rates remain high. Dexamethasone, a synthetic glucocorticoid with potent anti-inflammatory and metabolic effects, has been proven to have a favorable effect on certain complications. However, the role it plays in post-pancreatectomy patients has not been systematically evaluated. The aim of this study is to assess the effect of dexamethasone on postoperative complications after PD. METHODS: The PANDEX trial is an investigator-initiated, multicentric, prospective, randomized, double-blinded, placebo-control, pragmatic study. The trial is designed to enroll 300 patients who are going to receive elective PD. Patients will be randomized to receive 0.2 mg/kg dexamethasone or saline placebo, administered as an intravenous bolus within 5 min after induction of anesthesia. The primary outcome is the Comprehensive Complication Index (CCI) score within 30 days after the operation. The secondary outcomes include postoperative major complications (Clavien-Dindo≥3), postoperative pancreatic fistula (POPF), post-pancreatectomy acute pancreatitis (PPAP), infection, and unexpected relaparotomy, as well as postoperative length of stay, 30-day mortality, and 90-day mortality. DISCUSSION: The PANDEX trial is the first randomized controlled trial concerning the effect of dexamethasone on postoperative complications of patients undergoing PD, with the hypothesis that the intraoperative use of dexamethasone can reduce the incidence of postoperative complications and improve short-term outcomes after PD. The results of the present study will guide the perioperative use of dexamethasone and help improve the clinical management of post-pancreatectomy patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT05567094. Registered on 30 September 30 2022.

Mesenchymal stem cells alleviate dexamethasone-induced muscle atrophy in mice and the involvement of ERK1/2 signalling pathway.

BACKGROUND: High dosage of dexamethasone (Dex) is an effective treatment for multiple diseases; however, it is often associated with severe side effects including muscle atrophy, resulting in higher risk of falls and poorer life quality of patients. Cell therapy with mesenchymal stem cells (MSCs) holds promise for regenerative medicine. In this study, we aimed to investigate the therapeutic efficacy of systemic administration of adipose-derived mesenchymal stem cells (ADSCs) in mitigating the loss of muscle mass and strength in mouse model of DEX-induced muscle atrophy. METHODS: 3-month-old female C57BL/6 mice were treated with Dex (20 mg/kg body weight, i.p.) for 10 days to induce muscle atrophy, then subjected to intravenous injection of a single dose of ADSCs ([Formula: see text] cells/kg body weight) or vehicle control. The mice were killed 7 days after ADSCs treatment. Body compositions were measured by animal DXA, gastrocnemius muscle was isolated for ex vivo muscle functional test, histological assessment and Western blot, while tibialis anterior muscles were isolated for RNA-sequencing and qPCR. For in vitro study, C2C12 myoblast cells were cultured under myogenic differentiation medium for 5 days following 100 [Formula: see text]M Dex treatment with or without ADSC-conditioned medium for another 4 days. Samples were collected for qPCR analysis and Western blot analysis. Myotube morphology was measured by myosin heavy chain immunofluorescence staining. RESULTS: ADSC treatment significantly increased body lean mass (10-20%), muscle wet weight (15-30%) and cross-sectional area (CSA) (~ 33%) in DEX-induced muscle atrophy mice model and down-regulated muscle atrophy-associated genes expression (45-65%). Hindlimb grip strength (~ 37%) and forelimb ex vivo muscle contraction property were significantly improved (~ 57%) in the treatment group. Significant increase in type I fibres (~ 77%) was found after ADSC injection. RNA-sequencing results suggested that ERK1/2 signalling pathway might be playing important role underlying the beneficial effect of ADSC treatment, which was confirmed by ERK1/2 inhibitor both in vitro and in vivo. CONCLUSIONS: ADSCs restore the pathogenesis of Dex-induced muscle atrophy with an increased number of type I fibres, stronger muscle strength, faster recovery rate and more anti-fatigue ability via ERK1/2 signalling pathway. The inhibition of muscle atrophy-associated genes by ADSCs offered this treatment as an intervention option for muscle-associated diseases. Taken together, our findings suggested that adipose-derived mesenchymal stem cell therapy could be a new treatment option for patient with Dex-induced muscle atrophy.

Dexamethasone intravitreal implant in diabetic macular oedema refractory to anti-vascular endothelial growth factors: the AUSSIEDEX study.

AIM: To evaluate effectiveness of dexamethasone intravitreal implant 0.7 mg (DEX) monotherapy in the AUSSIEDEX study non-responder subgroup, defined by diabetic macular oedema (DME) refractory to anti-vascular endothelial growth factor (anti-VEGF) agents. METHODS: This prospective, open-label, observational, real-world study included pseudophakic and phakic (scheduled for cataract surgery) eyes that did not achieve a ≥5-letter best corrected visual acuity (BCVA) gain and/or clinically significant central subfield retinal thickness (CRT) improvement after 3-6 anti-VEGF injections for DME (N=143 eyes), regardless of baseline BCVA and CRT. After an initial DEX injection (baseline visit), reinjection was permitted at ≥16-week intervals. PRIMARY ENDPOINTS: changes in mean BCVA and CRT from baseline to week 52. Safety assessments included adverse events. RESULTS: Of 143 eyes, 53 (37.1%) and 89 (62.2%) switched to DEX after 3-6 (early) and >6 (late) anti-VEGF injections, respectively; 1 (0.7%) had missing information. With 2.3 injections (mean) over 52 weeks, the change in mean BCVA from a baseline of 57.8 letters was not significant at week 52. Mean CRT improved significantly from a baseline of 417.8 µm at week 52 (mean change -60.9 µm; p<0.001). Outcomes were similar in eyes switched to DEX early and late. No unexpected adverse events were reported; no filtration surgeries were required. CONCLUSION: To date, AUSSIEDEX is the largest prospective, real-world study of DEX monotherapy for treatment-naïve or anti-VEGF-refractory DME. Following early or late switch from anti-VEGF agents, DEX significantly improved anatomic outcomes at 52 weeks without new safety concerns, supporting use in anti-VEGF-refractory DME. TRIAL REGISTRATION NUMBER: NCT02731911.

Mezigdomide plus Dexamethasone in Relapsed and Refractory Multiple Myeloma.

BACKGROUND: Despite recent progress, multiple myeloma remains incurable. Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide. METHODS: In this phase 1-2 study, we administered oral mezigdomide in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase 1 (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase 2. In phase 2 (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase 1. RESULTS: In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle. In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class-refractory multiple myeloma, 30 patients (30%) had received previous anti-B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9). CONCLUSIONS: The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects. (Funded by Celgene, a Bristol-Myers Squibb Company; CC-92480-MM-001 ClinicalTrials.gov number, NCT03374085; EudraCT number, 2017-001236-19.).

Systemic corticosteroids for the prevention of bronchopulmonary dysplasia, a network meta-analysis.

BACKGROUND: Despite considerable improvement in outcomes for preterm infants, rates of bronchopulmonary dysplasia (BPD) remain high, affecting an estimated 33% of very low birthweight infants, with corresponding long-term respiratory and neurosensory issues. Systemic corticosteroids can address the inflammation underlying BPD, but the optimal regimen for prevention of this disease, balancing of the benefits with the potentially meaningful risks of systemic corticosteroids, continues to be a medical quandary. Numerous studies have shown that systemic corticosteroids, particularly dexamethasone and hydrocortisone, effectively treat or prevent BPD. However, concerning short and long-term side effects have been reported and the optimal approach to corticosteroid treatment remains unclear. OBJECTIVES: To determine whether differences in efficacy and safety exist between high-dose dexamethasone, moderate-dose dexamethasone, low-dose dexamethasone, hydrocortisone, and placebo in the prevention of BPD, death, the composite outcome of death or BPD, and other relevant morbidities, in preterm infants through a network meta-analysis, generating both pairwise comparisons between all treatments and rankings of the treatments. SEARCH METHODS: We searched the Cochrane Library for all systematic reviews of systemic corticosteroids for the prevention of BPD and searched for completed and ongoing studies in the following databases in January 2023: Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and clinical trial databases. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in preterm infants (< 37 weeks' gestation) at risk for BPD that evaluated systemic corticosteroids (high-dose [≥ 4 mg/kg cumulative dose] dexamethasone, moderate-dose [≥ 2 to < 4 mg/kg] dexamethasone, low-dose [< 2 mg/kg] dexamethasone, or hydrocortisone) versus control or another systemic corticosteroid. DATA COLLECTION AND ANALYSIS: Our main information sources were the systematic reviews, with reference to the original manuscript only for data not included in these reviews. Teams of two paired review authors independently performed data extraction, with disagreements resolved by discussion. Data were entered into Review Manager 5 and exported to R software for network meta-analysis (NMA). NMA was performed using a frequentist model with random-effects. Two separate networks were constructed, one for early (< seven days) initiation of treatment and one for late (≥ seven days) treatment initiation, to reflect the different patient populations evaluated. We assessed the certainty of evidence derived from the NMA for our primary outcomes using principles of the GRADE framework modified for application to NMA. MAIN RESULTS: We included 59 studies, involving 6441 infants, in our analyses. Only six of the included studies provided direct comparisons between any of the treatment (dexamethasone or hydrocortisone) groups, forcing network comparisons between treatments to rely heavily on indirect evidence through comparisons with placebo/no treatment groups. Thirty-one studies evaluated early corticosteroid treatment, 27 evaluated late corticosteroid treatment, and one study evaluated both early and late corticosteroid treatments. Early treatment (prior to seven days after birth): Benefits:NMA for early treatment showed only moderate-dose dexamethasone to decrease the risk of BPD at 36 weeks' postmenstrual age (PMA) compared with control (RR 0.56, 95% CI 0.39 to 0.80; moderate-certainty evidence), although the other dexamethasone dosing regimens may have similar effects compared with control (high-dose dexamethasone, RR 0.71, 95% CI 0.50 to 1.01; low-certainty evidence; low-dose dexamethasone, RR 0.83, 95% CI 0.67 to 1.03; low-certainty evidence). Other early treatment regimens may have little or no effect on the risk of death at 36 weeks' PMA. Only moderate-dose dexamethasone decreased the composite outcome of death or BPD at 36 weeks' PMA compared with control (RR 0.77, 95% CI 0.60 to 0.98; moderate-certainty evidence). HARMS: Low-dose dexamethasone increased the risk for cerebral palsy (RR 1.92, 95% CI 1.12 to 3.28; moderate-certainty evidence) compared with control. Hydrocortisone may decrease the risk of major neurosensory disability versus low-dose dexamethasone (RR 0.65, 95% CI 0.41 to 1.01; low-certainty evidence). Late treatment (at seven days or later after birth): Benefits: NMA for late treatment showed high-dose dexamethasone to decrease the risk of BPD both versus hydrocortisone (RR 0.66, 95% CI 0.51 to 0.85; low-certainty evidence) and versus control (RR 0.72, CI 0.59 to 0.87; moderate-certainty evidence). The late treatment regimens evaluated may have little or no effect on the risk of death at 36 weeks' PMA. High-dose dexamethasone decreased risk for the composite outcome of death or BPD compared with all other treatments (control, RR 0.69, 95% CI 0.59 to 0.80, high-certainty evidence; hydrocortisone, RR 0.69, 95% CI 0.58 to 0.84, low-certainty evidence; low-dose dexamethasone, RR 0.73, 95% CI 0.60 to 0.88, low-certainty evidence; moderate-dose dexamethasone, RR 0.76, 95% CI 0.62 to 0.93, low-certainty evidence). HARMS: No effect was observed for the outcomes of major neurosensory disability or cerebral palsy. The evidence for the primary outcomes was of overall low certainty, with notable deductions for imprecision and heterogeneity across the networks. AUTHORS' CONCLUSIONS: While early treatment with moderate-dose dexamethasone or late treatment with high-dose dexamethasone may lead to the best effects for survival without BPD, the certainty of the evidence is low. There is insufficient evidence to guide this therapy with regard to plausible adverse long-term outcomes. Further RCTs with direct comparisons between systemic corticosteroid treatments are needed to determine the optimal treatment approach, and these studies should be adequately powered to evaluate survival without major neurosensory disability.

Can dexamethasone improve postoperative sleep and postoperative delirium in elderly patients undergoing robot-assisted laparoscopic radical prostatectomy? Protocol for a prospective, randomized, double-blind, controlled study.

BACKGROUND: Perioperative sleep disorders (PSD) are an independent risk factor for postoperative delirium (POD), which is a common complication after surgery. Elderly patients who undergo robot-assisted radical prostatectomy (RARP) often experience perioperative sleep disorders (PSD). Dexamethasone, a medication that works by inhibiting the hypothalamic-pituitary-suprarenal cortical axis, can reduce the negative effects of surgical stress. The objective of this study was to determine whether intravenous administration of dexamethasone at the time of anesthesia induction could improve postoperative sleep quality in elderly patients, thereby indirectly reducing the risk of postoperative cognitive impairment and accelerating postoperative rehabilitation. METHODS/DESIGN: This study is a randomized, double-blind, placebo-controlled trial that was conducted at a single center. A sample size of 116 patients was determined through calculation, and these patients were randomly assigned to either the dexamethasone group (group D, n = 58) or the blank control group (group C, n = 58). On the day of surgery, the anesthesia nurse prepared either diluted dexamethasone or saline in advance, according to the patient's assigned group. The blinded anesthesiologist administered the medication during induction, and a dedicated person followed up with the patient for three consecutive postoperative days. All other aspects of care were managed equally between the two groups. The primary outcome measure was sleep quality, while secondary outcome measures included postoperative sleep time, postoperative delirium (POD), pain scores, and other complications. Relevant test measures were recorded for analysis. DISCUSSION: This study aims to investigate the impact of intravenous dexamethasone on sleep quality and duration of patients undergoing robot-assisted radical prostatectomy (RARP). If the findings of this study protocol are affirmative, it could enhance the sleep quality of elderly patients after surgery, thereby minimizing the risk of postoperative delirium (POD), and providing substantial evidence for the perioperative enhanced recovery management of elderly patients. TRIAL REGISTRATION: Chinese clinical trial registry: ChiCTR2200063488, Registered on 5 October 2022.

Real-world experience on intravitreal dexamethasone implant in patients with macular edema scheduled to undergo cataract surgery.

BACKGROUND: Patients with pre-existing macular edema (ME) due to diabetes and retinal vein occlusions (RVO) make up a growing population receiving cataract surgery. Surgery is associated with an increased risk of worsening existing ME due to post-surgical inflammation that can be further exacerbated by pre-existing diabetic retinopathy (DR) and retinal vein occlusion. This study aimed to examine the pre-operative use of intravitreal dexamethasone (DEX) implants in patients with ME undergoing cataract surgery. METHODS: A retrospective study was conducted at National Cheng Kung University Hospital in Taiwan involving 19 eyes of 16 patients with DME or ME associated with RVO. All participants received a DEX implant at baseline and underwent phacoemulsification within 3 months after its insertion. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) and central subfield thickness (CST) were evaluated. RESULTS: DEX implants reduced the CST from baseline (357.8 µm) to pre-surgery (280.8 µm). This reduction below baseline continued to month 6 post-surgery (319.4 µm). From baseline (16.15 mmHg), the mean IOP initially increased pre-surgery (17.78 mmHg) before returning to the baseline value at month 6 post-surgery (16.15 mmHg). All patients improved their BCVA from logMAR 0.943 on average at baseline to logMAR 0.532 at month 6 post-surgery. CONCLUSIONS: The results of the study suggested that patients with ME could benefit from DEX implants before cataract surgery within 3 months to achieve sufficient postoperative inflammation management and limit ME deterioration. DEX implants did not increase IOP post-surgery and was similar to baseline levels.

Theophylline Prevents Dexamethasone-Induced Atrophy in C2C12 Myotubes.

Skeletal muscle mass is maintained by a balance between the synthesis and degradation of muscle proteins, the collapse of which causes muscle wasting. The prevention of muscle wasting improves the quality of life and extends a healthy life. The methyl xanthine theophylline showed strong preventive activity against dexamethasone-induced muscle atrophy, as determined using the expression level of myosin heavy chain in C2C12 myotubes. Mechanistically, theophylline inhibited the expression of ubiquitin ligases MuRF1 and Cbl-b, but not that of atrogin-1. Furthermore, theophylline inhibits glucocorticoid receptor translocation to the nucleus. A pull-down assay using a theophylline probe revealed that theophylline and dexamethasone competitively interacted with the glucocorticoid receptor, suggesting an antagonistic activity of theophylline on glucocorticoid receptors. Additionally, theophylline inhibited the dexamethasone-induced phosphorylation of p38 and FoxO3a in C2C12 myotubes. These findings suggest that theophylline is an effective food ingredient in the prevention of glucocorticoid-induced skeletal muscle atrophy.

Renal Glucose Release after Unilateral Renal Denervation during a Hypoglycemic Clamp in Pigs with an Altered Hypothalamic Pituitary Adrenal Axis after Late-Gestational Dexamethasone Injection.

Previously, we demonstrated in pigs that renal denervation halves glucose release during hypoglycaemia and that a prenatal dexamethasone injection caused increased ACTH and cortisol concentrations as markers of a heightened hypothalamic pituitary adrenal axis (HPAA) during hypoglycaemia. In this study, we investigated the influence of an altered HPAA on renal glucose release during hypoglycaemia. Pigs whose mothers had received two late-gestational dexamethasone injections were subjected to a 75 min hyperinsulinaemic-hypoglycaemic clamp (<3 mmol/L) after unilateral surgical denervation. Para-aminohippurate (PAH) clearance, inulin, sodium excretion and arterio-venous blood glucose difference were measured every fifteen minutes. The statistical analysis was performed with a Wilcoxon signed-rank test. PAH, inulin, the calculated glomerular filtration rate and plasma flow did not change through renal denervation. Urinary sodium excretion increased significantly (p = 0.019). Side-dependent renal net glucose release (SGN) decreased by 25 ± 23% (p = 0.004). At 25 percent, the SGN decrease was only half of that observed in non-HPAA-altered animals in our prior investigation. The current findings may suggest that specimens with an elevated HPAA undergo long-term adaptations to maintain glucose homeostasis. Nonetheless, the decrease in SGN warrants further investigations and potentially caution in performing renal denervation in certain patient groups, such as diabetics at risk of hypoglycaemia.

Risk Factors for Infusion Reactions in Patients with Breast Cancer Administered Trastuzumab Therapy.

Trastuzumab is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2) that is indicated for the treatment of HER2-positive breast cancer. The administration of biologics, such as trastuzumab, frequently causes infusion reactions (IRs) with fever and chills. This study aimed to clarify the risk factors for IRs in trastuzumab therapy. Between March 2013 and July 2022, 227 patients with breast cancer who started trastuzumab therapy were included in this study. The severity of IRs was graded according to the Common Terminology Criteria for Adverse Events, Version 5.0. The incidence of IRs in trastuzumab therapy was 27.3% (62/227). Dexamethasone administration was significantly different between the IR and non-IR groups in patients receiving trastuzumab therapy (univariate analysis, p < 0.001; multivariate analysis, p = 0.0002). Without dexamethasone, the severity of IRs in the pertuzumab combination group (Grade 1, 8/65; Grade 2, 23/65) was significantly higher than that in the non-pertuzumab group (Grade 1, 9/37; Grade 2, 3/37; p < 0.05). Our findings suggest that the risk of IRs is significantly higher in patients not premedicated with dexamethasone in trastuzumab therapy and that the concomitant use of pertuzumab without dexamethasone increases the severity of IRs caused by trastuzumab.

Anti-inflammatory Effects of Ziziphus Jujube Mill on LPS-induced Acute Lung Injury in Mice.

Ziziphus Jujuba Mill (Z.J) is a well-known ethnomedical source of biologically active compounds with anti-inflammatory effects. However, its significance in acute lung injury (ALI) has never been studied. The present study aimed to explore whether Z.J could attenuate lipopolysaccharide (LPS)-induced inflammatory responses in an experimental model of ALI. Male BALB/c mice received an intratracheal administration of LPS (n=32) or phosphate buffer saline (PBS) (control, n=8). Within 1, 11, and 23 h post-LPS injection, mice were randomly assigned to receive intraperitoneal treatments of saline, dexamethasone (2 mg/kg), and 100 and 200 mg/kg of Z.J extracts, respectively. 24 h after intratracheal administration of LPS, bronchoalveolar lavage fluid and lung tissues were harvested and assessed for inflammatory cell influx, tumor necrosis factor-α (TNF-α) levels, and histological assessments. Treatment with Z.J extracts (100 and 200 mg/kg) and dexamethasone effectively reduced LPS-induced neutrophil and other inflammatory cell influx into the lung tissue compared to the untreated group. additionally, both doses of Z.J extracts (100 and 200 mg/kg) significantly ameliorated the lung wet-to-dry ratio and histopathological damage. Furthermore, compared to the untreated ALI mice, Z.J extract at the highest dose could significantly reduce the TNF-α level.   The present findings indicated that Z.J could effectively ameliorate LPS-induced ALI inflammatory responses and might be considered a promising alternative therapy for the ALI phenotype.

[A case of progressive multifocal leukoencephalopathy associated with daratumumab, bortezomib, and dexamethasone for multiple myeloma].

An 83-year-old man presented with visual disturbance and right hemiparalysis, one month after daratumumab, bortezomib, and dexamethasone administration for multiple myeloma (MM). Blood screens revealed a CD4+ T-lymphocyte count of 132/µl. Diffusion weighted and fluid-attenuated inversion-recovery MR imaging showed high intensity signals in the both occipital lobes and left precentral area. The patient had no history of human immunodeficiency virus infection. Cerebrospinal fluid (CSF) JC virus (JCV) was positive (83 copies/ml), as indicated by PCR. The patient was diagnosed with progressive multifocal leukoencephalopathy (PML). MM treatment was discontinued, and mefloquine and mirtazapine therapy was started. However, the CSF JCV-DNA PCR count did not improve (111 copies/ml) after 30 days from starting mefloquine and mirtazapine therapy. The patient died six months after symptom onset. Conclusively, patients with decreased CD4+ T lymphocyte counts following DBd therapy for MM, the possibility of PML should be considered.

Class I HDAC inhibitors attenuate dexamethasone-induced muscle atrophy via increased protein kinase C (PKC) delta phosphorylation.

Skeletal muscle atrophy is defined by wasting or decrease in muscle mass owing to injury, aging, malnutrition, chronic disuse, or physical consequences of chronic illness. Under normal physiological conditions, a network of signal transduction pathways serves to balance muscle protein synthesis and proteolysis; however, metabolic shifts occur from protein synthesis to protein degradation that leads to a reduction in cross-sectional myofibers and can result in loss of skeletal muscle mass (atrophy) over time. Recent evidence highlights posttranslational modifications (PTMs) such as acetylation and phosphorylation in contractile dysfunction and muscle wasting. Indeed, histone deacetylase (HDAC) inhibitors have been shown to attenuate muscle atrophy and delay muscle damage in response to nutrient deprivation, in models of metabolic dysfunction and genetic models of muscle disease (e.g., muscle dystrophy). Despite our current understanding of lysine acetylation in muscle physiology, a role for HDACs in the regulation of muscle signal transduction remains a 'black box.' Using C2C12 myotubes stimulated with dexamethasone (Dex) as a model of muscle atrophy, we report that protein kinase C delta (PKCδ) phosphorylation decreased at threonine 505 (T505) and serine 643 (S643) in myotubes in response to muscle atrophy; these residues are important for PKCδ activity. Interestingly, PKCδ phosphorylation was restored/increased in myotubes treated with a pan-HDAC inhibitor or a class I selective HDAC inhibitor targeting HDACs1, -2, and - 3 in response to Dex. Moreover, we observed that Dex induced atrophy in skeletal muscle tissue in mice; this reduction in atrophy occurred rapidly, with weight loss noted by day 3 post-Dex and muscle weight loss noted by day 7. Similar to our findings in C2C12 myotubes, Dex attenuated phosphorylation of PKCδ at S643, while HDAC inhibition restored or increased PKCδ phosphorylation at both T505 and S643 in the tibialis anterior. Consistent with this hypothesis, we report that HDAC inhibition could not restore myotube size in response to Dex in the presence of a PKCδ inhibitor or when overexpressing a dominant negative PKCδ. Additionally, the overexpression of a constitutively active PKCδ prevented Dex-induced myotube atrophy. Combined, these data suggest that HDACs regulate muscle physiology via changes in intracellular signaling, namely PKCδ phosphorylation. Whether HDACs regulate PKCδ through canonical (e.g. gene-mediated regulation of phosphatases) or non-canonical (e.g. direct deacetylation of PKCδ to change phosphorylation states) mechanisms remain unclear and future research is needed to clarify this point.

Corticosteroid-Associated Avascular Necrosis of the Femoral Head in Patients with Severe COVID-19: A Single-Center Study.

BACKGROUND Avascular necrosis (AVN) of the femoral head can result from high-dose corticosteroid therapy. Given that severe COVID-19 pneumonia patients respond positively to corticosteroids, this study aimed to explore the incidence of femoral head AVN associated with corticosteroid therapy in 24 patients diagnosed with severe COVID-19 at a single center. MATERIAL AND METHODS The study included 24 patients who were diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection through real-time reverse transcription polymerase chain reaction test (rRT-PCR) and with COVID-19 pneumonia via high-resolution computed tomography (HRCT). Moderate cases received 2×4 mg Dexamethasone while severe cases were also administered with 3×40 mg Methylprednisolone. Diagnosis of femoral head AVN was confirmed with magnetic resonance imaging (MRI) and radiographs, which was subsequently treated by a total hip arthroplasty (THA) or a core decompression surgery (CDS) in line with the Ficat and Arlet classifications RESULTS Among the patients, 8 had a moderate infection course, while 16 were severe. The mean corticosteroid duration was 15±5 days for Dexamethasone and 30 days for Methylprednisolone. Severe patients presented with higher grade femoral head AVN and greater pain levels compared to moderate cases (p<0.05). Four patients developed bilateral AVN. The treatment resulted in 23 THAs and 5 CDSs CONCLUSIONS The data from this study corroborate earlier studies and case reports, suggesting an increased occurrence of AVN of the femoral head during the COVID-19 pandemic due to the high-dose corticosteroid therapy employed for patients hospitalized with severe COVID-19 pneumonia.

Local anaesthetic adjuncts for peripheral nerve blockade.

PURPOSE OF REVIEW: Moderate-to-severe pain is common and remains a significant problem. Compared with opioid analgesia alone, single-shot peripheral nerve blockade has been associated with improved pain relief and the potential of decreased side effects. Single-shot nerve blockade, however, is limited by its relatively short duration of action. In this review, we aim to summarize the evidence related to local anaesthetic adjuncts for peripheral nerve blockade. RECENT FINDINGS: Dexamethasone and dexmedetomidine exhibit characteristics that most closely resemble the ideal local anaesthetic adjunct. In upper limb block, dexamethasone has been demonstrated to be superior to dexmedetomidine regardless of administration route for the duration of sensory and motor blockade as well as the duration of analgesia. No clinically significant differences between intravenous and perineural dexamethasone were found. Perineural and intravenous dexamethasone have the potential to prolong sensory blockade to a greater extent than motor blockade. The evidence indicates that the mechanism of action of perineural dexamethasone in upper limb block is systemic in nature. Unlike perineural dexmedetomidine, intravenous dexmedetomidine has not been shown to result in differences in the characteristics of regional blockade compared with local anaesthetic alone. SUMMARY: Intravenous dexamethasone is the local anaesthetic adjunct of choice, increasing the duration of sensory and motor blockade as well as the duration of analgesia by 477, 289 and 478 min, respectively. In view of this, we recommend consideration of the intravenous administration of dexamethasone at a dose of 0.1-0.2 mg/kg for all patients undergoing surgery whatever the level of postoperative pain, mild, moderate or severe. Further research should focus on the potential synergism of action between intravenous dexamethasone and perineural dexmedetomidine.

Multi-institutional survey of antiemetic therapy in lung cancer patients treated with carboplatin in Hokushin region.

OBJECTIVE: Appropriate monitoring and management of chemotherapy-induced nausea and vomiting (CINV) with prophylactic antiemetics is important for cancer patients. This study was performed to validate the clinical practice of antiemetic use with carboplatin-based chemotherapy in lung cancer patients in the Hokushin region (Toyama, Ishikawa, Fukui, and Nagano prefectures), Japan. METHODS: We surveyed retrospective data of newly diagnosed and registered lung cancer patients initially treated with carboplatin-based chemotherapy in 21 principal hospitals in the Hokushin region linked with health insurance claims data between 2016 and 2017. RESULTS: A total of 1082 lung cancer patients (861 [79.6%] men, 221 [20.4%] women; median age 69.4 years [range, 33-89 years]). All patients received antiemetic therapy, with 613 (56.7%) and 469 patients (43.3%) receiving 5-hydroxytryptamine-3 receptor antagonist/dexamethasone double regimen and 5-hydroxytryptamine-3 receptor antagonist/dexamethasone/neurokinin-1 receptor antagonist triple regimen, respectively. However, the rates of double regimen and use of palonosetron were higher in Toyama and Fukui prefectures. Thirty-nine patients (3.6%) changed from double to triple regimen, while 41 patients (3.8%) changed from triple to double regimen after the second cycle, but six of these returned to triple antiemetics in subsequent cycles. CONCLUSION: Adherence to antiemetic guidelines in clinical practice was high in Hokushin region. However, rates of double and triple antiemetic regimens differed between the four prefectures. Simultaneous analysis of nationwide registry and insurance data was valuable for evaluating and comparing the differences in the status of antiemesis and management.