Is Antiviral Treatment with Remdesivir at the Acute Phase of SARS-CoV-2 Infection Effective for Decreasing the Risk of Long-Lasting Post-COVID Symptoms?

The aim of this study was to investigate the effects of administrating Remdesivir at the acute COVID-19 phase on developing post-COVID symptoms in previously hospitalized COVID-19 survivors by controlling factors such as age, sex, body mass index, and vaccination status. A case-control study was performed. Hospitalized COVID-19 survivors who had received intravenous Remdesivir during the acute phase (n = 216) were matched by age, sex, body mass index, and vaccination status with survivors who did not receive antiviral treatment (n = 216). Participants were asked to self-report the presence of any post-COVID symptom (defined as a symptom that started no later than three months after infection) and whether the symptom persisted at the time of study (mean: 18.4, SD: 0.8 months). Anxiety levels (HADS-A), depressive symptoms (HADS-D), sleep quality (PSQI), and severity/disability (FIC) were also compared. The multivariate analysis revealed that administration of Remdesivir at the acute COVID-19 phase was a protective factor for long-term COVID development (OR0.401, 95%CI 0.256-0.628) and specifically for the following post-COVID symptoms: fatigue (OR0.399, 95%CI 0.270-0.590), pain (OR0.368, 95% CI 0.248-0.548), dyspnea at rest (OR0.580, 95%CI 0.361-0.933), concentration loss (OR0.368, 95%CI 0.151-0.901), memory loss (OR0.399, 95%CI 0.270-0.590), hair loss (OR0.103, 95%CI 0.052-0.207), and skin rashes (OR0.037, 95%CI 0.005-0.278). This study supports the potential protective role of intravenous administration of Remdesivir during the COVID-19 acute phase for long-lasting post-COVID symptoms in previously hospitalized COVID-19 survivors.

Analysis of opioid analgesics consumption in Africa: a longitudinal study from a 20-year continental perspective.

BACKGROUND: Opioid analgesics are essential for managing acute and chronic pain in diseases such as cancer. Inadequate opioid access remains a major public health concern in low-income regions including Africa. This study aimed to provide updated and comprehensive data on changes in opioid consumption, specifically in Africa. METHODS: This longitudinal study has updated and expanded upon the International Narcotics Control Board data obtained from 1999 to 2021, assessing opioid consumption trends across all African countries. The defined daily doses for statistical purposes (SDDD) was used to determine the changes in opioid consumption in Africa. In addition, we used sub-analyses of the data to delve into individual substances, income levels, cancer incidence, cancer mortality, and sub-regional cluster analysis (based on the language spoken) to identify possible disparities and inform further research and tailored solutions. FINDINGS: Our results indicate a persistently low and stagnant trend in opioid consumption between 2001-03 and 2019-21, from 73 SDDD (95% CI 69-77) to 55 SDDD (32-79). In-depth analysis revealed a morphine consumption increase from 735 SDDD in 1999 to 1115 SDDD in 2021. Moreover, opioid consumption was closely related to country-level income levels, with most of the low-income and lower-middle-income African countries reporting low opioid consumption. Notably, the escalating incidence and mortality rates associated with cancer in Africa indicated a misalignment with the trajectory of opioid use. Additionally, French-speaking African countries exhibited lower opioid usage than the rest of the continent, suggesting avenues for research into cultural, political, and social aspects. INTERPRETATION: In the context of global doubling in opioid consumption, Africa has shown insufficient and stagnant opioid consumption during the last 20 years. These findings underscore the need for policy reform to facilitate safe and responsible opioid access in Africa, particularly for legitimate indications such as cancer pain and palliative care. FUNDING: None. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Prognostic value of preoperative mechanical hyperalgesia and neuropathic pain qualities for postoperative pain after total knee replacement.

BACKGROUND: Total knee replacement (TKR) is the gold standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. METHODS: This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6 and 12 months post-TKR. We assessed preoperative and postoperative (3 and 6 months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM) and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia and temporal summation to repeated pinprick stimulation. RESULTS: Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial knee undergoing TKR, and cuff pressure at the calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with preoperative KOA pain intensity. Moreover, preoperative pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6 and 12 months respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up. CONCLUSION: Our findings suggest that preoperative pinprick hyperalgesia and neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain. SIGNIFICANCE STATEMENT: This study's findings hold significant implications for chronic pain management in knee osteoarthritis patients, particularly those undergoing total knee replacement surgery (TKR). Mechanical hyperalgesia and neuropathic pain-like characteristics predict postoperative pain 1 year after TKR, emphasizing the importance of understanding pain phenotypes in OA for selecting appropriate pain management strategies. The normalization of hyperalgesia after surgery correlates with better long-term outcomes, further highlighting the therapeutic potential of addressing abnormal pain processing mechanisms pre- and post-TKR.

The polymorphism Val158Met in the COMT gene: disrupted dopamine system in fibromyalgia patients?

ABSTRACT: The single-nucleotide polymorphism (SNP) rs4680 in the catechol-O-methyltransferase gene ( COMT ) is a missense variant (Val158Met) associated with altered activity of the COMT enzyme and suggested as a predictive feature for developing some chronic pain conditions. However, there are controversial results on its role in fibromyalgia (FM). Here, the SNP Val158Met was analyzed in 294 FM patients (without comorbidities) and 209 healthy controls (without chronic pain). The concurrent impact of Val158Met genotypes and FM comorbid disorders (depression and sleep impairment) on FM risk were tested. In addition, the genotypic distribution of FM patients in relation to pain intensity was evaluated. The G allele (Val) resulted in being more represented in the FM group (57.8%) compared with the control group (48.8%; P = 0.037). Logistic regression highlighted that having the G/G (Val/Val) homozygous genotype was associated with 2 times higher risk of having FM compared with the A/A (Met/Met) carriers ( P = 0.038), whereas depression and sleep impairment increased FM risk by 12 and 8 times, respectively ( P < 0.001). However, considering only the FM patient group, the A/A homozygous genotype was significantly associated with severe pain intensity ( P = 0.007). This study highlighted associations between the SNP Val158Met and both FM and pain intensity, suggesting a link between dopaminergic dysfunction and vulnerability to chronic pain. Further studies should explore this SNP in FM patients in conjunction with COMT enzymatic activity and other symptoms connected with the dopaminergic system such as depression or sleep impairment.

Association of OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 polymorphisms with clinical phenotype among women with fibromyalgia.

To investigate the association between three selected pain polymorphisms and clinical, functional, sensory-related, psychophysical, psychological or cognitive variables in a sample of women with fibromyalgia (FMS). One hundred twenty-three (n = 123) women with FMS completed demographic (age, height, weight), clinical (years with pain, intensity of pain at rest and during daily living activities), functional (quality of life, physical function), sensory-related (sensitization-associated and neuropathic-associated symptoms), psychophysical (pressure pain thresholds), psychological (sleep quality, depressive and anxiety level) and cognitive (pain catastrophizing, kinesiophobia) variables. Those three genotypes of the OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 single nucleotide polymorphisms were obtained by polymerase chain reactions from no-stimulated whole saliva collection. No significant differences in demographic, clinical, functional, sensory-related, psychophysical, psychological and cognitive variables according to OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680 genotype were identified in our sample of women with FMS. A multilevel analysis did not either reveal any significant gene-to-gene interaction between OPRM1 rs1799971 x HTR1B rs6296, OPRM1 rs1799971 x COMT rs4680 and HTR1B rs6296 x COMT rs4680 for any of the investigated outcomes. This study revealed that three single nucleotide polymorphisms, OPRM1 rs1799971, HTR1B rs6296 or COMT rs4680, mostly associated with chronic pain were not involved in phenotyping features of FMS. Potential gene-to-gene interaction and their association with clinical phenotype in women with FMS should be further investigated in future studies including large sample sizes.

Small fibre neuropathy frequently underlies the painful long-COVID syndrome.

ABSTRACT: Approximately 10% to 20% of individuals with previous SARS-CoV-2 infection may develop long-COVID syndrome, characterized by various physical and mental health issues, including pain. Previous studies suggested an association between small fibre neuropathy and pain in long-COVID cases. In this case-control study, our aim was to identify small fibre neuropathy in patients experiencing painful long-COVID syndrome. Clinical data, quantitative sensory testing, and skin biopsies were collected from 26 selected patients with painful long-COVID syndrome. We also examined 100 individuals with past COVID-19 infection, selecting 33 patients with painless long-COVID syndrome, characterized mainly by symptoms such as brain fog and fatigue, and 30 asymptomatic post-COVID-19 controls. Demographic and clinical variables were compared among these groups. Among the 26 patients with painful long-COVID syndrome, 12 had skin biopsy and/or quantitative sensory testing abnormalities compatible with small fibre neuropathy. Demographic and clinical data did not differ across patients with small fibre neuropathy, patients with painless long-COVID syndrome, and asymptomatic post-COVID-19 controls. This case-control study showed that approximately 50% of patients experiencing painful long-COVID syndrome had small fibre neuropathy. However, in our patient cohort, this specific post-COVID-19 complication was unrelated to demographic and COVID-19 clinical variables. Approximately half of our sample of patients with painful long-COVID symptoms met diagnostic criteria for small fibre neuropathy.

Unravelling the essential elements for recombinant adeno-associated virus (rAAV) production in animal cell-based platforms.

Recombinant adeno-associated viruses (rAAVs) stand at the forefront of gene therapy applications, holding immense significance for their safe and efficient gene delivery capabilities. The constantly increasing and unmet demand for rAAVs underscores the need for a more comprehensive understanding of AAV biology and its impact on rAAV production. In this literature review, we delved into AAV biology and rAAV manufacturing bioprocesses, unravelling the functions and essentiality of proteins involved in rAAV production. We discuss the interconnections between these proteins and how they affect the choice of rAAV production platform. By addressing existing inconsistencies, literature gaps and limitations, this review aims to define a minimal set of genes that are essential for rAAV production, providing the potential to advance rAAV biomanufacturing, with a focus on minimizing the genetic load within rAAV-producing cells.

Sex moderates the association between quantitative sensory testing and acute and chronic pain after total knee/hip arthroplasty.

OBJECTIVES: Acute postsurgical pain (APSP) may persist over time and become chronic. Research on predictors for APSP and chronic postsurgical pain (CPSP) has produced inconsistent results. This observational study aimed to analyze psychological and psychophysical variables associated with APSP and CPSP after total knee or hip arthroplasty, and to explore the role of sex. METHODS: Assessments were conducted before surgery, 48 h, and 3 months postsurgery, including questionnaires (sociodemographic, pain related, and psychological) and quantitative sensory testing (QST). Hierarchical linear regression models analyzed potential predictors of APSP and CPSP, and moderation analyses evaluated the role of sex. RESULTS: The study included 63 participants undergoing total knee (34, 54%) or hip (29, 46%) arthroplasty. Thirty-one (49.2%) were female and 32 (50.8%) were male. APSP (48 h) was associated with impaired conditioned pain modulation (CPM) (ß = 0.301, p = 0.019). CPSP (3 months) was associated with being female (ß = 0.282, p = 0.029), longer presurgical pain duration (ß = 0.353, p = 0.006), knee arthroplasty (ß = -0.312, p = 0.015), higher APSP intensity (ß = 373, p = 0.004), and impaired CPM (ß = 0.126, p = 0.004). In multivariate analysis, these clinical variables were significant predictors of CPSP, unlike sex, and CPM (adj. R 2 = 0.349). Moderation analyses showed that wind-up ratio (WUR) was a significant predictor of APSP in men (WUR × sex: b = -1.373, p = 0.046) and CPM was a significant predictor of CPSP in women (CPM × sex: b = 1.625, p = 0.016). CONCLUSIONS: Specific QST parameters could identify patients at risk for high-intensity APSP and CPSP, with sex as a moderator. This has important clinical implications for patient care, paving the way for developing tailored preventive pain management strategies.

Socioeconomic Status and Overall Survival Among Patients With Hematological Malignant Neoplasms.

Importance: In recent years, there has been a focus on reducing the socioeconomic gap in survival for hematological malignant neoplasms. Understanding recent developments is important to develop further intervention to improve care. Objective: To investigate the temporal trend in associations of socioeconomic status (SES) with survival among 3 aggressive hematological malignant neoplasms: multiple myeloma (MM), acute myeloid leukemia (AML), and diffuse large B-cell lymphoma (DLBCL). Design, Setting, and Participants: This nationwide, population-based cohort study used retrospectively collected data from 3 clinical registries of patients diagnosed in Denmark between January 1, 2005, and December 31, 2020, with follow-up until December 31, 2021. Analyses were stratified by diagnosis year (2005-2009, 2010-2014, and 2015-2020). Participants were patients aged 25 to 65 years with hematological malignant neoplasms. Patients with missing data on education were excluded. Data were analyzed from October 14, 2022, to January 2, 2024. Exposure: Education was used as a proxy for SES and defined low- and high-SES groups based on the completion of tertiary education. Main Outcomes and Measures: The main outcome was overall survival (OS), analyzed using Kaplan-Meier (log rank) method and Cox proportional hazards regression adjusted for age, sex, performance status, comorbidities, and disease-specific prognostic indices. Two-year OS through time and survival difference were estimated using flexible parametric survival models. Results: A total of 5677 patients (median [IQR] age, 58 [51-62] years; 3177 [57.0%] male) were assessed, including 1826 patients with MM, 1236 patients with AML, and 2509 patients with DLBCL. The 2-year OS increased over time for patients with MM (78.8% [95% CI, 75.4%-82.3%] to 91.4% [95% CI, 89.3%-93.5%]), AML (42.2% [95% CI, 37.8%-47.1%] to 52.7% [95% CI, 48.0%-57.9%]), and DLBCL (80.1% [95% CI, 77.4%-82.8%] to 88.1% [95% CI, 86.0%-90.3%]). For MM and DLBCL, no association of SES with survival was observed after adjustment (MM: hazard ratio [HR], 0.99 [95% CI, 0.85-1.15]; DLBCL: HR, 1.08 [95% CI, 0.91-1.29]). For AML, a negative association was observed between low SES and survival (HR, 1.49 [95% CI, 1.25-1.76]), but the association was attenuated in recent years. The difference in hazard for patients with low SES and AML was observed in the first 2 years after diagnosis. Conclusions and Relevance: These findings suggest that survival has improved among patients with these hematological malignant neoplasms. While patients with MM and DLBCL had increased survival in all groups, disparities were observed in AML outcomes, primarily in the first years after diagnosis. These results suggest that differences originate in factors specific to AML.

A potential link between inflammatory profiles, clinical pain, pain catastrophizing and long-term outcomes after total knee arthroplasty surgery.

BACKGROUND: Chronic postoperative pain after total knee replacement (TKR) is a major clinical problem. It is still unclear if specific inflammatory mediators are associated with long-term postoperative pain complications. The current exploratory study aimed to (1) evaluate a multiplex of inflammatory mediators 5 years after TKR surgery in patients with different degrees of postoperative pain intensities and (2) study any association of the markers with clinical pain intensity, cognitive and functional outcomes. METHODS: Plasma samples were collected 5 years after TKR surgery from 76 knee patients (43 females; 33 males) and analysed for 44 inflammatory markers. Pain (using visual analogue scale, VAS), the pain catastrophizing scale (PCS) and the Oxford knee score (OKS) were evaluated. Patients were categorized as high or low groups based on VAS, PCS and OKS scores. Associations between inflammatory markers, VAS, PCS and OKS were analysed and the marker expressions were compared between groups. RESULTS: Pearson's correlations found 12 biomarkers associated with VAS (p < 0.05), 4 biomarkers with PCS and 3 biomarkers with OKS (p < 0.05). Four markers were altered in patients suffering from high compared to low chronic postoperative pain, three markers were altered in high compared to low catastrophizers and three markers were altered in patients with poor functional scores (p < 0.05). CONCLUSIONS: The present exploratory study suggests that low-grade inflammation might be present in a subset of patients with high pain, high catastrophizing and low function 5 years after TKR. These exploratory results provide insights into some of the long-term postoperative complications after TKR surgery. SIGNIFICANCE STATEMENT: This exploratory study evaluated a subset of inflammatory markers and the association to clinical pain intensity, knee function and pain catastrophizing in patients 5 years after total knee replacement surgery. Our results provide insights into the understanding of the underlying mechanisms that may drive the long experience of pain after TKR surgery.

Inflammatory Polymorphisms (IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252) Are Not Associated with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors.

The aim of this study was to identify the association between four selected inflammatory polymorphisms with the development of long-term post-COVID symptoms in subjects who had been hospitalized due to SARS-CoV-2 infection during the first wave of the pandemic. These polymorphisms were selected as they are associated with severe COVID-19 disease and cytokine storm, so they could be important to prognoses post-COVID. A total of 408 (48.5% female, age: 58.5 ± 14.0 years) previously hospitalized COVID-19 survivors participated. The three potential genotypes of the following four single-nucleotide polymorphisms, IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252, were obtained from non-stimulated saliva samples of the participants. The participants were asked to self-report the presence of any post-COVID symptoms (defined as symptoms that had started no later than one month after SARS-CoV-2 acute infection) and whether the symptoms persisted at the time of the study. At the time of the study (mean: 15.6, SD: 5.6 months after discharge), 89.4% of patients reported at least one post-COVID symptom (mean number of symptoms: 3.0; SD: 1.7). Fatigue (69.3%), pain (40.9%), and memory loss (27.2%) were the most prevalent post-COVID symptoms in the total sample. Overall, no differences in the post-COVID symptoms depending on the IL-6 rs1800796, IL-10 rs1800896, TNF-α rs1800629, and IFITM3 rs12252 genotypes were seen. The four SNPs assessed, albeit having been previously associated with inflammation and COVID-19 severity, did not cause a predisposition to the development of post-COVID symptoms in the previously hospitalized COVID-19 survivors.

Mechanical hyperalgesia and neuropathic pain qualities impart risk for chronic postoperative pain after total knee replacement.

Total knee replacement (TKR) is the gold-standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6, and 12 months post-TKR. We assessed baseline and postoperative (3- and 6-months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM), and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia, and mechanical temporal summation to repeated pinprick stimulation. Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial OA-affected knee and cuff pressure on the ipsilateral calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with baseline KOA pain intensity. Moreover, baseline pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6- and 12-months, respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up, and vice-versa. Our findings suggest that preoperative pinprick hyperalgesia and PainDETECT neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain.

Bridging the translational gap: adenosine as a modulator of neuropathic pain in preclinical models and humans.

OBJECTIVES: This review aims to analyse the published data on preclinical and human experimental and clinical adenosine modulation for pain management. We summarise the translatability of the adenosine pathway for further drug development and aim to reveal subgroups of pain patients that could benefit from targeting the pathway. CONTENT: Chronic pain patients suffer from inadequate treatment options and drug development is generally impaired by the low translatability of preclinical pain models. Therefore, validating the predictability of drug targets is of high importance. Modulation of the endogenous neurotransmitter adenosine gained significant traction in the early 2000s but the drug development efforts were later abandoned. With the emergence of new drug modalities, there is a renewed interest in adenosine modulation in pain management. In both preclinical, human experimental and clinical research, enhancing adenosine signalling through the adenosine receptors, has shown therapeutic promise. A special focus has been on the A1 and A3 receptors both of which have shown great promise and predictive validity in neuropathic pain conditions. SUMMARY: Adenosine modulation shows predictive validity across preclinical, human experimental and clinical investigations. The most compelling evidence is in the field of neuropathic pain, where adenosine has been found to alleviate hyperexcitability and has the potential to be disease-modifying. OUTLOOK: Adenosine modulation show therapeutic potential in neuropathic pain if selective and safe drugs can be developed. New drug modalities such as RNA therapeutics and cell therapies may provide new options.

Inflammatory biomarkers in patients with painful knee osteoarthritis: exploring the potential link to chronic postoperative pain after total knee arthroplasty-a secondary analysis.

ABSTRACT: Total knee arthroplasty (TKA) is the end-stage treatment of knee osteoarthritis (OA), and approximately 20% of patients experience chronic postoperative pain. Studies indicate that inflammatory biomarkers might be associated with pain in OA and potentially linked to the development of chronic postoperative pain after TKA. This study aimed to (1) evaluate preoperative serum levels of inflammatory biomarkers in patients with OA and healthy control subjects, (2) investigate preoperative differences of inflammatory biomarker profiles in subgroups of patients, and (3) compare subgroups of patients with and without postoperative pain 12 months after surgery. Serum samples from patients with OA scheduled for TKA (n = 127) and healthy participants (n = 39) were analyzed. Patients completed the Knee-injury-and-Osteoarthritis-Outcome-Score (KOOS) questionnaire and rated their clinical pain intensity using a visual analog scale (VAS) before and 12 months after TKA. Hierarchical cluster analysis and Orthogonal Partial Least Squares Discriminant Analysis were used to compare groups (patients vs control subjects) and to identify subgroups of patients in relation to postoperative outcomes. Difference in preoperative and postoperative VAS and KOOS scores were compared across subgroups. Twelve inflammatory markers were differentially expressed in patients when compared with control subjects. Cluster analysis identified 2 subgroups of patients with 23 proteins being significantly different ( P < 0.01). The 12-months postoperative VAS and KOOS scores were significantly different between subgroups of patients ( P < 0.05). This study identified differences in specific inflammatory biomarker profiles when comparing patients with OA and control subjects. Cluster analysis identified 2 subgroups of patients with OA, with one subgroup demonstrating comparatively worse 12-month postoperative pain intensity and function scores.

Mechanisms and treatment of opioid-induced pruritus: Peripheral and central pathways.

BACKGROUND AND OBJECTIVE: Pruritus (also known as itch) is defined as an unpleasant and irritating sensation of the skin that provokes an urge to scratch or rub. It is well known that opioid administration can cause pruritus, which is paradoxical as itch and pain share overlapping sensory pathways. Because opioids inhibit pain but can cause itching. Significant progress has been made to improve our understanding of the fundamental neurobiology of itch; however, much remains unknown about the mechanisms of opioid-induced pruritus. The prevention and treatment of opioid-induced pruritus remains a challenge in the field of pain management. The objective of this narrative review is to present and discuss the current body of literature and summarize the current understanding of the mechanisms underlying opioid-induced pruritus, and its relationship to analgesia, and possible treatment options. RESULTS: The incidence of opioid-induced pruritus differs with different opioids and routes of administration, and the various mechanisms can be broadly divided into peripheral and central. Especially central mechanisms are intricate, even at the level of the spinal dorsal horn. There is evidence that opioid receptor antagonists and mixed agonist and antagonists, especially µ-opioid antagonists and κ-opioid agonists, are effective in relieving opioid-induced pruritus. Various treatments have been used for opioid-induced pruritus; however, most of them are controversial and have conflicting results. CONCLUSION: The use of a multimodal analgesic treatment regimen combined with a mixed antagonist and κ agonists, especially µ-opioid antagonists, and κ-opioid agonists, seems to be the current best treatment modality for the management of opioid-induced pruritus and pain. SIGNIFICANCE: Opioids remain the gold standard for the treatment of moderate to severe acute pain as well as cancer pain. It is well known that opioid-induced pruritus often does not respond to regular antipruritic treatment, thereby posing a challenge to clinicians in the field of pain management. We believe that our review makes a significant contribution to the literature, as studies on the mechanisms of opioid-induced pruritus and effective management strategies are crucial for the management of these patients.

Perioperative Nerve Blockade Reduces Acute Postoperative Pain after Orthognathic Surgery.

Background: The role of perioperative pain management is not only to reduce acute postoperative pain (POP) but also to prevent chronic POP. It would be important to know the usefulness of nerve blockade for perioperative management. However, it has not been extensively studied in orofacial surgery. The objective of the study was to investigate whether perioperative nerve blockade reduces acute POP after orthognathic surgery. Methods: Patients scheduled for orthognathic surgery were retrospectively reviewed ("preblock group": the nerve blockade was performed before emergence from general anesthesia, and "no preblock group": the nerve blockade was not performed before emergence from general anesthesia). The visual analog scale (VAS; 0-100 mm)-POP intensity, the VAS-POP areas under the curves (VASAUCs (mm × day)) in addition to VASAUCs for postoperative hours 6 (VASAUC_6), 12 (VASAUC_12), 18 (VASAUC_18), and 24 (VASAUC_24), the analgesic requirement period (day), and the number of days with pain (day) were analyzed. Data are presented as median (interquartile range) values. Results: Fifty-six patients (preblock group, 22; no preblock group, 34) were included (21 males, 35 females; age: 22.0 [21.0-28.0] years). VASAUC_6, VASAUC_12, VASAUC_18, and VASAUC_24 in the preblock group were significantly smaller than those in the no preblock group (3.5 [2.0-7.2] vs. 7.4 [5.1-10.0], p = 0.0007; 9.5 [6.4-13.7] vs. 15.0 [7.2-22.9], p = 0.042; 15.7 [10.3-23.1] vs. 29.3 [18.9-37.2], p = 0.0002; and 17.6 [12.7-27.2] vs. 39.5 [22.9-46.9], p = 0.001, respectively). There were no significant differences between the 2 groups in VASAUC, the analgesic requirement period, and the number of days with pain (p > 0.05). Conclusions: Perioperative nerve blockade reduces POP after orthognathic surgery, especially for the acute postoperative period.

CRISPR-Cas12a-integrated transgenes in genomic safe harbors retain high expression in human hematopoietic iPSC-derived lineages and primary cells.

Discovery of genomic safe harbor sites (SHSs) is fundamental for multiple transgene integrations, such as reporter genes, chimeric antigen receptors (CARs), and safety switches, which are required for safe cell products for regenerative cell therapies and immunotherapies. Here we identified and characterized potential SHS in human cells. Using the CRISPR-MAD7 system, we integrated transgenes at these sites in induced pluripotent stem cells (iPSCs), primary T and natural killer (NK) cells, and Jurkat cell line, and demonstrated efficient and stable expression at these loci. Subsequently, we validated the differentiation potential of engineered iPSC toward CD34+ hematopoietic stem and progenitor cells (HSPCs), lymphoid progenitor cells (LPCs), and NK cells and showed that transgene expression was perpetuated in these lineages. Finally, we demonstrated that engineered iPSC-derived NK cells retained expression of a non-virally integrated anti-CD19 CAR, suggesting that several of the investigated SHSs can be used to engineer cells for adoptive immunotherapies.

Prognostic Factors for Postoperative Chronic Pain after Knee or Hip Replacement in Patients with Knee or Hip Osteoarthritis: An Umbrella Review.

Knee and hip osteoarthritis are highly prevalent in the older population. Management of osteoarthritis-related pain includes conservative or surgical treatment. Although knee or hip joint replacement is associated with positive outcomes, up to 30% of patients report postoperative pain in the first two years. This study aimed to synthesize current evidence on prognostic factors for predicting postoperative pain after knee or hip replacement. An umbrella review of systematic reviews was conducted to summarize the magnitude and quality of the evidence for prognostic preoperative factors predictive of postoperative chronic pain (>6 months after surgery) in patients who had received knee or hip replacement. Searches were conducted in MEDLINE, CINAHL, PubMed, PEDro, SCOPUS, Cochrane Library, and Web of Science databases from inception up to 5 August 2022 for reviews published in the English language. A narrative synthesis, a risk of bias assessment, and an evaluation of the evidence confidence were performed. Eighteen reviews (nine on knee surgery, four on hip replacement, and seven on both hip/knee replacement) were included. From 44 potential preoperative prognostic factors, just 20 were judged as having high or moderate confidence for robust findings. Race, opioid use, preoperative function, neuropathic pain symptoms, pain catastrophizing, anxiety, other pain sites, fear of movement, social support, preoperative pain, mental health, coping strategies, central sensitization-associated symptoms, and depression had high/moderate confidence for an association with postoperative chronic pain. Some comorbidities such as heart disease, stroke, lung disease, nervous system disorders, and poor circulation had high/moderate confidence for no association with postoperative chronic pain. This review has identified multiple preoperative factors (i.e., sociodemographic, clinical, psychological, cognitive) associated with postoperative chronic pain after knee or hip replacement. These factors may be used for identifying individuals at a risk of developing postoperative chronic pain. Further research can investigate the impact of using such prognostic data on treatment decisions and patient outcomes.

Expression of Apelin in Rotator Cuff Tears and Examination of Its Regulatory Mechanism: A Translational Study.

OBJECTIVES: Inflammatory mediators play important roles in the pain associated with rotator cuff tears (RCTs), but their underlying mechanisms are unclear. Apelin, a neuropeptide, is upregulated under inflammatory conditions and possibly contributes to pain induced by rotator cuff tears. This translational study aimed to examine apelin expression and regulation by tumor necrosis factor alpha (TNF-α) in patients with RCT and in rat RCT models. METHODS: Synovial tissues were harvested from the glenohumeral joints of the shoulders in 46 patients who underwent arthroscopic Bankart repair for recurrent shoulder dislocations (RSDs) or arthroscopic rotator cuff repair for RCTs. The harvested tissues were extracted and processed by reverse transcriptase-polymerase chain reaction (RT-PCR). Rats underwent sham or RCT surgery; the rotator cuff tissues were extracted 1, 7, 14, 28, and 56 days after surgery and analyzed for mRNA expression levels of the TNF-α and apelin using RT-PCR. The cultured rotator cuff cells (RCCs) were stimulated with TNF-α to examine their role in the regulation of apelin expression. RESULTS: Apelin expression was higher in the RCT group than in the RSD group and significantly correlated with pain intensity. In rats, the expression was also higher in RCT. Apelin expression significantly increased during the acute and chronic phases in rats. CONCLUSIONS: In cultured RCCs, apelin mRNA levels significantly increased after TNF-α stimulation. Apelin levels were regulated by TNF-α and were highly expressed in patients with RCT and rats in RCT models. Thus, apelin may be a new pain management target for RCTs.