A preliminary investigation of dissociation between subjective cognitive complaints and objective cognitive impairments in female patients with fibromyalgia: a role of information processing speed.

OBJECTIVES: Fibromyalgia (FM) is a chronic condition characterised by widespread pain, and cognitive difficulties represent one of the most common symptoms of FM. However, subjective cognitive complaints (SCC) may not necessarily indicate significant abnormalities in objective cognitive performances, and there is limited research investigating the relationship between these two aspects. This study thus aims to analyse the differences between SCC and objective cognitive performance in FM patients and to explore their associations. METHODS: A total of 32 FM female patients (age: 50.91±7.06; years since diagnosis: 4.34±4.53) recruited in this study underwent a comprehensive assessment covering four domains: pain, depression, trait anxiety, SCC, and objective cognitive functions (memory, executive function, and information processing speed). RESULTS: Eighty-seven percent of patients experienced significant negative impacts from pain; meanwhile, 91% and 62% showed marked tendencies towards trait anxiety and depression, respectively. Additionally, 56% of patients reported significantly higher levels of SCC. However, less than one-third of patients demonstrated impairments in various cognitive functions. SCC significantly correlated with pain intensity, depression, information processing speed, and trait anxiety, with pain intensity being a significant predictor (R2=.30). Furthermore, patients with significant SCC exhibited more abnormalities in pain, information processing speed, and trait anxiety compared to those without significant SCC. CONCLUSIONS: SCC may not necessarily correlate with objective cognitive impairments and might be specifically linked to defective information processing speed. It thus merits that clinical assessments for FM patients should incorporate measurements of information processing speed to gain a comprehensive understanding of SCC in FM patients.

Indigenizing and co-producing the ACGME anesthesiology milestone in Taiwan: a Delphi study and subgroup analysis.

BACKGROUND: To implement the ACGME Anesthesiology Milestone Project in a non-North American context, a process of indigenization is essential. In this study, we aim to explore the differences in perspective toward the anesthesiology competencies among residents and junior and senior visiting staff members and co-produce a preliminary framework for the following nation-wide survey in Taiwan. METHODS: The expert committee translation and Delphi technique were adopted to co-construct an indigenized draft of milestones. Descriptive analysis, chi-square testing, Pearson correlation testing, and repeated-measures analysis of variance in the general linear model were employed to calculate the F values and mean differences (MDs). RESULTS: The translation committee included three experts and the consensus panel recruited 37 participants from four hospitals in Taiwan: 9 residents, 13 junior visiting staff members (JVSs), and 15 senior visiting staff members (SVSs). The consensus on the content of the 285 milestones was achieved after 271 minor and 6 major modifications in 3 rounds of the Delphi survey. Moreover, JVSs were more concerned regarding patient care than were both residents (MD = - 0.095, P < 0.001) and SVSs (MD = 0.075, P < 0.001). Residents were more concerned regarding practice-based learning improvement than were JVSs (MD = 0.081; P < 0.01); they also acknowledged professionalism more than JVSs (MD = 0.072; P < 0.05) and SVSs (MD = 0.12; P < 0.01). Finally, SVSs graded interpersonal and communication skills lower than both residents (MD = 0.068; P < 0.05) and JVSs (MD = 0.065; P < 0.05) did. CONCLUSIONS: Most ACGME anesthesiology milestones are applicable and feasible in Taiwan. Incorporating residents' perspectives may bring insight and facilitate shared understanding to a new educational implementation. This study helped Taiwan generate a well-informed and indigenized draft of a competency-based framework for the following nation-wide Delphi survey.

Lysosomal-targeted doxorubicin delivery using RBC-derived vesicles to overcome drug-resistant cancer through mitochondrial-dependent cell death.

Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Nanoparticles as drug delivery systems (DDSs) show promise for MDR cancer therapy. However, current DDSs require sophisticated design and construction based on xenogeneic nanomaterials, evoking feasibility and biocompatibility concerns. Herein, a simple but versatile biological DDS (bDDS) composed of human red blood cell (RBC)-derived vesicles (RDVs) with excellent biocompatibility was surface-linked with doxorubicin (Dox) using glutaraldehyde (glu) to form Dox-gluRDVs that remarkably suppressed MDR in uterine sarcoma through a lysosomal-mitochondrial axis-dependent cell death mechanism. Dox-gluRDVs can efficiently deliver and accumulate Dox in lysosomes, bypassing drug efflux transporters and facilitating cellular uptake and retention of Dox in drug-resistant MES-SA/Dx5 cells. The transfer of lysosomal calcium to the mitochondria during mitochondria-lysosome contact due to lysosomal Dox accumulation may result in mitochondrial ROS overproduction, mitochondrial membrane potential loss, and activation of apoptotic signaling for the superior anti-MDR activity of Dox-gluRDVs in vitro and in vivo. This work highlights the great promise of RDVs to serve as a bDDS of Dox to overcome MDR cancers but also opens up a reliable strategy for lysosomal-mitochondrial axis-dependent cell death for fighting against other inoperable cancers.

Effects of Goal-Directed Hemodynamic Therapy Using a Noninvasive Finger-Cuff Monitoring Device on Intraoperative Cerebral Oxygenation and Early Delayed Neurocognitive Recovery in Patients Undergoing Beach Chair Position Shoulder Surgery: A Randomized Controlled Trial.

BACKGROUND: Perioperative cerebral desaturation events (CDEs) and delayed neurocognitive recovery are common among patients undergoing beach chair position (BCP) shoulder surgery and may be caused by cerebral hypoperfusion. This study tested the hypothesis that the application of goal-directed hemodynamic therapy (GDHT) would attenuate these conditions. METHODS: We randomly assigned 70 adult patients undergoing BCP shoulder surgery to GDHT group or control at a 1:1 ratio. Cerebral oxygenation was monitored using near-infrared spectroscopy, and GDHT was administered using the ClearSight pulse wave analysis system. The primary outcome was CDE duration, whereas the secondary outcomes were CDE occurrence, delayed neurocognitive recovery occurrence, and Taiwanese version of the Quick Mild Cognitive Impairment (Qmci-TW) test score on the first postoperative day (T 2 ) adjusted for the baseline score (on the day before surgery; T 1 ). RESULTS: CDE duration was significantly shorter in the GDHT group (0 [0-0] vs 15 [0-75] min; median difference [95% confidence interval], -8 [-15 to 0] min; P = .007). Compared with the control group, fewer patients in the GDHT group experienced CDEs (23% vs 51%; relative risk [95% confidence interval], 0.44 [0.22-0.89]; P = .025) and mild delayed neurocognitive recovery (17% vs 40%; relative risk [95% confidence interval], 0.60 [0.39-0.93]; P = .034). The Qmci-TW scores at T 2 adjusted for the baseline scores at T 1 were significantly higher in the GDHT group (difference in means: 4 [0-8]; P = .033). CONCLUSIONS: Implementing GDHT using a noninvasive finger-cuff monitoring device stabilizes intraoperative cerebral oxygenation and is associated with improved early postoperative cognitive scores in patients undergoing BCP shoulder surgery.

Elevated tau and ß-amyloid in the serum of fibromyalgia patients.

OBJECTIVE: Fibromyalgia (FM) is a chronic widespread pain syndrome. Although its mechanism remains relatively unknown, accelerated neurodegeneration in the brain has been reported in patients with FM. Sleep disturbance can increase the risk of neurocognitive disorders, which are associated with tau and beta-amyloid (Aß) protein accumulation. We hypothesize neurodegeneration in patients with FM may be associated with sleep disturbance. METHODS: In this case-control study, we analyzed serum tau and Aß levels and their association with symptom profiles for patients with FM, by recruiting 22 patients with FM and 22 age-matched healthy participants. The visual analog scale, Fibromyalgia Impact Questionnaire, pressure pain threshold test, Pittsburgh Sleep Quality Index (PSQI), Beck Depression Inventory-II, Beck Anxiety Inventory, and serum tau and beta-amyloid-42 (Aß-42) levels were recorded. The Mann-Whitney test was conducted to compare questionnaire and protein level results between the groups. Pearson correlation test was conducted to investigate the correlation of questionnaire scores with tau and Aß-42 levels in patients with FM. The significance level was set at P < .05. RESULTS: Serum tau and Aß-42 levels were significantly higher in patients with FM than in controls. A positive correlation between serum tau levels and PSQI scores was observed in patients with FM (r = 0.476, P = .025). We found that only sleep disturbance in patients with FM was significantly associated with higher serum tau levels among all symptom scores. CONCLUSIONS: We suggest sleep disturbance may play a vital role in the pathomechanism of accelerated neurodegeneration in FM.

Changes in the quick mild cognitive impairment test over time: A normative study in an adult sample in Taiwan.

BACKGROUND: The Quick Mild Cognitive Impairment (Qmci) test has been suggested to be an easy-to-use and precise screening tool for detecting postoperative cognitive dysfunction (POCD). To provide essential information for future POCD studies in Taiwan, the present study provided data regarding the Taiwan version of the Qmci (Qmci-TW) test conducted in the normative Taiwanese population and changes in them over time. METHODS: The present study recruited adult native Taiwanese volunteers without known neurologic or psychiatric diseases. All enrolled participants received protocolized serial Qmci-TW test at baseline, 2-day follow-up, and 6-month follow-up. RESULTS: In total, 30 participants, 15 men and 15 women, were enrolled in this study. The baseline Qmci-TW score ranged from 55 to 80, with a mean of 68.9 and a standard deviation (SD) of 7. At 2-day follow-up, the mean Qmci-TW test score was significantly higher (by 5.3; SD = 7.3) than that at baseline (P = 0.001). At 6-month follow-up, the mean Qmci-TW score was 71.3 (SD = 6.1), with no significant difference compared with that at baseline. The decline in Qmci-TW scores by > 9 points on postoperative day 1 and by > 11 points at 6-month follow-up was the criterion for POCD. CONCLUSION: The present study provided data regarding the Qmci-TW test conducted in the normative Taiwanese population and its time trajectory during the 6-month follow-up.

Solving the deficit of cancer pain management skills by education programs.

BACKGROUND: Suboptimal cancer pain management is a worldwide problem. We examined whether an educational program on cancer pain management implemented during training could benefit primary care physicians. METHODS: We enrolled all the primary care physicians who visited the oncology ward at a medical center for the first time. Educational classes on cancer pain management were conducted. The participants' abilities in cancer pain management were measured in a pretest before the classes and approximately 2 weeks later in the first posttest. The second posttest was conducted on participants who visited the oncology ward again. All 3 tests had the same set of questions and were scored on a scale of 0 to 100. RESULTS: In total, 247 participants were enrolled. Less than 10% of them considered their previous education on cancer pain management adequate. The test scores increased significantly from the pretest to the first posttest (mean 65.6 vs. 89.7, p < 0.001). The participants' self-reported cancer pain management abilities, on a scale of 0 to 100, also improved significantly (mean 57.8 vs. 75.5, p < 0.001). The pretest scores were not associated with the participants' self-reported abilities or their perceptions about the adequacy of previous training on cancer pain management. The mean score on the second posttest, conducted 234.5 days after the program, on an average, remained similar to that of the first posttest (p = 0.254). CONCLUSION: A specific educational program on cancer pain management provided to primary care physicians improved their pain management skills substantially, with persistent effects.

Increasing tramadol utilisation under strict regulatory control of opioid prescribing - A cross-sectional study in Taiwan from 2002 through 2016.

BACKGROUND/PURPOSE: Prescribing of opioids to patients with non-cancer pain is strictly regulated in Taiwan, but tramadol is not included in the regulation on chronic opioid prescribing. This study aims to identify the utilization trend of prescribing tramadol and other opioid analgesics and investigate the influence of government regulation on opioid prescribing in Taiwan. METHODS: This cross-sectional study used the Taiwan National Health Insurance claims database and the cancer registry from 2001 through 2016. The annual number of adult opioid users, opioid utilization (Defined Daily Doses [DDDs]/1000 registrants) and the number of supply days were enumerated for each calendar year and stratified by cancer or non-cancer patients. Descriptive statistics were used to report the trends in utilization for each calendar year. RESULTS: The regulation strictly limited persistent use of opioids for patients with non-cancer pain, of which only a small proportion of fentanyl (20%) and morphine (<2%) users were prescribed with an annual number of supply days greater than 28 days. The annual utilization of morphine (6.4-53.5 vs. 1.1 to 9.6 DDD/1000 registrants) and fentanyl (8.3-37.0 vs. 0.16 to 1.8 DDD/1000 registrants) to patients with cancer was consistently higher than patients without cancer. In contrast to morphine and fentanyl, the utilization of tramadol prescribed to patients without cancer increased 92.2-fold (3.7-341.2 DDD/1000 registrants) from 2002 to 2016. CONCLUSION: The regulation in Taiwan limited the prescribing of selective opioids for patients with non-cancer pain and the substitution of tramadol for other opioids may have safety implications.

Ultrasound-Guided Peripheral Nerve Stimulation for Knee Pain: A Mini-Review of the Neuroanatomy and the Evidence from Clinical Studies.

OBJECTIVES: Peri- and postoperative pain frequently develops after joint replacement for severe knee osteoarthritis. A continuous nerve block is commonly used for pain relief, but the risks of infection and catheter dislodgement should be considered. The present mini-review aimed to brief the innervation and neural sonoanatomy of the knee joint and summarize the newest evidence of peripheral nerve stimulation (PNS) use in the management of knee pain. METHODS: We used a systematic approach to search for relevant articles. We used the combination of "peripheral nerve stimulation" and "knee pain" as the key words for the literature search using the electronic database without language or article type restriction. The search period was from the earliest record to August 2019. RESULTS: The present review identified six studies, four of which were related to PNS for management of postoperative knee pain and two of which probed neuropathic pain. Most of the studies were either case series or case reports. Based on our search result, PNS is likely to be a feasible and safe treatment for knee pain, but its effectiveness remains uncertain. CONCLUSIONS: The present review reveals that PNS is feasible for the management of knee pain, especially in the postoperative period. The procedure is safe under ultrasound guidance used for proper placement of the electrodes near the target nerves. In the future, more prospective randomized controlled trials are needed to validate the effectiveness of PNS in acute and chronic knee pain.

Massively parallel sequencing analysis of nondegraded and degraded DNA mixtures using the ForenSeq™ system in combination with EuroForMix software.

Massively parallel sequencing (MPS) technologies enable the simultaneous analysis of short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs). MPS also enables the detection of alleles of the minor contributors in imbalanced DNA mixtures. In this study, 59 STRs (amelogenin, 27 autosomal STRs, 7 X-STRs, and 24 Y-STRs) and 94 identity-informative SNPs of 119 unrelated Taiwanese (50 men, 69 women) were sequenced using a commercial MPS kit. Forty-eight nondegraded and 44 highly degraded two-person artificial DNA mixtures with various minor to major ratios (1:9, 1:19, 1:29, 1:39, 1:79, and 1:99) were analyzed to examine the performance of this system for detecting the alleles of the minor contributors in DNA mixtures. Likelihood ratios based on continuous model were calculated using the EuroForMix for DNA mixture interpretation. The STR and SNP genotypes of these 119 Taiwanese were obtained. Several sequence variants of STRs were observed. Using EuroForMix software based on the sequence data of autosomal STRs and autosomal SNPs, 97.9% (47/48) and 97.7% (42/43) of minor donors were accurately inferred among the successfully analyzed nondegraded and degraded DNA mixtures, respectively. In conclusion, combined with EuroForMix software, this commercial kit is effective for assignment of the minor contributors in nondegraded and degraded DNA mixtures.

A single nucleotide polymorphism panel for individual identification and ancestry assignment in Caucasians and four East and Southeast Asian populations using a machine learning classifier.

Single nucleotide polymorphism (SNP) profiling is an effective means of individual identification and ancestry inferences in forensic genetics. This study established a SNP panel for the simultaneous individual identification and ancestry assignment of Caucasian and four East and Southeast Asian populations. We analyzed 220 SNPs (125 autosomal, 17 X-chromosomal, 30 Y-chromosomal, and 48 mitochondrial SNPs) of the DNA samples from 563 unrelated individuals of five populations (89 Caucasian, 234 Taiwanese Han, 90 Filipino, 79 Indonesian and 71 Vietnamese) and 18 degraded DNA samples. Informativeness for assignment (In) was used to select ancestry informative SNPs (AISNPs). A machine learning classifier, support vector machine (SVM), was used for ancestry assignment. Of the 220 SNPs, 62 were individual identification SNPs (IISNPs) (51 autosomal and 11 X-chromosomal SNPs) and 191 were AISNPs (100 autosomal, 13 X-chromosomal, 30 Y-chromosomal, and 48 mitochondrial SNPs). The 51 autosomal IISNPs offered cumulative random match probabilities (cRMPs) ranging from 1.56 × 10-21 to 3.16 × 10-22 among these five populations. Using AISNPs with the SVM, the overall accuracy rate of ancestry inference achieved in the testing dataset between Caucasian, Taiwanese Han, and Filipino populations was 88.9%, whereas it was 70.0% between Caucasians and each of the four East and Southeast Asian populations. For the 18 degraded DNA samples with incomplete profiling, the accuracy rate of ancestry assignment was 94.4%. We have developed a 220-SNP panel for simultaneous individual identification and ethnic origin differentiation between Caucasian and the four East and Southeast Asian populations. This SNP panel may assist with DNA analysis of forensic casework.

Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus.

This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human-to-Rodent Studies.

Opioid analgesics remain the most effective and widely used analgesics for the management of moderate to severe pain, including cancer pain and chronic non-cancer pain. However, the efficacy of long-term opioid analgesics is attenuated by tolerance and/or hyperalgesia after long-term use, preventing adequate pain relief under stable opioid dosages for chronic pain patients. Classical neuron-centered concepts about tolerance, such as internalization of opioid receptors, upregulation of N-methyl-D-aspartate receptor function, or downregulation of glutamate transporter activity, can only partially explain the phenomenon of tolerance. Recent evidence revealing glial activation and upregulation of inflammatory mediators in the rodent central nervous system has confirmed the pivotal role of neuroinflammation in neuropathic pain or opioid tolerance, or both. However, human evidence is still sparse.Based on our clinical practice, we conducted translational research by investigating the cerebrospinal fluid (CSF) cytokine and chemokine profiles of opioid-tolerant patients after research ethic committee approval. CSF samples from opioid-tolerant patients and opioid-naive subjects were compared. We found CXCL1, CXCL12, and leukemia inhibitory factor (LIF) were significantly upregulated among the opioid-tolerant patients and positively correlated with the opioid dosage.We translated these findings back to lab animal experiment; after induction of tolerance by morphine infusion, the spinal cord expression of CXCL1, CXCL12, and LIF were all upregulated. Although CXCL1 and CXCL12 infusion alone did not affect baseline tail-flick latency, morphine analgesic efficacy dropped significantly after intrathecal infusion of CXCL1 and CXCL12. After establishing tolerance by intrathecal continuous infusion of morphine, tolerance development was accelerated by co-administration of CXCL1 and CXCL12. In parallel, the effect was attenuated by co-administration of CXCL1- or CXCL12-neutralizing antibody or concordant receptor antagonists.On the contrary, although chronic morphine administration still induced LIF upregulation in rat spinal cords, intrathecal injection of LIF potentiated the analgesic action of morphine and delayed the development of morphine tolerance. Upregulation of endogenously released LIF by long-term use of opioids might counterbalance the tolerance induction effects of other pro-inflammatory cytokines.CXCL1, CXCL12, and LIF are upregulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance were affected by modulating the intrathecal CXCL1/CXCR2, CXCL12/CXCR4, and LIF signaling and could be novel drug targets for the treatment of opioid tolerance.

Right or left? Side selection for a totally implantable vascular access device: a randomised observational study.

BACKGROUND: Totally implantable vascular access device (TIVAD)-related complications interfere in the anticancer treatment and increase medical expenses. We examined whether the implantation side of central line TIVADs is associated with the occurrence of thrombotic or occlusion events. METHODS: We enrolled patients with cancer who required central line TIVADs and randomised them to receive the TIVAD implantation on either the left or right side. The primary endpoint was the occurrence of catheter-related thrombotic or occlusion events. RESULTS: We randomised 240 patients, of which 235 received TIVAD implantation according to the protocol. In the per-protocol cohort, 117 and 118 patients received implantation on the left and right sides, respectively. Catheter-related thrombotic or occlusion events occurred in 9 (4%) patients, accounting for 0.065 events per 1000 catheter-days. Between the patients with left- and right-sided implantations, the occurrence rates (P=0.333) and the time from catheter implantation to the occurrence of thrombotic or occlusion events (P=0.328) were both similar. In the multivariate analysis, the side of implantation remained unassociated with the occurrence of thrombotic or occlusion events. CONCLUSIONS: The side of central line TIVAD implantation was not associated with the occurrence of catheter-related thrombotic or occlusion events in patients with cancer.

Long-term outcomes of totally implantable venous access devices.

PURPOSE: Identifying risk factors for premature totally implantable venous access device (TIVAD) catheter removal is crucial; however, because of the diversity of study methodologies, there is no consensus on such factors. The objective of the present study was to identify such risk factors by applying a cohort design study with a long-term follow-up period. METHODS: For this cohort study, we selected cancer patients who had newly implanted TIVADs between July 2008 and December 2008. The follow-up period lasted until September 2012. Univariate analysis was performed for age, gender, cancer type, TIVAD brand, puncture site, sidedness of puncture, and catheter tip position. The hazard ratio (HR) of potential risk factors was calculated using the Cox proportional hazards regression model, and Kaplan-Meier curves were applied for catheter survival analysis. RESULTS: Our study consisted of 240 people, with 5 people lost to follow-up. The cumulative premature catheter removal rate of all TIVADs was 9.8%, with the most common reason for premature removal being port-associated blood stream infection (PABSI), which proved to be highest in patients with hematology cancer (27.8%) and upper gastrointestinal cancer (19.4%). Suboptimal tip position (HR 5.13, 95% confidence interval 1.73-15.21) was also a risk factor for premature removal, and it was correlated with symptomatic TIVAD occlusion (p = 0.0004). CONCLUSIONS: PABSI was the most common reason for premature catheter removal, with a varied incidence rate between different cancer types. Suboptimal tip position was also a risk factor. Confirming the final tip position after implantation is crucial. Infection control is important for TIVAD care, especially in high-risk cancer patients.

CXCL12/CXCR4 Signaling Contributes to the Pathogenesis of Opioid Tolerance: A Translational Study.

BACKGROUND: Long-term opioid therapy for chronic pain may lead to analgesic tolerance, especially when administered intrathecally, thus preventing adequate pain relief. Discovering drug targets to treat opioid tolerance using a mechanism-based approach targeting opioid-induced neuroinflammation provides new therapeutic opportunities. In this study, we provide translational evidence that CXCL12/CXCR4 signaling contributes to the pathogenesis of opioid tolerance. METHODS: The CXCL12 levels in the cerebrospinal fluid of opioid-tolerant patients were compared with those of opioid-naive subjects. For further investigation, a rodent translational study was designed using 2 clinically relevant opioid delivery paradigms: daily intraperitoneal morphine injections and continuous intrathecal morphine infusion. We measured rats' tail flick responses and calculated the percentage of maximum possible effects (%MPE) to demonstrate opioid acute antinociception and the development of analgesic tolerance. The effects of exogenous CXCL12, CXCL12 neutralizing antibody, and receptor antagonist AMD3100 were investigated by intrathecal administration. Data were presented as mean ± SEM. RESULTS: CXCL12 was significantly upregulated in the cerebrospinal fluid of opioid-tolerant patients for 892 ± 34 pg/mL (n = 27) versus 755 ± 33 pg/mL (n = 10) in naive control subjects (P = .03). Furthermore, after 2 and 5 days of intrathecal morphine infusion, rat lumbar spinal cord dorsal horn CXCL12 messenger RNA levels were significantly upregulated by 3.2 ± 0.7 (P = .016) and 3.4 ± 0.3 (P = .003) fold, respectively. Results from the daily intraperitoneal morphine injection experiments revealed that administering an intrathecal infusion of CXCL12 for 24 hours before the first morphine injection did not decrease antinociception efficacy on day 1 but accelerated tolerance after day 2 (%MPE 49.5% vs 88.1%, P = .0003). In the intrathecal morphine coinfusion experiments, CXCL12 accelerated tolerance development (%MPE 9.4% vs 43.4% on day 1, P < .0001), whereas coadministration with CXCL12 neutralizing antibody attenuated tolerance (72.5% vs 43.4% on day 1, P < .0001; 47.6% vs 17.5% on day 2, P < .0001). Coadministration of receptor antagonist AMD 3100 can persistently preserve morphine analgesic effects throughout the study period (27.9% ± 4.1% vs 0.9% ± 1.6% on day 5, P = .03). CONCLUSIONS: The CXCL12/CXCR4 pathway contributes to the pathogenesis of opioid tolerance. Our study indicates that intervening with CXCL12/CXCR4 signaling has therapeutic potential for opioid tolerance.

A panel of 130 autosomal single-nucleotide polymorphisms for ancestry assignment in five Asian populations and in Caucasians.

Ancestry informative single-nucleotide polymorphism (AISNP) panels for differentiating between East and Southeast Asian populations are scarce. This study aimed to identify AISNPs for ancestry assignment of five East and Southeast Asian populations, and Caucasians. We analyzed 145 autosomal SNPs of the 627 DNA samples from individuals of six populations (234 Taiwanese Han, 91 Filipinos, 79 Indonesians, 60 Thais, 71 Vietnamese, and 92 Caucasians) using arrays. The multiple logistic regression model and a multi-tier approach were used for ancestry classification. We observed that 130 AISNPs were effective for classifying the ethnic origins with fair accuracy. Among the 130 AISNPs, 122 were useful for stratification between these five Asian populations and 64 were effective for differentiating between Caucasians and these Asian populations. For differentiation between Caucasians and Asians, an accuracy rate of 100% was achieved in these 627 subjects with 50 optimal AISNPs among the 64 effective SNPs. For classification of the five Asian populations, the accuracy rates of ancestry inference using 20 to 57 SNPs for each of the two Asian populations ranged from 74.1% to 100%. Another 14 degraded DNA samples with incomplete profiling were analyzed, and the ancestry of 12 (85.7%) of those subjects was accurately assigned. We developed a 130-AISNP panel for ethnic origin differentiation between the five East and Southeast Asian populations and Caucasians. This AISNP set may be helpful for individual ancestral assignment of these populations in forensic casework.

Comparison of the Effectiveness of Suprascapular Nerve Block With Physical Therapy, Placebo, and Intra-Articular Injection in Management of Chronic Shoulder Pain: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: To explore the effectiveness of suprascapular nerve block (SSNB) at different timing after administration compared with physical therapy, placebo, and intra-articular injections in patients with chronic shoulder pain. DATA SOURCE: Two electronic data sources, PubMed and Scopus, were mainly searched from the earliest record to September 2015. STUDY SELECTION: Eleven randomized controlled trials that compared SSNB with physical therapy, placebo, and intra-articular injections were included, comprising 591 patients. DATA EXTRACTION: Patient demographics, regimens for SSNB and intra-articular injections, use of fluoroscopy or ultrasound guidance, conjunction with physical therapy, methods of randomization, and measurements of functional change and pain improvement were retrieved. The standardized mean differences (SMDs) of pain relief and functional improvement were calculated 1, 4, and 12 weeks after intervention. DATA SYNTHESIS: Regarding pain relief, SSNB provided better pain relief for 12 weeks compared with physical therapy (SMD=.75; 95% confidence interval [CI], .35-1.14) and placebo injections (SMD=.70; 95% CI, .40-1.00), but was not superior to intra-articular injections. Differences in patient populations and use of pulsed radiofrequency did not cause a significant variation in therapeutic efficacy, but guidance using ultrasound showed consistently better effectiveness than guidance using surface landmarks and fluoroscopy. CONCLUSIONS: This meta-analysis demonstrated the superiority of SSNB to placebo and physical therapy and a similar efficacy of SSNB compared with intra-articular injection for treatment of chronic shoulder pain. Ultrasound was the most preferable guidance tool, and future studies are advised to integrate physical therapy in order to improve the long-term effectiveness of SSNB.

Fast Track ultrasound protocol to detect acute complications after totally implantable venous access device placement.

BACKGROUND: The role of ultrasound examination in detection of postprocedure complications from totally implantable venous access devices (TIVAD) placement is still uncertain. In a cohort of 665 cancer outpatients, we assessed a quick ultrasound examination protocol in early detection of mechanical complications of catheterization. METHODS: Immediately after TIVAD placement, an ultrasound examination and chest radiography were performed to detect hemothorax, pneumothorax, and catheter malposition. The two methods were compared. RESULTS: Of the 668 catheters inserted, 628 were placed into axillary veins and 40 into internal jugular veins. The ultrasound examination took 2.5 ± 1.1 min. No hemothorax was detected, and neither pneumothorax nor catheter malposition was evident among the 40 internal jugular vein cannulations. Ultrasound and chest radiography examinations of the 628 axillary vein cannulations detected five and four instances of pneumothorax, respectively. Ultrasound detected all six catheter malpositions into the internal jugular vein. However, ultrasound failed to detect two out of three malpositions in the contralateral brachiocephalic vein and one kinking inside the superior vena cava. Without revision surgery, the operating time was 34.1 ± 15.6 min. With revision surgery, the operating time was shorter when ultrasound detected catheter malposition than when chest radiography was used (96.8 ± 12.9 vs. 188.8 ± 10.3 min, p < 0.001). CONCLUSIONS: Postprocedure ultrasound examination is a quick and sensitive method to detect TIVAD-related pneumothorax. It also precisely detects catheter malposition to internal jugular vein thus reduces time needed for revision surgery while chest radiography remains necessary to confirm catheter final position.

Role of spinal CXCL1 (GROα) in opioid tolerance: a human-to-rodent translational study.

BACKGROUND: The pivotal role of glial activation and up-regulated inflammatory mediators in the opioid tolerance has been confirmed in rodents but not yet in humans. Here, the authors investigated the intraspinal cytokine and chemokine profiles of opioid-tolerant cancer patients; and to determine if up-regulated chemokines could modify opioid tolerance in rats. METHODS: Cerebrospinal fluid samples from opioid-tolerant cancer patients and opioid-naive subjects were compared. The cerebrospinal fluid levels of tumor necrosis factor-alpha, CXCL1, CXCL10, CCL2, and CX3CL1 were assayed. The rat tail flick test was utilized to assess the effects of intrathecal CXCL1 on morphine-induced acute antinociception and analgesic tolerance. RESULTS: CXCL1 level in cerebrospinal fluid was significantly up-regulated in the opioid-tolerant group (n = 30, 18.8 pg/ml vs. 13.2 pg/ml, P = 0.02) and was positively correlated (r = 0.49, P < 0.01) with opioid dosage. In rat experiment, after induction of tolerance by morphine infusion, the spinal cord CXCL1 messenger RNA was up-regulated to 32.5 ± 11.9-fold. Although CXCL1 infusion alone did not affect baseline tail-flick latency, the analgesic efficacy of a single intraperitoneal injection of morphine dropped significantly on day 1 to day 3 after intrathecal infusion of CXCL1. After establishing tolerance by intrathecal continuous infusion of morphine, its development was accelerated by coadministration of CXCL1 and attenuated by coadministration of CXCL1-neutralizing antibody or CXCR2 antagonist. CONCLUSIONS: CXCL1 is up-regulated in both opioid-tolerant patients and rodents. The onset and extent of opioid tolerance was affected by antagonizing intrathecal CXCL1/CXCR2 signaling. Therefore, the CXCL1/CXCR2 signal pathway may be a novel target for the treatment of opioid tolerance.