Frailty recommendations and guidelines: an evaluation of the implementability and a critical appraisal of clinical applicability by the ISPRM Frailty Focus Group.

INTRODUCTION: Aging is associated with an increased burden of multi-morbidity and disease related functional loss and disability, widely impacting patients and health care systems. Frailty is a major actor in age-related disability and is an important target for rehabilitation interventions, considering that is a reversible condition. EVIDENCE ACQUISITION: A working group of members of the ISPRM, responding to WHO 2030 call for action to strengthen rehabilitation, was established to assess the quality and implementability of the existing guidelines for the rehabilitation of frailty. Guidelines were retrieved using a systematic search on Pubmed, Scopus and Web of Science and from the reference lists of screened articles. The included guidelines were evaluated using the AGREE II to assess their quality and using the AGREE-REX to assess their clinical credibility and implementability. Guidelines with a score >4 in the AGREE II item evaluating the overall quality of the guideline were considered for endorsement. Finally, nine external reviewers evaluated the applicability of each recommendation from the endorsed guidelines, providing comments about the barriers and facilitators for their implementation in their country. EVIDENCE SYNTHESIS: Ten guidelines were retrieved and evaluated by the working group, of which four guidelines, i.e. the WHO Guidelines on Integrated Care for Older People, the FOCUS guidelines, the Asia-Pacific Clinical Practice Guidelines for the Management of Frailty and the ICFSR International Clinical Practice Guidelines for Identification and Management of Frailty, were considered for endorsement. All these guidelines were rated as of adequate quality and implementability. CONCLUSIONS: The WHO Guidelines on Integrated Care for Older people (24) the ICFSR International Clinical Practice Guidelines for Identification and management of Frailty (15), the FOCUS guidelines (25) and the Asia Pacific Clinical Practice Guidelines (14) for the Management of Frailty have the best quality and applicability of the existing guidelines on the management of frailty, we suggest that should be employed to define the standards of care for patients with frailty. There are barriers for their implementation, as stated by our experts, to take into account, and some of them are country- or region-specific. Screening for frailty, exercise, nutrition, pharmacological management, social and psychological support, management of incontinence, and an overall comprehensive clinical management are the best tools to face upon frailty.

Development of a Dyad-Focused Intervention for Stroke Survivors and Their Family Caregivers: A Feasibility Study.

IMPORTANCE: Transitioning from the hospital to the community poses significant challenges for stroke survivors and their caregivers. OBJECTIVE: To examine the feasibility and preliminary effects of a dyad-focused strategy training intervention. DESIGN: Single-arm trial with data collection at baseline, postintervention, and 3-mo follow-up. SETTING: Rehabilitation settings in Taiwan. PARTICIPANTS: Sixteen stroke survivor-caregiver dyads. INTERVENTIONS: Dyad-focused strategy training was provided to stroke survivor-caregiver dyads twice a week over 6 wk. The training included shared decision-making, goal setting, performance evaluation, strategy development and implementation, and therapeutic guided discovery. OUTCOMES AND MEASURES: Feasibility indicators were Goal Attainment Scaling, Dyadic Relationship Scale, Participation Measure-3 Domains, 4 Dimensions, Activity Measure for Post-Acute Care, Montreal Cognitive Assessment, Trail Making Test, Stroop Color and Word Test, Preparedness for Caregiving Scale, and Zarit Burden Interview. RESULTS: In total, 15 dyads completed all intervention sessions with full attendance. Both stroke survivors and their caregivers demonstrated high engagement and comprehension and reported moderate to high satisfaction with the intervention. From baseline to postintervention, the effects on goal attainment, frequency and perceived difficulty of community participation, executive function, mobility function, and caregiver preparedness were significant and positive. CONCLUSIONS AND RELEVANCE: Our study supports the feasibility and preliminary efficacy of dyad-focused strategy training for stroke survivor-caregiver dyads transitioning from the hospital to the community in Taiwan. Our preliminary evidence indicates that dyads who receive strategy training exhibit advancement toward their goals and experience considerable enhancements in their individual outcomes. Plain-Language Summary: This study addresses the scarcity of interventions catering to both stroke survivors and their caregivers. By demonstrating the feasibility of our dyad-focused intervention, the research offers preliminary evidence that supports the potential advantages of involving both stroke survivors and their caregivers in the intervention process.

A combined circulating microRNA panel predicts the risk of vascular calcification in community-dwelling older adults with age strata differences.

BACKGROUND: Older adults have a higher risk of developing vascular calcification (VC). Circulating miRNAs can be potential risk indicators. However, prior studies used single miRNA mostly, whereas miRNA panels were rarely evaluated. We aimed to examine whether a miRNA panel outperformed each miRNA alone, and analyzed whether advanced age affected VC risk predictive performance offered by the miRNA panel. METHODS: We prospectively enrolled older adults (age ≥65 years) during their annual health checkup in 2017, and examined their VC severity followed by analyzing sera for VC regulatory miRNAs (miR-125b-5p, miR-125b-3p, and miR-378a-3p). We used multiple regression analyses to determine associations between each miRNA or a 3-combind panel and VC risk, followed by area under the receiver-operating-characteristics curve (AUROC) analysis. Participants were further divided to those of 65-75 and ≥75 years for comparison. RESULTS: From 199 older adults screened, 169 (median age, 73.3 years) with available calcification assessment were analyzed, among whom 74.6 % having VC. Those with VC had significantly lower circulating miR-125b-5p, miR-125b-3p, and miR-378a-3p levels than those without. Regression analyses showed that the 3-combined miRNA panel exhibited significant associations with VC risk, with significantly higher AUROC than those of models based on individual miRNA. Importantly, in those ≥75 years, the miRNA-predicted risk of VC was more prominent than that in the 65-75 years group. CONCLUSION: A miRNA panel for VC risk prediction might outperform individual miRNA alone in older adults, and advanced age modified the association between circulating miRNAs and the risk of VC.

Implementing strategy training in Taiwan: perspectives of individuals with Acquired brain injury.

PURPOSE: Strategy training is a rehabilitation intervention that aims to enhance problem-solving skills with respect to daily activity-related challenges and has achieved favorable results in Western countries. This study explored the perspectives of individuals with acquired brain injury (ABI) in Taiwan who received strategy training. MATERIALS AND METHODS: Semi-structured interviews with community-dwelling adults with ABI were conducted, and reflective memos made by research team members were recorded. Interviews and memos were analyzed through thematic analysis. RESULTS: This study included 55 participants. The analysis of the participants' interview responses and memos yielded nine themes under three categories: 1) expectations regarding strategy training, 2) perceived benefits of strategy training, and 3) barriers affecting the process and outcomes of strategy training. CONCLUSIONS: All the participants endorsed strategy training through different gains. Most participants' expectations before the intervention were uncertain. Including family members into the strategy training is of key importance for a successfulness of their goals. The participants' experiences about strategy training were affected by various barriers (i.e., health and medical problems, the physical environment, and natural events). Clinicians and researchers should consider these expectations, benefits, and barriers when studying and implementing strategy training in non-Western contexts.IMPLICATIONS FOR REHABILITATIONStrategy training provides clients the opportunity to actively engage in their own goal setting and decision making.Strategy training increases the client's confidence in their ability to participate in the community, communicate, and perform daily living and physical activities.Therapists should consider the health conditions and physical environment of clients when helping them set goals and before facilitating their engagement in the community.Taiwanese family members play a crucial role in supporting acquired brain injury survivors in strategy training.

Social network associated with depressed mood and sarcopenia among older adults in Taiwan.

BACKGROUND: Social isolation is increasing in aging societies; however, its relationship with depressed mood and sarcopenia is not well studied. This study aims to examine the influence of social network on depressed mood and sarcopenia among community-dwelling older adults in Taiwan. METHODS: We collected data from a sample of 981 older adults residing in the community. These individuals received government-subsidized preventive healthcare services for adults at a district hospital in Taipei in 2021. The social network of the older adults who participated was assessed using the Lubben Social Network Scale, while depressed mood was assessed using the Geriatric Depression Scale. The definition of sarcopenia used in this study was based on the 2019 Asian Working Group for Sarcopenia. RESULTS: According to this study, sarcopenia was present in approximately 15 % of older adults. Multiple logistic regression analysis showed that older adults who had poor social network and did not meet the recommended 150 min of regular physical activity per week were more likely to have depressed mood. Additionally, older adults who were older, underweight, did not engage in regular physical activity, and had poor social network were more likely to have sarcopenia. CONCLUSION: Poor social network was associated with increased risks of depressed mood and sarcopenia among older adults.

Enhanced serum levels of tumor necrosis factor-α, interleukin-1ß, and -6 in sarcopenia: alleviation through exercise and nutrition intervention.

BACKGROUND: Limited research has been conducted on the post-intervention inflammatory status in sarcopenic patients, despite previous studies revealing elevated pro-inflammatory markers. This study aimed to investigate the potential elevation of specific pro-inflammatory cytokines in sarcopenic patients and evaluate the effects of exercise and nutritional support interventions on these cytokine levels. METHODS: In this post-hoc analysis of a randomized controlled trial (RCT), 57 individuals with sarcopenia from the RCT and 57 non-sarcopenic participants from the same geriatric community cohort that did not participate in the RCT were enrolled. Grip strength and body composition measurements were recorded. Tumor necrotizing factor (TNF)-α, interleukin (IL)-1ß, IL-6, and IL-15 levels were assessed at baseline for both groups and after a 12-week intervention consisting of resistive exercise and supplementation with branched-chain amino acids, calcium, and vitamin D3 in the patients with sarcopenia. RESULTS: The sarcopenic group demonstrated significantly lower body weight, body mass index, grip strength, and skeletal muscle mass index. Moreover, sarcopenic patients exhibited higher levels of TNF-α (p=0.007), IL-1ß (p<0.001), and IL-6 (p<0.001), while no significant difference was observed in IL-15 (p=0.345) between participants with and those without sarcopenia. Following the intervention, the sarcopenic group experienced significant improvements in grip strength and skeletal muscle mass index with a notable reduction in TNF-α (p=0.003), IL-1ß (p=0.012) and IL-6 (p=0.001) levels. CONCLUSIONS: Sarcopenic patients exhibit elevated levels of TNF-α, IL-1ß, and IL-6, which declined after nutrition support and exercise interventions. However, further research is necessary to evaluate the long-term impact of these interventions on cytokine levels.

The Influence of Hemoglobin and Swallowing Ability on Daily Living Activities After Hospital Discharge in Taiwanese Stroke Patients: A Longitudinal Study.

OBJECTIVE: This study aimed to examine the mediating effect of swallowing ability on hemoglobin levels and activities of daily living (ADL). DESIGN: Prospective longitudinal study. SETTING: Two rehabilitation wards in a national referral center for Northern Taiwan, followed by discharge. PARTICIPANTS: 101 participants were admitted for first or recurrent infarction or hemorrhagic stroke and transferred to the rehabilitation ward of a medical center (N=101). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Hemoglobin data were collected from medical records. Swallowing ability and ADL were measured using the Functional Oral Intake Scale and Barthel Index, respectively, with higher scores indicating better functioning. RESULTS: Mediation analysis performed using path analysis illustrated that hemoglobin at the time of transfer to the rehabilitation ward had a direct and positive effect on swallowing ability at 1-3 days before discharge (path coefficient=0.21, 95% confidence interval [CI]: 0.04-0.35, P=.018), and swallowing ability at 1-3 days before discharge had a direct and positive effect on ADL at 1 month after discharge (path coefficient=0.36, 95% CI: 0.13-0.57, P=.002). Hemoglobin level at the time of transfer to the rehabilitation ward did not directly influence ADL 1 month after discharge (path coefficient=0.12, 95% CI: -0.05-0.28, P=.166). These results indicate that swallowing ability substantially mediates the relation between previous hemoglobin levels and subsequent ADL. CONCLUSION: Low hemoglobin levels and poor swallowing ability should be concurrently addressed to improve ADL performance.

Acidosis-related pain and its receptors as targets for chronic pain.

Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception.

Involvement of ASIC3 and Substance P in Therapeutic Ultrasound-Mediated Analgesia in Mouse Models of Fibromyalgia.

Therapeutic ultrasound (tUS) is widely used in chronic muscle pain control. However, its analgesic molecular mechanism is still not known. Our objective is to reveal the mechanism of the tUS-induced analgesia in mouse models of fibromyalgia. We applied tUS in mice that have developed chronic hyperalgesia induced by intramuscular acidification and determined the tUS frequency at 3 MHz, dosage at 1 W/cm2 (measured output as 6.3 mW/cm2) and 100% duty cycle for 3 minutes having the best analgesic effect. Pharmacological and genetic approaches were used to probe the molecular determinants involved in tUS-mediated analgesia. A second mouse model of fibromyalgia induced by intermittent cold stress was further used to validate the mechanism underlying the tUS-mediated analgesia. The tUS-mediated analgesia was abolished by a pretreatment of NK1 receptor antagonist-RP-67580 or knockout of substance P (Tac1-/-). Besides, the tUS-mediated analgesia was abolished by ASIC3-selective antagonist APETx2 but not TRPV1-selective antagonist capsazepine, suggesting a role for ASIC3. Moreover, the tUS-mediated analgesia was attenuated by ASIC3-selective nonsteroid anti-inflammation drugs (NSAIDs)-aspirin and diclofenac but not by ASIC1a-selective ibuprofen. We next validated the antinociceptive role of substance P signaling in the model induced by intermittent cold stress, in which tUS-mediated analgesia was abolished in mice lacking substance P, NK1R, Asic1a, Asic2b, or Asic3 gene. tUS treatment could activate ASIC3-containing channels in muscle afferents to release substance P intramuscularly and exert an analgesic effect in mouse models of fibromyalgia. NSAIDs should be cautiously used or avoided in the tUS treatment. PERSPECTIVE: Therapeutic ultrasound showed analgesic effects against chronic mechanical hyperalgesia in the mouse model of fibromyalgia through the signaling pathways involving substance P and ASIC3-containing ion channels in muscle afferents. NSAIDs should be cautiously used during tUS treatment.

Oxidative stress involves phenotype modulation of morbid soreness symptoms in fibromyalgia.

OBJECTIVES: Muscle soreness occurs after exercise and also in musculoskeletal diseases, such as fibromyalgia (FM). However, the nosography and pathoetiology of morbid soreness in FM remain unknown. This study aimed to investigate the morbid soreness of FM, evaluate its therapeutic responses and probe its pathophysiology with metabolomics profiling. METHODS: Patients with newly diagnosed FM were prospectively recruited and completed self-report questionnaires pertaining to musculoskeletal symptoms. The phenotypes and metabotypes were assessed with variance, classification and correlation analyses. RESULTS: Fifty-one patients and 41 healthy controls were included. Soreness symptoms were prevalent in FM individuals (92.2%). In terms of manifestations and metabolomic features, phenotypes diverged between patients with mixed pain and soreness symptoms (FM-PS) and those with pain dominant symptoms. Conventional treatment for FM did not ameliorate soreness severity despite its efficacy on pain. Moreover, despite the salient therapeutic efficacy on pain relief in FM-PS cases, conventional treatment did not improve their general disease severity. Metabolomics analyses suggested oxidative metabolism dysregulation in FM, and high malondialdehyde level indicated excessive oxidative stress in FM individuals as compared with controls (p=0.009). Contrary to exercise-induced soreness, lactate levels were significantly lower in FM individuals than controls, especially in FM-PS. Moreover, FM-PS cases exclusively featured increased malondialdehyde level (p=0.008) and a correlative trend between malondialdehyde expression and soreness intensity (r=0.337, p=0.086). CONCLUSIONS: Morbid soreness symptoms were prevalent in FM, with the presentation and therapeutic responses different from FM pain conditions. Oxidative stress rather than lactate accumulation involved phenotype modulation of the morbid soreness in FM. TRIAL REGISTRATION NUMBER: NCT04832100.

Application of Repetitive Transcranial Magnetic Stimulation in Neuropathic Pain: A Narrative Review.

Neuropathic pain, affecting 6.9-10% of the general population, has a negative impact on patients' quality of life and potentially leads to functional impairment and disability. Repetitive transcranial magnetic stimulation (rTMS)-a safe, indirect and non-invasive technique-has been increasingly applied for treating neuropathic pain. The mechanism underlying rTMS is not yet well understood, and the analgesic effects of rTMS have been inconsistent with respect to different settings/parameters, causing insufficient evidence to determine its efficacy in patients with neuropathic pain. This narrative review aimed to provide an up-to-date overview of rTMS for treating neuropathic pain as well as to summarize the treatment protocols and related adverse effects from existing clinical trials. Current evidence supports the use of 10 Hz HF-rTMS of the primary motor cortex to reduce neuropathic pain, especially in patients with spinal cord injury, diabetic neuropathy and post-herpetic neuralgia. However, the lack of standardized protocols impedes the universal use of rTMS for neuropathic pain. rTMS was hypothesized to achieve analgesic effects by upregulating the pain threshold, inhibiting pain impulse, modulating the brain cortex, altering imbalanced functional connectivity, regulating neurotrophin and increasing endogenous opioid and anti-inflammatory cytokines. Further studies are warranted to explore the differences in the parameters/settings of rTMS for treating neuropathic pain due to different disease types.

Clinical practice guidelines for the prevention and treatment of osteoporosis in Taiwan: 2022 update.

Osteoporosis greatly increases the risk of fractures. Osteoporotic fractures negatively impact quality of life, increase the burden of care, and increase mortality. Taiwan is an area with a high prevalence of osteoporosis. This updated summary of guidelines has been developed by experts of the Taiwan Osteoporosis Association with the intention of reducing the risks of osteoporotic fractures and improving the quality of care for patients with osteoporosis. The updated guidelines compile the latest evidence to provide clinicians and other healthcare professionals with practical recommendations for the prevention, diagnosis, and management of osteoporosis under clinical settings in Taiwan.

Impact of sarcopenia on the prognosis and treatment of lung cancer: an umbrella review.

BACKGROUND: Lung cancer is the leading cause of cancer-related mortality worldwide. Sarcopenia, defined as the loss of muscle mass and function, is known to cause adverse health outcomes. The purpose of this umbrella review was to integrate published systematic reviews and meta-analyses exploring sarcopenia and lung cancer to provide comprehensive knowledge on their relationship. METHODS: Eligible studies were searched from scientific databases until June 28, 2022. Critical appraisal was performed using A Measurement Tool to Assess Systematic Reviews (AMSTAR) 2. The impact of sarcopenia on the pathophysiology, prevalence, and prognosis of lung cancer is summarized at the level of systematic reviews or meta-analyses. RESULTS: Fourteen reviews and meta-analyses were conducted. The methodological quality was high for one review, low for nine, and critically low for four. The most common standard for diagnosing sarcopenia in the lung cancer population is computed tomography (CT) to measure the skeletal muscle index at the third lumbar vertebra (L3). Sarcopenia was highly prevalent among patients with lung cancer, with a pooled prevalence ranging from 42.8% to 45.0%. The association between sarcopenia and increased postoperative complications and decreased disease control rates with immune checkpoint inhibitors has been demonstrated. Mortality was significantly higher in sarcopenic patients than in non-sarcopenic patients with lung cancer, regardless of the stage of disease or type of treatment. CONCLUSIONS: Sarcopenia is a poor prognostic factor for lung cancer. Future studies are necessary to clarify the pathophysiology of sarcopenia and develop effective interventions for sarcopenia in patients with lung cancer.

A multicenter study to compare the effectiveness of the inpatient post acute care program versus traditional rehabilitation for stroke survivors.

There is insufficient evidence to prove the effect of the Post-acute Care (PAC) program on post-stroke recovery. This study aimed to determine the effectiveness of the PAC versus traditional inpatient rehabilitation (non-PAC) for middle- and old-aged stroke survivors. This multicenter cohort study enrolled 334 stroke patients admitted for post-stroke rehabilitation. The outcome variables included the Barthel Index (BI), Functional Oral Intake Scale (FOIS), Mini Nutritional Assessment-Short Form (MNA-SF), EuroQoL-5D (EQ-5D), Lawton-Brody Instrumental Activities of Daily Living (ADL) Scale, and Mini-Mental State Examination (MMSE). The inverse-probability-of-treatment-weighting method was used to analyze the differences in outcomes between the PAC and non-PAC groups. The PAC group showed better improvements in BI, MNA-SF, EQ-5D, Instrumental ADL, and MMSE compared to the non-PAC group, with differences in effect sizes of 0.54 (95% confidence interval [CI] 0.38-0.71), 0.26 (95% CI 0.10-0.42), 0.50 (95% CI 0.33-0.66), 0.44 (95% CI 0.28-0.60) and 0.34 (95% CI 0.17-0.50), respectively. The PAC project showed more improvement in basic and instrumental ADL and status of swallowing, nutrition, and cognition than those of non-PAC, which had less length of stay restricted by the National Health Insurance. More studies are warranted to investigate the influence of hospital stay and duration from stroke onset on the PAC's effectiveness.

Differences in the gut microbiome and reduced fecal butyrate in elders with low skeletal muscle mass.

BACKGROUND AND AIMS: Despite animal studies revealing a causal link between the gut microbiota and skeletal muscle mass, the role of the gut microbiome and its metabolites in humans having low muscle mass remains unclear. METHODS: Eighty-eight subjects older than 65 years were measured for sarcopenia-related parameters, including body composition, grip strength, gait speed and flexibility. Participants were divided into normal muscle mass group (NM, n = 52) and low muscle mass group (LM, n = 36) and fresh fecal samples were collected for metagenome and short chain fatty acids (SCFAs) analysis. RESULTS: The richness and evenness of gut microbiota diversity were significantly decreased in the subjects with low muscle mass, including observed ASVs, Shannon and Chao 1 index. A significant difference of gut microbiota profile was noted between NM group and LM group. The Firmicutes/Bacteroidetes ratio was significantly reduced in the LM group. A significant decrease in the abundance of a SCFA-producer, Marvinbryantia spp., whereas a remarkable enrichment of a flavonoid degrader, Flavonifractor spp., was observed in the LM elders. Comparing with the NM group, the fecal butyrate significantly diminished in the LM group and correlated with skeletal muscle mass index. CONCLUSIONS: This is the first study that demonstrates the reduced fecal butyrate in elders with low muscle mass and highlights the associated gut microbiome changes. The identified gut microbial features and fecal butyrate level may serve as potential biomarkers for early detection of sarcopenic patients.

Ultrasound Imaging of the Facial Muscles and Relevance with Botulinum Toxin Injections: A Pictorial Essay and Narrative Review.

High-resolution ultrasound is preferred as the first-line imaging modality for evaluation of superficial soft tissues, such as the facial muscles. In contrast to magnetic resonance imaging and computed tomography, which require specifically designated planes (axial, coronal and sagittal) for imaging, the ultrasound transducer can be navigated based on the alignment of facial muscles. Botulinum toxin injections are widely used in facial cosmetic procedures in recent times. Ultrasonography is recognized as a useful tool for pre-procedure localization of target muscles. In this pictorial review, we discuss the detailed sonoanatomy of facial muscles and their clinical relevance, particularly with regard to botulinum toxin injections. Furthermore, we have summarized the findings of clinical studies that report ultrasonographic imaging of facial muscles.

Metabolomic and proteomic characterization of sng and pain phenotypes in fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is characterized by chronic widespread pain. Its pathophysiological mechanisms remain poorly understood, and effective diagnosis and treatments are lacking. This study aimed to identify significantly changed biosignatures in FM and propose a novel classification for FM based on pain and soreness (sng) symptoms. METHODS: Urine and serum samples from 30 FM patients and 25 controls underwent metabolomic and proteomic profiling. RESULTS: Compared with controls, FM patients showed significant differential expression of three metabolites in urine and five metabolites and eight proteins in serum. Of them, DETP, 4-guanidinobutanoic acid, SM(d18:1/18:0), PC(20:1(11Z)/18:0), S100A7, SERPINB3, galectin-7 and LYVE1 were first reported as potential biomarkers for FM. Furthermore, lactate, 2-methylmaleate and cotinine in urine and lactate, SM(d18:1/25:1), SM(d18:1/26:1) and prostaglandin D2 (PGD2) and PCYOX1, ITIH4, PFN1, LRG1, C8G, C8A, CP, CDH5 and DBH in serum could differentiate pain- (PG) and sng-dominant groups (SG). Lactate, 2-methylmaleate, cotinine, PCYOX1, ITIH4, PFN1 and DBH have a higher level in SG. SM(d18:1/25:1), SM(d18:1/26:1), PGD2, LRG1, C8G, C8A, CP and CDH5 in SG are lower than PG. The omics results indicated disordered free radical scavenging, and lipid and amino acid metabolism networks and resulting NF-κB-dependent cytokine generation in FM. Lactate level was altered simultaneously in urine and serum and significantly higher in sng-dominant patients than others. CONCLUSIONS: In this study, we identified potential biomarkers from FM patients. The selected biomarkers could discriminate sng and pain phenotypes in FM patients. These results could help elucidate the underlying pathological mechanisms for more effective diagnosis and therapy for FM.

A role for substance P and acid-sensing ion channel 1a in prolotherapy with dextrose-mediated analgesia in a mouse model of chronic muscle pain.

ABSTRACT: Prolotherapy is widely used in pain control and tissue repair in pain medicine. The classical mode is injection with hypertonic dextrose in muscle or perimysium. However, the analgesic mechanism is still not known. Here, we successfully established dextrose-mediated antinociception in a mouse model of fibromyalgia. The antinociceptive effects of dextrose injections were evaluated in a mouse model of fibromyalgia, in which bilateral chronic mechanical hyperalgesia was induced by unilateral intramuscular acid injection. The injectant (dextrose), dose (≥5%), and volume (>10 µL), but not osmolarity, were essential for the prolotherapy. Further studies showed that the activation of acid-sensing ion channel 1a (ASIC1a), neural activation, and the release of substance P from muscle afferents were required in the dextrose-induced reduction of mechanical hypersensitivity. Both pharmacological blockade and genetic deletion of ASIC1a or substance P as well as lidocaine abolished the dextrose-induced antinociception in mice with chronic hyperalgesia. Moreover, intramuscular dextrose injection induced phosphorylated extracellular signal-regulated kinase expression in dorsal root ganglion neurons expressing substance P; the phosphorylated extracellular signal-regulated kinase expression was inhibited by the ASIC1a antagonist PcTx1. The optimal settings for prolotherapy in fibromyalgia-like pain are dextrose dependent and volume dependent, and the peripheral antinociception involves ASIC1a and substance P signaling in muscle afferents. This study suggests a possible mechanism of action of dextrose prolotherapy in noninflammatory muscle pain such as fibromyalgia and provides insights into treating other types of chronic pain.