Treatment outcome and germline predictive factors of ropeginterferon alpha-2b in myeloproliferative neoplasm patients.

BACKGROUND: Studies have shown that some single nucleotide polymorphisms (SNPs) could serve as excellent markers in foretelling the treatment outcome of interferon (IFN) in myeloproliferative neoplasms (MPN). However, most work originated from western countries, and data from different ethnic populations have been lacking. METHODS: To gain insights, targeted sequencing was performed to detect myeloid-associated mutations and SNPs in eight loci across three genes (IFNL4, IFN-γ, and inosine triphosphate pyrophosphatase [ITPA]) to explore their predictive roles in our cohort of 21 ropeginterferon alpha-2b (ROPEG)-treated MPN patients, among whom real-time quantitative PCR was also performed periodically to monitor the JAK2V617F allele burden in 19 JAK2V617F-mutated cases. RESULTS: ELN response criteria were adopted to designate patients as good responders if they achieved complete hematological responses (CHR) within 1 year (CHR1) or attained major molecular responses (MMR), which occurred in 70% and 45% of the patients, respectively. IFNL4 and IFN-γ gene SNPs were infrequent in our population and were thus excluded from further analysis. Two ITPA SNPs rs6051702 A>C and rs1127354 C>A were associated with an inferior CHR1 rate and MMR rate, respectively. The former seemed to be linked to grade 2 or worse hepatotoxicity as well, although the comparison was of borderline significance only (50%, vs. 6.7% in those with common haplotype, p = 0.053). Twelve patients harbored 19 additional somatic mutations in 12 genes, but the trajectory of these mutations varied considerably and was not predictive of any response. CONCLUSIONS: Overall, this study provided valuable information on the ethnics- and genetics-based algorithm in the treatment of MPN.

Association of JAK2V617F allele burden and clinical correlates in polycythemia vera: a systematic review and meta-analysis.

Janus kinase 2 (JAK2) V617F mutation is present in most patients with polycythemia vera (PV). One persistently puzzling aspect unresolved is the association between JAK2V617F allele burden (also known as variant allele frequency) and the relevant clinical characteristics. Numerous studies have reported associations between allele burden and both hematologic and clinical features. While there are strong indications linking high allele burden in PV patients with symptoms and clinical characteristics, not all associations are definitive, and disparate and contradictory findings have been reported. Hence, this study aimed to synthesize existing data from the literature to better understand the association between JAK2V617F allele burden and relevant clinical correlates. Out of the 1,851 studies identified, 39 studies provided evidence related to the association between JAK2V617F allele burden and clinical correlates, and 21 studies were included in meta-analyses. Meta-analyses of correlation demonstrated that leucocyte and erythrocyte counts were significantly and positively correlated with JAK2V617F allele burden, whereas platelet count was not. Meta-analyses of standardized mean difference demonstrated that leucocyte and hematocrit were significantly higher in patients with higher JAK2V617F allele burden, whereas platelet count was significantly lower. Meta-analyses of odds ratio demonstrated that patients who had higher JAK2V617F allele burden had a significantly greater odds ratio for developing pruritus, splenomegaly, thrombosis, myelofibrosis, and acute myeloid leukemia. Our study integrates data from approximately 5,462 patients, contributing insights into the association between JAK2V617F allele burden and various hematological parameters, symptomatic manifestations, and complications. However, varied methods of data presentation and statistical analyses prevented the execution of high-quality meta-analyses.

Exacerbated gastrointestinal symptoms and long COVID in IBD patients with SARS-CoV-2 infection: A multi-center study from taiwan.

BACKGROUND/PURPOSE: Limited studies have addressed the exacerbation of symptoms and long COVID in inflammatory bowel disease (IBD) patients following non-severe COVID-19 infection, particularly with post-COVID-19 vaccination. We aim to investigate factors associated with exacerbated gastrointestinal symptoms (EGS) and long COVID in IBD patients with non-severe COVID-19, which is most common situation in daily practice. METHODS: This is an observational study by multiple centers in Taiwan from May 2020 to March 2023. We collected clinical manifestation, data, and medication information from IBD patients with non-severe COVID-19. EGS was defined as increased frequency of diarrhea, bloody stool, and abdomen pain within 14 days after SARS-COV-2 infection. Long COVID was defined following the guidelines of the World Health Organization. RESULTS: Out of 90 patients, most of them (88.9%) received at least standard two doses of COVID-19 vaccination and the majority (87.8%) were mild diseases of COVID-19.30% of patients experienced EGS during COVID-19 with higher ESR levels serving as a predictive factor (Odds ratio: 3.6, 95% confidence interval: 1.2-10.5, P = 0.02). 38.1% of those patients developed long COVID. The patients who experienced EGS during COVID-19 and with a history of longer IBD duration showed a significant association with long COVID (p = 0.03 and p = 0.02). CONCLUSIONS: Our study revealed that EGS and long COVID occurred in one third of IBD patients with non-severe COVID-19, even though most of them had received the standard plus booster vaccination. We identified associated factors for EGS and long COVID, emphasizing the importance of post-COVID-19 follow-up in IBD patients.

Correction: Accelerated weight gain, prematurity, and the risk of childhood obesity: A meta-analysis and systematic review.

[This corrects the article DOI: 10.1371/journal.pone.0232238.].

Comparing Surgical Site Infection Rate Between Primary Closure and Rhomboid Flap After Stoma Reversal.

BACKGROUND: Primary closure (PC) is a common wound closure procedure after stoma reversal and is associated with a high rate of surgical site infection (SSI). This study introduced a new method of skin closure, a rhomboid flap (RF), for skin closure after stoma reversal and compared the SSI rate between the 2 techniques. METHODS: This is a single-center retrospective study. Patients who underwent colostomy or ileostomy closure performed using either rotation flap (n = 33) or PC (n = 121) techniques for skin closure after stoma reversal between April 2019 and July 2022 were enrolled in this study. Medical records were retrospectively reviewed to obtain data. Both groups were followed up postoperatively at 1 month for wound infection. Wound infection within 30 days after surgery was indicated by the presence of purulent discharge, erythema, local heat, or positive culture for bacteria. RESULTS: In the PC group, the infection rate was 25.6% (n = 121) compared with 12.1% (n = 33) in the RF group (P = 0.158). Among the patients who underwent colostomy reversal, the infection rate of the RF group was significantly lower compared with that of the PC group (11.1% vs 36.9%, P = 0.045). Among the patients who underwent ileostomy reversal, no significant differences in the infection rates between the groups were found (13.3% vs 12.5%, P = 1.000). CONCLUSIONS: Although the RF technique requires slightly longer operative time for flap design in practice than the linear closure method, the technique can significantly reduce the SSI rate after colostomy reversal through the dissection of the surrounding inflammatory tissues and obliteration of the dead space. Additional studies are required to evaluate this technique, compare it with other existing methods, and explore long-term complications.

Role of proprioceptors in chronic musculoskeletal pain.

Proprioceptors are non-nociceptive low-threshold mechanoreceptors. However, recent studies have shown that proprioceptors are acid-sensitive and express a variety of proton-sensing ion channels and receptors. Accordingly, although proprioceptors are commonly known as mechanosensing neurons that monitor muscle contraction status and body position, they may have a role in the development of pain associated with tissue acidosis. In clinical practice, proprioception training is beneficial for pain relief. Here we summarize the current evidence to sketch a different role of proprioceptors in 'non-nociceptive pain' with a focus on their acid-sensing properties.

Genetic exploration of roles of acid-sensing ion channel subtypes in neurosensory mechanotransduction including proprioception.

Although acid-sensing ion channels (ASICs) are proton-gated ion channels responsible for sensing tissue acidosis, accumulating evidence has shown that ASICs are also involved in neurosensory mechanotransduction. However, in contrast to Piezo ion channels, evidence of ASICs as mechanically gated ion channels has not been found using conventional mechanoclamp approaches. Instead, ASICs are involved in the tether model of mechanotransduction, with the channels gated via tethering elements of extracellular matrix and intracellular cytoskeletons. Methods using substrate deformation-driven neurite stretch and micropipette-guided ultrasound were developed to reveal the roles of ASIC3 and ASIC1a, respectively. Here we summarize the evidence supporting the roles of ASICs in neurosensory mechanotransduction in knockout mouse models of ASIC subtypes and provide insight to further probe their roles in proprioception.

Analgesic Effect of Low-Level Laser Therapy before Heel Lance for Pain Management in Healthy Term Neonates: A Randomized Controlled Trial.

Currently, the prevention, assessment, and management of procedural pain in neonates continues to challenge clinicians and researchers. Objective. To investigate the analgesic effect of low-level laser therapy (LLLT) during heel lance compared to breast milk (BM) feeding in healthy term neonates. In this randomized controlled trial, healthy term neonates who underwent heel lance were randomly assigned to an LLLT or a BM group. The LLLT group received laser therapy to the heel lance site for 20 s before heel lance. The BM group received 5 mL expressed BM via a syringe before heel lance. The primary outcomes were behavioral responses. The secondary outcomes were physiological responses and levels of salivary cortisol and α-amylase. A total of 125 neonates were included, of whom 55 in the LLLT group and 59 in the BM group completed the study. There were no significant differences in latency to first cry and cry duration between the two groups. The squeeze time was significantly shorter in the LLLT group than in the BM group (p = 0.047). There were no significant differences in pain scores, heart rate, respiratory rate, oxygen saturation, and blood pressure before and after heel lance between the two groups. There were no significant differences in salivary cortisol and α-amylase levels in the LLLT group before and after heel lance; however, the differences were significant in the BM group. These findings suggest that the analgesic effect of LLLT is similar to that of BM during heel lance in healthy term neonates. LLLT has potential as an analgesic treatment.

Myalgia! Where does it come from?

Myalgia (also called muscle pain or muscle ache) is a symptom associated with many diseases, including fibromyalgia, neurodegenerative diseases, degenerative spine diseases, etc. Myalgia is a major medical problem affecting 60~85% of the population (lifetime prevalence). However, our understanding of chronic myalgia is still limited and effective treatment for intractable myalgia like fibromyalgia is still lacking. Although multifactorial, one known source of muscle pain is tissue acidosis. Experimental muscle pain can be induced by the intramuscular infusion of a buffered acidic solution in humans. As well, animal studies have revealed that acidic infusion activates chemosensitive nociceptors via the proton-sensing ion channels and receptors. Intriguingly, acid signaling in muscle afferents is promiscuous and could be either pro-nociceptive or antinociceptive, so we have coined the term sngception to describe the somatosensory function of acid sensation. Recent single-cell RNAseq studies have shown proton-sensing ion channels and receptors are expressed in all subpopulations of the somatosensory neurons, including nociceptors and non-nociceptive mechanoreceptors. Here, we address how the acid signaling is integrated in muscle afferents and why muscle pain can be chronic and intractable in mouse models of fibromyalgia. Besides acidosis, we have recently found oxidative stress can be another factor to activate proton-sensing ion channels and thus trigger fibromyalgia-like pain in mice. Together, understanding how the acid signaling works in muscle afferents will provide novel therapeutic strategies for myalgia.

Heart Murmur Classification Using a Capsule Neural Network.

The healthcare industry has made significant progress in the diagnosis of heart conditions due to the use of intelligent detection systems such as electrocardiograms, cardiac ultrasounds, and abnormal sound diagnostics that use artificial intelligence (AI) technology, such as convolutional neural networks (CNNs). Over the past few decades, methods for automated segmentation and classification of heart sounds have been widely studied. In many cases, both experimental and clinical data require electrocardiography (ECG)-labeled phonocardiograms (PCGs) or several feature extraction techniques from the mel-scale frequency cepstral coefficient (MFCC) spectrum of heart sounds to achieve better identification results with AI methods. Without good feature extraction techniques, the CNN may face challenges in classifying the MFCC spectrum of heart sounds. To overcome these limitations, we propose a capsule neural network (CapsNet), which can utilize iterative dynamic routing methods to obtain good combinations for layers in the translational equivariance of MFCC spectrum features, thereby improving the prediction accuracy of heart murmur classification. The 2016 PhysioNet heart sound database was used for training and validating the prediction performance of CapsNet and other CNNs. Then, we collected our own dataset of clinical auscultation scenarios for fine-tuning hyperparameters and testing results. CapsNet demonstrated its feasibility by achieving validation accuracies of 90.29% and 91.67% on the test dataset.

Levels of organophosphate flame retardants and their metabolites among 391 volunteers in Taiwan: difference between adults and children.

Background: Organophosphate flame retardants (OPFRs) are ubiquitous in the environment. The compositions and concentrations of different OPFRs metabolites vary in different environments depending on different human activities. The objective of the present study was to evaluate the exposure of different age groups to OPFRs in Taiwan. Methods: Volunteers provided urine samples and responded to questionnaires including demographic factors, underlying disease, lifestyle information, and occupation from October 2021 to January 2022. OPFR measurements were performed using a Waters Acquity Ultra-Performance Liquid Chromatography system coupled with a Waters Xevo TQ-XS mass spectrometer. Results: A total of 391 volunteers (74 children and 317 adults) were enrolled in this study. The concentrations (presented as µg/g creatinine) of bis(1,3-dichloro-2-propyl) phosphate (BDCPP, p = 0.029) and tri-n-butyl phosphate (TNBP, p = 0.008) were higher in the adult group, while the concentrations of bis-2-chloroethyl phosphate (BCEP, p = 0.024), diphenyl phosphate (DPHP, p < 0.001), tris(1,3-dichloro-2-propyl) phosphate (TDCPP, p = 0.009), and Tris(2-butoxyethyl) phosphate (TBEP, p = 0.007) were higher in the child group. Compared with school age children (>6 years), the concentration of di(2-n-butoxyethyl) phthalate (DBEP, 1.14 vs. 0.20 µg/g creatinine, p = 0.001), DPHP (1.23 vs. 0.54 µg/g creatinine, p = 0.036), TBEP (1.63 vs. 0.29 µg/g creatinine, p < 0.001), and the sum of OPFR metabolites (ΣOPFRs, 6.58 vs. 2.04 µg/g creatinine, p < 0.001) were statistically higher in preschool-aged children. After adjusting for confounding factors, pre-school age [odds ratio (OR): 4.579, 95% confidence interval (CI): 1.389-13.115] and current smoker (OR: 5.328, 95%CI: 1.858-14.955) were independently associated with the risk of ΣOPFRs higher than 90 percentile. Conclusion: This study revealed the distribution of different OPFRs metabolites in children and adults. DBEP, DPHP, TBEP, and ΣOPFR were higher in preschool-aged children. Pre-school age and current smoking status were independent risk factors for ΣOPFRs higher than 90 percentile.

Development of the Chronic Pain Cognition Scale: A Culture-Sensitive Pain Measurement in Chinese.

Purpose: People with pain problems are highly vulnerable to cultural disparities, and it is imperative to reduce these inequalities. This cross-sectional study aimed to develop a culturally sensitive Chronic Pain Cognition Scale (CPCS) for Chinese-/Chinese dialect-speaking populations and investigate its psychometric properties. Patients and Methods: Adult patients with chronic low back pain or chronic neck pain who visited pain clinics at a medical center in northern Taiwan were enrolled. Participants completed the demographic, intensity of pain, and two other related sensations, "Sng ()" and "Ma ()", often reported in Chinese-speaking populations, CPCS, Chronic Pain Acceptance Questionnaire-8, and Pain Self-Efficacy Questionnaire. Results: 200 patients were included. Patients' mean age was 64.84 ± 14.33, 126 (63.0%) were female, and 83 (41.5%) had 13+ years of education. The average duration of pain was 77.25 ± 97.46 months, the intensity of pain was 6.04 ± 2.50, Ma was 3.43 ± 3.24, and Sng was 4.54 ± 3.14. The CPCS comprised four factors: pain impact (how pain impact one's life), losing face (how one being disrespected due to pain), helplessness, and avoidance, with good structural validity and adequate reliability (Cronbach α, 0.60-0.81) and satisfactory criterion-related validity. Moreover, losing face, an essential concept in Chinese relationalism, was significantly related to pain, Sng, and Ma (r = 0.19, 0.15 and 0.16), but not to pain acceptance or self-efficacy, indicating a culturally specific element in pain measurement. Conclusion: The CPCS has good psychometric properties and is suitable for evaluating chronic pain in the clinical setting, and might be generalizable to other Chinese-/Chinese dialect-speaking populations.

Probing the Effect of Acidosis on Tether-Mode Mechanotransduction of Proprioceptors.

Proprioceptors are low-threshold mechanoreceptors involved in perceiving body position and strain bearing. However, the physiological response of proprioceptors to fatigue- and muscle-acidosis-related disturbances remains unknown. Here, we employed whole-cell patch-clamp recordings to probe the effect of mild acidosis on the mechanosensitivity of the proprioceptive neurons of dorsal root ganglia (DRG) in mice. We cultured neurite-bearing parvalbumin-positive (Pv+) DRG neurons on a laminin-coated elastic substrate and examined mechanically activated currents induced through substrate deformation-driven neurite stretch (SDNS). The SDNS-induced inward currents (ISDNS) were indentation depth-dependent and significantly inhibited by mild acidification (pH 7.2~6.8). The acid-inhibiting effect occurred in neurons with an ISDNS sensitive to APETx2 (an ASIC3-selective antagonist) inhibition, but not in those with an ISNDS resistant to APETx2. Detailed subgroup analyses revealed ISDNS was expressed in 59% (25/42) of Parvalbumin-positive (Pv+) DRG neurons, 90% of which were inhibited by APETx2. In contrast, an acid (pH 6.8)-induced current (IAcid) was expressed in 76% (32/42) of Pv+ DRG neurons, 59% (21/32) of which were inhibited by APETx2. Together, ASIC3-containing channels are highly heterogenous and differentially contribute to the ISNDS and IAcid among Pv+ proprioceptors. In conclusion, our findings highlight the importance of ASIC3-containing ion channels in the physiological response of proprioceptors to acidic environments.

The predictive role of platelet count for bleeding in patients with hepatitis B virus and hepatitis C virus infection.

The impact of platelet count on bleeding in hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected patients is unclear. We aimed to evaluate the relationship between platelet count and bleeding in patients with viral hepatitis. We selected patients with HBV and HCV infection. All esophagogastroduodenoscopy, colonoscopy, and brain imaging reports were reviewed to document upper gastrointestinal bleeding (UGIB), lower gastrointestinal bleeding (LGIB), and central nervous system bleeding (CNSB), respectively. We analyzed risk factors for first bleeding events by using Cox proportional hazards models. Incidence rate ratios (IRRs) were used to compare bleeding incidences between viral types and platelet levels. A total of 2522 HCV and 2405 HBV patients were enrolled. The HCV-to-HBV IRRs of UGIB, LGIB, and CNSB were significant at 1.797, 2.255, and 2.071, respectively. The common risk factors in both groups were thrombocytopenia, hypoalbuminemia, high alkaline phosphatase level, and cirrhosis for UGIB, whereas thrombocytopenia and hypoalbuminemia for LGIB. Hypoalbuminemia was the only risk for CNSB. After adjusting platelet count, the higher bleeding rates in the HCV patients diminished. Using a reference platelet count less than 100 x 10 9 /l, bleeding risk elevated at platelet count less than 70 x 10 9 /l and less than 40 x 10 9 /l for UGIB and LGIB in the HCV patients, respectively, compared with less than 60 x 10 9 /l for UGIB in the HBV patients. The incidence of CNSB was not related to platelet levels. HCV patients had a higher risk for major bleeding. Thrombocytopenia was a significant predictor. Monitoring and management of thrombocytopenia in addition to cirrhotic status was important in these patients.

Novel Pulsed Ultrahigh-frequency Spinal Cord Stimulation Inhibits Mechanical Hypersensitivity and Brain Neuronal Activity in Rats after Nerve Injury.

BACKGROUND: Spinal cord stimulation (SCS) is an important pain treatment modality. This study hypothesized that a novel pulsed ultrahigh-frequency spinal cord stimulation (pUHF-SCS) could safely and effectively inhibit spared nerve injury-induced neuropathic pain in rats. METHODS: Epidural pUHF-SCS (± 3V, 2-Hz pulses comprising 500-kHz biphasic sinewaves) was implanted at the thoracic vertebrae (T9 to T11). Local field brain potentials after hind paw stimulation were recorded. Analgesia was evaluated by von Frey-evoked allodynia and acetone-induced cold allodynia. RESULTS: The mechanical withdrawal threshold of the injured paw was 0.91 ± 0.28 g lower than that of the sham surgery (24.9 ± 1.2 g). Applying 5-, 10-, or 20-min pUHF-SCS five times every 2 days significantly increased the paw withdrawal threshold to 13.3 ± 6.5, 18.5 ± 3.6, and 21.0 ± 2.8 g at 5 h post-SCS, respectively (P = 0.0002, < 0.0001, and < 0.0001; n = 6 per group) and to 6.1 ± 2.5, 8.2 ± 2.7, and 14.3 ± 5.9 g on the second day, respectively (P = 0.123, 0.013, and < 0.0001). Acetone-induced paw response numbers decreased from pre-SCS (41 ± 12) to 24 ± 12 and 28 ± 10 (P = 0.006 and 0.027; n = 9) at 1 and 5 h after three rounds of 20-min pUHF-SCS, respectively. The areas under the curve from the C component of the evoked potentials at the left primary somatosensory and anterior cingulate cortices were significantly decreased from pre-SCS (101.3 ± 58.3 and 86.9 ± 25.5, respectively) to 39.7 ± 40.3 and 36.3 ± 20.7 (P = 0.021, and 0.003; n = 5) at 60 min post-SCS, respectively. The intensity thresholds for pUHF-SCS to induce brain and sciatic nerve activations were much higher than the therapeutic intensities and thresholds of conventional low-frequency SCS. CONCLUSIONS: Pulsed ultrahigh-frequency spinal cord stimulation inhibited neuropathic pain-related behavior and paw stimulation evoked brain activation through mechanisms distinct from low-frequency SCS.

Urinary levels of organophosphate flame retardants metabolites in a young population from Southern Taiwan and potential health effects.

Background: Organophosphate flame retardants (OPFRs) are widely distributed in the environment and their metabolites are observed in urine, but little is known regarding OPFRs in a broad-spectrum young population from newborns to those aged 18 years. Objectives: Investigate urinary levels of OPFRs and OPFR metabolites in Taiwanese infants, young children, schoolchildren, and adolescents within the general population. Methods: Different age groups of subjects (n=136) were recruited from southern Taiwan to detect 10 OPFR metabolites in urine samples. Associations between urinary OPFRs and their corresponding metabolites and potential health status were also examined. Results: The mean level of urinary Σ10 OPFR in this broad-spectrum young population is 2.25 µg/L (standard deviation (SD) of 1.91 µg/L). Σ10 OPFR metabolites in urine are 3.25 ± 2.84, 3.06 ± 2.21, 1.75 ± 1.10, and 2.32 ± 2.29 µg/L in the age groups comprising of newborns, 1-5 year-olds, 6-10 year-olds, and 11-18 year-olds, respectively, and borderline significant differences were found in the different age groups (p=0.125). The OPFR metabolites of TCEP, BCEP, DPHP, TBEP, DBEP, and BDCPP predominate in urine and comprise more than 90% of the total. TBEP was highly correlated with DBEP in this population (r=0.845, p<0.001). The estimated daily intake (EDI) of Σ5OPFRs (TDCPP, TCEP, TBEP, TNBP, and TPHP) was 2,230, 461, 130, and 184 ng/kg bw/day for newborns, 1-5 yr children, 6-10 yr children, and 11-17 yr adolescents, respectively. The EDI of Σ5OPFRs for newborns was 4.83-17.2 times higher than the other age groups. Urinary OPFR metabolites are significantly correlated with birth length and chest circumference in newborns. Conclusion: To our knowledge, this is the first investigation of urinary OPFR metabolite levels in a broad-spectrum young population. There tended to be higher exposure rates in both newborns and pre-schoolers, though little is known about their exposure levels or factors leading to exposure in the young population. Further studies should clarify the exposure levels and factor relationships.

The Impact of Human Platelet Antigen Allele on Antiplatelet Antibodies and Cryoglobulins in Patients with Primary Immune Thrombocytopenia and Hepatitis C Virus-Associated Immune Thrombocytopenia.

Background And Objectives: Human platelet antigens (HPAs) are alloantigens associated with antiplatelet alloantibodies and the risk of immune thrombocytopenia (ITP). However, few studies have investigated associations among HPAs, antiplatelet autoantibodies, and cryoglobulins. Methods: We enrolled 43 patients with primary ITP, 47 with hepatitis C virus-associated ITP (HCV-ITP), 21 with hepatitis B virus-associated ITP (HBV-ITP), 25 controls with HCV, and 1013 normal controls. We analyzed HPA allele frequencies, including HPA1-6 and 15, antiplatelet antibodies binding to platelet glycoprotein (GP) IIb/IIIa, Ia/IIa, Ib/IX, IV, human leukocyte antigen class I, cryoglobulin IgG/A/M, and their associations with thrombocytopenia. Results: In the ITP cohort, HPA2ab, rather than HPA2aa, predicted a low platelet count. HPA2b was associated with the risk of developing ITP. HPA15b was correlated with multiple antiplatelet antibodies. In HCV-ITP patients, HPA3b was correlated with anti-GPIIb/IIIa antibodies. HCV-ITP patients with anti-GPIIb/IIIa antibodies had a higher positive rate of cryoglobulin IgG and IgA compared with those without anti-GPIIb/IIIa antibodies. Overlapping detection was also found among other antiplatelet antibodies and cryoglobulins. Like the antiplatelet antibodies, cryoglobulins were associated with clinical thrombocytopenia, implying their close relationship. Finally, we extracted cryoglobulins to confirm the exhibition of cryoglobulin-like antiplatelet antibodies. In contrast, in primary ITP patients, HPA3b was correlated with cryoglobulin IgG/A/M rather than anti-GPIIb/IIIa antibodies. Conclusion: HPA alleles were associated with antiplatelet autoantibodies and had different impacts in primary ITP and HCV-ITP patients. HCV-ITP was considered to be a symptom of mixed cryoglobulinemia in HCV patients. The pathophysiology may differ between these two groups.

Mutation-Driven S100A8 Overexpression Confers Aberrant Phenotypes in Type 1 CALR-Mutated MPN.

Numerous pathogenic CALR exon 9 mutations have been identified in myeloproliferative neoplasms (MPN), with type 1 (52bp deletion; CALRDEL) and type 2 (5bp insertion; CALRINS) being the most prevalent. Despite the universal pathobiology of MPN driven by various CALR mutants, it is unclear why different CALR mutations result in diverse clinical phenotypes. Through RNA sequencing followed by validation at the protein and mRNA levels, we found that S100A8 was specifically enriched in CALRDEL but not in CALRINS MPN-model cells. The expression of S100a8 could be regulated by STAT3 based on luciferase reporter assay complemented with inhibitor treatment. Pyrosequencing demonstrated relative hypomethylation in two CpG sites within the potential pSTAT3-targeting S100a8 promoter region in CALRDEL cells as compared to CALRINS cells, suggesting that distinct epigenetic alteration could factor into the divergent S100A8 levels in these cells. The functional analysis confirmed that S100A8 non-redundantly contributed to accelerated cellular proliferation and reduced apoptosis in CALRDEL cells. Clinical validation showed significantly enhanced S100A8 expression in CALRDEL-mutated MPN patients compared to CALRINS-mutated cases, and thrombocytosis was less prominent in those with S100A8 upregulation. This study provides indispensable insights into how different CALR mutations discrepantly drive the expression of specific genes that contributes to unique phenotypes in MPN.

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.