Agalactosyl IgG induces liver fibrogenesis via Fc gamma receptor 3a on human hepatic stellate cells.

The relevance of aberrant serum IgG N-glycosylation in liver fibrosis has been identified; however, its causal effect remains unclear. Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG N-glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG1 N-glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG1 with agalactosyl N-glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (FcγR) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of FcγRIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast-like morphology, enhanced migration and invasion capabilities, and enhanced expression of the FcγRIIIa downstream tyrosine-protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)-ß1, total collagen, platelet-derived growth factor subunit B and its receptors, pro-collagen I-α1, α-smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed FCGR3A and were reduced in FCGR3A knockout cells. Agalactosyl IgG and TGF-ß1 each increased FCGR3A in HSCs. Furthermore, serum TGF-ß1 concentrations in patients were positively correlated with agalactosyl IgG1 levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC-FcγRIIIa, and TGF-ß1. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through FcγRIIIa. © 2024 The Pathological Society of Great Britain and Ireland.

Membranome-based identification of amino acid substitution in Haemophilus influenzae multidrug efflux pump HmrM for reduced chloramphenicol susceptibility.

A decreased chloramphenicol susceptibility in Haemophilus influenzae is commonly caused by the activity of chloramphenicol acetyltransferases (CATs). However, the involvement of membrane proteins in chloramphenicol susceptibility in H. influenzae remains unclear. In this study, chloramphenicol susceptibility testing, whole-genome sequencing, and analyses of membrane-related genes were performed in 51 H. influenzae isolates. Functional complementation assays and structure-based protein analyses were conducted to assess the effect of proteins with sequence substitutions on the minimum inhibitory concentration (MIC) of chloramphenicol in CAT-negative H. influenzae isolates. Six isolates were resistant to chloramphenicol and positive for type A-2 CATs. Of these isolates, A3256 had a similar level of CAT activity but a higher chloramphenicol MIC relative to the other resistant isolates; it also had 163 specific variations in 58 membrane genes. Regarding the CAT-negative isolates, logistic regression and receiver operator characteristic curve analyses revealed that 48T > G (Asn16Lys), 85 C > T (Leu29Phe), and 88 C > A (Leu30Ile) in HI_0898 (emrA), and 86T > G (Phe29Cys) and 141T > A (Ser47Arg) in HI_1177 (artM) were associated with enhanced chloramphenicol susceptibility, whereas 997G > A (Val333Ile) in HI_1612 (hmrM) was associated with reduced chloramphenicol susceptibility. Furthermore, the chloramphenicol MIC was lower in the CAT-negative isolates with EmrA-Leu29Phe/Leu30Ile or ArtM-Ser47Arg substitution and higher in those with HmrM-Val333Ile substitution, relative to their counterparts. The Val333Ile substitution was associated with enhanced HmrM protein stability and flexibility and increased chloramphenicol MICs in CAT-negative H. influenzae isolates. In conclusion, the substitution in H. influenzae multidrug efflux pump HmrM associated with reduced chloramphenicol susceptibility was characterised.

MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model.

The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both Gq-mediated calcium mobilization and G protein-independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug-evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo-electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design.

Peripheral blood stem cell harvesting in young children weighing less than 15 kg.

Autologous peripheral blood stem cell (PBSC) transplantation is crucial in pediatric cancer treatment, and tandem transplantation is beneficial in certain malignancies. Collecting PBSCs in small children with low body weight is challenging. We retrospectively analyzed data of pediatric cancer patients weighing <15 kg who underwent autologous PBSC harvesting in our hospital. Collections were performed in the pediatric intensive care unit over 2 or 3 consecutive days, to harvest sufficient stem cells (goal ≥2 × 106 CD34+ cells/kg per apheresate). From April 2006 to August 2021, we performed 129 collections after 50 mobilizations in 40 patients, with a median age of 1.9 (range, 0.6-5.6) years and a body weight of 11.0 (range, 6.6-14.7) kg. The median CD34+ cells in each apheresate were 4.2 (range, 0.01-40.13) × 106/kg. 78% and 56% of mobilizations achieved sufficient cell dose for single or tandem transplantation, respectively, without additional aliquoting. The preapheresis hematopoietic progenitor cell (HPC) count was highly correlated with the CD34+ cell yield in the apheresate (r = 0.555, P < 0.001). Granulocyte colony-stimulating factor alone was not effective for mobilization in children ≥2 years of age, even without radiation exposure. By combining the preapheresis HPC count ≥20/µL and the 3 significant host factors, including age <2 years, no radiation exposure and use of chemotherapy, the prediction rate of goal achievement was increased (area under the curve 0.787).

Most total pancreatectomies for ductal adenocarcinoma potentially can Be replaced by whipple over the splenic artery: a before and after study.

INTRODUCTION: Recently, more and more total pancreatectomy (TP) has been performed for central-located pancreatic ductal cell adenocarcinoma (PDCA) which abuts or involves both gastroduodenal and splenic arteries and demands transaction of both of them for a complete resection. Spiked by Warshaw's procedure (spleen-preserving distal pancreatectomy with excision of splenic vessels), we developed a new procedure "Whipple over the splenic artery (WOTSA)" to replace TP by leftward extension of pancreatic parenchyma transaction line and preservation of pancreatic tail and spleen after excision of splenic artery. This uncontrolled before and after study assesses the safety and efficacy of a new technique "Whipple over the splenic artery (WOTSA)" as a treatment for PDAC which traditionally requires total pancreatectomy (TP) for a complete excision. METHODS: The study group comprised 40 consecutive patients who underwent WOTSA for PDAC between August 2019 and September 2022. Their clinicopathological characteristics and survival were compared with those of a historical control group comprising 30 consecutive patients who underwent TP between January 2016 and July 2019. RESULTS: None of the 40 patients in the WOTSA group required reoperation due to infarction of the pancreas and/or spleen remnant. DM medication after WOTSA were none in 19, oral hypoglycemic agents in 19, and insulin preparations in 2 patients. Compared with TP, patients who underwent WOTSA exhibited similar rates of major operative complications, clear pancreatic parenchyma transaction margin, and number of harvested positive lymph nodes, but higher rate of adjuvant chemotherapy completion and a trend toward better median disease free survival (14 vs. 7.5 mo, P=0.023). CONCLUSIONS: Compared to TP, WOTSA can be safely performed and have much better postoperative glycemic status without cost of higher operative risk or impaired surgical radicality. These findings indicate that most TPs for PDAC potentially can be replaced by WOTSAs.

Recovery from antibody-mediated biliary ductopenia and multiorgan inflammation after COVID-19 vaccination.

The coronavirus disease 2019 (COVID-19) pandemic has caused significant morbidity and mortality. Spike messenger RNA (mRNA)-based vaccines against severe acute respiratory syndrome coronavirus 2 may contribute to immune-mediated injuries. Here we present a case of a previously healthy 47-year-old man, who developed progressive jaundice 2 weeks after receiving his 3rd COVID-19 vaccination (1st mRNA-based vaccine). Apart from elevated serum total bilirubin levels (peaked at >70 mg/dL), deteriorating renal (blood urea nitrogen: peak, 108.5 mg/dL; creatinine: peak, 6 mg/dL) and exocrine pancreas (amylase: peak, 1717 U/L; lipase: peak, 5784 U/L) profiles were also seen. Vanishing bile duct syndrome characterized by ductopenia and cholangiocyte vacuolation, positive C4d deposition, and high titer of anti-angiotensin II type 1 receptor antibody consistently explain the overall antibody-mediated pathogenesis resembling antibody-mediated "rejection" in the solid organ transplant setting. Corticosteroids and plasmapheresis were administered, leading to gradual resolution of the symptoms, and the jaundice completely resolved 2 months later. In conclusion, we reported a case of antibody-mediated multiorgan injury after an mRNA COVID-19 vaccine, characterized by severe cholangiopathy. The patient recovered with corticosteroids and plasmapheresis, and long-term follow-up is necessary.

Longitudinal analysis of liver transplant candidates for hepatocellular carcinoma in a single center.

BACKGROUND: Wailitst lost is an critical issue and we investigated the long-term effect of insufficient liver functional reserve at liver transplantation evaluation on waitlist outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Clinical data of patients with HCC waitlisted for liver transplantation were retrospectively collected from a single hospital cohort during the period from 2014 to 2021. Parameters of liver reserve, including cirrhosis, Child-Pugh grade, and Model for End-Stage Liver Disease (MELD) scores, were analyzed for patient survival, after adjustment for tumor factors. RESULTS: Of 292 eligible patients, 94.2% had cirrhosis, 55.8% had Child-Pugh grade B or C, and the median MELD score was 13.2. The median follow-up time was 2.2 years, with a dropout rate of 62.7%. Eighty-nine candidates (30.5%) eventually received liver transplant, including 67 from live donors. The estimated 1-year mortality rate reached 40.6% in 203 patients who remained on the waitlist without receiving a transplant, of whom 143 died. Most deaths were attributed to liver failure (37.1%) and cancer death (35.7%). After we adjusted for tumor confounders, including alpha fetoprotein, primary HCC stage, tumor number at evaluation, and sequential cancer treatment before and while waiting, hazard ratios (HRs) for patient survival were 1.69 (95% confidence interval, 1.18-2.41) for cirrhotic stage B or C, 1.07 (1.04-1.10) for MELD scores, and 1.14 (1.04-1.25) for tumor size at transplant evaluation. Transplantation was a protective disease modifier with adjusted HR 0.22 (0.14-0.33). CONCLUSION: Insufficient liver functional reserve poses more risk than expected to liver transplant waitlist outcomes with HCC.

Targeting Macrophages: Therapeutic Approaches in Diabetic Kidney Disease.

Diabetes is not solely a metabolic disorder but also involves inflammatory processes. The immune response it incites is a primary contributor to damage in target organs. Research indicates that during the initial phases of diabetic nephropathy, macrophages infiltrate the kidneys alongside lymphocytes, initiating a cascade of inflammatory reactions. The interplay between macrophages and other renal cells is pivotal in the advancement of kidney disease within a hyperglycemic milieu. While M1 macrophages react to the inflammatory stimuli induced by elevated glucose levels early in the disease progression, their subsequent transition to M2 macrophages, which possess anti-inflammatory and tissue repair properties, also contributes to fibrosis in the later stages of nephropathy by transforming into myofibroblasts. Comprehending the diverse functions of macrophages in diabetic kidney disease and regulating their activity could offer therapeutic benefits for managing this condition.

Automated liver volumetry and hepatic steatosis quantification with magnetic resonance imaging proton density fat fraction.

BACKGROUND: Preoperative imaging evaluation of liver volume and hepatic steatosis for the donor affects transplantation outcomes. However, computed tomography (CT) for liver volumetry and magnetic resonance spectroscopy (MRS) for hepatic steatosis are time consuming. Therefore, we investigated the correlation of automated 3D-multi-echo-Dixon sequence magnetic resonance imaging (ME-Dixon MRI) and its derived proton density fat fraction (MRI-PDFF) with CT liver volumetry and MRS hepatic steatosis measurements in living liver donors. METHODS: This retrospective cross-sectional study was conducted from December 2017 to November 2022. We enrolled donors who received a dynamic CT scan and an MRI exam within 2 days. First, the CT volumetry was processed semiautomatically using commercial software, and ME-Dixon MRI volumetry was automatically measured using an embedded sequence. Next, the signal intensity of MRI-PDFF volumetric data was correlated with MRS as the gold standard. RESULTS: We included the 165 living donors. The total liver volume of ME-Dixon MRI was significantly correlated with CT (r = 0.913, p < 0.001). The fat percentage measured using MRI-PDFF revealed a strong correlation between automatic segmental volume and MRS (r = 0.705, p < 0.001). Furthermore, the hepatic steatosis group (MRS ≥5%) had a strong correlation than the non-hepatic steatosis group (MRS <5%) in both volumetric (r = 0.906 vs. r = 0.887) and fat fraction analysis (r = 0.779 vs. r = 0.338). CONCLUSION: Automated ME-Dixon MRI liver volumetry and MRI-PDFF were strongly correlated with CT liver volumetry and MRS hepatic steatosis measurements, especially in donors with hepatic steatosis.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical allodynia. The role of skin mechanoreceptors in the development of mechanical allodynia is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin-keratinocyte specific BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.

Risk factors, patterns, and outcome predictors of late recurrence in patients with hepatocellular carcinoma after curative resection: A large cohort study with long-term follow-up results.

BACKGROUND: Late recurrence of hepatocellular carcinoma after curative resection significantly influences long-term patient survival outcomes, and yet it remains understudied. This study aims to explore the risk factors and patterns of late recurrence and predictors of subsequent outcome. METHODS: This single-center retrospective study analyzed 1,701 consecutive patients who achieved a disease-free survival period exceeding 2 years after curative resection for hepatocellular carcinoma between 2001 and 2018. Univariate and multivariate analyses of factors associated with late recurrence and death after recurrence were conducted using Cox's models. RESULTS: The mean age of patients was 60.2 years, with 76.8% being male. During a median follow-up of 8.1 years, 653 patients (38.4%) experienced late recurrence, with median time to recurrence being 4.0 years (interquartile range, 2.7-6.0). Factors such as age >60, chronic hepatitis C, cirrhosis, high albumin-bilirubin grade, absence of family history, multiple tumors, satellite nodules, alpha-fetoprotein levels <400 ng/mL, and minor hepatic resection were identified as risk factors for late recurrence. Among patients with late recurrence, 131 (20.1%) underwent surgical treatment, 272 (41.7%) received radiofrequency ablation, and 27 (4.1%) exhibited extrahepatic lesions. A higher-high albumin-bilirubin grade, recurrent tumor >3 cm, and nonsurgical treatment emerged as predictors of death after late recurrence. CONCLUSION: Over one-third of patients who remain disease-free for more than 2 years postresection will experience late recurrence during subsequent follow-up. For 2-year disease-free survivors, risk factors for late recurrence differ from early recurrence. Treating underlying hepatitis is of paramount importance, given its association with both the risk of late recurrence and survival outcomes post-recurrence.

Uncovering the microbiome landscape in sashimi delicacies.

It is widely believed that a significant portion of the gut microbiota, which play crucial roles in overall health and disease, originates from the food we consume. Sashimi is a type of popular raw seafood cuisine. Its microbiome, however, remained to be thoroughly explored. The objective of this study is to explore the microbiome composition in sashimi at the time when it is served and ready to be eaten. Specifically, our tasks include investigating the diversity and characteristics of microbial profiles in sashimi with respect to the fish types. We utilized the Sanger-sequencing based DNA barcoding technology for fish species authentication and next-generation sequencing for sashimi microbiome profiling. We investigated the microbiome profiles of amberjack, cobia, salmon, tuna and tilapia sashimi, which were all identified using the MT-CO1 DNA sequences regardless of their menu offering names. Chao1 and Shannon indexes, as well as Bray-Curtis dissimilarity index were used to evaluate the alpha and beta diversities of sashimi microbiome. We successfully validated our previous observation that tilapia sashimi has a significantly higher proportions of Pseudomonas compared to other fish sashimi, using independent samples (P = 0.0010). Salmon sashimi exhibited a notably higher Chao1 index in its microbiome in contrast to other fish species (P = 0.0031), indicating a richer and more diverse microbial ecosystem. Non-Metric Multidimensional Scaling (NMDS) based on Bray-Curtis dissimilarity index revealed distinct clusters of microbiome profiles with respect to fish types. Microbiome similarity was notably observed between amberjack and tuna, as well as cobia and salmon. The relationship of microbiome similarity can be depicted as a tree which resembles partly the phylogenetic tree of host species, emphasizing the close relationship between host evolution and microbial composition. Moreover, salmon exhibited a pronounced relative abundance of the Photobacterium genus, significantly surpassing tuna (P = 0.0079), observed consistently across various restaurant sources. In conclusion, microbiome composition of Pseudomonas is significantly higher in tilapia sashimi than in other fish sashimi. Salmon sashimi has the highest diversity of microbiome among all fish sashimi that we analyzed. The level of Photobacterium is significantly higher in salmon than in tuna across all the restaurants we surveyed. These findings provide critical insights into the intricate relationship between the host evolution and the microbial composition. These discoveries deepen our understanding of sashimi microbiota, facilitating our decision in selecting raw seafood.

The Effect of Exercise-Induced Central Fatigue on Cervical Spine Joint Position Error, Strength, and Endurance.

Background: Fatigue is common in sports, impairing performance and increasing injury risk, yet little is known regarding fatigue and concussion. Impaired neck neuromuscular function may contribute to concussion at baseline, where central fatigue may further impair neck function resulting in increased concussion risk. These effects may be magnified in athletes with a history of concussion. Purpose: To determine the effect of exercise induced central fatigue on neck joint position error, strength, and endurance in healthy subjects and those with a history of concussion. The investigators hypothesized that EICF would have a negative effect on all variables. Study Design: Healthy subjects were examined using a single factor, within-subjects repeated measures design. Concussion history subjects were examined using a single-subject design. Methods: Nineteen healthy subjects and five subjects with a history of concussion were recruited for the study. Cervical joint position error, muscle strength, and neck flexor endurance were tested before and after exercise induced fatigue. Results: There was a significant increase in constant (p = 0.0027) and absolute joint position error (JPE) (p < 0.001); decrease in neck flexor endurance (p < 0.001); and decrease neck strength into cervical flexion (p = 0.01) in healthy subjects following fatigue. Among concussion history subjects, five demonstrated a significant increase in absolute and constant JPE (p < 0.05); four demonstrated a significant decrease in neck flexor endurance (p < 0.05); one in neck flexion muscle strength (p < 0.05); and three in neck extension and rotation muscle strength (p < 0.05) following fatigue. Conclusions: Cervical neuromuscular function deteriorated following fatigue in healthy subjects. Resulting impairments may affect force alterations in cervical control, potentially increasing concussion risk. Concussion history subjects descriptively demonstrated similar results, however further research should examine formal comparisons involving subjects with and without concussion history. Level of Evidence: 3b.

What Is Hot and New in Basic and Translational Science in Liver Transplantation in 2023? Report of the Basic and Translational Research Committee of the International Liver Transplantation Society.

The 2023 Joint Annual Congress of the International Liver Transplantation Society, European Liver and Intestine Transplant Association, and Liver Intensive Care Group of Europe were held in Rotterdam, the Netherlands, from May 3 to 6, 2023. This year, all speakers were invited to attend the Congress in person for the first time since the COVID-19 pandemic. The congress was attended by 1159 registered delegates from 54 countries representing 5 continents, with the 10 countries comprising the bulk of the delegates. Of the 647 abstracts initially submitted, 542 were eventually presented at the meeting, coming from 38 countries (mainly North America, Europe, and Asia) and 85% of them (462 abstracts) came from only 10 countries. Fifty-three (9.8%) abstracts, originated from 17 countries, were submitted under the Basic/Translational Scientific Research category, a similar percentage as in 2022. Abstracts presented at the meeting were classified as (1) ischemia and reperfusion injury, (2) machine perfusion, (3) bioengineering and liver regeneration, (4) transplant oncology, (5) novel biomarkers in liver transplantation, (6) liver immunology (rejection and tolerance), and (7) artificial intelligence and machine learning. Finally, we evaluated the number of abstracts commented in the Basic and Translational Research Committee-International Liver Transplantation Society annual reports over the past 5 y that resulted in publications in peer-reviewed journals to measure their scientific impact in the field of liver transplantation.

Exploring the therapeutic potential of DV-B-120 as an inhibitor of dengue virus infection.

Dengue fever, an infectious disease prevalent in subtropical and tropical regions, currently lacks effective small-molecule drugs as treatment. In this study, we used a fluorescence peptide cleavage assay to screen seven compounds to assess their inhibition of the dengue virus (DENV) NS2B-NS3 protease. DV-B-120 demonstrated superior inhibition of NS2B-NS3 protease activity and lower toxicity compared to ARDP0006. The selectivity index of DV-B-120 was higher than that of ARDP0006. In vivo assessments of the antiviral efficacy of DV-B-120 against DENV replication demonstrated delayed mortality of suckling mice treated with the compound, with 60-80% protection against life-threatening effects, compared to the outcomes of DENV-infected mice treated with saline. The lower clinical scores of DENV-infected mice treated with DV-B-120 indicated a reduction in acute-progressive illness symptoms, underscoring the potential therapeutic impact of DV-B-120. Investigations of DV-B-120's ability to restore the antiviral type I IFN response in the brain tissue of DENV-infected ICR suckling mice demonstrated its capacity to stimulate IFN and antiviral IFN-stimulated gene expression. DV-B-120 not only significantly delayed DENV-2-induced mortality and illness symptoms but also reduced viral numbers in the brain, ultimately restoring the innate antiviral response. These findings strongly suggest that DV-B-120 holds promise as a therapeutic agent against DENV infection and highlight its potential contribution in addressing the current lack of effective treatments for this infectious disease.IMPORTANCEThe prevalence of dengue virus (DENV) infection in tropical and subtropical regions is escalating due to factors like climate change and mosquito vector expansion. With over 300 million annual infections and potentially fatal outcomes, the urgent need for effective treatments is evident. While the approved Dengvaxia vaccine has variable efficacy, there are currently no antiviral drugs for DENV. This study explores seven compounds targeting the NS2B-NS3 protease, a crucial protein in DENV replication. These compounds exhibit inhibitory effects on DENV-2 NS2B-NS3, holding promise for disrupting viral replication and preventing severe manifestations. However, further research, including animal testing, is imperative to assess therapeutic efficacy and potential toxicity. Developing safe and potent treatments for DENV infection is critical in addressing the rising global health threat posed by this virus.

Mechanisms of COVID-19-associated olfactory dysfunction.

Olfactory dysfunction is one of the most common symptoms of COVID-19. In the first 2 years of the pandemic, it was frequently reported, although its incidence has significantly decreased with the emergence of the Omicron variant, which has since become the dominant viral strain. Nevertheless, many patients continue to suffer from persistent dysosmia and dysgeusia, making COVID-19-associated olfactory dysfunction an ongoing health concern. The proposed pathogenic mechanisms of COVID-19-associated olfactory dysfunction are complex and likely multifactorial. While evidence suggests that infection of sustentacular cells and associated mucosal inflammation may be the culprit of acute, transient smell loss, alterations in other components of the olfactory system (e.g., olfactory receptor neuron dysfunction, olfactory bulb injury and alterations in the olfactory cortex) may lead to persistent, long-term olfactory dysfunction. This review aims to provide a comprehensive summary of the epidemiology, clinical manifestations and current understanding of the pathogenic mechanisms of COVID-19-associated olfactory dysfunction.

Impact of preoperative factors and waiting time on post-appendectomy complications: a retrospective study.

BACKGROUND: Several factors are associated with increased postoperative complications after appendectomies. However, few studies combined these potential factors for comprehensive prediction of surgical outcomes. Whether high-risk patients benefit from a shorter waiting time for surgery remains unclear. This study aimed to explore the impact of surgical waiting time and potential risk factors on postoperative complications. METHODS: A total of 1343 patients diagnosed with acute appendicitis requiring an emergent appendectomy were included from 2013 to 2018. The preoperative risk factors associated with postoperative complications were selected and the probability of postoperative complications was calculated by multivariate logistic regression model. Patients were divided into four groups based on the risk (high & low) and time to surgery (> 12 & ≤12 hours). The odds ratios for complications were evaluated between groups. RESULTS: The selected risk factors included age, neutrophil-lymphocyte ratio, systemic inflammatory response syndrome and abdominal pain duration. Compared with low-risk patients with time to surgery ≤12 hours, high-risk patients with time to surgery > 12 hours had significant increased overall postoperative complication rate (16.85% vs. 8.16%, p = 0.002) and a trend toward increased surgical site infection rate (10.99% vs. 6.46%, p = 0.058). When operated within 12 hours, there was no difference in outcomes between high- and low-risk patients. On the other hand, time to surgery > 12 hours did not increase complication rate in low-risk patients. CONCLUSIONS: The surgical outcome may be affected by preoperative factors and time to surgery. It is suggested that high-risk patients receive appendectomy within 12 hours to avoid increased postoperative complications.

Anti-inflammatory constituents from a sea anemone-derived fungus Arthrinium arundinis MA30.

In this study, preliminary field-sampling of bioactive fungal strains and bioassay-guided selection were conducted. A number of fungal strains were isolated from sea anemones along the northeastern coast of Badouzi, Keelung, Taiwan. Among them, Arthrinium arundinis MA30 showed significant anti-inflammatory activity and was thus selected for further chemical investigation. After a series of purification and isolation using different chromatographic techniques on the fermented products of A. arundinis MA30, thirty-one compounds were identified, five of which were previously unreported, including arthrinoic acid, hexylaconitic anhydride methyl ester, (3S,8R)-8-hydroxy-3-carboxy-2-methylenenonanoic acid, and arthripenoids G and H. These compounds were subjected to comprehensive spectroscopic data analysis. Of all the isolates, 1,3,5,6-tetrahydroxy-8-methylxanthone and arthripenoid C demonstrated the most distinctive inhibitory activities against nitric oxide production in mouse microglial BV-2 cells, with their respective inhibitory rates being 71% and 81% at 10 µM concentration, and their respective IC50 values were further determined to be 5.3 ± 0.6 and 1.6 ± 0.4 µM. These compounds showed no significant cytotoxicity, and curcumin was used as a positive control in this study.

Skin keratinocyte-derived SIRT1 and BDNF modulate mechanical allodynia in mouse models of diabetic neuropathy.

Diabetic neuropathy is a debilitating disorder characterized by spontaneous and mechanical pain. The role of skin mechanoreceptors in the development of mechanical pain (allodynia) is unclear. We discovered that mice with diabetic neuropathy had decreased sirtuin 1 (SIRT1) deacetylase activity in foot skin, leading to reduced expression of brain-derived neurotrophic factor (BDNF) and subsequent loss of innervation in Meissner corpuscles, a mechanoreceptor expressing the BDNF receptor TrkB. When SIRT1 was depleted from skin, the mechanical allodynia worsened in diabetic neuropathy mice, likely due to retrograde degeneration of the Meissner-corpuscle innervating Aß axons and aberrant formation of Meissner corpuscles which may have increased the mechanosensitivity. The same phenomenon was also noted in skin BDNF knockout mice. Furthermore, overexpression of SIRT1 in skin induced Meissner corpuscle reinnervation and regeneration, resulting in significant improvement of diabetic mechanical allodynia. Overall, the findings suggested that skin-derived SIRT1 and BDNF function in the same pathway in skin sensory apparatus regeneration and highlighted the potential of developing topical SIRT1-activating compounds as a novel treatment for diabetic mechanical allodynia.