Effects of ON101 for Hard-to-Heal Diabetic Foot Ulcers in A Randomized Phase III Trial: A Post hoc Analysis.

OBJECTIVE: Hard-to-heal diabetic foot ulcers (DFUs) are associated with higher mortality rates and an increased medical burden for patients. ON101, a new topical cream, exhibited better healing efficacy than the control dressing in a Phase III trial. In this post-hoc analysis, we further identify whether ON101 can improve the healing of ulcers with hard-to-heal risk factors in this cohort of DFU patients. APPROACH: To compare the efficacy of ON101 with absorbent dressing among various hard-to-heal wounds in patients with DFU, a post hoc analysis of a randomized phase III trial included 276 DFU patients was performed by subgrouping those patients based on ulcer depth, location, size, duration, and patients' glycated hemoglobin (HbA1c) levels and body mass index (BMI). RESULTS: In the full analysis set, the proportion of patients achieving healing was 61.7% in the ON101 group and 37.0% in the comparator (P =0.0001). In sub-group analysis according to risk factors, ON101 demonstrated superior healing capacity on Wagner grade 2 ulcers (P < 0.0001); plantar ulcers (P = 0.0016), ulcers size ≥5 cm² (P = 0.0122), ulcers duration ≥3 months (P = 0.0043); for patients with HbA1c ≥9% (P = 0.0285); and patients with BMI ≥25 (P = 0.0005). INNOVATION: ON101, a novel therapeutic drug, can modulate the functions of macrophages and demonstrate superior healing rates to conventional absorbent dressing in patients with hard-to-heal DFUs. CONCLUSIONS: The results of this post hoc study suggest that ON101 is a better therapeutic option than conventional dressing used in treatment for DFU patients with higher HbA1c, BMI, or ulcers with complex conditions such as longer duration, deeper wounds, larger size, and plantar location.

Effects of Human Leukocyte Antigen DRB1 Genetic Polymorphism on Anti-Cyclic Citrullinated Peptide (ANTI-CCP) and Rheumatoid Factor (RF) Expression in Rheumatoid Arthritis (RA) Patients.

Rheumatoid arthritis (RA) is a systemic disease characterized by non-infectious inflammation of the joints and surrounding tissues, which can cause severe health problems, affect the patient's daily life, and even cause death. RA can be clinically diagnosed by the occurrence of blood serological markers, rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (anti-CCP). However, about 20% of RA patients exhibit negative results for both markers, which makes RA diagnosis difficult and, therefore, may delay the effective treatment. Previous studies found some evidence that human leukocyte antigen (HLA)-related genes might be the susceptibility genes for RA and their polymorphisms might contribute to varieties of susceptibility and disease severity. This study aimed for the genetic polymorphisms of the RA patient genome and their effects on the RA patient's serological makers, RF and anti-CCP. A total of 4580 patients' electronic medical records from 1992 to 2020 were retrieved from the China Medical University Hospital database. The most representative single-nucleotide polymorphisms (SNPs) were identified through a genome-wide association study (GWAS) followed by enzyme-linked immunosorbent assay (ELISA) validation using the blood from 30 additional RA patients. The results showed significant changes at the position of chromosome 6 with rs9270481 being the most significant locus, which indicated the location of the HLA-DRB1 gene. Further, patients with the CC genotype at this locus were more likely to exhibit negative results for RF and anti-CCP than those with the TT genotype. The C allele was also more likely to be associated with negative results for RF and anti-CCP. The results demonstrated that a genetic polymorphism at rs9270481 affected the expression of RF and anti-CCP in RA patients, which might indicate the necessity to develop a personalized treatment plan for each individual patient based on the genetic profile.

Antiviral and Immunomodulatory Activities of Clinacanthus nutans (Burm. f.) Lindau.

Clinacanthus nutans (Burm. f.) Lindau has been used as a traditional herbal medicine for treating snake bites, scalds, burns, and viral and bacterial infections. It has been attracting an increasing amount of attention because of its biological activities, including its antidiabetic, antioxidant, antibacterial, anticancer, anti-inflammatory, antiviral, and immunoregulatory activities. Here, we conducted a panoramic survey of the literature regarding the immunoregulatory, anti-inflammatory, and antiviral activities of C. nutans. We discovered that C. nutans extracts have virucidal activities against herpes simplex virus types 1 and 2, varicella-zoster virus, cyprinid herpesvirus 3, porcine reproductive and respiratory syndrome virus, mosquito-borne chikungunya virus, and potentially SARS-CoV-2; such activities likely result from C. nutans interfering with the entry, penetration, infection, and replication of viruses. We also reviewed the phytochemicals in C. nutans extracts that exhibit anti-inflammatory and immunoregulatory activities. This updated review of the antiviral, anti-inflammatory, and immunoregulatory activities of C. nutans may guide future agricultural practices and reveal clinical applications of C. nutans.

Enhancing patient self-management after a first stroke: An application of the wearable devices and the health management platform.

BACKGROUND: Post-stroke disability restricts a patient's physical activity, affects the patient's quality of life, and leads to higher medical costs. Therefore, it is essential to promote patients' continuous exercise during this period of recovery. OBJECTIVE: This study aimed to verify the effectiveness of applying a health management platform combined with wearable devices to enhance stroke patients' self-management of recovery and to allow comparisons with active care intervention management. METHOD: This quasi-experimental study aimed at examining those participants who had sustained a stroke for the first time. A 90-day experiment was implemented with the intervention of monitoring and active care from the researchers who also interviewed the selected participants at the end of the study. A total of 26 participants were examined (14 in the experimental group and 12 in the control group). RESULT: The participants in the experimental group made significant progress between the pre- and post-tests. Firstly, their six-minute walking distance improved by 89.5 m (p < 0.001). Secondly, their sit-to-stand transfers in 60 s improved 2.85 times (p = 0.017), and their Berg balance test improved by 6.36 points (p = 0.003). Finally, the Partners in Health scale (PIH) scores also improved. According to the data collected in the interviews, the researchers' intervention improved the patients' self-management ability. CONCLUSION: The short-term physical performance in the experimental group after the intervention was better than that in the control group. In clinical practice, it is suggested that continuous interaction between medical staff and patients be sustained while applying wearable devices to promote the patient's self-management ability.

Knowledge Sharing Types as Predictors of Job Performance Mediated by Problem-Solving Self-Efficacy in the Information System Integration Service Industry.

Knowledge sharing is an essential approach to creative problem solving in technology firms, but few studies have considered the information system integration service industry. To address this gap, drawing on the micro-ecology theory, we developed a research model to explore the mediating role of four types of knowledge sharing (i.e., automatic response, rational reflection, ridiculed reflection, and stolen reflection) in the relationship between problem solving self-efficacy (PSSE) and IT workers' job performance. Data were collected from 307 System Integration IT workers by using the snowball sampling method via a Google questionnaire. Structural equation modeling was used to test the hypotheses of the relationships between the variables. The results showed that PSSE can positively predict four knowledge sharing types; except for stolen reflection, the others can positively predict job performance. The implication of this study is that automatic response systems and rational reflection systems in knowledge sharing can enhance job performance, supported by PSSE. It is hoped that managers can generate System Integration workers' rational reflection to effectively evoke knowledge sharing.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

Recent Advancement in Anticancer Activity of Clinacanthus nutans (Burm. f.) Lindau.

Clinacanthus nutans is a traditional medicinal herb that is applied for the therapy of snake bites, skin infection, herpes infection, burns, scalds, dysentery, and diabetes. Clinacanthus nutans is also used to treat several cancers, including breast, cervical, colon, gastric, head and neck, liver, lung, pancreatic, and skin cancers, as well as lymphoma and leukemia; however, the underlying mechanisms of its anticancer activity remained undetermined. We searched PubMed and Google with key words "Clinacanthus nutans and cancer" and collected recent papers of Clinacanthus nutans with anticancer activity. We focused on the preparation, effects, and action mechanisms of Clinacanthus nutans extracts on various types of cancers. We hope that this mini review can help update our knowledge about active components, effects, and molecular mechanisms of extracts from this promising herb Clinacanthus nutans for ongoing studies and speed up its clinical application in the future.

Modified Clavien-Dindo Classification and Outcome Prediction in Free Flap Reconstruction among Patients with Head and Neck Cancer.

Because of limitations caused by unique complications of free flap reconstruction, the Clavien-Dindo classification was modified to include grade "IIIc" for "partial or total free flap failure." From 2013 to 2018, 116 patients who had undergone free flap reconstruction for head and neck cancer with grade III or higher postoperative complications were grouped using the "Modified" Clavien-Dindo classification. Alcoholism displayed significant predictive effects between grade IIIb and IIIc (72.7% vs. 50%, p = 0.028). Significant differences were observed between grade IIIb and IIIc in the duration of hospital stay (23.1 ± 10.1 vs. 28.6 ± 11.9 days, p = 0.015), duration of intensive care unit stay (6.0 ± 3.4 vs. 8.7 ± 4.3 days, p = 0.001), reoperation times during the current hospitalization (1.4 ± 0.8 vs. 2.0 ± 1.0 times, p < 0.001), and wound infection rate (29.9% vs. 62.5%, p = 0.002). The severity levels were significantly positively correlated with reoperation times during the current hospitalization (p < 0.001), ICU stay (p = 0.001), and hospital stay (p < 0.001). The modified Clavien-Dindo classification with grade IIIc describes the perioperative complications of head and neck free flap reconstruction to predict clinical outcomes based on severity.

Effects of Casein Kinase 2 Alpha 1 Gene Expression on Mice Liver Susceptible to Type 2 Diabetes Mellitus and Obesity.

Diabetes mellitus (DM) is a chronic disease found worldwide. Notably, BKS.Cg- Dock7m +/+ Leprdb/JNarl mice are useful animal models for studying type 2 diabetes mellitus (T2DM). In this study, we investigated casein kinase 2 alpha 1 (CSNK2A1) gene and protein expression in the liver tissues of mice at different ages (4, 16, and 32 weeks) using real-time quantitative polymerase chain reactions, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay. Our data paved the way for exploring BKS.Cg- Dock7m +/+ Leprdb/JNarl in the mouse model by demonstrating a significant increase in gene and protein expression in T2DM (+Leprdb/+Leprdb) mouse liver when compared to control (+Dock7m/+Dock7m) mouse liver. We also observed that CSNK2A1 protein level in the serum of T2DM patient group was higher than that of the control group, although the data was not statistically significant. Based on our findings, we can now understand the role of CSNK2A1 gene upregulation when encountering T2DM pathologies.

The Associations between Functional Fitness Test Performance and Abdominal Obesity in Healthy Elderly People: Results from the National Physical Fitness Examination Survey in Taiwan.

The relationships between different functional fitness performance and abdominal obesity among the elderly have not been widely discussed in the literature. The present study aimed to investigate the associations between functional fitness test performance and abdominal obesity in Taiwanese elderly people. A total of 22,399 items of data from the National Physical Fitness Survey Databases in Taiwan (NPFSD 2014-15) were reviewed and analyzed. The quartiles of functional fitness test results were identified as the dependent variable in the multiple linear regression analysis to examine the association between functional fitness and abdominal obesity status. The results showed that body balance (odds ratios (ORs) listed from 1.18 to 2.29, p < 0.05) and flexibility (ORs listed from 1.23 to 2.16, p < 0.05) were critically associated with abdominal obesity. However, measurements related to muscle strength revealed the limited effect sizes for abdominal obesity. From a disability prevention perspective, the development of muscle strength in the elderly should be emphasized and encouraged to maintain their daily capabilities instead of satisfaction with a lean body.

Fusarium infection-induced partial failure of free anterolateral thigh musculocutaneous flap: Case report.

Fusarium species, a soil-borne fungi, causes disease in animals and humans, particularly in immunocompromized patients. A 62-year-old male presented with type II diabetes mellitus, diagnosed 4 years ago. He had a motorcycle accident-caused open tibiofibular fracture of the left lower extremity (Gustilo grade IIIb). With open reduction and internal fixation, an anterolateral thigh musculocutaneous flap was harvested for coverage of exposed bone and defect reconstruction. Partial failure of the flap occurred 9 days following reconstruction, and histological examination revealed Fusarium spp. After treatment with antifungal drugs and debridement, we performed a split-thickness skin graft. At 2-year follow-up, the flap was viable with adequate bone union. This is the first reported case of partial flap failure due to a Fusarium spp. infection. Possibility of fungal infections in patients with late-onset flap failure should be noted. Prompt diagnosis and treatment are needed to prevent repeated free-tissue transfer and/or devastating outcomes.

Use of the Ipsilateral Anteromedial Thigh Flap for Immediate Rescue of Nonviable Anterolateral Thigh Flaps in Head and Neck Cancer Reconstruction.

BACKGROUND: It is not always possible to use the anatomically variable free anterolateral thigh (ALT) flap for reconstructive surgery. An anteromedial thigh (AMT) flap serves as a good alternative, and shares the same vascular pedicle as the ALT flap. METHODS: Of 698 reconstructions performed in 2006 to 2013 following head and neck tumor ablation surgery, ALT flaps were used in 653 patients. Eighteen free AMT flaps were harvested to replace variant nonviable ALT flaps. RESULTS: The lack of a sizable perforator in the ALT flap territory was the main reason for changing the reconstruction plan. Anteromedial thigh flap size ranged from 10 × 4 to 30 × 8 cm. The flap survival rate was 100%. The follow-up period ranged from 3 to 56 months. CONCLUSION: During head and neck reconstruction, when no sizable perforator is available during harvest of the ALT flap, successful reconstruction can be achieved using the ipsilateral AMT flap without additional donor-site morbidity.

Rheumatoid arthritis is associated with rs17337023 polymorphism and increased serum level of the EGFR protein.

OBJECTIVE: We have previously described the association of rheumatoid arthritis (RA) prevalence and two epidermal growth factor receptor (EGFR) SNPs (rs17337023 and rs2227983) among the Taiwanese population. This present study aimed to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. METHODS: The cohort study included 366 Taiwan's Han Chinese RA patients and 326 age and gender matched healthy controls. Blood samples collected from the participants were analyzed to determine their serum EGFR levels and to identify EGFR SNPs from their genomic DNA. Genotyping for EGFR SNPs was performed by restriction fragment length polymorphism (RFLP) assay. The relationship between EGFR SNP and the clinical manifestations of RA was evaluated. RESULTS: Our results showed that a statistically significant difference in genotype frequency distributions at rs17337023 SNP for RA patients and controls (p ˂ 0.05). In addition, compared with the haplotype frequencies between case and control groups, the RA patient with the GT haplotype appeared to be a significant "protective" haplotype compared with other haplotypes (OR: 0.73, 95% CI: 0.59-0.91; p = 0.005). Furthermore, the increased serum level of EGFR was also observed in RA patients (p ˂ 0.001). CONCLUSION: Our study showed that RA is associated with rs17337023 SNP in EGFR gene and increased serum level of the EGFR protein. These findings suggest EGFR is worthy of further investigation as a therapeutic target for RA.

Apigenin-induced lysosomal degradation of ß-catenin in Wnt/ß-catenin signaling.

The bioflavonoid apigenin has been shown to possess cancer-preventive and anti-cancer activities. In a drug screening, we found that apigenin can inhibit Wnt/ß-catenin signaling, a pathway that participates in pivotal biological functions, which dis-regulation results in various human diseases including cancers. However, the underlying mechanism of apigenin in this pathway and its link to anti-cancer activities remain largely unknown. Here we showed that apigenin reduced the amount of total, cytoplasmic, and nuclear ß-catenin, leading to the suppression in the ß-catenin/TCF-mediated transcriptional activity, the expression of Wnt target genes, and cell proliferation of Wnt-stimulated P19 cells and Wnt-driven colorectal cancer cells. Western blotting and immunofluorescent staining analyses further revealed that apigenin could induce autophagy-mediated down-regulation of ß-catenin in treated cells. Treatment with autophagy inhibitors wortmannin and chloroquine compromised this effect, substantiating the involvement of autophagy-lysosomal system on the degradation of ß-catenin during Wnt signaling through inhibition of the AKT/mTOR signaling pathway. Our data not only pointed out a route for the inhibition of canonical Wnt signaling through the induction of autophagy-lysosomal degradation of key player ß-catenin, but also suggested that apigenin or other treatments which can initiate this degradation event are potentially used for the therapy of Wnt-related diseases including cancers.

A 'silent' skull metastatic follicular thyroid carcinoma mimicking as a benign scalp tumor in a pregnant woman.

Thyroid cancer with cranial metastasis in a pregnant woman is very rare. In the literature, most cases are diagnosed early from neurogenic signs or symptomatic thyroid gland. Pregnancy also contributes to a hesitation toward early surgical and medical treatments. We reported a scalp tumor in a physically healthy 37-year-old pregnant female with a follicular thyroid carcinoma (FTC) with lung, bone and cranial metastasis in initial presentation. Silent neurogenic and physical examinations make an early diagnosis very challenging. Resection of scalp and intracranial tumor, a thyroidectomy, post-operative radioactive iodine therapy and tyrosine kinase inhibitors were employed as treatment. The scalp tumor was confirmed as a metastatic follicular thyroid carcinoma via positive immunoreactivity for thyroglobulin and thyroid transcription factor 1 in tumor cells. Blood examination revealed an elevated thyroglobulin level (>5335 ng/mL). The patient was discharged without any neurological deficit. An asymptomatic scalp tumor in a pregnant woman with a normal thyroid disease history needs differential diagnosis from intracranial origin. Rapid progression and an elevated thyroglobulin level are the indicators that further image study is needed. Aggressive surgical excision of resectable thyroid gland and metastatic tumor are essential for a longer survival rate. There is nothing to indicate that a post-partum operation will worsen prognosis. LEARNING POINTS: Follicular thyroid cancer with cranial metastasis in initial presentation can be asymptomatic.Follicular thyroid cancer with cranial metastasis in a pregnant woman can be treated after delivery.Rapid enlargement of scalp tumor is indicated for further image study even in a patient without any neurological deficit.

Polymorphism and protein expression of MUTYH gene for risk of rheumatoid arthritis.

BACKGROUND: We have previously described the association between rheumatoid arthritis (RA) prevalence and the two mutY Homolog (E. coli) (MUTYH) SNPs (rs3219463 and rs3219476) among the Taiwanese population. This present study will aim to elucidate whether the SNPs can alter the expression of EGFR in the progression of RA. METHODS: The cohort study included 368 Taiwan's Han Chinese RA patients and 364 healthy controls. Blood samples collected from the participants were analyzed to determine their serum MUTYH levels and to identify rs3219463 SNP of MUTYH from their genomic DNA. RESULTS: Our data resulted in a statistically significant difference in genotype frequency distributions at rs3219463 for RA patients and controls (p < 0.0002). Also, the patients with G carrier at rs3219463 were less likely to suffer from painful joints (p < 0.006) and DAS28 scores (p < 0.003). Furthermore, the increase in serum level of MUTYH was also observed in RA patients (p < 0.005). CONCLUSIONS: Our study showed that RA is associated with rs3219463 SNP in EGFR gene and an increased serum level of the MUTYH protein. These findings suggest MUTYH is worthy of further investigation as a therapeutic target for RA.

Choroid vascular occlusion and ischemic optic neuropathy after facial calcium hydroxyapatite injection- a case report.

BACKGROUND: We reported a case of sudden monocular vision loss after calcium hydroxyapatite (CaHA) injection into the nasal tip and dorsum with detailed retina images. CASE PRESENTATION: A healthy, 35-year-old woman received CaHA filler injection for nose augmentation. Ten minutes after the procedure, she developed nausea, vomiting, headache, ptosis, and left periorbital pain. After 30 minutes, she complained of progressively blurring vision in the left eye. The best-corrected visual acuity (BCVA) in her left eye was 30 cm ahead of hand motion. Left exotropia was noted in primary gaze. Limitations in adduction, supraduction, and infraduction of the left eye were also observed. Slit lamp examination of the left eye revealed a pink conjunctiva, a clear cornea, a mild anterior chamber reaction, a sluggish papillary light reflex, and a semi-dilated pupil. A positive relative afferent pupillary defect was observed in the left eye. Fundus examination revealed optic disc edema and some linear whitish opacity over the superior and temporal sites in the left eye, suggesting multiple CaHA emboli in the choroid vessels. CONCLUSIONS: Although the majority of adverse reactions are mild and transient, surgeons should be alert about extremely rare serious adverse events such as visual loss.

Functional Outcome Analysis After Anterolateral Thigh Flap Reconstruction of Pharyngoesophageal Defect.

BACKGROUND: Pharyngoesophageal defects are traditionally reconstructed with jejunal or radial forearm flaps. Recently, anterolateral thigh flaps have served for pharyngoesophageal reconstruction. We tell of our experience with anterolateral thigh flap for the reconstruction of pharyngoesophageal defect for the past 5 years. This study presents another modified flap design and refinement of surgical techniques. METHODS: In all, 45 pharyngoesophageal reconstructions were performed during 2006 to 2011, namely patch (n = 18), near-circumferential (n = 8), and circumferential defect (n = 19) reconstructed by 2 plastic surgeons with the same trapezoid anterolateral thigh flap design. RESULTS: Total flap loss occurred in 2 patients (4%). Two patients experienced partial flap necrosis. Fistulas occurred in 8 patients, but only 5 of these needed further suture ligation or local flap treatment. Postoperative strictures without tumor recurrence were identified in 4 patients (9%). Forty patients (88.9%) could tolerate oral diet; 34 of these ate soft or solid food. CONCLUSIONS: Anterolateral thigh flap offers good coverage and swallowing function in the reconstruction of hypopharyngeal defect. Trapezoid drawing of anterolateral thigh flap makes the design simplified, with an accepted complication rate.