Factors associated with neurofeedback and mindfulness-based combination therapy for patients with substance use disorder: A multicenter study

Background and objectives Substance use disorder (SUD) has become a major concern in public health globally, and there is an urgent need to develop an integrated psychosocial intervention. The aims of the current study are to test the efficacy of the integrated treatment with neurofeedback and mindfulness-based therapy for SUD and identify the predictors of the efficacy. Methods This study included 110 participants with SUD into the analysis. Outcome of measures includes demographic characteristics, severity of dependence, quality of life, symptoms of depression, and anxiety. Independent t test is used to estimate the change of scores at baseline and three months follow-up. Generalized estimating equations are applied to analyze the effect of predictors on the scores of dependence severity over time by controlling for the effects of demographic characteristics. Results A total of 22 (20 %) participants were comorbid with major mental disorder (MMD). The decrement of the severity in dependence, anxiety, and depression after treatment are identified. Improved scores of qualities of life in generic, psychological, social, and environmental domains are also noticed. After controlling for the effects of demographic characteristics, the predictors of poorer outcome are comorbid with MMD, lower quality of life, and higher level of depression and anxiety. Conclusion The present study implicates the efficacy of integrated therapy. Early identification of predictors is beneficial for healthcare workers to improve the treatment efficacy. (AU)

Association of nirmatrelvir-ritonavir with post-acute sequelae and mortality in patients admitted to hospital with COVID-19: a retrospective cohort study.

BACKGROUND: Studies have established the short-term efficacy of nirmatrelvir-ritonavir in managing COVID-19, yet its effect on post-COVID-19 condition, especially in patients admitted to hospital, remains understudied. This study aimed to examine the effect of nirmatrelvir-ritonavir on post-COVID-19 condition among patients admitted to hospital in Hong Kong. METHODS: This retrospective cohort study used real-world, territory-wide inpatient records, vaccination records, and confirmed COVID-19 case data from the Hong Kong Hospital Authority and Department of Health, The Government of the Hong Kong Special Administrative Region. Patients aged 18 years and older who tested positive for SARS-CoV-2 between March 11, 2022, and Oct 10, 2023, and who were admitted to hospital with COVID-19 were included. The treatment group included patients prescribed nirmatrelvir-ritonavir within 5 days of symptom onset, excluding those prescribed molnupiravir within 21 days, and the control group had no exposure to either nirmatrelvir-ritonavir or molnupiravir. The outcomes were post-acute inpatient death and 13 sequelae (congestive heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, seizure, anxiety, post-traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were evaluated starting at 21 days after the positive RT-PCR date in each respective cohort constructed for the outcome. Standardised mortality ratio weights were applied to balance covariates, and Cox proportional hazards regression was used to investigate the relationship between nirmatrelvir-ritonavir and outcomes. FINDINGS: 136 973 patients were screened for inclusion, among whom 50 055 were eligible and included in the analysis (24 873 [49·7%] were female and 25 182 [50·3%] were male). 15 242 patients were prescribed nirmatrelvir-ritonavir during acute COVID-19 and 23 756 patients were included in the control group; 11 057 patients did not meet our definition for the exposed and unexposed groups. Patients were followed up for a median of 393 days (IQR 317-489). In the nirmatrelvir-ritonavir group compared with the control group, there was a significantly lower hazard of post-acute inpatient death (hazard ratio 0·62 [95% CI 0·57-0·68]; p<0·0001), congestive heart failure (0·70 [0·58-0·85]; p=0·0002), atrial fibrillation (0·63 [0·52-0·76]; p<0·0001), coronary artery disease (0·71 [0·59-0·85]; p=0·0002), chronic pulmonary disease (0·68 [0·54-0·86]; p=0·0011), acute respiratory distress syndrome (0·71 [0·58-0·86]; p=0·0007), interstitial lung disease (0·17 [0·04-0·75]; p=0·020), and end-stage renal disease (0·37 [0·18-0·74]; p=0·0049). There was no evidence indicating difference between the groups in deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis. INTERPRETATION: This study showed extended benefits of nirmatrelvir-ritonavir for reducing the risk of post-acute inpatient death as well as cardiovascular and respiratory complications among patients admitted to hospital with COVID-19. Further research is essential to uncover the underlying mechanisms responsible for these observed negative associations and to devise effective strategies for preventing the onset of post-acute sequelae. FUNDING: Health and Medical Research Fund, Research Grants Council theme-based research schemes, and Research Grants Council Collaborative Research Fund.

Rehabilitation Program for Post-Laryngectomy Patients Following Ileocolon Flap Transfer for Voice Reconstruction--An essential part of success.

BACKGROUND: Speech restoration is important for communication and social activities after pharyngolaryngectomy in head and neck cancer or corrosive injury. Several techniques of voice restoration have been developed to improve life quality. The aim of this paper was to focus on the microsurgical transfer of ileocolon flap and outcome of further voice rehabilitation. PATIENTS AND METHODS: From 2010 to 2022, 69 patients had ileocolon flap at our hospital with postoperative speech training and regular follow-up for over one year. The patients received deglutition training first, followed by voice rehabilitation. Voice outcomes were evaluated at an interval of 3 months and finally at 12 months of voice training rehabilitation. Among other examinations, the speech function was evaluated using a 4-point Likert scale and senior surgeon (HCC) scoring system. RESULTS: The results showed that speech function reached 13.1% of excellent voice, 65.1% of good voice, 13.1% of fair result, and 8.7% of poor result by Likert scales. Meanwhile, the senior surgeon (HCC) score showed 17.4 % of excellent, 63.8% of moderate, and 18.8% of poor results. About voice lab results, maximal phonation time (MPT) was 11.0 sec, and the average number counted in one breath was 15. Loudness and frequency showed 56.0dB and 105.0 Hz respectively. CONCLUSION: The study showed that after voice reconstruction with ileocolon flap followed by the voice rehabilitation program, the patients would have a better understanding of the altered anatomical structures and practice in a more efficient way. Adequate recommendation by the therapists to plastic surgeons for revision surgeries optimized voice function of the patients.

Association between meteorological variations and the superspreading potential of SARS-CoV-2 infections.

BACKGROUND: While many investigations examined the association between environmental covariates and COVID-19 incidence, none have examined their relationship with superspreading, a characteristic describing very few individuals disproportionally infecting a large number of people. METHODS: Contact tracing data of all the laboratory-confirmed COVID-19 cases in Hong Kong from February 16, 2020 to April 30, 2021 were used to form the infection clusters for estimating the time-varying dispersion parameter (kt), a measure of superspreading potential. Generalized additive models with identity link function were used to examine the association between negative-log kt (larger means higher superspreading potential) and the environmental covariates, adjusted with mobility metrics that account for the effect of social distancing measures. RESULTS: A total of 6,645 clusters covering 11,717 cases were reported over the study period. After centering at the median temperature, a lower ambient temperature at 10th percentile (18.2 °C) was significantly associated with a lower estimate of negative-log kt (adjusted expected change: -0.239 [95 % CI: -0.431 to -0.048]). While a U-shaped relationship between relative humidity and negative-log kt was observed, an inverted U-shaped relationship with actual vapour pressure was found. A higher total rainfall was significantly associated with lower estimates of negative-log kt. CONCLUSIONS: This study demonstrated a link between meteorological factors and the superspreading potential of COVID-19. We speculated that cold weather and rainy days reduced the social activities of individuals minimizing the interaction with others and the risk of spreading the diseases in high-risk facilities or large clusters, while the extremities of relative humidity may favor the stability and survival of the SARS-CoV-2 virus.

The hiPSC-derived corneal endothelial progenitor-like cell recovers the rabbit model of corneal endothelial dystrophy.

INTRODUCTION: Corneal endothelial dysfunction results in cornea opacity, damaging sightedness, and affecting quality of life. A corneal transplant is the current effective intervention. Due to the scarcity of donated cornea, such an unmet medical need requires a novel therapeutic modality. OBJECTIVES: Customizing patients' corneal endothelial progenitor cells with proliferative activity and lineage restriction properties shall offer sufficient therapeutic cells for corneal endothelial dystrophy. METHODS: The customized induced human corneal endothelial progenitor-like cell (iHCEPLC) was obtained through cell fate conversions starting from PBMC (peripheral blood mononuclear cell), hiPSC (human induced pluripotent stem cell), and hNCC (human neural crest cell), while it finally reached the iHCEPLC state via a series of induction. Several molecular diagnoses were applied to depict its progenitor state, including RNAseq, FlowCytometer, immunostainings, and rtPCR. Significantly, it can be induced to gain differentiation maturity through contact inhibition. In addition, a BAK-mediated rabbit model of corneal endothelial dystrophy was established in the present study to test the therapeutic effectiveness of the iHCEPLC. RESULTS: After inducing cell fate conversion, the specific HCEC markers were detected by rtPCR and immunostaining in iHCEPLC. Further, RNAseq was applied to distinguish its progenitor-like cell fate from primary human corneal endothelial cells (HECE). FlowCytometry profiled the heterogeneity subpopulation, consistently displaying a subtle difference from primary HCEC. A terminal differentiation can be induced in iHCEPLC, addressing its progenitor-like fate. iHCEPLC can restore the BAK-based rabbit model of corneal endothelial dystrophy. Immunohistochemistry verified that such acuity restoration of the BAK-treated cornea is due to the introduced iHCEPLC, and such therapeutic effectiveness is observed in the long term. CONCLUSION: Here, we demonstrated that customized iHCEPLC has long-term therapeutic efficacy. As a progenitor cell, our iHCEPLC has a restricted cell lineage nature and can proliferate in vitro, supporting sufficient therapeutic candidate cells. Due to the immune-privileged nature of the cornea, our iHCEPLC proves the principle of therapeutical feasibility in both autogenic and allogeneic modalities.

The Interrelationship of Benefit Finding, Demoralization, and Stigma among Patients with Parkinson's Disease and Their Caregivers.

Parkinson's disease (PD) is a debilitating neurodegenerative disease with a relentlessly progressive course of illness. This study aimed to assess the dyadic dynamics of benefit finding (BF), demoralization, and stigma on the depression severity of PD patients and their caregivers. This study used a cross-sectional design with purposive sampling. In total, 120 PD patients and 120 caregivers were recruited from the neurological ward or neurological outpatient clinic of a medical center in Taiwan from October 2021 to September 2022. PD patients and their caregivers were enrolled and assessed using the Mini International Neuropsychiatric Interview, the Benefit Finding scale, Demoralization Scale, Stigma Subscale of the Explanatory Model Interview Catalogue, and Taiwanese Depression Questionnaire. Among the 120 patients and 120 caregivers that successfully completed the study, 41.7% (N = 50) and 60% (N = 72) were female, respectively. The most common psychiatric diagnoses of both the PD patients (17.5%) and their caregivers (13.3%) were depressive disorders. Using structural equation modeling, we found that the stigma, BF, and demoralization of PD patients might contribute to their depression severity. Demoralization and stigma of PD patients' caregivers might also contribute to the depression severity of PD patients. Caregivers' BF and demoralization were significantly linked with their depression severity. PD patients' BF degree and their caregivers' BF degree had significant interactive effects. Both patients' and their caregivers' stigma levels had significant interactive effects. Clinicians should be aware of and manage these contributing factors between PD patients and their caregivers in order to prevent them from exacerbating each other's depression.

Clinical Outcomes in Type 2 Diabetes Patients After Acute Myocardial Infarction: A Comparison of Sodium-Glucose Cotransporter 2 Inhibitors vs. Non-Users.

To compare clinical outcomes in patients with type 2 diabetes (T2D) after acute myocardial infarction (AMI) using sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. non-use of SGLT2i. A national cohort study based on the Taiwan National Health Insurance Research Database enrolled 944 patients with T2D who had experienced AMI and were treated with SGLT2i and 8,941 patients who did not receive SGLT2i, respectively, from May 1, 2016, to December 31, 2019. We used propensity score matching to balance covariates across study groups. The follow-up period was from the index date to the independent occurrence of the study outcomes, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. The SGLT2i group exhibited a significantly lower incidence of cardiovascular death (0.865% per year vs. 2.048% per year; hazard ratio (HR): 0.42; 95% confidence interval (CI): 0.24-0.76; P = 0.0042), heart failure hospitalization (1.987% per year vs. 3.395% per year; HR: 0.59; 95% CI: 0.39-0.89; P = 0.0126), and all-cause mortality (3.406% per year vs. 4.981% per year, HR: 0.69; 95% CI: 0.50-0.95; P = 0.0225) compared with the non-SGLT2i group. There were no significant differences between the two groups in the incidence of AMI, ischemic stroke, coronary revascularization, major adverse cardiovascular events, composite renal outcomes, or lower limb amputation. These findings suggest that the use of SGLT2i may have favorable effects on clinical outcomes in patients with T2D after AMI.

Protective Effects of Pear Extract on Skin from In Vitro and In Vivo UVA-Induced Damage.

The ancient Chinese medical book "Compendium of Materia Medica" records that pears can relieve symptoms of respiratory-related diseases. Previous research has shown that pear Pyrus Pyrifolia (Burm.f.) Nakai has antioxidant and anti-inflammatory properties. However, the anti-inflammatory, antioxidant, and anti-photoaging protective effects of Pyrus pyrifolia (Burm.f.) Nakai seed components have not been studied. Ultraviolet light (UV) causes skin inflammation, damages the skin barrier, and is an important cause of skin photoaging. Therefore, UV light with a wavelength of 365 nm was used to irradiate HaCaT and mice. Western blot, real-time quantitative polymerase chain reaction, and fluorescence imaging system were used to explore its anti-UVA mechanism. Dialysis membrane and nuclear magnetic resonance were used for the chemical constituent analysis of pear seed water extract (PSWE). We found that PSWE can significantly reduce UVA-induced skin cell death and mitogen-activated protein kinase phosphorylation and can inhibit the mRNA expression of UVA-induced cytokines (including IL-1ß, IL-6, and TNF-α). In addition, PSWE can also reduce the generation of oxidative stress within skin cells. In vivo experimental studies found that PSWE pretreatment effectively reduced transepidermal water loss, inflammation, redness, and dryness in hairless mice. The molecular weight of the active part of pear water extract is approximately 384. Based on the above results, we first found that pear seeds can effectively inhibit oxidative stress and damage caused by UVA. It is a natural extract with antioxidant properties and anti-aging activity that protects skin cells and strengthens the skin barrier.

Corneal thickness and endothelial change after use of ocular hypotensive agents.

Corneal transplantation can restore visual function when visual impairment is caused by a corneal disease. However, this treatment is associated with the scarcity of cornea donors. The suitability of corneal donation from patients with glaucoma using ocular hypotensive agents (OHAs) is controversial. This study aimed to elucidate changes in corneal thickness, corneal endothelial cell density, and corneal endothelial cell hexagonality after OHA use in patients with primary open-angle glaucoma. We retrospectively reviewed the data of 53 glaucoma suspect eyes without OHA use and 106 primary open-angle glaucoma eyes under OHA use. All participants underwent corneal parameter assessment using SP-3000P (Topcon Corp., Tokyo, Japan) at the time of diagnosis and the final visit. The OHA dose and timing of use were recorded. The ocular hypotensive agents score (OHAS) was determined based on the number, formula, frequency, and duration of OHA use. Baseline data showed no significant differences between the two groups with and without OHA use. At the final visit, the OHA-treated group showed significantly lower corneal thickness and corneal endothelial cell density than those of the control group. A weak positive correlation between the OHAS and changes in corneal endothelial cell hexagonality was noted. However, no correlation was observed between the OHAS and changes in corneal thickness or endothelial cell density. In conclusion, patients with glaucoma and using OHAs should undergo the corneal structural properties examinations before donation to ensure the quality of donor cornea.

Corneal Endothelial Morphology and Ocular Biometric Indexes in Premature Children With and Without Retinopathy of Prematurity.

Purpose: The purpose of this study was to analyze human corneal endothelial cells (HCECs) morphology and ocular biometrics in premature (PM) children with or without retinopathy of prematurity (ROP). Methods: Retrospective data on patient demographics, HCECs status, and ocular biometrics with at least 2 visits between 2016 and 2021 were reviewed. The main outcomes were endothelial cell density (ECD), coefficient of variation (CV), hexagonal cell ratio (HEX), central corneal thickness (CCT), axial length, anterior chamber depth, keratometry, corneal diameter, pupil diameter, and refraction status. Generalized estimating equation was used to evaluate the differences between PM no-ROP and ROP groups. We also analyzed the trend of ECD, CV, HEX, and CCT change with age between groups. Results: The study included 173 PM patients without ROP and 139 patients with ROP. A total of 666 and 544 measurements were recorded in the PM no-ROP and ROP groups, respectively. The ROP group had higher spherical power, myopic spherical equivalent (SE), and steeper steep keratometry (K; P < 0.05). The ROP group had higher CV (P = 0.0144), lower HEX (P = 0.0012) and thicker CCT (P = 0.0035). In the HCECs parameters, the ROP group had slower ECD decrement (P < 0.0001), faster CV decrement (P = 0.0060), and faster HEX increment (P = 0.0001). A difference in corneal morphology changes between the ROP and PM no-ROP groups were prominent in patients with lower gestational age (GA) in the subgroup analysis. Conclusions: Worse HCECs morphology and higher myopic status were initially observed in patients with prior ROP but not in PM patients with no-ROP. ECD and HCECs morphology improved with age, especially in patients with low GA.

RNA-Based Antipsoriatic Gene Therapy: An Updated Review Focusing on Evidence from Animal Models.

Psoriasis presents as a complex genetic skin disorder, characterized by the interaction between infiltrated immune cells and keratinocytes. Substantial progress has been made in understanding the molecular mechanisms of both coding and non-coding genes, which has positively impacted clinical treatment approaches. Despite extensive research into the genetic aspects of psoriasis pathogenesis, fully grasping its epigenetic component remains a challenging endeavor. In response to the pressing demand for innovative treatments to alleviate inflammatory skin disorders, various novel strategies are under consideration. These include gene therapy employing antisense nucleotides, silencing RNA complexes, stem cell therapy, and antibody-based therapy. There is a pressing requirement for a psoriasis-like animal model that replicates human psoriasis to facilitate early preclinical evaluations of these novel treatments. The authors conduct a comprehensive review of various gene therapy in different psoriasis-like animal models utilized in psoriasis research. The animals included in the list underwent skin treatments such as imiquimod application, as well as genetic and biologic injections, and the results of these interventions are detailed. Animal models play a crucial role in translating drug discoveries from the laboratory to clinical practice, and these models aid in improving the reproducibility and clinical applicability of preclinical data. Numerous animal models with characteristics similar to those of human psoriasis have proven to be useful in understanding the development of psoriasis. In this review, the article focuses on RNA-based gene therapy exploration in different types of psoriasis-like animal models to improve the treatment of psoriasis.

Neonatal jaundice is associated with increased risks of congenital anomalies of the kidney and urinary tract and concomitant urinary tract infection.

The link between neonatal jaundice and urinary tract infection (UTI) remains debated, with congenital kidney and urinary tract anomalies (CAKUT) potentially playing a role. This population-based study aimed to analyze the correlations between neonatal jaundice, CAKUT, and concomitant UTI. The study cohort consisted of 2,078,122 live births from 2004 to 2014. We linked several population-based datasets in Taiwan to identify infants with unexplained neonatal jaundice and their mothers. The primary outcome was the rate of CAKUT occurring within 3 years after delivery, and the presence of concomitant UTI during neonatal jaundice hospitalization. Infants with neonatal jaundice had a significantly higher risk of CAKUT (adjusted odds ratio [aOR] 1.24, 95% confidence interval [CI] 1.11-1.39) during early childhood. Among the subtypes of CAKUT, obstructive uropathy, vesicoureteral reflux and other CAKUT were associated with an increased risk of neonatal jaundice. Infants who underwent intensive phototherapy, had a late diagnosis (> 14 days of postnatal age) or underwent a prolonged duration of phototherapy (> 3 days) exhibited a higher risk of concomitant UTI compared to other infants with jaundice. Our findings indicate a notable association between neonatal jaundice and increased risks of UTIs in the context of CAKUT. This study underscore the importance of vigilant monitoring and timely interventions for neonates presenting with jaundice, while acknowledging the complexity and variability in the progression of CAKUT and its potential connection to UTIs.

Maternal folic acid supplementation during pregnancy in association with childhood overweight or obesity.

OBJECTIVE: This study aimed to examine associations of maternal folic acid supplementation (FAS) during pregnancy with childhood overweight or obesity (OWO) or adiposity. METHODS: In a population-based cohort of 1479 children, maternal FAS during pregnancy was assessed retrospectively by questionnaires. BMI and body fat percentages were measured at a mean age of 6.4 years. Pertinent factors were accounted for in data analyses. RESULTS: Maternal FAS during pregnancy was negatively associated with OWO (adjusted odds ratio: 0.70; 95% CI: 0.50 to 0.99). There were inverse associations of maternal FAS during pregnancy with BMI z score (ß: -0.22; 95% CI: -0.39 to -0.05), whole body fat percentage (ß: -1.28; 95% CI: -2.27 to -0.30), trunk fat percentage (ß: -1.41; 95% CI: -2.78 to -0.04), and limb fat percentage (ß: -1.31; 95% CI: -2.32 to -0.30). Stratified analyses found inverse associations of FAS during pregnancy with OWO, BMI z score, and body fat percentages predominantly among children without breastfeeding and whose parents had a below-tertiary educational level. CONCLUSIONS: This study provides novel evidence that maternal FAS during pregnancy was significantly associated with a decreased risk of childhood OWO and adiposity, particularly among children with no breastfeeding and lower parental educational level.

Supercharge end-to-side nerve transfer from anterior interosseous nerve to augment intrinsic recovery in high ulnar nerve injuries of varying magnitudes.

BACKGROUND: High ulnar nerve injuries result in intrinsic muscle weakness and are inconvenient for patients. Moreover, conventional surgical techniques often fail to achieve satisfactory motor recovery. A potential reconstructive solution in the form of the supercharge end-to-side (SETS) anterior interosseous nerve (AIN) transfer method has emerged. Therefore, this study aims to compare surgical outcomes of patients with transected and in-continuity high ulnar nerve lesions following SETS AIN transfer. METHODS: Between June 2015 and May 2023, patients with high ulnar palsy in the form of transection injuries or lesion-in-continuity were recruited. The assessment encompassed several objective results, including grip strength, key pinch strength, compound muscle action potential, sensory nerve action potential, and two-point discrimination tests. The muscle power of finger abduction and adduction was also recorded. Additionally, subjective questionnaires were utilized to collect data on patient-reported outcomes. Overall, the patients were followed up for up to 2 years. RESULTS: Patients with transected high ulnar nerve lesions exhibited worse baseline performance than those with lesion-in-continuity, including motor and sensory functions. However, they experienced greater motor improvement but less sensory recovery, resulting in comparable final motor outcomes in both groups. In contrast, the transection group showed worse sensory outcomes. CONCLUSIONS: Our findings suggest that SETS AIN transfer benefits patients with high ulnar nerve palsy, regardless of the lesion type. Nonetheless, improvements may be more pronounced in patients with transected lesions.

Interplay of p62-mTORC1 and EGFR signaling promotes cisplatin resistance in oral cancer.

Cisplatin resistance poses a major challenge in the treatment of oral squamous cell carcinoma (OSCC). Deeper investigations into the mechanisms underlying this drug resistance is of great importance. Here, we used cellular assays and clinical immunohistochemistry to examine molecular pathways involved in both innate and acquired cisplatin resistance. We demonstrated that the p62-mTORC1 signaling complex plays a pivotal role, and is driven by the EGFR signaling network, specifically through the PI3K-Akt axis and the transcription factor C/EBP-ß. Elevated p-mTOR expression was associated with cancer relapse and poor prognosis among oral cancer patients. Additionally, we illustrated that mTOR inhibitors enhance the cytotoxic effect of cisplatin, by employing cancer stem cell characteristics. Our work unveils fundamental mechanisms for cisplatin resistance, thereby presenting therapeutic implications for OSCC.

Mechanistic and Kinetic Insights into Cellular Uptake of Biomimetic Dinitrosyl Iron Complexes and Intracellular Delivery of NO for Activation of Cytoprotective HO-1.

Dinitrosyl iron unit (DNIU), [Fe(NO)2], is a natural metallocofactor for biological storage, delivery, and metabolism of nitric oxide (NO). In the attempt to gain a biomimetic insight into the natural DNIU under biological system, in this study, synthetic dinitrosyl iron complexes (DNICs) [(NO)2Fe(µ-SCH2CH2COOH)2Fe(NO)2] (DNIC-COOH) and [(NO)2Fe(µ-SCH2CH2COOCH3)2Fe(NO)2] (DNIC-COOMe) were employed to investigate the structure-reactivity relationship of mechanism and kinetics for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective heme oxygenase (HO)-1. After rapid cellular uptake of dinuclear DNIC-COOMe through a thiol-mediated pathway (tmax = 0.5 h), intracellular assembly of mononuclear DNIC [(NO)2Fe(SR)(SCys)]n-/[(NO)2Fe(SR)(SCys-protein)]n- occurred, followed by O2-induced release of free NO (tmax = 1-2 h) or direct transfer of NO to soluble guanylate cyclase, which triggered the downstream HO-1. In contrast, steady kinetics for cellular uptake of DNIC-COOH via endocytosis (tmax = 2-8 h) and for intracellular release of NO (tmax = 4-6 h) reflected on the elevated activation of cytoprotective HO-1 (∼50-150-fold change at t = 3-10 h) and on the improved survival of DNIC-COOH-primed mesenchymal stem cell (MSC)/human corneal endothelial cell (HCEC) under stressed conditions. Consequently, this study unravels the bridging thiolate ligands in dinuclear DNIC-COOH/DNIC-COOMe as a switch to control the mechanism, kinetics, and efficacy for cellular uptake of DNICs, intracellular delivery of NO, and activation of cytoprotective HO-1, which poses an implication on enhanced survival of postengrafted MSC for advancing the MSC-based regenerative medicine.

Metabolic dysfunction-associated profiles and subsequent site-specific risk of obesity-related cancers among Chinese patients with diabetes: a retrospective cohort study.

OBJECTIVES: To compare metabolic dysfunction-associated profiles between patients with diabetes who developed different obesity-related site-specific cancers and those who remained free of cancer during follow-up. DESIGN: Retrospective cohort study. SETTING: Public general outpatient clinics in Hong Kong. PARTICIPANTS: Patients with diabetes without a history of malignancy (n=391 921). PRIMARY OUTCOME MEASURES: The outcomes of interest were diagnosis of site-specific cancers (colon and rectum, liver, pancreas, bladder, kidney and stomach) during follow-up. Cox proportional hazards regression was applied to assess the associations between metabolic dysfunction and other clinical factors with each site-specific cancer. RESULTS: Each 0.1 increase in waist-to-hip ratio was associated with an 11%-35% elevated risk of colorectal, bladder and liver cancers. Each 1% increase in glycated haemoglobin was linked to a 4%-9% higher risk of liver and pancreatic cancers. While low-density lipoprotein cholesterol and triglycerides were inversely associated with the risk of liver and pancreatic cancers, high-density lipoprotein cholesterol was negatively associated with pancreatic, gastric and kidney cancers, but positively associated with liver cancer. Furthermore, liver cirrhosis was linked to a 56% increased risk of pancreatic cancer. No significant association between hypertension and cancer risk was found. CONCLUSIONS: Metabolic dysfunction-associated profiles contribute to different obesity-related cancer outcomes differentially among patients with diabetes. This study may provide evidence to help identify cancer prevention targets during routine diabetes care.

Microsurgical Debridement for Persistent Ulcers Due to Rare Fungus Infection: Case Report and Literature Review.

A patient suffered from chronic ulcer due to recalcitrant fungal infection for 3.5 years. Five antifungal agents and 40 times of debridement-all failed. Finally, radical microscopic debridement was performed for eradication of fungal conidiospores. Since then, there was no recurrence at 2 years of follow-up. Scopulariopsis brevicaulis is one of the rarest pathogens of cutaneous fungal infections, for which multidrug resistance increased the complexity and difficulty of treatment. Radical excision, especially microscopic debridement, was the key for eradication of fungal conidiospores in this case.