Chiral α-Aminophosphonates as Ligands in Copper-Catalyzed Asymmetric Oxidative Coupling of 2-Naphthols.

Chiral α-aminophosphonates with adjacent carbon and phosphonate stereogenic centers have been employed as ligands in the copper-catalyzed oxidative coupling of 2-naphthols, resulting in the production of chiral BINOLs in favorable yields and moderate to good enantiomeric excess. This represents the first application of chiral P-based ligands to enable such a transformation. The synthesis of these chiral α-aminophosphonate ligands offers a significant advantage over approaches that typically necessitate elaborate synthetic processes for chiral ligand production.

Eight-Membered Palladacycle Intermediate Enabled Synthesis of Cyclic Biarylphosphonates.

Transition-metal-catalyzed coupling reactions that involve the direct functionalization of insert C-H bond represent one of the most efficient strategies for forming carbon-carbon bonds. Herein, a palladium-catalyzed intramolecular C-H bond arylation of triaryl phosphates is reported to access seven-membered cyclic biarylphosphonate targets. The reaction is achieved via a unique eight-membered palladacyclic intermediate and shows good functional group compatibility. Meanwhile, the product can be readily converted into other valuable phosphate compounds.

Clinical characteristics and immune profiles of patients with immune-mediated alopecia associated with COVID-19 vaccinations.

BACKGROUND: The clinical characteristics and pathomechanism for immune-mediated alopecia following COVID-19 vaccinations are not clearly characterized. OBJECTIVE: We investigated the causality and immune mechanism of COVID-19 vaccines-related alopecia areata (AA). STUDY DESIGN: 27 new-onset of AA patients after COVID-19 vaccinations and 106 vaccines-tolerant individuals were enrolled from multiple medical centers for analysis. RESULTS: The antinuclear antibody, total IgE, granulysin, and PARC/CCL18 as well as peripheral eosinophil count were significantly elevated in the patients with COVID-19 vaccines-related AA compared with those in the tolerant individuals (P = 2.03 × 10-5-0.039). In vitro lymphocyte activation test revealed that granulysin, granzyme B, and IFN-γ released from the T cells of COVID-19 vaccines-related AA patients could be significantly increased by COVID-19 vaccine excipients (polyethylene glycol 2000 and polysorbate 80) or spike protein (P = 0.002-0.04). CONCLUSIONS: Spike protein and excipients of COVID-19 vaccines could trigger T cell-mediated cytotoxicity, which contributes to the pathogenesis of immune-mediated alopecia associated with COVID-19 vaccines.

Metformin increases pathological responses to rectal cancers with neoadjuvant chemoradiotherapy: a systematic review and meta-analysis.

BACKGROUND: To summarize the chemo-radio effect of metformin in rectal cancers with neoadjuvant chemoradiotherapy on pathological response, tumor regression grade (TRG), and T/N downstaging. METHODS: PubMed, MEDLINE, Embase, and Cochrane Database of collected reviews were searched up to June 30, 2022. This study conducted systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) sheet. Odds ratios (ORs) and confidence intervals (CIs) which calculated by random-effects models were displayed in forest plots. Newcastle-Ottawa scale was used to assess the risk of bias of the observational cohort studies. RESULTS: This systematic review and meta-analysis comprised eight cohorts out of seven studies, with 2294 patients in total. We performed two-way comparison for metformin in diabetic patients vs (1) non-metformin drugs in diabetic patients and (2) nondiabetic patients. In diabetes patient studies, the metformin group had a significantly increased pathological response on TRG (OR: 3.28, CI: 2.01-5.35, I2 = 0%, p < 0.001) and T downstaging (OR: 2.14, CI: 1.24-3.67, I2 = 14%, p = 0.006) in comparison with a non-metformin group. When compared with nondiabetic patients, the pathological response on TRG (OR: 2.67, CI: 1.65-4.32, I2 = 43%, p < 0.001) and T downstaging (OR: 1.96, CI: 1.04-3.71, I2 = 66%, p = 0.04) were also higher in metformin group. The limitation was that no randomized controlled trials were available based on current literature review. Small sample sizes for diabetic metformin or non-metformin users in rectal cancer patients reduced the power of the study. CONCLUSIONS: For patients with rectal cancer and treated with neoadjuvant chemoradiotherapy, metformin administration in diabetic patients increased the pathological response on tumor-regression grade and T downstaging. Further well-designed, high-quality randomized controlled trials are required to reveal the actual effect of metformin.

The Efficacy of Lactobacillus-Containing Probiotic Supplementation in Hemodialysis Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVES: This study was performed to determine the effects of probiotic supplementation on cholesterol-triglyceride ratio, an indirect marker of insulin resistance, protein-bound uremic toxins, biomarkers of inflammation, and microbial translocation in end-stage renal disease patients on hemodialysis. METHODS: Fifty-six patients aged 39-75 years were assigned into two groups to receive either probiotic sachets (n = 28) or a placebo (n = 28) in a randomized double-blinded placebo-controlled clinical trial. The patients in the probiotic group received twice daily sachets that contained a mixture of three viable and freeze-dried strains: Lactococcus lactis subsp. Lactis LL358, Lactobaccillus salivarius LS159, and Lactobaccillus pentosus LPE588 at high dose (100 billion; 1 × 1011 cfu/day) for 6 months. RESULTS: A total of 50 patients were available for final analysis. Probiotic supplementation did not have a significant influence on cholesterol-triglyceride ratio. Probiotic supplementation for 6 months caused a significant decrease in serum levels of indoxyl sulfate. Compared with the placebo, probiotic supplementation did not result in significant changes in hemoglobin levels, blood urea nitrogen, blood glucose, serum p-cresyl sulfate, inflammatory, and microbial translocation markers. No clinically significant changes in body composition were observed between the two groups during the study period. The probiotic supplementation was well tolerated by all subjects with minimal adverse effects during the 6-month-long study. CONCLUSION: Our results suggest that high-dose multistrain lactobaccillus probiotic supplementation over 6 months as a monotherapy did not significantly decrease markers of insulin resistance, cholesterol-triglyceride ratio, and most of the studied markers, with the exception of levels of indoxyl sulfate in patients on HD.

Disseminated intravascular coagulation in Stevens-Johnson syndrome and toxic epidermal necrolysis.

BACKGROUND: Patients with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) have high mortality rates. Disseminated intravascular coagulation has been reported in SJS/TEN patients. The influence of this lethal complication in patients with SJS/TEN is not well known. OBJECTIVE: This study aimed to investigate the risk and outcomes of disseminated intravascular coagulation in patients with SJS/TEN. METHODS: We analyzed the disseminated intravascular coagulation profiles of patients receiving a diagnosis of SJS/TEN between 2010 and 2019. RESULTS: We analyzed 150 patients with SJS/TEN (75 with SJS, 22 with overlapping SJS/TEN, and 53 with TEN) and their complete disseminated intravascular coagulation profiles. Disseminated intravascular coagulation was diagnosed in 32 patients (21.3%), primarily those with TEN. It was significantly associated with systemic complications, including gastrointestinal bleeding, respiratory failure, renal failure, liver failure, infection, and bacteremia. Additionally, SJS/TEN patients with disseminated intravascular coagulation had elevated procalcitonin levels. Among patients with SJS/TEN, disseminated intravascular coagulation was associated with a greater than 10-fold increase in mortality (78.1% vs 7%). LIMITATIONS: The study limitations include small sample size and a single hospital system. CONCLUSION: Disseminated intravascular coagulation is a potential complication of SJS/TEN and associated with higher mortality. Early recognition and appropriate management of this critical complication are important for patients with SJS/TEN.

Development and validation of a multifrequency bioimpedance spectroscopy equation to predict appendicular skeletal muscle mass in hemodialysis patients.

BACKGROUND & AIMS: The Body Composition Monitor (BCM), a multifrequency bioimpedance spectroscopy device, has been widely used to assess body composition in hemodialysis patients because its measurement is not affected by overhydration commonly seen in chronic kidney disease. We aimed to develop and validate an equation for obtaining appendicular skeletal muscle mass (ASM) from BCM taking dual-energy X-ray absorptiometry (DXA) as the reference among hemodialysis patients. METHODS: A total of 322 consecutive body composition measurements with BCM and DXA in 263 hemodialysis patients were randomly divided at a ratio of 2:1 into development and validation groups. Stepwise multiple regression modeling was applied to develop the ASM prediction equation. We evaluated the model as a diagnostic tool for sarcopenia using cutoffs of ASM defined by the Asian Working Group for Sarcopenia (AWGS). We further explored the association between ASM predicted by the BCM equation and all-cause mortality in two independent cohorts: one with 326 stage 3-5 CKD patients and one with 629 hemodialysis patients. RESULTS: BCM yielded the following equation: ASM (kg) = -1.838 + 0.395 × total body water (L) + 0.105 × body weight (kg) + 1.231 × male sex - 0.026 × age (years) (R2 = 0.914, standard error of estimate = 1.35 kg). In the validation group, Bland-Altman reliability analysis showed no significant bias of 0.098 kg and limits of agreement ±2.440 kg. Using the AWGS criteria, the model was found to have a sensitivity of 94.1%, a specificity of 98.8%, a positive predictive value of 84.2%, and a negative predictive value of 99.6% for the diagnosis of sarcopenia. Low ASM predicted by the BCM equation was associated with significantly worse overall survival among CKD patients but not hemodialysis patients. CONCLUSIONS: The new BCM equation provides a feasible and valid option for assessing ASM in hemodialysis patients.

Attenuation of Wnt/ß-catenin signaling in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

Change in body weight and body mass index in psoriasis patients receiving biologics: A systematic review and network meta-analysis.

BACKGROUND: Previous studies have suggested that biologic therapy for psoriasis might relate to body weight gain. OBJECTIVE: To assess the changes in body weight and body mass index (BMI) in psoriasis patients after receiving various biologics. METHODS: We conducted a systematic review and network meta-analysis to evaluate the changes in body weight and BMI in psoriasis patients receiving biologics. On March 1, 2019, we searched Medline, Embase, and Cochrane Central Register of Controlled Trials for relevant studies. The Newcastle-Ottawa scale was used to assess the risk of bias. RESULTS: We included 6 studies with 862 psoriasis patients. Compared with conventional systemic treatments, treatment with tumor necrosis factor α inhibitors was associated with a significant increase in body weight (mean difference 1.40 kg, 95% confidence interval 0.88-1.93 kg) and BMI (0.39 kg/m2, 95% confidence interval 0.24-0.54 kg/m2). In contrast, no significant increase in body weight or BMI was found among patients receiving anti-interleukin (IL)-12/23 or anti-IL-17 biologics. LIMITATIONS: Only 1 study reported body weight and BMI for patients receiving the anti-IL-17 biologic. CONCLUSION: Tumor necrosis factor α inhibitor treatment appears to be associated with an increase in body weight and BMI, and treatment with anti-IL-12/23 and anti-IL-17 biologics do not. This association should be considered before initiating biologics for overweight and obese patients.

Psoriasiform drug eruption secondary to sorafenib: case series and review of the literature.

The expanding use of novel targeted anticancer agents such as sorafenib has led to an increasing number of dermatologic adverse events. Although cutaneous adverse events are commonly described in patients taking sorafenib, there are few reports describing psoriasis secondary to this medication. In this report, we describe 3 patients with sorafenib-induced psoriasiform drug eruption and review the available literature of similar patient cases. Our findings highlight shared characteristics among affected patients and potential treatment options for patients in whom sorafenib cannot be discontinued. Increased awareness of such drug eruptions and management options is critical to prevent suboptimal dosing and decreased quality of life.

The Role of Immune Checkpoint Receptors in Regulating Immune Reactivity in Lupus.

Immune checkpoint receptors with co-stimulatory and co-inhibitory signals are important modulators for the immune system. However, unrestricted co-stimulation and/or inadequate co-inhibition may cause breakdown of self-tolerance, leading to autoimmunity. Systemic lupus erythematosus (SLE) is a complex multi-organ disease with skewed and dysregulated immune responses interacting with genetics and the environment. The close connections between co-signaling pathways and SLE have gradually been established in past research. Also, the recent success of immune checkpoint blockade in cancer therapy illustrates the importance of the co-inhibitory receptors in cancer immunotherapy. Moreover, immune checkpoint blockade could result in substantial immune-related adverse events that mimic autoimmune diseases, including lupus. Together, immune checkpoint regulators represent viable immunotherapeutic targets for the treatment of both autoimmunity and cancer. Therefore, it appears reasonable to treat SLE by restoring the out-of-order co-signaling axis or by manipulating collateral pathways to control the pathogenic immune responses. Here, we review the current state of knowledge regarding the relationships between SLE and the co-signaling pathways of T cells, B cells, dendritic cells, and neutrophils, and highlight their potential clinical implications. Current clinical trials targeting the specific co-signaling axes involved in SLE help to advance such knowledge, but further in-depth exploration is still warranted.

Severe cutaneous adverse reactions induced by targeted anticancer therapies and immunotherapies.

With the increasing use of targeted anticancer drugs and immunotherapies, there have been a substantial number of reports concerning life-threatening severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug rash with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, and acute generalized exanthematous pustulosis. Although the potential risks and characteristics for targeted anticancer agent- and immunotherapy-induced SCAR were not well understood, these serious adverse reactions usually result in morbidity and sequela. As a treatment guideline for this devastating condition is still unavailable, prompt withdrawal of causative drugs is believed to be a priority of patient management. In this review, we outline distinct types of SCARs caused by targeted anticancer therapies and immunotherapies. Also, we discuss the clinical course, latency, concomitant medication, tolerability of rechallenge or alternatives, tumor response, and mortality associated with these devastating conditions. Imatinib, vemurafenib, and rituximab were the top three offending medications that most commonly caused SJS/TEN, while EGFR inhibitors were the group of drugs that most frequently induced SJS/TEN. For drug rash with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome and acute generalized exanthematous pustulosis, imatinib was also the most common offending drug. Additionally, we delineated 10 SCAR cases related to innovative immunotherapies, including PD1 and CTLA4 inhibitors. There was a wide range of latency periods: 5.5-91 days (median). Only eight of 16 reported patients with SCAR showed clinical responses. Targeted anticancer drugs and immunotherapies can lead to lethal SCAR (14 deceased patients were identified as suffering from SJS/TEN). The mortality rate of TEN was high: up to 52.4%. The information compiled herein will serve as a solid foundation to formulate ideas for early recognition of SCAR and to discontinue offending drugs for better management.

Anticancer Drugs Induced Severe Adverse Cutaneous Drug Reactions: An Updated Review on the Risks Associated with Anticancer Targeted Therapy or Immunotherapies.

Cutaneous adverse drug reactions are commonly seen in patients with anticancer drug treatment. Anticancer drugs, including chemotherapy, target therapy, and recent immunotherapy causing skin reactions ranging from mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) with increase morbidity and mortality while they are receiving cancer treatments, have been proposed to be a result of direct skin toxicity or drug hypersensitivity reactions (these are proposed mechanism, not definite). Differentiating SCARs from other more commonly seen reactions with a better outcome help prevent discontinuation of therapy and inappropriate use of systemic immunosuppressants for presumable allergic reactions, of which will affect the clinical outcome. In this article, we have reviewed published articles from 1950 to August 2017 for SJS/TEN associated with anticancer drugs, including chemotherapy, targeted therapy, and immunotherapy. We aimed to provide an overview of SJS/TEN associated with anticancer drugs to increase clinician recognition and accelerate future studies on the pathomechanism and managements.

Impaired Gut Epithelial Tight Junction Expression in Hemodialysis Patients Complicated with Intradialytic Hypotension.

BACKGROUND: There is accumulating evidence pointing to uremia-induced impairment of the intestinal epithelial barrier structure in advanced chronic kidney disease (CKD) and hemodialysis (HD) patients. In this study, the impact of intradialytic hypotension on intestinal barrier integrity is being explored. METHODS: Immunohistochemical staining was used to detect the expression of 4 types of tight junction (TJ) proteins such as occludin, zonula occludens-1 (ZO-1), claudin-1, and claudin-4, in colonic samples of a group of patients receiving segmental colectomy. Five patients with nondialysis CKD (group 2), 5 HD patients with intradialytic hypotension (group 3), and 5 non-CKD subjects (group 1) were examined. RESULTS: Both patients' groups 2 and 3 demonstrated significantly reduced expression of occludin as compared to group 1 (p < 0.05 and p < 0.01, resp.). Except for claudin-4, expression of all markers of TJ proteins was significantly reduced in patients' group 3 as compared to control (p < 0.01). In addition, decreased expressions of claudin-1 and ZO-1 were also more pronounced in group 3 when compared to group 2. CONCLUSIONS: This study extends the earlier finding by demonstrating that dialysis-related hypotension caused even marked depletion of the key protein constituents of the epithelial TJ.

Sandwich compression with rubbery tourniquet sheets and cotton balls for auricular pseudocyst.

OBJECTIVES/HYPOTHESIS: Pseudocyst of the auricle is a benign, noninflammatory cystic disease that is more common in Asians than in Caucasians. When managed conservatively, the results are often unsatisfactory and recurrences are common. We aimed to introduce a novel modified surgical method that involves a deroofing technique followed by a sandwich compression suture using two rubber tourniquet sheets and an iodine-soaked cotton ball for the treatment of auricular pseudocysts and to ascertain its effectiveness. STUDY DESIGN: Case series with or without comparison. METHODS: The charts of 100 patients with auricular pseudocysts who were treated with this new method from 2004 to 2016 in a university-affiliated tertiary teaching hospital were retrospectively reviewed and analyzed. RESULTS: The mean patient age was 37.7 years, and 84% were male. All of the patients had unilateral lesions, with right-side lesions (53.0%) being slightly predominant. The cymba concha (44.1%) was the most common site. Seven patients (7.0%) had trauma to the ear within 3 months before presentation. Previous aspiration or drainage had been performed for the cysts in 35 patients (35.0%), and the recurrences had been treated conservatively. In comparison, 98 of the 100 patients recovered smoothly from surgery without further recurrence or complications after follow-up for at least 1 year. CONCLUSIONS: Based on our experience, not only does this surgical procedure yield reliable results in the treatment of pseudocysts of auricles, but it also has advantages such as using readily available materials, being simple to perform, improving efficacy, and lowering recurrence rates. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1653-1657, 2018.

Proportions of Proinflammatory Monocytes Are Important Predictors of Mortality Risk in Hemodialysis Patients.

Despite the continuous progression in dialysis medicine, mortality and the burden of cardiovascular disease (CVD) among hemodialysis patients are still substantial. Substantial evidence suggests that proinflammatory (CD16+) monocytes contribute to the development of atherosclerosis. A cohort of 136 stable hemodialysis patients (follow-up: 6.25 year) was assessed to investigate the association between the proportion of CD16+ monocytes for all-cause and CVD mortalities. The CD16+ monocytes were associated with both mortalities after adjusting for a preexisting CVD history. Compared to the reference group (CD16+ monocytes within [15.6-18.6], the first and second quartile), patients with CD16+ monocytes above the highest quartile level (>21.5) had an adjusted hazard ratio (HR) of 30.85 (95% confidence interval [CI]: 7.12-133.8) for CVD mortality and 5.28 (2.07-13.49) for all-cause mortality, and those with CD16+ monocytes below the lowest quartile ≤15.6), had significantly elevated death risks after 3.5-year follow-up (HR [95% CI]: 10.9 [2.42-48.96] and 4.38 [1.45-13.24] for CV and all-cause mortalities, respectively). The hemodialysis patients with CD16+ monocyte level in a low but mostly covering normal range also portended a poor prognosis. The findings shed some light for nephrologists on future prospects of early recognizing immune dysfunction and improving early intervention outcomes.

Role of Cilostazol Therapy in Hemodialysis Patients with Asymptomatic Peripheral Arterial Disease: A Retrospective Cohort Study.

Background. Peripheral arterial disease (PAD) and its relevant complications are more common in hemodialysis (HD) patients, while the evidence regarding antiplatelet therapy in CKD patients is scarce. We retrospectively analyzed the efficacy of cilostazol on outcomes in HD patients with asymptomatic PAD (aPAD). Methods. This cohort study enrolled 217 HD patients (median follow-up time: 5.75 years). Associations between cilostazol use and the outcomes were evaluated by time-dependent Cox regression analysis. Results. During follow-up, 39.5% (47/119) patients used cilostazol for aPAD and 31.8% (69/217) patients died. Cilostazol users had significantly lower CVD and all-cause mortalities (adjusted HR [95% CI]: 0.11 [0.03, 0.51] and 0.2 [0.08, 0.52]) than nonusers. Both death risks were nonsignificantly higher in cilostazol users than in HD patients without aPAD. The unadjusted and adjusted HR [95% CI] of CVD death risk were 0.4 [0.07, 2.12] and 0.14 [0.02, 0.8] for patients with aPAD during follow-up and were 0.74 [0.16, 3.36] and 0.19 [0.04, 0.93] for those with aPAD at initial. Conclusions. In HD patients with aPAD, lower CVD and all-cause mortality rates were observed in low-dose cilostazol user. Further evidences from large-scale prospective study and randomization trial are desired to confirm the effect of cilostazol.

Serum oxidized albumin and cardiovascular mortality in normoalbuminemic hemodialysis patients: a cohort study.

BACKGROUND: Substantial evidence suggests that increased oxidative stress in hemodialysis (HD) patients may contribute to cardiovascular complications. Oxidative modifications of human serum albumin (HSA), the largest thiol pool in plasma, alter its biological properties and may affect its antioxidant potential in HD patients. METHODS: We conducted a long-term follow-up study in a cohort of normoalbuminemic HD patients to examine the impact of redox state of serum albumin on patients' survival by measuring the human nonmercaptoalbumin (HNA) fraction of HSA. RESULTS: After adjusting for potential demographic, anthropometric, and clinical confounders, a positive association of HNA level with the risk of death from cardiovascular disease (CVD) and all-cause mortality was observed in normoalbuminemic HD patients. Using stratified analysis, we found a stronger association between HNA level and the risk of death from CVD and all-cause mortality in patients with pre-existing CVD. CONCLUSIONS: Serum HNA level is a positive predictor of mortality in normoalbuminemic HD patients, especially among those with pre-existing CVD. Increased oxidative stress resulting from biological changes in serum albumin levels could contribute to accelerated atherosclerosis and the development of cardiovascular disease in HD patients.