Porous Hydrogels for Immunomodulatory Applications.

Cancer immunotherapy relies on the insight that the immune system can be used to defend against malignant cells. The aim of cancer immunotherapy is to utilize, modulate, activate, and train the immune system to amplify antitumor T-cell immunity. In parallel, the immune system response to damaged tissue is also crucial in determining the success or failure of an implant. Due to their extracellular matrix mimetics and tunable chemical or physical performance, hydrogels are promising platforms for building immunomodulatory microenvironments for realizing cancer therapy and tissue regeneration. However, submicron or nanosized pore structures within hydrogels are not favorable for modulating immune cell function, such as cell invasion, migration, and immunophenotype. In contrast, hydrogels with a porous structure not only allow for nutrient transportation and metabolite discharge but also offer more space for realizing cell function. In this review, the design strategies and influencing factors of porous hydrogels for cancer therapy and tissue regeneration are first discussed. Second, the immunomodulatory effects and therapeutic outcomes of different porous hydrogels for cancer immunotherapy and tissue regeneration are highlighted. Beyond that, this review highlights the effects of pore size on immune function and potential signal transduction. Finally, the remaining challenges and perspectives of immunomodulatory porous hydrogels are discussed.

[The Three-dimensional Environment of Type â Collagen Gels With Varying Stiffness Modulates the Immunological Functions of NK Cells]. / 不同刚度â 型胶原凝胶三维环境调控NKç»†èƒžå ç–«åŠŸèƒ½.

Objective: To construct type Ⅰ collagen gels with different stiffness and to investigate the effects of three-dimensional (3D) culture environments of the gels on the morphology, free migration ability, and cell killing function of natural killer (NK) cells. Methods: Type Ⅰ collagen was isolated from the tails of Sprague Dawley (SD) rats and collagen gels with different levels of stiffnesses were prepared accordingly. The microstructure of the collagen gels was observed by laser confocal microscopy. The stiffness of the collagen gels was assessed by measuring the plateau modulus with a rheometer. NK-92MI cells were cultured in collagen gels with different levels of stiffness. The morphology of NK-92MI cells was observed by inverted microscope. High content imaging system was used to record the free migration process of NK-92MI cells and analyze the migration speed and distance. NK-92MI cells were cultured with type Ⅰ collagen gels with different levels of stiffness for 24 h and 48 h and, then, co-cultured with human colorectal DLD-1, a human adenocarcinoma epithelial cell line. CCK8 assay was performed to determine the proliferation rate of DLD-1 cells and analyze the cell killing ability of NK-92MI cells. Results: Low-stiffness type Ⅰ collagen gel and high-stiffness type Ⅰ collagen gel with the respective stiffness of (10.970±2.10) Pa and (114.50±3.40) Pa were successfully prepared. Compared with those cultured with the low-stiffness type Ⅰ collagen gel, the NK-92MI cells in the high-stiffness type Ⅰ collagen gel showed a more elongated shape (P<0.05), the mean area of the cells was reduced ([69.88±26.97] µm2 vs. [46.59±21.62] µm2, P<0.05), the roundness of the cells decreased (0.82±0.12 vs. 0.78±0.18, P<0.05), cell migration speed decreased ([2.50±0.91] µm/min vs. [1.70±0.72] µm/min, P<0.001) and the migration distance was shortened ([147.10±53.74] µm vs. [98.03± 40.95] µm, P<0.0001), with all the differences being statistically significant. Compared with those cultured with the low-stiffness type Ⅰ collagen gel, NK-92MI cells cultured with high-stiffness type Ⅰ collagen gel for 24 h could promote DLD-1 cell proliferation, with the proliferation rate being (46.39±12.79)% vs. (65.87±4.45)% (P<0.05) and reduce the cell killing ability. Comparison of the cells cultured for 48 h led to similar results, with the proliferation rates being (31.36±2.88)% vs. (74.57±2.16)% (P<0.05), and the differences were all statistically significant. Conclusion: The 3D culture environment of type Ⅰ collagen gels with different levels of stiffness alters the morphology, migration ability, and killing function of NK-92MI cells. This study provides the research basis for exploring and understanding the mechanisms by which the biomechanical microenvironment affects the immune response of NK cells, as well as laying the theoretical foundation for optimizing immunotherapy protocols.

Tunable Yellow to Near-Infrared Fluorescent Boron-Amino-Chelating Complexes with Stokes Shifts >100 nm.

A series of diphenylboron-chelating N-substituent 8-aminoquinoline, 5-aminoquinoxaline, and 1-aminophenazine were prepared. They exhibit lowest energy absorption peaks of 444-766 nm, emission peaks of 563-820 nm, and quantum yields of up to 46.5%. Electrochemical and theoretical studies indicate that the N-substituent mainly determines the HOMO and the framework determines the LUMO, thus allowing for a wide-tuning of absorptions/emissions. Intramolecular charge transfer transition leads to large Stokes shifts of up to 166 nm. One selected compound showed satisfactory cytocompatibility and cytoplasm-targeting cell imaging ability.

Antibiotic-associated vanishing bile duct syndrome: a real-world retrospective and pharmacovigilance database analysis.

PURPOSE: Vanishing bile duct syndrome (VBDS) is a rare, but potentially fatal adverse reaction triggered by certain medications. Few real-world studies have shown association between antibiotics and VBDS. We sought to quantify the risk and evaluate the clinical features of VBDS associated with antibiotics. METHODS: Data from 2004 to 2022 on VBDS events induced by antibiotics were retrieved from the FDA Adverse Event Reporting System (FAERS) database and disproportionality analyses were conducted. Furthermore, case reports from 2000 to 31 December 2022 on antibiotics-induced VBDS were retrieved for retrospective analysis. RESULTS: We collected 132 VBDS reports from the FAERS database. Fluoroquinolones had the greatest proportion and highest positive signal values of VBDS. The RORs (95% CIs) for antibiotics were fluoroquinolones 23.68 (18.12-30.95), macrolides 19.37 (13.58-27.62), carbapenems 17.39 (7.77-38.96), beta-lactam 13.28 (9.69-18.20), trimethoprim/sulfamethoxazole 9.05 (5.57-14.7), and tetracycline 4.02 (1.50-10.77). Twenty-three cases from 22 studies showed evidence of VBDS, beta-lactam (52.2%) was the most frequently reported agent. The median age was 45 years, the typical initial symptoms included rash (30.4%), fatigue/asthenia (26.1%), dark urine (21.7%) and Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) (21.7%). The median time to onset of VBDS was 2 weeks. All cases had abnormal liver function test, and the median level of total bilirubin was 23.6 mg/dl (range 3.2-80 mg/dl). Cessation of culprit drugs and treatment with ursodeoxycholic acid (83.3%) were not associated with improved outcomes (57.1%). CONCLUSION: This study identified thirteen antibacterial agents with significant reporting associations with VBDS. Fluoroquinolones may be a neglected agent of inducing VBDS.

Spectrum of voriconazole-associated periostitis in clinical characteristics, diagnosis and management.

PURPOSE: Previous knowledge about the relationship between voriconazole exposure and periostitis was mainly based on limited case reports and few retrospective studies. The purpose of this study was to assess the clinical characteristics, diagnosis and management of voriconazole-associated periostitis. METHODS: Case reports and case series from 1998 to November 30, 2021 on periostitis induced by voriconazole were collected for retrospective analysis. RESULTS: Forty four patients (18 male and 26 female) from 34 studies were included in total. The median age was 58 years (29-74). The majority of patients had undergone organ transplantation (50.0%) or suffered from hematologic malignancy (31.81%). The median onset time of symptoms was 6 months after the start of voriconazole. The most common initial symptom was diffuse skeletal pain (68.28%) which can be severe and even disabling (66.7%). Ribs (37.21%), femurs (32.56%), scapulae (25.58%), humerus (23.26%), and clavicle (23.26%) were the common involved locations. Most cases were accompanied by different degrees of elevated serum alkaline phosphatase and fluoride level, while some presented with elevated bone-specific alkaline phosphatase. The main radiological features included periosteal reaction and multifocal high radiotracer uptake on bone scintigraphy. The formation of new bone was characterized with bilateral, irregular, nodular, as well as high density. The resolution of symptoms was observed with discontinuation of voriconazole in all patients, of whom 18 patients (52.94%) were relieved within a week. Itraconazole, posaconazole or isavuconazole were safe alternatives to voriconazole in voriconazole-induced periostitis. CONCLUSION: Voriconazole-induced periostitis is an infrequent complication characterized by bone inflammation involving one or multiple skeletal areas. Bony pain, elevated serum alkaline phosphatase as well as fluoride level are suspicious signs during voriconazole treatment.

Analysis of the Clinical Characteristics of Dipeptidyl Peptidase-4 Inhibitor-Induced Bullous Pemphigoid.

OBJECTIVE: To analyze and discuss the clinical characteristics of dipeptidyl peptidase-4 inhibitor (DPP4i)-induced bullous pemphigoid (BP). DATA SOURCES: We collected case reports of DPP4i-induced BP by searching databases from 2006 to mid-May 2021, as a retrospective analysis. STUDY SELECTION AND DATA EXTRACTION: Relevant case reports and case analyses of DPP4i-induced BP were included. DATA SYNTHESIS: The median time of symptom onset was 9 months (range 0.5-59 months). BP most often occurred in patients receiving vildagliptin (52.63%) followed by linagliptin (27.19%) and sitagliptin (17.54%). Tense bullae and blisters (85.51%) and erythema (82.61%) on the extremities and trunk were the most common presenting symptoms. In total, 64.06% of BP patients were anti-BP180 autoantibody positive, 58.97% were BP180NC16a autoantibody positive, and 31.25% were anti-BP230 autoantibody positive. Skin biopsy revealed subepidermal bulla eosinophil infiltration in 93.85% of BP patients, lymphocyte infiltration in 56.93%, and neutrophil infiltration in 44.62%. Direct immunofluorescence was positive in 98.94% of BP patients with linear deposition of IgG (97.80%) and/or complement C3 (98.94%) along the basement membrane zone. Indirect immunofluorescence was positive in 87.88% of BP patients. Complete remission of BP was achieved in 83.64% of patients on DPP4i withdrawal and after 4 months (range 0.13-72 months) of follow-up. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review analyzes and discusses the clinical characteristics of DPP4i-induced BP and provides a reference for the safe and reasonable clinical application of DPP4i. CONCLUSIONS: DPP4i drugs are related to the occurrence of BP in diabetic patients, especially elderly men taking vildagliptin.

Celecoxib-induced drug fever: A rare case report and literature review.

WHAT IS KNOWN AND OBJECTIVE: Drug fever is frequently misdiagnosed, especially during concurrent infection. Celecoxib causes various adverse effects; however, celecoxib-induced drug fever is rarely reported. CASE SUMMARY: A 32-year-old man presented with pyrexia after 17 days of celecoxib therapy, which was reintroduced following 3-day total drug cessation. His fever recurred after this unsuspected rechallenge, which aided in the ultimate identification of the offending drug. A Naranjo Score of 8 led us to infer that drug fever was "probably" caused by celecoxib. WHAT IS NEW AND CONCLUSION: This is the first report of celecoxib-induced drug fever, aimed at assisting its diagnosis, particularly with rarely suspected causative drugs.

Retrospective analysis of skin photosensitivity induced by pirfenidone.

WHAT IS KNOWN AND OBJECTIVE: Knowledge regarding the association between photosensitivity and pirfenidone is based mainly on case reports. The purpose of this article was to evaluate the clinical characteristics of photosensitivity associated with pirfenidone. METHODS: We collected studies on photosensitivity induced by pirfenidone published from 2008 to 31 August 2021 in Chinese and English for a retrospective analysis. RESULTS AND DISCUSSION: The median age was 70 years (range 57-80) in 22 patients with pirfenidone-induced photosensitivity. The dose at the onset of symptoms ranged from 600 to 2403 mg for the treatment of idiopathic pulmonary fibrosis. Pirfenidone-induced photosensitivity occurred within 1 week in some patients and up to 8 months in others. The most common clinical manifestation of photosensitivity caused by pirfenidone was itching on body parts exposed to sunlight (back of hands, face, neck, and limbs) in 15 patients followed by erythema in 13 patients. Histopathological examination revealed necrotic keratinocytes, lymphocytic inflammatory cell infiltrate, hyperkeratosis and liquefaction degeneration in 5 patients. The photosensitivity test showed a markedly decreased minimum erythema dose (MED) of 7-228 mJ/cm2 UV-B in 4 patients and 4.86-12 J/cm2 UV-A in 5 patients. The clinical symptoms were significantly improved or completely relieved with a median time of 4 weeks (range 1-8) after drug withdrawal, dose reduction or systemic and topical glucocorticoid therapy. WHAT IS NEW AND CONCLUSION: Clinicians should be aware of the potential phototoxic effects of pirfenidone and should inform patients to take pirfenidone during (or after) a meal, avoid sun exposure, wear protective clothing, and apply broad-spectrum sunscreen with high ultraviolet UVA and UVB protection.

External evaluation of published population pharmacokinetic models of polymyxin B.

OBJECTIVES: Several population pharmacokinetics (popPK) models for polymyxin B have been constructed to optimize therapeutic regimens. However, their predictive performance remains unclear when extrapolated to different clinical centers. Therefore, this study aimed to evaluate the predictive ability of polymyxin B popPK models. METHODS: A literature search was conducted, and the predictive performance was determined for each selected model using an independent dataset of 20 patients (92 concentrations) from the Third Xiangya Hospital. Prediction- and simulation-based diagnostics were used to evaluate model predictability. The influence of prior information was assessed using Bayesian forecasting. RESULTS: Eight published studies were evaluated. In prediction-based diagnostics, the prediction error within ± 30% was over 50% in two models. In simulation-based diagnostics, the prediction- and variability-corrected visual predictive check (pvcVPC) showed satisfactory predictivity in three models, while the normalized prediction distribution error (NPDE) tests indicated model misspecification in all models. Bayesian forecasting demonstrated a substantially improvement in the model predictability even with one prior observation. CONCLUSION: Not all published models were satisfactory in prediction- and simulation-based diagnostics; however, Bayesian forecasting improved the predictability considerably with priors, which can be applied to guide polymyxin B dosing recommendations and adjustments for clinicians.

Analysis of the clinical characteristics of insulin autoimmune syndrome induced by alpha-lipoic acid.

WHAT IS KNOWN AND OBJECTIVE: Alpha-lipoic acid (ALA) is widely used as a dietary supplement and antiageing agent. Insulin autoimmune syndrome (IAS) is the most serious adverse reaction reported with the use of ALA. The purpose of this study was to explore the clinical characteristics of ALA-induced IAS and provide a scientific reference for clinical diagnosis, treatment and prevention. METHODS: We collected literature on IAS cases induced by ALA for retrospective analysis in Chinese and English. RESULTS AND DISCUSSION: The median age of 37 patients (28 females and 9 males) was 61 years (range 32-82). The symptoms occurred at night and in the early morning (60.7%), in the late postprandial period (50.0%) or after fasting (35.7%), within hours in some patients and up to 2 months in others after stopping ALA or during medication treatment. Autonomic nervous system symptoms (81.1%) and neurological hypoglycaemia (64.9%) are the main clinical manifestations of hypoglycaemia. The blood glucose concentration at the onset of hypoglycaemia was 2.19 mmol/L (median, range 1.09-3.52), the insulin concentration was ≥100 µIU/ml (94.6%), and the C-peptide concentration was ≤20 ng/ml (83.3%). Testing for IgG insulin autoantibodies (IAAs) was positive in 37 patients. Pancreatic imaging was unremarkable on computed tomography (CT), magnetic resonance imaging (MRI) and abdominal sonography. Hypoglycaemia disappeared within 5 days to 8 months after withdrawing ALA alone or using corticosteroid treatment. IAA turned negative in 7 months (median; range 2-36). Follow-up showed no recurrent hypoglycaemic episodes at 7.25 months (median; range 1-36). WHAT IS NEW AND CONCLUSION: ALA-induced IAS is a clinically rare autoimmune disease with hypoglycaemia that occurs during medication treatment or after drug withdrawal that should be treated promptly.

Analysis of the clinical characteristics of acute arthritis induced by clopidogrel.

WHAT IS KNOWN AND OBJECTIVE: Knowledge regarding the association between clopidogrel exposure and acute arthritis is based mainly on case reports. The purpose of this article was to assess the clinical characteristics of clopidogrel-induced acute arthritis. METHODS: We collected literature from 1998 to 2020 in Chinese and English on acute arthritis induced by clopidogrel for retrospective analysis. RESULTS AND DISCUSSION: The median age of 21 patients (6 females and 15 males) was 63 years (range 34-77). The median time of symptom onset was 10 days (range 0.21-21) overall. The median onset time of symptoms of clopidogrel-induced arthritis was 14 days (range 3-21) and 3 days (range 0.21-7) in patients with and without a loading dose of clopidogrel, respectively. Arthralgias (100%), joint swelling (61.9%), fever (57.1%), rash (33.3%) and pruritus (28.6%) were the most common accompanying symptoms. Most cases were accompanied by different degrees of acute inflammation markers: the median ESR was 68 mm/h (range 10-120), and the median CRP was 142.4 mg/L (range 2.3-408). X-ray films were unremarkable. Symptoms disappeared completely in all patients at a median time of 4 days (range 0.17-30) after the discontinuation of clopidogrel. Prasugrel, ticagrelor and ticlopidine can be used as safe alternatives to clopidogrel in patients with clopidogrel-induced acute arthritis with no recurrence of arthritis. WHAT IS NEW AND CONCLUSION: Clopidogrel-induced arthritis is a rare adverse reaction and should be suspected in patients with arthralgia and fever during clopidogrel use.

Rhabdomyolysis associated with newer-generation anti-seizure medications (ASMs): a real-world retrospective and pharmacovigilance study.

Objective: Rhabdomyolysis is a potentially fatal adverse reaction mostly triggered by certain medications. Few real-world studies have shown a clear association between newer-generation anti-seizure medications (ASMs) and rhabdomyolysis. We sought to quantify the risk and evaluate the clinical features and management of rhabdomyolysis associated with newer-generation ASMs. Methods: Data were retrieved from the US FDA Adverse Event Reporting System database (FAERS) from 2018 to 2022 on newer-generation ASMs to identify rhabdomyolysis events, and disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports from 2012 to 31 December 2022 on newer-generation ASMs-induced rhabdomyolysis were retrieved for retrospective analysis. Results: A total of 1,130 rhabdomyolysis reports from the FAERS database were considered. Levetiracetam had the greatest proportion and the highest positive signal values of rhabdomyolysis. The RORs (95% CIs) for newer-generation ASMs were, in descending order, levetiracetam 8.01 (7.26-8.84), lamotrigine 3.78 (3.25-4.40), oxcarbazepine 3.47 (2.53-4.75), pregabalin 2.75 (2.43-3.12), lacosamide 1.85 (1.29-2.65), topiramate 1.64 (1.25-2.15), and gabapentin 1.32 (1.13-1.55). Twenty-six case reports showed evidence of rhabdomyolysis, and levetiracetam (65.4%) was the most frequently reported agent. The median age was 32 years; typical initial symptoms included muscle weakness (34.8%), myalgia (34.8%), backache (17.4%), fatigue (13.0%) and leg pain (8.7%). The median time to onset of rhabdomyolysis was 2 days. All cases had elevated creatine phosphokinase (CPK), and some cases were accompanied by elevated creatinine (57.1%) and myoglobinuria (53.8%). Cessation of ASMs could lead to complete clinical remission. The median time for creatine phosphokinase (CPK) normalization was 8 days. Conclusion: This study identified 7 newer-generation ASMs with significant rhabdomyolysis reporting associations. Prescribers should be more aware of this risk and teach patients to recognize rhabdomyolysis signs/symptoms early.

Clinical characteristics, management, and outcome of eosinophilic pneumonia associated with daptomycin.

OBJECTIVE: The association between daptomycin exposure and eosinophilic pneumonia (EP) is mainly based on case reports. The purpose of this study was to evaluate the clinical characteristics and provide more evidence for better identify and management of daptomycin-induced eosinophilic pneumonia in clinical practice. METHODS: Literature from 1991 to October 31, 2021 on EP induced by daptomycin were collected for retrospective analysis. RESULTS: A total of 47 patients (40 male and 7 female) from 35 studies were included. The median age was 67 years (range 28-89), and 78.7% of patients were ≥60 years. Daptomycin was mainly used in patients undergoing osteoarticular infections (63.8%). Typical initial symptoms were fever (91.5%), cough (55.3%) and dyspnea (59.6%). The median onset time of symptom was 3 weeks. EP recurred in 14.9% of patients after the re-administration of daptomycin, and 57.1% of EP recurred within 24h. Most cases were accompanied by marked accumulation of eosinophils in peripheral (41 cases) and/or bronchoalveolar lavage fluid (27 cases). The main radiological features were pulmonary infiltration, ground glass opacity or consolidation in CT/CXR. All patients had symptom resolution after discontinuation of daptomycin except for one patient died due to the progression of the primary disease, the median time to symptoms relief was 3 days. Corticosteroids have been shown to help symptoms relief in some cases (59.6%). CONCLUSION: Daptomycin-induced eosinophilic pneumonia is a rare and serious complication. Physicians should consider eosinophilic pneumonia as a differential diagnosis when receiving daptomycin therapy, particularly in elderly male patients.

IL-17 inhibitor-associated inflammatory bowel disease: A study based on literature and database analysis.

Objective: Few real-world studies have shown clear association between interleukin (IL)-17 inhibitors and inflammatory bowel disease (IBD) onset. This study investigated the reporting prevalence and evaluated the clinical features and management of IL-17 inhibitor-related IBD events. Methods: We used the US FDA Adverse Event Reporting System database and retrieved data, from 2015 to 2022, on IL-17 inhibitors to identify gastrointestinal inflammatory events and conduct disproportionality analyses by estimating the reporting odds ratios (RORs) and corresponding 95% confidence intervals (CIs). Furthermore, case reports and case series, from 2015 to 30 November 2022, on IBD induced by IL-17 inhibitors were collected for retrospective analysis. Results: A total of 388 cases of primary suspected IL-17 inhibitor-associated gastrointestinal events were reported (268 IBD and 120 colitis), including 348 cases involving secukinumab (SEC), 36 cases involving ixekizumab (IXE), and 4 cases involving brodalumab (BRO). Statistically significant reporting rates of total IBD events were observed for SEC and IXE (ROR = 2.13, 95% CI [1.96-2.30] and ROR = 2.79, 95% CI [2.39-3.27], respectively), whereas BRO did not trigger a safety signal. Twenty-nine studies, which included 34 cases, showed evidence of IBD, following SEC (79.4%) and IXE (20.6%) treatment. The median age was 42 years; typical initial symptoms included diarrhea (90.9%), abdominal pain (57.6%), bloody diarrhea (51.5%), and fever (36.4%). The median time to onset of IBD symptoms was 2.9 months. Some cases were accompanied by elevated white blood cell (WBC) count (87.5%), erythrocyte sedimentation rate (ESR; 85.7%), C-reactive protein (CRP; 100%), and fecal calprotectin (FC; 100%). Cessation of IL-17 inhibitors plus treatment with corticosteroids and TNF antagonists, as either monotherapy or in combination, could lead to complete clinical remission. The median time to remission after IL-17 inhibitor discontinuation was 4 weeks. Conclusion: IL-17 inhibitor treatment is associated with exacerbation and new onset of IBD and colitis. Obtaining a detailed patient history before initiation of treatment and monitoring gastrointestinal symptoms and intestinal inflammatory biomarkers during IL-17 inhibitor treatment is important for safe use of these drugs.

Analysis of the clinical characteristics of dabigatran-induced oesophagitis.

OBJECTIVES: Dabigatran-induced oesophagitis has emerged in recent years. However, the incidence and clinical characteristics of patients with dabigatran-induced oesophagitis have not yet been clarified. The aim of this study was to examine the clinical characteristics of the disease. METHODS: A retrospective analysis was undertaken of the literature on dabigatran-induced oesophagitis in Chinese and English from 2008 onwards. RESULTS: There were 20 men (74.07%) and seven women (25.93%) in the study; their median age was 75 years (range 37-90). The main clinical symptoms were dysphagia (42.31%), odynophagia (26.92%), retrosternal pain (23.08%) and heartburn (23.08%). Endoscopy mainly showed sloughing mucosal casts (14 cases, 56%), ulcers (8 cases, 32%) and erosion (6 cases, 24%). The main injury sites were the mid to lower oesophagus (32%) and the mid oesophagus (32%). Withdrawal of dabigatran or giving the correct medication regimen resulted in rapid recovery of clinical symptoms from 1 day in some patients and up to 4 weeks, and mucosal recovery (2-5 weeks) in a median time of 3 weeks (range 0.29-48) in all patients. CONCLUSIONS: Oesophagitis is a rare complication of dabigatran with a good prognosis. Patients should be given proper medication instructions to prevent the occurrence of dabigatran-induced oesophagitis.

Engineering Hydrogels for Modulation of Dendritic Cell Function.

Dendritic cells (DCs), the most potent antigen-presenting cells, are necessary for the effective activation of naïve T cells. DCs encounter numerous microenvironments with different biophysical properties, such as stiffness and viscoelasticity. Considering the emerging importance of mechanical cues for DC function, it is essential to understand the impacts of these cues on DC function in a physiological or pathological context. Engineered hydrogels have gained interest for the exploration of the impacts of biophysical matrix cues on DC functions, owing to their extracellular-matrix-mimetic properties, such as high water content, a sponge-like pore structure, and tunable mechanical properties. In this review, the introduction of gelation mechanisms of hydrogels is first summarized. Then, recent advances in the substantial effects of developing hydrogels on DC function are highlighted, and the potential molecular mechanisms are subsequently discussed. Finally, persisting questions and future perspectives are presented.

Analysis of the clinical characteristics of pembrolizumab-induced bullous pemphigoid.

Background: Pembrolizumab, a programmed cell death protein 1 checkpoint inhibitor, is a novel drug used to treat a variety of advanced malignancies. However, it can also result in many immune-related adverse events, with cutaneous toxicities being the most frequent. Regarding pembrolizumab-induced skin adverse reactions, bullous pemphigoid (BP) has the worst effects on quality of life. Recently, there have been more and more reports of BP incidents resulting from pembrolizumab therapy in patients with cancer. This study aimed to define the clinical characteristics, diagnosis and management of pembrolizumab-induced BP and identify potential differences between classical BP and pembrolizumab-induced BP. Methods: Case reports, case series, and case analyses of pembrolizumab-induced BP up to 10 December 2022 were collected for retrospective analysis. Results: Our study included 47 patients (33 males and 14 females) from 40 studies. The median age was 72 years (range 42-86 years). The median time to cutaneous toxicity was 4 months (range 0.7-28 months), and the median time to bullae formation was 7.35 months (range 0.7-32 months). The most common clinical features were tense bullae and blisters (85.11%), pruritus (72.34%), and erythema (63.83%) on the limbs and trunk. In 20 of the 22 cases tested, the serum anti-BP180 autoantibodies were positive. However, in 10 cases (91.90%, 10/11) the circulating autoantibodies of anti-BP230 were negative. 40 patients had skin biopsies and the skin biopsy revealed subepidermal bullae or blister eosinophil infiltration in 75.00% of patients with pembrolizumab-induced BP, 10.00% of patients with lymphocyte infiltration and 20.00% of patients with neutrophil infiltration. There were 20 patients (50%) with eosinophilic infiltration around the superficial dermis vessels, 8 patients (20.00%) with lymphocyte infiltration around the superficial dermis vessels, and 4 patients (10.00%) with neutrophil infiltration around the superficial dermis vessels. Direct immunofluorescence detected linear immunoglobulin G (IgG) IgG and/or complement C3 along the dermo-epidermal junction in 36 patients (94.74%) with BP. IgG positivity was detected by indirect immunofluorescence in 81.82% of patients with BP. All patients were in complete remission (95.65%,44/46) or partial remission (4.35%, 2/46) of BP, whereas 9/46 patients had a relapse or refractory. The majority of patients achieved BP remission after discontinuation of pembrolizumab with a combination of topically and systemically administered steroid treatments, or other medications. The median duration of BP remission was 2 months (range 0.3-15 months). Conclusion: A thorough diagnosis of pembrolizumab-induced BP should be made using clinical signs, biochemical markers, histopathological and immunopathological tests. Pembrolizumab-induced BP had similar clinical characteristics to classic BP. Temporary or permanent discontinuation of pembrolizumab therapy may be required in patients with perbolizumab-induced BP depending on the severity of BP and the response to medication. Pembrolizumab-induced BP may be effectively treated using topical and systemic steroid treatments in combination with other medications (e.g., doxycycline, niacinamide, dapsone, rituximab, intravenous immunoglobulins, dupilumab, cyclophosphamide, methotrexate, mycophenolate mofetil, and infliximab). Clinicians should provide better management to patients with BP receiving pembrolizumab to prevent progression and ensure continuous cancer treatment.

Proton pump inhibitors-related subacute cutaneous lupus erythematosus: Clinical characteristics, management, and outcome.

PURPOSE: Previous knowledge about the association between proton pump inhibitors (PPIs) exposure and subacute cutaneous lupus erythematosus (SCLE) was mainly based on limited case reports or few review studies. We aim to evaluate the clinical characteristics, management, and outcome in patients with PPIs-induced SCLE. METHODS: Case reports and case series from 2000 to December 31, 2021, on SCLE induced by PPIs were collected and retrospectively analyzed. RESULTS: A total of 29 patients (6 male and 23 female) were included from 19 studies, the median age was 61 years (range 19-85), and 65.5% of patients were ≥60 years old. 37.9% of patients had the history of autoimmune diseases. The incubation period of PPIs intro to SCLE was 6 weeks for PPI-naive patients and 2 weeks for those re-administration of PPIs. The most common symptoms were annular and polycyclic erythematous (74.1%), rash or maculopapular (48.1%), and scaly plaques (40.7%). Trunk (69.2%), extremities (69.2%), face (26.9%), chest (26.9%), and back (26.9%) were common involved locations. Antinuclear antibodies, anti-Ro/SSA antibodies, and anti-La/SSB antibodies were positive in 24 patients (82.8%), 24 patients (82.8%), and 6 patients (20.7%), respectively. Direct immunofluorescence was positive in 50% of cases. Complete clinical remission (92.6%) was observed (median time: 4 weeks) with discontinuation of PPIs and treatment of oral corticosteroids (61.1%), hydroxychloroquine (44.4%), or topical steroids (16.7%). CONCLUSION: PPIs-related SCLE is a rare adverse reaction based on clinical manifestations associated with immunological abnormalities and suggestive histological findings. PPIs should be suspected when considering possible culprits for drug-related SCLE.

External Evaluation of Population Pharmacokinetic Models to Inform Precision Dosing of Meropenem in Critically Ill Patients.

Routine clinical meropenem therapeutic drug monitoring data can be applied to model-informed precision dosing. The current study aimed to evaluate the adequacy and predictive capabilities of the published models with routine meropenem data and identify the dosing adaptations using a priori and Bayesian estimation. For this, 14 meropenem models for the external evaluation carried out on an independent cohort of 134 patients with 205 meropenem concentrations were encoded in NONMEM 7.3. The performance was determined using: 1) prediction-based and simulation-based diagnostics; and 2) predicted meropenem concentrations by a priori prediction using patient covariates only; and Bayesian forecasting using previous observations. The clinical implications were assessed according to the required dose adaptations using the meropenem concentrations. All assessments were stratified based on the patients with or without continuous renal replacement therapy. Although none of the models passed all tests, the model by Muro et al. showed the least bias. Bayesian forecasting could improve the predictability over an a priori approach, with a relative bias of -11.63-68.89% and -302.96%-130.37%, and a relative root mean squared error of 34.99-110.11% and 14.78-241.81%, respectively. A dosing change was required in 40.00-68.97% of the meropenem observation results after Bayesian forecasting. In summary, the published models couldn't adequately describe the meropenem pharmacokinetics of our center. Although the selection of an initial meropenem dose with a priori prediction is challenging, the further model-based analysis combining therapeutic drug monitoring could be utilized in the clinical practice of meropenem therapy.

Analysis of the clinical characteristics of olanzapine-induced acute pancreatitis.

Numerous case reports of acute pancreatitis (AP) induced by olanzapine have been published. Little is, however, known about the clinical features of olanzapine-induced AP. The aim of the study was to explore the clinical characteristics of olanzapine-induced AP. We collected literature on AP cases induced by olanzapine from 1996 to April 2021 for retrospective analysis in Chinese and English. The median time to onset of olanzapine-induced acute pancreatic symptoms was 12 (range = 0.86-216) weeks in 25 patients. The clinical features of AP range from asymptomatic elevation of blood amylase/lipase levels to digestive system symptoms (abdominal pain, vomiting, and nausea) and even death in a small number of patients. Laboratory tests showed varying degrees of elevated serum amylase and lipase levels, along with high blood sugar and high triglyceride levels in some patients. Computed tomography showed acute edematous pancreatitis, acute hemorrhagic pancreatitis, and acute necrotizing pancreatitis in the patients. The patients' symptoms were completely relieved and high triglyceride levels gradually returned to normal levels after olanzapine was stopped. Some patients with hyperglycemia still needed hypoglycemic therapy. AP is a rare adverse effect of olanzapine. Clinicians should be aware of such complications and monitor pancreatin.