Copper/ruthenium relay catalysis enables 1,6-double chiral inductions with stereodivergence.

The dual catalysis strategy is an efficient and powerful tool to fulfill the stereodivergent synthesis of stereoisomeric products from the same set of starting materials. Great attention has been given to the construction of chiral compounds with two contiguous stereocenters. However, the synthesis of two remote noncontiguous stereocenters is more challenging and is less developed, despite the high demand for synthetic tactics. We herein developed an unprecedented example of the stereodivergent preparation of synthetically useful and biologically important chiral ζ-hydroxy amino ester derivatives containing remote 1,6-noncontiguous stereocenters and a unique ß,γ-unsaturation moiety. This cascade dehydrogenation/1,6-Michael addition/hydrogenation protocol between readily-available ketoimine esters and racemic branched dienyl carbinols was rationally realized with bimetallic copper/ruthenium relay catalysis. The key features of the process were atom economy, step economy, and redox-neutrality. All four stereoisomers of chiral ζ-hydroxy amino ester derivatives were easily achieved by the orthogonal permutations of a chiral copper catalyst and chiral ruthenium catalyst. Importantly, a much more challenging stereodivergent synthesis of all eight stereoisomers of chiral peptide products containing three remote stereocenters was accomplished with excellent results through the cooperation of two chiral catalyst pairs and substrate enantiomers.

Stereodivergent synthesis of α-fluoro α-azaaryl γ-butyrolactones via cooperative copper and iridium catalysis.

The development of stereodivergent synthetic methods to access all four stereoisomers of biologically important α-fluoro γ-butyrolactones containing vicinal stereocenters is of great importance and poses a formidable challenge owing to ring strain and steric hindrance. Herein, a novel asymmetric [3+2] annulation of α-fluoro α-azaaryl acetates with vinylethylene carbonate was successfully developed through Cu/Ir-catalyzed cascade allylic alkylation/lactonization, affording a variety of enantioenriched α-fluoro γ-butyrolactones bearing vicinal stereogenic centers with high reaction efficiency and excellent levels of both stereoselectivity and regioselectivity (up to 98% yield, generally >20:1 dr and >99% ee). Notably, all four stereoisomers of these pharmaceutically valuable molecules could be accessed individually via simple permutations of two enantiomeric catalysts. In addition, other azaaryl acetates bearing α-methyl, α-chlorine or α-phenyl group were tolerated well in this transformation. Reaction mechanistic investigations were conducted to explore the process of this bimetallic catalysis based on the results of reaction intermediates, isotopic labelling experiments, and kinetic studies.

Clinical characteristics, treatment and outcome of pembrolizumab-induced acute pancreatitis.

Acute pancreatitis (AP) is a rare adverse event of pembrolizumab with unclear clinical features. This study investigated the clinical features of pembrolizumab-induced AP to provide a reference for prevention and treatment. Case reports, case series and clinical studies of pembrolizumab-induced AP were collected by searching Chinese and English databases up to January 31, 2024. Thirty-one patients were included, with a median age of 59 years (range 39, 82). The median time from administration to onset of AP was 5.05 months (range 0.5, 16) and the median cycle was 7 cycles (range 1, 35). Twenty-two (71.0%) patients had elevated pancreatic amylase with a median value of 860 IU/L (range 105-12562), and 16 (51.6%) patients had elevated lipase with a median value of 282 IU/L (range 153-1034). Pancreatic biopsy showed neutrophil infiltration (9.7%) and lymphocyte infiltration (6.5%). Immunohistochemical staining showed CD8 dominated inflammatory infiltration (6.5%). The computed tomography showed diffuse enlargement (51.6%) and focal enlargement (51.6%) of the pancreas. Endoscopic ultrasound showed enlarged hypoechoic pancreas(16.1%). PET/CT showed increased FDG uptake (16.1%). The magnetic resonance cholangial pancreatography showed narrowing of main pancreatic duct (12.9%). AP symptoms and pancreatic enzymes improved after discontinuation of pembrolizumab and administration of steroids and infliximab. Clinicians should be aware that AP is a rare adverse reaction to pembrolizumab. Pembrolizumab induced AP can be initiated with steroids for control, and infliximab can be initiated with steroid-refractory AP.

Visible-light-enabled stereoselective synthesis of functionalized cyclohexylamine derivatives via [4 + 2] cycloadditions.

An unprecedented intermolecular [4 + 2] cycloaddition of benzocyclobutylamines with α-substituted vinylketones, enabled by photoredox catalysis, has been developed. The current method enables facile access to highly functionalized cyclohexylamine derivatives that were otherwise inaccessible, in moderate to good yields with excellent diastereoselectivities. This protocol has some excellent features, such as full atom economy, good functional-group compatibility, mild reaction conditions, and an overall redox-neutral process. Additionally, an asymmetric version of this cycloaddition was preliminarily investigated via the incorporation of a chiral phosphoric acid (CPA), and moderate to good enantioselectivity could be effectively realized with excellent diastereoselectivity. Synthetic applications were demonstrated via a scale-up experiment and elaborations to access amino alcohol and cyclobutene derivatives. Based on the results of control experiments, a reasonable reaction mechanism was proposed to elucidate the reaction pathway.

Clinical Characteristics and Outcomes of Pembrolizumab Induced Gastritis: A Systematic Review of the Literature.

BACKGROUND: Pembrolizumab is associated with the development of gastritis, but its clinical features have not been characterized. To explore the clinical features of pembrolizumab induced gastritis and provide reference for the prevention and treatment of gastritis. METHODS: Case reports and case series related to pembrolizumab induced gastritis were retrospectively analyzed by searching the database from inception to September 30, 2023. RESULTS: Thirty-nine patients with gastritis entered the study with a median age of 63 years (range 34, 81). The median time to gastritis was 11.1 months (range 0.3, 60) and 7 cycles (range 1, 27) after administration. Epigastric pain (24 cases, 61.5%), nausea (17 cases, 43.6%), and vomiting (16 cases, 41.0%) were the most frequently complained symptoms. Esophagogastroduodenoscopy mainly showed erythematous (16 cases, 41.0%), hemorrhage (14 cases, 35.9%) and erosions (11 cases, 28.2%). Gastric mucosal biopsy shows chronic active gastritis with lymphocytic infiltration. These patients' symptoms and gastric mucosa improved or recovered after receiving systemic steroid and proton pump inhibitor therapy regardless of whether pembrolizumab was discontinued. These patients' symptoms and gastric mucosa improved or recovered after treatment with systemic steroids, proton pump inhibitors, and biological agents. CONCLUSIONS: Gastritis is an extremely rare adverse effect of pembrolizumab. When patients receiving pembrolizumab complain of abdominal symptoms, endoscopy, tissue biopsy, and immunohistochemical staining should be actively performed for early identification and diagnosis of gastritis.

Clinical features, treatment, and outcomes of patients with carfilzomib induced thrombotic microangiopathy.

BACKGROUND: Thrombotic microangiopathy (TMA) is associated with carfilzomib, and knowledge of carfilzomib-induced TMA is based mainly on case reports. This study investigated the clinical characteristics of patients with carfilzomib-induced TMA and provided a reference for the rational use of carfilzomib. METHODS: Reports of carfilzomib-induced TMA were collected for retrospective analysis by searching the Chinese and English databases from inception to January 31, 2024. RESULTS: Sixty-six patients were included, with a median age of 63 years (range 39, 85). The median time to onset of TMA was 42 days (range 1, 1825) from initial administration, and the median number of cycles was 3 cycles (range 1, 15). Hemolytic anemia was recorded in 64 patients, with a median of 8.3 g/dL (range 4.6, 13). Sixty-three patients had thrombocytopenia with a median of 18 × 109/L (range 1, 139). The median value of increased LDH was 1192 IU/L (range 141, 5378). ADAMTS13 activity was normal in 41 (62.1 %) of the 42 patients. Mutations were found in 9 (13.6 %) of the 15 patients. Fifty-seven patients achieved a clinical response after discontinuing carfilzomib and receiving therapeutic plasma exchange (53.0 %), eculizumab (24.2 %), or hemodialysis (39.4 %). CONCLUSION: Carfilzomib-induced TMA is an important adverse event that should be considered in patients receiving carfilzomib for multiple myeloma with anemia, thrombocytopenia, and acute kidney injury. Withdrawal of carfilzomib and treatment with eculizumab have proven successful in some patients.

Clinical features, treatment, and outcome of pembrolizumab induced cholangitis.

Pembrolizumab induced hepatitis has received increasing attention, while pembrolizumab induced cholangitis is poorly understood. This study investigated the clinical features, treatment, and outcome of pembrolizumab induced cholangitis. Case reports, case series and clinical studies of pembrolizumab induced cholangitis were collected by retrieving English and Chinese database from inception until October 30, 2023. Fifty patients with cholecystitis entered our study with a median age of 68 years (range 48, 89). The median time to onset of cholecystitis was 1.1 months (range 0.3, 24), and the median number of cycles was 5 cycles (range 1, 27) after initial administration. Most of the patients had no clinical symptoms and only showed elevated biliary enzymes (24 cases, 48.0%), while some patients showed jaundice (12 cases, 24.0%), abdominal pain (10 cases, 20.0%) and fever (7 cases, 14.0%). The median alkaline phosphatase value was 1111 IU(range 130, 3515) and the median glutamyltransferase value was 649.5 IU(range 159, 3475). The imaging features of gallbladder were bile duct dilatation, stenosis and bile duct wall thickening and irregularity. Bile duct biopsy showed inflammatory infiltration, mainly CD8 + T cell infiltration. Immunosuppression treatment resulted in complete response in 4 cases (8.0%), partial response in 28 cases (56.0%), and poor response in 15 cases (30.0%). Cholangitis is a rare and serious adverse effect of pembrolizumab. Clinicians should be aware of the possibility of cholangitis when administering pembrolizumab. Steroids may not be effective in most patients with cholecystitis, and ursodeoxycholic acid may be an option.

Iridium-catalyzed asymmetric cascade dearomative allylation/acyl transfer rearrangement: access to chiral N-substituted 2-pyridones.

Iridium-catalyzed dearomative allylation/acyl transfer rearrangement has been developed using easily available 2-pyridinyl benzoates and vinyl ethylene carbonate. This protocol enabled the expedient synthesis of a variety of chiral N-substituted 2-pyridones in good to high yields with excellent enantioselectivity. It has the advantages of high atom economy, wide substrate scope, gram-scale synthesis, and versatile synthetic transformations.

Non-cytopathic bovine viral diarrhea virus (BVDV) inhibits innate immune responses via induction of mitophagy.

Bovine viral diarrhea virus (BVDV) belongs to the genus Pestivirus within the family Flaviviridae. Mitophagy plays important roles in virus-host interactions. Here, we provide evidence that non-cytopathic (NCP) BVDV shifts the balance of mitochondrial dynamics toward fission and induces mitophagy to inhibit innate immune responses. Mechanistically, NCP BVDV triggers the translocation of dynamin-related protein (Drp1) to mitochondria and stimulates its phosphorylation at Ser616, leading to mitochondrial fission. In parallel, NCP BVDV-induced complete mitophagy via Parkin-dependent pathway contributes to eliminating damaged mitochondria to inhibit MAVS- and mtDNA-cGAS-mediated innate immunity responses, mtROS-mediated inflammatory responses and apoptosis initiation. Importantly, we demonstrate that the LIR motif of ERNS is essential for mitophagy induction. In conclusion, this study is the first to show that NCP BVDV-induced mitophagy plays a central role in promoting cell survival and inhibiting innate immune responses in vitro.

Machine learning for the early prediction of acute respiratory distress syndrome (ARDS) in patients with sepsis in the ICU based on clinical data.

Background: Acute respiratory distress syndrome (ARDS) is a fatal outcome of severe sepsis. Machine learning models are helpful for accurately predicting ARDS in patients with sepsis at an early stage. Objective: We aim to develop a machine-learning model for predicting ARDS in patients with sepsis in the intensive care unit (ICU). Methods: The initial clinical data of patients with sepsis admitted to the hospital (including population characteristics, clinical diagnosis, complications, and laboratory tests) were used to predict ARDS, and screen out the crucial variables. After comparing eight different algorithms, namely, XG boost, logistic regression, light GBM, random forest, GaussianNB, complement NB, support vector machine (SVM), and K nearest neighbors (KNN), rebuilding a prediction model with the best one. When remodeling with the best algorithm, 10% was randomly selected to test, and the remaining was trained for cross-validation. Using the area under the curve (AUC), sensitivity, accuracy, specificity, positive and negative predictive value, F1 score, kappa value, and clinical decision curve to evaluate the model's performance. Eventually, the application in the model illustrated by the SHAP package. Results: Ten critical features were screened utilizing the lasso method, namely, PaO2/PAO2, A-aDO2, PO2(T), CRP, gender, PO2, RDW, MCH, SG, and chlorine. The prior ranking of variables demonstrated that PaO2/PAO2 was the most significant variable. Among the eight algorithms, the performance of the Gaussian NB algorithm was significantly better than that of the others. After remodeling with the best algorithm, the AUC in the training and validation sets were 0.777 and 0.770, respectively, and the algorithm performed well in the test set (AUC = 0.781, accuracy = 78.6%, sensitivity = 82.4%, F1 score = 0.824). A comparison of the overlap factors with those of previous models revealed that the model we developed performs better. Conclusion: Sepsis-associated ARDS can be accurately predicted early via a machine learning model based on existing clinical data. These findings are helpful for accurate identification and improvement of the prognosis in patients with sepsis-associated ARDS.

Research on Computing Resource Measurement and Routing Methods in Software Defined Computing First Network.

Computing resource measurement and computing routing are essential technologies in the computing first network (CFN), serving as its foundational elements. This paper introduces a Software Defined Computing First Network (SD-CFN) architecture. Building upon this framework, a Dynamic-Static Integrated Computing Resource Measurement Mechanism (DCRMM) is proposed, incorporating methods such as the entropy weight method and K-Means clustering. The DCRMM algorithm outperforms the Maximum-closest Static Algorithm (MSA) and Maximum Closest Dynamic Algorithm (MDA) in terms of node stability, node utilization, and node matching accuracy. Additionally, a Reinforcement Learning and Software Defined Computing First Networking Routing (RSCR) algorithm is presented as a software-defined computing routing solution within the SD-CFN. RSCR introduces a knowledge plane responsible for computing routing calculations. It comprehensively considers factors such as link latency, available bandwidth, and packet loss rate. Simulation experiments conducted on the GÉANT topology demonstrate that RSCR outperforms the OSPF algorithm in terms of link latency, packet loss rate, and throughput. DCRMM and RSCR offer innovative solutions for computing resource measurement and computing routing in computing first networks.

Modular access to chiral bridged piperidine-γ-butyrolactones via catalytic asymmetric allylation/aza-Prins cyclization/lactonization sequences.

Chiral functionalized piperidine and lactone heterocycles are widely spread in natural products and drug candidates with promising pharmacological properties. However, there remains no general asymmetric methodologies that enable rapid assemble both critical biologically important units into one three-dimensional chiral molecule. Herein, we describe a straightforward relay strategy for the construction of enantioenriched bridged piperidine-γ-butyrolactone skeletons incorporating three skipped stereocenters via asymmetric allylic alkylation and aza-Prins cyclization/lactonization sequences. The excellent enantioselectivity control in asymmetric allylation with the simplest allylic precursor is enabled by the synergistic Cu/Ir-catalyzed protocol; the success of aza-Prins cyclization/lactonization can be attributed to the pivotal role of the ester substituent, which acts as a preferential intramolecular nucleophile to terminate the aza-Prins intermediacy of piperid-4-yl cation species. The resulting chiral piperidine-γ-butyrolactone bridged-heterocyclic products show impressive preliminary biological activities against a panel of cancer cell lines.

Clinical characteristics, diagnosis, treatment, and prognosis of nivolumab induced gastritis.

Gastritis has recently been reported to be associated with nivolumab, and the clinical characteristics of nivolumab induced gastritis remain unclear. To explore the clinical characteristics of nivolumab induced gastritis, and to provide reference for the classification and treatment guidelines of immune checkpoint inhibitors -related gastritis. Case reports, case series, and clinical studies of nivolumab induced gastritis were retrospectively analyzed by searching the database from the establishment of the database until September 30, 2023. Forty-seven were included, with a median age of 57 years (range 16, 93). The median time of symptom onset was 6 months (range 0.5,36) and 6.5 cycles (range 2, 62). Nausea (29 cases, 61.7%), vomiting (29 cases, 61.7%), and epigastric pain (28 cases, 59.6%) were the most common complaints. Esophagogastroduodenoscopy mainly showed erythema (28 cases, 59.6%). Gastric mucosa biopsy showed epithelial inflammatory cell infiltration (22 cases, 46.8%) and apoptosis (15 cases, 31.9%). Most patients' symptoms and gastric mucosa improved or recovered after receiving systemic steroid and proton pump inhibitor therapy regardless of whether nivolumab was discontinued. Two patients died from gastritis related events. Gastritis should be considered as the cause of unexplained epigastric symptoms in the administration of nivolumab. Understanding the clinical features of nivolumab induced gastritis is very important for accurate diagnosis and timely management of these patients.

Comparison of clinical outcomes among patients with isolated axial vs muscular calf vein thrombosis: A systematic review and meta-analysis.

OBJECTIVE: Thrombi in the axial calf veins have quite different anatomical and physiological characteristics from that in the muscular calf veins, but their treatment was usually addressed in the same manner. We performed a meta-analysis of randomized and cohort studies to compare clinical outcomes among patients with isolated axial vs muscular calf deep vein thrombosis (DVT). METHODS: Recurrent venous thromboembolism (VTE) was selected as the primary outcome. Resolution, proximal propagation of calf DVT, pulmonary embolism (PE), major bleeds, and clinically relevant non-major bleeds were separately analyzed as secondary outcomes. Data were pooled and compared with risk ratio (RR) and 95% confidence interval (CI). RESULTS: Thirteen studies, consisting of 4889 patients, met the inclusion criteria and were included for analysis. A greater rate of recurrent VTE (FE model: RR, 1.23; 95% CI, 1.00-1.53; I2 = 29%), resolution (FE model: RR, 1.32; 95% CI, 1.01-1.72; I2 = 31%), proximal propagation (FE model: RR, 1.63; 95% CI, 1.10-2.41; I2 = 40%), and PE (FE model: RR, 2.79; 95% CI, 1.31-5.95; I2 = 0%) in the axial group compared with the muscular group. There was no difference in the pooled estimates for major bleeds (FE model: RR, 1.09; 95% CI, 0.61-1.95; I2 = 0%), and clinically relevant non-major bleeds (FE model: RR, 1.80; 95% CI, 0.93-3.48) in the axial and muscular arms. CONCLUSIONS: Patients with calf DVT limited to muscular veins might have a lower rate of recurrent VTE, resolution, proximal propagation, and PE vs those with axial calf vein involvement and exhibited similar safety outcomes.

Copper/Ruthenium Relay Catalysis for Stereodivergent Access to δ-Hydroxy α-Amino Acids and Small Peptides.

An atom- and step-economical and redox-neutral cascade reaction enabled by asymmetric bimetallic relay catalysis by merging a ruthenium-catalyzed asymmetric borrowing-hydrogen reaction with copper-catalyzed asymmetric Michael addition has been realized. A variety of highly functionalized 2-amino-5-hydroxyvaleric acid esters or peptides bearing 1,4-non-adjacent stereogenic centers have been prepared in high yields with excellent enantio- and diastereoselectivity. Judicious selection and rational modification of the Ru catalysts with careful tuning of the reaction conditions played a pivotal role in stereoselectivity control as well as attenuating undesired α-epimerization, thus enabling a full complement of all four stereoisomers that were otherwise inaccessible in previous work. Concise asymmetric stereodivergent synthesis of the key intermediates for biologically important chiral molecules further showcases the synthetic utility of this methodology.

Clinical characteristics, treatments, and outcomes of interferon-beta-induced thrombotic microangiopathy: a literature-based retrospective analysis.

Background: Thrombotic microangiopathy (TMA) is a rare side effect of interferon-beta (IFN-ß) therapy. The clinical characteristics of IFN-ß-induced TMA are unknown. Objectives: To explore the clinical characteristics of IFN-ß-induced TMA and provide reference for the prevention of TMA. Design: Articles on IFN-ß-induced TMA were collected by searching the literature in relevant Chinese and English databases from inception to 31 July 2023. Methods: Data in the articles were extracted and analyzed retrospectively. Results: Forty-seven patients, with a median age of 41 years (range 22, 66), were included in the analysis. The median time to the diagnosis of IFN-ß-induced TMA was 8 years (range 0.1-30) after administration. The main clinical symptoms were neurological symptoms (51.1%), hypertension (78.7%), dyspnea (19.1%), edema (19.1%), asthenia/fatigue (19.1%), and digestive symptoms (17.0%). Most patients presented with hemolytic anemia (76.6%), thrombocytopenia (63.8%), and acute kidney injury (70.2%). All patients stopped IFN-ß and received plasma exchange therapy (53.2%), systemic steroids (46.8%), antihypertensive therapy (46.8%), eculizumab (12.8%), and rituximab (12.8%). Kidney damage was not completely reversible; 40.4% of patients achieved renal function and hematology remission, 27.7% developed chronic kidney disease, 25.5% developed end-stage renal disease, and 2.1% died. Conclusion: IFN-ß-induced TMA is a rare but serious complication that can be life-threatening. It may occur after many years of IFN-ß therapy, and patients taking IFN-ß should be monitored for symptoms such as headache and hypertension.

Organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles via de novo indole formation.

The first organocatalytic atroposelective synthesis of axially chiral N,N'-pyrrolylindoles based on o-alkynylanilines was successfully established via de novo indole formation catalyzed by chiral phosphoric acid (CPA). This new synthetic strategy introduced CPA-catalyzed asymmetric 5-endo-dig cyclization of new well-designed o-alkynylanilines containing a pyrrolyl unit, resulting in a wide range of axially chiral N,N'-pyrrolylindoles in high yields with exclusive regioselectivity and excellent enantioselectivity (up to 99% yield, >20 : 1 rr, 95 : 5 er). Considering the potential biological significance of N-N atropisomers, preliminary biological activity studies were performed and revealed that these structurally important N,N'-pyrrolylindoles had a low IC50 value with promising impressive cytotoxicity against several kinds of cancer cell lines. DFT studies reveal that the N-nucleophilic cyclization mediated by CPA is the rate- and stereo-determining step, in which ligand-substrate dispersion interactions facilitate the axial chirality of the target products.

Clinical characteristics, treatment, and management of pembrolizumab induced hemophagocytic lymphohistiocytosis.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare and fatal adverse reaction to pembrolizumab. The clinical characteristics of pembrolizumab induced HLH are unknown. Exploring the clinical features of pembrolizumab induced HLH is crucial for the treatment and prevention of immune checkpoint inhibitor-induced HLH. METHODS: The literature related to pembrolizumab induced HLH was collected for retrospective analysis by searching the Chinese and English databases from inception until August 31, 2023. RESULTS: A total of 24 patients were included, including 17 men (70.8%) with a median age of 61 years (41,80). The time between the last infusion and the start of HLH ranged from 2 to 46 days, with a median time of 14 days. Fever (100%) was the most common symptom, accompanied by splenomegaly (14 cases, 58.3%) and hepatomegaly (6 cases, 25.0%). Laboratory examination revealed revealed anemia (18 cases, 75.0%), leukopenia (12 cases, 50.0%), thrombocytopenia (20 cases, 83.3%), hypertriglyceridemia (11 cases, 45.8%), hypofibrinogenemia (11 cases, 45.8%). decreased natural killer cell function (7 cases, 29.2%), and elevated soluble CD25(15 cases, 62.5%). All patients developed hyperferriinemia, with a median of 30,808 ng/mL (range 1303 ~ 100,000). Bone marrow biopsy showed hemophagocytosis (15 cases, 62.5%). After discontinuation of pembrolizumab and treatment with steroids, etoposide, intravenous immunoglobulin, cytokine blocking, and immunosuppression, 17 patients recovered or improved, and 5 patients eventually died. CONCLUSION: HLH should be suspected when unexplained fever, cytopenia, splenomegaly, and elevated aminotransferase occur in patients using pembrolizumab. Screening for risk factors before treatment with pembrolizumab may be necessary to prevent HLH.

Clinical Characteristics, Diagnosis, and Management of Aseptic Meningitis Induced by Trimethoprim-Sulfamethoxazole.

Objective: Trimethoprim sulfamethoxazole (TMP-SMX) is related to aseptic meningitis. However, a detailed description of its phenotype is lacking, which easily leads to misdiagnosis. The purpose of this article is to explore the clinical characteristics of TMP-SMX-induced aseptic meningitis (TSIAM). Methods: We collected literature related to TSIAM published before July 31, 2023, by searching Chinese and English databases. Data were extracted and analyzed descriptively. Results: The 55 patients were mostly female (60.0%), with a median age of 43 years (range: 2.5-90 years). The first onset time was from a few minutes to 3 months after administration, and the time of reonset was within 12 hours. Fever (98.2%), headache (78.2%), altered mental status (42.3%), nausea and vomiting (41.8%), and neck pain (34.5%) were the most common symptoms. In severe cases, patients presented with low blood pressure, seizures, unconsciousness, or coma. Typical cerebrospinal fluid analysis showed elevated white blood cell counts, with polymorphonuclear leukocytes predominating, elevated protein levels, and normal glucose levels. Brain imaging usually showed no abnormalities. Symptoms resolved rapidly after the discontinuation of TMP-SMX, within a median time of 2 days (range: 1, 60). Readministration of TMP-SMX led to another relapse of aseptic meningitis. Aseptic meningitis usually culminated in a full recovery, although one patient experienced permanent paraplegia. Conclusion: Clinicians should be aware that aseptic meningitis is a rare adverse effect of TMP-SMX. TMP-SMX should be discontinued in patients with TSIAM to reduce unnecessary testing and treatment, and readministration of TMP-SMX should be avoided.

Clinical characterization, treatment, and outcome of nivolumab-induced bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a serious and rare complication of nivolumab. This study aimed to explore the clinical characteristics of nivolumab-induced BP and provide a reference for prevention and treatment of BP. METHODS: Literature on nivolumab-induced BP was collected for retrospective analysis by searching both Chinese and English databases as of July 31, 2023. RESULTS: Sixty patients were included, with a median age of 71 years (range 30 to 85 years), and they were predominantly male (78.3%). The median time to onset of BP was 31 weeks (range 2.4, 216) after nivolumab administration. Tense bullae (93.3%), pruritus (55.0%), and urticarial plaques (31.7%) were the most common manifestations. Lesions were found on the limbs (50.0%), trunk (38.3%), palms and soles (15.0%). Skin biopsies mainly showed subepidermal bullous/blister (50.0%) and eosinophilic infiltration (46.7%). Direct immunofluorescence showed mainly linear deposition of C3 and IgG (46.7%) at the dermal-epidermal junction. The patients stopped taking nivolumab and received systemic steroids (73.3%), topical steroids (63.3%), monoclonal antibodies (21.7%), doxycycline/minocycline (30.0%) and other treatments. Symptoms improved or were relieved in 88.4% of patients but did not improve in 8.3% of patients. CONCLUSION: Clinicians should closely monitor symptoms of BP in those receiving and discontinuing nivolumab, especially in older men. Early diagnosis and timely initiation of treatment may improve patient outcomes.