Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid–binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17–driven inflammatory skin conditions such as psoriasis

Evaluation of Protocol Uniformity Concerning Laparoscopic Cholecystectomy in The Netherlands

Background: Iatrogenic bile duct injury remains a current complication of laparoscopic cholecystectomy. One uniform and standardized protocol, based on the "critical view of safety" concept of Strasberg, should red

2020 WSES guidelines for the detection and management of bile duct injury during cholecystectomy.

Bile duct injury (BDI) is a dangerous complication of cholecystectomy, with significant postoperative sequelae for the patient in terms of morbidity, mortality, and long-term quality of life. BDIs have an estimated incidence of 0.4-1.5%, but considering the number of cholecystectomies performed worldwide, mostly by laparoscopy, surgeons must be prepared to manage this surgical challenge. Most BDIs are recognized either during the procedure or in the immediate postoperative period. However, some BDIs may be discovered later during the postoperative period, and this may translate to delayed or inappropriate treatments. Providing a specific diagnosis and a precise description of the BDI will expedite the decision-making process and increase the chance of treatment success. Subsequently, the choice and timing of the appropriate reconstructive strategy have a critical role in long-term prognosis. Currently, a wide spectrum of multidisciplinary interventions with different degrees of invasiveness is indicated for BDI management. These World Society of Emergency Surgery (WSES) guidelines have been produced following an exhaustive review of the current literature and an international expert panel discussion with the aim of providing evidence-based recommendations to facilitate and standardize the detection and management of BDIs during cholecystectomy. In particular, the 2020 WSES guidelines cover the following key aspects: (1) strategies to minimize the risk of BDI during cholecystectomy; (2) BDI rates in general surgery units and review of surgical practice; (3) how to classify, stage, and report BDI once detected; (4) how to manage an intraoperatively detected BDI; (5) indications for antibiotic treatment; (6) indications for clinical, biochemical, and imaging investigations for suspected BDI; and (7) how to manage a postoperatively detected BDI

ADAR1 interaction with Z-RNA promotes editing of endogenous double-stranded RNA and prevents MDA5-dependent immune activation

Loss of function of adenosine deaminase acting on double-stranded RNA (dsRNA)-1 (ADAR1) causes the severe autoinflammatory disease Aicardi-Goutières syndrome (AGS). ADAR1 converts adenosines into inosines within dsRNA. This process called A-to-I editing masks self-dsRNA from detection by the antiviral dsRNA sensor MDA5. ADAR1 binds to dsRNA in both the canonical A-form and the poorly defined Z conformation (Z-RNA). Mutations in the Z-RNA-binding Zα domain of ADAR1 are common in patients with AGS. How loss of ADAR1/Z-RNA interaction contributes to disease development is unknown. We demonstrate that abrogated binding of ADAR1 to Z-RNA leads to reduced A-to-I editing of dsRNA structures formed by base pairing of inversely oriented short interspersed nuclear elements. Preventing ADAR1 binding to Z-RNA triggers an MDA5/MAVS-mediated type I interferon response and leads to the development of lethal autoinflammation in mice. This shows that the interaction between ADAR1 and Z-RNA restricts sensing of self-dsRNA and prevents AGS development.</p

ADAR1 prevents autoinflammation by suppressing spontaneous ZBP1 activation

The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) limits the accumulation of endogenous immunostimulatory double-stranded RNA (dsRNA)(.) In humans, reduced ADAR1 activity causes the severe inflammatory disease Aicardi-Goutieres syndrome (AGS). In mice, complete loss of ADAR1 activity is embryonically lethal, and mutations similar to those found in patients with AGS cause autoinflammation. Mechanistically, adenosine-to-inosine (A-to-I) base modification of endogenous dsRNA by ADAR1 prevents chronic overactivation of the dsRNA sensors MDA5 and PKR. Here we show that ADAR1 also inhibits the spontaneous activation of the left-handed Z-nucleic acid sensor ZBP1. Activation of ZBP1 elicits caspase-8-dependent apoptosis and MLKL-mediated necroptosis of ADAR1-deficient cells. ZBP1 contributes to the embryonic lethality of Adar-knockout mice, and it drives early mortality and intestinal cell death in mice deficient in the expression of both ADAR and MAVS. The Z-nucleic-acid-binding Z alpha domain of ADAR1 is necessary to prevent ZBP1-mediated intestinal cell death and skin inflammation. The Z alpha domain of ADAR1 promotes A-to-I editing of endogenous Alu elements to prevent dsRNA formation through the pairing of inverted Alu repeats, which can otherwise induce ZBP1 activation. This shows that recognition of Alu duplex RNA by ZBP1 may contribute to the pathological features of AGS that result from the loss of ADAR1 function

Scapula fractures: interobserver reliability of classification and treatment

OBJECTIVES:There is substantial variation in the classification and the management of scapula fractures. The first purpose of this study was to analyze the interobserver reliability of the OTA/AO and the New International Classification of scapula fractures. The second purpose was to assess the proportion of agreement among orthopaedic surgeons on operative or nonoperative treatment. DESIGN:: Web-based reliability study SETTING:: Independent orthopaedic surgeons from several countries were invited to classify scapular fractures in an online survey. PARTICIPANTS:One-hundred and three orthopaedic surgeons evaluated 35 movies of 3DCT-reconstruction of selected scapular fractures, representing a full spectrum of fracture patterns. MAIN OUTCOME MEASUREMENTS:Fleiss' kappa (κ) was used to assess the reliability of agreement between the surgeons. RESULTS:: The overall agreement on the OTA/AO Classification was moderate for the types (A, B, and C, κ = 0.54) with a 71% proportion of rater agreement (PA) as well as for the nine groups (A1 to C3, κ = 0.47) with a 57% PA. For the New International Classification, the agreement about the intra-articular extension of the fracture (Fossa (F), κ = 0.79) was substantial, the agreement about a fractured body (Body (B), κ = 0.57) or process was moderate (Process (P), κ = 0.53), however PAs were more than 81%. The agreement on the treatment recommendation was moderate (κ = 0.57) with a 73% PA. CONCLUSIONS:The New International Classification was more reliable. Body and process fractures generated more disagreement than intra-articular fractures and need further clear definitions