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Ca2+ entry into mitochondria is mediated by the Ca2+ uniporter-channel complex containing MCU, the Ca2+-selective pore, and associated regulatory proteins. The roles of MICU proteins are controversial. MICU1 was proposed to be necessary for MCU activity, whereas subsequent studies suggested it inhibits the channel in the low-cytoplasmic Ca2+ ([Ca2+]c) regime, a mechanism referred to as “gatekeeping,” that imposes a [Ca2+]c threshold for channel activation at ∼1–3 μM. Here, we measured MCU activity over a wide range of quantitatively controlled and recorded [Ca2+]c. MICU1 alone can mediate gatekeeping as well as highly cooperative activation of MCU activity, whereas the fundamental role of MICU2 is to regulate the threshold and gain of MICU1-mediated inhibition and activation of MCU. Our results provide a unifying model for the roles of the MICU1/2 heterodimer in MCU-channel regulation and suggest an evolutionary role for MICU2 in spatially restricting Ca2+ crosstalk between single inositol 1,4,5-trisphosphate receptor (InsP3R) and MCU channels.

The mitochondrial uniporter (MCU) is an ion channel that mediates Ca2+ uptake into the matrix to regulate metabolism, cell death, and cytoplasmic Ca2+ signaling. Matrix Ca2+ concentration is similar to that in cytoplasm, despite an enormous driving force for entry, but the mechanisms that prevent mitochondrial Ca2+ overload are unclear. Here, we show that MCU channel activity is governed by matrix Ca2+ concentration through EMRE. Deletion or charge neutralization of its matrix-localized acidic C terminus abolishes matrix Ca2+ inhibition of MCU Ca2+ currents, resulting in MCU channel activation, enhanced mitochondrial Ca2+ uptake, and constitutively elevated matrix Ca2+ concentration. EMRE-dependent regulation of MCU channel activity requires intermembrane space-localized MICU1, MICU2, and cytoplasmic Ca2+. Thus, mitochondria are protected from Ca2+ depletion and Ca2+ overload by a unique molecular complex that involves Ca2+ sensors on both sides of the inner mitochondrial membrane, coupled through EMRE.

Abstract Objectives Present follow‐up data comparing transoral and transfacial parotid gland procedures for stone removal to offer insight addressing technical considerations and complications. Methods Retrospective study of a consecutive series of surgical treatments for parotid sialolithiasis from 2013 to 2018 at an academic institution by one surgeon provided review of 16 transoral and 10 transfacial procedures supplemented by long‐term follow‐up through telephone or mail. Clinical and radiographic parameters, additional treatment, and persistence of symptoms were evaluated. Results Four of 10 patients treated with the transfacial approach had parotid‐cutaneous fistulas addressed with transdermal scopolamine patches and pressure dressings (one also with intraductal steroid infusion) with closure at a median of 12.5 days. A fifth fistula failed to resolve at 23 days and was addressed with parotidectomy. All 8 patients who were contacted (median: 106 months) reported complete resolution of symptoms. None had facial weakness. Six of 16 patients treated by a transoral approach had persistent stone fragments at the conclusion of operation. Four of these 6 patients underwent subsequent procedures (two transoral, one transfacial, one parotidectomy). Among the 11 patients who responded to long‐term follow‐up (median: 107 months), one reported mild symptoms insufficient to request treatment. Larger stone size coupled with proximal location correlated with the conversion from transoral to include transfacial approach. Conclusion Patients with retained stone remnants at the conclusion of transoral stone removal are more likely to require additional procedures that result in long‐term favorable results. The transfacial approach to stone removal offers long‐term favorable results following the common short‐term complication of salivary fistula. Level of Evidence OCEBM Level 4.

Rerouting of the parotid ducts posteriorly to drain into the tonsillar fossae (Wilkie procedure) was initially designed to address drooling in patients with cerebral palsy. This procedure was subsequently modified to include bilateral submandibular gland excision and extended to apply to other etiologies of sialorrhea. Our literature review failed to identify report of long-term follow-up beyond 2 decades following this procedure. We describe a 33-year-old female with spastic cerebral palsy who underwent the Wilkie procedure to treat sialorrhea and, 25 years later, developed right-sided facial swelling and dental infections in association with xerostomia. CT imaging showed symmetric atrophy of the parotid glands with fat replacement interspersed with fibrosis. Ultrasound analysis with shear wave elastography offered the additional interpretation of a greater degree of gland stiffness involving the tail of the recently inflamed right parotid gland compared to the left. This case report identifies long-term complications associated with xerostomia following initial success employing the Wilkie procedure to address sialorrhea. The radiographic evaluation supports the contention that rerouting of Stensen's duct may be associated with chronic obstructive changes to the parotid gland. Ultrasound shear wave elastography supplemented CT imaging by identifying asymmetric stiffness of the parotid glands as was consistent with the more recent right parotid inflammation.

Parastomal hernias (PSH) are a frequent problem mostly developing 2–3 years after index surgery impairing the life quality of affected patients. Therefore, effective prevention and treatment seems of utmost importance. However, many different surgical techniques for the treatment of PSH have been described with partially contradicting results and a low level of evidence. Therefore, this article focuses on a systematic overview of prevention and treatment for PSH. Regarding the prevention of PSH mesh-based techniques are suggested to reduce the rate of subsequent PSH, although the “keyhole” mesh, which is often used, has been shown to be ineffective for many reasons. For the treatment of PSH, the use of “funnel-shaped” meshes or Sugarbaker repair provides the most promising results. The keyhole mesh repair of PSH should be abandoned.

Abstract Objectives Reinke's edema is a chronic disease of the respiratory tract that occurs in adults with a history of chronic smoke exposure. Also known as polypoid corditis, polypoid laryngitis, and polypoid degeneration of the vocal fold, it is strongly associated with smoking, frequently with vocal misuse/abuse, and occasionally with laryngopharyngeal reflux. Reinke's edema remains a cause of chronic dysphonia that is difficult to manage. This review provides perspectives on current and future management of Reinke's edema. Results Reinke's edema impacts

Introduction: Botulinum Toxin A (BTA) has gained increasing interest in hernia surgery, especially when dealing with complex ventral hernias. The goal of using BTA is the preoperative reduction of the transverse hernia diameter achieving a higher primary fascial closure rate, avoiding a potential additional component separation. However, high evidence data are sparse and the treatment protocols of BTA and patient selection are heterogenic. In this article, we review the most recent literature; discuss indications for BTA, the ideal patient selection, and available BTA protocols. Also, we provide our own data and discuss the potential future role of BTA in treating complex ventral hernias. Materials and Methods: We reviewed the available literature and analyzed our own data from patients with complex ventral hernias undergoing preoperative BTA application retrospectively. We present our BTA protocol and measured abdominal wall muscle and hernia parameters before BTA application and before surgery using CT scans. Results: In total 22 patients with a median diameter of the incisional hernias of 11.75 cm (IQR 10.9–13.4) were included in our study. BTA administration was performed 4 weeks prior to surgery. In CT scans a significant reduction of the thickness and an elongation of the lateral abdominal wall muscle compartment were seen in all patients. Also, the transverse hernia diameter decreased in all cases from median 11.8 cm (IQR 10.9–13.4) pre-BTA to 9.1 cm (IQR 7.6–10.2) presurgery. Primary fascial closure was achieved in all cases with additional component separation in three cases. Conclusion: BTA administration in the lateral abdominal wall muscle compartment is a helpful tool to simplify surgery of complex ventral hernias. It has a visible effect on the muscle parameters in the CT scans and subsequently may increase the rate of primary fascial closure. Further multicenter studies are necessary to gain data with higher evidence.

Cardiovascular diseases (CVDs) are the primary cause of all death globally. Timely and accurate identification of people at risk of developing an atherosclerotic CVD and its sequelae is a central pillar of preventive cardiology. One widely used approach is risk prediction models; however, currently available models consider only a limited set of risk factors and outcomes, yield no actionable advice to individuals based on their holistic medical state and lifestyle, are often not interpretable, were built with small cohort sizes or are based on lifestyle data from the 1960s, e.g. the Framingham model. The risk of developing atherosclerotic CVDs is heavily lifestyle dependent, potentially making many occurrences preventable. Providing actionable and accurate risk prediction tools to the public could assist in atherosclerotic CVD prevention. Accordingly, we developed a benchmarking pipeline to find the best set of data preprocessing and algorithms to predict absolute 10-year atherosclerotic CVD risk. Based on the data of 464,547 UK Biobank participants without atherosclerotic CVD at baseline, we used a comprehensive set of 203 consolidated risk factors associated with atherosclerosis and its sequelae (e.g. heart failure). Our two best performing absolute atherosclerotic risk prediction models provided higher performance, (AUROC: 0.7573, 95% CI: 0.755-0.7595) and (AUROC: 0.7544, 95% CI: 0.7522-0.7567), than Framingham (AUROC: 0.680, 95% CI: 0.6775-0.6824) and QRisk3 (AUROC: 0.725, 95% CI: 0.7226-0.7273). Using a subset of 25 risk factors identified with feature selection, our reduced model achieves similar performance (AUROC 0.7415, 95% CI: 0.7392-0.7438) while being less complex. Further, it is interpretable, actionable and highly generalizable. The model could be incorporated into clinical practice and might allow continuous personalized predictions with automated intervention suggestions.

Objective: To assess current management of diverticulitis in Switzerland.Methods: Prospective observational study of diverticulitis management and outcomes in surgical departments over a 3-month time period. Hospital category was graded according to the Swiss Medical Association (FMH) as: U: University; A: Cantonal; B: Regional; P: Private.Results: 75 participating hospitals treated 1,015 patients, among whom 214 patients (21%) had elective sigmoid resections in 49 hospitals. Indication for elective resection were recurrent diverticulitis, previous complicated diverticulitis, fistulas, and stenosis. Surgeries were performed completely laparoscopically in 185 cases (86%) and required conversion to open in 19 cases (9%). Overall postoperative complication rate was 18% (n = 39) and no mortality was observed. Operation time, surgeons experience and hospital stay differed considerably between hospital categories.Conclusions: Elective sigmoid resection for diverticulitis in Switzerland was mainly performed laparoscopically with low postoperative morbidity. Different practices and outcomes between institutions were observed.

PURPOSE: Our primary aim was to evaluate the inhospital mortality (IHM) of elderly patients undergoing inguinal or femoral hernia repair (groin hernia repair GHR), since this growing population is associated with increased perioperative risks. MATERIALS AND METHODS: Totally 179,806 patients undergoing GHR between 2005 and 2015 in Switzerland were divided into three cohorts: 80 years) represent 8.86% (n = 15,750) of our sample. The IHM for elective GHR in these patients is low (0.15% for octogenarians and 0.8% for nonagenarians). For emergency surgery, it increases substantially (4.1% and 7.5%, respectively). In emergency cases with a combined bowel resection (n = 755), the IHM has a fivefold increase for nonagenarians when compared to the younger population. The IHM was significantly higher with femoral hernia repair, especially in the elderly (4.75% – octogenarians and 11.4% – nonagenarians). When adjusting for other variables, there is a twofold risk of death with femoral hernia repair. Patients with a Charlson Comorbidity Index (CCI) ≥2 have a 7.5 times higher risk of dying after GHR. All of these results were statistically significant (P < 0.0001). CONCLUSIONS: This retrospective analysis highlights the increased operative risk in emergency compared to elective GHR in the elderly. This should be considered when opting for watchful waiting in minimally symptomatic octo- and nonagenarians.

In this article, we put forward the substantial challenges in cyber resilience in the domain of autonomous systems and outline foundational solutions to address these challenges. These solutions fall into two broad themes: resilience-by-design and resilience-by-reaction. We use several application drivers from autonomous systems to motivate the challenges in cyber resilience and to demonstrate the benefit of the solutions. We focus on some autonomous systems in the near horizon (autonomous ground and aerial vehicles) and also a little more distant (autonomous rescue and relief). For resilience-by-design, we focus on design methods in software that are needed for our cyber systems to be resilient. In contrast, for resilience-by-reaction, we discuss how to make systems resilient by responding, reconfiguring, or recovering at runtime when failures happen. We also discuss the notion of adaptive execution to improve resilience, execution transparently and adaptively among available execution platforms (mobile/embedded, edge, and cloud). For each of the two themes, we survey the current state, and the desired state and ways to get there. We conclude the paper by looking at the research challenges we will have to solve in the short and the mid-term to make the vision of resilient autonomous systems a reality. This article came out of discussions that started at the NSF-sponsored Grand Challenges in Resilience Workshop held at Purdue in 2019 with the co-authors contributing to going into the depth of the issues and then this article.

Abstract Background The World Health Organization (WHO) Surgical Safety Checklist is used globally to ensure patient safety during surgery. Two years after its implementation in the University Hospital Basel’s operating rooms, adherence to the protocol was evaluated. Methods This mixed method observational study took place in the surgical department of the University Hospital of Basel, Switzerland from April to August 2017. Data collection was via individual structured interviews with selected OR team members regarding checklist adherence and on-site non-participant observations of Team Time Out and Team Sign Out sequences in the OR. Data were subjected to thematic analysis and descriptive statistics compiled. Results Comprehensive local expert interviews indicated that individual, procedural and contextual variables influenced the application of the checklist. Facilitating factors included well-informed specialists who advocated the use of the Checklist, as well as teams focused on the checklist’s intended process and on its content. In contrast, factors such as staff insecurity, a generally negative attitude towards the checklist, a lack of teamwork, and hesitance to complete the checklist, hindered its implementation. The checklist’s application was evaluated in 104 on-site observations comprising of 72 Team Time Out (TTO) and 32 Team Sign Out (TSO) sections. Adherence to the protocol ranged between 96 and 100% in TTO and 22% in TSO respectively. Lack of implementation of the TSO was mainly due to the absence of one of the key OR team members, who were busy with other tasks or no longer present in the operating room. Conclusion The study illustrates factors, which foster and hinder consistent application of the WHO surgical safety checklist namely individual, procedural and contextual. It also demonstrates that the TTO was consistently and correctly applied, while the unavailability of key OR team members at sign-out time was the most common reason for omission or incomplete use of the TSO.

Even though the receptor activator of the nuclear factor-κB ligand (RANKL) and its receptor RANK have an exclusive role in osteoclastogenesis, the possibility of RANK/RANKL-independent osteoclastogenesis has been the subject of a long-standing debate in bone biology. In contrast, it has been reported that calvarial injection of TNF-ɑ elicits significant osteoclastogenesis in the absence of RANK/RANKL in NF-κB2- and RBP-J-deficient mice, suggesting that inflammatory challenges and secondary gene manipulation are the prerequisites for RANK/RANKL-deficient mice to develop osteoclasts in vivo. Here we report that, even in the absence of RANKL (Rankl−/−), cherubism mice (Sh3bp2KI/KI) harboring the homozygous gain-of-function mutation in SH3-domain binding protein 2 (SH3BP2) develop tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts spontaneously. The Sh3bp2KI/KI Rankl−/− mice exhibit an increase in tooth exposure and a decrease in bone volume/total volume compared to Sh3bp2+/+ Rankl−/− mice. The multinucleated cells were stained positively for cathepsin K. Osteoclastic marker gene expression in bone and serum TRAP5b levels were elevated in Sh3bp2KI/KI Rankl−/− mice. Elevation of the serum TNF-ɑ levels suggested that TNF-ɑ is a driver for the RANKL-independent osteoclast formation in Sh3bp2KI/KI mice. Our results provide a novel mutant model that develops osteoclasts independent of RANKL and establish that the gain-of-function of SH3BP2 promotes osteoclastogenesis not only in the presence of RANKL but also in the absence of RANKL.

Abstract Background The Rearranged during Transfection (RET) protein is overexpressed in a subset of Estrogen Receptor (ER) positive breast cancer, with both signalling pathways functionally interacting. This cross-talk plays a pivotal role in the resistance of breast cancer cells to anti-endocrine therapies, and RET expression is assumed to correlate with poor prognosis based on findings in small patient cohorts. The aim of our study was to investigate the impact of RET expression on patient outcome in human breast cancer. Methods We performed an immunohistochemical analysis of RET protein expression on a tissue microarray encompassing 990 breast cancer patients and correlated its expression with clinicopathological parameters and survival data. Results Expression of RET was detected in 409 out of 990 cases (41.3%). RET and ER expression significantly correlated (p

INTRODUCTION: Thromboembolic prophylaxis (TP) is an effective strategy to reduce the risk of thromboembolic events such as deep vein thrombosis and pulmonary embolism. In the absence of patient- and procedure-related risk factors, the risk of thromboembolic events is considerably low among surgical patients. Since hernia repair is thought to be a low-risk procedure, the role of TP in patients undergoing hernia surgery is a matter of debate. METHODS: A systematic search of the literature was conducted in Medline/PubMed and the Cochrane database. Forty-eight relevant publications were identified. RESULTS: Overall, there is a paucity of studies specifically investigating the impact of TP in patients undergoing hernia surgery. Available studies demonstrate that the risk of thromboembolic events with TP in inguinal hernia repair is approximately 0.1%, comparable to other low-risk procedures. Lower rates of thromboembolic events are seen in outpatient surgery. Laparoscopy and implanted mesh in the groin do not increase the risk of thromboembolic events. CONCLUSION: Due to the limited data, no recommendation for or against TP in hernia surgery can be made. Further studies are urgently needed to investigate the effect of TP on the risk of thromboembolic events in patients undergoing hernia repair.

Background: Dystonia is a heterogeneous hyperkinetic disorder. The anatomical location of the dystonia helps clinicians guide their evaluation and treatment plan. When dystonia involves masticatory, lingual, and pharyngeal muscles, it is referred to as oromandibular dystonia (OMD).Methods: We identified patients diagnosed with OMD in a Movement Disorders Clinic and Laryngeal Movement Disorders Clinic from a single institution. Demographic, etiological, clinical, and therapeutic information was retrospectively reviewed for patients with jaw‐opening (O‐OMD) and jaw‐closing (C‐OMD) OMD.Results: Twenty‐seven patients were included. Their average age of onset was in the sixth decade of life and there was a female predominance. Etiological factors linked in this study to OMD included a family history of dystonia or essential tremor, occupation, cerebellar disease, a dental disorder, and tardive syndrome. Clinically, patients with C‐OMD presented with more prominent feeding difficulties, but seemed to respond better to therapy than those with O‐OMD. In addition to the known benefits of botulinum toxin therapy, patients who described sensory tricks obtained benefit from the use of customized dental prosthesis.Discussion: This works provides useful information on potential etiological factors for OMD and its response to therapy, and highlights the potential benefit of dental prosthesis for the treatment of OMD.

BACKGROUND: Whilst surgery will face an imminent workforce shortage, an increasing majority of students decide against a surgical career. This study evaluated the current career expectations of medical students and tested a hands-on virtual reality (VR) intervention as a tool to increase their interest in surgery. METHODS: Randomly selected medical students of the University of Basel received a short questionnaire to rank their interest in five different postgraduate working environments prior to a lecture. After the lecture they participated in a hands-on VR demonstration. Thereafter an online questionnaire regarding workplace expectations, surgery and VR was sent to the students. RESULTS: The online questionnaire response rate was 87% (225/258). Before using the VR intervention, a nonsurgical career was preferred by the majority of students, followed by a surgical career, cross-disciplinary specialties, research and, finally, nonclinical work. Surgery (n = 99, 44%) and emergency medicine (n = 111, 49%) were rated as incompatible with a good work-life balance. Further drawbacks to surgery were apprehension of competitive mentality, unclear career perspectives and longer working hours. The VR intervention had limited impact on re-ranking the five working sectors and slightly increased the students’ interest in surgery. CONCLUSION: Students’ work environment expectations, their declining interest in a surgical career and the increasing need for surgeons represent challenges for surgical societies to address, in order to improve the attractiveness of surgery amongst students. VR sessions may be integrated as part of the actions required to improve students’ interest in a surgical career and should be further evaluated within controlled study designs.

Introduction: Surgical site infections (SSI) are the most common hospital-acquired infections among surgical patients, with significant impact on patient morbidity and health care costs. The Basel SSI Cohort Study was performed to evaluate risk factors and validate current preventive measures for SSI. The objective of the present article was to review the main results of this study and its implications for clinical practice and future research. Summary of methods of the Basel SSI Cohort Study: The prospective observational cohort study included 6,283 consecutive general surgery procedures closely monitored for evidence of SSI up to 1 year after surgery. The dataset was analysed for the influence of various potential SSI risk factors, including timing of surgical antimicrobial prophylaxis (SAP), glove perforation, anaemia, transfusion and tutorial assistance, using multiple logistic regression analyses. In addition, post hoc analyses were performed to assess the economic burden of SSI, the efficiency of the clinical SSI surveillance system, and the spectrum of SSI-causing pathogens. Review of main results of the Basel SSI Cohort Study: The overall SSI rate was 4.7% (293/6,283). While SAP was administered in most patients between 44 and 0 minutes before surgical incision, the lowest risk of SSI was recorded when the antibiotics were administered between 74 and 30 minutes before surgery. Glove perforation in the absence of SAP increased the risk of SSI (OR 2.0; CI 1.4–2.8; p 1 year after surgery. More than eighty patient and procedure variables were recorded, including age, sex, American Society of Anaesthesiologists (ASA) score, type of procedure, surgical team members, division of surgical speciality, timing of SAP, wound class, duration of surgery, compromised asepsis, and many other known and suspected SSI risk factors. We used an electronically readable form created by Cardiff TELEForm Software (Cardiff TELEForm Desktop V 8.0, 2002, Verity Inc., Sunnyvale, CA) to export the data into an Excel file (Windows Microsoft Excel 2003, Microsoft Corporation). The primary predictor variable of the first analysis was SAP timing. We divided time into intervals, and chose the cutoffs of 120 and 0 minutes before surgery on the basis of the findings of Classen et al. [7]. SAP was administered intravenously by the anaesthetists via single-shot infusion of 1.5 g cefuroxime in 20 ml sodium chloride solution over a few minutes in combination with metronidazole (500 mg, intravenous, 5 minutes) in colorectal patients. The exact time in minutes when the infusion of SAP ended was prospectively recorded by the anaesthesia team. The main predictor variable of the second analysis was compromised asepsis due to glove perforation. The operating room nurse was responsible for the detection and registration, either directly when glove perforation itself was visible or indirectly when liquid was detected inside a glove. When double gloves were used, leakage of the inner glove was noted. The main predictor variables of the third analysis were perioperative ABT and preoperative anaemia. Perioperative ABT was performed by the anesthesia team in the operating room. The number of allogeneic blood units was monitored. All blood donations were leukocyte-depleted (leukocytes