Structural basis for CCR6 modulation by allosteric antagonists.

The CC chemokine receptor 6 (CCR6) is a potential target for chronic inflammatory diseases. Previously, we reported an active CCR6 structure in complex with its cognate chemokine CCL20, revealing the molecular basis of CCR6 activation. Here, we present two inactive CCR6 structures in ternary complexes with different allosteric antagonists, CCR6/SQA1/OXM1 and CCR6/SQA1/OXM2. The oxomorpholine analogues, OXM1 and OXM2 are highly selective CCR6 antagonists which bind to an extracellular pocket and disrupt the receptor activation network. An energetically favoured U-shaped conformation in solution that resembles the bound form is observed for the active analogues. SQA1 is a squaramide derivative with close-in analogues reported as antagonists of chemokine receptors including CCR6. SQA1 binds to an intracellular pocket which overlaps with the G protein site, stabilizing a closed pocket that is a hallmark of inactive GPCRs. Minimal communication between the two allosteric pockets is observed, in contrast to the prevalent allosteric cooperativity model of GPCRs. This work highlights the versatility of GPCR antagonism by small molecules, complementing previous knowledge of CCR6 activation, and sheds light on drug discovery targeting CCR6.

The sword of Damocles for the splenectomised: death by OPSI.

The overwhelming post splenectomy infection (OPSI) in splenectomised patients is a rare but severe infection mostly caused by encapsulated bacteria. We analyse the case of a 65-year-old female patient who was presented with clinical and laboratory findings indicating gastroenteritis. Two years years before admission, the patient underwent a splenectomy for a two stage splenic rupture following resuscitation for pulmonary embolism. Immunisation of the patient was complete and timely. As a result of the unspecific clinical presentation, there was a delay in administration of antibiotics. However, administration of antibiotics induced a fulminant shock. The patient died 4 hours after attending the hospital due to a pneumococcal sepsis. The discussion highlights epidemiological and pathophysiological aspects and potential prevention strategies in the international context. Vaccination failed in our patient as the isolated pneumococcal strain (serogroup: 12F) is usually covered by the 23-valent pneumococcal polysaccharide vaccination (Pneumovax(®)). The case reported here indicates that there may be a potential benefit of prophylactic antibiotic treatment within the first 3 years after splenectomy for patients above the age of 65 years. Awareness of OPSI (prevention strategies, symptoms and treatment) among patients and their treating physicians is crucial for the improvement of prognosis. We partly address these issues in a standard operating procedure for the assessment of splenectomised patients in our departments of emergency medicine.

Symptoms and clinical course of EHEC O104 infection in hospitalized patients: a prospective single center study.

OBJECTIVES: Shiga-toxin producing O157:H7 Entero Haemorrhagic E. coli (STEC/EHEC) is one of the most common causes of Haemolytic Uraemic Syndrome (HUS) related to infectious haemorrhagic colitis. Nearly all recommendations on clinical management of EHEC infections refer to this strain. The 2011 outbreak in Northern Europe was the first to be caused by the serotype O104:H4. This EHEC strain was found to carry genetic features of Entero Aggregative E. coli (EAEC) and extended spectrum ß lactamase (ESBL). We report symptoms and complications in patients at one of the most affected centres of the 2011 EHEC O104 outbreak in Northern Germany. METHODS: The courses of patients admitted to our hospital due to bloody diarrhoea with suspected EHEC O104 infection were recorded prospectively. These data include the patients' histories, clinical findings, and complications. RESULTS: EHEC O104 infection was confirmed in 61 patients (female = 37; mean age: 44±2 years). The frequency of HUS was 59% (36/61) in our cohort. An enteric colonisation with co-pathogens was found in 57%. Thirty-one (51%) patients were treated with plasma-separation/plasmapheresis, 16 (26%) with haemodialysis, and 7 (11%) with Eculizumab. Patients receiving antibiotic treatment (n = 37; 61%) experienced no apparent change in their clinical course. Twenty-six (43%) patients suffered from neurological symptoms. One 83-year-old patient died due to comorbidities after HUS was successfully treated. CONCLUSIONS: EHEC O104:H4 infections differ markedly from earlier reports on O157:H7 induced enterocolitis in regard to epidemiology, symptomatology, and frequency of complications. We recommend a standard of practice for clinical monitoring and support the renaming of EHEC O104:H4 syndrome as "EAHEC disease".

The First View Concept: introduction of industrial flow techniques into emergency medicine organization.

The number of patients seeking treatment in emergency departments is rising, although many governments are seeking to reduce expenditure on health. Emergency departments must achieve more with the same resources or perform the same functions with fewer resources. Patients demand higher emergency clinical care quality, with low waiting times viewed as a key quality criterion by many patients. The objective of this study was to create an improved working system in emergency departments that cuts patient waiting times for first specialty physician contact. Techniques from industrial flow management were applied to the working process of an emergency department and the concept was named 'First View.' A total of 3269 patient contacts using the First View Concept during a treatment month showed statistical significance. Before introduction, a total 3230 patients in a comparative treatment month had a median waiting time before the first doctor contact of 47.6 min, a first quartile waiting time of 36.1 min, and a third quartile waiting time of 62.7 min. After introduction, 3269 patients had a median waiting time before first specialty physician contact of 11.2 min, a first quartile waiting time of 9.1 min, and a third quartile waiting time of 15.2 min. Industrial flow concepts can achieve significant improvements in emergency department workflows in countries in which sufficient numbers of specialty physicians are available. More attention to the organization of emergency department working processes is needed, especially involving lean management.

International perspectives on emergency department crowding.

The maturation of emergency medicine (EM) as a specialty has coincided with dramatic increases in emergency department (ED) visit rates, both in the United States and around the world. ED crowding has become a public health problem where periodic supply and demand mismatches in ED and hospital resources cause long waiting times and delays in critical treatments. ED crowding has been associated with several negative clinical outcomes, including higher complication rates and mortality. This article describes emergency care systems and the extent of crowding across 15 countries outside of the United States: Australia, Canada, Denmark, Finland, France, Germany, Hong Kong, India, Iran, Italy, The Netherlands, Saudi Arabia, Catalonia (Spain), Sweden, and the United Kingdom. The authors are local emergency care leaders with knowledge of emergency care in their particular countries. Where available, data are provided about visit patterns in each country; however, for many of these countries, no national data are available on ED visits rates or crowding. For most of the countries included, there is both objective evidence of increases in ED visit rates and ED crowding and also subjective assessments of trends toward higher crowding in the ED. ED crowding appears to be worsening in many countries despite the presence of universal health coverage. Scandinavian countries with robust systems to manage acute care outside the ED do not report crowding is a major problem. The main cause for crowding identified by many authors is the boarding of admitted patients, similar to the United States. Many hospitals in these countries have implemented operational interventions to mitigate crowding in the ED, and some countries have imposed strict limits on ED length of stay (LOS), while others have no clear plan to mitigate crowding. An understanding of the causes and potential solutions implemented in these countries can provide a lens into how to mitigate ED crowding in the United States through health policy interventions and hospital operational changes.