Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases

Polyketide synthases (PKSs) are biosynthetic factories that produce natural products with important biological and pharmacological activities1, 2, 3. Their exceptional product diversity is encoded in a modular architecture. Modular PKSs (modPKSs) catalyse reactions colinear to the order of modules in an assembly line3, whereas iterative PKSs (iPKSs) use a single module iteratively as exemplified by fungal iPKSs (fiPKSs)3. However, in some cases non-colinear iterative action is also observed for modPKSs modules and is controlled by the assembly line environment4, 5. PKSs feature a structural and functional separation into a condensing and a modifying region as observed for fatty acid synthases6. Despite the outstanding relevance of PKSs, the detailed organization of PKSs with complete fully reducing modifying regions remains elusive. Here we report a hybrid crystal structure of Mycobacterium smegmatis mycocerosic acid synthase based on structures of its condensing and modifying regions. Mycocerosic acid synthase is a fully reducing iPKS, closely related to modPKSs, and the prototype of mycobacterial mycocerosic acid synthase-like7, 8 PKSs. It is involved in the biosynthesis of C20–C28 branched-chain fatty acids, which are important virulence factors of mycobacteria9. Our structural data reveal a dimeric linker-based organization of the modifying region and visualize dynamics and conformational coupling in PKSs. On the basis of comparative small-angle X-ray scattering, the observed modifying region architecture may be common also in modPKSs. The linker-based organization provides a rationale for the characteristic variability of PKS modules as a main contributor to product diversity. The comprehensive architectural model enables functional dissection and re-engineering of PKSs

Injury patterns and outcomes in motorcycle driver crashes in the United States: The effect of helmet use.

BACKGROUND Motorcycle crashes pose a persistent public health problem with disproportionate rates of severe injuries and mortality. This study aims to analyze injury patterns and outcomes with regard to helmet use. We hypothesized that helmet use is associated with fewer head injuries and does not increase the risk of cervical spine injuries. METHODS The National Trauma Data Bank was queried for all motorcycle driver crashes between 2007-2017. Univariable analysis was used to compare demographics, clinical data, injury patterns using abbreviated injury scale, and outcomes between helmeted motorcycle drivers and non-helmeted motorcycle drivers who were injured in traffic crashes. Independent factors associated with mortality were determined by regression analysis after adjustment for potential confounders. RESULTS A total of 315,258 patients were included for analysis, 66 % of these patients were helmeted. The sample was 92.5 % male and the median age was 41 years. Non-helmeted motorcycle drivers were more likely to sustain severe head trauma (head abbreviated injury scale ≥ 3: 28.5 % vs. 13.3 %, p < 0.001), had higher intensive care unit-admission (38 % vs. 30.2 %, p<0.001), mechanical ventilation (20.1 % vs. 13 %, p<0.001) and overall mortality rates (6.2 % vs. 3.9 %, p<0.001). Cervical spine injuries occurred in 10.6 % of non-helmeted motorcycle drivers and in 9.5 % of helmeted motorcycle drivers (p<0.001). Helmet use was identified as an independent factor associated with lower mortality [OR 0.849 (0.809-0.891), p<0.001]. CONCLUSION Helmet use is protective for severe head injuries and associated with decreased mortality. Helmet use was not associated with increased rates of cervical spine injuries. On the contrary, fewer injuries were observed in helmeted motorcycle drivers. Public health initiatives should be aimed at enforcement of universal helmet laws within the United States and across the world

Surgical Repair vs Splenectomy in Patients With Severe Traumatic Spleen Injuries.

IMPORTANCE The spleen is often removed in laparotomy after traumatic abdominal injury, with little effort made to preserve the spleen. OBJECTIVE To explore the association of surgical management (splenic repair vs splenectomy) with outcomes in patients with traumatic splenic injuries undergoing laparotomy and to determine whether splenic repair is associated with lower mortality compared with splenectomy. DESIGN, SETTING, AND PARTICIPANTS This is a trauma registry-based cohort study using the American College of Surgeons Trauma Quality Improvement Program database from January 2013 to December 2019. Participants included adult patients with severe splenic injuries (Abbreviated Injury Scale [AIS] grades 3-5) undergoing laparotomy after traumatic injury within 6 hours of admission. Data analysis was performed from April to August 2023. EXPOSURES Splenic repair vs splenectomy in patients with severe traumatic splenic injury. MAIN OUTCOMES AND MEASURES The primary outcome was in-hospital mortality. Outcomes were compared using different statistical approaches, including 1:1 exact matching with consecutive conditional logistic regression analysis as the primary analysis and multivariable logistic regression, propensity score matching, and inverse-probability weighting as sensitivity analyses. RESULTS A total of 11 247 patients (median [IQR] age, 35 [24-52] years; 8179 men [72.7%]) with a severe traumatic splenic injury undergoing laparotomy were identified. Of these, 10 820 patients (96.2%) underwent splenectomy, and 427 (3.8%) underwent splenic repair. Among patients who underwent an initial splenic salvage procedure, 23 (5.3%) required a splenectomy during the subsequent hospital stay; 400 patients with splenic preservation were matched with 400 patients who underwent splenectomy (matched for age, sex, hypotension, trauma mechanism, AIS spleen grade, and AIS groups [0-2, 3, and 4-5] for head, face, neck, thorax, spine, and lower and upper extremity). Mortality was significantly lower in the splenic repair group vs the splenectomy group (26 patients [6.5%] vs 51 patients [12.8%]). The association of splenic repair with lower mortality was subsequently verified by conditional regression analysis (adjusted odds ratio, 0.4; 95% CI, 0.2-0.9; P = .03). Multivariable logistic regression, propensity score matching, and inverse-probability weighting confirmed this association. CONCLUSIONS AND RELEVANCE In this retrospective cohort study, splenic repair was independently associated with lower mortality compared with splenectomy during laparotomy after traumatic splenic injury. These findings suggest that efforts to preserve the spleen might be indicated in selected cases of severe splenic injuries

Spontaneous Atraumatic Rupture of a Liver Hemangioma as a Rare Cause of Syncope.

BACKGROUND Syncope is common in emergency medicine, but only a minority of syncopes is caused by hemorrhage. Liver hemangioma is the most frequent benign liver tumor, and they rarely lead to symptoms or complications. Case Presentation. We describe the case of an 81-year-old man with hemorrhagic shock due to an atraumatic rupture of a hepatic hemangioma while on oral anticoagulation. The patient presented to the emergency department after three episodes of syncope before admission, nausea, vomiting, mild epigastric abdominal pain, but with clinical signs of peritonitis. On admission, the patient had a mild tachycardia with a heart rate of 107/min and a blood pressure of 102/83 mmHg. Initial hemoglobin was 122 g/L, and lactate was slightly elevated (2.5 mmol/L). Bedside sonography revealed free intraabdominal fluid. The subsequent computed tomography showed a ruptured hemangioma of the liver with ongoing hemorrhage. After the CT scan, the patient became increasingly tachycardic and the blood pressure dropped to 94/62 mmHg. After administration of blood products and intravenous fluids, the patient responded with improved hemodynamics and was transferred to angiology for emergency embolization. After the intervention, the patient spent two days in the intermediate care unit and was discharged after 10 days of hospitalization. CONCLUSION Atraumatic rupture of a hemangioma with consecutive hemorrhagic shock is extremely rare. In selected cases of spontaneously ruptured hemangiomas with hemoperitoneum, endovascular embolization can be an alternative to surgery. Furthermore, this case emphasizes the importance of sonographic examination as an additional diagnostic tool in syncope and concomitant abdominal pain

Cattle-related trauma: a 10-year retrospective cohort study of patients admitted to a single tertiary trauma centre in Switzerland.

AIMS OF THE STUDY Switzerland is traditionally an agricultural country with more than 50,000 farms and 1.5 million registered cows. However, contemporary literature on cattle-related trauma in Switzerland remain limited. The purpose of this study was to examine injury patterns and outcomes of patients who presented to a tertiary trauma centre in Switzerland following cattle-related trauma. METHODS Retrospective single-centre study over a 10-year period (2012-2021) including all patients experiencing cattle-related trauma. From retrieved charts demographics, injury data, and outcomes were collected and subsequently analysed. RESULTS A total of 94 patients with cattle-related injuries were identified. The median age was 52 years (interquartile range [IQR] 37-63) and 75% were male. Cattle-related injuries were most frequent among farmers (73%) and were most often caused by cows (86%), followed by bulls (10%). Blunt trauma (89%) was the leading mechanism of injury including headbutt (36%), kick (35%), physical contact (20%) and trampling injury (12%). Penetrating injury occurred in 11%, all caused by headbutt. Contusions (82%) and lacerations (45%) were the leading injuries, followed by face fractures (28%), closed head trauma (19%) and chest injuries (17%). Overall, 10% of all patients had a head abbreviated injury scale (AIS) score of ≥3 and 8% had a chest AIS of ≥3. The hospital admission rate was 49% for cow-related injury vs 90% for bull-related injuries, p = 0.023. Overall, in-hospital mortality was 3% and the median length of stay was 4.5 days (IQR 3-8) among patients admitted to the hospital. CONCLUSIONS Cattle-related injuries in Switzerland mainly affect farmers and are associated with considerable morbidity, especially when caused by bulls. Facial fractures, head injuries and chest injuries are common, and the latter two in particular can be severe. The results of the present study can be used for the implementation of data-driven prevention measures for the safe handling of cattle in Switzerland

The forgotten cohort-lessons learned from prehospital trauma death: a retrospective cohort study.

BACKGROUND Trauma related deaths remain a relevant public health problem, in particular in the younger male population. A significant number of these deaths occur prehospitally without transfer to a hospital. These patients, sometimes termed "the forgotten cohort", are usually not included in clinical registries, resulting in a lack of information about prehospitally trauma deaths. The aim of the present study was to compare patients who died prehospital with those who sustained life-threatening injuries in order to analyze and potentially improve prehospital strategies. METHODS This cohort study included all primary operations carried out by Switzerland's largest helicopter emergency medical service (HEMS) between January 1, 2011, and December 31, 2021. We included all adult trauma patients with life-threatening or fatal conditions. The outcome of this study is the vital status of the patient at the end of mission, i.e. fatal or life-threatening. Injury, rescue characteristics, and interventions of the forgotten trauma cohort, defined as patients with a fatal injury (NACA score of VII), were compared with life-threatening injuries (NACA score V and VI). RESULTS Of 110,331 HEMS missions, 5534 primary operations were finally analyzed, including 5191 (93.8%) life-threatening and 343 (6.2%) fatal injuries. More than two-thirds of patients (n = 3772, 68.2%) had a traumatic brain injury without a significant difference between the two groups (p > 0.05). Thoracic trauma (44.6% vs. 28.7%, p < 0.001) and abdominal trauma (22.2% vs. 16.1%, p = 0.004) were more frequent in fatal missions whereas pelvic trauma was similar between the two groups (13.4% vs. 12.9%, p = 0.788). Pneumothorax decompression rate (17.2% vs. 3.7%, p < 0.001) was higher in the forgotten cohort group and measures for bleeding control (15.2% vs. 42.7%, p < 0.001) and pelvic belt application (2.9% vs. 13.1% p < 0.001) were more common in the life-threating injury group. CONCLUSION Chest decompression rates and measures for early hemorrhage control are areas for potential improvement in prehospital care

Risk factors for thromboembolic complications in isolated severe head injury.

PURPOSE Patients with traumatic brain injury (TBI) are at high risk for venous thromboembolism (VTE). The aim of the present study is to identify factors independently associated with VTE events. Specifically, we hypothesized that the mechanism of penetrating head trauma might be an independent factor associated with increased VTE events when compared with blunt head trauma. METHODS The ACS-TQIP database (2013-2019) was queried for all patients with isolated severe head injuries (AIS 3-5) who received VTE prophylaxis with either unfractionated heparin or low-molecular-weight heparin. Transfers, patients who died within 72 h and those with a hospital length of stay < 48 h were excluded. Multivariable analysis was used as the primary analysis to identify independent risk factors for VTE in isolated severe TBI. RESULTS A total of 75,570 patients were included in the study, 71,593 (94.7%) with blunt and 3977 (5.3%) with penetrating isolated TBI. Penetrating trauma mechanism (OR 1.49, CI 95% 1.26-1.77), increasing age (age 16-45: reference; age > 45-65: OR 1.65, CI 95% 1.48-1.85; age > 65-75: OR 1.71, CI 95% 1.45-2.02; age > 75: OR 1.73, CI 95% 1.44-2.07), male gender (OR 1.53, CI 95% 1.36-1.72), obesity (OR 1.35, CI 95% 1.22-1.51), tachycardia (OR 1.31, CI 95% 1.13-1.51), increasing head AIS (AIS 3: reference; AIS 4: OR 1.52, CI 95% 1.35-1.72; AIS 5: OR 1.76, CI 95% 1.54-2.01), associated moderate injuries (AIS = 2) of the abdomen (OR 1.31, CI 95% 1.04-1.66), spine (OR 1.35, CI 95% 1.19-1.53), upper extremity (OR 1.16, CI 95% 1.02-1.31), lower extremity (OR 1.46, CI 95% 1.26-1.68), craniectomy/craniotomy or ICP monitoring (OR 2.96, CI 95% 2.65-3.31) and pre-existing hypertension (OR 1.18, CI 95% 1.05-1.32) were identified as independent risk factors for VTE complications in isolated severe head injury. Increasing GCS (OR 0.93, CI 95% 0.92-0.94), early VTE prophylaxis (OR 0.48, CI 95% 0.39-0.60) and LMWH compared to heparin (OR 0.74, CI 95% 0.68-0.82) were identified as protective factors for VTE complications. CONCLUSION The identified factors independently associated with VTE events in isolated severe TBI need to be considered in VTE prevention measures. In penetrating TBI, an even more aggressive VTE prophylaxis management may be justified as compared to that in blunt

Prehospital and Emergency Room Airway Management in Traumatic Brain Injury

Airway management in trauma is critical and may impact patient outcomes. Particularly in traumatic brain injury (TBI), depressed level of consciousness may be associated with compromised protective airway reflexes or apnea, which can increase the risk of aspiration or result in hypoxemia and worsen the secondary brain damage. Therefore, patients with TBI and Glasgow Coma Scale (GCS) ≤ 8 have been traditionally managed by prehospital or emergency room (ER) endotracheal intubation. However, recent evidence challenged this practice and even suggested that routine intubation may be harmful. This chapter will address the indications and optimal method of securing the airway, prehospital and in the ER, in patients with traumatic brain injury

Multi-Component Imaging of the Fermi Gamma-ray Sky in the Spatio-spectral Domain

We perform two distinct spatio-spectral reconstructions of the gamma-ray sky in the range of 0.56-316 GeV based on Fermi Large Area Telescope (LAT) data. Both describe the sky brightness to be composed of a diffuse-emission and a point-source component. The first model requires minimal assumptions and provides a template-free reconstruction as a reference. It makes use of spatial and spectral correlations to distinguish between the different components. The second model is physics-informed and further differentiates between diffuse emission of hadronic and leptonic origin. For this, we assume parametric, but spatially varying energy spectra to distinguish between the processes and use thermal Galactic dust observations to indicate the preferred sites of hadronic interactions. To account for instrumental effects we model the point-spread, the energy dispersion, and the exposure of the telescope throughout the observation. The reconstruction problem is formulated as a Bayesian inference task, that is solved by variational inference. We show decompositions of the Gamma-ray flux into diffuse and point-like emissions, and of the diffuse emissions into multiple physically motivated components. The diffuse decomposition provides an unprecedented view of the Galactic leptonic diffuse emission. It shows the Fermi bubbles and their spectral variations in high fidelity and other areas exhibiting strong cosmic ray electron contents, such as a thick disk in the inner Galaxy and outflow regions. Furthermore, we report a hard spectrum gamma ray arc in the northern outer bubble co-spatial with the reported X-ray arc by the eROSITA collaboration. All our spatio-spectral sky reconstructions and their uncertainty quantification are publicly available