Hypusination Maintains Intestinal Homeostasis and Prevents Colitis and Carcinogenesis by Enhancing Aldehyde Detoxification.

BACKGROUND & AIMS: The amino acid hypusine, synthesized from the polyamine spermidine by the enzyme deoxyhypusine synthase (DHPS), is essential for the activity of eukaryotic translation initiation factor 5A (EIF5A). The role of hypusinated EIF5A (EIF5AHyp) remains unknown in intestinal homeostasis. Our aim was to investigate EIF5AHyp in the gut epithelium in inflammation and carcinogenesis. METHODS: We used human colon tissue messenger RNA samples and publicly available transcriptomic datasets, tissue microarrays, and patient-derived colon organoids. Mice with intestinal epithelial-specific deletion of Dhps were investigated at baseline and in models of colitis and colon carcinogenesis. RESULTS: We found that patients with ulcerative colitis and Crohn's disease exhibit reduced colon levels of DHPS messenger RNA and DHPS protein and reduced levels of EIF5AHyp. Similarly, colonic organoids from colitis patients also show down-regulated DHPS expression. Mice with intestinal epithelial-specific deletion of Dhps develop spontaneous colon hyperplasia, epithelial proliferation, crypt distortion, and inflammation. Furthermore, these mice are highly susceptible to experimental colitis and show exacerbated colon tumorigenesis when treated with a carcinogen. Transcriptomic and proteomic analysis on colonic epithelial cells demonstrated that loss of hypusination induces multiple pathways related to cancer and immune response. Moreover, we found that hypusination enhances translation of numerous enzymes involved in aldehyde detoxification, including glutathione S-transferases and aldehyde dehydrogenases. Accordingly, hypusination-deficient mice exhibit increased levels of aldehyde adducts in the colon, and their treatment with a scavenger of electrophiles reduces colitis. CONCLUSIONS: Hypusination in intestinal epithelial cells has a key role in the prevention of colitis and colorectal cancer, and enhancement of this pathway via supplementation of spermidine could have a therapeutic impact.

Time and Risk Factors of Trauma-Related Mortality: A 5-Year Retrospective Analysis From a National Level I Trauma Center.

Background: We aimed to analyze in-hospital timing and risk factors for mortality in a level 1 trauma center. Methods: This is a retrospective analysis of all trauma-related mortality between 2013 and 2018. Patients were divided and analyzed based on the time of mortality (early (≤48 h) vs late (>48 h)), and within different age groups. Multivariate regression analysis was performed to predict in-hospital mortality. Results: 8624 trauma admissions and 677 trauma-related deaths occurred (47.7% at the scene and 52.3% in-hospital). Among in-hospital mortality, the majority were males, with a mean age of 35.8 ± 17.2 years. Most deaths occurred within 3-7 days (35%), followed by 33% after 1 week, 20% on the first day, and 12% on the second day of admission. Patients with early mortality were more likely to have a lower Glasgow coma scale, a higher shock index, a higher chest and abdominal abbreviated injury score, and frequently required exploratory laparotomy and massive blood transfusion (P < .005). The injury severity scores and proportions of head injuries were higher in the late mortality group than in the early group. The severity of injuries, blood transfusion, in-hospital complications, and length of intensive care unit stay were comparable among the age groups, whereas mortality was higher in the age group of 19 to 44. The higher proportions of early and late in-hospital deaths were evident in the age group of 24 to 29. In multivariate analysis, the shock index (OR 2.26; 95%CI 1.04-4.925; P = .04) was an independent predictor of early death, whereas head injury was a predictor of late death (OR 4.54; 95%CI 1.92-11.11; P = .001). Conclusion: One-third of trauma-related mortalities occur early after injury. The initial shock index appears to be a reliable hemodynamic indicator for predicting early mortality. Therefore, timely hemostatic resuscitation and appropriate interventions for bleeding control may prevent early mortality.

Presentations and management of hospitalized patients with upper extremity fractures at a level 1 trauma center: a 5-year observational study.

BACKGROUND: Upper extremity injuries (UEIs) are common in the emergency departments, yet they are under-reported in developing countries. This study examined the frequency, injury characteristics, and treatment approaches of upper extremity fractures (UEFs) among hospitalized trauma patients in a nationally representative population. METHODS: We conducted a retrospective, observational study including all the hospitalized patients with UEFs in the only level 1 trauma center in Qatar between July 2015 and August 2020. Comparative analyses were performed according to injury mechanisms, severity, and management approach. RESULTS: A total of 2,023 patients sustained UEIs with an average age of 34.4 ± 12.9 years, and 92% were males. Motor vehicle crashes (MVCs; 42.3%) were the primary cause of shoulder girdle injuries in 48.3% of cases. Fractures of the radius, ulna, and hands occurred in 30.8, 16.5 and 14.5%, respectively. Young adults were more involved in MVCs and motorcycle crashes (MCCs), while pedestrians who were typically older had a higher rate of humerus fractures. Patients with MCCs had a higher rate of clavicle and ulna fractures. Pedestrians were at risk of serious injuries, with a higher mean injury severity score and lower Glasgow Coma Scale. CONCLUSION: Most UEFs patients were young males and mainly affected by MVCs. Shoulder girdle, particularly clavicle and scapula/glenoid fractures, emerged as common injury sites. The study highlighted the potential risk of pedestrian injuries, as reflected in higher injury severity, concomitant injuries, and higher mortality. Future studies are needed to optimize preventive measures by incorporating insights into specific injury mechanisms and patterns of UEIs.

Protective Role of Spermidine in Colitis and Colon Carcinogenesis.

BACKGROUND & AIMS: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. METHODS: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. RESULTS: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.

Predisposing Factors and Outcome of Acute Kidney Injury After Blunt Trauma: A 10-Year Study.

INTRODUCTION: Acute kidney injury (AKI) indicates an impairment of the renal function following blunt trauma. It is multifactorial and associated with an increased risk of morbidity and mortality. The incidence and risk factors of AKI in young patients with trauma are not well-described. This study aimed to evaluate the incidence, clinical characteristics, and outcomes of post-traumatic AKI. We hypothesized that AKI is associated with worse outcomes in patients with trauma. METHODS: This was a retrospective study of all adult trauma patients admitted to a level 1 trauma center between 2011 and 2021. AKI was diagnosed on the basis of the Kidney Disease Improving Global Outcomes criteria. Data were collected and analyzed for patients with and without AKI using chi-square test and Student's t-test. Multivariate logistic regression analysis and Kaplan-Meier curves were performed. RESULTS: A total of 17,341 patients with trauma were evaluated, of which 140 (0.8%) developed AKI. Patients with AKI were older (40 ± 20 versus 32 ± 16 y), had more comorbidities, and had a higher injury severity score (ISS) and in-hospital mortality (65% versus 3.2%) than non-AKI patients. Direct trauma to the kidney was reported in only nine (6.4%) patients in the AKI group. Among patients with AKI, nonsurvivors had a higher ISS and were more likely to have hypotension, elevated serum lactate, positive troponin, and a lower platelet-to-lymphocyte ratio than survivors. Multiple logistic regression analyses showed that age, ISS, acute respiratory distress syndrome, blood transfusion, diabetes mellitus, onadmission Glasgow coma scale score, and shock index were predictors of AKI in trauma patients, whereas ISS (odds ratio (OR) = 1.05; 95% confidence interval (CI):1.003-1.100; P = 0.03), serum lactate level (OR = 1.25; 95% CI: 1.019-1.533; P = 0.03), and hypotension (OR = 3.22; 95% CI: 1.044-9.945; P = 0.04) were independent predictors of mortality in patients with posttraumatic AKI. Kaplan-Meier survival analysis showed significant differences in mortality among the three stages of AKI (P = 0.03), with the worst outcome in stage III. However, after adjusting for age, hypotension, and ISS, the Cox regression model showed that only stage I had better survival than stages II and III, whereas no survival difference was noted between stages II and III (P = 0.06). CONCLUSIONS: AKI in young trauma patients is uncommon and associated with a prolonged hospital course and higher mortality. This study identified factors that independently predicted the development of AKI and its outcomes in patients with trauma. However, further prospective and multicenter studies are required to minimize the incidence and complications of posttraumatic AKI.

Shock Index for the Prediction of Interventions and Mortality in Patients With Blunt Thoracic Trauma.

INTRODUCTION: Shock index (SI) is a bedside simple scoring tool; however, it has not yet been tested in blunt thorax trauma (BTT). We sought to evaluate the prognostic value of SI for chest interventions (thoracostomy tube or thoracotomy), blood transfusion, and mortality in patients with BTT. We hypothesized that high SI is associated with worse outcomes in patients with BTT. METHODS: We conducted a retrospective analysis of all BTT patients (chest Abbreviated Injury Score [AIS] > 1) hospitalized in a level 1 trauma center between 2011 and 2020. Patients with AIS >1 for head or abdominal injuries and patients undergoing open reduction and internal fixation surgery or penetrating injuries were excluded. Patients were categorized into two groups (low SI <0.80 versus high SI ≥0.80) based on the receiver operating characteristic curve analysis. Multivariable regression analysis was performed to identify the predictors of mortality. RESULTS: A total of 1645 patients were admitted with BTT; of them, 24.5% had high SI. The mean age was 39.2 ± 15.2 y, and most were males (91%). Patients with high SI were younger, had sustained severer injuries, and required more chest interventions (P = 0.001), blood transfusion (P = 0.001), and massive transfusion protocol activation (P = 0.001) compared with low SI group. The overall in-hospital mortality rate was 2.6%, which was more in the high SI group (8.2% versus 0.8%; P = 0.001). SI significantly correlated with age (r = -0.281), injury severity score (r = 0.418), Glasgow Come Score on arrival (r = -0.377), Trauma and Injury Severity Score (r = -0.144), Revised Trauma Score (r = -0.219), serum lactate (r = 0.434), blood transfusion units (r = 0.418), and chest AIS (r = 0.066). SI was an independent predictor of mortality (odds ratio 3.506; 95% confidence interval 1.389-8.848; P = 0.008), and this effect persisted after adjustment for chest intervention (odds ratio 2.923; 95% confidence interval 1.146-7.455; P = 0.02). CONCLUSIONS: The present study highlights the prognostic value of SI as a rapid bedside tool to predict the use of interventions and the risk of mortality in patients with BTT. The study findings help the emergency physicians for early and appropriate risk stratification and triaging of patients with BTT.

Dicarbonyl Electrophiles Mediate Inflammation-Induced Gastrointestinal Carcinogenesis.

BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.

The Clinical Significance of Transfer RNAs Present in Extracellular Vesicles.

Extracellular vesicles (EVs) are important for intercellular signalling in multi-cellular organisms. However, the role of mature transfer RNAs (tRNAs) and tRNA fragments in EVs has yet to be characterised. This systematic review aimed to identify up-to-date literature on tRNAs present within human EVs and explores their potential clinical significance in health and disease. A comprehensive and systematic literature search was performed, and the study was conducted in accordance with PRISMA guidelines. Electronic databases MEDLINE and EMBASE were searched up until 1 January 2022. From 685 papers, 60 studies were identified for analysis. The majority of papers reviewed focussed on the role of EV tRNAs in cancers (31.7%), with numerous other conditions represented. Blood and cell lines were the most common EV sources, representing 85.9% of protocols used. EV isolation methods included most known methods, precipitation being the most common (49.3%). The proportion of EV tRNAs was highly variable, ranging between 0.04% to >95% depending on tissue source. EV tRNAs are present in a multitude of sources and show promise as disease markers in breast cancer, gastrointestinal cancers, and other diseases. EV tRNA research is an emerging field, with increasing numbers of papers highlighting novel methodologies for tRNA and tRNA fragment discovery.

Resumption of professional football league with spectators during the COVID-19 pandemic: The implementation of Bio-secure bubble protocol.

BACKGROUND: Elite professional sports events involving mass gatherings carry a high risk of viral transmission during the coronavirus disease of 2019 (COVID-19) pandemic. We describe the potential impact of resuming professional football leagues involving international participants adhering to a strict Bio-secure bubble protocol and investigate the consequences of spectators/fan attendance at such mass events during the ongoing COVID-19 pandemic in Qatar. METHODS: We conducted a descriptive cohort study involving football players, referees, match officials, local organizing committee (LOC) members, hotel and security staff working in close coordination, and over 10,000 spectators from the Asian Football Confederation (AFC) Champions League (East) and the final match. The study covered almost four weeks of the event (November 19 to December 19, 2020) under a robust Bio-secure bubble protocol. It included extensive severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RT-PCR (reverse transcription-polymerase chain reaction) every 3-6 days and clinical symptom monitoring on and off the field. Target variables included positive RT-PCR results and clinical symptom monitoring among participants, and rapid antigen testing for fan attendance to examine their safe return to the stadiums. RESULTS: A total of 12,250 RT-PCR tests involving 3158 individuals in the Bio-secure bubble were done over one month for all the AFC (East) matches, including the final match. Overall, 44 matches involving 16 teams were played. During the championship, only five individuals (three LOC members and two match officials) returned positive for COVID-19 infections. Four individuals (three team staff/officials and one person outside the Bio-secure bubble) had reactive results. None of the players tested positive for COVID-19 infection. All individuals testing positive were asymptomatic or had mild symptoms, with no one requiring hospitalization other than symptomatic treatment. The overall positivity rate was 0.15% for the entire duration of the AFC (East) Champions League. For the final match, a total of 10,320 rapid antigen tests were done for spectators, of which only one test was positive for COVID-19. CONCLUSIONS: This report shows a very low incidence rate of COVID-19 infections during mass gathering events at the international level. For the resumption of football with spectators, careful mitigation strategies should be considered to reduce the risk of transmission to a sufficiently safe level. This may require proper coordination and measures (i.e., physical distancing, testing, entry, and exit routes in the stadium, and seating arrangement inside the stadium with limited attendance). Based on this, during the ongoing COVID-19 pandemic, the supervised and controlled resumption of football matches with spectators can be done safely provided that a strict Bio-secure bubble protocol has been implemented.

Patterns and Effects of Admission Hyperglycemia and Inflammatory Response in Trauma Patients: A Prospective Clinical Study.

BACKGROUND: The constellation of the initial hyperglycemia, proinflammatory cytokines and severity of injury among trauma patients is understudied. We aimed to evaluate the patterns and effects of on-admission hyperglycemia and inflammatory response in a level 1 trauma center. We hypothesized that higher initial readings of blood glucose and cytokines are associated with severe injuries and worse in-hospital outcomes in trauma patients. METHODS: A prospective, observational study was conducted for adult trauma patients who were admitted and tested for on-admission blood glucose, hemoglobin A1c, interleukin (IL)-6, IL-18 and hs-CRP. Patients were categorized into four groups [non-diabetic normoglycemic, diabetic normoglycemic, diabetic hyperglycemic (DH) and stress-induced hyperglycemic (SIH)]. The inflammatory markers were measured on three time points (admission, 24 h and 48 h). Generalized estimating equations (GEE) were used to account for the correlation for the inflammatory markers. Pearson's correlation test and logistic regression analysis were also performed. RESULTS: During the study period, 250 adult trauma patients were enrolled. Almost 13% of patients presented with hyperglycemia (50% had SIH and 50% had DH). Patients with SIH were younger, had significantly higher Injury Severity Score (ISS), higher IL-6 readings, prolonged hospital length of stay and higher mortality. The SIH group had lower Revised Trauma Score (p = 0.005), lower Trauma Injury Severity Score (p = 0.01) and lower GCS (p = 0.001). Patients with hyperglycemia had higher in-hospital mortality than the normoglycemia group (12.5% vs 3.7%; p = 0.02). A significant correlation was identified between the initial blood glucose level and serum lactate, IL-6, ISS and hospital length of stay. Overall rate of change in slope 88.54 (95% CI:-143.39-33.68) points was found more in hyperglycemia than normoglycemia group (p = 0.002) for IL-6 values, whereas there was no statistical significant change in slopes of age, gender and their interaction. The initial IL-6 levels correlated with ISS (r = 0.40, p = 0.001). On-admission hyperglycemia had an adjusted odds ratio 2.42 (95% CI: 1.076-5.447, p = 0.03) for severe injury (ISS > 12) after adjusting for age, shock index and blood transfusion. CONCLUSIONS: In trauma patients, on-admission hyperglycemia correlates well with the initial serum IL-6 level and is associated with more severe injuries. Therefore, it could be a simple marker of injury severity and useful tool for patient triage and risk assessment. TRIAL REGISTRATION: This study was registered at the ClinicalTrials.gov (Identifier: NCT02999386), retrospectively Registered on December 21, 2016. https://clinicaltrials.gov/ct2/show/NCT02999386 .

Clinical characteristics, injury pattern and management of pediatric pelvic fracture: An observational retrospective study from a level I trauma center.

BACKGROUND: Pediatric pelvic fractures (PPF) are uncommon among children requiring hospitalization after blunt trauma. The present study explored our experience for the prevalence, patients demographics, clinical characteristics, injury pattern and management of pediatric pelvic fractures in a level I trauma center. METHODS: This is a retrospective review of prospectively collected data obtained from trauma registry database for all pediatrics trauma patients of age ≤18 years. Data were analyzed according to different aspects relevant to the clinical applications such as Torode classification for pelvic ring fracture (Type I-IV), open versus closed triradiate cartilage, and surgical versus non-surgical management. RESULTS: During the study period (3 and half years), a total of 119 PPF cases were admitted at the trauma center (11% of total pediatric admissions); the majority had pelvic ring fractures (91.6%) and 8.4% had an acetabular fracture. The mean age of patients was 11.5 ± 5.7, and the majority were males (78.2%). One hundred and four fractures were classified as type I (5.8%), type II (13.5%), type III (68.3%) and type IV (12.5%). Patients in the surgical group were more likely to have higher pelvis AIS (p = 0.001), type IV fractures, acetabular fractures and closed triradiate cartilage as compared to the conservative group. Type III fractures and open triradiate cartilage were significantly higher in the conservative group (p < 0.05). Patients with closed triradiate cartilage frequently sustained spine, head injuries, acetabular fracture and had higher mean ISS and pelvis AIS (p < 0.01) than the open group. However, the rate of in-hospital complications and mortality were comparable among different groups. The overall mortality rate was 2.5%. CONCLUSION: PPF are uncommon and mainly caused by high-impact trauma associated with multisystem injuries. The majority of PPF are stable, despite the underlying high-energy mechanism. Management of PPF depends on the severity of fracture as patients with higher grade fractures require surgical intervention. Furthermore, larger prospective study is needed to understand the age-related pattern and management of PPF.

Rotterdam and Marshall Scores for Prediction of in-hospital Mortality in Patients with Traumatic Brain Injury: An observational study.

Background: We aimed to assess the prognostic value of Rotterdam and Marshall scoring systems to predict in-hospital mortality in patients with traumatic brain injury (TBI).Methods: A retrospective analysis was conducted for patients with TBI who underwent head computerized tomography (CT) scan at a Level I trauma center between 2011 and 2018. Receiver operating characteristic (ROC) curves were used to determine the cutoff values for predicting in-hospital mortality.Results: A total of 1035 patients with TBI were included with a mean age of 30 years. The mean Rotterdam and Marshall scores were higher among non-survivors (p = .001). Patients with higher Rotterdam (>3) or Marshall (>2) CT scores were older, had higher injury severity scores and in-hospital mortality and had lower GCS and blood ethanol levels than those with lower scores. The cutoff point of Rotterdam score was 3.5 (sensitivity, 61.2%; specificity, 85.6%) and Marshall score was 2.5 (74.3% sensitivity and 76.3% specificity). Multivariable logistic regression analyses showed that Marshall and Rotterdam scoring systems were independent predictors of mortality (odds ratio 8.4; 95% confidence interval 4.95-14.17 and odds ratio 4.4; 95% confidence interval 2.36-9.39, respectively).Conclusion: Rotterdam and Marshall CT scores have independent prognostic values in patients with TBI even in alcoholic patients.

Diagnosis, management and outcome of Spinal Cord Injury without Radiographic Abnormalities (SCIWORA) in adult patients with trauma: a case series.

BACKGROUND: Spinal cord injury without radiographic abnormality (SCIWORA) in adults causes diagnostic and prognostic dilemma as radiography and/or computed tomography does not clearly detect bone lesions during the initial assessment. Herein, we report our experience on 11 spinal cord injury cases without radiographic abnormality, regarding the clinicoradiological features, management, and outcomes. METHODS: We conducted a case series of adult patients with SCIWORA who were admitted at the level 1 trauma center at Hamad General Hospital from January 2008 to July 2018. All patients underwent initial head and spine X-ray imaging, computed tomography, magnetic resonance imaging, and 12 months of clinical follow-up. RESULTS: Eleven patients (mean age, 46.5 ± 14.4 years) met the criteria of SCIWORA. The neurologic status on admission and 12 months after hospital discharge were classified according to the American Spinal Injury Association (ASIA) impairment scale (AIS). On admission, 6 (54.5%) patients had ASIA grade C: 2 (18.2%) each had AIS grade D and B and 1 (9.1%) had AIS grade A. Five cases were treated conservatively with rehabilitation and physiotherapy, and five were treated surgically by anterior cervical discectomy with fusion. One patient who declined surgery was managed with a sternal occipital mandibular immobilizer brace and underwent rehabilitation. CONCLUSION: SCIWORA requires higher clinical suspicion and thorough neurological and radiologic assessment to prevent secondary spinal cord injuries and complications.

Demographics and clinical characteristics of alcohol-related admissions in a tertiary care hospital in Qatar: Does age matter?

BACKGROUND: Alcohol consumption is a major cause of acute and chronic health conditions associated with comorbidities and traumatic injuries, despite its partial prohibition in some countries. Moreover, alcohol-related hospital admissions increase the burden on the healthcare system. More than 80% of the population in Qatar comprises expatriates. This study aimed to analyze the demographics and clinical characteristics of subjects with alcohol-related emergency department (ED) visits/hospitalization with respect to different age groups in a single tertiary hospital in Qatar. METHODS: It is a retrospective observational study of adult patients who visited the ED at Hamad General Hospital between January 2013 and March 2015 and were screened positive for alcohol use. Collected data included sociodemographic characteristics, blood alcohol concentration (BAC), pattern of admission, previous medical history, laboratory investigations, treatment, hospital course, and mortality. Data were compared with respect to the distribution of age groups such as < 25, 25-34, 35-44, 45-54, and >55 years. RESULTS: In total, 1506 consecutively admitted patients screened positive for alcohol use were included in the study; the majority of them were males (95.6%), non-Qatari nationals (71.1%), and aged 35-44 years (30.9%). The age groups 35-44 years and 45-54 years showed the highest median BAC ([0.24 interquartile range (IQR: 0.14-0.33)] and [0.24 (IQR: 0.13-0.33)], respectively) as compared to the other age groups (P = 0.001). The pattern of hospital admission, sociodemographic status, presence of comorbidities, laboratory investigations, and mortality showed specific age-related distribution. Particularly, young adults were more likely to have a previous ED visit due to trauma, whereas older patients' previous hospital admissions were mostly related to various underlying comorbidities. CONCLUSION: This study highlighted the patterns of age and clinico-epidemiological status of patients with alcohol-attributable hospital admissions. Our study showed that alcohol consumption was higher among the working-age group. Further studies are needed to investigate changes in the alcohol consumption patterns that may help plan for allocation of health resources and prevention of alcohol-related problems.

Ornithine decarboxylase regulates M1 macrophage activation and mucosal inflammation via histone modifications.

Macrophage activation is a critical step in host responses during bacterial infections. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine metabolism, has been well studied in epithelial cells and is known to have essential roles in many different cellular functions. However, its role in regulating macrophage function during bacterial infections is not well characterized. We demonstrate that macrophage-derived ODC is a critical regulator of M1 macrophage activation during both Helicobacter pylori and Citrobacter rodentium infection. Myeloid-specific Odc deletion significantly increased gastric and colonic inflammation, respectively, and enhanced M1 activation. Add-back of putrescine, the product of ODC, reversed the increased macrophage activation, indicating that ODC and putrescine are regulators of macrophage function. Odc-deficient macrophages had increased histone 3, lysine 4 (H3K4) monomethylation, and H3K9 acetylation, accompanied by decreased H3K9 di/trimethylation both in vivo and ex vivo in primary macrophages. These alterations in chromatin structure directly resulted in up-regulated gene transcription, especially M1 gene expression. Thus, ODC in macrophages tempers antimicrobial, M1 macrophage responses during bacterial infections through histone modifications and altered euchromatin formation, leading to the persistence and pathogenesis of these organisms.

Multiple organ dysfunction syndrome: Contemporary insights on the clinicopathological spectrum.

Multiorgan dysfunction syndrome (MODS) remains a major complication and challenge to treat patients with critical illness in different intensive care unit settings. The exact mechanism and pathophysiology of MODS is complex and remains unexplored. We reviewed the literature from January 2011 to August 2019 to analyze the underlying mechanisms, prognostic factors, MODS scoring systems, organ systems dysfunctions, and the management of MODS. We used the search engines PubMed, MEDLINE, Scopus, and Google Scholar with the keywords "multiple organ dysfunction syndrome," "intensive care units," "multiorgan failure," "MODS scoring system," and "MODS management." The initial search yielded 3550 abstracts, of which 91 articles were relevant to the scope of the present article. A better understanding of a disease course will help differentiate the signs of an intense inflammatory response from the early onset of sepsis and minimize the inappropriate use of medications. This, in turn, will promote organtargeted therapy and prevent occurrence and progression of MODS.

Prognostic Role of Shock Index in Traumatic Pelvic Fracture: A Retrospective Analysis.

BACKGROUND: We aimed to validate the utility of shock index (SI) in predicting the need of blood transfusion and outcomes in patients with traumatic pelvic fracture (TPF). MATERIALS AND METHODS: We conducted a retrospective analysis for patients who sustained TPF between 2012 and 2016 in a level 1 trauma center. Patients were categorized into patients with low versus high SI based on the cutoff obtained from the receiver operating characteristic curves to predict mortality. RESULTS: A total of 966 patients sustained TPF (28.5% had SI ≥ 0.9 based on receiver operating characteristic curves) with a median age of 33 (IQR 25-47) y. Type B and C pelvic fractures significantly had higher SI. The frequency of blood transfusion use was greater in patients with high SI (P = 0.001). SI correlated significantly with Injury Severity Score (r = 0.32), Revised Trauma Score (r = -0.40), and transfused blood units (r = 0.35). Patients with high SI had prolonged hospital length of stay and higher mortality (P = 0.001). SI ≥ 0.9 showed high sensitivity and negative predictive value to identify the need of massive blood transfusion (77% and 86%, respectively) and mortality (73.5% and 98.1%, respectively). For hospital mortality, high SI had a sensitivity of 73.5%, specificity 74%, negative predictive value 98%, and negative likelihood ratio of 0.36. After adjustment for age, sex, Injury Severity Score, Glasgow Coma Scale, pelvis Abbreviated Injury Scale, blood transfusion, and Tile classification, the multivariate analysis models showed that high SI was an independent predictor of blood transfusion (odd ratio 5.6) and mortality (odd ratio 3.63). CONCLUSIONS: SI is a potentially useful instant tool for the prediction of massive transfusion and mortality in patients with TPF. Further prospective studies are warranted to support our findings.

Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis.

OBJECTIVE: Gastric cancer is the third leading cause of cancer death worldwide and infection by Helicobacter pylori is the strongest risk factor. We have reported increased epidermal growth factor receptor (EGFR) phosphorylation in the H. pylori-induced human carcinogenesis cascade, and association with DNA damage. Our goal was to determine the role of EGFR activation in gastric carcinogenesis. DESIGN: We evaluated gefitinib, a specific EGFR inhibitor, in chemoprevention of H. pylori-induced gastric inflammation and cancer development. Mice with genetically targeted epithelial cell-specific deletion of Egfr (EfgrΔepi mice) were also used. RESULTS: In C57BL/6 mice, gefitinib decreased Cxcl1 and Cxcl2 expression by gastric epithelial cells, myeloperoxidase-positive inflammatory cells in the mucosa and epithelial DNA damage induced by H. pylori infection. Similar reductions in chemokines, inflammatory cells and DNA damage occurred in infected EgfrΔepi versus Egfrfl/fl control mice. In H. pylori-infected transgenic insulin-gastrin (INS-GAS) mice and gerbils, gefitinib treatment markedly reduced dysplasia and carcinoma. Gefitinib blocked H. pylori-induced activation of mitogen-activated protein kinase 1/3 (MAPK1/3) and activator protein 1 in gastric epithelial cells, resulting in inhibition of chemokine synthesis. MAPK1/3 phosphorylation and JUN activation was reduced in gastric tissues from infected wild-type and INS-GAS mice treated with gefitinib and in primary epithelial cells from EfgrΔepi versus Egfrfl/fl mice. Epithelial EGFR activation persisted in humans and mice after H. pylori eradication, and gefitinib reduced gastric carcinoma in INS-GAS mice treated with antibiotics. CONCLUSIONS: These findings suggest that epithelial EGFR inhibition represents a potential strategy to prevent development of gastric carcinoma in H. pylori-infected individuals.

Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer.

Tumour cells sustain their high proliferation rate through metabolic reprogramming, whereby cellular metabolism shifts from oxidative phosphorylation to aerobic glycolysis, even under normal oxygen levels. Hypoxia-inducible factor 1A (HIF1A) is a major regulator of this process, but its activation under normoxic conditions, termed pseudohypoxia, is not well documented. Here, using an integrative approach combining the first genome-wide mapping of chromatin binding for an endocytic adaptor, ARRB1, both in vitro and in vivo with gene expression profiling, we demonstrate that nuclear ARRB1 contributes to this metabolic shift in prostate cancer cells via regulation of HIF1A transcriptional activity under normoxic conditions through regulation of succinate dehydrogenase A (SDHA) and fumarate hydratase (FH) expression. ARRB1-induced pseudohypoxia may facilitate adaptation of cancer cells to growth in the harsh conditions that are frequently encountered within solid tumours. Our study is the first example of an endocytic adaptor protein regulating metabolic pathways. It implicates ARRB1 as a potential tumour promoter in prostate cancer and highlights the importance of metabolic alterations in prostate cancer.

The L-Arginine Transporter Solute Carrier Family 7 Member 2 Mediates the Immunopathogenesis of Attaching and Effacing Bacteria.

Solute carrier family 7 member 2 (SLC7A2) is an inducible transporter of the semi-essential amino acid L-arginine (L-Arg), which has been implicated in immune responses to pathogens. We assessed the role of SLC7A2 in murine infection with Citrobacter rodentium, an attaching and effacing enteric pathogen that causes colitis. Induction of SLC7A2 was upregulated in colitis tissues, and localized predominantly to colonic epithelial cells. Compared to wild-type mice, Slc7a2-/-mice infected with C. rodentium had improved survival and decreased weight loss, colon weight, and histologic injury; this was associated with decreased colonic macrophages, dendritic cells, granulocytes, and Th1 and Th17 cells. In infected Slc7a2-/-mice, there were decreased levels of the proinflammatory cytokines G-CSF, TNF-α, IL-1α, IL-1ß, and the chemokines CXCL1, CCL2, CCL3, CCL4, CXCL2, and CCL5. In bone marrow chimeras, the recipient genotype drove the colitis phenotype, indicative of the importance of epithelial, rather than myeloid SLC7A2. Mice lacking Slc7a2 exhibited reduced adherence of C. rodentium to the colonic epithelium and decreased expression of Talin-1, a focal adhesion protein involved in the attachment of the bacterium. The importance of SLC7A2 and Talin-1 in the intimate attachment of C. rodentium and induction of inflammatory response was confirmed in vitro, using conditionally-immortalized young adult mouse colon (YAMC) cells with shRNA knockdown of Slc7a2 or Tln1. Inhibition of L-Arg uptake with the competitive inhibitor, L-lysine (L-Lys), also prevented attachment of C. rodentium and chemokine expression. L-Lys and siRNA knockdown confirmed the role of L-Arg and SLC7A2 in human Caco-2 cells co-cultured with enteropathogenic Escherichia coli. Overexpression of SLC7A2 in human embryonic kidney cells increased bacterial adherence and chemokine expression. Taken together, our data indicate that C. rodentium enhances its own pathogenicity by inducing the expression of SLC7A2 to favor its attachment to the epithelium and thus create its ecological niche.