Citations

Background The Global Burden of Disease Study (GBD) has historically produced estimates of causes of injury such as falls but not the resulting types of injuries that occur. The objective of this study was to estimate the global incidence, prevalence and years lived with disability (YLDs) due to facial fractures and to estimate the leading injurious causes of facial fracture. Methods We obtained results from GBD 2017. First, the study estimated the incidence from each injury cause (eg, falls), and then the proportion of each cause that would result in facial fracture being the most disabling injury. Incidence, prevalence and YLDs of facial fractures are then calculated across causes. Results Globally, in 2017, there were 7 538 663 (95% uncertainty interval 6 116 489 to 9 493 113) new cases, 1 819 732 (1 609 419 to 2 091 618) prevalent cases, and 117 402 (73 266 to 169 689) YLDs due to facial fractures. In terms of age-standardised incidence, prevalence and YLDs, the global rates were 98 (80 to 123) per 100 000, 23 (20 to 27) per 100 000, and 2 (1 to 2) per 100 000, respectively. Facial fractures were most concentrated in Central Europe. Falls were the predominant cause in most regions. Conclusions Facial fractures are predominantly caused by falls and occur worldwide. Healthcare systems and public health agencies should investigate methods of all injury prevention. It is important for healthcare systems in every part of the world to ensure access to treatment resources.

AbstractBackgroundThere is a huge difference in the standard of surgical training in different countries around the world. The disparity is more obvious in the various models of surgical training in low‐ and middle‐income countries (LMICs) compared to high‐income countries. Although the global training model of surgeons is evolving from an apprenticeship model to a competency‐based model with additional training using simulation, the training of surgeons in LMICs still lacks a standard pathway of training.MethodsThis is a qualitative, descriptive, and collaborative study conducted in six LMICs across Asia, Africa, and South America. The data were collected on the status of surgical education in these countries as per the guidelines designed for the ASSURED project along with plans for quality improvement in surgical education in these countries.ResultsThe training model in these selected LMICs appears to be a hybrid of the standard models of surgical training. The training models were tailored to the country's need, but many fail to meet international standards. There are many areas identified that can be addressed in order to improve the quality of surgical education in these countries.ConclusionsMany areas need to be improved for a better quality of surgical training in LMICs. There is a need of financial, technical, and research support for the improvement in these models of surgical education in LMICs.

Objectives: In 2014, the Tele-ICU Committee of the Society of Critical Care Medicine published an article regarding the state of ICU telemedicine, one better defined today as tele-critical care. Given the rapid evolution in the field, the authors now provide an updated review. Data Sources and Study Selection: We searched PubMed and OVID for peer-reviewed literature published between 2010 and 2018 related to significant developments in tele-critical care, including its prevalence, function, activity, and technologies. Search terms included electronic ICU, tele-ICU, critical care telemedicine, and ICU telemedicine with appropriate descriptors relevant to each sub-section. Additionally, information from surveys done by the Society of Critical Care Medicine was included given the relevance to the discussion and was referenced accordingly. Data Extraction and Data Synthesis: Tele-critical care continues to evolve in multiple domains, including organizational structure, technologies, expanded-use case scenarios, and novel applications. Insights have been gained in economic impact and human and organizational factors affecting tele-critical care delivery. Legislation and credentialing continue to significantly influence the pace of tele-critical care growth and adoption. Conclusions: Tele-critical care is an established mechanism to leverage critical care expertise to ICUs and beyond, but systematic research comparing different models, approaches, and technologies is still needed.

T cell lymphoblastic leukemia (T-ALL) is an aggressive cancer arising from transformed thymocytes. Most human T-ALL involves hyperactive NOTCH signaling that is often caused by activating NOTCH mutations. However, the identification of specific molecular signals that might induce or select for mutation and transformation are incompletely understood. We report that an understudied low-frequency, natural thymocyte subset expresses αβ T cell antigen receptor (TCR) earlier than most cells in mice and humans; engagement of the early αβTCR by major histocompatibility complexes (MHC) can cause outgrowth of NOTCH1 mutant clones and T-ALL leukemogenesis in a mouse model of T-ALL. Assessment of 5 recent human T-ALL cases found one to present this unique CD4-CD8- double- negative (DN) stage as the earliest identifiable developmental stage. These studies present a model of T-ALL leukemogenesis that identifies (i) a natural cell stage of origin susceptible to transformation, (ii) a matching mouse model showing that a signaling receptor (αβTCR) and its ligand (MHC) drive leukemogeneis and outgrowth of tumors bearing activating NOTCH1 mutations, and (iii) a human case that presents with a tumor consistent with this model and mechanism. In past work, the pre-TCR has been shown to impact T-ALL development in mice (Campese et al, Blood 2006), but an oncogenic role for the mature αβTCR is less well characterized and somewhat surprising. This is because, although T-ALL tumor cells may express variable levels of surface αβTCR/CD3, the earliest cell stages that are thought to transform are also thought to precede stages with αβTCR expression. Most conventional αβ thymocytes rearrange TCRβ and TCRα loci in separate, ordered developmental stages. However, some thymocytes in the conventional pathway rearrange both at DN stage thus exhibiting 'precocious' αβTCR (PAT) expression. Importantly, these PAT cells are indeed part of the conventional αβ lineage, being a 'subset' only due to early αβTCR expression but without known distinction in ultimate immune function (Aifantis et al, JEM 2006). We found that ~0.01% of mouse and human thymocytes are such PAT cells at steady state. To interrogate the PAT thymocyte surface phenotype, we performed multi-parametric flow cytometry with Spanning-tree Progression Analysis of Density-normalized Events (SPADE). This revealed that PAT thymocytes constitute a DN subset that is not associated with other well-described unconventional DN thymocytes known to express αβTCR, consistent with as the expectation that PATs are part of the conventional developmental pathway. We observed that the OT1 TCR transgene is expressed in mice with parallel timing and level to the natural PAT subset, allowing use of this model to study antigen-dependent signaling and oncogenesis. In a cohort study, no T-ALL was observed in wild-type C57BL/6 or OT-1.β2M-/- mice (deficient in endogenous antigen presentation), but MHC-sufficient OT-1 mice developed PAT-stage-specific T-ALL with activating NOTCH1 mutations. Transplant experiments corroborated a requirement for antigen presentation and TCR signaling for tumor maintenance as transplanted tumors grew in MHC+ but not MHC-deficient mice. This predicted that PAT thymocytes might have an unusual ability to signal through αβTCR even without coreceptor expression. When cultured in the presence of either exogenously added β2M or antigen presenting cells, both untransformed and neoplastic PAT cells upregulated CD69 in response to the OT-1 antigenic peptide, OVA. Furthermore, ex vivo analysis of PAT cells from polyclonal C57BL/6 versus MHC-deficient mice showed intrinsic upregulation of TCR-signaling-dependent Nur77 in an MHC-dependent manner. These data revealed a unique ability of PAT cells to engage in co-receptor independent but antigen-dependent signaling. Microarray analysis showed that the gene expression profile of neoplastic PAT cells from OT-1 T-ALL most closely resembled that of conventional post β-selection DN thymocytes, in agreement with the natural PAT stage during normal T cell development. These data support a model in which transformation occurred in the naturally occurring αβ PAT thymocyte subset as cell-of-origin. Collectively, our data suggest that precocious αβTCR expression and coreceptor-independent antigen engagement can cause activating NOTCH mutation and T-ALL development. Disclosures No relevant conflicts of interest to declare.

Abstract Pathogenic sequence variants (PSV) in BRCA1 or BRCA2 (BRCA1/2) are associated with increased risk and severity of prostate cancer. We evaluated whether PSVs in BRCA1/2 were associated with risk of overall prostate cancer or high grade (Gleason 8+) prostate cancer using an international sample of 65 BRCA1 and 171 BRCA2 male PSV carriers with prostate cancer, and 3,388 BRCA1 and 2,880 BRCA2 male PSV carriers without prostate cancer. PSVs in the 3′ region of BRCA2 (c.7914+) were significantly associated with elevated risk of prostate cancer compared with reference bin c.1001-c.7913 [HR = 1.78; 95% confidence interval (CI), 1.25–2.52; P = 0.001], as well as elevated risk of Gleason 8+ prostate cancer (HR = 3.11; 95% CI, 1.63–5.95; P = 0.001). c.756-c.1000 was also associated with elevated prostate cancer risk (HR = 2.83; 95% CI, 1.71–4.68; P = 0.00004) and elevated risk of Gleason 8+ prostate cancer (HR = 4.95; 95% CI, 2.12–11.54; P = 0.0002). No genotype–phenotype associations were detected for PSVs in BRCA1. These results demonstrate that specific BRCA2 PSVs may be associated with elevated risk of developing aggressive prostate cancer. Significance: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk individual.

Abstract Background Cardiac implantable electronic device-related infective endocarditis (CIED-IE) comprises 10–57% of total CIED infections. Patients with definite CIED-IE who fulfill both major modified Duke criteria have not been well characterized. Methods Data from the Multicenter Electrophysiologic Device Infection Cohort, a prospective, multinational study of CIED infections were used to describe a subset of patients with CIED-IE who met both major Duke criteria for definite IE (bloodstream infection and intracardiac vegetations [VEG]). Results Of 433 patients with CIED infection, 144 (33.3%) had definite CIED-IE. The median age was 68 years and 77.1% were male. Twelve (8.3%) had past CIED infection. Seventy-seven patients (53.5%) had permanent pacemakers, 38 (26.4%) had implantable cardioverter defibrillators, and 29 (20.1%) had combination devices. The median time following the last device procedure was 550 days. CIED-IE was early in 60 patients (41.7%) and late in 84 (58.3%). Most patients presented with fever (77.8%) and sepsis (44.4%) with a median symptom duration of 7 days. On echocardiography, lead VEG was noted in 125 patients (86.8%) and valvular VEG in 54 patients (37.5%) with the tricuspid valve involved in 56.5%. On the basis of VEG location, there were 90 patients (62.5%) with isolated lead-associated IE (LAE), 19 patients (13.2%) with isolated valve-associated IE (VAE), and 35 patients (24.3%) with both (LVAE). All patients had positive blood cultures and 63/119 (52.9%) had positive lead cultures. The predominant organism in blood was Staphylococcus aureus (42.4%), followed by coagulase-negative staphylococci (20.1%). CIED removal occurred in 131 patients (91%). There were 25 deaths during the index hospitalization and 34 total deaths (24.3%) by 6 months. Mortality correlated with age >75 (P = 0.023) and sepsis on presentation (P = 0.052). Infecting organism, site of VEG, and device removal did not impact the risk of death. Conclusion Definite CIED-IE is relatively common. The majority of patients tend to have late-onset infection and often present with sepsis. S. aureus is the dominant organism causing definite CIED-IE. Isolated LAE occurs in 63% of patients. Older age and sepsis on admission are associated with higher mortality. Disclosures All authors: No reported disclosures.

AbstractBackgroundInappropriate sinus tachycardia (IST) remains a clinical challenge because patients often are highly symptomatic and not responsive to medical therapy.ObjectiveTo study the safety and efficacy of stellate ganglion (SG) block and cardiac sympathetic denervation (CSD) in patients with IST.MethodsTwelve consecutive patients who had drug‐refractory IST (10 women) were studied. According to a prospectively initiated protocol, five patients underwent an electrophysiologic study before and after SG block (electrophysiology study group). The subsequent seven patients had ambulatory Holter monitoring before and after SG block (ambulatory group). All patients underwent SG block on the right side first, and then on the left side. Selected patients who had heart rate reduction ≥15 beats per minute (bpm) were recommended to consider CSD.ResultsThe mean (SD) baseline heart rate (HR) was 106 (21) bpm. The HR significantly decreased to 93 (20) bpm (P = .02) at 10 minutes after right SG block and remained significantly slower at 97(19) bpm at 60 minutes. Left SG block reduced HR from 99 (21) to 87(16) bpm (P = .02) at 60 minutes. SG block had no significant effect on blood pressure or HR response to isoproterenol or exercise (all P > .05). Five patients underwent right (n = 4) or bilateral (n = 1) CSD. The clinical outcomes were heterogeneous: one patient had complete and two had partial symptomatic relief, and two did not have improvement.ConclusionSG blockade modestly reduces resting HR but has no significant effect on HR during exercise. Permanent CSD may have a modest role in alleviating symptoms in selected patients with IST.

Abstract The JAK2V617F mutation is present in the majority of cases of myeloproliferative disease, including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF), and is an attractive candidate for molecularly targeted therapy. However, the potential toxicities of JAK2 inhibition in vivo, and identification of appropriate surrogate endpoints for response, are challenges that may limit clinical usefulness in treatment of these relatively indolent diseases. We report efficacy and assessment of surrogate endpoints for response of a small molecule JAK2 inhibitor, TG101348 in a murine model of polycythemia vera. TG101348 is selective for JAK2 with an in vitro IC50 of ∼3 nM that is ∼334 fold more potent than for inhibition of JAK3. TG101348 showed therapeutic efficacy in the murine model of PV that included a statistically significant reduction in hematocrit, normalization of white blood cell count, a dose dependent reduction/elimination of extramedullary hematopoiesis in the spleen and liver, and marked attenuation of myelofibrosis. Consistent with its selective inhibition of JAK2 and not JAK3, there was no significant change in T-cell number in treated animals. These clinical responses correlated with surrogate endpoints for response, including reduction or elimination of JAK2V617F expressing clones based on quantitative genomic PCR, suppression of JAK2V617F positive endogenous erythroid colony growth of JAK2V617F MPD bone marrow, and inhibition of JAK-STAT signal transduction as assessed by phosphoflow cytometry for phosphorylated STAT5. Thus, TG101348 is efficacious in treatment of a murine model of PV, and surrogate endpoints have been identified that may be of value in clinical trials in humans.