Citations

AbstractAlthough anticoagulation without hemorrhage is a primary aim, this vision has remained as yet out of reach. Even despite the superior safety profile of the direct oral anticoagulants, hemorrhage remains a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation, specifically coagulation factor XI (FXI) and/or factor XII (FXII), has now substantial epidemiologic and preclinical data supporting the notion that these factors contribute to pathologic thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way, targeting FXI and FXII may revolutionize the future anticoagulation landscape. Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Each of these drugs have demonstrated favorable safety profiles in their phases 1 and 2 studies to date, with preclinical data also supporting efficacy of abrogating thrombosis in various animal models. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy.

AbstractThis study aimed to evaluate the influence of physical activity on incidence of acute mountain sickness (AMS) by continuous activity monitoring in a free-living sample of South Pole workers over the initial 72 h at altitude exposure of 2,840 m (9,318 ft). Body Media activity monitors were worn by 47 healthy participants. AMS was defined by the Lake Louise symptom questionnaire. Venous blood samples were taken at sea level and approximately 48 h after high altitude exposure. AMS incidence was 34% (n=16/47) over the first 48 h and 40% (n=19/47) over 72 h. On day 2 at high altitude, individuals with AMS demonstrated a significantly greater increase in the percent change in physical activity metrics from baseline: total energy expenditure 19±13 vs. 5±7%, total steps 65±51 vs. 10±18%, metabolic equivalent of tasks 21±13 vs. 7±13%, and time spent performing moderate to vigorous physical activity 114±79 vs. 26±27% for individuals with AMS vs. no AMS, respectively, p<0.05. In addition, erythropoietin and vascular endothelial growth factor were 1.69 and 1.75 times higher, respectively, in those with AMS. In conclusion, workers who engaged in increased physical activity and activity intensity during initial exposure to the South Pole were more susceptible to developing AMS.

AbstractSedation is an essential therapeutic strategy in the care of neurocritical patients. Intravenous sedative agents are the most widely used, with promising alternatives (dexmedetomidine, ketamine, and volatile agents) to propofol and midazolam arising. Studies designed to evaluate superiority and avoid biases are required. A neurological awakening test is safe in most patients. Potential risks and benefits of limiting deep sedation and daily interruption of sedation in these patients remain unclear. The aim of this review was to report recent clinical evidence on sedation in this subgroup of patients, focusing on its effects on clinical prognosis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disorder that characteristically causes joint inflammation and damage. In addition, many patients develop extraarticular manifestations which may cause significant comorbidity and premature mortality.Some respiratory tract involvement of the upper and lower airways and parenchymal disease features are unique to RA, including cricoarytenoid arthritis and RA pulmonary nodulosis, and others, especially the interstitial parenchymal involvement, occur in many other idiopathic and autoimmune diseases. The pathophysiology of lung disease is not well understood. Rheumatoid lung disease may even predate the onset of joint disease, and could be triggered by chronic airway and alveolar epithelial injury. Chronic systemic inflammation and risk factors such as cigarette smoking, infection, host genetics, and immune dysregulation are contributors. Treatment of the respiratory disease is directed at reducing the systemic inflammation of RA. Less well understood is the management of the interstitial lung disease of RA, for which antifibrotic and immune suppressive agents may be helpful. The management of RA-related lung disease is perhaps the major remaining hurdle in reduction of the disease burden related to extraarticular manifestations of this disease.

5038 Background: Platinum-based chemotherapy has shown palliative and radiographic benefit in small unselected studies of metastatic castration-resistant prostate cancer (mCRPC). Alterations in DNA damage repair genes (DDRmut), which occur in ~25% of patients with mCRPC, may sensitize to platinum-based chemotherapy, and may aid in the selection of patients for this therapy. We sought to evaluate the efficacy of platinum-based chemotherapy in DDRmut mCRPC. Methods: We performed a retrospective review of patients with prostate cancer who underwent tumor genomic profiling and received platinum-based chemotherapy. Deleterious alterations in a panel including BRCA2, BRCA1, ATM, FANCA, CDK12 or PALB2 were classified as DDRmut. Absence of deleterious alterations in those genes was classified as DDRwt. MSI-H cases were excluded from analysis. Electronic charts, PSA values, and scans were reviewed to assess for outcomes. Results: From October 2013 to July 2018, 109 patients with mCRPC received platinum-based chemotherapy. 64/109 had prior taxane progression and were PARP inhibitor (PARPi) naïve at the time of platinum-based chemotherapy. DDRmut was found in 16/64 (25%) of patients ( BRCA2, n = 6; ATM, n = 2; CDK12, n = 4; FANCA, n = 4; PALB2, n = 1). Visceral metastasis occurred in 4/16 (25%) of DDRmut patients and in 22/48 (46%) of DDRwt patients. PSA50 responses were more common among DDRmut (8/15 evaluable = 53%, 95% CI, 30-75%) than among DDRwt patients (5/42 evaluable = 12%, 95% CI, 5-25%). Time on platinum-based chemotherapy tended to be longer in the DDRmut group (median 3.1 vs 1.8 months; HR 0.73, 95% CI 0.42-1.26). Of 8 DDRmut patients ( BRCA2, n = 6; BRCA1, n = 1; ATM, n = 2) who received platinum-based chemotherapy after progression on a PARPi, 3/7 evaluable patients (43%) had RECIST response or stable disease, and 2/7 evaluable patients (29%) had a PSA50 response. Of 4 patients with ATM deleterious mutations, none had a radiographic or PSA50 response to platinum-based chemotherapy. Conclusions: Platinum-based chemotherapy showed activity in DDRmut mCRPC patients before and after PARPi treatment.

Background There is no consensus exists regarding which reconstructive approach, if any, should be used after performing transcranial lateral orbital wall resections. Rigid reconstruction is often done to prevent enophthalmos; however, it is not clear if this is a risk with extensive orbital wall resections for transcranial surgery. Objective To assess globe position dynamics in patients that underwent transcranial lateral and superior orbital wall resections without rigid reconstruction to determine if enophthalmos is a significant risk. Methods Preoperative (PO) and postoperative data were retrospectively collected from the electronic medical records of 55 adult patients undergoing lateral and superior orbital wall resections as part of a skull base approach. The globe positions were assessed radiologically at all available time points and used to track relative globe displacements over time. Results An evaluation of PO variables identified a relationship between maximum lesion diameters and globe positions dynamics. The composition of globe position presentations in the population remained relatively stable over time, with only 1 out of 55 patients (1.81%) developing postoperative enophthalmos. An assessment of mean globe displacements revealed improvements in the patients presenting with PO exophthalmos, and stability in the patients presenting with normal PO globe positions. Conclusions Excellent results in long-term postoperative globe position dynamics can be achieved without the use of rigid reconstruction after transcranial lateral and superior orbital wall resections, regardless of the PO globe positioning.

Abstract Lymphedema refers to the accumulation of protein-rich fluid in the interstitial spaces. This can occur secondary to congenital malformation of the lymphatic channels or nodes or as a result of an insult that damages appropriately formed channels and nodes. Stagnant, protein-rich lymph initiates an inflammatory response that leads to adipocyte proliferation, fibrous tissue deposition, and increased susceptibility to infections. The end result is permanent disfigurement and dermal changes. Early and accurate diagnosis is essential, since lymphedema is a chronic and progressive problem. When lymphedema affects the lower extremity, it is important to manage it in a way that preserves function and mobility. Early diagnosis also allows for a proactive rather than reactive approach to treatment and utilization of novel physiologic procedures, such as lymphovenous anastomosis and vascularized lymph node transfer. Such interventions slow down disease progression and reduce morbidity by allowing the surgeon to salvage the remaining functional lymphatic channels. When physiologic procedures fail or when faced with a delayed presentation, the addition of excisional procedures can provide a more comprehensive treatment of this debilitating disease. The aim of this article is to review the most current concepts in the surgical management of lower extremity lymphedema.