Anticoagulants carry a significant risk of gastrointestinal bleeding (GIB). Data regarding the safety of anticoagulation continuation/cessation after GIB are limited. We sought to determine the ...safety and risk of continuation of anticoagulation after GIB.
We conducted a prospective observational cohort study on consecutive patients admitted to the hospital who had GIB while on systemic anticoagulation. Patients were classified into two groups at hospital discharge after GIB: those who resumed anticoagulation and those who had anticoagulation discontinued. Patients in both groups were contacted by phone 90 days after discharge to determine the following outcomes: (i) thromboembolic events, (ii) hospital readmissions related to GIB, and (iii) mortality. Univariate and multivariate Cox proportional hazards were used to determine factors associated with thrombotic events, rebleeding, and death.
We identified 197 patients who developed GIB while on systemic anticoagulation (n=145, 74% on warfarin). Following index GIB, anticoagulation was discontinued in 76 patients (39%) at discharge. In-hospital transfusion requirements, need for intensive care unit care, and etiology of GIB were similar between the two groups. During the follow-up period, 7 (4%) patients suffered a thrombotic event and 27 (14%) patients were readmitted for GIB. Anticoagulation continuation was independently associated on multivariate regression with a lower risk of major thrombotic episodes within 90 days (hazard ratio (HR)=0.121, 95% confidence interval (CI)=0.006-0.812, P=0.03). Patients with any malignancy at time of GIB had an increased risk of thromboembolism in follow-up (HR=6.1, 95% CI=1.18-28.3, P=0.03). Anticoagulation continuation at discharge was not significantly associated with an increased risk of recurrent GIB at 90 days (HR=2.17, 95% CI=0.861-6.67, P=0.10) or death within 90 days (HR=0.632, 95% CI=0.216-1.89, P=0.40).
Restarting anticoagulation at discharge after GIB was associated with fewer thromboembolic events without a significantly increased risk of recurrent GIB at 90 days. The benefits of continuing anticoagulation at discharge may outweigh the risks of recurrent GIB.
Despite good results in the treatment of hematological malignancies, Natural killer (NK) cells have shown limited effectiveness in solid tumors, such as ovarian cancer (OvCa). Here, we assessed the ...potential of an oncolytic adenovirus expressing a variant interleukin-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, to enhance NK cell therapy efficacy in human OvCa ex vivo. Human OvCa surgical specimens were processed into single-cell suspensions and NK cells were expanded from healthy blood donors. OvCa sample digests were co-cultured ex vivo with NK cells and vIL-2 virus and cancer cell killing potential assessed in real time through cell impedance measurement. Proposed therapeutic combination was evaluated in vivo with an OvCa patient-derived xenograft (PDX) in mice. Addition of vIL-2 virus significantly enhanced NK cell therapy killing potential in treated OvCa co-cultures. Similarly, vIL-2 virus in combination with NK cell therapy promoted the best in vivo OvCa tumor control. Mechanistically, vIL-2 virus induced higher percentages of granzyme B in NK cells, and CD8+ T cells, while T regulatory cell proportions remained comparable to NK cell monotherapy in vivo. Ad5/3-E2F-d24-vIL2 virus treatment represents a promising strategy to boost adoptive NK cell therapeutic effect in human OvCa.
Summary
Background
Oesophageal food bolus impaction (OFBI) is a common gastrointestinal emergency.
Aim
To describe contemporary aetiologies of OFBI, and variables that may predict eosinophilic ...esophagitis (EoE) related OFBI as well as complications.
Methods
Patients presenting to the Emergency Department between 2004 and 2014 with OFBI who underwent oesophagogastroduodenoscopy (EGD) were included. Clinical and endoscopic variables, as well as complications, were recorded. Aetiology of OFBI was determined by reviewing endoscopy reports. A diagnosis of EoE was confirmed via pathology (>15 eosinophils/high‐powered field) at the index or follow‐up EGD. Logistic regression was used to report associations of variables and complications.
Results
Of the 173 patients with OFBI, 139 (80%) had an aetiology recognised, the most frequent being EoE (27%, n = 47), Schatzki's ring (20%, n = 34) and oesophageal stricture (13%, n = 22). Six patients (3%) had oesophageal cancer. Patients with EoE‐related OFBI tended to be younger (42 vs. 69 years, P < 0.001), male (81% vs. 52%, P = 0.001), have a prior history of OFBI (45% vs. 18%, P = 0.001), and present during spring or summer (62% vs. 44%, P = 0.04). Eighteen patients (10%) had a complication associated with OFBI, with 3 (2%) perforations. On multivariate regression, patients with EoE‐related OFBI were not more likely to have a complication (OR 1.07, P = 0.92), although hypoxia at presentation (OR 59.7, P = 0.006) was associated with complications.
Conclusions
Eosinophilic esophagitis accounts for over a quarter of patients with oesophageal food bolus impaction. Overall complication rate was 10%, with a 2% perforation rate. Clinical characteristics of patients with eosinophilic esophagitis differ from other patients with oesophageal food bolus impaction.
While the presence of tumor-infiltrating lymphocytes (TILs) associates with improved survival prognosis in ovarian cancer (OvCa) patients, TIL therapy benefit is limited. Here, we evaluated an ...oncolytic adenovirus coding for a human variant IL-2 (vIL-2) cytokine, Ad5/3-E2F-d24-vIL2 (vIL-2 virus), also known as TILT-452, as an immunotherapeutic strategy to enhance TIL responsiveness towards advanced stage OvCa tumors. Fragments of resected human OvCa tumors were processed into single-cell suspensions, and autologous TILs were expanded from said samples. OvCa tumor specimens were co-cultured with TILs plus vIL-2 virus, and cell killing was assessed in real time through cell impedance measurement. Combination therapy was further evaluated in vivo through a patient-derived xenograft (PDX) ovarian cancer murine model. The combination of vIL-2 virus plus TILs had best cancer cell killing ex vivo compared to TILs monotherapy. These results were supported by an in vivo experiment, where the best OvCa tumor control was obtained when vIL-2 virus was added to TIL therapy. Furthermore, the proposed therapy induced a highly cytotoxic phenotype demonstrated by increased granzyme B intensity in NK cells, CD4+ T, and CD8+ T cells in treated tumors. Our results demonstrate that Ad5/3-E2F-d24-vIL2 therapy consistently improved TILs therapy cytotoxicity in treated human OvCa tumors.
To determine which risk factors and subtypes of lower gastrointestinal bleeding (LGIB) are associated with adverse outcomes after hospital discharge (30-day readmissions, recurrent LGIB, and death).
...We conducted a prospective observational study of consecutive patients admitted with LGIB to Beth Israel Deaconess Medical Center from April 1, 2013, through March 30, 2014. Patients were contacted 30 days after discharge to determine hospital readmissions, recurrent LGIB, and death. Multivariable Cox proportional hazards regression models were used to describe associations of variables with 30-day readmissions or recurrent LGIB. Logistic regression was used to determine association with mortality.
There were 277 patients hospitalized with LGIB. Of the 271 patients surviving to discharge, 21% (n=57) were readmitted within 30 days, 21 of whom were admitted for recurrent LGIB. The following factors were associated with 30-day readmissions: developing in-hospital LGIB (hazard ratio HR, 2.26; 95% CI, 1.08-4.28), anticoagulation (HR, 1.82; 95% CI, 1.05-3.10), and active malignancy (HR, 2.33; 95% CI, 1.11-4.42). Patients discharged while taking anticoagulants had higher rates of recurrent bleeding (HR, 2.93; 95% CI, 1.15-6.95). Patients with higher Charlson Comorbidity Index scores (odds ratio OR, 1.57; 95% CI, 1.25-2.08), active malignancy (OR, 6.57; 95% CI, 1.28-28.7), and in-hospital LGIB (OR, 11.5; 95% CI, 2.56-52.0) had increased 30-day mortality risk.
In-hospital LGIB, anticoagulation, and active malignancy are risk factors for 30-day readmissions in patients hospitalized with LGIB. In-hospital LGIB, Charlson Comorbidity Index scores, and active malignancy are risk factors for 30-day mortality.
From October 4 to November 2, 2001, the first 10 confirmed cases of inhalational anthrax caused by intentional release of Bacillus anthracis were identified in the United States. Epidemiologic ...investigation indicated that the outbreak, in the District of Columbia, Florida, New Jersey, and New York, resulted from intentional delivery of B. anthracis spores through mailed letters or packages. We describe the clinical presentation and course of these cases of bioterrorism-related inhalational anthrax. The median age of patients was 56 years (range 43 to 73 years), 70% were male, and except for one, all were known or believed to have processed, handled, or received letters containing B. anthracis spores. The median incubation period from the time of exposure to onset of symptoms, when known (n=6), was 4 days (range 4 to 6 days). Symptoms at initial presentation included fever or chills (n=10), sweats (n=7), fatigue or malaise (n=10), minimal or nonproductive cough (n=9), dyspnea (n=8), and nausea or vomiting (n=9). The median white blood cell count was 9.8 X 10(3)/mm(3) (range 7.5 to 13.3), often with increased neutrophils and band forms. Nine patients had elevated serum transaminase levels, and six were hypoxic. All 10 patients had abnormal chest X-rays; abnormalities included infiltrates (n=7), pleural effusion (n=8), and mediastinal widening (seven patients). Computed tomography of the chest was performed on eight patients, and mediastinal lymphadenopathy was present in seven. With multidrug antibiotic regimens and supportive care, survival of patients (60%) was markedly higher (<15%) than previously reported.
AbstractObjectiveTo describe liver disease related mortality in the United States during 1999-2016 by age group, sex, race, cause of liver disease, and geographic region.DesignObservational cohort ...study.SettingDeath certificate data from the Vital Statistics Cooperative, and population data from the US Census Bureau compiled by the Center for Disease Control and Prevention’s Wide-ranging Online Data for Epidemiologic Research (1999-2016).ParticipantsUS residents.Main outcome measureDeaths from cirrhosis and hepatocellular carcinoma, with trends evaluated using joinpoint regression.ResultsFrom 1999 to 2016 in the US annual deaths from cirrhosis increased by 65%, to 34 174, while annual deaths from hepatocellular carcinoma doubled to 11 073. Only one subgroup—Asians and Pacific Islanders—experienced an improvement in mortality from hepatocellular carcinoma: the death rate decreased by 2.7% (95% confidence interval 2.2% to 3.3%, P<0.001) per year. Annual increases in cirrhosis related mortality were most pronounced for Native Americans (designated as “American Indians” in the census database) (4.0%, 2.2% to 5.7%, P=0.002). The age adjusted death rate due to hepatocellular carcinoma increased annually by 2.1% (1.9% to 2.3%, P<0.001); deaths due to cirrhosis began increasing in 2009 through 2016 by 3.4% (3.1% to 3.8%, P<0.001). During 2009-16 people aged 25-34 years experienced the highest average annual increase in cirrhosis related mortality (10.5%, 8.9% to 12.2%, P<0.001), driven entirely by alcohol related liver disease. During this period, mortality due to peritonitis and sepsis in the setting of cirrhosis increased substantially, with respective annual increases of 6.1% (3.9% to 8.2%) and 7.1% (6.1% to 8.4%). Only one state, Maryland, showed improvements in mortality (−1.2%, −1.7% to −0.7% per year), while many, concentrated in the south and west, observed disproportionate annual increases: Kentucky 6.8% (5.1% to 8.5%), New Mexico 6.0% (4.1% to 7.9%), Arkansas 5.7% (3.9% to 7.6%), Indiana 5.0% (3.8% to 6.1%), and Alabama 5.0% (3.2% to 6.8%). No state showed improvements in hepatocellular carcinoma related mortality, while Arizona (5.1%, 3.7% to 6.5%) and Kansas (4.3%, 2.8% to 5.8%) experienced the most severe annual increases.ConclusionsMortality due to cirrhosis has been increasing in the US since 2009. Driven by deaths due to alcoholic cirrhosis, people aged 25-34 have experienced the greatest relative increase in mortality. White Americans, Native Americans, and Hispanic Americans experienced the greatest increase in deaths from cirrhosis. Mortality due to cirrhosis is improving in Maryland but worst in Kentucky, New Mexico, and Arkansas. The rapid increase in death rates among young people due to alcohol highlight new challenges for optimal care of patients with preventable liver disease.
AIM: Granite outcrops are prominent throughout the world and harbour many endemic species. Their topographic complexity and range of environments have led to the hypothesis that they act as refugia ...facilitating the persistence of species through climate change. We evaluate this hypothesis by investigating the phylogeographic patterns in a common granite endemic shrub. LOCATION: Granite outcrops of the Southwest Australian Floristic Region. METHODS: Chloroplast haplotypes of 89 Kunzea pulchella individuals from 16 granite outcrops were determined from sequences of three chloroplast intergenic spacer regions. Phylogenetic reconstruction and divergence dating was inferred using Bayesian and Parsimony analyses and phylogenetic relationships between haplotypes were examined in relation to geographic distributions. Nuclear diversity and differentiation of populations were assessed through analysis of 11 nuclear microsatellite loci across 384 individuals from the 16 granite outcrops. RESULTS: Kunzea pulchella exhibited low haplotype and allelic diversity within outcrops and high levels of divergence among outcrops, indicating an ancient restriction to specific outcrops with genetic drift as the main driver of evolution. Two divergent lineages were revealed in the chloroplast phylogeny dating to the Pliocene and potentially reflecting the initial impact of increased aridity prior to isolation on individual outcrops. MAIN CONCLUSIONS: Rather than uncovering the typical pattern for Pleistocene refugia with contraction to, and expansion from particular granite outcrops, we observed persistence, prolonged isolation and divergence of populations. We suggest the persistence of K. pulchella on multiple outcrops through a period of considerable climatic change may be a result of broad climatic tolerances or contraction and expansion dynamics operating at microrefugial scales within outcrops. Our observations of low haplotype and allelic diversity within populations of K. pulchella provide some support for the latter. The enduring nature of K. pulchella and evolutionary potential of populations on individual outcrops accentuates the value of these environments for biodiversity conservation planning in a changing climate.
Chronic exposure to nicotine elicits physical dependence in smokers, yet the mechanism and neuroanatomical bases for withdrawal symptoms are unclear. As in humans, rodents undergo physical withdrawal ...symptoms after cessation from chronic nicotine characterized by increased scratching, head nods, and body shakes.
Here we show that induction of physical nicotine withdrawal symptoms activates GABAergic neurons within the interpeduncular nucleus (IPN). Optical activation of IPN GABAergic neurons via light stimulation of channelrhodopsin elicited physical withdrawal symptoms in both nicotine-naive and chronic-nicotine-exposed mice. Dampening excitability of GABAergic neurons during nicotine withdrawal through IPN-selective infusion of an NMDA receptor antagonist or through blockade of IPN neurotransmission from the medial habenula reduced IPN neuronal activation and alleviated withdrawal symptoms. During chronic nicotine exposure, nicotinic acetylcholine receptors containing the β4 subunit were upregulated in somatostatin interneurons clustered in the dorsal region of the IPN. Blockade of these receptors induced withdrawal signs more dramatically in nicotine-dependent compared to nicotine-naive mice and activated nonsomatostatin neurons in the IPN.
Together, our data indicate that therapeutic strategies to reduce IPN GABAergic neuron excitability during nicotine withdrawal, for example, by activating nicotinic receptors on somatostatin interneurons, may be beneficial for alleviating withdrawal symptoms and facilitating smoking cessation.
•Nicotine withdrawal activates GABAergic neurons in the IPN•Activation of GAD2-expressing IPN neurons triggers physical withdrawal symptoms•Neurotransmission from MHb afferents is necessary for somatic withdrawal expression•Blockade of IPN β4 nAChRs elicits somatic nicotine withdrawal symptoms
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