Severity of gastrointestinal bleeding is similar between patients receiving direct oral anticoagulants or vitamin K antagonists

Background: gastrointestinal bleeding (GIB) is a commonadverse event related to anticoagulation therapy. However,evidence comparing the severity, etiology and outcome ofGIB in patients taking direct oral anticoagulants (DOAC) vs.vitamin K antagonists (VKA) is scarce.Aim: to evaluate the severity, etiology and outcomes of GIBin patients under DOACs compared to VKA.Methods: patients under oral anticoagulant therapy admitted to the emergency department with acute GIB wereprospectively recruited from July 2016 to January 2018 ata tertiary referral hospital. Demographic and clinical out comes were obtained from medical records. GIB severitywas classified as mild, major, or severe according to theclinical presentation and type of support needed. Etiologyand location of bleeding, number of packed red blood cells(PRBC) transfused, and length of hospital stay were recorded until discharge or in-hospital death.Results: a total of 208 patients with acute GIB under oralanticoagulant treatment were recruited: 119 patients wereon VKA and 89 patients on DOAC, with similar characteristics. Thirty-one patients had severe GIB; 134 had major and43 had mild GIB, with no differences in severity, numberof PRBC, and length of hospital stay between the groups.Peptic disease was the most frequent etiology of GIB inpatients on VKA (20.2 % vs. 13.6 %, p = 0.20). Diverticularbleeding was the most frequent adverse event in patientson DOAC (14.3 % vs. 24.8 %, p = 0.056).Conclusions: severity and clinical outcomes of GIB aresimilar between patients on DOAC and patients on VKA,regardless of GIB etiology. (AU)

Principles, mechanisms and functions of entrainment in biological oscillators.

Entrainment is a phenomenon in which two oscillators interact with each other, typically through physical or chemical means, to synchronize their oscillations. This phenomenon occurs in biology to coordinate processes from the molecular to organismal scale. Biological oscillators can be entrained within a single cell, between cells or to an external input. Using six illustrative examples of entrainable biological oscillators, we discuss the distinctions between entrainment and synchrony and explore features that contribute to a system's propensity to entrain. Entrainment can either enhance or reduce the heterogeneity of oscillations within a cell population, and we provide examples and mechanisms of each case. Finally, we discuss the known functions of entrainment and discuss potential functions from an evolutionary perspective.

Time-series transcriptomics and proteomics reveal alternative modes to decode p53 oscillations.

The cell stress-responsive transcription factor p53 influences the expression of its target genes and subsequent cellular responses based in part on its dynamics (changes in level over time). The mechanisms decoding p53 dynamics into subsequent target mRNA and protein dynamics remain unclear. We systematically quantified p53 target mRNA and protein expression over time under two p53 dynamical regimes, oscillatory and rising, using RNA-sequencing and TMT mass spectrometry. Oscillatory dynamics allowed for a greater variety of dynamical patterns for both mRNAs and proteins. Mathematical modeling of empirical data revealed three distinct mechanisms that decode p53 dynamics. Specific combinations of these mechanisms at the transcriptional and post-transcriptional levels enabled exclusive induction of proteins under particular dynamics. In addition, rising induction of p53 led to higher induction of proteins regardless of their functional class, including proteins promoting arrest of proliferation, the primary cellular outcome under rising p53. Our results highlight the diverse mechanisms cells employ to distinguish complex transcription factor dynamics to regulate gene expression.

Severity of gastrointestinal bleeding is similar between patients receiving direct oral anticoagulants or vitamin K antagonists.

BACKGROUND: Gastrointestinal bleeding (GIB) is a common adverse event related to anticoagulation therapy. However, evidence comparing the severity, etiology and outcome of GIB in patients taking direct oral anticoagulants (DOAC) vs. vitamin K antagonists (VKA) is scarce. AIMS: To evaluate the severity, etiology and outcomes of GIB in patients under DOACs compared to VKA. METHODS: Patients under oral anticoagulant therapy admitted to the emergency department with acute GIB were prospectively recruited from July 2016 to January 2018 at a tertiary referral hospital. Demographic and clinical outcome were obtained from medical records. Severity of the GIB event was classified as mild, major or severe according to clinical presentation and the type of support needed. Etiology and location of bleeding, number of packed red blood cells transfused (PRBC) and length of hospital stay were recorded until discharge or in-hospital death. RESULTS: A total of 208 patients with acute GIB under oral anticoagulant treatment were recruited: 119 patients were on VKA and 89 patients on DOAC with similar characteristics. Thirty-one patients had severe GIB; 134 major and 43 mild, with no differences in severity, number of PRBC and length of hospital stay between the groups. Peptic disease was the most frequent etiology of GIB in patients on VKA (20.2 % vs. 13.6%, p=0.20). Diverticular bleeding was the most frequent adverse event in patients on DOAC (14.3% vs. 24.8%, p= 0.056). CONCLUSIONS: Severity and clinical outcomes of GIB are similar between patients on DOAC and patients on VKA, regardless of etiology of GIB.

Delayed introduction of sirolimus in paediatric intestinal transplant recipients: indications and long-term benefits.

To review our experience using sirolimus in a single centre paediatric intestinal transplantation cohort. Intestinal transplant patients with more than 3 months follow-up were divided into two groups according to their immunosuppression regimen: tacrolimus, (TAC group, n = 45 grafts) or sirolimus (SRL group, n = 38 grafts), which included those partially or completely converted from tacrolimus to sirolimus. The indications to switch were tacrolimus side effects and immunological complications. Survival and complications were retrospectively analysed comparing both groups. SRL was introduced 9 months (0 months-16.9 years) after transplant. The main cause for conversion was worsening renal function (45%), followed by haemolytic anaemia (21%) and graft-versus-host-disease (16%). Both groups showed a similar overall patient/graft survival (P = 0.76/0.08) and occurrence of rejection (24%/17%, P = 0.36). Immunological complications did not recur after conversion. Renal function significantly improved in most SRL patients. After a median follow-up of 65.17 months, 28/46 survivors were on SRL, 26 with monotherapy, with good graft function. Over one-third of our patients eventually required SRL conversion that allowed to improve their kidney function and immunological events, without entailing additional complications or survival impairment. Further trials are warranted to clarify the potential improvement of the standard tacrolimus maintenance by sirolimus conversion or addition.

Long-term follow-up of olfactory and gustatory dysfunction in COVID-19: 6 months case-control study of health workers.

PURPOSE: The study aimed to determine the incidence and long-term evolution of COVID-related olfactory (OD) and gustatory (GD) dysfunction, the recovery timeline, and the association with other symptoms. The secondary objective was to identify the predictive clinical factors for the evolution of these symptoms. METHODS: A prospective case-control study was conducted from March 15 to October 15, 2020, in health workers with COVID-19 related symptoms in a tertiary care hospital. 320 patients were included after 6 months of follow-up: 195 in the case group and 125 in the control group. Olfactory dysfunction (OD), dysosmia, and gustatory dysfunction (GD) onset and recovery rate after 6 months follow-up are analyzed in both groups. RESULTS: There were 125 (64.1%) in case group patients with OD and 118 (60.5%) with GD. Total or partial recovery OD and GD was found in 89%, mainly in the first 2 months. In the control group, there were 14 (11.2%) patients with OD and 33 (26.4%) patients with GD, with 100% of total/partial recovery. CONCLUSION: In both groups, OD and GD showed high-resolution rates during the first two months after the onset of symptoms. Nevertheless, 11% of the case group patients did not show any recovery, and the partial resolution was present in 30% of our patients, at the 6 months follow-up. We found a high correlation between OD and GD, both in the appearance of symptoms and in their recovery. Nasal obstruction and dyspnea have been identified as risk factors for the persistence of symptoms.

Vibration-induced nystagmus and head impulse test screening for vestibular schwannoma.

LEVEL OF EVIDENCE: II-2. BACKGROUND: Vestibular schwannomas are benign tumors of the eight cranial nerve that may cause asymmetric sensorineural hearing loss (ASHL) and vestibular dysfunction. OBJECTIVE: The aim of this study was to assess the role of the video head impulse test (vHIT) and vibration-induced nystagmus (VIN) test in diagnosing vestibular schwannoma in a population of patients with Asymmetric sensorineural hearing loss. MATERIAL AND METHODS: For this prospective case-control study, 23 consecutive patients with ASHL and normal magnetic resonance were enrolled in the control group, and 33 consecutive patients with ASHL and vestibular schwannoma were enrolled in the case group. Gold standard was magnetic resonance imaging. Audiometry, vHIT, and VIN tests were performed for each patient. Significance of VIN and vHIT testing was determined by evaluation of their sensitivity, specificity, and correlation with vestibular function tests. RESULTS: Regarding the vHIT, sensitivity and specificity were 45.5% and 82.6%, respectively, for horizontal canal gain, 60.6% and 87.6%, respectively, for posterior canal gain, and 45.5% and 78.3%, respectively, when analyzing superior canal gains. Regarding the VIN test, the sensitivity and specificity were 81.8% and 73.9%, respectively, when based on the presence of a VIN with any mastoid stimulation. CONCLUSIONS: Our results suggest that using the VIN test may be an efficient approach to screen for vestibular schwannoma in patients with asymmetric sensorineural hearing loss. SIGNIFICANCE: Our results suggest that using the VIN test may be an efficient approach to screen for vestibular schwannoma in patients with ASHL.

Upside-down kidney placement: An alternative in pediatric renal transplantation.

PURPOSE: "Upside-down" kidney placement has been reported as an acceptable alternative in cases of technical difficulty in kidney transplantation but there are few reports in the pediatric population. The aim of our study is to analyze whether the placement of the upside-down kidney could affect graft outcome or produce more complications. MATERIALS AND METHODS: A retrospective study was conducted of pediatric kidney transplants performed in our center between 2005 and 2017 with at least 6 months' follow-up. Epidemiological and anthropometric data, type of donor (deceased/living), graft position (normal/upside-down), reason for the upside-down placement, early, medium and long-term complications and renal function were analyzed and compared with patients transplanted in the same period with a normal graft placement. RESULTS: From 181 transplants, 167 grafts were placed in a normal position (mean age: 10 y and mean weight: 30 kg) and 14 were placed upside-down (10 y, 37 kg) mainly because of vessel shortness after laparoscopic nephrectomy. Male predominance was observed in both groups. 57% of grafts from the control group and 64% of those from study group came from a living donor. Four vascular and two ureteral re-anastomoses were recorded in the control group and two vascular and one ureteral re-anastomosis in the study group (p > 0.05). In the latter group, no grafts have been lost due to vascular or urological causes and no patients have required dialysis. CONCLUSIONS: When necessary, an upside-down placement for the renal graft is a safe alternative in the pediatric population. LEVEL OF EVIDENCE: Level III.

The effects of proliferation status and cell cycle phase on the responses of single cells to chemotherapy.

DNA-damaging chemotherapeutics are widely used in cancer treatments, but for solid tumors they often leave a residual tumor-cell population. Here we investigated how cellular states might affect the response of individual cells in a clonal population to cisplatin, a DNA-damaging chemotherapeutic agent. Using a live-cell reporter of cell cycle phase and long-term imaging, we monitored single-cell proliferation before, at the time of, and after treatment. We found that in response to cisplatin, cells either arrested or died, and the ratio of these outcomes depended on the dose. While we found that the cell cycle phase at the time of cisplatin addition was not predictive of outcome, the proliferative history of the cell was: highly proliferative cells were more likely to arrest than to die, whereas slowly proliferating cells showed a higher probability of death. Information theory analysis revealed that the dose of cisplatin had the greatest influence on the cells' decisions to arrest or die, and that the proliferation status interacted with the cisplatin dose to further guide this decision. These results show an unexpected effect of proliferation status in regulating responses to cisplatin and suggest that slowly proliferating cells within tumors may be acutely vulnerable to chemotherapy.

Inferring Leading Interactions in the p53/Mdm2/Mdmx Circuit through Live-Cell Imaging and Modeling.

The tumor-suppressive transcription factor p53 is a master regulator of stress responses. In non-stressed conditions, p53 is maintained at low levels by the ubiquitin ligase Mdm2 and its binding partner Mdmx. Mdmx depletion leads to a biphasic p53 response, with an initial post-mitotic pulse followed by oscillations. The mechanism underlying this dynamical behavior is unknown. Two different roles for Mdmx have been proposed: enhancing p53 ubiquitination by Mdm2 and inhibiting p53 activity. Here, we developed a mathematical model of the p53/Mdm2/Mdmx network to investigate which Mdmx functions quantitatively affect specific features of p53 dynamics under various conditions. We found that enhancement of Mdm2 activity was the most critical role of Mdmx under unstressed conditions. The model also accurately predicted p53 dynamics in Mdmx-depleted cells following DNA damage. This work outlines a strategy for rapidly testing possible network interactions to reveal those most impactful in regulating the dynamics of key proteins.

Mueller matrix study of the dichroism in nanorods dimers: rod separation effects.

We have studied the optical response of chiral metastructures composed of a disordered array of couples of plasmonic Au nanorods helically piled along the vertical direction. The fabrication is based on the use of multiaxial and multimaterial evaporation of the different metastructure building blocks through nanohole masks. From the analysis of the Mueller Matrix elements of the system, obtained both experimentally and from dedicated numerical simulations in forward and backward illumination conditions, we have been able to determine the linear and circular dichroic response of the system, as well as to sort out the optical anisotropy and intrinsic circular dichroism contributions to the circular differential extinction. We have also analyzed the dependence of the optical properties as a function of the angle between the rods and of the thickness of the dielectric separator. The study of quasi-planar as well as three-dimensional structures allows unraveling the role played by interactions between the constituting building blocks and, in particular, the distance between rods. We have experimentally and theoretically observed a decrease of the circular dichroic contribution and a change of the optical anisotropic contribution when the structures evolve from non-planar to planar.

Synthetic circuits reveal how mechanisms of gene regulatory networks constrain evolution.

Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe-a pivotal pattern in embryonic development. The two parental circuits produce the same phenotype, but create it through different regulatory mechanisms. We show that mutations cause distinct novel phenotypes in the two networks and use a combination of experimental measurements, mathematical modelling and DNA sequencing to understand why mutations bring forth only some but not other novel gene expression phenotypes. Our results reveal that the regulatory mechanisms of networks restrict the possible phenotypic variation upon mutation. Consequently, seemingly equivalent networks can indeed be distinct in how they constrain the outcome of further evolution.

Holographic Phonons.

We present a class of holographic massive gravity models that realize a spontaneous breaking of translational symmetry-they exhibit transverse phonon modes whose speed relates to the elastic shear modulus according to elasticity theory. Massive gravity theories thus emerge as versatile and convenient theories to model generic types of translational symmetry breaking: explicit, spontaneous, and a mixture of both. The nature of the breaking is encoded in the radial dependence of the graviton mass. As an application of the model, we compute the temperature dependence of the shear modulus and find that it features a glasslike melting transition.