Jittering: A computationally efficient method for generating realistic route networks from origin-destination data

Origin-destination (OD) data is a vital source of information on travel patterns but its utility is limited by reliance on zone centroids. This paper presents a reproducible and open two-stage ‘jittering’ approach to tackling this problem, which (1) uses random points to represent unique start and end points (sampling), and (2) splits OD pairs representing many trips into many ‘sub-OD’ pairs. We find that route networks generated from jittered OD data are more diffuse and potentially realistic based on an example from Edinburgh. Further work is needed to validate the approach and to find optimal parameters for sampling and disaggregation.

Comparison of Intracoronary Epinephrine and Adenosine for No-Reflow in Normotensive Patients With Acute Coronary Syndrome (COAR Trial)

Background: Intracoronary epinephrine has been effectively used in treating refractory no-reflow, but there is a dearth of data on its use as a first-line drug in normotensive patients in comparison to the widely used adenosine. Methods: In this open-labeled randomized clinical trial, 201 patients with no-reflow were randomized 1:1 into intracoronary epinephrine as the treatment group and intracoronary adenosine as the control group and followed for 1 month. The primary end points were improvement in coronary flow, as assessed by TIMI (Thrombolysis in Myocardial Infarction) flow, frame counts, and myocardial blush. Secondary end points were in-hospital and short-term mortality and major adverse cardiac events. Results: In all, 101 patients received intracoronary epinephrine and 100 patients received adenosine. Epinephrine was generally well tolerated with no immediate table death or ventricular fibrillation. No-reflow was more effectively improved with epinephrine with final TIMI III flow (90.1% versus 78%, P =0.019) and final corrected TIMI frame count (24±8.43 versus 26.63±9.22, P =0.036). However, no significant difference was observed in final grade III myocardial blush (55.4% versus 45%, P =0.139), mean reduction of corrected TIMI frame count (−25.71±11.79 versus −26.08±11.71, P =0.825), in-hospital and short-term mortality, and major adverse cardiac events. Conclusions: Epinephrine is relatively safe to use in no-reflow in normotensive patients. A significantly higher frequency of post-treatment TIMI III flow grade and lower final corrected TIMI frame count with relatively better achievement of myocardial blush grade III translate into it displaying relatively better efficacy than adenosine. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04699110.

SOD1 mutations associated with amyotrophic lateral sclerosis analysis of variant severity

Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.

Enhanced recovery after surgery protocol versus conventional care in emergency abdominal trauma surgery: a prospective, randomised, controlled study

Background: Since 1990s there has been a defined role of ERAS in elective surgeries, to optimize the peri-operative care, reducing post-operative complications and length of stay and hence, the overall costs. However, there is paucity of literature in its effectiveness in emergency trauma surgeries. The aim of the study was to investigate the feasibility and outcomes of ERAS protocol in emergency abdominal surgery in the setting of trauma.Methods: Institutional IEC approved study. A prospective randomized of 52 patients with abdominal trauma undergoing emergency laprotomy were included in the study and divided into two groups: ERP and conventional group. The ERP included early feeding, early urinary catheter removal, early mobilization/physiotherapy, early intravenous line removal and early optimal oral analgesia. The primary end-points were the length of hospital stay and secondary end-points included complication rate and re-admission rate.Results: The two groups were comparable with regards to age, gender, mechanism of injury and ISS score. Hospital stay was significantly shorter in the ERAS group: 4.67 days verses 13.36 days (p<0.001). There were 15 and 11 complications in the control and study group respectively. When graded as per the Clavien-Dindo classification there was no significant difference in the 2 groups (p=0.306).Conclusions: This study shows that early recovery programs can be successfully implemented with significant shorter hospital stays without any increase in postoperative complications in trauma patients undergoing emergency laparotomy for abdominal trauma.

Типові керовані форми дієслів руху / переміщення в українській літературній мові

In the article, on the basis of valence, a typical set of valence-driven governed components dependent on verbs of movement / moving is analyzed, a hierarchy of governed case and prepositional-case forms of these verbs is proposed, the main morphological means of their expression and their morphological variants are determined. According to such sets of governed components, a typology of verbal government is suggested. The differences between the traditional interpretation of grammatical government and the interpretation offered by the researchers of the latest Ukrainian linguistics are emphasized. The valence-determined government makes it possible to consider governed only notional verbally dependent components with semantic functions of the object, the addressee, the instrument (tool or means of action) and the locality (location, initial and end points of the motion, path of motion). The maximum quantity of typical governed components is shown by the verbs of movement / moving, they belong to multivalent ones. In typical expressions these verbs can have up to six governed components.

Extending the Quality of Secure Service Model to Multi-Hop Networks

Rarely are communications networks point-to-point. In most cases, transceiver relay stations exist between transmitter and receiver end-points. These relay stations, while essential for controlling cost and adding flexibility to network architectures, reduce the overall security of the respective network. In an effort to quantify that reduction, we extend the Quality of Secure Service (QoSS) model to these complex networks, specifically multi-hop networks. In this approach, the quantification of security is based upon probabilities that adversarial listeners and disruptors gain access to or manipulate transmitted data on one or more of these multi-hop channels. Message fragmentation and duplication across available channels provides a security performance trade-space, with its consequent QoSS. This work explores that trade-space and the corresponding QoSS model to describe it.

Validation of Cardiovascular End Points Ascertainment Leveraging Multisource Electronic Health Records Harmonized Into a Common Data Model in the ADAPTABLE Randomized Clinical Trial

Background: The ADAPTABLE trial (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) is the first randomized trial conducted within the National Patient-Centered Clinical Research Network to use the electronic health record data formatted into a common data model as the primary source of end point ascertainment, without confirmation by standard adjudication. The objective of this prespecified study is to assess the validity of nonfatal end points captured from the National Patient-Centered Clinical Research Network, using traditional blinded adjudication as the gold standard. Methods: A total of 15 076 participants with established atherosclerotic cardiovascular disease were randomized to two doses of aspirin (81 mg and 325 mg once daily). Nonfatal end points (hospitalization for nonfatal myocardial infarction, nonfatal stroke, and major bleeding requiring transfusion of blood products) were captured with the use of programming algorithms applied to National Patient-Centered Clinical Research Network data. A random subset of end points was independently reviewed by a disease-specific expert adjudicator. The positive predictive value of the programming algorithms were calculated separately for end points listed as primary and as nonprimary diagnoses. Results: A total of 225 end points were identified (91 myocardial infarction events, 89 stroke events, and 45 bleeding events), including 142 (63%) that were listed as primary diagnoses. Complete source documents were missing for 14% of events. The positive predictive value were 90%, 72%, and 93% for hospitalizations for myocardial infarction, stroke, and major bleeding, respectively, as compared to adjudication. When only primary diagnoses were considered, positive predictive value were 93%, 91%, and 97%, respectively. When only nonprimary diagnoses were considered, positive predictive value were 82%, 36%, and 71%. Conclusions: As compared with blinded adjudication, clinical end point ascertainment from queries of the National Patient-Centered Clinical Research Network distributed harmonized data was valid to identify hospitalizations for myocardial infarction in ADAPTABLE. The proportion of contradicted events was high for hospitalizations for bleeding and strokes when nonprimary diagnoses were analyzed, but not when only primary diagnoses were considered.

Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe COVID-19 Pneumonia: A Randomized Clinical Trial

Background Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with COVID-19 pneumonia, but the optimal dose is unknown. Methods Patients hospitalized for moderate-to-severe COVID-19 pneumonia were randomized 1:1 to receive standard care treatment and 1 to 2 doses of intravenous tocilizumab 4 or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble IL-6R (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. Results Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg group, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8-mg/kg within the first 2 weeks. Conclusions In patients with moderate-to-severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID pneumonia.