bluuebunny/crossref_metadata_2025 huggingface dataset:
Detection and quantification of type C viral proteins in tissues and sera with an enzyme immunoassay
Authors: Schetters H , Hehlmann R , Erfle V , Ramanarayanan M
Published: June 2021

The detection and quantification of retroviral proteins in cells, tumors, and sera by an enzyme immunoassay technique (enzyme-linked immunosorbent assay [ELISA]) is described. The ELISA technique has been applied to three viral systems: murine leukemia virus, baboon endogenous virus, and simian sarcoma virus. By detecting 0.1 nf of retroviral antigen, the sensitivity of the ELISA is comparable to that of the competition radioimmunoassay technique.
Respiratory Tract Explant Infection Dynamics of Influenza A Virus in California Sea Lions, Northern Elephant Seals, and Rhesus Macaques
Authors: Liu Hongwei , Plancarte Magdalena , Ball Erin E. , Weiss Christopher M. , Gonzales-Viera Omar , Holcomb Karen , Ma Zhong-Min , Allen A. Mark , Reader J. Rachel , Duignan Pádraig J. , Halaska Barbie , Khan Zenab , Kriti Divya , Dutta Jayeeta , van Bakel Harm , Jackson Kenneth , Pesavento Patricia A. , Boyce Walter M. , Coffey Lark L.
Published: June 2021

Although influenza A virus can infect marine mammals, a dearth of marine mammal cell lines and ethical and logistical challenges prohibiting experimental infections of living marine mammals mean that little is known about IAV infection kinetics in these species. We circumvented these limitations by adapting a respiratory tract explant model first to establish the approach with rhesus macaques and then for use with explants from wild marine mammals euthanized for nonrespiratory medical conditions.
Hsp90 Is Required for Snakehead Vesiculovirus Replication via Stabilization of the Viral L Protein
Authors: Zhang Yanwei , Zhang Yong-An , Tu Jiagang
Published: June 2021

It has long been proposed that cellular proteins are involved in viral RNA synthesis via interacting with the viral polymerase protein. This study focused on identifying cellular proteins interacting with the SHVV L protein, studying the effects of their interactions on SHVV replication, and revealing the underlying mechanisms.
Integrative transformation of Candida albicans, using a cloned Candida ADE2 gene
Authors: Kurtz M B , Cortelyou M W , Kirsch D R
Published: June 2021

Candida albicans is a diploid dimorphic yeast with no known sexual cycle. The development of a DNA transformation system would greatly improve the prospects for genetic analyses of this yeast. Plasmids were isolated from a Candida Sau3A partial library which complements the ade2-1 and ade2-5 mutations in Saccharomyces cerevisiae. These plasmids contain a common region, part of which, when subcloned, produces ade2 complementation. Among the small number of auxotrophs previously isolated in C. albicans, red adenine-requiring mutants had been identified by several groups. In two of these strains, the cloned Candida DNA transformed the mutants to ADE+ at frequencies of 0.5 to 5 transformants per micrograms of DNA. In about 50% of the transformants, plasmid DNA sequences became stably integrated into the host genome and, in the several cases analyzed by Southern hybridization, the DNA was integrated at the site of the ADE2 gene in one of the chromosomal homologs.
Expression of the intracisternal A-particle is elevated during differentiation of embryonal carcinoma cells
Authors: Howe C C , Overton G C
Published: June 2021

Three cDNA clones coding for the 3' region of the intracisternal A-particle (IAP), a mouse endogenous retrovirus, were isolated during screening of a library for genes whose expression was modulated during the retinoic acid-induced differentiation of the embryonal carcinoma cell line F9 into parietal endoderm-like (PE-like) cells. In contrast to previously reported results, no IAP transcripts were detected in either F9 cells or two pluripotent cell lines tested. Instead, IAP transcripts as well as IAPs were abundant in the PE-like cells PYS-2 and F9AcCl 9 and in retinoic acid-induced F9 cells but not in the other differentiated cell types of teratocarcinoma origin which were examined. A comparison of the nucleotide sequences of the three IAP cDNA clones with a genomically integrated proviral sequence (MIA14) demonstrated heterogeneity in both length and sequence among the clones. The position of the poly(A) addition site was determined to be 15 nucleotides from the proposed poly(A) addition signal and to occur after the sequence CAGA, not CA, as previously proposed. Length heterogeneity was greatest in a region of TC repeats 80 base pairs 5' to the poly(A) addition site. Additionally, the putative TATAA box found in MIA14 was deleted in the cDNA clones and in the long terminal repeat regions from two other genomic clones examined. The heterogeneity evident among the cDNA clones further demonstrated that at least two distinct IAP genes are activated during differentiation. An analysis of the rate of transcription in isolated nuclei indicated that the activation of expression of IAP genes in PE-like cells is the result of transcriptional regulation. Together, these observations suggest that the modulation of IAP transcription is regulated autonomously rather than by the fortuitous integration of an IAP sequence adjacent to a developmentally regulated cellular gene.
Using the Theory of Planned Behavior as a Framework for the Evaluation of a Professional Development Workshop
Authors: PATTERSON ROBIN R.
Published: June 2021

This purpose of this study was to use a theoretical framework based on several decades of attitudinal research to assess the intentions of Microbial Discovery Workshop participants to incorporate the inquiry activities presented at the workshop into their curricula, to evaluate the participants actual use of these activities after the workshop, and to uncover the barriers and enablers the participants faced in doing so. As a framework, the theory of planned behavior was ascertained to be an appropriate means of assessment and it was revealed that participants’ intention to use the workshop activities significantly correlated with their actual use. The participants’ attitudes toward using the activities influenced their use more than the participants’ perceptions of the social pressures that would influence their decision to use the activities or their belief as to how easy or difficult it would be to incorporate a given activity. The participants were found to be highly self-efficacious pertaining to their ability to implement the activities, but perceived self-efficacy was not a significant predictor of the participants’ intentions to incorporate the activities into their teaching-learning repertoire. The study also uncovered other behaviors the participants displayed as a result of attending the workshop consistent with the goals and objectives of the workshop organizers.
Genome Sequence of Lactiplantibacillus plantarum DmPark25_157, a Bacterial Strain Isolated from Drosophila melanogaster
Authors: Giles Hunter H. , Petersen Samara C. , Call Gerald B. , Chaston John M.
Published: June 2021

We present the genome sequence of a bacterial strain isolated from

park
25

mutants of
Drosophila melanogaster
as part of efforts to better understand the microbial communities in
D. melanogaster
. We isolated and sequenced a
Lactiplantibacillus plantarum
strain. We present a preliminary comparative analysis with a closely related strain.
Haemiballism/haemichorea: an atypical presentation of ischaemic stroke
Authors: Nohria Raman , Bennett Stacey , O'Keefe Yasmin Ali
Published: June 2021

A 76-year-old man was admitted to the hospital with acute onset of involuntary movements of the left side of his body. His neurological examination revealed he was oriented only to himself, and aforementioned movements of his left arm and leg. CT head demonstrated old infarcts in his right aspect of his pons and basal ganglia. Cerebrospinal fluid analysis was unremarkable. He initially had a normal blood glucose with an elevated anion gap and elevated creatine kinase. Brain MRI showed a small lacunar-type ischaemic infarct within the anteromedial aspect of the right cerebral peduncle, which localised to his haemiballism. To prevent worsening rhabdomyolysis associated with his haemiballism, the primary team initiated both tetrabenazine and diazepam. His movements improved after 1 week of medication therapy. This report discusses a thorough workup for this movement disorder and when to intervene for this distressing condition.
Intracranial response after extracranial radiation in a patient with rapidly progressing metastatic melanoma
Authors: Piercey Oliver , Tomaszewski Jonathan Mark , Smith Kortnye
Published: June 2021

Growing literature supports the synergistic effect of radiation as a primer for renewed enhanced systemic immunological responses in patients receiving immunotherapy for metastatic melanoma. Radiographic regression of extracranial tumours after treatment of intracranial metastatic lesions has been reported and these observations point to an abscopal effect that traverses the blood–brain barrier. We describe a patient with rapidly progressing metastatic melanoma despite combined immune checkpoint blockade, who achieved a complete metabolic response of both his extracranial and intracranial disease after the commencement of palliative radiation to his axilla. This is the first published case, to our knowledge, of a sustained, complete intracranial abscopal response from extracranial radiation. We discuss potential mechanistic relations between radiation, the blood–brain barrier and the abscopal effect.
Ipsilateral orbital metastasis following enucleation of intraocular ciliochoroidal melanoma: a rare occurrence
Authors: Ghose Neha , Jakati Saumya , Kaliki Swathi
Published: June 2021

This case report demostrates an unusual occurence of orbital metastasis along with liver metastasis 5 years following enucleation for ciliochoroidal melanoma with no extraocular extension. It exemplifies that metastasis of the tumour can occur in the ipsilateral orbit after enucleation. Importance of close clinical follow-up after enucleation for choroidal melanoma, careful socket examination, and regular systemic metastatic workup is demonstrated. To the best of our knowledge, this is the first case report of uveal melanoma with ipsilateral orbital metastasis.
Quality of systematic reviews supporting the 2017 ACC/AHA and 2018 ESC/ESH guidelines for the management of hypertension
Authors: Kanukula Raju , Dhurjati Rupasvi , Vidyasagar Kota , Rehana Nusrath , Talari Arun , Salam Abdul , Rodgers Anthony , Page Matthew J
Published: June 2021

Objective

To assess the methodological and reporting quality of systematic reviews (SRs) that informed recommendations in the recent American and European hypertension guidelines.

Design and settings

Meta-epidemiological study. We identified SRs that were cited for class I recommendations based on Level of Evidence-A in the 2017 American College of Cardiology/American Heart Association (ACC/AHA) and the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) hypertension guidelines.

Main outcome measures

Methodological and reporting quality of the SRs was assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR-2) checklist and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, respectively.

Results

A total of 40 SRs was included in the analysis (28 from 2017 ACC/AHA; 22 from 2018 ESC/ESH and 10 were included in both). Based on the AMSTAR-2 assessment, only 7.5% SRs were found to be of high methodological quality, 47.5% were of moderate, each 22.5% were of low and critically low quality. Based on the PRISMA checklist assessment, a mean of 24 items (SD (2.76) were reported appropriately, and only five SRs reported all 27 items appropriately.

Conclusion

Methodological and reporting quality of SRs were found to vary considerably. Lack of information on the funding source of included studies, use of a protocol, integration of risk of bias assessments while interpreting findings and reporting of excluded studies were major methodological deficiencies.
A network meta-analysis of psychosocial interventions for refugees and asylum seekers with PTSD
Authors: Turrini Giulia , Tedeschi Federico , Cuijpers Pim , Del Giovane Cinzia , Kip Ahlke , Morina Nexhmedin , Nosè Michela , Ostuzzi Giovanni , Purgato Marianna , Ricciardi Chiara , Sijbrandij Marit , Tol Wietse , Barbui Corrado
Published: June 2021

Introduction

Refugees and asylum seekers are vulnerable to common mental disorders, including post-traumatic stress disorder (PTSD). Using a network meta-analysis (NMA) approach, the present systematic review compared and ranked psychosocial interventions for the treatment of PTSD in adult refugees and asylum seekers.

Methods

Randomised studies of psychosocial interventions for adult refugees and asylum seekers with PTSD were systematically identified. PTSD symptoms at postintervention was the primary outcome. Standardised mean differences (SMDs) and ORs were pooled using pairwise and NMA. Study quality was assessed with the Cochrane Risk of Bias (RoB) tool, and certainty of evidence was assessed through the Confidence in Network Meta-Analysis application.

Results

A total of 23 studies with 2308 participants were included. Sixteen studies were conducted in high-income countries, and seven in low-income or middle-income countries. Most studies were at low risk of bias according to the Cochrane RoB tool. NMA on PTSD symptoms showed that cognitive behavioural therapy (CBT) (SMD=−1.41; 95% CI −2.43 to −0.38) and eye movement desensitisation and reprocessing (EMDR) (SMD=−1.30; 95% CI −2.40 to −0.20) were significantly more effective than waitlist (WL). CBT was also associated with a higher decrease in PTSD symptoms than treatment as usual (TAU) (SMD −1.51; 95% CI −2.67 to −0.36). For all other interventions, the difference with WL and TAU was not significant. CBT and EMDR ranked best according to the mean surface under the cumulative ranking. Regarding acceptability, no intervention had less dropouts than inactive interventions.

Conclusion

CBT and EMDR appeared to have the greatest effects in reducing PTSD symptoms in asylum seekers and refugees. This evidence should be considered in guidelines and implementation packages to facilitate dissemination and uptake in refugee settings.
Reliability of parental assessment of auditory skills in young children: a cross-sectional study in Italian language
Authors: Orzan Eva , Battelino Saba , Ciciriello Elena , Bonifacio Serena , Pellizzoni Sandra , Saksida Amanda
Published: June 2021

Objective

Hearing impairments (HIs) that progress or have later onset may have specific effects on language and cognitive development, but are difficult to suspect during routine primary care visits. Family concern regarding hearing is thought to represent an important risk factor requiring audiological examination. Yet it is not clear how successful parents are in recognising the consequences or specific suspect elements of HI in young children. The aim of this study is to verify whether parents of at-risk children recognise the presence of HI through a parental questionnaire that draws attention to auditory skills development and compares them with language and communication skills.

Design

Observational study.

Setting

From 2013 to 2019, parents were administered the Questionnaire on Hearing and Communication Abilities before audiological evaluation of their children at a secondary care institute.

Participants

309 Italian children (1–36 months old) at risk of HI.

Primary and secondary outcome measures

Questionnaire sensitivity in predicting the presence and type of HI.

Results

Parents report a decrease in auditory skills for children with sensorineural HI (Χ2(2)=14.4, p=0.003), with an increased concern expressed in 59% compared with 24% in normally hearing children. Both auditory (r=−0.18, p=0.002) and comprehension (r=−0.13, p=0.057) skills weakly but negatively correlated with a diagnosis of HI. On discriminant analysis, the positive predictive value of the questionnaire was 0.78, but with low sensitivity (0.39).

Conclusions

Parents of children with a verified risk of HI have some capacity to recognise non-typical auditory behaviour. Thus, it is important to assess parental concerns during primary care health visits, and a targeted questionnaire on auditory abilities can complement existing screening procedures. However, given the low sensitivity of the questionnaire, we conclude that for a reliable detection of HIs that progress or have later onset an objective screening tool is always required.
Acute sore throat and Fusobacterium necrophorum in primary healthcare: a systematic review and meta-analysis
Authors: Malmberg Stefan , Petrén Susanna , Gunnarsson Ronny , Hedin Katarina , Sundvall Pär-Daniel
Published: June 2021

Purpose

The main objective of this review was to describe and quantify the association between Fusobacterium necrophorum (FN) and acute sore throat in primary healthcare (PHC).

Methods

In this systematic review and meta-analysis, we searched Scopus and PubMed for case–control studies reporting the prevalence of FN in patients attending primary care for an uncomplicated acute sore throat as well as in healthy controls. Only studies published in English were considered. Publications were not included if they were case studies, or if they included patients prescribed antibiotics before the throat swab, patients with a concurrent malignant disease, on immunosuppression, having an HIV infection, or patients having another acute infection in addition to a sore throat. Inclusion criteria and methods were specified in advance and published in PROSPERO. The primary outcome was positive etiologic predictive value (P-EPV), quantifying the probability for an association between acute sore throat and findings of FN in the pharynx. For comparison, our secondary outcome was the corresponding P-EPV for group A Streptococcus (GAS).

Results

PubMed and Scopus yielded 258 and 232 studies, respectively. Removing duplicates and screening the abstracts resulted in 53 studies subsequently read in full text. For the four studies of medium to high quality included in the meta-analysis, the cumulative P-EPV regarding FN was 64% (95% CI 33% to 83%). GAS, based on data from the same publications and patients, yielded a positive EPV of 93% (95% CI 83% to 99%).

Conclusions

The results indicate that FN may play a role in PHC patients with an acute sore throat, but the association is much weaker compared with GAS.
Prospective observational cohort study on epidemiology, treatment and outcome of patients with traumatic brain injury (TBI) in German BG hospitals
Authors: Schwenkreis Peter , Gonschorek Andreas , Berg Florian , Meier Ullrich , Rogge Witold , Schmehl Ingo , Kern Bodo Christian , Meisel Hans-Jörg , Wohlfarth Kai , Gross Stefan , Sczesny-Kaiser Matthias , Tegenthoff Martin , Boschert Jürgen , Bruckmoser Ralf , Fürst Andrea , Schaan Marc , Strowitzki Martin , Pingel Andreas , Jägers Lisa Linnea , Rudolf Henrik , Trampisch Hans-Joachim , Lemcke Johannes
Published: June 2021

Objectives

Since 2000/2001, no large-scale prospective studies addressing traumatic brain injury (TBI) epidemiology in Germany have been published. Our aim was to look for a possible shift in TBI epidemiology described in other European countries, to look for possible changes in TBI management and to identify predictors of 1-year outcome especially in patients with mild TBI.

Design

Observational cohort study.

Setting

All patients suffering from a TBI of any degree between 1 October 2014 and 30 September 2015, and who arrived in one of the seven participating BG hospitals within 24 hours after trauma, were included.

Participants

In total, 3514 patients were included.

Outcome measures

Initial care, acute hospital care and rehabilitation were documented using standardised documentation forms. A standardised telephone interview was conducted 3 and 12 months after TBI in order to obtain information on outcome.

Results

Peaks were identified in males in the early 20s and mid-50s, and in both sexes in the late 70s, with 25% of all patients aged 75 or older. A fall was the most frequent cause of TBI, followed by traffic accidents (especially bicyclists). The number of head CT scans increased, and the number of conventional X-rays of the skull decreased compared with 2000/2001. Besides, more patients were offered rehabilitation than before. Though most TBI were classified as mild, one-third of the patients participating in the telephone interview after 12 months still reported troubles attributed to TBI. Negative predictors in mild TBI were female gender, intracranial bleeding and Glasgow Coma Scale (GCS) 13/14.

Conclusion

The observed epidemiologic shift in TBI (ie, elderly patients, more falls, more bicyclists) calls for targeted preventive measures. The heterogeneity behind the diagnosis ‘mild TBI’ emphasises the need for defining subgroups not only based on GCS.
Spiritual distress: symptoms, quality of life and hospital utilisation in home-based palliative care
Authors: Cipta Andre , Turner Bethany , Haupt Eric C , Werch Henry , Reinke Lynn , Mularski Richard A , Nguyen Huong Q
Published: June 2021

Objectives

The purpose of this study was to use a spiritual screening question to quantify the prevalence of spiritual distress (SD) in a large cohort of seriously ill patients at admission to home-based palliative care (HBPC) and to examine the associations between SD with symptom burden, quality of life and hospital-based utilisation up to 6 months after admission to HBPC.

Methods

Data for this cohort study (n=658) were drawn from a pragmatic comparative-effectiveness trial testing two models of HBPC. At admission to HBPC, SD was measured using a global question (0–10-point scale: none=0; mild=1–4; moderate-to-severe=5+); symptoms and quality of life were measured with the Edmonton Symptom Assessment Scale (ESAS) and PROMIS-10. Hospital utilisation was captured using electronic records and claims. Median regression and proportional hazard competing risk models assessed the association between SD with symptoms and quality of life, and hospital utilisation, respectively.

Results

Nearly half of the patients/proxies reported some level of SD. Increasing SD was significantly associated with higher symptom burden (increase of 7–14 points on ESAS) and worse mental well-being (decrease of 2.7 to 4.6 points on PROMIS-10-mental) in adjusted models. Compared with patients/proxies who reported no SD, those with at least some level of SD were not at increased risk for hospital-based utilisation over a median follow-up period of 2 months.

Conclusion

While SD is cross-sectionally associated with worse symptoms and mental well-being, it did not predict downstream hospital-based utilisation. Our results highlight the importance of assessing for and managing SD in patients with serious illness.
Simulated airway drills as a tool to measure and guide improvements in endotracheal intubation preparation in the paediatric emergency department
Authors: Wong Kei U , Gross Isabel , Emerson Beth L , Goldman Michael P
Published: June 2021

Introduction

Emergent paediatric intubation is an infrequent but high-stakes procedure in the paediatric emergency department (PED). Successful intubations depend on efficient and accurate preparation. The aim of this study was to use airway drills (brief in-situ simulations) to identify gaps in our paediatric endotracheal intubation preparation process, to improve on our process and to demonstrate sustainability of these improvements over time in a new staff cohort.

Method

This was a single-centre, simulation-based improvement study. Baseline simulated airway drills were used to identify barriers in our airway preparation process. Drills were scored for time and accuracy on an iteratively developed 16-item rubric. Interventions were identified and their impact was measured using simulated airway drills. Statistical analysis was performed using unpaired t-tests between the three data collection periods.

Results

Twenty-five simulated airway drills identified gaps in our airway preparation process and served as our baseline performance. The main problem identified was that staff members had difficulty locating essential airway equipment. Therefore, we optimised and implemented a weight-based airway cart. We demonstrated significant improvement and sustainability in the accuracy of obtaining essential airway equipment from baseline to postintervention (62% vs 74%; p=0.014), and postintervention to sustainability periods (74% vs 77%; p=0.573). Similarly, we decreased and sustained the time (in seconds) required to prepare for a paediatric intubation from baseline to postintervention (173 vs 109; p=0.001) and postintervention to sustainability (109 vs 103; p=0.576).

Conclusions

Simulated airway drills can be used as a tool to identify process gaps, measure and improve paediatric intubation readiness.
Upper arm length along with mid-upper arm circumference to enhance wasting prevalence estimation and diagnosis: sensitivity and specificity in 6–59-months-old children
Authors: Barro Mouhamed , Baro Mohamed Daouda , Cisse Djibril , Zagre Noel , Ba Thierno , Neff Baro Shanti , Diagana Yacouba
Published: June 2021

Objective

To evaluate the added value of the use of upper arm length (UAL) along with mid-upper arm circumference (MUAC) to diagnose and estimate the prevalence of wasting in comparison to current WHO standard and other MUAC-based methods.

Design

UAL and usual anthropometric measurements were collected during a national cross-sectional nutritional survey. Children were classified into three upper arm length groups (UALGs): UALG1, UALG2 and UALG3 according to the following UAL limits: ≤150, 151–180 and ≥181 mm, respectively. Receiver operating characteristic curves were used to determine the best MUAC cut-off for each group using weight-for-height Z-score (WHZ) as a reference standard. Wasting prevalence, sensitivity and specificity of all diagnostic methods were compared.

Setting

This study was conducted in Mauritania.

Participants

National representative sample of children from 6 to 59 months old.

Results

In total, 12 590 children were included in the study. Wasting prevalence was 16.1%, 5.0% and 12.5% when diagnosed by WHZ <−2, MUAC <125 mm and MUAC–UALG methods, respectively. Using the MUAC–UALG method increased the sensitivity for wasting diagnosis from 17.98% with MUAC <125 mm to 39.43% with MUAC–UALG. The specificity decreased from 97.49% with MUAC <125 mm to 92.71% with MUAC–UALG. With MUAC–height Z score and MUAC <138 mm, sensitivity was 26.04% and 69.76% and specificity were 97.40% and 75.64% respectively.

Conclusion

This alternative method using MUAC tape to measure UAL increases the wasting diagnosis accuracy and allows for a better estimation of wasting prevalence. This method could be used as a potential alternative method for quick surveys in emergency settings such as Corona virus disease 2019 context.
Electrocardiographic biomarkers to predict atrial fibrillation in sinus rhythm electrocardiograms
Authors: Sanz-García Ancor , Cecconi Alberto , Vera Alberto , Camarasaltas Juan Miguel , Alfonso Fernando , Ortega Guillermo Jose , Jimenez-Borreguero Jesus
Published: June 2021

Objective

Early prediction of atrial fibrillation (AF) development would improve patient outcomes. We propose a simple and cheap ECG based score to predict AF development.

Methods

A cohort of 16 316 patients was analysed. ECG measures provided by the computer-assisted ECG software were used to identify patients. A first group included patients in sinus rhythm who showed an ECG with AF at any time later (n=505). A second group included patients with all their ECGs in sinus rhythm (n=15 811). By using a training set (75% of the cohort) the initial sinus rhythm ECGs of both groups were analysed and a predictive risk score based on a multivariate logistic model was constructed.

Results

A multivariate regression model was constructed with 32 variables showing a predictive value characterised by an area under the curve (AUC) of 0.776 (95% CI: 0.738 to 0.814). The subsequent risk score included the following variables: age, duration of P-wave in aVF, V4 and V5; duration of T-wave in V3, mean QT interval adjusted for heart rate, transverse P-wave clockwise rotation, transverse P-wave terminal angle and transverse QRS complex terminal vector magnitude. Risk score values ranged from 0 (no risk) to 5 (high risk). The predictive validity of the score reached an AUC of 0.764 (95% CI: 0.722 to 0.806) with a global specificity of 61% and a sensitivity of 55%.

Conclusions

The automatic assessment of ECG biomarkers from ECGs in sinus rhythm is able to predict the risk for AF providing a low-cost screening strategy for early detection of this pathology.
Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors
Authors: Hurkmans Daan P. , Sassen Sebastiaan D.T. , de Joode Karlijn , Putter Lisanne , Basak Edwin A. , Wijkhuijs Annemarie J.M. , Joerger Markus , Debets Reno , Koch Birgit C.P. , Van der Leest Cor H. , Schreurs Marco W.J. , van der Veldt Astrid A.M. , Aerts Joachim G.J.V. , Mathijssen Ron H.J. , Koolen Stijn L.W.
Published: June 2021

Background

Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I–III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting.

Methods

Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs).

Results

588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and −1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(Vd; 0.34). A significant inverse CL–OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07–2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade>3 irAEs (p=0.70).

Conclusions

High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on Vd). A strong inverse CL–OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored.
Attenuating CD3 affinity in a PSMAxCD3 bispecific antibody enables killing of prostate tumor cells with reduced cytokine release
Authors: Dang Kevin , Castello Giulia , Clarke Starlynn C , Li Yuping , Balasubramani Aarti , Boudreau Andrew , Davison Laura , Harris Katherine E , Pham Duy , Sankaran Preethi , Ugamraj Harshad S , Deng Rong , Kwek Serena , Starzinski Alec , Iyer Suhasini , van Schooten Wim , Schellenberger Ute , Sun Wenchao , Trinklein Nathan D , Buelow Roland , Buelow Ben , Fong Lawrence , Dalvi Pranjali
Published: June 2021

Background

Therapeutic options currently available for metastatic castration-resistant prostate cancer (mCRPC) do not extend median overall survival >6 months. Therefore, the development of novel and effective therapies for mCRPC represents an urgent medical need. T cell engagers (TCEs) have emerged as a promising approach for the treatment of mCRPC due to their targeted mechanism of action. However, challenges remain in the clinic due to the limited efficacy of TCEs observed thus far in solid tumors as well as the toxicities associated with cytokine release syndrome (CRS) due to the usage of high-affinity anti-CD3 moieties such as OKT3.

Methods

Using genetically engineered transgenic rats (UniRat and OmniFlic) that express fully human IgG antibodies together with an NGS-based antibody discovery pipeline, we developed TNB-585, an anti-CD3xPSMA TCE for the treatment of mCRPC. TNB-585 pairs a tumor-targeting anti-PSMA arm together with a unique, low-affinity anti-CD3 arm in bispecific format. We tested TNB-585 in T cell-redirected cytotoxicity assays against PSMA+ tumor cells in both two-dimensional (2D) cultures and three-dimensional (3D) spheroids as well as against patient-derived prostate tumor cells. Cytokines were measured in culture supernatants to assess the ability of TNB-585 to induce tumor killing with low cytokine release. TNB-585-mediated T cell activation, proliferation, and cytotoxic granule formation were measured to investigate the mechanism of action. Additionally, TNB-585 efficacy was evaluated in vivo against C4-2 tumor-bearing NCG mice.

Results

In vitro, TNB-585 induced activation and proliferation of human T cells resulting in the killing of PSMA+ prostate tumor cells in both 2D cultures and 3D spheroids with minimal cytokine release and reduced regulatory T cell activation compared with a positive control antibody that contains the same anti-PSMA arm but a higher affinity anti-CD3 arm (comparable with OKT3). In addition, TNB-585 demonstrated potent efficacy against patient-derived prostate tumors ex vivo and induced immune cell infiltration and dose-dependent tumor regression in vivo.

Conclusions

Our data suggest that TNB-585, with its low-affinity anti-CD3, may be efficacious while inducing a lower incidence and severity of CRS in patients with prostate cancer compared with TCEs that incorporate high-affinity anti-CD3 domains.
Baseline and early functional immune response is associated with subsequent clinical outcomes of PD-1 inhibition therapy in metastatic melanoma patients
Authors: Gérard Alexandre , Doyen Jerome , Cremoni Marion , Bailly Laurent , Zorzi Kevin , Ruetsch-Chelli Caroline , Brglez Vesna , Picard-Gauci Alexandra , Troin Laura , Esnault Vincent L.M. , Passeron Thierry , Montaudié Henri , Seitz-Polski Barbara
Published: June 2021

Background

Despite significant progress with antiprogrammed cell death protein 1 (PD-1) therapy, a substantial fraction of metastatic melanoma patients show upfront therapy resistance. Biomarkers for outcome are missing and the association of baseline immune function and clinical outcome remains to be determined. We assessed the in vitro nonspecific stimulation of immune response at baseline and during anti-PD-1 therapy for metastatic melanoma.

Methods

Previously untreated metastatic melanoma patients received nivolumab and radiotherapy as part of the multicentric phase II trial NIRVANA (NCT02799901). The levels of Th1, Th2 and Th17 cytokines on in vitro non-specific stimulation of innate and adaptive immune cells were measured in patient sera before treatment, and at week 2 and week 6 after the beginning of the treatment, and correlated with tumorous response, progression-free survival (PFS) and occurrence of immune-related adverse events (irAEs). The results in melanoma patients were compared with those of a cohort of 9 sex and age-matched healthy donors.

Results

Seventeen patients were enrolled in this ancillary study. Median follow-up was 16 months (2.2–28.4). The 12-month PFS rate was 67.7%. The incidence of irAEs of any grade was 58.8%. Without in vitro stimulation no differences in cytokines levels were observed between responders and non-responders. On in vitro stimulation, metastatic patients had lower Th1 cytokine levels than healthy donors at baseline for tumor necrosis factor-α and interferon-γ (IFN-γ) (1136 pg/mL vs 5558 pg/mL, p<0.0001; and 3894 pg/mL vs 17 129 pg/mL, p=0.02, respectively). Responders exhibited increasing cytokine levels from baseline to week 6. Non-responders had lower interleukin 17A (IL-17A) levels at baseline than responders (7 pg/mL vs 32 pg/mL, p=0.03), and lower IFN-γ levels at week 6 (3.3 ng/mL vs 14.5 ng/mL, p=0.03). A lower level of IL-17A at week 2 and a lower level of IFN-γ at week 6 correlated with worse PFS (p=0.04 and p=0.04 respectively). At baseline, patients who developed irAEs had higher IL-6 levels (19.3 ng/mL vs 9.2 ng/mL, p=0.03) and higher IL-17A levels (52.5 pg/mL vs 2.5 pg/mL, p=0.009) than those without irAEs.

Conclusions

Our findings indicate that cytokine levels after in vitro non-specific stimulation could be a promising biomarker to predict the outcome of PD-1 inhibition therapy.
Translating 6 key insights from research on leadership and management in times of crisis
Authors: Reyes Denise Lucia , Bisbey Tiffany , Day David , Salas Eduardo
Published: June 2021

Background

Certain leadership behaviours are particularly helpful for healthcare teams remain effective through crisis situations, such as the Covid-19 pandemic. This paper summarizes evidence-based insights based on their importance and prevalence in the crisis leadership literature to provide recommendations that apply to medical team leaders broadly construed. We recommend that leaders adopt these behaviours in conditions of intense difficulty, uncertainty, as well as physical and psychological peril.

Results

We draw from research on workplace resilience, as well as leadership literature (ie, team leadership, transformational leadership, shared leadership, and crisis leadership) to provide six key insights along with evidence and practical guidance for healthcare leaders to help their teams in the midst of a crisis: (1) remain optimistic when communicating a vision, (2) adapt to the changing situation by deferring to team members’ expertise, (3) support organizational resilience by providing relational resources, (4) be present to signal commitment, (5) be empathetic to help prevent burnout, and (6) be transparent in order to remain trustworthy.
Effects of geometric frustration in Kitaev chains
Authors: Maiellaro Alfonso , Romeo Francesco , Citro Roberta
Published: June 2021

We study the topological phase transitions of a Kitaev chain frustrated by the addition of a single long-range hopping. In order to study the topological properties of the resulting legged-ring geometry (Kitaev tie model), we generalize the transfer matrix approach through which the emergence of Majorana edge modes is analyzed. We find that geometric frustration gives rise to a topological phase diagram in which non-trivial phases alternate with trivial ones at varying the range of the hopping and the chemical potential. Robustness to disorder of non-trivial phases is also proven. Moreover, geometric frustration effects persist when translational invariance is restored by considering a multiple-tie system. These findings shed light on an entire class of experimentally realizable topological systems with long-range couplings.
The massless irreducible representation in E theory and how bosons can appear as spinors
Authors: Glennon Keith , West Peter
Published: June 2021

We study in detail the irreducible representation of [Formula: see text] theory that corresponds to massless particles. This has little algebra [Formula: see text] and contains 128 physical states that belong to the spinor representation of [Formula: see text]. These are the degrees of freedom of maximal supergravity in eleven dimensions. This smaller number of the degrees of freedom, compared to what might be expected, is due to an infinite number of duality relations which in turn can be traced to the existence of a subaglebra of [Formula: see text] which forms an ideal and annihilates the representation. We explain how these features are inherited into the covariant theory. We also comment on the remarkable similarity between how the bosons and fermions arise in [Formula: see text] theory.
POLICY APPROACHES TOWARD INFORMAL SECTOR ENTREPRENEURSHIP: AN OVERVIEW
Authors: WILLIAMS COLIN C
Published: June 2021

This paper reviews the policy options and measures available for tackling informal sector entrepreneurship. Four possible policy options are critically reviewed: doing nothing, eradicating informal entrepreneurship; eradicating formal entrepreneurship and formalizing informal entrepreneurship. Concluding that the latter is the most feasible option, policy measures for formalizing informal entrepreneurship are then reviewed. On the one hand, the range of policy measures that can be used by enforcement authorities (tax authorities, labor inspectorates and social security institutions) responsible for tackling informal entrepreneurship are evaluated. On the other hand, and to tackle the broader structural determinants of informal entrepreneurship, macro-level reforms are identified by evaluating critically the validity of the purported determinants proposed in the modernization, political economy, neo-liberal and neo-institutionalist theories. The outcome is an understanding of the full range of policy initiatives required by governments seeking to formalize informal sector entrepreneurship.
A Systematic Framework to Identify Violations of Scenario-dependent Driving Rules in Autonomous Vehicle Software
Authors: Zhang Qingzhao , Hong David Ke , Zhang Ze , Chen Qi Alfred , Mahlke Scott , Mao Z. Morley
Published: June 2021

Safety compliance is paramount to the safe deployment of autonomous vehicle (AV) technologies in real-world transportation systems. As AVs will share road infrastructures with human drivers and pedestrians, it is an important requirement for AVs to obey standard driving rules. Existing AV software testing methods, including simulation and road testing, only check fundamental safety rules such as collision avoidance and safety distance. Scenario-dependent driving rules, including crosswalk and intersection rules, are more complicated because the expected driving behavior heavily depends on the surrounding circumstances. However, a testing framework is missing for checking scenario-dependent driving rules on various AV software.

In this paper, we design and implement a systematic framework AVChecker for identifying violations of scenario-dependent driving rules in AV software using formal methods. AVChecker represents both the code logic of AV software and driving rules in proposed formal specifications and leverages satisfiability modulo theory (SMT) solvers to identify driving rule violations. To improve the automation of systematic rule-based checking, AVChecker provides a powerful user interface for writing driving rule specifications and applies static code analysis to extract rule-related code logic from the AV software codebase. Evaluations on two open-source AV software platforms, Baidu Apollo and Autoware, uncover 19 true violations out of 28 real-world driving rules covering crosswalks, traffic lights, stop signs, and intersections. Seven of the violations can lead to severe risks of a collision with pedestrians or blocking traffic.
Nudge: Stochastically Improving upon FCFS
Authors: Grosof Isaac , Yang Kunhe , Scully Ziv , Harchol-Balter Mor
Published: June 2021

The First-Come First-Served (FCFS) scheduling policy is the most popular scheduling algorithm used in practice. Furthermore, its usage is theoretically validated: for light-tailed job size distributions, FCFS has weakly optimal asymptotic tail of response time. But what if we don't just care about the asymptotic tail? What if we also care about the 99th percentile of response time, or the fraction of jobs that complete in under one second? Is FCFS still best? Outside of the asymptotic regime, only loose bounds on the tail of FCFS are known, and optimality is completely open.

In this paper, we introduce a new policy, Nudge, which is the first policy to provably stochastically improve upon FCFS. We prove that Nudge simultaneously improves upon FCFS at every point along the tail, for light-tailed job size distributions. As a result, Nudge outperforms FCFS for every moment and every percentile of response time. Moreover, Nudge provides a multiplicative improvement over FCFS in the asymptotic tail. This resolves a long-standing open problem by showing that, counter to previous conjecture, FCFS is not strongly asymptotically optimal.
Real-time Approximate Routing for Smart Transit Systems
Authors: Périvier Noémie , Hssaine Chamsi , Samaranayake Samitha , Banerjee Siddhartha
Published: June 2021

We study real-time routing policies in smart transit systems, where the platform has a combination of cars and high-capacity vehicles (e.g., buses or shuttles) and seeks to serve a set of incoming trip requests. The platform can use its fleet of cars as a feeder to connect passengers to its high-capacity fleet, which operates on fixed routes. Our goal is to find the optimal set of (bus) routes and corresponding frequencies to maximize the social welfare of the system in a given time window. This generalizes the Line Planning Problem, a widely studied topic in the transportation literature, for which existing solutions are either heuristic (with no performance guarantees), or require extensive computation time (and hence are impractical for real-time use). To this end, we develop a 1-1/e-ε approximation algorithm for the Real-Time Line Planning Problem, using ideas from randomized rounding and the Generalized Assignment Problem. Our guarantee holds under two assumptions: (i) no inter-bus transfers and (ii) access to a pre-specified set of feasible bus lines. We moreover show that these two assumptions are crucial by proving that, if either assumption is relaxed, the łineplanningproblem does not admit any constant-factor approximation. Finally, we demonstrate the practicality of our algorithm via numerical experiments on real-world and synthetic datasets, in which we show that, given a fixed time budget, our algorithm outperforms Integer Linear Programming-based exact methods.
SADPonzi: Detecting and Characterizing Ponzi Schemes in Ethereum Smart Contracts
Authors: Chen Weimin , Li Xinran , Sui Yuting , He Ningyu , Wang Haoyu , Wu Lei , Luo Xiapu
Published: June 2021

Ponzi schemes are financial scams that lure users under the promise of high profits. With the prosperity of Bitcoin and blockchain technologies, there has been growing anecdotal evidence that this classic fraud has emerged in the blockchain ecosystem. Existing studies have proposed machine-learning based approaches for detecting Ponzi schemes, i.e., either based on the operation codes (opcodes) of the smart contract binaries or the transaction patterns of addresses. However, state-of-the-art approaches face several major limitations, including lacking interpretability and high false positive rates. Moreover, machine-learning based methods are susceptible to evasion techniques, and transaction-based techniques do not work on smart contracts that have a small number of transactions. These limitations render existing methods for detecting Ponzi schemes ineffective. In this paper, we propose SADPonzi, a semantic-aware detection approach for identifying Ponzi schemes in Ethereum smart contracts. Specifically, by strictly following the definition of Ponzi schemes, we propose a heuristic-guided symbolic execution technique to first generate the semantic information for each feasible path in smart contracts and then identify investor-related transfer behaviors and the distribution strategies adopted. Experimental result on a well-labelled benchmark suggests that SADPonzi can achieve 100% precision and recall, outperforming all existing machine-learning based techniques. We further apply SADPonzi to all 3.4 million smart contracts deployed by EOAs in Ethereum and identify 835 Ponzi scheme contracts, with over 17 million US Dollars invested by victims. Our observations confirm the urgency of identifying and mitigating Ponzi schemes in the blockchain ecosystem.