bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship Between Clinical Features and the Arc and Length of Dehiscence in SCDS: A Single Center Review of 42 Cases
Authors: Darr Adnan , Thomas Charlotte , Rainsbury James , Banga Rupan , Irving Richard , Chavda Swarupsinh
Published: October 2021

Introduction:

Superior canal dehiscence syndrome (SCDS) is a rare disorder characterized by an array of audiovestibular symptoms due to a dehiscence of bone overlying the superior semicircular canal (SSC). In the presence of debilitating symptoms, surgical management, to plug or resurface the SCC is performed. Although computed tomography (CT) may overestimate the size or presence of a dehiscence due to a partial volume effect, it remains an invaluable diagnostic tool.

Objectives:

To assess for correlation between the arc and length of dehiscence and clinical symptomology.

Method:

A single-center, single-operator retrospective analysis of 42 patients who underwent trans mastoid plugging of SCC with confirmed radiological dehiscence of their SSC between January 2008 and July 2019 was undertaken. Patients were assessed based on seven predefined clinical symptoms. Length and arc of dehiscence's were evaluated by means of high resolution (0.5 mm) CT (HRCT), using multiplanar reconstruction (MPR). Receiver operating characteristics (ROC), and more specifically the area under the ROC curve (AUROC) were used to assess for statistical significance.

Results:

Our results demonstrate overall very little correlation between the arc and size of the dehiscence and symptoms. The only statistically significant correlation we found was between length of dehiscence and the presence of aural fullness.

Conclusion:

SCDS is a debilitating condition with an array of symptoms on presentation. While dehiscence length demonstrated a correlation with aural fullness, no other symptomology in patients with radiologically evident SCDS demonstrated a statistically significant correlation either against the length or arc of dehiscence.
Effects of vibegron on ambulatory blood pressure in patients with overactive bladder: results from a double-blind, placebo-controlled trial
Authors: Weber Michael A. , Haag-Molkenteller Cornelia , King Jennifer , Walker Ann , Mudd Paul N. , White William B.
Published: October 2021

Objectives

To characterize the blood pressure (BP) profile of the new β3-adrenergic receptor agonist, vibegron, in patients with overactive bladder.

Methods

Patients were randomized to once-daily vibegron 75 mg or placebo for 28 days and underwent ambulatory BP monitoring. The primary endpoint was change from baseline (CFB) to day 28 in mean daytime ambulatory systolic BP (SBP). Secondary endpoints were CFB in mean 24-h SBP and in mean daytime and mean 24-h ambulatory diastolic BP (DBP) and heart rate (HR). Safety was assessed through adverse event reporting.

Results

Of 214 patients randomized, 96 receiving vibegron and 101 receiving placebo had evaluable baseline and day 28 measurements. Overall, 39.6 and 30.7% of patients receiving vibegron and placebo, respectively, had preexisting hypertension. The least squares mean difference (LSMD; 90% confidence interval) between vibegron and placebo in CFB in mean daytime SBP was 0.8 (–0.9, 2.5) mmHg. LSMD in CFB in mean daytime DBP and HR was 0.0 mmHg and 0.9 bpm, respectively. No significant differences between treatments were seen in CFB in mean 24-h SBP (LSMD, 0.6 mmHg), DBP (–0.2 mmHg) or HR (1.0 bpm). The most common treatment-emergent adverse event was hypertension, with rates comparable between groups [vibegron: n = 5 (4.7%); placebo: n = 4 (3.7%)]. One patient receiving vibegron took a prohibited medication (phentermine) known to increase BP.

Conclusions

Once-daily vibegron had no statistically significant or clinically relevant effects on BP or HR.
Pediatric Mycosis Fungoides: Retrospective Analysis of a Series With CD8+ Profile and Female Predominance
Authors: Purnak Seda , Mark Lawrence A.
Published: October 2021

Background:

Mycosis fungoides (MF) in children is a rare disease and there are limited data regarding the behavior of the disease in this age group. We aimed to collect additional data to better understand the clinicopathologic features of MF in children.

Materials and Methods:

This study was a retrospective analysis of pediatric MF patients (diagnosed at age 0 to 18 y).

Results:

Thirteen pediatric patients with MF were identified. Female predominance was observed with a ratio of 1.6:1. Median values for age of onset of skin lesions and age at the time of histologic diagnosis were 5 and 12 years, respectively. All patients had early stage (stage IA to IIA) of MF at the time of diagnosis. Hypopigmented MF comprised 77% of all study patients, followed by classic MF (15%) and pagetoid reticulosis (8%). The lower extremity (especially proximal leg) followed by trunk and upper extremity were most commonly affected sites. Seven of 9 patients who had available immunohistochemistry data showed CD8+ predominance. Five of 8 patients whose follow-up data was available, achieved complete response with narrowband ultraviolet B treatment, while 2 and 1 had near complete response and partial response, respectively.

Conclusions:

Our study demonstrated female sex and CD8+ profile predominance. Hypopigmented MF constituted the majority of cases. We observed good responses with narrowband ultraviolet B treatment.
The Role of Follicle-stimulating Hormone in Vascular Dysfunction Observed in Hematopoietic Cell Transplant Recipients
Authors: Roelofs Erica J. , Dengel Donald R. , Wang Qi , Hodges James S. , Steinberger Julia , Baker K. Scott
Published: October 2021

Childhood cancer survivors who receive a hematopoietic cell transplantation (HCT) are at increased risk for follicle-stimulating hormone (FSH) abnormalities, which may have a substantial negative impact on vascular function. The purpose of this study was to examine the association of vascular function with FSH in HCT recipients, non-HCT recipients and healthy controls. The study included childhood cancer survivors who were HCT recipients (n=24) and non-HCT recipients (n=308), and a control group of healthy siblings (n=211) all between 9 and 18 years old. Vascular measures of carotid artery structure and function (compliance and distensibility), brachial artery flow-mediated dilation and endothelial-independent dilation were measured using ultrasound imaging. A fasting blood sample was collected to measure hormone levels. FSH was significantly higher in HCT recipients compared with non-HCT recipients and healthy controls (P<0.01). Carotid compliance and distensibility were significantly lower in HCT and non-HCT recipients compared with healthy controls (P<0.05). Higher FSH was associated with decreased carotid compliance (P<0.05). This study’s results suggest that higher levels of FSH in HCT recipients may result in significant reductions in vascular function compared with non-HCT recipients and healthy controls. Therefore, gonadotropin endocrine dysfunction, particularly abnormal FSH levels, may be an underlying mechanism of vascular dysfunction.
The Impact of Panel Reactive Antibodies and Different Desensitization Methods on Pediatric Allogeneic Hematopoietic Stem Cell Transplantation Outcomes
Authors: Akinci Burcu , Akçay Arzu , Demir Yenigürbüz Fatma , Atay Didem , Öztürk Gülyüz
Published: October 2021

Introduction:

In highly sensitized patients who have panel reactive antibodies (PRAs) before hematopoietic stem cell transplantation, primary graft failure risk may increase. In this study, we aimed to determine the association of PRA with engraftment, and graft versus host disease (GVHD) in pediatric patients.

Materials and Methods:

Forty-three PRA-positive and 42 PRA-negative patients were taken into study. Both groups were compared in terms of graft failure, acute GVHD, viral infection and survival rates. PRA-positive group was also divided into 2 according to treatment modality (steroid-only group/combination therapy) and compared for the same parameters.

Results:

There was no difference in PRA-positive and negative patients in terms of graft failure, acute GVHD and viral infections. Analysis of the PRA-positive group in itself showed that there was also no difference in terms of graft failure and viral infection frequency. The only difference is that acute grade 3 to 4 GVHD was higher in the steroid-only group. The 100-day overall survival was 90.2% and 90.4% for the PRA-positive and negative groups, respectively.

Conclusions:

Different treatment strategies like plasmapheresis, steroid, rituximab, or combination therapies can be used for the desensitization of PRA-positive patients before hematopoietic stem cell transplantation. Patient-specific treatment modality for sensitized patients before transplant can increase the success rate.
The Effectiveness of Cognitive Behavioral Therapy Techniques for the Treatment of Substance Use Disorders
Authors: Zamboni Lorenzo , Centoni Francesco , Fusina Francesca , Mantovani Elisa , Rubino Francesca , Lugoboni Fabio , Federico Angela
Published: October 2021

Substance use disorders (SUDs) are characterized by a recurrent and maladaptive use of drugs and/or alcohol. Cognitive behavioral therapies (CBTs) comprise different types of interventions: traditional CBT and the more recent “third wave” behavior therapies, such as acceptance and commitment therapy (ACT), dialectical behavior therapy (DBT), mindfulness-based cognitive therapy (MBCT), and schema therapy (ST). We searched English-language articles published between 2014 and present. This review includes randomized controlled trials (RCTs), quasi-RCTs, pilot studies, and reviews of CBTs for SUDs available on PubMed. Results seem to indicate that CBT and MBCT are effective interventions for SUDs; however, the studies showed a high degree of heterogeneity, so no exhaustive conclusions could be outlined at this time. ACT and DBT in SUD management are limited to few studies and results are therefore inconclusive.
Client and Clinical Utility of the Assessment of Personality Disorders
Authors: Weekers Laura C. , Hutsebaut Joost , Kamphuis Jan H.
Published: October 2021

Clinical utility and client utility are important desirable properties when developing and evaluating a new classification system for mental disorders. This study reports on four focus groups followed up by a Delphi study among clinicians working with clients with personality disorders (PD) and clients with PD themselves to harness both user groups' perspectives on the utility of PD diagnosis. Our findings show that the client and clinician views of the concept of utility were closely aligned and include aspects of transparency of communication and the ability of an assessment to enhance hope, curiosity, motivation, and insight into a client's personality patterns. Unique to clinicians' appraisal was the ability of an assessment to capture both vulnerabilities and resilience of clients and to give information about the prognosis in treatment. Unique to clients' appraisal was the ability of an assessment to be destigmatizing and collaborative. These findings may serve to expand our definition and measurement of clinical utility, in that collaborative and nonstigmatizing procedures likely promote client acceptability. To capture both aspects, we offer two preliminary questionnaires (i.e., item sets open to further empirical testing) based on the data derived from the Delphi procedure.
Nursing Faculty Workload
Authors: Ludwig-Beymer Patti , Vottero Beth , Coates Annette , Blodgett Nicole , Rogers Julia , McGonigal-Kenney Meghan
Published: October 2021

Background:

Nursing faculty and nursing program administrators share the goal of equitable faculty workload. Faculty teaching assignments and other academic workload can affect productivity and faculty satisfaction.

Problem:

Models for workload calculation need to account for multiple factors including mission, faculty position and rank, faculty expertise, and financial resources. The nursing faculty shortage, organizational structure, and fluctuations in student volumes further complicate achievement of a balanced workload model.

Approach:

A task force identified existing parameters for workload and assessed faculty satisfaction and teaching assignment preferences at a Midwest metropolitan university college of nursing.

Outcomes:

A new workload model was developed and accepted. The work highlighted course load expectations, financial realities, and negotiations between nursing faculty and nursing program administrators.

Conclusions:

Lessons learned suggest considering the academic year overall rather than each semester separately and reaffirm the importance of continual, clear communications between nursing faculty and nursing program administrators.
Tacrolimus in Gastrointestinal Bleeding in a Young Boy With Hereditary Hemorrhagic Telangiectasia
Authors: Pruijsen Jessica M. , Kroon Steven , Mager Johannes J. , Bungener Laura B. , van der Doef Hubert P. J.
Published: October 2021

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disease in which gastrointestinal bleeding is a rare presenting symptom in children. Gastrointestinal bleeding in children is treated locally by endoscopy. When a focus of bleeding cannot be reached by endoscopy, management of these patients can be challenging. Previous reports showed a favorable outcome of treatment with tacrolimus in an adult HHT patient with liver vascular malformations and epistaxis and in a HHT patient with pulmonary hypertension. We report the first pediatric HHT patient who benefited from tacrolimus treatment. Our case demonstrated a remarkable decline in blood transfusions and better quality of life during the period of tacrolimus treatment.
Bullous Pemphigoid
Authors: Martinez Nicole , Gadler Tracie , Benson Akeela , Lalicata Katarzyna , Truman Laura
Published: October 2021

Bullous pemphigoid is the most common autoimmune bullous skin disease and primarily affects patients older than 60 years. This chronic disease can lead to significant morbidity characterized by spontaneous remissions and exacerbations. Although the etiopathogenesis is uncertain, it is proposed that certain drugs (especially polypharmacy), vaccinations, infections, and exposures precede the dermatological presentation. Bullous pemphigoid patients initially present with moderate-to-severe pruritis with or without eczematous or urticarial lesions, followed by the development of cutaneous bullae weeks to months later testing with a notable false-positive Nikolsky sign. As frontline providers, emergency department nurse practitioners should be aware of these skin diseases in the elderly. Prompt recognition of bullous pemphigoid leads to an earlier diagnosis and management of this common autoimmune bullous skin disease and requires clinicians to have critical observation skills.
Venomous Snakebites
Authors: Bagnall Lisa , Taliaferro Donna
Published: October 2021

In the United States, 7,000–8,000 people are bitten by a venomous snake each year, out of which approximately 5 die. Although common practice is to treat any and all victims of envenomation with repeated doses of antivenom, this approach is not without its risks. The gold standard for treating venomous snakebites with severe symptoms is antivenom. Although a standardized approach to treating envenomation is needed, it cannot be developed without first delineating current practices. This article discusses the ways in which advanced practice emergency nurses should manage bites from a variety of venomous snakes. It is divided into 4 main sections: (1) the types of venomous snakes found in the United States, their habitat, and the effects of their venom; (2) priorities of care in treating venomous snakebites; (3) preparation and administration of antivenom; and (4) other considerations for the advanced practice emergency department nurse.
A Review Electroconvulsive Therapy in Cochlear Implant Patients
Authors: Albertsen Laerke Noergaard , Lauridsen Jesper Krogh
Published: October 2021

The use of electroconvulsive therapy (ECT) in cochlear implant (CI) users is debatable. Currently, no consensus statement exists about the safety for the patients and the implants. Here, we present a summary of the existing literature on ECT in CI users, consisting of 4 case reports and a cadaveric study. No harm to the patients or the CIs was reported. Based on our review, we have found no evidence to indicate that ECT in CI users is contraindicated.
Decision-making Capacity for Treatment After Electroconvulsive Therapy for Depression
Authors: Loughran Orlaith , Finnegan Martha , Dud Iulia , Galligan Toni , Kennedy Miriam , McLoughlin Declan M.
Published: October 2021

Objectives

Depression can impair decision-making capacity (DMC) for health care decisions. However, it is unclear whether DMC improves after treatments for depression such as electroconvulsive therapy (ECT). There is limited evidence available on DMC for treatment in patients with depression referred for ECT, and it is unknown whether ECT has any impact on DMC. We hypothesized that ECT will improve DMC in severely depressed patients and that this change will be associated with reduced depressive symptom severity.

Methods

Using the MacArthur Competence Assessment Tool—Treatment, 4 abilities related to DMC were evaluated: Understanding, Appreciation, Reasoning, and Expressing a choice. This prospective study compared DMC abilities, depression severity, and cognition scores in 24 patients hospitalized with a major depressive episode before and 3 to 5 days after a course of ECT.

Results

Although Understanding scores significantly improved after ECT (P = 0.004, r = 0.41), there was no change in other abilities related to DMC or cognition scores. As expected, there was a large improvement in mood ratings after ECT, but the change in DMC abilities was not associated with change in depressive symptoms.

Conclusions

To our knowledge, this is the first study to provide data on the effects of ECT on DMC in patients with depression. Abilities related to DMC that may be affected in this group before treatment include Understanding and Reasoning. Findings indicate that DMC to consent to treatment mostly does not change after a course of ECT and some aspects can improve in patients with depression.
Human influence on brown trout juvenile body size during metapopulation expansion
Authors: Aulus-Giacosa L. , Guéraud F. , Gaudin P. , Buoro M. , Aymes J. C. , Labonne J. , Vignon M.
Published: October 2021

Change in body size can be driven by social (density) and non-social (environmental and spatial variation) factors. In expanding metapopulations, spatial sorting by means of dispersal on the expansion front can further drive the evolution of body size. However, human intervention can dramatically affect these founder effects. Using long-term monitoring of the colonization of the remote Kerguelen islands by brown trout, a facultative anadromous salmonid, we analyse body size variation in 32 naturally founded and 10 human-introduced populations over 57 years. In naturally founded populations, we find that spatial sorting promotes slow positive changes in body size on the expansion front, then that body size decreases as populations get older and local density increases. This pattern is, however, completely different in human-introduced populations, where body size remains constant or even increases as populations get older. The present findings confirm that changes in body size can be affected by metapopulation expansion, but that human influence, even in very remote environments, can fully alter this process.
A small RNA is functional in Escherichia fergusonii despite containing a large insertion
Authors: Wright Austin P , Dutcher H Auguste , Butler Brianna , Nice Timothy J , Raghavan Rahul
Published: October 2021

Bacterial small RNAs (sRNAs) are important regulators of gene expression; however, the impact of natural mutations on sRNA functions has not been studied extensively. Here we show that the sRNA MgrR contains a unique 53 bp insertion in

Escherichia fergusonii

, a close relative of

Escherichia coli

and

Salmonella enterica

. The insertion is a repetitive extragenic palindromic (REP) sequence that could block transcription, but full-length MgrR is produced in

E. fergusonii

, showing that the insertion has not affected sRNA production. Additionally, despite containing the large insertion, the sRNA appears to be functional because deletion of mgrR made

E. fergusonii

more susceptible to H2O2. The molecular details of MgrR’s roles in H2O2defence are yet to be defined, but our results suggest that having an alternative function allowed the sRNA to be retained in

E. fergusonii

despite it sustaining a large, potentially disruptive mutation.
Practices, norms, and aspirations regarding the construction, validation, and reuse of code sets in the analysis of real-world data
Authors: Gold Sigfried , Lehmann Harold , Schilling Lisa , Lutters Wayne
Published: October 2021

Objective

Code sets play a central role in analytic work with clinical data warehouses, as components of phenotype, cohort, or analytic variable algorithms representing specific clinical phenomena. Code set quality has received critical attention and repositories for sharing and reusing code sets have been seen as a way to improve quality and reduce redundant effort. Nonetheless, concerns regarding code set quality persist. In order to better understand ongoing challenges in code set quality and reuse, and address them with software and infrastructure recommendations, we determined it was necessary to learn how code sets are constructed and validated in real-world settings.

Methods

Survey and field study using semi-structured interviews of a purposive sample of code set practitioners. Open coding and thematic analysis on interview transcripts, interview notes, and answers to open-ended survey questions.

Results

Thirty-six respondents completed the survey, of whom 15 participated in follow-up interviews. We found great variability in the methods, degree of formality, tools, expertise, and data used in code set construction and validation. We found universal agreement that crafting high-quality code sets is difficult, but very different ideas about how this can be achieved and validated. A primary divide exists between those who rely on empirical techniques using patient-level data and those who only rely on expertise and semantic data. We formulated a method- and process-based model able to account for observed variability in formality, thoroughness, resources, and techniques.

Conclusion

Our model provides a structure for organizing a set of recommendations to facilitate reuse based on metadata capture during the code set development process. It classifies validation methods by the data they depend on — semantic, empirical, and derived — as they are applied over a sequence of phases: (1) code collection; (2) code evaluation; (3) code set evaluation; (4) code set acceptance; and, optionally, (5) reporting of methods used and validation results. This schematization of real-world practices informs our analysis of and response to persistent challenges in code set development. Potential re-users of existing code sets can find little evidence to support trust in their quality and fitness for use, particularly when reusing a code set in a new study or database context. Rather than allowing code set sharing and reuse to remain separate activities, occurring before and after the main action of code set development, sharing and reuse must permeate every step of the process in order to produce reliable evidence of quality and fitness for use.
Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant
Authors: Hoorntje Edgar T. , Burns Charlotte , Marsili Luisa , Corden Ben , Parikh Victoria N. , te Meerman Gerard J. , Gray Belinda , Adiyaman Ahmet , Bagnall Richard D. , Barge-Schaapveld Daniela Q.C.M. , van den Berg Maarten P. , Bootsma Marianne , Bosman Laurens P. , Correnti Gemma , Duflou Johan , Eppinga Ruben N. , Fatkin Diane , Fietz Michael , Haan Eric , Jongbloed Jan D.H. , Hauer Arnaud D. , Lam Lien , van Lint Freyja H.M. , Lota Amrit , Marcelis Carlo , McCarthy Hugh J. , van Mil Anneke M. , Oldenburg Rogier A. , Pachter Nicholas , Planken R. Nils , Reuter Chloe , Semsarian Christopher , van der Smagt Jasper J. , Thompson Tina , Vohra Jitendra , Volders Paul G.A. , van Waning Jaap I. , Whiffin Nicola , van den Wijngaard Arthur , Amin Ahmad S. , Wilde Arthur A.M. , van Woerden Gijs , Yeates Laura , Zentner Dominica , Ashley Euan A. , Wheeler Matthew T. , Ware James S. , van Tintelen J. Peter , Ingles Jodie
Published: October 2021

Background

Truncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy (ACM), however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics ofDSPtv cardiomyopathy.

Methods

Individuals withDSPtv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reportedDSPtv performed.

Results

There were 98 probands and 72 family members (mean age at diagnosis 43 ± 18 years, 59% female) with aDSPtv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals.DSPtv location and proband status were independent risk factors for ventricular arrhythmia, while prior risk factors showed no association. Further, gene region was important with variants in cases (cohort n=98, Clinvar n=168) more likely to occur in the regions resulting in nonsense mediated decay of both majorDSPisoforms, compared to n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%], p<0.0001).

Conclusions

In the largest series of individuals withDSPtv, we demonstrate variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow precision-based clinical management.
From Feasibility to Utility: A Meta-Analysis of Amygdala-Neurofeedback
Authors: Goldway Noam , Jalon Itamar , Keynan Jackob N , Hellrung Lydia , Horstmann Annette , Paret Christian , Hendler Talma
Published: October 2021

Amygdala dysregulation is core to multiple psychiatric disorders. Real-time fMRI enables Amygdala self-modulation through NeuroFeedback (NF).

Despite a surge in Amygdala-NF studies, a systematic quantification of self-modulation is lacking. Amygdala-NF dissemination is further restricted by absence of unifying framework dictating design choices and insufficient understanding of neural changes underlying successful self-modulation.

The current meta-analysis of Amygdala-NF literature found that real-time feedback facilitates learned self-modulation more than placebo. Intriguingly, while we found that variability in design choices could be explained by the targeted domain, this was rarely highlighted by authors. Lastly, reanalysis of six fMRI data-sets (n=151), revealed that successful Amygdala down-modulation is coupled with deactivation of posterior insula and Default-Mode-Network major nodes, pointing to regulation related processes.

While findings point to Amygdala self-modulation as a learned skill that could modify brain functionality, further placebo-controlled trials are necessary to prove clinical efficacy. We further suggest that studies should explicitly target neuro-behavioral domain, design studies accordingly and include ‘target engagement’ measures. We exemplify this idea through a ‘process-based’ NF approach for PTSD.
Evaluating Visual Photoplethysmography Method
Authors: de Deus Luis Felipe , Sehgal Nikhil , Talukdar Debjyoti
Published: October 2021

Regular monitoring of common physiological signs, including heart rate, blood pressure, and oxygen saturation, can be an effective way to either prevent or detect many kinds of chronic conditions. In particular, cardiovascular diseases (CVDs) are a worldwide concern. According to the World Health Organization, 32% of all deaths worldwide are from CVDs. In addition, stress-related issues cost $190 billion in healthcare costs per year. Currently, contact devices are required to extract most of an individual’s physiological information, which can be uncomfortable for users and can cause discomfort. However, in recent years, remote photoplethysmography (rPPG) technology is gaining growing interest, which enables contactless monitoring of the blood volume pulse signal using a regular camera, and ultimately can provide the same physiological information as a contact device. In this paper, we propose a benchmark comparison using a new multimodal database consisting of 56 subjects where each subject was submitted to three different tasks. Each subject wore a wearable device capable of extracting photoplethysmography signals and was filmed to allow simultaneous rPPG signal extraction. Several experiments were conducted, including a comparison between information from contact and remote signals and stress state recognition. Results have shown that in this dataset, rPPG signals were capable of dealing with motion artifacts better than contact PPG sensors and overall had better quality if compared to the signals from the contact sensor. Moreover, the statistical analysis of the variance method had shown that at least two HRV features, NNi 20 and SAMPEN were capable of differentiating between Stress and Non-Stress states. In addition, three features, IBI, NNi 20, and SAMPEN were capable of differentiating between tasks relating to different levels of difficulty. Furthermore, using machine learning to classify a ‘stressed’ or ‘unstressed’ state, the models were able to achieve an accuracy score of 83.11%.
Challenges at the APOE locus: A robust quality control approach for accurate APOE genotyping
Authors: Belloy Michael E. , Eger Sarah J. , Guen Yann Le , Damotte Vincent , Ahmad Shahzad , Ikram M. Arfan , Ramirez Alfredo , Tsolaki Anthoula C. , Rossi Giacomina , Jansen Iris E. , de Rojas Itziar , Parveen Kayenat , Sleegers Kristel , Ingelsson Martin , Hiltunen Mikko , Amin Najaf , Andreassen Ole , Sánchez-Juan Pascual , Kehoe Patrick , Amouyel Philippe , Sims Rebecca , Frikke-Schmidt Ruth , van der Flier Wiesje M. , Lambert Jean-Charles ,   for the European Alzheimer DNA BioBank (EADB), He Zihuai , Han Summer S. , Napolioni Valerio , Greicius Michael D.
Published: October 2021

Background

Genetic variants within the APOE locus may modulate Alzheimer’s disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1,801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.

Methods

We used thirty-two AD-related cohorts, with genetic data from various high-density single- nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n=65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches

Results

Using more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in- phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost.

Conclusions

We showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.
Translational Modeling Identifies Synergy between Nanoparticle-Delivered miRNA-22 and Standard-of-Care Drugs in Triple Negative Breast Cancer
Authors: Dogra Prashant , Ramírez Javier Ruiz , Butner Joseph D. , Peláez Maria J. , Chung Caroline , Hooda-Nehra Anupama , Pasqualini Renata , Arap Wadih , Cristini Vittorio , Calin George A. , Ozpolat Bulent , Wang Zhihui
Published: October 2021

The downregulation of miRNA-22 in triple negative breast cancer (TNBC) is associated with upregulation of eukaryotic elongation 2 factor kinase (eEF2K) protein, which regulates tumor growth, chemoresistance, and tumor immunosurveillance. Moreover, exogenous administration of miRNA-22, loaded in nanoparticles to prevent degradation and improve tumor delivery (termed miRNA-22 nanotherapy), to suppress eEF2K production has shown potential as an investigational therapeutic agentin vivo. To evaluate the translational potential of miRNA-22 nanotherapy, we developed a multiscale mechanistic model, calibrated to publishedin vivodata and extrapolated to the human scale, to describe and quantify the pharmacokinetics and pharmacodynamics of miRNA-22 in virtual patient populations. Our analysis revealed the dose-response relationship, suggested optimal treatment frequency for miRNA-22 nanotherapy, and highlighted key determinants of therapy response, from which combination with immune checkpoint inhibitors was identified as a candidate strategy for improving treatment outcomes. More importantly, drug synergy was identified between miRNA-22 and standard-of-care drugs for TNBC, providing a basis for rational therapeutic combinations for improved response.
Topology-Aware Optimisation of Vaccination Strategy for Minimising Virus Spreading
Authors: Guzzi Pietro Hiram , Petrizzelli Francesco , Mazza Tommaso
Published: October 2021

Vaccination is currently the primary way for mitigating the COVID-19 out-break without severe lockdown. Despite its importance, the available number of vaccines worldwide is insufficient, and the production rates are hard to be increased in a short time. Therefore, vaccination needs to follow strict prioritization criteria. In this regard, almost all countries have prioritized similar classes of exposed workers: healthcare professionals and the elderly obtaining to maximize the survival of patients and years of life saved. Nevertheless, the virus is currently spreading at high rates, and any prioritization criterion so far adopted did not show to account for the topology of the contact networks. We consider that a network in which nodes are people while the edges represent their contacts may model the virus’s spreading efficiently. In such a model, it is already known that spreading may be efficiently stopped by disconnecting the network, i.e., by vaccinating more central or relevant nodes, therefore, eliminating “bridge edges”. Consequently, we introduce such a model and discuss the use of a topology-aware versus an age-based vaccination strategy.
Preclinical and clinical validation of a novel injected molded swab for molecular assay detection of SARS-CoV-2 virus
Authors: Ghezzi Chiara E. , Hartigan Devon R. , Hardick Justin , Gore Rebecca , Adelfio Miryam , Diaz Anyelo R. , McGuinness Pamela D. , Robinson Matthew L. , Buchholz Bryan O. , Manabe Yukari C.
Published: October 2021

During the COVID-19 public health emergency, many actions have been undertaken to help ensure that patients and health care providers had timely and continued access to high-quality medical devices to respond effectively. The development and validation of new testing supplies and equipment, including collection swab, help expand the availability and capability for various diagnostic, therapeutic, and protective medical devices in high demand during the COVID-19 emergency. Here, we report the validation of a new injection-molded anterior nasal swab, ClearTip™, that was experimentally validated in a laboratory setting as well as in independent clinical studies in comparison to gold standard flocked swabs. We have also developed an in vitro anterior nasal tissue model, that offers an efficient and clinically relevant validation tool to replicate with high fidelity the clinical swabbing workflow, while being accessible, safe, reproducible, time and cost effective. ClearTip™ displayed a greater efficiency of release of inactivated virus in the benchtop model, confirmed by greater ability to report positive samples in a clinical study in comparison to flocked swabs. We also quantified in multi-center pre-clinical and clinical studies the detection of biological materials, as proxy for viral material, that showed a statistically significant difference in one study and a slight reduction in performance in comparison to flocked swabs. Taken together these results underscore the compelling benefits of non-absorbent injected molded anterior nasal swab for COVID-19 detection, comparable to standard flocked swabs. Injection-molded swabs, as ClearTip™, could have the potential to support future swab shortage, due to its manufacturing advantages, while offering benefits in comparison to highly absorbent swabs in terms comfort, limited volume collection, and potential multiple usage.
Neutralizing Antibody Response to Pseudotype SARS-CoV-2 Differs between mRNA-1273 and BNT162b2 COVID-19 Vaccines and by History of SARS-CoV-2 Infection
Authors: Tyner Harmony L. , Burgess Jefferey L , Grant Lauren , Gaglani Manjusha , Kuntz Jennifer L. , Naleway Allison L. , Thornburg Natalie J. , Caban-Martinez Alberto J. , Yoon Sarang K. , Herring Meghan K. , Beitel Shawn C. , Blanton Lenee , Nikolich-Zugich Janko , Thiese Matthew S. , Pleasants Jessica Flores , Fowlkes Ashley L. , Lutrick Karen , Dunnigan Kayan , M.Yoo Young , Rose Spencer , Groom Holly , Meece Jennifer , Wesley Meredith G. , Schaefer-Solle Natasha , Louzado-Feliciano Paola , Edwards Laura J. , Olsho Lauren E. W. , Thompson Mark G.
Published: October 2021

Background

Data on the development of neutralizing antibodies against SARS-CoV-2 after SARS-CoV-2 infection and after vaccination with messenger RNA (mRNA) COVID-19 vaccines are limited.

Methods

From a prospective cohort of 3,975 adult essential and frontline workers tested weekly from August, 2020 to March, 2021 for SARS-CoV-2 infection by Reverse Transcription- Polymerase Chain Reaction (RT-PCR) assay irrespective of symptoms, 497 participants had sera drawn after infection (170), vaccination (327), and after both infection and vaccination (50 from the infection population). Serum was collected after infection and each vaccine dose. Serum- neutralizing antibody titers against USA-WA1/2020-spike pseudotype virus were determined by the 50% inhibitory dilution. Geometric mean titers (GMTs) and corresponding fold increases were calculated using t-tests and linear mixed effects models.

Results

Among 170 unvaccinated participants with SARS-CoV-2 infection, 158 (93%) developed neutralizing antibodies (nAb) with a GMT of 1,003 (95% CI=766-1,315). Among 139 previously uninfected participants, 138 (99%) developed nAb after mRNA vaccine dose-2 with a GMT of 3,257 (95% CI = 2,596-4,052). GMT was higher among those receiving mRNA-1273 vaccine (GMT =4,698, 95%CI= 3,186-6,926) compared to BNT162b2 vaccine (GMT=2,309, 95%CI=1,825-2,919). Among 32 participants with prior SARS-CoV-2 infection, GMT was 21,655 (95%CI=14,766-31,756) after mRNA vaccine dose-1, without further increase after dose- 2.

Conclusions

A single dose of mRNA vaccine after SARS-CoV-2 infection resulted in the highest observed nAb response. Two doses of mRNA vaccine in previously uninfected participants resulted in higher nAb to SARS-CoV-2 than after one dose of vaccine or SARS- CoV-2 infection alone. Neutralizing antibody response also differed by mRNA vaccine product.

Main Point Summary

One dose of mRNA COVID-19 vaccine after previous SARS-CoV-2 infection produced the highest neutralizing antibody titers; among those without history of infection, two doses of mRNA vaccine produced the most robust response.
Lower RNA expression of ALDH1A1 distinguishes the favorable risk group in acute myeloid leukemia
Authors: Dancik Garrett M. , Voutsas Ioannis F. , Vlahopoulos Spiros
Published: October 2021

The expression and activity of enzymes that belong to the aldehyde dehydrogenases is a characteristic of both normal and malignant stem cells. ALDH1A1 is an enzyme critical in cancer stem cells. In acute myeloid leukemia (AML), ALDH1A1 protects leukemia-initiating cells from a number of antineoplastic agents, which include inhibitors of protein tyrosine kinases. Furthermore, ALDH1A1 proves vital for the establishment of human AML xenografts in mice. We review here important studies characterizing the role of ALDH1A1 in AML and its potential as a therapeutic target. We also analyze datasets from leading studies, and show that decreased ALDH1A1 RNA expression consistently characterizes the AML patient risk group with a favorable prognosis, while there is a consistent association of high ALDH1A1 RNA expression with high risk and poor overall survival. Our review and analysis reinforces the notion to employ both novel as well as existing inhibitors of the ALDH1A1 protein against AML.
COVID-19 breakthrough infections and pre-infection neutralizing antibody
Authors: Yamamoto Shohei , Maeda Kenji , Matsuda Kouki , Tanaka Akihito , Horii Kumi , Okudera Kaori , Takeuchi Junko S. , Mizoue Tetsuya , Konishi Maki , Ozeki Mitsuru , Sugiyama Haruhito , Aoyanagi Nobuyoshi , Mitsuya Hiroaki , Sugiura Wataru , Ohmagari Norio
Published: October 2021

Background

While increasing coverage of effective vaccines against coronavirus disease 2019 (COVID-19), emergent variants raise concerns about breakthrough infections. Data are limited, however, whether breakthrough infection during the epidemic of the variant is ascribed to insufficient vaccine-induced immunogenicity.

Methods

We described incident COVID-19 in relation to the vaccination program among workers of a referral hospital in Tokyo. During the predominantly Delta epidemic, we followed 2,473 fully vaccinated staff (BNT162b2) for breakthrough infection and selected three matched controls. We measured pre-infection neutralizing antibodies against the wild-type, Alpha (B.1.1.7), and Delta (B.1.617.2) strains using live viruses and anti-spike antibodies using quantitative assays, and compared them using the generalized estimating equation model between the two groups.

Results

No COVID-19 cases occurred 1–2 months after the vaccination program during the fourth epidemic wave in Japan, dominated by the Alpha variant, while 22 cases emerged 2–4 months after the vaccination program during the fifth wave, dominated by the Delta variant. In the vaccinated cohort, all 17 cases of breakthrough infection were mild or asymptomatic and had returned to work early. There was no measurable difference between cases and controls in pre-infection neutralizing antibody titers against the wild-type, Alpha, and Delta, and anti-spike antibody titers, while neutralizing titers against the variants were considerably lower than those against the wild-type.

Conclusions

Pre-infection neutralizing antibody titers were not decreased among patients with breakthrough infection under the Delta variant rampage. The result points to the importance of infection control measures in the post-vaccination era, irrespective of immunogenicity profile.
“My friends would believe my word”: appropriateness and acceptability of respondent-driven sampling in recruiting young tertiary student men who have sex with men for HIV/STI research in Nairobi, Kenya
Authors: Mwaniki Samuel Waweru , Kaberia Peter Mwenda , Mugo Peter Mwangi , Palanee-Phillips Thesla
Published: October 2021

Background

Tertiary student men who have sex with men (TSMSM) may engage in behaviors that increase their risk of infection with human immunodeficiency virus (HIV) and sexually transmitted infections (STI). Respondent-driven sampling (RDS) has become a popular method for discretely recruiting marginalized populations into HIV/STI research. We conducted formative research to assess appropriateness and acceptability of RDS in recruiting TSMSM into a prospective HIV/STI bio-behavioral survey in Nairobi, Kenya.

Methods

Between September and October 2020, semi-structured qualitative interviews were held with service providers from organizations that serve MSM (n=3), and TSMSM (n=13). Interviews explored social networks of TSMSM, acceptability of using RDS as a sampling method, potential RDS implementation challenges, and proposed solutions to these challenges. Interviews were done in English, audio-recorded and transcribed then analyzed thematically using NVivo version 11.

Results

Service providers reflected that TSMSM had large though concealed networks, thus making RDS an appropriate sampling method. Risk of ineligible persons attempting to participate due to the associated double incentive was noted, and using student identification documents as part of eligibility screening recommended. TSMSM also perceived RDS to be an acceptable strategy based on their large social network sizes (10-40), and the trust amongst themselves. TSMSM were concerned about participating due to the risk of being outed as MSM, seeing as same sex behavior is criminalized in Kenya, and hence emphasized that researchers needed to assure them of their confidentiality, and include MSM as part of the study team to encourage participation. TSMSM suggested coupons should indicate value of reimbursement, be pocket-sized and placed in an envelope to avoid loss, and provide directions to and contacts of the survey site for easy access.

Conclusion

RDS was perceived as both an appropriate and acceptable sampling method. Anticipated challenges of RDS implementation were highlighted, and possible solutions to these challenges suggested.
On Multiply Robust Mendelian Randomization (MR2) With Many Invalid Genetic Instruments
Authors: Sun Baoluo , Liu Zhonghua , Tchetgen Eric Tchetgen
Published: October 2021

Mendelian randomization (MR) is a popular instrumental variable (IV) approach, in which genetic markers are used as IVs. In order to improve efficiency, multiple markers are routinely used in MR analyses, leading to concerns about bias due to possible violation of IV exclusion restriction of no direct effect of any IV on the out-come other than through the exposure in view. To address this concern, we introduce a new class of Multiply Robust MR (MR2) estimators that are guaranteed to remain consistent for the causal effect of interest provided that at least one genetic marker is a valid IV without necessarily knowing which IVs are invalid. We show that the proposed MR2 estimators are a special case of a more general class of estimators that remain consistent provided that a set of at least k† out of K candidate instrumental variables are valid, for k†≤ K set by the analyst ex ante, without necessarily knowing which IVs are invalid. We provide formal semiparametric theory supporting our results, and characterize the semiparametric efficiency bound for the exposure causal effect which cannot be improved upon by any regular estimator with our favorable robustness property. We conduct extensive simulation studies and apply our methods to a large-scale analysis of UK Biobank data, demonstrating the superior empirical performance of MR2 compared to competing MR methods.