bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Manual Lymphatic Drainage on Breast Cancer–Related Postmastectomy Lymphedema
Authors: Qiao Jia , Yang Li-ning , Kong Yu-han , Huang Xin , Li Yi , Bai Ding-qun
Published: March 2022

Background

Manual lymphatic drainage (MLD) is widely used in the treatment of breast cancer–related postmastectomy lymphedema (BCRL). However, the therapeutic benefit of MLD on BCRL remains controversial.

Objective

The aim of this study was to analyze the efficacy of MLD for BCRL.

Method

Four electronic databases were systematically searched for trials comparing MLD and no MLD treatment as options for BCRL. Comparative treatment results included reduction of upper extremity limb volume with subgroup analysis by the number and duration of treatments.

Results

A total of 457 patients were included in the analysis. There was no significant difference in the amount of upper extremity edema between the MLD treatment and control or no MLD groups (P = .11). However, when the treatment course was ≥20 sessions, there was a significant reduction in the upper extremity volume (P = .03). There was also a significant reduction in the upper extremity volume when treatment duration was >2 weeks (P = .03).

Conclusion

Manual lymphatic drainage treatment statistically did not reduce the upper extremity limb volume of BCRL, but upper extremity volume was reduced at statistically significant levels when treatment number were ≥20 sessions or the duration of treatment was >2 weeks.

Implication for Practice

Reduction in upper limb volume is dependent on the number and duration of treatments. When treatment number were ≥20 sessions, or the duration of treatment was >2 weeks, reduction of upper limb volume was statistically achieved. Manual lymphatic drainage treatment can be clinically recommended to treat BCRL according to these parameters.
Quality of Life in Women With Breast Cancer Receiving Chemotherapy and the Moderating Role of Cortisol
Authors: Pereira Inês , Pereira Marta , Leite Ângela , Pereira M. Graça
Published: March 2022

Background

Quality of life (QoL) is severely affected by breast cancer (BC) and its treatment, particularly chemotherapy treatment. Psychological morbidity, illness perceptions, and self-efficacy for coping are important variables that impact QoL during the treatment of BC. The impact of cortisol on QoL has been poorly studied.

Objective

The aim of this study was to identify the contributing variables to QoL in women with BC receiving adjuvant chemotherapy, as well as the moderating role of cortisol in the relationship between treatment adverse effects and QoL.

Methods

This cross-sectional study included 112 women with BC undergoing chemotherapy who answered the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire, the Supplementary Questionnaire Breast Cancer Module, the Illness Perception Questionnaire, the Cancer Behavior Inventory—Brief Version, and the Hospital Anxiety and Depression Scale. In addition, salivary cortisol concentrations were also assessed.

Results

The strongest contributor to lower QoL was treatment adverse effects. The illness perception and the cancer stage also contributed to a lower QoL. Nadir cortisol moderated the relationship between adverse effects and QoL.

Conclusion

Breast cancer chemotherapy and illness perceptions, even at the beginning of treatment, showed a great impact on QoL.

Implications for Practice

It is important during chemotherapy to assess women’s illness perceptions, as well as their stress levels to help women cope with the stress associated with treatment adverse effects. Monitoring cortisol is important as cortisol moderated the relationship between adverse effects and QoL. For those women struggling with stress, a reference to a mental health provider is warranted.
Gender Differences in Psychological Safety, Academic Safety, Cognitive Load, and Debriefing Satisfaction in Simulation-Based Learning
Authors: Roh Young Sook , Jang Kie In , Issenberg S. Barry
Published: March 2022

Background:

As there is an increasing trend in the number of male-identifying learners in undergraduate nursing education, a need exists to identify the gender differences in learners' perceptions regarding simulation-based learning.

Purpose:

This study aimed to identify the gender differences in psychological safety, academic safety, cognitive load, and debriefing satisfaction in simulation-based nursing education.

Methods:

A cross-sectional descriptive survey was implemented with 97 female and 95 male nursing students. Data were analyzed using Mann-Whitney U tests or independent-samples t tests.

Results:

Female nursing students reported a lower academic safety and higher intrinsic load than male nursing students. Male nursing students perceived a higher germane load than female nursing students.

Conclusions:

The significance of the present study was the identification of gender differences in participant perception of the simulation learning experience for effective simulation design.
Are Future Nurses Ready for Digital Health?
Authors: Kleib Manal , Nagle Lynn M. , Furlong Karen E. , Paul Pauline , Duarte Wisnesky Uira , Ali Shamsa
Published: March 2022

Background:

Research continues to show significant gaps in nursing graduates' preparedness in digital health.

Purpose:

The aim of this study was to explore nursing students' self-perceived nursing informatics competency and preparedness in digital health, describe learning opportunities available, and identify perceived learning barriers and facilitators to developing informatics competency.

Methods:

A sequential mixed-methods design, using a cross-sectional survey and interviews, was used. Senior undergraduate students (n = 221) in BScN programs in a Western Canadian Province participated.

Results:

Participants self-reported being somewhat competent in nursing informatics. Three themes were identified: struggling to make sense of informatics nursing practice; learning experiences; and preparedness for future practice.

Conclusion:

Addressing inconsistencies in informatics education is an urgent priority so that nursing graduates are competent upon joining the workforce. Implications for nursing education, practice, and policy are discussed.
Differential Impact of Work Overload on Physicians’ Attention: A Comparison Between Residential Fields
Authors: Dolev Talya , Zubedat Salman , Manor Iris , Bloch Boaz , Blondheim Orna , Avital Avi
Published: March 2022

Objectives

Medical errors cause tens of thousands of deaths annually and have a major impact on quality of care and management; however, it receives scant research and public awareness. This study aimed to examine the relation between workload-induced lack of sleep and attention failure, as indications for medical errors risk, among young residents.

Methods

We performed an evaluation of young physicians by the Test of Variables of Attention, before and after a 24-hour shift.

Results

Workload was manifested by 13% overall attention impairment at baseline, which increased to 34% with deficiencies below the normal range after the shift. Attention measures differed between physicians of each residential field at baseline, but to greater extent after the shift.

Conclusions

Traditional working schedule is strongly associated with attention failure. Based on the literature linking attention failures to medical errors, we suggest a regulatory change regarding residents’ shift duration to decrease preventable errors.
Obtaining patient torso geometry for the design of scoliosis braces. A study of the accuracy and repeatability of handheld 3D scanners
Authors: Sanz-Pena Inigo , Arachchi Shanika , Curtis-Woodcock Niven , Silva Pujitha , McGregor Alison H. , Newell Nicolas
Published: March 2022

Objective:

Obtaining patient geometry is crucial in scoliosis brace design for patients with adolescent idiopathic scoliosis. Advances in 3D scanning technologies provide the opportunity to obtain patient geometries quickly with fewer resources during the design process compared with the plaster-cast method. This study assesses the accuracy and repeatability of such technologies for this application.

Methods:

The accuracy and repeatability of three different handheld scanners and phone-photogrammetry was assessed using different mesh generation software. Twenty-four scans of a single subject's torso were analyzed for accuracy and repeatability based on anatomical landmark distances and surface deviation maps.

Results:

Mark II and Structure ST01 scanners showed maximum mean surface deviations of 1.74 ± 3.63 mm and 1.64 ± 3.06 mm, respectively. Deviations were lower for the Peel 1 scanner (maximum of −0.35 ± 2.8 mm) but higher with the use of phone-photogrammetry (maximum of −5.1 ± 4.8 mm). The mean absolute errors of anatomical landmark distance measurements from torso meshes obtained with the Peel 1, Mark II, and ST01 scanners were all within 9.3 mm (3.6%), whereas phone-photogrammetry errors were as high as 18 mm (7%).

Conclusions:

Low-cost Mark II and ST01 scanners are recommended for obtaining torso geometries because of their accuracy and repeatability. Subject’s breathing/movement affects the resultant geometry around the abdominal and anterolateral regions.
Isolated Myeloperoxidase–Antineutrophil Cytoplasmic Antibody–Associated Hypertrophic Pachymeningitis
Authors: Maneval Jeffrey , Bryant Bronwyn , Ulano Adam , Waheed Waqar , Nevares Alana
Published: March 2022

A 65-year-old man with no pertinent medical history presented with 1 month of progressive holocephalic positional headaches (worse supine), photophobia, progressive gait instability resulting in multiple falls (ambulatory to walker in only 2 months), and weight loss. Testing found positive ANCA 1:160 perinuclear patter, myeloperoxidase >8.0. Cerebrospinal fluid found lymphocytic pleocytosis. We present his neuroimaging of isolated hypertrophic pachymeningitis with clinicoradiographic resolution after immunomodulatory pharmacotherapy along with histology from his meningeal biopsy. Isolated vasculitic myeloperoxidase–antineutrophil cytoplasmic antibody hypertrophic pachymeningitis is quite rare.
To Clap or Not to Clap
Authors: Díaz-Agea José L. , Pujalte-Jesús María J. , García-Méndez Juan A. , Adánez-Martínez Gracia , Jiménez-Rodríguez Diana , Leal-Costa César
Published: March 2022

Introduction

Applause is a common behavior during simulation case learning sessions. Some simulation facilitators believe that this should not be allowed, arguing that it can mislead students when they make mistakes during simulation. This study was conducted to explore the opinions of students about spontaneous applause (initiated by the participants), as a habitual behavior in the simulation sessions, in the undergraduate and postgraduate nursing degrees.

Methods

A qualitative research study was conducted based on the content analysis of 7 focus groups composed of simulation students (N = 101, both undergraduate and graduate students). The participants were asked to conduct a debate about the following question: What is your opinion about the spontaneous applause given to participants by their peers at the completion of the scenario as they go to the debriefing, and why? An inductive method of content analysis was used to interpret the data.

Results

The majority considered applause as a sign of support; one student disapproved of the practice. For most participants, receiving spontaneous applause from their peers after finishing the simulation represented a spontaneous example of moral support that reduced the participants' stress.

Conclusions

Applause within the context of clinical simulation is a motivational act, which should not be repressed by the facilitator, as long as it is a spontaneous and genuine act by the participants once the simulation experience ends.
Sex differences associate with late microbiome alterations after murine surgical sepsis
Authors: Efron Philip Alexander , Darden Dijoia B. , Li Eric C. , Munley Jennifer , Kelly Lauren , Fenner Brittany , Nacionales Dina C. , Ungaro Ricardo F. , Dirain Marvin L. , Rincon Jaimar , Mankowski Robert T. , Leeuwenburgh Christiaan , Moore Fredrick A. , Brakenridge Scott C. , Foster Thomas C. , Laitano Orlando , Casadesus Gemma , Moldawer Lyle L. , Mohr Alicia M. , Thomas Ryan M.
Published: March 2022

BACKGROUND

Sepsis-induced gut microbiome alterations contribute to sepsis-related morbidity and mortality. Given evidence for improved postsepsis outcomes in females compared with males, we hypothesized that female mice maintain microbiota resilience versus males.

METHODS

Mixed-sex C57BL/6 mice underwent cecal ligation and puncture (CLP) with antibiotics, saline resuscitation, and daily chronic stress and were compared with naive (nonsepsis/no antibiotics) controls. For this work, the results of young (3–5 months) and old (18–22 months) adult mice were analyzed by sex, independent and dependent of age. Mice were sacrificed at days 7 and 14, and 16S rRNA gene sequencing was performed on fecal bacterial DNA. α and β diversity were determined by Shannon index and Bray-Curtis with principal coordinate analysis, respectively. False discovery rate (FDR) correction was implemented to account for potential housing effect.

RESULTS

In control mice, there was no difference in α or β diversity between male and female mice (FDR, 0.76 and 0.99, respectively). However, male mice that underwent CLP with daily chronic stress had a decrease in microbiota α diversity at 7 days post-CLP (Shannon FDR, 0.005), which was sustained at 14 days post-CLP (Shannon FDR, 0.001), compared with baseline. In addition, male mice maintained differences in β diversity even at day 14 compared with controls (FDR, <0.0001). In contrast, female mice had a decreased microbiota α diversity (Shannon FDR, 0.03) and β diversity (FDR, 0.02) 7 days post-CLP but recovered their α and β diversity by post-CLP day 14 (Shannon FDR, 0.5, and FDR, 0.02, respectively). Further analysis of females revealed that only young female mice were not different (β diversity) post-CLP day 14 to controls.

CONCLUSION

Although sepsis-induced perturbations of the intestinal microbiota occur initially in both male and female C57BL/6 mice, females demonstrate different microbiota by day 14. This may be seen primarily in younger females. This difference in recovery may play a role in outcome differences between sexes after sepsis.
Preceptors' Knowledge, Skills, and Attitudes Toward Precepting Dietetic Interns and Training Perceptions
Authors: Benoit Teresa , Montes Alina , Shreim Somir , Andrade Jeanette M.
Published: March 2022

Dietetic preceptors play a critical role in educating and mentoring future registered dietitian nutritionists throughout the internship. A mixed-methods research study was conducted from September to October 2019 to examine US dietetic preceptors' knowledge, skills, and attitudes (KSAs) toward precepting and training. Of the 141 participants who completed the quantitative survey, their KSAs were high (4.5/5). From the qualitative feedback, preceptors (n = 15) expressed the need for further training in the areas of communication, teaching, and evaluation and preferred training online or through webinars. This provides an opportunity for developing tailored training materials to support preceptors as they educate future dietitians.
Adaptation Study of the Newest Vital Sign on Adolescents With Type 1 Diabetes and Healthy Adolescents in Turkish
Authors: Bayındır Gümüş Aylin , Keser Alev , Şıklar Zeynep , Berberoğlu Merih
Published: March 2022

The current study aimed to establish validity and reliability of the Newest Vital Sign (NVS) in 255 Turkish adolescents aged 11 to 18 years with and without type 1 diabetes and evaluate their health literacy with age, gender, and health status. The t values of items in the NVS were found to be statistically significant and the calculated Cronbach's α coefficient value indicated that the reliability is at a medium level; 7.5%, 42%, and 56.5% of adolescents had respectively inadequate, limited, and adequate health literacy. There is a negative relationship between the health literacy of adolescents with diabetes and their HbA1c (P < .05). This study confirms that the NVS is a valid and reliable tool for Turkish adolescents.
Shifting Clinical Trial Endpoints in Kidney Transplantation: The Rise of Composite Endpoints and Machine Learning to Refine Prognostication
Authors: Anwar Imran J. , Srinivas Titte R. , Gao Qimeng , Knechtle Stuart J.
Published: March 2022

The measurement of outcomes in kidney transplantation has been more accurately documented than almost any other surgical procedure result in recent decades. With significant improvements in short- and long-term outcomes related to optimized immunosuppression, outcomes have gradually shifted away from conventional clinical endpoints (ie, patient and graft survival) to surrogate and composite endpoints. This article reviews how outcomes measurements have evolved in the past 2 decades in the setting of increased data collection and summarizes recent advances in outcomes measurements pertaining to clinical, histopathological, and immune outcomes. Finally, we discuss the use of composite endpoints and Bayesian concepts, specifically focusing on the integrative box risk prediction score, in conjunction with machine learning to refine prognostication.
Animal Models in Epileptic Spasms and the Development of Novel Treatment Options
Authors: Barrett Karlene T. , Choudhary Anamika , Charkhand Behshad , Scantlebury Morris H.
Published: March 2022

The infantile spasms (IS) syndrome is a catastrophic developmental epileptic encephalopathy syndrome characterized by an age-specific expression of epileptic spasms that are associated with extremely abnormal, oftentimes described as chaotic, interictal EEG pattern known as hypsarrhythmia. Patients with IS generally have poor neurodevelopmental outcomes, in large part because of the frequent epileptic spasms and interictal EEG abnormalities. Current first-line treatments such as adrenocorticotropic hormone or vigabatrin are often ineffective and are associated with major toxic side effects. There is therefore a need for better and safer treatments for patients with IS, especially for the intractable population. Hope is on the horizon as, over the past 10 years, there has been robust progress in the development of etiology-specific animal models of IS. These models have been used to identify potential new treatments for IS and are beginning to provide some important insights into the pathophysiological substrates for this disease. In this review, we will highlight strengths and weaknesses of the currently available animal models of IS in addition to new insights into the pathophysiology and treatment options derived from these models.
Scoring Systems for the Evaluation of Hypsarrhythmia
Authors: Lachhwani Deepak
Published: March 2022

Hypsarrhythmia is a well-recognized EEG pattern and it has been long known as a feature of one of the more severe forms of epilepsy early in life with adverse consequences if not recognized and treated promptly. Yet, it has been difficult to objectively quantify its varied manifestations and link them to the clinical severity of epilepsy, implications for treatment, or the overall seizure and developmental outcome of young patients. This is not for want of effort, for there have been several approaches to score hypsarrhythmia ever since its initial recognition as a unique EEG pattern. In this article, we review the different methods proposed to score hypsarrhythmia and highlight the challenges inherent to each one of them.
An assessment of the evidence for antibacterial activity of stinging nettle (Urtica dioica) extracts
Authors: Harrison Freya , Furner-Pardoe Jessica , Connelly Erin
Published: March 2022

Stinging nettles (Urtica spp.) have been used in a diverse range of traditional and historical medicines from around the world for the treatment of skin diseases, wounds, urinary disorders, respiratory diseases, bone and joint pain, anaemia and other circulatory problems, as well as in cosmetic preparations for skin and haircare. As part of an interdisciplinary exploration of nettle-based remedies, we performed a systematic review of published evidence for the antimicrobial activity of Urtica spp. extracts against bacteria and fungi that commonly cause skin, soft tissue and respiratory infections. We focussed on studies in which minimum inhibitory concentration (MIC) assays of U. dioica were conducted on the common bacterial opportunistic pathogens

Escherichia coli

,

Pseudomonas aeruginosa

,

Klebsiella pneumoniae

and

Staphylococcus aureus

. No studies used fresh leaves (all were dried prior to use), and no studies prepared nettles in weak acid (corresponding to vinegar) or in fats/oils, which are common combinations in historical and traditional preparations. We addressed this gap by conducting new antibacterial tests of extracts of fresh U. dioica leaves prepared in vinegar, butter or olive oil against

P. aeruginosa

and

S. aureus

. Our systematic review and additional experimental data leads us to conclude that there is no strong evidence for nettles containing molecules with clinically useful antimicrobial activity. It seems most likely that the utility of nettles in traditional topical preparations for wounds may simply be as a ‘safe’ absorbent medium for keeping antibacterial (vinegar) or emollient (oils) ingredients at the treatment site.
Conventional polymers may unintentionally refill in vivo with unassociated drugs
Authors: Young Kathleen , Dogan Alan B. , Hernandez Christopher , Exner Agata A. , von Recum Horst A.
Published: March 2022

Polymers used as drug delivery devices are ultimately limited by how much drug they can hold; with the device failing if the drug is depleted before the disease is cured. Our lab discovered a means to use thermodynamic driving forces to refill certain classes of polymer after implantation, for additional drug delivery windows. These same, refillable polymers can be used as additives, to provide refilling capacity to classical, non-refillable polymers such as poly(methyl methacrylate) (PMMA). In this paper, we investigated the refilling capacity of another conventional polymer: poly(lactic-co-glycolic acid) or PLGA. We explored both unmodified PLGA implants as well as implants supplemented with polymerized cyclodextrin (pCD) in microparticle form, previously shown to add refillability to poly(methyl methacrylate) (PMMA) implants which were otherwise not refillable. Assessments of in situ forming PLGA implants with and without pCD additives were made, including drug loading capacity in a liquid medium, drug refilling through a tissue-mimicking gel medium, and refilling in ex vivo and in vivo conditions. Implant cross-sections were imaged via fluorescence microscopy. Drug release from refilled implants, polymer swelling, degradation, phase inversion characteristics were assessed, and drug/monomer computational simulation studies were performed. While generally, the incorporation of cyclodextrin into implants led to significant increases in the amount of refilled drug; unexpectedly, PLGA implants with no incorporated pCD also showed refilling capability. Moreover, in two out of three in vivo conditions in rats, PLGA alone showed the potential to refill with comparable, if not greater, amounts of drug than PLGA with pCD incorporated. This contrasts predictions, since PLGA has no specifically designed affinity structure, like pCD does. We theorize that the mechanism for PLGA’s refilling depends on nano-patterning of hydrophilic and hydrophobic molecular domains, giving rise to its affinity-like behavior. The fact that PLGA implants can be refilled with unassociated drugs, gives rise to concerns about the fate of all implants made of poly alpha-hydroxy esters, and likely other polymers as well, and will likely lead to new directions of study such as of unintended polymer / drug interactions.
Fast & Scrupulous: Gesture-Based Alarms Improve Accuracy and Reaction Times Under Various Mental Workload Levels. An ERSP Study
Authors: Fabre Eve Floriane , Somon Bertille , Baragona Valeria , Uhl Quentin , Causse Mickaël
Published: March 2022

In high-risk environments, fast and accurate responses to warning systems are essential to efficiently handle emergency situations. The aim of the present study was twofold: 1) investigating whether hand action videos (i.e., gesture alarms) trigger faster and more accurate responses than text alarm messages (i.e., written alarms), especially when mental workload (MWL) is high; and 2) investigating the brain activity in response to both types of alarms as a function of MWL. Regardless of MWL, participants (N = 28) were found to be both faster and more accurate when responding to gesture alarms than to written alarms. Brain electrophysiological results suggest that this greater efficiency might be due to a facilitation of the action execution, reflected by the decrease in mu and beta power observed around the response time window. These results suggest that gesture alarms may improve operators’ performances in emergency situations.
Galanin Analogs Prevent Seizure-Induced Respiratory Arrest
Authors: Collard Ryley , Aziz Miriam C. , Rapp Kevin , Cutshall Connor , Duyvesteyn Evalien , Metcalf Cameron S.
Published: March 2022

Objective

Sudden Unexpected Death in Epilepsy (SUDEP) accounts for 20% of mortality in those with recurrent seizures. While risk factors, monitoring systems, and standard practices are in place, the pathophysiology of SUDEP is still not well understood. Better knowledge of SUDEP and its potential mechanisms of action is crucial to reducing risk in this patient population and developing potential treatment options. Clinical studies and animal models of SUDEP suggest that diminished post-ictal respiratory control may be the dominant mechanism contributing to mortality. Recently, it was demonstrated that the depletion of the neuropeptide galanin in the amygdala occurs in human SUDEP. The amygdala plays a key role in the central integration of respiratory signaling; the depletion of galanin may represent a critical change that predisposes individuals to SUDEP.

Methods

To evaluate the potential benefit of enhancing galaninergic signaling as a means to protect against SUDEP, we studied seizure-induced respiratory arrest (S-IRA) following central (intracerebroventricular, intra-amygdala) and systemic (intraperitoneal, subcutaneous) administration of galanin agonists. Seizure naïve and seizure experienced (fully kindled) mice were tested.

Results

Central and systemically-administered galanin analogs protect against S-IRA in naïve C57Bl/6J mice. Differential efficacy between receptor subtype-selective analogs varied based on the route of administration. Sub-chronic systemic administration at doses that reduced 6 Hz seizures also protected against S-IRA. Acute treatment benefits also extended to fully kindled mice subjected to tonic extension.

Significance

These data demonstrate that galanin agonists may be protective against post-ictal respiratory collapse.

KEY POINTS

Central and systemic galanin agonists prevent seizure-induced respiratory arrest.

Efficacy was observed in three separate mouse strains under various experimental conditions.

Sub-chronic administration demonstrated galanin agonist protection against respiratory arrest.

Acute systemic administration also conferred protection against respiratory arrest following tonic extension.

Galanin analogs may represent a novel potential therapy in SUDEP-susceptible individuals.
Integrative Analysis of Checkpoint Blockade Response in Advanced Non-Small Cell Lung Cancer
Authors: Ravi Arvind , Gainor Justin F. , Arniella Monica B. , Holton Mark , Freeman Samuel S. , Stewart Chip , Leshchiner Ignaty , Kim Jaegil , Akiyama Yo , Griffin Aaron T. , Vokes Natalie I. , Sakhi Mustafa , Kamesan Vashine , Rizvi Hira , Ricciuti Biagio , Forde Patrick M. , Anagnostou Valsamo , Riess Jonathan W. , Gibbons Don L. , Pennell Nathan A. , Velcheti Vamsidhar , Digumarthy Subba R. , Mino-Kenudson Mari , Califano Andrea , Heymach John V. , Herbst Roy S. , Brahmer Julie R. , Schalper Kurt A. , Velculescu Victor E. , Henick Brian S. , Rizvi Naiyer , Jänne Pasi A. , Awad Mark M. , Chow Andrew , Greenbaum Benjamin D. , Luksza Marta , Shaw Alice T. , Wolchok Jedd , Hacohen Nir , Getz Gad , Hellmann Matthew D.
Published: March 2022

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). While our understanding of the biology underlying immune checkpoint blockade in NSCLC is still incomplete, studies to date have established predictive roles for PD-L1 tumor expression and tumor mutational burden (TMB). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up 2 Cancer - Mark Foundation (SU2C-MARK) Cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including: 1) favorable (e.g., ATM altered), and unfavorable (e.g., TERT amplified) genomic subgroups, 2) distinct immune infiltration signatures associated with wound healing (unfavorable) and immune activation (favorable), and 3) a novel de-differentiated tumor-intrinsic subtype characterized by expression of endodermal lineage genes, immune activation, and enhanced response rate. Taken together, results from this cohort extend our understanding of NSCLC-specific predictors, providing a rich set of molecular and immunologic hypotheses with which to further our understanding of the biology of checkpoint blockade in NSCLC.
The gut microbiome is a significant risk factor for future chronic lung disease
Authors: Liu Yang , Teo Shu Mei , Meric Guillaume , Tang Howard H.F. , Zhu Qiyun , Sanders Jon G , Vazquez-Baeza Yoshiki , Verspoor Karin , Vartiainen Ville A , Jousilahti Pekka , Lahti Leo , Niiranen Teemu , Havulinna Aki S. , Knight Rob , Salomaa Veikko , Inouye Michael
Published: March 2022

Background

The gut-lung axis is generally recognized, but there are few large studies of the gut microbiome and incident respiratory disease in adults.

Objectives3

To investigate the associations between gut microbiome and respiratory disease and to construct predictive models from baseline gut microbiome profiles for incident asthma or chronic obstructive pulmonary disease (COPD).

Methods

Shallow metagenomic sequencing was performed for stool samples from a prospective, population-based cohort (FINRISK02; N=7,115 adults) with linked national administrative health register derived classifications for incident asthma and COPD up to 15 years after baseline. Generalised linear models and Cox regressions were utilised to assess associations of microbial taxa and diversity with disease occurrence. Predictive models were constructed using machine learning with extreme gradient boosting. Models considered taxa abundances individually and in combination with other risk factors, including sex, age, body mass index and smoking status.

Results

A total of 695 and 392 significant microbial associations at different taxonomic levels were found with incident asthma and COPD, respectively. Gradient boosting decision trees of baseline gut microbiome predicted incident asthma and COPD with mean area under the curves of 0.608 and 0.780, respectively. For both incident asthma and COPD, the baseline gut microbiome had C-indices of 0.623 for asthma and 0.817 for COPD, which were more predictive than other conventional risk factors. The integration of gut microbiome and conventional risk factors further improved prediction capacities. Subgroup analyses indicated gut microbiome was significantly associated with incident COPD in both current smokers and non-smokers, as well as in individuals who reported never smoking.

Conclusions

The gut microbiome is a significant risk factor for incident asthma and incident COPD and is largely independent of conventional risk factors.
Patients’ Experiences of Using Smartphone Apps to Manage their Gestational Diabetes Diagnosis: A Systematic Review - protocol (version 1)
Authors: Anis Ali , Plüddemann Annette , Choksey Anurag , Portwood Clara , Mitra Vikram , Heneghan Carl
Published: March 2022

Background

Gestational diabetes is a strong predictor of type 2 diabetes onset. However, women who make healthy dietary and lifestyle choices can significantly reduce their risk. There is a need to understand the factors facilitating or preventing women from using smartphone apps that may encourage these behaviours.

Methods

We plan to conduct a systematic review of patient experiences when using mobile health applications to manage gestational diabetes. We will include primary studies of qualitative data around patient experiences of using these applications, as well as the barriers and facilitators to using technologies. We will search the following electronic databases: Medline, Embase, PsycINFO, Global Health, Web of Science, Cochrane Central Register of Controlled Trials (CENTRAL), AMED and CINAHL and manually search the reference lists of included studies. We will include primary studies involving direct user interviews and where the results have been analysed using qualitative methods. To assess the quality of included studies, we will use the CASP qualitative research checklist.

Expected results

We intend to use summary tables to report the characteristics of the study population, the overarching themes that emerged, and recommendations for research and practice.
An uncommon garden experiment: microenvironment has stronger influence on phenotypic variation than epigenetic memory in the clonal Lombardy poplar
Authors: Rodríguez Bárbara Díez , Peña Cristian , Pérez Bello Paloma , Bette Julius , Lerbs Lena , Mackenbach Tabea , Wulle Sven , De Paoli Emanuele , Verhoeven Koen J.F. , Heer Katrin , Opgenoorth Lars
Published: March 2022

Environmental changes can trigger phenotypic variation in plants through epigenetic mechanisms, but strong genetic influences on epigenetic variation and phenotypes make it difficult to isolate and study these effects. We investigated phenotypic plasticity using the Lombardy poplar (Populus nigra cv. ‘Italica’ Duroi), a globaly distributed clonal tree. We surveyed 14 functional traits related to tree growth, ecophysiological and phenological processes in poplar ramets collected along a wide geographical range in Europe and planted under common garden conditions. We investigated whether phenotypic variation was related to geography and historical bioclimatic data of the ramets’ sites of origin using linear mixed effect models. We found significant differences in among ramets from different geographic origins in tree height, number of stems per ramet and duration of bud flush. However, microenvironmental variation in the common garden, captured via block effects, had an even bigger impact on phenotypic variation than the environmental conditions at the sites of origin. Our results show that phenotypic variation in the ramets might be associated to the climate origin from different climates, suggesting possible epigenetic memory. However, such legacy effects might be quickly outweighed by new environmental conditions.
Context-dependent triggering of STING-interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients
Authors: Liu Xiuting , Hogg Graham D. , Zuo Chong , Baer John M , Lander Varintra E. , Kang Liang , Borcherding Nicholas C. , Knolhoff Brett L. , Osterhout Robin E. , Galkin Anna V. , Bruey Jean-Marie , Carter Laura L. , Mpoy Cedric , Schwarz Julie K. , Park Haeseong , Gupta Vineet , DeNardo David G.
Published: March 2022

Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Herein we used a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist GB1275 to identify the mechanism of action of this approach and identify combinations for further testing. We found that CD11b agonism altered tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome and was not context dependent. In contrast, CD11b agonism triggered mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling. The magnitude of CD11b agonist induction of STING/IFN signaling was dependent on the tumor microenvironment and was significantly amplified by cytotoxic therapies. Using tissues from phase I clinical trials, we demonstrated that GB1275 treatment activated STING and STAT1 signaling in TAMs in human tumors. Together, these mechanisms allowed macrophages to augment anti-tumor T cell immunity. These studies identified potential mechanism-based therapeutic strategies for CD11b agonist use and identified potential patient populations more likely to benefit from them.

Statement of significance

CD11b agonists are a novel approach to reprogram myeloid cells in solid tumors. We show that GB1275, a CD11b-agonist, amplified STING/IFN signaling in TAMs to support anti-tumor immunity and this signaling is amplified further by cytotoxic therapy. These studies support new treatment strategies for advanced solid tumors with myeloid immunosuppression.
Targeting Reductive Metabolic Shifts by T315I Mutation in BCR-ABL Myeloid Leukemia for Therapy
Authors: Huang Chang-Yu , Chung Yin-Hsuan , Wu Sheng-Yang , Wang Hsin-Yang , Lin Zhi-Yu , Yang Tsung-Jung , Feng Jim-Ming , Hu Chun-Mei , Chang Zee-Fen
Published: March 2022

T315I mutation of Bcr-Abl in chronic myeloid leukemia (CML) leads to therapeutic resistance. It is known that Bcr-Abl transformation causes ROS-induced DNA damages and replication stress, which can be exploited for anti-nucleotide therapy. We developed a small compound, JMF4073, which inhibited pyrimidylate kinases and selectively eliminated Bcr-Abl-transformed, but not untransformed myeloid cells, due to dTTP exhaustion and ROS-induced replication stress. However, T315I-Bcr-Abl-transformed cells were less vulnerable to JMF4073 because of higher dTTP pool and low replication stress. Unlike WT-Bcr-Abl-transformed cells, T315I-Bcr-Abl cells lacked Sirt1- regulated OXPHOS with increased glutamine flux to reductive carboxylation in TCA cycle and glutathione synthesis. Blocking mitochondrial pyruvate carrier (MPC) by UK-5099 reduced NADH and glutathione levels with replication stress induction, thereby converting T315I-Bcr-Abl cells sensitive to JMF4073 with dTTP and dCTP depletion. The combination of JMF4073 with UK-5099 showed in vivo eradication of T315I-Bcr-Abl-CML. These data reveal that T315I mutation causes reductive metabolic shifts in Bcr-Abl-CML, and demonstrate the therapeutic option by co-targeting MPC and pyrimidylate kinases.
Screening of Relevant Metabolism-Disrupting Chemicals on Pancreatic β-Cells: Evaluation of Murine and Human in Vitro Models
Authors: Al-Abdulla Ruba , Ferrero Hilda , Soriano Sergi , Boronat-Belda Talía , Alonso-Magdalena Paloma
Published: March 2022

Endocrine-disrupting chemicals (EDCs) are chemical substances that can interfere with the normal function of the endocrine system. EDCs are ubiquitous and can be found in a variety of consumer products such as food packaging materials, personal care and household products, plastic additives, and flame retardants. Over the last decade, the impact of EDCs on human health has been widely acknowledged as they have been associated with different endocrine diseases. Among them, a subset called metabolism-disrupting chemicals (MDCs) are able to promote metabolic changes that can lead to the development of metabolic disorders such as diabetes, obesity, hepatic steatosis, and metabolic syndrome, among others. Despite this, today, there are still no definitive and standardized in vitro tools to support the metabolic risk assessment of existing and emerging MDCs for regulatory purposes. Here, we evaluated two different pancreatic cell-based in vitro systems, the murine pancreatic β-cell line MIN6 as well as the human pancreatic β-cell line EndoC- βH1. Both were challenged with a range of relevant concentrations of seven well-known EDCs (bisphenol-A (BPA), bisphenol-S (BPS), bisphenol-F (BPF), perfluorooctanesulfonic acid (PFOS), di(2-ethylhexyl) phthalate (DEHP), cadmium chloride (CdCl2) and dichlorodiphenyldichloroethylene (DDE)). The screening revealed that most of the tested chemicals have detectable deleterious effects on glucose-stimulated insulin release, insulin content, electrical activity, gene expression, and/or viability. Our data provide new molecular information on the direct effects of the selected chemicals on key aspects of pancreatic β-cell function such as the stimulus-secretion coupling and ion channel activity. In addition, we found that, in general, the sensitivity and responses were comparable to those from other in vivo studies reported in the literature. Overall, our results suggest that both systems can serve as effective tools for rapid screening of potential MDC effects on pancreatic β-cell physiology as well for deciphering and better understanding the molecular mechanisms that underlie their action.
Development of in vitro test methods in a model of human pancreatic β-cells to identify metabolism disrupting chemicals with diabetogenic activity
Authors: Dos Santos Reinaldo Sousa , Medina-Gali Regla María , Babiloni-Chust Ignacio , Marroqui Laura , Nadal Angel
Published: March 2022

There is a need to develop identification tests for Metabolism Disrupting Chemicals (MDCs) with diabetogenic activity. Here we used the human EndoC-βH1 β-cell line, the rat β-cell line INS-1E and dispersed mouse islet cells to assess the effects of endocrine disruptors on cell viability and glucose-stimulated insulin secretion (GSIS). We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 μM). Bisphenol-A (BPA) and tributyltin (TBT) were used as controls while four other chemicals, namely perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS) and dichlorodiphenyldichloroethylene (DDE), were used as “unknowns”. Regarding cell viability, BPA and TBT increased cell death as previously observed. Their mode of action involved the activation of estrogen receptors and PPARγ, respectively. ROS production was a consistent key event in BPA- and TBT-treated cells. None of the other MDCs tested modified viability or ROS production. Concerning GSIS, TBT increased insulin secretion while BPA produced no effects. PFOA decreased GSIS, suggesting that this chemical could be a “new” diabetogenic agent. Our results indicate that the EndoC-βH1 cell line is a suitable human β-cell model for testing diabetogenic MDCs. Optimization of the test methods proposed here could be incorporated into tier protocols for the identification of MDCs.
Human CD4+/CD8α+ regulatory T cells induced by Faecalibacterium prausnitzii protect against intestinal inflammation
Authors: Touch Sothea , Godefroy Emmanuelle , Rolhion Nathalie , Danne Camille , Oeuvray Cyriane , Straube Marjolène , Galbert Chloé , Brot Loïc , Salgueiro Iria Alonso , Chadi Sead , Ledent Tatiana , Chatel Jean-Marc , Langella Philippe , Jotereau Francine , Altare Frédéric , Sokol Harry
Published: March 2022

Faecalibacterium prausnitzii (F. prausnitzii), a dominant bacterium of the human microbiota, is decreased in patients with inflammatory bowel diseases (IBD) and exhibits anti-inflammatory effects. In human, colonic lamina propria contains IL-10-positive, Foxp3-negative regulatory T cells (Treg) characterized by a double expression of CD4 and CD8α (DP8α) and a specificity for F. prausnitzii. This Treg subset is decreased in IBD. The in vivo effect of DP8α cells has not been evaluated yet. Here, using a humanized model of NOD.Prkcscid IL2rγ-/- (NSG) immunodeficient mouse strain that expresses human leucocyte antigen D-related 4 (HLA-DR4) but not murine class II (NSG-Ab° DR4), we demonstrated a protective effect of DP8α Tregs combined with F. prausnitzii administration in a colitis model. In a cohort of patients with IBD, we showed an independent association between the frequency of circulating DP8α cells and disease activity. Finally, we pointed out a positive correlation between F. prausnitzii-specific DP8α Tregs and the amount of F. prausnitzii in fecal microbiota in healthy individuals and patients with ileal Crohn’s disease.
Structural architecture and brain network efficiency links polygenic scores to intelligence
Authors: Genç Erhan , Metzen Dorothea , Fraenz Christoph , Schlüter Caroline , Voelkle Manuel C. , Arning Larissa , Streit Fabian , Nguyen Huu Phuc , Güntürkün Onur , Ocklenburg Sebastian , Kumsta Robert
Published: March 2022

Intelligence is highly heritable. Genome-wide association studies (GWAS) have shown that thousands of alleles contribute to variation in intelligence with small effect sizes. Polygenic scores (PGS), which combine these effects into one genetic summary measure, are increasingly used to investigate polygenic effects in independent samples. Whereas PGS explain a considerable amount of variance in intelligence, it is largely unknown how brain structure and function mediate this relationship. Here we show that individuals with higher PGS for educational attainment and intelligence had higher scores on cognitive tests, larger surface area, and more efficient fiber connectivity derived by graph theory. Fiber network efficiency as well as surface of brain areas partly located in parieto-frontal regions were found to mediate the relationship between PGS and cognitive performance. These findings are a crucial step forward in decoding the neurogenetic underpinnings of intelligence, as they identify specific regional networks that link polygenic predisposition to intelligence.
Rethinking the Methods and Algorithms for Inner Speech Decoding - and Making them Reproducible
Authors: Simistira Liwicki Foteini , Gupta Vibha , Saini Rajkumar , De Kanjar , Liwicki Marcus
Published: March 2022

This study focuses on the automatic decoding of inner speech using noninvasive methods, such as electroencephalography (EEG)). While inner speech has been a research topic in philosophy and psychology for half a century, recent attempts have been made to decode nonvoiced spoken words by using various brain-computer interfaces. The main shortcomings of existing work are reproducibility and the availability of data and code. In this work, we investigate various methods (using Convolutional Neural Network (CNN), Gated Recurrent Unit (GRU), Long Short-Term Memory Networks (LSTM)) for the detection task of 5 vowels and 6 words on a publicly available EEG dataset. The main contributions of this work are (1) subject dependent vs. subject-independent approaches, (2) the effect of different preprocessing steps (Independent Component Analysis (ICA), down-sampling and filtering), and (3) word classification (where we achieve state-of-the-art performance on a publicly available dataset). Overall we achieve a performance accuracy of 35.20% and 29.21% when classifying 5 vowels and 6 words respectively in a publicly available dataset, using our tuned iSpeech-CNN architecture. All of our code and processed data are publicly available to ensure reproducibility. As such, this work contributes to a deeper understanding and reproducibility of experiments in the area of inner speech detection.