bluuebunny/crossref_metadata_2025_split huggingface dataset:
Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy
Authors: Berrien-Elliott Melissa M. , Becker-Hapak Michelle , Cashen Amanda F. , Jacobs Miriam , Wong Pamela , Foster Mark , McClain Ethan , Desai Sweta , Pence Patrick , Cooley Sarah , Brunstein Claudio , Gao Feng , Abboud Camille N. , Uy Geoffrey L. , Westervelt Peter , Jacoby Meagan A. , Pusic Iskra , Stockerl-Goldstein Keith E. , Schroeder Mark A. , DiPersio John F. , Soon-Shiong Patrick , Miller Jeffrey S. , Fehniger Todd A. 
Published: November 2021

Abstract
Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.
Comparison of carbohydrate ABC importers from Mycobacterium tuberculosis
Authors: De la Torre Lilia I. , Vergara Meza José G. , Cabarca Sindy , Costa-Martins André G. , Balan Andrea 
Published: November 2021

Abstract
Background
Mycobacterium tuberculosis, the etiological agent of tuberculosis, has at least four ATP-Binding Cassette (ABC) transporters dedicated to carbohydrate uptake: LpqY/SugABC, UspABC, Rv2038c-41c, and UgpAEBC. LpqY/SugABC transporter is essential for M. tuberculosis survival in vivo and potentially involved in the recycling of cell wall components. The three-dimensional structures of substrate-binding proteins (SBPs) LpqY, UspC, and UgpB were described, however, questions about how these proteins interact with the cognate transporter are still being explored. Components of these transporters, such as SBPs, show high immunogenicity and could be used for the development of diagnostic and therapeutic tools. In this work, we used a phylogenetic and structural bioinformatics approach to compare the four systems, in an attempt to predict functionally important regions.

Results
Through the analysis of the putative orthologs of the carbohydrate ABC importers in species of Mycobacterium genus it was shown that Rv2038c-41c and UgpAEBC systems are restricted to pathogenic species. We showed that the components of the four ABC importers are phylogenetically separated into four groups defined by structural differences in regions that modulate the functional activity or the interaction with domain partners. The regulatory region in nucleotide-binding domains, the periplasmic interface in transmembrane domains and the ligand-binding pocket of the substrate-binding proteins define their substrates and segregation in different branches. The interface between transmembrane domains and nucleotide-binding domains show conservation of residues and charge.

Conclusions
The presence of four ABC transporters in M. tuberculosis dedicated to uptake and transport of different carbohydrate sources, and the exclusivity of at least two of them being present only in pathogenic species of Mycobacterium genus, highlights their relevance in virulence and pathogenesis. The significant differences in the SBPs, not present in eukaryotes, and in the regulatory region of NBDs can be explored for the development of inhibitory drugs targeting the bacillus. The possible promiscuity of NBDs also contributes to a less specific and more comprehensive control approach.
Land use and life history constrain adaptive genetic variation and reduce the capacity for climate change adaptation in turtles
Authors: Byer Nathan W. , Fountain Emily D. , Reid Brendan N. , Miller Kristen , Kulzer Paige J. , Peery M. Zachariah 
Published: November 2021

Abstract
Background
Rapid anthropogenic climate change will require species to adapt to shifting environmental conditions, with successful adaptation dependent upon current patterns of genetic variation. While landscape genomic approaches allow for exploration of local adaptation in non-model systems, most landscape genomics studies of adaptive capacity are limited to exploratory identification of potentially important functional genes, often without a priori expectations as to the gene functions that may be most important for climate change responses. In this study, we integrated targeted sequencing of genes of known function and genotyping of single-nucleotide polymorphisms to examine spatial, environmental, and species-specific patterns of potential local adaptation in two co-occuring turtle species: the Blanding’s turtle (Emydoidea blandingii) and the snapping turtle (Chelydra serpentina).

Results
We documented divergent patterns of spatial clustering between neutral and putatively adaptive genetic variation in both species. Environmental associations varied among gene regions and between species, with stronger environmental associations detected for genes involved in stress response and for the more specialized Blanding’s turtle. Land cover appeared to be more important than climate in shaping spatial variation in functional genes, indicating that human landscape alterations may affect adaptive capacity important for climate change responses.

Conclusions
Our study provides evidence that responses to climate change will be contingent on species-specific adaptive capacity and past history of exposure to human land cover change.
MSMEG_3955 from Mycobacterium smegmatis is a FMN bounded homotrimeric NAD(P)H:Flavin mononucleotide (FMN) oxidoreductase
Authors: Khosla Neha , Thayil Seema Madhumal , Kaur Rajinder , Kesavan Anup Kumar 
Published: November 2021

Abstract
Background
Tuberculosis (TB) remains an important public health problem since it is the major cause of elevated morbidity and mortality globally. Previous works have shown that Mycobacterium tuberculosis (Mtb); the prime causative agent of the deadly disease has dormancy survival regulator (DosR) regulon, a two-component regulatory system which controls the transcription of more than 50 genes. However, the structure and detailed functions of these DosR regulated genes are largely undetermined. Out of many DosR regulon genes, Rv3131 gets up regulated in hypoxic conditions and was believed to encode for a nitroreductase flavoprotein. The utilization of mycobacteria-specific model systems has greatly added to our understanding of the molecular mechanisms involved in the life cycle and pathogenesis of Mtb.

Results
In this study the non-pathogenic mycobacterial model organism Mycobacterium smegmatis (Msmeg) was used to reveal the structure and function of MSMEG_3955; which is a homologue of Rv3131 from Mtb. Using chromatography and spectroscopy techniques it was revealed that cofactor flavin mononucleotide (FMN) was bound to flavoprotein MSMEG_3955. Consistent with the homology modelling predictions, Circular Dichroism (CD) analysis indicated that the MSMEG_3955 is composed of 39.3% α-helix and 24.9% β-pleated sheets. In contrast to the current notions, the enzymatic assays performed in the present study revealed that MSMEG_3955 was not capable of reducing nitro substrates but showed NADPH dependent FMN oxidoreductase activity. Also, gel permeation chromatography, dynamic light scattering and native acidic gels showed that MSMEG_3955 exists as a homotrimer. Furthermore, the presence of NADPH dependent FMN oxidoreductase and homotrimeric existence could be an alternative function of the protein to help the bacteria survive in dormant state or may be involved in other biochemical pathways.

Conclusion
MSMEG_3955 is a FMN bound flavoprotein, which exits as a trimer under in vitro conditions. There is no disulphide linkages in between the three protomers of the homotrimer MSMEG_3955. It has a NADPH dependent FMN oxidoreductase activity.
Urgent transcatheter aortic valve implantation in an all-comer population: a single-centre experience
Authors: Lux Arpad , Veenstra Leo F. , Kats Suzanne , Dohmen Wim , Maessen Jos G. , van ’t Hof Arnoud W. J. , Maesen Bart 
Published: November 2021

Abstract
Background
When compared with older reports of untreated symptomatic aortic valve stenosis (AoS), urgent transcatheter aortic valve implantation (u-TAVI) seems to improve mortality rates. We performed a single centre, retrospective cohort analysis to characterize our u-TAVI population and to identify potential predictors of worse outcomes.

Methods
We performed a retrospective analysis of 631 consecutive TAVI patients between 2013 and 2018. Of these patients, 53 were categorized as u-TAVI. Data was collected from the local electronic database.

Results
Urgent patients had more often a severely decreased left ventricular ejection fraction (LVEF < 30%) and increased creatinine levels (115.5 [88–147] vs 94.5 [78–116] mmol/l; p = 0.001). Urgent patients were hospitalised for 18 [10–28] days before and discharged 6 [4–9] days after the implantation. The incidence of peri-procedural complications and apical implantations was comparable among the study groups. Urgent patients had higher in-hospital (11.3% vs 3.1%; p = 0.011) and 1-year mortality rates (28.2% vs 8.5%, p < 0.001). An increased risk of one-year mortality was associated with urgency (HR 3.5; p < 0.001), apical access (HR 1.9; p = 0.016) and cerebrovascular complications (HR 4.3; p = 0.002). Within the urgent group, the length of pre-hospital admission was the only significant predictor of 1-year mortality (HR 1.037/day; p = 0.003).

Conclusions
Compared to elective procedures, u-TAVI led to increased mortality and comparable complication rates. This detrimental effect is most likely related to the length of pre-procedural hospitalisation of urgent patients.
Impact of anemia on in-stent restenosis after percutaneous coronary intervention
Authors: Hu Huilin , Wang Shijun , Tang Guanmin , Zhai Changlin , Shen Liang 
Published: November 2021

Abstract
Background
Anemia is a common risk factor for post-percutaneous coronary intervention (PCI) adverse events; however, data on its association with in-stent restenosis (ISR) is limited.

Methods
538 patients who underwent PCI between January 2017 and September 2019 and follow-up angiography 9–12 months after the initial PCI were enrolled in this study. Baseline clinical and procedural characteristics were compared between the ISR and non-ISR groups, and independent predictors of ISR were determined using propensity score matching.

Results
The incidence of anemia was 53.5% in patients with ISR and 19.0% in those without ISR. Univariable logistic regression analyses showed that anemia (OR, 4.283; 95% CI, 1.949–9.410; P < 0.001), diabetes mellitus (OR, 2.588; 95% CI, 1.176–5.696; P = 0.018), chronic kidney disease (OR, 3.058; 95% CI, 1.289–7.252; P = 0.011), multiple stenting (OR, 2.592; 95% CI, 1.205–5.573; P = 0.015), bifurcation lesion (OR, 2.669; 95% CI, 1.236–5.763; P = 0.012), and calcification (OR, 3.529; 95% CI, 1.131–11.014; P = 0.030) were closely associated with ISR. Low-density lipoprotein cholesterol (LDL-c) levels and stent diameter were also significantly linked to ISR, as was anemia (P = 0.009) after propensity score matching.

Conclusion
Anemia is closely associated with post-PCI ISR, and patients with lower hemoglobin levels are at a higher risk of ISR.
Impact of the COVID-19 pandemic on symptoms of anxiety and depression and health-related quality of life in older patients with chronic kidney disease
Authors: Voorend C. G. N. , van Oevelen M. , Nieberg M. , Meuleman Y. , Franssen C. F. M. , Joosten H. , Berkhout-Byrne N. C. , Abrahams A. C. , Mooijaart S. P. , Bos W. J. W. , van Buren M. ,   on behalf of the POLDER investigators, van Alphen Arjan , Berkhout-Byrne Noeleen , van Breda G. F. , van Buren Marjolijn , Boom Henk , Bos Willem Jan , Diepenbroek Adry , Emmelot-Vonk Marielle , Franssen Casper , Gaillard Carlo A. J. M. , Groeneweg-Peeters Nel , Hoekstra Bettie , Hommes Nienke , Hoornaar Francoise , Joosten Hanneke , Lagro Joep , Litjens Elisabeth , Molenaar Femke , Mooijaart Simon P. , Neradova Aegida , Peters Mike , Veldman Wilma , Voorend Carlijn , Westerbos Lidwien , Westerman-van der Wijden Carlijne , Wierdsma Judith 
Published: November 2021

Abstract
Background
Older patients with advanced chronic kidney disease are at increased risk for a severe course of the coronavirus disease-2019 (COVID-19) and vulnerable to mental health problems. We aimed to investigate prevalence and associated patient (demographic and clinical) characteristics of mental wellbeing (health-related quality of life [HRQoL] and symptoms of depression and anxiety) before and during the COVID-19 pandemic in older patients with advanced chronic kidney disease.

Methods
An ongoing Dutch multicentre prospective cohort study enrols patients of ≥70 years with an eGFR < 20 mL/min/1.73m2 from October 2018 onward. With additional questionnaires during the pandemic (May–June 2020), disease-related concerns about COVID-19 and general anxiety symptoms were assessed cross-sectionally, and depressive symptoms, HRQoL, and emotional symptoms longitudinally.

Results
The 82 included patients had a median age of 77.5 years (interquartile range 73.9–82.1), 77% were male and none had tested positive for COVID-19. Cross-sectionally, 67% of the patients reported to be more anxious about COVID-19 because of their kidney disease, and 43% of the patients stated that their quality of life was reduced due to the COVID-19 pandemic. Compared to pre-COVID-19, the presence of depressive symptoms had increased (11 to 22%; p = .022) and physical HRQoL declined (M = 40.4, SD = 10.1 to M = 36.1, SD = 10.4; p < .001), particularly in males. Mental HRQoL (M = 50.3, SD = 9.6 to M = 50.4, SD = 9.9; p = .913) and emotional symptoms remained similar.

Conclusions
Older patients with advanced chronic kidney disease suffered from disease-related anxiety about COVID-19, increased depressive symptoms and reduced physical HRQoL during the COVID-19 pandemic. The impact of the pandemic on this vulnerable patient group extends beyond increased mortality risk, and awareness of mental wellbeing is important.

Trial registration
The study is registered at the Netherlands Trial Register (NTR), trial number NL7104. Date of registration: 06-06-2018.
Factors associated with mobility decrease leading to disability: a cross-sectional nationwide study in Japan, with results from 8681 adults aged 20-89 years
Authors: Yamada Keiko , Yamaguchi Satoshi , Ito Yoichi M. , Ohe Takashi 
Published: November 2021

Abstract
Background
Mobility decrease leading to disability can gradually develop during early life, however, its related factors are not well clarified. Therefore, we investigate the related factors of mobility decrease at various levels, using nationwide data in Japan.

Methods
In total, 8681 independent community dwellers aged 20-89 years were analysed (average age, 51.6 years; 58.5% women). Three stages of mobility decrease were based on the locomotive syndrome risk test: Stage 1, emerging; Stage 2, progressing; Stage 3, progressed to restrict social engagement. Age was analysed using a simple quadratic function model.

Results
The prevalence of Stages 1-3 was 31.6% (n = 2746), 5.8% (n = 504), and 3.2% (n = 278), respectively. On the multivariable logistic regression, increased age in participants aged ≥40 years (stage 1: odds ratio[OR] 1.05-1.20, stage 2: OR 1.04-1.22, stage 3: OR 1.05-1.22), female (stage 1: OR 2.28, 95% confidence interval [CI] 1.99-2.61, stage 2: OR 2.40, 95% CI 1.77-3.25, stage 3: OR 1.80, 95% CI 1.19-2.72), overweight status (stage 1: OR 1.56, 95% CI 1.34-1.82, stage 2: OR 3.19, 95% CI 2.38-4.27, stage 3: OR 2.87, 95% CI 1.90-4.32), hypertension (stage 1: OR 1.20, 95% CI 1.01-1.41, stage 2: OR 1.99, 95% CI 1.49-2.64, stage 3: OR 2.10, 95% CI 1.44-3.05), and diabetes mellitus (stage 1: OR 1.62, 95% CI 1.17-2.24, stage 2: OR 1.57, 95% CI 0.93-2.66, stage 3: OR 2.10, 95% CI 1.13-3.90) were positively associated. The frequency of physical activity/sports, even a few per month, was inversely associated with all stages (stage 1: OR 0.59-0.72, stage 2: OR 0.50-0.67, stage 3: 0.36-0.53). A one-year increase in age had a stronger impact on mobility decrease in older adults than in younger ones. Increased age in participants aged < 40 years and smoking were associated with Stage 1, while intake of various foods was inversely associated with Stages 1 and 2.

Conclusion
Increased age (< 40 years) was associated with emerging mobility decrease, while that (≥ 40 years) was associated with any levels of mobility decrease. Female, lifestyle habits, including physical activities and overweight status, were associated with mobility decrease at every level.
Adenocarcinoma in situ and minimally invasive adenocarcinoma in lungs of smokers: image feature differences from those in lungs of non-smokers
Authors: Sugawara Haruto , Watanabe Hirokazu , Kunimatsu Akira , Abe Osamu , Watanabe Shun-ichi , Yatabe Yasushi , Kusumoto Masahiko 
Published: November 2021

Abstract
Purpose
We aimed to examine the characteristics of imaging findings of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) in the lungs of smokers compared with those of non-smokers.

Materials and methods
We included seven cases of AIS and 20 cases of MIA in lungs of smokers (pack-years ≥ 20) and the same number of cases of AIS and MIA in lungs of non-smokers (pack-years = 0). We compared the diameter of the entire lesion and solid component measured on computed tomography (CT) images, pathological size and invasive component diameter measured from pathological specimens, and CT values of the entire lesion and ground-glass opacity (GGO) portions between the smoker and non-smoker groups.

Results
The diameters of AIS and MIA on CT images and pathological specimens of the smoker group were significantly larger than those of the non-smoker group (p = 0.036 and 0.008, respectively), whereas there was no significant difference in the diameter of the solid component on CT images or invasive component of pathological specimens between the two groups. Additionally, mean CT values of the entire lesion and GGO component of the lesions in the smoker group were significantly lower than those in the non-smoker group (p = 0.036 and 0.040, respectively).

Conclusion
AIS and MIA in smoker’s lung tended to have larger lesion diameter and lower internal CT values compared with lesions in non-smoker’s lung. This study calls an attention on smoking status in CT-based diagnosis for early stage adenocarcinoma.
Patient experience of lasting negative effects of psychological interventions for anxiety and depression in secondary mental health care services: a national cross-sectional study
Authors: McQuaid Aisling , Sanatinia Rahil , Farquharson Lorna , Shah Prisha , Quirk Alan , Baldwin David S. , Crawford Mike 
Published: November 2021

Abstract
Background
Patients who undergo psychological treatment can report both negative and positive effects, but evidence of factors influencing the likelihood of negative effects is limited.

Aims
To identify aspects of the organisation and delivery of secondary care psychological treatment services that are associated with patient experiences of negative effects.

Method
Cross-sectional survey of people with anxiety and depression who ended psychological treatment delivered by 50 NHS trusts in England. Respondents were asked about how their treatment was organised and delivered and whether they experienced lasting negative effects.

Results
Of 662 respondents, 90 (14.1%) reported experiencing lasting negative effects. People over the age of 65 were less likely than younger respondents to report negative effects. There was an association between reporting neutral or negative effects and not being referred at what respondents considered to be the right time (OR = 1.712, 95% CI = 1.078–2.726), not receiving the right number of sessions (OR = 3.105, 95% CI = 1.934–4.987), and not discussing progress with their therapist (OR 2.063, 95% CI = 1.290–3.301).

Conclusions
One in seven patients who took part in this survey reported lasting negative effects from psychological treatment. Steps should be taken to prepare people for the potential for negative experiences of treatment, and progress reviewed during therapy in an effort to identify and prevent negative effects.
How can the utilisation of help for mental disorders be improved? A quasi-experimental online study on the changeability of stigmatising attitudes and intermediate variables in the process of utilisation
Authors: McLaren Thomas , Peter Lina-Jolien , Tomczyk Samuel , Muehlan Holger , Stolzenburg Susanne , Schomerus Georg , Schmidt Silke 
Published: November 2021

Abstract
Background
Epidemiological studies show that even in highly developed countries many people with depression do not seek help for their mental health issues, despite promising prevention approaches encouraging people to seek help and reduce self-stigma. Therefore, an anti-stigma intervention study to support help-seeking behaviour will be developed on the basis of the newly explicated “Seeking Mental Health Care Model”.

Methods
A quasi-experimental online study will be carried out to assess the effect of different intervention variables relevant for the help-seeking process. The study is conceived as a fractional factorial design. Participants will be screened for depressive complaints (PHQ-9 sum score ≥ 8) and current psychiatric/psychotherapeutic treatment. After baseline assessment the participants will be randomly allocated into one of the 24 study groups receiving different combinations of the vignette-based intervention aiming to reduce stigma and support help-seeking. Next, relevant outcome measures will be administered a second time. In a 3- and 6-month follow-up help-seeking behaviour will be measured. Gamified elements and avatar-choice techniques will be used to heighten study immersion and adherence.

Discussion
On the basis of the project results, promising research and intervention perspectives can be developed. Results, firstly, allow for a more detailed empirical investigation and conceptualisation of the stages of mental health care utilisation, as well as an examination of theoretical approaches to stigmatisation. Secondly, our online study could provide insights for an evidence-based design and evaluation of online interventions for people with a mental illness.

Trial registration
German Clinical Trials Register: DRKS00023557. Registered 11 December 2020. World Health Organization, Universal Trial Number: U1111–1264-9954. Registered 16 February 2021.