bluuebunny/crossref_metadata_2025 huggingface dataset:
A mexicana Myriam Moscona e a renovação do judeu espanhol: ladino e português em proximidade.
Authors: Paraizo Wedja Maria do , Amâncio Moacir
Published: October 2021

O judeu espanhol, ou ladino, idioma dos judeus sefarditas fixados no antigo Império Otomano, após a expulsão dos judeus da Espanha. O idioma, hoje popularizado pela Internet, que confere visibilidade à atuação de seus falantes e pesquisadores, com realização de eventos que contam com a presença de especialistas e herdeiros da cultura judaica provenientes da Ibéria. Ao mesmo tempo, surgem textos que retomam a tradição do ladino em prosa e verso. A poeta mexicana Myriam Moscona é uma das autoras que se destacam nesse movimento de memória e renovação cultural verificado em diversos países.
Clinical Characteristics, Management Strategies, and Outcomes of Non–ST‐Segment–Elevation Myocardial Infarction Patients With and Without Prior Coronary Artery Bypass Grafting
Authors: Shoaib Ahmad , Rashid Muhammad , Berry Colin , Curzen Nick , Kontopantelis Evangelos , Timmis Adam , Ahmad Ayesha , Kinnaird Tim , Mamas Mamas A.
Published: October 2021

Background

There are limited data on the management strategies, temporal trends and clinical outcomes of patients who present with non–ST‐segment–elevation myocardial infarction and have a prior history of CABG.

Methods and Results

We identified 287 658 patients with non–ST‐segment–elevation myocardial infarction between 2010 and 2017 in the United Kingdom Myocardial Infarction National Audit Project database. Clinical and outcome data were analyzed by dividing into 2 groups by prior history of coronary artery bypass grafting (CABG): group 1, no prior CABG (n=262 362); and group 2, prior CABG (n=25 296). Patients in group 2 were older, had higher GRACE (Global Registry of Acute Coronary Events) risk scores and burden of comorbid illnesses. More patients underwent coronary angiography (69% versus 63%) and revascularization (53% versus 40%) in group 1 compared with group 2. Adjusted odds of receiving inpatient coronary angiogram (odds ratio [OR], 0.91; 95% CI, 0.88–0.95;
P
<0.001) and revascularization (OR, 0.73; 95% CI, 0.70–0.76;
P
<0.001) were lower in group 2 compared with group 1. Following multivariable logistic regression analyses, the OR of in‐hospital major adverse cardiovascular events (composite of inpatient death and reinfarction; OR, 0.97; 95% CI, 0.90–1.04;
P
=0.44), all‐cause mortality (OR, 0.96; 95% CI, 0.88–1.04;
P
=0.31), reinfarction (OR, 1.02; 95% CI, 0.89–1.17;
P
=0.78), and major bleeding (OR, 1.01; 95% CI, 0.90–1.11;
P
=0.98) were similar across groups. Lower adjusted risk of inpatient mortality (OR, 0.67; 95% CI, 0.46–0.98;
P
=0.04) but similar risk of bleeding (OR,1.07; CI, 0.79–1.44;
P
=0.68) and reinfarction (OR, 1.13; 95% CI, 0.81–1.57;
P
=0.47) were observed in group 2 patients who underwent percutaneous coronary intervention compared with those managed medically.

Conclusions

In this national cohort, patients with non–ST‐segment–elevation myocardial infarction with prior CABG had a higher risk profile, but similar risk‐adjusted in‐hospital adverse outcomes compared with patients without prior CABG. Patients with prior CABG who received percutaneous coronary intervention had lower in‐hospital mortality compared with those who received medical management.
Favorable Atrial Remodeling After Percutaneous Pulmonary Valve Implantation and Its Association With Changes in Exercise Capacity and Right Ventricular Function
Authors: Latus Heiner , Born Danik , Shehu Nerejda , Stern Heiko , Hager Alfred , Georgiev Stainimir , Tanase Daniel , Meierhofer Christian , Ewert Peter , Eicken Andreas , Tutarel Oktay
Published: October 2021

Background

Right atrial (RA) dilatation and impaired right ventricular (RV) filling are common in patients with RV outflow tract dysfunction. We aimed to study potential correlations between atrial function with clinically relevant hemodynamic parameters and to assess the predictive impact of atrial performance on the recovery of exercise capacity and RV pump function after percutaneous pulmonary valve implantation (PPVI).

Methods and Results

Altogether, 105 patients with right ventricular outflow tract dysfunction (median age at PPVI, 19.2 years; range, 6.2–53.4 years) who underwent cardiac magnetic resonance imaging before and 6 months after PPVI were included. RA and left atrial maximal and minimal volumes as well as atrial passive and active emptying function were assessed from axial cine slices. RA emptying function was inversely related to invasive RV end‐diastolic pressure, and RA passive emptying correlated significantly with peak oxygen uptake. After PPVI, a significant decrease in RA minimum volume was observed, whereas RA passive emptying function improved, and RA active emptying function decreased significantly. Patients with predominant right ventricular outflow tract stenosis showed more favorable changes in RA active and left atrial passive emptying than those with primary volume overload. None of the RA and left atrial emptying parameters was predictive for recovery of peak oxygen uptake or RV ejection fraction.

Conclusions

In patients with right ventricular outflow tract dysfunction, impaired RA emptying assessed by cardiac magnetic resonance imaging was associated with increased RV filling pressures and lower exercise capacity. PPVI leads to a reduction in RA size and improved passive RA emptying function. However, RA function was not associated with improved exercise performance and RV pump function.
Long‐Term Exposure to Air Pollution, Road Traffic Noise, and Heart Failure Incidence: The Danish Nurse Cohort
Authors: Lim Youn‐Hee , Jørgensen Jeanette T. , So Rina , Cole‐Hunter Tom , Mehta Amar J. , Amini Heresh , Bräuner Elvira V. , Westendorp Rudi G. J. , Liu Shuo , Mortensen Laust H. , Hoffmann Barbara , Loft Steffen , Ketzel Matthias , Hertel Ole , Brandt Jørgen , Jensen Steen Solvang , Backalarz Claus , Simonsen Mette K. , Tasic Nebojsa , Maric Matija , Andersen Zorana J.
Published: October 2021

Background

We examined the association of long‐term exposure to air pollution and road traffic noise with incident heart failure (HF).

Methods And Results

Using data on female nurses from the Danish Nurse Cohort (aged >44 years), we investigated associations between 3‐year mean exposures to air pollution and road traffic noise and incident HF using Cox regression models, adjusting for relevant confounders. Incidence of HF was defined as the first hospital contact (inpatient, outpatient, or emergency) between cohort baseline (1993 or 1999) and December 31, 2014, based on the Danish National Patient Register. Annual mean levels of particulate matter with a diameter <2.5 µm since 1990 and NO
2
and road traffic noise since 1970 were estimated at participants' residences. Of the 22 189 nurses, 484 developed HF. We detected associations with all 3 pollutants, with hazard ratios (HRs) of 1.17 (95% CI, 1.01–1.36), 1.10 (95% CI, 0.99–1.22), and 1.12 (95% CI, 0.99–1.26) per increase of 5.1 µg/m
3
in particulate matter with a diameter <2.5 µm, 8.6 µg/m
3
in NO
2
, and 9.3 dB in road traffic noise, respectively. We observed an enhanced risk of HF incidence for those exposed to high levels of the 3 pollutants; however, the effect modification of coexposure was not statistically significant. Former smokers and nurses with hypertension showed the strongest associations with particulate matter with a diameter <2.5 µm (
P
effect modification
<0.05).

Conclusions

We found that long‐term exposures to air pollution and road traffic noise were independently associated with HF.
Vascular Stiffening Mediated by Rho‐Associated Coiled‐Coil Containing Kinase Isoforms
Authors: Li Yuxin , Tai Haw‐Chih , Sladojevic Nikola , Kim Hyung‐Hwan , Liao James K.
Published: October 2021

Background

The pathogenesis of vascular stiffening and hypertension is marked by non‐compliance of vessel wall because of deposition of collagen fibers, loss of elastin fibers, and increased vascular thickening. Rho/Rho‐associated coiled‐coil containing kinases 1 and 2 (ROCK1 and ROCK2) have been shown to regulate cellular contraction and vascular remodeling. However, the role of ROCK isoforms in mediating pathogenesis of vascular stiffening and hypertension is not known.

Methods and Results

Hemizygous
Rock
mice (
Rock1
+/−
and
Rock2
+/−
) were used to determine the role of ROCK1 and ROCK2 in age‐related vascular dysfunction. Both ROCK activity and aortic stiffness increased to a greater extent with age in wild‐type mice compared with that of
Rock1
+/−
and
Rock2
+/−
mice. As a model for age‐related vascular stiffening, we administered angiotensin II (500 ng/kg per minute) combined with nitric oxide synthase inhibitor, L‐N
ω
‐nitroarginine methyl ester (0.5 g/L) for 4 weeks to 12‐week‐old male
Rock1
+/−
and
Rock2
+/−
mice. Similar to advancing age, angiotensin II/L‐N
ω
‐nitroarginine methyl ester caused increased blood pressure, aortic stiffening, and vascular remodeling, which were attenuated in
Rock2
+/−
, and to a lesser extent,
Rock1
+/−
mice. The reduction of aortic stiffening in
Rock2
+/−
mice was accompanied by decreased collagen deposition, relatively preserved elastin content, and less aortic wall hypertrophy. Indeed, the upregulation of collagen I by transforming growth factor‐β1 or angiotensin II was greatly attenuated in
Rock2
−/−
mouse embryonic fibroblasts.

Conclusions

These findings indicate that ROCK1 and ROCK2 mediate both age‐related and pharmacologically induced aortic stiffening, and suggest that inhibition of ROCK2, and to a lesser extent ROCK1, may have therapeutic benefits in preventing age‐related vascular stiffening.
DNA metabarcoding reveals fine scale geographical differences of consumed algae in the Galápagos marine iguanas (Amblyrhynchus cristatus)
Authors: Anslan Sten , Dalgo Denisse , Reinhardt Timm , Peñafiel Nicolás , Guayasamin Juan , Páez-Rosas Diego , Vences Miguel , Steinfartz Sebastian
Published: October 2021

Galápagos marine iguanas are primarily associated with the marine environment and show special nutritional adaptations. They are the only lizards worldwide that forage on marine macroalgae. Until now, consumed algae have been identified by direct observations during their feeding activities and microscopic identification in faeces samples. In this study, we use a novel DNA metabarcoding approach to identify consumed algal species from the faeces of marine iguanas. We developed primers for the ribulose-bisphosphate carboxylase (rbcL) gene and applied a metabarcoding approach to 25 individual faeces samples collected in four representative sites of two subspecies (Amblyrhynchus cristatus mertensi and A. c. godzilla), found in the San Cristóbal Island. We detected 18 consistently occurring macroalgal operational taxonomic units (OTUs). Most of the OTUs were assigned to Rhodophyta (red algae) and only one OTU to Chlorophyta (green algae). Despite the number of consumed algal species did not differ between two subspecies (OTU richness; P = 0.383), diet overlap level between A. c. mertensi and A. c. godzilla was low (Schoener index = 0.345), suggesting that both subspecies consumed different algal species in their natural environment. Further studies are needed to understand whether the difference of consumed algae reflects disparities in the abundance of algal species between sites, or whether iguanas of the two genetically differentiated subspecies prefer distinct algal species.
Phasmarhabditis quinamensis sp. n. (Nematoda: Rhabditidae) from tropical terrestrial gastropods in southern Vietnam
Authors: Ivanova Elena S. , Spiridonov Sergei E.
Published: October 2021

Phasmarhabditis quinamensis sp. n. was recovered from several tropical terrestrial gastropod species collected in Cat Tien National Park in southern Vietnam with the snail, Sesara sp., designated as the type host. Phasmarhabditis quinamensis sp. n. is recognised by males and females with a lip region set off by the circle of six triangular low probolae, three bilobed, separated lips, stoma nearly as wide as long, the first genital papilla in males not incorporated into the bursa, the ensheathed dauer juveniles more than 1 mm long and with two circles of papillae at the head end and prominent amphidial apertures, a long filamentous tail and, when exsheathed, with a short, conical tail ending with two tiny spikes. The head structure of P. quinamensis sp. n. differentiates it from all nominal species of Phasmarhabditis. Phasmarhabditis quinamensis sp. n. is the second species of the genus found in Cat Tien National Park. The sympatric species P. meridionalis was also found during the present study. Phylogenetically, both species belong to different lineages within Phasmarhabditis. The molecular analysis based on partial sequences of LSU rDNA, and ITS rDNA regions showed P. kenyaensis to be the closest species to P. quinamensis sp. n.
Heterodera amaranthusiae n. sp. (Nematoda: Heteroderidae), a new cyst nematode parasitising Amaranthus retroflexus L. in China
Authors: Jiang Ru , Hu Xianqi , Li Yunqing , Bian Yong , Huang Liqiang , Gu Jianfeng , Liu Pei , Huang Wenkun , Kong Lingan , Liu Shiming , Peng Huan , Peng Deliang
Published: October 2021

A new species of cyst-forming nematode, Heterodera amaranthusiae n. sp., is described and illustrated from the weed, Amaranthus retroflexus, in a potato field in Yunnan Province, China. It is characterised by having canary to russet-brown and asymmetric lemon-shaped cyst, distinct neck, bifenestrate vulval cone, relatively short vulval slit of 29 (28-32) μm, bullae absent and underbridge absent or weak if present. Second-stage juveniles are characterised by a well-developed stylet of 23 (22-25) μm with robust shaft and basal knobs concave anteriorly, tail conoid, 51 (48-58) μm long and hyaline region comprising 48 (41-53)% of its length. Morphologically and morphometrically it most resembles H. vallicola in the Humuli group. The ITS, 28S and COI gene sequences of H. amaranthusiae n. sp. clearly differentiate it from other Heterodera species. For diagnostic purposes, restriction enzyme analysis of the ITS region and three restriction enzymes, AluI, BsuRI (HaeIII) and CfoI (HhaI), were selected, clearly distinguishing H. amaranthusiae n. sp. from representative species in the Humuli group. Phylogenetic relationships with other species of the genus, inferred from two ribosomal regions and the cytochrome oxidase c subunit 1 region, based on Bayesian analysis, consistently showed that H. amaranthusiae n. sp. clustered with high support with other Humuli group species but with separate species status.
The taxonomy of spider crabs of the genera Eurynome, Choniognathus, Seiitaiodes and Kasagia (Crustacea: Brachyura: Majidae) from southwest Indian Ocean
Authors: DE FORGES BERTRAND RICHER , LEE BEE YAN , NG PETER K. L.
Published: October 2021

The taxonomy of majid spider crabs collected from recent southwest Indian Ocean cruises belonging to Eurynome Leach, 1814, and allied genera is treated. Eurynome longimana Stimpson, 1857, long synonymised with the European E. aspera (Pennant, 1777), is here recognised as a distinct species. Stimpson’s (1857) species can be distinguished by the armature of granules on the third maxilliped, proportions and armature of the ambulatory merus, relatively shorter ambulatory dactylus, structure of the male sternopleonal cavity and relative proportions of the male first gonopod. The composition of Choniognathus Rathbun, 1932, is discussed and the type species, C. koreensis Rathbun, 1932, is figured. One species, C. verhoeffi (Balss, 1929), is not considered to be a member of Choniognathus and its taxonomy is discussed. A new spinose species, C. spinosus, is also described. Seiitaoides Griffin & Tranter, 1986, is revised, and two new species, S. mirabilis and S. kabuto, are described and compared with S. orientalis (Sakai, 1961) and S. stimpsoni (Miers, 1884). The poorly known Eurynome elegans Stebbing, 1921 is rediscovered, its taxonomy clarified and the species is shown to belong to Kasagia Richer de Forges & Ng, 2007. A second species of Kasagia, K. sudhakari Padate, Manjebrayakath & Ng, 2019, recently described from the Arabian Sea is recorded from southwest Indian Ocean.
Machine learning predictive models of LDL-C in the population of eastern India and its comparison with directly measured and calculated LDL-C
Authors: P P Anudeep , Kumari Suchitra , Rajasimman Aishvarya S , Nayak Saurav , Priyadarsini Pooja
Published: October 2021

Background

LDL-C is a strong risk factor for cardiovascular disorders. The formulas used to calculate LDL-C showed varying performance in different populations. Machine learning models can study complex interactions between the variables and can be used to predict outcomes more accurately. The current study evaluated the predictive performance of three machine learning models—random forests, XGBoost, and support vector Rregression (SVR) to predict LDL-C from total cholesterol, triglyceride, and HDL-C in comparison to linear regression model and some existing formulas for LDL-C calculation, in eastern Indian population.

Methods

The lipid profiles performed in the clinical biochemistry laboratory of AIIMS Bhubaneswar during 2019–2021, a total of 13,391 samples were included in the study. Laboratory results were collected from the laboratory database. 70% of data were classified as train set and used to develop the three machine learning models and linear regression formula. These models were tested in the rest 30% of the data (test set) for validation. Performance of models was evaluated in comparison to best six existing LDL-C calculating formulas.

Results

LDL-C predicted by XGBoost and random forests models showed a strong correlation with directly estimated LDL-C (r = 0.98). Two machine learning models performed superior to the six existing and commonly used LDL-C calculating formulas like Friedewald in the study population. When compared in different triglycerides strata also, these two models outperformed the other methods used.

Conclusion

Machine learning models like XGBoost and random forests can be used to predict LDL-C with more accuracy comparing to conventional linear regression LDL-C formulas.
Multi‐institutional Study of Otolaryngology Resident Intraoperative Experiences for Key Indicator Procedures
Authors: Chen Jenny X. , Deng Francis , Filimonov Andrey , Shuman Elizabeth A. , Marchiano Emily , George Brian C. , Thorne Marc , Pletcher Steven D. , Platt Michael , Teng Marita S. , Kozin Elliott D. , Gray Stacey T.
Published: October 2021

Objective

There is concern that current otolaryngology residents may not receive adequate surgical training. We aimed to characterize residents’ surgical experiences at 5 academic centers performing the 14 key indicator procedures (KIPs) outlined by the Accreditation Council for Graduate Medical Education.

Study Design

Prospective study.

Setting

Five otolaryngology training programs.

Methods

Data were gathered from December 2019 to December 2020 with a smartphone application from the Society for Improving Medical Professional Learning. After each operation, residents and faculty rated trainee autonomy on a 4‐level Zwisch scale and performance on a 5‐level modified Dreyfus scale.

Results

Residents and attendings (n = 92 and 78, respectively) logged 2984 evaluations. Attending ratings of resident autonomy and performance increased with training level (P < .001). Resident self‐assessments of autonomy and performance were lower than paired attending assessments (P < .001). Among attending evaluations of KIPs performed by senior residents (postgraduate year 4 or 5), 55% of cases were performed with meaningful autonomy (passive help or supervision only). Similarly, attendings rated 55% of these cases as a practice‐ready or exceptional performance. Senior residents had meaningful autonomy for ≥50% of cases for most KIPs, with the exception of flaps and grafts (40%), pediatric/adult airway (39%), and stapedectomy/ossiculoplasty (33%). Similarly, senior residents received practice‐ready or exceptional performance ratings for ≥50% of cases across all KIPs other than pediatric/adult airway (42%) and stapedectomy/ossiculoplasty (33%).

Conclusion

In this multicenter study, resident surgical autonomy and performance varied across otolaryngology KIPs. The development of nationwide benchmarks will help programs and residents set educational goals.

Level of evidence

2.
Exploring Aromatic Medicinal Compounds for the Treatment of Amyotrophic Lateral Sclerosis
Authors: Shah Fahad Hassan , Kim Song Ja
Published: October 2021

Purpose: Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative condition, in which motor neurons start to degenerate due to the accumulation of protein aggregates in the neuron cytoplasm. The formation of aggregates causes neurotoxicity, facilitated by the N-terminal domain (NTD) of the transactive response DNA-binding protein-43 (TDP-43). Therapies used to treat ALS manage secondary symptoms, but do not stop the activity of the rogue NTD domain of TDP-43. Therefore, new drug candidates should be designed to deal efficiently with this disease by inhibiting the domains involved in the development of ALS. This study determined the chemical affinity of aromatic medicinal compounds with NTD. Screening of 1323 medicinal compounds was conducted with PYRX 0.9 software against NTD. Compounds obtained from this analysis were further used to predict absorption, distribution, metabolism, excretion, and toxic (ADMET) properties and their effect on major gene targets of ALS. Results: From 1300 + compounds, acetovanillone showed binding affinity for NTD and had good ADMET and drug likeness attributes. This compound reduced the expression of CXCL2, NOP56, and SOD1 genes implicated in ALS pathogenesis. Conclusion: These results concluded that acetovanillone is a candidate drug for in vitro and clinical studies into the exploitation of drugs within ALS therapeutics.
Exploring the relationship between the usability of a goal-oriented mobile health application and non-usage attrition in patients with multimorbidity: A blended data analysis approach
Authors: Tahsin Farah , Tracy Shawn , Chau Edward , Harvey Sarah , Loganathan Mayura , McKinstry Brian , Mercer Stewart W , Nie Jason , Ramsay Tim , Thavorn Kednapa , Palen Ted , Sritharan Jasvinei , Steele Gray Carolyn
Published: October 2021

Background

Mobile health applications are increasingly used to support the delivery of health care services to a variety of patients. Based on data obtained from a pragmatic trial of the electronic Patient Reported Outcome (ePRO) app designed to support goal-oriented care primary care, this study aims to (1) examine how patient-reported usability changed over the one-year intervention period, and (2) explore participant attrition rate of the electronic Patient Reported Outcome app over one year study period.

Methods

We performed a secondary analysis of 44 older adults with complex chronic needs enrolled in the electronic Patient Reported Outcome-digital health intervention. App usage and attrition were measured using device-generated usage logs; usability was measured using the patient-reported post-study system usability questionnaire collected at 3, 6, 9, and 12 months. Research memos were used to interpret potential contextual contributing factors to patients’ overall usage and usability score pattern. A data triangulation method of both quantitative and qualitative data was used to analyze and interpret study findings.

Results

While there was gradual attrition in the use of the ePRO app, patients’ usability scores remained consistent throughout the study period. Qualitative memos suggested patients’ encounters with technical difficulties and relationship dynamics with primary providers influenced patients’ adherence to the ePRO app.

Conclusion

This study highlights that the patient–provider relationship is a key determining factor that influences complex patients’ continued engagement with a Mobile health app. The finding calls attention to the measurement of usability of a Mobile health app, its impact on attrition, and contributing factors that influence patients’ attrition. Trial registration: Clinicaltrials.gov Identified NCT02917954.
A CIBERSORTx-based immune cell scoring system could independently predict the prognosis of patients with myelodysplastic syndromes
Authors: Wang Yu-Hung , Hou Hsin-An , Lin Chien-Chin , Kuo Yuan-Yeh , Yao Chi-Yuan , Hsu Chia-Lang , Tseng Mei-Hsuan , Tsai Cheng-Hong , Peng Yen-Ling , Kao Chein-Jun , Chou Wen-Chien , Tien Hwei-Fang
Published: October 2021

Aside from cell intrinsic factors such as genetic alterations, immune dysregulation in the bone marrow (BM) microenvironment plays a role in the development and progression of myelodysplastic syndromes (MDS). However, the prognostic implications of various immune cells in patients with MDS remain unclear. We adopted CIBERSORTx to estimate the relative fractions of 22 subtypes of immune cells in the BM of 316 patients with MDS and correlated the results with clinical outcomes. A lower fraction of unpolarized M0 macrophages and higher fractions of M2 macrophages and eosinophils were significantly associated with inferior survival. An immune cell scoring system (ICSS) was constructed based on the proportion of these 3 immune cells in the BM. The ICSS high-risk patients had higher BM blast counts, higher frequencies of poor-risk cytogenetics, and more NPM1, TP53, and WT1 mutations than intermediate- and low-risk patients. The ICSS could stratify patients with MDS into 3 risk groups with distinct leukemia-free survival and overall survival among the total cohort and in the subgroups of patients with lower and higher disease risk based on the revised International Prognostic Scoring System (IPSS-R). The prognostic significance of ICSS was also validated in another independent cohort. Multivariable analysis revealed that ICSS independently predicted prognosis, regardless of age, IPSS-R, and mutation status. Bioinformatic analysis demonstrated a significant correlation between high-risk ICSS and nuclear factor κB signaling, oxidative stress, and leukemic stem cell signature pathways. Further studies investigating the mechanistic insight into the crosstalk between stem cells and immune cells are warranted.
Graft rejection markers in children undergoing hematopoietic cell transplant for bone marrow failure
Authors: Sabulski Anthony , Myers Kasiani C. , Bleesing Jack J. , Duell Alexandra , Lane Adam , Teusink-Cross Ashley , Davies Stella M. , Jodele Sonata
Published: October 2021

Graft rejection (GR) is a poorly understood complication of hematopoietic cell transplant (HCT). GR risk factors are well published, but there are no reliable biomarkers or therapies known. Fever is the most common symptom of GR, but no study has evaluated fever kinetics as a diagnostic marker of GR. The objectives of this study were to identify mechanisms, biomarkers, and potential therapies for GR after HCT. Chemokine ligand 9 (CXCL9), B-cell activating factor (BAFF), and complement markers (sC5b-9, C3a, and C5a) were measured in 7 patients with GR and compared with 15 HCT controls. All patients had a diagnosis of aplastic anemia, Fanconi anemia, or genetically undefined chromosomal fragility syndrome. All patients with GR were febrile during GR; therefore, control patients who underwent HCT were matched for diagnosis and early fevers after HCT. Patients withh GR had significantly higher CXCL9, BAFF, and sC5b-9 at the time of fever and GR compared with control patients who underwent HCT at the time of fever. The maximum fever was significantly higher and occurred significantly later in the transplant course in patients with GR compared with febrile HCT controls. These data support the use of CXCL9, BAFF, sC5b-9, and fever kinetics as GR markers. Two patients with GR underwent a second HCT that was complicated by high fevers. Both patients received interferon and complement blockers during their second HCT, and both preserved their graft. These laboratory and clinical findings support larger studies to evaluate the safety and efficacy of interferon, complement, and BAFF inhibitors for the prevention and treatment of GR after HCT.
Orthopedic toxicities among adolescents and young adults treated in DFCI ALL Consortium Trials
Authors: Valtis Yannis K. , Stevenson Kristen E. , Place Andrew E. , Silverman Lewis B. , Vrooman Lynda M. , Gotti Giacomo , Brunner Andrew M. , Nauffal Mary , DeAngelo Daniel J. , Luskin Marlise R.
Published: October 2021

Adolescent and young adult patients with acute lymphoblastic leukemia (ALL) have superior outcomes when treated on pediatric regimens. Pediatric ALL regimens rely heavily on corticosteroids and asparaginase and are known to increase the risk of osteonecrosis (ON) and fractures in children, particularly adolescents. Orthopedic toxicity among young adults treated on pediatric-inspired regimens is not well described. Here, we report the symptomatic orthopedic toxicities of patients aged 15 to 50 years treated on sequential Dana-Farber Cancer Institute ALL Consortium protocols. Among 367 patients with a median age of 23 years (range, 15-50 years; 68% aged <30 years), 60 patients were diagnosed with ON (5-year cumulative incidence, 17%; 95% confidence interval [CI], 13-22), and 40 patients experienced fracture (5-year cumulative incidence, 12%; 95% CI, 8-15). Patients aged <30 years were significantly more likely to be diagnosed with ON (5-year cumulative incidence, 21% vs 8%; P = .004). Patients treated more recently on pegaspargase-based protocols were significantly more likely to be diagnosed with ON compared with those treated on earlier trials with native Escherichia coli asparaginase (5-year cumulative incidence, 24% vs 5%; P < .001). Of the 54 ON events for which adequate information was available, surgery was performed in 25 (46%). Patients with ON had superior overall survival (OS) compared with those without (multivariable OS hazard ratio, 0.15; 95% CI, 0.05-0.46; P = .001; ON included as a time-varying exposure). Increased rates of orthopedic toxicity in late-generation protocols may be driven by the pharmacokinetic drug interaction between pegaspargase and dexamethasone, leading to higher dexamethasone exposure.
Adoptive T-cell therapy for Hodgkin lymphoma
Authors: Ho Carrie , Ruella Marco , Levine Bruce L. , Svoboda Jakub
Published: October 2021

Although CAR T-cell therapy is US Food and Drug Administration–approved for B-cell non-Hodgkin lymphomas, the development of adoptive immunotherapy for the treatment of classic Hodgkin lymphoma (cHL) has not accelerated at a similar pace. Adoptive T-cell therapy with Epstein-Barr virus–specific cytotoxic T lymphocytes and CD30 CAR T cells have demonstrated significant clinical responses in early clinical trials of patients with cHL. Additionally, CD19 and CD123 CAR T cells that target the immunosuppressive tumor microenvironment in cHL have also been investigated. Here we discuss the landscape of clinical trials of adoptive immunotherapy for patients with cHL with a view toward current challenges and novel strategies to improve the development of CAR T-cell therapy for cHL.
Comparative transcriptomic analysis reveals gene regulation mediated by caspase activity in a chordate organism
Authors: Krasovec Gabriel , Karaiskou Anthi , Quéinnec Éric , Chambon Jean-Philippe
Published: October 2021

Background

Apoptosis is a caspase regulated cell death present in all metazoans defined by a conserved set of morphological features. A well-described function of apoptosis is the removal of excessive cells during development and homeostasis. Recent studies have shown an unexpected signalling property of apoptotic cells, affecting cell fate and/or behaviour of neighbouring cells. In contrast to the apoptotic function of cell elimination, this new role of apoptosis is not well understood but seems caspase-dependent. To deepen our understanding of apoptotic functions, it is necessary to work on a biological model with a predictable apoptosis pattern affecting cell fate and/or behaviour. The tunicate Ciona intestinalis has a bi-phasic life cycle with swimming larvae which undergo metamorphosis after settlement. Previously, we have shown that the tail regression step during metamorphosis, characterized by a predictable polarized apoptotic wave, ensures elimination of most tail cells and controls primordial germ cells survival and migration.

Results

We performed differential transcriptomic analysis between control metamorphosing larvae and larvae treated with the pan-caspase inhibitor Z-VAD-fmk in order to explore the transcriptional control of apoptotic cells on neighbouring cells that survive and migrate. When caspase activity was impaired, genes known to be involved in metamorphosis were downregulated along with other implicated in cell migration and survival molecular pathways.

Conclusion

We propose these results as a confirmation that apoptotic cells can control surrounding cells fate and as a reference database to explore novel apoptotic functions in animals, including those related to migration and differentiation.
Repertoire analysis of γδ T cells in the chicken enables functional annotation of the genomic region revealing highly variable pan-tissue TCR gamma V gene usage as well as identifying public and private repertoires
Authors: Dixon Robert , Preston Stephen G. , Dascalu Stefan , Flammer Patrik G. , Fiddaman Steven R. , McLoughlin Kirstie , Boyd Amy , Volf Jiri , Rychlik Ivan , Bonsall Michael B. , Kaspers Bernd , Smith Adrian L.
Published: October 2021

Background

Despite increasing interest in γδ T cells and their non-classical behaviour, most studies focus on animals with low numbers of circulating γδ T cells, such as mice and humans. Arguably, γδ T cell functions might be more prominent in chickens where these cells form a higher proportion of the circulatory T cell compartment. The TCR repertoire defines different subsets of γδ T cells, and such analysis is facilitated by well-annotated TCR loci. γδ T cells are considered at the cusp of innate and adaptive immunity but most functions have been identified in γδ low species. A deeper understanding of TCR repertoire biology in γδ high and γδ low animals is critical for defining the evolution of the function of γδ T cells. Repertoire dynamics will reveal populations that can be classified as innate-like or adaptive-like as well as those that straddle this definition.

Results

Here, a recent discrepancy in the structure of the chicken TCR gamma locus is resolved, demonstrating that tandem duplication events have shaped the evolution of this locus. Importantly, repertoire sequencing revealed large differences in the usage of individual TRGV genes, a pattern conserved across multiple tissues, including thymus, spleen and the gut. A single TRGV gene, TRGV3.3, with a highly diverse private CDR3 repertoire dominated every tissue in all birds. TRGV usage patterns were partly explained by the TRGV-associated recombination signal sequences. Public CDR3 clonotypes represented varying proportions of the repertoire of TCRs utilising different TRGVs, with one TRGV dominated by super-public clones present in all birds.

Conclusions

The application of repertoire analysis enabled functional annotation of the TCRG locus in a species with a high circulating γδ phenotype. This revealed variable usage of TCRGV genes across multiple tissues, a pattern quite different to that found in γδ low species (human and mouse). Defining the repertoire biology of avian γδ T cells will be key to understanding the evolution and functional diversity of these enigmatic lymphocytes in an animal that is numerically more reliant on them. Practically, this will reveal novel ways in which these cells can be exploited to improve health in medical and veterinary contexts.
Prevalence and factors associated with severe anaemia post-caesarean section at a tertiary Hospital in Southwestern Uganda
Authors: Sivahikyako Sylvie Atosa , Owaraganise Asiphas , Tibaijuka Leevan , Agaba David Collins , Kayondo Musa , Ngonzi Joseph , Mugisha Julius , Kanyesigye Hamson
Published: October 2021

Background

Severe anaemia after caesarean section adversely affects the woman and the new-born. While prenatal anaemia is extensively studied, the literature on post-caesarean section anaemia is limited and characteristics of women at the highest risk of developing severe anaemia after caesarean section are unknown. This study aimed to determine the prevalence and factors associated with severe anaemia on day three post caesarean section.

Methods

On the third day after caesarean section, women were consecutively enrolled in a cross-sectional study at Mbarara Regional Referral Hospital (MRRH). Women who got transfused peripartum were excluded. For every woman, we measured haemoglobin (Hb) concentration and collected data on sociodemographic, obstetric, and medical characteristics. The primary outcome was severe anaemia after caesarean section, defined as Hb < 7 g/dl. We used logistic regression analysis to determine factors associated with severe anaemia after caesarean section. P-value < 0.05 was considered statistically significant.

Results

From December 2019 to March 2020, 427 of 431 screened women were enrolled in the study. Their mean age was 26.05 (SD ± 5.84) years. Three hundred thirteen (73.3%) had attended at least four antenatal care visits. The prevalence of severe anaemia post-caesarean section was 6.79%. Foetus with macrosomia (aOR 7.9 95%CI: 2.18–28.85, p <  0.01) and having mild or moderate anaemia pre-caesarean section (aOR:9.6, 95%CI: 3.91–23.77, p <  0.01) were the factors associated with severe anaemia after caesarean section.

Conclusion

Severe anaemia in women post-caesarean section is relatively uncommon at our institution. It is associated with preoperative anaemia and macrosomic birth. Women with a low preoperative Hb concentration and those whose foetus have macrosomia could be targeted for haemoglobin optimisation before and during caesarean section.
Family support on intensive care units during the COVID-19 pandemic: a qualitative evaluation study into experiences of relatives
Authors: Klop Hanna T. , Nasori Mana , Klinge Tjitske W. , Hoopman Rianne , de Vos Mirjam A. , du Perron Chantal , van Zuylen Lia , Steegers Monique , ten Tusscher Birkitt L. , Abbink Floor C. H. , Onwuteaka-Philipsen Bregje D. , Pasman H. Roeline W.
Published: October 2021

Background

During the first peak of the COVID-19 pandemic in the Netherlands, relatives of patients with COVID-19 admitted to Intensive Care Units (ICUs) were severely restricted in visiting their relatives and in communicating with treating physicians. Family communication is a core element of critical care, however, this pandemic forced medical ICU staff to arrange alternative family support for instance by Family Support Teams (FSTs), consisting of non-ICU affiliated staff who telephonically contacted relatives. This study aims to examine relatives’ experiences with FSTs on two ICUs of a Dutch university medical centre, and to evaluate its working strategies. .

Methods

In a semi-structured interview study, relatives of patients with COVID-19 admitted to ICU’s, who had been supported by the FSTs, were sampled purposively. Twenty-one interviews were conducted telephonically by three researchers. All interviews were topic list guided and audio-recorded. Data was analysed thematically.

Results

All participants indicated they went through a rough time. Almost all evaluated the FSTs positively. Four major themes were identified. First, three important pillars of the FSTs were providing relatives with transparency about the patients’ situation, providing attention to relatives’ well-being, and providing predictability and certainty by calling on a daily basis in a period characterised by insecurity. Second, relatives appeared to fulfil their information needs by calls of the FSTs, but also by calling the attending ICU nurse. Information provided by the FSTs was associated with details and reliability, information provided by nurses was associated with the patient’s daily care. Third, being a primary family contact was generally experienced as both valuable and as an emotional burden. Last, participants missed proper aftercare. Family support often stopped directly after the patient died or had left the ICU. Relatives expressed a need for extended support after that moment since they had strong emotions after discharge or death of the patient.

Conclusions

Family support in times of the extreme COVID-19 situation is important, as relatives are restricted in communication and have a strong need for information and support. Relatives feel encouraged by structure, frequency, support and understanding by FSTs. However, remote family support should be tailored to the needs of relatives. A fixed contact person on de ICU and video calling might be good extra options for family support, also in future post COVID-19 care, but cannot replace physical visits.
Activated gut-homing CD8+ T cells for coeliac disease diagnosis on a gluten-free diet
Authors: Fernández-Bañares Fernando , López-Palacios Natalia , Corzo María , Arau Beatriz , Rubio Mercedes , Fernández-Prieto Marta , Tristán Eva , Pujals Mar , Farrais Sergio , Horta Saúl , Hernández Juana María , Gomez-Perosanz Marta , Reche Pedro A. , Esteve María , Núñez Concepción
Published: October 2021

Background

The diagnosis of coeliac disease (CD) in individuals that have started a gluten-free diet (GFD) without an adequate previous diagnostic work-out is a challenge. Several immunological assays such as IFN-γ ELISPOT have been developed to avoid the need of prolonged gluten challenge to induce the intestinal damage. We aimed to evaluate the diagnostic accuracy of activated gut-homing CD8+ and TCRγδ+ T cells in blood after a 3-day gluten challenge and to compare it with the performance of IFN-γ ELISPOT in a HLA-DQ2.5 subsample.

Methods

A total of 22 CD patients and 48 non-CD subjects, all of them following a GFD, underwent a 3-day 10-g gluten challenge. The percentage of two T cell subsets (CD8+ CD103+ β7hi CD38+/total CD8+ and TCRγδ+ CD103+ β7hi CD38+/total TCRγδ+) in fresh peripheral blood drawn baseline and 6 days after the challenge was determined by flow cytometry. IFN-γ ELISPOT assays were also performed in HLA-DQ2.5 participants. ROC curve analysis was used to assess the diagnostic performance of the CD8+ T cell response and IFN-γ ELISPOT.

Results

Significant differences between the percentage of the two studied subsets of CD8+ and TCRγδ+ cells at days 0 and 6 were found only when considering CD patients (p < 10−3 vs. non-CD subjects). Measuring activated CD8+ T cells provided accurate CD diagnosis with 95% specificity and 97% sensitivity, offering similar results than IFN-γ ELISPOT.

Conclusions

The results provide a highly accurate blood test for CD diagnosis in patients on a GFD of easy implementation in daily clinical practice.
The downgrading of pain sufferers’ credibility
Authors: Tosas Mar Rosàs
Published: October 2021

Background

The evaluation of pain remains one of the most difficult challenges that healthcare practitioners face. Chronic pain appears to affect more than 35% of the population in the West, and indeed, pain is the most common reason patients seek medical care. Despite its ubiquity, studies in the last decades reveal that many patients feel their pain is dismissed by healthcare practitioners and that, as a result, they are denied proper medical care. Buchman, Ho, and Goldberg (J Bioethic Inq 14:31-42, 2017) point to this phenomenon as a form of “epistemic injustice”: an unfair and harmful downgrading of credibility affecting some individuals and groups, which prevents them from receiving appropriate and beneficial medical care.

Methods

By exploring the existing literature on this downgrading of patients’ credibility written by healthcare professionals and scholars in medical humanities, I identify and examine the reasons patients are often not believed about their pain and why healthcare is too-often unhelpful or hurtful to people presenting with chronic pain. I also explore to what extent it is possible to forge an alternative epistemological model.

Results

I suggest that most of the causes of this downgrading of patient’s credibility result from either thedifficulty in communicating painor the widespread belief that pathology is always the result ofobjective tissue damage. I examine whether pain has to be effectively communicated and have an objective cause in order for it to be deemed credible. In the end, I argue that in the case of pain, both communication and objectivity are highly problematic.

Conclusions

I conclude by suggesting that, although alternative epistemological models might be impossible to build, believing patients has both moral and clinical benefits, and this warrants further research.
Spontaneous recovery from sunitinib-induced disruption of sarcomere in human iPSC-cardiomyocytes and possible involvement of the Hippo pathway
Authors: Matsui Toshikatsu , Shinozawa Tadahiro
Published: October 2021

Background

Sunitinib is known to cause cardiotoxicity in clinical settings. However, among sunitinib-treated patients experiencing adverse cardiac events, decreased cardiac function was reportedly reversible in > 50% of the patients. We previously showed that anti-cancer drugs such as sunitinib cause marked sarcomere disruption in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and the extent of sarcomere disruption can be used to predict drug-induced cardiotoxicity in humans. The aim of this study is to investigate whether the reversibility of sunitinib-induced cardiac events in clinical settings can be mimicked in vitro, and to examine the molecular mechanism responsible for sunitinib-induced cardiotoxicity focusing on the Hippo pathway.

Methods

iPSC-CMs were stimulated with sunitinib for 72 h and the morphology of sarcomere structures were analyzed by high-content analysis before and after sunitinib washout. To examine the involvement of the Hippo pathway in the sunitinib-induced sarcomere disruption, the extent of nuclear localization of YAP1 (yes-associated protein 1, a Hippo signaling target) was determined. iPSC-CMs were also stimulated with sunitinib and a small molecule inhibitor of the Hippo pathway, XMU-MP-1 and sarcomere structures were analyzed.

Results

We observed a spontaneous recovery in cardiac sarcomeres in iPSC-CMs that were significantly disrupted by sunitinib treatment after a 72 h or 144 h washout of sunitinib. The extent of nuclear localization of YAP1 was significantly reduced after sunitinib stimulation and tended to return to normal levels after drug washout. Simultaneous stimulation of iPSC-CM with sunitinib and XMU-MP-1 suppressed the sunitinib-induced disruption of sarcomeres.

Conclusions

These results indicate that iPSC-CMs have the ability to recover from sunitinib-induced sarcomere disruption, and the Hippo pathway plays a role in the process of sunitinib-induced disruption of sarcomere and its recovery. Inhibition of the Hippo pathway may help to develop a co-medication strategy for mitigating the risk of sunitinib-induced adverse cardiac events.