bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two SERPINC1 variants affecting N-glycosylation of Asn224 cause severe thrombophilia not detected by functional assays
Authors: de la Morena-Barrio Maria Eugenia , Suchon Pierre , Jacobsen Eva Marie , Iversen Nina , Miñano Antonia , de la Morena-Barrio Belén , Bravo-Pérez Carlos , Padilla Jose , Cifuentes Rosa , Asenjo Susana , Deleuze Jean François , Trégouët David Alexandre , Lozano Maria Luisa , Vicente Vicente , Sandset Per Morten , Morange Pierre Emmanuel , Corral Javier 
Published: April 2022

Abstract
Antithrombin deficiency, the most severe congenital thrombophilia, might be underestimated, as some pathogenic variants are not detected by routine functional methods. We have identified 2 new SERPINC1 variants, p.Glu227Lys and p.Asn224His, in 4 unrelated thrombophilic patients with early and recurrent thrombosis that had normal antithrombin activity. In one case, the mutation was identified by whole genome sequencing, while in the 3 remaining cases, the mutation was identified by sequencing SERPINC1 based on a single functional positive finding supporting deficiency. The 2 variants shared a common functional defect, an impaired or null N-glycosylation of Asn224 according to a eukaryotic expression model. Carriers had normal anti-FXa or anti-FIIa activities but impaired anti-FVIIa activity and a detectable loss of inhibitory function when incubating the plasma for 1 hour at 41°C. Moreover, the β glycoform of the variants, lacking 2 N-glycans, had reduced secretion, increased heparin affinity, no inhibitory activity, and a potential dominant–negative effect. These results explain the increased thrombin generation observed in carriers. Mutation experiments reflected the role that Lysine residues close to the N-glycosylation sequon have in impairing the efficacy of N-glycosylation. Our study shows new elements involved in the regulation of N-glycosylation, a key posttranslational modification that, according to our results, affects folding, secretion, and function, providing new evidence of the pathogenic consequence of an incorrect N-glycosylation of antithrombin. This study supports that antithrombin deficiency is underestimated and encourages the development of new functional and genetic tests to diagnose this severe thrombophilia.
Thrombocytopenia and splenic platelet-directed immune responses after IV ChAdOx1 nCov-19 administration
Authors: Nicolai Leo , Leunig Alexander , Pekayvaz Kami , Esefeld Max , Anjum Afra , Rath Justina , Riedlinger Eva , Ehreiser Vincent , Mader Magdalena , Eivers Luke , Hoffknecht Marie-Louise , Zhang Zhe , Kugelmann Daniela , Rossaro Dario , Escaig Raphael , Kaiser Rainer , Polewka Vivien , Titova Anna , Petzold Tobias , Spiekermann Karsten , Iannacone Matteo , Thiele Thomas , Greinacher Andreas , Stark Konstantin , Massberg Steffen 
Published: April 2022

AbstractVaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are based on a range of novel platforms, with adenovirus-based approaches (like ChAdOx1 nCov-19) being one of them. Recently, a novel complication of SARS-CoV-2–targeted adenovirus vaccines has emerged: immune thrombocytopenia, either isolated, or accompanied by thrombosis (then termed VITT). This complication is characterized by low platelet counts, and in the case of VITT, also by platelet-activating platelet factor 4 antibodies reminiscent of heparin-induced thrombocytopenia, leading to a prothrombotic state with clot formation at unusual anatomic sites. Here, we detected antiplatelet antibodies targeting platelet glycoprotein receptors in 30% of patients with proven VITT (n = 27) and 42% of patients with isolated thrombocytopenia after ChAdOx1 nCov-19 vaccination (n = 26), indicating broad antiplatelet autoimmunity in these clinical entities. We use in vitro and in vivo models to characterize possible mechanisms of these platelet-targeted autoimmune responses leading to thrombocytopenia. We show that IV but not intramuscular injection of ChAdOx1 nCov-19 triggers platelet-adenovirus aggregate formation and platelet activation in mice. After IV injection, these aggregates are phagocytosed by macrophages in the spleen, and platelet remnants are found in the marginal zone and follicles. This is followed by a pronounced B-cell response with the emergence of circulating antibodies binding to platelets. Our work contributes to the understanding of platelet-associated complications after ChAdOx1 nCov-19 administration and highlights accidental IV injection as a potential mechanism of platelet-targeted autoimmunity. Hence, preventing IV injection when administering adenovirus-based vaccines could be a potential measure against platelet-associated pathologies after vaccination.
Anaplasma phagocytophilum in Marmota himalayana
Authors: Duan Ran , Lv Dongyue , Fan Rong , Fu Guoming , Mu Hui , Xi Jinxiao , Lu Xinmin , Chun Hua , Hua Jun , He Zhaokai , Qin Shuai , Huang Yanyan , Xiao Meng , Yang Jinchuan , Jing Huaiqi , Wang Xin 
Published: April 2022

Abstract
Background
Human granulocytic anaplasmosis is a tick-borne zoonotic disease caused by Anaplasma phagocytophilum. Coinfections with A. phagocytophilum and other tick-borne pathogens are reported frequently, whereas the relationship between A. phagocytophilum and flea-borne Yersnia pestis is rarely concerned.

Results
A. phagocytophilum and Yersnia pestis were discovered within a Marmota himalayana found dead in the environment, as determined by 16S ribosomal rRNA sequencing. Comparative genomic analyses of marmot-derived A. phagocytophilum isolate demonstrated its similarities and a geographic isolation from other global strains. The 16S rRNA gene and GroEL amino acid sequence identity rates between marmot-derived A. phagocytophilum (JAHLEX000000000) and reference strain HZ (CP000235.1) are 99.73% (1490/1494) and 99.82% (549/550), respectively. 16S rRNA and groESL gene screenings show that A. phagocytophilum is widely distributed in marmots; the bacterium was more common in marmots found dead (24.59%, 15/61) than in captured marmots (19.21%, 29/151). We found a higher Y. pestis isolation rate in dead marmots harboring A. phagocytophilum than in those without it (2 = 4.047, p < 0.05). Marmot-derived A. phagocytophilum was able to live in L929 cells and BALB/c mice but did not propagate well.

Conclusions
In this study, A. phagocytophilum was identified for the first time in Marmota himalayana, a predominant Yersinia pestis host. Our results provide initial evidence for M. himalayana being a reservoir for A. phagocytophilum; moreover, we found with the presence of A. phagocytophilum, marmots may be more vulnerable to plague. Humans are at risk for co-infection with both pathogens by exposure to such marmots.
Inter-observer agreement of preoperative cardiopulmonary exercise test interpretation in major abdominal surgery
Authors: Franssen Ruud F. W. , Eversdijk Anne J. J. , Kuikhoven Mayella , Klaase Joost M. , Vogelaar F. Jeroen , Janssen-Heijnen Maryska L. G. , Bongers Bart C. 
Published: April 2022

Abstract
Background
Accurate determination of cardiopulmonary exercise test (CPET) derived parameters is essential to allow for uniform preoperative risk assessment. The objective of this prospective observational study was to evaluate the inter-observer agreement of preoperative CPET-derived variables by comparing a self-preferred approach with a systematic guideline-based approach.

Methods
Twenty-six professionals from multiple centers across the Netherlands interpreted 12 preoperative CPETs of patients scheduled for hepatopancreatobiliary surgery. Outcome parameters of interest were oxygen uptake at the ventilatory anaerobic threshold (V̇O2VAT) and at peak exercise (V̇O2peak), the slope of the relationship between the minute ventilation and carbon dioxide production (V̇E/V̇CO2-slope), and the oxygen uptake efficiency slope (OUES). Inter-observer agreement of the self-preferred approach and the guideline-based approach was quantified by means of the intra-class correlation coefficient.

Results
Across the complete cohort, inter-observer agreement intraclass correlation coefficient (ICC) was 0.76 (95% confidence interval (CI) 0.57–0.93) for V̇O2VAT, 0.98 (95% CI 0.95–0.99) for V̇O2peak, and 0.86 (95% CI 0.75–0.95) for the V̇E/V̇CO2-slope when using the self-preferred approach. By using a systematic guideline-based approach, ICCs were 0.88 (95% CI 0.74–0.97) for V̇O2VAT, 0.99 (95% CI 0.99–1.00) for V̇O2peak, 0.97 (95% CI 0.94–0.99) for the V̇E/V̇CO2-slope, and 0.98 (95% CI 0.96–0.99) for the OUES.

Conclusions
Inter-observer agreement of numerical values of CPET-derived parameters can be improved by using a systematic guideline-based approach. Effort-independent variables such as the V̇E/V̇CO2-slope and the OUES might be useful to further improve uniformity in preoperative risk assessment in addition to, or in case V̇O2VAT and V̇O2peak are not determinable.
Self-reported chronic kidney disease and the risk of all-cause and cause-specific mortality: outcome-wide association study of 54 causes of death in the National Health Interview Survey
Authors: Aune Dagfinn , Sun Xibin , Nie Jing , Huang Wentao , Liao Bing , Wang Yafeng 
Published: April 2022

Abstract
Background
A diagnosis of chronic kidney disease has been strongly associated with cardiovascular disease and mortality in a number of studies, but the association with specific causes of death has not been assessed in detail. We analysed the association between chronic kidney disease and all-cause mortality and 54 causes of death in the National Health Interview Survey, a prospective study of 210,748 US adults.

Methods
We used multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality associated with self-reported chronic kidney disease. Men and women aged 18–84 years were recruited between 1997 and 2004 and followed up for mortality through December 31, 2006.

Results
During an average of 6 years follow-up, 9564 deaths occurred. A history of chronic kidney disease vs. no chronic kidney disease was associated with increased risk of all-cause mortality (HR = 2.69, 95% CI: 2.38–3.04), and mortality from septicemia (5.65, 2.84–11.25), viral hepatitis (10.67, 2.43–46.95), other infectious parasitic diseases (10.58, 3.59–31.21), total cancer (1.48, 1.05–2.09), lung cancer (1.94, 1.10–3.44), kidney cancer (4.74, 1.81–12.41), diabetes mellitus (8.57, 5.60–13.11), circulatory disease overall (3.36, 2.70–4.18) and 11 specific circulatory diseases with the strongest associations observed for primary hypertension/renal disease (13.60, 6.42–28.84), hypertensive heart/renal disease (10.72, 2.47–46.49), and other diseases of circulatory system (7.36, 3.22–16.81). Elevated risk was also observed for alcoholic liver disease (5.63, 1.90–16.66), other chronic liver disease (4.41, 1.74–11.17), kidney failure (13.07, 8.23–20.77), and five other causes of death.

Conclusions
A history of chronic kidney disease was associated with increased risk of all-cause mortality and 27 out of 54 causes of death. Further studies are needed to clarify associations with less common causes of death.
Epidemiology and outcomes in patients with anemia of CKD not on dialysis from a large US healthcare system database: a retrospective observational study
Authors: Lamerato Lois , James Glen , van Haalen Heleen , Hedman Katarina , Sloand James A. , Tang Amy , Wittbrodt Eric T. , Yee Jerry 
Published: April 2022

Abstract
Background
Optimal management of anemia of chronic kidney disease (CKD) remains controversial. This retrospective study aimed to describe the epidemiology and selected clinical outcomes of anemia in patients with CKD in the US.

Methods
Data were extracted from Henry Ford Health System databases. Adults with stages 3a–5 CKD not on dialysis (estimated glomerular filtration rate < 60 mL/min/1.73m2) between January 1, 2013 and December 31, 2017 were identified. Patients on renal replacement therapy or with active cancer or bleeding were excluded. Patients were followed for ≥12 months until December 31, 2018. Outcomes included incidence rates per 100 person-years (PY) of anemia (hemoglobin < 10 g/dL), renal and major adverse cardiovascular events, and of bleeding and hospitalization outcomes. Adjusted Cox proportional hazards models identified factors associated with outcomes after 1 and 5 years.

Results
Among the study cohort (N = 50,701), prevalence of anemia at baseline was 23.0%. Treatments used by these patients included erythropoiesis-stimulating agents (4.1%), iron replacement (24.2%), and red blood cell transfusions (11.0%). Anemia incidence rates per 100 PY in patients without baseline anemia were 7.4 and 9.7 after 1 and 5 years, respectively. Baseline anemia was associated with increased risk of renal and major cardiovascular events, hospitalizations (all-cause and for bleeding), and transfusion requirements. Increasing CKD stage was associated with increased risk of incident anemia, renal and major adverse cardiovascular events, and hospitalizations.

Conclusions
Anemia was a prevalent condition associated with adverse renal, cardiovascular, and bleeding/hospitalization outcomes in US patients with CKD. Anemia treatment was infrequent.
Palliative sedation in amyotrophic lateral sclerosis: results of a nationwide survey among neurologists and palliative care practitioners in Germany
Authors: Salzmann Laura , Alt-Epping Bernd , Simon Alfred 
Published: April 2022

Abstract
Background
Palliative sedation has become widely accepted as a method to alleviate refractory symptoms in terminally ill patients. Controversies regarding this topic especially concern the use of palliative sedation for psychological symptoms, the use in patients who are not imminently dying and the simultaneous withdrawal of life-sustaining measures. Amyotrophic lateral sclerosis (ALS) is characterized by symptoms including muscle weakness, dysphagia, dysarthria, muscle spasms and progressive respiratory insufficiency. Due to these characteristic symptoms, palliative sedation might be considered to be necessary to alleviate refractory suffering in ALS patients. However, palliative sedation in ALS is only rarely discussed in current medical literature and guidelines.

Methods
A questionnaire survey was conducted among neurologists and palliative care practitioners in Germany. The participants were asked to evaluate the use of palliative sedation in different situations.

Results
Two hundred and ninety-six completed questionnaires were analyzed. The results suggest high levels of support for the use of palliative sedation in ALS patients. 42% of the participants stated that they had already used palliative sedation in the treatment of ALS patients. Acceptance of palliative sedation was higher in case of physical symptoms than in case of psychological symptoms. Refusal of artificial nutrition did not lead to a lower acceptance of palliative sedation. Doctors with specialist training in palliative care had already used palliative sedation in ALS patients more often and they were more likely to accept palliative sedation in different situations than the participants without a background in palliative care.

Conclusion
Our survey showed that palliative sedation in ALS is widely accepted by the attending doctors. In case of psychological symptoms, palliative sedation is looked at with more concern than in case of physical symptoms. The refusal of artificial nutrition does not result in a decreased acceptance of palliative sedation. Doctors with specialist training in palliative care are more likely to approve of palliative sedation in ALS.
Preventing hemorrhoids during pregnancy: a multicenter, randomized clinical trial
Authors: Poskus Tomas , Sabonyte-Balsaitiene Zivile , Jakubauskiene Lina , Jakubauskas Matas , Stundiene Ieva , Barkauskaite Gabija , Smigelskaite Mante , Jasiunas Eugenijus , Ramasauskaite Diana , Strupas Kestutis , Drasutiene Grazina 
Published: April 2022

Abstract
Background
To compare specific dietary and behavioral recommendations for hemorrhoids prevention during pregnancy.

Methods
This was a randomized, single-blind, multicenter trial conducted in three different clinical centers. Patients were randomly allocated into two groups in a ratio of 1:1. Intervention consisted of specific dietary and behavioral counseling. The primary outcome of this study was the rate of hemorrhoids at the time of discharge from the obstetrics unit. Categorical variables were compared by the Chi-Squared or Fisher exact tests, as appropriate. Continuous variables were compared using either the Student's t-test or the Mann–Whitney U test. Binary logistic regression model was used to identify independent predictors of hemorrhoids after delivery. This analysis was performed on factors with a p-value < 0.10 in univariate analysis. Statistical analysis was performed using IBM SPSS 23.0 and GraphPad Prism 9 software. A P-value of less than 0.05 was considered significant for all tests.

Results
We observed a significantly lower hemorrhoids rate in the intervention group at the time of discharge from the obstetrics unit after delivery (intention-to-treat (ITT) (the relative risk (RR) 0.38; 95% the confidence interval (CI) 0.24–0.59; p < 0.001) per-protocol (PP) (RR 0.42; 95% CI 0.27–0.64; p < 0.001). There was no significant difference in spontaneous miscarriage rate between the groups for both ITT and PP analysis. Additional binary logistic regression analysis revealed that the intervention applied in this study was the only protective factor. Both, the history of hemorrhoids before pregnancy and the increase of newborn height was associated with a higher risk of hemorrhoids.

Conclusions
Our suggested intervention, aimed to modify dietary and behavioral habits, significantly reduces the rate of hemorrhoids after pregnancy and can be safely recommended to pregnant women.

Trial registration
Date of registration: 2016–05-09; Date of initial patient enrollment: 2016–06-02; Trial registration number: 158200–16-843–357; Trial registration site URL:
https://www.mf.vu.lt/mokslas/vilniaus-regioninis-biomedicininiu-39tyrimu-etikos-komitetas#isduoti40vrbtek-leidimai.
Use of non-pharmacological methods in managing labour pain: experiences of nurse-midwives in two selected district hospitals in eastern Tanzania
Authors: Mwakawanga Dorkasi L. , Mselle Lilian T. , Chikwala Victor Z. , Sirili Nathanael 
Published: April 2022

Abstract
Background
Labour pain usually brings with it many concerns for a parturient and her family. The majority of the women in labour pain may require some sort of pain relief method during this period, be it pharmacological or non-pharmacological. In Tanzania, the use of non-pharmacological methods to relief labour pain remains low among nurse-midwives. We analysed the experiences of nurse-midwives in the use of non-pharmacological methods to manage labour pain, in two selected districts of Pwani and Dar es Salaam regions in eastern Tanzania. This paper describes Non-pharmacological Methods (NPMs) currently used by nurse-midwives, the facilitators, myths and fears related to the use of NPMs.

Materials and Methods
An exploratory qualitative study using in-depth interviews was conducted with 18 purposively recruited nurse-midwives working in labour wards in two selected district hospitals in Pwani and Dar es Salaam regions in eastern Tanzania. Qualitative conventional content analysis was used to generate categories describing the experience of using non-pharmacological methods in managing labour pain.

Results
This study revealed that nurse-midwives encouraged women to tolerate labour pain and instructed them to change positions and to do deep breathing exercises as a means to relief labour pain. Nurse-midwives’ inner motives facilitated the use of non-pharmacological strategies for labour pain relief despite the fear of using them and myths that labour pain is necessary for childbirth.

Conclusion
This study generates information about the use of non-pharmacological strategies to relief labour pain. Although nurse-midwives are motivated to apply various non-pharmacological strategies to relief labour pain, fear and misconceptions about the necessity of labour pain during childbirth prohibit the effective use of these strategies. Therefore, together with capacity building the nurse-midwives in the use of non-pharmacological strategies to relief labour pain, efforts should be made to address the misconceptions that may partly be of socio-cultural origin.
Evaluation of CSTB and DMBT1 expression in saliva of gastric cancer patients and controls
Authors: Koopaie Maryam , Ghafourian Marjan , Manifar Soheila , Younespour Shima , Davoudi Mansour , Kolahdooz Sajad , Shirkhoda Mohammad 
Published: April 2022

Abstract
Background
Gastric cancer (GC) is the fifth most common cancer and the third cause of cancer deaths globally, with late diagnosis, low survival rate, and poor prognosis. This case-control study aimed to evaluate the expression of cystatin B (CSTB) and deleted in malignant brain tumor 1 (DMBT1) in the saliva of GC patients with healthy individuals to construct diagnostic algorithms using statistical analysis and machine learning methods.

Methods
Demographic data, clinical characteristics, and food intake habits of the case and control group were gathered through a standard checklist. Unstimulated whole saliva samples were taken from 31 healthy individuals and 31 GC patients. Through ELISA test and statistical analysis, the expression of salivary CSTB and DMBT1 proteins was evaluated. To construct diagnostic algorithms, we used the machine learning method.

Results
The mean salivary expression of CSTB in GC patients was significantly lower (115.55 ± 7.06, p = 0.001), and the mean salivary expression of DMBT1 in GC patients was significantly higher (171.88 ± 39.67, p = 0.002) than the control.
Multiple linear regression analysis demonstrated that GC was significantly correlated with high levels of DMBT1 after controlling the effects of age of participants (R2 = 0.20, p < 0.001).
Considering salivary CSTB greater than 119.06 ng/mL as an optimal cut-off value, the sensitivity and specificity of CSTB in the diagnosis of GC were 83.87 and 70.97%, respectively. The area under the ROC curve was calculated as 0.728. The optimal cut-off value of DMBT1 for differentiating GC patients from controls was greater than 146.33 ng/mL (sensitivity = 80.65% and specificity = 64.52%). The area under the ROC curve was up to 0.741.
As a result of the machine learning method, the area under the receiver-operating characteristic curve for the diagnostic ability of CSTB, DMBT1, demographic data, clinical characteristics, and food intake habits was 0.95. The machine learning model’s sensitivity, specificity, and accuracy were 100, 70.8, and 80.5%, respectively.

Conclusion
Salivary levels of DMBT1 and CSTB may be accurate in diagnosing GCs. Machine learning analyses using salivary biomarkers, demographic, clinical, and nutrition habits data simultaneously could provide affordability models with acceptable accuracy for differentiation of GC by a cost-effective and non-invasive method.