bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the sphingosine axis in immune regulation: A dichotomy in the anti-inflammatory effects between sphingosine kinase 1 and sphingosine kinase 2-dependent pathways
Authors: Ishay Yuval , Rotnemer-Golinkin Dvorah , Ilan Yaron
Published: November 2021

Background: Sphingosine kinase has been identified as playing a central role in the immune cascade, being a common mediator in the cellular response to a variety of signals. The different effects of sphingosine kinase 1 and 2 (SphK1 and SphK2, respectively) activity have not been completely characterized. Aim: To determine the different roles played by SphK1 and SphK2 in the regulation of immune-mediated disorders. Methods: Nine groups of mice were studied. Concanavalin A (ConA) injection was used to induce immune-mediated hepatitis. Mice were treated with SphK1 inhibitor (termed SphK-I) and SphK2 inhibitor (termed ABC294640), prior to ConA injection, and effects of treatment on liver enzymes, subsets of T lymphocytes, and serum levels of cytokines were observed. Results: While liver enzyme elevation was ameliorated by administration of SphK1 inhibitor, SphK2 inhibitor-treated mice did not show this tendency. A marked decrease in expression of CD25+ T-cells and Foxp+ T-cells was observed in mice treated with a high dose of SphK1 inhibitor. Alleviation of liver damage was associated with a statistically significant reduction of serum IFNγ levels in mice treated with SphK1 inhibitor and not in those treated with SphK2 inhibitor. Conclusions: Early administration of SphK1 inhibitor in a murine model of immune-mediated hepatitis alleviated liver damage and inflammation with a statistically significant reduction in IFN-γ levels. The data support a dichotomy in the anti-inflammatory effects of SphK1 and SphK2, and suggests that isoenzyme-directed therapies can improve the effect of targeting these pathways.
What Are the Main Risk Factors for Lower Extremity Running-Related Injuries? A Retrospective Survey Based on 3669 Respondents
Authors: Sanfilippo Damien , Beaudart Charlotte , Gaillard Allan , Bornheim Stephen , Bruyere Olivier , Kaux Jean-François
Published: November 2021

Background:

Despite the many studies on running-related injuries (RRIs), risk factors for injury remain unclear in the literature.

Purpose:

To investigate the risk factors of RRIs.

Study Design:

Case-control study; Level of evidence, 3.

Methods:

An online survey was conducted among 3669 injured and noninjured runners. Injury was defined as pain of various kinds, without attention to its consequences on running practice. The survey included 41 questions on 5 main categories—personal characteristics, daily lifestyle, training and running characteristics, practice of other sporting activities, and prevention habits—as well as information about the occurrence of RRI over the previous 12 months. Continuous and qualitative variables were analyzed by Student t test and chi-square test, respectively. Sixteen variables were selected for multivariate binary logistic analysis.

Results:

Among the 3669 runners, 1852 (50.5%) reported at least 1 injury over the previous 12 months. Overuse injuries were largely represented (60.6%). The variables associated with RRIs that remained significant in the fully adjusted model were previous injury (odds ratio [OR], 1.62; 95% CI, 1.42-1.86), higher weight (OR, 1.006; 95% CI, 1.00-1.012), competitive running (OR, 1.53; 95% CI, 1.19-1.98), running >2 h/wk (OR, 1.28; 95% CI, 1.01-1.62), running >20 km/wk (OR, 1.25; 95% CI, 1.001-1.55), and stretching before running (OR, 1.46; 95% CI, 1.25-1.71).

Conclusion:

Previous injury remains the most relevant risk factor for RRIs according to the current study and previous data. Many training characteristics seem to be involved but still have to be confirmed in view of conflicting data in the literature. Further research would help clinicians better understand RRIs and how to prevent them.
Chondromyxoid Fibroma-Like Osteosarcoma in a 13 Years Old Girl: A Report of a New Case
Authors: Derqaoui Sabrine , Marbouh Oussama , Madhi Tarik , Najat Lamalmi , Rouas Lamia
Published: November 2021

Osteosarcoma (OS) is the most common primary non hematopoietic malignant tumor of bone with a strict histologic definition: the presence of unequivocal osteoid produced by neoplastic cells. Rare variants displaying low-grade histological features have been described; among which chondromyxoid fibroma-like (CMF-OS) is the rarest. However, despite its bland morphology; CMF-like OS has an aggressive clinical behavior and a poor prognosis. To the best of our knowledge, only 3 cases of CMF-OS have been previously reported in children. Because of its atypicality and scarcity; misdiagnosis is more likely to occur. Herein we describe a new case of CMF-OS in a 13 years old girl with fatal outcome. Diagnosis was based on focal malignant bone formation and correlation with imaging studies. The aim of the present case presentation is to raise awareness of this rare entity and to highlight the challenging diagnosis
Associations between long-term conditions and upper gastrointestinal cancer incidence: A prospective population-based cohort of UK Biobank participants
Authors: Marley Jennifer , Nicholl Barbara I , Macdonald Sara , Mair Frances S , Jani Bhautesh D
Published: November 2021

Background/Aims

Upper gastrointestinal cancers (oesophageal/stomach) have high mortality rates and are often diagnosed after the disease has progressed, making it important to identify populations at greater risk of upper gastrointestinal (UGI) cancer to promote earlier diagnosis. This study aims to determine if there is an association between a broad range of long-term conditions (LTCs) and incidence of UGI cancers.

Method

A prospective-based cohort of 487,798 UK Biobank participants (age 37–73 years) after excluding previous UGI cancer. Least Absolute Shrinkage and Selection Operator (LASSO) regression used to identify candidate LTCs as predictors for UGI cancer. Strength of association was studied using Cox’s regression adjusting for demographics and lifestyle factors.

Results

After median follow-up period of 86 months, 598 participants developed oesophageal cancer; 397 developed stomach cancer. In fully adjusted models, participants with alcohol addiction (Hazard Ratio-HR 4.11, 95% Confidence Interval-CI 2.01–8.43), Barrett’s oesophagus (HR 5.68, 95% CI 3.36–9.58), bronchiectasis (HR 2.72, 95% CI 1.01–7.31), diabetes (HR 1.38, 95% CI 1.06–1.81), hiatus hernia (HR 1.69, 95% CI 1.16–2.45), Parkinson’s disease (HR 3.86, 95% CI 1.60–9.37) and psoriasis/eczema (HR 1.53, 95% 1.08–2.17) were observed to have a higher risk of oesophageal cancer. Stomach cancer incidence was higher among participants with anorexia/bulimia (HR 8.86, 95% CI 1.20–65.14), Barrett’s oesophagus (HR 3.37, 95% 1.39–8.14), chronic fatigue syndrome (HR 3.36, 95% CI 1.25–9.03), glaucoma (HR 2.06, 95% CI 1.16–3.67), multiple sclerosis (HR 4.60, 95% CI 1.71–12.34), oesophageal stricture (HR 1.04, 95% CI 1.46–74.46) and pernicious anaemia (HR 6.93, 95% CI 3.42–14.03).

Conclusion

Previously unrecognised LTCs may have a role in symptom appraisal and risk assessment of UGI cancer in primary care. Further research should explore mechanisms underpinning these findings and determine whether they are replicable in other populations.
Tiotropium treatment for bronchiectasis: a randomised, placebo-controlled, crossover trial
Authors: Jayaram Lata , Vandal Alain C. , Chang Catherina L. , Lewis Chris , Tong Cecilia , Tuffery Christine , Bell Jill , Fergusson Wendy , Jeon Gene , Milne David , Jones Stuart , Karalus Noel , Hotu Sandra , Wong Conroy
Published: November 2021

Background

Tiotropiumviathe HandiHaler device is an established long-acting, anticholinergic bronchodilator that prevents exacerbations and improves lung function in patients with chronic obstructive pulmonary disease. We hypothesised that tiotropium would reduce pulmonary exacerbations and improve lung function in patients with stable bronchiectasis and airflow limitation, and assessed the effect of tiotropium on these outcomes.

Methods

In a randomised, double-blind, two-period crossover trial, we recruited adult patients from three hospitals in New Zealand. Patients were excluded if they had a smoking history of >20 pack-years. Patients were assigned to either the tiotropium–placebo or placebo–tiotropium sequence in a 1:1 ratio, using randomly permuted blocks stratified by centre. Participants and investigators were masked to treatment allocation. Eligible patients received tiotropium 18 μgviaHandiHaler daily for 6 months followed by 6 months of placebo, orvice versa, with a washout period of 4 weeks. The primary end-point was rate of event-based exacerbations during the 6-month period. Primary analyses were carried out in an intention-to-treat set.

Results

90 patients were randomly assigned and 85 completed both treatment cycles. The rate of exacerbations was 2.17 per year under the tiotropium treatment and 2.27 per year under placebo (rate ratio 0.96, 95% CI 0.72–1.27; p=0.77). Tiotropium, compared with placebo, improved forced expiratory volume in 1 s by 58 mL (95% CI 23–92 mL; p=0.002). Adverse events were similar under both treatments.

Conclusions

TiotropiumviaHandiHaler over 6 months significantly improved lung function but not frequency of exacerbations. Further research is required to understand the clinical context and significance of these findings.
The impact of long-term azithromycin on antibiotic resistance in HIV-associated chronic lung disease
Authors: Abotsi Regina E. , Nicol Mark P. , McHugh Grace , Simms Victoria , Rehman Andrea M. , Barthus Charmaine , Ngwira Lucky G. , Kwambana-Adams Brenda , Heyderman Robert S. , Odland Jon Ø. , Ferrand Rashida A. , Dube Felix S.
Published: November 2021

Selection for resistance to azithromycin (AZM) and other antibiotics such as tetracyclines and lincosamides remains a concern with long-term AZM use for treatment of chronic lung diseases (CLD). We investigated the impact of 48 weeks of AZM on the carriage and antibiotic resistance of common respiratory bacteria among children with HIV-associated CLD.

Nasopharyngeal (NP) swabs and sputa were collected at baseline, 48 and 72 weeks from participants with HIV-associated CLD randomised to receive weekly AZM or placebo for 48 weeks and followed post-intervention until 72 weeks. The primary outcomes were prevalence and antibiotic resistance ofStreptococcus pneumoniae(SP),Staphylococcus aureus(SA),Haemophilus influenzae(HI) andMoraxella catarrhalis(MC) at these timepoints. Mixed-effects logistic regression and Fisher's exact test were used to compare carriage and resistance, respectively.

Of 347 (174 AZM, 173 placebo) participants (median age 15 years (IQR 13–18), female 49%), NP carriage was significantly lower in the AZM (n=159) compared to placebo (n=153) arm for SP (18%versus41%,p<0.001), HI (7%versus16%, p=0.01) and MC (4%versus11%, p=0.02); SP resistance to AZM (62% (18 out of 29)versus13% (8 out of 63),p<0.0001) or tetracycline (60% (18 out of 29)versus21% (13 out of 63),p<0.0001) was higher in the AZM arm. Carriage of SA resistant to AZM (91% (31 out of 34)versus3% (1 out of 31),p<0.0001), tetracycline (35% (12 out of 34)versus13% (4 out of 31), p=0.05) and clindamycin (79% (27 out of 34)versus3% (1 out of 31),p<0.0001) was also significantly higher in the AZM arm and persisted at 72 weeks. Similar findings were observed for sputa.

The persistence of antibiotic resistance and its clinical relevance for future infectious episodes requiring treatment needs further investigation.
GLRX3, a novel cancer stem cell-related secretory biomarker of pancreatic ductal adenocarcinoma
Authors: Jo Jung Hyun , Kim Sun A , Lee Jeong Hoon , Park Yu Rang , Kim Chanyang , Park Soo Been , Jung Dawoon E. , Lee Hee Seung , Chung Moon Jae , Song Si Young
Published: November 2021

Background

Cancer stem cells (CSCs) are implicated in carcinogenesis, cancer progression, and recurrence. Several biomarkers have been described for pancreatic ductal adenocarcinoma (PDAC) CSCs; however, their function and mechanism remain unclear.

Method

In this study, secretome analysis was performed in pancreatic CSC-enriched spheres and control adherent cells for biomarker discovery. Glutaredoxin3 (GLRX3), a novel candidate upregulated in spheres, was evaluated for its function and clinical implication.

Results

PDAC CSC populations, cell lines, patient tissues, and blood samples demonstrated GLRX3 overexpression. In contrast, GLRX3 silencing decreased the in vitro proliferation, migration, clonogenicity, and sphere formation of cells. GLRX3 knockdown also reduced tumor formation and growth in vivo. GLRX3 was found to regulate Met/PI3K/AKT signaling and stemness-related molecules. ELISA results indicated GLRX3 overexpression in the serum of patients with PDAC compared to that in healthy controls. The sensitivity and specificity of GLRX3 for PDAC diagnosis were 80.0 and 100%, respectively. When GLRX3 and CA19–9 were combined, sensitivity was significantly increased to 98.3% compared to that with GLRX3 or CA19–9 alone. High GLRX3 expression was also associated with poor disease-free survival in patients receiving curative surgery.

Conclusion

Overall, these results indicate GLRX3 as a novel diagnostic marker and therapeutic target for PDAC targeting CSCs.
Frequently assessed and used prognostic factors for outcome after macular hole surgery: which is better?
Authors: Roth M. , Schön N. , Jürgens L. , Engineer D. , Kirchhoff K. , Guthoff R. , Schmidt J.
Published: November 2021

Background

The aim of this retrospective study was to evaluate commonly used clinical and OCT-morphological parameters, including perifoveal pseudocysts, as prognostic factors for postoperative outcome after macular hole surgery in a retinal referral clinic in North Rhine-Westphalia, Germany.

Methods and material

This was a retrospective analysis of all patients who underwent surgery because of idiopathic MH between 2011 and 2017 in Augenklinik Tausendfensterhaus, Duisburg, Germany. Statistical evaluation of clinical and OCT-based parameters, including the areas of intraretinal pseudocysts, was conducted. The main statistical outcomes were surgical success and visual acuity. Only parameters with a highly significant correlation to the outcome parameters (postoperative visual acuity (VA); surgical success) in univariate analysis were entered in linear and logistic regression analyses.

Results

A total of 189 eyes of 178 patients (71.4% female; mean age 67.5 ± 8.2 a) who underwent surgery because of MH were included. The overall closure rate was 86.8%. The mean best corrected VA increased from 0.7 ± 0.3 logMAR before surgery to 0.5 ± 0.3 logMAR (p < 0.0001). While several clinical and OCT-based parameters as well as calculated indices showed a significant correlation with the outcome measures, the regression analysis showed that the minimum linear diameter was the only parameter that both predicted surgical success (p = 0.015) and was correlated with postoperative VA (p < 0.001).

Conclusion

The minimum linear diameter serves as an easily assessed prognostic factor with the best predictive properties. This result is of great importance for clinical practice, as it simplifies the postsurgical prognosis.
Prostaglandin E2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 channels
Authors: Al-Kandery Al-Shaimaa A. , Rao Muddanna S. , El-Hashim Ahmed Z.
Published: November 2021

Background

Cough hypersensitivity is a major characteristic feature associated with several types of cough, including chronic cough, but its underlying mechanisms remain to be fully understood. Inflammatory mediators, such as prostaglandin E2 (PGE2), have been implicated in both peripheral induction and sensitization of the cough reflex. In this study, using a conscious guinea pig model of cough, we investigated whether PGE2 can sensitize the cough reflex via central actions and, if so, via which mechanisms.

Methods

All drugs were administered by intracerebroventricular (i.c.v.) route and whole-body plethysmograph set-up was used for both induction, using aerosolized citric acid (0.2 M), and recording of cough. Immunohistochemistry was performed to confirm the expression of NaV 1.8 channels in the nucleus tractus solitarius (nTS).

Results

We show that both PGE2 and the non-selective EP1/EP3 agonist, sulprostone, dose-dependently enhanced the citric acid-induced cough (P ≤ 0.001, P ≤ 0.01, respectively). Pretreatment with the EP1 antagonist, ONO-8130, did not affect the sulprostone-induced cough sensitization, whilst the EP3 antagonist, L-798,106, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, treatment with either the EP2 agonist, butaprost or the EP4 agonist, L-902,688, had no effect on cough sensitization. Additionally, pretreatment with either the TRPV1 antagonist, JNJ-17203212 or the TRPA1 antagonist, HC-030031, alone or in combination, nor with the NaV 1.1, 1.2, 1.3, 1.4, 1.6 and 1.7 channel blocker, tetrodotoxin, had any effect on the cough. In contrast, pretreatment with the NaV 1.8 antagonist, A-803467, dose-dependently inhibited this effect (P ≤ 0.05). Furthermore, NaV 1.8 channels were shown to be expressed in the nTS.

Conclusion

Collectively, our findings show that PGE2 sensitizes the cough reflex centrally via EP3 receptor-dependent activation of NaV 1.8 but independently of TRPV1,TRPA1 and TTX-sensitive sodium channel activation. These results indicate that PGE2 plays an important role in central sensitization of the cough reflex and suggest that central EP3 receptors and/or NaVv 1.8 channels may represent novel antitussive molecular targets.

Graphical Abstract
Treatment outcomes of re-irradiation using stereotactic ablative radiotherapy to lung: a propensity score matching analysis
Authors: Lee Tae Hoon , Kim Dong-Yun , Wu Hong-Gyun , Lee Joo Ho , Kim Hak Jae
Published: November 2021

Background

The purpose of this study was to compare the treatment efficacy and safety of re-irradiation (re-RT) using stereotactic ablative radiotherapy (SABR) and initial SABR for primary, recurrent lung cancer or metastatic lung tumor.

Methods

A retrospective review of the medical records of 336 patients who underwent lung SABR was performed. Re-RT was defined as the overlap of the 70% isodose line of second-course SABR with that of the initial radiotherapy, and 20 patients were classified as the re-RT group. The median dose of re-RT using SABR was 54 Gy (range 48–60 Gy), and the median fraction number was 4 (range 4–6). One-to-three case-matched analysis with propensity score matching was used, and 60 patients were included in the initial SABR group of the matched cohort.

Results

The 1- and 2-year local control rates for the re-RT group were 73.9% and 63.3% and those for the initial SABR group in the matched cohort were 92.9% and 87.7%, respectively (P = 0.013). There was no difference in distant metastasis-free, progression-free, and overall survival rates. The crude grade ≥ 2 toxicity rates were 40.0% for the re-RT group and 25.0% for the initial SABR group (P = 0.318). Re-RT group had higher acute grade ≥ 2 toxicity rates (25.0% vs 5.0%,P = 0.031). One incident of grade 3 toxicity (pulmonary) was reported in the re-RT group; there was no grade 4‒5 toxicity.

Conclusions

The local control rate of the in-field re-RT SABR was lower than that of the initial SABR without compromising the survival rates. The toxicity of re-RT using SABR was acceptable.
Correlation between neutrophil-to-lymphocyte ratio and postoperative mortality in elderly patients with hip fracture: a meta-analysis
Authors: Chen Yu-Hang , Chou Ching-Hsin , Su Hsin-Hsien , Tsai Yu-Ting , Chiang Ming-Hsiu , Kuo Yi-Jie , Chen Yu-Pin
Published: November 2021

Introduction

The neutrophil-to-lymphocyte ratio (NLR) is a crucial prognosis predictor following several major operations. However, the association between NLR and the outcome after hip fracture surgery is unclear. In this meta-analysis, we investigated the correlation between NLR and postoperative mortality in geriatric patients following hip surgery.

Method

PubMed, Embase, Cochrane library, and Google Scholar were searched for studies up to June 2021 reporting the correlation between NLR and postoperative mortality in elderly patients undergoing surgery for hip fracture. Data from studies reporting the mean of NLR and its 95% confidence interval (CI) were pooled. Both long-term (≥ 1 year) and short-term (≤ 30 days) mortality rates were included for analysis.

Result

Eight retrospective studies comprising a total of 1563 patients were included. Both preoperative and postoperative NLRs (mean difference [MD]: 2.75, 95% CI: 0.23–5.27; P = 0.03 and MD: 2.36, 95% CI: 0.51–4.21; P = 0.01, respectively) were significantly higher in the long-term mortality group than in the long-term survival group. However, no significant differences in NLR were noted between the short-term mortality and survival groups (MD: − 1.02, 95% CI: − 3.98 to 1.93; P = 0.5).

Conclusion

Higher preoperative and postoperative NLRs were correlated with a higher risk of long-term mortality following surgery for hip fracture in the geriatric population, suggesting the prognostic value of NLR for long-term survival. Further studies with well-controlled confounders are warranted to clarify the predictive value of NLR in clinical practice in geriatric patients with hip fracture.
Use of a suspended and straightened knee joint position when fixing steel plates can prevent the increase in postoperative posterior tibial slope after open‑wedge high tibial osteotomy
Authors: Ma Wenru , Han Zengshuai , Sun Shengnan , Chen Jinli , Zhang Yi , Yu Tengbo
Published: November 2021

Background

Posterior tibial slope (PTS) increases after medial open-wedge high tibial osteotomy (OWHTO) is challenging for patients. This study aims to determine whether use of a suspended and straightened knee joint position during the fixing of steel plates can prevent an increase in the PTS after OWHTO.

Methods

This study retrospectively analyzed 112 subjects (122 knees) [34 males, 78 females; mean age 59.1 ± 6.6 (range 48–76) years; mean body mass index 28.06 ± 3.61 kg/m2] who underwent OWHTO. A total of 78 knees that were suspended and extended by placing a sterile cloth ball under the ipsilateral ankle during the fixing of steel plates comprised the suspended and straightened knee joint position (SSP) group, and 44 knees that were kept naturally straightened without placing a sterile cloth ball under the ipsilateral ankle during the fixing of steel plates comprised the naturally straightened knee joint position (NSP) group. Patients were clinically assessed according to the visual analog pain scale (VAS), the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, the Knee Society Scores (KSS) knee and function scores, the Hospital for Special Surgery (HSS) knee scores and the Lysholm knee scores. Radiological assessment was performed according to the changes in the PTS between preoperation, 1-day postoperation, and the final follow-up periods. Ultimately, the difference in postoperative PTS changes between the two groups was statistically analyzed. The median follow-up period was 2.2 years (range 1.6–3.7 years).

Results

In the final follow-up period, significant improvements were observed in the clinical VAS scores, WOMAC scores, KSS knee and function scores, HSS scores and the Lysholm knee scores in both groups (P < 0.001), and no difference was found between the two groups. Radiological assessment showed that there was no statistical difference in the preoperative PTS between the two groups. The 1-day postoperative PTS and the most recent follow-up PTS were significantly greater than the preoperative PTS in the NSP group (t = − 3.213, − 6.406, allP < 0.001), but no significant increase was seen in the SSP group (P > 0.05). The increase in PTS in the NSP group was significantly greater than that in the SSP group at the 1-day postoperative (t = 2.243,P = 0.030) and final follow-up periods (t = 6.501,P < 0.001).

Conclusions

For OWHTO, the use of a suspended and straightened knee joint position rather than a naturally straightened knee joint position during the fixing of steel plates could effectively prevent the increase in postoperative PTS.

Level of Evidence: Retrospective Study Level III.
Predictors of heart failure symptoms in hereditary hemorrhagic telangiectasia patients with hepatic arteriovenous malformations
Authors: Cusumano Lucas R. , Tesoriero Joseph A. , Wilsen Craig B. , Sayre James , Quirk Matthew , McWilliams Justin P.
Published: November 2021

Background

Hepatic arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT) patients are most commonly hepatic artery to hepatic venous shunts which can result in high-output heart failure. This condition can be debilitating and is a leading cause of liver transplantation in HHT patients. However, it is not known what characteristics can discriminate between asymptomatic patients and those who will develop heart failure symptoms.

Results

176 patients with HHT were evaluated with computed tomography angiography (CTA) between April 2004 and February 2019 at our HHT Center of Excellence. 63/176 (35.8%) patients were found to have hepatic AVMs on CTA. 18 of these patients were excluded because of the presence of another condition which could confound evaluation of heart failure symptoms. In the remaining 45 patients included in our cohort, 25/45 (55.6%) patients were classified as asymptomatic and 20/45 (44.4%) were classified as symptomatic, and these groups were compared.

In symptomatic patients, mean common hepatic artery (CHA) diameter was significantly higher (11.1 versus 8.4 mm) and mean hemoglobin levels were significantly lower (10.7 vs 12.6 g/dL). A stepwise multiple logistic regression analysis demonstrated that both CHA diameter and hemoglobin level were independent predictors of heart failure symptoms with ORs of 2.554 (95% CI 1.372–4.754) and 0.489 (95% CI 0.299–0.799), respectively. The receiver operator characteristic (ROC) curve of our analysis demonstrated an AUC of 0.906 (95% CI 0.816–0.996), sensitivity 80.0% (95% CI 55.7–93.4%), and specificity 75.0% (95% CI 52.9–89.4%).

Conclusions

CTA is an effective and easily reproducible method to evaluate hepatic involvement of HHT. Utilizing CTA, clinical, and laboratory data we determined CHA diameter and hemoglobin level were independent predictors of heart failure symptoms.
The genetic analysis of Chinese patients with clonal cytopenias using targeted next-generation sequencing
Authors: Zhang Lijuan , Shi YuYe , Chen Yue , Tao Shandong , Shi Wenting , He Zhengmei , Chen Kankan , Wang Chunling , Yu Liang
Published: November 2021

Background

Clonal hematopoiesis (CH) can be found in various myeloid neoplasms (MN), such as myelodysplastic syndromes (MDS), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), also in pre-MDS conditions.

Methods

Cytogenetics is an independent prognostic factor in MDS, and fluorescence in-situ hybridization (FISH) can be used as an adjunct to karyotype analysis. In the past 5 years, only 35 of 100 newly diagnosed MDS and MDS/MPN patients were identified abnormalities, who underwent the FISH panel. In addition, we examined a cohort of 51 cytopenic patients suspected MDS or MDS/MPN with a 20-gene next generation sequencing (NGS), including 35 newly diagnosed MN patients and 16 clonal cytopenias of undetermined significance (CCUS) patients.

Results

Compared with the CCUS group, the MN group had higher male ratio (22/13 vs 10/6), cytogenetics abnormalities rate (41.4% vs 21.4%) and frequency of a series of mutations, such as ASXL1 (28.6% vs 25%), U2AF1 (25.7% vs 25%), RUNX1 (20% vs 0.0%); also, higher adverse mutations proportion (75% vs 85.2%), and double or multiple mutations (54.3% vs 43.75%). There were 7 MN patients and 4 CCUS patients who experienced cardio-cerebrovascular embolism events demonstrated a significant difference between the two groups (25% vs 20%). Ten of the 11 patients had somatic mutations, half had DNA methylation, while the other half had RNA splicing. Additionally, six patients had disease transformation, and four patients had mutated U2AF1, including two CCUS cases and two MDS-EB cases. Following up to January 2021, there was no significant difference in over survival between the CCUS and MN groups.

Conclusion

NGS facilitates the diagnosis of unexplained cytopenias. The monitoring and management of CCUS is necessary, also cardio-cerebrovascular embolism events in patients with CH need attention in the clinical practice.
Conditional deletion of ROCK2 induces anxiety-like behaviors and alters dendritic spine density and morphology on CA1 pyramidal neurons
Authors: Weber Audrey J. , Adamson Ashley B. , Greathouse Kelsey M. , Andrade Julia P. , Freeman Cameron D. , Seo Jung Vin , Rae Rosaria J. , Walker Courtney K. , Herskowitz Jeremy H.
Published: November 2021

Rho-associated kinase isoform 2 (ROCK2) is an attractive drug target for several neurologic disorders. A critical barrier to ROCK2-based research and therapeutics is the lack of a mouse model that enables investigation of ROCK2 with spatial and temporal control of gene expression. To overcome this, we generated ROCK2fl/fl mice. Mice expressing Cre recombinase in forebrain excitatory neurons (CaMKII-Cre) were crossed with ROCK2fl/fl mice (Cre/ROCK2fl/fl), and the contribution of ROCK2 in behavior as well as dendritic spine morphology in the hippocampus, medial prefrontal cortex (mPFC), and basolateral amygdala (BLA) was examined. Cre/ROCK2fl/fl mice spent reduced time in the open arms of the elevated plus maze and increased time in the dark of the light–dark box test compared to littermate controls. These results indicated that Cre/ROCK2fl/fl mice exhibited anxiety-like behaviors. To examine dendritic spine morphology, individual pyramidal neurons in CA1 hippocampus, mPFC, and the BLA were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and neuronal 3D reconstructions for morphometry analysis. In dorsal CA1, Cre/ROCK2fl/fl mice displayed significantly increased thin spine density on basal dendrites and reduced mean spine head volume across all spine types on apical dendrites. In ventral CA1, Cre/ROCK2fl/fl mice exhibited significantly increased spine length on apical dendrites. Spine density and morphology were comparable in the mPFC and BLA between both genotypes. These findings suggest that neuronal ROCK2 mediates spine density and morphology in a compartmentalized manner among CA1 pyramidal cells, and that in the absence of ROCK2 these mechanisms may contribute to anxiety-like behaviors.
Immunoassay standardization for the detection of immunoglobulin A (IgA) against Porphyromonas gingivalis antigens in saliva of individuals with and without leprosy
Authors: Calheira Mariana Costa , Trindade Soraya Castro , Falcão Michelle Miranda Lopes , Barbosa Luciana Sales Conceição , Carvalho Gislene Regina Batista , Machado Paulo Roberto Lima , Gomes-Filho Isaac Suzart , de Jesus Campos Elisangela , de Carvalho-Filho Paulo Cirino , Xavier Márcia Tosta , de Farias Antonio Pedro Fróes , Filho José Tadeu Raynal Rocha , de Santana Passos-Soares Johelle
Published: November 2021

Leprosy reactions are immune processes that cause neural damage in individuals with leprosy. As periodontitis is an infectious disease related to its development, specific antibodies to periodontal pathogens must be evaluated to better understand the humoral mechanisms underlying this relationship. Therefore, the objective of this study was to standardize an immunoassay to measure IgA specific to P. gingivalis antigens in the saliva of individuals with leprosy. An ELISA checkerboard titration was performed. A validation test involving 53 individuals with leprosy, 24 with and 19 without periodontitis, was conducted and a ROC curve constructed to calculate sensitivity and specificity. The coefficient of the optical densities was 2.21 and 2.66 for P. gingivalis crude extract and the recombinant protein HmuY, respectively. Sensitivity and specificity for the P. gingivalis crude extract were 66.7% and 73.7%, respectively, and for HmuY, were 62.5% and 52.6%, respectively. Specific recognition of P. gingivalis occurred predominantly in individuals with periodontitis, which validates the use of this test for studying periodontitis in individuals with leprosy.

Trial registration CAEE 64476117.3.0000.0049, 21/07/2017, retrospectively registered
Infection with severe fever with thrombocytopenia virus in healthy population: a cohort study in a high endemic region, China
Authors: Ye Xiao-Lei , Dai Ke , Lu Qing-Bin , Huang Yan-Qin , Lv Shou-Ming , Zhang Pan-He , Li Jia-Chen , Zhang Hai-Yang , Yang Zhen-Dong , Cui Ning , Yuan Chun , Liu Kun , Zhang Xiao-Ai , Zhang Jiu-Song , Li Hao , Yang Yang , Fang Li-Qun , Liu Wei
Published: November 2021

Background

Severe fever with thrombocytopenia (SFTS) caused by SFTS virus (SFTSV) was a tick-borne hemorrhagic fever that posed significant threat to human health in Eastern Asia. The study was designed to measure the seroprevalence of SFTSV antibody in healthy population residing in a high endemic region.

Methods

A cohort study was performed on healthy residents in Shangcheng County in Xinyang City from April to December in 2018, where the highest SFTS incidence in China was reported. Anti-SFTSV IgG was measured by indirect enzyme-linked immunosorbent assay and neutralizing antibody (NAb) was detected by using PRNT50. The logistic regression models were performed to analyze the variables that were associated with seropositive rates.

Results

Totally 886 individuals were recruited. The baseline seroprevalence that was tested before the epidemic season was 11.9% (70/587) for IgG and 6.8% (40/587) for NAb, which was increased to 13.4% (47/350) and 7.7% (27/350) during the epidemic season, and further to 15.8% (80/508) and 9.8% (50/508) post epidemic. The IgG antibody-based seropositivity was significantly related to the patients aged ≥ 70 years old [adjusted odds ratio (OR) = 2.440, 95% confidence interval (CI): 1.334–4.461 compared to the group of < 50 years old, P = 0.004], recent contact with cats (adjusted OR = 2.195, 95% CI: 1.261–3.818, P = 0.005), and working in tea garden (adjusted OR = 1.698, 95% CI: 1.002–2.880, P = 0.049) by applying multivariate logistic regression model. The NAb based seropositivity was similarly related to the patients aged ≥ 70 years old (adjusted OR = 2.691, 95% CI: 1.271–5.695 compared to the group of < 50 years old, P = 0.010), and recent contact with cats (OR = 2.648, 95% CI: 1.419–4.941, P = 0.002). For a cohort of individuals continually sampled with 1-year apart, the anti-SFTSV IgG were maintained at a stable level, while the NAb level reduced.

Conclusions

Subclinical infection might not provide adequate immunity to protect reinfection of SFTSV, thus highlighting the ongoing threats of SFTS in endemic regions, which called for an imperative need for vaccine development. Identification of risk factors might help to target high-risk population for public health education and vaccination in the future.

Graphical Abstract
Improved quantitative microbiome profiling for environmental antibiotic resistance surveillance
Authors: Ott Amelie , Quintela-Baluja Marcos , Zealand Andrew M. , O’Donnell Greg , Haniffah Mohd Ridza Mohd , Graham David W.
Published: November 2021

Background

Understanding environmental microbiomes and antibiotic resistance (AR) is hindered by over reliance on relative abundance data from next-generation sequencing. Relative data limits our ability to quantify changes in microbiomes and resistomes over space and time because sequencing depth is not considered and makes data less suitable for Quantitative Microbial Risk Assessments (QMRA), critical in quantifying environmental AR exposure and transmission risks.

Results

Here we combine quantitative microbiome profiling (QMP; parallelization of amplicon sequencing and 16S rRNA qPCR to estimate cell counts) and absolute resistome profiling (based on high-throughput qPCR) to quantify AR along an anthropogenically impacted river. We show QMP overcomes biases caused by relative taxa abundance data and show the benefits of using unified Hill number diversities to describe environmental microbial communities. Our approach overcomes weaknesses in previous methods and shows Hill numbers are better for QMP in diversity characterisation.

Conclusions

Methods here can be adapted for any microbiome and resistome research question, but especially providing more quantitative data for QMRA and other environmental applications.
Risk of drug-induced cardiac arrhythmia during COVID-19 therapeutic treatment
Authors: Vitiello Antonio , Ferrara Francesco
Published: November 2021

Therapeutic treatment of severe COVID-19 infection involves the administration of multiple pharmacologic agents to reduce the risk of serious complications; this may result in drug interactions and possible adverse reactions and induced cardiotoxicity. The risk–benefit ratio associated with the use of medications to treat COVID-19 should be carefully monitored. In addition, the severe COVID-19 patient may experience cardiac damage, and alteration of normal cardiac electrophysiology function. Severe COVID-19 with cardiac involvement and the risk of drug-induced adverse reactions may cause cardiac arrhythmias, including long qt syndrome, which in some cases may lead to sudden death. In this short review we briefly review the pharmacological agents used to treat severe COVID-19 with increased risk of causing long qt forms.
Cerebral venous sinus thrombosis (CVST) associated with SARS-CoV-2 vaccines: clues for an immunopathogenesis common to CVST observed in COVID-19
Authors: Mazzeo Anna Teresa , Noto Alberto , Asmundo Alessio , Granata Francesca , Galletta Karol , Mallamace Raffaella , De Gregorio Cesare , Puliatti Francesco , Fazio Maria Carolina , Germano’ Antonino , Musolino Caterina , Ferlazzo Guido
Published: November 2021

Severe acute respiratory syndrome coronavirus type 2 has been responsible for an unprecedented pandemic, and nowadays, several vaccines proved to be effective and safe, representing the only available strategy to stop the pandemic. While millions of people have safely received vaccine, rare and unusual thrombotic events have been reported and are undergoing investigations to elucidate their nature. Understanding initial trigger, underlying pathophysiology and the reasons for specific site localization of thrombotic events are a matter of debate.

We here propose that rare cases of cerebral venous sinus thrombosis, a clinical event that may rapidly evolve to brain death, reported after COVID-19 vaccine, might be consequent to an immune response resulting in inflamed/damaged endothelium, an event similar to that described for cases of cerebral venous sinus thrombosis reported during COVID-19 and not necessarily related to anti-Platelets Factor 4 antibodies, as recently described. Remarkably, in the two patients presenting at our hospital with cerebral venous sinus thrombosis and evolved to brain death, proper tissue perfusion and function maintenance allowed organ donation despite extensive thrombosis in the organ donors, with favorable outcome at 6 months.

Increased vigilance, close multidisciplinary collaboration, and further prospective research will help to better elucidate a very rare and still not fully understood pathophysiological event associated with vaccines for severe acute respiratory syndrome coronavirus 2.
Venetoclax in Previously Treated Waldenström Macroglobulinemia
Authors: Castillo Jorge J. , Allan John N. , Siddiqi Tanya , Advani Ranjana H. , Meid Kirsten , Leventoff Carly , White Timothy P. , Flynn Catherine A. , Sarosiek Shayna , Branagan Andrew R. , Demos Maria G. , Guerrera Maria L. , Kofides Amanda , Liu Xia , Munshi Manit , Tsakmaklis Nicholas , Xu Lian , Yang Guang , Patterson Christopher J. , Hunter Zachary R. , Davids Matthew S. , Furman Richard R. , Treon Steven P.
Published: November 2021

PURPOSE

BCL2 is overexpressed and confers prosurvival signaling in malignant lymphoplasmacytic cells in Waldenström macroglobulinemia (WM). Venetoclax is a potent BCL2 antagonist and triggers in vitro apoptosis of WM cells. The activity of venetoclax in WM remains to be clarified.

PATIENTS AND METHODS

We performed a multicenter, prospective phase II study of venetoclax in patients with previously treated WM ( NCT02677324 ). Venetoclax was dose-escalated from 200 mg to a maximum dose of 800 mg daily for up to 2 years.

RESULTS

Thirty-two patients were evaluable, including 16 previously exposed to Bruton tyrosine kinase inhibitors (BTKis). All patients were MYD88 L265P–mutated, and 17 carried CXCR4 mutations. The median time to minor and major responses was 1.9 and 5.1 months, respectively. Previous exposure to BTKis was associated with a longer time to response (4.5 v 1.4 months; P < .001). The overall, major, and very good partial response rates were 84%, 81%, and 19%, respectively. The major response rate was lower in those with refractory versus relapsed disease (50% v 95%; P = .007). The median follow-up time was 33 months, and the median progression-free survival was 30 months. CXCR4 mutations did not affect treatment response or progression-free survival. The only recurring grade ≥ 3 treatment-related adverse event was neutropenia (n = 14; 45%), including one episode of febrile neutropenia. Laboratory tumor lysis without clinical sequelae occurred in one patient. No deaths have occurred.

CONCLUSION

Venetoclax is safe and highly active in patients with previously treated WM, including those who previously received BTKis. CXCR4 mutation status did not affect treatment response.
Research Evaluating Staff Training Online for Resilience (RESTORE): Protocol for a single-arm feasibility study of an online Acceptance and Commitment Therapy intervention to improve staff wellbeing in palliative care settings
Authors: Finucane Anne , Hulbert-Williams Nicholas J , Swash Brooke , Spiller Juliet A , Lydon Brigid , Gillanders David
Published: November 2021

Background

Palliative care workers commonly experience workplace stress and distress. General stressors include unmanageable workloads and staff shortages.  Stressors specific to palliative care include regular exposure to death, loss and grief.  The COVID pandemic exacerbated exhaustion and burnout across the healthcare system, including for those providing palliative care.  Evidence based psychological support interventions, tailored to the needs and context of palliative care workers, are needed.  Acceptance and Commitment Therapy (ACT) is an established form of cognitive behavioural therapy which uses behavioural psychology, values, acceptance, and mindfulness techniques to improve mental health and wellbeing. ACT is effective in improving workplace wellbeing in many occupational settings.  Our study examines the acceptability and feasibility of an online ACT-based intervention to improve mental health and wellbeing in staff caring for people with an advanced progressive illness.

Methods

A single-arm feasibility trial.  We will seek to recruit 30 participants to take part in an 8- week online ACT-based intervention, consisting of three synchronous facilitated group sessions and five asynchronous self-directed learning modules.  We will use convergent mixed methods to evaluate the feasibility of the intervention. Quantitative feasibility outcomes will include participant recruitment and retention rates, alongside completion rates of measures assessing stress, quality of life, wellbeing, and psychological flexibility.  Focus groups and interviews will explore participant perspectives on the intervention. We will run a stakeholder workshop to further refine the intervention and identify outcomes for use in a future evaluation.

Results

We will describe participant perspectives on intervention acceptability, format, content, and perceived impact alongside rates of intervention recruitment, retention, and outcome measure completion.

Conclusion

We will show whether a brief, online ACT intervention is acceptable to, and feasible for palliative care workers.  Findings will be used to further refine the intervention and provide essential information on outcome assessment prior to a full-scale evaluation.
Quantifying the economic burden of unintended pregnancies due to drug–drug interactions with hormonal contraceptives from the United States payer perspective
Authors: Srinivasan Meenakshi , White Annesha , Lott Jason , Williamson Todd , Kong Sheldon X , Plouffe Leo
Published: November 2021

Background:In the United States of America (USA), nearly 10 million women use oral contraceptives (OCs). Concomitant administration of certain medications can result in contraceptive failure, and consequently unintended pregnancies due to drug–drug interactions (DDIs). The objective of this analysis was to estimate the economic impact of unintended pregnancies due to DDIs among women of reproductive age using an OC alone or in combination with an enzyme inducer co-medication in the USA from a payer perspective.

Methods:A Markov model using a cohort of 1,000 reproductive-age women was developed to estimate costs due to contraceptive failure for OC aloneversusOC with concomitant enzyme inducer drugs. All women were assumed to begin an initial state, continuing until experiencing an unintended pregnancy. Unintended pregnancies could result in birth, induced abortion, spontaneous abortion, or ectopic pregnancy. The cohort was analyzed over a time horizon of 1 year with a cycle length of 1 month. Estimates of costs and probabilities of unintended pregnancy outcomes were obtained from the literature. Probabilities from the Markov cohort trace was used to estimate number of pregnancy outcomes.

Results:On average, enzyme inducers resulted in 20 additional unintended pregnancies with additional unadjusted and adjusted costs median (range) of USD136,304 (USD57,436–USD320,093) and USD65,146 (USD28,491–USD162,635), respectively. The major component of the direct cost is attributed to the cost of births. Considering the full range of events, DDIs with enzyme inducers could result in 16–25 additional unintended pregnancies and total unadjusted and adjusted costs ranging between USD46,041 to USD399,121 and USD22,839 to USD202,788 respectively.

Conclusion:The direct costs associated with unintended pregnancies due to DDIs may be substantial and are potentially avoidable. Greater awareness of DDI risk with oral contraceptives among payers, physicians, pharmacists and patients may reduce unintended pregnancies in at-risk populations.