bluuebunny/crossref_metadata_2025 huggingface dataset:
Chlamydia Treatment Practices and Time to Treatment in Massachusetts: Directly Observed Therapy Versus Pharmacy Prescriptions
Authors: Platt Laura , Elder Heather , Bassett Ingrid V. , Molotnikov Lauren , Klevens Monina , O’Connor Erin , Leach Dylan , Roosevelt Kathleen , Hsu Katherine
Published: September 2021

Background

Directly observed therapy (DOT) is recommended for the treatment of chlamydia, however pharmacy prescriptions are frequently used. Adherence to DOT and the association between treatment method and time to treatment is unknown.

Methods

We conducted a retrospective review of a randomized 2% of laboratory-confirmed chlamydia infections reported to the Massachusetts Department of Public Health from January 1, 2019 to May 31, 2019. Clinicians and pharmacies were contacted to ascertain treatment methods and timing. We assessed frequency of DOT and pharmacy prescriptions in the treatment of chlamydia infection in Massachusetts. We used log rank test to compare time to treatment initiation for patients receiving DOT versus pharmacy prescriptions. Data were stratified according to whether treatment was empiric or laboratory-driven.

Key results

We ascertained full outcomes for 199 patients. Eighty patients received DOT and 119 patients received pharmacy prescriptions. DOT was more common among those receiving empiric treatment and pharmacy prescriptions were more common among those receiving laboratory-driven treatment. The median time to treatment was 1.5 days for patients treated with DOT and 3 days for those treated with pharmacy prescriptions. For both groups, the median time to treatment for empiric therapy was 0 days and for laboratory-driven therapy was 4 days. The differences in time to treatment were not statistically significant.

Conclusions

Pharmacy prescriptions are frequently used for the treatment of chlamydia in Massachusetts. We did not observe a significant difference in the time to treatment between DOT and pharmacy prescriptions.
Body Composition in Community-Dwelling Older Adults Before and After SARS-CoV-2 Infection: A Longitudinal Prospective Study in a Rural Village Struck by the Pandemic
Authors: Del Brutto Oscar H. , Mera Robertino M. , Rumbea Denisse A. , Pérez Pedro , Recalde Bettsy Y. , Sedler Mark J.
Published: September 2021

Background:

Information on the body composition of inhabitants of remote communities during the SARS-CoV-2 pandemic is limited. Using a longitudinal population-based study design, we assessed the association between SARS-CoV-2 infection and changes in body composition.

Methods:

Community-dwelling older adults living in a rural Ecuadorian village received body composition determinations before and 1 year after the pandemic as well as serological tests for detection of SARS-CoV-2 antibodies. The independent association between SARS-CoV-2 infection and abnormalities in body composition at follow-up was assessed by fitting linear mixed models for longitudinal data.

Results:

Of 327 enrolled individuals, 277 (85%) received baseline and follow-up body composition determinations, and 175 (63%) of them became SARS-CoV-2 seropositive. Overall, diet and physical activity deteriorated during the follow-up. Multivariate random-effects generalized least squares regression models that included the impact of time and seropositivity on follow-up body composition, showed that neither variable contributed to a worsening in body composition. Multivariate logistic regression models disclosed that the serological status at follow-up cannot be predicted by differences in body composition and other baseline covariates.

Conclusions:

Study results suggest no increased susceptibility to SARS-CoV-2 infection among older adults with abnormal body composition and no significant changes as a result of worse physical activity and dietary habits or seropositivity during the length of the study. Together with a previous study in the same population that showed decrease in hand-grip strength after SARS-CoV-2, results confirm that dynapenia (and not sarcopenia) is associated with SARS-CoV-2 infection in older adults.
South African Executives Propensity to Use, Diffuse, and Adopt the Humanitarian Logistics Digital Business Ecosystem (HLDBE)
Authors: Baffoe Benjamin Ohene Kwapong , Luo Wenping
Published: September 2021

The employment of advanced technology in sustaining South African humanitarian organizations and business logistics firms has been a crucial concern for many years. The aim of this study is to examine the propensity of senior executives to use, diffuse, and adopt Humanitarian Logistics Digital Business Ecosystem (HLDBE) as another future sustainable tool. A PLS-SEM multivariate analysis was conducted using technology innovation theories to understand their perceived interest. The findings indicated that donor/top-level management support (D_TLMS), normative pressure (NP), perceived compatibility (PC), and perceived safety and security concerns (PSSC) served as essential factors that influenced decision-makers decision to use, diffuse, and adopt HLDBE with their noted concerns indicated. An IPMA analysis was also used in assisting executives on important factors to improve. Implications, limitations, and further research directions are therein proposed.
Intraoperative Measurement of Endotracheal Tube Cuff Pressure and Its Change During Surgery in Correlation With Recurrent Laryngeal Nerve Palsies, Hoarseness, and Dysphagia After Anterior Cervical Discectomy and Fusion: A Prospective Randomized Controlled Trial
Authors: Sejkorová Alena , Bolcha Martin , Beneš Jan , Kalhous Jiří , Sameš Martin , Vachata Petr
Published: September 2021

Study Design

Prospective randomized controlled trial.

Objectives

Adjustment of endotracheal tube cuff pressure (ETCP) in anterior cervical discectomy and fusion (ACDF) may influence the incidence of complications such as recurrent laryngeal nerve palsy (RLNP), hoarseness, and dysphagia.

Methods

The prospective randomized controlled trial was designed to investigate the influence of ETCP on the incidence of postoperative complications. All eligible patients underwent vocal cord examination before and after ACDF and were randomized into a control group (CG) and intervention group (IG). Endotracheal tube cuff pressure was passively monitored in CG, and in IG, it was maintained at 20 mmHg. Outcomes were evaluated during hospitalization and during follow-up.

Results

A total of 98 patients were randomized, each group consisted of 49 patients. Statistical analysis showed that gender and age did not influence the incidence of complications. In CG, duration of retractor placement and extent of approach significantly impacted the occurrence of complications. The incidence of postoperative RLNP was 8.2% in IG and 12.2% in CG, hoarseness and dysphonia were present in 18.4% in IG and in 37.5% in CG, and dysphagia in 20.8% in IG and in 22.5% in CG. Hoarseness was significantly present more in CG ( P = .018). Only one patient from CG presented with RLNP after 1 year, the remaining nine patients spontaneously recovered.

Conclusions

Unregulated ETCP can lead to a significantly higher incidence of hoarseness; however, its improvement rate is 100%. The early postoperative complication rate was higher in CG, and after one year, 1 patient had RLNP and 1 patient had dysphagia.
Employee Voice, Employee Involvement, and Organizational Change Readiness: Mediating Role of Commitment-to-Change and Moderating Role of Transformational Leadership
Authors: Potnuru Rama Krishna Gupta , Sharma Rohini , Sahoo Chandan Kumar
Published: September 2021

This study explores the antecedents for organizational change readiness for altering the status quo and empirically validates few potent tools which facilitate change. By drawing on change management literature, this study examines the influence of employee voice (EV) and employee involvement (EI) on commitment-to-change (CTC), considering the latter as a mediating variable in the relation between antecedent human resources practices (EV and EI) and organizational change readiness (OCR). Subsequently, the moderating role of transformational leadership was analyzed on these posited relationships. The hypotheses proposed in the research model are tested on a sample of 516 employees from an Indian public sector organization, applying Baron and Kenny’s (1986) technique for establishing mediation and Ping’s approach to moderated structured equation modeling for moderation. The findings suggest that CTC partially mediates the relationship between EV and OCR, but it does not mediate between EI and OCR. Likewise, the study results also empirically validate that the relationship between EV and CTC is enhanced if leadership is transformational, also the hypothesis positing the moderating role of transformational leadership between EI and CTC was supported.
Hamstrings Contraction Regulates the Magnitude and Timing of the Peak ACL Loading During the Drop Vertical Jump in Female Athletes
Authors: Ueno Ryo , Navacchia Alessandro , Schilaty Nathan D. , Myer Gregory D. , Hewett Timothy E. , Bates Nathaniel A.
Published: September 2021

Background:

Anterior cruciate ligament (ACL) injury reduction training has focused on lower body strengthening and landing stabilization. In vitro studies have shown that quadriceps forces increase ACL strain, and hamstring forces decrease ACL strain. However, the magnitude of the effect of the quadriceps and hamstrings forces on ACL loading and its timing during in vivo landings remains unclear.

Purpose:

To investigate the effect and timing of knee muscle forces on ACL loading during landing.

Study Design:

Descriptive laboratory study.

Methods:

A total of 13 young female athletes performed drop vertical jump trials, and their movements were recorded with 3-dimensional motion capture. Lower limb joint motion and muscle forces were estimated with OpenSim and applied to a musculoskeletal finite element (FE) model to estimate ACL loading during landings. The FE simulations were performed with 5 different conditions that included/excluded kinematics, ground-reaction force (GRF), and muscle forces.

Results:

Simulation of landing kinematics without GRF or muscle forces yielded an estimated median ACL strain and force of 5.1% and 282.6 N. Addition of GRF to kinematic simulations increased ACL strain and force to 6.8% and 418.4 N ( P < .05). Addition of quadriceps force to kinematics + GRF simulations nonsignificantly increased ACL strain and force to 7.2% and 478.5 N. Addition of hamstrings force to kinematics + GRF simulations decreased ACL strain and force to 2.6% and 171.4 N ( P < .001). Addition of all muscles to kinematics + GRF simulations decreased ACL strain and force to 3.3% and 195.1 N ( P < .001). With hamstrings force, ACL loading decreased from initial contact (time of peak: 1-18 milliseconds) while ACL loading without hamstrings force peaked at 47 to 98 milliseconds after initial contact ( P = .024-.001). The knee flexion angle increased from 20.9° to 73.1° within 100 milliseconds after initial contact.

Conclusion:

Hamstrings activation had greater effect relative to GRF and quadriceps activation on ACL loading, which significantly decreased and regulated the magnitude and timing of ACL loading during in vivo landings.

Clinical Relevance:

Clinical training should focus on strategies that influence increased hamstrings activation during landing to reduce ACL loads.
Transcriptome-wide Gene Expression Analysis in Peri-implantitis Reveals Candidate Cellular Pathways
Authors: Martin A. , Zhou P. , Singh B.B. , Kotsakis G.A.
Published: September 2021

Objective:

Peri-implantitis is a condition resulting in destructive inflammation in the peri-implant soft tissue barrier. Clinically, it demonstrates vast clinical differences to periodontitis that suggest distinct inflammatory mechanisms. Implant-derived titanium particles (i-TiPs) frequently found around diseased implants appear to alter the microenvironment and confer resistance to antibiotic treatments. Studies in orthopedic implants have demonstrated potent inflammatory responses to i-TiPs involving a variety of cell types in aseptic conditions. Nonetheless, the genetic programs of cells surveilling and supporting the peri-implant soft tissue barrier in response to the combined challenges of biomaterial degradation products and oral bacteria are poorly defined. Thus, we studied gene expression specific to oral peri-implant inflammatory disease.

Methods:

Peri-implant tissues were collected from healthy or diseased implants (N = 10) according to the 2018 classification criteria. Following RNA extraction and purification, a gene-level view of the transcriptome was obtained via a next-generation transcriptome-wide microarray profiling workflow (Clariom S; Applied Biosystems) that covers >20,000 well-annotated genes. A discovery analysis assessed global differential expression of genes and identified pathways in peri-implant health versus disease.

Results:

Genes involved in the endosomal-lysosomal pathway, such as actin polymerization, were strongly upregulated in diseased tissues (P < .05), proposing increased intracellular activities in response to bacteria and i-TiPs. Cellular respiration pathways involved in oxidative stress were highly transcribed in all peri-implant samples, suggesting that implant-specific factors may trigger a constant state of oxidative stress.

Conclusion:

Within the limitations of this discovery study, expressive upregulation of genes in the endosomal-lysosomal and oxidative stress pathway suggests that inflammation related to receptor-driven responses to extracellular signals, such as i-TiPs and pathogens, may have a crucial role in peri-implantitis. Results warrant external replication in validation cohorts.

Knowledge Transfer Statement:

Our findings regarding physiologic processes affected by peri-implantitis could advance knowledge of the mechanisms and consequences of the disease. Understanding the cellular programs that partake in peri-implant inflammation has the potential to translate to novel treatment strategies for patients with peri-implantitis.
Patients’ Willingness to Share Limited Endoscopic Resources: A Brief Report on the Results of a Large Regional Survey
Authors: Piper Marc S. , Zikmund-Fisher Brian J. , Maratt Jennifer K. , Kurlander Jacob , Metko Valbona , Waljee Akbar K. , Saini Sameer D.
Published: September 2021

Background. In some health care systems, patients face long wait times for screening colonoscopy. We sought to assess whether patients at low risk for colorectal cancer (CRC) would be willing to delay their own colonoscopy so higher-risk peers could undergo colonoscopy sooner. Methods. We surveyed 1054 Veterans regarding their attitudes toward repeat colonoscopy and risk-based prioritization. We used multivariable regression to identify patient factors associated with willingness to delay screening for a higher-risk peer. Results. Despite a physician recommendation to stop screening, 29% of respondents reported being “not at all likely” to stop. However, 94% reported that they would be willing to delay their own colonoscopy for a higher-risk peer. Greater trust in physician and greater health literacy were positively associated with willingness to wait, while greater perceived threat of CRC and Black or Latino race/ethnicity were negatively associated with willingness to wait. Conclusion. Despite high enthusiasm for repeat screening, patients were willing to delay their own colonoscopy for higher-risk peers. Appealing to altruism could be effective when utilizing scarce resources.
Association of Asthma and Rhinitis with Epigenetics of Coronavirus Related Genes
Authors: Rathod Aniruddha , Rathod Rutu , Zhang Hongmei , Rahimabad Parnian Kheirkhah , Karmaus Wilfried , Arshad Hasan
Published: September 2021

Introduction:

Susceptibility factors for coronavirus disease 2019 (COVID-19) include sex and medical conditions such as asthma and rhinitis. DNA methylation (DNAm) is associated with asthma, rhinitis, and several viruses. We examined associations of asthma/rhinitis with DNAm at CpGs located on coronavirus related genes, and if these associations were sex-specific.

Methods:

In total, n = 242 subjects aged 26 years from the Isle of Wight Birth Cohort were included in the study. Linear regressions were used to examine sex specific and non-specific associations of DNAm at CpGs on coronavirus related genes with asthma/rhinitis status. Associations of DNAm with gene expression in blood were assessed for functional relevance of identified CpGs.

Results:

Statistically significant interaction effects of asthma or rhinitis with sex were identified at 40 CpGs for asthma and 27 CpGs for rhinitis. At 21 CpGs, DNAm was associated with asthma, and at 45 CpGs with rhinitis, regardless of sex. Assessment of functional relevance of the identified CpGs indicated a potential of epigenetic regulatory functionality on gene activity at 14 CpGs for asthma and 17 CpGs for rhinitis, and of those 6 CpGs for asthma and 7 CpGs for rhinitis were likely to be sex-specific.

Conclusion:

Subjects with asthma/rhinitis may have altered susceptibility to COVID-19 due to changes in their DNAm associated with these conditions. Sex specificity on association of asthma/rhinitis with DNAm at certain CpGs, and on the association of DNAm at asthma/rhinitis-linked CpGs with gene expression have the potential to explain the reported sex-specificity in COVID-19 morbidity and mortality.
Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma
Authors: Wang Ying , Li Chunrui , Xia Jieyun , Li Ping , Cao Jiang , Pan Bin , Tan Xu , Li Hujun , Qi Kunming , Wang Xiangmin , Shi Ming , Jing Guangjun , Yan Zhiling , Cheng Hai , Zhu Feng , Sun Haiying , Sang Wei , Li Depeng , Zhang Xi , Li Zhenyu , Zheng Junnian , Liang Aibin , Zhou Jianfeng , Xu Kailin
Published: September 2021

Systematic and dynamic humoral immune reconstitution is little-known for patients with relapsed/refractory (R/R) multiple myeloma (MM) who received anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy. We investigated the kinetics of B-cell, normal plasma cell, and immunoglobulin recovery in 40 patients who achieved ongoing response after anti-BCMA CAR T-cell therapy. All patients developed B-cell aplasia and the median duration of B-cell aplasia was 70 days (range, 23-270). The B-cell count reached its nadir on median day 7 and returned to baseline level on median day 97. BCMA+ cells in bone marrow turned undetectable on median day 28 (13-159) in 94.87% (37 of 39) of patients. Normal plasma cells in bone marrow were first redetected on median day 212. All patients developed a significant decrease in serum IgG, IgA, and IgM on median day 60. At year 1, recovery of serum IgG, IgM, and IgA was observed in 53.33% (8 of 15; non-IgG MM), 73.08% (19 of 26; non-IgM MM), and 23.81% (5 of 21;non-IgA MM) of the patients, respectively. Median time to IgG, IgM, and IgA recovery were days 386, 254, and not reached during follow-up, respectively. Virus-specific IgG levels decreased with loss of protection. Twenty-three of 40 (57.5%) patients had a total of 44 infection events. There were no infection-related deaths. These results reveal a 7-month aplasia of bone marrow normal plasma cells and longer period of hypogammaglobulinemia, suggesting a profound and lasting humoral immune deficiency after anti-BCMA CAR T-cell therapy, especially for IgA.
Rational biomarker development for the early and minimally invasive monitoring of AML
Authors: Abdelhamed Sherif , Butler John T. , Jung Seul , Chen Ding-Wen , Jenkins Gaye , Gao Lina , Lim Jeong Y. , Klco Jeffery M. , Horton Terzah M. , Kurre Peter
Published: September 2021

Recurrent disease remains the principal cause for treatment failure in acute myeloid leukemia (AML) across age groups. Reliable biomarkers of AML relapse risk and disease burden have been problematic, as symptoms appear late and current monitoring relies on invasive and cost-ineffective serial bone marrow (BM) surveillance. In this report, we discover a set of unique microRNA (miRNA) that circulates in AML-derived vesicles in the peripheral blood ahead of the general dissemination of leukemic blasts and symptomatic BM failure. Next-generation sequencing of extracellular vesicle-contained small RNA in 12 AML patients and 12 controls allowed us to identify a panel of differentially incorporated miRNA. Proof-of-concept studies using a murine model and patient-derived xenografts demonstrate the feasibility of developing miR-1246, as a potential minimally invasive AML biomarker.
FlowCT for the analysis of large immunophenotypic data sets and biomarker discovery in cancer immunology
Authors: Botta Cirino , Maia Catarina , Garcés Juan-José , Termini Rosalinda , Perez Cristina , Manrique Irene , Burgos Leire , Zabaleta Aintzane , Alignani Diego , Sarvide Sarai , Merino Juana , Puig Noemi , Cedena María-Teresa , Rossi Marco , Tassone Pierfrancesco , Gentile Massimo , Correale Pierpaolo , Borrello Ivan , Terpos Evangelos , Jelinek Tomas , Paiva Artur , Roccaro Aldo , Goldschmidt Hartmut , Avet-Loiseau Hervé , Rosinol Laura , Mateos Maria-Victoria , Martinez-Lopez Joaquin , Lahuerta Juan-José , Bladé Joan , San-Miguel Jesús F. , Paiva, Bruno
Published: September 2021

Large-scale immune monitoring is becoming routinely used in clinical trials to identify determinants of treatment responsiveness, particularly to immunotherapies. Flow cytometry remains one of the most versatile and high throughput approaches for single-cell analysis; however, manual interpretation of multidimensional data poses a challenge when attempting to capture full cellular diversity and provide reproducible results. We present FlowCT, a semi-automated workspace empowered to analyze large data sets. It includes pre-processing, normalization, multiple dimensionality reduction techniques, automated clustering, and predictive modeling tools. As a proof of concept, we used FlowCT to compare the T-cell compartment in bone marrow (BM) with peripheral blood (PB) from patients with smoldering multiple myeloma (SMM), identify minimally invasive immune biomarkers of progression from smoldering to active MM, define prognostic T-cell subsets in the BM of patients with active MM after treatment intensification, and assess the longitudinal effect of maintenance therapy in BM T cells. A total of 354 samples were analyzed and immune signatures predictive of malignant transformation were identified in 150 patients with SMM (hazard ratio [HR], 1.7; P < .001). We also determined progression-free survival (HR, 4.09; P < .0001) and overall survival (HR, 3.12; P = .047) in 100 patients with active MM. New data also emerged about stem cell memory T cells, the concordance between immune profiles in BM and PB, and the immunomodulatory effect of maintenance therapy. FlowCT is a new open-source computational approach that can be readily implemented by research laboratories to perform quality control, analyze high-dimensional data, unveil cellular diversity, and objectively identify biomarkers in large immune monitoring studies. These trials were registered at www.clinicaltrials.gov as #NCT01916252 and #NCT02406144.
t(4;12)(q12;p13) ETV6-rearranged AML without eosinophilia does not involve PDGFRA: relevance for imatinib insensitivity
Authors: Mueller Sarah B. , Dal Cin Paola , Le Long P. , Dias-Santagata Dora , Lennerz Jochen K. , Iafrate A. John , Marble Hetal Desai , Brunner Andrew M. , Weinstock Matthew J. , Luskin Marlise R. , De Angelo Daniel J. , Stone Richard M. , Nardi Valentina
Published: September 2021

Acute myeloid leukemia (AML) with t(4;12)(q12;p13) translocation is rare and often associated with an aggressive clinical course and poor prognosis. Previous reports based on fluorescence in situ hybridization (FISH) analysis have suggested that ETV6::PDGFRA fusions are present in these patients, despite the absence of eosinophilia, which is typically found in other hematopoietic malignancies with PDGFRA-containing fusions. We first detected an ETV6-SCFD2 fusion by targeted RNA sequencing in a patient with t(4;12)(q12;p13) who had been diagnosed with an ETV6-PDGFRA fusion by FISH analysis but failed to respond to imatinib. We then retrospectively identified 4 additional patients with AML and t(4;12)(q12;p13) with apparent ETV6-PDGFRA fusions using chromosome and FISH analysis and applied targeted RNA sequencing to archival material. We again detected rearrangements between ETV6 and non-PDGFRA 4q12 genes, including SCFD2, CHIC2, and GSX2. None of the 3 patients who received imatinib based on the incorrect assumption of an ETV6-PDGFRA fusion responded. Our findings highlight the importance of using a sequencing-based assay to confirm the presence of targetable gene fusions, particularly in genomic regions, such as 4q12, with many clinically relevant genes that are too close to resolve by chromosome or FISH analysis. Finally, combining our data and review of the literature, we show that sequence-confirmed ETV6-PDGFRA fusions are typically found in eosinophilic disorders (3/3 cases), and patients with t(4;12)(q12;p13) without eosinophilia are found to have other 4q12 partners on sequencing (17/17 cases).
VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis
Authors: Kennedy Vanessa E. , Wong Chelsea C. , Hong Jessica M. , Peng Theodore , Brondfield Sam , Reilly Linda M. , Cornett Patricia , Leavitt Andrew D.
Published: September 2021

We report a case of vaccine-induced immune thrombotic thrombocytopenia (VITT) in a young man diagnosed 13 days after Ad26.COV2.S COVID-19 (Johnson & Johnson/Janssen) vaccination. He presented to us with 5 days of progressive left leg pain, thrombocytopenia, hypofibrinogenemia, and markedly elevated d-dimers, but without radiographically demonstrable thrombosis. Despite negative imaging, we initiated treatment of presumptive VITT given the striking clinical picture that included the timing of his recent adenovirus-based COVID-19 vaccine, leg symptoms, marked thrombocytopenia, and consumptive coagulopathy. He received intravenous immune globulin, prednisone, and argatroban and was discharged 7 days later much improved. His positive platelet factor 4 enzyme-linked immunosorbent assay antibody test returned after treatment was initiated. To our knowledge, this is the first reported case of VITT following Ad26.COV2.S vaccination presenting without radiographically demonstrable thrombosis. Our patient highlights the importance of knowing vaccine status and initiating treatment as soon as possible in the right clinical setting, even in the absence of radiographic evidence of thrombus. Early VITT recognition and treatment provide an opportunity to prevent serious thrombotic complications.
Association of early-life factors with prematurity-associated lung disease: prospective cohort study
Authors: Hart Kylie , Cousins Michael , Watkins W. John , Kotecha Sarah J. , Henderson A. John , Kotecha Sailesh
Published: September 2021

Background

Although bronchopulmonary dysplasia (BPD) is associated with lung function deficits in childhood, many who develop BPD have normal lung function in childhood and many without BPD, including those born at 33–34 weeks of gestation, have lung dysfunction in childhood. Since the predictability of BPD for future lung deficits is increasingly doubted, we prospectively recruited preterm-born children to identify early-life factors associated with lung function deficits after preterm birth.

Methods

From 767 children aged 7–12 years who had their respiratory symptoms assessed, and had spirometry before and after a bronchodilator in our Respiratory Health Outcomes in Neonates (RHiNO) study, 739 (544 preterm-born at ≤34 weeks of gestation and 195 term-born) had satisfactory lung function. Data were analysed using multivariable logistic regression and mediation.

Results

When preterm-born children were classified according to their lung function, low lung function (prematurity-associated lung disease (PLD)) was associated with BPD, gestation and intra-uterine growth restriction (IUGR) on univariable logistic regression analyses. However, on multivariable logistic regression analyses, gestation (β= –0.153,se0.051; p=0.003) and IUGR (OR 1.783, 95% CI 1.06–3.00; p=0.029) remained significantly associated with later deficits of lung function, but BPD (OR 0.99, 95% CI 0.52–1.89; p=0.974) did not. Mediation analyses confirmed these results.

Conclusions

Although traditionally BPD has been associated with low lung function in later life, the data show that gestation and IUGR are significantly associated with PLD in childhood, but BPD is not. By identifying children with PLD, we can better understand the underlying mechanisms and develop optimal therapies.
Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension
Authors: Toshner Mark , Church Colin , Harbaum Lars , Rhodes Christopher , Villar Moreschi Sofia S. , Liley James , Jones Rowena , Arora Amit , Batai Ken , Desai Ankit A. , Coghlan John G. , Gibbs J. Simon R. , Gor Dee , Gräf Stefan , Harlow Louise , Hernandez-Sanchez Jules , Howard Luke S. , Humbert Marc , Karnes Jason , Kiely David G. , Kittles Rick , Knightbridge Emily , Lam Brian , Lutz Katie A. , Nichols William C. , Pauciulo Michael W. , Pepke-Zaba Joanna , Suntharalingam Jay , Soubrier Florent , Trembath Richard C. , Schwantes-An Tae-Hwi L. , Wort S. John , Wilkins Martin R. , Gaine Sean , Morrell Nicholas W. , Corris Paul A.
Published: September 2021

Background

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling.

Methods

We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg−1) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a mendelian randomisation study was undertaken on 11 744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels.

Results

We recruited 29 patients (male/female 10/19; mean±sdage 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the leadIL6Rvariant on risk of PAH (OR 0.99, p=0.88).

Conclusion

Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
ROSE: radiology, obstruction, symptoms and exposure – a Delphi consensus definition of the association of COPD and bronchiectasis by the EMBARC Airways Working Group
Authors: Traversi Letizia , Miravitlles Marc , Martinez-Garcia Miguel Angel , Shteinberg Michal , Bossios Apostolos , Dimakou Katerina , Jacob Joseph , Hurst John R. , Paggiaro Pier Luigi , Ferri Sebastian , Hillas Georgios , Vogel-Claussen Jens , Dettmer Sabine , Aliberti Stefano , Chalmers James D. , Polverino Eva
Published: September 2021

Introduction

The coexistence of COPD and bronchiectasis seems to be common and associated with a worse prognosis than for either disease individually. However, no definition of this association exists to guide researchers and clinicians.

Methods

We conducted a Delphi survey involving expert pulmonologists and radiologists from Europe, Turkey and Israel in order to define the “COPD– [bronchiectasis] BE association”.

A panel of 16 experts from EMBARC selected 35 statements for the survey after reviewing scientific literature. Invited participants, selected on the basis of expertise, geographical and sex distribution, were asked to express agreement on the statements. Consensus was defined as a score of ≥6 points (scale 0 to 9) in ≥70% of answers across two scoring rounds.

Results

102 (72.3%) out of 141 invited experts participated in the first round. Their response rate in the second round was 81%. The final consensus definition of “COPD–BE association” was: “The coexistence of (1) specific radiological findings (abnormal bronchial dilatation, airways visible within 1 cm of pleura and/or lack of tapering signin ≥1 pulmonary segment and in >1 lobe) with (2) an obstructive pattern on spirometry ([forced expiratory volume in 1 s] FEV1/[forced vital capacity] FVC <0.7), (3) at least two characteristic symptoms (cough, expectoration, dyspnoea, fatigue, frequent infections) and (4) current or past exposure to smoke(≥10 pack-years) or other toxic agents (biomass, etc.)”. These criteria form the acronym “ROSE” (Radiology, Obstruction, Symptoms, Exposure).

Conclusions

The Delphi process formulated a European consensus definition of “COPD–BE association”. We hope this definition will have broad applicability across clinical practice and research in the future.
Natural toxins: environmental contaminants calling for attention
Authors: Hansen Hans Christian Bruun , Hilscherova Klara , Bucheli Thomas D.
Published: September 2021

Biosynthetic toxic compounds from plants and cyanobacteria constitute a chemically diverse family of at least 20,000 compounds. Recent work with natural toxin databases and toxin characterization shows that the majority of natural toxins are polar and mobile, with toxicity ranging from low to very high, while persistence is highly variable. Natural toxins may be produced in high quantities—some exceeding 10 g/m2/year—resulting in high environmental loads. Recent phytotoxin monitoring indicates that one or more natural toxin is always present in a surface water sample, but that concentrations are highly variable often with pulses during rain events. Phytotoxins belong to many classes, but often with flavonoids and alkaloids dominating. Likewise, advanced monitoring discovers a wide spectrum of cyanobacterial metabolites that are released directly into surface waters during water blooms. Except of the few known cyanobacterial toxins, we have very limited info regarding their environmental fate and toxicity.

The 16 papers in this article collection present examples of natural toxin occurrence, properties, fate and toxicity. The overarching conclusion is that natural toxins should be monitored and characterized regarding their risk potential, and that natural toxins of greatest expected risk should be evaluated as thoroughly as industrial xenobiotics. Cyanotoxins are well known water contaminants that should be removed for producing drinking water, while for phytotoxins the current knowledge base is very limited. We advocate to intensify research on natural toxins, and to address the evident knowledge gaps on natural toxin analysis/monitoring, physical–chemical properties and degradation/pathways, transport modelling, and toxicity. The complex and dynamic interplays between biotic and site conditions such as vegetation, toxic plant densities, climate, soil types, nutrients and radiation, play decisive roles for both biotoxin formation and fate. Environmental and toxicological research in biosynthesized compounds extends beyond natural toxins, with important perspectives for risk assessment of biopesticides, growth regulators and biomedicine (or biologicals collectively) produced by plants and microorganisms.
Detecting selection in low-coverage high-throughput sequencing data using principal component analysis
Authors: Meisner Jonas , Albrechtsen Anders , Hanghøj Kristian
Published: September 2021

Background

Identification of selection signatures between populations is often an important part of a population genetic study. Leveraging high-throughput DNA sequencing larger sample sizes of populations with similar ancestries has become increasingly common. This has led to the need of methods capable of identifying signals of selection in populations with a continuous cline of genetic differentiation. Individuals from continuous populations are inherently challenging to group into meaningful units which is why existing methods rely on principal components analysis for inference of the selection signals. These existing methods require called genotypes as input which is problematic for studies based on low-coverage sequencing data.

Materials and methods

We have extended two principal component analysis based selection statistics to genotype likelihood data and applied them to low-coverage sequencing data from the 1000 Genomes Project for populations with European and East Asian ancestry to detect signals of selection in samples with continuous population structure.

Results

Here, we present two selections statistics which we have implemented in the framework. These methods account for genotype uncertainty, opening for the opportunity to conduct selection scans in continuous populations from low and/or variable coverage sequencing data. To illustrate their use, we applied the methods to low-coverage sequencing data from human populations of East Asian and European ancestries and show that the implemented selection statistics can control the false positive rate and that they identify the same signatures of selection from low-coverage sequencing data as state-of-the-art software using high quality called genotypes.

Conclusion

We show that selection scans of low-coverage sequencing data of populations with similar ancestry perform on par with that obtained from high quality genotype data. Moreover, we demonstrate that outperform selection statistics obtained from called genotypes from low-coverage sequencing data without the need for ad-hoc filtering.
The expression landscape of JAK1 and its potential as a biomarker for prognosis and immune infiltrates in NSCLC
Authors: Shen Kaikai , Wei Yuqing , Lv Tangfeng , Song Yong , Jiang Xiaogan , Lu Zhiwei , Zhan Ping , Wang Xianghai , Fan Meng , Lu Weihua
Published: September 2021

Background

Janus-activated kinase-1 (JAK1) plays a crucial role in many aspects of cell proliferation, differentiation, apoptosis and immune regulation. However, correlations of JAK1 with prognosis and immune infiltration in NSCLC have not been documented.

Methods

We analyzed the relationship between JAK1 expression and NSCLC prognosis and immune infiltration using multiple public databases.

Results

JAK1 expression was significantly decreased in NSCLC compared with that in paired normal tissues. JAK1 overexpression indicated a favourable prognosis in NSCLC. In subgroup analysis, high JAK1 expression was associated with a preferable prognosis in lung adenocarcinoma (OS: HR, 0.74, 95% CI from 0.58 to 0.95, log-rank P = 0.017), not squamous cell carcinoma. In addition, data from Kaplan–Meier plotter revealed that JAK1 overexpression was associated with a preferable prognosis in male and stage N2 patients and patients without distant metastasis. Notably, increased levels of JAK1 expression were associated with an undesirable prognosis in patients with stage 1 (OS: HR, 1.46, 95% CI from 1.06 to 2.00, P = 0.02) and without lymph node metastasis (PFS: HR, 2.18, 95% CI from 1.06 to 4.46, P = 0.029), which suggests that early-stage NSCLC patients with JAK1 overexpression may have a bleak prognosis. Moreover, multiple immune infiltration cells, including NK cells, CD8 + T and CD4 + T cells, B cells, macrophages, neutrophils, and dendritic cells (DCs), in NSCLC were positively correlated with JAK1 expression. Furthermore, diverse immune markers are associated with JAK1 expression.

Conclusions

JAK1 overexpression exhibited superior prognosis and immune infiltration in NSCLC.
Combination antibiotic therapy versus monotherapy in the treatment of acute exacerbations of chronic obstructive pulmonary disease: an open-label randomized trial
Authors: Thu Phuong Nguyen Thi , Huong Minh Ngo Thị , Thi Ngan Tran , Thanh Hoi Nguyen , Minh Khue Pham
Published: September 2021

Background

The role of antibiotics in the treatment of chronic obstructive pulmonary disease (COPD) exacerbations and their effectiveness in combination have not been clearly established. To determine whether using a combination of fluoroquinolones and beta-lactams improves the clinical and microbiological efficacy of antibiotics on day 20 of treatment, we conducted an open-label randomized trial based on clinical outcomes, microbiological clearance, spirometry tests, and signs of systemic inflammation in patients hospitalized with acute exacerbations of COPD.

Methods

We enrolled 139 subjects with COPD exacerbations, defined as acute worsening of respiratory symptoms leading to additional treatment. Patients were divided randomly into two groups: 79 patients using beta-lactam antibiotics alone and 60 using beta-lactam antibiotics plus fluoroquinolones. Clinical and microbiological responses, spirometry tests, symptom scores, and serum C-reactive protein (CRP) levels were evaluated.

Results

Clinical success, lung function, and symptoms were similar in patients with or without fluoroquinolone administration on days 10 and 20. Combination therapy was superior in terms of microbiological outcomes and reduction in serum CRP value. Although equivalent to monotherapy in terms of clinical success, the combination showed superiority in terms of microbiological success and a decrease in CRP. The combination therapy group had a higher microbiological success rate with gram-negative bacteria than the monotherapy group with Pseudomonas aeruginosa (100% vs. 33.3%, respectively) and Acinetobacter baumanii (100% vs. 20%, respectively) (P < 0.05).

Conclusions

Concomitant use of fluoroquinolone and beta-lactam antibiotics for bacterial infections during COPD exacerbations caused by gram-negative bacteria appear to be effective and should be applied in clinical practice.
Effectiveness of interventions to prevent falls for people with multiple sclerosis, Parkinson’s disease and stroke: an umbrella review
Authors: O’Malley Nicola , Clifford Amanda M. , Conneely Mairéad , Casey Bláthín , Coote Susan
Published: September 2021

Background

The implementation of condition-specific falls prevention interventions is proving challenging due to lack of critical mass and resources. Given the similarities in falls risk factors across stroke, Parkinson’s Disease (PD) and Multiple Sclerosis (MS), the development of an intervention designed for groups comprising of people with these three neurological conditions may provide a pragmatic solution to these challenges. The aims of this umbrella review were to investigate the effectiveness of falls prevention interventions in MS, PD and stroke, and to identify the commonalities and differences between effective interventions for each condition to inform the development of an intervention for mixed neurological groups.

Methods

A systematic literature search was conducted using 15 electronic databases, grey literature searches and hand-screening of reference lists. Systematic reviews of studies investigating the effects of falls prevention interventions in MS, PD and stroke were included. Methodological quality of reviews was assessed using the A MeaSurement Tool to Assess Systematic Reviews 2. A matrix of evidence table was used to assess the degree of overlap. The Grading of Recommendations Assessments, Development and Evaluation framework was used to rate the quality of evidence. Findings were presented through narrative synthesis and a summary of evidence table.

Results

Eighteen reviews were included; three investigating effectiveness of falls prevention interventions in MS, 11 in PD, three in stroke, and one in both PD and stroke. Exercise-based interventions were the most commonly investigated for all three conditions, but differences were identified in the content and delivery of these interventions. Low to moderate quality evidence was found for the effectiveness of exercise-based interventions at reducing falls in PD. Best available evidence suggests that exercise is effective at reducing falls in stroke but no evidence of effect was identified in MS.

Conclusions

The findings suggest that exercise-based interventions are effective at reducing falls in PD, however, the evidence for MS and stroke is less conclusive. A strong theoretical rationale remains for the use of exercise-based interventions to address modifiable physiological falls risk factors for people with MS, PD and stroke, supporting the feasibility of a mixed-diagnosis intervention. Given the high overlap and low methodological quality of primary studies, the focus should be on the development of high-quality trials investigating the effectiveness of falls prevention interventions, rather than the publication of further systematic reviews.
The attitudes of psychiatric patients towards COVID-19 vaccination in China: a cross-sectional study
Authors: Ren Xin , Shen Fang , Gui Yan , Wang Weixin , Xing Baoping , Huang Wanli
Published: September 2021

Background

The COVID-19 pandemic has become a global health catastrophe. By far, there has been no specific antiviral treatment for COVID-19. Developing a vaccine against COVID-19 appeared to be the most cost-effective strategy to stop the repeated outbreak. This study aimed to investigate the attitudes of psychiatric patients with regards to COVID-19 vaccination and potential factors that might influence their decision-making process.

Methods

Psychiatric patients participated in this cross-sectional survey in China. Family caregivers, usually a guardian or next of kin completed the questionnaire when the patient is unable to consent. Data was collected via an online self-administered questionnaire. This questionnaire focused on four main attributes: (1) sociology-demographic characteristics, such as age and sex; (2) questions relating to the COVID-19 pandemic, such as perceived risk of COVID-19; (3) Flu vaccination history; and (4) attitude towards COVID-19 vaccination and affected factors, such as preferred vaccine type and vaccination site. The associated factors that influenced vaccination acceptance were analyzed by Chi-square analysis and binary logistic regression.

Results

In total, 416 individuals were recruited, from which 408: 229 patients and 179 family caregivers completed the online survey (response rate: 98.1%). 78.7% of the participants (178 patients and 143 family caregivers) said they intended to receive vaccination once the COVID-19 vaccine became available on the market. Our results showed that participants would have a greater likelihood of joining the COVID-9 immunization programme if the people they knew (community residents or their friends and relatives) presented with high vaccine coverage (OR = 0.24; 95% CI:0.09–0.59). If the pandemic returns, participants were also more likely to accept vaccination (OR = 0.21; 95% CI:0.07–0.62). Moreover, those who believed that the vaccination was an important way to control the COVID-19 pandemic also showed a tendency to receive vaccination (OR = 0.21; 95% CI:0.11–0.40). For those who did not intend to get vaccinated either for themselves or their psychiatric family member, the safety of vaccine was their main concern (71.3%).

Conclusions

This study showed a high acceptance rate for COVID-19 vaccination amongst psychiatric patients, while worries about the safety of vaccine led to refusal towards vaccination. To increase vaccination uptake amongst this vulnerable group, the public health messaging should include updated vaccination coverage in local communities, and the number of newly COVID-19 infected cases. Specific information about vaccine safety concerning psychiatric patients; as well as the importance of vaccination in controlling the pandemic should be explained in detail.