bluuebunny/crossref_metadata_2025 huggingface dataset:
Statistical methods for evaluating the fine needle aspiration cytology procedure in breast cancer diagnosis
Authors: El Chamieh Carolla , Vielh Philippe , Chevret Sylvie
Published: February 2022

Background

Statistical issues present while evaluating a diagnostic procedure for breast cancer are non rare but often ignored, leading to biased results. We aimed to evaluate the diagnostic accuracy of the fine needle aspiration cytology(FNAC), a minimally invasive and rapid technique potentially used as a rule-in or rule-out test, handling its statistical issues: suspect test results and verification bias.

Methods

We applied different statistical methods to handle suspect results by defining conditional estimates. When considering a partial verification bias, Begg and Greenes method and multivariate imputation by chained equations were applied, however, and a Bayesian approach with respect to each gold standard was used when considering a differential verification bias. At last, we extended the Begg and Greenes method to be applied conditionally on the suspect results.

Results

The specificity of the FNAC test above 94%, was always higher than its sensitivity regardless of the proposed method. All positive likelihood ratios were higher than 10, with variations among methods. The positive and negative yields were high, defining precise discriminating properties of the test.

Conclusion

The FNAC test is more likely to be used as a rule-in test for diagnosing breast cancer. Our results contributed in advancing our knowledge regarding the performance of FNAC test and the methods to be applied for its evaluation.
Psychosocial aspects and support networks associated with disability in two longevous populations in Brazil: a cross-sectional study
Authors: Nóbrega Júlia Cristina Leite , Medeiros Juliana Barbosa , da Silva Freitas Javanna Lacerda Gomes , Silva Jaíza M. M. , Simões Raisa Fernandes Mariz , Olinda Ricardo , de Ferreira Santos Jair Lício , Menezes Tarciana Nobre , de Oliveira Duarte Yeda Aparecida , Zatz Mayana , Matheson David , Santos Silvana
Published: February 2022

Background

Among the oldest old, aged 80 years and over, the prevalence of disability is higher than in other age groups and can be considered a predictor of mortality.

Objective

To evaluate how psychosocial aspects and support networks influence the disability of these oldest-old individuals, performing a comparison between two longevous populations, one living in one of the poorest regions of Brazil, in the backlands of Paraíba, and another living in one of the largest urban centres in Latin America.

Method

A cross-sectional study in which 417 oldest-old persons aged 80 years and older were interviewed, with data collected through the “Health, Welfare and Ageing” survey conducted in two Brazilian cities. Disability was assessed by reporting the need for assistance in Activities of Daily Living (ADLs) and Instrumental Activities of Daily Living (IADLs). Bivariate and multiple analyses were performed using R statistical software.

Results

Food insufficiency in the first years of life had negative repercussions on the disability of oldest old people living in the northeast. On the other hand, in this region, older people have a higher rate of support and live longer with their peers, which may contribute to reducing feelings of loneliness, depressive symptoms, and worse self-perception of health. In the Southeast, financial constraints, subjective poverty, and unmet needs may favour the development of functional limitations between long-lived people.

Conclusion

Our findings indicate that regional differences in Brazil may influence the disability of older people aged 80 and older. In northeast Brazil, having no partner may contribute to disability for ADLs and IADLs; while, in the longevous population of São Paulo, having a worse self-rated health may contribute to disability for IADLs.
The validity and reliability of the PHQ-9 on screening of depression in neurology: a cross sectional study
Authors: Sun Yajing , Kong Zhifei , Song Yuqing , Liu Jing , Wang Xilin
Published: February 2022

Background

This study aimed to explore the validity and reliability of the Patient Health Questionnaire-9 (PHQ-9) on screening of depression among patients with neurological disorders, and to explore factors influencing such patients.

Methods

In this study, 277 subjects who were admitted to the department of neurology of our hospital due to different neurological disorders completed the PHQ-9 questionnaire. The Mini-International Neuropsychiatric Interview (MINI) and Hamilton Rating Scale for Depression (HAMD) were employed to evaluate the depressive symptoms of patients who completed the PHQ-9 questionnaire. The internal consistency, criterion validity, structural validity, and optimal cut-off values of PHQ-9 were evaluated, and the consistency assessment was conducted between the depression severity as assessed by PHQ-9, HAMD and MINI. Logistic regression analysis was used to calculate the risk factors of depression.

Results

The Cronbach’s α coefficient of the PHQ-9 was 0.839. The Pearson’s correlation coefficient among the 9 items of the PHQ-9 scale was 0.160 ~ 0.578 (P < 0.01), and the Pearson’s correlation coefficient between each item and the total score was at the range of 0.608 ~ 0.773. Taking the results of MINI as the gold standard, the area under the receiver operating characteristic (ROC) curve of the PHQ-9 results for all the subjects (n = 277) was 0.898 (95% confidence interval (CI): 0.859 ~ 0.937, P < 0.01). When the cut-off score was equal to 5, the values of sensitivity, specificity, and the Youden’s index were 91.2, 76.6%, and 0.678, respectively. Multivariate logistic regression analysis showed that the influence of unemployment on the occurrence of depression was statistically significant (P = 0.027, OR = 3.080, 95%CI: 1.133 ~ 8.374).

Conclusions

The application of PHQ-9 for screening of depression among Chinese patients with neurological disorders showed a good reliability and validity.
Cost-effectiveness and cost-utility evaluation of individual vs. group transdiagnostic psychological treatment for emotional disorders in primary care (PsicAP-Costs): a multicentre randomized controlled trial protocol
Authors: Aguilera-Martín Ángel , Gálvez-Lara Mario , Cuadrado Fátima , Moreno Eliana , García-Torres Francisco , Venceslá José F. , Corpas Jorge , Jurado-González Francisco J. , Muñoz-Navarro Roger , González-Blanch César , Ruiz-Rodríguez Paloma , Barrio-Martínez Sara , Prieto-Vila Maider , Carpallo-González María , Cano-Vindel Antonio , Moriana Juan A.
Published: February 2022

Background

Emotional disorders are common, and they have become more prevalent since the COVID-19 pandemic. Due to a high attendance burden at the specialized level, most emotional disorders in Spain are treated in primary care, where they are usually misdiagnosed and treated using psychotropic drugs. This contributes to perpetuate their illness and increase health care costs. Following the IAPT programme and the transdiagnostic approach, the PsicAP project developed a brief group transdiagnostic cognitive-behavioural therapy (tCBT) as a cost-effective alternative. However, it is not suitable for everyone; in some cases, one-on-one sessions may be more effective. The objective of the present study is to compare, in cost-benefit terms, group and individual tCBT with the treatment usually administered in Spanish primary care (TAU).

Methods

A randomized, controlled, multicentre, and single-blinded trial will be performed. Adults with mild to moderate emotional disorders will be recruited and placed in one of three arms: group tCBT, individual tCBT, or TAU. Medical data and outcomes regarding emotional symptoms, disability, quality of life, and emotion regulation biases will be collected at baseline, immediately after treatment, and 6 and 12 months later. The data will be used to calculate incremental cost-effectiveness and cost-utility ratios.

Discussion

This trial aims to contribute to clinical practice research. The involvement of psychologists in primary care and the implementation of a stepped-care model for mental disorders are recommended. Group therapy and a transdiagnostic approach may help optimize health system resources and unblock waiting lists so that people can spend less time experiencing mental health problems.

Trial registration

ClinicalTrials.gov: NCT04847310; Protocols.io: bx2npqde. (April 19, 2021)
A systematic review and meta-analysis of studies on screening for mild cognitive impairment in primary healthcare
Authors: Karimi Leila , Mahboub–Ahari Alireza , Jahangiry Leila , Sadeghi-Bazargani Homayoun , Farahbakhsh Mostafa
Published: February 2022

Background

Cognitive disorders and dementia have an important effect on individual independence and orientation. According to the Alzheimer's Disease International (ADI) 75% of people with dementia are not diagnosed; this may be as high as 90% in some low- and middle-income countries. This systematic review and meta-analysis aimed to identify the test performance of screening tools and compare them pairwise. The findings of our study can support countries in planning to establish and care for mild cognitive impairment in primary health centers.

Methods

Medline (PubMed), Scopus, Cochrane, Dare, All EBM Reviews, CRD (OVID), and Proquest were searched from 2012 to November 2021. The risk of bias was assessed through the QUADAS-2 instrument. Given the high heterogeneity between studies, a random-effects model was used to calculate the pooled effect sizes for diagnostic accuracy measures (sensitivity, specificity, and area under curve indices). I2 test was used for assessing heterogeneity and predefined subgroup analyses were performed using participants’ age, country’s income, and sample size of studies.

Results

A systematic search identified 18,132 records, of which, 20 studies were included in the quality assessment, and six were included in quantitative analysis. None of the studies had examined the feasibility or efficiency of mass screening. According to a pairwise comparison, IQCODE, AD8 and GPCOG showed equal or better diagnostic performance relative to the MMSE in terms of sensitivity and specificity. The random-effect model for the MMSE showed the pooled sensitivity equal to 0.73 (95% CI 0.57–0.90), the pooled specificity equal to 0.83 (95% CI 0.75—0.90), and the pooled AUC equal to 0.88 (95% CI 0.83–0.93).

Conclusion

Several benefits have been attached to short tests making them a suitable choice for use in primary healthcare settings. Considering factors such as accuracy, time of application, ease of scoring, and utilization charges, tests such as IQCODE, AD8, and GPCOG or appropriate combination with counterpart tools seem to be good alternatives to the use of the MMSE in primary care.
Prevalence and determinants of anxiety and depression in long-term breast cancer survivors
Authors: Breidenbach Clara , Heidkamp Paula , Hiltrop Kati , Pfaff Holger , Enders Anna , Ernstmann Nicole , Kowalski Christoph
Published: February 2022

Background

There is a significant number of long-term breast cancer survivors in Germany. However, research on the psychological challenges of cancer survivors is limited. This analysis describes prevalence, development and determinants of depression and anxiety 5 to 6 years after diagnosis and identifies predictors for an increase of anxiety and depression over time.

Methods

Data from 164 women was collected by survey and tumour documentation during post-operative hospital stay, 40 weeks and 5 to 6 years after diagnosis. Anxiety and depression were measured by the Hospital Anxiety and Depression Scale. Sankey-diagrams were created for visual presentation of prevalence over time. Logistic and linear regression models were calculated to identify determinants of anxiety and depression.

Results

Respondents had higher levels of depression and anxiety 5 to 6 years than 40 weeks after the diagnosis. Lower vocational status and having children were associated with depression, surgery type was correlated with anxiety, and age, as well as comorbidities, were predictors for both anxiety and depression 5 to 6 years after diagnosis. An increase of depression over time was more likely when having children and comorbidities. An increase in anxiety was less likely after cancer recurrence.

Conclusions

Findings highlight that anxiety and depression are relevant burdens for breast cancer survivors in Germany. Several sociodemographic and clinical predictors are identified. There is need for psychosocial support after acute treatment and in the long-term. Research on psychological burdens of long-term breast cancer survivors in the identified vulnerable groups is needed.
Profiling the variability and inequity in the residential environment in Cyprus according to citizens’ ratings: a cross-sectional internet-based “Place Standard” survey
Authors: Kleopa Daphne , Panayiotou Andrie , Kouta Christiana , Kaiafa Chrystalla , Middleton Nicos
Published: February 2022

Background

The “Place Standard Tool” (PST) offers a practical framework for structuring conversations about physical and social dimensions of Place which impact on health and well-being. The aim of this study was to survey citizens’ perceptions of Place across diverse settings in Cyprus. While the PST has been extensively used in the context of community engagement, its properties as a measurement tool haven’t been explored.

Methods

An open call was addressed to citizens to rate their neighbourhood environment across the 14 PST items (1: large to 7: little room for improvement). Exploratory factor, cluster and regression analyses were used to explore the dimensionality of the scale, depict neighbourhood profiles and explore differences in ratings according to socio-demographic characteristics, area-level census indicators and residents’ assessment of neighbourhood social position (10-step ladder).

Results

With the exception of safety (M = 4.4, SD = 1.7), 492 participants (mean age 42, 50% residents for > 10 years) from 254 postcodes (21.7% islandwide) did not rate other features favourably, with lowest scores for “influence and sense of control” and “public transport”. A stepwise pattern of dissatisfaction was observed along the social position continuum both for features rated less as well as more favourably (e.g. social contact). For instance, among participants who placed their neighbourhood at the three top steps of the ladder, 48.8% gave a low rating for “influence and sense of control”, while the equivalent figure was 81.0% at the bottom three steps (OR = 4.5, 95% CI 2.3, 8.6). A clear dimensionality of Built (6 items, Cronbach’s α = 0.798), Physical (3 items, α = 0.765), Social (2 items, α = 0.749) and Service (3 items, α = 0.58) environment was identified. A social gradient was evident according to census measures of socio-economic disadvantage (e.g. pre-1980 housing, single-parent households) with larger differences in terms of the built than the social environment.

Conclusions

The study profiled the variability and documented the inequity in the health-related neighbourhood environment across Cypriot communities. The readily interpretable dimensionality of the scale supports its construct validity, allowing calculation of composite scores. The PST can be used as measurement tool in research as well as public health practice to advocate for neighbourhood initiatives which support and enhance citizens’ participation.
Readiness to enter the workforce: perceptions of health professions students at a regional Australian university
Authors: Malau-Aduli Bunmi S. , Jones Karina , Alele Faith , Adu Mary D. , Drovandi Aaron , Knott Gillian , Young Louise , Jo Clara
Published: February 2022

Background

Perceived readiness for practice can help mitigate the stress and uncertainty associated with transitioning from university into the workforce. This study aimed to identify factors influencing the readiness for clinical practice among final-year medical, dental, and pharmacy students at an Australian regional university.

Methods

The study utilised a sequential explanatory mixed-methods approach with surveys administered for the quantitative phase and interviews/focus groups for the qualitative phase. Descriptive statistics and inductive thematic analysis were utilised for the quantitative and qualitative data, respectively. Triangulation of findings from both phases facilitated in-depth understanding of the factors that influenced participants’ self-perceived readiness for clinical practice.

Results

From the three disciplines, 132 students completed the survey and 14 participated in the focus groups and interviews. Students felt most prepared in their patient-centred capabilities, core skills, and advanced consultation skills, and least prepared in their system-related capabilities and clinical care skills. Themes identified as essential enablers and confidence builders in relation to workforce readiness in all three disciplines were: gained knowledge and skills, value of clinical placement experiences, support from peers, family and staff. However, students felt their work-readiness was impaired by heavy academic workloads and poor knowledge of health care systems, which affected skills development. Participants suggested additional support in health care system and clinical governance, mental healthcare, and induction to placement sites to further improve their work readiness.

Conclusions

The findings of this study suggest that improving work-readiness of healthcare students requires alignment of learning needs to real-world practice opportunities, ensuring support systems are appropriate, and early familiarisation with the healthcare system.
Mutant C. elegans mitofusin leads to selective removal of mtDNA heteroplasmic deletions across generations to maintain fitness
Authors: Meshnik Lana , Bar-Yaacov Dan , Kasztan Dana , Neiger Tali , Cohen Tal , Kishner Mor , Valenci Itay , Dadon Sara , Klein Christopher J. , Vance Jeffery M. , Nevo Yoram , Züchner Stephan , Ovadia Ofer , Mishmar Dan , Ben-Zvi Anat
Published: February 2022

Background

Mitochondrial DNA (mtDNA) is present at high copy numbers in animal cells, and though characterized by a single haplotype in each individual due to maternal germline inheritance, deleterious mutations and intact mtDNA molecules frequently co-exist (heteroplasmy). A number of factors, such as replicative segregation, mitochondrial bottlenecks, and selection, may modulate the exitance of heteroplasmic mutations. Since such mutations may have pathological consequences, they likely survive and are inherited due to functional complementation via the intracellular mitochondrial network. Here, we hypothesized that compromised mitochondrial fusion would hamper such complementation, thereby affecting heteroplasmy inheritance.

Results

We assessed heteroplasmy levels in three Caenorhabditis elegans strains carrying different heteroplasmic mtDNA deletions (ΔmtDNA) in the background of mutant mitofusin (fzo-1). Animals displayed severe embryonic lethality and developmental delay. Strikingly, observed phenotypes were relieved during subsequent generations in association with complete loss of ΔmtDNA molecules. Moreover, deletion loss rates were negatively correlated with the size of mtDNA deletions, suggesting that mitochondrial fusion is essential and sensitive to the nature of the heteroplasmic mtDNA mutations. Introducing the ΔmtDNA into a fzo-1;pdr-1;+/ΔmtDNA (PARKIN ortholog) double mutant resulted in a skewed Mendelian progeny distribution, in contrast to the normal distribution in the fzo-1;+/ΔmtDNA mutant, and severely reduced brood size. Notably, the ΔmtDNA was lost across generations in association with improved phenotypes.

Conclusions

Taken together, our findings show that when mitochondrial fusion is compromised, deleterious heteroplasmic mutations cannot evade natural selection while inherited through generations. Moreover, our findings underline the importance of cross-talk between mitochondrial fusion and mitophagy in modulating the inheritance of mtDNA heteroplasmy.
CPNE1 is a potential prognostic biomarker, associated with immune infiltrates and promotes progression of hepatocellular carcinoma
Authors: Su Jinfang , Huang Yongbiao , Wang Yali , Li Rui , Deng Wanjun , Zhang Hao , Xiong Huihua
Published: February 2022

Background

Copine1 (CPNE1), the first discovered CPNE1 family member, participates in the process of carcinogenesis and development of diverse tumors. Our study aimed to investigate the expression and prognostic value of CPNE1 gene in hepatocellular carcinoma (HCC), to explore its functional network in HCC and its effects on biological behaviors.

Methods

HCCDB, CCLE, HPA and LinkedOmics online databases were used to explore the expression of CPNE1 gene and analyze the co-expression network of CPNE1 in hepatocellular carcinoma. Gene set enrichment analysis (GSEA) was used for GO functional annotation, KEGG pathway enrichment analysis and regulators of CPNE1 networks in LIHC. HepG2 and MHCC-97H cells were selected to construct CPNE1 knockdown cell lines by transfection with siRNA, and Hep3B cell was selected to construct CPNE1 overexpression cell line by transfection with plasmid. The effect of CPNE1 on the proliferation of hepatocellular carcinoma cells was examined by CCK8 assay and clone formation assay; the effect of CPNE1 on the migration ability of hepatocellular carcinoma cells was assessed by cell scratch assay and Transwell cell migration assay; finally, the expression of related signaling pathway proteins was examined by Western Blot. The correlation of CPNE1 expression with immune infiltration and immune checkpoint molecules in HCC tissues was analyzed using TIMER online database and GSEA.

Results

CPNE1 was highly expressed in HCC tissues and significantly correlated with sex, age, cancer stage and tumor grade. Overall survival (OS) was significantly lower in patients with high CPNE1 expression than in patients with low CPNE1 expression, and CPNE1 could be used as an independent prognostic indicator for HCC. Knockdown of CPNE1 gene inhibited the AKT/P53 pathway, resulting in decreased proliferation, migration and invasion of HCC cells. Overexpression of CPNE1 gene showed the opposite results. The level of CPNE1 expression in HCC was significantly and positively correlated with the level of infiltration of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (P < 0.001). GSEA results also showed that CPNE1 of LIHC was involved in some immune response regulating signaling pathways.

Conclusions

Our study firstly found the expression of CPNE1 was significantly higher in LIHC tissues than in normal liver tissues, and high CPNE1 expression was associated with poor prognosis. In addition, we identified the possible mechanism by which CPNE1 functioned in LIHC. CPNE1 influenced AKT/P53 pathway activation and LIHC cell proliferation and migration. There was a significant correlation between CPNE1 expression and tumor immune infiltration in LIHC.
Race and sex differences in HDL peroxide content among American adults with and without type 2 diabetes
Authors: Flaherty Shelby M. , Wood Elizabeth K. , Ryff Carol D. , Love Gayle D. , Kelesidis Theodoros , Berkowitz Loni , Echeverría Guadalupe , Rivera Katherine , Rigotti Attilio , Coe Christopher L.
Published: February 2022

Background

High-density lipoprotein (HDL) plays a critical role in protection against atherosclerosic and cardiovascular disease (ASCVD). In addition to contributing to clearing excess vascular cholesterol, HDL particles exhibit antioxidative functions, helping to attenuate adverse effects of oxidized low-density lipoproteins. However, these beneficial properties can be undermined by oxidative stress, inflammation, and unhealthy lifestyles and diet, as well as influenced by race and sex. Thus, when assessing cardiovascular risk, it is important to consider multifactorial aspects of HDL, including antioxidant activity rather than just total amount and type of HDL-cholesterol (HDL-C) particles. Because prior research showed HDL peroxide content (HDLperox) can be inversely associated with normal anti-oxidant HDL activity, elevated HDLperox may serve as a bioindicator of HDL dysfunction.

Methods

In this study, data from a large national cohort of Americans was utilized to determine the impact of sex, race, and diabetes status on HDLperox in middle-aged and older adults. A previously developed cell-free fluorometric method was utilized to quantify HDLperox in serum depleted of apo-B containing lipoproteins.

Results

In keeping with predictions, white men and diabetics exhibited HDLperox in the atypical upper range, suggestive of less functional HDL. White men had higher HDLperox levels than African American males (13.46 ± 6.10 vs. 10.88 ± 5.81, p < .001). There was also a significant main effect of type 2 diabetes (F(1,1901) = 14.9, p < .0001). Overall, African Americans evinced lower HDLperox levels, despite more obesity (10.3 ± 4.7 vs.11.81 ± 5.66 for Whites) suggesting that other aspects of lipid metabolism and psychosocial factors account for the higher prevalence of ASCVD in African Americans.

Conclusion

This research helps to provide a more comprehensive understanding of HDL function in a racially and metabolically diverse adult population. HDLperox content was significantly different in adults with type 2 diabetes, and distinctive in nondiabetic White males, and suggests other processes account for the higher prevalence of ASCVD among African Americans.
The effects of extracellular vesicles derived from Krüppel-Like Factor 2 overexpressing endothelial cells on the regulation of cardiac inflammation in the dilated cardiomyopathy
Authors: Zhang Wenfeng , Chen Ziwei , Qiao Shuaihua , Chen Siyuan , Zheng Hongyan , Wei Xuan , Li Qiaoling , Xu Biao , Huang Wei
Published: February 2022

Background

Dilated cardiomyopathy (DCM) is one of the common causes of heart failure. Myocardial injury triggers an inflammatory response and recruits immune cells into the heart. High expression of Krüppel-like factor 2 (KLF2) in endothelial cells (ECs) potentially exerts an anti-inflammatory effect. However, the role of extracellular vesicles (EVs) from KLF2-overexpressing ECs (KLF2-EVs) in DCM remains unclear.

Methods and results

EVs were separated from the supernatant of KLF2-overexpressing ECs by gradient centrifugation. Mice were repeatedly administered low-dose doxorubicin (DOX) and then received KLF2-EVs through an intravenous injection. Treatment with KLF2-EVs prevented doxorubicin-induced left ventricular dysfunction and reduced the recruitment of Ly6high Mo/Mø in the myocardium. We used flow cytometry to detect Ly6high monocytes in bone marrow and spleen tissues and to elucidate the mechanisms underlying this beneficial effect. KLF2-EVs increased the retention of Ly6Chigh monocytes in the bone marrow but not in the spleen tissue. KLF2-EVs also significantly downregulated C–C chemokine receptor 2 (CCR2) protein expression in cells from the bone marrow.

Conclusions

EVs derived from KLF2-overexpressing ECs reduced cardiac inflammation and ameliorated left ventricular dysfunction in DCM mice by targeting the CCR2 protein to inhibit Ly6Chigh monocyte mobilization from the bone marrow.

Graphical Abstract
Hospital efficiency measurement in the west of Iran: data envelopment analysis and econometric approach
Authors: Yousefi Nayer Mohamad , Fazaeli Ali Akbar , Hamidi Yadollah
Published: February 2022

Objective

Measuring hospital efficiency is one of the way how to use resources.The optimal hospital performance is the goals of healthcare policymakers. This study aimed to the current study was conducted to evaluate the efficiency the current study was conducted to evaluate the efficiency and assess the association between hospital size and hospital area population with technical efficiency in public hospitals.

Methods

In this descriptive-analytical study, the statistical population consisted of 15 public hospitals in the west of Iran. First, the data envelopment analysis (DEA) method was used to evaluate technical efficiency. inputs included staff and beds, and outputs consisted of the number of surgeries, the number of patients, and the average length of stay. Then, according to the public ownership of all hospitals, their educational and therapeutic activities, as well as their size and population were considered as the environmental factor affecting efficiency. Thus, regression was applied to measure their effects on efficiency.

Results

The average technical efficiency of the studied hospitals, the average management efficiency, and the average efficiency of the scale were 0.935, 0.961, and 0.987, respectively. Out of the total evaluated hospitals, six and nine hospitals had an efficiency of less than one and one, respectively. Moreover, the size of the hospital and the population as the environment variable were significant in the Tobit model. Our regression demonstrated that although the size of the hospital is positively associated with its technical efficiency, the hospital population negatively affects hospital efficiency.

Conclusion

According to the size and area population of the hospitals, they decrease their inputs to maximize their efficacy by optimizing their surplus amounts. Tobit regression analysis concludes that hospital size and population covered by the hospital significant effect on hospitals' efficiency.
Controlled human exposure to diesel exhaust: results illuminate health effects of traffic-related air pollution and inform future directions
Authors: Long Erin , Carlsten Christopher
Published: February 2022

Air pollution is an issue of increasing interest due to its globally relevant impacts on morbidity and mortality. Controlled human exposure (CHE) studies are often employed to investigate the impacts of pollution on human health, with diesel exhaust (DE) commonly used as a surrogate of traffic related air pollution (TRAP). This paper will review the results derived from 104 publications of CHE to DE (CHE-DE) with respect to health outcomes. CHE-DE studies have provided mechanistic evidence supporting TRAP’s detrimental effects on related to the cardiovascular system (e.g., vasomotor dysfunction, inhibition of fibrinolysis, and impaired cardiac function) and respiratory system (e.g., airway inflammation, increased airway responsiveness, and clinical symptoms of asthma). Oxidative stress is thought to be the primary mechanism of TRAP-induced effects and has been supported by several CHE-DE studies. A historical limitation of some air pollution research is consideration of TRAP (or its components) in isolation, limiting insight into the interactions between TRAP and other environmental factors often encountered in tandem. CHE-DE studies can help to shed light on complex conditions, and several have included co-exposure to common elements such as allergens, ozone, and activity level. The ability of filters to mitigate the adverse effects of DE, by limiting exposure to the particulate fraction of polluted aerosols, has also been examined. While various biomarkers of DE exposure have been evaluated in CHE-DE studies, a definitive such endpoint has yet to be identified. In spite of the above advantages, this paradigm for TRAP is constrained to acute exposures and can only be indirectly applied to chronic exposures, despite the critical real-world impact of living long-term with TRAP. Those with significant medical conditions are often excluded from CHE-DE studies and so results derived from healthy individuals may not apply to more susceptible populations whose further study is needed to avoid potentially misleading conclusions. In spite of limitations, the contributions of CHE-DE studies have greatly advanced current understanding of the health impacts associated with TRAP exposure, especially regarding mechanisms therein, with important implications for regulation and policy.
Incidence of calcaneal apophysitis (Sever’s disease) and return-to-play in adolescent athletes of a German youth soccer academy: a retrospective study of 10 years
Authors: Belikan Patrick , Färber Lars-Christopher , Abel Frédéric , Nowak Tobias E. , Drees Philipp , Mattyasovszky Stefan G.
Published: February 2022

Background

Calcaneal apophysitis, or Sever's disease, is the most common cause of heel pain in childhood and adolescence. It is regarded as an overuse syndrome. Studies on the incidence of calcaneal apophysitis in young athletes and their associated return-to-play time are lacking in the current literature. The aim of our current study was to identify the incidence of calcaneal apophysitis in professional youth soccer, the associated time to return-to-play, predisposing factors and their impact on time to return-to-play.

Methods

Retrospective evaluation of injury data gathered from a German youth soccer academy in the years 2009–2018. In total, 4326 injury cases in 612 players were included in the study. The diagnosis and the follow-up visits were carried out in a weekly consultation hour at the youth academy.

Results

During the observation period of 10 years, 22 cases of calcaneal apophysitis were detected. The incidence of calcaneal apophysitis per 100 athletes per year was found to be 0.36. The mean age of the affected athletes at the time of diagnosis was 11.8 ± 2.1 years (MW ± SD). The complaints were unilateral in 20 and bilateral in two cases. Three of the 22 detected cases of calcaneal apophysitis (13.6%) were recurrent injuries. The mean time to return-to-play of the affected athletes was 60.7 ± 64.9 days (MW ± SD). Athletes with recurrent complaints showed longer recovery time and time to return-to-play when compared to players with primary diagnosed disease. Our results could show that neither age nor body mass index at the time of diagnosis had an impact on time to return-to-play.

Conclusions

This is the first study investigating the incidence of calcaneal apophysitis and the associated time to return-to-play in youth elite soccer. Calcaneal apophysitis results in substantial time loss for the athletes. Further prospective clinical studies are required to fully understand the etiology and risk factors for calcaneal apophysitis and therefore develop preventive strategies.
A large-scale genome and transcriptome sequencing analysis reveals the mutation landscapes induced by high-activity adenine base editors in plants
Authors: Li Shaofang , Liu Lang , Sun Wenxian , Zhou Xueping , Zhou Huanbin
Published: February 2022

Background

The high-activity adenine base editors (ABEs), engineered with the recently-developed tRNA adenosine deaminases (TadA8e and TadA9), show robust base editing activity but raise concerns about off-target effects.

Results

In this study, we perform a comprehensive evaluation of ABE8e- and ABE9-induced DNA and RNA mutations in Oryza sativa. Whole-genome sequencing analysis of plants transformed with four ABEs, including SpCas9n-TadA8e, SpCas9n-TadA9, SpCas9n-NG-TadA8e, and SpCas9n-NG-TadA9, reveal that ABEs harboring TadA9 lead to a higher number of off-target A-to-G (A>G) single-nucleotide variants (SNVs), and that those harboring CRISPR/SpCas9n-NG lead to a higher total number of off-target SNVs in the rice genome. An analysis of the T-DNAs carrying the ABEs indicates that the on-target mutations could be introduced before and/or after T-DNA integration into plant genomes, with more off-target A>G SNVs forming after the ABEs had integrated into the genome. Furthermore, we detect off-target A>G RNA mutations in plants with high expression of ABEs but not in plants with low expression of ABEs. The off-target A>G RNA mutations tend to cluster, while off-target A>G DNA mutations rarely clustered.

Conclusion

Our findings that Cas proteins, TadA variants, temporal expression of ABEs, and expression levels of ABEs contribute to ABE specificity in rice provide insight into the specificity of ABEs and suggest alternative ways to increase ABE specificity besides engineering TadA variants.
An improved repertoire of splicing variants and their potential roles in Arabidopsis photomorphogenic development
Authors: Huang Chun-Kai , Lin Wen-Dar , Wu Shu-Hsing
Published: February 2022

Background

Light switches on the photomorphogenic development of young plant seedlings, allowing young seedlings to acquire photosynthetic capacities and gain survival fitness. Light regulates gene expression at all levels of the central dogma, including alternative splicing (AS) during the photomorphogenic development. However, accurate determination of full-length (FL) splicing variants has been greatly hampered by short-read RNA sequencing technologies.

Result

In this study, we adopt PacBio isoform sequencing (Iso-seq) to overcome the limitation of the short-read RNA-seq technologies. Normalized cDNA libraries used for Iso-seq allows for comprehensive and effective identification of FL AS variants. Our analyses reveal more than 30,000 splicing variant models from approximately 16,500 gene loci and additionally identify approximately 700 previously unannotated genes. Among the variants, approximately 12,000 represent new gene models. Intron retention (IR) is the most frequently observed form of variants, and many IR-containing AS variants show evidence of engagement in translation. Our study reveals the formation of heterodimers of transcription factors composed of annotated and IR-containing AS variants. Moreover, transgenic plants overexpressing the IR forms of two B-BOX DOMAIN PROTEINs exhibits light-hypersensitive phenotypes, suggesting their regulatory roles in modulating optimal light responses.

Conclusions

This study provides an accurate and comprehensive portrait of full-length transcript isoforms and experimentally confirms the presence of de novo synthesized AS variants that impose regulatory functions in photomorphogenic development in Arabidopsis.
Time to response for clinical and patient-reported outcomes in patients with psoriatic arthritis treated with tofacitinib, adalimumab, or placebo
Authors: Gladman Dafna D. , Coates Laura C. , Wu Joseph , Fallon Lara , Bacci Elizabeth D. , Cappelleri Joseph C. , Bushmakin Andrew G. , Helliwell Philip S.
Published: February 2022

Background

This study examined the time to clinically meaningful response in patients with active psoriatic arthritis treated with tofacitinib, adalimumab, or placebo switching to tofacitinib.

Methods

Data were from two phase 3 studies, OPAL Broaden (12 months) and OPAL Beyond (6 months). Patients received tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg once every 2 weeks (OPAL Broaden only), or placebo switching to tofacitinib 5 or 10 mg BID at month 3. Baseline to initial response time was according to pre-defined clinically meaningful criteria on Health Assessment Questionnaire-Disability Index (HAQ-DI; ≥ 0.35-point improvement), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F; ≥ 4-point improvement), Psoriatic Arthritis Disease Activity Score (PASDAS; post-baseline score ≤ 3.2 and > 1.6-point improvement from baseline), and minimal disease activity (MDA; meeting at least 5 of 7 criteria) composite.

Results

In OPAL Broaden, median time to initial HAQ-DI score response was 29, 53, and 30 days in patients treated with tofacitinib 5 mg BID, tofacitinib 10 mg BID, or adalimumab, compared with 162 and 112 days in patients treated with placebo switching to tofacitinib 5 or 10 mg BID at month 3, respectively. Across studies, median time to initial FACIT-F total score response was shorter in patients receiving tofacitinib 5 mg BID (31 days) vs other groups (84–92 days). Median time to initial response was approximately 11 (MDA)/6–9 months (PASDAS) in tofacitinib/adalimumab groups in OPAL Broaden.

Conclusion

This analysis demonstrates tofacitinib’s efficacy on most patient-reported and clinical endpoints over time and shows a shorter time to initial, clinically meaningful response in patients receiving tofacitinib vs patients switching from placebo to tofacitinib.

Trial registration

ClinicalTrials.gov, NCT01877668. Registered June 12, 2013.ClinicalTrials.gov, NCT01882439. Registered June 18, 2013.
A comparison between tau and amyloid-β cerebrospinal fluid biomarkers in chronic traumatic encephalopathy and Alzheimer disease
Authors: Turk Katherine W. , Geada Alexandra , Alvarez Victor E. , Xia Weiming , Cherry Jonathan D. , Nicks Raymond , Meng Gaoyuan , Daley Sarah , Tripodis Yorghos , Huber Bertrand R. , Budson Andrew E. , Dwyer Brigid , Kowall Neil W. , Cantu Robert C. , Goldstein Lee E. , Katz Douglas I. , Stern Robert A. , Alosco Michael L. , Mez Jesse , McKee Ann C. , Stein Thor D.
Published: February 2022

Background

Cerebrospinal fluid (CSF) tau and beta-amyloid levels in chronic traumatic encephalopathy (CTE), a disease which can be clinically indistinguishable from Alzheimer’s disease (AD), are largely unknown. We examined postmortem CSF analytes among participants with autopsy confirmed CTE and AD.

Methods

In this cross-sectional study 192 participants from the Boston University AD Research Center, VA-BU-CLF Center, and Framingham Heart Study (FHS) had post-mortem CSF collected at autopsy. Participants were divided into pathological groups based on AD and CTE criteria, with 61 CTE participants (18 low, 43 high stage), 79 AD participants (23 low, 56 intermediate to high), 11 participants with CTE combined with AD, and 41 participants lacking both CTE and AD neuropathology. The Meso Scale Discovery immunoassay system was utilized to measure amyloid-beta (Aβ1-40, Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau181 and p-tau231). CSF analytes were then compared across the pathological groups: no CTE/no AD (control), Low CTE, Low AD, High CTE, Intermediate/High AD, and AD+CTE.

Results

Among the Low disease state groups, the Low CTE group had significantly higher levels of p-tau231 versus the control group and compared to the Low AD group. The Low CTE group was also found to have significantly lower levels of Aβ1-42 compared to the control group. The high CTE group had higher levels of p-tau231 and lower levels of Aβ1-42 compared to Intermediate/High AD group.

Conclusions

Importantly, p-tau231 and Aβ1-42 were predictors of diagnosis of CTE vs. control and CTE vs. AD. Increased CSF p-tau231 is a promising potentially sensitive biomarker of CTE, and CSF Aβ1-42 needs further investigation in CTE.
Duplication and expression patterns of CYCLOIDEA-like genes in Campanulaceae
Authors: Tong Jingjing , Knox Eric B. , Morden Clifford W. , Cellinese Nico , Mossolem Fatima , Zubair Aarij S. , Howarth Dianella G.
Published: February 2022

Background

CYCLOIDEA (CYC)-like transcription factors pattern floral symmetry in most angiosperms. In core eudicots, two duplications led to three clades ofCYC-like genes:CYC1,CYC2,andCYC3, with orthologs of theCYC2clade restricting expression dorsally in bilaterally symmetrical flowers. Limited data fromCYC3suggest that they also play a role in flower symmetry in some asterids. We examine the evolution of these genes in Campanulaceae, a group that contains broad transitions between radial and bilateral floral symmetry and 180° resupination (turning upside-down by twisting pedicle).

Results

We identify here all three paralogousCYC-likeclades across Campanulaceae. Similar to other core eudicots, we show thatCamCYC2duplicated near the time of the divergence of the bilaterally symmetrical and resupinate Lobelioideae. However, in non-resupinate, bilaterally symmetrical Cyphioideae,CamCYC2appears to have been lost andCamCYC3duplicated, suggesting a novel genetic basis for bilateral symmetry in Cyphioideae. We additionally, utilized qRT-PCR to examine the correlation betweenCYC-like gene expression and shifts in flower morphology in four species of Lobelioideae. As expected,CamCYC2gene expression was dorsoventrally restricted in bilateral symmetrical flowers. However, because Lobelioideae have resupinate flowers, bothCamCYC2AandCamCYC2Bare highly expressed in the finally positioned ventral petal lobes, corresponding to the adaxial side of the flower relative to meristem orientation.

Conclusions

Our sequences across Campanulaceae of all three of these paralogous groups suggests that radially symmetrical Campanuloideae duplicatedCYC1, Lobelioideae duplicatedCYC2and lostCYC3early in their divergence, and that Cyphioideae lostCYC2and duplicatedCYC3. This suggests a dynamic pattern of duplication and loss of major floral patterning genes in this group and highlights the first case of a loss ofCYC2in a bilaterally symmetrical group. We illustrate here thatCYCexpression is conserved along the dorsoventral axis of the flower even as it turns upside-down, suggesting that at least lateCYCexpression is not regulated by extrinsic factors such as gravity. We additionally show that while the pattern of dorsoventral expression of each paralog remains the same,CamCYC2Ais more dominant in species with shorter relative finally positioned dorsal lobes, andCamCYC2Bis more dominant in species with long dorsal lobes.
Subtyping of high grade serous ovarian carcinoma: histopathological and immunohistochemical approach
Authors: Khashaba Marwa , Fawzy Mohamed , Abdel-Aziz Azza , Eladawei Ghada , Nagib Reham
Published: February 2022

Background

High-grade serous ovarian carcinoma (HGSOC) is classified into four molecular subtypes; mesenchymal, proliferative, immunoreactive, and differentiated, with suggested different prognosis. Addressing the presence of histopathological and immunohistochemical differences in HGSOC that parallel the molecular subtypes can help in tailoring the management protocol to improve therapeutic response and patient outcome.

Methods

This retrospective study was conducted on 85 specimens for cases of HGSOC. Cases were classified according to histopathological findings into mesenchymal, proliferative, immunoreactive, and differentiated subtypes. Cases were immunostained with ER, PR, Ki67, CD8, E-cadherin, and vimentin.

Results

By applying histopathological data, cases were subdivided into 4 groups; mesenchymal type represented by 25 cases, proliferative type which included 14 cases, the immunoreactive type included 14 cases, and differentiated type represented by 32 cases; 13 of them had SET features and 19 had papillary architectural features. A significant correlation was found between Ki67 and proliferative subtype, as well as between CD8 and immunoreactive subtype. ER showed significantly higher expression in proliferative subtype in the group treated by primary debulking. CD8 showed a significant correlation with solid endometroid transitional (SET) pattern in the group that underwent interval debulking. In terms of prognosis, the shortest median progression-free survival (PFS) was for mesenchymal subtype, while the longest median PFS was for differentiated subtype with SET architectural pattern with statistically significant correlation. No correlation was found between any of the studied parameters and overall survival.

Conclusion

Histopathological features and immunohistochemistry can help to stratify HGSOC into prognostic distinct groups.