bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating Systolic Blood Pressure Intervention Trial Participant Posttrial Survival Using Pooled Epidemiologic Cohort Data
Authors: Bellows Brandon K. , Zhang Yiyi , Zhang Zugui , Lloyd‐Jones Donald M. , Bress Adam P. , King Jordan B. , Kolm Paul , Cushman William C. , Johnson Karen C. , Tamariz Leonardo , Oelsner Elizabeth C. , Shea Steven , Newman Anne B. , Ives Diane G. , Couper David , Moran Andrew E. , Weintraub William S.
Published: May 2021

Background

Intensive systolic blood pressure treatment (<120 mm Hg) in SPRINT (Systolic Blood Pressure Intervention Trial) improved survival compared with standard treatment (<140 mm Hg) over a median follow‐up of 3.3 years. We projected life expectancy after observed follow‐up in SPRINT using SPRINT‐eligible participants in the NHLBI‐PCS (National Heart, Lung, and Blood Institute Pooled Cohorts Study).

Methods and Results

We used propensity scores to weight SPRINT‐eligible NHLBI‐PCS participants to resemble SPRINT participants. In SPRINT participants, we estimated in‐trial survival (<4 years) using a time‐based flexible parametric survival model. In SPRINT‐eligible NHLBI‐PCS participants, we estimated posttrial survival (≥4 years) using an age‐based flexible parametric survival model and applied the formula to SPRINT participants to predict posttrial survival. We projected overall life expectancy for each SPRINT participant and compared it to parametric regression (eg, Gompertz) projections based on SPRINT data alone. We included 8584 SPRINT and 10 593 SPRINT‐eligible NHLBI‐PCS participants. After propensity weighting, mean (SD) age was 67.9 (9.4) and 68.2 (8.8) years, and 35.5% and 37.6% were women in SPRINT and NHLBI‐PCS, respectively. Using the NHLBI‐PCS–based method, projected mean life expectancy from randomization was 21.0 (7.4) years with intensive and 19.1 (7.2) years with standard treatment. Using the Gompertz regression, life expectancy was 11.2 (2.3) years with intensive and 10.5 (2.2) years with standard treatment.

Conclusions

Combining SPRINT and NHLBI‐PCS observed data likely offers a more realistic estimate of life expectancy than parametrically extrapolating SPRINT data alone. These results offer insight into the potential long‐term effectiveness of intensive SBP goals.
Unequal Local Progress Towards Healthy People 2020 Objectives for Stroke and Coronary Heart Disease Mortality
Authors: Woodruff Rebecca C. , Casper Michele , Loustalot Fleetwood , Vaughan Adam S.
Published: May 2021

Background and Purpose:

Healthy People establishes objectives to monitor the nation’s health. Healthy People 2020 included objectives to reduce national stroke and coronary heart disease (CHD) mortality by 20% (to 34.8 and 103.4 deaths per 100 000, respectively). Documenting the proportion and geographic distribution of counties meeting neither the Healthy People 2020 target nor an equivalent proportional reduction can help identify high-priority geographic areas for future intervention.

Methods:

County-level mortality data for stroke (
International Classification of Diseases, Tenth Revision
codes I60–I69) and CHD (I20–I25) and bridged-race population estimates were used. Bayesian spatiotemporal models estimated age-standardized county-level death rates in 2007 and 2017 which were used to calculate and map the proportion and 95% credible interval of counties achieving neither the national Healthy People 2020 target nor a 20% reduction in mortality.

Results:

In 2017, 45.8% of counties (credible interval, 42.9–48.3) met neither metric for stroke mortality. These counties had a median stroke death rate of 42.2 deaths per 100 000 in 2017, representing a median 12.8% decline. For CHD mortality, 26.1% (credible interval, 25.0–27.8) of counties met neither metric. These counties had a median CHD death rate of 127.1 deaths per 100 000 in 2017, representing a 10.2% decline. For both outcomes, counties achieving neither metric were not limited to counties with traditionally high stroke and CHD death rates.

Conclusions:

Recent declines in stroke and CHD mortality have not been equal across US counties. Focusing solely on high mortality counties may miss opportunities in the prevention and treatment of cardiovascular disease and in learning more about factors leading to successful reductions in mortality.
Διαθήκη in Ptolemaic Documentary Papyri and LXX Genesis
Authors: Kim Kyu Seop
Published: May 2021

In this article, we observe that in Ptolemaic testament papyri the full proprietorship of the patrimony was not immediately transferred to heirs, and that, by διαθήκη, heirs could acquire only the “usufruct” (the right to use the land) during the lifetime of the testator. From this perspective, this study proposes that the translators of LXX Genesis selected the Greek equivalent διαθήκη for the Hebrew word בְּרִית because the term διαθήκη referred to the bestowal of the usufruct. In LXX Genesis, Abraham, Isaac, and all living beings did not possess the proprietorship of the land by διαθήκη even though they could use the land.
Prolonged Occupation and Exploitation of Natural Resources
Authors: Pabian Emilia
Published: May 2021

During recent years, natural gas reserves have been located off the coast of Cyprus and their possible exploitation has drawn the attention of Turkey, which has been in occupation of Northern Cyprus for decades. This contribution explores whether the law of occupation could provide a legal basis for the exploitation by Turkey of Northern Cyprus’ natural gas, specifically considering the prolonged nature of the occupation. It argues that Turkey is obliged to comply with the restrictive rules governing the use of natural resources in occupied territories. Furthermore, this contribution discusses the argument that during prolonged occupations an occupying power should be granted more leeway in imposing wider ranging initiatives to prevent the local population’s developmental stagnation, including more extensive natural resource exploitation. However, this contribution argues that granting such leeway has the potential to entrench the authority of the occupant into a state of permanency under the guise of legitimacy.
Johnson on Van Til: A Rejoinder
Authors: Frame John , Hays Steve
Published: May 2021

John Johnson has taken the position that Van Tilian apologetics can at most prove a generic theism, but not Christian theism. He further alleges that a Muslim apologist could just as well deploy a presuppositional defense because, in Johnson’s opinion, Van Tilian apologetics offers no way to broker rival religious claims. His final contention is that the presuppositional method robs the Christian apologist of appeal to the Resurrection, in direct contravention of NT practice.

It is the contention of this paper that Johnson’s critique suffers from a scanty acquaintance with the relevant literature and a sim plistic overview of the alternatives.
Two new species of Metamasius Horn, 1873 (Coleoptera: Curculionidae: Dryophthorinae) from Ecuador and Colombia
Authors: ANDERSON ROBERT S.
Published: May 2021

Two new species of South American Metamasius Horn (Coleoptera: Curculionidae: Dryophthorinae) are described: Metamasius onorei new species from Cotopaxi, Ecuador and Metamasius pilirostris new species from west of Río Yurumangui, Colombia. Diagnostic characters and images are provided for both new species to facilitate identification.
A new genus and species of groundwater isopod of the family Protojaniridae (Isopoda: Asellota: Gnathostenetroidoidea) from southern Chile
Authors: PÉREZ-SCHULTHEISS JORGE , WILSON GEORGE D. F.
Published: May 2021

A new asellotan isopod of the family Protojaniridae Fresi, Idato & Scipione, 1980 is described from freshwater springs in the Osorno province, Los Lagos region, southern Chile. Wiyufiloides osornoensis gen. & sp. n. is the third South American protojanirid species and the first known groundwater isopod in Chile. The new genus and species is principally characterized by the presence of a vestigial antennal scale, a strongly subchelate pereiopod I and the absence of an apical lobe on the protopod of pleopod II. The new taxon is described in detail and figures are given.
Description of the larva of Planiplax sanguiniventris (Calvert, 1907) (Odonata: Libellulidae)
Authors: NOVELO-GUTIÉRREZ RODOLFO
Published: May 2021

The last instar larva of Planiplax sanguiniventris (Calvert, 1907) is described and illustrated in detail based on one specimen collected in the municipality of Tenosique, Tabasco, Mexico. It is compared with the larvae of P. phoenicura Ris, 1912 and a congeneric unidentified species from Colombia. The main structural features are the number of setae on palp and prementum, the size of dorsal protuberance on S3, and the length of posterolateral spines on S8–9 and caudal appendages.
Diurnal Cycle of Precipitation Features Observed during DYNAMO
Authors: Rocque Marquette N. , Rutledge Steven A.
Published: May 2021

This study uses shipborne (R/V Roger Revelle and R/V Mirai) radar, upper-air, ocean, and surface meteorology datasets from the DYNAMO field campaign to investigate the diurnal cycle (DC) of precipitation over the central Indian Ocean related to two distinct Madden–Julian oscillations (MJOs) observed. This study extends earlier studies on the MJO DC by examining the relationship between the DC of convective organization and the local environment and comparing these results on- and off-equator. During the suppressed phase on-equator, the DC of rain rates exhibited two weak maxima at 1500 and 0100 LT, which was largely controlled by the presence of sub-MCS nonlinear precipitation features (PFs). During the active phase on-equator, MCS nonlinear features dominated the rain volume, and the greatest increase in rain rates occurred between 2100 and 0100 LT. This maximum coincided with the maxima in convective available potential energy (CAPE) and sensible heat flux, and the column moistened significantly overnight. Off-equator, the environment was much drier and there was little large-scale upward motion as a result of limited deep convection. The DC of rain rates during the active phase off-equator was most similar to the DC observed during the suppressed phase on-equator, while rainfall off-equator during the suppressed phase did not vary much throughout the day. The DC of MCS nonlinear PFs closely resembled the DC of rainfall during both phases off-equator, and the DC of environmental parameters, including sea surface temperature, CAPE, and latent heat flux, was typically much weaker off-equator compared to on-equator.
Dying from COVID-19 in nursing homes-sex differences in symptom occurrence
Authors: Martinsson Lisa , Strang Peter , Bergström Jonas , Lundström Staffan
Published: May 2021

Background

Coronavirus disease 2019 (COVID-19), is a disease with diverse presentation. Several studies have shown different occurrence of symptoms for women and men, but no studies have been found examining sex differences in clinical presentation for nursing home residents dying from COVID-19.

The objective of this study was to describe sex and age differences and the impact of a dementia diagnosis on symptom occurrence during the last week in life for persons dying from COVID-19 in nursing homes.

Methods

This is a population-based retrospective study based on data from the Swedish Register of Palliative Care. A total of 1994 residents aged 65 or older who died from COVID-19 in nursing homes were identified. The impact of sex, age and a dementia diagnosis on six different symptoms was analysed using chi2-test and multivariate logistic regression.

Results

Residents dying from COVID-19 were more often men (p < .002). Men more often had dyspnoea and death rattles (p < .001). Nausea was more common in women (p < .001). No sex differences in the occurrence of pain, anxiety or confusion were seen. Dyspnoea and nausea were less commonly reported in residents with dementia (p < .001).

Conclusions

We found sex differences in symptom presentation for fatal COVID-19 in nursing home settings which remained after adjusting for age. Residents with a dementia diagnosis had fewer symptoms reported before death compared to those without dementia.

Clinical presentation of fatal COVID-19 differs between women and men in nursing homes. Residents with fatal COVID-19 present with more unspecific and less prominent symptoms when also suffering from dementia.
Association between baseline LDL-C and prognosis among patients with coronary artery disease and advanced kidney disease
Authors: Wang Bo , Chen Shiqun , Liu Jin , Liang Yan , Meng Liangguang , Yan Xiaoming , Huang Haozhang , Chen Guanzhong , Huang Zhidong , Xu Danyuan , Li Min , Liang Jingjing , Liu Shuangxin , Chen Jiyan , Liu Yong , Tan Ning
Published: May 2021

Background

Lower low-density lipoprotein cholesterol (LDL-C) is significantly associated with improved prognosis in patients with coronary artery disease (CAD). However, LDL-C reduction does not decrease all-cause mortality among CAD patients when renal function impairs. The association between low baseline LDL-C (< 1.8 mmol/L) and mortality is unknown among patients with CAD and advanced kidney disease (AKD). The current study aimed to evaluate prognostic value of low baseline LDL-C level for all-cause death in these patients.

Methods

In this observational study, 803 CAD patients complicated with AKD (eGFR < 30 mL/min/1.73 m2) were enrolled between January 2008 to December 2018. Patients were divided into two groups (LDL-C < 1.8 mmol/L, n = 138; LDL-C ≥ 1.8 mmol/L, n = 665). We used Kaplan-Meier methods and Cox regression analyses to assess the association between baseline low LDL-C levels and long-term all-cause mortality.

Results

Among 803 participants (mean age 67.4 years; 68.5% male), there were 315 incidents of all-cause death during a median follow-up of 2.7 years. Kaplan–Meier analysis showed that low LDL-C levels were associated with worse prognosis. After adjusting for full 24 confounders (e.g., age, diabetes, heart failure, and dialysis, etc.), multivariate Cox regression analysis revealed that lower LDL-C level (< 1.8 mmol/L) was significantly associated with higher risk of all-cause death (adjusted HR, 1.38; 95% CI, 1.01–1.89).

Conclusions

Our data demonstrated that among patients with CAD and AKD, a lower baseline LDL-C level (< 1.8 mmol/L) did not present a higher survival rate but was related to a worse prognosis, suggesting a cautiousness of too low LDL-C levels among patients with CAD and AKD.
Overexpression of TNFα induces senescence, autophagy and mitochondrial dysfunctions in melanoma cells
Authors: Tyciakova Silvia , Valova Valeria , Svitkova Barbora , Matuskova Miroslava
Published: May 2021

Background

Tumor necrosis factor alpha (TNFα) is a pleiotropic cytokine with both anti-tumorigenic and pro-tumorigenic activity, affecting tumor cell biology, the balance between cell survival and death. The final effect of TNFα is dependent on the type of malignant cells, with the potential to arrest cancer progression.

Methods

In order to explain the diverse cellular response to TNFα, we engineered melanoma and colorectal carcinoma cell lines stably overexpressing this cytokine.

Results

Under the TNFα overexpression, significant upregulation of two genes was observed: proinflammatory cytokine IL6 gene in melanoma cells A375 and gene for pro-apoptotic ligand TRAIL in colorectal carcinoma cells HT29, both mediated by TNFα/TNFR1 signaling. Malignant melanoma line A375 displayed also increased autophagy on day 3, followed by premature senescence on day 6. Both processes seem to be interconnected, following earlier apoptosis induction and deregulation of mitochondrial functions. We documented altered mitochondrial status, lowered ATP production, lowered mitochondrial mass, and changes in mitochondrial morphology (shortened and condensed mitochondria) both in melanoma and colorectal carcinoma cells. Overexpression of TNFα was not linked with significant affection of the subpopulation of cancer stem-like cells in vitro. However, we could demonstrate a decrease in aldehyde dehydrogenase (ALDH) activity up to 50%, which is associated with to the stemness phenotype.

Conclusions

Our in vitro study of direct TNFα influence demonstrates two distinct outcomes in tumor cells of different origin, in non-epithelial malignant melanoma cells of neural crest origin, and in colorectal carcinoma cells derived from the epithelium.
The effects of secondary iron overload and iron chelation on a radiation-induced acute myeloid leukemia mouse model
Authors: Chan Lap Shu Alan , Gu Lilly ChunHong , Wells Richard A.
Published: May 2021

Background

Patients with myelodysplastic syndrome (MDS) require chronic red blood cell (RBC) transfusion due to anemia. Multiple RBC transfusions cause secondary iron overload and subsequent excessive generation of reactive oxygen species (ROS), which leads to mutations, cell death, organ failure, and inferior disease outcomes. We hypothesize that iron loading promotes AML development by increasing oxidative stress and disrupting important signaling pathways in the bone marrow cells (BMCs). Conversely, iron chelation therapy (ICT) may reduce AML risk by lowering iron burden in the iron-loaded animals.

Methods

We utilized a radiation-induced acute myeloid leukemia (RI-AML) animal model. Iron overload was introduced via intraperitoneal injection of iron dextran, and iron chelation via oral gavage of deferasirox. A total of 86 irradiated B6D2F1 mice with various levels of iron burden were monitored for leukemia development over a period of 70 weeks. The Kaplan-Meier estimator was utilized to assess AML free survival. In addition, a second cohort of 30 mice was assigned for early analysis at 5 and 7 months post-irradiation. The BMCs of the early cohort were assessed for alterations of signaling pathways, DNA damage response and gene expression. Statistical significance was established using Student’s t-test or ANOVA.

Results

Iron loading in irradiated B6D2F1 mice accelerated RI-AML development. However, there was a progressive decrease in AML risk for irradiated mice with increase in iron burden from 7.5 to 15 to 30 mg. In addition, ICT decreased AML incidence in the 7.5 mg iron-loaded irradiated mice, while AML onset was earlier for the 30 mg iron-loaded irradiated mice that received ICT. Furthermore, analysis of BMCs from irradiated mice at earlier intervals revealed accelerated dysregulation of signaling pathways upon iron loading, while ICT partially mitigated the effects.

Conclusions

We concluded that iron is a promoter of leukemogenesis in vivo up to a peak iron dose, but further iron loading decreases AML risk by increasing cell death. ICT can partially mitigate the adverse effects of iron overload, and to maximize its benefit this intervention should be undertaken prior to the development of extreme iron overload.
Baseline spirometry parameters as predictors of airway hyperreactivity in adults with suspected asthma
Authors: Peled Michael , Ovadya David , Cohn Jennifer , Seluk Lior , Pullerits Teet , Segel Michael J. , Onn Amir
Published: May 2021

Background

Methacholine challenge tests (MCTs) are used to diagnose airway hyperresponsiveness (AHR) in patients with suspected asthma where previous diagnostic testing has been inconclusive. The test is time consuming and usually requires referral to specialized centers. Simple methods to predict AHR could help determine which patients should be referred to MCTs, thus avoiding unnecessary testing. Here we investigated the potential use of baseline spirometry variables as surrogate markers for AHR in adults with suspected asthma.

Methods

Baseline spirometry and MCTs performed between 2013 and 2019 in a large tertiary center were retrospectively evaluated. Receiver-operating characteristic curves for the maximal expiratory flow-volume curve indices (angle β, FEV1, FVC, FEV1/FVC, FEF50%, FEF25–75%) were constructed to assess their overall accuracy in predicting AHR and optimal cutoff values were identified.

Results

A total of 2983 tests were analyzed in adults aged 18–40 years. In total, 14% of all MCTs were positive (PC20 ≤ 16 mg/ml). All baseline spirometry parameters were significantly lower in the positive group (p < 0.001). FEF50% showed the best overall accuracy (AUC = 0.688) and proved to be useful as a negative predictor when applying FEF50% ≥ 110% as a cutoff level.

Conclusions

This study highlights the role of FEF50% in predicting AHR in patients with suspected asthma. A value of ≥ 110% for baseline FEF50% could be used to exclude AHR and would lead to a substantial decrease in MCT referrals.
A qualitative exploration of priorities for quality improvement amongst Aboriginal and Torres Strait Islander primary health care services
Authors:   With the LEAP Learning Community, Carlisle Karen , Matthews (Quandamooka) Veronica , Redman-MacLaren Michelle , Vine Kristina , Turner (Anmatyerre/Jaru) Nalita Nungarrayi , Felton-Busch Catrina , Taylor Judy , Thompson Sandra , Whaleboat Donald , Larkins Sarah
Published: May 2021

Background

Achieving quality improvement in primary care is a challenge worldwide, with substantial gaps between best practice and actual practice. Within the context of Australia, Aboriginal and Torres Strait Primary Health Care (PHC) services have great variation across settings, structures and context. Research has highlighted how these contextual differences can critically influence the success of Quality Improvement (QI) interventions and outcomes. Less understood is the interaction between local context and other factors, which may impact the implementation of QI interventions. This paper aims to explore the strengths and challenges in QI for Aboriginal and Torres Strait Islander PHC services and their priorities for improvement.

Methods

A multiple case study design was adopted, working with eight Aboriginal and Torres Strait Islander PHC services in Northern Territory, Queensland and Western Australia. Data were collected via a health service survey, semi-structured interviews with health service staff and service users and researcher observations, to explore QI and perceptions of care quality at the service level. Data reported here were analysed using an iterative thematic technique, within-case and across-case.

Results

A total of 135 interviews were conducted with health service staff, service users and community members. Participants emphasised the centrality of resilient community, committed workforce and valued Aboriginal and Torres Strait Islander team members in delivering care. A shared purpose around improving the health of community was a significant driver. Key challenges included staff turnover and shortages, a complex and overwhelming acute and chronic care workload, building relationships and trust between health services and the community. Service-suggested priority areas for improvement were categorised into five themes: i) cultural safety (community driving health and planning for culturally safe services); ii) community engagement (through clinical activities in the community); iii) shared ownership and a team approach around QI; iv) strengthening systems and consistent ways of doing things in the health service; and v) strengthening local workforce (and resources for a culturally safe workforce).

Conclusions

These findings advance understandings of relational, community and cultural factors which are identified priorities for the delivery of quality care in Aboriginal and Torres Strait Islander PHC services across varied contexts.
Costs associated with depression and obesity among cardiovascular patients: medical expenditure panel survey analysis
Authors: Tápias Felipe Saia , Otani Victor Henrique Oyamada , Vasques Daniel Augusto Corrêa , Otani Thais Zelia Santos , Uchida Ricardo Riyoiti
Published: May 2021

Background

There is a lack of information on the cost of depression associated with metabolic syndrome and cardiovascular diseases in the literature.

Methods

We evaluated the synergistic effects of depression and obesity on total expenditures for cardiovascular conditions using data from the Medical Expenditure Panel Survey (MEPS) database. We analyzed MEPS data from 1996 to 2017 comprising adult cardiovascular subjects. We categorized individuals following a combination of International Classification of Diseases ICD-9-CM and ICD-10 codes, and depression symptoms as evaluated using the Patient Health Questionnaire-2 (PHQ-2) depression screening tool. Our sample comprised cardiovascular patients aged 18 years and older, with a body mass index (BMI) between 18.5 and 60. Our study comprised unweighted sample of 96,697 (weighted sample of 938,835,031) adults, a US-nationwide representative sample of cardiovascular disease patients. The four response categories were: no depression; unrecognized depression; asymptomatic depression; and symptomatic depression. Our evaluated outcomes were total annual healthcare expenditures, including dental, emergency room, hospital outpatient, hospital inpatient, office-based, prescription, and home health care expenses.

Results

Asymptomatic and symptomatic depression was more frequent among obese individuals than in individuals with a normal BMI (p <  0.001). Total expenditure was highest among symptomatic depression individuals (17,536) and obese (9871) with cardiovascular disease. All the expenditure outcomes were significantly higher among symptomatic depression individuals than those without depression (p <  0.001), except for dental costs. All healthcare expenditures associated with obesity were higher compared to individuals with normal BMI withp <  0.001, except for emergency and home healthcare costs. Most importantly, among obese individuals, all healthcare expenditures were significantly higher (p <  0.001) in those with symptomatic depression than those without depression, except for dental costs, where the difference was not significant (0.899). Therefore, obesity and depression entail increased expenses in patients with cardiovascular disease.

Conclusions

We found incremental expenditures among unrecognized, asymptomatic, and symptomatic depressed individuals with obesity compared to non-depressed, non-obese subjects. However, these are preliminary results that should be further validated using different methodologies.
The association between insulin sensitivity indices, ECG findings and mortality: a 40-year cohort study
Authors: Moshkovits Yonatan , Rott David , Chetrit Angela , Dankner Rachel
Published: May 2021

Background

Type 2 Diabetes is a major risk factor for cardiovascular (CV) mortality. Insulin resistance can be evaluated non-invasively by insulin sensitivity indices (ISI) such as the Mcauley index (MCAi), which is a function of the fasting insulin and triglycerides. Currently, the association between ISIs and ECG findings and all-cause and CV mortality is still not established in a large scale and heterogeneous population.

Method

In a prospective study of the Israel cohort on Glucose Intolerance, Obesity and Hypertension (GOH) second phase (1979–1982) 1830 men and women were followed until December-2016 for CV-mortality and December-2019 for all-cause mortality. ECGs were recorded and OGTTs performed during baseline. ISIs were categorized into quartiles and evaluated against ECG findings and all-cause and CV-mortality.

Results

Mean age at baseline was 52.0 ± 8.1 years, and 75 (15.2%) and 47 (25.3%) participants in the upper quartiles (Q2-4) and the lower quartile (Q1) of the MCAi, presented with Ischemic changes on ECG respectively (p = 0.02). Multivariable analysis showed higher odds for ECG ischemic changes, for individuals in Q1-MCAi (adjusted-OR = 1.7, 95% CI 1.02–2.8), compared with Q2-4-MCAi, which attenuated when excluding individuals with diabetes (adjusted-OR = 1.6, 95% CI 0.9–2.7, p = 0.09).

Median follow up for all-cause and for cardiovascular mortality was 31 years and 37 years, respectively. Cox proportional-hazards regression showed an increased risk for all-cause mortality for individuals in Q1-MCAi (HR = 1.2, 95% CI 1.02–1.3) as well as an increased risk for CV-mortality (HR = 1.4, 95%CI 1.1–1.8) compared with Q2-4-MCAi. Individuals in Q4-Ln Homeostatic model assessment- Insulin Resistance (HOMA-IR) and Q1- Quantitative Insulin Sensitivity Check Index (QUICKI) also presented with increased risk for all-cause-mortality (HR = 1.2, 95%CI 1.04–1.4; and HR = 1.2, 95% CI 1.04–1.4, respectively). Other ISIs did not show significant associations with CV-mortality.

Conclusion

Higher insulin-resistance, according to the MCAi, associated with ECG-changes, and with greater risk for all-cause and CV-mortality over a 40-year follow-up. The MCAi may be considered as an early predictive and prognostic biomarker for CV-morbidity and mortality in adults.
Efficacy and safety of artemether–lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in Ethiopia: a systematic review and meta-analysis
Authors: Abamecha Abdulhakim , Yilma Daniel , Adissu Wondimagegn , Yewhalaw Delenasaw , Abdissa Alemseged
Published: May 2021

Background

Regular monitoring of anti-malarial drug efficacy is vital for establishing rational malaria treatment guidelines and ensuring adequate treatment outcomes. This study aimed to synthesize the available evidence on the efficacy of artemether–lumefantrine for the management of uncomplicated falciparum malaria in Ethiopia.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Relevant published studies were searched from the databases (PubMed, Google Scholar and Clinical trial registry) on published artemether–lumefantrine therapeutic efficacy studies conducted in Ethiopia from 2004 to 2020. The retrieved studies were assessed for quality using the modified Newcastle Ottawa Scale for observational studies and modified Jadad scale for interventional studies. Risk of bias was also assessed by using ROBINS-I tool. OpenMeta-Analyst software was used for the statistical analysis. The review protocol is registered in PROSPERO, number CRD42020201859.

Results

Fifteen studies (1523 participants) were included in the final analysis. The overall PCR-uncorrected pooled proportion of treatment success of artemether–lumefantrine therapy for uncomplicated falciparum malaria was 98.4% (95%CI 97.6–99.1). A random-effects model was used because of considerable heterogeneity [χ2 = 20.48,df(14),P = 0.011 and I2 = 31.65]. PCR-corrected pooled proportion of treatment success of artemether–lumefantrine therapy was 98.7% (95% CI 97.7–99.6). A random-effects model was used [χ2 = 7.37,df(6),P = 0.287 and I2 = 18.69]. Most studies included in the present review achieved a rapid reduction of fevers and parasitaemia between D0 and D3 of assessment. Adverse events were mostly mild and only two cases were reported as serious, but were not directly attributed to the drug.

Conclusion

The present meta-analysis suggests that artemether–lumefantrine therapy is efficacious and safe in treating uncomplicated falciparum malaria in Ethiopia. However, owing to the high risk of bias in the included studies, strong conclusions cannot be drawn. Further high-quality RCTs assessing anti-malarial efficacy and safety should be performed to demonstrates strong evidence of changes in parasite sensitivity to artemether–lumefantrine in Ethiopia.
Embryo CHH hypermethylation is mediated by RdDM and is autonomously directed in Brassica rapa
Authors: Chakraborty Tania , Kendall Timmy , Grover Jeffrey W. , Mosher Rebecca A.
Published: May 2021

Background

RNA-directed DNA methylation (RdDM) initiates cytosine methylation in all contexts and maintains asymmetric CHH methylation. Mature plant embryos show one of the highest levels of CHH methylation, and it has been suggested that RdDM is responsible for this hypermethylation. Because loss of RdDM inBrassica rapacauses seed abortion, embryo methylation might play a role in seed development. RdDM is required in the maternal sporophyte, suggesting that small RNAs from the maternal sporophyte might translocate to the developing embryo, triggering DNA methylation that prevents seed abortion. This raises the question of whether embryo hypermethylation is autonomously regulated by the embryo itself or influenced by the maternal sporophyte.

Results

Here, we demonstrate thatB. rapaembryos are hypermethylated in both euchromatin and heterochromatin and that this process requires RdDM. Contrary to the current models,B. rapaembryo hypermethylation is not correlated with demethylation of the endosperm. We also show that maternal somatic RdDM is not sufficient for global embryo hypermethylation, and we find no compelling evidence for maternal somatic influence over embryo methylation at any locus. Decoupling of maternal and zygotic RdDM leads to successful seed development despite the loss of embryo CHH hypermethylation.

Conclusions

We conclude that embryo CHH hypermethylation is conserved, autonomously controlled, and not required for embryo development. Furthermore, maternal somatic RdDM, while required for seed development, does not directly influence embryo methylation patterns.
Evaluating the impact of COVID-19 on rare disease support groups
Authors: McMullan Julie , Crowe Ashleen L. , Bailie Caitlin , McKnight Amy Jayne
Published: May 2021

Objectives

The impact of the current COVID-19 pandemic has been felt worldwide. Many vulnerable populations rely heavily on peer support provided by individual or collaborative groups. This study aimed to evaluate the impact of COVID-19 on groups supporting patients with a rare disease(s). Anecdotally the current pandemic significantly changed the way in which these groups operate and the services they can provide.

Data description

A targeted survey was conducted online with rare disease individual or collaborative groups. The results of the survey highlight the challenges individual and collaborative groups are facing during this pandemic and help to identify what support should be put in place to enable them to sustain their much-valued service through these trialing times. Groups have experienced an increase in calls to their helplines as well as followers to their websites and social media feeds. Groups are no longer meeting in person and so online meetings, webinars and zoom chats have become a regular occurrence. Fundraising was highlighted as an area of concern for such groups. It is hoped that this data might be used to highlight the support individual and collaborative groups require while also raising awareness of the value they bring to many.
Alpha 2-antiplasmin deficiency in a Sudanese child: a case report
Authors: Mohammed Bashir Abdrhman Bashir
Published: May 2021

Background

The plasma serine protease inhibitor alpha 2-antiplasmin (α2-AP, otherwise known as α2-plasmin inhibitor) is a rapid-acting plasmin inhibitor recently found in human plasma, which seems to have a significant role in the regulation of in vivo fibrinolysis. Congenital deficiency of α2-AP is extremely uncommon.

Case presentation

We report here a case of absolute deficiency of α2-AP in an 11-year-old Sudanese boy, who had a lifelong intermittent hemorrhagic tendency (gum bleeding, epistaxis, and exaggerated bleeding after trauma). Coagulation tests including prothrombin time, partial thromboplastin time, thrombin time, bleeding time, platelet count, clot retraction test, antithrombin, and factor VIII levels were within normal limits. Hepatic function tests and complete blood count were also normal. The main interesting finding in this patient was that the whole blood clot lysis was extremely fast, completed within 5–8 hours. The second abnormal finding is that the euglobulin clot lysis time was short. Nevertheless, the concentration of α2-AP in the patient's plasma was 0.2 IU/ml (reference range is 0.80–1.20 IU/ml). The addition of pooled plasma (with normal α2-AP) to the patient's whole blood corrected the accelerated fibrinolysis.

Conclusion

The study showed that α2-AP deficiency resulted in uninhibited fibrinolysis that caused the hemorrhagic tendency in this patient. Thus, this report demonstrates the significant role of α2-AP in coagulation.
Mesenchymal stem and non-stem cell surgery, rescue, and regeneration in glaucomatous optic neuropathy
Authors: Limoli Paolo Giuseppe , Limoli Celeste , Vingolo Enzo Maria , Franzone Federica , Nebbioso Marcella
Published: May 2021

Background

Glaucomatous optic neuropathy (GON) is an anatomofunctional impairment of the optic nerve triggered by glaucoma. Recently, growth factors (GFs) have been shown to produce retinal neuroenhancement. The suprachoroidal autograft of mesenchymal stem cells (MSCs) by the Limoli retinal restoration technique (LRRT) has proven to achieve retinal neuroenhancement by producing GF directly into the choroidal space. This retrospectively registered clinical study investigated the visual function changes in patients with GON treated with LRRT.

Methods

Twenty-five patients (35 eyes) with GON in progressive disease conditions were included in the study. Each patient underwent a comprehensive ocular examination, including the analysis of best corrected visual acuity (BCVA) for far and near visus, sensitivity by Maia microperimetry, and the study of the spectral domain-optical coherence tomography (SD-OCT). The patients were divided into two groups: a control group, consisting of 21 eyes (average age 72.2 years, range 50–83), and an LRRT group, consisting of 14 eyes (average age 67.4, range 50–84).

Results

After 6 months, the BCVA, close-up visus, and microperimetric sensitivity significantly improved in the LRRT-treated group (p<0.05), whereas the mean increases were not statistically significant in controls (p>0.5).

Conclusions

Patients with GON treated with LRRT showed a significant increase in visual performance (VP) both in BCVA and sensitivity and an improvement of residual close-up visus, in the comparison between the LRRT results and the control group. Further studies will be needed to establish the actual significance of the reported findings.
Umbilical mesenchymal stem cell-derived extracellular vesicles as enzyme delivery vehicle to treat Morquio A fibroblasts
Authors: Flanagan Michael , Pathak Isha , Gan Qi , Winter Linda , Emnet Ryan , Akel Salem , Montaño Adriana M.
Published: May 2021

Background

Mucopolysaccharidosis IVA (Morquio A syndrome) is a lysosomal storage disease caused by the deficiency of enzymeN-acetylgalactosamine-6-sulfate sulfatase (GALNS), which results in the accumulation of the glycosaminoglycans (GAGs), keratan sulfate, and chondroitin-6-sulfate in the lysosomes of all tissues causing systemic dysfunction. Current treatments include enzyme replacement therapy (ERT) which can treat only certain aspects of the disease such as endurance-related biological endpoints. A key challenge in ERT is ineffective enzyme uptake in avascular tissues, which makes the treatment of the corneal, cartilage, and heart valvular tissue difficult. The aim of this study was to culture human umbilical mesenchymal stem cells (UMSC), demonstrate presence of GALNS enzyme activity within the extracellular vesicles (EVs) derived from these UMSC, and study how these secreted EVs are taken up by GALNS-deficient cells and used by the deficient cell’s lysosomes.

Methods

We obtained and cultured UMSC from the umbilical cord tissue from anonymous donors from the Saint Louis Cord Blood Bank. We characterized UMSC cell surface markers to confirm phenotype by cell sorting analyses. In addition, we confirmed that UMSC secrete GALNS enzyme creating conditioned media for co-culture experiments with GALNS deficient cells. Lastly, we isolated EVs derived from UMSC by ultracentrifugation to confirm source of GALNS enzyme.

Results

Co-culture and confocal microscopy experiments indicated that the lysosomal content from UMSC migrated to deficient cells as evidenced by the peak signal intensity occurring at 15 min. EVs released by UMSC were characterized indicating that the EVs contained the active GALNS enzyme. Uptake of GALNS within EVs by deficient fibroblasts was not affected by mannose-6-phosphate (M6P) inhibition, suggesting that EV uptake by these fibroblasts is gradual and might be mediated by a different means than the M6P receptor.

Conclusions

UMSC can deliver EVs containing functional GALNS enzyme to deficient cells. This enzyme delivery method, which was unaffected by M6P inhibition, can function as a novel technique for reducing GAG accumulation in cells in avascular tissues, thereby providing a potential treatment option for Morquio A syndrome.
Complex PTSD and borderline personality disorder
Authors: Ford Julian D. , Courtois Christine A.
Published: May 2021

Background

This article builds on a previous review (Ford and Courtois, Borderline Personal Disord Emot Dysregul 1:9, 2014) which concluded that complex posttraumatic stress disorder (cPTSD) could not be conceptualized as a sub-type of either PTSD or BPD. Recent research is reviewed that extends and clarifies the still nascent understanding of the relationship between cPTSD and BPD.

Main body

The circumscribed formulation of adult cPTSD that has been developed, validated, and included in the 11th Edition of the International Classification of Diseases has spurred research aimed at differentiating cPTSD and BPD both descriptively and empirically. A newly validated Developmental Trauma Disorder (DTD) syndrome for children and adolescents provides a basis for systematic research on the developmental course and origins of adult cPTSD and BPD. This review summarizes recent empirical findings regarding BPD, PTSD, and cPTSD in terms of: (1) prevalence and comorbidity; (2) clinical phenomenology; (3) traumatic antecedents; (4) psychobiology; (5) emotion dysregulation; (6) dissociation; and (7) empirically supported approaches to clinical assessment and psychotherapeutic treatment.

Conclusion

The evidence suggests that PTSD, cPTSD, and BPD are potentially comorbid but distinct syndromes. A hypothesis is advanced to stimulate scientific research and clinical innovation defining and differentiating the disorders, positing that they may represent a continuum paralleling the classic conceptualization of the stress response, with dissociation potentially involved in each disorder.
The cultural and heritage tourist, SEM analysis: the case of The Citadel of the Catholic King
Authors: Hernández-Rojas Ricardo David , del Río Juan Antonio Jimber , Fernández Alberto Ibáñez , Vergara-Romero Arnaldo
Published: May 2021

This study researches the loyalty of travelers to destinations which include material cultural heritage. It analyzes the loyalty of visitors to a destination with cultural heritage sites in order to provide results which can be used to improve the management of the destination. This research used Warp-PLS 7.0 software with a structural equations model to evaluate the 8 proposed and validated hypotheses. A questionnaire was given to a sample of 499 tourists who visited The Citadel of the Catholic King in Córdoba and the statistical study of the replies gave results about the loyalty of visitors to a destination which includes cultural heritage. This study adds an innovative component by analyzing the moderating effect of perceived heritage quality and perceived cultural quality on the relationship of perceived value and visitor satisfaction. This study shows that visitor loyalty to The Citadel of the Catholic King depends on the visitor satisfaction with the cultural heritage, it also analyses how the quality perceived by the tourist modulates to varying degrees the relationship between perceived value and tourist satisfaction. Areas which can be improved at cultural heritage sites have been identified and these include the professionalization of tour guides specialized in cultural heritage sites, improving and showing the cultural importance of the heritage, the information available about the heritage and the access to the heritage. These findings are important for city managers when preparing projects to increase the loyalty and competitiveness of the city compared to other similar destinations with cultural heritage.
Feasibility, safety and acceptability of select outcome measures in a physiotherapy study protocol for boys with haemophilia
Authors: Thorpe Nicola , Harniess Phillip , Main Eleanor , Hubert Nicola , Rand Sarah , Stephensen David , Liesner Ri , Bladen Melanie
Published: May 2021

Background

There is a lack of functional performance measures for children and young people with haemophilia (CYPwH) with associated control data from typically developing boys (TDB). The literature advocates development of a core set of outcome measures for different chronic conditions. As medical treatment improves, CYPwH are experiencing better outcomes; therefore, more challenging measures are required to monitor physical performance. Such testing is not performed routinely, due to practical and safety concerns.

Aim

Evaluate the feasibility, safety and acceptability of select outcome measures as part of a study protocol testing CYPwH; including myometry, 10 metre incremental shuttle walk test (10-m ISWT), iSTEP (an incremental step test, with data from TDB), and 1 week of accelerometry-wear at home.

Methods

Sixty-six boys aged 6–15 years with mild, moderate or severe haemophilia A or B (including inhibitors) attending routine clinics at Great Ormond Street Hospital were approached to participate. Descriptive statistics and content analysis were used to assess outcomes of feasibility, safety and acceptability, which included recruitment/retention rates, protocol completion within routine appointment timeframes, performance testing without serious adverse events/reactions (SAE/SARs), and acceptability to CYPwH of high-level performance measures.

Results

Outcomes were met: 43 boys completed testing at clinic review (Jan–Nov 2018) within a 10-month timeframe, retention was 95% at completion of protocol and no SAE/SARs were reported throughout testing.

Conclusion

Feasibility, safety and acceptability of the study protocol have been established in this population. Both high-level performance tests, iSTEP and 10-m ISWT, were an acceptable addition to boys’ routine clinic appointments and could be safe, acceptable choices of outcome measure as part of a core set of tests for CYPwH. Further investigation of the psychometric properties for the iSTEP is now justified, in order for it to be used as a standardised, validated, reliable outcome measure in clinical or research settings.

Trial registration

Retrospectively registered on September 3, 2019, on ClinicalTrials.gov (ID: NCT04076306).
Development and implementation of a novel, mandatory competency-based medical education simulation program for pediatric emergency medicine faculty
Authors: Pirie Jonathan , Fayyaz Jabeen , Gharib Mireille , Simone Laura , Glanfield Carrie , Kempinska Anna
Published: May 2021

Background

Maintaining acute care physician competence is critically important. Current maintenance of certification (MOC) programs has started to incorporate simulation-based education (SBE). However, competency expectations have not been defined. This article describes the development of a mandatory annual SBE, competency-based simulation program for technical and resuscitation skills for pediatric emergency medicine (PEM) physicians.

Methods

The competency-based medical education (CBME) program was introduced in 2016. Procedural skill requirements were based on a needs assessment derived from Royal College PEM training guidelines. Resuscitation scenarios were modified versions of pre-existing in-situ mock codes or critical incident cases. All full-time faculty were required to participate annually in both sessions. Delivery of educational content included a flipped classroom website, deliberate practice, and stop-pause debriefing. All stations required competency checklists and global rating scales.

Results

Between 2016 and 2018, 40 physicians and 48 registered nurses attended these courses. Overall course evaluations in 2018 were 4.92/5 and 4.93/5. Barriers to implementation include the need for many simulation education experts, time commitment, and clinical scheduling during course events.

Conclusion

We have developed a mandatory simulation-based, technical, and resuscitation CBME program for PEM faculty. This simulation-based CBME program could be adapted to other acute care disciplines. Further research is required to determine if these skills are enhanced both in a simulated and real environment and if there is an impact on patient outcomes.