bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of norms in variation in cancer centers’ end-of-life quality: qualitative case study protocol
Authors: Knutzen Kristin E. , Schifferdecker Karen E. , Murray Genevra F. , Alam Shama S. , Brooks Gabriel A. , Kapadia Nirav S. , Butcher Rebecca , Barnato Amber E.
Published: August 2020

Background

A critical barrier to improving the quality of end-of-life (EOL) cancer care is our lack of understanding of the mechanisms underlying variation in EOL treatment intensity. This study aims to fill this gap by identifying 1) organizational and provider practice norms at major US cancer centers, and 2) how these norms influence provider decision making heuristics and patient expectations for EOL care, particularly for minority patients with advanced cancer.

Methods

This is a multi-center, qualitative case study at six National Comprehensive Cancer Network (NCCN) and National Cancer Institute (NCI) Comprehensive Cancer Centers. We will theoretically sample centers based upon National Quality Forum (NQF) endorsed EOL quality metrics and demographics to ensure heterogeneity in EOL intensity and region. A multidisciplinary team of clinician and non-clinician researchers will conduct direct observations, semi-structured interviews, and artifact collection. Participants will include: 1) cancer center and clinical service line administrators; 2) providers from medical, surgical, and radiation oncology; palliative or supportive care; intensive care; hospital medicine; and emergency medicine who see patients with cancer and have high clinical practice volume or high local influence (provider interviews and observations); and 3) adult patients with metastatic solid tumors and whom the provider would not be surprised if they died in the next 12 months and their caregivers (patient and caregiver interviews). Leadership interviews will probe about EOL institutional norms and organization. We will observe inpatient and outpatient care for two weeks. Provider interviews will use vignettes to probe explicit and implicit motivations for treatment choices. Semi-structured interviews with patients near EOL, or their family members and caregivers will explore past, current, and future decisions related to their cancer care. We will import transcribed field notes and interviews into Dedoose software for qualitative data management and analysis, and we will develop and apply a deductive and inductive codebook to the data.

Discussion

This study aims to improve our understanding of organizational and provider practice norms pertinent to EOL care in U.S. cancer centers. This research will ultimately be used to inform a provider-oriented intervention to improve EOL care for racial and ethnic minority patients with advanced cancer.

Trial registration

Clinicaltrials.gov;NCT03780816; December 19, 2018.
Nutritional status impacts dengue virus infection in mice
Authors: Chuong Christina , Bates Tyler A. , Akter Shamima , Werre Stephen R. , LeRoith Tanya , Weger-Lucarelli James
Published: August 2020

Background

Dengue virus (DENV) is estimated to infect 390 million people annually. However, few host factors that alter disease severity are known. Malnutrition, defined as both over- and undernutrition, is a growing problem worldwide and has long been linked to dengue disease severity by epidemiological and anecdotal observations. Accordingly, we sought to establish a mouse model to assess the impact of nutritional status on DENV disease severity.

Results

Using transiently immunocompromised mice, we established a model of mild dengue disease with measurable viremia. We then applied it to study the effects of healthy weight, obese, and low-protein diets representing normal, over-, and undernutrition, respectively. Upon infection with DENV serotype 2, obese mice experienced more severe morbidity in the form of weight loss and thrombocytopenia compared to healthy weight groups. Additionally, obesity altered cytokine expression following DENV infection. Although low protein-fed mice did not lose significant weight after DENV2 infection, they also experienced a reduction in platelets as well as increased spleen pathology and viral titers.

Conclusions

Our results indicate that obese or undernourished mice incur greater disease severity after DENV infection. These studies establish a role for nutritional status in DENV disease severity.
Comparing stroke prevention therapy of direct oral anticoagulants and vitamin K antagonists in patients with atrial fibrillation: a nationwide retrospective observational study
Authors: Paschke Lena M. , Klimke Kerstin , Altiner Attila , von Stillfried Dominik , Schulz Maike
Published: August 2020

Background

Direct oral anticoagulants (DOACs) are not only increasingly being used for the initial stroke prevention therapy but progressively also substitute vitamin K antagonist (VKA) treatment in patients with non-valvular atrial fibrillation (AF). DOACs have been compared regarding therapeutic efficacy and adverse outcomes to warfarin in several pivotal studies and showed non-inferiority in terms of stroke prevention and superiority in terms of bleeding complications. However, comprehensive comparative studies are lacking for phenprocoumon, a VKA prescribed frequently outside the USA and the UK and accounting for 99% of all VKA prescriptions in Germany. Patients treated with phenprocoumon seem to meet more often international normalized ratio values in the therapeutic range, which may have implications concerning their efficacy and safety. This study aims at comparing the risk of stroke and bleeding in phenprocoumon- and DOAC-treated patients with AF in an adequately powered observational study population.

Methods

Retrospective analysis of stroke and bleeding incidence of 837,430 patients (1.27 million patient years) treated with DOAC or phenprocoumon for stroke prevention in German ambulatory care between 2010 and 2017. Relative risks of stroke and bleeding were estimated by calculating cox regression-derived hazard ratios (HR) and 95% confidence intervals (CI) of propensity score-matched cohorts.

Results

Patients treated with DOAC had an overall higher risk for stroke (HR 1.32; CI 1.29–1.35) and a lower risk for bleeding (0.89; 0.88–0.90) compared to phenprocoumon. When analyzed separately, the risk for stroke was higher for dabigatran (1.93; 1.82–2.03), apixaban (1.52; 1.46–1.58), and rivaroxaban (1.13; 1.10–1.17) but not for edoxaban (0.88; 0.74–1.05). The risk for bleeding was lower for dabigatran (0.85; 0.83–0.88), apixaban (0.71; 0.70–0.73), and edoxaban (0.74; 0.68–0.81) but not for rivaroxaban (1.03; 1.01–1.04).

Conclusions

This study provides a comprehensive view of the stroke and bleeding risks associated with phenprocoumon and DOAC use in Germany. Phenprocoumon may be preferable to DOAC treatment for the prevention of strokes in AF in a real-world population cared for in ambulatory care.
Clinical leishmaniosis in a captive Eurasian otter (Lutra lutra) in Spain: a case report
Authors: Cantos-Barreda Ana , Navarro Ricardo , Pardo-Marín Luis , Martínez-Subiela Silvia , Ortega Elena , Cerón José J. , Tecles Fernando , Escribano Damián
Published: August 2020

Background

Captive and free-ranging wild mammals have been recognized as potential reservoirs of Leishmania infantum infection. The aim of this study was to describe the first clinical case of leishmaniosis in the Eurasian otter.

Case presentation

A case of clinical leishmaniosis is reported in a 4-year-old male Eurasian otter housed at a wildlife park (Murcia, South Eastern Spain). The Eurasian otter showed bilateral epistaxis, anorexia, apathy, and weight loss. A complete blood cell count and biochemical analyses revealed hyperproteinemia, hyperglobulinemia, decreases of paraoxonase-1, increases of haptoglobin and ferritin, and proteinuria. Bilateral nephropathy with hydronephrosis, mesenteric lymphadenomegaly, and ascites were also observed. L. infantum infection was confirmed by microscopy (amastigotes were detected in macrophages from spleen aspirate), molecular diagnosis (L. infantum DNA was detected by real-time polymerase chain reaction), and serology (anti-Leishmania IgG2 antibodies were detected by time-resolved immunofluorometry). The animal was treated with allopurinol for 3 months and gained weight, the epistaxis disappeared, and the ferritin concentration decreased.

Conclusions

This is the first report of clinical leishmaniosis in the Eurasian otter. Our results suggest that Eurasian otters are susceptible to infection with L. infantum and can develop clinical leishmaniosis in endemic areas.
Crossed renal ectopia with fusion in a pelvic inlet area, atypical portal vein and coccygeal deformation in a young female cat
Authors: Hebel Mateusz , Ruszkowski Jakub Jędrzej , Giza Elżbieta , Pomorska-Mól Małgorzata
Published: August 2020

Background

The case report describes a rare congenital anomaly, crossed fused renal ectopia (CFRE), with coexistence of two other abnormalities – atypical portal vein and coccygeal vertebrae malformation in a domestic cat. The concomitance of those 3 congenital defects has not been described previously.

Case presentation

An 8-month-old female, domestic cat suffering from chronic diarrhea was referred to the diagnostic imaging unit. The patient showed no other clinical symptoms. An abdominal ultrasonographic examination was performed in order to evaluate the condition of abdominal organs, particularly the gastrointestinal tract. The ultrasound examination showed an ectopic duplex kidney at instead of kidneys in their typical location. Computed tomography (CT) with angiographic phase and excretory urography was requested to evaluate the condition of the kidneys and ureters. The final diagnosis was CFRE, atypical portal vein and coccygeal deformation in an asymptomatic cat with no changes in renal function and normal blood parameters.

Conclusions

Crossed fused renal ectopia is a rare congenital anomaly and is easily detectable by an abdominal ultrasonographic examination and CT, which allows more complete assessment of both anatomical relations and secretory function of the kidney. The occurrence of CFRE, abnormal portal vein and spinal malformation in a clinically healthy patient is the evidence that congenital malformations may simultaneously involve various, not directly related structures and systems, without significant influence on blood and urine parameters. Thus the most useful tool in the evaluation of the morphological and functional changes is the diagnostic imaging, especially contrast enhanced CT. Our results show that renal fusions should be considered in the differential diagnosis of caudal abdominal masses.
Constructing cancer patient-specific and group-specific gene networks with multi-omics data
Authors: Lee Wook , Huang De-Shuang , Han Kyungsook
Published: August 2020

Background

Cancer is a complex and heterogeneous disease with many possible genetic and environmental causes. The same treatment for patients of the same cancer type often results in different outcomes in terms of efficacy and side effects of the treatment. Thus, the molecular characterization of individual cancer patients is increasingly important to find an effective treatment. Recently a few methods have been developed to construct cancer sample-specific gene networks based on the difference in the mRNA expression levels between the cancer sample and reference samples.

Methods

We constructed a patient-specific network with multi-omics data based on the difference between a reference network and a perturbed reference network by the patient. A network specific to a group of patients was obtained using the average change in correlation coefficients and node degree of patient-specific networks of the group.

Results

In this paper, we present a new method for constructing cancer patient-specific and group-specific gene networks with multi-omics data. The main differences of our method from previous ones are as follows: (1) networks are constructed with multi-omics (mRNA expression, copy number variation, DNA methylation and microRNA expression) data rather than with mRNA expression data alone, (2) background networks are constructed with both normal samples and cancer samples of the specified type to extract cancer-specific gene correlations, and (3) both patient individual-specific networks and patient group-specific networks can be constructed. The results of evaluating our method with several types of cancer show that it constructs more informative and accurate gene networks than previous methods.

Conclusions

The results of evaluating our method with extensive data of seven cancer types show that the difference of gene correlations between the reference samples and a patient sample is a more predictive feature than mRNA expression levels and that gene networks constructed with multi-omics data show a better performance than those with single omics data in predicting cancer for most cancer types. Our approach will be useful for finding genes and gene pairs to tailor treatments to individual characteristics.
Clinically relevant radioresistant rhabdomyosarcoma cell lines: functional, molecular and immune-related characterization
Authors: Petragnano Francesco , Pietrantoni Ilaria , Camero Simona , Codenotti Silvia , Milazzo Luisa , Vulcano Francesca , Macioce Giampiero , Giordani Ilenia , Tini Paolo , Cheleschi Sara , Gravina Giovanni Luca , Festuccia Claudio , Rossetti Alessandra , Delle Monache Simona , Ordinelli Alessandra , Ciccarelli Carmela , Mauro Annunziata , Barbara Barboni , Antinozzi Cristina , Schiavetti Amalia , Maggio Roberto , Di Luigi Luigi , Polimeni Antonella , Marchese Cinzia , Tombolini Vincenzo , Fanzani Alessandro , Bernabò Nicola , Megiorni Francesca , Marampon Francesco
Published: August 2020

Background

The probability of local tumor control after radiotherapy (RT) remains still miserably poor in pediatric rhabdomyosarcoma (RMS). Thus, understanding the molecular mechanisms responsible of tumor relapse is essential to identify personalized RT-based strategies. Contrary to what has been done so far, a correct characterization of cellular radioresistance should be performed comparing radioresistant and radiosensitive cells with the same isogenic background.

Methods

Clinically relevant radioresistant (RR) embryonal (RD) and alveolar (RH30) RMS cell lines have been developed by irradiating them with clinical-like hypo-fractionated schedule. RMS-RR cells were compared to parental isogenic counterpart (RMS-PR) and studied following the radiobiological concept of the “6Rs”, which stand for repair, redistribution, repopulation, reoxygenation, intrinsic radioresistance and radio-immuno-biology.

Results

RMS-RR cell lines, characterized by a more aggressive and in vitro pro-metastatic phenotype, showed a higher ability to i) detoxify from reactive oxygen species; ii) repair DNA damage by differently activating non-homologous end joining and homologous recombination pathways; iii) counteract RT-induced G2/M cell cycle arrest by re-starting growth and repopulating after irradiation; iv) express cancer stem-like profile. Bioinformatic analyses, performed to assess the role of 41 cytokines after RT exposure and their network interactions, suggested TGF-β, MIF, CCL2, CXCL5, CXCL8 and CXCL12 as master regulators of cancer immune escape in RMS tumors.

Conclusions

These results suggest that RMS could sustain intrinsic and acquire radioresistance by different mechanisms and indicate potential targets for future combined radiosensitizing strategies.
Maternal and infant outcomes in sarcoidosis pregnancy: a Swedish population-based cohort study of first births
Authors: Köcher Laura , Rossides Marios , Remaeus Katarina , Grunewald Johan , Eklund Anders , Kullberg Susanna , Arkema Elizabeth V.
Published: August 2020

Background

It is unclear whether sarcoidosis, a multisystem inflammatory disease, is associated with adverse pregnancy outcomes. We aimed to assess the risk of adverse maternal and infant outcomes in sarcoidosis pregnancies, focused on first births.

Methods

Using a population-based cohort study design and Swedish national registers (2002–2013), we identified 182 singleton first pregnancies in the Medical Birth Register with at least two maternal ICD-coded sarcoidosis visits prior to pregnancy in the National Patient Register. Modified Poisson regression models estimated relative risks (RR) of adverse outcomes in sarcoidosis pregnancies compared to the general population adjusted for maternal age at delivery, calendar year and educational level. Some models were additionally adjusted for maternal body mass index and smoking status.

Results

The prevalence of pre-existing diabetes and hypertension was higher in mothers with sarcoidosis than those without sarcoidosis. Mothers with sarcoidosis had an increased risk of preeclampsia/eclampsia (RR 1.6; 95%CI 1.0, 2.6) and cesarean delivery (RR 1.3; 95%CI 1.0, 1.6). There were < 5 stillbirths and cases of infection and no cases of placental abruption, venous thromboembolism, cardiac arrest or maternal death. Newborns of first-time mothers with sarcoidosis had a 70% increased risk of preterm birth (RR 1.7; 95%CI 1.1, 2.5). There was an increased risk of birth defects (RR 1.6; 95%CI 0.9, 2.8) the majority of which were non-cardiac.

Conclusions

Sarcoidosis is associated with increased risks for preeclampsia/eclampsia, cesarean delivery, preterm birth and some birth defects. Awareness of these conditions may prevent possible pregnancy complications in mothers with sarcoidosis and their newborns.
Prevalence and determinants of malaria infection among children of local farmers in Central Malawi
Authors: Chilanga Emmanuel , Collin-Vézina Delphine , MacIntosh Heather , Mitchell Claudia , Cherney Katrina
Published: August 2020

Background

Malaria is a leading cause of morbidity and mortality among children under 5 years in Malawi, and especially among those from rural areas of central Malawi. The goal of this study was to examine the prevalence and determinants of malaria infection among children in rural areas of Dowa district in central Malawi.

Methods

A multistage, cross-sectional study design was used to systematically sample 523 child-mother dyads from postnatal clinics. A survey was administered to mothers and a rapid malaria infection diagnostic test was administered to children. The main outcome was positive malaria diagnostic tests in children. Logistic regressions were used to determine risk factors associated with malaria among children aged 2 to 59 months.

Results

The prevalence of malaria among children under 5 years was 35.4%. Results suggest that children of mothers who experienced recent intimate partner violence (IPV) were more likely to be diagnosed with malaria (AOR: 1.88, 95% CI 1.19–2.97;P = 0.007) than children of mothers who did not. Children of mothers who had no formal education were more likely to be diagnosed with malaria (AOR: 2.77, 95% CI 1.24–6.19;P = 0.013) than children of mothers who had received secondary education. Children aged 2 to 5 months and 6 to 11 months were less likely to be diagnosed with malaria (AOR: 0.21, 95% CI 0.10–0.46;P = 0.000 and AOR: 0.43; 95% CI 0.22–0.85;P = 0.016, respectively) than children aged 24 to 59 months.

Conclusion

The prevalence of malaria infection among children in the study area was comparable to the national level. In addition to available malaria control programmes, further attention should be paid to children whose mothers have no formal education, children aged 24 to 59 months, and children of mothers that are exposed to IPV in the area.
Engaging parents in digital sexual and reproductive health education: evidence from the JACK trial
Authors: Aventin Áine , Gough Aisling , McShane Theresa , Gillespie Kathryn , O’Hare Liam , Young Honor , Lewis Ruth , Warren Emily , Buckley Kelly , Lohan Maria
Published: August 2020

Background

Research evidence and international policy highlight the central role that parents play in promoting positive sexual behaviour and outcomes in their children, however they can be difficult to engage in sexual and reproductive health (SRH) education programmes. Digital health promotion that uses online and mobile technologies (OMTs) to promote parent-child communication may offer an innovative solution to reach parents, however, few programmes have used OMTs to involve parents in SRH, and none have reported lessons learned in relation to optimising engagement. This study addresses this gap in the literature by reporting acceptability and feasibility of using OMTs to engage parents in SRH education. Findings will be relevant for those wishing to develop and implement digital SRH programmes with parents internationally.

Methods

The Jack Trial is a UK-wide cluster randomised controlled trial recruiting over 8000 adolescents from 66 socially and religiously diverse post-primary schools. An embedded mixed-methods process evaluation explored user engagement with parent components of the If I Were Jack SRH education programme, which include online animated films and a parent-teen homework exercise.

Results

A total of 109 adolescents, teachers, parents and SRH policy experts took part in semi-structured interviews and focus groups, 134 parents responded to an online survey, and 3179 adolescents completed a programme engagement and satisfaction questionnaire. Parents who accessed the materials were positive about them; 87% rated them as ‘good or excellent’ and 67% said they helped them have conversations with their child about SRH. Web analytics revealed that 27% of contacted parents accessed the digital materials, with 9% viewing the animated films. Only 38% of teachers implemented the homework exercise, mainly because they assumed that students would not complete it or it might result in backlash from parents.

Conclusions

While digital parental materials show promise for engaging parents in SRH education, this study suggests that in order to optimise engagement, parental components that give parents the necessary skills to have conversations with their children about sex should be coupled with efforts to increase school and teacher confidence to communicate with parents on sensitive topics.

Trial registration

ISRCTN99459996.
Multicentre clinical radiotherapy audit in rectal cancer: results of the IROCA project
Authors: Fundowicz Magdalena , Aguiar Artur , de Castro Carla Lopes , Torras Maria Glòria , Deantonio Letizia , Konstanty Ewelina , Kruszyna-Mochalska Marta , Macia Miquel , Canals Eugeni , Caro Monica , Pisani Carla , Zwierzchowska Dorota , Molero Jaume , Eraso Arantxa , Lencart Joana , Muñoz-Montplet Carles , Carvalho Luisa , Krengli Marco , Malicki Julian , Guedea Ferran
Published: August 2020

Purpose

To perform a clinical audit to assess adherence to standard clinical practice for the diagnosis, treatment, and follow-up of patients undergoing radiotherapy for rectal cancer treatment in four European countries.

Materials and methods

Multi-institutional, retrospective cohort study of 221 patients treated for rectal cancer in 2015 at six European cancer centres. Clinical indicators applicable to general radiotherapy processes were evaluated. All data were obtained from electronic medical records.

Results

The audits were performed in the year 2017. We found substantial inter-centre variability in adherence to standard clinical practices: 1) presentation of cases at departmental clinical sessions (range, 0–100%) or multidisciplinary tumour board (50–95%); 2) pretreatment MRI (61.5–100%) and thoracoabdominal CT (15.0–100%). Large inter-centre differences were observed in the mean interval between biopsy and first visit to the radiotherapy department (range, 21.6–58.6 days) and between the first visit and start of treatment (15.1–38.8 days). Treatment interruptions ≥ 1 day occurred in 43.9% (2.5–90%) of cases overall. Treatment compensation was performed in 2.1% of cases. Treatment was completed in the prescribed time in 55.7% of cases.

Conclusions

This multi-institutional clinical audit revealed that most centres adhered to standard clinical practices for most of the radiotherapy processes-related variables assessed. However, the audit revealed marked inter-centre variability for certain quality indicators, particularly inconsistent record keeping. Multiple targets for improvement and/or harmonisation were identified, confirming the value of routine clinical audits to detect potential deviations from standard clinical practice.
Patient and surgical prognostic factors for inpatient functional recovery following THA and TKA: a prospective cohort study
Authors: Hewlett-Smith Nicola A. , Pope Rodney P. , Hing Wayne A. , Simas Vini P. , Furness James W.
Published: August 2020

Background

The introduction of enhanced recovery pathways has demonstrated both patient and organisational benefits. However, enhanced recovery pathways implemented for total hip arthroplasty (THA) and total knee arthroplasty (TKA) vary between health-care organisations, as do their measures of success, particularly patient-related outcomes. Despite inpatient functional recovery being essential for safe and timely hospital discharge, there is currently no gold standard method for its assessment, and the research undertaken to establish prognostic factors is limited. This study aimed to identify prognostic factors and subsequently develop prognostic models for inpatient functional recovery following primary, unilateral THA and TKA; identify factors associated with acute length of stay; and assess the relationships between inpatient function and longer-term functional outcomes.

Methods

Correlation and multiple regression analyses were used to determine prognostic factors for functional recovery (assessed using the modified Iowa Level of Assistance Scale on day 2 post-operatively) in a prospective cohort study of 354 patients following primary, unilateral THA or TKA.

Results

For the overall cohort and TKA group, significant prognostic factors included age, sex, pre-operative general health, pre-operative function, and use of general anaesthesia, local infiltration analgesia, and patient-controlled analgesia. In addition, arthroplasty site was a prognostic factor for the overall cohort, and surgery duration was prognostic for the TKA group. For the THA group, significant prognostic factors included pre-operative function, Risk Assessment and Prediction Tool score, and surgical approach. Several factors were associated with acute hospital length of stay. Inpatient function was positively correlated with functional outcomes assessed at 6 months post-operatively.

Conclusions

Prognostic models may facilitate the prediction of inpatient flow thus optimising organisational efficiency. Surgical prognostic factors warrant consideration as potential key elements in enhanced recovery pathways, associated with early post-operative functional recovery. Standardised measures of inpatient function serve to evaluate patient-centred outcomes and facilitate the benchmarking and improvement of enhanced recovery pathways.
Increasing the level of cytoskeletal protein Flightless I reduces adhesion formation in a murine digital flexor tendon model
Authors: Jackson Jessica E. , Kopecki Zlatko , Anderson Peter J. , Cowin Allison J.
Published: August 2020

Background

Surgical repair of tendons is common, but function is often limited due to the formation of flexor tendon adhesions which reduce the mobility and use of the affected digit and hand. The severity of adhesion formation is dependent on numerous cellular processes many of which involve the actin cytoskeleton. Flightless I (Flii) is a highly conserved cytoskeletal protein, which has previously been identified as a potential target for improved healing of tendon injuries. Using human in vitro cell studies in conjunction with a murine model of partial laceration of the digital flexor tendon, we investigated the effect of modulating Flii levels on tenocyte function and formation of adhesions.

Methods

Human tenocyte proliferation and migration was determined using WST-1 and scratch wound assays following Flii knockdown by siRNA in vitro. Additionally, mice with normal and increased levels of Flii were subjected to a partial laceration of the digital flexor tendon in conjunction with a full tenotomy to immobilise the paw. Resulting adhesions were assessed using histology and immunohistochemistry for collagen I, III, TGF-β1and -β3

Results

Flii knockdown significantly reduced human tenocyte proliferation and migration in vitro. Increasing the expression of Flii significantly reduced digital tendon adhesion formation in vivo which was confirmed through significantly smaller adhesion scores based on collagen fibre orientation, thickness, proximity to other fibres and crimping. Reduced adhesion formation was accompanied with significantly decreased deposition of type I collagen and increased expression of TGF-β1 in vivo.

Conclusions

These findings suggest that increasing the level of Flii in an injured tendon may be beneficial for decreasing tendon adhesion formation.
CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma
Authors: Maddineni Prabhavathi , Kasetti Ramesh B. , Patel Pinkal D. , Millar J. Cameron , Kiehlbauch Charles , Clark Abbot F. , Zode Gulab S.
Published: August 2020

Background

Glaucoma is a leading neurodegenerative disease affecting over 70 million individuals worldwide. Early pathological events of axonal degeneration and retinopathy in response to elevated intraocular pressure (IOP) are limited and not well-defined due to the lack of appropriate animal models that faithfully replicate all the phenotypes of primary open angle glaucoma (POAG), the most common form of glaucoma. Glucocorticoid (GC)-induced ocular hypertension (OHT) and its associated iatrogenic open-angle glaucoma share many features with POAG. Here, we characterized a novel mouse model of GC-induced OHT for glaucomatous neurodegeneration and further explored early pathological events of axonal degeneration in response to elevated IOP.

Methods

C57BL/6 J mice were periocularly injected with either vehicle or the potent GC, dexamethasone 21-acetate (Dex) once a week for 10 weeks. Glaucoma phenotypes including IOP, outflow facility, structural and functional loss of retinal ganglion cells (RGCs), optic nerve (ON) degeneration, gliosis, and anterograde axonal transport deficits were examined at various stages of OHT.

Results

Prolonged treatment with Dex leads to glaucoma in mice similar to POAG patients including IOP elevation due to reduced outflow facility and dysfunction of trabecular meshwork, progressive ON degeneration and structural and functional loss of RGCs. Lowering of IOP rescued Dex-induced ON degeneration and RGC loss, suggesting that glaucomatous neurodegeneration is IOP dependent. Also, Dex-induced neurodegeneration was associated with activation of astrocytes, axonal transport deficits, ON demyelination, mitochondrial accumulation and immune cell infiltration in the optic nerve head (ONH) region. Our studies further show that ON degeneration precedes structural and functional loss of RGCs in Dex-treated mice. Axonal damage and transport deficits initiate at the ONH and progress toward the distal end of ON and target regions in the brain (i.e. superior colliculus). Most of anterograde transport was preserved during initial stages of axonal degeneration (30% loss) and complete transport deficits were only observed at the ONH during later stages of severe axonal degeneration (50% loss).

Conclusions

These findings indicate that ON degeneration and transport deficits at the ONH precede RGC structural and functional loss and provide a new potential therapeutic window for rescuing neuronal loss and restoring health of damaged axons in glaucoma.
Longitudinal changes of inflammatory parameters and their correlation with disease severity and outcomes in patients with COVID-19 from Wuhan, China
Authors: Zeng Zhilin , Yu Haijing , Chen Huilong , Qi Weipeng , Chen Liang , Chen Guang , Yan Weiming , Chen Tao , Ning Qin , Han Meifang , Wu Di
Published: August 2020

Background

Coronavirus disease 2019 (COVID-19) is a newly emerging infectious disease and rapidly escalating epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogenesis of COVID-19 remains to be elucidated. We aimed to clarify correlation of systemic inflammation with disease severity and outcomes in COVID-19 patients.

Methods

In this retrospective study, baseline characteristics, laboratory findings, and treatments were compared among 317 laboratory-confirmed COVID-19 patients with moderate, severe, or critically ill form of the disease. Moreover, the longitudinal changes of serum cytokines, lactate dehydrogenase (LDH), high-sensitivity C-reactive protein (hsCRP), and hsCRP to lymphocyte count ratio (hsCRP/L) as well as their associations with disease severity and outcomes were investigated in 68 COVID-19 patients.

Results

Within 24 h of admission, the critically ill patients showed higher concentrations of inflammatory markers including serum soluble interleukin (IL)-2 receptor, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), ferritin, procalcitonin, LDH, hsCRP, and hsCRP/L than patients with severe or moderate disease. The severe cases displayed the similar response patterns when compared with moderate cases. The longitudinal assays showed the levels of pro-inflammatory cytokines, LDH, hsCRP, and hsCRP/L gradually declined within 10 days post admission in moderate, severe cases or those who survived. However, there was no significant reduction in cytokines, LDH, hsCRP, and hsCRP/L levels in critically ill or deceased patients throughout the course of illness. Compared with female patients, male cases showed higher serum concentrations of soluble IL-2R, IL-6, ferritin, procalcitonin, LDH, and hsCRP. Multivariate logistic regression analysis revealed that IL-6 > 50 pg/mL and LDH > 400 U/L on admission were independently associated with disease severity in patients with COVID-19.

Conclusion

Exuberant inflammatory responses within 24 h of admission in patients with COVID-19 may correlate with disease severity. SARS-CoV-2 infection appears to elicit a sex-based differential immune response. IL-6 and LDH were independent predictive parameters for assessing the severity of COVID-19. An early decline of these inflammation markers may be associated with better outcomes.
Performance of a universal PCR assay to identify different Leishmania species causative of Old World cutaneous leishmaniasis
Authors: Nateghi Rostami Mahmoud , Darzi Fatemeh , Farahmand Mahin , Aghaei Mohsen , Parvizi Parviz
Published: August 2020

Background

The characterization of Leishmania species is important for clinical management of the diseases and the epidemiological control of the parasite distribution. Most of the published polymerase chain reaction (PCR) amplification methods lack the ability to identify all species complexes, have low performance and usually need post-PCR procedures. There is a need for improving the diagnosis of CL by development of an accurate affordable PCR method to identify all Leishmania species in clinical specimens.

Methods

We designed an optimized a PCR amplifying the internal transcribed spacer 2 sequence of the ribosomal RNA gene (ITS2) aligned from different strains of CL-causing Leishmania species in the Old World. The performance of the method was evaluated on lesion samples from several CL suspected patients and the limit of detection (LOD) was determined on DNA of promastigotes from reference strains.

Results

The universal PCR enabled simultaneous discrimination of L. major, L. tropica and L. infantum using one primer pair in one reaction. Stained smear microscopy and Novy-MacNeal-Nicolle (NNN) medium culture alone detected 77.27% (17/22) and 72.73% (16/22) of the positive CL samples, respectively. The PCR assay showed 100% sensitivity (22/22) (95% CI: 84.56–100%) and 100% specificity (3/3) (95% CI: 29.24–100%) for species identification on isolates from lesion scraping/exudate and 100% sensitivity (13/13) (95% CI: 75.29–100%) and 100% specificity (11/11) (95% CI: 71.51–100%) for species identification on biopsy samples of CL patients, while being capable to successfully amplify as little as 0.01–0.1 pg of Leishmania DNA from cultured promastigotes.

Conclusions

We present a validated easy-to-use affordable universal PCR assay to identify the most common Old World Leishmania species causing CL. This PCR assay could be used as a sensitive/specific technique to diagnose CL-causing Leishmania species in clinical samples with high accuracy.
The fusiform gyrus exhibits an epigenetic signature for Alzheimer’s disease
Authors: Ma Dingailu , Fetahu Irfete S. , Wang Mei , Fang Rui , Li Jiahui , Liu Hang , Gramyk Tobin , Iwanicki Isabella , Gu Sophie , Xu Winnie , Tan Li , Wu Feizhen , Shi Yujiang G.
Published: August 2020

Background

Alzheimer’s disease (AD) is the most common type of dementia, and patients with advanced AD frequently lose the ability to identify family members. The fusiform gyrus (FUS) of the brain is critical in facial recognition. However, AD etiology in the FUS of AD patients is poorly understood. New analytical strategies are needed to reveal the genetic and epigenetic basis of AD in FUS.

Results

A complex of new analytical paradigms that integrates an array of transcriptomes and methylomes of normal controls, AD patients, and “AD-in-dish” models were used to identify genetic and epigenetic signatures of AD in FUS. Here we identified changes in gene expression that are specific to the FUS in brains of AD patients. These changes are closely linked to key genes in the AD network. Profiling of the methylome (5mC/5hmC/5fC/5caC) at base resolution identified 5 signature genes (COL2A1, CAPN3, COL14A1, STAT5A, SPOCK3) that exhibit perturbed expression, specifically in the FUS and display altered DNA methylome profiles that are common across AD-associated brain regions. Moreover, we demonstrate proof-of-principle that AD-associated methylome changes in these genes effectively predict the disease prognosis with enhanced sensitivity compared to presently used clinical criteria.

Conclusions

This study identified a set of previously unexplored FUS-specific AD genes and their epigenetic characteristics, which may provide new insights into the molecular pathology of AD, attributing the genetic and epigenetic basis of FUS to AD development.
An investigation of the predictability of the Brazilian three-modal hand-based behavioural biometric: a feature selection and feature-fusion approach
Authors: Goncalves de A. S. Marques Julliana Caroline , Lima Do Nascimento Tuany Mariah , Vasiljevic Brenda , Alves dos Santos Santana Laura Emmanuella , Costa-Abreu Márjory Da
Published: August 2020

New security systems, methods or techniques need to have their performance evaluated in conditions that closely resemble a real-life situation. The effectiveness with which individual identity can be predicted in different scenarios can benefit from seeking a broad base of identity evidence. Many approaches to the implementation of biometric-based identification systems are possible, and different configurations are likely to generate significantly different operational characteristics. The choice of implementational structure is, therefore, very dependent on the performance criteria, which is most important in any particular task scenario. The issue of improving performance can be addressed in many ways, but system configurations based on integrating different information sources are widely adopted in order to achieve this. Thus, understanding how each data information can influence performance is very important. The use of similar modalities may imply that we can use the same features. However, there is no indication that very similar (such as keyboard and touch keystroke dynamics, for example) basic biometrics will perform well using the same set of features. In this paper, we will evaluate the merits of using a three-modal hand-based biometric database for user prediction focusing on feature selection as the main investigation point. To the best of our knowledge, this is the first thought-out analysis of a database with three modalities that were collected from the same users, containing keyboard keystroke, touch keystroke and handwritten signature. First, we will investigate how the keystroke modalities perform, and then, we will add the signature in order to understand if there is any improvement in the results. We have used a wide range of techniques for feature selection that includes filters and wrappers (genetic algorithms), and we have validated our findings using a clustering technique.
Prenatal to early postnatal neurotrophic treatment prevents Alzheimer-like behavior and pathology in mice
Authors: Wei Wei , Wang Yifan , Liu Yinghua , Dai Chun-Ling , Tung Yunn-Chyn , Liu Fei , Iqbal Khalid
Published: August 2020

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease.

Methods

We investigated for the first time the effect of oral treatment during prenatal to early postnatal development with a neurotrophic compound, P021 (Ac-DGGLAG-NH2), on neurobehavior and AD-like pathology in 3xTg-AD, a transgenic mouse model of AD. The transgenic and control wild-type female mice were treated from prenatal day 8 to postnatal day 21 with a custom-made diet containing P021 or a vehicle diet, followed by a standard diet. AD-type cognitive function and pathological features were studied during adulthood and old age.

Results

The P021 treatment rescued cognitive deficits at 4 months, reduced abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology–associated sites, and decreased Aβ plaque load at 22 months in 3xTg-AD mice. Prenatal to early postnatal treatment with P021 also ameliorated certain markers of postsynaptic deficits, including PSD-95 levels and CREB activity, and decreased one measure of neuroinflammation, GFAP level in the brain at 4 and 22 months in 3xTg mice.

Conclusions

These findings suggest that neurotrophic impairment during early development can be one of the etiopathogenic factors of AD and that the neurotrophic peptide mimetic is a potential early prevention strategy for this disease.
Risk factors for gambling and problem gambling: a protocol for a rapid umbrella review of systematic reviews and meta-analyses
Authors: Beynon Caryl , Pearce-Smith Nicola , Clark Rachel
Published: August 2020

Background

Gambling and problem gambling are increasingly being viewed as a public health issue. European surveys have reported a high prevalence of gambling, and according to the Gambling Commission, in 2018, almost half of the general population aged 16 and over in England had participated in gambling in the 4 weeks prior to being surveyed. The potential harms associated with gambling and problem are broad, including harms to individuals, their friends and family, and society. There is a need to better understand the nature of this issue, including its risk factors. The purpose of this study is to identify and examine the risk factors associated with gambling and problem gambling.

Methods

An umbrella review will be conducted, where systematic approaches will be used to identify, appraise and synthesise systematic reviews and meta-analyses of risk factors for gambling and problem gambling. The review will include systematic reviews and meta-analyses published between 2005 and 2019, in English language, focused on any population and any risk factor, and of quantitative or qualitative studies. Electronic searches will be conducted in Ovid MEDLINE, Ovid Embase, Ovid PsycInfo, NICE Evidence and SocIndex via EBSCO, and a range of websites will be searched for grey literature. Reference lists will be scanned for additional papers and experts will be contacted. Screening, quality assessment and data extraction will be conducted in duplicate, and quality assessment will be conducted using AMSTAR-2. A narrative synthesis will be used to summarise the results.

Discussion

The results of this review will provide a comprehensive and up-to-date understanding of the risk factors associated with gambling and problem gambling. It will be used by Public Health England as part of a broader evidence review of gambling-related harms.

Systematic review registration

PROSPERO CRD42019151520
A global QP-free algorithm for mathematical programs with complementarity constraints
Authors: Li Jian Ling , Zhang Qi
Published: August 2020

In this paper, a primal–dual interior point QP-free algorithm for mathematical programs with complementarity constraints is presented. Firstly, based on Fischer–Burmeister function and smoothing techniques, the investigated problem is approximated by a smooth nonlinear constrained optimization problem. Secondly, combining with an effective penalty function technique and working set, a QP-free algorithm is proposed to solve the smooth constrained optimization problem. At each iteration, only two reduced linear equations with the same coefficient matrix are solved to obtain the search direction. Under some mild conditions, the proposed algorithm possesses global convergence. Finally, some numerical results are reported.
Linear conformable differential system and its controllability
Authors: Younas Awais , Abdeljawad Thabet , Batool Rida , Zehra Anum , Alqudah Manar A.
Published: August 2020

This article deals with the sequential conformable linear equations. We have focused on the solution techniques of these equations and particularly on the controllability conditions of the time-invariant system. For the controllability conditions and results, we have defined the conformable controllability Gramian matrix, the conformable fundamental matrix, and the conformable controllability matrix.
Degenerate poly-Bernoulli polynomials arising from degenerate polylogarithm
Authors: Kim Taekyun , Kim Dansan , Kim Han-Young , Lee Hyunseok , Jang Lee-Chae
Published: August 2020

Recently, degenerate polylogarithm functions were introduced by Kim and Kim. In this paper, we introduce degenerate poly-Bernoulli polynomials by means of the degenerate polylogarithm functions and investigate some their properties. In more detail, we find certain explicit expressions for those polynomials in terms of the Carlitz degenerate Bernoulli polynomials and the degenerate Stirling numbers of the second kind. Furthermore, we obtain some expressions for differences of the degenerate poly-Bernoulli polynomials.