bluuebunny/crossref_metadata_2025_split huggingface dataset:
Calcitriol-mediated hypercalcemia as an immune-related adverse event in a patient receiving nivolumab and ipilimumab for metastatic renal cell carcinoma, case report
Authors: Johnson Kai , Issa Majd , Parikh Anish , Monk Paul , Yin Ming , Mortazavi Amir , Yang Yuanquan 
Published: April 2021

Abstract
Background
Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors.

Case presentation
We report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia.

Conclusion
This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.
Skin autofluorescence and the complexity of complications in patients with type 2 diabetes mellitus: a cross-sectional study
Authors: Wang Xian , Zhao Xingwang , Lian Tingting , Wei Juanjin , Yue Wanxu , Zhang Senwei , Chen Qiu 
Published: April 2021

Abstract
Background
The accumulation of advanced glycation end products (AGEs) occurring in skin tissues can be measured as skin autofluorescence (SAF). Here, we assessed the correlation between SAF values and the complexity and severity of type 2 diabetes mellitus (T2DM) complications.

Methods
The basic clinical information of 825 patients with T2DM was collected through an electronic system, and SAF was measured by adapting a DM-Scan, a non-invasive optical signal detector. Diabetic complications were diagnosed based on clinical criteria by experienced doctors. Linear regression analysis was used to evaluate the independent determinants of SAF, and multiple logistic regression analysis was performed to assess independent determinants that influence the severity of the complications.

Results
SAF was significantly associated with the complexity of T2DM complications. Similarly, independent relationships between SAF and age (β = 0.389, P <  0.001), sex (β = − 2.221, P = 0.004), 2-h C-peptide (β = − 0.182, P = 0.017), aminotransferase (ALT, β = − 0.158, P = 0.041), blood creatinine (BCr, β = 0.206, P = 0.009), and fatty liver (β = 0.161, P = 0.026) were observed. With the increasing number of complications, the SAF values increased significantly after adjusting for related risk factors. The SAF values correlated with diabetic retinopathy, diabetic kidney diseases, cardiovascular disease, and diabetic peripheral neuropathy when compared with patients without any T2DM-associated complications. Moreover, the AGE-based diabetic complication risk score for each complication demonstrated a relationship with the presence or absence of certain complications.

Conclusion
SAF is an independent marker for diabetic retinopathy, diabetic kidney diseases, cardiovascular disease, and diabetic peripheral neuropathy, and it is also a predictor of the complexity of T2DM complications. Moreover, the diabetic complication risk score is capable of predicting the risk of diabetic complications in patients with T2DM.
Plant-based oral care product exhibits antibacterial effects on different stages of oral multispecies biofilm development in vitro
Authors: Kommerein Nadine , Weigel Almut Johanna , Stiesch Meike , Doll Katharina 
Published: April 2021

Abstract
Background
Excessive biofilm formation on surfaces in the oral cavity is amongst the main reasons for severe infection development like periodontitis and peri-implantitis. Mechanical biofilm removal as well as the use of adjuvant antiseptics supports the prevention of pathogenic biofilm formation. Recently, the antibacterial effect of the oral care product REPHA-OS®, based on medicinal plant extracts and essential oils, has been demonstrated on oral pathogens grown on agar plates. In the present study, the effectiveness of the product on medical relevant oral biofilm development should be demonstrated for the first time.

Methods
An established in vitro oral multispecies biofilm, composed of Streptococcus oralis, Actinomyces naeslundii, Veillonella dispar and Porphyromonas gingivalis, was used to analyze the antibacterial effect of different REPHA-OS® concentrations on planktonic bacteria, biofilm formation and mature biofilms. It was quantified using metabolic activity assays and live/dead fluorescence staining combined with three-dimensional confocal laser-scanning microscopy. Additionally, effects on species distribution inside the biofilm were assessed by means of quantitative real-time PCR.

Results
REPHA-OS® showed statistically significant antimicrobial effects on all stages of biofilm development: a minimal inhibitory concentration of 5% could be detected for both, for planktonic bacteria and for biofilm formation. Interestingly, only a slightly higher concentration of 10% was necessary to completely kill all bacteria in mature biofilms also. In contrast, an influence on the biofilm matrix or the species distribution could not be observed. The effect could be attributed to the herbal ingredients, not to the contained ethanol.

Conclusion
The strong antibacterial effect of REPHA-OS® on different stages of oral biofilm development strengthens its application as an alternative adjuvant in oral care therapies.
Improvement of SCD morbimortality in children: experience in a remote area of an African country
Authors: Mbiya Benoît Mukinayi , Kalombo Didier Kalenda , Mukendi Yannick Nkesu , Daubie Valery , Mpoyi John Kalenda , Biboyi Parola Mukendi , Disashi Ghislain Tumba , Gulbis Béatrice 
Published: April 2021

Abstract
Background
Sickle cell disease (SCD) is a public health problem in the Democratic Republic of Congo. While reference sickle cell centers have been implemented in capital cities of African countries and have proven to be beneficial for SCD patients. In the Democratic Republic of Congo, they have never been set up in remote areas for families with low or very low sources of income.

Method
A cohort of 143 children with SCD aged 10 years old (IQR (interquartile range): 6–15 years) (sex ratio male/female = 1.3) were clinically followed for 12 months without any specific intervention aside from the management of acute events, and then for 12 months with a monthly medical visit, biological follow-up, and chemoprophylaxis (folic acid/penicillin), adequate fluids and malaria prevention.

Results
The median age of patients at the diagnosis of SCD was 2 years (IQR: 1–5). The implementation of standardized and regular follow-ups in a new sickle cell reference center in a remote city showed an increase in the annual mean hemoglobin level from 50 to 70 g/L (p = 0.001), and a decrease in the lymphocyte count and spleen size (p < 0.001). A significant decrease (p < 0.001) in the average annual number of hospitalizations and episodes of vaso-occlusive crises, blood transfusions, infections, and acute chest syndromes were also observed.

Conclusions
The creation of a sickle cell reference center and the regular follow-up of children with sickle cell disease are possible and applicable in the context of a remote city of an African country and represent simple and accessible measures that can reduce the morbimortality of children with sickle cell disease.
Cost-effectiveness modelling to optimise active screening strategy for gambiense human African trypanosomiasis in endemic areas of the Democratic Republic of Congo
Authors: Davis Christopher N. , Rock Kat S. , Antillón Marina , Miaka Erick Mwamba , Keeling Matt J. 
Published: April 2021

Abstract
Background
Gambiense human African trypanosomiasis (gHAT) has been brought under control recently with village-based active screening playing a major role in case reduction. In the approach to elimination, we investigate how to optimise active screening in villages in the Democratic Republic of Congo, such that the expenses of screening programmes can be efficiently allocated whilst continuing to avert morbidity and mortality.

Methods
We implement a cost-effectiveness analysis using a stochastic gHAT infection model for a range of active screening strategies and, in conjunction with a cost model, we calculate the net monetary benefit (NMB) of each strategy. We focus on the high-endemicity health zone of Kwamouth in the Democratic Republic of Congo.

Results
High-coverage active screening strategies, occurring approximately annually, attain the highest NMB. For realistic screening at 55% coverage, annual screening is cost-effective at very low willingness-to-pay thresholds (<DOLLAR/>20.4 per disability adjusted life year (DALY) averted), only marginally higher than biennial screening (<DOLLAR/>14.6 per DALY averted). We find that, for strategies stopping after 1, 2 or 3 years of zero case reporting, the expected cost-benefits are very similar.

Conclusions
We highlight the current recommended strategy—annual screening with three years of zero case reporting before stopping active screening—is likely cost-effective, in addition to providing valuable information on whether transmission has been interrupted.
Oxytocin in bovine saliva: validation of two assays and changes in parturition and at weaning
Authors: López-Arjona Marina , Mainau Eva , Navarro Elena , Contreras-Aguilar María Dolores , Escribano Damián , Mateo Sandra V. , Manteca Xavier , Cerón José Joaquín , Martínez-Subiela Silvia 
Published: April 2021

Abstract
Background
The possible use of oxytocin in saliva as an indicator of positive emotions in bovine species has been poorly investigated. In the present study, two new assays (one using a monoclonal antibody and the other using a polyclonal antibody) for the measurement of oxytocin in bovine saliva were developed and validated. Also, the changes in oxytocin in saliva were explored in two different situations. One was around parturition, and for this purpose, saliva samples from 13 cows were collected at three different times: 7 days before the parturition, the day of parturition and 7 days after the parturition. The second situation was weaning and grouping of calves, and for this purpose, saliva from 25 calves was collected at three different times: 1 day before weaning, 2 days after weaning or milk withdrawal and 4 days after grouping calves.

Results
In cows, oxytocin concentrations showed an increase on the day of parturition with both assays, while in calves, oxytocin concentrations showed a decrease 4 days after the grouping.

Conclusions
The assays validated in this report could be used for the measurement of oxytocin in bovine saliva and detect changes in this analyte that can occur in different physiological or productive situations such as parturition and weaning.
Feedback activation of NF-KB signaling leads to adaptive resistance to EZH2 inhibitors in prostate cancer cells
Authors: Jin Mengyuan , Duan Jiachen , Liu Wei , Ji Jing , Liu Bin , Zhang Mingzhi 
Published: April 2021

Abstract
Background
Prostate cancer (PCa) is the most common malignant tumor in developed countries, which has seriously threatened men’s lifestyle and quality of life. The up-regulation of EZH2 is associated with advanced PCa and poor prognosis, making it a promising therapeutic target. However, the EZH2 inhibitors-based treatment is basically ineffective against PCa, which limits its clinical application.

Methods
Microarray data (GSE107779) from LNCaP cells treated with either siRNA against EZH2 or a EZH2 inhibitor EPZ6438 was analyzed by Limma R package. Western blot, real-time PCR and luciferase reporter assays were used to determine the EZH2-SOX9-TNFRSF11A axis and the activity of NF-κB signaling in PCa cells. CCK-8 assay was used to determine the viability of PCa cells following various treatments.

Results
Genetic ablation or pharmacological inhibition of EZH2 leads to feedback activation of NF-κB signaling in PCa cells. EZH2-dependent SOX9 expression regulates the activation of NF-κB signaling. TNFRSF11A, also known as receptor activator of NF-κB (RANK), is a downstream target of SOX9 in PCa cells. SOX9 recognizes two putative SOX9 response elements in the promoter region of TNFRSF11A gene to drive TNFRSF11A expression and downstream NF-κB signaling activation. Suppression of the NF-κB signaling by either TNFRSF11A silencing or BAY11-7082 treatment rendered PCa cells to EZH2 inhibitors.

Conclusion
Collectively, our finding reveals a EZH2-SOX9-TNFRSF11A axis in the regulation of activity of NF-κB signaling in PCa cells and suggests that a combination of EZH2 inhibitors and BAY11-7082 would be an effective approach for the treatment of PCa patients in the future.
Retrospective evaluation of the effectiveness of indoor residual spray with pirimiphos‐methyl (Actellic) on malaria transmission in Zambia
Authors: Keating Joseph , Yukich Joshua O. , Miller John M. , Scates Sara , Hamainza Busiku , Eisele Thomas P. , Bennett Adam 
Published: April 2021

AbstractBackgroundWidespread insecticide resistance to pyrethroids could thwart progress towards elimination. Recently, the World Health Organization has encouraged the use of non-pyrethroid insecticides to reduce the spread of insecticide resistance. An electronic tool for implementing and tracking coverage of IRS campaigns has recently been tested (mSpray), using satellite imagery to improve the accuracy and efficiency of the enumeration process. The purpose of this paper is to retrospectively analyse cross-sectional observational data to provide evidence of the epidemiological effectiveness of having introduced Actellic 300CS and the mSpray platform into IRS programmes across Zambia.MethodsHealth facility catchment areas in 40 high burden districts in 5 selected provinces were initially targeted for spraying. The mSpray platform was used in 7 districts in Luapula Province. An observational study design was used to assess the relationship between IRS exposure and confirmed malaria case incidence. A random effects Poisson model was used to quantify the effect of IRS (with and without use of the mSpray platform) on confirmed malaria case incidence over the period 2013–2017; analysis was restricted to the 4 provinces where IRS was conducted in each year 2014–2016.ResultsIRS was conducted in 283 health facility catchment areas from 2014 to 2016; 198 health facilities from the same provinces, that received no IRS during this period, served as a comparison. IRS appears to be associated with reduced confirmed malaria incidence; the incidence rate ratio (IRR) was lower in areas with IRS but without mSpray, compared to areas with no IRS (IRR = 0.91, 95% CI 0.84–0.98). Receiving IRS with mSpray significantly lowered confirmed case incidence (IRR = 0.75, 95% CI 0.66–0.86) compared to no IRS. IRS with mSpray resulted in lower incidence compared to IRS without mSpray (IRR = 0.83, 95% CI 0.72–0.95).ConclusionsIRS using Actellic-CS appears to substantially reduce malaria incidence in Zambia. The use of the mSpray tool appears to improve the effectiveness of the IRS programme, possibly through improved population level coverage. The results of this study lend credence to the anecdotal evidence of the effectiveness of 3GIRS using Actellic, and the importance of exploring new platforms for improving effective population coverage of areas targeted for spraying.
Cord blood acrylamide levels and birth size, and interactions with genetic variants in acrylamide-metabolising genes
Authors: Hogervorst Janneke , Vesper Hubert W. , Madhloum Narjes , Gyselaers Wilfried , Nawrot Tim 
Published: April 2021

Abstract
Background
Up to now, 3 epidemiological studies have shown clear inverse associations between prenatal acrylamide exposure and birth size. In addition to studying the association between acrylamide and birth size, we investigated the interaction between acrylamide and polymorphisms in acrylamide-metabolising genes, with the aim of probing the causality of the inverse relationship between acrylamide and fetal growth.

Methods
We investigated the association between prenatal acrylamide exposure (acrylamide and glycidamide hemoglobin adduct levels (AA-Hb and GA-Hb) in cord blood) and birth weight, length and head circumference in 443 newborns of the ENVIRONAGE (ENVIRonmental influence ON AGEing in early life) birth cohort. In addition, we studied interaction with single nucleotide polymorphisms (SNPs) in CYP2E1, EPHX1 and GSTP1, using multiple linear regression analysis.

Results
Among all neonates, the body weight, length and head circumference of neonates in the highest quartile was − 101 g (95% CI: − 208, 7; p for trend = 0.12), − 0.13 cm (95% CI: − 0.62, 0.36; p for trend = 0.69) and − 0.41 cm (− 0.80, − 0.01; p for trend = 0.06) lower, respectively, compared to neonates in the lowest quartile of AA-Hb in cord blood, For GA-Hb, the corresponding effect estimates were − 222 g (95% CI: − 337, − 108; p for trend = 0.001), − 0.85 (95% CI: − 1.38, − 0.33; p for trend = 0.02) and − 0.55 (95% CI: − 0.98, − 0.11; p for trend = 0.01), respectively. The associations for GA-Hb were similar or stronger in newborns of non-smoking mothers. There was no statistically significant interaction between acrylamide exposure and the studied genetic variations but there was a trend of stronger inverse associations with birth weight and head circumference among newborns with homozygous wildtypes alleles for the CYP2E1 SNPS and with variant alleles for a GSTP1 SNP (rs1138272).

Conclusions
Prenatal dietary acrylamide exposure, specifically in the form of its metabolite glycidamide, was inversely associated with birth weight, length and head circumference. The interaction pattern with SNPs in CYP2E1, although not statistically significant, is an indication for the causality of this association. Other studies are needed to corroborate this finding.
Developmental exposure to DDT or DDE alters sympathetic innervation of brown adipose in adult female mice
Authors: vonderEmbse Annalise N. , Elmore Sarah E. , Jackson Kyle B. , Habecker Beth A. , Manz Katherine E. , Pennell Kurt D. , Lein Pamela J. , La Merrill Michele A. 
Published: April 2021

Abstract
Background
Exposure to the bioaccumulative pesticide dichlorodiphenyltrichloroethane (DDT) and its metabolite dichlorodiphenyldichloroethylene (DDE) has been associated with increased risk of insulin resistance and obesity in humans and experimental animals. These effects appear to be mediated by reduced brown adipose tissue (BAT) thermogenesis, which is regulated by the sympathetic nervous system. Although the neurotoxicity of DDT is well-established, whether DDT alters sympathetic innervation of BAT is unknown. We hypothesized that perinatal exposure to DDT or DDE promotes thermogenic dysfunction by interfering with sympathetic regulation of BAT thermogenesis.

Methods
Pregnant C57BL/6 J mice were administered environmentally relevant concentrations of DDTs (p,p’-DDT and o,p’-DDT) or DDE (p,p’-DDE), 1.7 mg/kg and 1.31 mg/kg, respectively, from gestational day 11.5 to postnatal day 5 by oral gavage, and longitudinal body temperature was recorded in male and female offspring. At 4 months of age, metabolic parameters were measured in female offspring via indirect calorimetry with or without the β3 adrenergic receptor agonist, CL 316,243. Immunohistochemical and neurochemical analyses of sympathetic neurons innervating BAT were evaluated.

Results
We observed persistent thermogenic impairment in adult female, but not male, mice perinatally exposed to DDTs or p,p’-DDE. Perinatal DDTs exposure significantly impaired metabolism in adult female mice, an effect rescued by treatment with CL 316,243 immediately prior to calorimetry experiments. Neither DDTs nor p,p’-DDE significantly altered BAT morphology or the concentrations of norepinephrine and its metabolite DHPG in the BAT of DDTs-exposed mice. However, quantitative immunohistochemistry revealed a 20% decrease in sympathetic axons innervating BAT in adult female mice perinatally exposed to DDTs, but not p,p’-DDE, and 48 and 43% fewer synapses in stellate ganglia of mice exposed to either DDTs or p,p’-DDE, respectively, compared to control.

Conclusions
These data demonstrate that perinatal exposure to DDTs or p,p’-DDE impairs thermogenesis by interfering with patterns of connectivity in sympathetic circuits that regulate BAT.

Graphical abstract
Nanotechnology: new opportunities for the development of patch‐clamps
Authors: Gao Jia , Liao Chunyang , Liu Sijin , Xia Tian , Jiang Guibin 
Published: April 2021

AbstractThe patch-clamp technique is one of the best approaches to investigate neural excitability. Impressive improvements towards the automation of the patch-clamp technique have been made, but obvious limitations and hurdles still exist, such as parallelization, volume displacement in vivo, and long-term recording. Nanotechnologies have provided opportunities to overcome these hurdles by applying electrical devices on the nanoscale. Electrodes based on nanowires, nanotubes, and nanoscale field-effect transistors (FETs) are confirmed to be robust and less invasive tools for intracellular electrophysiological recording. Research on the interface between the nanoelectrode and cell membrane aims to reduce the seal conductance and further improve the recording quality. Many novel recording approaches advance the parallelization, and precision with reduced invasiveness, thus improving the overall intracellular recording system. The combination of nanotechnology and the present intracellular recording framework is a revolutionary and promising orientation, potentially becoming the next generation electrophysiological recording technique and replacing the conventional patch-clamp technique. Here, this paper reviews the recent advances in intracellular electrophysiological recording techniques using nanotechnology, focusing on the design of noninvasive and greatly parallelized recording systems based on nanoelectronics.