bluuebunny/crossref_metadata_2025 huggingface dataset:
Robotic tests for position sense and movement discrimination in the upper limb reveal that they each are highly reproducible but not correlated in healthy individuals
Authors: Lowrey Catherine R. , Blazevski Benett , Marnet Jean-Luc , Bretzke Helen , Dukelow Sean P. , Scott Stephen H.
Published: July 2020

Background

Robotic technologies for neurological assessment provide sensitive, objective measures of behavioural impairments associated with injuries or disease such as stroke. Previous robotic tasks to assess proprioception typically involve single limbs or in some cases both limbs. The challenge with these approaches is that they often rely on intact motor function and/or working memory to remember/reproduce limb position, both of which can be impaired following stroke. Here, we examine the feasibility of a single-arm Movement Discrimination Threshold (MDT) task to assess proprioception by quantifying thresholds for sensing passive limb movement without vision. We use a staircase method to adjust movement magnitude based on subject performance throughout the task in order to reduce assessment time. We compare MDT task performance to our previously-designed Arm Position Matching (APM) task. Critically, we determine test-retest reliability of each task in the same population of healthy controls.

Method

Healthy participants (N = 21, age = 18–22 years) completed both tasks in the End-Point Kinarm robot. In the MDT task the robot moved the dominant arm left or right and participants indicated the direction moved. Movement displacement was systematically adjusted (decreased after correct answers, increased after incorrect) until the Discrimination Threshold was found. In the APM task, the robot moved the dominant arm and participants “mirror-matched” with the non-dominant arm.

Results

Discrimination Threshold for direction of arm displacement in the MDT task ranged from 0.1–1.3 cm. Displacement Variability ranged from 0.11–0.71 cm. Test-retest reliability of Discrimination Threshold based on ICC confidence intervals was moderate to excellent (range, ICC = 0.78 [0.52–0.90]). Interestingly, ICC values for Discrimination Threshold increased to 0.90 [0.77–0.96] (good to excellent) when the number of trials was reduced to the first 50. Most APM parameters had ICC’s above 0.80, (range, ICC = [0.86–0.88]) with the exception of variability (ICC = 0.30). Importantly, no parameters were significantly correlated across tasks as Spearman rank correlations across parameter-pairings ranged from − 0.27 to 0.30.

Conclusions

The MDT task is a feasible and reliable task, assessing movement discrimination threshold in ~ 17 min. Lack of correlation between the MDT and a position-matching task (APM) indicates that these tasks assess unique aspects of proprioception that are not strongly related in young, healthy individuals.
The decisive role of molecular pathology in presumed somatic metastases of type II testicular germ cell tumors: report of 2 cases
Authors: Kranendonk Mariëtte E. G. , Hackeng Wenzel M. , Offerhaus G. Johan A. , Morsink Folkert H. M. , Jonges Geertruida N. , Groenewegen Gerard , Krijtenburg Pieter-Jaap , Klümpen Heinz-Josef , de Leng Wendy W. J. , Looijenga Leendert H. J. , Brosens Lodewijk A. A.
Published: July 2020

Background

Molecular diagnostics can be decisive in the differential diagnosis between a somatic metastasis of type II testicular germ cell tumor (TGCT) or a second primary carcinoma. This is in line with recent recommendations from the International Society of Urological Pathology, based on an international survey which showed that molecular testing is currently only performed by a minority of urological pathologists.

Case presentations

This case report illustrates the necessity of molecular testing in two patients with a history of type II TGCT and a metastatic (retro) peritoneal carcinoma years later. The genetic hallmark of type II TGCT, chromosome 12p gain, was studied by fluorescence in situ hybridization and whole genome methylation profiling in case 1, and by single nucleotide polymorphism (SNP)-array in case 2. Next generation sequencing (NGS) was used to further explore clonality between the primary TGCT and peritoneal metastasis in case 2. In case 1, chromosome 12p gain was found in the primary type II TGCT and in the acinar cell carcinoma of the metastatic malignancy. In case 2, SNP array showed 12p gain in the epithelial component of the primary teratomatous TGCT but not in the peritoneal adenocarcinoma. Furthermore, NGS showed no mutations in the primary teratomatous TGCT but a KRAS and GNAS mutation in the peritoneal adenocarcinoma, suggestive of an appendicular origin.

Conclusions

Without the molecular data, both cases would have been regarded as a metastatic TGCT with development of somatic-type malignancy, which appeared a wrong diagnosis for case 2. These cases demonstrate the importance of molecular methods as an adjunct in today’s pathology practice.
The efficacy and dosimetry analysis of CT-guided 125I seed implantation assisted with 3D-printing non-co-planar template in locally recurrent rectal cancer
Authors: Wang Lu , Wang Hao , Jiang Yuliang , Ji Zhe , Guo Fuxin , Jiang Ping , Li Xuemin , Chen Yi , Sun Haitao , Fan Jinghong , Li Weiyan , Li Xu , Wang Junjie
Published: July 2020

Background

Locally recurrent rectal cancer (LRRC) after surgery or external beam radiotherapy (EBRT) is a serious challenge for which no standard treatment is defined. In the present study, we investigated the feasibility of computed tomography (CT)-guided radioactive 125I seed (RIS) implantation assisted with three-dimensional printing non-coplanar template (3D-PNCT) in LRRC patients who previously received surgery or EBRT.

Methods

Sixty-six patients with LRRC treated by CT-guided RIS implantation in our institute from December 2015 to May 2019 were included. The treatment procedure included: preoperative CT localization, planning design, the printing of 3D individualized template, CT-guided RIS implantation assisted with 3D-PNCT, and postoperative dose evaluation. Therapeutic outcomes including local control (LC) and overall survival (OS) were retrospectively evaluated, as well as side effects.

Results

All the patients had previously received surgery or EBRT. The median follow-up time was 12.2 (range, 2.5–35.9) months. The median radioactive activity of a single RIS was 0.6 (range, 0.43–0.72) mCi. The median number of RIS was 60, ranging from 10 to 175. The dosimetric parameters included D90 (140.7 ± 33.1) Gy, D100 (90.3 ± 138.6) Gy, and V100 (91.0 ± 13.3) %. Pain relief was achieved in 85.1% (40/47) of patients. Besides, 9.1% (6/66) of patients had severe side effects (≥grade 3), including perianal skin ulcer in 1 case, fistula, radiation proctitis, and intestinal obstruction each in two cases. Median OS time was 14.7 (95% confidence interval (CI): 13.0–16.3) months, and median LC time was 12.2 (95% CI: 9.1–15.2) months. Univariate analysis revealed that when D90 > 130 Gy or D100 > 55 Gy or V100 > 90%, the LC time was remarkably prolonged. However, none of the parameters significantly affected OS.

Conclusions

CT-guided RIS implantation assisted with 3D-PNCT is an effective and safe salvage treatment strategy for patients with LRRC after EBRT or surgery. D90, D100, and V100 can be used as prognostic predictors.

Trial registration

NCT03890926.
Estimation and influence of blood loss under endoscope for percutaneous endoscopic lumbar discectomy (PELD): a clinical observational study combined with in vitro experiment
Authors: Sun Dong Dong , Lv Dan , Wu Wei Zhou , Ren He Fei , Bao Bu He , Liu Qun , Sun Ming Lin
Published: July 2020

Purpose

The purpose of this study is to come up with new methods to quantitate the blood loss under endoscope and explore the influence of blood loss on percutaneous endoscopic lumbar discectomy (PELD).

Methods

Clinical research and in vitro experiment are combined. In the in vitro experiment, 2.0-ml blood was diluted in different ratio to simulate the rinse solution of PELD, the hematocrit method (HCT-M) and red blood cell count method (RBC-M) were came up to estimate blood loss and the new methods were calibrated with the direct measurement method (Direct-M). In clinical research, 74 patients with L5/S1 disk herniation were treated with PELD, and HCT-M and the empirical method (EMP-M) were used to estimate the blood loss under endoscope. According to blood loss, all patients were divided into group A (≤ 10 ml) and group B (> 10 ml). The blood loss, operation time, fluoroscopy frequency, visual analog scale (VAS), and Oswestry Disability Index (ODI) scores were compared between the two groups.

Results

In the in vitro experiment, the hematocrit of the rinse solution was always stable over time. The estimated blood loss by HCT-M was stable and quite approximate to actual blood volume (2.0 ml) whatever the blood dilution ratio, while according to RBC-M, the estimated blood loss was close to the actual blood volume only when the dilution ratio was greater than 300 times. In clinical research, the blood loss estimated by HCT-M was higher than that by EMP-M in both groups (P < 0.05). There was a significant difference between group A and group B in blood loss (7.40 ± 1.61 vs 19.91 ± 10.94 ml), operation time (80.51 ± 34.70 vs 136.51 ± 41.88 min), and fluoroscopy frequency (6.92 ± 1.52 vs 11.11 ± 2.32 times) (P < 0.05). The VAS and ODI scores in group B were higher than that in group A 1 week after operation (P < 0.05); however, the scores were not different between the two groups at pre-operation (P > 0.05).

Conclusion

HCT-M is a reliable method to estimate endoscopic blood loss in PELD. The amount of endoscopic blood loss affects the operative procedure in operation time and fluoroscopy frequency, as well as clinical effects in VAS and ODI scores after operation in short term.
Atrial septal defect closure in a young patient presenting with recurrent cryptogenic stroke: a case report
Authors: Nazer Rakan I.
Published: July 2020

Background

Having an inter-atrial shunt in the form of a patent foramen ovale or atrial septal defect increases the risk of developing cryptogenic stroke. Prompt action is required in order to prevent stroke recurrence. The source of embolization may not be clear on stroke workup.

Case presentation

A young female acutely presented with recurrent embolizations to the eye and brain. She was found to have an atrial septal defect. No clear intra-cardiac source of embolization was detected on workup including trans-esophageal echocardiography. Given the options between surgical versus device closure, the attending team opted for the surgical closure which yielded on direct left heart inspection small organized clots adherent to the tips of the mitral valve leaflets.

Conclusions

The case report illustrates the potential advantages of the direct surgical closure in detecting and extracting the embolization source in patients who present with recurrent cryptogenic stroke.
Two different troponin isoforms for detecting early myocardial injury after curative resection of oesophageal cancer
Authors: Gu Wei , Tang Wei , Zhang Zuojing , Xu Meiying , Wu Jingxiang
Published: July 2020

Background

The objective of this study was to explore the consistency and correlation of two troponin (cTn) subtypes, troponin I (cTnI) and high-sensitivity troponin T (hs-cTnT), which can be used to judge early myocardial injury after curative resection of oesophageal cancer.

Methods

This study is a secondary analysis of data obtained from a previous randomized controlled trial on postoperative myocardial injury in 70 patients undergoing elective curative resection of oesophageal cancer who were randomly assigned to undergo aggressive body temperature management (nasopharyngeal temperature 36.61 ± 0.18 °C) or standard body temperature management (35.80 ± 0.18 °C, n = 35 in each arm). The serum cTnI and hs-cTnT levels were measured in each patient at the 4 time points: before the operation and 6 h ~ 12 h, 24 h and 48 h after the operation. The diagnostic criteria of myocardial injury followed the third edition ESC/ACCF definition of myocardial infarction. The primary outcomes included the following: (1) the incidence of myocardial injury and the relationship between hs-cTnT and cTn and (2) the consistency and correlation of the two cTn subtypes.

Results

A total of 280 pairs of cTn samples were tested. The incidence of postoperative day 2 myocardial injury was 8.6% (3/35) among patients receiving aggressive body temperature management and 31.4% (11/35) among patients receiving standard body temperature management (P < 0.05). Among 3 patients who experienced myocardial injury in the aggressive body temperature management group, 2 met the diagnostic criteria for cTnI and hs-cTnT and only 1 met the diagnostic criteria for hs-cTnT. Among the 11 patients who experienced myocardial injury in the standard body temperature management group, 7 met the diagnostic criteria for cTnI and hs-cTnT and only 3 met the diagnostic criteria for hs-cTnT; only 1 met the diagnostic criteria for cTnI. The bias of cTnI and hs-cTnT was − 8.82 ± 31.91 ng/L. The consistency limit was − 71.37 ~ 53.73 ng/L. The proportion within the scope of the consistency of its corresponding boundary was 98.57%. The correlation coefficient of cTnI and hs-cTnT was 0.845 (P < 0.05).

Conclusions

In the evaluation of postoperative myocardial injury in patients undergoing curative resection of oesophageal cancer, cTnI and hs-cTnT exhibit high consistency and a good correlation. The combination of cTnI and hs-cTnT can improve the detection rate of myocardial injury, thus providing a better reference than a single measure alone for reducing the risk of perioperative myocardial injury in patients.

Trial registration

ChiCTR-INR-17011621. Registered June 10, 2017.
An effective UFLC–MS/MS method used to study pharmacokinetics of major constituents of Fukeqianjin formula in rat plasma
Authors: Wang Kanghua , Liu Lu , Yang Yanfang , Liu Xiaoyan , Zhang Lei , Xu Wei , Zhang Yingtao , Yang Xiuwei , Zhang Peng , Peng Kaifeng , Gong Yun , Liu Nifu
Published: July 2020

Background

Fukeqianjin formula (FKQJF) is a Chinese medicine prescription, which has been widely used individually or in combination with other western medicine for the treatment of various gynecological inflammatory diseases, including chronic cervicitis, chronic pelvic inflammatory disease and endometritis, so on and so force.

Methods

The ultra-fast liquid chromatography coupled with triple quadrupole tandem mass spectrometry (UFLC–MS/MS), a quick and efficient method was established and applied to quantify the major constituents of Fukeqianjin formula in rat plasma, and its pharmacokinetics of oral absorption was studied. Nineteen components in Fukeqianjin formula were detected and identified as the major compounds absorbed into the blood according to their chromatographic behavior, molecular weight, ion fragments and other information of these compounds. Furthermore, the plasma drug concentration–time curves were established and the related kinetic parameters were analyzed.

Results

The results showed that all the 19 compounds could be rapidly absorbed by the gastrointestinal tract, the plasma drug concentration of most compounds could reach a peak at around 1–2 h, and the double-peaks on behalf of the enterohepatic circulation were found in most drug concentration–time curves. The method used in this experiment was validated comprehensively including specificity, linearity, precision, accuracy, stability, matrix effect, and recovery.

Conclusions

These results showed that the developed method was suitable for pharmacokinetic analysis of the main components of Fukeqianjin formula in rat plasma, and may provide useful information for the subsequent distribution studies in vivo.
Lessons learned evaluating the baby friendly spaces program for south Sudanese refugees in Gambella, Ethiopia: strengthening research and programmatic partnerships to address maternal and child health and psychosocial needs in humanitarian emergencies
Authors: Lasater M. E. , Woldeyes G. M. , Le Roch K. , Phan X. , Solomon-Osborne A. , Murray S. M.
Published: July 2020

Background

During humanitarian crises, women and children are particularly vulnerable to morbidity and mortality. To address this problem, integrated child health interventions that include support for the well-being of mothers must be adapted and assessed in humanitarian settings. Baby Friendly Spaces (BFS) is a holistic program that aims to improve the health and wellbeing of pregnant and lactating women and their children under two years of age by providing psychosocial support and enhancing positive infant and young child-care practices. Using a mixed-methods, pre-post design, this study explored ways to strengthen the implementation and acceptability of the BFS program, and assess outcomes associated with participation among South Sudanese mothers and their children living in the Nguenyyiel refugee camp in Gambella, Ethiopia.

Discussion

A stronger evidence-base for integrated maternal and child health interventions, like BFS, in humanitarian emergencies is needed, but effectively conducting this type of research in unstable settings means encountering and working through myriad challenges. In this paper we discuss lessons learned while implementing this study, including, challenges related to ongoing local political and tribal conflicts and extreme conditions; implementation of a new digital data monitoring system; staff capacity building and turnover; and measurement were encountered. Strategies to mitigate such challenges included hiring and training new staff members. Regular weekly skype calls were held between Action Against Hunger Paris headquarters, the Action Against Hunger team in Gambella and Johns Hopkins’ academic partners to follow study implementation progress and troubleshoot any emerging issues. Staff capacity building strategies included holding brief and focused trainings continuously throughout the study for both new and current staff members. Lastly, we engaged local Nuer staff members to help ensure study measures and interview questions were understandable among study participants.

Conclusions

Research focused on strengthening program implementation is critically important for improving maternal and child health in humanitarian emergencies. Research in such settings demands critical problem-solving skills, strong supervision systems, flexibility in timeline and logistics, and tailor-made training for program and research staff members and context- adapted strategies for retaining existing staff.
The value of the “Surgical Risk Preoperative Assessment System” (SURPAS) in preoperative consultation for elective surgery: a pilot study
Authors: Bronsert Michael R. , Lambert-Kerzner Anne , Henderson William G. , Hammermeister Karl E. , Atuanya Chisom , Aasen Davis M. , Singh Abhinav B. , Meguid Robert A.
Published: July 2020

Background

Risk assessment is essential to informed decision making in surgery. Preoperative use of the Surgical Risk Preoperative Assessment System (SURPAS) providing individualized risk assessment, may enhance informed consent. We assessed patient and provider perceptions of SURPAS as a risk assessment tool.

Methods

A convergent mixed-methods study assessed SURPAS’s trial implementation, concurrently collecting quantitative and qualitative data, separately analyzing it, and integrating the results. Patients and providers were surveyed and interviewed on their opinion of how SURPAS impacted the preoperative encounter. Relationships between patient risk and patient and provider assessment of SURPAS were examined.

Results

A total of 197 patients were provided their SURPAS postoperative risk estimates in nine surgeon’s clinics. Of the total patients, 98.8% reported they understood their surgical risks very or quite well after exposure to SURPAS; 92.7% reported SURPAS was very helpful or helpful. Providers shared that 83.4% of the time they reported SURPAS was very or somewhat helpful; 44.7% of the time the providers reported it changed their interaction with the patient and this change was beneficial 94.3% of the time. As patient risk increased, providers reported that SURPAS was increasingly helpful (p < 0.0001).

Conclusions

Patients and providers reported the use of SURPAS helpful and informative during the preoperative risk assessment of patients, thus improving the surgical decision making process. Patients thought that SURPAS was helpful regardless of their risk level, whereas providers thought that SURPAS was more helpful in higher risk patients.
Sirt6 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling
Authors: Yang Juan , Li Ying , Zhang Ya , Fang Xiaosheng , Chen Na , Zhou Xiangxiang , Wang Xin
Published: July 2020

Background

Sirtuin 6 (Sirt6) is a highly conserved ADP-ribosylase and NAD+ dependent deacylase, involved in broad cellular processes. This molecule possesses contradictory roles in carcinogenesis, as it has been documented to both suppressing and augmenting tumor growth. This project aimed to explore the expression and functions of Sirt6 in diffuse large B-cell lymphoma (DLBCL), especially with regards to the regulatory role of OSS_128167, a novel small molecular inhibitor targeting Sirt6.

Methods

Immunohistochemistry (IHC) was conducted to assess the expression of Sirt6 on paraffin-embedded tissues. Microarray dataset GSE32918 and GSE83632 were obtained from Gene Expression Omnibus and survival analysis was performed. Lentivirus vectors either encoding shSirt6, lvSirt6 or empty lentiviral vector were stably transfected into DLBCL cells. LY1 cell transfected with shSirt6 were performed RNA-sequencing (RNA-seq) analysis, functional enrichment analyses of gene ontology (GO) and gene set enrichment analysis (GSEA). DLBCL cells were subcutaneously injected to SCID beige mice to establish xenograft models.

Results

Sirt6 is found to be overexpressed in DLBCL, and is related to poor prognosis. Sirt6-deprived DLBCL cells displayed augmented sensitivity towards chemotherapy, higher rates of apoptosis, dysfunctional cell proliferation, and arrested cell cycle progression between the G2 and M phases. Selective OSS_128167-mediated Sirt6 blockage resulted in similar anti-lymphoma effects when compared to Sirt6 knocked-down DLBCL cells. PI3K signaling along with phosphorylation of its downstream targets was reduced upon Sirt6 downregulation. Xenograft models subjected to either OSS_128167 treatment or Sirt6-knockdown showed suppressed tumor growth and lower Ki-67 level.

Conclusions

These findings provide mechanistic insights into the oncogenic activity of Sirt6 in DLBCL for the first time and highlighted the potency of OSS_128167 for novel therapeutic strategies in DLBCL.
MAPK4 deletion enhances radiation effects and triggers synergistic lethality with simultaneous PARP1 inhibition in cervical cancer
Authors: Tian Shuzhen , Lou Lili , Tian Mengyuan , Lu Guangping , Tian Jianghua , Chen Xi
Published: July 2020

Background

Cervical cancer is one of the most common cancers among females worldwide and advanced patients have extremely poor prognosis. However, adverse reactions and accumulating resistance to radiation therapy require further investigation.

Methods

The expression levels of mitogen-activated protein kinase 4 (MAPK4) mRNA were analyzed by real-time PCR and its association with overall survival was analyzed using Kaplan-Mier method. Colony formation, immunofluorescence and western blotting were used to examine the effects of MAPK4 knockout or over-expression on cervical cancer cells after radiation treatment. Drug-sensitivity of cervical cancer cells to PARP1 inhibitors, olaparib or veliparib, was analyzed by CCK-8 cell viability assays, and the 50% inhibitory concentration (IC50) was quantified using GraphPad Prism. The functional effects of MAPK4 knockout on the sensitivity of cervical cancer to radiation treatment and PARP1 inhibitors were further examined using xenograft tumor mouse models in vivo.

Results

Cervical cancer patients with high MAPK4 mRNA expression have lower survival rate. After radiation treatment, the colony number of MAPK4 knockout cells was markedly reduced, and the markers for DNA double-chain breakage were significantly up-regulated. In addition, MAPK4 knockout reduced protein kinase B (AKT) phosphorylation, whereas its over-expression resulted in opposite effects. In MAPK4 KO cells with irradiation treatment, inhibition of AKT phosphorylation promoted DNA double-chain breakage. Constitutive activation of AKT (CA-AKT) increased the levels of phosphorylated-AKT (p-AKT), and DNA repair-related proteins, phosphorylated-DNA-dependent protein kinase (p-DNA-PK) and RAD51 recombinase (RAD51). Furthermore, MAPK4 knockout was found to affect the sensitivity of cervical cancer cells to poly ADP-ribose polymerase 1 (PARP1) inhibitors by activating the phosphorylation of AKT. Moreover, in vivo results demonstrated that MAPK4 knockout enhanced the sensitivity of cervical cancer to radiation and PARP1 inhibitors in mouse xenograft models.

Conclusions

Collectively, our data suggest that combined application of MAPK4 knockout and PARP1 inhibition can be used as therapeutic strategy in radiation treatment for advanced cervical carcinoma.
WISP2 promotes cell proliferation via targeting ERK and YAP in ovarian cancer cells
Authors: Shi Zi-Qing , Chen Zi-Yan , Han Yao , Zhu Heng-Yan , Lyu Meng-Dan , Zhang Han , Zhang Yi , Yang Liu-Qing , Pan Wei-Wei
Published: July 2020

Background

Wnt-inducible signaling pathway protein 2 (WISP2) is a wnt1-induced signaling pathway protein 2. Although studies indicate that WISP2 may promote the development of various tumors, its role in ovarian cancer remains unclear. The objective of the current study was to analyze the effects of WISP2 on the proliferation and migration of ovarian cancer cells in vitro and in vivo.

Results

Immunohistochemistry and western blotting indicated that WISP2 was highly expressed in various ovarian cancer tissues and cell lines, but weakly expressed in normal ovary tissue. WISP2 deletion inhibited cell growth, clone formation, and migration of ovarian cancer cells while promoting cell apoptosis and affecting the cell cycle. This growth inhibitory effect caused by WISP2 loss is due to the inhibition of phosphorylated extracellular signal-related kinase (p-ERK)1/2, as well as CCAAT/enhancer-binding protein α (CEBPα) and CEPBβ. In addition, WISP2 deletion also activated the Yes-associated protein (YAP).

Conclusion

WISP2 deletion inhibits ovarian cancer cell proliferation by affecting ERK signaling pathways.
Digital technologies for an improved management of respiratory allergic diseases: 10 years of clinical studies using an online platform for patients and physicians
Authors: Tripodi Salvatore , Giannone Andrea , Sfika Ifigenia , Pelosi Simone , Dramburg Stephanie , Bianchi Annamaria , Pizzulli Antonio , Florack Jakob , Villella Valeria , Potapova Ekaterina , Matricardi Paolo Maria
Published: July 2020

Background

Digital health technologies carry the great potential of assisting physicians in making well-informed diagnostic and therapeutic decisions. In allergy care, electronic clinical diaries have been recently used to prospectively collect patient data and improve diagnostic precision.

Objective

This review summarizes the clinical and scientific experience we gathered over 10 years of using a digital platform for patients suffering from seasonal allergic rhinitis.

Methods

The mobile application and back-office of AllergyMonitor (TPS software production, Rome, Italy) enable patients to record their daily allergy symptoms as well as drug and immunotherapy intake plus possible side effects in a customizable way. The results can be accessed by the patient and attending physician as concise reports via a smartphone or computer. This technology has been used in several clinical studies and routine practice since 2009.

Results

Our studies showed that A) the etiological diagnosis of SAR may be supported by matching prospectively registered symptoms with pollen counts; B) it is possible to perform a short-term prediction of SAR-symptoms at individual level; C) the adherence to daily symptom monitoring can remain high (> 80%) throughout several weeks when prescribed and thoroughly explained by the treating doctor; D) the use of mobile technology can improve adherence to symptomatic drugs as well as allergen-specific immunotherapy and E) the choice of the correct symptom-severity-score is critical at patient level, but not at group level.

Conclusion

The studies and clinical practice based on the use of AllergyMonitor have proven the reliability and positive impact of a digital platform including an electronic diary (eDiary) on the diagnostic precision of SAR in poly-sensitized patients as well as patient adherence to both, drug therapy and allergen immunotherapy.
BRCAness digitalMLPA profiling predicts benefit of intensified platinum-based chemotherapy in triple-negative and luminal-type breast cancer
Authors: Lips Esther H. , Benard-Slagter Anne , Opdam Mark , Scheerman Caroline E. , Wesseling Jelle , Hogervorst Frans B. L. , Linn Sabine C. , Savola Suvi , Nederlof Petra M.
Published: July 2020

Background

We previously showed that BRCA-like profiles can be used to preselect individuals with the highest risk of carrying BRCA mutations but could also indicate which patients would benefit from double-strand break inducing chemotherapy. A simple, robust, and reliable assay for clinical use that utilizes limited amounts of formalin-fixed, paraffin-embedded tumor tissue to assess BRCAness status in both ER-positive and ER-negative breast cancer (BC) is currently lacking.

Methods

A digital multiplex ligation-dependent probe amplification (digitalMLPA) assay was designed to detect copy number alterations required for the classification of BRCA1-like and BRCA2-like BC. The BRCA1-like classifier was trained on 71 tumors, enriched for triple-negative BC; the BRCA2-like classifier was trained on 55 tumors, enriched for luminal-type BC. A shrunken centroid-based classifier was developed and applied on an independent validation cohort. A total of 114 cases of a randomized controlled trial were analyzed, and the association of the classifier result with intensified platinum-based chemotherapy response was assessed.

Results

The digitalMLPA BRCA1-like classifier correctly classified 91% of the BRCA1-like samples and 82% of the BRCA2-like samples. Patients with a BRCA-like tumor derived significant benefit of high-dose chemotherapy (adjusted hazard ratio (HR) 0.12, 95% CI 0.04–0.44) which was not observed in non-BRCA-like patients (HR 0.9, 95% CI 0.37–2.18) (p = 0.01). Analysis stratified for ER status showed borderline significance.

Conclusions

The digitalMLPA is a reliable method to detect a BRCA1- and BRCA2-like pattern on clinical samples and predicts platinum-based chemotherapy benefit in both triple-negative and luminal-type BC.
Conducting clinical trials in sub-Saharan Africa: challenges and lessons learned from the Malawi Cryptosporidium study
Authors: Toto Neema , Douglas Elaine , Gmeiner Markus , Barrett Lynn K. , Lindblad Robert , Makhaza Lumbani , Nedi Wilfred , Phulusa Jacob , Quinnan Gerald V. , Sawyer Leigh A. , Thole Herbert , Van Voorhis Wesley C. , Iroh Tam Pui-Ying
Published: July 2020

Background

An effective drug to treat cryptosporidial diarrhea in HIV-infected individuals is a global health priority. Promising drugs need to be evaluated in endemic areas which may be challenged by both lack of resources and experience to conduct International Committee of Harmonisation-Good Clinical Practice (ICH-GCP)-compliant clinical trials.

Methods

We present the challenges and lessons learned in implementing a phase 2A, randomized, double-blind, placebo-controlled trial of clofazimine, in treatment of cryptosporidiosis among HIV-infected adults at a single site in Malawi.

Results

Primary challenges are grouped under study initiation, study population, study implementation, and cultural issues. The lessons learned primarily deal with regulatory system and operational barriers, and recommendations can be applied to other human experimental trials in low- and middle-income countries, specifically in sub-Saharan Africa.

Conclusion

This study demonstrated that initiating and implementing human experimental trials in sub-Saharan Africa can be challenging. However, solutions exist and successful execution requires careful planning, ongoing evaluation, responsiveness to new developments, and oversight of all trial operations.
Accuracy of time to treatment estimates in the CRASH-3 clinical trial: impact on the trial results
Authors: Mansukhani Raoul , Frimley Lauren , Shakur-Still Haleema , Sharples Linda , Roberts Ian
Published: July 2020

Background

Early treatment with tranexamic acid may reduce deaths after traumatic brain injury (TBI). In mild and moderate TBI, there is a time to treatment interaction, with early treatment being most beneficial. Time to treatment was recorded by clinicians and is subject to error. Using monitoring data from the CRASH-3 trial, we examine the impact of errors in time to treatment on estimated treatment effects.

Methods

The CRASH-3 trial was a randomised trial of the effect of tranexamic acid on death and vascular occlusive events in 12,737 TBI patients. This analysis includes the 8107 patients with a Glasgow coma scale score of 9 to 15 since previous analyses showed that these patients benefit most from early treatment. Clinician-recorded time to treatment was checked against ambulance and hospital records for 1368/12,737 (11%) patients. Patients who died were preferentially selected for monitoring and we monitored 36% of head injury deaths. We describe measurement errors using Bland-Altman graphs. We model the effect of tranexamic acid on head injury death using logistic regression with a time-treatment interaction term. We use regression calibration, multiple imputation and Bayesian analysis to estimate the impact of time to treatment errors.

Results

Clinicians rounded times to the nearest half or full hour in 66% of cases. Monitored times were also rounded and were identical to clinician times in 63% of patients. Times were underestimated by an average of 9 min (95% CI − 85, 66). There was more variability between clinician-recorded and monitored times in low- and middle-income countries than in high-income countries. The treatment effect estimate at 1 h was greater for monitored times OR = 0.61 (95% CI 0.47, 0.81) than for clinician-recorded times OR = 0.63 (95% CI 0.48, 0.83). All three adjustment methods gave similar time to treatment interactions. For Bayesian methods, the treatment effect at 1 h was OR = 0.58 (95% CI 0.43, 0.78). Using monitored times increased the time-treatment interaction term from 1.15 (95% CI 1.03, 1.27) to 1.16 (95% CI 1.05, 1.28).

Conclusions

Accurate estimation of time from injury to treatment is challenging, particularly in low resource settings. Adjustment for known errors in time to treatment had minimal impact on the trial results.

Trial registration

ClinicalTrials.gov NCT01402882. Registered on 25 July 2011
Synthesis, density functional theory study and in vitro antimicrobial evaluation of new benzimidazole Mannich bases
Authors: Marinescu Maria , Cinteză Ludmila Otilia , Marton George Iuliu , Chifiriuc Mariana-Carmen , Popa Marcela , Stănculescu Ioana , Zălaru Christina-Marie , Stavarache Cristina-Elena
Published: July 2020

The tri-component synthesis of novel chiral benzimidazole Mannich bases, by reaction between benzimidazole, aqueous 30% formaldehyde and an amine, the biological evaluation and DFT studies of the new compounds are reported here. The 1H-NMR, 13C-NMR, FTIR spectra and elemental analysis confirm the structures of the new compounds. All synthesized compounds were screened by qualitative and quantitative methods for their in vitro antibacterial activity against 4 bacterial strains. DFT studies were accomplished using GAMESS 2012 software and HOMO–LUMO analysis allowed the calculation of electronic and structural parameters of the chiral Mannich bases. The geometry of 1-methylpiperazine, the cumulated Mullikan atomic charges of the two heteroatoms and of the methyl, and the value of the global electrophilicity index (ω = 0.0527) of the M-1 molecule is correlated with its good antimicrobial activity. It was found that the presence of saturated heterocycles from the amine molecule, 1-methyl piperazine and morpholine, respectively, contributes to an increased biological activity, compared to aromatic amino analogs, diphenylamino-, 4-nitroamino- and 4-aminobenzoic acid. The planarity of the molecules, specific bond lengths and localization of HOMO–LUMO orbitals is responsible for the best biological activities of the compounds.
Eimeria tenella Eimeria-specific protein that interacts with apical membrane antigen 1 (EtAMA1) is involved in host cell invasion
Authors: Li Cong , Zhao Qiping , Zhu Shunhai , Wang Qingjie , Wang Haixia , Yu Shuilan , Yu Yu , Liang Shashan , Zhao Huanzhi , Huang Bing , Dong Hui , Han Hongyu
Published: July 2020

Background

Avian coccidiosis is a widespread, economically significant disease of poultry, caused by several Eimeria species. These parasites have complex and diverse life-cycles that require invasion of their host cells. This is mediated by various proteins secreted from apical secretory organelles. Apical membrane antigen 1 (AMA1), which is released from micronemes and is conserved across all apicomplexans, plays a central role in the host cell invasion. In a previous study, some putative EtAMA1-interacting proteins of E. tenella were screened. In this study, we characterized one putative EtAMA1-interacting protein, E. tenella Eimeria -specific protein (EtEsp).

Methods

Bimolecular fluorescence complementation (BiFC) and glutathione S-transferase (GST) fusion protein pull-down (GST pull-down) were used to confirm the interaction between EtAMA1 and EtEsp in vivo and in vitro. The expression of EtEsp was analyzed in different developmental stages of E. tenella with quantitative PCR and western blotting. The secretion of EtEsp protein was tested with staurosporine when sporozoites were incubated in complete medium at 41 °C. The localization of EtEsp was analyzed with an immunofluorescence assay (IFA). An in vitro invasion inhibition assay was conducted to assess the ability of antibodies against EtEsp to inhibit cell invasion by E. tenella sporozoites.

Results

The interaction between EtAMA1 and EtEsp was confirmed with BiFC and by GST pull-down. Our results show that EtEsp is differentially expressed during distinct phases of the parasite life-cycle. IFA showed that the EtEsp protein is mainly distributed on the parasite surface, and that the expression of this protein increases during the development of the parasite in the host cells. Using staurosporine, we showed that EtEsp is a secreted protein, but not from micronemes. In inhibition tests, a polyclonal anti-rEtEsp antibody attenuated the capacity of E. tenella to invade host cells.

Conclusion

In this study, we show that EtEsp interacts with EtAMA1 and that the protein is secreted protein, but not from micronemes. The protein participates in sporozoite invasion of host cells and is maybe involved in the growth of the parasite. These data have implications for the use of EtAMA1 or EtAMA1-interacting proteins as targets in intervention strategies against avian coccidiosis.
Neospora caninum infection induces an isolate virulence-dependent pro-inflammatory gene expression profile in bovine monocyte-derived macrophages
Authors: García-Sánchez Marta , Jiménez-Pelayo Laura , Horcajo Pilar , Collantes-Fernández Esther , Ortega-Mora Luis Miguel , Regidor-Cerrillo Javier
Published: July 2020

Background

Neospora caninumis an obligate intracellular parasite, and its ability to survive inside host immune cells may be a key mechanism for the establishment of infection in cattle.In vitrostudies carried out by our group have shown thatN. caninumis able to replicate in bovine macrophages (MØs), alter their microbicidal mechanisms and exploit their motility. Furthermore, host-cell control seems to be isolate virulence-dependent.

Methods

To investigate the molecular basis underlying the innate responses in MØs againstN. caninumand the mechanisms of parasite manipulation of the host cell environment, the transcriptome profile of bovine monocyte-derived MØs infected with high-virulence (Nc-Spain7) or low-virulence (Nc-Spain1H)N. caninumisolates was studied.

Results

Functional enrichment revealed upregulation of genes involved in chemokine signalling, inflammation, cell survival, and inhibition of genes related with metabolism and phagolysosome formation. MØs activation was characterized by the induction of a predominantly M1 phenotype with expression ofTLR2,TLR3andTLR9and activation of the NF-ƙB signalling pathway. Heat-killedN. caninumtachyzoites failed to activate NF-ƙB, and to inhibit lysosomal activity and apoptosis, which indicates active modulation by the parasite. The FoxO signalling pathway, Th1-Th2 differentiation, glycosaminoglycan degradation and apoptosis were pathways enriched only for low virulent Nc-Spain1H infection. In addition, Nc-Spain1H infection upregulated theIL12AandIL8pro-inflammatory cytokines, whereasIL23was downregulated by high virulent Nc-Spain7.

Conclusions

This study revealed mechanisms implicated in the recognition ofN. caninumby bovine MØs and in the development of the subsequent immune response. NF-ƙB seems to be the main signalling pathway implicated in the pro-inflammatory bovine MØs response against this pathogen. Apoptosis and phagolysosome maturation are processes repressed byN. caninuminfection, which may guarantee its intracellular survival. The results also indicate that Nc-Spain7 may be able to partially circumvent the pro-inflammatory response whereas Nc-Spain1H induces a protective response to infection, which may explain the more efficient transmission of the high-virulence Nc-Spain7 isolate observedin vivo.
Assessing the effect of interventions for axial spondyloarthritis according to the endorsed ASAS/OMERACT core outcome set: a meta-research study of trials included in Cochrane reviews
Authors: Andreasen Rikke A. , Kristensen Lars E. , Baraliakos Xenofon , Strand Vibeke , Mease Philip J. , de Wit Maarten , Ellingsen Torkell , Hansen Inger Marie J. , Kirkham Jamie , Wells George A. , Tugwell Peter , Maxwell Lara , Boers Maarten , Egstrup Kenneth , Christensen Robin
Published: July 2020

The Assessment of SpondyloArthritis international Society (ASAS) has defined core sets for (i) symptom-modifying anti-rheumatic drugs (SM-ARD), (ii) clinical record keeping, and (iii) disease-controlling anti-rheumatic therapy (DC-ART). These include the following domains for all three core sets: “physical function,” “pain,” “spinal mobility,” “spinal stiffness,” and “patient’s global assessment” (PGA). The core set for clinical record keeping further includes the domains “peripheral joints/entheses” and “acute phase reactants,” and the core set for DC-ART further includes the domains “fatigue” and “spine radiographs/hip radiographs.” The Outcome Measures in Rheumatology (OMERACT) endorsed the core sets in 1998.

Using empirical evidence from axSpA trials, we investigated the efficacy (i.e., net benefit) according to the ASAS/OMERACT core outcome set for axSpA across all interventions tested in trials included in subsequent Cochrane reviews. For all continuous scales, we combined data using the standardized mean difference (SMD) to meta-analyze outcomes involving the same domains. Also, through meta-regression analysis, we examined the effect of the separate SMD measures (independent variables) on the primary endpoint (log [OR], dependent variable) across all trials.

Based on 11 eligible Cochrane reviews, from these, 85 articles were screened; we included 43 trials with 63 randomized comparisons. Mean (SD) number of ASAS/OMERACT core outcome domains measured for SM-ARD/physical therapy trials was 4.2 (1.7). Six trials assessed all proposed domains. Mean (SD) for number of core outcome domains for DC-ART trials was 5.8 (1.7). No trials assessed all nine domains. Eight trials (16%) were judged to have inadequate (i.e., high risk of) selective outcome reporting bias. The most responsible core domains for achieving success in meeting the primary objective per trial were pain, OR (95% CI) 5.19 (2.28, 11.77), and PGA, OR (95% CI) 1.87 (1.14, 3.07). In conclusion, selective outcome reporting (and “missing data”) should be reduced by encouraging the use of the endorsed ASAS/OMERACT outcome domains in clinical trials. Overall outcome reporting was good for SM-ARD/physical therapy trials and poor for DC-ART trials. Our findings suggest that both PGA and pain provide a valuable holistic construct for the assessment of improvement beyond more objective measures of spinal inflammation.
Does periodontitis affect the treatment response of biologics in the treatment of rheumatoid arthritis?
Authors: Tachibana Masahiro , Yonemoto Yukio , Okamura Koichi , Suto Takahito , Sakane Hideo , Kaneko Tetsuya , Dam Trang Thuy , Okura Chisa , Tajika Tsuyoshi , Tsushima Yoshito , Chikuda Hirotaka
Published: July 2020

Background

Rheumatoid arthritis (RA) and periodontitis (PD) have been suggested to share many clinical and pathological features. However, few reports have investigated the relationship between the degree of PD and the treatment response to RA.

This study aimed to examine the relationship between the extent of PD and the treatment response to biologics in RA patients using FDG-PET/CT.

Methods

Sixty RA patients (male, n = 14; female, n = 46; average age, 58.3 years) treated with biologic agents were included in this study. FDG-PET/CT was performed at baseline and 6 months after the initiation of biological therapy. The maximum standardized uptake value (SUVmax) was used as a representative value for the assessment of the FDG uptake in periodontal tissue and joints including the bilateral shoulders, elbows, wrists, hip, knees, and ankle joints. The Disease Activity Score (DAS) 28-CRP and the following clinical parameters were assessed: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti-cyclic citrullinated peptide antibody (ACPA), rheumatoid factor (RF), and matrix metalloproteinase 3 (MMP-3). The relationship between the treatment response of RA and the baseline SUVmax of the periodontal tissue was evaluated.

Results

The baseline periodontal SUVmax was related to patient age (r = 0.302, p = 0.009) and the ACPA level (r = 0.265, p = 0.025). The DAS28-CRP, CRP, ESR, MMP-3, and joint SUVmax values were significantly decreased after 6 months of biological therapy. However, the mean periodontal SUVmax, ACPA, and RF showed no significant changes after treatment. There was a significantly negative correlation between the baseline periodontal SUVmax and the treatment response of DAS28-CRP (r = − 0.369, p = 0.004).

Conclusion

There was a negative correlation between the extent of PD at baseline and the treatment response of RA patients who received biological therapy. The evaluation of the periodontal condition is considered to be an essential part for the management of RA.