bluuebunny/crossref_metadata_2025 huggingface dataset:
Normofractionated stereotactic radiotherapy versus CyberKnife-based hypofractionation in skull base meningioma: a German and Italian pooled cohort analysis
Authors: Alfredo Conti , Carolin Senger , Güliz Acker , Anne Kluge , Antonio Pontoriero , Alberto Cacciola , Stefano Pergolizzi , Antonino Germanò , Harun Badakhshi , Markus Kufeld , Franziska Meinert , Phuong Nguyen , Franziska Loebel , Peter Vajkoczy , Volker Budach , David Kaul
Published: November 2019

Background

This retrospective German and Italian multicenter analysis aimed to compare the role of normofractionated stereotactic radiotherapy (nFSRT) to CyberKnife-based hypofractionated stereotactic radiotherapy (CK-hFSRT) for skull base meningiomas.

Methods

Overall, 341 patients across three centers were treated with either nFSRT or CK-hFSRT for skull base meningioma. Treatment planning was based on computed tomography (CT) and magnetic resonance imaging (MRI) following institutional guidelines. Most nFSRT patients received 33 × 1.8 Gy, and most CK-hFSRT patients received 5 × 5 Gy. The median follow-up time was 36 months (range: 1–232 months).

Results

In the CK-hFSRT group, the 1-, 3-, and 10-year local control (LC) rates were 99.4, 96.8, and 80.3%, respectively. In the nFSRT group, the 1-, 3-, and 10-year LC rates were 100, 99, and 79.1%, respectively. There were no significant differences in LC rates between the nFSRT and CK-hFSRT groups (p = 0.56, hazard ratio = 0.76, 95% confidence interval, 0.3–1.9). In the CK-hFSRT group, only one case (0.49%) of severe toxicity (CTCAE 4.0 ≥ 3) was observed. In the nFSRT group, three cases (2.1%) of grade III toxicity were observed.

Conclusion

This analysis of pooled data from three centers showed excellent LC and low side effect rates for patients treated with CK-hFSRT or nFSRT. The efficacy, safety, and convenience of a shortened treatment period provide a compelling case for the use of CK-hFSRT in patients with moderate size skull base meningioma and provided that OAR constraints are met.
Preliminary evaluation of autologous pericardium ring for tricuspid Annuloplasty: a two-year follow-up study
Authors: Jiang Wei , Long Xiao-Mao , Li Si-Cong , Zhong Yong-Long , He Bang-Fu , Lin Hui
Published: November 2019

Objective

To evaluate the effectiveness of autologous pericardium ring in tricuspid annuloplasty surgery for the treatment of tricuspid regurgitation (TR).

Methods

From December 2010 to December 2012, a total of 107 patients with secondary TR underwent tricuspid annuloplasty. The patients were divided into three groups: autologous pericardium ring group (n = 38), Edwards-MC3 ring group (n = 35), and DeVega group (n = 34). The patients were followed-up for two years. The survival rates and free from hospital readmission rates were measured and analyzed. The patients also received transthoracic echocardiography (TTE) in order to obtain TR regurgitant jet area to right atrial area (STR/STA), diastolic tricuspid annuloplasty diameter (DTAD), right atrial diameter (RAD), and right ventricular diameter (RVD).

Results

One patient from DeVega group and one patient from autologous pericardium ring died from low cardiac output syndrome during the perioperative period. In the two-year follow-up period, each group has one instance of death for unclear reasons. One month after operation, the STR/STA, DTAD, RAD, and RVD values in all groups were significantly lower than the pre-operation values (P < 0.05). During the two year follow-up period, DTAD values of patients from DeVega group increased significantly as compared to the values at one month post operation (P<0.05), which is different from the other two groups in which DTAD values remained stable (P>0.05). In both pericardium ring group and Edwards-MC3 group, STR/SRA, remained stable (P>0.05) during the follow-up period, whereas STR/SRA of the DeVega group had showed a tendency of increase (although statistically insignificant, P>0.05). There was no significant difference in the survival rates among three study groups (P > 0.05), but the rate of free from hospital readmission in the DeVega group was significantly lower than those in the other two groups (P < 0.05) during the two-year follow-up period.

Conclusions

Autologous pericardium tissue based ring annuloplasty demonstrated remarkable clinical utility for treating tricuspid regurgitation. It shows similar beneficial results to Edwards-MC3 annuloplasty within a short-term follow-up period, and outperforms the widely used DeVega annuloplasty. Autologous pericardium tissue annuloplasty represents a promising technique for tricuspid annuloplasty and holds great potential for treating tricuspid valve dysfunctions.
The attenuated end of the phenotypic spectrum in MPS III: from late-onset stable cognitive impairment to a non-neuronopathic phenotype
Authors: Nijmeijer Stephanie C. M. , van den Born L. Ingeborg , Kievit Anneke J. A. , Stepien Karolina M. , Langendonk Janneke , Marchal Jan Pieter , Roosing Susanne , Wijburg Frits A. , Wagenmakers Margreet A. E. M.
Published: November 2019

Background

The phenotypic spectrum of many rare disorders is much wider than previously considered. Mucopolysaccharidosis type III (Sanfilippo syndrome, MPS III), is a lysosomal storage disorder traditionally considered to be characterized by childhood onset, progressive neurocognitive deterioration with a rapidly or slowly progressing phenotype. The presented MPS III case series demonstrates adult onset phenotypes with mild cognitive impairment or non-neuronopathic phenotypes.

Methods

In this case series all adult MPS III patients with a mild- or non-neuronopathic phenotype, who attend the outpatient clinic of 3 expert centers for lysosomal storage disorders were included. A mild- or non-neuronopathic phenotype was defined as having completed regular secondary education and attaining a level of independency during adulthood, involving either independent living or a paid job.

Results

Twelve patients from six families, with a median age at diagnosis of 43 years (range 3–68) were included (11 MPS IIIA, 1 MPS IIIB). In the four index patients symptoms which led to diagnostic studies (whole exome sequencing and metabolomics) resulting in the diagnosis of MPS III; two patients presented with retinal dystrophy, one with hypertrophic cardiomyopathy and one with neurocognitive decline. The other eight patients were diagnosed by family screening. At a median age of 47 years (range 19–74) 9 out of the 12 patients had normal cognitive functions. Nine patients had retinal dystrophy and 8 patients hypertrophic cardiomyopathy.

Conclusion

We show the very mild end of the phenotypic spectrum of MPS III, ranging from late-onset stable neurocognitive impairment to a fully non-neuronopathic phenotype. Awareness of this phenotype could lead to timely diagnosis and genetic counseling.
Clinical characteristics and prognosis of Chinese patients with hereditary transthyretin amyloid cardiomyopathy
Authors: He Shan , Tian Zhuang , Guan Hongzhi , Li Jian , Fang Quan , Zhang Shuyang
Published: November 2019

Background

Hereditary transthyretin amyloid cardiomyopathy (ATTR-CM) is an increasingly recognized progressive cardiomyopathy with heterogenous clinical manifestations that lead to its misdiagnosis and poor prognosis. This study was performed to describe the clinical characteristics and natural history of Chinese patients to improve clinical awareness of this condition.

Methods

In this study, we retrospectively investigated 23 patients with a confirmed diagnosis of hereditary ATTR-CM in Peking Union Medical College hospital from From January 1, 2000 to December 31, 2018.

Results

In all, 16 patients (69.6%) were males, the median age at disease onset was 45 (33,55) years old. The median duration from symptom onset to diagnosis was 30 (18,46) months. Phenotypes were classified as exclusively cardiac (n = 1, 4.3%) and mixed type (n = 22, 95.6%). The common mutations were Gly47Arg (7 patients [30.4%]) and Val30Ala (3 patients [13%]). Ventricular hypertrophy was observed in 23 (100%) patients, the mean thickness of the ventricular septum was 16.1 ± 3.9 mm, the mean thickness of the left ventricular posterior wall was 15.1 ± 2.8 mm. The mean left ventricle ejection fraction (LVEF) was 57.3 ± 11.9% and only 5 patients (21.7%) had LVEF < 50%. 18 (78.3%) patients had abnormal electrocardiography and the most common feature was pseudoinfarct pattern (56.5%). Overall survival at 12, 24, 36, 48, and 60 months after diagnosis was 77.8, 55.6, 38.9, 27.8, and 11.1%, respectively. Survival was better in patients with EF ≥50% than in those with EF < 50% [log Rank (Mantel-Cox), χ2 = 4.03, P = 0.045].

Conclusions

The clinical characteristics of ATTR are heterogeneous: men are more likely to be affected and onset symptoms are not obvious in the heart and mainly include peripheral neuropathy and autonomic neuropathy; however, LV hypertrophy, especially a thick ventricular septum and posterior wall with preserved LVEF, are often detected on echocardiography. Abnormal ECG manifestations are common. The prognosis is poor, and patients with EF > 50% have better survival. Clinicians should be more aware of the complex clinical profile of ATTR amyloidosis to avoid misdiagnosis in practice.
Nonclonal chromosomal alterations and poor survival in cytopenic patients without hematological malignancies
Authors: Imataki Osamu , Kubo Hiroyuki , Takeuchi Akihiro , Uemura Makiko , Kadowaki Norimitsu
Published: November 2019

Background

Clonal chromosomal alterations (CCAs) reflect recurrent genetic changes derived from a single evolving clone, whereas nonclonal chromosomal alterations (NCCAs) comprise a single or nonrecurrent chromosomal abnormality. CCAs and NCCAs in hematopoietic cells have been partially investigated in cytopenic patients without hematological malignancies.

Methods

This single-center retrospective study included 253 consecutive patients who underwent bone marrow aspiration to determine the cause of cytopenia between 2012 and 2015. Patients with hematological malignancies were excluded. CCA was defined as a chromosomal aberration detected in more than two cells, and NCCA was defined as a chromosomal aberration detected in a single cell.

Results

The median age of the patients was 66 years. There were 135 patients without hematological malignancies (median age, 64 years; 69 females); of these, 27 patients (median age, 69 years; 8 females) harbored chromosomal abnormalities. CCAs were detected in 14 patients; the most common CCA was −Y in eight patients, followed by inv.(9) in three patients and mar1+, inv. (12), and t (19;21) in one patient each. NCCAs were detected in 13 patients; the most frequent NCCA was +Y in four patients, followed by del (20), + 8, inv. (2), − 8, and add (6) in one patient each. Moreover, nonclonal translocation abnormalities, including t (9;14), t (14;16), and t (13;21), were observed in three patients. One patient had a complex karyotype in a single cell. The remaining 106 patients with normal karyotypes comprised the control group (median age, 65 years; range, 1–92 years; 56 females). Further, follow-up analysis revealed that the overall survival of the NCCA group was worse than that of the CCA and the normal karyotype groups (P < 0.0001; log-rank test).

The survival of the NCCA-harboring cytopenic patients was worse than that of the CCA-harboring cytopenic patients without hematological malignancies, suggesting that follow-up should be considered for both CCA- and NCCA-harboring cytopenic patients.
Behavioral analysis in mice deficient for GAREM2 (Grb2-associated regulator of Erk/MAPK subtype2) that is a subtype of highly expressing in the brain
Authors: Nishino Tasuku , Tamada Kota , Maeda Akane , Abe Takaya , Kiyonari Hiroshi , Funahashi Yasuhiro , Kaibuchi Kozo , Takumi Toru , Konishi Hiroaki
Published: November 2019

Grb2-associated regulator of Erk/MAPK (GAREM), is an adaptor protein related to the several cell growth factor receptor-signaling. The GAREM family has two subtypes, GAREM1 and GAREM2, both encoded in the human and mouse genome. Recent genome-wide research identified GAREM2 as a candidate of neurodegenerative diseases. Here, we use knockout (KO) mice to show the role of GAREM2, that is highly expressed in the brain. According to the comprehensive behavioral battery, they exhibited less anxiety both in elevated plus maze and open field tests, mildly increased social approaching behavior in the reciprocal social interaction test, and longer latency to immobility in the tail suspension test as compared to wild-type (WT). Additionally, the extension of neurites in the primary cultured neurons was suppressed in ones derived from GAREM2 KO mice. Furthermore, we also identified Intersectin, as a binding partner of GAREM2 in this study. Intersectin is also a multi-domain adaptor protein that regulates endocytosis and cell signaling, which can potentially alter the subcellular localization of GAREM2. The important molecules, such as the neurotrophin receptor and Erk family, that are involved in the signaling pathway of the neural cell growth in the mouse brain, have been reported to participate in emotional behavior. As GAREM plays a role in the cellular growth factor receptor signaling pathway, GAREM2 may have a common role related to the transduction of Erk signaling in the higher brain functions.
Programmed cell death ligand-1-mediated enhancement of hexokinase 2 expression is inversely related to T-cell effector gene expression in non-small-cell lung cancer
Authors: Kim Sehui , Jang Ji-Young , Koh Jaemoon , Kwon Dohee , Kim Young A. , Paeng Jin Chul , Ock Chan-Young , Keam Bhumsuk , Kim Miso , Kim Tae Min , Heo Dae Seog , Chung Doo Hyun , Jeon Yoon Kyung
Published: November 2019

Background

We investigated the role of PD-L1 in the metabolic reprogramming of non-small cell lung cancer (NSCLC).

Methods

Changes in glycolysis-related molecules and glycolytic activity were evaluated in PD-L1low and PD-L1high NSCLC cells after transfection or knockdown of PD-L1, respectively. Jurkat T-cell activation was assessed after co-culture with NSCLC cells. The association between PD-L1 and immune response-related molecules or glycolysis were analyzed in patients with NSCLC and The Cancer Genome Atlas (TCGA).

Results

Transfecting PD-L1 in PD-L1low cells enhanced hexokinase-2 (HK2) expression, lactate production, and extracellular acidification rates, but minimally altered GLUT1 and PKM2 expression and oxygen consumption rates. By contrast, knocking-down PD-L1 in PD-L1high cells decreased HK2 expression and glycolysis by suppressing PI3K/Akt and Erk pathways. Interferon-γ (IFNγ) secretion and activation marker expression was decreased in stimulated Jurkat T-cells when co-cultured with HK2-overexpressing vector-transfected tumor cells rather than empty vector-transfected tumor cells. Immunohistochemistry revealed that PD-L1 expression was positively correlated with HK2 expression in NSCLC (p < 0.001). In TCGA, HK2 exhibited a positive linear association with CD274 (PD-L1) expression (p < 0.001) but an inverse correlation with the expression of CD4, CD8A, and T-cell effector function-related genes in the CD274high rather than CD274low group. Consistently, there were fewer CD8+ T-cells in PD-L1positive/HK2high tumors compared to PD-L1positive/HK2low tumors in squamous cell carcinoma.

Conclusions

PD-L1 enhances glycolysis in NSCLC by upregulating HK2, which might dampen anti-tumor immunity. PD-L1 may contribute to NSCLC oncogenesis by inducing metabolic reprogramming and immune checkpoint.
PES1 promotes BET inhibitors resistance and cells proliferation through increasing c-Myc expression in pancreatic cancer
Authors: Jin Xin , Fang Rui , Fan Ping , Zeng Lipeng , Zhang Bin , Lu Xiaoming , Liu Tao
Published: November 2019

Abstracts

Background

Overexpressed PES1 promotes carcinogenesis in various types of malignant tumors. However, the biological role and clinical significance of PES1 in pancreatic cancer are still unexplored.

Methods

The expression level of PES1 in pancreatic cancer cell lines and pancreatic cancer patient samples was determined using Western Blotting analysis, RT-qPCR analysis, immunohistochemical (IHC) analysis of tissue microarray, and the GEPIA web tool. MTS assay, colony formation assay, and xenograft tumor assay were used to evaluate the tumor growth ability of pancreatic cancer cells.

Results

We established that the expression of PES1 was abnormally increased in pancreatic cancer tissues and led to poor prognosis of pancreatic cancer patients. We also found that PES1 was responsible for promoting cell growth and contributed to bromodomain and cancer cell resistance to extra-terminal (BET) inhibitors in pancreatic cancer. Furthermore, we showed that PES1 interacted with BRD4 to enhance c-Myc expression, which is the primary cause of cancer cell resistance to BET inhibitors in pancreatic cancer. Finally, CDK5 inhibitors were proven to destabilize PES1 and overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.

Conclusions

We have shown that PES1 could be one of the promoting factors of tumor growth and a prognosis-related protein of pancreatic cancer. Targeting PES1 with CDK5 inhibitors might help overcome cancer cell resistance to BET inhibitors in pancreatic cancer cells.
Prognostic ability of the sequential organ failure assessment score in accidental hypothermia: a multi-institutional retrospective cohort study
Authors: Kandori Kenji , Okada Yohei , Matsuyama Tasuku , Morita Sachiko , Ehara Naoki , Miyamae Nobuhiro , Jo Takaaki , Sumida Yasuyuki , Okada Nobunaga , Watanabe Makoto , Nozawa Masahiro , Tsuruoka Ayumu , Fujimoto Yoshihiro , Okumura Yoshiki , Kitamura Tetsuhisa , Iiduka Ryoji
Published: November 2019

Background

Severe accidental hypothermia (AH) is life threatening. Thus, prognostic prediction in AH is essential to rapidly initiate intensive care. Several studies on prognostic factors for AH are known, but none have been established. We clarified the prognostic ability of the Sequential Organ Failure Assessment (SOFA) score in comparison with previously reported prognostic factors among patients with AH.

Methods

The J-point registry database is a multi-institutional retrospective cohort study for AH in 12 Japanese emergency departments. From this registry, we enrolled patients who were treated at the intensive care unit (ICU) in various critical care medical centers. In-hospital mortality was the primary outcome. We investigated the discrimination ability of each candidate prognostic factor and the in-hospital mortality by applying the logistic regression models with areas under the receiver operating characteristic curve (AUROC) with 95% confidence interval (CI).

Results

Of the 572 patients with AH registered in the J-point registry, 220 were eligible for the analyses. The in-hospital mortality was 23.2%. The AUROC of the SOFA score (0.80; 95% CI: 0.72–0.86) was the highest among all factors. The other factors were serum potassium (0.65; 95% CI: 0.55–0.73), lactate (0.67; 95% CI: 0.57–0.75), quick SOFA (qSOFA) (0.55; 95% CI: 0.46–0.65), systemic inflammatory response syndrome (SIRS) (0.60; 95% CI: 0.50–0.69), and 5A severity scale (0.77; 95% CI: 0.68–0.84).

Discussion

Although serum potassium and lactate had relatively good discrimination ability as mortality predictors, the SOFA score had slightly better discrimination ability. The reason is that lactate and serum potassium were mainly reflected by the hemodynamic state; conversely, the SOFA score is a comprehensive score of organ failure, basing on six different scores from the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Meanwhile, the qSOFA and SIRS scores underestimated the severity, with low discrimination abilities for mortality.

Conclusions

The SOFA score demonstrated better discrimination ability as a mortality predictor among all known prognostic factors in patients with AH.
Microalbuminuria risks and glomerular filtration in children with sickle cell anaemia in Nigeria
Authors: Ocheke I. E. , Mohamed S. , Okpe E. S. , Bode-Thomas F. , McCullouch M. I.
Published: November 2019

Introduction

Evidence of kidney damage is observed in children with sickle cell anaemia (SCA) and this continues through adulthood with progression to severe functional impairment in some. One of the earliest features of kidney damage associated with SCA is microalbuminuria. Our objective was to determine the risk factors of microalbuminuria in these children and its relationship with estimated glomerular filtration rate.

Methods

This was a cross-sectional and comparative study involving three hundred and twenty three children with SCA in steady state and equal numbers of apparently healthy age and sex matched haemoglobin AA (HbAA) control, aged 6 months to 18 years. They were consecutively recruited over a 6 month period.

Result

Microalbuminuria was present in 26% of the study subjects compared with 1.85% of controlP = 0.001). Anaemia and high estimated glomerular filtration rate (eGFR) showed strong positive correlation with microalbuminuria (OR = 3.19, CI 0.953–1.116,p = 0.003 and OR = 1.7, CI 1.042–1.066,p = 0.001 respectively). Similarly, eGFR was higher in subjects with SCA than in controls and as well as in those with microalbuminuria compared with those who do not (p = < 0.01).

Conclusions

The two most important risk factors for microalbuminuria were anaemia and high eGFR. Age category was associated more with microalbuminuria than just age as a variable. Glomerular filtration rate was higher in children with microalbuminuria than those who do not and it was also higher in children with SCA than in control.
Long-term cognitive impairment after acute respiratory distress syndrome: a review of clinical impact and pathophysiological mechanisms
Authors: Sasannejad Cina , Ely E. Wesley , Lahiri Shouri
Published: November 2019

Acute respiratory distress syndrome (ARDS) survivors experience a high prevalence of cognitive impairment with concomitantly impaired functional status and quality of life, often persisting months after hospital discharge. In this review, we explore the pathophysiological mechanisms underlying cognitive impairment following ARDS, the interrelations between mechanisms and risk factors, and interventions that may mitigate the risk of cognitive impairment. Risk factors for cognitive decline following ARDS include pre-existing cognitive impairment, neurological injury, delirium, mechanical ventilation, prolonged exposure to sedating medications, sepsis, systemic inflammation, and environmental factors in the intensive care unit, which can co-occur synergistically in various combinations. Detection and characterization of pre-existing cognitive impairment imparts challenges in clinical management and longitudinal outcome study enrollment. Patients with brain injury who experience ARDS constitute a distinct population with a particular combination of risk factors and pathophysiological mechanisms: considerations raised by brain injury include neurogenic pulmonary edema, differences in sympathetic activation and cholinergic transmission, effects of positive end-expiratory pressure on cerebral microcirculation and intracranial pressure, and sensitivity to vasopressor use and volume status. The blood-brain barrier represents a physiological interface at which multiple mechanisms of cognitive impairment interact, as acute blood-brain barrier weakening from mechanical ventilation and systemic inflammation can compound existing chronic blood-brain barrier dysfunction from Alzheimer’s-type pathophysiology, rendering the brain vulnerable to both amyloid-beta accumulation and cytokine-mediated hippocampal damage. Although some contributory elements, such as the presenting brain injury or pre-existing cognitive impairment, may be irreversible, interventions such as minimizing mechanical ventilation tidal volume, minimizing duration of exposure to sedating medications, maintaining hemodynamic stability, optimizing fluid balance, and implementing bundles to enhance patient care help dramatically to reduce duration of delirium and may help prevent acquisition of long-term cognitive impairment.
Population-specific factors associated with fractional excretion of uric acid
Authors: Narang Ravi K. , Vincent Zoe , Phipps-Green Amanda , Stamp Lisa K. , Merriman Tony R. , Dalbeth Nicola
Published: November 2019

Background

Reduced renal clearance of uric acid is a major contributor to hyperuricemia. The aim of this study was to examine clinical and genetic variables associated with fractional excretion of uric acid (FEUA).

Methods

Participants (with and without gout) in the Genetics of Gout in Aotearoa study with available genotyping and FEUA data were included (n = 1713). Ten FEUA-associated loci detected within a genome-wide association study for serum urate in a European population were analysed. A polygenic score for FEUA was calculated in each ancestry group to model the cumulative effects of the genetic variants on FEUA. Associations between FEUA and both clinical variables and polygenic score were tested using linear regression models.

Results

The mean (SD) FEUA was 5.13 (2.70) % in Eastern Polynesian participants, 4.70 (5.89) % in Western Polynesian participants, and 5.89 (2.73) % in New Zealand European participants. Although association with FEUA was observed for SLC2A9 rs11942223 in New Zealand European participants (P = 2.39 × 10− 8), this association was not observed in Eastern or Western Polynesian participants. The polygenic score was positively associated with FEUA in all ancestry groups. In New Zealand European participants, body mass index, diuretic use, polygenic score, and male sex were associated with FEUA and explained 22% of FEUA variance in the regression model. In Eastern and Western Polynesian participants, the tested variables explained 10% and 4% of FEUA variance respectively.

Conclusions

Both clinical and genetic variables contribute to renal clearance of uric acid. SLC2A9 exerts effects on FEUA variance in people of European ancestry, but not in those of Polynesian ancestry. There is a large unexplained variance in FEUA, particularly in people of Polynesian ancestry.
Live and let die: epigenetic modifications of Survivin and Regucalcin in non-small cell lung cancer tissues contribute to malignancy
Authors: Nitschkowski Dörte , Marwitz Sebastian , Kotanidou Sousana A. , Reck Martin , Kugler Christian , Rabe Klaus F. , Ammerpohl Ole , Goldmann Torsten
Published: November 2019

Recently, it was shown that the epigenetic age of non-small cell lung cancer (NSCLC) tissues is different from the chronological age of patients. Here, we demonstrate that Regucalcin and Survivin, molecules which are known to be involved in the process of aging and overcoming aging, are epigenetically modified in NSCLC tissues compared to corresponding tumor-free tissues from the same donors by using methylome bead chip and corresponding transcriptome analyses. A high expression of Survivin on the RNA level was negatively correlated with patients’ survival in adenocarcinomas while a high Regucalcin expression was correlated positively. In stage 1 adenocarcinomas, this separation is even sharper for both genes. Within these, adenocarcinomas, smokers with low expression of Survivin show a better outcome, while the high expression of Regucalcin seems to be protective in never smokers. On the protein level, these molecules were detected by immunohistochemistry using tissue microarrays. Since Survivin can be secreted and we observed a high abundance of the protein also in the adjacent immune cells of the tumor microenvironment, an effect on benign cells can be assumed. These findings show that epigenetic re-programming of Survivin and Regucalcin in non-small cell lung cancer leads to enhanced expression of Survivin and reduced expression of Regucalcin, with a possible role of both molecules as predictive markers.
Review of the Manitoba cohort of patients with hereditary angioedema with normal C1 inhibitor
Authors: McKibbin Lundy , Barber Colin , Kalicinsky Chrystyna , Warrington Richard
Published: November 2019

Background

Hereditary angioedema with normal C1 inhibitor (HAE-nC1 INH) is a rare, underappreciated condition characterized by recurrent subcutaneous angioedema. The underlying pathophysiology and diagnostic criteria continues to evolve. There is a significant overlap between HAE-nC1 INH and idiopathic nonhistaminergic angioedema, ultimately this may be found to be the same condition. Characterization of cohorts suspected to have either of these conditions is warranted to help refine diagnosis, pathophysiology, and treatment response.

Methods

A retrospective chart review of 418 patients diagnosed with angioedema was conducted. The following inclusion criteria was used: lack of response to antihistamines, steroids, and epinephrine; normal C4, C1 inhibitor (C1 INH) level and function; lack of urticaria or pruritus; occurrence without offending drugs; and positive family history. Enzyme immunoassays for C1 INH function were performed at the Mayo Clinic. Charts meeting these criteria were reviewed for frequency and type of episodes as well as use and response to therapies.

Results

6 patients met the above criteria. 3 of these completed genetic testing, none were found to have factor XII abnormalities. None had angiopoietin 1 or plasminogen gene sequencing. 5 of 6 patients were successfully treated with C1 INH or tranexamic acid for acute treatment of attacks (4 with C1 INH and 1 with tranexamic acid). 4 patients have used Icatibant with good response (typically under 40 min for near full recovery); of these, 3 required Icatibant as acute treatment after other therapies (C1 inhibitor and tranexamic acid) were ineffective. There were 9 patients who otherwise met criteria, but due to a lack of family history were classified as having idiopathic non-histaminergic angioedema.

Conclusions

This retrospective chart review found 6 HAE-nC1 INH patients in Manitoba. 1 responded to tranexamic acid and not C1 INH, 4 typically responded to C1 INH, and 1 responded exclusively to Icatibant. All patients—4 total—who used Icatibant responded; of these 4 patients, 3 required Icatibant after other therapies had failed.
Dataset’s chemical diversity limits the generalizability of machine learning predictions
Authors: Glavatskikh Marta , Leguy Jules , Hunault Gilles , Cauchy Thomas , Da Mota Benoit
Published: November 2019

The QM9 dataset has become the golden standard for Machine Learning (ML) predictions of various chemical properties. QM9 is based on the GDB, which is a combinatorial exploration of the chemical space. ML molecular predictions have been recently published with an accuracy on par with Density Functional Theory calculations. Such ML models need to be tested and generalized on real data. PC9, a new QM9 equivalent dataset (only H, C, N, O and F and up to 9 “heavy” atoms) of the PubChemQC project is presented in this article. A statistical study of bonding distances and chemical functions shows that this new dataset encompasses more chemical diversity. Kernel Ridge Regression, Elastic Net and the Neural Network model provided by SchNet have been used on both datasets. The overall accuracy in energy prediction is higher for the QM9 subset. However, a model trained on PC9 shows a stronger ability to predict energies of the other dataset.
Multi-task learning with a natural metric for quantitative structure activity relationship learning
Authors: Sadawi Noureddin , Olier Ivan , Vanschoren Joaquin , van Rijn Jan N. , Besnard Jeremy , Bickerton Richard , Grosan Crina , Soldatova Larisa , King Ross D.
Published: November 2019

The goal of quantitative structure activity relationship (QSAR) learning is to learn a function that, given the structure of a small molecule (a potential drug), outputs the predicted activity of the compound. We employed multi-task learning (MTL) to exploit commonalities in drug targets and assays. We used datasets containing curated records about the activity of specific compounds on drug targets provided by ChEMBL. Totally, 1091 assays have been analysed. As a baseline, a single task learning approach that trains random forest to predict drug activity for each drug target individually was considered. We then carried out feature-based and instance-based MTL to predict drug activities. We introduced a natural metric of evolutionary distance between drug targets as a measure of tasks relatedness. Instance-based MTL significantly outperformed both, feature-based MTL and the base learner, on 741 drug targets out of 1091. Feature-based MTL won on 179 occasions and the base learner performed best on 171 drug targets. We conclude that MTL QSAR is improved by incorporating the evolutionary distance between targets. These results indicate that QSAR learning can be performed effectively, even if little data is available for specific drug targets, by leveraging what is known about similar drug targets.
“Death is inevitable – a bad death is not” report from an international workshop
Authors: Shaulov Adir , Baddarni Kassim , Cherny Nathan , Shaham Dorith , Shvartzman Pesach , Tellem Rotem , Clarfield A. Mark
Published: November 2019

Palliative care is an approach meant to improve the quality of life of patients facing life-threatening illness and to support their families. An international workshop on palliative care took place in Caesarea, Israel under the auspices of the National Institute for Health Policy Research on July 4-5th, 2018, with the goal of discussing challenges to the development and integration of palliative care services in Israel. At the workshop, both national and international figures in the field of palliative care and health policy addressed several issues, including truth telling, religious approaches to end of life care, palliative care in the community, pediatric palliative care, Israel’s Dying Patient Act, the Ministry of Health’s National Plan for palliative care, and challenges in using advance directives. We summarize the topics addressed, challenges highlighted, and directions for further advancement of palliative care in the future, emphasizing the critical role of the Ministry of Health in providing a framework for development of palliative care.
Noise-tolerant continuous-time Zhang neural networks for time-varying Sylvester tensor equations
Authors: Min Sun , Jing Liu
Published: November 2019

In this paper, to solve the time-varying Sylvester tensor equations (TVSTEs) with noise, we will design three noise-tolerant continuous-time Zhang neural networks (NTCTZNNs), termed NTCTZNN1, NTCTZNN2, NTCTZNN3, respectively. The most important characteristic of these neural networks is that they make full use of the time-derivative information of the TVSTEs’ coefficients. Theoretical analyses show that no matter how large the unknown noise is, the residual error generated by NTCTZNN2 converges globally to zero. Meanwhile, as long as the design parameter is large enough, the residual errors generated by NTCTZNN1 and NTCTZNN3 can be arbitrarily small. For comparison, the gradient-based neural network (GNN) is also presented and analyzed to solve TVSTEs. Numerical examples and results demonstrate the efficacy and superiority of the proposed neural networks.
Staff perceptions of prescription and over-the-counter drug dependence services in England: a qualitative study
Authors: Coombes Heidi , Cooper Richard J.
Published: November 2019

Background

Dependence to prescription and over-the-counter (OTC) drugs represents an increasing public health and clinical problem both in England and internationally. However, relatively little is known about those affected, particularly in relation to their management at drug dependence treatment centres. This study aimed to explore the views and experiences of health care professionals (HCPs) working in formal drug treatment services in relation to supporting clients with prescription and OTC drug dependence.

Methods

An exploratory, qualitative design was used involving semi-structured telephone interviews. 15 staff were recruited using purposive sampling to represent a variety of different professional roles, funding (NHS, charity and local government) and geographical locations across England. Transcribed interviews were analysed using Braun and Clarke’s six stage thematic analysis.

Results

Current services were considered to be inappropriate for the treatment of OTC and prescription drug dependence, which was perceived to be a significantly under-recognised issue affecting a range of individuals but particularly those taking opioid analgesics. Negativity around current treatment services involved concerns that these were more suited for illicit drug users and this was exacerbated by a lack of specific resources, funding and commissioning. There was a perceived variation in service provision in different areas and a further concern about the lack of formal treatment guidelines and care pathways. Participants felt there to be stigma for affected clients in both the diagnosis of OTC or prescription drug dependence and also attendance at drug treatment centres which adversely impacted service engagement. Suggested service improvements included commissioning new specific services in general practices and pain management clinics, developing national guidelines and care pathways to ensure equal access to treatment and increasing awareness amongst the public and HCPs.

Conclusions

This study reveals considerable negativity and concern about current treatment services for prescription and OTC drug dependence in England from the perspective of those working in such services. Policy and practice improvement are suggested to improve outcomes for this neglected group in relation to increasing funding, guidelines and awareness.
CT lymphography for sentinel lymph node mapping of clinically N0 early oral cancer
Authors: Sugiyama Satomi , Iwai Toshinori , Izumi Toshiharu , Ishiguro Keita , Baba Junichi , Oguri Senri , Mitsudo Kenji
Published: November 2019

Background

The objectives of this retrospective study were to evaluate the usefulness of computed tomography lymphography (CTL) and to clarify the optimal timing of CTL in sentinel lymph node (SLN) mapping of clinically N0 early oral cancer.

Methods

Twenty patients with clinically N0 early oral cancer underwent CTL with a 128 multi-detector row CT scanner to detect SLN the day before resection of primary tumor and SLN biopsy with indocyanine green (ICG) fluorescence guidance. CT scanning was performed in the first 10 patients at 2, 5, and 10 min after submucosal injection of iopamidol and in the remaining 10 patients at 2, 3.5, 5, and 10 min after the injection of contrast medium. We evaluated the SLN detection rate at each scan timing and the number and location of SLNs. We evaluated whether CTL-enhanced SLNs could be identified intraoperatively as ICG fluorescent lymph nodes.

Results

SLNs were detected by CTL in 19 of the 20 patients (95.0%), and the mean number of SLNs was 2 (range, 1–4). All SLNs were located on the ipsilateral side; 35 of 37 SLNs were located at level I and II, and 2 SLNs were lingual lymph nodes. All SLNs could be detected 2 min and 3.5–5 min after contrast medium injection, and CTL-enhanced SLNs could be identified intraoperatively as fluorescent lymph nodes.

Conclusions

CTL could facilitate the detection of SLNs in early oral cancer, and the optimal timing of CT scanning was at 2 and 5 min after injection of contrast medium.
Vaginal cuff dehiscence following controlled ovarian stimulation recognized during egg retrieval
Authors: Peyser Alexandra , Hershlag Avner , Sakaris Antoinette , Singer Tomer
Published: November 2019

Background

Vaginal cuff dehiscence is a rare complication of hysterectomy. Those who choose to undergo controlled ovarian stimulation (COS) and oocyte cryopreservation following hysterectomy must be aware that elevated abdominal pressure from stimulation as well as transvaginal ultrasound use during monitoring may increase the risk of cuff dehiscence.

Case

We present a case of a 25-year-old patient who had undergone a hysterectomy four months prior for endometrial cancer who was found to have vaginal cuff dehiscence which was recognized at the time of egg retrieval after COS. Prompt recognition and appropriate management led to successful treatment.

Conclusion

Patients presenting for oocyte cryopreservation following hysterectomy are at risk for cuff dehiscence. Providers should allow ample time for proper cuff healing prior to COS and oocyte cryopreservation.
Pathological complete response after afatinib treatment of stage IV oligometastatic adenocarcinoma of the lung: the role of pulmonary surgery
Authors: Tsai Ping-Chung , Yeh Yi-Chen , Huang Chien-Sheng , Chiu Chao-Hua
Published: November 2019

Background

Some oligometastatic lung cancer patients, after induction systemic chemotherapy or tyrosine kinases inhibitor treatment, followed by aggressive radical consolidative treatment, have improved overall survival. Unfortunately, clinical criteria cannot assess such patients.

Case presentation

We hereby reported the case of a 55-year-old female with lower back pain and bilateral lower leg numbness for months and who had an osteolytic bone lesion over the third lumbar vertebra. In February 2017, a third lumbar vertebra biopsy showed metastatic adenocarcinoma, compatible with lung origin (thyroid transcription factor-1 positive [TTF-1], L858R mutation positive). Complete imaging of the right lower lobe (RLL) showed a spiculated mass of about 3.4 × 2.2 cm, and a trans-bronchoscopic lung biopsy revealed non-small cell carcinoma of lung origin (positive for TTF-1 and negative for p40). Tentative diagnosis was RLL adenocarcinoma, cT2aN0M1b, with bone metastasis at L3. The epidermal growth factor receptor-tyrosine kinase inhibitor afatinib was prescribed beginning April 2017. A November 2018 follow-up CT scan showed regression in the RLL lung mass. A whole-body positron emission tomography-computed tomography showed RLL lung nodule with faint uptake and mildly increased uptake in the L3 vertebra. After providing informed consent, the patient received uniportal video-assisted thoracoscopic RLL lobectomy and radical mediastinal lymph node dissection on December 25, 2018. The final pathology report was fibrotic scar with no residual tumor cells, compatible with post-treatment status, ypT0N0. Curative intent radiotherapy was also applied to the L3 vertebra after the operation. The patient is still alive for more than 32 months after initially diagnosed with metastatic lung adenocarcinoma.

Conclusions

Our case provides additional data to support that tissue assessment through primary lung tumor resection after systemic treatment of oligometastic lung cancer by minimally invasive surgery can reveal the treatment effect and potentially provide a surrogate endpoint in further clinical trials.
Therapist perceptions of a rehabilitation research study in the intensive care unit: a trinational survey assessing barriers and facilitators to implementing the CYCLE pilot randomized clinical trial
Authors: Reid Julie C. , McCaskell Devin S. , Kho Michelle E.
Published: November 2019

Background

Rehabilitation interventions, including novel technologies such as in-bed cycling, could reduce critical illness-associated morbidity. Frontline intensive care unit (ICU) therapists often implement these interventions; however, little is known about their perceptions of engaging in clinical research evaluating these technologies.

Objective

To understand frontline therapist perceptions of barriers and facilitators to implementing a pilot randomized controlled trial (RCT) of early in-bed cycling with mechanically ventilated patients in the ICU and outcome measures (CYCLE Pilot RCT; NCT02377830).

Methods

We developed a 115-item, self-administered, electronic survey informed by 2 complementary knowledge translation (KT) models: the Capability-Opportunity-Motivation-Behaviour (COM-B) system and the Theoretical Domains Framework (TDF). We included demographics and 3 sections: Rehabilitation Practice and Research, Cycling, and Physical Outcome Measures. Each section contained items related to the COM-B system and TDF domains. Item formats included 7-point Likert-type scale questions (1 = strongly disagree, 7 = strongly agree) and free-text responses. We invited therapists (physiotherapists, occupational therapists, and therapy assistants) who participated in the international, multi-center, CYCLE Pilot RCT to complete this cross-sectional survey. We descriptively analyzed results by survey section, COM-B attribute, TDF domain, and individual question within and across sections. We identified barriers based on items with median scores < 4/7.

Results

Our response rate was 85% (45/53). Respondents were from Canada (67%), the USA (21%), and Australia (11%). The majority had a physiotherapy background (87%) and previous research experience (87%). By section, Rehabilitation Practice and Research (85%; 95% confidence interval (CI) [82%, 87%]) was higher than Cycling (77%; 95% CI [73%, 80%]) and Outcome Measures (78%; 95% CI [75%, 82%]). Across the 3 sections, Motivation was lower than Capability and Opportunity. The most common Motivation barrier was the emotion TDF domain, related to the time required to conduct cycling and outcome measures (median [1st, 3rd quartiles] 3/7 [2, 6]).

Conclusions

Frontline ICU therapists had positive perceptions of research engagement. However, we identified barriers related to Motivation, and concerns regarding time to implement the research protocol. Our results can inform specific KT strategies to engage frontline ICU therapists and optimize protocol implementation in critical care rehabilitation research.
Supervised and home-based physical exercise in patients newly diagnosed with multiple myeloma—a randomized controlled feasibility study
Authors: Larsen Rikke Faebo , Jarden Mary , Minet Lisbeth Rosenbek , Frølund Ulf Christian , Abildgaard Niels
Published: November 2019

Background

The study evaluated the feasibility and safety of the exercise intervention and physical test procedures of our ongoing randomized controlled trial, examining the effect of physical exercise in newly diagnosed patients with multiple myeloma.

Methods

Patients are randomized 1:1 to a control group (usual care) or an intervention group (usual care and exercise) by block randomization with stratification of planned treatment, WHO performance status, and study site. The exercise intervention consists of eight supervised exercise sessions combined with home-based exercise over a 10-week period. Bone disease is systematically evaluated to determine limitations regarding physical testing and/or exercise. Feasibility outcome measures were study eligibility, acceptance, and attrition, and furthermore attendance, adherence, tolerability, and safety to the exercise intervention. Additionally, test completion, pain, and adverse events during the physical test procedures were evaluated. Outcome assessors were blinded to allocation.

Results

Of 49 patients screened, 30 were included. The median age was 69 years, range 38–90, 77% were males, and 67% had bone disease. Study eligibility was 82%, acceptance 75%, and attrition 20%. Attendance at supervised exercise sessions was 92%, and adherence to supervised exercise sessions and home-based exercise sessions was 99% and 89%, respectively. No serious adverse events attributed to exercise or physical tests were reported. All patients completed the physical tests, except for two patients, where physical test procedures were modified due to bone disease.

Discussion

The exercise intervention and physical test procedures were feasible and safe in patients with multiple myeloma, even in older patients with multiple myeloma and in patients with myeloma bone disease.

Trial registration

ClinicalTrials.gov. ID NCT02439112. Registered on May 7, 2015.