bluuebunny/crossref_metadata_2025 huggingface dataset:
Management of paroxysmal atrial flutter that occurred in an outpatient prior to dental surgery: a case report
Authors: Shimoda Hajime , Takahashi Tetsu
Published: December 2019

Background

It is essential to accomplish the appropriate emergency care particularly in patients undergoing stressful dento-oral surgical procedures. Atrial flutter may be induced by sympathetic hypertonia due to excessive mental and physical stress. There is no report regarding dental care in patients with atrial flutter. Herein, we describe a rare case of the antiarrhythmic management in an outpatient who presented with an electrocardiographic finding of paroxysmal atrial flutter before the initiation of the dento-oral surgical procedure.

Case presentation

A 60-year-old male patient was scheduled for a dental extraction. He had a history of angina pectoris, diabetes mellitus, and paroxysmal atrial fibrillation with medication. The preoperative electrocardiogram (ECG) revealed left ventricular hypertrophy and ST-T segment abnormality. Immediately before the dental extraction, II-lead ECG revealed atrial flutter; however, he complained of few subjective symptoms, such as precordial discomfort or palpitation. Observing the vital signs, ECG findings, and the general condition of the patient, low dose diltiazem was immediately administered by continuous infusion in order to control the heart rate and prevent atrial flutter-induced supraventricular tachyarrhythmia. Special attention was paid to prevent any critical cardiovascular condition under a preparation of intravenous disopyramide and verapamil and a defibrillator. The intravenous administration of diltiazem progressively restored the sinus rhythm after converting atrial flutter into atrial fibrillation, resulting in the prevention of tachycardia, and then was found to be appropriate as a prophylactic therapy of tachyarrhythmia.

Conclusions

The present case suggests that it is possible to successfully manage some of such patients using our method during dento-oral surgery which is likely to be associated with mental and physical stress. Therefore, it is essential to accomplish an initial emergency care in parallel to the differential diagnosis of unforeseen serious medical conditions or paroxysmal arrhythmia such as atrial flutter.
Risk factors, costs and complications of delayed hospital discharge from internal medicine wards at a Canadian academic medical centre: retrospective cohort study
Authors: Bai Anthony D. , Dai Cathy , Srivastava Siddhartha , Smith Christopher A. , Gill Sudeep S.
Published: December 2019

Background

Hospitalized patients are designated alternate level of care (ALC) when they no longer require hospitalization but discharge is delayed while they await alternate disposition or living arrangements. We assessed hospital costs and complications for general internal medicine (GIM) inpatients who had delayed discharge. In addition, we developed a clinical prediction rule to identify patients at risk for delayed discharge.

Methods

We conducted a retrospective cohort study of consecutive GIM patients admitted between 1 January 2015 and 1 January 2016 at a large tertiary care hospital in Canada. We compared hospital costs and complications between ALC and non-ALC patients. We derived a clinical prediction rule for ALC designation using a logistic regression model and validated its diagnostic properties.

Results

Of 4311 GIM admissions, 255 (6%) patients were designated ALC. Compared to non-ALC patients, ALC patients had longer median length of stay (30.85 vs. 3.95 days p < 0.0001), higher median hospital costs ($22,459 vs. $5003 p < 0.0001) and more complications in hospital (25.5% vs. 5.3% p < 0.0001) especially nosocomial infections (14.1% vs. 1.9% p < 0.0001). Sensitivity analyses using propensity score and pair matching yielded similar results. In a derivation cohort, seven significant risk factors for ALC were identified including age > =80 years, female sex, dementia, diabetes with complications as well as referrals to physiotherapy, occupational therapy and speech language pathology. A clinical prediction rule that assigned each of these predictors 1 point had likelihood ratios for ALC designation of 0.07, 0.25, 0.66, 1.48, 6.07, 17.13 and 21.85 for patients with 0, 1, 2, 3, 4, 5, and 6 points respectively in the validation cohort.

Conclusions

Delayed discharge is associated with higher hospital costs and complication rates especially nosocomial infections. A clinical prediction rule can identify patients at risk for delayed discharge.
Causal association of type 2 diabetes with amyotrophic lateral sclerosis: new evidence from Mendelian randomization using GWAS summary statistics
Authors: Zeng Ping , Wang Ting , Zheng Junnian , Zhou Xiang
Published: December 2019

Background

Associations between type 2 diabetes (T2D) and amyotrophic lateral sclerosis (ALS) were discovered in observational studies in both European and East Asian populations. However, whether such associations are causal remains largely unknown.

Methods

We employed a two-sample Mendelian randomization approach to evaluate the causal relationship of T2D with the risk of ALS in both European and East Asian populations. Our analysis was implemented using summary statistics obtained from large-scale genome-wide association studies with ~660,000 individuals for T2D and ~81,000 individuals for ALS in the European population, and ~191,000 individuals for T2D and ~4100 individuals for ALS in the East Asian population. The causal relationship between T2D and ALS in both populations was estimated using the inverse-variance-weighted methods and was further validated through extensive complementary and sensitivity analyses.

Results

Using multiple instruments that were strongly associated with T2D, a negative association between T2D and ALS was identified in the European population with the odds ratio (OR) estimated to be 0.93 (95% CI 0.88–0.99, p = 0.023), while a positive association between T2D and ALS was observed in the East Asian population with OR = 1.28 (95% CI 0.99–1.62, p = 0.058). These results were robust against instrument selection, various modeling misspecifications, and estimation biases, with the Egger regression and MR-PRESSO ruling out the possibility of horizontal pleiotropic effects of instruments. However, no causal association was found between T2D-related exposures (including glycemic traits) and ALS in the European population.

Conclusion

Our results provide new evidence supporting the causal neuroprotective role of T2D on ALS in the European population and provide empirically suggestive evidence of increasing risk of T2D on ALS in the East Asian population. Our results have an important implication on ALS pathology, paving ways for developing therapeutic strategies across multiple populations.
Reverse zoonotic tuberculosis transmission from an emerging Uganda I strain between pastoralists and cattle in South-Eastern Nigeria
Authors: Adesokan Hezekiah Kehinde , Akinseye Victor Oluwatoyin , Streicher Elizabeth Maria , Van Helden Paul , Warren Rob Mark , Cadmus Simeon Idowu
Published: December 2019

Background

Tuberculosis remains a major public health challenge globally with increasing risks for inter-transmission between pastoralists and cattle in Nigeria. This study was aimed at using molecular tools to establish zoonotic transmission of tuberculosis between pastoralists and their cattle in Ebonyi State, Nigeria. Sputum (n = 149) and milk (n = 144) samples from pastoralists and cattle, respectively were screened on the assumption of subclinical infections considering unguarded human-livestock interactions. Isolates obtained were analysed using deletion typing, spoligotyping and 24-Mycobacterial Interspersed Repetitive Unit-Variable Number Tandem Repeats (MIRU-VNTR).

Results

Fifty-four MTC were confirmed by deletion typing and were differentiated accordingly (M. tuberculosis: pastoralists =42, cattle = 2; M. bovis: pastoralists =1; M. africanum: pastoralists =9). Spoligotyping indicated 59.2% Uganda I/SIT46 (pastoralists =28; cattle = 1), 16.3% Latin American Mediterranean/SIT61 (pastoralists =8), 2.0% T/SIT53 (pastoralists =1) strains of M. tuberculosis and new strains of M. bovis and M. africanum. The 24-MIRU-VNTR of selected predominant cluster isolates shared by cattle and pastoralists (Uganda I/SIT46: pastoralists =9; cattle = 1) showed the same number of copies at each of the repetitive loci.

Conclusions

Mycobacterium bovis was confirmed in humans and a reverse zoonotic tuberculosis transmission from an emerging Uganda I M. tuberculosis strain between pastoralists and cattle in Nigeria evidenced by MIRU-VNTR. Using molecular tools will help mitigate disease burden through informed epidemiological insights.
Impaired training-induced angiogenesis process with loss of pericyte-endothelium interactions is associated with an abnormal capillary remodelling in the skeletal muscle of COPD patients
Authors: Blervaque Léo , Passerieux Emilie , Pomiès Pascal , Catteau Matthias , Héraud Nelly , Blaquière Marine , Bughin François , Ayoub Bronia , Molinari Nicolas , Cristol Jean-Paul , Perez-Martin Antonia , Mercier Jacques , Hayot Maurice , Gouzi Fares
Published: December 2019

Chronic obstructive pulmonary disease (COPD) is associated with exercise intolerance and limits the functional gains in response to exercise training in patients compared to sedentary healthy subjects (SHS). The blunted skeletal muscle angiogenesis previously observed in COPD patients has been linked to these limited functional improvements, but its underlying mechanisms, as well as the potential role of oxidative stress, remain poorly understood. Therefore, we compared ultrastructural indexes of angiogenic process and capillary remodelling by transmission electron microscopy in 9 COPD patients and 7 SHS after 6 weeks of individualized moderate-intensity endurance training. We also assessed oxidative stress by plasma-free and esterified isoprostane (F2-IsoP) levels in both groups. We observed a capillary basement membrane thickening in COPD patients only (p = 0.008) and abnormal variations of endothelial nucleus density in response to exercise training in these patients when compared to SHS (p = 0.042). COPD patients had significantly fewer occurrences of pericyte/endothelium interdigitations, a morphologic marker of capillary maturation, than SHS (p = 0.014), and significantly higher levels of F2-IsoP (p = 0.048). Last, the changes in pericyte/endothelium interdigitations and F2-IsoP levels in response to exercise training were negatively correlated (r = − 0.62, p = 0.025). This study is the first to show abnormal capillary remodelling and to reveal impairments during the whole process of angiogenesis (capillary creation and maturation) in COPD patients.

Trial registration

NCT01183039 & NCT01183052, both registered 7 August 2010 (retrospectively registered).
Hepatitis C drug prescriptions and Medicaid policies--four states, Indian health care system, USA 2018
Authors: Reilley Brigg , Miller Matt , Hudson Matt , Haverkate Rick , Leston Jessica
Published: December 2019

Medicaid, the state-level public insurance in the United States, has widely differing criteria treatment for hepatitis C virus (HCV) such as stage of liver fibrosis, documented sobriety, and specialist consultation. In a rural health network, facilities located in two less restrictive states prescribed HCV drugs at a significantly higher rate than two more restrictive states (rate ratio 4.7, CI 2.6–8.5). Prescription rates per population were highly associated with HCV treatment policies.
Triglyceride to high-density lipoprotein cholesterol ratio as a predictor of long-term mortality in patients with coronary artery disease after undergoing percutaneous coronary intervention: a retrospective cohort study
Authors: Dai Xin-Ya , Zheng Ying-Ying , Tang Jun-Nan , Yang Xu-Ming , Guo Qian-Qian , Zhang Jian-Chao , Cheng Meng-Die , Song Feng-Hua , Liu Zhi-Yu , Wang Kai , Jiang Li-Zhu , Fan Lei , Yue Xiao-Ting , Bai Yan , Zhang Zeng-Lei , Zheng Ru-Jie , Zhang Jin-Ying
Published: December 2019

Background

It has been confirmed that the triglyceride to high-density lipoprotein cholesterol ratio (THR) is associated with insulin resistance and metabolic syndrome. However, to the best of our knowledge, only a few studies with small sample sizes have investigated the relationship between THR and coronary artery disease (CAD). Therefore, we aimed to assess the correlation between the THR and long-term mortality in patients with CAD after undergoing percutaneous coronary intervention (PCI) in our study that enrolled a large number of patients.

Methods

A total of 3269 post-PCI patients with CAD were enrolled in the CORFCHD-ZZ study from January 2013 to December 2017. The mean follow-up time was 37.59 ± 22.24 months. Patients were divided into two groups according to their THR value: the lower group (THR < 2.84, n = 1232) and the higher group (THR ≥ 2.84, n = 2037). The primary endpoint was long-term mortality, including all-cause mortality (ACM) and cardiac mortality (CM). The secondary endpoints were major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs).

Results

In our study, ACM occurred in 124 patients: 30 (2.4%) in the lower group and 94 (4.6%) in the higher group (P = 0.002). MACEs occurred in 362 patients: 111 (9.0%) in the lower group and 251 (12.3%) in the higher group (P = 0.003). The number of MACCEs was 482: 152 (12.3%) in the lower group and 320 (15.7%) in the higher group (P = 0.008). Heart failure occurred in 514 patients: 89 (7.2%) in the lower group and 425 (20.9%) in the higher group (P < 0.001). Kaplan–Meier analyses showed that elevated THR was significantly related to long-term ACM (log-rank, P = 0.044) and the occurrence of heart failure (log-rank, P < 0.001). Multivariate Cox regression analyses showed that the THR was an independent predictor of long-term ACM (adjusted HR = 2.042 [1.264–3.300], P = 0.004) and heart failure (adjusted HR = 1.700 [1.347–2.147], P < 0.001).

Conclusions

An increased THR is an independent predictor of long-term ACM and heart failure in post-PCI patients with CAD.
Isolation of microglia-derived extracellular vesicles: towards miRNA signatures and neuroprotection
Authors: Lemaire Quentin , Raffo-Romero Antonella , Arab Tanina , Van Camp Christelle , Drago Francesco , Forte Stefano , Gimeno Jean-Pascal , Begard Séverine , Colin Morvane , Vizioli Jacopo , Sautière Pierre-Eric , Salzet Michel , Lefebvre Christophe
Published: December 2019

The functional preservation of the central nervous system (CNS) is based on the neuronal plasticity and survival. In this context, the neuroinflammatory state plays a key role and involves the microglial cells, the CNS-resident macrophages. In order to better understand the microglial contribution to the neuroprotection, microglia-derived extracellular vesicles (EVs) were isolated and molecularly characterized to be then studied in neurite outgrowth assays. The EVs, mainly composed of exosomes and microparticles, are an important cell-to-cell communication process as they exhibit different types of mediators (proteins, lipids, nucleic acids) to recipient cells. The medicinal leech CNS was initially used as an interesting model of microglia/neuron crosstalk due to their easy collection for primary cultures. After the microglia-derived EV isolation following successive methods, we developed their large-scale and non-targeted proteomic analysis to (i) detect as many EV protein markers as possible, (ii) better understand the biologically active proteins in EVs and (iii) evaluate the resulting protein signatures in EV-activated neurons. The EV functional properties were also evaluated in neurite outgrowth assays on rat primary neurons and the RNAseq analysis of the microglia-derived EVs was performed to propose the most representative miRNAs in microglia-derived EVs. This strategy allowed validating the EV isolation, identify major biological pathways in EVs and corroborate the regenerative process in EV-activated neurons. In parallel, six different miRNAs were originally identified in microglia-derived EVs including 3 which were only known in plants until now. The analysis of the neuronal proteins under the microglial EV activation suggested possible miRNA-dependent regulation mechanisms. Taken together, this combination of methodologies showed the leech microglial EVs as neuroprotective cargos across species and contributed to propose original EV-associated miRNAs whose functions will have to be evaluated in the EV-dependent dialog between microglia and neurons.
Network topology dynamics of circulating biomarkers and cognitive performance in older Cytomegalovirus-seropositive or -seronegative men and women
Authors: Di Benedetto Svetlana , Müller Ludmila , Rauskolb Stefanie , Sendtner Michael , Deutschbein Timo , Pawelec Graham , Müller Viktor
Published: December 2019

Background

Cytokines are signaling molecules operating within complex cascade patterns and having exceptional modulatory functions. They impact various physiological processes such as neuroendocrine and metabolic interactions, neurotrophins’ metabolism, neuroplasticity, and may affect behavior and cognition. In our previous study, we found that sex and Cytomegalovirus (CMV)-serostatus may modulate levels of circulating pro- and anti-inflammatory cytokines, metabolic factors, immune cells, and cognitive performance, as well as associations between them.

Results

In the present study, we used a graph-theoretical approach to investigate the network topology dynamics of 22 circulating biomarkers and 11 measures of cognitive performance in 161 older participants recruited to undergo a six-months training intervention. For network construction, we applied coefficient of determination (R2)that was calculated for all possible pairs of variables (N = 33) in four groups (CMV−men and women; CMV+men and women). Network topology has been evaluated by clustering coefficient (CC) and characteristic path length (CPL) as well as local (Elocal) and global (Eglobal) efficiency, showing the degree of network segregation (CCandElocal) and integration (CPLandEglobal). We found that networks under consideration showed small-world networks properties with more random characteristics. MeanCC,as well as local and global efficiency were highest andCPLshortest in CMV−males (having lowest inflammatory status and highest cognitive performance). CMV−and CMV+females did not show any significant differences. Modularity analyses showed that the networks exhibit in all cases highly differentiated modular organization (withQ-value ranged between 0.397 and 0.453).

Conclusions

In this work, we found that segregation and integration properties of the network were notably stronger in the group with balanced inflammatory status. We were also able to confirm our previous findings that CMV-infection and sex modulate multiple circulating biomarkers and cognitive performance and that balanced inflammatory and metabolic status in elderly contributes to better cognitive functioning. Thus, network analyses provide a useful strategy for visualization and quantitative description of multiple interactions between various circulating pro- and anti-inflammatory biomarkers, hormones, neurotrophic and metabolic factors, immune cells, and measures of cognitive performance and can be in general applied for analyzing interactions between different physiological systems.
The effect of orthopaedic surgeons’ and interventional radiologists’ availability on the priority treatment sequence for hemodynamically unstable pelvic fractures: a survey of US Level I trauma centers
Authors: Jarvis S. , Orlando A. , Blondeau B. , Banton K. , Reynolds C. , Berg G. M. , Patel N. , Meinig R. , Carrick M. , Bar-Or D.
Published: December 2019

Background

Most guidelines recommend both pelvic packing (PP) and angioembolization for hemodynamically unstable pelvic fractures, however their sequence varies. Some argue to use PP first because orthopaedic surgeons are more available than interventional radiologists; however, there is no data confirming this.

Methods

This cross-sectional survey of 158 trauma medical directors at US Level I trauma centers collected the availability of orthopaedic surgeons and interventional radiologists, the number of orthopaedic trauma surgeons trained to manage pelvic fractures, and priority treatment sequence for hemodynamically unstable pelvic fractures. The study objective was to compare the availability of orthopaedic surgeons to interventional radiologists and describe how the availability of orthopaedic surgeons and interventional radiologists affects the treatment sequence for hemodynamically unstable pelvic fractures. Fisher’s exact, chi-squared, and Kruskal-Wallis tests were used, alpha = 0.05.

Results

The response rate was 25% (40/158). Orthopaedic surgeons (86%) were on-site more often than interventional radiologists (54%), p = 0.003. Orthopaedic surgeons were faster to arrive 39% of the time, and interventional radiologists were faster to arrive 6% of the time. There was a higher proportion of participants who prioritized PP before angioembolization at centers with above the average number (> 3) of orthopaedic trauma surgeons trained to manage pelvic fractures, as among centers with equal to or below average, p = 0.02. Arrival times for orthopaedic surgeons did not significantly predict prioritization of angioembolization or PP.

Conclusions

Our results provide evidence that orthopaedic surgeons typically are more available than interventional radiologists but contrary to anecdotal evidence most participants used angioembolization first. Familiarity with the availability of orthopaedic surgeons and interventional radiologists may contribute to individual trauma center’s treatment sequence.
Cutaneous neurofibromas: patients’ medical burden, current management and therapeutic expectations: results from an online European patient community survey
Authors: Guiraud Marlene , Bouroubi Athmane , Beauchamp Roxane , Bocquet Arnaud , Grégoire Jean-Marc , Rauly-Lestienne Isabelle , Blanco Ignacio , Wolkenstein Pierre , Schmitt Anne-Marie
Published: December 2019

Background

Neurofibromatosis type 1 is an inherited condition with variable phenotypic expression and a high medical and social burden.

The objectives of this patient survey were to better understand the real-world experiences of patients living with cutaneous neurofibromas (cNF), to perceive their satisfaction and feelings about cNF current management (only laser and surgery are currently available), and to highlight their expectations of new therapeutic modalities.

Results

One hundred seventy patients from 4 European countries took part in the study, 65% (n = 110) were women and mean age was 39 years old. 96% (n = 164) of respondents have cNF on visible parts of the body and the survey confirmed that total number of cNF and visibility increase with age.

Patients reported that cNF mainly impacts everyday mood, general daily life and social life. The visibility of cNF had a higher impact than their number.

92% (n = 156) of patients have a regular and multidisciplinary medical follow-up. The dermatologist is one of the most consulted healthcare professionals.

76% (n = 130) of respondents have treated their cNF: 65% (n = 111) had surgery and 38% (n = 64) had multiple laser sessions. Frequency of operations and regrowth of cNF were the two most unsatisfactory aspects with both treatments for patients. Indeed, after removal, new cNF appear in more than 75% (n = 128) of cases.

As a future treatment, patients expected a topical (30%, n = 51) or oral medication (29%, n = 50). Around 2 out of 3 patients would agree to take it at least once a day or more for life but they would like a well-tolerated treatment.

According to patients, the most important effectiveness criteria of a new treatment are to block cNF growth and reduce their number. 70% (n = 119) of patients would consider a future treatment moderately effective to very effective if it could clear 30% of cNF.

Conclusions

This first cNF European patient community survey confirmed that the visible stigma and unaesthetic aspect of cNF have an important impact on patients’ quality of life. The survey highlighted that patients were not entirely satisfied with the actual surgery and laser treatments and revealed their clear and realistic expectations for future treatment of cNF.
Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease
Authors: Jia Lin , Piña-Crespo Juan , Li Yonghe
Published: December 2019

Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling is an essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, Wnt/β-catenin signaling is not only crucial for neuronal survival and neurogenesis, but it plays important roles in regulating synaptic plasticity and blood-brain barrier integrity and function. Moreover, activation of Wnt/β-catenin signaling inhibits amyloid-β production and tau protein hyperphosphorylation in the brain. Critically, Wnt/β-catenin signaling is greatly suppressed in AD brain via multiple pathogenic mechanisms. As such, restoring Wnt/β-catenin signaling represents a unique opportunity for the rational design of novel AD therapies.
RT2 PCR array screening reveals distinct perturbations in DNA damage response signaling in FUS-associated motor neuron disease
Authors: Wang Haibo , Rangaswamy Suganya , Kodavati Manohar , Mitra Joy , Guo Wenting , Guerrero Erika N. , Van Den Bosch Ludo , Hegde Muralidhar L.
Published: December 2019

Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease that has been linked to defective DNA repair. Many familial ALS patients harbor autosomal dominant mutations in the gene encoding the RNA/DNA binding protein ‘fused in sarcoma’ (FUS) commonly inducing its cytoplasmic mislocalization. Recent reports from our group and others demonstrate a role of FUS in maintaining genome integrity and the DNA damage response (DDR). FUS interacts with many DDR proteins and may regulate their recruitment at damage sites. Given the role of FUS in RNA transactions, here we explore whether FUS also regulates the expression of DDR factors. We performed RT2 PCR arrays for DNA repair and DDR signaling pathways in CRISPR/Cas9 FUS knockout (KO) and shRNA mediated FUS knockdown (KD) cells, which revealed significant (> 2-fold) downregulation of BRCA1, DNA ligase 4, MSH complex and RAD23B. Importantly, similar perturbations in these factors were also consistent in motor neurons differentiated from an ALS patient-derived induced pluripotent stem cell (iPSC) line with a FUS-P525L mutation, as well as in postmortem spinal cord tissue of sporadic ALS patients with FUS pathology. BRCA1 depletion has been linked to neuronal DNA double-strand breaks (DSBs) accumulation and cognitive defects. The ubiquitin receptor RAD23 functions both in nucleotide excision repair and proteasomal protein clearance pathway and is thus linked to neurodegeneration. Together, our study suggests that the FUS pathology perturbs DDR signaling via both its direct role and the effect on the expression of DDR genes. This underscors an intricate connections between FUS, genome instability, and neurodegeneration.
LSD1/KDM1A inhibitors in clinical trials: advances and prospects
Authors: Fang Yuan , Liao Guochao , Yu Bin
Published: December 2019

Histone demethylase LSD1 plays key roles during carcinogenesis, targeting LSD1 is becoming an emerging option for the treatment of cancers. Numerous LSD1 inhibitors have been reported to date, some of them such as TCP, ORY-1001, GSK-2879552, IMG-7289, INCB059872, CC-90011, and ORY-2001 currently undergo clinical assessment for cancer therapy, particularly for small lung cancer cells (SCLC) and acute myeloid leukemia (AML). This review is to provide a comprehensive overview of LSD1 inhibitors in clinical trials including molecular mechanistic studies, clinical efficacy, adverse drug reactions, and PD/PK studies and offer prospects in this field.
Clinical correlates of blood-derived circulating tumor DNA in pancreatic cancer
Authors: Patel Hitendra , Okamura Ryosuke , Fanta Paul , Patel Charmi , Lanman Richard B. , Raymond Victoria M. , Kato Shumei , Kurzrock Razelle
Published: December 2019

Background

Treatment outcomes for patients with advanced pancreatic ductal adenocarcinoma (PDAC) remain dismal. There are unmet needs for understanding the biologic basis of this malignancy using novel next-generation sequencing technologies. Herein, we investigated the clinical utility of circulating tumor DNA (ctDNA) (the liquid biopsy) in this malignancy.

Methods

ctDNA was analyzed in 112 patients with PDAC (54–73 genes) and tissue DNA in 66 patients (315 genes) (both clinical-grade next-generation sequencing). Number of alterations, %ctDNA, concordance between ctDNA and tissue DNA, and correlation of ctDNA results with survival were assessed.

Results

The most common genes altered in ctDNA were TP53 (46% of patients, N = 51) and KRAS (44%, N = 49). Median number of characterized ctDNA alterations per patient was 1 (range, 0–6), but patients with advanced PDAC had significantly higher numbers of ctDNA alterations than those with surgically resectable disease (median, 2 versus 0.5, P = 0.04). Overall, 75% (70/94) of advanced tumors had ≥ 1 ctDNA alteration. Concordance rate between ctDNA and tissue DNA alterations was 61% for TP53 and 52% for KRAS. Concordance for KRAS alterations between ctDNA and tissue DNA from metastatic sites was significantly higher than between ctDNA and primary tumor DNA (72% vs 39%, P = 0.01). Importantly, higher levels of total %ctDNA were an independent prognostic factor for worse survival (hazard ratio, 4.35; 95% confidence interval, 1.85–10.24 [multivariate, P = 0.001]). A patient with three ctDNA alterations affecting the MEK pathway (GNAS, KRAS, and NF1) attained a response to trametinib monotherapy ongoing at 6 months.

Conclusions

Our findings showed that ctDNA often harbored unique alterations some of which may be targetable and that significantly greater numbers of ctDNA alterations occur in advanced versus resectable disease. Furthermore, higher ctDNA levels were a poor prognostic factor for survival.
Italian guidelines for the prevention and management of dental trauma in children
Authors: Cagetti Maria Grazia , Marcoli Piero Alessandro , Berengo Mario , Cascone Piero , Cordone Livio , Defabianis Patrizia , De Giglio Osvalda , Esposito Nicola , Federici Antonio , Laino Alberto , Majorana Alessandra , Nardone Michele , Pinchi Vilma , Pizzi Silvia , Polimeni Antonella , Privitera Maria Grazia , Talarico Valentina , Zampogna Stefania
Published: December 2019

Dental trauma is a frequent occurrence in children and adolescent and a correct diagnosis and treatment are essential for a favourable long-term prognosis. The present Guidelines aim to formulate evidence-based recommendations to assist dentists, paediatricians, surgeons, teachers, school and sport staff, parents in the prevention and first aid of dental trauma in children and to provide a careful assessment of the medico-legal implications, reviewing the first draft of the guidelines published in 2012. A multidisciplinary panel on the behalf of the Italian Ministry of Health and in collaboration with the WHO Collaborating Centre for Epidemiology and Community Dentistry of Milan, developed this document. The following four queries were postulated: 1) Which kind of precautions the health personnel, parents, sports and educational personnel must activate in order to prevent the dental trauma damage? 2) How an orofacial trauma in paediatric patients should be managed either in the Emergency Care Unit and/or in private dental office? 3) What criteria should be adopted by a dentist private practitioner to fill in a certificate in cases of dental and/or tempomandibular joint trauma occurring in children and adolescents? 4) What are the elements that should lead clinicians to suspect a non-accidental dental trauma? A systematic review and analysis of the scientific literature published in English, Italian and French from 2007 to 2017 regarding dental trauma in children and adolescents aged 0–18 years was performed, and about 100 papers were analysed and included. The following four domains were analysed and discussed: Dental Trauma Prevention Strategies and Health Education, First aid in orofacial and dental trauma, Certificate of the dental trauma, Oral and dental signs of child abuse and neglect. Twenty-eight recommendations were draw up and codified by the panel according to the Methodological handbook, produced by the Istituto Superiore di Sanità, in order to guide physicians in the prevention and first aid of dental trauma in children and adolescents. In addition, a careful assessment of the medico-legal implications is reported in this document.
Association of a novel circulating tumor DNA next-generating sequencing platform with circulating tumor cells (CTCs) and CTC clusters in metastatic breast cancer
Authors: Davis Andrew A. , Zhang Qiang , Gerratana Lorenzo , Shah Ami N. , Zhan Youbin , Qiang Wenan , Finkelman Brian S. , Flaum Lisa , Behdad Amir , Gradishar William J. , Platanias Leonidas C. , Cristofanilli Massimo
Published: December 2019

Purpose

Liquid biopsies, including circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), can be used to understand disease prognosis, tumor heterogeneity, and dynamic response to treatment in metastatic breast cancer (MBC). We explored a novel, 180-gene ctDNA panel and the association of this platform with CTCs and CTC clusters.

Methods

A total of 40 samples from 22 patients with MBC were included in the study. For the primary analysis, all patients had ctDNA sequencing using the PredicinePLUS™ platform. CTCs and CTC clusters were examined using the CellSearch™ System. Clinical and pathological variables were reported using descriptive analyses. Associations between CTC count and specific genomic alterations were tested using the Mann-Whitney U test.

Results

Of 43 sequenced patients, 40 (93%) had at least one detectable genomic alteration with a median of 6 (range 1–22). Fifty-seven different genes were altered, and the landscape of genomic alterations was representative of MBC, including the commonly encountered alterations TP53, PTEN, PIK3CA, ATM, BRCA1, CCND1, ESR1, and MYC. In patients with predominantly hormone-receptor-positive MBC, the number of CTCs was significantly associated with alterations in ESR1 (P < 0.005), GATA3 (P < 0.05), CDH1 (P < 0.0005), and CCND1 (P < 0.05) (Mann-Whitney U test). Thirty-six percent of patients had CTC clusters, which were associated with alterations in CDH1, CCND1, and BRCA1 (all P < 0.05, Mann-Whitney U test). In an independent validation cohort, CTC enumeration confirmed significant associations with ESR1 and GATA3, while CTC clusters were significantly associated with CDH1.

Conclusions

We report on a novel ctDNA platform that detected genomic alterations in the vast majority of tested patients, further indicating potential clinical utility for capturing disease heterogeneity and for disease monitoring. Detection of CTCs and CTC clusters was associated with particular genomic profiles.
Secukinumab efficacy on resolution of enthesitis in psoriatic arthritis: pooled analysis of two phase 3 studies
Authors: Coates Laura C. , Wallman Johan K. , McGonagle Dennis , Schett Georg A. , McInnes Iain B. , Mease Philip J. , Rasouliyan Lawrence , Quebe-Fehling Erhard , Asquith Darren L. , Fasth Andreas E. R. , Pricop Luminita , Gaillez Corine
Published: December 2019

Background

Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies.

Method

Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3–6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment.

Results

A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3–6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg.

Conclusion

Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis.

Trial registration

FUTURE 2:ClinicalTrials.gov,NCT01752634(date of study registration: December 19, 2012), and EudraCT,2012-004439-22(date of study registration: December 12, 2012)

FUTURE 3:ClinicalTrials.gov,NCT01989468(date of study registration: November 21, 2013), and EudraCT,2013-004002-25(date of study registration: December 17, 2013)
Survey of knowledge for diagnosing and managing prediabetes in Latin-America: cross-sectional study
Authors: Garay Jennifer , Camacho Paul A. , Lopez-Lopez Jose , Alvernia Juliana , Garcia Marcela , Cohen Daniel D. , Calderon Carlos , Lopez-Jaramillo Patricio
Published: December 2019

Background

Prediabetes has been proposed as a risk factor for the development of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD). Despite the clinical importance of prediabetes, little is known about the level of knowledge, beliefs and barriers to screening and treating prediabetes amongst care health providers in Latin America. The aim of the present survey was to evaluate the knowledge and beliefs about prediabetes amongst in Latin American health care providers.

Methodology

In a cross-sectional study, we adapted the written survey designed by the Johns Hopkins University group, and applied it to health care providers across Latin America during three meetings, in 2017, and with physicians from primary care centers in Bucaramanga, Colombia convened in 2017. The survey consisted of questions under four headings, diabetes screening, management of prediabetes, pharmacological treatment—metformin use, and demographic information. We perform a descriptive analysis to determine the differences in responses between different medical specialties.

Results

The majority of the care providers that answered the survey were Colombian physicians, 54.5% of respondents had 10 years or more since completing their training and more women responded. Only 9.5% identified the 12 prediabetes risk factors described in the literature. The most common risk factor identified was a family history of diabetes, followed by overweight, a sedentary lifestyle and dyslipidemia, while ethnicity was the risk factor least commonly. 47.1% answered that laboratory tests to detect prediabetes are fasting glucose and HbA1C, 82.5% correctly identified fasting plasma glucose as the best test, 35.9% correctly responded that to the recommended weight loss goal is 5 to 7% and 49.1% that 150 min is considered the minimum level of physical activity per week. 78% agreed that the identification and treatment of prediabetes is important. 56% believed that patients with prediabetes progress more rapidly to diabetes and 40.6% considered that metformin could reduce the risk of diabetes in patients already diagnosed with prediabetes.

Conclusion

These results demonstrate that there are important gaps in the knowledge of the diagnosis, clinical implications and management of prediabetes amongst Latin America health providers.
Gene expression analysis of membrane progesterone receptors in women with recurrent spontaneous abortion: a case control study
Authors: Rahnama Reyhane , Rafiee Mitra , Fouladi Saloomeh , Akbari-Fakhrabadi Maryam , Mehrabian Ferdos , Rezaei Abbas
Published: December 2019

Objective

Recurrent spontaneous abortion (RSA) is a condition which is defined as three consecutive pregnancy losses prior to 20 weeks from the last menstrual period. Progesterone is a steroid hormone that has an essential role in the implantation and maintenance of pregnancy. The progesterone signaling is performed by nuclear progesterone receptors (NPRs) and membrane progesterone receptors (mPR). The aim of this study was to analyze gene expression ofmPR-α,mPR-βand NPR in the endometrium of patients with a history of RSA compared to normal fertile women.

Results

In this study, endometrial samples were obtained from 10 women with a history of RSA and 10 fertile women during days 10–14 of menstrual cycle. Relative expression ofmPR-α,mPR-βandNPRgenes were studied by a quantitative real time polymerase chain reaction (qRT-PCR) and compared between the two groups. The mean relative expression ofmPR-βgene was significantly lower in the case group compared to the fertile women (p < 0.05). However, the gene expression ofmPR-αandNPRshowed no significant difference between two groups. The findings suggest a reduction of endometrial gene expression ofmPR-βin RSA patients may play an important role in pathogenesis of RSA.
Use of ecological momentary assessment to detect variability in mood, sleep and stress in bipolar disorder
Authors: Li Han , Mukherjee Dahlia , Krishnamurthy Venkatesh Basappa , Millett Caitlin , Ryan Kelly A. , Zhang Lijun , Saunders Erika F. H. , Wang Ming
Published: December 2019

Objective

Our aim was to study within-person variability in mood, cognition, energy, and impulsivity measured in an Ecological Momentary Assessment paradigm in bipolar disorder by using modern statistical techniques. Exploratory analyses tested the relationship between bipolar disorder symptoms and hours of sleep, and levels of pain, social and task-based stress. We report an analysis of data from a two-arm, parallel group study (bipolar disorder group N = 10 and healthy control group N = 10, with 70% completion rate of 14-day surveys). Surveys of bipolar disorder symptoms, social stressors and sleep hours were completed on a smartphone at unexpected times in an Ecological Momentary Assessment paradigm twice a day. Multi-level models adjusted for potential subject heterogeneity were adopted to test the difference between the bipolar disorder and health control groups.

Results

Within-person variability of mood, energy, speed of thoughts, impulsivity, pain and perception of skill of tasks was significantly higher in the bipolar disorder group compared to health controls. Elevated bipolar disorder symptom domains in the evening were associated with reduced sleep time that night. Stressors were associated with worsening of bipolar disorder symptoms. Detection of symptoms when an individual is experiencing difficulty allows personalized, focused interventions.
Reconstruction of the pelvis after traumatically induced bilateral partial hemipelvectomy: a case report
Authors: Kamitomo Ayako , Hayashi Minoru , Tokunaka Ryohei , Yoshida Yuki , Tatsuta Sayo , Sasaki Yoshie
Published: December 2019

Background

Traumatic hemipelvectomy is a catastrophic fracture of the pelvis as a result of high-energy trauma, such as in a car accident. There have been few case reports of traumatic hemipelvectomy because many of these patients die before they are transferred to a hospital. However, an increasing number of patients are being saved and admitted to hospital due to improvements in resuscitation and the emergency response system. Accordingly, there has been a growing body of reports on the management and reconstruction of traumatic hemipelvectomy.

Case presentation

A healthy 20-year-old Japanese man was trapped beneath a 3-ton steel frame while working on a crane. We describe here a very challenging case of traumatically induced bilateral partial hemipelvectomy with successful reconstruction of our patient’s pelvis using a unilateral anterolateral thigh flap.

Conclusion

To the best of our knowledge, there have been few reports of bilateral hemipelvectomy and our case is the first to be successfully treated with a unilateral anterolateral thigh flap.
Combination of FDG-PET and FMISO-PET as a treatment strategy for patients undergoing early-stage NSCLC stereotactic radiotherapy
Authors: Watanabe Shiro , Inoue Tetsuya , Okamoto Shozo , Magota Keiichi , Takayanagi Ayumi , Sakakibara-Konishi Jun , Katoh Norio , Hirata Kenji , Manabe Osamu , Toyonaga Takuya , Kuge Yuji , Shirato Hiroki , Tamaki Nagara , Shiga Tohru
Published: December 2019

Background

We investigated the prognostic predictive value of the combination of fluorodeoxyglucose (FDG)- and fluoromisonidazole (FMISO)-PET in patients with non-small cell lung carcinoma (NSCLC) treated with stereotactic body radiation therapy (SBRT).

Patients and methods

We prospectively examined patients with pathologically proven NSCLC; all underwent FDG and FMISO PET/CT scans before SBRT. PET images were acquired using a whole-body time-of-flight PET-CT scanner with respiratory gating. We classified them into recurrent and non-recurrent groups based on their clinical follow-ups and compared the groups' tumor diameters and PET parameters (i.e., maximum of the standardized uptake value (SUVmax), metabolic tumor volume, tumor-to-muscle ratio, and tumor-to-blood ratio). We performed univariate analysis to evaluate the impact of the PET variables on the patients' progression-free survival (PFS). We divided the patients by thresholds of FDG SUVmax and FMISO SUVmax obtained from receiver operating characteristic analysis for assessment of recurrence rate and PFS.

Results

Thirty-two NSCLC patients (19 male and 13 females; median age, 83 years) were enrolled. All received SBRT. At the study endpoint, 23 patients (71.9%) were non-recurrent and nine patients (28.1%) had recurrent disease. Significant between-group differences were observed in tumor diameter and all the PET parameters, demonstrating that those were significant predictors of the recurrence in all patients. In the 22 patients with tumors > 2 cm, tumor diameter and FDG SUVmax were not significant predictors. Thirty-two patients were divided into three patterns from the thresholds of FDG SUVmax (6.81) and FMISO SUVmax (1.89); A, low FDG and low FMISO (n = 14); B, high FDG and low FMISO (n = 8); C, high FDG and high FMISO (n = 10). No pattern A patient experienced tumor recurrence, whereas two pattern B patients (25%) and seven pattern C patients (70%) exhibited recurrence. A Kaplan-Meier analysis of all patients revealed a significant difference in PFS between patterns A and B (p = 0.013) and between patterns A and C (p < 0.001). In the tumors > 2 cm patients, significant differences in PFS were demonstrated between pattern A and C patients (p = 0.002).

Conclusion

The combination of FDG- and FMISO-PET can identify patients with a baseline risk of recurrence and indicate whether additional therapy might be performed to improve survival.