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Purpose: Prisoners have a higher risk of suicide compared to non-incarcerated individuals. One aim of suicide prevention for prisoners is to identify risk factors in order to put stronger support mechanisms in place for the more vulnerable detainees. This study investigates the suicide risk (SR) in offence-related sub-populations in a representative German sample and differentiates between SR for adolescent and adult prisoners.
Methods: Conducting a national study with data from public German records on the entire prison population from 2000 to 2016 and suicide numbers in German prisons in the same period, SR was calculated for the total male prison population as well as for both subgroups, adolescent and adult male prisoners.
Results: In the study period, male prisoners spent 959.584 life years (LY) in German criminal detention. Among those, 524 prisoners died of suicide. SR was higher for detainees imprisoned for an offence resulting in extensive physical harm for another person, e.g. homicide (suicide rate = 134,8 suicides per 100.000 LY; OR = 2,47; CI95%: 1,98–3,08), bodily injury (suicide rate = 87,3; OR = 1,60; CI95%: 1,29–1,99), and sexual offences (suicide rate = 84,2; OR = 1,54; CI95%: 1,18–2,01) compared with the SR of the total prison population (suicide rate = 54.6). Age differences between offence-related SR were found for theft, with adolescents (suicide rate = 69,3; OR = 1,25; CI95%: 0,85–1,84) showing higher SR than adults (suicide rate = 38,2; OR = 0,7; CI95%: 0,54–0,92).
Conclusion: The index offence of detainees is associated with SR and age-related differences exist. Suicide prevention in prisons should take both into account to determine populations at risk.
Paclitaxel is a frontline drug for the treatment of epithelial ovarian cancer (EOC). However, following paclitaxel-platinum based chemotherapy, tumor recurrence occurs in most ovarian cancer patients. Chromosomal instability (CIN) is a hallmark of cancer and represents genetic variation fueling tumor adaptation to cytotoxic effects of anticancer drugs. In this study, our Kaplan-Meier analysis including 263 ovarian cancer patients (stages I/II) revealed that high Polo-like kinase (PLK) 1 expression correlates with bad prognosis. To evaluate the role of PLK1 as potential cancer target within a combinatorial trial, we induced strong mitotic arrest in ovarian cancer cell lines by synergistically co-targeting microtubules (paclitaxel) and PLK1 (BI6727) followed by pharmaceutical inhibition of the Anaphase-Promoting Complex (APC/C) using proTAME. In short- and long-term experiments, this triple treatment strongly activated apoptosis in cell lines and primary ovarian cells derived from cancer patients. Mechanistically, BI6727/paclitaxel/proTAME stabilize Cyclin B1 and trigger mitotic arrest, which initiates mitochondrial apoptosis by inactivation of antiapoptotic BCL-2 family proteins, followed by activation of caspase-dependent effector pathways. This triple treatment prevented endoreduplication and reduced CIN, two mechanisms that are associated with aggressive tumors and the acquisition of drug resistance. This “two-punch strategy” (strong mitotic arrest followed by blocking mitotic exit) has important implications for developing paclitaxel-based combinatorial treatments in ovarian cancer.
Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis
(2019)
Background: Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated.
Methods: Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein.
Results: While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001).
Conclusions: Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis.
Trial registration: ClinicalTrials.gov identifier: NCT03584204.
Background: Outcomes of catheter ablation of atrial fibrillation (AF) are variable and the predictors of success require further elucidation since the identification of correctable risk factors could help to optimize therapy. We aimed to assess the impact of body mass index (BMI) in the overall safety and efficacy of catheter ablation of AF, with emphasis on the use of cryoballoon ablation and novel oral anticoagulants.
Methods and Results: There were 2497 consecutive patients undergoing catheter ablation of AF in 7 European high volume centers were stratified according to BMI (normal weight <25 kg/m2, pre‐obese 25–30 kg/m2, obesity 30–35 kg/m2, and morbid obesity ≥35 kg/m2) and comparisons of procedural outcomes evaluated. Pre‐obese and obese patients presented more comorbidities (hypertension, diabetes mellitus, and sleep apnea), and had higher rates of non‐paroxysmal AF ablation procedures. The rate of atrial 12‐month arrhythmia relapse increased alongside with BMI (35.2%, 35.7%, 43.6%, and 48.0% P<0.001). During a median follow‐up of 18.8 months (interquartile range 11–28), after adjusting for all baseline differences, BMI was an independent predictor of relapse (hazard ratio=1.01 per kg/m2; 95% CI 1.01–1.02; P=0.002), adding incremental predictive value to obstructive sleep apnea. BMI was not a predictor for any of the reported complications. Using novel oral anticoagulants and cryoballoon ablation was safe and efficacy was comparable with vitamin‐K antagonists and radiofrequency ablation.
Conclusions: Obese patients present with a more adverse comorbidity profile, more advanced forms of AF, and have lower chances of being free from AF relapse after ablation. Use of novel oral anticoagulants and cryoballoon ablation may be an option in this patient group.
Intact-cell maldi-tof mass spectrometry for the authentication of drug-adapted cancer cell lines
(2019)
The use of cell lines in research can be affected by cell line misidentification. Short tandem repeat (STR) analysis is an effective method, and the gold standard, for the identification of the genetic origin of a cell line, but methods that allow the discrimination between cell lines of the same genetic origin are lacking. Here, we use intact cell MALDI-ToF mass spectrometry analysis, routinely used for the identification of bacteria in clinical diagnostic procedures, for the authentication of a set of cell lines consisting of three parental neuroblastoma cell lines (IMR-5, IMR-32 and UKF-NB-3) and eleven drug-adapted sublines. Principal component analysis (PCA) of intact-cell MALDI-ToF mass spectrometry data revealed clear differences between most, but not all, of the investigated cell lines. Mass spectrometry whole-cell fingerprints enabled the separation of IMR-32 and its clonal subline IMR-5. Sublines that had been adapted to closely related drugs, for example, the cisplatin- and oxaliplatin-resistant UKF-NB-3 sublines and the vincristine- and vinblastine-adapted IMR-5 sublines, also displayed clearly distinctive patterns. In conclusion, intact whole-cell MALDI-ToF mass spectrometry has the potential to be further developed into an authentication method for mammalian cells of a common genetic origin.
Background: Right ventricular (RV) dysfunction is frequently observed in patients with aortic stenosis (AS). Nevertheless, assessment of regional RV deformation is yet not performed. The aim of the study was to analyze the impact of moderate and severe AS on global and regional RV function by a multisegmental approach using tissue Doppler imaging (TDI).
Methods: In 50 patients (Group I – AS [n = 25] and Group II – normal controls [n = 25]), additional echocardiographic views of the RV were prospectively performed. The TDI sample volume was placed in the basal myocardial region of the anterior (RV-anterior), inferior (RV-inferior), and free RV wall (RV-free wall) to assess the following parameters: S'RV, E'RV, and A'RV waves; IVCTRV; IVRTRV; and myocardial performance index (MPIRV).
esults: In AS patients, left ventricular (LV) mass index, left atrial (LA) volume index, and LV end-diastolic pressure were significantly increased. Moreover, AS patients had higher systolic pulmonary artery pressure (sPAP) and lower values for PV AccT (P < 0.0001), but TAPSE was not different between the two groups (P = 0.062). In AS patients, IVRTRV-anterior, IVRTRV-inferior, and IVRTRV-freewall and MPIRV were statistically increased (P < 0.0001). A significant correlation between IVRTRV (evaluated at all three regions) and the parameters including sPAP, PV AccT, and ELV/e'LV ratio was observed in AS. A strong correlation was observed between IVRTRV-freewall/inferior and AS severity by evaluation of velocities, gradient, and aortic valve area (P < 0.0001).
Conclusions: The present study reports a correlation between the severity of AS and the increase of IVRTRV and MPIRV. Thus, a distinct analysis of RV performance is important for echocardiographic evaluation of patients with AS.
Background: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact.
Methods: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data.
Results: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041).
Conclusion: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.
Objective: Patients with electrical injury are considered to be at high risk of cardiac arrhythmias. Due to the small number of studies, there is no widely accepted guideline regarding the risk assessment and management of arrhythmic complications after electrical accident (EA). Our retrospective observational study was designed to determine the prevalence of ECG abnormalities and cardiac arrhythmias after EA, to evaluate the predictive value of cardiac biomarkers for this condition and to assess in-hospital and 30-day mortality.
Methods: Consecutive patients presenting after EA at the emergency department of our institution between 2011 and 2016 were involved in the current analysis. ECG abnormalities and arrhythmias were analyzed at admission and during ECG monitoring. Levels of cardiac troponin I, CK and CK-MB were also collected. In-hospital and 30-day mortality data were obtained from hospital records and from the national insurance database.
Results: Of the 480 patients included, 184 (38.3%) had suffered a workplace accident. The majority of patients (96.2%) had incurred a low-voltage injury (< 1000 V). One hundred and four (21.7%) patients had a transthoracic electrical injury while 13 (2.7%) patients reported loss of consciousness. The most frequent ECG disorders at admission were sinus bradycardia (< 60 bpm, n = 50, 10.4%) and sinus tachycardia (> 100 bpm, n = 21, 4.4%). Other detected arrhythmias were as follows: newly diagnosed atrial fibrillation (n = 1); frequent multifocal atrial premature complexes (n = 1); sinus arrest with atrial escape rhythm (n = 2); ventricular fibrillation terminated out of hospital (n = 1); ventricular bigeminy (n = 1); and repetitive nonsustained ventricular tachycardia (n = 1). ECG monitoring was performed in 182 (37.9%) patients for 12.7 ± 7.1 h at the ED. Except for one case with regular supraventricular tachycardia terminated via vagal maneuver and one other case with paroxysmal atrial fibrillation, no clinically relevant arrhythmias were detected during the ECG monitoring. Cardiac troponin I was measured in 354 (73.8%) cases at 4.6 ± 4.3 h after the EA and was significantly elevated only in one resuscitated patient. CK elevation was frequent, but CK-MB was under 5% in all patients. Both in-hospital and 30-day mortality were 0%.
Conclusions: Most of cardiac arrhythmias in patients presenting after EA can be diagnosed by an ECG on admission, thus routine ECG monitoring appears to be unnecessary. In our patient cohort cardiac troponin I and CK-MB were not useful in risk assessment after EA. Late-onset malignant arrhythmias were not observed.
Incorporation of doxorubicin in different polymer nanoparticles and their anticancer activity
(2019)
Background: Nanoparticles are under investigation as carrier systems for anticancer drugs. The expression of efflux transporters such as the ATP-binding cassette (ABC) transporter ABCB1 is an important resistance mechanism in therapy-refractory cancer cells. Drug encapsulation into nanoparticles has been shown to bypass efflux-mediated drug resistance, but there are also conflicting results. To investigate whether easy-to-prepare nanoparticles made of well-tolerated polymers may circumvent transporter-mediated drug efflux, we prepared poly(lactic-co-glycolic acid) (PLGA), polylactic acid (PLA), and PEGylated PLGA (PLGA-PEG) nanoparticles loaded with the ABCB1 substrate doxorubicin by solvent displacement and emulsion diffusion approaches and assessed their anticancer efficiency in neuroblastoma cells, including ABCB1-expressing cell lines, in comparison to doxorubicin solution.
Results: The resulting nanoparticles covered a size range between 73 and 246 nm. PLGA-PEG nanoparticle preparation by solvent displacement led to the smallest nanoparticles. In PLGA nanoparticles, the drug load could be optimised using solvent displacement at pH 7 reaching 53 µg doxorubicin/mg nanoparticle. These PLGA nanoparticles displayed sustained doxorubicin release kinetics compared to the more burst-like kinetics of the other preparations. In neuroblastoma cells, doxorubicin-loaded PLGA-PEG nanoparticles (presumably due to their small size) and PLGA nanoparticles prepared by solvent displacement at pH 7 (presumably due to their high drug load and superior drug release kinetics) exerted the strongest anticancer effects. However, nanoparticle-encapsulated doxorubicin did not display increased efficacy in ABCB1-expressing cells relative to doxorubicin solution.
Conclusion: Doxorubicin-loaded nanoparticles made by different methods from different materials displayed substantial discrepancies in their anticancer activity at the cellular level. Optimised preparation methods resulted in PLGA nanoparticles characterised by increased drug load, controlled drug release, and high anticancer efficacy. The design of drug-loaded nanoparticles with optimised anticancer activity at the cellular level is an important step in the development of improved nanoparticle preparations for anticancer therapy. Further research is required to understand under which circumstances nanoparticles can be used to overcome efflux-mediated resistance in cancer cells.
Rhythmic actions benefit from synchronization with external events. Auditory-paced finger tapping studies indicate the two cerebral hemispheres preferentially control different rhythms. It is unclear whether left-lateralized processing of faster rhythms and right-lateralized processing of slower rhythms bases upon hemispheric timing differences that arise in the motor or sensory system or whether asymmetry results from lateralized sensorimotor interactions. We measured fMRI and MEG during symmetric finger tapping, in which fast tapping was defined as auditory-motor synchronization at 2.5 Hz. Slow tapping corresponded to tapping to every fourth auditory beat (0.625 Hz). We demonstrate that the left auditory cortex preferentially represents the relative fast rhythm in an amplitude modulation of low beta oscillations while the right auditory cortex additionally represents the internally generated slower rhythm. We show coupling of auditory-motor beta oscillations supports building a metric structure. Our findings reveal a strong contribution of sensory cortices to hemispheric specialization in action control.
Aim: Evaluation of long‐term results after connective tissue graft (CTG) using the envelope technique and the effect on patient‐centred outcomes (Oral Health Impact Profile: OHIP) in a private practice setting.
Materials and Methods: Fifteen patients (11 female, mean age: 45.0 ± 8.88 years) underwent root coverage procedure using a CTG involving maxillary Miller class I teeth. Pre‐operatively, 3 and 120 ± 12 months after surgery, all patients were examined, completed OHIP questionnaire, and were asked to assess improvement and their satisfaction with the results of surgery. All procedures were performed by the same investigator.
Results: Recession depth at 3 months of 1.19 ± 0.93 mm was reduced to that of 0.63 ± 0.64 mm at 120 ± 12 months after surgery (p = .117). Recession width (−1.23 ± 2.27 mm) decreased as well (p = .117), while relative root coverage increased from 48.46 ± 32.18% at 3 months to 71.22 ± 30.86% at 120 months (p = .011). The number of cases with complete root coverage increased from two (15.4%) to six (40.0%) from 3 to 120 months (p = .046). OHIP score (12.07 ± 10.15) did not change after 10 years (12.13 ± 9.86, p = .889). Ten years after surgery, 12 patients (80%) reported they would make the decision again to undergo CTG transplantation.
Conclusions: Within the limitations of the study design with a high risk of bias in a practice setting, long‐term stability of recession reduction, OHIP and patient‐perceived satisfaction remained stable over 10 years.
Production of free radicals and oxidative damage during physical activity is a topic that is intensively studied and paid a lot of attention, first of all in professional sports. Marathon is categorized as extremely demanding sports discipline, as it induces high energy consumption and also requires special mental self-control. We presented cases of two athletes of different age, who have been on dissimilar level of sports readiness, and also had various approach to physical activity and exercise. During 10 days they ran out 10 marathons, partly on a flat terrain, and partly on hilly, which produced different level of effort in conquering the terrain. Also, both athletes had complex supplementation scheme in order to prevent electrolyte imbalance and excessive production of free radicals. Blood samples were taken in the morning and immediately after the end of the marathon. Measured oxidative stress biomarkers changed without a noticeable pattern, but these changes did not vary greatly among themselves. Catalase activity in both marathon runners was higher after marathon almost after every race for 10 days. On the other hand, amount of reduced glutathione was lower after marathon in both athletes in the same manner. Based on the obtained results we can conclude that adequate supplementation could have crucial role in prevention of oxidative damage.
Objective: To compare discomfort/pain following periodontal probing around teeth and peri‐implant probing around implants with or without platform switching.
Methods: Two dentists recruited and examined 65 patients, each of them exhibiting a dental implant with a contralateral tooth. Only two types of implants were included: one with and one without platform switching. Periodontal and peri‐implant probing depths (PPD) and probing attachment level (PAL) were assessed. Whether implant or tooth was measured first was randomly assigned. Immediately after probing, patients scored discomfort/pain using a visual analogue scale (VAS). The emergence profiles of implant crowns were assessed as angles between interproximal surfaces on radiographs.
Results: Sixty‐five patients (age 69; 63/76 years [median; lower/upper quartile]; 38 females, 11 smokers) were examined. With the exception of mean PPD and PAL (p < .05) clinical parameters (PPD, PAL, bleeding on probing, suppuration) were well balanced between implants and teeth. Peri‐implant probing (VAS: 10; 0.75/16.25) caused significantly (p < .001) more discomfort/pain than periodontal probing (4; 0/10). Logistic regression analysis identified a larger difference between discomfort/pain for peri‐implant and periodontal probing in the maxilla than the mandible (p = .003). Comparing discomfort/pain between implants maxilla (p = .006) and emergence profile (p = .015) were associated with discomfort/pain. Type of implant (with/without platform switching) had no significant effect on discomfort/pain.
Conclusions: Peri‐implant probing caused significantly more discomfort/pain than periodontal probing. Implant design with/without platform switching failed to have a significant effect on discomfort/pain.
After removal of a dental implant or extraction of a tooth in the upper jaw, the closure of an oroantral fistula (OAF) or oroantral communication (OAC) can be a difficult problem confronting the dentist and surgeon working in the oral and maxillofacial region. Oroantral communication (OAC) acts as a pathological pathway for bacteria and can cause infection of the antrum, which further obstructs the healing process as it is an unnatural communication between the oral cavity and the maxillary sinus. There are different ways to perform the surgical closure of the OAC. The decision-making in closure of oroantral communication and fistula is influenced by many factors. Consequently, it requires a combination of knowledge, experience, and information gathering. Previous narrative research has focused on assessments and comparisons of various surgical techniques for the closure of OAC/OAF. Thus, the decision-making process has not yet been described comprehensively.
The present study aims to illustrate all the factors that have to be considered in the management of OACs and OAFs that determine optimal treatment.
Paul Ehrlich's concept of the magic bullet, by which a single drug induces pharmacological effects by interacting with a single receptor has been a strong driving force in pharmacology for a century. It is continually thwarted, though, by the fact that the treated organism is highly dynamic and the target molecule(s) is (are) never static. In this article, we address some of the factors that modify and cause the mobility and plasticity of drug targets and their interactions with ligands and discuss how these can lead to unexpected (lack of) effects of drugs. These factors include genetic, epigenetic, and phenotypic variability, cellular plasticity, chronobiological rhythms, time, age and disease resolution, sex, drug metabolism, and distribution. We emphasize four existing approaches that can be taken, either singly or in combination, to try to minimize effects of pharmacological plasticity. These are firstly, to enhance specificity using target conditions close to those in diseases, secondly, by simultaneously or thirdly, sequentially aiming at multiple targets, and fourthly, in synchronization with concurrent dietary, psychological, training, and biorhythm‐synchronizing procedures to optimize drug therapy.
High-resolution cryo-EM structures of respiratory complex I: Mechanism, assembly, and disease
(2019)
Respiratory complex I is a redox-driven proton pump, accounting for a large part of the electrochemical gradient that powers mitochondrial adenosine triphosphate synthesis. Complex I dysfunction is associated with severe human diseases. Assembly of the one-megadalton complex I in the inner mitochondrial membrane requires assembly factors and chaperones. We have determined the structure of complex I from the aerobic yeast Yarrowia lipolytica by electron cryo-microscopy at 3.2-Å resolution. A ubiquinone molecule was identified in the access path to the active site. The electron cryo-microscopy structure indicated an unusual lipid-protein arrangement at the junction of membrane and matrix arms that was confirmed by molecular simulations. The structure of a complex I mutant and an assembly intermediate provide detailed molecular insights into the cause of a hereditary complex I-linked disease and complex I assembly in the inner mitochondrial membrane.
Cardiovascular diseases (CVDs) remain the leading cause of death worldwide. Many studies have provided evidence that both genetic and environmental factors induce atherosclerosis, leading thus to cardiovascular complications. Atherosclerosis is an inflammatory disease, and aging is strongly associated with the development of atherosclerosis. Recent experimental evidence suggests that clonal hematopoiesis (CH) is an emerging cardiovascular risk factor that contributes to the development of atherosclerosis and cardiac dysfunction and exacerbates cardiovascular diseases. CH is caused by somatic mutations in recurrent genes in hematopoietic stem cells, leading to the clonal expansion of mutated blood cell clones. Many of the mutated genes are known in the context of myeloid neoplasms. However, only some individuals carrying CH mutations develop hematologic abnormalities. CH is clearly age dependent and is not rare: at least 10%–20% of people >70 years old carry CH. The newly discovered association between myeloid leukemia-driver mutations and the progression of CVDs has raised medical interest. In this review, we summarize the current view on the contribution of CH in different cardiovascular diseases, CVD risk assessment, patient stratification, and the development of novel therapeutic strategies.
Despite advances in the medical and interventional clinical management of patients, cardiovascular diseases (CVDs) remain the leading cause of death worldwide. It is well appreciated that atherosclerosis represents the underlying cause of most CVDs [1]. Atherosclerosis is a chronic inflammatory disease that leads to the formation of atheromatous lesions in the vessel associated with increased recruitment, adhesion, and proliferation of different leukocyte subsets to the endothelium [1]. Several cardiovascular risk factors (CRFs) have been found to enhance the risk of CVD (Figure 1), including hypercholesterolemia (HC), diabetes mellitus (DM), hypertension, metabolic syndrome, obesity, and smoking [2]. Inflammation plays a crucial role in the development of CVDs and several studies have reported that CRFs enhance production of myeloid cells and multipotent hematopoietic progenitors in the bone marrow and in this way may promote atherosclerosis and disease development [3].
Changes of left ventricular systolic function in patients undergoing coronary artery bypass grafting
(2019)
AIM: This prospective study was designed to evaluate the changes in left ventricular (LV) systolic function after coronary artery bypass grafting (CABG) in patients with both normal and abnormal pre-operative systolic function. METHODS: During the period from October 2017 to October 2018, forty-seven consecutive patients undergoing CABG were enrolled in this prospective study. Transthoracic echocardiography was performed within 1 week before CABG as well as 4 to 6 months after surgery. All measurements were made by a single experienced investigator. RESULTS: While the mean LV ejection fraction (LVEF) showed neither improvement nor significant reduction in the whole group of patients following CABG (from 54.21 ± 15.36 to 53.66 ± 11.56%, p = 0.677), significant improvement in LVEF was detected in the subgroup of patients with pre-operative LV dysfunction (from 40.05 ± 8.65 to 45.85 ± 9.04%, p = 0.008). On the other hand, there was a significant decline in LEFT in the subgroup of patients with normal pre-operative LEFT (from 64.70 ± 9.72 to 59.44 ± 9.75%, p = 0.008). As for the other parameters of systolic function, significant decrease in LV end-diastolic volume index (LVEDVI) (p = 0.001), LV end-systolic volume index (LVESVI) (p = 0.0001), wall motion score index (WMSI) (p = 0.013) and LVmass index in male patients (p = 0.011) was shown only in patients with decreased LVEF after CABG. Patients with improved postoperative LVEF (53.2% of all patients) had significantly lower baseline LVEF (p = 0.0001), higher LVESVI (0.009) and higher WMSI (p = 0.006) vs patients with worsened postoperative LVEF (38.3% of all patients). Postoperative improvement of LVEF was correlated with stabile angina, lack of preoperative myocardial infarction and smoking, higher baseline WMSI, higher LV internal diameters and indexed volumes in diastole and systole and lower baseline LVEF. In stepwise linear regression analysis the value of baseline LVEF appeared as independent predictor of improved LVEF after CABG (B = 0,836%; 95% CI 0.655-1.017; p = 0.0001). CONCLUSION: Our study showed that LVEF, internal baseline diameters and indexed volumes of LV in diastole and systole are important determinants of postoperative change in LVEF. In patients with preoperative depressed myocardial function, there is an improvement in systolic function, whereas in patients with preserved preoperative myocardial function, the decline in postoperative LVEF was detected.
Background: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
Methods: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Results: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
Conclusion: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
Trial registration: ClinicalTrials.gov identifier: NCT01915524.
Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder. In recent years, genetic studies have revealed several risk gene variants associated with ADHD; however, these variants could only be partly replicated and are responsible for only a fraction of the whole heritability of ADHD estimated from family and twin studies. One factor that could potentially explain the ‘missing heritability’ of ADHD is that childhood and adult or persistent ADHD could be genetically distinct subtypes, which therefore need to be analyzed separately. Another approach to identify this missing heritability could be combining the investigation of both common and rare gene risk variants as well as polygenic risk scores. Finally, environmental factors are also thought to play an important role in the etiology of ADHD, acting either independently of the genetic background or more likely in gene–environment interactions. Environmental factors might additionally convey their influence by epigenetic mechanisms, which are relatively underexplored in ADHD. The aforementioned mechanisms might also influence the response of patients with ADHD to stimulant and other ADHD medication. We conducted a selective review with a focus on risk genes of childhood and adult ADHD, gene–environment interactions, and pharmacogenetics studies on medication response in childhood and adult ADHD.