Journal of Clinical Medicine

Although several cochleo-vestibular symptoms are commonly associated with migraine, only a limited number of studies have been done in this regard. Some reported abnormalities in audiometry, auditory brainstem response and vestibular tests, considering these manifestations mainly related to central etiology. However, increasing evidence also suggests a peripheral involvement of the inner ear in migraine. The aim of this study was to investigate the peripheral auditory pathway in migraineurs using otoacoustic emissions (OAEs), to detect alteration of cochlear functioning and possible relationship with disease severity. Sixty-two migraineurs and sixty matched controls were enrolled in the study and underwent a routine neuro-otolaryngology examination; self-administered questionnaires were used to evaluate subjective perception of hearing disability. DPOAE and their suppression were lower in migraineurs compared to controls and significantly related to the disease duration. Altered DPOAE exposed migraineurs to the risk of affecting by migraine without aura, of presenting with ocular and/or auditory symptoms during attack and of using more painkillers. Concomitant dopaminergic symptoms and/or allodynia such as the acute non-consumption of triptans were significant determinants of decreased contralateral suppression of DPOAE among migraineurs. This potential subclinical cochlear impairment in migraine detected by OAEs may represent the earliest sign of sensorineural damage in these patients, providing a promising tool for the initial diagnosis and an opportunity to monitor disease course and treatment response over time. Full article

Background: Mini dental implant (MDI) overdenture rehabilitation for the edentulous maxilla is a valuable, less invasive and affordable treatment alternative for complete removable dentures (CRD). However, comparative quantification of masticatory performance in different oral conditions are scarce. Purpose: This study compares objective masticatory performance of dentate groups, maxillary CRD and MDI overdentures and subjective masticatory performance in maxillary CRD and MDI overdentures. Materials and Methods: Four groups were defined, age 20+ dentate dental students (DS), age 50+ complete dentate subjects (DP), age 50+ maxillary CRD or MDI overdentures/dentate mandible. Objective masticatory performance was evaluated by measuring circular Variance of Hue (VOH) or the mixture degree of two-color chewing gum (Hue-check View Gum^® Test). Additionally, subjective masticatory comparison was investigated in the CRD and MDI groups, with a visual analogue scale (VAS) for different food consistencies and the Oral Health Related Quality of Life (OHRQL) OHIP-14 questionnaire. Results: The mean VOH was 0.11 (SD 0.50, range 0.05–0.27) for the dentate dental 20+ students, 0.13 (SD 0.08, range 0.03–0.31) for the 50+ dentate group (p = 0.774), 0.41 (SD 0.41, range 0.14–0.76) for the CRD group and 0.39 (SD 0.18, range 0.07–0.76) for the MDI group (p = 0.725). Based on the VAS scores, no improvement was found between the CRD and the MDI overdenture group (p > 0.050). The mean OHIP-14 total score was 12.10 (SD 15.87, range 0–56) for CRD, while the MDI group (p = 0.039) saw a significant improvement to 2.85 (SD 2.85, range 0–15). Conclusion: Comparable results in objective masticatory performance were registered in dentate 20+ and 50+ subjects with a remarkable inferior outcome for the CRD and MDI group. Compared to CRD, MDI overdentures revealed no substantial improvement in subjective and objective masticatory performance. However, for MDI a significant increase in OHRQL was apparent. Full article

Acute kidney injury (AKI) is a major contributor to in-hospital morbidity and mortality. Vancomycin, one of the most commonly used antibiotics in a clinical setting, is associated with AKI, with its incidence ranging up to 43%. Despite the high demand, few studies have investigated serum biomarkers to detect vancomycin-induced kidney injury (VIKI). Here, we evaluated the diagnostic value of nine candidate serum biomarkers for VIKI. A total of 23,182 cases referred for vancomycin concentration measurement from January 2018 to December 2019 were screened and 28 subjects with confirmed VIKI were enrolled (VIKI group). Age- and sex- matched control group consisted of 21 subjects who underwent vancomycin therapy without developing VIKI (non-VIKI group), and 23 healthy controls (HC group). The serum concentrations of clusterin, retinol binding protein 4 (RBP4), interleukin-18 (IL-18), tumor necrosis factor receptor 1 (TNF-R1), C-X-C motif chemokine ligand 10 (CXCL10), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin, trefoil factor-3 (TFF3), and cystatin C were compared among the three groups, and their correlations with estimated glomerular filtration rate (eGFR) and diagnostic values for VIKI were assessed. All of the biomarkers except clusterin and RBP4 exhibited significant elevation in the VIKI group. Serum TFF3, cystatin C, TNF-R1, and osteopontin demonstrated an excellent diagnostic value for VIKI (TFF3, area under the curve (AUC) 0.932; cystatin C, AUC 0.917; TNF-R1, AUC 0.866; osteopontin, AUC 0.787); and except osteopontin, a strong negative correlation with eGFR (TFF3, r = −0.71; cystatin C, r = −0.70; TNF-R1, r = −0.60). IL-18, CXCL10, and NGAL showed weak correlation with eGFR and moderate diagnostic value for VIKI. This study tested multiple serum biomarkers for VIKI and showed that serum TFF3, cystatin C, TNF-R1, and osteopontin could efficiently discriminate VIKI patients. Further studies are warranted to clarify the diagnostic value of these biomarkers in VIKI. Full article

Revolving Door (RD) is a frequent phenomenon afflicting children and adolescents with psychiatric diagnoses. Nevertheless, risk factors for RD are still a matter of debate. To better understand RD phenomenon, we conducted a retrospective study on 224 children and adolescents (165 females and 59 males, aged 6–16 years) with a psychiatric hospitalization, taking the multiple risk factors together. At this aim, 108 patients with multiple hospitalizations and 116 patients with only one hospitalization were compared on demographic characteristics, clinical conditions, psychiatric ward stay, and post-discharge management factors. More than half of psychiatric patients were readmitted within three months of discharge. RD patients presented greater severity of illness, needed longer stays, and were more frequently placed in residential facilities than non-RD patients. Non-suicidal self-injurious and adoption were the main predictors of RD. Clinical instruments that detected behavioural and emotional symptoms, suicidal ideation severity, and level of impairment of the person’s functioning were useful to identify patients at high risk for RD. In conclusion, our findings pointed out that several risk factors have to be considered to better understand and, in the future, prevent RD phenomenon. Full article

Head and neck cancer (HNC) is the sixth most common cancer worldwide. Yet, less than 60% of HNC survivors receive adequate therapy for treatment-related sequelae. The objective of this study was to determine the efficacy of myofascial induction therapy (MIT) in improving cervical and shoulder pain and range of motion, maximal mouth opening, and cervical muscle function in HNC survivors. This crossover, blinded, placebo-controlled study involved 22 HNC survivors (average age 56.55 ± 12.71) of which 13 were males (59.1%) who received, in a crossover fashion, both a single 30-min session of MIT in the form of manual unwinding and simulated pulsed shortwave therapy (placebo), with a 4-week washout interval between the two. Cervical and shoulder pain (visual analogue scale) and range of motion (cervical range of motion device and goniometer), maximum mouth opening (digital caliper), and cervical muscle function (deep cervical flexor endurance test) were measured before and after the treatment and placebo sessions. A single session of MIT improved cervical and affected side shoulder pain, cervical range of motion, maximum mouth opening, and cervical muscle function. The associated effect sizes ranged from moderate to large. The present study suggests that MIT, in the form of manual unwinding, improves cervical (−3.91 ± 2.77) and affected-side shoulder (−3.64 ± 3.1) pain, cervical range of motion (flexion: 8.41 ± 8.26 deg; extension: 12.23 ± 6.55; affected-side rotation: 14.27 ± 11.05; unaffected-side rotation: 11.73 ± 8.65; affected-side lateroflexion: 7.95 ± 5.1; unaffected-side lateroflexion: 9.55 ± 6.6), maximum mouth opening (3.36 ± 3.4 mm), and cervical muscle function (8.09 ± 6.96 s) in HNC survivors. Full article

Development of cataracts is a well-known adverse effect of ionizing radiation, but little information is available on their incidence in patients after other medical procedures, such as cardiac catheterizations. The study objective was to determine the incidence of cataracts in a cohort of patients undergoing percutaneous coronary intervention (PCI) for chronic coronary total occlusion (CTO) and its association with radiation dose. The study analyzed the incidence of cataracts during the follow-up of 126 patients who underwent chronic total coronary PCI, using Cox regression to identify predictive factors of cataract development. The study included 126 patients, 86.9% male, with a mean age of 60.5 years (range, 55.0–68.0 years). Twenty-three (18.2% n = 23) developed cataracts during a mean follow-up of 49.5 months (range 37.3–64.5 months). A higher incidence was observed in patients who received more than 5 Gy (29.0% vs. 14.7%, Hazard ratio (HR = 2.84 [1.19–6.77]). Multivariate analysis revealed a relationship between cataract development during the follow-up and a receipt of radiation dose >5 Gy (HR = 2.60, 95% confidence interval [CI 1.03–6.61]; p = 0.03), presence or history of predisposing eye disease (HR = 4.42, CI:1.57–12.40), diabetes (HR = 3.33 [1.22–9.24]), and older age, as in >57 (HR, 6.40 [1.81–22.61]). An elevated incidence of cataracts was observed in patients after PCI for CTO. The onset of cataracts is related to the radiation dose during catheterization, which is a potentially avoidable effect of which operators should be aware. Full article

Restless legs syndrome (RLS) is a neurological disorder that causes uncomfortable sensations in the legs. The purpose of this study was to evaluate the symptoms of RLS in patients with spinal disorders and the impact of RLS on the clinical outcomes of lumbar spinal stenosis (LSS). The records of 278 patients (age range 65–92 years) with spinal disorders who visited our outpatient clinic were reviewed. We used a survey to identify subjects with RLS based on the International RLS Study Group diagnostic criteria. We further recorded patient characteristics, surgical outcomes, sleeping time, mental health condition, and the occurrence of leg cramps. Thirty-two patients (11.5%) met the criteria for RLS. The prevalence of anxiety (46.9% vs. 26.6%, p = 0.023) and leg cramps (90.6% vs. 73.2%, p = 0.030) was higher in patients with RLS than in those without. RLS was present in 12.3% of LSS patients. The visual analog scale score for lower back pain before surgery and at the final follow-up was significantly higher in LSS patients with RLS than in those without. However, the Japanese Orthopaedic Association (JOA) score, JOA score improvement ratio, and VAS score for leg numbness were not significantly different between the groups. Full article

Although castration-resistant prostate cancer (CRPC) as a whole, by its name, refers to the tumors that relapse and/or regrow independently of androgen after androgen deprivation therapy (ADT), untreated tumor, even in early-stage primary prostate cancer (PCa), contains androgen-independent (AI) PCa cells. The transformation of androgen-dependent (AD) PCa to AI PCa under ADT is a forced evolutionary process, in which the small group of AI PCa cells that exist in primary tumors has the unique opportunity to proliferate and expand selectively and dominantly, while some AD PCa cells that have escaped from ADT-induced death acquire the capability to survive in an androgen-depleted environment. The adaptation and reprogramming of both PCa cells and the tumor microenvironment (TME) under ADT make PCa much stronger than primary tumors so that, currently, there are no effective therapeutic methods available for the treatment of CRPC. Many mechanisms have been found to be related to the emergence and maintenance of PCa castration resistance; in this review, we focus on the role of inflammatory signaling in both PCa cells and the TME for the emergence and maintenance of CRPC and summarize the recent advances of therapeutic strategies that target inflammatory signaling for the treatment of CRPC. Full article

Protein phosphatase 2A (PP2A) is a ubiquitously expressed intracellular serine/threonine phosphatase. Deregulation of PP2A is a common event associated with adenocarcinomas of the colon and rectum. We have previously shown that breast cancer cell lines are sensitive to the PP2A activator FTY720, and that sensitivity is predicted by high Aurora kinase A (AURKA) mRNA expression. In this study, we hypothesized that high relative AURKA expression could predict sensitivity to FTY720-induced apoptosis in colorectal cancer (CRC). The CRC cell lines NCI H716, COLO320DM, DLD-1, SW480, and HT-29 show a high relative AURKA expression as compared to LS411N, T84, HCT116, SW48, and LOVO. Following viability assays, LS411N, T84, HCT116, and SW480 were shown to be sensitive to FTY720, whereas DLD-1 and HT-29 were non-sensitive. Hence, AURKA mRNA expression does not predict sensitivity to FTY720 in CRC cell lines. Differentially expressed genes (DEGs) were obtained by comparing the sensitive CRC cell lines (LS411N and HCT116) against the non-sensitive (HT-29 and DLD-1). We found that 253 genes were significantly altered in expression, and upregulation of CERS4, PPP2R2C, GNAZ, PRKCG, BCL2, MAPK12, and MAPK11 suggests the involvement of the sphingolipid signaling pathway, known to be activated by phosphorylated-FTY720. In conclusion, although AURKA expression did not predict sensitivity to FTY720, it is evident that specific CRC cell lines are sensitive to 5 µM FTY720, potentially because of the differential expression of genes involved in the sphingolipid pathway. Full article

Background: Conflicting results from previous studies have led to dissent over whether surgical mesh is safe and effective in ventral hernia repair. A newer class of mesh known as a reinforced tissue matrix, combining a biologic scaffold and minimal polymer reinforcement, offers promise in reducing inflammatory response and increasing abdominal wall support. This study sought to assess the clinical utility of a reinforced tissue matrix (OviTex) in ventral hernia repair 12 months after implantation. Methods: This is a prospective, single-arm, multi-center study to evaluate the clinical performance of OviTex^® 1S Permanent (OviTex) in the repair of primary or recurrent ventral hernias (VH) in consecutive patients (ClinicalTrials.gov/NCT03074474). The rate of surgical site occurrences (SSOs) was evaluated 90 days post-surgery as the primary endpoint. Hernia recurrence and the incidence of postoperative events were evaluated between three and 12 months as secondary endpoints. The incidence of other complications and patient-reported outcomes were also recorded. Results: Ninety-two (92) patients were enrolled in the study, of whom seventy-six (76) reached the 12-month follow-up. All patients were at least 18 years of age with a BMI of <40 kg/m². Hernia defects were <20 × 20 cm, classified as class I–III according to the CDC wound classification system. Of the 76 patients who reached 12-month follow-up, twenty-six (34%) had previous VH repairs and thirteen (17%) had previous surgical infection. Sixty (79%) had factors known to increase the risk of recurrence. Twenty patients (26%) experienced SSOs, with ten (13%) requiring procedural intervention. Two of the 75 patients (2.7%) experienced a recurrence. Conclusions: The low rate of hernia recurrence and SSOs requiring intervention illustrates the potential that reinforced tissue matrices, and OviTex 1S, in particular, have to improve outcomes in VH repairs. Follow-up to 24 months is ongoing. Full article

A febrile state may provoke a Brugada electrocardiogram (ECG) pattern and trigger ventricular tachyarrhythmias in susceptible individuals. However, the prognostic value of fever-induced Brugada ECG pattern remains unclear. We analyzed the clinical and extended long-term follow-up data of consecutive febrile patients with a type 1 Brugada ECG presented to the emergency department. A total of 21 individuals (18 males; mean age, 43.7 ± 18.6 years at diagnosis) were divided into symptomatic (resuscitated cardiac arrest in one, syncope in two) and asymptomatic (18, 86%) groups. Sustained polymorphic ventricular tachycardias were inducible in two patients with previous syncope. All 18 asymptomatic patients had no spontaneous type 1 Brugada ECG recorded at second intercostal space and no family history of sudden death. Among asymptomatic individuals, 4 had a total 12 of repeated non-arrhythmogenic febrile episodes all with recurrent type 1 Brugada ECGs, and none had a ventricular arrhythmic event during 116 ± 19 months of follow-up. In the symptomatic group, two had defibrillator shocks for a new arrhythmic event at 31- and 49 months follow-up, respectively, and one without defibrillator therapy died suddenly at 8 months follow-up. A previous history of aborted sudden death or syncope was significantly associated with adverse outcomes in symptomatic compared with asymptomatic individuals (log-rank p < 0.0001). In conclusion, clinical presentation or history of syncope is the most important parameter in the risk stratification of febrile patients with type 1 Brugada ECG. Asymptomatic individuals with a negative family history of sudden death and without spontaneous type 1 Brugada ECG, have an exceptionally low future risk of arrhythmic events. Careful follow-up with timely and aggressive control of fever is an appropriate management option. Full article

The aim of the present systematic review was to investigate the effect of residual bone height (RBH) and vertical bone gain on new bone formation (NBF) and graft shrinkage after lateral sinus lifts using different biomaterials. Methods: An electronic search was conducted on three databases to identify randomized controlled trials (RCTs) published until January 2021 with at least one follow-up at 6 months and at least five patients treated, comparing biomaterials used for maxillary sinus augmentation with a lateral approach. Graft volumetric changes, RBH, vertical bone gain, implant failure, and post-operative complications were evaluated. The risk of bias was assessed using the Cochrane tool. Results: We used 4010 identified studies, of which 21 were RCTs. Overall, 412 patients and 533 sinuses were evaluated. Only three publications had an overall low risk of bias. After 6 months, xenograft (XG) showed the least volume reduction (7.30 ± 15.49%), while autogenous graft (AU) was the most reabsorbed (41.71 ± 12.63%). NBF appeared to not be directly correlated with RBH; on the contrary, the overall linear regression analysis showed that NBF significantly decreased by 1.6% for each mm of postoperative vertical graft gain. This finding suggests that the greater the augmentation, the lower the NBF. A similar tendency, with a regression coefficient even higher than the overall one, was also observed with alloplast (AP) and XG. Conclusions: The present results suggested that NBF was essentially independent of preoperative bone height. On the contrary, the smaller the volume was of the graft placed, the higher the amount of new bone formed, and the smaller the graft shrinkage was. Minimizing the augmentation volume might be beneficial to graft healing and stability especially when using AP and XG. Full article

In order to investigate the possible role of Epstein–Barr virus (EBV) in systemic lupus erythematosus (SLE) and its associated oral lesions, a pilot case–control study was performed. A total of 31 patients (18 females and 13 males) were enrolled in the study and divided into two groups: group A included 16 patients with diagnosis of SLE and group B included 15 healthy individuals. Salivary swab samples were collected and subjected to molecular screening by real-time quantitative PCR (qPCR) for the detection of EBV DNA. EBV DNA was significantly detected in 8/16 (50%) SLE patients and in 5/7 (71.4%) subjects with SLE-associated oral lesions. Since EBV is one of the most common viruses in the human population, it is difficult to understand if it is the causative agent of SLE or, vice versa, if SLE is able to trigger the reactivation of EBV. This study highlights a significant association between the presence of EBV and both SLE and SLE-related oral lesions and provides rationale for further investigation into the role of EBV in SLE pathogenesis. Full article

Background/Aim: To evaluate the association between baseline [18F]FDG-PET/CT tumor burden parameters and disease progression rate after first-line target therapy or immunotherapy in advanced melanoma patients. Materials and Methods: Forty four melanoma patients, who underwent [18F]FDG-PET/CT before first-line target therapy (28/44) or immunotherapy (16/44), were retrospectively analyzed. Whole-body and per-district metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. Therapy response was assessed according to RECIST 1.1 on CT scan at 3 (early) and 12 (late) months. PET parameters were compared using the Mann–Whitney test. Optimal cut-offs for predicting progression were defined using the ROC curve. PFS and OS were studied using Kaplan–Meier analysis. Results: Median (IQR) MTVwb and TLGwb were 13.1 mL and 72.4, respectively. Non-responder patients were 38/44, 26/28 and 12/16 at early evaluation, and 33/44, 21/28 and 12/16 at late evaluation in the whole-cohort, target, and immunotherapy subgroup, respectively. At late evaluation, MTVbone and TLGbone were higher in non-responders compared to responder patients (all p < 0.037) in the whole-cohort and target subgroup and MTVwb and TLGwb (all p < 0.022) in target subgroup. No significant differences were found for the immunotherapy subgroup. No metabolic parameters were able to predict PFS. Controversially, MTVlfn, TLGlfn, MTVsoft + lfn, TLGsoft + lfn, MTVwb and TLGwb were significantly associated (all p < 0.05) with OS in both the whole-cohort and target therapy subgroup. Conclusions: Higher values of whole-body and bone metabolic parameters were correlated with poorer outcome, while higher values of whole-body, lymph node and soft tissue metabolic parameters were correlated with OS. Full article

Prader–Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder characterized by hypotonia and hyperphagia. Consequently, individuals with PWS are at high risk of choking, and choking is a leading cause of morbidity and mortality. The aim of this quality improvement (QI) project is to provide choking prevention and first aid education from 0% to 80% of PWS caregivers seen in a multidisciplinary PWS clinic, and to assess the effectiveness of this education program. A QI initiative was developed to standardize and implement choking prevention and first aid education for PWS caregivers. Using a Likert scale, pre- and post-education assessments were conducted to measure caregiver (1) awareness of the PWS choking risk, (2) self-reported knowledge of choking prevention strategies, and (3) comfort in providing choking first aid. The American Heart Association Family and Friends^® CPR (Dallas, TX, USA) curriculum was utilized. Education was provided during a regularly scheduled PWS clinic appointment. At project conclusion, 45/52 (87%) of PWS caregivers received education. A post-education assessment revealed an improvement in PWS caregivers’ awareness of choking risk, self-reported knowledge of choking prevention strategies, and comfort in providing choking first aid. This QI project supports a practice change to implement choking prevention and first aid education as standard process within our PWS clinic. Full article

Fibromyalgia (FM) has been explained as a result of gene-environment interactions. The present study aims to verify DNA methylation differences in eleven candidate genome regions previously associated to FM, evaluating DNA methylation patterns as potential disease biomarkers. DNA methylation was analyzed through bisulfite sequencing, comparing 42 FM women and their 42 healthy sisters. The associations between the level of methylation in these regions were further explored through a network analysis. Lastly, a logistic regression model investigated the regions potentially associated with FM, when controlling for sociodemographic variables and depressive symptoms. The analysis highlighted significant differences in the GCSAML region methylation between patients and controls. Moreover, seventeen single CpGs, belonging to other genes, were significantly different, however, only one cytosine related to GCSAML survived the correction for multiple comparisons. The network structure of methylation sites was different for each group; GRM2 methylation represented a central node only for FM patients. Logistic regression revealed that depressive symptoms and DNA methylation in the GRM2 region were significantly associated with FM risk. Our study encourages better exploration of GCSAML and GRM2 functions and their possible role in FM affecting immune, inflammatory response, and central sensitization of pain. Full article

Introduction: Thymomas are the most common tumors of the mediastinum. Traditionally, thymectomies have been performed through a transsternal (TS) approach. With the development of robot-assisted thoracic surgery (RATS), a promising, minimally invasive, alternative surgical technique for performing a thymectomy has been developed. In the current paper, the oncological and surgical outcomes of the TS vs. RATS thymectomies are discussed. Methods: For the RATS thymectomy, two 8 mm working ports and one 12 mm camera port were used. In the transsternal approach, we performed a median sternotomy and resected the thymic tissue completely, in some cases en bloc with part of the lung and/or, more frequently, a partial pericardiectomy with consequent reconstruction using a bovine pericardial patch. The decisions for using the TS vs. RATS methods were mainly based on the suspected tumor invasion of the surrounding structures on the preoperative CT scan and tumor size. Results: Between January 2010 and November 2020, 149 patients were submitted for an anterior mediastinal tumor resection at our institution. A total of 104 patients met the inclusion criteria. One procedure was performed through a hemi-clamshell incision. A total of 81 (78%) patients underwent RATS procedures, and 22 (21.1%) patients were treated using a transsternal (TS) tumor resection. Thymoma was diagnosed in 53 (51%) cases. In the RATS group, the median LOS was 3.2 ± 2.8 days and the median tumor size was 4.4 ± 2.37 cm compared to the TS group, which had a median LOS of 9 ± 7.3 days and a median tumor size of 10.4 ± 5.3 cm. Both differences were statistically significant (p < 0.001). Complete resection was achieved in all patients. Conclusion: While larger and infiltrating tumors (i.e., thymic carcinomas) were usually resected via a sternotomy, the RATS procedure is a good alternative for the resection of thymomas of up to 9.5 cm, and the thymectomy is a strong approach for myasthenia gravis. The oncological outcomes and survival rates were not influenced by the chosen approach. Full article

Therapeutic drug monitoring (TDM) is a useful strategy to optimize biologic medications for inflammatory bowel disease not responsive to standard dosing regimens. TDM is cost effective for anti-tumor necrosis factor agents in the setting of loss of response (reactive TDM). Optimizing drug dosing when patients are in remission (proactive TDM) may be beneficial in certain circumstances. However, frequently the serum drug concentration in isolation becomes the focus TDM. Additionally, the lines of reactive and proactive TDM can quickly blur in many common clinical settings. Physicians employing a TDM based strategy need to place the drug concentration in context with the inflammatory status of the patient, the underlying pharmacokinetics and pharmacodynamics of the drug, the risk of immunogenicity, and the therapeutic goals for the patient. Physicians should understand the limits of TDM and feel comfortable making therapeutic decisions with imperfect information. The goal of this narrative review is to provide a framework of questions that physicians can use to employ TDM effectively in practice. Full article

Background: The angiotensin receptor-neprilysin inhibitor (ARNI) decreases cardiovascular mortality in patients with chronic heart failure with a reduced ejection fraction (HFrEF). Data regarding the impact of ARNI on the outcome in HFrEF patients according to heart failure etiology are limited. Methods and results: One hundred twenty-one consecutive patients with HFrEF from the years 2016 to 2017 were included at the Medical Centre Mannheim Heidelberg University and treated with ARNI according to the current guidelines. Left ventricular ejection fraction (LVEF) was numerically improved during the treatment with ARNI in both patient groups, that with ischemic cardiomyopathy (n = 61) (ICMP), and that with non-ischemic cardiomyopathy (n = 60) (NICMP); p = 0.25. Consistent with this data, the NT-proBNP decreased in both groups, more commonly in the NICMP patient group. In addition, the glomerular filtration rate (GFR) and creatinine changed before and after the treatment with ARNI in both groups. In a one-year follow-up, the rate of ventricular tachyarrhythmias (ventricular tachycardia and ventricular fibrillation) tended to be higher in the ICMP group compared with the NICMP group (ICMP 38.71% vs. NICMP 17.24%; p = 0.07). The rate of one-year all-cause mortality was similar in both groups (ICMP 6.5% vs. NICMP 6.6%; log-rank = 0.9947). Conclusions: This study shows that, although the treatment with ARNI improves the LVEF in ICMP and NICMP patients, the risk of ventricular tachyarrhythmias remains higher in ICMP patients in comparison with NICMP patients. Renal function is improved in the NICMP group after the treatment. Long-term mortality is similar over a one-year follow-up. Full article