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BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P

Magenkarzinome und Adenokarzinome des osophagogastralen Ubergangs werden in Studien und Leitlinien trotz der teils unterschiedlichen Pathogenese, Tumorbiologie und klinischen Behandlungsalgorithmen haufig gemeinsam untersucht. Die Unterscheidung nach der Lokalisation ist jedoch insbesondere fur die lokalen Therapiemasnahmen entscheidend. Bei der onkologischen Resektion mit systematischer Lymphadenektomie unterscheiden sich Lymphabflusswege erheblich und verschiedene chirurgische Zugangswege sind zu berucksichtigen. Auch fur strahlentherapeutische Therapieoptionen spielt die Tumorlokalisation eine wichtige Rolle. Im vorliegenden Beitrag wird detailliert auf folgende Themen eingegangen: Pathogenese und Pathologie, Primardiagnostik und Staging, kurative chirurgische und endoskopische Therapie, perioperative Therapie, palliative Systemtherapie, nichtmedikamentose Supportiv- und Palliativtherapie.

Abstract introduction Odontogenic Keratocysts are benign, developmental, locally aggressive odontogenic cystic lesions with a high risk of recurrence. As such, the most effective treatment modalities remain controversial. The mainstay of treatment remains enucleation with or without decompression. The use of adjunctive therapies is widely reported. Aims To review our experience of OKCs and therefore identify the treatment modality, if any single one, with the lowest rate of recurrence. We also aimed to identify any common themes linking those patients experiencing cystic recurrence. Methods Data was collected on 50 patients treated at UHCW NHS Trust over a 14 year period (2005-2018) via an anonymised database. Surgical pathways were analysed, including details of the location of the cysts and the use of adjunctive therapies, namely; mechanical debridement, cryotherapy, and the use of Carnoy’s solution. Results 56 keratocysts, both primary (91%, n = 51) and recurrent (9%, n = 5) were included. 6% of patients had a pre-existing diagnosis of Gorlin-Goltz Syndrome (n = 3). Enucleation was performed in an approximately 3:1 ratio to decompression with secondary enucleation (n = 41:15). 27% patients had adjunctive therapies (n = 15). There was a 12% recurrence rate (n = 6) found only within the group of primary cysts that had been enucleated alone. Notably, there were no recurrences in those cysts that had undergone adjunctive therapy. None of the cysts that underwent initial decompression or marsupialisation recurred. Following surgical intervention, no tertiary recurrent cysts were detected post-operatively. Conclusions This study demonstrates the advantage of establishing a correct diagnosis prior to definitive treatment. Initial decompression in selected patients followed by enucleation, along with adjunctive therapies show a benefit in reducing recurrences. However, in the absence of high-quality evidence for the most effective management of Odontogenic Keratocysts, finding a common approach will remain controversial.

Objective\ud To determine the characteristics and outcomes of pregnancy in women with Turner Syndrome\ud \ud Design\ud Retrospective 20-year cohort study (2000-2020)\ud \ud Setting\ud 16 tertiary referral maternity units in the UK\ud \ud Population or Sample\ud 81 women with Turner syndrome who became pregnant\ud \ud Methods\ud Retrospective chart analysis\ud \ud Main Outcome Measures\ud Mode of conception, pregnancy outcomes\ud \ud Results\ud We obtained data on 127 pregnancies in 81 women with a Turner phenotype. All non-spontaneous pregnancies (54/127 (42.5%)) were by egg donation. Only 9/31 (29%) of pregnancies in women with karyotype 45,X were spontaneous, compared with 53/66 (80.3%) with mosaic karyotype 45,X/46,XX (p

Neurons in the organum vasculosum of the lamina terminalis (OVLT) sense extracellular NaCl and angiotensin II concentrations to regulate body fluid homeostasis and arterial blood pressure. Lesion of the anteroventral third ventricular region or OVLT attenuates multiple forms of neurogenic hypertension. However, the extent by which OVLT neurons directly regulate sympathetic nerve activity to produce hypertension is not known. Therefore, the present study tested this hypothesis by using a multi-faceted approach including optogenetics, single-unit and multifiber nerve recordings, and chemogenetics. First, optogenetic activation of OVLT neurons in conscious Sprague-Dawley rats (250–400 g) produced frequency-dependent increases in arterial blood pressure and heart rate. These responses were not altered by the vasopressin receptor antagonist (β-mercapto-β,β-cyclopentamethylenepropionyl1,O-me-Tyr2,Arg8)–vasopressin but eliminated by the ganglionic blocker chlorisondamine. Second, optogenetic activation of OVLT neurons significantly elevated renal, splanchnic, and lumbar sympathetic nerve activity. Third, single-unit recordings revealed optogenetic activation of the OVLT significantly increased the discharge of bulbospinal, sympathetic neurons in the rostral ventrolateral medulla. Lastly, chronic chemogenetic activation of OVLT neurons for 7 days significantly increased 24-hour fluid intake and mean arterial blood pressure. When the 24-hour fluid intake was clamped at baseline intakes, chemogenetic activation of OVLT neurons still produced a similar increase in arterial blood pressure. Neurogenic pressor activity assessed by the ganglionic blocker chlorisondamine was greater at 7 days of OVLT activation versus baseline. Collectively, these findings indicate that acute or chronic activation of OVLT neurons produces a sympathetically mediated hypertension.

As blood clots age, many thrombolytic techniques become less effective. In order to fully evaluate these techniques for potential clinical use, a large animal, aged-clot model is needed. Previous minimally invasive attempts to allow clots to age in an in-vivo large animal model were unsuccessful due to the clot clearance associated with relatively high level of cardiac health of readily available research pigs. Prior models have thus subsequently utilized invasive surgical techniques with the associated morbidity, animal stress, and cost. We propose a method for forming sub-acute venous blood clots in an in-vivo porcine model. The age of the clots can be controlled and varied. By using an intravenous scaffold to anchor the clot to the vessel wall during the aging process, we can show that sub-acute clots can consistently be formed with a minimally invasive, percutaneous approach. The clot formed in this study remained intact for at least one week in all subjects. Therefore, we established a new minimally invasive, large animal aged-clot model for evaluation of thrombolytic techniques.

BACKGROUND Therapeutic drug monitoring is recommended to guide tacrolimus dosing because of its narrow therapeutic window and considerable pharmacokinetic variability. This study assessed tacrolimus dosing and monitoring practices in heart transplant recipients and evaluated the predictive performance of a Bayesian forecasting software using a renal transplant-derived tacrolimus model to predict tacrolimus concentrations. METHODS A retrospective audit of heart transplant recipients (n = 87) treated with tacrolimus was performed. Relevant data were collected from the time of transplant to discharge. The concordance of tacrolimus dosing and monitoring according to hospital guidelines was assessed. The observed and software-predicted tacrolimus concentrations (n = 931) were compared for the first 3 weeks of oral immediate-release tacrolimus (Prograf) therapy, and the predictive performance (bias and imprecision) of the software was evaluated. RESULTS The majority (96%) of initial oral tacrolimus doses were guideline concordant. Most initial intravenous doses (93%) were lower than the guideline recommendations. Overall, 36% of initial tacrolimus doses were administered to transplant recipients with an estimated glomerular filtration rate of

BACKGROUND AND AIM Identification of the most appropriate population pharmacokinetic model-based Bayesian estimation is required prior to its implementation in routine clinical practice to inform tacrolimus dosing decisions. This study aimed to determine the predictive performances of relevant population pharmacokinetic models of tacrolimus developed from various solid organ transplant recipient populations in adult heart transplant recipients, stratified based on concomitant azole antifungal use. Concomitant azole antifungal therapy alters tacrolimus pharmacokinetics substantially, necessitating dose adjustments. METHODS Population pharmacokinetic models of tacrolimus were selected (n = 17) for evaluation from a recent systematic review. The models were transcribed and implemented in NONMEM version 7.4.3. Data from 85 heart transplant recipients (2387 tacrolimus concentrations) administered the oral immediate-release formulation of tacrolimus (Prograf) were obtained up to 391 days post-transplant. The performance of each model was evaluated using: (i) prediction-based assessment (bias and imprecision) of the individual predicted tacrolimus concentration of the fourth dosing occasion (MAXEVAL = 0, FOCE-I) from 1-3 prior dosing occasions; and (ii) simulation-based assessment (prediction-corrected visual predictive check). Both assessments were stratified based on concomitant azole antifungal use. RESULTS Regardless of the number of prior dosing occasions (1-3) and concomitant azole antifungal use, all models demonstrated unacceptable individual predicted tacrolimus concentration of the fourth dosing occasion (n = 152). The prediction-corrected visual predictive check graphics indicated that these models inadequately predicted observed tacrolimus concentrations. CONCLUSION All models evaluated were unable to adequately describe tacrolimus pharmacokinetics in adult heart transplant recipients included in this study. Further work is required to describe tacrolimus pharmacokinetics for our heart transplant recipient cohort.

Background Hospitals throughout the United Kingdom face significant challenges in regards to inpatient bed capacity, leading to growing interest in day case arthroplasty. Day case Unicompartmental Knee Replacement (UKR) has been offered within our unit since 2010, with successive evaluations of pathway outcomes performed in 2011 and 2015. Since then, our day case UKR pathway has expanded. This study aims to evaluate the safety, efficiency and patient satisfaction with this expanded pathway. Methods Data was prospectively collected for all patients undergoing a UKR between January 2017 and August 2019. Data collected included the pathway planned, date of admission, date of discharge and re-admissions to hospital within 30 days of surgery. Patient satisfaction was evaluated via a follow-up questionnaire. Results 109 patients underwent a UKR between January 2017 and August 2019. 83 patients (76%) were planned through the day case pathway. 63 patients were successfully discharged on the day of surgery. One day case pathway and two inpatient pathway patients were re-admitted within 30 days of surgery with medical conditions. A high level of patient satisfaction with our day case pathway was identified. Conclusion UKR with planned discharge on the day of surgery is possible for a large proportion of patients provided that robust pathway and protocol design is undertaken. Following 10 years’ experience, our day case UKR pathway has increasingly become the default for the majority of our patients. We report high patient satisfaction and low 30-day re-admission rates. However, 100% success rate for day of surgery discharge remains challenging.

BACKGROUND: Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. METHODS: Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. RESULTS: Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. CONCLUSIONS: Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.

To assess the precision of MRI radiomics features in hepatocellular carcinoma (HCC) tumors and liver parenchyma. The study population consisted of 55 patients, including 16 with untreated HCCs, who underwent two repeat contrast-enhanced abdominal MRI exams within 1 month to evaluate: (1) test–retest repeatability using the same MRI system (n = 28, 10 HCCs); (2) inter-platform reproducibility between different MRI systems (n = 27, 6 HCCs); (3) inter-observer reproducibility (n = 16, 16 HCCs). Shape and 1st- and 2nd-order radiomics features were quantified on pre-contrast T1-weighted imaging (WI), T1WI portal venous phase (pvp), T2WI, and ADC (apparent diffusion coefficient), on liver regions of interest (ROIs) and HCC volumes of interest (VOIs). Precision was assessed by calculating intraclass correlation coefficient (ICC), concordance correlation coefficient (CCC), and coefficient of variation (CV). There was moderate to excellent test–retest repeatability of shape and 1st- and 2nd-order features for all sequences in HCCs (ICC: 0.53–0.99; CV: 3–29%), and moderate to good test–retest repeatability of 1st- and 2nd-order features for T1WI sequences, and 2nd-order features for T2WI in the liver (ICC: 0.53–0.73; CV: 12–19%). There was poor inter-platform reproducibility for all features and sequences, except for shape and 1st-order features on T1WI in HCCs (CCC: 0.58–0.99; CV: 3–15%). Good to excellent inter-observer reproducibility was found for all features and sequences in HCCs (CCC: 0.80–0.99; CV: 4–15%) and moderate to good for liver (CCC: 0.45–0.86; CV: 6–25%). MRI radiomics features have acceptable repeatability in the liver and HCC when using the same MRI system and across readers but have low reproducibility across MR systems, except for shape and 1st-order features on T1WI. Data must be interpreted with caution when performing multiplatform radiomics studies. • MRI radiomics features have acceptable repeatability when using the same MRI system but less reproducible when using different MRI platforms. • MRI radiomics features extracted from T1 weighted-imaging show greater stability across exams than T2 weighted-imaging and ADC. • Inter-observer reproducibility of MRI radiomics features was found to be good in HCC tumors and acceptable in liver parenchyma.

Changes in discharge disposition and delays in discharge negatively impact the patient and hospital system. Our objectives wereDischarge dispositions and barriers to discharge for 200 TEGS patients were predicted individually by members of the multidisciplinary TEGS team within 24 h of patient admission. Univariate analyses and multivariable logistic least absolute shrinkage and selection operator regressions determined the associations between patient characteristics and correct predictions.A total of 1,498 predictions of discharge disposition were made by the multidisciplinary TEGS team for 200 TEGS patients. Providers correctly predicted 74% of discharge dispositions. Prediction accuracy was not associated with clinical experience or job title. Incorrect predictions were independently associated with older age (OR 0.98; P0.001), trauma admission as compared to emergency general surgery (OR 0.33; P0.001), higher Injury Severity Scores (OR 0.96; P0.001), longer lengths of stay (OR 0.90; P0.001), frailty (OR 0.43; P = 0.001), ICU admission (OR 0.54; P0.001), and higher Acute Physiology and Chronic Health Evaluation II scores (OR 0.94; P = 0.006).The TEGS team can accurately predict the majority of discharge dispositions. Patients with risk factors for unpredictable dispositions should be flagged to better allocate appropriate resources and more intensively plan their discharges.

Objective To compare therapeutic hypothermia (TH) treatment of term and near-term neonates with hypoxic-ischemic encephalopathy (HIE) between neonatal units. Study design Population-based, retrospective analysis of TH initiation and maintenance, and of diagnostic imaging. The comparison between units was based on crude data analysis, indirect standardization, and adjusted logistic regression. Results TH was provided to 570 neonates with HIE between 2011 and 2018 in 10 Swiss units. We excluded 121 off-protocol cooled neonates to avoid selection bias. Of the remaining 449 neonates, the outcome was favorable to international benchmarks, but there were large unit-to-unit variations in baseline perinatal data and TH management. A total of 5% neonates did not reach target temperature within 7 h (3–10% between units), and 29% experienced over- or undercooling (0–38%). Conclusion Although the neonates had favorable short-term outcomes, areas for improvement remain for Swiss units in both process and outcome measures.

Simulationsbasierte Aus- und Weiterbildung wird von aktuellen Reanimationsrichtlinien empfohlen. Die Nutzung von simulationsbasierten Trainings ist jedoch insbesondere im deutschsprachigen Raum divers und uneinheitlich. Aus diesem Grund machte es sich die Arbeitsgruppe „Padiatrische Simulation und Patient*innensicherheit“ der Osterreichischen Gesellschaft fur Kinder- und Jugendheilkunde zum Ziel, Standards fur das (innerklinische) Simulatortraining von Basisreanimationsmasnahmen zu definieren. Neunzehn Expert*innen aus den Bereichen Kinder- und Jugendheilkunde, Neonatologie, padiatrische Intensivmedizin, Kinder- und Jugendlichenpflege, Aus- und Weiterbildung sowie medizinische Simulation definierten im Rahmen eines Arbeitsgruppentreffens Ausrichtung und Struktur des angestrebten Positionspapiers. Fur die jeweiligen Unterkapitel wurden in Kleingruppen wissenschaftliche Literatur gesucht und Textentwurfe formuliert, die im Anschluss von der gesamten Autor*innengruppe begutachtet und revidiert wurden. Die in mehreren Arbeitsschritten erstellte vorlaufige Endversion wurde im Rahmen einer abschliesenden Delphi-Runde an alle Mitglieder der Arbeitsgruppe zur Begutachtung ausgesandt. Nach Prufung und Einarbeitung der im Rahmen der Delphi-Runde aufgeworfenen Anregungen wurde das sechzehnseitige Dokument im November 2020 mit uber 90 %iger Zustimmung von den Arbeitsgruppenmitgliedern akkordiert. Das vorliegende Positionspapier definiert (Mindest‑)Standards fur Zielgruppen, Trainer*innenqualifikation, Inhalte, praktische Durchfuhrung, Frequenz und Lernumgebung von Basiswiederbelebungstrainings und dient damit der Qualitatssicherung solch wesentlicher Aus- und Weiterbildungsmasnahmen.

Background and purpose Reduced renal blood flow triggers activation of the renin-angiotensin-aldosterone system (RAAS) leading to renovascular hypertension. Renal vascular smooth muscle expression of the NO receptor, soluble GC (sGC), modulates the vasodilator response needed to control renal vascular tone and blood flow. Here, we tested if angiotensin II (Ang II) affects sGC expression via an AT1 receptor-forkhead box subclass O (FoxO) transcription factor dependent mechanism. Experimental approach Using a murine two-kidney-one-clip (2K1C) renovascular hypertension model, we measured renal artery vasodilatory function and sGC expression. Additionally, we conducted cell culture studies using rat renal pre-glomerular smooth muscle cells (RPGSMCs) to test the in vitro mechanistic effects of Ang II treatment on sGC expression and downstream function. Key results Contralateral, unclipped renal arteries in 2K1C mice showed increased NO-dependent vasorelaxation compared to sham control mice. Immunofluorescence studies revealed increased sGC protein expression in 2K1C contralateral renal arteries over sham controls. RPGSMCs treated with Ang II caused a significant up-regulation of sGC mRNA and protein expression as well as downstream sGC-dependent signalling. Ang II signalling effects on sGC expression occurred through an AT1 receptor and FoxO transcription factor-dependent mechanism at both the mRNA and protein expression levels. Conclusion and implications Renal artery smooth muscle, in vivo and in vitro, up-regulates expression of sGC following RAAS activity. In both cases, up-regulation of sGC leads to increased downstream cGMP signalling, suggesting a previously unrecognized protective mechanism to improve renal blood flow in the uninjured contralateral renal artery.

Introduction: Patients with symptoms (Sx) of gastrointestinal (GI) motor disorders have limitations in physical strength and mobility. We hypothesized that physical frailty correlated with severity of GI symptoms, and that a motility frailty index (MFI) could be constructed. Patients: We conducted a prospective pilot study on 40 patients, (38 F, 2 M, mean age 39.9 years) with the following diagnoses: 10 with diabetes mellitus and 30 with non-diabetic/idiopathic disorders. Upper and lower GI Sx were quantified using an FDA-compliant, traditional patient-reported outcomes (PRO) system. Methods: Patients underwent a series of physical performance measures involving standing balance (SB), usual walk speed (UW), and chair sit-and-stands (CS). A GI motility frailty index (MFI) was constructed by fitting several models with a combination of physical performance measures and correlating with PRO. Pearson’s correlation compared the constructed index with the GI Sx PRO to construct a GI MFI. Results: The studied patients collectively showed marked limitations in mobility compared with standard performance values with mean (sd) ratios of SB = 0.87 (0.20), UW = 0.45 (0.13), and CS = 0.38 (0.17). Correlations between physical mobility and GI Sx were noted for upper GI Sx (rho = 0.47, p = 0.002) but not for lower GI Sx. Conclusions: In this pilot study of patients with GI motility disorders, we found increased physical limitations on performance-based testing, which had a statistically significant positive correlation with severity of upper GI motor Sx using a standardized PRO system. A motility frailty index has been constructed that may serve as a basis for better quantifying limitations in patient mobility.

According to current German and European clinical practice guidelines perioperative chemotherapy is the recommended standard of care for localized gastric cancer beyond early cancers, i.e. in stage IB (T2 N0 M0 and T1 N1 M0) or greater. For patients who are able to tolerate intensive chemotherapy, the FLOT regimen (5-fluorouracil, folinic acid, oxaliplatin, docetaxel) should be administered preoperatively and postoperatively for four cycles each. Locally advanced nonmetastatic adenocarcinoma of the esophagogastric junction (AEG) should be treated with perioperative chemotherapy as for gastric cancer or alternatively with neoadjuvant chemoradiotherapy. The best approach for AEG is currently being investigated in ongoing clinical trials. The recommendation of perioperative treatment applies to all histopathological subtypes of gastric cancer. The article summarizes the contemporary data and provides an outlook on current progress in the field of medicinal perioperative treatment.

The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway upregulates key cellular defenses. Clinical trials are utilizing pharmacologic Nrf2 inducers such as bardoxolone methyl to treat chronic kidney disease, but Nrf2 activation has been linked to a paradoxical increase in proteinuria. To understand this effect, we examined genetically engineered mice with elevated Nrf2 signaling due to reduced expression of the Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1). These Keap1FA/FA mice lacked baseline proteinuria but exhibited increased proteinuria in experimental models evoked by adriamycin, angiotensin II, or protein overload. After injury, Keap1FA/FA mice had increased glomerulosclerosis, nephrin disruption and shedding, podocyte injury, foot process effacement, and interstitial fibrosis. Keap1FA/FA mice also had higher daytime blood pressures and lower heart rates measured by radiotelemetry. Conversely, Nrf2 knockout mice were protected from proteinuria. We also examined the pharmacologic Nrf2 inducer CDDO-Im. Compared to angiotensin II alone, the combination of angiotensin II and CDDO-Im significantly increased proteinuria, a phenomenon not observed in Nrf2 knockout mice. This effect was not accompanied by additional increases in blood pressure. Finally, Nrf2 was found to be upregulated in the glomeruli of patients with focal segmental glomerulosclerosis, diabetic nephropathy, fibrillary glomerulonephritis, and membranous nephropathy. Thus, our studies demonstrate that Nrf2 induction in mice may exacerbate proteinuria in chronic kidney disease.

Purpose The importance and impact of determining which trauma patients need to be transferred between hospitals, especially considering prehospital triage systems, is evident. The objective of this study was to investigate the association between mortality and primary admission and secondary transfer of patients to level I and II trauma centers, and to identify predictors of primary and secondary admission to a designated level I trauma center. Methods Data from the Dutch Trauma Registry South West (DTR SW) was obtained. Patients ≥ 18 years who were admitted to a level I or level II trauma center were included. Patients with isolated burn injuries were excluded. In-hospital mortality was compared between patients that were primarily admitted to a level I trauma center, patients that were transferred to a level I trauma center, and patients that were primarily admitted to level II trauma centers. Logistic regression models were used to adjust for potential confounders. A subgroup analysis was done including major trauma (MT) patients (ISS > 15). Predictors determining whether patients were primarily admitted to level I or level II trauma centers or transferred to a level I trauma center were identified using logistic regression models. Results A total of 17,035 patients were included. Patients admitted primarily to a level I center, did not differ significantly in mortality from patients admitted primarily to level II trauma centers (Odds Ratio (OR): 0.73; 95% confidence interval (CI) 0.51–1.06) and patients transferred to level I centers (OR: 0.99; 95%CI 0.57–1.71). Subgroup analyses confirmed these findings for MT patients. Adjusted logistic regression analyses showed that age (OR: 0.96; 95%CI 0.94–0.97), GCS (OR: 0.81; 95%CI 0.77–0.86), AIS head (OR: 2.30; 95%CI 2.07–2.55), AIS neck (OR: 1.74; 95%CI 1.27–2.45) and AIS spine (OR: 3.22; 95%CI 2.87–3.61) are associated with increased odds of transfers to a level I trauma center. Conclusions This retrospective study showed no differences in in-hospital mortality between general trauma patients admitted primarily and secondarily to level I trauma centers. The most prominent predictors regarding transfer of trauma patients were age and neurotrauma. These findings could have practical implications regarding the triage protocols currently used.

Background: Vancomycin pharmacokinetics are best described using a 2-compartment model. However, 1-compartment population models are commonly used as the basis for dose prediction software.Therefore, the validity of using a 1-compartment model to guide vancomycin drug dosing was examined Methods: Published plasma concentration-time data from adult subjects (n = 30) with stable renal function administered a single intravenous infusion of vancomycin were extracted from previous studies. The vancomycin area under the curve (AUC0-N) was calculated for each subject using noncompartmental methods (AUCNCA) and by fitting 1- (AUC1CMT), 2- (AUC2CMT), and 3- (AUC3CMT)compartment infusion models. The optimal model fit was determined using the Akaike information criterion and visual inspection of the residual plots. The individual compartmental AUC0-N values from the 1- and 2-compartment models were compared with AUCNCA values using one-way repeated measures analysis of variance Results: The mean (6SD) AUC estimates were similar for the different methods: AUCNCA 180 6 86 mg$h/L, AUC1CMT 167 679 mg$h/L, and AUC2CMT 183 6 88 mg$h/L. Despite the overlapping AUC values, AUC2CMT and AUCNCA were significantly greater than AUC1CMT (P , 0.05). The 3-compartment model was excluded from the analysis because of the failure to converge in some instances Conclusions: Dose prediction software using a 1-compartmentmodel as the basis for Bayesian forecasting underestimates drug exposure (estimated as the AUC) by less than 10%. This is unlikely to be clinically significant with respect to dose adjustment.Therefore, a 1-compartment model may be sufficient to guide vancomycin dosing in adult patients with stable renal function. Refereed/Peer-reviewed

Gastroparesis, which can be viewed as a syndrome featuring nausea, vomiting, and abdominal pain, and associated other symptoms and findings, is increasingly seen by surgeons. Gastroparesis is associated with a number of gastrointestinal anatomic and physiologic findings. This article reviews the use of bioelectric therapy of neuromodulation, via gastric electrical stimulation, for patients with drug refractory gastroparesis syndromes including surgical aspects of device placement and subsequent management. In addition to an overall approach to the placement and subsequent management of gastric electrical stimulation devices, several newer concepts are discussed. The role of pyloric dysfunction in gastroparesis is also discussed including how stimulation devices and pyloric therapies may be used in concert. The additions of full-thickness gastrointestinal biopsies along with other physiologic, including GI electrophysiology, as well as some serologic measures, are also discussed. In addition, evolving approaches and emerging technologies for bioelectric neuromodulation of the gastrointestinal tract are introduced. Gastroparesis syndromes can be approached in a systematic manner based on known pathophysiology and when indicated can be helped with surgical therapies including neuromodulation.

To (1) develop a fully automated deep learning (DL) algorithm based on gadoxetic acid–enhanced hepatobiliary phase (HBP) MRI and (2) compare the diagnostic performance of DL vs. MR elastography (MRE) for noninvasive staging of liver fibrosis. This single-center retrospective study included 355 patients (M/F 238/117, mean age 60 years; training, n = 178; validation, n = 123; test, n = 54) who underwent gadoxetic acid–enhanced abdominal MRI, including HBP and MRE, and pathological evaluation of the liver within 1 year of MRI. Cropped liver HBP images from a custom-written fully automated liver segmentation were used as input for DL. A transfer learning approach based on the ImageNet VGG16 model was used. Different DL models were built for the prediction of fibrosis stages F1-4, F2-4, F3-4, and F4. ROC analysis was performed to evaluate the performance of DL in training, validation, and test sets and of MRE liver stiffness in the test set. AUC values of DL were 0.99/0.70/0.77 (F1-4), 0.92/0.71/0.91 (F2-4), 0.91/0.78/0.90 (F3-4), and 0.98/0.83/0.85 (F4) for training/validation/test sets, respectively. The AUCs of MRE liver stiffness in the test set were 0.86 (F1-4), 0.87 (F2-4), 0.92 (F3-4), and 0.86 (F4). AUCs of MRE and DL were not significantly different for any of the fibrosis stages (p > 0.134). The fully automated DL models based on HBP gadoxetic acid MRI showed good-to-excellent diagnostic performance for staging of liver fibrosis, with similar diagnostic performance to MRE. After validation in independent sets, the DL algorithm may allow for noninvasive liver fibrosis assessment without the need for additional MRI hardware. • The developed deep learning algorithm, based on routine standard-of-care gadoxetic acid–enhanced MRI data, showed good-to-excellent diagnostic performance for noninvasive staging of liver fibrosis. • The diagnostic performance of the deep learning algorithm was equivalent to that of MR elastography in a separate test set.

Objectives To estimate the population prevalence of clinically significant symptoms of depression, generalised anxiety, thoughts of being better off dead, irritability, and high optimism about the future, and of direct experience of COVID‐19, loss of employment caused by COVID‐19 restrictions, worry about contracting COVID‐19, or major disadvantage because of the restrictions; to examine the relationship between these experiences and reporting mental symptoms. Design, setting, participants Anonymous online survey of adult Australian residents, 3 April – 2 May 2020. Main outcome measures Self‐reported psychological status during the preceding fortnight assessed with the Patient Health Questionnaire 9 (PHQ‐9; symptoms of depression) and the Generalised Anxiety Disorder Scale (GAD‐7). Optimism about the future was assessed with a 10‐point study‐specific visual analogue scale. Results 13 829 respondents contributed complete response data. The estimated prevalence of clinically significant symptoms of depression (PHQ‐9 ≥ 10) was 27.6% (95% CI, 26.1–29.1%) and of clinically significant symptoms of anxiety (GAD‐7 ≥ 10) 21.0% (95% CI, 19.6–22.4%); 14.6% of respondents (95% CI, 13.5–16.0%) reported thoughts of being better off dead or self‐harm (PHQ‐9, item 9) on at least some days and 59.2% (95% CI, 57.6–60.7%) that they were more irritable (GAD‐7, item 6). An estimated 28.3% of respondents (95% CI, 27.1–29.6%) reported great optimism about the future (score ≥ 8). People who had lost jobs, were worried about contracting COVID‐19, or for whom the restrictions had a highly adverse impact on daily life were more likely to report symptoms of depression or anxiety, and less likely to report high optimism than people without these experiences. Conclusions Mental health problems were widespread among Australians during the first month of the stage two COVID‐19 restrictions; in addition, about one‐quarter of respondents reported mild to moderate symptoms of depression or anxiety. A public mental health response that includes universal, selective and indicated clinical interventions is needed.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a major advance in the fields of diabetology, nephrology, and cardiology. The cardiovascular and renal benefits of SGLT2 inhibitors are likely largely independent of their glycaemic effects, and this understanding is central to the use of these agents in the high-risk population of people with type 2 diabetes and chronic kidney disease. There are a number of potential safety issues associated with the use of SGLT2 inhibitors. These include the rare but serious risks of diabetic ketoacidosis and necrotising fasciitis of the perineum. The data regarding a possibly increased risk of lower limb amputation and fracture with SGLT2 inhibitor therapy are conflicting. This article aims to explore the potential safety issues associated with the use of SGLT2 inhibitors, with a particular focus on the safety of these drugs in people with type 2 diabetes and chronic kidney disease. We discuss strategies that clinicians can implement to minimise the risk of adverse effects including diabetic ketoacidosis and volume depletion. Risk mitigation strategies with respect to SGLT2 inhibitor-associated diabetic ketoacidosis are of particular importance during the current coronavirus disease 2019 (COVID-19) pandemic.

(1) Determine inter-observer reproducibility and test-retest repeatability of 4D flow parameters in renal allograft vessels; (2) determine if 4D flow measurements in the renal artery (RA) and renal vein (RV) can distinguish between functional and dysfunctional allografts; (3) correlate haemodynamic parameters with estimated glomerular filtration rate (eGFR), perfusion measured with dynamic contrast-enhanced MRI (DCE-MRI) and histopathology. Twenty-five prospectively recruited renal transplant patients (stable function/chronic renal allograft dysfunction, 12/13) underwent 4D flow MRI at 1.5 T. 4D flow coronal oblique acquisitions were performed in the transplant renal artery (RA) (velocity encoding parameter, VENC = 120 cm/s) and renal vein (RV) (VENC = 45 cm/s). Test-retest repeatability (n = 3) and inter-observer reproducibility (n = 10) were assessed by Cohen’s kappa, coefficient of variation (CoV) and Bland-Altman statistics. Haemodynamic parameters were compared between patients and correlated to the estimated glomerular filtration rate, DCE-MRI parameters (n = 10) and histopathology from allograft biopsies (n = 15). For inter-observer reproducibility, kappa was > 0.99 and 0.62 and CoV of flow was 12.6% and 7.8% for RA and RV, respectively. For test-retest repeatability, kappa was > 0.99 and 0.5 and CoV of flow was 27.3% and 59.4%, for RA and RV, respectively. RA (p = 0.039) and RV (p = 0.019) flow were both significantly reduced in dysfunctional allografts. Both identified chronic allograft dysfunction with good diagnostic performance (RA: AUC = 0.76, p = 0.036; RV: AUC = 0.8, p = 0.018). RA flow correlated negatively with histopathologic interstitial fibrosis score ci (ρ = − 0.6, p = 0.03). 4D flow parameters had better repeatability in the RA than in the RV. RA and RV flow can identify chronic renal allograft dysfunction, with RA flow correlating with histopathologic interstitial fibrosis score. • Inter-observer reproducibility of 4D flow measurements was acceptable in both the transplant renal artery and vein, but test-retest repeatability was better in the renal artery than in the renal vein. • Blood flow measurements obtained with 4D flow MRI in the renal artery and renal vein are significantly reduced in dysfunctional renal transplants. • Renal transplant artery flow correlated negatively with histopathologic interstitial fibrosis score.

BackgroundNational economies are increasingly facing the challenge of having to finance the prevention and treatment of human diseases, and of having to compensate for the resulting loss of economic production. Physical inactivity is demonstrably closely related to the risk of developing certain disease group. Physical inactivity results in direct and indirect burdens that the present study intends to quantify in Hungary for the period between 2005 and 2017.MethodsBased on the data of the Hungarian public finances, this study determines the direct and indirect costs incurred by Hungary due to illnesses, and, through the PAR method, it quantifies the financial burden of physical inactivity incurred by the Hungarian Treasury.ResultsThe total financial burden of illnesses in Hungary showed a decreasing tendency from 2005 to 2017, even though the year 2017 saw an increase in costs compared to 2014. Similarly, while total public expenditure on illnesses associated with physical inactivity increased by 2017 when compared to 2009, the total amount attributable to medical conditions stemming from physical inactivity still showed a decrease of 2 billion HUF in the overall period. The biggest economic burden is posed by cardiovascular diseases, hypertension and type 2 diabetes.ConclusionsThe increase in the economic burden associated with physical inactivity can be attributed to the combined effect of two factors: changes in total expenditure on specific disease groups (which showed an increase in the period under review) and changes in the physical activity levels of the Hungarian population (which showed an improvement over the period under review). Initiatives in Hungary aimed at encouraging an active lifestyle from childhood onwards should be continued since – beyond the initial impact that has already been felt to some extent in recent years - these initiatives will come to their full fruition in the coming decades.

Acute kidney injury (AKI) is a risk factor for the development of chronic kidney disease (CKD). One mechanism for this phenomenon is renal microvascular rarefaction and subsequent chronic impairment in perfusion. However, diagnostic tools to monitor the renal microvasculature in a noninvasive and quantitative manner are still lacking. Ultrasound super-resolution imaging is an emerging technology that can identify microvessels with unprecedented resolution. Here, we applied this imaging technique to identify microvessels in the unilateral ischemia-reperfusion injury mouse model of AKI-to-CKD progression in vivo. Kidneys from 21 and 42 day post- ischemia-reperfusion injury, the contralateral uninjured kidneys, and kidneys from sham-operated mice were examined by ultrasound super-resolution and histology. Renal microvessels were successfully identified by this imaging modality with a resolution down to 32 μm. Renal fibrosis was observed in all kidneys with ischemia-reperfusion injury and was associated with a significant reduction in kidney size, cortical thickness, relative blood volume, and microvascular density as assessed by this imaging. Tortuosity of the cortical microvasculature was also significantly increased at 42 days compared to sham. These vessel density measurements correlated significantly with CD31 immunohistochemistry (R(2)=0.77). Thus, ultrasound super-resolution imaging provides unprecedented resolution and is capable of noninvasive quantification of renal vasculature changes associated with AKI-to-CKD progression in mice. Hence, this technique could be a promising diagnostic tool for monitoring progressive kidney disease.

While medical nutrition therapy is an essential part of the care for critically ill patients, uncertainty exists about the right form, dosage, timing and route in relation to the phases of critical illness. As enteral nutrition (EN) is often withheld or interrupted during the intensive care unit (ICU) stay, combined EN and parenteral nutrition (PN) may represent an effective and safe option to achieve energy and protein goals as recommended by international guidelines. We hypothesise that critically ill patients at high nutritional risk may benefit from such a combined approach during their stay on the ICU. Therefore, we aim to test if an early combination of EN and high-protein PN (EN+PN) is effective in reaching energy and protein goals in patients at high nutritional risk, while avoiding overfeeding. This approach will be tested in the here-presented EFFORTcombo trial. Nutritionally high-risk ICU patients will be randomised to either high (≥2·2 g/kg per d) or low protein (≤1·2 g/kg per d). In the high protein group, the patients will receive EN+PN; in the low protein group, patients will be given EN alone. EN will be started in accordance with international guidelines in both groups. Efforts will be made to reach nutrition goals within 48–96 h. The efficacy of the proposed nutritional strategy will be tested as an innovative approach by functional outcomes at ICU and hospital discharge, as well as at a 6-month follow-up.

Gout is the most common form of inflammatory arthritis in men, yet both patients and the public often do not recognise gout as a form of arthritis. Instead, due to historical misconceptions, gout is typically seen as a lifestyle disease caused by poor diet. In reality, there are a number of risk factors that contribute to gout, including genetic factors. Views of gout as precipitated by lifestyle alone can lead to stigma, and maladaptive beliefs that it should be treated primarily through dietary changes. This is thought to contribute to poor uptake of, and adherence to, effective pharmaceutical treatments. Gout has some of the poorest medication adherence rates of any chronic disease, contributing to suboptimal health outcomes for patients. Recent research suggests that when gout is referred to as 'urate crystal arthritis' (a rarely used name for gout), the perception of the disease by members of the public was more accurate. It was viewed as being less under personal control (i.e. less appropriately managed by behaviours such as dietary intake), and more appropriately managed by long-term medical treatment. This finding raises the possibility that patients themselves might also benefit from gout being explicitly labelled as arthritis. Indeed, parallels can be drawn between this case and other diseases that have recently had their names changed to improve outcomes, namely primary biliary cirrhosis and schizophrenia. A movement away from the term gout may benefit those living with the disease by changing illness perceptions and increasing uptake of, and adherence to, guideline-recommended treatment(s).

Human epidermal growth factor-receptor-2 (HER2) is a membrane-tyrosine-kinase that is amplified/overexpressed up to 20% in breast cancer. HER2 positive status is associated with faster disease progression, higher metastatic potential, and shorter disease-free/overall survival and also has emerged as an important therapeutic target in breast cancer. HER2 status can be determined by in-situ-hybridization (ISH) or immunohistochemistry (IHC). Although the concordance rate between ISH and IHC is well-known, the prognostic power of both technologies if tested in parallel on the same tumor has not been studied extensively. In this study we retrospectively analyzed a large HER2 positive breast cancer cohort tested both with fluorescence labeled ISH (FISH) and IHC in parallel on each case. We stratified HER2 positive results by FISH and IHC with long-term overall survival, 5-year survival and metastases/recurrence rates. Positive HER2 status both FISH and IHC was available in 364 patients. The number of HER2 FISH-positive and FISH-negative patients was 342 and 22, respectively. The number of HER2 IHC 0/1 + , IHC 2 + , and IHC 3 + patients was 12, 42, and 310, respectively. Among the patients with IHC 3 + status, 288 were FISH-positive and 22 FISH-negative. HER2 status determined by FISH correlated with clinical outcomes (overall survival and with metastases/recurrence, p = 0.036, p = 0.039), whereas HER2 status determined by IHC did not. Our results indicate that prognostic information in HER2 positive breast cancer also depends on the methodology of how positivity was determined. In our cohort, FISH was superior to IHC based positive HER2 status.

Children who undergo open-heart surgery in the first year of life for congenital heart disease (CHD) are at high-risk for impaired development across multiple domains. International recommendations include systematic periodic developmental surveillance into adolescence and the establishment of long-term follow-up programmes. This article describes the establishment and evolution of the Queensland Paediatric Cardiac Service neurodevelopmental follow-up programme - CHD LIFE (Long-term Improvement in Functional hEalth). Contextualising best practice recommendations to ensure a family-centred and sustainable approach to understand and support the long-term functional health needs of high-risk children with CHD as standard care was needed. We describe the transition from a centralised pilot Programme to the implementation of an integrated statewide approach aimed at delivering consistent high-level standards of care and a platform to evaluate therapeutic interventions.

For clinically significant, locally confined prostate cancer, whole-gland radical prostatectomy and radiotherapy are established effective treatment strategies that, however, come at a cost of significant morbidity related to urinary and sexual side effects. The concept of risk stratification paired with a better understanding of prognostic factors has led to the development of alternative management options including active surveillance and focal therapy for appropriately selected patients with localized disease. High-intensity focused ultrasound (HIFU) is one such minimally invasive, image-guided treatment option for prostate cancer. Due to the relative novelty of HIFU and the increased use of magnetic resonance imaging in prostate cancer, many radiologists are not yet familiar with imaging findings related to HIFU, their temporal evolution as well as imaging appearance of recurrent disease after this type of focal therapy. HIFU induces sharply demarcated, localized coagulative necrosis of a tumor through thermal energy delivered via an endorectal or transurethral ultrasound transducer. In this pictorial review, we aim at providing relevant background information that will guide the reader through the general principles of HIFU in the prostate, as well as demonstrate the imaging appearance of expected post-HIFU changes versus recurrent tumor.

The strongest genetic risk factor for Alzheimer’s disease (AD) is the ε4 allele of Apolipoprotein E (APOE) and recent genome-wide association meta-analyses have confirmed additional associated genetic loci with smaller effects. The aim of this study was to investigate the ability of an AD polygenic risk score (PRS) and APOE status to predict clinical diagnosis of AD, vascular (VD), mixed (MD), and all-cause dementia in a community-based cohort prospectively followed over 17 years and secondarily across age, sex, and education strata. A PRS encompassing genetic variants reaching genome-wide significant associations to AD (excluding APOE) from the most recent genome-wide association meta-analysis data was calculated and APOE status was determined in 5203 participants. During follow-up, 103, 111, 58, and 359 participants were diagnosed with AD, VD, MD, and all-cause dementia, respectively. Prediction ability of AD, VD, MD, and all-cause dementia by the PRS and APOE was assessed by multiple logistic regression and receiver operating characteristic curve analyses. The PRS per standard deviation increase in score and APOE4 positivity (≥1 ε4 allele) were significantly associated with greater odds of AD (OR, 95% CI: PRS: 1.70, 1.45–1.99; APOE4: 3.34, 2.24–4.99) and AD prediction accuracy was significantly improved when adding the PRS to a base model of age, sex, and education (ASE) (c-statistics: ASE, 0.772; ASE + PRS, 0.810). The PRS enriched the ability of APOE to discern AD with stronger associations than to VD, MD, or all-cause dementia in a prospective community-based cohort.

Clinical Manifestations and Therapeutic Implications of Peritonitis Abstract. Peritonitis is a heterogenous disease, commonly classified into three types. Primary peritonitis, defined by the absence of another directly related intraabdominal abnormality, can often be treated conservatively and is thus distinguished from secondary peritonitis, which results from an independent diagnosis like the perforation or necrosis of an intraabdominal organ and usually requires surgical therapy. The more recently defined tertiary peritonitis is a form of secondary peritonitis that relapses or persists after 48 hours of adequate therapy with no surgically removable focus. This article addresses three important clinical manifestations of peritonitis and their therapeutic implications: spontaneous bacterial peritonitis as the mayor manifestation of primary peritonitis; postoperative peritonitis as a severe subform of secondary peritonitis; and peritoneal dialysis-associated peritonitis as a distinctive clinical picture.

Renovascular hypertension is characterized by activation of the renin-angiotensin-aldosterone system, blunted natriuretic responses, and elevated sympathetic nerve activity. Excess dietary salt intake exaggerates arterial blood pressure (ABP) in multiple models of experimental hypertension. The present study tested whether a high-salt diet exaggerated ABP and vascular dysfunction in a 2-kidney, 1-clip (2K1C) murine model. Male C57BL/6J mice (8–12 wk) were randomly assigned, and fed a 0.1% or 4.0% NaCl diet, and instrumented with telemetry units to measure ABP. Then, the 2K1C model was produced by placing a cuff around the right renal artery. Systolic, diastolic, and mean ABP were significantly higher in mice fed 4.0% vs. 0.1% NaCl at 1 wk but not after 3 wk. Interestingly, 2K1C hypertension progressively increased arterial pulse pressure in both groups; however, the magnitude was significantly greater in mice fed 4.0% vs. 0.1% NaCl at 3 wk. Moreover, pulse wave velocity was significantly greater in 2K1C mice fed 4.0% vs. 0.1% NaCl diet or sham-operated mice fed either diet. Histological assessment of aortas indicated no structural differences among groups. Finally, endothelium-dependent vasodilation was significantly and selectively attenuated in the aorta but not mesenteric arteries of 2K1C mice fed 4.0% NaCl vs. 0.1% NaCl or sham-operated control mice. The findings suggest that dietary salt loading transiently exaggerates 2K1C renovascular hypertension but promotes chronic aortic stiffness and selective aortic vascular dysfunction. NEW & NOTEWORTHY High dietary salt exaggerates hypertension in multiple experimental models. Here we demonstrate that a high-salt diet produces a greater increase in arterial blood pressure at 1 wk after induction of 2-kidney, 1-clip (2K1C) hypertension but not at 3 wk. Interestingly, 2K1C mice fed a high-salt diet displayed an exaggerated pulse pressure, elevated pulse wave velocity, and reduced endothelium-dependent vasodilation of the aorta but not mesenteric arteries. These findings suggest that dietary salt may interact with underlying cardiovascular disease to promote selective vascular dysfunction and aortic stiffness.

Factors underlying gastroparesis are not well defined. We hypothesized that multiple systems may be involved in patients with gastroparesis symptoms and performed a comparative physiologic study. We studied 43 consecutive eligible patients with gastroparetic symptoms categorized by GI symptoms, metabolic status, illness quantification, and gastric physiology. Patients were evaluated by two methods in each of five core areas: inflammatory, autonomic, enteric, electrophysiologic, and hormonal with abnormalities examined by correlations. Patients had similar GI symptoms regardless of baseline gastric emptying or diabetic/idiopathic status, and all patients demonstrated abnormalities in each of the 5 areas studied. Nearly all patients presented with elevated markers of serum TNFα (88%) and serum IL-6 (91%); elevated cutaneous electrogastrogram frequency (95%); and interstitial cells of Cajal count abnormalities (inner: 97%, outer: 100%). Measures of inflammation correlated with a number of autonomic, enteric anatomy, electrophysiologic and hormonal abnormalities. We conclude that patients with the symptoms of gastroparesis have multiple abnormalities, when studied by traditional, as well as newer, diagnostic assessments. Inflammation appears to be a fundamental abnormality that affects other organ systems in symptomatic patients. Future work on gastroparetic syndromes and their treatment may benefit from a focus on the diffuse nature of their illness, diverse pathophysiologic mechanisms involved, especially the possible causes of underlying inflammation and disordered hormonal status. This study is registered with Clinicaltrials.gov under study # NCT03178370 https://clinicaltrials.gov/ct2/show/NCT03178370 .

Introduction Prospective studies on a potential association of 8-iso-prostaglandin F2α (8-iso-PGF2α ) levels, a biomarker of lipid peroxidation, with dementia are limited. Methods Multivariate Cox regression models were used to assess potential associations of urinary 8-iso-PGF2α levels with all-cause, Alzheimer's disease (AD), and vascular dementia (VD) incidence in 5853 older adults from a German, population-based cohort. Results Over 14 years of follow-up, 365 all-cause dementia cases including 127 VD and 109 AD cases were diagnosed. Participants in the top compared to the bottom 8-iso-PGF2α tertile had a 45% increased risk of all-cause dementia incidence (hazard ratio [95% confidence interval]: 1.45 [1.12 to 1.88]). Interaction with the apolipoprotein E (APOE) ԑ4/ԑ4 genotype was detected (P = .02). Furthermore, continuously modeled, logarithmized 8-iso-PGF2α levels were statistically significantly associated with all-cause dementia and AD incidence. Discussion Oxidative stress may be involved in the pathogenesis of dementia. Individuals with increased 8-iso-PGF2α levels and the APOE ԑ4/ԑ4 genotype showed a considerably increased dementia risk.

Background Therapeutic drug monitoring (TDM) is recommended to guide voriconazole therapy. Objectives To determine compliance of hospital-based voriconazole dosing and TDM with the Australian national guidelines and evaluate the predictive performance of a one-compartment population pharmacokinetic voriconazole model available in a commercial dose-prediction software package. Methods A retrospective audit of voriconazole therapy at an Australian public hospital (1 January to 31 December 2016) was undertaken. Data collected included patient demographics, dosing history and plasma concentrations. Concordance of dosing and TDM with Australian guidelines was assessed. Observed concentrations were compared with those predicted by dose-prediction software. Measures of bias (mean prediction error) and precision (mean squared prediction error) were calculated. Results Adherence to dosing guidelines for 110 courses of therapy (41% for prophylaxis and 59% for invasive fungal infections) was poor, unless oral formulation guidelines recommended a 200 mg dose, the most commonly prescribed dose (56% of prescriptions). Plasma voriconazole concentrations were obtained for 82% (90/110) of courses [median of 3 (range: 1–27) obtained per course]. A minority (27%) of plasma concentrations were trough concentrations [median concentration: 1.5 mg/L (range: 5.0 mg/L)]. Of trough concentrations, 57% (58/101) were therapeutic, 37% (37/101) were subtherapeutic and 6% (6/101) were supratherapeutic. The dose-prediction software performed well, with acceptable bias and precision of 0.09 mg/L (95% CI −0.08 to 0.27) and 1.32 (mg/L)2 (95% CI 0.96–1.67), respectively. Conclusions Voriconazole dosing was suboptimal based on published guidelines and TDM results. Dose-prediction software could enhance TDM-guided therapy.

To study the effects of an Antimicrobial Stewardship (AMS) programme designed as a once-weekly “Prospective Audit with Feedback and Intervention” in a surgical intensive care unit. Retrospective, pre-/post-observational comparison of antimicrobial drug use, patient safety, and cost of care. During the 12-month AMS period the consumption of antimicrobials dropped by 18.3%. While the consumption of broad-spectrum antibiotics decreased by 17.4% the consumption of narrow spectrum penicillins increased by 89.9%, reaching 26.3% of the total antibiotic consumption. Treatment outcomes and rates of Clostridioides difficile infections before and during the programme were not significantly different. The reduction in antimicrobial costs of 46,393€ was offset by an expenditure of 8,047€, for both human resources and additional radiological procedures, resulting in a net saving of 38,346€. 92% of the antibiotic related savings were due to the reduced use of tigecycline and linezolid, and decreases in drug retail prices. AMS programmes can both reduce the consumption of antimicrobials and modify their spectrum in intensive care without negatively affecting treatment outcomes. The resulting cost savings are negligible. The incentive to implement such programmes cannot, therefore, be immediate institutional cost savings, but should be rather the long-term goal of reducing antibiotic resistance, and its consequences, in terms of long-term health care costs.

Background Gastroesophageal reflux (GER) in recipients of lung transplant (LTX) is associated with chronic allograft rejection, presumably via microaspiration that damages airway epithelium. Most LTX programs perform a single post-LTX esophageal study to evaluate for GER; the efficacy of this test is unclear. Methods Patients with 1 year of post-LTX follow-up, including routine bronchoscopies with bronchoalveolar lavage fluid (BALF) samples as well as high-resolution esophageal manometry and pH probe monitoring (HREMpH), were evaluated. BALF samples were analyzed with competitive enzyme-linked immunosorbent assay to detect bile salts, which are indicative of aspiration. These results were compared to results of HREMpH studies post LTX. Results Ninety BALF samples were analyzed for bile salts and acted as disease positive for this evaluation. Of the 13 HREMpH cases, 8 were positive for GER, but only 3 were positive for bile salts via assay. Of the 5 HREMpH-negative cases, 2 experienced aspiration. A solitary HREMpH study had 60.0% sensitivity and 37.5% specificity with positive and negative likelihood ratios: 0.96 and 1.07, respectively. Conclusion Microaspiration appears to be an intermittent phenomenon, and HREMpH screening poorly correlates with BALF evidence of aspiration; which may not be adequate. As aspiration detection is crucial in this population, further analysis is warranted.

Objectives Psychotropic medication is commonly used among people with dementia (PWD), but it shows modest efficacy and it has been associated with severe adverse events. Hospitalizations are an opportunity for medication management as well as treatment recommendations for outpatient physicians. The aim of this study was to asses factors associated with new use of psychotropic medication after hospitalization among PWD. Methods We conducted a retrospective dynamic cohort study from 2004 to 2015 using claims data from a German health insurance company. PWD were identified by an algorithm that included ICD-10 diagnosis and diagnostic measures. The medication classes included were antidepressants, antipsychotics, anxiolytics or hypnotics/sedatives, and Alzheimer's medication. The assessment period was up to 30 days after discharge from the hospital across four hospitalizations. Results The main predictors for new use of psychotropic medication were similar across medication classes. Neuropsychiatric symptoms (NPS) and the need of care were associated with higher odds of new use of antidepressants, antipsychotics, and anxiolytics or hypnotics/sedatives. A hospital stay due to dementia was an independent predictor for new use across medication classes as well. Delirium increased the odds for new use of antipsychotics and anxiolytics or hypnotics/sedatives. Conclusions Factors associated with new use of psychotropic medication included delirium, NPS, and the need of care in PWD. The findings highlight the need for preventive interventions and non-medical treatment options in regards to delirium and NPS as well as for a more intensive use of screening tools for inappropriate medication use among PWD. Key points The percentage of new users was 1.8%, 7.1%, 2.1%, and 2.5% across hospitalizations for antidepressants, antipsychotics, anxiolytics or hypnotics/sedatives, and Alzheimer's medication, respectively. 83.0%, 61.9%, 56.9%, and 88.1% of new users received antidepressants, antipsychotics, anxiolytics or hypnotics/sedatives, and Alzheimer's medication for more than 6 weeks. Delirium and neuropsychiatric symptoms were associated with significantly increased odds of new psychotropic medication use. Hospital stays due to dementia and the need of care were predictors for new use of psychotropic medication.

Zusammenfassung. Die Magnetresonanztomographie (MRI) der Leber spielt eine wichtige Rolle bei der Detektion und Charakterisierung fokaler und diffuser Lebererkrankungen und hat viele Vorteile gegenüber anderen bildgebenden Verfahren. Mit Hilfe einer MR-Untersuchung der Leber können die meisten benignen und malignen Läsionen detektiert und diagnostiziert werden. Neben der Evaluierung fokaler Leberläsionen haben sich in den letzten Jahren neue MR-Techniken zur nicht-invasiven Quantifizierung von Fett und Eisen in der Leber etabliert. Durch diese technischen Fortschritte wird eine akkurate Diagnose von fokalen als auch diffusen Lebererkrankungen ohne die Notwenigkeit einer Leberbiopsie möglich. Es ist jedoch wichtig, die richtigen Indikationen als auch die Kontraindikationen und Limitationen des MRI zu kennen. Der folgende Artikel gibt einen Überblick über die wichtigsten diagnostischen Möglichkeiten und Limitationen des Leber MRI als auch einen Ausblick auf neuartige Einsatzgebiete.

Objectives The aim of this study was to retrospectively compare the characteristics, procedural courses, and outcomes of patients presenting with concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) in the TriValve (Transcatheter Tricuspid Valve Therapies) and TRAMI (Transcatheter Mitral Valve Interventions) registries. Background Transcatheter mitral edge-to-edge valve repair (TMVR) has been shown to be successful in patients with severe MR. Lately, edge-to-edge repair has also emerged as a possible treatment for severe TR in patients at high risk for cardiac surgery. In patients with both severe MR and TR, the yield of concomitant transcatheter mitral and tricuspid valve repair (TMTVR) for patients at high surgical risk is unknown. Methods The characteristics, procedural data, and 1-year outcomes of all patients in the international multicenter TriValve registry and the German multicenter TRAMI registry, who presented with both severe MR and TR, were retrospectively compared. Patients in TRAMI (n = 106) underwent isolated TMVR, while those in TriValve (n = 122) additionally underwent concurrent TMTVR in compassionate and/or off-label use. Results All 228 patients (mean age 77 ± 8 years, 44.3% women) presented with significant dyspnea at baseline (New York Heart Association functional class III or IV in 93.9%), without any differences in the rates of pulmonary hypertension and chronic pulmonary disease. The proportion of patients with left ventricular ejection fraction Conclusions Concurrent TMTVR was associated with a higher 1-year survival rate compared with isolated TMVR in patients with both MR and TR. Further randomized trials are needed to confirm these results.

Gout is increasing in prevalence despite effective pharmacotherapies. Barriers to effective management are largely educational deficiencies. Sufferers, usually men, need to understand more about gout, especially that maintaining serum urate below 0.36 mmol/L will eliminate recurrent attacks. Also, of great importance is appreciating that sub-optimal adherence to urate-lowering therapy (ULT) will result in a return of attacks. Prescribers also need to understand that acute attacks are likely to occur in the first few months of urate-lowering therapy (ULT), but these can be mitigated by commencing with a dose of ULT reflective of renal function and escalating the dose slowly, every 2–5 weeks until target serum urate is achieved. Prophylaxis against acute attacks over the initial 6 months period of ULT can be enhanced further with concomitant colchicine or nonsteroidal anti-inflammatory drugs (NSAIDs). Gout is largely managed in primary care. Rates of adherence to ULT are 50% or less, worse than most other chronic illnesses. Efforts at educating primary care physicians to, firstly, manage gout effectively and, secondly, to educate their gout patients sufficiently have not been successful. Allied health practitioners, such as nurses, working with prescribers in primary care settings and given the mandate to educate and manage patients with gout, have been spectacularly effective. However, this approach is resource intensive. ‘Personalised’ eHealth interventions show promise as an alternative strategy, notably in improving adherence to ULT. Numerous applications for smart phones (apps) are now available to assist people with chronic health conditions. Their design needs to accommodate the barriers and enablers perceived by patients to maintaining adherence to prescribed therapies. Personalised feedback of serum urate may represent an important enabler of adherence to ULT in the case of gout. Harnessing mobile apps to support patients managing their chronic illnesses represents an important opportunity to enhance health outcomes. Rigorous, patient-centred and driven development is critical. These tools also require careful evaluation for effectiveness.

To compare interreader agreement and diagnostic accuracy of LI-RADS v2018 categorization using quantitative versus qualitative MRI assessment of arterial phase hyperenhancement (APHE) and washout (WO) of focal liver lesions. Sixty patients (19 female; mean age, 56 years) at risk for HCC with 71 liver lesions (28 HCCs, 43 benign) who underwent contrast-enhanced MRI were included in this retrospective study. Four blinded radiologists independently assigned a qualitative LI-RADS score per lesion. Two other radiologists placed ROIs within the lesion, adjacent liver parenchyma, and paraspinal musculature on pre- and post-contrast MR images. The percentage of arterial enhancement and the liver-to-lesion contrast ratio were calculated for quantification of APHE and WO. Using these quantitative parameters, a quantitative LI-RADS score was assigned. Interreader agreement and AUCs were calculated. Interreader agreement was similar for qualitative and quantitative LI-RADS (κ = 0.38 vs. 0.40–0.47) with a tendency towards improved agreement for quantitatively assessed APHE (κ = 0.65 vs. 0.81) and WO (κ = 0.53 vs. 0.78). Qualitative LI-RADS showed an AUC of 0.86, 0.94, 0.94, and 0.91 for readers 1, 2, 3, and 4, respectively. The quantitative LI-RADS score where APHE/WO/or both were replaced showed an AUC of 0.89/0.84/0.89, 0.95/0.92/0.92, 0.93/0.91/0.89, and 0.91/0.86/0.88 for readers 1, 2, 3, and 4, respectively. Sensitivity of LR-4/5 slightly increased, while specificity slightly decreased using quantitative APHE. Qualitative and quantitative LI-RADS showed similar performance. Quantitatively assessed APHE showed the potential to increase interreader agreement and sensitivity of HCC diagnosis, whereas quantitatively assessed WO had the opposite effect and needs to be redefined. • Quantitative assessment of arterial phase hyperenhancement shows the potential to increase interreader agreement and sensitivity to diagnose hepatocellular carcinoma. • Adding quantitative measurements of major LI-RADS features does not improve accuracy over qualitative assessment alone according to the LI-RADS v2018 algorithm.

The organum vasculosum of the lamina terminalis (OVLT) contains NaCl-sensitive neurons to regulate thirst, neuroendocrine function, and autonomic outflow. The OVLT also expresses the angiotensin II (AngII) type1 receptor, and AngII increases Fos expression in OVLT neurons. The present study tested whether individual OVLT neurons sensed both NaCl and AngII to regulate thirst and body fluid homeostasis. A multifaceted approach, includingin vitrowhole-cell patch recordings,in vivosingle-unit recordings, and optogenetic manipulation of OVLT neurons, was used in adult, male Sprague Dawley rats. First, acute intravenous infusion of hypertonic NaCl or AngII produced anatomically distinct patterns of Fos-positive nuclei in the OVLT largely restricted to the dorsal cap versus vascular core, respectively. However,in vitropatch-clamp recordings indicate 66% (23 of 35) of OVLT neurons were excited by bath application of both hypertonic NaCl and AngII. Similarly,in vivosingle-unit recordings revealed that 52% (23 of 44) of OVLT neurons displayed an increased discharge to intracarotid injection of both hypertonic NaCl and AngII. In marked contrast to Fos immunoreactivity, neuroanatomical mapping of Neurobiotin-filled cells from bothin vitroandin vivorecordings revealed that NaCl- and AngII-responsive neurons were distributed throughout the OVLT. Next, optogenetic excitation of OVLT neurons stimulated thirst but not salt appetite. Conversely, optogenetic inhibition of OVLT neurons attenuated thirst stimulated by hypernatremia or elevated AngII but not hypovolemia. Collectively, these findings provide the first identification of individual OVLT neurons that respond to both elevated NaCl and AngII concentrations to regulate thirst and body fluid homeostasis.SIGNIFICANCE STATEMENTBody fluid homeostasis requires the integration of neurohumoral signals to coordinate behavior, neuroendocrine function, and autonomic function. Extracellular NaCl concentrations and the peptide hormone angiotensin II (AngII) are two major neurohumoral signals that regulate body fluid homeostasis. Herein, we present the first compelling evidence that individual neurons located in the organum vasculosum of the lamina terminalis detect both NaCl and AngII. Furthermore, optogenetic interrogations demonstrate that these neurons play a pivotal role in the regulation of thirst stimulated by NaCl and AngII. These novel observations lay the foundation for future investigations for how such inputs as well as others converge onto unique organum vasculosum of the lamina terminalis neurons to coordinate body fluid homeostasis and contribute to disorders of fluid balance.