Abstract This paper examines the persistence of real exchange rates across 151 countries. We employ univariate time series techniques on a country-by-country basis allowing for deterministic structural breaks and nonlinearities in the adjustment process. Our findings suggest that bilateral exchange rates display higher rates of persistence than multilateral exchange rates, with the latter (former) exhibiting half-lives of less than 1 (2) year(s). Assessing country results by stage of economic development, we find that industrial countries display higher levels of exchange rate inertia than developing countries. We retrieve evidence indicating that higher inflation, nominal exchange rate volatility, trade openness and proximity to reference country are associated with faster rates of real exchange rate convergence. Conversely, international financial integration is found to only play a role at the country group level, with differential effects across cohorts.

Molecular tweezers (MTs) are supramolecular host molecules equipped with two aromatic pincers linked together by a spacer (Gakh, 2018). They are endowed with fascinating properties originating from their ability to hold guests between their aromatic pincers (Chen and Whitlock, 1978; Zimmerman, 1991; Harmata, 2004). MTs are finding an increasing number of medicinal applications, e.g., as bis-intercalators for DNA such as the anticancer drug Ditercalinium (Gao et al., 1991), drug activity reverters such as the bisglycoluril tweezers Calabadion 1 (Ma et al., 2012) as well as radioimmuno detectors such as Venus flytrap clusters (Paxton et al., 1991). We recently embarked on a program to create water-soluble tweezers which selectively bind the side chains of lysine and arginine inside their cavity. This unique recognition mode is enabled by a torus-shaped, polycyclic framework, which is equipped with two hydrophilic phosphate groups. Cationic amino acid residues are bound by the synergistic effect of disperse, hydrophobic, and electrostatic interactions in a kinetically fast reversible process. Interactions of the same kind play a key role in numerous protein-protein interactions, as well as in pathologic protein aggregation. Therefore, these particular MTs show a high potential to disrupt such events, and indeed inhibit misfolding and self-assembly of amyloidogenic polypeptides without toxic side effects. The mini-review provides insight into the unique binding mode of MTs both toward peptides and aggregating proteins. It presents the synthesis of the lead compound CLR01 and its control, CLR03. Different biophysical experiments are explained which elucidate and help to better understand their mechanism of action. Specifically, we show how toxic aggregates of oligomeric and fibrillar protein species are dissolved and redirected to form amorphous, benign assemblies. Importantly, these new chemical tools are shown to be essentially non-toxic in vivo. Due to their reversible moderately tight binding, these agents are not protein-, but rather process-specific, which suggests a broad range of applications in protein misfolding events. Thus, MTs are highly promising candidates for disease-modifying therapy in early stages of neurodegenerative diseases. This is an outstanding example in the evolution of supramolecular concepts toward biological application.

In this paper, a stochastic simulation procedure for energy assessment of PV systems is developed and tested. The method is especially adequate for urban applications since the impact of surrounding obstacles both for direct and diffuse irradiance is taken into account. The main input is the system location along with its monthly average irradiance and temperature statistics. Based on the input data, the program generates a set of random years represented by hourly sequences of global horizontal irradiance and ambient temperature. The generated sequences are then converted into the module plane-of-array irradiance and module temperature time series and, consequently, the AC energy production is estimated for each simulated year. The final results are presented in a form of probability density function of the system annual energy output.

Abstract Background In 2017 a new PN led clinic was established for immunotherapy patients. At the 1-year mark to ensure patients were satisfied with the service provision, a patient experience survey was conducted. The survey explored if patients felt comfortable in discussing side effects with the PN and if they felt part of their treatment related decisions. Importantly patients were asked if they had confidence and trust in the PN. Methods The survey was provided to all patients whom attended the PN led clinic from May 2017 to May 2018. The survey consisted of 10 closed questions using the Likert scale, with spaces provided for personal comments. Data collection period was 1.06.18 to 29.06.18. Estimated number of patients was 10. Results Questionnaires were provided to a total of 10 patients. Three questionnaires could not be provided to 3 patients whom attended the PN led clinic as they had died. Two patients did not respond back. 6/8 patients strongly agreed (SAg) to feeling comfortable in discussing treatment related side effects and 2/8 patients agreed (Ag). This same result was found when patients were asked if they felt involved in the decisions related to their care e.g. stopping immunotherapy treatment at 2 yrs. With respect to having confidence and trust with the advice and care provided by the PN, 7 patients SAg and 1 Ag. All patients felt that they were being listened to and had the opportunity to ask questions during their consultations (7 patients SAg and 1 Ag). Reassuringly all 8 patients said that they would recommend this service to their friends and family (7 patients SAg and 1 Ag). Conclusions This survey was to ensure patients were satisfied with being reviewed by a PN and as the service was new to the melanoma unit in 2017; it was vital that the patients had the opportunity to evaluate the service provision. With this positive feedback the clinic was expanded from September 2018 and to date 36 patients have now been seen within the PN led immunotherapy clinic and another patient experience survey is due. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Abstract Background Intratumour heterogeneity is recognised across different tumour types and has implications for therapeutic resistance. At present, clinical practice often relies upon molecular information derived from a single biopsy of a primary or metastatic tumour. This information guides treatment choice but may not be representative of the diversity of the tumour. It is currently difficult to evaluate how effectively a single region guides treatment decisions because the formalin-fixed residual surgical sample that is not paraffin embedded for diagnostic purposes is typically thrown away. Retention and homogenisation – ‘blending’- of this residual formalin-fixed leftover tumour tissue creates a more representative sample for analysis. DNA may be extracted from this sample for sequencing. Pilot data in kidney cancer has demonstrated the potential of this methodology for robust mutational calling, accurate determination of cancer cell fraction and the ability to discern clonal from subclonal variants. Such information may be clinically relevant; for example, discerning resistant subclones prior to treatment, or identifying clonal neoantigens worth targeting with immunotherapy. Trial design In order to establish the feasibility of homogenization as a potential companion diagnostic tool, our study aims to 1) identify the proportion of primary tumour cases that have left over tissue amenable to homogenization across multiple tumour types and 2) pilot homogenization across multiple tumour types. The molecular profile of the homogenate will be compared to that obtained from the diagnostic specimen using next generation sequencing techniques. This is a prospective non-interventional study (NCT03832062). Patients undergoing surgical intervention at The Royal Marsden Hospital (NHS Foundation Trust) with leftover tumour tissue from primary breast, colorectal, gastric, pancreatic, ovarian, renal cancer and sarcoma surgeries, as well as melanoma lymph node dissections will be included in the feasibility assessment. We plan to homogenise 500 cases across different tumour types. The study opened in September 2018 and is expected to run for 2 years. Clinical trial identification NCT03832062; Release date: February 2019. Legal entity responsible for the study Royal Marsden NHS Foundation Trust. Funding Ventana Medical Systems (a subsidiary of Roche). Disclosure L. Gallegos: Full / Part-time employment: Roche. S. Hill: Full / Part-time employment: Roche. A. Barhoumi: Full / Part-time employment: Roche. S. Stanislaw: Full / Part-time employment: Roche. M. Mendoza: Full / Part-time employment: Roche. J.M.G. Larkin: Research grant / Funding (institution): Roche; Advisory / Consultancy: Roche. N. Alexander: Full / Part-time employment: Roche; Shareholder / Stockholder / Stock options: Roche. S. Turajlic: Research grant / Funding (institution): Ventana Medical Systems (subsidiary of Roche). All other authors have declared no conflicts of interest.

Abstract Background ADATPeR is the first prospective study evaluating the role of anti-PD1 agents in the neoadjuvant setting prior to cytoreductive nephrectomy in treatment-naive patients with metastatic clear cell renal cell carcinoma (mccRCC). We performed multi-omic analyses to resolve spatial heterogeneity and temporal dynamics in putative biomarkers of response to anti-PD1 blockade. Methods In a single center study, patients received nivolumab (3mg/kg every 2 weeks) pre- and post-operatively until progressive disease (PD). Primary endpoint was safety, secondary endpoints were response evaluation and exploratory biomarker analysis. Multiregion tumour biopsies were obtained at baseline, on-treatment (week 9) and at PD. Whole-exome sequencing was performed to infer somatic mutations and predict candidate neoantigens (NAs). Tumour immune microenvironment was evaluated using a RNA-seq-derived immune signature and by stromal and intraepithelial tumour infiltrating lymphocytes (TILs) assessments. Results 15 patients were treated. At median follow-up of 12.5 months(m), nivolumab had an acceptable side-effect profile. Overall response rate was 37%. Preliminary transcriptome analyses of pre-treatment biopsies (33 samples from 14 patients; up to 4 regions per case) revealed enrichment for primary-resistance (defined as PD within 2m; n = 4) with immune ‘cold’ tumours, distinct from ’hot’ tumours. Histologic TILs scoring showed concordant immune phenotypic clusters. Primary-resistant cases demonstrated 0% on-treatment stromal- and IE-TILs (2 evaluable patients). In contrast, we observed heavy on-treatment stromal TILs (70-90%) and intraepithelial TILs (30-90%) across 7 regions at nephrectomy in an exceptional responder receiving ongoing treatment (>24 cycles). Conclusions ADATPeR is the first neoadjuvant immune checkpoint inhibitor study pre-cytoreductive nephrectomy, and incorporated multi-omic analyses of putative biomarkers. Baseline immune gene expression signature is distinct in responders compared with non-responders. On-treatment intraepithelial TILs were prominent in those deriving durable clinical benefit. Integrative analyses are ongoing. Clinical trial identification NCT02446860. Legal entity responsible for the study The authors. Funding Bristol-Myers Squibb; The National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research; Cancer Research UK (CRUK). Disclosure All authors have declared no conflicts of interest.

In modern market it is very important to deliver products to customers fast. That delivery can be on site or to customer's homes. In order to achieve that it is important to have enough goods stored in warehouses and prepared for delivery. It is not a good decision to clutter up warehouses with the goods because space is limited and expensive and it makes it more complicated to collect orders. Those are the reasons why it is important that number of stored goods converge to the exact number of product units that will be ordered in the future. Demand forecasting tries to solve that problem. In this work demand forecasting algorithm based on Long Short-Term Memory recurrent neural network is described and compared with demand forecasting algorithms developed by authors before.

A number of industrial wireless technologies have emerged over the last decade, promising to replace the need for wires in a variety of use cases. Except for customized time division multiple access (TDMA)-based wireless technologies that can achieve ultralow latency over a very limited area, wireless communication generally has reliability and latency issues when it comes to industrial applications. Closed loop communication requires high reliability (over 99%), limited jitter and latency, which poses a challenge especially over a wide area measuring in hundreds of meters. Extended coverage is promised with the advent of sub-GHz technologies, one of them being IEEE 802.11ah which is the only one that offers sufficient data rate for frequent bidirectional communication. Thus, we evaluated IEEE 802.11ah for low-latency time-critical control loops. We propose the network setup for adjusting the network dynamics to that of control loops, enabling limited jitter and high reliability. We explore the scalability of IEEE 802.11ah network hosting both control loops and monitoring sensors that periodically transmit measurements. Assigning the control loop end-nodes to dedicated restricted access window (RAW) slot results in over 99.99% successful deliveries. Furthermore, interpacket delay is concentrated around the cycle-time in the following or preceding beacon interval in case the beacon interval is at least half the value of the shortest cycle-time. Adjusting the beacon interval to the fastest control loop in the network ensures latency requirements at the cost of maximum achievable throughput and energy consumption.

Cilj rada bio je ispitati odnos opšteg samopoštovanja, procijenjenog preko Rosenbergove skale samopoštovanja, i prilagodbe na studij, operacionalizirane preko skorova na Baker-Siryk-ovoj skali prilagodbe na studij SACQ. Prilagodba na studij modelirana je preko četiri dimenzije prilagodbe: emocionalne, socijalne, akademske, i institucionalne. Studija je provedena na uzorku od 808 studenata (62.9% ženski; M = 21.88; SD = 2.35). Diskriminativnom analizom preko četiri modaliteta prilagodbe procijenjena je alokacija studenata na grupu visoko/nisko samopoštovanje. Izdvojena je značajna diskriminativna funkcija koja bi se mogla svesti na aspekte emocionalno-socijalne prilagodbe. Ukupno je obuhvaćeno oko 17% preklapanja između studentske prilagodbe i samopoštovanja. Studenti sa višim stepenom samopoštovanja imali su u prosjeku statistički značajno viši nivo prilagodbe na studij u odnosu na studente s nižim samopoštovanjem.

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) is rare, but life-threatening condition. The treatment of choice in patients with ALCAPA is the establishment of a dual coronary artery system with surgical reimplantation of the left coronary artery in the left coronary sinus. Percutaneous coronary intervention is infrequent in the pediatric population but can be a life-saving by promptly restoring flow to an obstructed coronary artery. It is a highly demanding and high-risk procedure in infants due to the technical difficulties and the small coronary artery diameter in infants.

Results of currently available randomized trials have shown divergent outcomes in diabetic patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The 2018 ESC/EACTS guidelines on myocardial revascularization do not recommend PCI in patients with diabetes and SYNTAX score ≥23. We aimed to compare the all-cause 4-year mortality after revascularization for complex coronary artery disease (CAD) in diabetics. The study group comprised consecutive diabetics with angiographically proven three-vessel CAD (≥50% diameter stenosis) and/or unprotected left main CAD (≥50% diameter stenosis) without major hemodynamic instability, who were treated in two institutions with PCI or referred for CABG between 2008 and 2010. All-cause mortality was ascertained by telephone contacts and/or from Mortality Registries. Using the hospital data system, 5145 patients were screened and 4803 elected not to follow the inclusion criteria. Out of 342 included patients, 177 patients underwent PCI and 165 patients were referred for CABG. Patients with whom CABG was performed were significantly older (64.69±8.8 vs. 62.6±9.4, p=0.03), more often on insulin treatment (91/165=55.2% vs. 26/177=14.7%, p<0.01), had more complex anatomical characteristics i.e. higher SYNTAX scores (32.5 IQR (15) vs. 18.0 IQR (15), p<0.01) and with left main stenosis (70/165=42.4% vs. 7/177=4.0%, p<0.01), compared to patients treated with PCI. The cumulative incidence rates of all-cause death were significantly different between PCI and CABG at 4 years (16/177=9.0% vs. 26/165=15.7%, respectively, log-rank p=0.03). There was a higher incidence of all-cause mortality in PCI patients with intermediate (23–32) and high (≥33) SYNTAX scores compared with those with low (0–22) SYNTAX scores (6/32=18.8% vs. 6/124=4.8%, log-rank p=0.01; 4/21=19.1% vs. 6/124=4.8%, log-rank p=0.02, respectively). On the contrary, patients who underwent CABG displayed similar morality rates irrespective of the SYNTAX scores (SYNTAX 0–22: 5/34=14.7%; SYNTAX 23–32: 9/54=16.7%; SYNTAX ≥33: 12/77=15.6%; log-rank p=0.9). Finally, when compared with CABG, more deaths were observed following PCI with intermediate and high SYNTAX scores (intermediate SYNTAX (23–32) PCI: 6/32=18.8% vs. CABG: 26/165=15.8%, log-rank p=0.94; high SYNTAX (≥33) PCI: 4/21=19.1% vs. CABG 26/165=15.8%, log-rank p=0.87). During a 4-year follow-up, CABG in comparison with PCI was associated with a higher rate of all-cause death, which can be accounted for by older age and comorbidities. In diabetics, our analysis is suggestive that PCI probably should be avoided in patients with SYNTAX ≥23, which is in concordance with the most recent guidelines. Individualized risk assessment as well as quantification of CAD by SYNTAX score remains essential in choosing appropriate revascularization method in patients with diabetes and complex CAD. None

Pulmonary embolism (PE) can lead to multi-organ damage including an acute renal dysfunction which is associated with adverse events and high long-term mortality rate. The aim of our study was to investigate the predictive role of renal dysfunction on intrahospital mortality risk in patients hospitalized due to PE. The study was performed in intensive care units of six university hospitals. The prospective cohort study comprised 665 consecutive patients with acute PE which was confirmed using MDCT. All patients underwent echocardiography examination on admission and blood samples were collected for troponin I (TnI), B-type natriuretic peptide (BNP) and routine laboratory analyses. Based on estimated glomerular filtration rate (GFR), patients were divided into three groups: first with the GFR <30ml/min, second with GFR 30–60 ml/min, and third with GFR >60 ml/min. During hospitalization in the first group the overall incidence of death was recorded in 28 (45.9%), in the second in 42 (18.9%), and in the third in 30 (7.9%) patients (p<0.0001). Pulmonary embolism as a cause of death was recorded in the first group in 18 (29.5%) patients, in the second in 25 (11.3%) and in the third in 17 (4.5%) patients (p<0.0001). Fatal bleeding was recorded in the first group in 1 (1.6%), in the second in 1 (0.5%) and in the third group in 3 (0.8%) patients (p<0.05). There were no significant differences regarding major bleeding frequency among the groups. Multivariate analysis showed that age, comorbidities, hemodynamic status, TnI, and GFR were strongly associated with an overall mortality rate and with death due to PE, while the use of anticoagulation therapy influenced the fatal bleeding rate. After controlling for age, we found that GFR on admission had a significant effect on in-hospital survival. Compared with patients in the third group, those from the second group had more than 2 fold increased mortality risk [OR 2.17 (CI 1.301–3.625), p=0.001], and patients in the first group had 6 fold higher risk of mortality [OR 6.006 (CI 3.487–6.006)]. In the ROC analysis GFR showed significant predictive value for intra-hospital mortality risk in PE patients [AUC= 0.725, 95% CI (0.68–0.78), p<0.001]. The highest sensitivity (64%) and specificity (70%) had GFR “cutoff” value of 59.12/min. Renal dysfunction, on admission, in patients with acute PE is strongly associated with high intrahospital mortality risk and fatal bleeding. The estimation of GFR in these patients is important not only for prediction of the outcome but also for the prevention of bleeding complications, regarding the optimal dosage of anticoagulants. Even though it seems that GFR calculation is not still the clinical routine in PE.