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BACKGROUND: There is lack of data on long-term outcomes of patients with Budd-Chairi Syndrome (BCS) treated with medical therapy including anticoagulation alone. METHODS: Consecutive patients (N = 138, mean [standard deviation, SD] age 29.3 [12.9] years; 66 men) with BCS, treated with medical therapy alone including anticoagulation, with minimum follow-up of 12 months were included. Initial response was classified as complete (CR), partial (PR) or nonresponse (NR) and on follow-up as loss of response (LoR) or maintenance of response (MoR). The association of baseline, clinical and biochemical parameters with different responses was evaluated. RESULTS: Seventy-six patients (55.1%) had CR, 26 (18.8%) had PR and 36 (26.1%) had NR. None with PR or NR had CR later. At a median follow-up of 40 (range 12–174) months, LoR was more common in PR group than in CR group (12 [46.2%] vs 18 [23.7%], P = 0.03). LoR was associated with presence of ascites (odds ratio [OR] 1.5; 95% confidence interval [CI] 0.06–0.71), gastrointestinal bleed (OR 1.33; 95% CI 0.09–0.82) or jaundice (OR 1.01; 95% CI 0.11–0.97) at baseline and duration of follow-up (OR 0.018; 95% CI 1.006–1.030). Mortality was higher in NR (28 [77.8%]) compared with CR (15 [19.7%], P = 0.001) and PR (8 [30.8%], P = 0.001). On binary logistic regression analysis, presence of ascites at baseline was associated with LoR (OR 0.303 [0.098–0.931]). CONCLUSION: Patients with initial CR have better survival than nonresponders. One-third had LoR on follow-up. The presence of ascites at baseline is associated with LoR.

To evaluate the long-term efficacy of high-dose dexamethasone (HD-DXM) treatment for immune thrombocytopenia (ITP), we retrospectively analysed 36 newly diagnosed ITP patients treated with HD-DXM as a first-line treatment. An initial response was obtained in 23 (63.9%) patients, including 11 with a complete response (CR) and 12 with a partial response (PR). Six months after HD-DXM treatment, 26 of 33 (78.8%) evaluable patients achieved objective responses, including 18 CR and 8 PR. Among 13 patients without initial response, very early increased platelet count within a week (VEIP) was observed in 7 patients, 5 (71.4%) of whom achieved a response at 6 months. In 29 patients who had available platelet count within a week, patients showing VEIP revealed longer survival than those who did not (p = 0.026). HD-DXM was an effective treatment for newly diagnosed ITP patients. VEIP after HD-DXM treatment initiation was associated with a long-term objective response in newly diagnosed ITP patients.

The finite element analysis are performed to investigate a long-term response of flexible pipe buried in sand trench embedded in native soft clay. The investigated long-term behaviors are due to effects of backfill soil structure rearrangement and native clay consolidation. The finite element results suggest that the short-term response of pipe depends strongly on trench widths but independent of trench depths due to the dependence of arching effect with trench width. However, the effects of trench width become less important for long-term pipe response. Moreover, the mechanism of this long-term response is likely due to backfill soil structure rearrangement, which occurs within a shorter time, not consolidation of native clay. The importance of finite element modelling of interface between sand backfill and clay trench and modelling of construction sequence on the obtained pipe-soil interaction are investigated. For long-term consideration, modelling of interface between sand backfill and clay trench is important; however, modelling of construction sequences is not so. Prism load seems to give better results for long-term load. Available analytical solutions cannot accurately estimate both vertical load and pipe deflection at short term for narrow trench due to a strong influence of arching effect after backfilling. At long term, Iowa formula under-predicts the horizontal pipe deflection by the ratios of 0.40–0.52 which correspond with a deflection lag factor DL of 1.9–2.5. The time lags of narrow trench obtained from this study are 1.6–1.9 and they become smaller for wide trench.

BACKGROUND Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neuroendocrine neoplasia, with high risk of recurrence and metastasis and poor survival. Immune checkpoint inhibitors, like the anti-programmed death-ligand 1 agent avelumab, were recently approved for the treatment of advanced MCC. We, herein, report the first case of advanced MCC with oligoprogression managed with avelumab and local radical treatment. CASE SUMMARY A 61-year-old man was presented to the hospital with sporadic fever and an exudative malodorous mass (10 cm of diameter), located on the right gluteal region. The final diagnosis was MCC, cT4N3M1c (AJCC, TNM staging 8th edition, 2017), with invasion of adjacent muscle, in-transit metastasis, and bone lesions. Patient started chemotherapy (cisplatin and etoposide), and after six cycles, the main tumor increased, evidencing disease progression. Two months later, the patient started second line treatment with avelumab (under an early access program). After two cycles of treatment, the lesion started to decrease, achieving a major response. Local progression was documented after 16 cycles. However, as the tumor became resectable, salvage surgery was performed, while keeping the systemic treatment with avelumab. Since the patient developed bilateral pneumonia, immunotherapy was suspended. More than 2.5 years after surgery (last 19 mo without systemic therapy), the patient maintains complete local response and stable bone lesions. CONCLUSION This report highlights the efficacy and long-term response of avelumab on the management of a chemotherapy resistant advanced MCC, with evidence of oligoprogression, in combination with local radical treatment.

This study presents the long time effects of varying temperature conditions on pH-responsive films deposited on glass slides. The films were fabricated from Brilliant Yellow and poly (allylamine hydrochloride) through ionically self-assembled monolayer technique using an automated slide strainer. The absorbance of the films was monitored and the effect of varying temperature on the optical properties of the films was studied. We found that as the films are maintained at increasing temperatures their absorbance slightly decreased. As the temperature increased the percent change decreased reaching a plateau. Films kept at low temperatures of 3.24 °C and below freezing (-9.02 °C) had a small increase in absorbance. Finally, we monitored the absorbance of films kept at room temperature over a long time (128 days) and found that the films showed decreased absorbance by 19%.

BACKGROUND: Digital mucous cysts (DMCs) are benign myxoid pseudocysts that develop on the distal interphalangeal joint's lateral or dorsal aspects. Management consists either of a surgical approach, conservative therapy, or simple follow-up. OBJECTIVE: To correlate the initial and long-term response with clinical and ultrasound parameters in DMCs treated with intralesional steroids as first-line therapy. METHODS: A single-center prospective open-label study recruited 15 patients affected by DMCs, who had been treated with a cycle of up to 3 steroid injections at a 6 to 9 week time interval. RESULTS: At the first follow-up visit, 53.3% of patients were cleared of DMCs, achieving a complete response, whereas 46.7% experienced a >30% decrease in their DMC volume, and were considered partial responders. After 1 year of follow-up, the cure rate decreased to 40%, and the recrudescence rate was 27.3%. Clinical and sonographic characteristics that positively correlated with a maintained complete response at follow-up were as follows: young age, absence of osteophytes, low volume, complete clearance at T1, and short disease duration (p < .05). CONCLUSION: Intralesional steroid therapy is an easy approach for DMC, with minimal side effects; identifying predictive hallmarks is useful to offer a straightforward surgical treatment to patients who have nonresponder characteristics.

Climate change is increasing weather unpredictability, causing more intense, frequent and longer extreme events including droughts, precipitation, and both heat and cold waves. The performance of parasites, and host-parasite interactions, under these unpredictable conditions, are directly influenced by the ability of parasites to cope with extremes and their capacity to adapt to the new conditions. Here, we review some of the structural, behavioural, life history and ecological characteristics of parasitic nematodes that allow them to persist and adapt to extreme and changing environmental conditions. We focus primarily, but not exclusively, on parasitic nematodes in the Arctic, where temperature extremes are pronounced, climate change is happening most rapidly, and changes in host-parasite interactions are already documented. We discuss how life-history traits, phenotypic plasticity, local adaptation and evolutionary history can influence the short and long term response of parasites to new conditions. A detailed understanding of the complex ecological processes involved in the survival of parasites in extreme and changing conditions is a fundamental step to anticipate the impact of climate change in parasite dynamics., Graphical abstract Image 1, Highlights • The adaptations of parasites to extreme environments are relevant to understand parasite dynamics in a changing world. • Life cycle, plasticity and thermal adaptation are important to effectively anticipate impacts of climate change in parasites. • The evolutionary history of parasites is a window to study their adaptive capacity to climate change.

Neuroblastoma (NB) is the most frequent pediatric extracranial solid tumor characterized by extreme biological heterogeneity with variable clinical course. Older age is an important risk factor. These patients may lack other common risk features but still have a chemoresistant disease with dismal prognosis. As there is currently no consensus on optimal treatment for patients with primary resistant NB, a number of clinical options is being explored including immunotherapy-based approaches. Immunotherapy with dinutuximab beta (DB) have proven its effectiveness as maintenance therapy. Allogeneic stem cell transplantation from haploidentical donor (haplo-HSCT) may be an effective consolidation in some cases. However, all forms of immunotherapy are much less effective in patients with large residual tumor. While there is no data on immune checkpoints inhibitors effectiveness in NB, some patients may benefit from this option as a part of complex immunotherapy strategy. Case presentation A 12-year old girl with gross paravertebral thoracic and abdominal tumor was diagnosed with undifferentiated neuroblastoma and bone metastases. While there was no response to several lines of chemotherapy, and only partial tumor resection was possible, the hematopoietic stem cell transplantation from haploidentical donor (haplo-HSCT) was performed as salvage therapy. Since there was only minor decrease in tumor volume with good dynamics by MIBG scan, additional post-transplant therapy was initiated. External beam radiotherapy was given for local control. The patient also received combined immunotherapy with DB and nivolumab. Currently, 3.5 years post haplo-HSCT, despite still gross residual tumor mass, it is MIBG-negative and shows signs of differentiation. Conclusion The combination of haplo-HSCT with post-transplant anti-GD2 and nivolumab may lead to a long-term response in an adolescent with primary resistant NB in spite of a large residual tumor mass.

Fatigue is a primary concern for railroad bridge owners because railroad bridges typically have high live load to dead load ratios and high stress cycle frequencies. However, existing inspection and post-inspection analysis methods are unable to accurately consider the full influence of bridge behavior on the fatigue life of bridge components. Reliability-based fatigue analysis methods have emerged to account for uncertainties in analysis parameters such as environmental and mechanical properties. While existing literature proposes probabilistic fatigue assessment of bridge components, this body of work relies on train parameter estimates, finite element model simulations, or controlled loading tests to augment monitoring data. This article presents a probabilistic fatigue assessment of monitored railroad bridge components using only continuous, long-term response data in a purely data-driven reliability framework that is compatible with existing inspection methods. As an illustrative example, this work quantifies the safety profile of a fracture-critical assembly comprising of six parallel eyebars on the Harahan Bridge (Memphis, TN). The monitored eyebars are susceptible to accelerated fatigue damage because changes in the boundary conditions cause some eyebars to carry a greater proportion of the total assembly load than assumed during design and analysis; existing manual inspection practices aim to maintain an equal loading distribution across the eyebars. Consequently, the limit state function derived in this article accounts for the coupled behavior between fatigue and relative tautness of the parallel eyebars. The reliability index values for both the element (i.e. individual eyebars) and system (i.e. full eyebar assembly) reliability problems are assessed and indicate that under the conservative assumption that progressive failure is brittle, first failure within the parallel eyebar system is generally equivalent to system failure. The proposed method also serves as an intervention strategy that can quantify the influence of eyebar realignment on the future evolution of the reliability index.

Background Electrochemotherapy (ECT) is a local cancer treatment based on electroporation where the electric field is used to enhance cell membrane permeability and thereby facilitating the transition of chemotherapeutic agents into the cell. For the treatment of non-melanoma skin cancer, a standard dosage of 15,000 IU/m2 bleomycin (BLM) is used. The aim of the present study was to evaluate the long-term ECT response in the group of elderly patients with non-melanoma skin cancer treated with a reduced dose of BLM in comparison to the outcome in the patients treated with the standard dose of BLM. Patients and methods Twenty-eight patients older than 65 years, with a total of 52 non-melanoma skin lesions were included in the study. Twelve patients (24 lesions) in the experimental group received a reduced dose of BLM (10,000 IU/m2), 16 patients (28 lesions) were treated with a standard dose of BLM (15,000 IU/m2). Results No statistically significant difference in tumor control was observed between both groups. In the experimental group, tumors recurred in 39.0% of treated lesions in a median follow-up time of 28 months. In the control group, the recurrence rate of treated lesions was 15.4% in a median follow-up time of 40 months. Conclusions ECT with a reduced dose of BLM is a feasible treatment option for elderly patients with equal efficacy to standard dose treatment and should be considered as a treatment modality in advanced aged patients with comorbidities, where overall life expectancy is poor.

Aims Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long-term treatment response. Methods This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. Results A single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95% CI = -0.0195, -0.0003; P = .0430), absolute frontal EEG parameters in alpha (-14.9; 95% CI = -21.0, -8.3; P = .0002), beta (-12.6; 95% CI = -19.4, -5.3; P = .0019) and theta (-17.9; 95% CI = -25.0, -10.0; P = .0001) frequencies. Relative frontal (-1.669; 95% CI = -2.999, -0.339; P = .0156) and occipital (-1.856; 95% CI = -3.339, -0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95% CI = -31.6, -7.47; P = .0046), beta (-15.7; 95% CI = -28.3, -0.93; P = .0390) and theta (-25.9; 95% CI = -38.4, -10.9; P = .0024) EEG parameters and of relative frontal theta power (-3.27%; 95% CI = -5.96, -0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non-responders (n = 32) after 6 months. Conclusions This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

Objective: To compare different bed planting systems: narrow beds (80 cm), wide beds (100 cm), and flat soil, on the growth and yield of wheat under conservation system. Design/methodology/approach: Treatments were established on a complete block design with three replicates; also, wheat crop was grown during five seasons. Treatments were as follow: A) wide beds (furrows at 100 cm), B) narrow beds (furrows at 80 cm) and C) flat soil. Response variables were dry weight of 50 stems, weight of 1000 grains, number of spikes (m2), harvest index and yield. Also, the relationship between relative yield and cold units and degree-days were measured. Results: Flat soil reach the highest dry weight of 50 stems, whereas narrow beds had the maximum number of spikes per m2. Yield was equal between flat soil and narrow beds. No differences were found in the harvest index (HI) among the evaluated treatments. When comparing results between years, dry weight of 50 stems increased and the HI index decreased, affecting negatively the yield. A negative association was found between chill hours and yield. Findings/conclusions: Despite yield was equal between flat soil and narrow beds, reduction on yields was mainly associated with of reduction in chill hours occurring in each season.

This paper deals with statistical and modeling uncertainty on the estimation of long-term extrapolated extreme responses in a monopile offshore wind turbine. The statistical uncertainty is addressed by studying the effect of simulation length. Modeling uncertainty is explored by evaluating the effects of considering a rigid and flexible foundation. The soil's flexibility is taken into account by considering the improved apparent fixity method. To identify the most relevant environmental conditions, the modified environmental contour method is used. The analysis focuses on the fore-aft shear force (FASF) and the fore-aft bending moment (FABM) at the mudline. The results show that using a simulation length of 10 min does not provide sufficient accuracy. It was found that for the FASF, simulation lengths of at least 30 min are required to achieve an accuracy of about +/−5%. For the FABM, it was found that both the extrapolations made with 20 min and 30 min simulations achieved similar levels of accuracy of about 20%. Meanwhile, the results obtained from 10 min simulations reached deviations of about 40%. Finally, from the comparison made between a rigid and flexible foundation, it was found that the extrapolated responses exhibit maximum deviations up to around 5% and 10% for the FASF and the FABM, respectively. Also, for the FABM, it was observed that the consideration of a flexible foundation causes the critical wind speed to shift from 16.5 m/s (rigid) to 18 m/s (flexible).

Background Despite the availability of multiple interventions, treatment-resistant depression (TRD) is still a major clinical challenge that has multiple factors associated with its development. Depression is a highly dynamic condition, and both the triggers which underlie its pathogenesis and the loss of response to drugs continuously change. These, along with large interpatient and intrapatient unpredictability, further complicate overcoming decreased response to drugs which may worsen the prognosis in some patients. Aims In this review, we discuss mechanisms associated with loss of response to antidepressants and focus on the potential role of the autonomic nervous system and chronobiology in the pathogenesis of the disease and subsequent response to therapy. Results We introduce a novel treatment strategy which is based on individualized variability and guided by chronotherapy regimens. We also suggest the implementation of a personalized algorithm which comprises quantifiable signatures associated with the mechanisms of the disease and which underlie the loss of response to drugs. To overcome the deleterious compensatory responses in a highly dynamic system in patients with depression, we propose a closed-loop therapeutic regimen tailored to patients that enables improved responses to current therapies. Conclusion Implementing guided algorithms tailored to patients are expected to shed light on some of the mechanisms involved in the development of TRD, and will enable the development of new therapeutic strategies for improving the long-term drug response.

ΕισαγωγήΗ ρευματοειδής αρθρίτιδα (ΡΑ) και οι σπονδυλοαρθρίτιδες (ΣπΑ) είναι χρόνιες φλεγμονώδεις νόσοι με μακροχρόνιες συνέπειες που επηρεάζουν 2-3% του πληθυσμού. Η έλευση των βιολογικών παραγόντων, όπως οι αναστολείς του παράγοντα νέκρωσης όγκων (tumor necrosis factor –TNF), έχει αλλάξει δραματικά τη θεραπεία αυτών των ασθενειών. Η αποτελεσματικότητα των αναστολέων του TNF σε σχέση με εικονικό φάρμακο και η βραχυπρόθεσμη ασφάλειά τους έχουν αποδειχτεί σε πολλές τυχαιοποιημένες κλινικές μελέτες. Ωστόσο, πολλά από τα ερωτήματα που τίθενται στη θεραπεία ασθενών της καθημερινής κλινικής πράξης δεν απαντώνται επαρκώς από τις τυχαιοποιημένες κλινικές μελέτες. Οι μακροχρόνιες μελέτες παρατήρησης και τα δεδομένα από αρχεία παρακολούθησης ασθενών έχουν συμπληρωματικό ρόλο στο να παρέχουν πολύτιμες πληροφορίες για τη βελτιστοποίηση της κλινικής χρήσης αυτών των νέων και σημαντικού κόστους φαρμάκων. Ελληνικά εθνικά δεδομένα σχετικά με την αποτελεσματικότητα και την ασφάλεια των αναστολέων του TNF σε ασθενείς με ΡΑ και ΣπΑ δεν υπάρχουν. Τα δεδομένα αυτά θα ήταν σημαντικά λόγω της διαφοροποίησης στη σοβαρότητα και τις πρακτικές αντιμετώπισή τους στα εθνικά συστήματα υγείας διαφορετικών χωρών. ΣτόχοιΣτην παρούσα μελέτη επιδιώξαμε να αξιολογήσουμε την αποτελεσματικότητα και την ασφάλεια της θεραπείας με αναστολείς του TNF σε Έλληνες ασθενείς με ΡΑ και ΣπΑ. Στοχεύσαμε να εκτιμήσουμε την αποτελεσματικότητα, την παραμονή στη θεραπεία («επιβίωση του φαρμάκου») και την ασφάλεια συγκριτικά για τους τρεις ΤNF αναστολείς infliximab, adalimumab και etanercept. Επίσης, επιδιώξαμε να προσδιορίσουμε παράγοντες που θα μπορούσαν να προβλέψουν καλύτερη ανταπόκριση, μεγαλύτερη παραμονή στη θεραπεία και τις σοβαρές ανεπιθύμητες ενέργειες κατά τη χρήση τους. Μέθοδοι Οργανώθηκε το «Ελληνικό Αρχείο Βιολογικών Θεραπειών (ΕΑΒΘ)», μια κοόρτη που περιελάμβανε όλους τους ασθενείς που ξεκινούσαν βιολογική θεραπεία για φλεγμονώδεις αρθρίτιδες σε 8 νοσοκομεία της Ελλάδας. Οι ασθενείς παρακολουθούνταν προοπτικά και, σύμφωνα με το πρωτόκολλο, συλλέγονταν δημογραφικά δεδομένα, στοιχεία νόσου και φαρμακευτική θεραπεία στην έναρξη του βιολογικού παράγοντα. Δεδομένα ενεργότητας νόσου, λειτουργικότητας και ποιότητας ζωής συλλέγονταν στην έναρξη και κάθε 6 μήνες για τα 2 πρώτα χρόνια και ετησίως στη συνέχεια, ενώ όλα τα ανεπιθύμητα συμβάματα καταγράφονταν κατά τη χρονική στιγμή που εμφανίζονταν. Για την πρώτη μελέτη, αναλύθηκαν 1208 ενήλικες ασθενείς με ΡΑ που ξεκίνησαν infliximab, adalimumab ή etanercept μεταξύ 1/2004 και 12/2009 (παρακολούθηση μέχρι 5/2011). Η απάντηση στη θεραπεία αξιολογήθηκε με διάφορους δείκτες ανταπόκρισης (DAS28, CDAI, απάντηση κατά EULAR). Στη δεύτερη μελέτη αναλύσαμε 1077 ενήλικες ασθενείς με σπονδυλοαρθρίτιδα που ξεκίνησαν την πρώτη θεραπεία με αναστολέα του TNF μεταξύ του 2004 και του τέλους του 2014 (παρακολούθηση μέχρι 5/2015). Η απάντηση στη θεραπεία υπολογίστηκε με τη χρήση τυποποιημένων δεικτών ανταπόκρισης (BASDAI50, ASDAS) στους 6 και 12 μήνες αγωγής. Χρησιμοποιήθηκαν τυπικές περιγραφικές στατιστικές, καμπύλες Kaplan-Meier και μοντέλα παλινδρόμησης (λογιστική παλινδρόμηση, παλινδρόμηση του Cox). Στη δεύτερη μελέτη χρησιμοποιήθηκε η μέθοδος του πολλαπλού καταλογισμού (multiple imputation) για την αντικατάσταση των ελλιπών τιμών στην έναρξη για τις κύριες αναλύσεις παλινδρόμησης Cox, αλλά πραγματοποιήσαμε και αναλύσεις ξεχωριστά μόνο με τους ασθενείς με πλήρη δεδομένα (complete-case analysis).Αποτελέσματα Στους ασθενείς με ΡΑ, η ανταπόκριση κατά EULAR (καλή και μέτρια) επιτεύχθηκε σε 79% των ασθενών στους 12 μήνες θεραπείας, όμως τα ποσοστά ύφεσης (βάσει DAS28) ήταν χαμηλά: 13-16% και 15-23% των ασθενών στους 6 και 12 μήνες αντίστοιχα και ήταν συγκρίσιμα μεταξύ των τριών αντι-TNF φαρμάκων. Στις πολυπαραγοντικές αναλύσεις, το adalimumab συσχετίστηκε με μεγαλύτερες πιθανότητες για ύφεση [προσαρμοσμένος λόγος πιθανοτήτων (adjusted odds ratio; OR) για ύφεση σύμφωνα με τα EULAR/ACR κριτήρια στους 12 μήνες (αναφορικά με το infliximab): 4,1 για adalimumab και 2,7 για etanercept]. Άλλοι ανεξάρτητοι προγνωστικοί παράγοντες ύφεσης ήταν το ανδρικό φύλο (OR 2.2), η χρήση κορτικοειδών (OR 2.2) και οι οιδηματώδεις αρθρώσεις (>7, OR 0.26) στην έναρξη της θεραπείας. Η 5-ετής επιβίωση των TNF αναστολέων ήταν 31%, 43% και 49% για το infliximab, το adalimumab και το etanercept αντίστοιχα (log-rank p = 0.010). Η χαμηλότερη ενεργότητα νόσου, η υψηλότερη CRP και η χρήση των κορτικοειδών στην έναρξη της θεραπείας προέβλεπαν μεγαλύτερη επιβίωση φαρμάκου σχετιζόμενη με την αποτελεσματικότητα. Η μικρότερη ηλικία, η χρήση μεθοτρεξάτης, η χρήση του adalimumab και του etanercept και ο μικρότερος αριθμός προηγούμενων DMARDs προέβλεπαν μεγαλύτερη επιβίωση σχετιζόμενη με την ασφάλεια. Είναι ενδιαφέρον ότι η προσαρμοσμένη 5ετής επιβίωση των TNF αναστολέων ήταν υψηλότερη στους ασθενείς με σταθερή (στους 6 και 12 μήνες) ύφεση με βάση το δείκτη DAS28 σε σύγκριση με ασθενείς με φτωχότερες κλινικές αποκρίσεις κατά τη διάρκεια του 1ου έτους (p 10, OR 1,86) και η χρήση κορτικοειδών σε δόση > 35 mg/εβδομάδα (OR 1,83).Όσον αφορά στους ασθενείς με ΣπΑ, αναλύσαμε 561 με ΑΣ, 375 με ΨΑ, 108 με αδΣπΑ και 33 με εντεροπαθητική ΣπΑ. Η 5-ετής και 10-ετής επιβίωση των αναστολέων του TNF ήταν 60% και 49% αντιστοίχως. Στις μη προσαρμοσμένες αναλύσεις, η επιβίωση συσχετίστηκε με μεμονωμένη αξονική νόσο (p = 0,001) ενώ, αναφορικά με τους διαφορετικούς τύπους ΣπΑ, οι ασθενείς με ΑΣ είχαν μεγαλύτερη επιβίωση φαρμάκου σε σύγκριση με τους ασθενείς με αδΣπΑ και ΨΑ (στατιστικά σημαντική διαφορά μετά τα πρώτα 2,5 (p = 0,003) και 7 έτη (p

Introduction Challenges with personalised prophylaxis in haemophilia remain, including designing unique dosing schedules that require continual adjustments and monitoring using complex sampling procedures. Aim To assess long-term efficacy and pharmacokinetic outcomes with fixed-dose N8-GP prophylaxis. Methods Descriptive analyses were performed on data from the pathfinder 2 and pathfinder 5 trials of patients with severe haemophilia A. Bleed frequency and reoccurrence were assessed in relation to several clinical criteria of interest. Bleed risk relative to time since last dose was assessed using calculated annualised bleeding rate (ABR). Long-term ABR and mean factor VIII (FVIII) trough levels were assessed in patients who received consistent N8-GP prophylaxis every 4 days (Q4D). Results During pathfinder 2, 117/136 patients with study-drug exposure of ≥600 days experienced bleeding episodes; 8.6% of bleeds were reoccurring bleeds; bleed reoccurrence decreased over time. For patients who received consistent Q4D prophylaxis across the trial (n = 61), mean ABR decreased from 3.5 bleeds/year (Year 1) to 1.6 bleeds/year (Year 6); mean FVIII trough levels stabilised at approximately 5% (Year 6). Across patients who received prophylaxis at some point during pathfinder 2 (n = 177), 125/126 (99%) reoccurring bleeds were joint bleeds. For patients receiving Q4D prophylaxis, bleeding risk generally increased as the time since the last prophylaxis dose increased. A similar reduction in ABR and stabilisation of trough level was observed in pathfinder 5. Conclusion Long-term exposure (> 5 years) to fixed-dose N8-GP prophylaxis resulted in a protective haemostatic effect, with reduction in bleed frequency and reoccurrence, and stabilisation of FVIII trough level over time.

Mobile ecological momentary assessments (mEMAs) require substantial user efforts to complete, resulting in low user compliance. One major source of incompliance is triggering mEMAs at inopportune moments. In this work, we propose a framework for implementing adaptive mEMAs using reinforcement learning (RL) to address the timing and context challenge, aiming to improve long term response compliance. To effectively model user state, we also propose a two-level user model with both momentary and routine state features. A novel k-routine mining algorithm is developed to extract routine state from passive sensing data. Using real mobile sensing data collected from 220 participants for over two weeks, we show that our proposed RL strategies consistently outperform the baseline methods including a random strategy and a supervised strategy in user compliance.

Made available in DSpace on 2022-04-29T08:38:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-11-03 Objective: Thyrotropin-stimulated thyroglobulin (STg) after total thyroidectomy is a prognosis marker for differentiated thyroid carcinoma (DTC). As Tg level is influenced by thyrotropin (TSH), perhaps the STg/TSH ratio is also a prognosis marker for these tumours. We aimed to compare STg/TSH ratio and first STg level in differentiated thyroid carcinoma patients for their ability to predict the long-term response to initial treatment. Methods: This retrospective study evaluated data from 181 DTC patients for first (1st) STg and STg/TSH ratio, at 1-3 months post-total thyroidectomy and before iodine-131 therapy, according to response to initial therapy [Excellent/Indeterminate or Incomplete (Biochemical/Structural)] observed at final evaluation, and with the survival time with excellent/indeterminate response. Results: Cases with incomplete response presented higher STg level [225.13 ± 585.26 ng/mL versus (vs) 20.4 ± 192.9 ng/mL; p < 0.001] and STg/TSH ratio (3.01 ± 7.8 vs 0.27 ± 2.58; p < 0.001). Cutoffs of 5 ng/mL for STg and 0.085 for STg/TSH displayed sensitivities of 76.7% and 76.9%, and specificities of 79.2% and 82.6%, respectively, in predicting response to therapy. Values below these cutoffs were associated with longer survival time in excellent/indeterminate response (140.4 vs 15.9 and 144.6 vs 15.9 months, respectively). Conclusion: STg/TSH ratio has a similar performance to the 1st STg in predicting long-term response to initial therapy. Departamento de Clínica Médica Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Oftalmologia Otorrinolaringologia e Cirurgia de Cabeça e Pescoço Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Patologia Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Medicina Nuclear Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Clínica Médica Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Oftalmologia Otorrinolaringologia e Cirurgia de Cabeça e Pescoço Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Patologia Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp) Departamento de Medicina Nuclear Faculdade de Medicina de Botucatu Universidade Estadual Paulista (Unesp)

A case of 73-year-old patient with metastatic colorectal cancer who underwent trifluridine/tipiracil therapy within the VI line was presented. Treatment with trifluridine/tipiracil allowed to achieve stabilization of the existing cancer for nearly 7 months.

The non‐lethal effects of predation can significantly influence animal behavior and population composition. Research has often centered around prey response to predator exposure in the short term, but fewer studies have highlighted the effects of long‐term predator exposures. In addition, studies of responses to predation risk are not always calibrated against the ecological history of predation risk in specific populations. We address these gaps by examining the effects of both long‐ and short‐term predator exposure on the behavior of individuals from populations that have different ecological histories of predation risk. We exposed individuals from high‐predation and low‐predation populations of the live‐bearing freshwater poeciliid, Heterandria formosa, to predators to assess changes in male reproductive behavior toward females. We also assessed longer‐term reproductive responses by exposing male and female H. formosa to predators at a random time of day, every day, for 30 days. In the presence of a predator, in the short term, males changed the frequency of their behaviors and females varied in their concentration of cortisol, demonstrating immediate responses to the perceived risk. The magnitude of these changes was larger in the population without a long history of predator exposure. However, we found that males and females did not change their reproductive output when exposed to predators over longer periods of time, suggesting that individuals acclimatize to the level of predation risk they experience. These results also suggest that short‐term variation in behavior or stress hormone responses should not be used as proxies for long‐term responses or fitness effects. Future work should assess both short‐term behavior and long‐term responses while simultaneously considering the ecological history of populations.

The standard of care for patients with refractory or relapsed Hodgkin lymphoma is salvage chemotherapy followed by autologous hematopoietic stem cell transplantation. This method is not always effective, however. For patient who do not respond or those who relapse again treatment opportunities are limited. Before of the brentuximab vedotin ”era” the prognosis of such patients was poor, with a 5-year overall survival not exceeding 30%. Allogeneic stem cell transplantation (allo-HSCT) may be curative, but its success is highly dependent on prior good disease control. Brentuximab vedotin can be effective bridging treatment before allo-HSCT because 34% of patients can achive complete remission. In addition, in some patients, used as monotherapy without additional consolidation treatment allows for long-term responses.

Background Levodopa is the most efficacious medication in controlling the motor symptoms of Parkinson's disease (PD). There continues to be a controversy as to whether levodopa remains effective after years of therapy. Objective To assess the long-term effectiveness of levodopa in PD patients. Methods The response to levodopa in PD patients undergoing a levodopa challenge for deep brain stimulation (DBS) surgery evaluation from June 1997 through March 2017 were evaluated. The patients were broken into four groups based on disease duration (Group I: 0- 5 years, Group II: 6- 10 years, Group III: 11- 15 years, and Group IV:≥16 years). Levodopa response was calculated based on the changes in Unified Parkinson's Disease Rating Scale (UPDRS) motor and activities of daily living (ADL) scores in the medication ON and OFF states. Results A total of 361 PD patients were included. The mean age in Group I was 59.4 years with a mean disease duration of 3.9 years (n = 29), Group II was 61 years with a mean disease duration of 8.1 years (n = 131), Group III was 64 years with a mean disease duration of 12.8 years (n = 143), and IV was 66.5 years with a mean disease duration of 18.5 years (n = 58). There was a significant improvement in UPDRS motor and ADL scores after the levodopa challenge for all groups. Conclusions In a subgroup of PD patients who were evaluated for DBS surgery, there was a marked improvement in UPDRS motor and ADL scores which did not decrease with disease progression.

For clarifying the relationship between a leaf-to-fruit ratio (LFR) and photosynthesis, LFR manipulation was performed with Juglans regia cv. Xinxin2 in order to test the photosynthesis response to LFR in source leaves. Results showed that LFR with one and two leaves was positively correlated with net photosynthetic rate (PN), chlorophyll content, and specific leaf mass, implying extremely low LFR inhibited the leaf development. However, LFR with five leaves was negatively correlated with PN, positively correlated with starch, but not related to intercellular CO2 concentration, indicating the high LFR caused the nonstomatal limitation and feedback inhibition of photosynthetic production. No significant differences in PN between LFRs (with three and four leaves) probably indicated a balanced state of coordinated supply and demand between the source leaf and sink fruit. The above results indicated that the response of photosynthesis in the source leaves to LFR depends on the variation range of LFR.

An experiment was conducted to determine the effects of banded phosphorus (P) applications at differing rates in irrigated and nonirrigated pecan (Carya illinoinensis) plots on P movement within the soil, P uptake and movement within pecan trees, and the yield and quality of nuts. On 20 Mar. 2015, P applications of 0 kg·ha−1 (0×), 19.6 kg·ha−1 (1×), 39.2 kg·ha−1 (2×), and 78.5 kg·ha−1 (4×) were administered to bands of triple superphosphate to randomly selected trees in nonirrigated and irrigated plots of a ‘Desirable’ orchard bordered by ‘Elliot’ trees. When P was applied at the 2× and 4× rates, the total soil test P decreased linearly by 35% and 54%, respectively, in nonirrigated plots and by 41% and 59%, respectively, in irrigated plots over the course of the experiment. There was no change in soil test P over time at the 0× rate for either irrigation regimen; however, at the 1× rate, soil test P decreased 44% in the irrigated plot but did not change in the nonirrigated plot. The largest linear decrease of the soil test P from the start of the experiment to the end of the experiment occurred in the top 0 to 7.6 cm. In contrast, soil test P at a depth of 15.2 to 22.9 cm decreased linearly by 23% in the nonirrigated plot, but it did not decrease over time in the irrigated plot. Increasing the P application rate increased foliar P quadratically in the nonirrigated plot, but only the 4× application rate increased foliar P compared with the 0× control. In the irrigated plot, foliar P concentrations decreased linearly from 2015 to 2017, and foliar P concentrations were not influenced by the P application rate. No differences in pecan yield or quality were observed in either irrigated or nonirrigated plots. Overall, P banding may not be the most sustainable way to increase foliar concentrations of P quickly or to maintain concentrations of the nutrient in the long term.

Plant long-term response against chewing insects could become stronger than initial reactions and even turn into systemic. The objectives of the present study were 1) to evaluate whether the long-running attack to the stem by corn borers can improve the stem antibiotic properties; 2) to check whether hydroxycinnamic acids could be involved in this antibiotic response; 3) and to check whether elicitation by Sesamia nonagrioides Lef. (Lepidoptera: Noctuidae) regurgitant could activate long-term plant responses. In this sense, we observed that long-term feeding by S. nonagrioides larvae induced genotype-dependent changes in stem antibiosis and phenolic profiles, but the hydroxycinnamate content does not have a significant role in the systemic defense induced by the attack. In addition, response to long-term feeding by larvae could not be fully mimicked by elicitation using S. nonagrioides regurgitant alone. For the first time, it has been demonstrated that 'long-term' attack to the stem by corn borers can increase the stem antibiotic properties, and this has to be considered attending to breeding strategies.

Background/Aim: Sunitinib is a tyrosine kinase inhibitor routinely used as first-line therapy in metastatic renal cell carcinoma (mRCC). Emerging evidence suggests that microRNAs (miRNAs) could be suitable biomarkers with predictive potential in mRCC. The aim of this study was to identify miRNA-based predictive biomarkers of therapy response to avoid unnecessary therapy to non-responding patients. Patients and Methods: High-throughput miRNA microarray profiling was performed on a cohort of 47 patients treated with sunitinib. Validation of candidate miRNAs was carried out on an independent cohort of 132 mRCC patients using qRT-PCR. Results: Out of 158 miRNAs (65 down-regulated, 93 up-regulated), six miRNAs were chosen for independent validation and miR-376b-3p was confirmed to be differentially expressed in tumors of patients with primary resistance versus long-term response (p

Background: Growth hormone deficiency (GHD) remains the most common indication for use of recombinant human growth hormone (rhGH) therapy in clinical practice. However, there is a paucity of studies focusing on long-term response to rhGH therapy in the Indian context. Aim: To determine the response to rhGH therapy and its predictors in children with GHD followed up at a tertiary care center in North India. Materials and Methods: We performed a retrospective review of the records of children with GHD who received rhGH therapy for at least 1 year. The relevant anthropometric, biochemical and radiological data at baseline and follow-up were recorded. Results: A total of 99 children (64 boys, 35 girls; 61 isolated GHD, 38 multiple pituitary hormone deficiency) were studied. The mean (±SD) age and height SDS at treatment initiation were 12.4 (±3.0) years and −4.0 (±1.1) respectively, while median (IQR) serum insulin-like growth factor 1 (IGF-1) and peak growth hormone level on clonidine stimulation were 73 (25-167) ng/ml and 1.1 (0.4-3.6) ng/ml respectively. The height velocity was highest during the first year of treatment (10.6 ± 3.0 cm/year), declining to 8.7 ± 2.7 and 7.9 ± 2.2 cm/year during second and third year, respectively. Over the subsequent years, there was further graded fall in height velocity, declining to 4.8 ± 3.6 cm/year (n = 2) during the seventh year. The height gain during first year was negatively correlated with age at initiation of treatment, baseline height SDS, baseline serum IGF-1 and peak serum GH level on GH stimulation test, while it showed a positive correlation with bone age delay at baseline. Only baseline height SDS was found to have a significant negative correlation with height gain during the second year. Conclusions: This study provides data on long-term response to rhGH therapy and its predictors in Indian children with GHD.

Estimating the longevity of an individual's immune response to the Sars-Cov-2 virus is vital for future planning, particularly of vaccine requirements. Neutralising antibodies (Nabs) are increasingly being recognised as a correlate of protection and whilst there are many studies which follow the response of a cohort of people, each study alone is not enough to predict the long term response. Studies use different assays to measure Nabs making them hard to combine. We present a modelling method which can combine multiple datasets and can be updated as more detailed data becomes available. Combining data from six published datasets we predict that after a short period of rapid decay the half-life of the NAb response is approximately one year giving optimism that the response will be long-lived.

Background Familial hypercholesterolemia (FH) may arise from deleterious monogenic variants in FH‐causing genes as well as from a polygenic cause. We evaluated the relationships between monogenic FH and polygenic hypercholesterolemia in influencing the long‐term response to therapy and the risk of atherosclerosis. Methods and Results A cohort of 370 patients with clinically diagnosed FH were screened for monogenic mutations and a low‐density lipoprotein‐rising genetic risk score >0.69 to identify polygenic cause. Medical records were reviewed to estimate the response to lipid‐lowering therapies and the occurrence of major atherosclerotic cardiovascular events during a median follow‐up of 31.0 months. A subgroup of patients (n=119) also underwent coronary computed tomographic angiography for the evaluation of coronary artery calcium score and severity of coronary stenosis as compared with 135 controls. Two hundred nine (56.5%) patients with hypercholesterolemia were classified as monogenic (FH/M+), 89 (24.1%) as polygenic, and 72 (19.5%) genetically undefined (FH/M−). The response to lipid‐lowering therapy was poorest in monogenic, whereas it was comparable in patients with polygenic hypercholesterolemia and genetically undetermined. Mean coronary artery calcium score and the prevalence of coronary artery calcium >100 units were significantly higher in FH/M+ as compared with both FH/M− and controls. Finally, after adjustments for confounders, we observed a 5‐fold higher risk of incident major atherosclerotic cardiovascular events in FH/M+ (hazard ratio, 4.8; 95% CI, 1.06–21.36; P adj =0.041). Conclusions Monogenic cause of FH is associated with lower response to conventional cholesterol‐lowering therapies as well as with increased burden of coronary atherosclerosis and risk of atherosclerotic‐related events. Genetic testing for hypercholesterolemia is helpful in providing important prognostic information.

Osimertinib is a potent and irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that selectively acts on both EGFR‐sensitive and EGFR T790M‐resistant mutations. Patients with pre‐treatment EGFR T790M mutations (de novo EGFR T790M) respond poorly to existing EGFR‐TKIs, whereas osimertinib has positive effects. However, the safety data for first‐line osimertinib treatment in patients aged >75 years are insufficient. We treated two elderly patients with de novo EGFR T790M mutations with osimertinib as the first‐line therapy. We found that the first‐line treatment with osimertinib was safe and resulted in a long‐term response in elderly patients with de novo EGFR T790M‐mutated lung adenocarcinoma., There are no safety data on the first‐line osimertinib treatment in patients aged 75 years or older, defined as the elderly in Japan, and very few reports exist on the efficacy of first‐line therapy for de novo epidermal growth factor receptor (EGFR) T790M‐positive lung cancer in elderly patients. We report a safe and long‐term response to the first‐line treatment with osimertinib in de novo EGFR T790M‐positive patients older than 75 years.

The long-term response of chlorophyll-a (chl-a) to changing lake water nutrient concentrations and increasing water temperature was investigated in Lough Neagh, a large, hypereutrophic lake in Northern Ireland. Trends in external and internal nutrient loading and their relation to lake nutrient concentrations were also established. Lake water concentrations of total P (TP) have increased since the 1990s but were not correlated with catchment inputs, which showed no trend. The characteristics of internal loading of P have changed since the mid-1990s, with an earlier and larger mass of P released from the sediments each summer. Catchment inputs of total oxidised N (NOx) decreased from the peak value of 10,186T/yr in 1995 to 5,396T/yr in 2011, coinciding with a reduction in lake water concentrations. External inputs and lake concentrations of NOx were highly correlated (R=0.88). Water temperature increased approximately 1C and was a predictor of variation in chl-a from 1974 to 2012. After the peak chl-a concentration in 1993, dissolved inorganic N (DIN) also became an important predictor, accounting for almost half of the 44% variance explained by a hierarchical partition model. Decreasing log (DIN:TP) ratios suggest that N limitation of chl-a has become more important in the lake recently.

Ship structure design process begins with the evaluation of environmental conditions a ship is expected to withstand. This paper deals with wave data, and more specifically with global wave dataset that can be used to evaluate waves encountered by a ship along its lifetime track. Benchmark of existing global hindcast datasets is performed, having in mind its use to assess extreme ship response. The presented comparison is thus not limited to the mean and standard deviation but includes also extreme significant wave height. Wave period that can significantly modify ship behaviour is also investigated. Five different hindcast datasets are selected for the present analysis and compared with buoy and altimeter data. Area of interest is region far from the coast, and more specifically the North-Atlantic, which is currently considered the most severe for sailing ships. In such area, the global wave models are expected to provide decent results (as opposed to near shore area where a local mesh would be required). Two datasets are provided by ECMWF (ERA5 and ERA-Interim) that uses WAM model, two others are from NOaAA/NCEP and Ifremer and use WaveWatchIII, finally WAV-ERYS dataset is provided by the Copernicus program, and uses MFWAM. Some differences are observed in the wave parameters projected by different models, especially on extremes. Reasons for this scatter are briefly discussed, but more emphasis is put on the consequence for ship response. This work has been performed within IACS (International Association of Classification Societies) framework.

Introduction Nivolumab is a fully human programmed death control immune point 1 immune checkpoint inhibitor antibody which promotes antitumor immunity. Cutaneous toxicity associated with nivolumab, immune system related, could be linked to a more durable response in patients with squamous cell lung cancer. Case report We present the case of a 62-year-old male diagnosed with metastatic squamous cell lung cancer, who was treated with nivolumab after cytotoxic chemotherapy. After treatment discontinuation, due to grade 2 cutaneous toxicity, the patient is maintaining with durable partial response for more than one year with close follow-up. Management and outcome Cumulative doses of nivolumab could cause immunological toxicities that may prolong survival of these patients even after discontinuation of treatment. Discussion Nivolumab was approved by European Medicines Agency (EMA), as second-line therapeutic, for the treatment of squamous cell lung cancer, showing a median of 9.23 months of overall survival. The development of immune-related skin toxicities has been associated with greater clinical benefit in patients with lung cancer. When cutaneous toxicity forces to nivolumab suspension, in certain cases, the option of not starting again and closely following up the patient may appear reasonable, even though there are no survival data in this context. Suspension of treatment with close monitoring of these patients until progression may be an alternative, since immune-related skin toxicities could be related to a greater clinical benefit and a durable response to nivolumab.

CMML is clinically diverse malignant clonal hematopoietic stem cell disorder characterized by persistent peripheral monocytosis, bone marrow dysplasia and with features of both myelodysplastic and myeloproliferative neoplasms (1). Generally, long term prognosis is poor with a median overall survival of 30 months and a relatively high risk of leukemic transformation, up to 30 % (2). Hypomethylating agents belong to a class of drugs which inhibit DNA methyltransferase and consequently reduce DNA methylation. Utilization of HMA in CMML has been reported with seemingly unsatisfying results with overall response rates between 30 and 60% and median overall survival between 12 and 37 months (3,4). Previously only a few predictive factors (increased bone marrow blast count and proliferative features) were found to be associated with shorter survival (5). Surprisingly only age, but none of the other disease characteristics, was a prediction for a response(6). In this case report, we describe an effective long term use of azacitidine in a patient with CMML and tried to find factors, which may contribute to long term azacitidine efficacy.