Coarse graining of slow variables in dynamic simulations of soft matter

A new Brownian dynamics model is presented to describe the coarse grain dynamics of particles with long-lived memory. Instead of solving a set of generalized Langevin equations we introduce a set of variables describing the slowly fluctuating thermodynamic state of the ignored degrees of freedom. These variables give rise to additional transient forces on the simulated particles, whose interpretation provides a new way of thinking about memory effects in soft-matter physics. We illustrate the proposed method by simulating shear thinning of synthetic resins.\u

The new CFS Divisia monetary aggregates: design, construction, and data sources

The Center for Financial Stability (CFS) has initiated a new Divisia monetary aggregates database, maintained within the CFS program called Advances in Monetary and Financial Measurement (AMFM). The Director of the program is William A. Barnett, who is the originator of Divisia monetary aggregation and more broadly of the associated field of aggregation-theoretic monetary aggregation. The international section of the AMFM web site is a centralized source for Divisia monetary aggregates data and research for over 40 countries throughout the world. The components of the CFS Divisia monetary aggregates for the United States reflect closely those of the current and former simple-sum monetary aggregates provided by the Federal Reserve. The first five levels, M1, M2, M2M, MZM, and ALL, are composed of currency, deposit accounts, and money market accounts. The liquid asset extensions to M3, M4-, and M4 resemble in spirit the now discontinued M3 and L aggregates, including repurchase agreements, large denomination time deposits, commercial paper, and Treasury bills. When the Federal Reserve discontinued publishing M3 and L, the Fed stopped providing the consolidated, seasonally adjusted components. Also the Fed no longer provides the interest rates on the components. With so much of the needed component quantity and interest-rate data no longer available from the Federal Reserve, decisions about data sources needed in construction of the CFS aggregates have been far from easy and sometimes required regression interpolation. This paper documents the decisions of the CFS regarding United States data sources at the present time, with particular emphasis on Divisia M3 and M4

The new CFS Divisia monetary aggregates: design, construction, and data sources

The Center for Financial Stability (CFS) has initiated a new Divisia monetary aggregates database, maintained within the CFS program called Advances in Monetary and Financial Measurement (AMFM). The Director of the program is William A. Barnett, who is the originator of Divisia monetary aggregation and more broadly of the associated field of aggregation-theoretic monetary aggregation. The international section of the AMFM web site is a centralized source for Divisia monetary aggregates data and research for over 40 countries throughout the world. The components of the CFS Divisia monetary aggregates for the United States reflect closely those of the current and former simple-sum monetary aggregates provided by the Federal Reserve. The first five levels, M1, M2, M2M, MZM, and ALL, are composed of currency, deposit accounts, and money market accounts. The liquid asset extensions to M3, M4-, and M4 resemble in spirit the now discontinued M3 and L aggregates, including repurchase agreements, large denomination time deposits, commercial paper, and Treasury bills. When the Federal Reserve discontinued publishing M3 and L, the Fed stopped providing the consolidated, seasonally adjusted components. Also the Fed no longer provides the interest rates on the components. With so much of the needed component quantity and interest-rate data no longer available from the Federal Reserve, decisions about data sources needed in construction of the CFS aggregates have been far from easy and sometimes required regression interpolation. This paper documents the decisions of the CFS regarding United States data sources at the present time, with particular emphasis on Divisia M3 and M4

Teeltsturing Spathiphyllum

In de teelt van Spathiphyllum komen grote verschillen in ontwikkeling, met name ten aanzien van de bloei binnen en tussen partijen voor. Enerzijds treedt soms veel voorbloei op die verwijderd moet worden en anderzijds bloeien de planten zeer onregelmatig. Het seizoen heeft duidelijk invloed op de groei, ontwikkeling en bloei. Jaarrond wil men eenzelfde product afzetten. Planning is hierdoor moeilijk te realiseren, wat resulteert in een relatief grote leegloop. Tevens kan onvoldoende worden ingespeeld op de vraag vanuit de afzetkant waardoor rendementsverliezen ontstaan. Temperatuur speelt een belangrijke rol bij de teeltsturing van Spathiphyllum. Door de liberalisering van de energiemarkt en de normen die gesteld zijn binnen het Besluit Glastuinbouw (voorheen AMvB Glastuinbouw 2010) zal kritisch gekeken moeten worden naar het energieverbruik. Ook vanuit de maatschappij en individuele consument neemt de vraag naar verantwoord geteelde producten toe. Door een beter inzicht in de rol van temperatuur (mogelijkheden temperatuurintegratie) op de sturing van het gewas (groei, ontwikkeling en bloei) kunnen partijen meer planmatig geteeld worden en kan efficiënter met energie omgegaan worden. Daarnaast kan met een gerichte sturing betere voldaan worden aan de wensen vanuit en afspraken met de handel. De doelstelling van het project is het opstellen en toetsen van teeltsturingsschema’s Spathiphyllum voor jaarrond teelt op bedrijfsniveau, waarbij een vooraf gedefinieerd product wordt geteeld binnen de kaders van het Besluit Glastuinbouw (voorheen AMvB Glastuinbouw 2010). De te verwachten resultaten zijn: • Inzicht verkrijgen van de invloed en de samenhang van diverse teeltfactoren, met name temperatuur en licht, op groei, ontwikkeling en bloei Spathiphyllum. • Teeltsturingsschema’s Spathiphyllum jaarrond Hiermee kan jaarrond een kwalitatief goed product geteeld worden met een minimum aan leegloop en binnen de normen van het beslui

Randomised controlled trial of first-line tyrosine-kinase inhibitor (TKI) versus intercalated TKI with chemotherapy for EGFR-mutated nonsmall cell lung cancer

Introduction Previous studies have shown interference between epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and chemotherapy in the cell cycle, thus reducing efficacy. In this randomised controlled trial we investigated whether intercalated erlotinib with chemotherapy was superior compared to erlotinib alone in untreated advanced EGFR-mutated nonsmall cell lung cancer (NSCLC). Materials and methods Treatment-naïve patients with an activating EGFR mutation, ECOG performance score of 0–3 and adequate organ function were randomly assigned 1:1 to either four cycles of cisplatin-pemetrexed with intercalated erlotinib (day 2–16 out of 21 days per cycle) followed by pemetrexed and erlotinib maintenance (CPE) or erlotinib monotherapy. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival, objective response rate (ORR) and toxicity. Results Between April 2014 and September 2016, 22 patients were randomised equally into both arms; the study was stopped due to slow accrual. Median follow-up was 64 months. Median PFS was 13.7 months (95% CI 5.2–18.8) for CPE and 10.3 months (95% CI 7.1–15.5; hazard ratio (HR) 0.62, 95% CI 0.25–1.57) for erlotinib monotherapy; when compensating for number of days receiving erlotinib, PFS of the CPE arm was superior (HR 0.24, 95% CI 0.07–0.83; p=0.02). ORR was 64% for CPE versus 55% for erlotinib monotherapy. Median overall survival was 31.7 months (95% CI 21.8–61.9 months) for CPE compared to 17.2 months (95% CI 11.5–45.5 months) for erlotinib monotherapy (HR 0.58, 95% CI 0.22–1.41 months). Patients treated with CPE had higher rates of treatment-related fatigue, anorexia, weight loss and renal toxicity. Conclusion Intercalating erlotinib with cisplatin-pemetrexed provides a longer PFS compared to erlotinib alone in EGFR-mutated NSCLC at the expense of more toxicity

Extending the IMQ Model:Deep Characterization of the Human TLR7 Response for Early Drug Development

Imiquimod (IMQ; brand name Aldara®) is a registered topical agent that has been proven to induce local inflammation via the Toll-like receptor (TLR)7 pathway. The purpose of this study was to characterize TLR7-mediated inflammation following 7 days (168 h) of topical IMQ exposure in healthy volunteers, and to compare the effects of short exposure (48 h-72 h) with prolonged exposure (120 h-168 h). IMQ (100mg) was applied under occlusion to 5 different tape-stripped treatment sites on the back of 10 healthy participants for a maximum of 7 consecutive days. Erythema and skin perfusion were measured daily up to 168h. Biopsies for immunohistochemical staining and RNA sequencing were collected at 0h, 48h, 72h, 120h and 168h post IMQ application. IMQ triggered an inflammatory response starting at 48h after application, including erythema and perfusion of the skin. At the transcriptomic level, IMQ induced TLR7 signalling, IRF involvement and activation of TNF signalling via NF-κB. Furthermore, an enhanced inflammatory response at the cellular level was observed after prolonged IMQ exposure, with cellular infiltration of dendritic cells, macrophages and T cells which was also corroborated by transcriptomic profiles. No difference was found in the erythema and perfusion response after 168h of IMQ exposure compared to 72h. Prolonged IMQ exposure revealed enhanced cellular responses and additional pathways with modulated activity compared to short exposure and can therefore be of interest as a model for investigational compounds targeting innate and adaptive immune responses.</p

Automatic identification and segmentation of slice of minimal hiatal dimensions in transperineal ultrasound volumes

OBJECTIVE: To develop and validate a tool for automatic selection of the slice of minimal hiatal dimensions (SMHD) and segmentation of the urogenital hiatus (UH) in transperineal ultrasound (TPUS) volumes. METHODS: Manual selection of the SMHD and segmentation of the UH was performed in TPUS volumes of 116 women with symptomatic pelvic organ prolapse (POP). These data were used to train two deep-learning algorithms. The first algorithm was trained to provide an estimation of the position of the SMHD. Based on this estimation, a slice was selected and fed into the second algorithm, which performed automatic segmentation of the UH. From this segmentation, measurements of the UH area (UHA), anteroposterior diameter (APD) and coronal diameter (CD) were computed automatically. The mean absolute distance between manually and automatically selected SMHD, the overlap (dice similarity index (DSI)) between manual and automatic UH segmentation and the intraclass correlation coefficient (ICC) between manual and automatic UH measurements were assessed on a test set of 30 TPUS volumes. RESULTS: The mean absolute distance between manually and automatically selected SMHD was 0.20 cm. All DSI values between manual and automatic UH segmentations were above 0.85. The ICC values between manual and automatic UH measurements were 0.94 (95% CI, 0.87-0.97) for UHA, 0.92 (95% CI, 0.78-0.97) for APD and 0.82 (95% CI, 0.66-0.91) for CD, demonstrating excellent agreement. CONCLUSIONS: Our deep-learning algorithms allowed reliable automatic selection of the SMHD and UH segmentation in TPUS volumes of women with symptomatic POP. These algorithms can be implemented in the software of TPUS machines, thus reducing clinical analysis time and simplifying the examination of TPUS data for research and clinical purposes. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology

3D ultrasound strain imaging of puborectal muscle with and without unilateral avulsion

INTRODUCTION AND HYPOTHESIS: The puborectal muscle (PRM), one of the female pelvic floor (PF) muscles, can get damaged during vaginal delivery, leading to disorders such as pelvic organ prolapse. Current diagnosis involves ultrasound (US) imaging of the female PF muscles, but functional information is limited. Previously, we developed a method for strain imaging of the PRM from US images in order to obtain functional information. In this article, we hypothesize that strain in the PRM would differ from intact to the avulsed end. METHODS: We calculated strain in PRMs at maximum contraction, along their muscle fiber direction, from US images of two groups of women, which consisted of women with intact (n 1  = 8) and avulsed PRMs (unilateral) (n 2  = 10). Normalized strain ratios between both ends of the PRM (avulsed or intact) and the mid region were calculated. Subsequently, the difference in ratio between the avulsed and intact PRMs was determined. RESULTS: We observe from the obtained results that the contraction/strain pattern of intact and undamaged PRMs is different from PRMs with unilateral avulsion. Normalized strain ratios between avulsed and intact PRMs were statistically significant (p = 0.04). CONCLUSION: In this pilot study, we were able to show that US strain imaging of PRMs can show differences between intact PRMs and PRMs with unilateral avulsion

Switch-maintenance gemcitabine after first-line chemotherapy in patients with malignant mesothelioma (NVALT19):an investigator-initiated, randomised, open-label, phase 2 trial

Background Almost all patients with malignant mesothelioma eventually have disease progression after first-line therapy. Previous studies have investigated maintenance therapy, but none has shown a great effect. We aimed to assess the efficacy and safety of switch-maintenance gemcitabine in patients with malignant mesothelioma without disease progression after first-line chemotherapy. Methods We did a randomised, open-label, phase 2 trial in 18 hospitals in the Netherlands (NVALT19). We recruited patients aged older than 18 years with unresectable malignant mesothelioma with no evidence of disease progression after at least four cycles of first-line chemotherapy (with platinum and pemetrexed), who had a WHO performance status of 0-2, adequate organ function, and measurable or evaluable disease. Exclusion criteria were active uncontrolled infection or severe cardiac dysfunction, serious disabling conditions, symptomatic CNS metastases, radiotherapy within 2 weeks before enrolment, and concomitant use of any other drugs under investigation. Patients were randomly assigned (1:1), using the minimisation method, to maintenance intravenous gemcitabine (1250 mg/m(2) on days 1 and 8, in cycles of 21 days) plus supportive care, or to best supportive care alone, until disease progression, unacceptable toxicity, serious intercurrent illness, patient request for discontinuation, or need for any other anticancer agent, except for palliative radiotherapy. A CT scan of the thorax or abdomen (or both) and pulmonary function tests were done at baseline and repeated every 6 weeks. The primary outcome was progression-free survival in the intention-to-treat population. Safety was analysed in all participants who received one or more doses of the study drug or had at least one visit for supportive care. Recruitment is now closed; treatment and follow-up are ongoing. This study is registered with the Netherlands Trial Registry, NTR4132/NL3847. Findings Between March 20, 2014, and Feb 27, 2019, 130 patients were enrolled and randomly assigned to gemcitabine plus supportive care (65 patients [50%]) or supportive care alone (65 patients [50%]). No patients were lost to follow-up; median follow-up was 36.5 months (95% CI 34.2 to not reached), and one patient in the supportive care group withdrew consent. Progression-free survival was significantly longer in the gemcitabine group (median 6.2 months [95% CI 4.6-8.7]) than in the supportive care group (3.2 months [2.8-4.1]; hazard ratio [HR] 0.48 [95% CI 0.33-0.71]; p=0.0002). The benefit was confirmed by masked independent central review (HR 0.49 [0.33-0.72]; p=0.0002). Grade 3-4 adverse events occurred in 33 ( 52%) of 64 patients in the gemcitabine group and in ten (16%) of 62 patients in the supportive care group. The most frequent adverse events were anaemia, neutropenia, fatigue or asthenia, pain, and infection in the gemcitabine group, and pain, infection, and cough or dyspnoea in the supportive care group. One patient (2%) in the gemcitabine group died, due to a treatment-related infection. Interpretation Switch-maintenance gemcitabine, after first-line chemotherapy, significantly prolonged progression-free survival compared with best supportive care alone, among patients with malignant mesothelioma. This study confirms the activity of gemcitabine in treating malignant mesothelioma