International Financial Integration

In recent decades, foreign assets and liabilities in advanced countries have grown rapidly relative to GDP, with the increase in gross cross-holdings far exceeding the size of net positions. Moreover, the portfolio equity and FDI categories have grown in importance relative to international debt stocks. In this paper, we describe the broad trends in international financial integration for a sample of industrial countries, and seek to explain the cross-country and time-series variation in the size of international balance sheets. We also examine the behaviouur of the rates of return on foreign assets and liabilities, relating them to 'market' returns.

Faster Approximate String Matching for Short Patterns

We study the classical approximate string matching problem, that is, given strings $P$ and $Q$ and an error threshold $k$, find all ending positions of substrings of $Q$ whose edit distance to $P$ is at most $k$. Let $P$ and $Q$ have lengths $m$ and $n$, respectively. On a standard unit-cost word RAM with word size $w \geq \log n$ we present an algorithm using time $$O(nk \cdot \min(\frac{\log^2 m}{\log n},\frac{\log^2 m\log w}{w}) + n)$$ When $P$ is short, namely, $m = 2^{o(\sqrt{\log n})}$ or $m = 2^{o(\sqrt{w/\log w})}$ this improves the previously best known time bounds for the problem. The result is achieved using a novel implementation of the Landau-Vishkin algorithm based on tabulation and word-level parallelism.Comment: To appear in Theory of Computing System

Evaluating the Age-Based Recommendations for Long-Term Follow-Up in Breast Cancer

Background: After 5 years of annual follow-up following breast cancer, Dutch guidelines are age based: annual follow-up for women &lt;60 years, 60–75 years biennial, and none for &gt;75 years. We determined how the risk of recurrence corresponds to these consensus-based recommendations and to the risk of primary breast cancer in the general screening population. Subjects, Materials, and Methods: Women with early-stage breast cancer in 2003/2005 were selected from the Netherlands Cancer Registry (n = 18,568). Cumulative incidence functions were estimated for follow-up years 5–10 for locoregional recurrences (LRRs) and second primary tumors (SPs). Risks were compared with the screening population without history of breast cancer. Alternative cutoffs for age were determined by log-rank tests. Results: The cumulative risk for LRR/SP was lower in women &lt;60 years (5.9%, 95% confidence interval [CI] 5.3–6.6) who are under annual follow-up than for women 60–75 (6.3%, 95% CI 5.6–7.1) receiving biennial visits. All risks were higher than the 5-year risk of a primary tumor in the screening population (ranging from 1.4% to 1.9%). Age cutoffs &lt;50, 50–69, and &gt; 69 revealed better risk differentiation and would provide more risk-based schedules. Still, other factors, including systemic treatments, had an even greater impact on recurrence risks. Conclusion: The current consensus-based recommendations use suboptimal age cutoffs. The proposed alternative cutoffs will lead to a more balanced risk-based follow-up and thereby more efficient allocation of resources. However, more factors should be taken into account for truly individualizing follow-up based on risk for recurrence. Implications for Practice: The current age-based recommendations for breast cancer follow-up after 5 years are suboptimal and do not reflect the actual risk of recurrent disease. This results in situations in which women with higher risks actually receive less follow-up than those with a lower risk of recurrence. Alternative cutoffs could be a start toward risk-based follow-up and thereby more efficient allocation of resources. However, age, or any single risk factor, is not able to capture the risk differences and therefore is not sufficient for determining follow-up. More risk factors should be taken into account for truly individualizing follow-up based on the risk for recurrence.</p

Computing the first eigenpair of the p-Laplacian via inverse iteration of sublinear supersolutions

We introduce an iterative method for computing the first eigenpair $(\lambda_{p},e_{p})$ for the $p$-Laplacian operator with homogeneous Dirichlet data as the limit of $(\mu_{q,}u_{q})$ as $q\rightarrow p^{-}$, where $u_{q}$ is the positive solution of the sublinear Lane-Emden equation $-\Delta_{p}u_{q}=\mu_{q}u_{q}^{q-1}$ with same boundary data. The method is shown to work for any smooth, bounded domain. Solutions to the Lane-Emden problem are obtained through inverse iteration of a super-solution which is derived from the solution to the torsional creep problem. Convergence of $u_{q}$ to $e_{p}$ is in the $C^{1}$-norm and the rate of convergence of $\mu_{q}$ to $\lambda_{p}$ is at least $O(p-q)$. Numerical evidence is presented.Comment: Section 5 was rewritten. Jed Brown was added as autho

Lithium isotopes in speleothems: temperature-controlled variation in silicate weathering during glacial cycles

Terrestrial chemical weathering of silicate minerals is a fundamental component of the global cycle of carbon and other elements. Past changes in temperature, rainfall, ice cover, sea-level and physical erosion are thought to affect weathering but the relative impact of these controls through time remains poorly constrained. This problem could be addressed if the nature of past weathering could be constrained at individual sites. In this study, we investigate the use of speleothems as local recorders of the silicate weathering proxy, Li isotopes. We analysed 7Li and [Li] in speleothems that formed during the past 200 ka in two well-studied Israeli caves (Soreq and Tzavoa), as well as in the overlying soils and rocks. Leaching and mass balance of these soils and rocks show that Li is dominantly sourced from weathering of the overlying aeolian silicate soils. Speleothem 7Li values are ubiquitously higher during glacials (~23‰) than during interglacials (~10‰), implying more congruent silicate weathering during interglacials (where “congruent” means a high ratio of primary mineral dissolution to secondary mineral formation). These records provide information on the processes controlling weathering in Israel. Consideration of possible processes causing this change of weathering congruency indicates a primary role for temperature, with higher temperatures causing more congruent weathering (lower 7Lispeleo). The strong relationship observed between speleothem d7Li and climate at these locations suggests that Li isotopes may be a powerful tool with which to understand the local controls on weathering at other sites, and could be used to assess the distribution of weathering changes accompanying climate change, such as that of Pleistocene glacial cycles

The need of data harmonization to derive robust empirical relationships between soil conditions and vegetation.

Question: Is it possible to improve the general applicability and significance of empirical relationships between abiotic conditions and vegetation by harmonization of temporal data? Location: The Netherlands. Methods: Three datasets of vegetation, recorded after periods with different meteorological conditions, were used to analyze relationships between soil moisture regime (expressed by the mean spring groundwater level - MSLt calculated for different periods) and vegetation (expressed by the mean indicator value for moisture regime Fm). For each releve, measured groundwater levels were interpolated and extrapolated to daily values for the period 1970-2000 by means of an impulse-response model. Sigmoid regression lines between MSLt and Fm were determined for each of the three datasets and for the combined dataset. Results: A measurement period of three years resulted in significantly different relationships between Fm and MSLt for the three datasets (F-test,/? <0.05>. The three regression lines only coincided for the mean spring groundwater level computed over the period 1970-2000 (AfSLclimate) and thus provided a general applicable relationship. Precipitation surplus prior to vegetation recordings strongly affected the relationships. Conclusions: Harmonization of time series data (1) eliminates biased measurements, (2) results in generally applicable relationships between abiotic and vegetation characteristics and (3) increases the goodness of fit of these relationships. The presented harmonization procedure can be used to optimize many relationships between soil and vegetation characteristics. © IAVS; Opulus Press Uppsala

Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage

Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use metagenomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.info:eu-repo/semantics/publishedVersio

Trends in treatment and survival of gallbladder cancer in the Netherlands; Identifying gaps and opportunities from a nation-wide cohort

Gallbladder cancer (GBC) is rare in Western populations and data about treatment and outcomes are scarce. This study aims to analyze survival and identify opportunities for improvement using population-based data from a low-incidence country. GBC patients diagnosed between 2005 and 2016 with GBC were identified from the Netherlands Cancer Registry. Patients were grouped according to time period (2005-2009/2010-2016) and disease stage. Trends in treatment and overall survival (OS) were analyzed. In total 1834 patients were included: 661 (36%) patients with resected, 278 (15%) with non-resected non-metastatic, and 895 (49%) with metastatic GBC. Use of radical versus simple cholecystectomy (12% vs. 26%, p < 0.001) in early (pT1b/T2) GBC increased. More patients with metastatic GBC received chemotherapy (11% vs. 29%, p < 0.001). OS improved from 4.8 months (2005-2009) to 6.1 months (2010-2016) (p = 0.012). Median OS increased over time (2005-2009 vs. 2010-2016) in resected (19.4 to 26.8 months, p = 0.038) and metastatic (2.3 vs. 3.4 months, p = 0.001) GBC but not in unresected, non-metastatic GBC. In early GBC, patients with radical cholecystectomy had a median OS of 76.7 compared to 18.4 months for simple cholecystectomy (p < 0.001). Palliative chemotherapy showed superior (p < 0.001) survival in metasta

Integrative analysis of neuroblastoma by single-cell RNA sequencing identifies the NECTIN2-TIGIT axis as a target for immunotherapy

Pediatric patients with high-risk neuroblastoma have poor survival rates and urgently need more effective treatment options with less side effects. As novel and improved immunotherapies may fill this need, we dissected the immunoregulatory interactions in neuroblastoma by single-cell RNA-sequencing of 25 tumors (10 pre- and 15 post-chemotherapy, including 5 pairs) to identify strategies for optimizing immunotherapy efficacy. Neuroblastomas were infiltrated by NK, T and B cells, and immunosuppressive myeloid populations. NK cells showed reduced cytotoxicity and T cells had a dysfunctional profile. Interaction analysis revealed a vast immunoregulatory network and identified NECTIN2-TIGIT as a crucial immune checkpoint. Combined blockade of TIGIT and PD-L1 significantly reduced neuroblastoma growth, with complete responses in vivo. Moreover, addition of TIGIT blockade to standard relapse treatment in a chemotherapy-resistant Th-ALKF1174L/MYCN 129/SvJ syngeneic model significantly improved survival. Concluding, our integrative analysis of neuroblastoma’s vast immunoregulatory network provides novel targets and a rationale for immunotherapeutic combination strategies

Lenalidomide in combination with dexamethasone at first relapse in comparison with its use as later salvage therapy in relapsed or refractory multiple myeloma

This subset analysis of data from two phase III studies in patients with relapsed or refractory multiple myeloma (MM) evaluated the benefit of initiating lenalidomide plus dexamethasone at first relapse. Multivariate analysis showed that fewer prior therapies, along with β2-microglobulin (≤2.5 mg/L), predicted a better time to progression (TTP; study end-point) with lenalidomide plus dexamethasone treatment. Patients with one prior therapy showed a significant improvement in benefit after first relapse compared with those who received two or more therapies. Patients with one prior therapy had significantly prolonged median TTP (17.1 vs. 10.6 months; P=0.026) and progression-free survival (14.1 vs. 9.5 months, P=0.047) compared with patients treated in later lines. Overall response rates were higher (66.9% vs. 56.8%, P=0.06), and the complete response plus very good partial response rate was significantly higher in first relapse (39.8% vs. 27.7%, P=0.025). Importantly, overall survival was significantly prolonged for patients treated with lenalidomide plus dexamethasone with one prior therapy, compared with patients treated later in salvage (median of 42.0 vs. 35.8 months, P=0.041), with no differences in toxicity, dose reductions, or discontinuations despite longer treatment. Therefore, lenalidomide plus dexamethasone is both effective and tolerable for second-line MM therapy and the data suggest that the greatest benefit occurs with earlier use