Predictive ability of logistic regression, auto-logistic regression and neural network models in empirical land-use change modeling: a case study

The objective of this study is to compare the abilities of logistic, auto-logistic and artificial neural network (ANN) models for quantifying the relationships between land uses and their drivers. In addition, the application of the results obtained by the three techniques is tested in a dynamic land-use change model (CLUE-s) for the Paochiao watershed region in Taiwan. Relative operating characteristic curves (ROCs), kappa statistics, multiple resolution validation and landscape metrics were used to assess the ability of the three techniques in estimating the relationship between driving factors and land use and its subsequent application in land-use change models. The validation results illustrate that for this case study ANNs constitute a powerful alternative for the use of logistic regression in empirical modeling of spatial land-use change processes. ANNs provide in this case a better fit between driving factors and land-use pattern. In addition, auto-logistic regression performs better than logistic regression and nearly as well as ANNs. Auto-logistic regression and ANNs are considered especially useful when the performance of more conventional models is not satisfactory or the underlying data relationships are unknown. The results indicate that an evaluation of alternative techniques to specify relationships between driving factors and land use can improve the performance of land-use change models

Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort

Rapid and highly variable warming of lake surface waters around the globe

In this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade−1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors—from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade−1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade−1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes.Peer reviewe

Rapid and highly variable warming of lake surface waters around the globe

peer reviewedIn this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade-1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors - from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade-1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade-1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes. © 2015. American Geophysical Union. All Rights Reserved

Rapid and highly variable warming of lake surface waters around the globe

Peer reviewed. ©2015. The Authors.This is an open access article under theterms of the Creative CommonsAttribution-NonCommercial-N oDerivsLicense, which permits use and distri-bution in any medium, provided theoriginal work is properly cited, the use isnon-commerc ial and no modificationsor adaptations are made.In this first worldwide synthesis of in situ and satellite-derived lake data, we find that lake summer surface water temperatures rose rapidly (global mean = 0.34°C decade 1) between 1985 and 2009. Our analyses show that surface water warming rates are dependent on combinations of climate and local characteristics, rather than just lake location, leading to the counterintuitive result that regional consistency in lake warming is the exception, rather than the rule. The most rapidly warming lakes are widely geographically distributed, and their warming is associated with interactions among different climatic factors —from seasonally ice-covered lakes in areas where temperature and solar radiation are increasing while cloud cover is diminishing (0.72°C decade 1) to ice-free lakes experiencing increases in air temperature and solar radiation (0.53°C decade 1). The pervasive and rapid warming observed here signals the urgent need to incorporate climate impacts into vulnerability assessments and adaptation efforts for lakes

High dose chemotherapy and autologous hematopoietic stem cell transplantation for rheumatoid arthritis

This thesis describes clinical and immunological aspects of immunoablative therapy and autologous stem cell transplantation (HDC + SCT) in patients with refractory rheumatoid arthritis (RA). Rheumatoid arthritis is a chronic systemic disease of unknown etiology, characterized by multiple immune abnormalities. Chapter 1 addresses the backgrounds and rationale of this treatment modality in experimental and human rheumatic autoimmune diseases. Its rationale is based on the premise that the immune abnormalities underlying human autoimmune disease can be corrected by HDC and that SCT ensures recapitulation of a naive , self-tolerant, immune system. HDC + SCT was shown to be effective in animal models with autoimmune diseases and patients with an hematological malignancy and concomitant rheumatic disease. Based on these observations a study protocol for patients with refractory rheumatoid arthritis was developed. Chapter 2 describes the result of a decision analysis that was undertaken to investigate whether any beneficial effects of HDC + SCT outweigh its attending risks and treatment-related mortality (TRM) in a chronic but nonlethal disease like RA. A Markov model was employed because it allows summation of consecutive health states. In this model we compared HDC+SCT versus continued pharmacological treatment in patients with active disease who have previously failed standard treatments (methotrexate, combination therapy, TNF-blockade) taking into account the possibility that events and outcomes vary or recur in time. With a TRM < 3.3%, HDC+SCT appeared to be the preferred treatment. The efficacy required to compensate for a TRM of 10% (e.g. after HLA-identical allogeneic SCT) was found to represent a potentially realistic scenario: a 50-70% improvement would need to be attained after transplantation in 60% of patients and maintained for 6 months, with a durable good clinical response being required in 20% of patients. Chapter 3 describes the results of a survey on treatment preference in RA patients and rheumatologists. Specifically, it was examined whether the risks of HDC + ASCT are acceptable to RA patients and rheumatologists and whether risk taking by patients was associated with disease characteristics, socio-economic parameters and/or personality traits. This was based on a realistic scenario by means of a patient preference method in which the trade-off between short-term risks and possible long-term gain of HSCT was investigated. It was shown that patients willing to accept risk of death had significantly higher VAS disease activity, VAS pain and HAQ. The patients who were willing to accept a risk of TRM related to HSCT the median required duration of benefit given a TRM of 2 % was 5 years (range 1-15). Physicians also required a median duration of benefit of 5 years. Chapter 4 describes the clinical and immunological effects of HDC + SCT in fourteen patients with intractable RA. From a technical viewpoint the treatment steps appeared feasible in all patients. The consecutive procedures of the treatment were well tolerated by most patients. Hematological recovery was uneventful in all patients, showing an inverse relationship with the age of the patient. Longlasting lymphopenia was observed, which could mainly be attributed to slow recovery of naive CD4+ T lymphocytes. With respect to efficacy, mobilization resulted in transient amelioration of disease activity in 5/14 patients (defined as ACR20 before conditioning), which was reinforced by the intensification of conditioning and transplantation procedures. In 8/12 of the patients clinical meaningful improvements (defined as good response according to EULAR response criteria) were recorded in more than 50% of follow-up visits. 4/12 patients failed to improve. The individual clinical response at 3 months was found to be predictive for the subsequent disease course. These disease courses displayed a dichotomous pattern, enabling categorization in 'responders' and 'nonresponders'. Nonresponders did not differ from responders with respect to disease or patient related variables, such as age, disease activity and duration, previous therapy, presence of rheumatoid factor. Chapter 5 reports the effects of high dose chemotherapy and autologous stem cell transplantation (HDC + ASCT) on joint damage in patients with severe rheumatoid arthritis (RA). Eight patients with intractable RA treated with HDC + ASCT at a a single center institution were longitudinally monitored for disease activity and joint damage. Profound effects on DAS and joint damage were documented during the 2 years following the intervention. As for the DAS, the beneficial effects persisted although DMARDs ultimately needed to be reinstituted in all patients at different intervals after HDC + ASCT to maintain low levels of disease activity. The robust effects of HDC + ASCT on disease activity translated into a significant reduction in the rate of joint damage by 85% that was most marked in the first year after the intervention when most patients were off-DMARDs. This study thus demonstrates that a short and intensive immunosuppressive treatment with a single agent retards the rate of joint reduction, even at extended follow-up. Chapter 6 was undertaken to advance our understanding of the immunological effects of high dose chemotherapy and autologous stem cell transplantation (HDC+ASCT) in rheumatoid arthritis (RA). The induction of (partial) remission was associated with strong baseline expression and subsequent reduction of CD3, CD4, and the differentiation markers CD27 and the CD45-isoforms (RA,RB,RO) in synovium, while expression of these markers had returned to baseline levels at the 1-year biopsy, at a time disease had relapsed to varying extents in most patients. Of interest was the high proportion of CD45RB+ CD3+ T cells at 3 months post-transplant. This subset has recently been reported to be increased in peripheral blood of RA patients versus healthy controls, reflecting accelerated differentiation of naive CD45RA T cells under the influence of inflammation. These data provide strong evidence for an active role of T cells in the perpetuation of disease activity. Chapter 7 showes that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor T-cell reconstitution in RA following high dose chemotherapy. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the TREC content of CD4 T-cell demonstrating a direct effect of IL-7 on thymic activity. The aim of chapter 8 was to analyse whether HDC + HSCT can increase the quality of life and the perception of general health of previously therapy-resistant, progressive RA patients. The quality of life during 5 years following HDC + HSCT in eight patients with refractory RA was investigated. This study demonstrates significant improvement of the quality of life, notably in the first 2 years post-tranplantation. It was also shown that the utility scores of transplanted patients improved and that the gained QALYs for RA patients treated with HDC + HSCT outweighs a TRM lower than 2.8 %. In parallel with our study, other phase I/II studies were initiated to assess feasibility, toxicity and efficacy in small groups of patients. The results from these heterogeneous studies are difficult to compare, but the treatment steps appeared feasible and safe in all patients. No unexpected major toxicity or treatment related mortality occurred, although in several patients infectious complications necessitating extra hospital admissions for parenteral antibiotic treatment were observed. One patient died as a consequence of sepsis. Recurrence of disease activity occurred in most patients usually within 2 years. Therefore this procedure is unlikely to be curative, however the use of disease modifying antirheumatic drugs (DMARDs) after recurrence of disease resulted in substantial improvement of disease activity in a majority of patients. Interestingly, patients had been refractory to these drugs (even in higher doses) before transplantation, suggesting that some degree of sensitivity to conventional drugs had been regained. Long term remissions as well as relapses and progressive disease have been reported both in RA and other autoimmune diseases with the various regimens used but no definite conclusions with regard to T-cell depletion of the graft and/or conditioning regimen can be drawn. Brodsky et al. [7] reported that a conditioning regimen of cyclophosphamide 200 mg/kg without stem cell rescue resulted in duration of aplasia that lasted longer than seen after autologous transplantation. Apparently enough stem cells survive this conditioning regimen to regenerate the immune system. Moore et al. conducted a randomized trial to compare T cell depleted versus unmanipulated SCT after high dose chemotherapy (cyclophosphamide 200 mg/kg). 17 patients with T cell depleted autologous SCT and 14 patients with unmanipulated autologous SCT were treated. There were no significant differences with respect to length or quality of remissions between the two groups [11]. An analysis of the EBMT/EULAR database on 73 RA patients treated with high dose chemotherapy and autologous SCT found a significant response (at least ACR 50% response) in 67% of patients. Some disease activity was seen during follow-up, but the severity of flares was reported to be less in many and about half showed a response to antirheumatic medication that they had failed previously [12]. McColl et al described a patient with refractory, active RA who was treated with cyclophosphamide 50 mg/kg antithymocyte globulin 90 mg/kg and SCT from his identical twin brother [13]. Four years posttransplantation the patient was still free of disease symptoms (Wicks, personal communication) without antirheumatic medication. Syngeneic lymphocytes from the healthy donor or new populations of T cells derived from donor stem cells could have dispelled host T cells. These data do not allow definitive conclusions on whether the immunological effects of the treatment are only quantitative ('debulking' of inflammatory load) or qualitative as well (e.g. tolerization of pathogenic T lymphocytes). Based on the results of Brodsky [1] (conditioning regimen with high dose cyclophosphamide without SCT) one can speculate on the role of the autologous graft. Stem cells are capable of surviving high dose treatment with cyclophosphamide and disease remissions can apparantly be caused by the cyclophosphamide-induced immunoablation itself without the possible immunomodulation of the SCT. The question remains whether autologous SCT is capable of immunomodulation by regeneration of naive tolerant lymphocytes or merely serves as a rescue to shorten the aplastic period. From a T-cell centered perspective it might be inferred from the present studies that not all pathogenic T lymphocytes were eradicated or that some had been reinfused with the graft. This would imply that remissions can only be achieved by further intensification, e.g. by in vivo T cell depletion. Clearly, this could add to the toxicity. From the patient's and treating physician's perspective, responses were clinically meaningful in a majority of patients with resultant enhanced quality of life. It remains to be shown that any superior efficacy of a more rigorous approach will compensate for increased toxicity in terms of quality-adjusted-life-expectancy [14]. The aformentioned studies indicate that autologous SCT is not curative for refractory RA. The observed reappearence of the autoimmune disease after autologous SCT can be attributed to many factors, including: 1. Survival of autoaggressive lymphocyte (either T- or B cells), synoviocytes or macophages despite high dose chemotherapy. 2. Reinfusion of autoaggressive lymphocytes together with the stem cells. 3. Renewed activation of autoaggressive lymphocytes as a result of exposure to novel autoantigens 4. Reapparence of the autoimmune disease because defective stem cells were reinfused or 5. A combination of the above. Most protocols used did not increase immunosuppression to the point of immunoablation. More intensive immunoablative conditioning regimen followed by autologous SCT might induce more prolonged remissions. The concept that remissions may be maximized by removing pathogenic cells from the stem cell product has not been shown in humans, so the role of T cells in the graft remains, thus far, unclear. Allogeneic transplantation has not yet been tested as a primary treatment for patients with RA due to risks of transplant related mortality and graft versus host disease. Allogeneic SCT may be more effective than autologous SCT if intrinsic stem cell abnormalities exist in RA and if host hematopoiesis and abnormal immune cell populations can be eradicated via a graft vs autoimmunity effect. Furthermore allogeneic SCT in RA would offer an opportunity to investigate whether self-tolerance can be restored. Recent advances in allografting have improved safety, thereby allowing application in non-malignant conditions such as RA. The described cases are limited in number and differ in ways of stem cell collection, T and B cell depletion of the graft and conditioning regimen. The disease severity and the response in patients with RA also differs greatly. Therefore it should be emphasized that progress in the development of this novel treatment modality can only be achieved by multicenter studies, employing uniform eligibility criteria, treatment regimens and study parameters. Adequate assessment of risk/benefit requires properly designed and conducted prospective randomized controlled trials with a long follow-up. The issue is whether intense immune suppression aimed at immunoablation is superior to continuous moderate immune suppression with respect to toxicity and efficacy. Furthermore it should be investigated whether these effects can be maintained during a longer follow-up

No survival difference after successful I-131 ablation between patients with initially low-risk and high-risk differentiated thyroid cancer

To compare disease-specific survival and recurrence-free survival (RFS) after successful I-131 ablation in patients with differentiated thyroid carcinoma (DTC) between those defined before ablation as low-risk and those defined as high-risk according to the European Thyroid Association 2006 consensus statement. Retrospective data from three university hospitals were pooled. Of 2009 consecutive patients receiving ablation, 509 were identified as successfully ablated based on both undetectable stimulated serum thyroglobulin in the absence of antithyroglobulin antibodies and a negative diagnostic whole-body scan in a follow-up examination conducted 8.1 +/- 4.6 months after ablation. Of these 509 patients, 169 were defined as high-risk. After a mean follow-up of 81 +/- 64 months (range 4-306 months), only three patients had died of DTC, rendering assessment of disease-specific survival differences impossible. Of the 509 patients, 12 (2.4%) developed a recurrence a mean 35 months (range 12-59 months) after ablation. RFS for the duration of follow-up was 96.6% according to the Kaplan-Meier method. RFS did not differ between high-risk and low-risk patients (p=0.68). RFS differed slightly but significantly between those with papillary and those with follicular thyroid carcinoma (p=0.03) and between those aged a parts per thousand currency sign45 years those aged > 45 years at diagnosis (p=0.018). After (near) total thyroidectomy and successful I-131 ablation, RFS does not differ between patients classified as high-risk and those classified as low-risk based on TNM stage at diagnosis. Consequently, the follow-up protocol should be determined on the basis of the result of initial treatment rather than on the initial tumour classification.Diabetes mellitus: pathophysiological changes and therap

Characterization of adverse joint outcomes in patients with osteoarthritis treated with subcutaneous tanezumab

Objective Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings. Method Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored. Results Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106). Conclusion In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT0252818