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This research analyzed the wintering population of rooks (Corvus frugilegus) in the Friuli Venezia Giulia region (Italy) from 2010 to 2020. The goal was to determine the population size, trend, and distribution over the decade by assessing census data and evaluating the study area's environmental suitability. It was important to identify the relationship between the region's environmental characteristics and the presence of the species by developing territory suitability models, processed using the maximum entropy algorithms and MaxEnt (maximum entropy) software. It was possible to determine the combinations of the factors potentially influencing habitat attendance, to develop environmental suitability maps, and to identify the area with the greater probability of the presence of the species, as well as those areas with potential suitability. Data for the presence of wintering rooks were derived from annual censuses, carried out by direct observation along pre-established transects in the Friuli Venezia Giulia region. Based on the census data, that total number of rooks in Friuli Venezia Giulia across the 10-year period had a maximum peak recorded in 2015 (1543) and a minimum in 2019 (853). The distribution of the species was concentrated in the central-southern areas of the region, with greater turnout in the areas characterized by agricultural land use, while the mountainous areas, located in the southern part of the region, were excluded. The environmental suitability models developed with MaxEnt on a regional scale demonstrated excellent predictive capacity, validating the species' ecological needs. Although the rook is not an endangered species, its range has been drastically reduced in Italy, at least in the last century, and MaxEnt could be used in the future as a management tool in order to outline conservation actions for the species, especially for its habitats. [ABSTRACT FROM AUTHOR]

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0–100 days, 101 days–1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4–108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1–7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3–5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. Conclusions: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies. [ABSTRACT FROM AUTHOR]

Hazard ratios are ubiquitously used in time to event analysis to quantify treatment effects. Although hazard ratios are invaluable for hypothesis testing, other measures of association, both relative and absolute, may be used to fully elucidate study results. Restricted mean survival time (RMST) differences between groups have been advocated as useful measures of association. Recent work focused on model-free estimates of the difference in restricted mean survival through follow-up times, instead of focusing on a single time horizon. The resulting curve can be used to quantify the association in time units with a simultaneous confidence band. In this work a model-based estimate of the curve is proposed using pseudo-values allowing for possible covariate adjustment. The method is easily implementable with available software and makes possible to compute a simultaneous confidence region for the curve. The pseudo-values regression using multiple restriction times is in good agreement with the estimates obtained by standard direct regression models fixing a single restriction time. Moreover, the proposed method is flexible enough to reproduce the results of the non-parametric approach when no covariates are considered. Examples where it is important to adjust for baseline covariates will be used to illustrate the different methods together with some simulations. [ABSTRACT FROM AUTHOR]

Hazard ratios are ubiquitously used in time to event analysis to quantify treatment effects. Although hazard ratios are invaluable for hypothesis testing, other measures of association, both relative and absolute, may be used to fully elucidate study results. Restricted mean survival time (RMST) differences between groups have been advocated as useful measures of association. Recent work focused on model-free estimates of the difference in restricted mean survival through follow-up times, instead of focusing on a single time horizon. The resulting curve can be used to quantify the association in time units with a simultaneous confidence band. In this work a model-based estimate of the curve is proposed using pseudo-values allowing for possible covariate adjustment. The method is easily implementable with available software and makes possible to compute a simultaneous confidence region for the curve. The pseudo-values regression using multiple restriction times is in good agreement with the estimates obtained by standard direct regression models fixing a single restriction time. Moreover, the proposed method is flexible enough to reproduce the results of the non-parametric approach when no covariates are considered. Examples where it is important to adjust for baseline covariates will be used to illustrate the different methods together with some simulations. [ABSTRACT FROM AUTHOR]

Summary: Allogeneic haematopoietic‐cell transplantation (allo‐HCT) is a potentially curative therapy for high‐risk myelodysplastic syndrome (MDS). Reduced‐intensity conditioning (RIC) is usually associated with lower non‐relapse mortality (NRM), higher relapse rate and similar overall‐survival (OS) as myeloablative‐conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced‐toxicity regimen with intense anti‐leukaemia activity and a favourable toxicity profile. We investigated post‐transplant outcomes in 1722 MDS patients following allo‐HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow‐up was 64 months (1–171). Five‐year relapse rates were 25% (21–30), 38% (34–42) and 25% (22–29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25–35), 27% (23–30) and 34% (31–38, P = 0·008), respectively. Five‐year OS was 50% (44–55), 43% (38–47), and 43% (39–47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo‐HCT in MDS. [ABSTRACT FROM AUTHOR]

Background: In autologous stem cell transplant (ASCT)‐eligible myeloma patients, prolonged induction does not necessarily improve the depth of response. Method: We analyzed 1222 ASCT patients who were classified based on (a) the interval between induction and stem cell collection, (b) the type of induction regimen: BID (Bortezomib, IMiDs, and Dexamethasone), Bortezomib‐based, or CTD (Cyclophosphamide, Thalidomide, and Dexamethasone), and (c) the time to best response (Early ie, best response within 4 or 5 months, depending on the regimen vs Late; Good ie, VGPR or better vs Poor). Results: The length of induction treatment required to achieve a Good response did not affect PFS (P =.65) or OS (P =.61) post‐ASCT. The three types of regimen resulted in similar outcomes: median PFS 31, 27.7 and 30.8 months (P =.31), and median OS 81.7, 92.7, and 77.4 months, respectively (P =.83). On multivariate analysis, neither the type nor the duration of the induction regimen affected OS and PFS, except for Early Good Responders who had a better PFS compared to Early Poor Responders (HR = 1.21, P‐value =.02). However, achieving a Good response at induction was associated with a better response (≥VGPR) post‐transplant. Conclusion: The kinetics of response did not affect outcomes. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to compare the effect of the intensity of conditioning approaches used in allogeneic transplantation in myeloma—reduced intensity conditioning (RIC), non‐myeloablative (NMA), myeloablative conditioning (MAC) or Auto‐AlloHCT—on outcomes in patients who had had a prior autologous transplant. Methods: A retrospective analysis of the EBMT database (1991‐2012) was performed. Results: A total of 344 patients aged between 40 and 60 years at the time of alloHCT were identified: 169 RIC, 69 NMA, 65 MAC and 41 Auto‐Allo transplants. At a median follow‐up of 54 months, the probabilities of overall survival (OS) at 5 years were 39% (95% CI 31%‐47%), 45% (95% CI 32%‐57%), 19% (95% CI 6%‐32%) and 34% (95% CI 17%‐51%), respectively. Status at allogeneic HCT other than CR or PR conferred a 70% higher risk of death and a 40% higher risk of relapse. OS was markedly lower in the MAC group (P =.004). MAC alloHCT was associated with a higher risk of death than RIC alloHCT until 2002 (HR = 4.1, P <.001) but not after 2002 (HR = 1.2, P =.276). Conclusion: From 1991 to 2002, MAC was associated with poorer OS. Between 2003 and 2012, there were no significant differences in outcomes based on these different approaches. [ABSTRACT FROM AUTHOR]

This research project aims at identifying a new network of routes and historical itineraries for the development and promotion of rural tourism in the Tuscany Region, by promoting forms of sustainable mobility in rural areas, particularly marginal ones. Religious tourism is defined as tourism, which includes visits to religious sites such as shrines, churches, abbeys, hermitages and sacred places; such places are an attraction for their religious essence as well as their artistic and cultural beauty. The ancient obsolete road system, which often survives as an archaeological relic as a precursor of the present road system, especially in rural areas, is more widespread than a layman would think. The paper refers the results of the study aimed at recovering the entire historical road that allowed pilgrims and travelers to reach La Verna (a place where St. Francis received the Stigmata) coming from Florence. [ABSTRACT FROM AUTHOR]

The article examines diseases characteristics as well as treating centre attitudes concerning the therapy and outcome of patients having aplastic anaemia and lymphoma. The evaluation was peformed by Severe Aplastic Anaemia Working Party of the European Society of Blood and Bone Marrow Transplantation.

Summary: Dyskeratosis congenita (DC) is a genetic multisystem disorder with frequent involvement of the bone marrow. Haematopoietic stem cell transplantation (HSCT) is the only definitive cure to restore haematopoiesis, even though it cannot correct other organ dysfunctions. We collected data on the outcome of HSCT in the largest cohort of DC (n = 94) patients ever studied. Overall survival (OS) and event‐free survival (EFS) at 3 years after HSCT were 66% and 62%, respectively. Multivariate analysis showed better outcomes in patients aged less than 20 years and in patients transplanted from a matched, rather than a mismatched, donor. OS and EFS curves tended to decline over time. Early lethal events were infections, whereas organ damage and secondary malignancies appeared afterwards, even a decade after HSCT. A non‐myeloablative conditioning regimen appeared to be most advisable. Organ impairment present before HSCT seemed to favour the development of chronic graft‐versus‐host disease and T‐B immune deficiency appeared to enhance pulmonary fibrosis. According to the present data, HSCT in DC is indicated in cases of progressive marrow failure, whereas in patients with pre‐existing organ damage, this should be carefully evaluated. Further efforts to investigate treatment alternatives to HSCT should be encouraged. [ABSTRACT FROM AUTHOR]

Anaortic coronary artery bypass proved to prevent early neurologic injury compared to on-pump CABG. The Cardica PAS-Port is a fully automated device that might be able to perform proximal aorto-venous anastomoses without an increased embolic risk. We evaluated early post-operative neurologic outcome in a matched population following clampless OPCAB (CCAB: either 'all-arterial' or with automatically anastomosed venous grafts) or on-pump CABG. 366 consecutive patients were submitted to isolated coronary bypass by a single surgeon experienced in both off and on-pump procedures between January 2009 and December 2013. Of these patients, 223 underwent a clampless off-pump revascularization. After propensity score matching, 143 pairs were selected, who received either off-pump or on-pump surgery. In the off-pump group, CCAB was performed with an all-arterial approach ( n = 33) or with automated proximal anastomosis of the venous graft(s) by means of the Cardica PAS-Port connector ( n = 110). Neurologic injury was defined as non-reversible (NRNI: lethal coma or stroke) or reversible (RNI: TIA or delirium). Operative mortality was 2.4 % (CCAB 1.4 %; CABG 3.5 %; p = 0.14). The global rate of early neurologic injury was 5.6 % (CCAB 2.1 vs. CABG 9.1 %; p = 0.006). Incidence was 1.4 % for NRNI (CCAB 0 vs. CABG 2.8 %; p = 0.04) and 4.2 % for RNI (CCAB 2.1 vs. CABG 6.3 %; p = 0.06). No differences were found among other major perioperative outcomes. CCAB prevents both early post-operative RNI and NRNI. This result can be achieved with a totally anaortic strategy and also with the aid of a fully automated device for proximal aorto-venous anastomoses. [ABSTRACT FROM AUTHOR]

In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p = 0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor. [ABSTRACT FROM AUTHOR]

The 'landmark' and 'Simon and Makuch' non-parametric estimators of the survival function are commonly used to contrast the survival experience of time-dependent treatment groups in applications such as stem cell transplant versus chemotherapy in leukemia. However, the theoretical survival functions corresponding to the second approach were not clearly defined in the literature, and the use of the 'Simon and Makuch' estimator was criticized in the biostatistical community. Here, we review the 'landmark' approach, showing that it focuses on the average survival of patients conditional on being failure free and on the treatment status assessed at the landmark time. We argue that the 'Simon and Makuch' approach represents counterfactual survival probabilities where treatment status is forced to be fixed: the patient is thought as under chemotherapy without possibility to switch treatment or as under transplant since the beginning of the follow-up. We argue that the 'Simon and Makuch' estimator leads to valid estimates only under the Markov assumption, which is however less likely to occur in practical applications. This motivates the development of a novel approach based on time rescaling, which leads to suitable estimates of the counterfactual probabilities in a semi-Markov process. The method is also extended to deal with a fixed landmark time of interest. [ABSTRACT FROM AUTHOR]

Reconstitution, engraftment kinetics and tumor cell clearance were analyzed after reduced intensity conditioning hematopoietic cell transplant (RIC-HCT) in patients with chronic lymphocytic leukemia (CLL). Patients were transplanted from unrelated ( n = 40) or related ( n = 10) donors after fludarabine and 2 Gy total body irradiation followed by cyclosporine and mycophenolate mofetil. The vast majority of patients (96%) engrafted with absolute neutrophil count (ANC) > 0.5 × 109/L at day + 22. CLL cells decreased (median 2%, range 0-69%) within 28 days, but disappeared by day + 180 after HCT. Donor T-cell chimerism increased to > 95% at day 56 and donor B-cell chimerism to 94% at day + 360. Overall survival was 51 ± 8%, incidence of progression 37 ± 7% and non-relapse related mortality (NRM) 30 ± 7% at 4 years. The most common causes of NRM were graft-versus-host disease (GvHD) (14%) and sepsis (6%). Disease status at HCT was significantly associated with early B-cell reconstitution ( p = 0.04) and with increased risk of relapse/progression in univariate and multivariate analysis ( p = 0.022). Tumor cells were undetectable by day + 180, although B-cell reconstitution did not occur until 1.5 years after RIC-HCT. The best predictors for progression-free survival (PFS) and overall survival (OS) were complete response (CR) or first partial response (PR1) and the absence of bulky disease at transplant, respectively. [ABSTRACT FROM AUTHOR]

In multi-state models, it has been the tradition to model all transition intensities on one time scale, usually the time since entry into the study ('clock-forward' approach). The effect of time since an intermediate event has been accommodated either by changing the time scale to time since entry to the new state ('clock-back' approach) or by including the time at entry to the new state as a covariate. In this paper, we argue that the choice of time scale for the various transitions in a multi-state model should be dealt with as an empirical question, as also the question of whether a single time scale is sufficient. We illustrate that these questions are best addressed by using parametric models for the transition rates, as opposed to the traditional Cox-model-based approaches. Specific advantages are that dependence of failure rates on multiple time scales can be made explicit and described in informative graphical displays. Using a single common time scale for all transitions greatly facilitates computations of probabilities of being in a particular state at a given time, because the machinery from the theory of Markov chains can be applied. However, a realistic model for transition rates is preferable, especially when the focus is not on prediction of final outcomes from start but on the analysis of instantaneous risk or on dynamic prediction. We illustrate the various approaches using a data set from stem cell transplant in leukemia and provide supplementary online material in R. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

This document explains some of the relevant methodological issues involved in planning a clinical study using survival and time-to-event outcome data, particularly in the field of haematopoietic stem cell transplantation, and indicates the appropriate statistical methods to use for the analysis. As the majority of these methods are commonly used in survival and event-history analysis, this document discusses their potential and limitations with reference to common SCT research situations. Some reference is given to methods, recently appearing in the literature that may be capable of handling complex investigations. These guidelines also address various practical issues, such as recoding or transforming variables in regression models or reporting results. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: The combined role of immunomodulators (IMM) and clinical characteristics of Inflammatory Bowel Disease (IBD) in determining the cancer risk is undefined. The aim was to assess whether clinical characteristics of IBD are independent risk factors for cancer, when considering thiopurines and anti-TNFs use. Methods: In a single-center cohort study, clinical characteristics of IBD patients with IBD duration ≥1year and ≥2 visits from 2000 to 2009 were considered. Tests for crude rates and survival analysis methods were used to assess differences of incidence of cancer between groups. The methods were adjusted for the time interval between diagnosis and immunomodulatory treatments. Results: IBD population included 1222 patients :615 Crohn''s disease (CD), 607 ulcerative colitis (UC). Cancer was diagnosed in 51 patients (34 CD,17 UC), with an incidence rate of 4.3/1000pt/year. The incidence rate of cancer was comparable between CD and UC (4.6/1000pt/year vs 2.9/1000pt/year ;p=n.s.). Cancer most frequently involved the breast, the GI tract, the skin. Lymphoma was diagnosed in CD (1HL,1NHL,0 HSTCL). Risk factors for cancer included older age at diagnosis of IBD (CD: HR 1.25;95%CI 1.08–1.45; UC:HR 1.33;95%CI 1.15–1.55 for an increase by 5years; p=0.0023; p=0.0002), fistulizing pattern in CD (HR 2.55; 95%CI 1.11–5.86,p=0.0275), pancolitis in UC (HR 2.79;95%CI 1.05–7.40 p=0.0396 vs distal). IMM and anti-TNFs did not increase the cancer risk in CD, neither IMM in UC (anti-TNFs risk in UC not feasible as no cases observed). Conclusions: Fistulizing pattern in CD, pancolitis in UC and older age at diagnosis of IBD are independent risk factors for cancer. [Copyright &y& Elsevier]

This randomized phase III clinical trial explored the efficacy of DaunoXome (DNX) versus Daunorubicin (DNR) in acute myeloid leukaemia (AML) patients aged >60 years. Three hundred and one AML patients were randomized to receive DNR (45 mg/m2 days 1–3) or DNX (80 mg/m2 days 1–3) plus cytarabine (AraC; 100 mg/m2 days 1–7). Patients in complete remission (CR) received a course of the same drugs as consolidation and then were randomized for maintenance with AraC+ all trans retinoic acid or no further treatment. Among 153 patients in the DNR arm, 78 (51·0%) achieved CR, 55 (35·9%) were resistant and 20 (13·1%) died during induction. Among 148 patients in the DNX arm, 73 (49·3%) achieved CR, 47 (31·8%) were resistant and 28 (18·9%) died during induction. Univariate analysis showed no difference as to induction results. After CR, DNX showed a higher incidence of early deaths (12·5% vs. 2·6% at 6 months, P = 0·053) but a lower incidence of relapse beyond 6 months (59% vs. 78% at 24 months, P = 0·064), with a cross in overall survival (OS) and disease-free survival (DFS) curves and a later advantage for DNX arm after 12 months from diagnosis. DNX seems to improve OS and DFS in the long-term follow-up, because of a reduction in late relapses. [ABSTRACT FROM AUTHOR]

We compared antithymocyte globulin (ATG) with alemtuzumab in 73 patients with multiple myeloma, who underwent reduced conditioning with melphalan/fludarabine, followed by allogeneic stem cell transplantation from human leucocyte antigen-matched or -mismatched unrelated donors. The ATG group had more prior high-dose chemotherapies (P < 0·001), while bone marrow was used more as the stem cell source in the alemtuzumab group (P < 0·001). Alemtuzumab resulted in faster engraftment of leucocytes (P = 0·03) and platelets (P = 0·02) and in a lower incidence of acute graftversushost disease (GvHD) grades II–IV (24% vs. 47%,P = 0·06). More cytomegalovirus (CMV) seropositive patients in the alemtuzumab group experienced CMV reactivation (100% vs. 47%,P = 0·001). The cumulative incidence of treatment-related mortality at 2 years was 26% [95% confidence interval (CI) = 12–37%] for ATG vs. 28% (95% CI = 15–55%) for alemtuzumab,P = 0·7. There was no significant difference in the estimated 2-year overall and progression-free survival between ATG and alemtuzumab: 54% (95% CI: 39–75%) vs. 45% (95% CI: 28–73%) and 30% (95% CI: 16–55%) vs. 36% (95% CI: 20–62%) respectively. In multivariate analysis, treatment with alemtuzumab had a higher risk for relapse (hazard ratio: 2·37;P = 0·05) while killer immunoglobulin-like receptor (KIR)-ligand mismatch was protective for relapse (P < 0·0001). We conclude that alemtuzumab produced less acute GvHD, but higher probability of relapse. The data implicated a major role of KIR-ligand mismatched transplantation in multiple myeloma. [ABSTRACT FROM AUTHOR]

Novel drugs have improved survival for patients with multiple myeloma in recent years. However, the disease is still fatal. Allogeneic stem cell transplantation (Allo) has proven to cure some patients with the disease, but its role is controversial due to relatively high transplant-related toxicity and mortality (nonrelapse mortality, NRM). Using nonmyeloablative reduced-intensity conditioning (RIC), both toxicity and NRM can be reduced, and RICAllo is, therefore, an option for subgroups of patients. Upfront tandem autologous/RICAllo (Auto/RICAllo) was shown to be superior to single Auto or tandem Auto/Auto in both progression-free (PFS) and overall survival (OS) in two prospective studies with long-term follow-up, while three similarly designed studies did not detect a difference. A recent update of pooled patient data from four of these studies showed significantly superior PFS and OS with Auto/RICAllo. Importantly, none of these studies showed inferior results with Auto/RICAllo in patients less than 70 years of age. Auto/RICAllo appears to overcome some poor risk cytogenetic markers. Encouraging results have also been seen in treatment of relapsed patients. Combining Allo with new proteasome inhibitors and immunomodulatory drugs may further improve results. Other encouraging new cell therapies such as with CAR T-cells, NK- and CAR NK-cells may well have a place in combination with RICAllo. Such studies are warranted. [ABSTRACT FROM AUTHOR]