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The Large Hadron Collider forward (LHCf) experiment is designed to use the LHC to verify the hadronic-interaction models used in cosmic-ray physics. Forward baryon production is one of the crucial points to understand the development of cosmic-ray showers. We report the neutron-energy spectra for LHC s=7 TeV proton–proton collisions with the pseudo-rapidity η ranging from 8.81 to 8.99, from 8.99 to 9.22, and from 10.76 to infinity. The measured energy spectra obtained from the two independent calorimeters of Arm1 and Arm2 show the same characteristic feature before unfolding the detector responses. We unfolded the measured spectra by using the multidimensional unfolding method based on Bayesian theory, and the unfolded spectra were compared with current hadronic-interaction models. The QGSJET II-03 model predicts a high neutron production rate at the highest pseudo-rapidity range similar to our results, and the DPMJET 3.04 model describes our results well at the lower pseudo-rapidity ranges. However, no model perfectly explains the experimental results over the entire pseudo-rapidity range. The experimental data indicate a more abundant neutron production rate relative to the photon production than any model predictions studied here.

Background: Post-traumatic elbow stiffness is a common consequence following trauma or surgery, resulting in significant limb disability, with a negative impact on daily life. Although conservative treatment is the first-line approach, it is not yet known which is most suitable and effective., Objective: To investigate the effectiveness of conservative treatments in patients with post-traumatic elbow stiffness., Method: A protocol for this systematic review was published in PROSPERO (CRD42024517823). PRISMA standards were followed. An extensive systematic search was conducted in six databases (PubMed, CINHAL, Cochrane Library, Web of Science, Scopus, and PEDro), and the CENTRAL trial register. Two reviewers independently assessed, selected results, collected data, rated the risk of bias (RoB) of included studies with the Cochrane risk of bias tool, synthesized the available evidence, and rated it using GRADE methodology., Results: Five studies were included in the review, although high variability in interventions and comparators precluded the synthesis of results into a meta-analysis. Large effect sizes were observed when conservative treatment was initiated immediately after immobilization, improving elbow functionality (SMD 3.07; 95%CI 1.91 to 4.23), and pain (SMD 1.83; 95%CI 0.91 to 2.76). Results indicate that Proprioceptive Neuromuscular Facilitation (SMD = -1.22; 95%CI [-1.90, -0.54]) and Graded Motor Imagery (SMD = -2.79; 95%CI [-3.59, -2.00]) were more effective than comparisons in recovering elbow functionality and pain reduction., Conclusion: Although conservative treatment is recommended as a first-line approach, the best conservative treatment cannot be determined with certainty due to the low to very low confidence in the results., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Human immunodeficiency virus (HIV) and hepatitis C (HCV) screening and human papillomavirus (HPV) vaccine uptake remain suboptimal. To improve HIV and HCV screening and HPV vaccination, the authors implemented a quality improvement project in three southwestern Pennsylvania family medicine residency practices., Methods: From June 1 to November 30, 2021, participating practices used universal screening and vaccination guidelines and chose from multiple strategies at the office (for example, standing orders), provider (for example, multiple forms of provider reminders), and patient (for example, incentives) levels derived from published literature and tailored to local context. Age-eligible patients for each recommendation with at least one in-person office visit during the intervention period were included. To assess the interventions' effect, the authors obtained testing and vaccination data from the electronic health record for the intervention period, contrasted it with identical data from June 1 to November 30, 2020, and used logistic regression controlling for patient age, sex, and race to determine differences in screening and vaccination between intervention and baseline periods., Results: A total of 14,920 and 15,523 patients were eligible in the baseline and intervention periods, respectively. Following the intervention, HIV lifetime screening but not first-time screening for patients 13-64 years old was significantly higher (78.9% vs. 76.1%, p = 0.004, and 39.6% vs. 36.6%, p = 0.152, respectively, adjusted odds ratio [aOR] 1.21, 95% confidence interval [CI] 1.06-1.38). HCV lifetime screening for patients 18-79 years old was significantly higher postintervention (62.5% vs. 53.5%, p < 0.001, aOR 1.51, 95% CI 1.4-1.64). For patients 9-26 years old, no change in HPV initiation was observed, but the percentage of patients who completed their HPV vaccinations in the observed period was significantly higher postintervention (7.0% vs 4.6%, p = 0.006, aOR 1.58, 95% CI 1.14-2.2). During the postintervention period, the researchers identified 0 new HIV diagnoses and 48 HCV diagnoses (19 eligible for treatment)., Conclusion: Family medicine residency office-based multistrategy efforts appear to successfully increase patient uptake of HIV and HCV screenings and maintain HPV vaccination rates., (Copyright © 2024 The Joint Commission. Published by Elsevier Inc. All rights reserved.)

Wildfires strongly alter hydrological processes and surface and groundwater quality in forested environments. The paired-watershed method, consisting of comparing a burnt (altered) watershed with an unburnt (control) watershed, is commonly adopted in studies addressing the hydrological effects of wildfires. This approach requires a calibration period to assess the pre-perturbation differences and relationships between the control and the altered watershed. Unfortunately, in many studies, the calibration phase is lacking due to the unpredictability of wildfires and the large number of processes that should be investigated. So far, no information is available on the possible bias induced by the lack of the calibration period in the paired-watershed method when assessing the hydrological impacts of wildfires. Through a literature review, the consequences of the lack of calibration on the assessment of wildfire hydrological changes were evaluated, along with the most used watershed pairing strategies. The literature analysis showed that if calibration is lacking, misestimation of wildfire impacts is likely, particularly when addressing low-severity or long-term wildfire effects. The Euclidean distance based on physical descriptors (geology, morphology, vegetation) was proposed as a metric of watersheds similarity and tested in mountain watersheds in Central Italy. The Euclidean distance proved to be an effective metric for selecting the most similar watershed pairs. This work raises awareness of biases exerted by lacking calibration in paired-watershed studies and proposes a rigorous and objective methodology for future studies on the hydrological effects of wildfires., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Data on cellular immunity mediators in the early phase of human leishmaniasis are still limited and controversial. In order to mimic the changes of humoral mediators during the early phase of human natural infection, some Th1, Th2, Treg, and Breg cytokines, MCP-1, and the nitric oxide (NO) from human PBMC, stimulated by Leishmania infantum, Leishmania major, Leishmania donovani and Leishmania tropica infective metacyclic promastigotes, were determined. After 4 h of L. major, L. donovani, and L. tropica challenge, TNFα, IL-1β, IL-6 levels were significantly higher than negative control cultures with saline (SF) instead of Leishmania promastigotes, unlike L. infantum-stimulated TNFα and L. major-stimulated IL-1β. We obtained higher levels of IL-4 and IL-10 cytokines after stimulation of human PBMCs by L. infantum and L. donovani, compared to those observed after the challenge of PBMCs by L. major and L. tropica. Regarding IL-35, such cytokine levels were significantly increased following infection with L. infantum and L. donovani, in contrast to L. major and L. tropica. Up to our knowledge, we are the first to study the effect of four different species of Leishmania on IL-35 levels in human cells. Our study highlights how several Leishmania species can up-regulate different groups of cytokines (Th1, Th2, Treg and Breg) and modulate NO release in a different way. This original aspect can be explained by different Leishmania cell products, such as LPG, obtained from different strains/species of live parasites. Our findings would contribute to the development of new therapeutics or vaccination strategies., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background: Diaphragm ultrasound (DUS) has been extensively used in critically ill patients while data on outpatients with interstitial lung disease (ILD) are limited. We hypothesized that diaphragm function, assessed by ultrasound, could be impaired in patients with ILD, considering both Idiopathic Pulmonary Fibrosis (IPF) and Connective Tissue Disease (CTD-ILD), compared to healthy subjects. Moreover, this impairment could impact clinical and functional parameters., Methods: All consecutive CTD-ILD and IPF patients followed in our center (March-October 2020) were screened. Diaphragm displacement (DD), inspiratory thickness (Ti), expiratory thickness (Te), thickening fraction (TF), and respiratory functional parameters were collected. The prevalence of diaphragmatic dysfunction (TF <30%) was then recorded., Results: Eighty-two consecutive patients (41 CTD-ILD, 41 IPF) and 15 age- and sex-matched controls were enrolled. In the overall population, 24 out of 82 (29%) presented diaphragmatic dysfunction. In CTD-ILD, DD and Ti were lower as compared to IPF (p = 0.021 and p = 0.036, respectively); while diaphragmatic dysfunction was more prevalent compared to controls (37% vs 7%, p = 0.043). TF positively correlated to patients' functional parameters in the CTD-ILD group (FVC%pred: p = 0.003; r = 0.45), while not in the IPF group. Diaphragmatic dysfunction was associated with moderate/severe dyspnea in both CTD-ILD and IPF (p = 0.021)., Conclusion: The prevalence of diaphragmatic dysfunction was 29% in patients with ILD and was associated with moderate/severe dyspnea. CTD-ILD presented lower DD compared with IPF and a higher prevalence of diaphragmatic dysfunction (TF<30%) compared with controls. TF was associated with lung function only in CTD-ILD patients, suggesting its potential role in the comprehensive patient assessment., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Sand dams are impermeable water harvesting structures built to collect and store water within the volume of sediments transported by ephemeral rivers. The artificial sandy aquifer created by the sand dam reduces evaporation losses relative to surface water storage in traditional dams. Recent years have seen a renaissance of studies on sand dams as an effective water scarcity adaptation strategy for drylands. However, many aspects of their functioning and effectiveness are still unclear. Literature reviews have pointed to a range of research gaps that need further scientific attention, such as river corridors and network dynamics, watershed-scale impacts, and interaction with social dynamics. However, the scattered and partially incomplete information across the different reviews would benefit from an integrated framework for directing future research efforts. This paper is a collaborative effort of different research groups active on sand dams and stems from the need to channel future research efforts on this topic in a thorough and coherent way. We synthesize the pivotal research gaps of a) unclear definition of "functioning" sand dams, b) lack of methodologies for watershed-scale analysis, c) neglect of social aspects in sand dam research, and d) underreported impacts of sand dams. We then propose framing future research to better target the synthesized gaps, including using the social-ecological systems framework to better capture the interconnected social and biophysical research gaps on sand dams, fully utilizing the potential of remote sensing in large-scale studies and collecting sand dam cases across the world to create an extensive database to advance evidence-based research on sand dams., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luigi Piemontese reports financial support was provided by Camões - Instituto da Cooperação e da Língua., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Disease course in Idiopathic Pulmonary Fibrosis (IPF) is highly heterogeneous and markers of disease progression would be helpful. Blood leukocyte count has been studied in cancer patients and a reduced lymphocyte to monocyte ratio (LMR) has been show to predict survival. Thus, we aimed to investigate the role of monocytes count and LMR in three distinct population of patients with IPF: 77 newly-diagnosed IPF, 40 with end-stage IPF and 17 IPF with lung cancer. In newly-diagnosed IPF patients, we observed a negative correlation between forced vital capacity (FVC) at diagnosis and both white blood cells and monocytes count (r = -0.24; p = 0.04 and r = -0.27; p = 0.01; respectively). Moreover, a high monocytes count was independently associated with functional decline (OR: 1.004, 95%CI 1.00-1.01; p = 0.03). In newly-diagnosed IPF, the LMR cut-off at diagnosis was 4.18 with an AUC of 0.67 (95%CI 0.5417-0.7960; p = 0.025), and overall survival was significantly worse in patients with a LMR<4.18 compared to patients with a LMR≥4.18 (HR: 6.88, 95%CI 2.55-18.5; p = 0.027). LMR was significantly lower in IPF patients with lung cancer compared to those newly diagnosed with IPF [2.2 (0.8-4.4), 3.5 (0.8-8.8); p < 0.0001] and those with end-stage disease [3.6 (2-6.5); p < 0.0001]. In conclusion, a LMR<4.18 is associated with significantly shorter survival in newly-diagnosed IPF patients. In addition, LMR is significantly lower in patients with IPF and lung cancer compared to patients with newly-diagnosed IPF. High monocytes count at baseline negatively correlates with FVC and is an independent predictor of disease progression in newly-diagnosed IPF patients., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The appropriate implementation of the concept of Water-related Ecosystem Services (WES) in water resources planning can support the development of productive activities and, at the same time, sustain local ecosystems. However, such implementation it is only possible when both WES supply and demand are evaluated, eventually with a spatially explicit method, for gaining insights into the ecohydrological behavior of a basin and the anthropogenic pressures on the available water resources. Based on the integration of hydrological modelling and Water Footprint (WF) analysis, this study aims at developing a methodology to analyze both the supply and demand of WES, evaluating a Water Ecosystem Services Footprint (WESF) associated with the agricultural sector. The proposed methodology is based on a 3-tiered approach: 1) evaluating the WES demand determined by the agricultural sector using the WF Assessment methodology; 2) quantifying the WES supply by applying the Soil Water Assessment Tool (SWAT); 3) estimating the green, blue, and gray WESF through dedicated indicators in order to identify the main hotspots. The methodology is applied to a specific case study in the upstream part of the Arno river basin (Central Italy). By means of subnational WF statistics the green, blue, and gray WF of the agricultural sector is calculated, determining the spatial distribution of WES demand in the catchment. SWAT results quantify the available water resources, pointing out the blue/green surface water partitioning, where precipitation is divided into 25% runoff and 46% evapotranspiration, and the associated WES supply. Merging the results, the WESF spatial pattern is evaluated, properly identifying the most critical areas in the catchment. WESF represents an operative tool to look at agricultural water management from an ecosystem-based perspective, supporting the identification of the strategies to explore the sustainable coupling of biosphere and anthroposphere., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Massively obese subjects frequently undergo pulmonary function tests nowadays. Obesity-associated decreases in key operating lung volumes (reduced inspiratory capacity and reduced vital capacity) are particularly concerning because they may shorten the "room" for tidal volume expansion with negative physiologic and sensory consequences., Research Question: Is massive obesity associated with reduced operating lung volumes? If so, is this effect more pronounced in men than women?, Study Design and Methods: We performed an observational, retrospective study in a tertiary, hospital-based laboratory. Pulmonary function test results from 248 super-obese (SO; BMI, 50 to 59.9 kg/m 2 ) and 83 super-super obese (SSO; BMI, ≥60 kg/m 2 ) men and women were analyzed. Electronic medical records were screened to ensure that subjects were free of any disease that potentially could interfere with lung volumes., Results: The prevalence of a low total lung capacity (restriction) was 26.9%, which increased to 38.6% in SSO. Despite the absence of between-sex differences in BMI and spirometric variables derived from the forced maneuver in both SO and SSO, men presented with higher prevalence of restriction (46.7%) than women (19.4%) (P < .05). Between-sex differences in residual volume differed according to the BMI group; SO men presented with higher values than SO women; the opposite was found in the SSO group. The prevalence of restriction with low operating lung volumes was approximately twice (SSO) and approximately thrice (SSO) as high in men compared with women (P < .01). Linear prediction equations as a function of sex, demographic, and anthropometric attributes markedly reduced the prevalence of these abnormalities across the population., Interpretation: Obesity-related restriction leading to low operating lung volumes is highly prevalent in the massively obese subject, particularly in men. These alterations that are associated with massive obesity should be taken into consideration for an accurate interpretation of pulmonary function tests in this growing population., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

In the arid regions of south eastern Tunisia, the land use is predominated by olive trees cropping, where two main cultivation strategies can be found: using of water harvesting techniques to overcome the scarcity and variability of rainfall (in the Matmata mountains) and dryland farming (in the Jeffara plain). In these arid areas, soil moisture is the main limiting factor for crop growth and it should be monitored to benchmark different management options. Different conventional methods are available for point soil moisture monitoring, but the increased availability of remotely sensed data offers major opportunities for spatial analyses. The aim of this paper is to perform a comparative study on the soil water status for rainfed olive tree growing in three major landscape areas: in the mountains with traditional water harvesting check dams (called jessour), in the piedmont on floodwater harvesting (called tabias), and in the plain with full dryland farming conditions. Time series of Normalized Difference Infrared Index (NDII), derived from Landsat 7 satellite, were retrieved from the novel Google Earth Engine platform. NDII values were related to measured soil water content, which was taken at non-regular time intervals between 2009 and 2017. The analysis of NDII data, indicating the water content of the vegetation, shows that jessour can adequately ensure water supply for olive trees. Increased soil moisture conditions in the jessour areas are visible both in the dry and the humid seasons, indicating the effectiveness of this traditional water harvesting system. Moreover, our results show that Landsat 7 NDII values are correlated with the root-zone soil moisture in the monitoring sites (r 2 ranging from 0.62 to 0.67), allowing the use of NDII to estimate soil water contents in our study area., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: FVC may underestimate the slow vital capacity (SVC) due to early closure of the small airways at low lung volumes in the forced maneuver. It remains unclear whether using SVC instead of FVC in the FEV 1 /vital capacity (VC) ratio increases the yield of spirometry in detecting airflow limitation or, alternatively, leads to a false-positive finding for obstruction., Methods: This study included 13,893 adult outpatients with FEV 1 /FVC and total lung capacity at or above the lower limit of normal. A cluster of clinical and physiological variables defined the probability of airway disease and dysfunction, respectively., Results: The prevalence of "discordance" (preserved FEV 1 /FVC but low FEV 1 /SVC) was 20.4%: discordant subjects had lower mid-expiratory flows, higher airway resistance, worse gas trapping, and ventilation distribution abnormalities than "concordant" subjects (both ratios preserved) (P < .05). Regardless of sex, age < 60 years, BMI > 30 kg/m 2 , and FEV 1 > 70% predicted were associated with discordance (P < .001). Discordant subjects with preserved FEV 1 /FVC but low FEV 1 /SVC were four times more likely to be diagnosed with an obstructive airway disease by a respirologist compared with those with preserved FEV 1 /SVC and FEV 1 /FVC. The only exception was in the elderly subgroup with discordance (age > 70 years): only 10% of these subjects were subsequently diagnosed with an airway disease (P > .05)., Conclusions: Using SVC instead of FVC in the FEV 1 /VC ratio enhances the yield of spirometry in detecting mild airflow obstruction in younger and obese subjects. The FEV 1 /SVC ratio, however, should be used with caution in elderly subjects with preserved FEV 1 /FVC because a low value may represent a false-positive finding for airflow limitation., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: To (1) identify strategies for financial justification of pharmacists integrated into team-based primary care, (2) describe the payment models currently used for integration of pharmacists into team-based primary care, and (3) elicit key factors facilitating sustainable pharmacist-provided patient care services in the primary care setting., Design: Qualitative analysis using semistructured interviews., Setting: Nonacademic outpatient primary care physician practices throughout the United States from January to April 2014., Participants: Pharmacists responsible for leadership of clinical pharmacists in primary care practices whose positions are supported through nondispensing patient care services., Main Outcome Measures: Current payment model, infrastructure, documentation strategies, and methods of quality assessment., Results: Twelve interviews were conducted. Practices included a combination of single- and mixed-payer models in integrated and nonintegrated health systems. Various billing strategies were used, particularly in nonintegrated models, to sustain pharmacists in primary care practices utilizing both fee-for-service (FFS) and value-based incentives payments. Five main themes were elicited: (1) Pharmacists are integrated and valuable members of health care teams; (2) pharmacists are documenting in an accessible electronic health record; (3) data tracking is a facilitator for justifying and adapting practice; (4) systematized processes for pharmacist integration exist in each practice; and (5) pharmacists' responsibilities on the team have grown and evolved over time., Conclusion: Pharmacists' contributions to improving patients' medication-related care are the same regardless of payment model. Financially sustainable integration of pharmacists on the team involves using a combination of FFS and value-based incentive payments, consistent documentation, meaningful collection of pharmacists' contributions to improve the quality of care, and a firm understanding of the practice's needs and financial structure. These themes can be used as a guide for pharmacists as they establish themselves in an FFS environment and adapt to a future in value-based care., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Advection fog is the sole source of water for many near-the-sea arid areas worldwide such as the lomas, i.e. fog-dependant landscapes of the coastal zone of Peru and Northern Chile, where deforestation occurred since 16th century, leading to a progressive and severe desertification. There, today's local socio-ecological systems suffer from lack of freshwater because they cannot rely anymore on the contribution of fog captured by vegetation. This paper presents the results of an experimental reforestation project carried out in Mejia (Peru), where tree seedlings of five native and exotic species were planted in two permanent plots in 1996. Part of the seedlings were irrigated during the first three years after planting, others not. The irrigation was carried out thanks to water harvesting by large fog collectors. From the third year onwards, all trees relied only on fog water collected by their canopy. Survival rate, height, and root-collar diameter were monitored until 2010, when also the soil carbon and nitrogen stocks were measured. Fifteen years after the planting, about 65% of trees were still alive and growing, and reforestation had induced substantial carbon sequestration both above- and below-ground. Of the tree species, Acacia saligna was definitely best performing than the other, with most of the above ground carbon stored in its biomass and a consequent high efficiency as natural fog collector. Overall, the combination of fog collection by nets and the plantation of trees showing good fog collection capacity, represented a successful strategy for allowing reforestation of arid environments and induced fast and substantial carbon sequestration. Greater efforts should be thus devoted for this purpose, paying special attention to the selection of the most suitable tree species to plant, especially looking at the local biodiversity. This work is dedicated to the memory of Professor Mario Falciai, passed away in 2015, who firstly conceived the experiment and attended all the work since 1996, bringing in our University the idea of Fog Collection for sustainable water management., (Copyright © 2018 Elsevier B.V. All rights reserved.)

It is generally conceded that selective combinations of transcription factors determine hematopoietic lineage commitment and differentiation. Here we show that in normal human hematopoiesis the transcription factor nuclear factor I-A (NFI-A) exhibits a marked lineage-specific expression pattern: it is upmodulated in the erythroid (E) lineage while fully suppressed in the granulopoietic (G) series. In unilineage E culture of hematopoietic progenitor cells (HPCs), NFI-A overexpression or knockdown accelerates or blocks erythropoiesis, respectively: notably, NFI-A overexpression restores E differentiation in the presence of low or minimal erythropoietin stimulus. Conversely, NFI-A ectopic expression in unilineage G culture induces a sharp inhibition of granulopoiesis. Finally, in bilineage E + G culture, NFI-A overexpression or suppression drives HPCs into the E or G differentiation pathways, respectively. These NFI-A actions are mediated, at least in part, by a dual and opposite transcriptional action: direct binding and activation or repression of the promoters of the beta-globin and G-CSF receptor gene, respectively. Altogether, these results indicate that, in early hematopoiesis, the NFI-A expression level acts as a novel factor channeling HPCs into either the E or G lineage.

The expression/function of vascular endothelial growth factor (VEGF) receptors (VEGFR1/Flt1 and VEGFR2/KDR/Flk1) in hematopoiesis is under scrutiny. We have investigated the expression of Flt1 and kinase domain receptor (KDR) on hematopoietic precursors, as evaluated in liquid culture of CD34(+) hematopoietic progenitor cells (HPCs) induced to unilineage differentiation/maturation through the erythroid (E), megakaryocytic (Mk), granulocytic (G), or monocytic (Mo) lineage. KDR, expressed on 0.5% to 1.5% CD34(+) cells, is rapidly downmodulated on induction of differentiation. Similarly, Flt1 is present at very low levels in HPCs and is downmodulated in E and G lineages; however, Flt1 is induced in the precursors of both Mo and Mk series; ie, its level progressively increases during Mo maturation, and it peaks at the initial-intermediate culture stages in the Mk lineage. Functional experiments indicate that Mk and E, but not G and Mo, precursors release significant amounts of VEGF in the culture medium, particularly at low O(2) levels. The functional role of VEGF release on Mk maturation is indicated by 2 series of observations. (1) Molecules preventing the VEGF-Flt1 interaction on the precursor membrane (eg, soluble Flt1 receptors) significantly inhibit Mk polyploidization. (2) Addition of exogenous VEGF or placenta growth factor (PlGF) markedly potentiates Mk maturation. Conversely, VEGF does not modify Mo differentiation/maturation. Altogether, our results suggest that in the hematopoietic microenvironment an autocrine VEGF loop contributes to optimal Mk maturation through Flt1. A paracrine loop involving VEGF release by E precursors may also operate. Similarly, recent studies indicate that an autocrine loop involving VEGF and Flt1/Flk1 receptors mediates hematopoietic stem cell survival and differentiation.

An enzyme-immunoassay was developed to evaluate the presence of anti-erythropoietin antibodies in plasma samples obtained from renal failure patients treated with recombinant human erythropoietin (rh-EPO). The assay was specific and reproducible. Normal donors had no antibodies to EPO, while 67% of treated patients were positive to the assay. While the specificity of anti-EPO IgG antibodies was high, their affinity for the antigen was low. This finding can be explained by the very small differences in the structure of rh-EPO compared to that of natural EPO. The assay described could be useful in evaluating the long-term effects of rh-EPO treatment on the control of anaemia in renal failure patients.

Background: A prospective study was conducted to assess the efficacy and toxicity of a salvage regimen consisting of CCNU, Melphalan, and VP-16 (CAV) given at 28-day intervals in patients with Hodgkin's disease (HD) relapsing after primary therapy or refractory to the alternating MOPP/ABVD regimen., Patients and Methods: This study included 58 patients (median age: 34 years), with resistant or relapsing HD. Primary therapy had consisted of alternating MOPP/ABVD (81%) or MOPP alone (19%); 38% of patients were relapsing from prior complete remission (CR) while 62% had resistant disease. Extranodal disease was present in 55% and B-symptoms in 72% of patients; one-fifth had bulky disease and/or bone marrow involvement. The CAV was used as first salvage in half of the patients., Results: Complete remission was obtained in 17 patients (29%); unfavorable factors for CR in univariate analysis were the presence of bulky disease and the failure to achieve CR with prior therapy. Nine patients (53% of remitters) have subsequently relapsed with a 10-month median duration of CR. The 3-year overall survival after CAV was 25% with an 18-month median survival; significant differences in survival were found according to the extent of disease, the presence of B-symptoms and the HD status (prior sensitive or resistant disease, first or subsequent relapse). Seven patients are long-term remitters (12%), and one of them has been given high-dose chemotherapy and autologous bone marrow transplantation at relapse after CAV. The CAV toxicity was mostly hematological; severe pancytopenia occurred in six cases with two cases of fatal infections and one of fatal hemorrhage., Conclusion: CAV therapy was moderately effective as third-line salvage in patients with HD resistant to alternating MOPP/ABVD or previously given two different regimens for relapse; the toxicity was mostly hematological and supportive therapy was needed in one-third of the patients.

Background: A prospective study was conducted to assess (a) the long-term results and toxicity of the alternating MOPP/ABVD regimen in advanced Hodgkin's disease; (b) the prognostic value of pretreatment variables and of drug dose intensity., Patients and Methods: A total 138 consecutive patients with advanced Hodgkin's disease entered this study; patient selection included stages IIB (33% of total), IIIB (26%), IV (25%), and stages IIA-IIIA (16%) with bulky disease and pulmonary hilum involvement. The MOPP/ABVD program was delivered in an 8-month program; adjuvant radiotherapy on sites of bulky disease was delivered in 24 patients., Results: Complete remission was obtained in 106 (77%) patients; significant factors for CR in univariate analysis were stage, symptoms, histology, and bone marrow involvement. The five-year relapse-free survival (RFS) was 83%; in a multivariate analysis, histology only correlated with RFS (p = 0.04). The five-year freedom from tumor mortality and overall survival (OS) were 79% and 67%, respectively. An adverse prognostic significance for OS was observed for B symptoms and bone marrow involvement. The median percentage of relative dose intensity (RDI) was as follows: Adriamycin 86, mechlorethamine 85, vincristine 73, vinblastine 84, bleomycin 79, procarbazine 74, dacarbazine 81. No significant association was found between RDI and clinical outcome. No severe pancytopenia or life-threatening complications occurred during therapy., Conclusions: Alternating MOPP and ABVD cured more than 65% of patients with advanced HD; acute and late toxicity were acceptable. Prognostic analysis defined subgroups with a lower chance of cure which may deserve a more intensive initial therapy.

Background: Controversy still exists over the optimal management of early-stage Hodgkin's disease (HD); presentation features may have a different prognostic impact according to initial therapy, and long-term toxicity must be fully evaluated., Patients and Methods: This study included 164 patients with stage IA-IIA HD treated with radiotherapy (RT) alone or combined radio- and chemotherapy (CT) according to presenting features and their attendant prognostic significance. The RT group included 88 patients with favorable prognostic features; the combined modality group included 76 patients with one or more unfavorable features. In the RT group, 85% of patients received extended-mantle or STNI; in the combined modality group, RT consisted of mantle- (49%), extended mantle- (37%), and involved-field irradiation (14%); CT consisted of 6 cycles of MOPP before 1984; 3 cycles of ABVD were substituted for MOPP thereafter., Results: Complete remission was obtained in 94% and 99% of patients of the RT and combined modality groups, respectively. The 10-year actuarial relapse-free survival (RFS) in the RT group was 62% and was influenced by stage (p = 0.04) and histology (p = 0.01); in the combined modality group, RFS was 88% and was influenced by the presence of bulky disease. Overall survival and tumor mortality between the therapy groups were comparable. RT-related toxicity consisted of mediastinal fibrosis (8 cases), myelitis (3), hypothyroidism (2); other long-term events included 2 cases of acute leukemia in the combined MOPP and RT group. Altogether, 8 of 20 patients who died were in their first complete remission., Conclusions: In stage IA-IIA HD, the combined modality therapy reduced the risk of relapse compared to radiation alone; long-term toxicity of RT was not negligible and relapses could occur late.