Interstitial lung disease in patients enrolled in early-phase clinical trials: the ILDE study.

BACKGROUND: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.

Unfavorable carcinoma of unknown primary with a gastrointestinal profile: a retrospective study.

BACKGROUND: Carcinoma of unknown primary (CUP) with a gastrointestinal profile is categorized by the European Society of Medical Oncology (ESMO) guidelines into favorable and unfavorable subsets. Favorable CUPs benefit from site-specific chemotherapy (CT), while the optimal treatment for unfavorable CUPs is still undefined. MATERIALS AND METHODS: We conducted a single-center retrospective study to describe outcomes of patients with CUP with a gastrointestinal profile referred to our center from January 2000 to August 2023. Favorable CUPs were defined as CK7-/CK20+/CDX2+ by immunohistochemistry, according to the ESMO definition; all other cases were considered unfavorable. The main endpoint was the progression-free survival (PFS) of first-line CT for advanced disease in all patients and in the unfavorable group. RESULTS: A total of 56 patients were included, of whom 46 (82%) had unfavorable CUPs. After a median follow-up of 43.9 months, the median overall survival (mOS) was 11.8 months [95% confidence interval (CI) 8.3-15.3 months]. At univariate analysis, the presence of peritoneal metastases and residual tumor after primary surgery were associated with a shorter OS. The median PFS (mPFS) was 6.1 months (95% CI 3.6-8.7 months). In the unfavorable CUP subgroup, the mOS was 12.6 months (95% CI 8.7-16.5 months), the mPFS was 6.1 months (95% CI 3.5-8.9 months) and none of the CT regimens used showed to portend better PFS. The most relevant altered genes included: KRAS (9/29; 31%), BRAF (1/26; 4%), NRAS (1/25; 4%), TP53 (9/23; 39%). CONCLUSIONS: CUPs with a gastrointestinal profile are characterized by poor prognosis and the absence of biomarker for treatment personalization. No CT regimen was superior in terms of PFS in patients with unfavorable CUPs.

Germline BRCA pathogenic variants in patients with ovarian cancer and post-poly (ADP-ribose) polymerase inhibitor myeloid neoplasms.

BACKGROUND: Among patients with advanced high-grade ovarian carcinoma (aHGOC) treated with poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), the presence of a germline BRCA pathogenic variant (gBRCA-PV) may increase the risk of bone marrow mutagenesis resulting in postcytotoxic therapy myelodysplastic neoplasms (MDS-pCT) or acute myeloid leukemia (AML-pCT), as it is expressed in heterozygosity also by hematopoietic progenitors. We aimed to investigate the occurrence of post-PARPi MDSs/AMLs-pCTs according to gBRCA-PV status. PATIENTS AND METHODS: We conducted a retrospective single-center study to evaluate MDS/AML-pCT in patients with aHGOC and a known gBRCA-PV status receiving at least 8 weeks of maintenance PARPi, in any line of therapy, from February 2017 to December 2022. The endpoint was the proportion of patients who experienced MDSs-pCT and AMLs-pCT during and after treatment with PARPi, in gBRCA-PV carriers and non-carriers. RESULTS: A total of 166 patients were included: 95 (57%) had a gBRCA-PV and 72% received PARPi for recurrent disease. The number of lines of chemotherapies before and after PARPi, median overall survival, and median follow-up were comparable between gBRCA-PV carriers and non-carriers. After a median follow-up of 40.0 (95% confidence interval: 35.7-44.3) months, 10 (6%) patients were diagnosed with an MDS-pCT and 4 (2%) with an AML-pCT. A higher proportion of MDSs/AMLs-pCT (10% versus 2%; P = 0.16) and, in particular, of MDSs-pCT (9% versus 1%; P = 0.04) was observed among gBRCA-PV carriers. CONCLUSIONS: The presence of a gBRCA-PV is associated with a higher risk of MDS-pCT and possibly of myeloid neoplasms after PARPi in patients with aHGOC who received PARPi, especially in the setting of recurrent disease.

Polyethylene microplastics alter root functionality and affect strawberry plant physiology and fruit quality traits.

Strawberry, a globally popular crop whose fruit are known for their taste and health benefits, were used to evaluate the effects of polyethylene microplastics (PE-MPs) on plant physiology and fruit quality. Plants were grown in 2-L pots with natural soil mixed with PE-MPs at two concentrations (0.2% and 0.02%; w/w) and sizes (⌀ 35 and 125 µm). Plant physiological responses, root histochemical and anatomical analyses as well as fruit biometric and quality features were conducted. Plants subjected to ⌀ 35 µm/0.2% PE-MPs exhibited the most severe effects in terms of CO2 assimilation due to stomatal limitations, along with the highest level of oxidative stress in roots. Though no differences were observed in plant biomass, the impact on fruit quality traits was severe in ⌀ 35 µm/0.2% MPs treatment resulting in a drop in fruit weight (-42%), soluble solid (-10%) and anthocyanin contents (-25%). The smallest sized PE-MPs, adsorbed on the root surface, impaired plant water status by damaging the radical apparatus, which finally resulted in alteration of plant physiology and fruit quality. Further research is required to determine if these alterations also occur with other MPs and to understand more deeply the MPs influence on fruit physio-chemistry.

Promising targetable biomarkers in pancreatic neuroendocrine tumours.

INTRODUCTION: In the treatment scenario of PanNETs-targeted therapies are desired but limited, as rarity and heterogeneity on PanNETs pose limitations to their development. AREAS COVERED: We performed a literature review searching for promising druggable biomarkers and potential treatments to be implemented in the next future. We focused on treatments which have already reached clinical experimentation, although in early phases. Six targets were identified, namely Hsp90, HIFa, HDACs, CDKs, uPAR, and DDR. Even though biological rational is strong, so far reported efficacy outcomes are quite disappointing. The reason of that should be searched in the patients' heterogeneity, lack of biomarker selection, poor knowledge of interfering mechanisms as well as difficulties in patients accrual. Moreover, different ways to assess treatment efficacy should be considered, other than response rate, in light of the more indolent nature of NETs. EXPERT OPINION: Development of targeted treatments in PanNETs is still an uncovered area, far behind other more frequent cancers. Rarity of NETs led to accrual of unselected populations, possibly jeopardizing the drug efficacy. Better patients' selection, both in terms of topography, grading and biomarkers is crucial and will help understanding which role targeted therapies can really play in these tumors.

Shedding light on the effects of LED streetlamps on trees in urban areas: Friends or foes?

Streetlamp illumination disturbs the natural physiological processes and circadian rhythms of living organisms, including photosynthesizing "citizens". The light-emitting diode (LED) technology has replaced high-pressure sodium lamps. Therefore, the effects of LED streetlamps on urban trees need to be elucidated as these new lamps have a different light spectrum (with a peak in the blue and red regions of the spectrum, i.e., highly efficient wavebands for photosynthesis) compared to older technologies. To address the above-mentioned issue, two widely utilised tree species in the urban environment, including Platanus × acerifolia (P) and Tilia platyphyllos (T), were grown with or without the effect of LED streetlamps using two realistic illumination intensities (300 and 700 µmol m-2 s-1). Gas exchanges and biochemical features (starch, soluble sugar, and chlorophyll content) of illuminated vs non-illuminated trees were compared during the whole vegetative season. Our results showed that both tree species were strongly influenced by LED streetlamps at physiological and biochemical levels. Specifically, the mature leaves of P and T streetlamp-illuminated trees had a lower CO2 assimilation rate at dawn and had higher chlorophyll content, with lower starch content than controls. Our results showed that the differences between the effects of the two selected light intensities on the physiochemical attributes of P and T trees were not statistically significant, suggesting the absence of a dose-dependent effect. The most significant difference between T and P trees concerning the LED-triggered species-specific effect was that the delay in winter dormancy occurred only in P individuals. This study provided insights into the extent of LED streetlamp disturbance on trees. Our findings might raise awareness of the necessity to provide less impacting solutions to improve the wellness of trees in the urban environment.

A pilot study investigating the feasibility of using a fully automatic software to assess the RENAL and PADUA score.

PURPOSE: Image-based morphometric scoring systems such as the RENAL and PADUA scores are useful to evaluate the complexity of partial nephrectomy for renal cell carcinoma (RCC). The main aim of this study was to develop a new imaging software to enable an automatic detection and a 3D visualization of RCC from CT angiography (CTA) and to address the feasibility to use it to evaluate the features of the RENAL and the PADUA scores. METHODS: A training dataset of 210 patients CTA-scans manually segmented was used to train a deep learning algorithm to develop the automatic detection and 3D-visualization of RCC. A trained operator blindly assessed the RENAL and PADUA scores on a testing dataset of 41 CTA from patients with RCC using a commercialized semi-automatic software (ground truth) and the new automatic software. Concordance between the two methods was evaluated. RESULTS: The median PADUA score was 9 (7-11) and the renal score was 8 (5.5-9). The automatic software enabled to automatically detect the tumoral kidney and provided a 3D-visualization in all cases, with a computational time less than 20 seconds. Concordances for staging the anatomical features of the RENAL scores were respectively: 87.8% for radius, 85.4% for exophytic rate, 82.9% for location to the polar lines and 92.7% for the antero-posterior location. For the PADUA scores, concordances were 90.2% for tumor size, 85.4% for exophytic rate, 87.8% for polar location and 100% for renal rim. CONCLUSION: By enabling an automatic 3D-visualization of tumoral kidney, this software could help to calculate morphometric scores, save time and improve reproducibility for clinicians.

Changes in admissions, and hospitalization outcomes of IBD patients in an Italian tertiary referral center over a 13-year period.

OBJECTIVE: The management of Inflammatory Bowel Disease (IBD) has changed significantly in recent years, mainly due to the introduction of biologic medications, however, other factors may also have a role. The aim of this study was to evaluate the evolution of IBD admissions, including trends, modality of admission and rates of surgical intervention, in a tertiary care center. PATIENTS AND METHODS: Hospitalization of patients with a diagnosis of Crohn's disease (CD) or ulcerative colitis (UC) were identified between 2000 and 2013, using ICD-9-CM codes for IBD, from our hospital database. The following parameters were evaluated for each admission: type of admission (ordinary vs. day care service), mode of admission (elective vs. emergency care, for ordinary admissions only), admission code, surgical procedures and complication rates. Comparison between pre- and post-biologic therapy introduction years was also performed. RESULTS: Between 2000 and 2013 a total of 8834 IBD-related admissions were recorded. Hospitalizations increased linearly reaching a peak in 2006, with a downward trend in the following years. The downward trend was especially marked for patients younger than 40 years. No significant differences in hospitalization trends between CD and UC were recorded. Disease flare represented the cause of hospitalization in approximately 50% of cases. Overall, 10.8% of patients underwent surgery with no difference between the two conditions. Complications occurred in 28.7% of admissions. CONCLUSIONS: Hospitalizations for IBD patients have decreased in recent years, especially in younger patients. However, a significant proportion of patients are still admitted to complete diagnostic workup, indicating the need to better implement outpatient services. A clear reduction in surgery occurrence over time could not be observed in our study.

Deep Chlorophyll Maxima in the Global Ocean: Occurrences, Drivers and Characteristics.

Stratified oceanic systems are characterized by the presence of a so-called Deep Chlorophyll a Maximum (DCM) not detectable by ocean color satellites. A DCM can either be a phytoplankton (carbon) biomass maximum (Deep Biomass Maximum, DBM), or the consequence of photoacclimation processes (Deep photoAcclimation Maximum, DAM) resulting in the increase of chlorophyll a per phytoplankton carbon. Even though these DCM (further qualified as either DBMs or DAMs) have long been studied, no global-scale assessment has yet been undertaken and large knowledge gaps still remain in relation to the environmental drivers responsible for their formation and maintenance. In order to investigate their spatial and temporal variability in the open ocean, we use a global data set acquired by more than 500 Biogeochemical-Argo floats given that DCMs can be detected from the comparative vertical distribution of chlorophyll a concentrations and particulate backscattering coefficients. Our findings show that the seasonal dynamics of the DCMs are clearly region-dependent. High-latitude environments are characterized by a low occurrence of intense DBMs, restricted to summer. Meanwhile, oligotrophic regions host permanent DAMs, occasionally replaced by DBMs in summer, while subequatorial waters are characterized by permanent DBMs benefiting from favorable conditions in terms of both light and nutrients. Overall, the appearance and depth of DCMs are primarily driven by light attenuation in the upper layer. Our present assessment of DCM occurrence and of environmental conditions prevailing in their development lay the basis for a better understanding and quantification of their role in carbon budgets (primary production and export).

Origanum vulgare essential oils inhibit glutamate and aspartate metabolism altering the photorespiratory pathway in Arabidopsis thaliana seedlings.

Essential oils (EOs) have been extensively studied as valuable eco-friendly compounds with herbicidal activity for weed management. Phytotoxic potential of EOs, extracted from a wild population of Origanum vulgare ssp. hirtum (Link) Ietswaart, has been here evaluated on plant model Arabidopsis, through a physiological and metabolomic approach. The EOs composition was mainly characterized by monoterpenes and sesquiterpenes, with a strong abundance of two monoterpenic phenols, namely carvacrol and thymol, and the monoterpene o-cymene. The in vitro bioassay confirmed a strong phytotoxic effect of EOs on Arabidopsis rosettes, showing by both a strong growth reduction and highly chlorotic leaves. In well-developed seedlings, EOs firstly caused growth reduction and leaf chlorosis, together with a series of interconnected metabolic alterations: i) impairing the nitrogen assimilation into amino acids, which affects in particular the glutamine metabolism; and as consequence ii) excessive accumulation of toxic ammonia into the leaves, associated with oxidative stress and damage; iii) declining the efficiency of the photosynthetic apparatus, connected to the reduced CO2 fixation and photooxidation protection; iv) impairing the photorespiratory pathway. Overall, the results highlights that EOs alters principally the ability of Arabidopsis seedlings to incorporate inorganic nitrogen into amino acids, principally glutamine, leading to a dramatic accumulation of ammonia in leaf cells. This primary effect induces, in turn, a cascade of reactions that limits the efficiency of PSII, inducing oxidative stress and finally causing a strong plant growth reduction, leaf necrosis and eventually plant death. These findings suggest that O. vulgare EOs might be proficiently exploited as a potential bioherbicide in an ecofriendly agriculture. Moreover, its multitarget activity could be advantageous in limiting weed resistance phenomenon.

Millimeter-Wave Beam Scattering by Field-Aligned Blobs in Simple Magnetized Toroidal Plasmas.

The first direct experimental measurements of the scattering of a millimeter-wave beam by plasma blobs in a simple magnetized torus are reported. The wavelength of the beam is comparable to the characteristic size of the blob. In situ Langmuir probe measurements show that fluctuations of the electron density induce correlated fluctuations of the transmitted power. A first-principles full-wave model, using conditionally sampled 2D electron density profiles, predicts fluctuations of the millimeter-wave power that are in agreement with experiments.

Do the morphological and functional traits of free-living marine nematodes mirror taxonomical diversity?

The taxonomical structure and diversity of nematode assemblages are the main attributes analyzed in ecology, but nematode adaptations to their habitats are still understudied. Accordingly, a survey on some known and other newly proposed morpho-functional traits was carried out in order to: determine if the morpho-functional diversity of nematodes mirrors their taxonomical diversity; and assess potential nematode adaptations to sediment type and hydrodynamic stress. Morpho-functional traits were investigated both singularly and together and showed significant differences related to these environmental factors. The greatest taxonomical and morpho-functional diversity was found in medium-coarse sand (M-CS) and at an intermedium energy level (IEL). The M-CS and IEL were probably richer in micro-habitats and subject to a low selective pressure, hosting nematodes with a wide range of adaptations. The mirroring of morpho-functional diversity with taxonomical diversity is crucial for the future growth of the use of nematodes in biomonitoring. This is because the study of their morpho-functional traits could reduce the level of work involved and the costs of any analyses.

Endothelial cells, endoplasmic reticulum stress and oxysterols.

Oxysterols are bioactive lipids that act as regulators of lipid metabolism, inflammation, cell viability and are involved in several diseases, including atherosclerosis. Mounting evidence linked the atherosclerosis to endothelium dysfunction; in fact, the endothelium regulates the vascular system with roles in processes such as hemostasis, cell cholesterol, hormone trafficking, signal transduction and inflammation. Several papers shed light the ability of oxysterols to induce apoptosis in different cell lines including endothelial cells. Apoptotic endothelial cell and endothelial denudation may constitute a critical step in the transition to plaque erosion and vessel thrombosis, so preventing the endothelial damaged has garnered considerable attention as a novel means of treating atherosclerosis. Endoplasmic reticulum (ER) is the site where the proteins are synthetized and folded and is necessary for most cellular activity; perturbations of ER homeostasis leads to a condition known as endoplasmic reticulum stress. This condition evokes the unfolded protein response (UPR) an adaptive pathway that aims to restore ER homeostasis. Mounting evidence suggests that chronic activation of UPR leads to cell dysfunction and death and recently has been implicated in pathogenesis of endothelial dysfunction. Autophagy is an essential catabolic mechanism that delivers misfolded proteins and damaged organelles to the lysosome for degradation, maintaining basal levels of autophagic activity it is critical for cell survival. Several evidence suggests that persistent ER stress often results in stimulation of autophagic activities, likely as a compensatory mechanism to relieve ER stress and consequently cell death. In this review, we summarize evidence for the effect of oxysterols on endothelial cells, especially focusing on oxysterols-mediated induction of endoplasmic reticulum stress.

Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.

BACKGROUND: Psoriasis is an emerging paradoxical side effect in patients with inflammatory bowel disease (IBD) when treated with anti-TNF alpha. Patients with severe skin lesions unresponsive to topical therapy need to withdraw from treatment. AIM: To estimate the incidence of paradoxical psoriasis in a large cohort of IBD patients treated with anti-TNF alpha and to analyse its clinical correlates. METHODS: A retrospective cohort study on all IBD patients who started anti-TNF alpha at our IBD Centre from January 2008 to December 2013 was performed. Proportional hazards regression models were used to estimate the association between each predictor and time to the development of psoriasis. Time-dependent predictors were updated at each available time point. RESULTS: Four hundred and two patients were included. Participants contributed a total of 839 person-years of follow-up, during which 42 incident cases of psoriasis were recorded, with an incidence rate of five per 100 person-years. Cox-regression survival analysis revealed smoking as independent predictor of psoriasis (HR: 2.37, 95% CI: 1.36-4.48; P = 0.008). Conversely, concomitant immunosuppressive therapy was inversely related to psoriasis (HR: 0.33, 95% CI: 0.12-0.92; P = 0.03). CONCLUSIONS: Paradoxical psoriasis is a relevant side effect of anti-TNF alpha therapy, with an incidence rate of five per 100 person-years. Smoking is confirmed as the main risk factor for developing lesions. The combination therapy with anti-TNF alpha plus immunosuppressants is associated with a reduced risk of paradoxical psoriasis.

Development of psoriasis scalp with alopecia during treatment of Crohn's disease with infliximab and rapid response to both diseases to ustekinumab.

Anti tumor necrosis factor antibodies are used to treat both psoriasis and inflammatory bowel disease. Several paradoxical cases of psoriatic skin lesions induced by tumor necrosis factor antagonist therapy have been described in IBD patients in the recent years. Ustekinumab, a fully human anti-interleukin-12/-23 monoclonal antibody, is the first drug of a new class of biologic therapy approved for the treatment of moderate to severe plaque psoriasis. Data on the efficacy of ustekinumab in patients with moderate-to-severe Crohn's disease, especially in patients previously treated with infliximab, have been recently published. We report about the effectiveness of ustekinumab in the treatment of both severe scalp psoriasis lesions with alopecia and active Crohn's disease.

Achievement of sustained deep remission with adalimumab in a patient with both refractory ulcerative colitis and seronegative erosive rheumatoid arthritis.

Inflammatory bowel disease (IBD) is commonly associated with peripheral inflammatory arthritis, and it has been estimated that as many as 12% of IBD patients report these manifestations. However, rheumatoid arthritis (RA) is rarely associated with ulcerative colitis (UC). Among all the biological agents available, nine have been currently approved for the treatment of RA. Conversely, only Infliximab and recently Adalimumab have been approved for UC. In particular, the efficacy of Adalimumab in UC has been demonstrated by both recent randomized controlled trials and real-life studies. Moreover, Adalimumab is a well-established treatment for RA. Herein, we describe a patient with RA and UC treated successfully with ADA.

Immune response to influenza A/H1N1 vaccine in inflammatory bowel disease patients treated with anti TNF-α agents: effects of combined therapy with immunosuppressants.

BACKGROUND AND AIMS: Our first objective was to evaluate the immune response to the adjuvanted 2009 A/H1N1 pandemic (pH1N1) vaccine in inflammatory bowel disease (IBD) patients treated with anti-TNF-α alone or combined with immunosuppressants (IS). Second and third aims were the safety of pH1N1 vaccine and the effects on IBD clinical activity. METHODS: 36 patients with Crohn's disease (CD) and 26 with ulcerative colitis (UC) and thirty-one healthy control (HC) subjects were enrolled. 47 patients were on anti TNF-α maintenance monotherapy and 15 on anti TNF-α combined with IS. Sera were collected at baseline (T0) and 4 weeks after the vaccination (T1) for antibody determination by hemagglutination inhibition (HAI). Disease activity was monitored at T0 and T1. RESULTS: Seroprotective titers (≥1:40) in patients were comparable to HC. Seroconvertion rate (≥4 fold increase in HAI titer) was lower than HC in IBD patients (p=0.009), either on anti TNF-α monotherapy (p=0.034) or combined with IS (p=0.011). Geometric mean titer (GMT) of antibodies at T1 was significantly lower in patients on combined therapy versus those on monotherapy (p=0.0017) and versus HC (p=0.011). The factor increase of GMT at T1 versus T0 was significantly lower in IBD patients versus HC (p=0.042), and in those on combined immunosuppression, both versus monotherapy (p=0.0048) and HC (p=0.0015). None of the patients experienced a disease flare. CONCLUSION: Our study has shown a suboptimal response to pH1N1 vaccine in IBD patients on therapy with anti TNF-α and IS compared to those on anti-TNF-α monotherapy and HC.

A case of pyoderma gangrenosum with ulcerative colitis treated with combined approach: infliximab and surgery.

Pyoderma gangrenosum (PG) is an ulcerating noninfectious disease of the skin seen in 1-2% of patients with inflammatory bowel disease (IBD). The pathogenesis of PG has yet to be determined, but may be related to abnormal T cell responses and the production of TNF-α, a pathway also involved in IBD pathogenesis. Infliximab, a chimeric monoclonal antibody to TNF-α, is used to treat moderate to severe IBD and several case reports and studies suggest the efficacy of infliximab in the treatment of PG. The surgical approach to PG is reserved to a few selected cases. We report here the case of a patient with ulcerative colitis (UC) and PG localized on the left breast, treated with a simultaneous combined medical and surgical approach.

Flows of research manuscripts among scientific journals reveal hidden submission patterns.

The study of science-making is a growing discipline that builds largely on online publication and citation databases, while prepublication processes remain hidden. Here, we report on results from a large-scale survey of the submission process, covering 923 scientific journals from the biological sciences in years 2006 to 2008. Manuscript flows among journals revealed a modular submission network, with high-impact journals preferentially attracting submissions. However, about 75% of published articles were submitted first to the journal that would publish them, and high-impact journals published proportionally more articles that had been resubmitted from another journal. Submission history affected post-publication impact: Resubmissions from other journals received significantly more citations than first-intent submissions, and resubmissions between different journal communities received significantly fewer citations.