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Background: Post-hoc analyses of clinical trials suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2i) lower the risk of hyperkalemia and facilitate the use of renin-angiotensin system inhibitors (RASi) in people with type 2 diabetes. Whether this is also observed in routine care is unclear. We investigated whether SGLT-2i lowered the risk of hyperkalemia and RASi discontinuation as compared to dipeptidyl peptidase 4 inhibitors (DPP-4i)., Methods: Using the target trial emulation framework, we studied adults with type 2 diabetes (T2D) who started SGLT-2i or DPP-4i in Stockholm, Sweden (2014-2021). The outcomes were incident hyperkalaemia (potassium > 5.0 mmol/L), mild hyperkalemia (potassium > 5-≤5.5 mmol/L) and moderate to severe hyperkalemia (potassium > 5.5 mmol/L). Among RASi users, we studied time to RASi discontinuation through evaluation of pharmacy fills. Cox regression with inverse probability of treatment weighting was used to estimate per-protocol hazard ratios (HRs)., Results: 29 849 individuals (15 326 SGLT-2i and 14 523 DPP-4i initiators) were included (mean age 66 years, 37% women). About one third of participants in each arm discontinued treatment within a year. Compared with DPP-4i, SGLT-2i use was associated with a lower rate of hyperkalemia (HR 0.77; 95% CI: 0.64-0.93), including both mild (0.76; 0.62-0.93) and moderate/severe (0.53; 0.40-0.69) hyperkalemia events. Of 19.116 participants that used RASi at baseline, 7% discontinued therapy. Initiation of SGLT-2i vs. DPP-4i was not associated with the rate of RASi discontinuation (0.97; 0.83-1.14). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function., Conclusions: In patients with diabetes managed in routine clinical care, the use of SGLT-2i was associated with lower rates of hyperkalemia compared with DPP-4i. Possibly because of a relatively high rate of treatment discontinuations, this was not accompanied by higher persistence on RASi therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Importance: Hyperkalemia is a common complication in people with type 2 diabetes (T2D) that may limit the use of guideline-recommended renin-angiotensin system inhibitors (RASis). Emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) increase urinary potassium excretion, which may translate into reduced hyperkalemia risk., Objective: To compare rates of hyperkalemia and RASi persistence among new users of GLP-1RAs vs dipeptidyl peptidase-4 inhibitors (DPP-4is)., Design, Setting, and Participants: This cohort study included all adults with T2D in the region of Stockholm, Sweden, who initiated GLP-1RA or DPP-4i treatment between January 1, 2008, and December 31, 2021. Analyses were conducted between October 1, 2023, and April 29, 2024., Exposures: GLP-1RAs or DPP-4is., Main Outcomes and Measures: The primary study outcome was time to any hyperkalemia (potassium level >5.0 mEq/L) and moderate to severe (potassium level >5.5 mEq/L) hyperkalemia. Time to discontinuation of RASi use among individuals using RASis at baseline was assessed. Inverse probability of treatment weights served to balance more than 70 identified confounders. Marginal structure models were used to estimate per-protocol hazard ratios (HRs)., Results: A total of 33 280 individuals (13 633 using GLP-1RAs and 19 647 using DPP-4is; mean [SD] age, 63.7 [12.6] years; 19 853 [59.7%] male) were included. The median (IQR) time receiving treatment was 3.9 (1.0-10.9) months. Compared with DPP-4i use, GLP-1RA use was associated with a lower rate of any hyperkalemia (HR, 0.61; 95% CI, 0.50-0.76) and moderate to severe (HR, 0.52; 95% CI, 0.28-0.84) hyperkalemia. Of 21 751 participants who were using RASis, 1381 discontinued this therapy. The use of GLP-1RAs vs DPP-4is was associated with a lower rate of RASi discontinuation (HR, 0.89; 95% CI, 0.82-0.97). Results were consistent in intention-to-treat analyses and across strata of age, sex, cardiovascular comorbidity, and baseline kidney function., Conclusions: In this study of patients with T2D managed in routine clinical care, the use of GLP-1RAs was associated with lower rates of hyperkalemia and sustained RASi use compared with DPP-4i use. These findings suggest that GLP-1RA treatment may enable wider use of guideline-recommended medications and contribute to clinical outcomes in this population.

Over the last two decades, we have witnessed great advancements in our understanding of the immunological pathways of asthma, leading to the development of targeted therapies, such as biologic drugs, that have radically and definitively changed the clinical outcomes of severe asthma. Despite the numerous therapeutic options available, ~4-10% of all people with asthma have severe or uncontrolled asthma, associated with an increased risk of developing chronic oral corticosteroid use, fixed airflow limitation, exacerbations, hospitalization and, finally, increased healthcare costs. The new concept of disease modification in asthma comes from the evolution of asthma management, which encompasses phenotyping patients with different inflammatory endotypes characterizing the disease, followed by the advent of more effective therapies capable of targeting the proximal factors of airway inflammation. This treat-to-target approach aims to achieve remission of the disease. Because the novel treatment paradigm for severe asthma with the advent of biologic therapies is no longer clinical control but rather clinical remission - a step closer to the concept of cure - a deeper and more accurate understanding of the critical causal mechanisms and endotypes of asthma is necessary to achieve the goal of clinical remission, which has the potential to generate real life-changing benefits for patients. This review aims to frame the evolution of the debated concept of clinical remission and provide clinicians with insights that may be helpful in achieving remission in the greatest number of patients., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2024/09/dic.2024-7-2-COI.pdf, (Copyright © 2024 Bosi A, Lombardi C, Caruso C, Cottini M, Baglivo I, Colantuono S, Menzella F.)

Chronic idiopathic neutropenia (CIN) is a rare benign condition  caused by an immune attack against neutrophils, either primary or in the context of other autoimmune conditions, lymphoproliferative syndromes, and inborn errors of immunity. In this single-center prospective study, 131 adult CIN patients were enrolled (median age 55 years, range: 20-93). At baseline, 56% had anti-neutrophil autoantibodies and 31% had autoimmune comorbidities. Over a median 3-year follow-up, the rate of grade ≥ 2 infections was 42%, with 10% grade ≥ 3, irrespective of neutrophil counts, demographics, and anti-neutrophil antibodies positivity, and G-CSF was used in 6 patients only. No malignant evolution nor deaths were observed. Bone marrow evaluation showed a large granular lymphocyte (LGL) infiltrate in 52%, mostly polyclonal, and hypocellularity in 31% of cases. Immune-histochemistry highlighted deposits of IgG, IgM, and complement fractions C3 and C4d in most cases. Interestingly, 19% of tested patients displayed somatic mutations of myeloid genes with an association with age. In conclusion, adult CIN appears to be a benign condition without life-threatening infections, yet deserving an extensive hematologic evaluation including bone marrow assessment to inform the differential diagnosis., (© 2024. The Author(s).)

Torque Teno Virus (TTV) is a ubiquitous component of the human virome, not associated with any disease. As its load increases when the immune system is compromised, such as in kidney transplant (KT) recipients, TTV load monitoring has been proposed as a method to assess immunosuppression. In this prospective study, TTV load was measured in plasma and urine samples from 42 KT recipients, immediately before KT and in the first 150 days after it. Data obtained suggest that TTV could be a relevant marker for evaluating immune status and could be used as a guide to predict the onset of infectious complications in the follow-up of KT recipients. Since we observed no differences considering distance from transplantation, while we found a changing trend in days before viral infections, we suggest to consider changes over time in the same subjects, irrespective of time distance from transplantation.

Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Methods: Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Results: Correlations between rs2010963 ( VEGFA gene) and sex ( P = 0.046), and rs1625895 ( TP53 gene) and stage ( P = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 ( NCF4 gene) and rs1800871 ( IL10 gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Conclusions: Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials., Competing Interests: Mini E is an Editorial Board Member of the journal Cancer Drug Resistance, while the other authors have declared that they have no conflicts of interest., (© The Author(s) 2024.)

Type 2 inflammation is a heterogeneous condition due to the complex activation of different immunological pathways. Rapid progress in research to evaluate the efficacy of biologics for chronic rhinosinusitis with nasal polyps and asthma has led to the availability of effective therapeutic options. These drugs are safe, but temporary iatrogenic hypereosinophilia may sometimes be associated with clinical symptoms or organ damage. Here, we describe a case of severe hypereosinophilia in a patient with chronic rhinosinusitis with nasal polyps and asthma treated with dupilumab and a subsequent therapeutic shift to mepolizumab that led to maintenance of symptom control and concomitant normalization of blood eosinophil count., Competing Interests: Disclosure and potential conflicts of interest: The authors declare that they have no conflicts of interest relevant to this manuscript. The International Committee of Medical Journal Editors (ICMJE) Potential Conflicts of Interests form for the authors is available for download at: https://www.drugsincontext.com/wp-content/uploads/2024/05/dic.2024-3-5-COI.pdf, (Copyright © 2024 Munari S, Ciotti G, Cestaro W, Corsi L, Tonin S, Ballarin A, Floriani A, Dartora C, Bosi A, Tacconi M, Gialdini F, Gottardi M, Menzella F.)

Background: The pharmacological management of hyperkalemia traditionally considered calcium or sodium polystyrene sulfonate and, since recently, the novel binders patiromer and sodium zirconium cyclosilicate. We evaluated their patterns of use, duration of treatment and relative effectiveness/safety in Swedish routine care., Methods: Observational study of adults initiating therapy with sodium polystyrene sulfonate or a novel binder (sodium zirconium cyclosilicate or patiromer) in Stockholm 2019-2021. We quantified treatment duration by repeated dispensations, compared mean achieved potassium concentration within 60 days, and potential adverse events between treatments., Results: A total of 1879 adults started treatment with sodium polystyrene sulfonate, and 147 with novel binders (n = 41 patiromer and n = 106 sodium zirconium cyclosilicate). Potassium at baseline for all treatments was 5.7 mmol/L. Sodium polystyrene sulfonate patients stayed on treatment a mean of 61 days (14% filled ≥3 consecutive prescriptions) compared to 109 days on treatment (49% filled ≥3 prescriptions) for novel binders. After 15 days of treatment, potassium similarly decreased to 4.6 (SD 0.6) and 4.8 (SD 0.6) mmol/L in the sodium polystyrene sulfonate and novel binder groups, respectively, and was maintained over the 60 days post-treatment. In multivariable regression, the odds ratio for novel binders (vs sodium polystyrene sulfonate) in reaching potassium ≤ 5.0 mmol/L after 15 days was 0.65 (95% CI 0.38-1.10) and after 60 days 0.89 (95% CI 0.45-1.76). Hypocalcemia, hypokalemia, and initiation of anti-diarrheal/constipation medications were the most-commonly detected adverse events. In multivariable analyses, the OR for these events did not differ between groups., Conclusion: We observed similar short-term effectiveness and safety for all potassium binders. However, treatment duration was longer for novel binders than for sodium polystyrene sulfonate., (© 2024. The Author(s).)

Background: A single albuminuria measurement is reported to be an independent predictor of cancer risk. Whether change in albuminuria is also independently associated with cancer is not known., Methods: We included 64 303 subjects of the Stockholm CREAtinine Measurements (SCREAM) project without a history of cancer and with at least two urine albumin-creatinine ratio (ACR) tests up to 2 years apart. Albuminuria changes were quantified by the fold-change in ACR over 2 years, and stratified into the absence of clinically elevated albuminuria (i.e. never), albuminuria that remained constant, and albuminuria that increased or decreased. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidences., Results: During a median follow-up of 3.7 (interquartile range 3.6-3.7) years, 5126 subjects developed de novo cancer. After multivariable adjustment including baseline estimated glomerular filtration rate and baseline ACR, subjects with increasing ACR over 2 years had a 19% (hazard ratio 1.19; 95% confidence interval 1.08-1.31) higher risk of overall cancer compared with those who never had clinically elevated ACR. No association with cancer risk was seen in the groups with decreasing or constant ACR. Regarding site-specific cancer risks, subjects with increasing ACR or constant ACR had a higher risk of developing urinary tract and lung cancer. No other associations between 2-year ACR changes and site-specific cancers were found., Conclusions: Increases in albuminuria over a 2-year period are associated with a higher risk of developing overall, urinary tract and lung cancer, independent of baseline kidney function and albuminuria. These data add important weight to the link that exists between albuminuria and cancer incidence., Competing Interests: R.A.d.B. has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Inc., Novo Nordisk and Roche, and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis and Roche. The other authors have no conflicts to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Inflammatory bowel diseases (IBDs) are characterized by a persistent low-grade inflammation that leads to an increased risk of colorectal cancer (CRC) development. Several factors are implicated in this pathogenetic pathway, such as innate and adaptive immunity, gut microbiota, environment, and xenobiotics. At the gut mucosa level, a complex interplay between the immune system and gut microbiota occurs; a disequilibrium between these two factors leads to an alteration in the gut permeability, called 'leaky gut'. Subsequently, an activation of several inflammatory pathways and an alteration of gut microbiota composition with a proliferation of pro-inflammatory bacteria, known as 'pathobionts', take place, leading to a further increase in inflammation. This narrative review provides an overview on the principal Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors (NLRs), focusing on their recognition mechanisms, signaling pathways, and contributions to immune responses. We also report the genetic polymorphisms of TLRs and dysregulation of NLR signaling pathways that can influence immune regulation and contribute to the development and progression of inflammatory disease and cancer.

Despite recent advancements, treatment of cytopenia due to bone marrow failures (BMF) and myeloid neoplasms remains challenging. Androgens promote renewal and maturation of blood cells and may be beneficial in these forms. Here we report a systematic review of androgens use as single agent in hematologic conditions. Forty-six studies, mainly retrospective with various androgen types and doses, were included: 12 on acquired aplastic anemia (AA), 11 on inherited BMF, 17 on myelodysplastic syndromes (MDS), and 7 on myelofibrosis. Responses ranged from 50 to 70% in inherited BMF, 40-50% in acquired AA and MDS, while very limited evidence emerged for myelofibrosis. In acquired AA, response was associated with presence of non-severe disease; in MDS androgens were more effective on thrombocytopenia or mild to moderate anemia, whilst limited benefit was observed for transfusion dependent anemia. Toxicity profile mainly consisted of virilization and liver enzyme elevation, whilst the risk of leukemic evolution remains controversial., Competing Interests: Declaration of Competing Interest All Authors declare that they have no relevant conflict of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Clinical guidelines recommend monitoring of creatinine and lithium throughout treatment with lithium. We here assessed the extent to which this occurs in healthcare in Sweden., Methods: This is an observational study of all adults with bipolar disorder starting lithium therapy in Stockholm, Sweden, during 2007-2018. The main outcome was monitoring of blood lithium and creatinine at therapy initiation and/or once annually. The secondary outcome was monitoring of calcium and thyroid-stimulating hormone (TSH). Patients were followed up until therapy cessation, death, out-migration, or to the end of 2018., Results: We identified 4428 adults with bipolar disorder who started lithium therapy and were followed up for up to 11 years. Their median age was 39 years, and 63% were women. The median duration on lithium therapy was 4.3 (IQR: 1.9-7.45) years, and the majority who discontinued therapy started another mood stabilizer soon after. Overall, 21% started lithium therapy without assessing the serum/plasma concentration of creatinine. The proportion of people who did not have both lithium and creatinine measured increased from 21% in the first year to 33% in the eleventh year. The proportion with annual testing for TSH or calcium was slightly lower. As few as 16% of patients had both lithium and creatinine tested once annually during their complete time on lithium., Conclusions: In a Swedish community sample, lithium and creatinine monitoring was inconsistent with guideline recommendations that call for measurement of annual biomarker levels., (© 2023 The Authors. Bipolar Disorders published by John Wiley & Sons Ltd.)

Primary tracheal tumors are rare, constituting approximately 0.1-0.4% of malignant diseases. Squamous cell carcinoma (SCC) and adenoid cystic carcinoma (ACC) account for about two-thirds of these tumors. Despite most primary tracheal cancers being eligible for surgery and/or radiotherapy, unresectable, recurrent and metastatic tumors may require systemic treatments. Unfortunately, the poor response to available chemotherapy as well as the lack of other real therapeutic alternatives affects the quality of life and outcome of patients suffering from more advanced disease. In this condition, target therapy against driver mutations could constitute an alternative to chemotherapy, and may help in disease control. The past two decades have seen extraordinary progress in developing novel target treatment options, shifting the treatment paradigm for several cancers such as lung cancer. The improvement of knowledge regarding the genetic and biological alterations, of major primary tracheal tumors, has opened up new treatment perspectives, suggesting the possible role of biological targeted therapies for the treatment of these rare tumors. The purpose of this review is to outline the state of knowledge regarding the molecular biology, and the preliminary data on target treatments of the main primary tracheal tumors, focusing on salivary-gland-derived cancers and squamous cell carcinoma.

The introduction of synthetic dyes completely changed the industrial production and use of colorants for art materials. From the synthesis of the first synthetic dye, mauveine, in 1856 until today, artists have enjoyed a wider range of colors and selection of chemical properties than was ever available before. However, the introduction of synthetic dyes introduced a wider variety and increased the complexity of the chemical structures of marketed dyes. This work looks towards the analysis of synthetically dyed objects in heritage collections, applying an extraction protocol based on the use of ammonia, which is considered favorable for natural anthraquinone dyes but has never before been applied to acid synthetic dyes. This work also presents an innovative cleanup step based on the use of an ion pair dispersive liquid-liquid microextraction for the purification and preconcentration of historical synthetic dyes before analysis. This approach was adapted from food science analysis and is applied to synthetic dyes in heritage science for the first time in this paper. The results showed adequate recovery of analytes and allowed for the ammonia-based extraction method to be applied successfully to 15 samples of suspected azo dyes from the Azienda Coloranti Nazionali e Affini (ACNA) synthetic dye collection, identified through untargeted HPLC-HRMS analyses.

To date, it is still not possible to obtain exhaustive information about organic materials in cultural heritage without sampling. Nonetheless, when studying unique objects with invaluable artistic or historical significance, preserving their integrity is a priority. In particular, organic dye identification is of significant interest for history and conservation research, but it is still hindered by analytes' low concentration and poor fastness. In this work, a minimally invasive approach for dye identification is presented. The procedure is designed to accompany noninvasive analyses of inorganic substances for comprehensive studies of complex cultural heritage matrices, in compliance with their soundness. Liquid extraction of madder, turmeric, and indigo dyes was performed directly from paint layers and textiles. The extraction was supported by hydrogels, which themselves can undergo multitechnique analyses in the place of samples. After extraction, Ag colloid pastes were applied on the gels for SERS analyses, allowing for the identification of the three dyes. For the HPLC-MS/MS analyses, re-extraction of the dyes was followed by a clean-up step that was successfully applied on madder and turmeric. The colour change perceptivity after extraction was measured with colorimetry. The results showed ΔE values mostly below the upper limit of rigorous colour change, confirming the gentleness of the procedure.

Importance: Among patients with bipolar disorder, discordant findings have been published on the nephrotoxic effects of lithium therapy., Objective: To quantify absolute and relative risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) in people who initiated lithium compared with valproate therapy and to investigate the association between cumulative use and elevated lithium levels and kidney outcomes., Design, Setting, and Participants: This cohort study had a new-user active-comparator design and used inverse probability of treatment weights to minimize confounding. Included patients initiated therapy with lithium or valproate from January 1, 2007, to December 31, 2018, and had a median follow-up of 4.5 years (IQR, 1.9-8.0 years). Data analysis began in September 2021, using routine health care data from the period 2006 to 2019 from the Stockholm Creatinine Measurements project, a recurrent health care use cohort of all adult residents in Stockholm, Sweden., Exposures: New use of lithium vs new use of valproate and high (>1.0 mmol/L) vs low serum lithium levels., Main Outcomes and Measures: Progression of CKD (composite of >30% decrease relative to baseline estimated glomerular filtration rate [eGFR] and kidney failure), AKI (by diagnosis or transient creatinine elevations), new albuminuria, and annual eGFR decrease. Outcomes by attained lithium levels were also compared in lithium users., Results: The study included 10 946 people (median [IQR] age, 45 [32-59] years; 6227 female [56.9%]), of whom 5308 initiated lithium therapy and 5638 valproate therapy. During follow-up, 421 CKD progression events and 770 AKI events were identified. Compared with patients who received valproate, those who received lithium did not have increased risk of CKD (hazard ratio [HR], 1.11 [95% CI, 0.86-1.45]) or AKI (HR, 0.88 [95% CI, 0.70-1.10]). Absolute 10-year CKD risks were low and similar: 8.4% in the lithium group and 8.2% in the valproate group. No difference in the risk of developing albuminuria or the annual rate of eGFR decrease was found between groups. Among more than 35 000 routine lithium tests, only 3% of results were in the toxic range (>1.0 mmol/L). Lithium values greater than 1.0 mmol/L, compared with lithium values of 1.0 mmol/L or less, were associated with increased risk of CKD progression (HR, 2.86; 95% CI, 0.97-8.45) and AKI (HR, 3.51; 95% CI, 1.41-8.76)., Conclusions and Relevance: In this cohort study, compared with new use of valproate, new use of lithium was meaningfully associated with adverse kidney outcomes, with low absolute risks that did not differ between therapies. However, elevated serum lithium levels were associated with future kidney risks, particularly AKI, emphasizing the need for close monitoring and lithium dose adjustment.

The identification of the dyes present on a linen fragment from the tomb of Pharaoh Tutankhamun is the objective of the present study. Fiber optic reflectance spectroscopy (FORS) was applied to the archaeological sample for preliminary identification of the dyes and to better choose the extraction methodology for different areas of the sample. The innovative gel-supported micro-extraction with agar gel and the Nanorestore Gel ® High Water Retention (HWR) gel were applied to the archaeological sample after testing of the best concentration for the extraction of the agar gels substrates, performed on laboratory mock-ups by means of UV-Vis transmittance spectroscopy. Immediately after extraction, Ag colloidal pastes were applied on the gel surface and Surface Enhanced Raman Scattering (SERS) analysis was performed directly on them. The combination of information deriving from FORS and SERS spectra resulted in the successful identification of both indigo and madder and, in hypothesis, of their degradation products.

Background: Studies investigating the association of chronic kidney disease and cancer have focused on estimated glomerular filtration (eGFR) rather than on albuminuria. This study aimed to examine whether albuminuria is associated with cancer incidence, and whether this association is independent of eGFR., Methods: We included subjects of the Stockholm Creatinine Measurements (SCREAM) project without a history of cancer-250 768 subjects with at least one urine albumin-creatinine ratio (ACR) test (primary cohort) and 433 850 subjects with at least one dipstick albuminuria test (secondary cohort). Albuminuria was quantified as KDIGO albuminuria stages. The primary outcome was overall cancer incidence. Secondary outcomes were site-specific cancer incidence rates. Multivariable Cox proportional hazards regression models adjusted for confounders including eGFR to calculate hazard ratios and 95% confidence intervals (HRs, 95% CIs)., Results: During a median follow-up of 4.3 (interquartile range 2.0-8.2) years, 21 901 subjects of the ACR cohort developed de novo cancer. In multivariable analyses, adjusting among others for eGFR, subjects with an ACR of 30-299 mg/g or ≥300 mg/g had a 23% (HR 1.23; 95% CI 1.19-1.28) and 40% (HR 1.40; 95% CI 1.31-1.50) higher risk of developing cancer, respectively, when compared with subjects with an ACR <30 mg/g. This graded, independent association was also observed for urinary tract, gastrointestinal tract, lung and hematological cancer incidence (all P  < .05). Results were similar in the dipstick albuminuria cohort., Conclusions: Albuminuria was associated with the risk of cancer independent of eGFR. This association was primarily driven by a higher risk of urinary tract, gastrointestinal tract, lung and hematological cancers., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

R-CHOP standard chemotherapy is successful in about 60% of diffuse large B-cell lymphoma (DLBCL) patients. Unresponsive patients have a poor prognosis, and predictive biomarkers of response to R-CHOP are lacking. We conducted the first prospective GWAS study aimed at exploring constitutional biomarkers predictive of R-CHOP efficacy and toxicity. Overall, 216 any-stage chemonaïve DLBCL patients candidate to R-CHOP were enrolled. The median age of the 185 eligible patients was 59.2 years, 49.7% were women and 45.4% were stage I-II patients. According to the Revised International Prognostic Index (R-IPI), 14.1%, 56.8% and 29.2% were in the very good, good and poor prognosis groups, respectively. Of the patients, 85.9% produced a complete response. Highly significant associations (i.e., p < 5 × 10 -8 ) were found between progression-free survival (PFS) and six SNPs (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241). Additionally, five SNPs (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569) were highly associated with overall survival (OS). Wild-type patients showed a prolonged PFS or OS compared with patients carrying deleterious alleles ( p < 0.001). No association with the adequate significant threshold was observed between SNPs and the objective response or toxicity. In the future, these SNPs, alone or in combination, after a proper validation in an independent cohort, could contribute to improving the prediction of R-CHOP response.

Introduction: Little is known about the comparative effects of sodium glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1-RA), or dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of acute kidney injury (AKI) in routine care, which may differ from the controlled setting of trials., Methods: Observational study comparing risks of AKI among new users of SGLT2i, GLP1-RA or DPP-4i in the region of Stockholm, Sweden, during 2008-2018. AKI was defined by ICD-10 codes and creatinine-based KDIGO criteria. We used inverse probability of treatment weighting (IPTW) to adjust for 60 potential confounders, weighted Kaplan-Meier curves and Cox regression to estimate hazard ratios and absolute risks., Results: We included 17,407 participants who newly initiated DPP-4i (N = 10,605), GLP1-RA (N = 4448) or SGLT2i (N = 2354). Mean age was 63 years (39% women) and median (IQR) eGFR was 89 (73-100) ml/min/1.73 m 2 . During a median follow-up of 2.5 years, 1411 participants experienced AKI. SGLT2i users had the lowest incidence rate of AKI, 18.3 [CI 95% 14.1-23.4] per 1000 person years, followed by GLP1-RA (22.5; 19.9-25.3) and DPP-4i (26.6; 25-28.2). The weighted 3-year absolute risk for AKI was 5.79% [3.63-8.52] in the SGLT2i group, compared with 7.03% [5.69-8.69] and 7.00% [6.43-7.58] in the GLP1-RA and DPP-4i groups, respectively. The adjusted hazard ratio was 0.73 [CI 95% 0.45-1.16] for SGLT2i vs. DPP-4i, and 0.98 [CI 95% 0.82-1.18] for GLP1-RA vs. DPP-4i., Conclusion: This study of routine care patients initiating novel glucose-lowering drugs showed similar occurrence of AKI between therapies, and suggests lower risk for SGLT2i., (© 2022. The Author(s).)

Competing Interests: The authors have no conflicts of interest to disclose.

Introduction: Combination of venetoclax and hypomethylating agents (HMAs) has become a standard of care in acute myeloid leukemia (AML) aged >75 years or who have comorbidities that preclude intensive induction chemotherapy., Methods: We conducted a monocentric retrospective analysis on adult patients affected by treatment-naïve AML not eligible for standard induction therapy or refractory/relapsed (R/R) AML treated with venetoclax combinations outside clinical trials. Venetoclax was administered at the dose of 400 mg/daily after a short ramp-up and reduced in case of concomitant CYP3A4 inhibitors., Results: Sixty consecutive AML were identified. Twenty-three patients (38%) were affected by treatment-naïve AML and 37 (62%) by R/R AML. Median age was 70 years. Among R/R AML 30% had received a prior allogeneic stem cell transplantation (allo-HSCT). In combination with venetoclax, 50 patients (83%) received azacitidine. Antifungal prophylaxis was performed in 33 patients (55%).Overall response rate was 60%, with 53% of complete remission (CR; 78% for treatment-naïve and 49% for R/R, p 0.017). Median overall survival was 130 days for R/R patients and 269 days for treatment-naïve patients; median event free survival was 145 days for R/R cohort and 199 days for treatment-naïve AML.Measurable residual disease was negative in 26% of evaluable patients in CR/CR with incomplete hematologic recovery after 2 cycles and in 50% after 4 cycles, with no significant association with survival.Eleven patients (18%) received an allo-HSCT after venetoclax combinations. Most common grade 3/4 adverse events were infectious (51% of the patients), or hematological without infections (25% of the patients). Use of CYP3A4 inhibitors was associated with a trend to shorter cytopenias and with a lower rate of infections. Invasive fungal infections were less frequent among patients receiving azole prophylaxis (6% vs 26%; p 0.0659)., Discussion: Venetoclax-based regimens are a viable option for AML considered not eligible for standard induction therapy and a valid rescue therapy in the R/R setting.Azole prophylaxis did not significantly affect response and it was associated with a lower rate of invasive fungal infections. Despite a limited number of patients, the association of venetoclax and HMAs proved to be also a feasible bridging therapy to transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sciumè, Bosi, Canzi, Ceparano, Serpenti, De Roberto, Fabris, Tagliaferri, Cavallaro, Onida and Fracchiolla.)

The rituximab biosimilar CT-P10 is approved for the treatment of non-Hodgkin lymphoma. Previous studies have demonstrated clinical similarity between CT-P10 and reference rituximab. However, real-world data relating to treatment in patients with DLBCL with rituximab biosimilars are limited. This study collected real-world data relating to the effectiveness and safety of CT-P10 treatment from the medical records of 389 patients with DLBCL (24 centers, five European countries). For the primary outcome (clinical effectiveness), overall survival (OS), progression-free survival (PFS), and best response (BR) were assessed. The percentage (95% confidence interval [95% CI]) of patients alive at 12-, 18-, and 30 months postindex (initiation of CT-P10) was 86% (82.4%-89.4%), 81% (76.9%-84.9%), and 76% (71.2%-80.1%), respectively. The PFS rate (percent, [95% CI]) at 12-, 18-, and 30 months postindex was 78% (74.2%-82.5%), 72% (67.9%-76.9%), and 67% (61.9%-71.7%), respectively. Median OS/PFS was not reached. For 82% ( n = 312) of patients, the BR to CT-P10 was a complete response. Adverse events were consistent with known effects of chemotherapy. This international, multicenter study provides real-world data on the safety and effectiveness profile of CT-P10 for DLBCL treatment and supports the adoption of CT-P10 for the treatment of DLBCL., Competing Interests: MB has received research funding from Takeda, Gilead, Roche, Abbvie; Travel/acc/expenses = Roche, Takeda, Gilead, Celltrion, Honararia Tevapharma, Roche, Celltrion; Advisory board = Beigene; Trial Management Group = Roche. GS has received in the last 12 months financial compensations for participating in advisory boards or consulting from: Abbvie, Bayer, Beigene, BMS/Celgene, Epizyme, Genentech/Roche, Genmab, Incyte, Janssen, Kite/Gilead, Loxo, Milteniy, Morphosys, Novartis, Rapt, Regeneron and Takeda. Shareholder: Owkin. PLZ has received personal fees for consulting from Verastem, EUSA Pharma, MSD and Novartis; personal fees for participating in a speaker's bureau from Verastem, Celltrion, Gilead, Janssen‐Cilag, BMS, Servier, MSG, TG Therapeutics, Takeda, Roche, EUSA Pharma, Kyowa Kirin, Novartis, Incyte and Beigene; and personal fees for participating in advisory boards from Verastem, Celltrion, Gilead, Janssen‐Cilag, BMS, Servier, Sandoz, MSG, TG Therapeutics, Takeda, Roche, EUSA Pharma, Kyowa Kirin, Novartis, ADC Therapeutics, Incyte and Beigene. SM has received educational grants to attend educational meetings, educational lecturing and attendance of pharmaceutical advisory boards for Novartis, Abbvie and AstraZeneca in the last year. KL has received research grants from Celltrion. Outside this work, KL has received research grants from AbbVie, Novartis, Takeda, Roche, Amgen, and Sandoz as well as personal fees from AbbVie, Novartis, Sandoz, Celgene, Jansen, and Amgen. SKK and YNL are employees of Celltrion Healthcare. CG, WK, MBo, DT, BS, JH, AB, JJB, and MW have no conflict of interest to disclose., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Intestinal ischemia and reperfusion (IRI) injury induces acute and long-lasting damage to the neuromuscular compartment and dysmotility. This study aims to evaluate the pathogenetic role of hyaluronan (HA), a glycosaminoglycan component of the extracellular matrix, as a modulator of the enteric neuronal and immune function and of the colonic microbiota during in vivo IRI in the rat small intestine., Methods: mesenteric ischemia was induced in anesthetized adult male rats for 60 min, followed by 24 h reperfusion. Injured, sham-operated and non-injured animals were treated with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU 25 mg/kg). Fecal microbiota composition was evaluated by Next Generation Sequencing. Neutrophil infiltration, HA homeostasis and toll like receptor (TLR2 and TLR4) expression in the small intestine were evaluated by immunohistochemical and biomolecular approaches (qRT-PCR and Western blotting). Neuromuscular responses were studied in vitro, in the absence and presence of the selective TLR2/4 inhibitor, Sparstolonin B (SsnB 10, 30 µM)., Results: 4-MU significantly reduced IRI-induced enhancement of potentially harmful Escherichia and Enterococcus bacteria. After IRI, HA levels, neutrophil infiltration, and TLR2 and TLR4 expression were significantly enhanced in the muscularis propria, and were significantly reduced to baseline levels by 4-MU. In the injured, but not in the non-injured and sham-operated groups, SsnB reduced both electrical field-stimulated (EFS, 0.1-40 Hz) contractions and EFS-induced (10 Hz) non-cholinergic non-adrenergic relaxations., Conclusions: enhanced HA levels after intestinal IRI favors harmful bacteria overgrowth, increases neutrophil infiltration and promotes the upregulation of bacterial target receptors, TLR2 and TLR4, in the muscularis propria , inducing a pro-inflammatory state. TLR2 and TLR4 activation may, however, underlay a provisional benefit on excitatory and inhibitory neuronal pathways underlying peristalsis.

Thrombosis in patients with thrombocytopenia has several risk factors, both disease-related and treatment-associated. Recently, COVID-19 infection was recognized as an additional risk factor, further complicating the delicate balance between thrombosis and bleeding in these patients. Here we describe the case of a patient with aplastic anaemia on eltrombopag who developed pulmonary embolism during COVID-19 pneumonia, despite receiving oral anticoagulation with edoxaban. Notably, he was also carrying a large paroxysmal nocturnal haemoglobinuria clone, although without evidence of haemolysis. The presented case recapitulates some of the open questions in thrombotic risk management of cytopenic patients, such as the management of thrombopoietin receptor agonists and the choice of anticoagulation in PNH, while also accounting for the additional thrombotic risk linked to COVID-19., (© 2022. The Author(s).)

Aims: Anomalies in dopaminergic machinery have been shown in inflammatory bowel disease (IBD) patients and preclinical models of IBD. Thus, we aimed to evaluate the impact of dextran sodium sulfate (DSS)-induced ileitis on enteric dopaminergic pathways., Materials and Methods: Male C57/Bl6 mice (10 ± 2 weeks old) received 2% DSS in drinking water for 5 days and were then switched to regular drinking water for 3 days. To measure ileitis severity inflammatory cytokines (IL-1β, TNFα, IL-6) levels were assessed. Changes in ileal muscle tension were isometrically recorded following: 1) cumulative addition of dopamine on basal tone (0.1-1000 μM); ii) 4-Hz electric field stimulation (EFS) in the presence of 30 μM dopamine with/without 10 μM SCH-23390 (dopamine D1 receptor (D1R) antagonist) or 10 μM sulpiride (D2R antagonist). Immunofluorescence distribution of the neuronal HuC/D protein, glial S100β marker, D1R, and dopamine transporter (DAT) were determined in longitudinal-muscle-myenteric plexus whole-mounts (LMMPs) by confocal microscopy. D1R and D2R mRNA transcripts were evaluated by qRT-PCR., Key Findings: DSS caused an inflammatory process in the small intestine associated to dysmotility and altered barrier permeability, as suggested by decreased fecal output and enhanced stool water content. DSS treatment caused a significant increase of DAT and D1R myenteric immunoreactivity as well as of D1R and D2R mRNA levels, accompanied by a significant reduction of dopamine-mediated relaxation, involving primarily D1-like receptors., Significance: Mouse ileitis affects enteric dopaminergic neurotransmission mainly involving D1R-mediated responses. These findings provide novel information on the participation of dopaminergic pathways in IBD-mediated neuromuscular dysfunction., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Aim of the Work: The aim of the current study was to explore under-considered psychosocial needs for lymphoma cancer group. A model of the role of psychosocial factors and Stressful Life Events was operationalized., Method: We used Discriminant Analysis to test predictive power of the model. 103 oncological patients (gender: 42.7 % vs 49.3 % of females 55.2 ±15.6 vs 53.7±14.9) were matched with 140healthy control groups in the study. The following instruments were utilized to conduct the study: the Florence Psychiatric Interview, Hospital Anxiety Depression Scale, Multidimensional Scale of Perceived Social Support, Beck Depression Inventory I, and Sense of Mastery., Results: The model satisfied the assumption criteria and were significant (Ʌ= .665, χ2= 105.83, p< .001)., Conclusion: Stressful events, depression and anxiety were adequate markers of the psychological status of lymphoma patients. Our results point out the relevance of taking into account psychosocial factors in hematology.

Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Recently, a growing body of evidence has emerged regarding the interplay between microbiota and the nervous system. This relationship has been associated with several pathological conditions and also with the onset and regulation of pain. Dysregulation of the axis leads to a huge variety of diseases such as visceral hypersensitivity, stress-induced hyperalgesia, allodynia, inflammatory pain and functional disorders. In pain management, probiotics have shown promising results. This narrative review describes the peripheral and central mechanisms underlying pain processing and regulation, highlighting the role of the gut-brain axis in the modulation of pain. We summarized the main findings in regard to the stress impact on microbiota's composition and its influence on pain perception. We also focused on the relationship between gut microbiota and both visceral and inflammatory pain and we provided a summary of the main evidence regarding the mechanistic effects and probiotics use.

Silica nanoparticles (SiO 2 NPs) are of increasing interest in nano-enabled agriculture, particularly as nanocarriers for the targeted delivery of agrochemicals. Their direct application in agricultural soils may lead to the release of SiO 2 NPs in the environment. Although some studies have investigated transport of solid SiO 2 NPs in porous media, there is a knowledge gap on how different SiO 2 NP structures incorporating significant porosities can affect the mobility of such particles under different conditions. Herein, we investigated the effect of pH and ionic strength (IS) on the transport of two distinct structures of SiO 2 NPs, namely solid SiO 2 NPs (SSNs) and porous hollow SiO 2 NPs (PHSNs), of comparable sizes (~200 nm). Decreasing pH and increasing ionic strength reduced the mobility of PHSNs in sand-packed columns more significantly than for SSNs. The deposition of PHSNs was approximately 3 times greater than that of SSNs at pH 4.5 and IS 100 mM. The results are non-intuitive given that PHSNs have a lower density and the same chemical composition of SSNs but can be explained by the greater surface roughness and ten-fold greater specific surface area of PHSNs, and their impacts on van der Waals and electrostatic interaction energies., 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 Inc. All rights reserved.)

The commensal microbiota plays a fundamental role in maintaining host gut homeostasis by controlling several metabolic, neuronal and immune functions. Conversely, changes in the gut microenvironment may alter the saprophytic microbial community and function, hampering the positive relationship with the host. In this bidirectional interplay between the gut microbiota and the host, hyaluronan (HA), an unbranched glycosaminoglycan component of the extracellular matrix, has a multifaceted role. HA is fundamental for bacterial metabolism and influences bacterial adhesiveness to the mucosal layer and diffusion across the epithelial barrier. In the host, HA may be produced and distributed in different cellular components within the gut microenvironment, playing a role in the modulation of immune and neuronal responses. This review covers the more recent studies highlighting the relevance of HA as a putative modulator of the communication between luminal bacteria and the host gut neuro-immune axis both in health and disease conditions, such as inflammatory bowel disease and ischemia/reperfusion injury.

We previously reported that t(14;18)-negative follicular lymphomas (FL) show a clear reduction of newly acquired N-glycosylation sites (NANGS) in immunoglobulin genes. We therefore aimed to investigate in-depth the occurrence of NANGS in a larger cohort of t(14;18)-positive and t(14;18)-negative FL, including early (I/II) and advanced (III/IV) stage treatment-naive and relapsed tumors. The clonotype was determined by using a next-generation sequencing approach in a series of 68 FL with fresh frozen material [36 t(14;18) positive and 32 t(14;18) negative]. The frequency of NANGS differed considerably between t(14;18)-positive and t(14;18)-negative FL stage III/IV, but no difference was observed among t(14;18)-positive and t(14;18)-negative FL stage I/II. The introduction of NANGS in all t(14;18)-negative clinical subgroups occurred significantly more often in the FR3 region. Moreover, t(14;18)-negative treatment-naive FL, specifically those with NANGS, showed a strong bias for IGHV4-34 usage compared with t(14;18)-positive treatment-naive cases with NANGS; IGHV4-34 usage was never recorded in relapsed FL. In conclusion, subgroups of t(14;18)-negative FL might use different mechanisms of B-cell receptor stimulation compared with the lectin-mediated binding described in t(14;18)-positive FL, including responsiveness to autoantigens as indicated by biased IGHV4-34 usage and strong NANGS enrichment in FR3., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Animal models used to study pathologies requiring rehabilitation therapy, such as cardiovascular and neurologic disorders or oncologic disease, must be as refined and translationally relevant as possible. Sometimes, however, experimental procedures such as those involving restraint may generate undesired effects which may act as a source of bias. However, the extent to which potentially confounding effects derive from such routine procedures is currently unknown. Our study was therefore aimed at exploring possible undesirable effects of acute restraint stress, whereby animals were exposed to a brightly lit enclosed chamber (R&L) similar to those that are commonly used for substance injection. We hypothesised that this would induce a range of unwanted physiological alterations [such as neuroinflammatory response and changes in body weight and in brown adipose tissue (BAT)] and behavioural modification, and that these might be mitigated via the use of non-aversive handling methods: Tunnel Handling (NAH-T) and Mechanoceptive Handling (NAH-M)) as compared to standard Tail Handling (TH)., Methods: Two indicators of physiological alterations and three potentially stress sensitive behavioural parameters were assessed. Physiological alterations were recorded via body weight changes and assessing the temperature of Brown Adipose Tissue (BAT) using infra-red thermography (IRT), and at the end of the experiment we determined the concentration of cytokines CXCL12 and CCL2 in bone marrow (BM) and activated microglia in the brain. Nest complexity scoring, automated home-cage behaviour analysis (HCS) and Elevated Plus Maze testing (EPM) were used to detect any behavioural alterations. Recordings were made before and after a 15-minute period of R&L in groups of mice handled via TH, NAH-T or NAH-M., Results: BAT temperature significantly decreased in all handling groups following R&L regardless of handling method. There was a difference, at the limit of significance (p = 0.06), in CXCL12 BM content among groups. CXCL12 content in BM of NAH-T animals was similar to that found in Sentinels, the less stressed group of animals. After R&L, mice undergoing NAH-T and NAH-M showed improved body-weight maintenance compared to those exposed to TH. Mice handled via NAH-M spent a significantly longer time on the open arms of the EPM. The HCS results showed that in all mice, regardless of handling method, R&L resulted in a significant reduction in walking and rearing, but not in total distance travelled. All mice also groomed more. No difference among the groups was found in Nest Score, in CCL2 BM content or in brain activated microglia., Conclusions: Stress induced by a common restraint procedure caused metabolic and behavioural changes that might increase the risk of unexpected bias. In particular, the significant decrease in BAT temperature could affect the important metabolic pathways controlled by this tissue. R&L lowered the normal frequency of walking and rearing, increased grooming and probably carried a risk of low-grade neuro-inflammation. Some of the observed alterations can be mitigated by Non-aversive handlings., Competing Interests: Authors declare that there are no conflicts of interest. Paolo Cappella is a full-time employee in E.M.C2 S.r.l. and has supported in vivo laboratory activities in accordance with authors requests. The Company has no commercial interests in the therapeutic area of this study and did not play any role in the study design, providing only financial support in the form of author Paolo Cappella’ salary.

Alternative nutrient sources to fishmeal for fish feed, such as insect meals, represent a promising sustainable supply. However, the consequences for fish digestive function have not been exhaustively investigated. In the present study we evaluated the effect of partial fishmeal substitution with 10% Hermetia illucens (Hi10) larvae meal on the neuromuscular function of proximal and distal intestine in gilthead sea bream. In animals fed with insect meal, weight and growth parameters were similar to controls fed with conventional fishmeal. In addition, no anomalies in intestinal gross morphology and no overt signs of inflammation were observed. The gastrointestinal transit was significantly reduced in Hi10 fed animals. In the proximal and distal intestine longitudinal muscle, Hi10 feeding downregulated the excitatory cholinergic and serotoninergic transmission. Sodium nitroprusside-induced inhibitory relaxations increased in the proximal intestine and decreased in the distal intestine after Hi10 meal. Changes in the excitatory and inhibitory components of peristalsis were associated with adaptive changes in the chemical coding of both proximal and distal intestine myenteric plexus. However, these neuromuscular function alterations were not associated with considerable variations in morphometric growth parameters, suggesting that 10% Hi meal may represent a tolerable alternative protein source for gilthead sea bream diets., (© 2021. The Author(s).)

In order to address the paucity of evidence on the association between childhood eating habits and urbanization, this cross-sectional study describes urban-rural differences in frequency of fruit, vegetable, and soft drink consumption in 123,100 children aged 6-9 years from 19 countries participating in the fourth round (2015-2017) of the WHO European Childhood Obesity Surveillance Initiative (COSI). Children's parents/caregivers completed food-frequency questionnaires. A multivariate multilevel logistic regression analysis was performed and revealed wide variability among countries and within macroregions for all indicators. The percentage of children attending rural schools ranged from 3% in Turkey to 70% in Turkmenistan. The prevalence of less healthy eating habits was high, with between 30-80% and 30-90% children not eating fruit or vegetables daily, respectively, and up to 45% consuming soft drinks on >3 days a week. For less than one third of the countries, children attending rural schools had higher odds (OR-range: 1.1-2.1) for not eating fruit or vegetables daily or consuming soft drinks >3 days a week compared to children attending urban schools. For the remainder of the countries no significant associations were observed. Both population-based interventions and policy strategies are necessary to improve access to healthy foods and increase healthy eating behaviors among children., (© 2021 World Obesity Federation. The World Health Organization retains copyright and all other rights in the manuscript of this article as submitted for publication.)

Background: To characterize the use of nephrotoxic medications in patients with chronic kidney disease (CKD) Stages G3-5 in routine care., Methods: We studied cohorts of adults with confirmed CKD G3-5 undergoing routine care from 1 January 2016 through 31 December 2018 in two health systems [Stockholm CREAtinine Measurements (SCREAM), Stockholm, Sweden ( N  = 57 880) and Geisinger, PA, USA ( N  = 16 255)]. We evaluated the proportion of patients receiving nephrotoxic medications within 1 year overall and by baseline kidney function, ranked main contributors and examined the association between receipt of nephrotoxic medication and age, sex, CKD G-stages comorbidities and provider awareness of the patient's CKD using multivariable logistic regression., Results: During a 1-year period, 20% (SCREAM) and 17% (Geisinger) of patients with CKD received at least one nephrotoxic medication. Among the top nephrotoxic medications identified in both cohorts were non-steroidal anti-inflammatory drugs (given to 11% and 9% of patients in SCREAM and Geisinger, respectively), antivirals (2.5% and 2.0%) and immunosuppressants (2.7% and 1.5%). Bisphosphonate use was common in SCREAM (3.3%) and fenofibrates in Geisinger (3.6%). Patients <65 years of age, women and those with CKD G3 were at higher risk of receiving nephrotoxic medications in both cohorts. Notably, provider awareness of a patient's CKD was associated with lower odds of nephrotoxic medication use {odds ratios [OR] 0.85[95% confidence interval (CI) 0.80-0.90] in SCREAM and OR 0.80 [95% CI 0.72-0.89] in Geisinger}., Conclusions: One in five patients with CKD received nephrotoxic medications in two distinct health systems. Strategies to increase physician's awareness of patients' CKD and knowledge of drug nephrotoxicity may reduce prescribing nephrotoxic medications and prevent iatrogenic kidney injury., (© The Author(s) 2021. Published by Oxford University Press on behalf of the ERA.)

Patients with acute asthma attack usually access the emergency room with severe functional impairment, despite low perception of symptoms. In this scenario, early functional assessment is essential focusing on vital parameters and respiratory function, alongside perceived dyspnea. Impairment of ventilatory mechanics due to progressive dynamic pulmonary hyperinflation should be promptly treated with medical inhalation and/or intravenous therapy, reserving intensive treatment in case of non-response and/or worsening of the clinical conditions. Therapeutic planning at patient's discharge is no less important than treatment management during emergency room access as educating the patient about therapeutic adherence significantly impact long-term outcomes of asthma. With this review we aimed at exploring current evidence on acute asthma attack management, focusing of pharmacological and ventilatory strategies of care and highlighting the importance of patient education once clinical stability allows discharge from the emergency department.

Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT +/- ) and wild-type (DAT +/+ ) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 μg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 μg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated., (© 2020 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The complex bidirectional communication system existing between the gastrointestinal tract and the brain initially termed the "gut-brain axis" and renamed the "microbiota-gut-brain axis", considering the pivotal role of gut microbiota in sustaining local and systemic homeostasis, has a fundamental role in the pathogenesis of Inflammatory Bowel Disease (IBD). The integration of signals deriving from the host neuronal, immune, and endocrine systems with signals deriving from the microbiota may influence the development of the local inflammatory injury and impacts also more distal brain regions, underlying the psychophysiological vulnerability of IBD patients. Mood disorders and increased response to stress are frequently associated with IBD and may affect the disease recurrence and severity, thus requiring an appropriate therapeutic approach in addition to conventional anti-inflammatory treatments. This review highlights the more recent evidence suggesting that alterations of the microbiota-gut-brain bidirectional communication axis may concur to IBD pathogenesis and sustain the development of both local and CNS symptoms. The participation of the main microbial-derived metabolites, also defined as "postbiotics", such as bile acids, short-chain fatty acids, and tryptophan metabolites in the development of IBD-associated gut and brain dysfunction will be discussed. The last section covers a critical evaluation of the main clinical evidence pointing to the microbiome-based therapeutic approaches for the treatment of IBD-related gastrointestinal and neuropsychiatric symptoms.

Natural killer (NK) cells, effector lymphocytes of the innate immunity, have been shown to be altered in several cancers, both at tissue and peripheral levels. We have shown that in Non-Small Cell Lung Cancer (NSCLC) and colon cancer, tumour associated circulating NK (TA-NK) and tumour infiltrating NK (TI-NK) exhibit pro-angiogenic phenotype/functions. However, there is still a lack of knowledge concerning the phenotype of peripheral blood (PB) NK (pNK) cells in prostate cancer (PCa). Here, we phenotypically and functionally characterized pNK from PCa patients (PCa TA-NKs) and investigated their interactions with endothelial cells and monocytes/macrophages. NK cell subset distribution in PB of PCa patients was investigated, by multicolor flow cytometry, for surface antigens expression. Protein arrays were performed to characterize the secretome on FACS-sorted pNK cells. Conditioned media (CM) from FACS-sorted PCa pTA-NKs were used to determine their ability to induce pro-inflammatory/pro-angiogenic phenotype/functions in endothelial cells, monocytes, and macrophages. CM from three different PCa (PC-3, DU-145, LNCaP) cell lines, were used to assess their effects on human NK cell polarization in vitro , by multicolor flow cytometry. We found that PCa pTA-NKs acquire the CD56 bright CD9 + CD49a + CXCR4 + phenotype, increased the expression of markers of exhaustion (PD-1, TIM-3) and are impaired in their degranulation capabilities. Similar effects were observed on healthy donor-derived pNK cells, exposed to conditioned media of three different PCa cell lines, together with increased production of pro-inflammatory chemokines/chemokine receptors CXCR4, CXCL8, CXCL12, reduced production of TNFα, IFNγ and Granzyme-B. PCa TA-NKs released factors able to support inflammatory angiogenesis in an in vitro model and increased the expression of CXCL8, ICAM-1, and VCAM-1 mRNA in endothelial cells. Secretome analysis revealed the ability of PCa TA-NKs to release pro-inflammatory cytokines/chemokines involved in monocyte recruitment and M2-like polarization. Finally, CMs from PCa pTA-NKs recruit THP-1 and peripheral blood CD14 + monocyte and polarize THP-1 and peripheral blood CD14 + monocyte-derived macrophage towards M2-like/TAM macrophages. Our results show that PCa pTA-NKs acquire properties related to the pro-inflammatory angiogenesis in endothelial cells, recruit monocytes and polarize macrophage to an M2-like type phenotype. Our data provides a rationale for a potential use of pNK profiling in PCa patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gallazzi, Baci, Mortara, Bosi, Buono, Naselli, Guarneri, Dehò, Capogrosso, Albini, Noonan and Bruno.)

Primary pulmonary lymphoma (PPL) is a rare disease with not well-defined optimal treatment. Outcomes and follow-up are variable in published data., Objectives: To define the outcome and optimal treatment strategies in PPL., Methods: We reviewed the medical records of 49 patients with PPL treated in three Italian Hematological Institutions between 2002 and 2018., Results: Thirty-eight (77.5%) cases were indolent PPL, and 11 (22.5%) cases were aggressive PPL. The majority of patients were asymptomatic at diagnosis, early stages (stages IE-IIE), normal serum LDH, no bone marrow involvement, and low or low-intermediate risks of IPI. Local therapy ± immunotherapy or immuno-chemotherapy was possible in 18/49 (37%) patients. Twenty-eight (57%) patients were treated with immuno-chemotherapy after biopsy. Waiting and watching were reported in 3 (6%) patients. Overall, the CR and ORR were 83.7% and 95.9%. With a median follow-up of 62.5 months (range 0.8-199 months), the estimated 5- and 10-year OS rates were 85% and 72.3% for all patients, 89.2% and 80.3% for indolent PPL, and 70.7% and 47.1% for aggressive PPL. Aggressive PPL tended to have a high risk of progression in the first months (P = .056). No advantages were found for indolent PPL who received immuno-chemotherapy or more conservative approaches., Conclusion: Our studies confirm the epidemiological and favorable survival of patients with PPL, suggesting a very conservative approach, particularly in indolent subtypes., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Minimal residual disease (MRD) assessment in acute myeloid leukemia (AML) is increasingly used in risk stratification. However, several issues around this use are unresolved, including, among others, the most suitable time-point(s) for its application. Overall, late assessments appear more effective at distinguishing outcome but, in some studies, the early evaluations were already highly informative, anticipating the value of later ones. Our work integrated MRD with peripheral blast clearance (PBC), a treatment-related biomarker previously demonstrated to be a powerful predictor of response. From 2007 to 2014, we have studied 120 patients treated according to the NILG 02-06 trial and who achieved CR after induction. Patients in PBC-defined categories (separated by a 1.5-log threshold) showed significantly different probabilities of attaining MRD negativity, after either induction (MRD1) or consolidation (MRD2). Peripheral blast clearance combined with MRD1 largely anticipated MRD2-related information: when both biomarkers predicted chemosensitive disease (PBC high /MRD1 neg ), the rate of MRD2-negativity was 90%, and DFS and OS estimates were 68% and 76% at 3 years, respectively. When both markers were unfavorable (PBC low /MRD1 pos ), rates of MRD2 negativity, DFS, and OS were 20%, 34%, and 24%, respectively, at 3 years. In fact, MRD2 added prognostic value only in cases with discordant PBC/MRD1 data. Our data support a reasoned timing for MRD-based therapeutic decisions, modulated on individual chemosensitivity, an approach we have implemented in a forthcoming prospective multi-center trial by Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)., (© 2020 Wiley Periodicals LLC.)

Acute myeloid leukemia (AML) "with myelodysplasia-related changes (MRC)" is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1 , FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS&#95;0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in "sterile" inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.