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Abstract A recent evidence gaps assessment of the clinical, health‐related quality of life, and economic burden associated with α‐thalassemia is lacking. We conducted a systematic literature review (SLR) following the methodological and reporting requirements of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and the Cochrane Handbook for Systematic Reviews, using available literature over the past decade. This SLR identified a considerable evidence gap with regard to understanding the current burden of α‐thalassemia as evident from paucity of studies published in the past 10 years. The limited data available still indicate that patients with α‐thalassemia experience substantial morbidity and quality of life/economic burden that is generally comparable to patients with β‐thalassemia.

Abstract Carbon dioxide is a key gas to monitor at volcanoes because its concentration and isotopic signature can indicate changes to magma supply and degassing behavior prior to eruptions, yet carbon isotopic fluctuations at volcanic summits are not well constrained. Here we present δ13C results measured from plume samples collected at Stromboli volcano, Italy, by Uncrewed Aerial Systems (UAS). We found contrasting volcanic δ13C signatures in 2018 during quiescence (−0.36 ± 0.59‰) versus 10 days before the 3 July 2019 paroxysm (−5.01 ± 0.56‰). Prior to the eruption, an influx of CO2‐rich magma began degassing at deep levels (∼100 MPa) in an open‐system fashion, causing strong isotopic fractionation and maintaining high CO2/St ratios in the gas. This influx occurred between 10 days and several months prior to the event, meaning that isotopic changes in the gas could be detected weeks to months before unrest.

Abstract Background Viral reactivations are frequent in hematologial patients due to their cancer‐related and drug‐induced immunosuppressive status. Daratumumab, an anti‐CD38 monoclonal antibody, is used for multiple myeloma (MM) treatment, and causes immunosuppression by targeting CD38‐expressing normal lymphocytes. In this single‐center two‐arm real‐life experience, we evaluated incidence of cytomegalovirus (CMV) reactivation in MM patients treated with daratumumab‐based regimens as first‐ or second‐line therapy. Methods A total of 101 consecutive MM patients were included in this study and were divided into two cohorts: daratumumab and nondaratumumab‐based (control) regimens. Patients treated with >2 lines of therapies were excluded to reduce the confounding factor of multi‐treated cases. Primary endpoint was the CMV reactivation rate. Results CMV reactivation rate was significantly higher in the daratumumab cohort compared to control group (33% vs. 4%; p 1000 UI/mL in 12% of cases; p

Abstract Soils are a major source of nitrogen oxides, which in the atmosphere help govern its oxidative capacity. Thus the response of soil nitric oxide (NO) emissions to forcings such as warming or forest loss has a meaningful impact on global atmospheric chemistry. We find that the soil emission rate of NO in Amazonia from a common inventory is biased low by at least an order of magnitude in comparison to tower‐based observations. Accounting for this regional bias decreases the modeled global methane lifetime by 1.4%–2.6%. In comparison, a fully deforested Amazonia, representing a 37% decrease in global emissions of isoprene, decreases methane lifetime by at most 4.6%, highlighting the sensitive response of oxidation rates to changes in emissions of NO compared to those of terpenes. Our results demonstrate that improving our understanding of soil NO emissions will yield a more accurate representation of atmospheric oxidative capacity.

Abstract The availability of microbial biobanks for the storage of individual gut microbiota members or their derived and artificially assembled consortia has become fundamental for in vitro investigation of the molecular mechanisms behind microbe–microbe and/or microbe–host interactions. However, to preserve bacterial viability, adequate storage and processing technologies are required. In this study, the effects on cell viability of seven different combinations of cryoprotective agents were evaluated by flow cytometry for 53 bacterial species representing key members of the human gut microbiota after one and 3 months of cryopreservation at −80°C. The obtained results highlighted that no universal cryoprotectant was identified capable of guaranteeing effective recovery of intact cells after cryopreservation for all tested bacteria. However, the presence of inulin or skimmed milk provided high levels of viability protection during cryoexposure. These results were further corroborated by cryopreserving 10 artificial gut microbiota produced through in vitro continuous fermentation system technology. Indeed, in this case, the inclusion of inulin or skimmed milk resulted in a high recovery of viable cells, while also allowing consistent and reliable preservation of the artificial gut microbiota biodiversity. Overall, these results suggest that, although the efficacy of various cryoprotective agents is species‐specific, some cryoprotectants based on glycerol and the addition of inulin or skimmed milk are preferable to retain viability and biodiversity for both single bacterial species and artificial gut microbiota.

Background The purpose of this study was to investigate a therapeutic approach targeting the inflammatory response and consequent remodeling from ischemic myocardial injury. Methods and Results Coronary thrombus aspirates were collected from patients at the time of ST‐segment–elevation myocardial infarction and subjected to array‐based proteome analysis. Clinically indistinguishable at myocardial infarction (MI), patients were stratified into vulnerable and resilient on the basis of 1‐year left ventricular ejection fraction and death. Network analysis from coronary aspirates revealed prioritization of tumor necrosis factor‐α signaling in patients with worse clinical outcomes. Infliximab, a tumor necrosis factor‐α inhibitor, was infused intravenously at reperfusion in a porcine MI model to assess whether infliximab‐mediated immune modulation impacts post‐MI injury. At 3 days after MI (n=7), infliximab infusion increased proregenerative M2 macrophages in the myocardial border zone as quantified by immunofluorescence (24.1%±23.3% in infliximab versus 9.29%±8.7% in sham; P

Background The optimal strategy for transferring patients to specialized acute stroke care remains controversial. This substudy of the Effect of Direct Transportation to Thrombectomy‐Capable Center vs Local Stroke Center on Neurological Outcomes in Patients with suspected Large‐Vessel Occlusion Stroke in Nonurban Areas (RACECAT) trial aims to investigate the impact of local hospital characteristics and performance on the optimal transport strategy and stroke outcomes. Methods This was a secondary post hoc analysis of the RACECAT trial, evaluating factors potentially associated with functional outcomes among patients initially evaluated at a local stroke center (Local‐SC) versus a thrombectomy‐capable center. The primary outcome was the shift in the 90‐day modified Rankin Scale score in the target population of the RACECAT trial. Door‐to‐needle time, level of care of the Local‐SC (telestroke versus primary stroke center), the specialty of the physician involved with therapeutic decisions, and Local‐SC case volume were assessed for subgroup analyses. Results Of the 1367 patients included in the analysis, 903 had acute ischemic strokes (modified intention to treat). The 90‐day modified Rankin Scale score was associated with door‐to‐needle time in the entire modified intention‐to‐treat cohort (P = 0.026) and in patients initially evaluated in a Local‐SC (P = 0.063), and with local hospital level of care (telestroke versus primary stroke center; P = 0.10). There was a trend favoring direct transport to thrombectomy‐capable center for patients whose assigned Local‐SC was a telestroke center (adjusted odds ratio [OR], 1.47 [95% CI, 0.93–2.33] versus 0.94 [95% CI, 0.71–1.24]; Pinteraction = 0.08) or had door‐to‐needle time over the global median (adjusted OR, 1.52 [95% CI, 0.97–2.40] versus 0.94 [95% CI, 0.71–1.25]; Pinteraction = 0.06). In patients with confirmed large‐vessel occlusion, the benefit of direct transport to thrombectomy‐capable centers when the Local‐SC was a telestroke center (Pinteraction = 0.04) or had longer door‐to‐needle time (Pinteraction = 0.07) was more evident. Conclusions Direct transport to thrombectomy‐capable centers may be preferable in areas primarily covered by telestroke or Local‐SCs with poorer performance, especially in patients with large‐vessel occlusion. These findings can contribute to refining prehospital triage strategies and optimizing stroke systems of care.

Abstract Background Renal injury related to Waldenström macroglobulinemia (WM) occurs in approximately 3% of patients. Kidney biopsy is crucial to discriminate between distinct histopathological entities such as glomerular (amyloidotic and non‐amyloidotic), tubulo‐interstitial and non‐paraprotein mediated renal damage. In this context, disease characterization, management, relationship between renal, and hematological response have been poorly explored. We collected clinical, genetic and laboratory data of seven cases of biopsy‐proven renal involvement by WM managed at our academic center and focused on three cases we judged paradigmatic discussing their histopathological patterns, clinical features, and therapeutic options. Case In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM‐related renal involvement, even if at present there are not precise cut‐off levels recommending the execution of a renal biopsy. In our series AL Amyloidosis (n = 3/7) and tubulo‐interstitial infiltration by lymphoma cells (n = 3/7) were the two more represented entities. BTKi did not seem to improve renal function (Case 1), while bortezomib‐based regimens demonstrated a beneficial activity on the hematological and organ response, even when used as second‐line therapy after chemoimmunotherapy (Case 3) and also with coexistence of anti‐MAG neuropathy (Case 2). In case of poor response to bortezomib, standard chemoimmunotherapy (CIT), such as rituximab‐bendamustine, represents an effective option (Case 1, 6, and 7). In our series, CIT generates durable responses more frequently in cases with amyloidogenic renal damage (Case 1, 5, and 7). Conclusion In this illustrative case series, we confirm that serum creatinine levels and 24 h proteinuria are parameters that when altered should prompt the clinical suspicion of WM‐related renal involvement, even if at present there are not precise cut‐off levels recommending the execution of a renal biopsy. Studies with higher numerosity are needed to better clarify the pathological and clinical features of renal involvement during WM and to determine the potential benefit of different therapeutic regimens according to the histopathological subtypes.

Abstract Objectives The main objective of this study was to evaluate how an apparently minor anomaly of the sphenoid bone, observed in a haploinsufficient mouse model for Sonic Hedgehog (Shh), affects the growth of the adult craniofacial region. This study aims to provide valuable information to orthodontists when making decisions regarding individuals carrying SHH mutation. Materials and Methods The skulls of embryonic, juvenile and adult mice of two genotypes (Shh heterozygous and wild type) were examined and measured using landmark‐based linear dimensions. Additionally, we analysed the clinical characteristics of a group of patients and their relatives with SHH gene mutations. Results In the viable Shh+/− mouse model, bred on a C57BL/6J background, we noted the presence of a persistent foramen at the midline of the basisphenoid bone. This particular anomaly was attributed to the existence of an ectopic pituitary gland. We discovered that this anomaly led to premature closure of the intrasphenoidal synchondrosis and contributed to craniofacial deformities in adult mice, including a longitudinally shortened skull base. This developmental anomaly is reminiscent of that commonly observed in human holoprosencephaly, a disorder resulting from a deficiency in SHH activity. However, sphenoid morphogenesis is not currently monitored in individuals carrying SHH mutations. Conclusion Haploinsufficiency of Shh leads to isolated craniofacial skeletal hypoplasia in adult mouse. This finding highlights the importance of radiographic monitoring of the skull base in all individuals with SHH gene mutations.

Abstract The objective of this article is to describe a case of suspected zonisamide‐induced immune‐mediated polyarthritis (IMPA) and anterior uveitis in a dog. A 7‐year‐old male neutered Siberian Husky with a history of refractory idiopathic epilepsy was presented for cluster seizures. Following the addition of zonisamide to the antiepileptic regime, the dog developed new IMPA and anterior uveitis. Within a few weeks of discontinuation of the zonisamide, the dog's IMPA and anterior uveitis resolved. These immune‐mediated conditions were thus presumed to be an idiosyncratic reaction to zonisamide. To our knowledge, this is the first report of IMPA and anterior uveitis in dogs associated with zonisamide administration at its recommended dose.

Abstract Background About 15%–20% of breast cancer (BC) cases is classified as Human Epidermal growth factor Receptor type 2 (HER2) positive. The Neoadjuvant chemotherapy (NAC) was initially introduced for locally advanced and inflammatory BC patients to allow a less extensive surgical resection, whereas now it represents the current standard for early‐stage and operable BC. However, only 20%–40% of patients achieve pathologic complete response (pCR). According to the results of practice‐changing clinical trials, the addition of trastuzumab to NAC brings improvements to pCR, and recently, the use of pertuzumab plus trastuzumab has registered further statistically significant and clinically meaningful improvements in terms of pCR. The goal of our work is to propose a machine learning model to predict the pCR to NAC in HER2‐positive patients based on a subset of clinical features. Method First, we evaluated the significant association of clinical features with pCR on the retrospectively collected data referred to 67 patients afferent to Istituto Tumori “Giovanni Paolo II.” Then, we performed a feature selection procedure to identify a subset of features to be used for training a machine learning‐based classification algorithm. As a result, pCR to NAC was associated with ER status, Pgr status, and HER2 score. Results The machine learning model trained on a subgroup of essential features reached an AUC of 73.27% (72.44%–73.66%) and an accuracy of 71.67% (71.64%–73.13%). According to our results, the clinical features alone are not enough to define a support system useful for clinical pathway. Conclusion Our results seem worthy of further investigation in large validation studies and this work could be the basis of future study that will also involve radiomics analysis of biomedical images.

Abstract Background and Aim Esophageal squamous papilloma (ESP) is a benign growth in the esophagus with unknown malignant potential. The mechanism underlying ESP formation is unknown, but human papillomavirus (HPV) infection has been proposed as a potential etiology. We sought to investigate the clinical characteristic of ESP in our population, review the current literature, and highlight the role of HPV. Methods This is a retrospective case–control study conducted at two referral centers. We selected the ESP population by free‐text search in the pathology department database and selected controls randomly from the general endoscopy population. Immunostains were used to evaluate ESP tissue for HPV. Results Between January 2016 and December 2021, we identified 66 patients with ESP, with a prevalence of 0.72%. ESP patients were younger, with a median age of 52 years (P = 0.021), and more likely African American (34.4 vs 7.5%, P

Abstract Background Inflammation in non‐small cell lung cancer (NSCLC) may impair the response to immune checkpoint inhibitors (ICIs) and can be indicated by peripheral blood inflammatory indexes. 2‐deoxy‐2‐[18F]fluoro‐D‐glucose positron emission tomography/computed tomography ([18F] FDG‐PET/CT) may be used as a marker of inflammation by measuring glucose metabolism in different colonic sites. Methods This retrospective analysis aimed to investigate the correlation between [18F] FDGPET/CT SUVratio in six gastrointestinal districts, the spleen, the pharynx and the larynx alongside the most avid tumor lesion with peripheral blood inflammatory indexes, including the neutrophil‐to‐lymphocyte ratio (NLR), systemic immune‐inflammatory index (SII, i.e., NLR times platelets) and lactate dehydrogenase (LDH), in patients with [18F] FDG‐PET/CT staged IV NSCLC who received first‐line immune checkpoint inhibitors (ICIs). The role of SUVratios and peripheral blood inflammatory indexes in predicting overall survival (OS) and progression‐free survival (PFS) was then explored. Results A total of 43 patients were treated with first‐line ICI alone (58%) or in combination with chemotherapy (42%). A significant correlation was only found between the rectosigmoid SUVratio and NLR (p = 0.0465). NLR >5.5 and LDH > 333.5 were associated with a worse OS (p = 0.033 and p = 0.009, respectively). The SII was associated with a worse PFS in patients treated with ICI alone (p = 0.033). None of the SUVratios were significantly associated with OS or PFS, although a high left colon SUVratio showed a trend toward a worse PFS. Conclusion There was no significant correlation between [18F]FDG PET/CT uptake in different anatomical sites, and in the tumor, and systemic immune‐inflammatory indexes. The prognostic role of high left colon SUVratio deserves further investigation.

Abstract Bifidobacteria are commensal microorganisms that typically inhabit the mammalian gut, including that of humans. As they may be vertically transmitted, they commonly colonize the human intestine from the very first day following birth and may persist until adulthood and old age, although generally at a reduced relative abundance and prevalence compared to infancy. The ability of bifidobacteria to persist in the human intestinal environment has been attributed to genes involved in adhesion to epithelial cells and the encoding of complex carbohydrate‐degrading enzymes. Recently, a putative mucin‐degrading glycosyl hydrolase belonging to the GH136 family and encoded by the perB gene has been implicated in gut persistence of certain bifidobacterial strains. In the current study, to better characterize the function of this gene, a comparative genomic analysis was performed, revealing the presence of perB homologues in just eight bifidobacterial species known to colonize the human gut, including Bifidobacterium bifidum and Bifidobacterium longum subsp. longum strains, or in non‐human primates. Mucin‐mediated growth and adhesion to human intestinal cells, in addition to a rodent model colonization assay, were performed using B. bifidum PRL2010 as a perB prototype and its isogenic perB‐insertion mutant. These results demonstrate that perB inactivation reduces the ability of B. bifidum PRL2010 to grow on and adhere to mucin, as well as to persist in the rodent gut niche. These results corroborate the notion that the perB gene is one of the genetic determinants involved in the persistence of B. bifidum PRL2010 in the human gut.

Abstract Cedirogant is an inverse agonist of retinoic acid‐related orphan receptor gamma thymus (RORγt) developed for the treatment of moderate to severe chronic plaque psoriasis. Here, we report the results from two phase I studies in which the pharmacokinetics (PK), safety, and efficacy of cedirogant in healthy participants and patients with moderate to severe chronic plaque psoriasis were evaluated. The studies consisted of single (20–750 mg) and multiple (75–375 mg once‐daily [q.d.]) ascending dose designs, with effect of food and itraconazole on cedirogant exposure also evaluated. Safety and PK were evaluated for both healthy participants and psoriasis patients, and efficacy was assessed in psoriasis patients. Following single and multiple doses, cedirogant mean terminal half‐life ranged from 16 to 28 h and median time to reach maximum plasma concentration ranged from 2 to 5 h across both populations. Cedirogant plasma exposures were dose‐proportional after single doses and less than dose‐proportional from 75 to 375 mg q.d. doses. Steady‐state concentrations were achieved within 12 days. Accumulation ratios ranged from approximately 1.2 to 1.8 across tested doses. Food had minimal effect and itraconazole had limited impact on cedirogant exposure. No discontinuations or serious adverse events due to cedirogant were recorded. Psoriasis Area and Severity Index (PASI) and Self‐Assessment of Psoriasis Symptoms (SAPS) assessments demonstrated numerical improvement with treatment of cedirogant 375 mg q.d. compared with placebo. The PK, safety, and efficacy profiles of cedirogant supported advancing it to phase II clinical trial in psoriasis patients.

Abstract Background The addition of immune checkpoint inhibitors (ICIs) to chemotherapy is the new standard of care in the first‐line treatment of small cell lung cancer (SCLC). However, although the concomitant use of immunotherapy and chemotherapy can increase the antitumor efficacy, it can also increase toxicity. The present study evaluated the tolerability of immune‐based combinations in the first‐line treatment of SCLC. Methods Relevant trials were identified by searching electronic databases and conference meetings. Seven phase II and III randomized controlled trials and 3766 SCLC patients were included in the meta‐analysis (immune‐based combinations = 2133; chemotherapy = 1633). Outcomes of interest included treatment‐related adverse events (TRAEs) and the rate of discontinuation due to TRAEs. Results Immune‐based combination treatment was associated with a higher risk of grade 3–5 TRAEs (odds ratio [OR], 1.16; 95% confidence interval [CI]: 1.01–1.35). Immune‐based combinations were associated with a higher risk of TRAEs leading to discontinuation (OR, 2.30; 95% CI: 1.17–4.54). No differences were observed in grade 5 TRAEs (OR, 1.56; 95% CI: 0.93–2.63). Conclusion This meta‐analysis indicates that the addition of immunotherapy to chemotherapy in SCLC patients is associated with a higher risk of toxicity and probably of treatment discontinuation. Tools for identifying SCLC patients that would not benefit from immune‐based therapy are urgently needed.

Introduction In stroke patients, accurate infarct volume assessment at 24 hours typically requires manual segmentation of lesions that often are not well defined. We aimed to validate an automated machine learning algorithm (MethinksFIV) specifically trained to automatically segment and measure subacute infarcts on non‐contrast CT (NCCT) scans. Methods We retrospectively studied stroke patients with a large vessel occlusion prospectively admitted to a comprehensive stroke center. The final infarct volume was segmented on the 24h NCCT manually (man‐FIV) and with the automated method (auto‐FIV). Both measurements were correlated with clinical outcomes. Results We included 346 patients. On 24h‐NCCT median auto‐FIV was lower than man‐FIV (8.6 ml [2.3‐40.7] vs. 16.9 ml [1.1‐70.8], p2 at three months (OR: 1.02 95%CI 1.01‐1.13, p=0.002) than manual segmentation (OR=1.01, 95%CI 1.00‐1.01, p=0.01). In a multivariable analysis, only auto‐FIV remained a significant predictor of mRS>2 at three months (aOR: 1.03 95% CI 1.01‐1.05, p=0.004). Conclusion An automated method to measure subacute infarct volumes in stroke patients is accurate and correlates well with further clinical outcomes. The method appears to outperform manual segmentation and may be used to facilitate infarct characterization in large clinical trials.

Abstract Over the past decade, we have conducted geochemical and isotopic monitoring of the fumarolic gases of the Peteroa volcano (Argentina‐Chile). Using the resulting data set, we constructed a conceptual model that describes the evolution of the magmatic‐hydrothermal system and identifies precursory geochemical signals of the last eruption. Our data set includes new chemical and isotopic analyses of fumarolic gas samples collected from 2016 to 2021, as well as previously published data from the 2010–2015 period. After an eruptive period in 2010–2011, the activity was characterized by low degassing rates and seismic activity. However, an increase in seismic activity and fumarolic gas emissions was observed from 2016 to 2018–2019 eruptive episode, leading to a major phreato‐magmatic eruption. Fumarole gases show different compositions during quiescent versus unrest/eruptive degassing related to the interaction of deep (magmatic) and shallow (hydrothermal) fluid contributions. During quiescent periods, fumaroles exhibited low SO2/H2S, HF/CO2, and HCl/CO2 ratios (

Abstract Interactions between atmospheric aerosols, clouds, and precipitation impact Earth's radiative balance and air quality, yet remain poorly constrained. Precipitating clouds serve as major sinks for particulate matter, but recent studies suggest that precipitation may also act as a particle source. The magnitude of the sources versus sinks, particularly for cloud condensation nuclei (CCN) numbers, remain unquantified. This study analyzes multi‐year in situ observations from tropical and boreal forests, as well as Arctic marine environment, showing links between recent precipitation and enhanced particle concentrations, including CCN‐sized particles. In some cases, the magnitude of precipitation‐related source equals or surpasses corresponding removal effect. Our findings highlight the importance of cloud‐processed material in determining near‐surface particle concentrations and the value of long‐term in situ observations for understanding aerosol particle life cycle. Robust patterns emerge from sufficiently long data series, allowing for quantitative assessment of the large‐scale significance of new phenomena observed in case studies.

Abstract INTRODUCTION The risk of developing Alzheimer's disease is associated with genes involved in microglial function. Inositol polyphosphate‐5‐phosphatase (INPP5D), which encodes Src homology 2 (SH2) domain–containing inositol polyphosphate 5‐phosphatase 1 (SHIP1), is a risk gene expressed in microglia. Because SHIP1 binds receptor immunoreceptor tyrosine‐based inhibitory motifs (ITIMs), competes with kinases, and converts PI(3,4,5)P3 to PI(3,4)P2, it is a negative regulator of microglia function. Validated inhibitors are needed to evaluate SHIP1 as a potential therapeutic target. METHODS We identified inhibitors and screened the enzymatic domain of SHIP1. A protein construct containing two domains was used to evaluate enzyme inhibitor potency and selectivity versus SHIP2. Inhibitors were tested against a construct containing all ordered domains of the human and mouse proteins. A cellular thermal shift assay (CETSA) provided evidence of target engagement in cells. Phospho‐AKT levels provided further evidence of on‐target pharmacology. A high‐content imaging assay was used to study the pharmacology of SHIP1 inhibition while monitoring cell health. Physicochemical and absorption, distribution, metabolism, and excretion (ADME) properties were evaluated to select a compound suitable for in vivo studies. RESULTS SHIP1 inhibitors displayed a remarkable array of activities and cellular pharmacology. Inhibitory potency was dependent on the protein construct used to assess enzymatic activity. Some inhibitors failed to engage the target in cells. Inhibitors that were active in the CETSA consistently destabilized the protein and reduced pAKT levels. Many SHIP1 inhibitors were cytotoxic either at high concentration due to cell stress or they potently induced cell death depending on the compound and cell type. One compound activated microglia, inducing phagocytosis at concentrations that did not result in significant cell death. A pharmacokinetic study demonstrated brain exposures in mice upon oral administration. DISCUSSION 3‐((2,4‐Dichlorobenzyl)oxy)‐5‐(1‐(piperidin‐4‐yl)‐1H‐pyrazol‐4‐yl) pyridine activated primary mouse microglia and demonstrated exposures in mouse brain upon oral dosing. Although this compound is our recommended chemical probe for investigating the pharmacology of SHIP1 inhibition at this time, further optimization is required for clinical studies. Highlights Cellular thermal shift assay (CETSA) and signaling (pAKT) assays were developed to provide evidence of src homology 2 (SH2) domain‐contaning inositol phosphatase 1 (SHIP1) target engagement and on‐target activity in cellular assays. A phenotypic high‐content imaging assay with simultaneous measures of phagocytosis, cell number, and nuclear intensity was developed to explore cellular pharmacology and monitor cell health. SHIP1 inhibitors demonstrate a wide range of activity and cellular pharmacology, and many reported inhibitors are cytotoxic. The chemical probe 3‐((2,4‐dichlorobenzyl)oxy)−5‐(1‐(piperidin‐4‐yl)−1H‐pyrazol‐4‐yl) pyridine is recommended to explore SHIP1 pharmacology.

Abstract In active volcanoes, magmatic fluids rising toward the surface may interact with shallow waters, thereby forming hydrothermal systems that record variations in magma dynamics at depth. Here, we report on a data set comprising the chemical and isotopic composition of thermal waters and dissolved gases from Stromboli Island (Aeolian Volcanic Arc, Southern Italy) that spans 14 years (2004–2018) of continuous observations. We show that the shallow thermal aquifer of Stromboli results from variable mixing between meteoric water, seawater and magmatic fluids. Gas‐water‐rock interactions occur, which induce a large spectrum of variation in both water and gas chemistry. These shallow processes do not affect the 3He/4He of helium dissolved in thermal waters, which records a magmatic signature that varies in response to changes in magma supply at depth. We show that in periods of more intense volcanic activity, the helium isotopic composition of thermal waters approaches that of the gas emitted from the magma residing at 7–10 km depth. Investigation of hydrothermal waters at active volcanoes is a promising tool to examine magmatic fluids and their shallow circulation, as well as to evaluate the state of activity of a volcano, particularly when summit areas are inaccessible.

Abstract The field of biomedical design and manufacturing has been rapidly evolving, with implants and grafts featuring complex 3D design constraints and materials distributions. By combining a new coding‐based design and modeling approach with high‐throughput volumetric printing, a new approach is demonstrated to transform the way complex shapes are designed and fabricated for biomedical applications. Here, an algorithmic voxel‐based approach is used that can rapidly generate a large design library of porous structures, auxetic meshes and cylinders, or perfusable constructs. By deploying finite cell modeling within the algorithmic design framework, large arrays of selected auxetic designs can be computationally modeled. Finally, the design schemes are used in conjunction with new approaches for multi‐material volumetric printing based on thiol‐ene photoclick chemistry to rapidly fabricate complex heterogeneous shapes. Collectively, the new design, modeling and fabrication techniques can be used toward a wide spectrum of products such as actuators, biomedical implants and grafts, or tissue and disease models.

Background Our goal is to evaluate whether the administration of thrombolytic treatment has varying effects on clinical and radiological outcomes in patients with large‐vessel occlusion stroke, based on the type of stroke center where the treatment was given (thrombectomy‐capable center versus local stroke center). Methods We included patients with an acute ischemic large‐vessel occlusion stroke who were directly admitted to thrombectomy‐capable centers and treated with endovascular thrombectomy, or were transferred from local stroke centers as thrombectomy candidates, in Catalonia, Spain, between 2017 and 2021. The primary outcome was the shift analysis on the modified Rankin scale score at 90 days. Secondary outcomes included death at 90 days and the rate of parenchymal hemorrhage and successful reperfusion. Inverse‐probability weighting clustered at the type of stroke center was used to estimate the effects. Results The analysis included 2268 patients directly admitted to thrombectomy‐capable centers, of whom 975 (49%) were treated with thrombolysis, and 938 patients transferred from local stroke centers, of whom 580 (66%) were treated with thrombolysis and 616 (67%) were treated with thrombectomy. Mean age was 72 (SD ±13) years, median National Institute of Health Stroke Scale score was 17 (interquartile range, 12–21), and 1363 patients were women (48%). Patients treated with intravenous thrombolysis were younger, had shorter time from onset to first image, higher Alberta Stroke Program Early Computed Tomography Score, and lower rates of wake‐up stroke, atrial fibrillation, and anticoagulation intake. Patients treated with thrombolysis had better functional outcome at 90 days, with no difference between patients directly admitted to thrombectomy‐capable centers (adjusted common odds ratio [acOR], 1.50 [95% CI, 1.24–1.81]) and patients transferred from local stroke centers (acOR, 1.44 [95% CI, 1.04–2.01]). Patients treated with intravenous thrombolysis had lower death rate, higher rate of parenchymal hematoma, and similar rate of successful reperfusion, with no difference according to type of center (Pinteraction>0.1). Conclusion Administration of intravenous thrombolysis in patients with a large‐vessel stroke with intention of thrombectomy was associated with lower degrees of disability, lower death rate, and higher rates of parenchymal hematoma both in thrombectomy‐capable centers and in local stroke centers.

The objective of this study was to assess the clinical impact and financial costs of next-generation sequencing (NGS) in 5 categories of pediatric and adult hematological cancers. NGS prescriptions were prospectively collected from 26 laboratories, with varied technical and reporting practice (all or only significant targets). Impact was defined by the identification of (1) an actionable mutation, (2) a mutation with prognostic and/or theranostic value, and/or (3) a mutation allowing nosological refinement, reported by local investigators. A microcosting study was undertaken in 4 laboratories, identifying the types and volumes of resources required for each procedural step. Individual index prescriptions for 3961 patients were available for impact analysis on the management of myeloid disorders (two thirds) and, mainly mature B, lymphoid disorders (one third). NGS results were considered to impact the management for 73.4% of prescriptions: useful for evaluation of prognostic risk in 34.9% and necessary for treatment adaptation (actionable) in 19.6%, but having no immediate individual therapeutic impact in 18.9%. The average overall cost per sample was 191 € for the restricted mature lymphoid amplicon panel. Capture panel costs varied from 369 € to 513 €. Unit costs varied from 0.5 € to 5.7 € per kb sequenced, from 3.6 € to 11.3 € per target gene/hot-spot sequenced and from 4.3 € to 73.8 € per target gene/hot-spot reported. Comparable costs for the Amplicon panels were 5–8 € per kb and 10.5–14.7 € per target gene/hot-spot sequenced and reported, demonstrating comparable costs with greater informativity/flexibility for capture strategies. Sustainable funding of precision medicine requires a transparent discussion of its impact on care pathways and its financial aspects.

Abstract Objective The aim of this study was to analyze whether physical exercise can contribute to improving the control and severity of exercise‐induced bronchospasm (EIB) in children and adolescents. Method This is a systematic review that used PubMed/Medline and Scopus databases as a search source, and using descriptors indexed to DeCS/Mesh. The articles were analyzed in three stages in the selection process. Methodological quality was assessed using the TESTEX scale. Result and discussion A total of 5867 articles were filtered in the initial search; however, only eight of these were included after the eligibility criteria. All presented improvements in cardiorespiratory fitness. Only two followed the international EIB diagnostic guidelines. Of these, only one described a reduction in FEV1 and considered that this improvement may influence the EIB response in children and adolescent athletes with a non‐asthmatic sample. Conclusion The studies analyzed in this review did not enable drawing a conclusion regarding the influence of physical exercise on EIB in asthmatics. The lack of clinical trials on EIB and physical exercise, as well as the difficulty in methodological standardization for EIB diagnosis evidence the lack of scientific knowledge in this area, serving as a stimulus for researchers to find more consolidated answers.

Abstract Introduction Our limited understanding of the mechanisms that trigger the emergence of Alzheimer's disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that the development of a non‐human primate model of AD will be an essential step toward overcoming limitations of other model systems and is crucial for investigating primate‐specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD. Methods A new consortium has been established with funding support from the National Institute on Aging aimed at the generation, characterization, and validation of Marmosets As Research Models of AD (MARMO‐AD). This consortium will study gene‐edited marmoset models carrying genetic risk for AD and wild‐type genetically diverse aging marmosets from birth throughout their lifespan, using non‐invasive longitudinal assessments. These include characterizing the genetic, molecular, functional, behavioral, cognitive, and pathological features of aging and AD. Results The consortium successfully generated viable founders carrying PSEN1 mutations in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community. Discussion By establishing marmoset models of AD, we will be able to investigate primate‐specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.

Abstract 55 million people worldwide suffer from Alzheimer's disease (AD). A definitive diagnosis of AD is made postmortem after a neuropathological examination of the brain. There is an urgent need for an innovative, noninvasive methodology that allows for an early and reliable diagnosis. Several engineered phages that recognized Aβ‐autoantibodies present in the sera of AD patients are previously identified. Here, novel phages are tested for their ability to accurately discriminate AD sera using immunophage‐polymerase chain reaction in a miniatured biochip. It is found that five of the six phages analyzed discriminate between healthy controls and AD patients. Further, by combining the response of two phages, non‐AD and severe AD cases are identified with 100% accuracy and mild‐to‐moderate cases with 90% accuracy. While the number of cases used here are relatively small and can be confirmed in larger cohorts, this first‐of‐a‐kind system represents an innovative methodology with the potential of having a major impact in the AD field: from a clinical perspective, it can aid physicians in making an accurate AD diagnosis; from a research perspective, it can be used as a surrogate for AD clinical trials.

Abstract Statin intolerance is a clinical syndrome whereby adverse effects (AEs) associated with statin therapy [most commonly statin‐associated muscle symptoms (SAMS)] result in the discontinuation of therapy and consequently increase the risk of adverse cardiovascular outcomes. However, complete statin intolerance occurs in only a small minority of treated patients (estimated prevalence of only 3–5%). Many perceived AEs are misattributed (e.g. physical musculoskeletal injury and inflammatory myopathies), and subjective symptoms occur as a result of the fact that patients expect them to do so when taking medicines (the nocebo/drucebo effect)—what might be truth even for over 50% of all patients with muscle weakness/pain. Clear guidance is necessary to enable the optimal management of plasma in real‐world clinical practice in patients who experience subjective AEs. In this Position Paper of the International Lipid Expert Panel (ILEP), we present a step‐by‐step patient‐centred approach to the identification and management of SAMS with a particular focus on strategies to prevent and manage the nocebo/drucebo effect and to improve long‐term compliance with lipid‐lowering therapy.

Abstract Background The clinical diagnosis of behavioral variant frontotemporal dementia (bvFTD) in patients with a history of primary psychiatric disorder (PPD) is challenging. PPD shows the typical cognitive impairments observed in patients with bvFTD. Therefore, the correct identification of bvFTD onset in patients with a lifetime history of PPD is pivotal for an optimal management. Methods Twenty‐nine patients with PPD were included in this study. After clinical and neuropsychological evaluations, 16 patients with PPD were clinically classified as bvFTD (PPD‐bvFTD+), while in 13 cases clinical symptoms were associated with the typical course of the psychiatric disorder itself (PPD‐bvFTD–). Voxel‐ and surface‐based investigations were used to characterize gray matter changes. Volumetric and cortical thickness measures were used to predict the clinical diagnosis at a single‐subject level using a support vector machine (SVM) classification framework. Finally, we compared classification performances of magnetic resonance imaging (MRI) data with automatic visual rating scale of frontal and temporal atrophy. Results PPD‐bvFTD+ showed a gray matter decrease in thalamus, hippocampus, temporal pole, lingual, occipital, and superior frontal gyri compared to PPD‐bvFTD– (p

Introduction Simultaneous tPA administration during mechanical thrombectomy may induce synergistic benefits (1). We aimed to characterize the hypoperfusion status after thrombectomy according to the timing of tPA administration and the degree of final recanalization. Methods We studied consecutive anterior circulation large vessel occlusion (LVO) stroke patients treated with mechanical thrombectomy who received a CT perfusion (CTP) immediately after endovascular procedure (2). Patients were divided in three groups according to: no iv tPA treatment (non‐tPA), tPA administration before 120 minutes (tPA>120) or iv tPA administration within 120 min (tPA< 120) of groin puncture. The extend of post‐procedure hypoperfusion (volume Tmax>6s) and relative hypoperfusion reduction compared with admission CTP (volume post‐procedure – admission Tmax>6s/admission Tmax>6s) according to final TICI scores were compared between the three study groups. Results One hundred and sixty‐nine patients were included in the study, mean age 72 years and median baseline NIHSS of 15. Thirty (17.8%) patients received iv tPA more than 2h before groin puncture (tPA>120), 32(18.9%) within 2h of the puncture (tPA < 120) and 107(63.3%) were non‐tPA. No difference on stroke severity, pre‐procedure hypoperfusion volume or occlusion location before thrombectomy were detected between groups. The rate of complete recanalization (TICI 3, 38.5%) was also similar in the 3 study groups (p = 0.12). Overall, the post‐procedure hypoperfusion volume was significantly lower in the tPA< 120 group (19.9±4.6cc vs 35.0±5.5, p = 0.04), and the relative hypoperfusion reduction was higher in tPA< 120 (0.86 vs 0.66, p = 0.05) as compared to non‐tPA. No significant differences were detected between non‐tPA and tPA>120 groups. For each final TICI score the post‐procedure hypoperfusion tended to be lower in the tPA< 120‐group, with a stronger reduction in patients with lower degree of recanalization (Figure). Conclusions A reduction of post‐thrombectomy hypoperfusion volumes was detected in patients treated with iv tPA during or shortly before thrombectomy, which could be a surrogate marker of the beneficial effect of tPA on the microcirculation. The specific reperfusion synergistic effect of tPA and mechanical thrombectomy beyond LVO recanalization warrants future studies.

Abstract In recent years, the development of novel photocrosslinking strategies and photoactivatable materials has stimulated widespread use of light‐mediated biofabrication techniques. However, despite great progress toward more efficient and biocompatible photochemical strategies, current photoresins still rely on photoinitiators (PIs) producing radical‐initiating species to trigger the so‐called free‐radical crosslinking/polymerization. In the context of bioprinting, where cells are encapsulated in the bioink, the presence of radicals raises concerns of potential cytotoxicity. In this work, a universal, radical‐free (RF) photocrosslinking strategy to be used for light‐based technologies is presented. Leveraging RF uncaging mechanisms and Michael addition, cell‐laden constructs are photocrosslinked by means of one‐ and two‐photon excitation with high biocompatibility. A hydrophilic coumarin‐based group is used to cage a universal RF photocrosslinker based on 4‐arm‐PEG‐thiol (PEG4SH). Upon light exposure, thiols are uncaged and react with an alkene counterpart to form a hydrogel. RF photocrosslinker is shown to be highly stable, enabling potential for off‐the‐shelf products. While PI‐based systems cause a strong upregulation of reactive oxygen species (ROS)‐associated genes, ROS are not detected in RF photoresins. Finally, optimized RF photoresin is successfully exploited for high resolution two‐photon stereolithography (2P‐SL) using remarkably low polymer concentration (

Abstract Flood hazard assessment is a fundamental step in flood risk mapping. Quantitative assessment requires hydrodynamic modelling of the flooding process in order to calculate the spatial distribution of suitable flood hazard indicators representative of flooding intensity and frequency, hence its potential to result in harm. Flood hazard indicators are usually defined by combining relevant flooding parameters, mainly flood depth and flow velocity, but also flooding arrival time, flooding duration, sediment or contamination load, and so forth. A flood hazard classification is commonly introduced to assign a hazard level to areas potentially subject to flooding. This article presents a systematic review of quantitative methods proposed in the scientific literature or prescribed by government authorities to assess the hazard associated with natural or anthropic flooding. Flood hazard classification methods are listed and compared by specifying their underlying approach (heuristic, conceptual, empirical), the exposed element which they were designed for (people, buildings, vehicles, etc.), and their fields of application (river overflow, dam‐break, levee breach, debris flow). Perspectives and future challenges in quantitative flood hazard analysis are also discussed. This review aims to help modellers and practitioners to select the most suitable flood hazard assessment method for the case study of interest.

Abstract Background During cancer cachexia, several alterations occur in peripheral tissues, and the adipose tissue may be involved during the catabolic state. We aimed at investigating histological rearrangement and infiltration of inflammatory cells in subcutaneous adipose tissue (SAT) of patients with cancer undergoing surgery, according to the presence/absence of cachexia. Methods We considered gastrointestinal cancer patients and controls with non‐malignant diseases undergoing surgery. We collected SAT samples and performed histomorphological analyses [cross‐sectional area (CSA) and per cent of fibrosis] and immunohistochemistry to characterize the inflammatory cells. By computed tomography (CT) scan, we calculated SAT and visceral adipose tissue (VAT). Results We enrolled 51 participants (31 gastrointestinal cancer patients and 20 controls). In cancer patients, cachexia was present in 13/31 (42%). The CSA (μm2) of the adipocytes from SAT was reduced in cancer patients vs. controls (3148, inter‐quartile range 2574–3755 vs. 4474, inter‐quartile range 3654–5183) (P

Abstract This work presents an end‐to‐end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14C‐labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100‐µg i.v. dose of cold‐labeled 13C‐venetoclax at the oral time of maximum concentration (Tmax). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography‐tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development.

Abstract Objectives The very rapidly approved mRNA‐based vaccines against SARS‐CoV‐2 spike glycoprotein, including Pfizer‐BioNTech BNT162b2, are effective in protecting from severe coronavirus disease 2019 (COVID‐19) in immunocompetent population. However, establishing the duration and identifying correlates of vaccine‐induced protection will be crucial to optimise future immunisation strategies. Here, we studied in healthy vaccine recipients and people with multiple sclerosis (pwMS), undergoing different therapies, the regulation of innate immune response by mRNA vaccination in order to correlate it with the magnitude of vaccine‐induced protective humoral responses. Methods Healthy subjects (n = 20) and matched pwMS (n = 22) were longitudinally sampled before and after mRNA vaccination. Peripheral blood mononuclear cell (PBMC)‐associated type I and II interferon (IFN)‐inducible gene expression, serum innate cytokine/chemokine profile as well as binding and neutralising anti‐SARS‐COV‐2 antibodies (Abs) were measured. Results We identified an early immune module composed of the IFN‐inducible genes Mx1, OAS1 and IRF1, the serum cytokines IL‐15, IL‐6, TNF‐α and IFN‐γ and the chemokines IP‐10, MCP‐1 and MIG, induced 1 day post second and third BNT162b2 vaccine doses, strongly correlating with magnitude of humoral response to vaccination in healthy and MS vaccinees. Moreover, induction of the early immune module was dramatically affected in pwMS treated with fingolimod and ocrelizumab, both groups unable to induce a protective humoral response to COVID‐19 vaccine. Conclusion Overall, this study suggests that the vaccine‐induced early regulation of innate immunity is mediated by IFN signalling, impacts on the magnitude of adaptive responses and it might be indicative of vaccine‐induced humoral protection.

Abstract Zhu‐Tokita‐Tachenouchi‐Kim syndrome (ZTTK) is a recently recognized malformation syndrome presenting with craniofacial dysmorphism, developmental delay/intellectual disability, seizures, anomalies involving brain white matter, and other body‐organs. In humans, the disorder is linked to the loss‐of‐function variants in the SON gene (MIM# 617140). Herewith, a new case of this syndrome is reported in a 2‐year‐old Caucasian child who presented the classical clinical features of the ZTTK syndrome in association with hydrocephalus and Chiari malformations type 1 an anomaly previously unreported. Exome analysis showed a de novo heterozygous variant in SON gene. Literature review of similar cases is reported.

Background Investigations into alternative treatments for hypertension are necessary because current treatments cannot fully reduce the risk for the development of cardiovascular diseases. Chronic activation of unfolded protein response attributable to the endoplasmic reticulum stress has been proposed as a potential therapeutic target for hypertension and associated vascular remodeling. Triggered by the accumulation of misfolded proteins, chronic unfolded protein response leads to downstream signaling of cellular inflammation and dysfunction. Here, we have tested our hypothesis that a novel chemical chaperone, 3‐hydroxy‐2‐naphthoic acid (3HNA) can attenuate angiotensin II (AngII)‐induced vascular remodeling and hypertension. Methods and Results Mice were infused with AngII for 2 weeks to induce vascular remodeling and hypertension with or without 3HNA treatment. We found that injections of 3HNA prevented hypertension and increase in heart weight body weight ratio induced by AngII infusion. Histological assessment revealed that 3HNA treatment prevented vascular medial thickening as well as perivascular fibrosis in response to AngII infusion. In cultured vascular smooth muscle cells, 3HNA attenuated enhancement in protein synthesis induced by AngII. In vascular adventitial fibroblasts, 3HNA prevented induction of unfolded protein response markers. Conclusions We present evidence that a chemical chaperone 3HNA prevents vascular remodeling and hypertension in mice with AngII infusion, and 3HNA further prevents increase in protein synthesis in AngII‐stimulated vascular smooth muscle cells. Using 3HNA may represent a novel therapy for hypertension with multiple benefits by preserving protein homeostasis under cardiovascular stress.