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Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

Hydrophilic polymer embolism (HPE) is a rare iatrogenic complication of the use of polymer-coated intravascular devices, which may affect several organ systems including the skin. Herein, we present a patient who developed a cutaneous eruption with associated neurologic manifestations secondary to localized HPE. This is a potentially underdiagnosed, life-threatening complication and physicians should consider HPE when evaluating skin eruptions in patients who have undergone endovascular procedures.

Merkel cell carcinoma (MCC) is a rare neuroendocrine neoplasm, warranting surgical excision with sentinel lymph node biopsy. In later stages, adjuvant chemotherapy and radiation are required owing to its aggressive malignant behavior. We describe a 62-year-old woman who presented with multifocal recurrence of MCC and was not a candidate for immunotherapy or surgery. The patient underwent four treatments of intratumoral talimogene laherparepvec (TVEC) and demonstrated a complete response with no histologic evidence of remaining MCC on four scouting biopsies. Although TVEC therapy is currently approved for the treatment of advanced stage melanoma, it is still being investigated in MCC. This case supports the use of TVEC as monotherapy in select patients with locally advanced MCC who are not candidates for surgery or systemic immunotherapy.

Background: The international surveillance of antimicrobial resistance (AMR) reports S. pneumoniae as one of leading causes of death associated with AMR. Against invasive disease, several vaccinations are available and a reduction in AMR in S. pneumoniae has been observed. Here, we evaluated the impact of anti-pneumococcal vaccination policy and the SARS-CoV2 outbreak on AMR in S. pneumoniae causing invasive disease. Methods: We collected all strains of S. pneumoniae causing invasive disease from 2008 in the Piedmont region (Italy). Each strain was typed in order to identify the serogroup and data about AMR were collected. The population under surveillance was classified as infants, children, adults, and the old population. Results: We collected n = 2076 S. pneumoniae strains, with 21.9% and 40.3% being resistant to penicillin G and erythromycin, respectively. We reported an increased risk of infection with penicillin-resistant S. pneumoniae among all populations and evaluated whether the infection was caused by a serotype included in the vaccine formulation. A similar increase was observed after the SARS-CoV2 outbreak. Conclusions: In the Piedmont region, subsequently to the introduction of anti-pneumococcal vaccination, a significant increase in the risk of penicillin G-resistant invasive pneumococcal disease among infants and old population was reported. No significant impact was found for the SARS-CoV2 outbreak.

Asthma is a chronic inflammatory lung disease. Refractory asthma poses a significant challenge in management due to its resistance to standard therapies. Key molecular pathways of refractory asthma include T2 inflammation mediated by Th2 and ILC2 cells, eosinophils, and cytokines including IL-4, IL-5, and IL-13. Additionally, non-T2 mechanisms involving neutrophils, macrophages, IL-1, IL-6, and IL-17 mediate a corticosteroid resistant phenotype. Mediators including alarmins (IL-25, IL-33, TSLP) and OX40L have overlap between T2 and non-T2 inflammation and may signify unique pathways of asthma inflammation. Therapies that target these pathways and mediators have proven to be effective in reducing exacerbations and improving lung function in subsets of severe asthma patients. However, there are patients with severe asthma who do not respond to approved therapies. Small molecule inhibitors, such as JAK-inhibitors, and monoclonal antibodies targeting mast cells, IL-1, IL-6, IL-33, TNFα, and OX40L are under investigation for their potential to modulate inflammation involved in refractory asthma. Understanding refractory asthma heterogeneity and identifying mediators involved are essential in developing therapeutic interventions for patients unresponsive to currently approved biologics. Further investigation is needed to develop personalized treatments based on these molecular insights to potentially offer more effective treatments for this complex disease.

Neuropathic pain, a chronic condition resulting from nerve injury or dysfunction, presents significant therapeutic challenges and is closely associated with oxidative stress and inflammation, both of which can lead to mitochondrial dysfunction. The nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a critical cellular defense mechanism against oxidative stress, has emerged as a promising target for neuropathic pain management. Nrf2 modulators enhance the expression of antioxidant and cytoprotective genes, thereby reducing oxidative damage, inflammation, and mitochondrial impairment. This review explores the antinociceptive effects of Nrf2, highlighting how pharmacological agents and natural compounds may be used as potential therapeutic strategies against neuropathic pain. Although preclinical studies demonstrate significant pain reduction and improved nerve function through Nrf2 activation, several clinical challenges need to be addressed. However, emerging clinical evidence suggests potential benefits of Nrf2 modulators in several conditions, such as diabetic neuropathy and multiple sclerosis. Future research should focus on further elucidating the molecular role of Nrf2 in neuropathic pain to optimize its modulation efficacy and maximize clinical utility.

Critical raw materials (CRMs) supply is a challenge that EU countries have to face, with many thinking about domestic procurement from natural ore deposits and anthropogenic deposits (landfills and extractive waste facilities). The present research focuses on the possibilities linked to the supply of CRMs and the potential for exploiting rare earth elements (REEs), investigating a large variety of extractive waste and siliceous rocks in the Piedmont region (Northern Italy). Indeed, the recovery of REEs from the extractive waste (EW) of siliceous quarries and other siliceous ore deposits can be a valuable way to reduce supply chain risks. Starting with a review of the literature on mining activities in Piedmont and continuing with the sampling and geochemical, mineralogical, petrographic, and environmental characterization of EW facilities connected to siliceous dimension stones, of kaolinitic gneiss ore deposits, and of soils present near the investigated areas, this study shows that the degree of REEs enrichment differs depending on the sampling area (soil or EW) and lithology. The concentration of REEs in the EW at some sampling sites fulfils the indicators of industrial-grade and industrial recovery; the high cumulative production and potential market values of EW and the positive recovery effects through proven methodologies indicate a viable prospect of REE recovery from EW. However, REE recovery industrialization faces challenges such as the difficulty in achieving efficient large-scale recovery due to large regional differences in REE abundance, the mismatch between potential market value and waste annual production, etc. Nonetheless, in the future, EW from dimension stone quarries could be differentially studied and reused based on the enrichment and distribution characteristics of trace elements. The present paper shows investigation procedures undertaken to determine both CRMs potentialities and environmental issues (on the basis of literature data employed to select the more-promising areas and on sampling and characterization activities in the selected areas), together with procedures to determine the waste quantities and tentative economic values of REEs present in the investigated areas. This approach, tested on a large area (Piedmont region), is replicable and applicable to other similar case studies (at EU and non-EU levels) and offers decision makers the possibility to acquire a general overview of the potential available resources in order to decide whether and where to concentrate efforts (including economic ones) in a more detailed study to evaluate the exploitable anthropogenic deposits.

Late-life depression (LLD) is a relatively common and debilitating mental disorder, also associated with cognitive dysfunctions and an increased risk of mortality. Considering the growing elderly population worldwide, LLD is increasingly emerging as a significant public health issue, also due to the rise in direct and indirect costs borne by healthcare systems. Understanding the neuroanatomical and neurofunctional correlates of LLD is crucial for developing more targeted and effective interventions, both from a preventive and therapeutic standpoint. This ALE meta-analysis aims to evaluate the involvement of specific neurofunctional changes in the neurophysiopathology of LLD by analysing functional neuroimaging studies conducted on patients with LLD compared to healthy subjects (HCs). We included 19 studies conducted on 844 subjects, divided into 439 patients with LLD and 405 HCs. Patients with LLD, compared to HCs, showed significant hypoactivation of the right superior and medial frontal gyri (Brodmann areas (Bas) 8, 9), left cingulate cortex (BA 24), left putamen, and left caudate body. The same patients exhibited significant hyperactivation of the left superior temporal gyrus (BA 42), left inferior frontal gyrus (BA 45), right anterior cingulate cortex (BA 24), right cerebellar culmen, and left cerebellar declive. In summary, we found significant changes in activation patterns and brain functioning in areas encompassed in the cortico–limbic–striatal network in LLD. Furthermore, our results suggest a potential role for areas within the cortico–striatal–cerebellar network in the neurophysiopathology of LLD.

Epinephrine autoinjectors (EAIs) are used for the treatment of severe allergic reactions in a community setting; however, their utility is limited by low prescription fulfillment rates, failure to carry, and failure to use due to fear of needles. Given that delayed administration of epinephrine is associated with increased morbidity/mortality, there has been a growing interest in developing needle-free, easy-to-use delivery devices. neffy (epinephrine nasal spray) consists of three Food and Drug Administration (FDA)-approved components: epinephrine, Intravail A3 (absorption enhancer), and a Unit Dose Spray (UDS). neffy’s development pathway was established in conjunction with the FDA and the European Medicines Agency and included multiple clinical trials to evaluate pharmacokinetic and pharmacodynamic responses under a variety of conditions, such as self-administration and allergic and infectious rhinitis, as well as an animal anaphylaxis model of severe hypotension, where neffy demonstrated a pharmacokinetic profile that is within the range of approved injection products and a pharmacodynamic response that is as good or better than injections. The increased pulse rate (PR) and blood pressure (BP) observed even one minute following the administration of neffy confirm the activation of α and β adrenergic receptors, which are the key components of epinephrine’s mechanism of action. The results suggest that neffy will provide a safe and effective needle-free option for the treatment of severe allergic reactions, including anaphylaxis.

Potent synthetic drugs, as well as biomolecules extracted from plants, have been investigated for their selectivity toward cancer cells. The main limitation in cancer treatment is the ability to bring such molecules within each single cancer cell, which requires accumulation in the peritumoral region followed by homogeneous spreading within the entire tissue. In the last decades, nanotechnology has emerged as a powerful tool due to its ability to protect the drug during blood circulation and allow enhanced accumulation around the leaky regions of the tumor vasculature. However, the ideal size for accumulation of around 100 nm is too large for effective penetration into the dense collagen matrix. Therefore, we propose a multistage system based on graphene oxide nanosheet-based quantum dots (GOQDs) with dimensions that are 12 nm, functionalized with hyaluronic acid (GOQDs-HA), and deposited using the layer-by-layer technique onto an oil-in-water nanoemulsion (O/W NE) template that is around 100 nm in size, previously stabilized by a biodegradable polymer, chitosan. The choice of a biodegradable core for the nanocarrier is to degrade once inside the tumor, thus promoting the release of smaller compounds, GOQDs-HA, carrying the adsorbed anticancer compound, which in this work is represented by curcumin as a model bioactive anticancer molecule. Additionally, modification with HA aims to promote active targeting of stromal and cancer cells. Cell uptake experiments and preliminary penetration experiments in three-dimensional microtissues were performed to assess the proposed multistage nanocarrier.

Neurodegenerative diseases are challenging for systems biology because of the lack of reliable animal models or patient samples at early disease stages. Induced pluripotent stem cells (iPSCs) could address these challenges. We investigated DNA, RNA, epigenetics, and proteins in iPSC-derived motor neurons from patients with ALS carrying hexanucleotide expansions in C9ORF72. Using integrative computational methods combining all omics datasets, we identified novel and known dysregulated pathways. We used a C9ORF72 Drosophila model to distinguish pathways contributing to disease phenotypes from compensatory ones and confirmed alterations in some pathways in postmortem spinal cord tissue of patients with ALS. A different differentiation protocol was used to derive a separate set of C9ORF72 and control motor neurons. Many individual -omics differed by protocol, but some core dysregulated pathways were consistent. This strategy of analyzing patient-specific neurons provides disease-related outcomes with small numbers of heterogeneous lines and reduces variation from single-omics to elucidate network-based signatures.

BackgroundIt is unclear whether the suggested link between COVID-19 during pregnancy and preeclampsia is an independent association or if these are caused by common risk factors.ObjectiveThis study aimed to quantify any independent association between COVID-19 during pregnancy and preeclampsia and to determine the effect of these variables on maternal and neonatal morbidity and mortality.Study designThis was a large, longitudinal, prospective, unmatched diagnosed and not-diagnosed observational study assessing the effect of COVID-19 during pregnancy on mothers and neonates. Two consecutive not-diagnosed women were concomitantly enrolled immediately after each diagnosed woman was identified, at any stage during pregnancy or delivery, and at the same level of care to minimize bias. Women and neonates were followed until hospital discharge using the standardized INTERGROWTH-21st protocols and electronic data management system. A total of 43 institutions in 18 countries contributed to the study sample. The independent association between the 2 entities was quantified with the risk factors known to be associated with preeclampsia analyzed in each group. The outcomes were compared among women with COVID-19 alone, preeclampsia alone, both conditions, and those without either of the 2 conditions.ResultsWe enrolled 2184 pregnant women; of these, 725 (33.2%) were enrolled in the COVID-19 diagnosed and 1459 (66.8%) in the COVID-19 not-diagnosed groups. Of these women, 123 had preeclampsia of which 59 of 725 (8.1%) were in the COVID-19 diagnosed group and 64 of 1459 (4.4%) were in the not-diagnosed group (risk ratio, 1.86; 95% confidence interval, 1.32-2.61). After adjustment for sociodemographic factors and conditions associated with both COVID-19 and preeclampsia, the risk ratio for preeclampsia remained significant among all women (risk ratio, 1.77; 95% confidence interval, 1.25-2.52) and nulliparous women specifically (risk ratio, 1.89; 95% confidence interval, 1.17-3.05). There was a trend but no statistical significance among parous women (risk ratio, 1.64; 95% confidence interval, 0.99-2.73). The risk ratio for preterm birth for all women diagnosed with COVID-19 and preeclampsia was 4.05 (95% confidence interval, 2.99-5.49) and 6.26 (95% confidence interval, 4.35-9.00) for nulliparous women. Compared with women with neither condition diagnosed, the composite adverse perinatal outcome showed a stepwise increase in the risk ratio for COVID-19 without preeclampsia, preeclampsia without COVID-19, and COVID-19 with preeclampsia (risk ratio, 2.16; 95% confidence interval, 1.63-2.86; risk ratio, 2.53; 95% confidence interval, 1.44-4.45; and risk ratio, 2.84; 95% confidence interval, 1.67-4.82, respectively). Similar findings were found for the composite adverse maternal outcome with risk ratios of 1.76 (95% confidence interval, 1.32-2.35), 2.07 (95% confidence interval, 1.20-3.57), and 2.77 (95% confidence interval, 1.66-4.63). The association between COVID-19 and gestational hypertension and the direction of the effects on preterm birth and adverse perinatal and maternal outcomes, were similar to preeclampsia, but confined to nulliparous women with lower risk ratios.ConclusionCOVID-19 during pregnancy is strongly associated with preeclampsia, especially among nulliparous women. This association is independent of any risk factors and preexisting conditions. COVID-19 severity does not seem to be a factor in this association. Both conditions are associated independently of and in an additive fashion with preterm birth, severe perinatal morbidity and mortality, and adverse maternal outcomes. Women with preeclampsia should be considered a particularly vulnerable group with regard to the risks posed by COVID-19.

Reflective practice serves as a powerful pedagogical strategy for teachers--especially those in low-resource, rural areas. This qualitative case study looked at secondary education pre-service teachers in their first education course. Analysis of focus observation essays data indicated that pre-service teachers were incorporating reflective practice in their field observations, but were not addressing issues of diversity -- specifically race and socio-economic status. This study is significant for understanding how pre-service teachers engage in reflective practices with respect to diversity.

The increasing diffusion of genetic analysis regarding the pathogenetic variants (PVs) of genes involved in DNA Damage Repair (DDR) mechanisms and the development of Poly ADP ribose polymerase (PARP) inhibitors (PARPis) led to the first valid precision medicine option tailored toward metastatic prostate cancer (mPC). The concept of anticipation in the systemic treatment of mPC was initially adopted for androgen receptor signaling inhibitors (ARSIs) to describe the expansion of their indications, from the setting of the late-stage second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) to first-line therapy in selected cases. There is already mounting evidence in favor of the anticipation of PARPis in the first line of mCRPC therapy, and further evidence in favor of mHSPC is emerging. Many studies have demonstrated the synergism between ARSIs and PARP inhibitors. Recent discoveries regarding the crosstalk between the androgen receptor (AR) and DNA repair mechanisms are disconnecting the use of PARPis from genetic analysis. The new message emerging is that the combination of PARPis with ARSIs may work independently of DDR mutational status. As a matter of fact, most of the recent trials analyzing the combination of PARPis with abiraterone or enzalutamide as a first-line therapy enrolled mCRPC patients irrespective of their mutational status. The PROPEL trial concluded that the advantage of the combination was independent of PV status, despite a higher advantage being reported in the BRCA1/2 mutated subgroup. The MAGNITUDE trial, however, showed a significant advantage only in the DDR mutated subgroup, and the DDR non-mutated cohort was closed for further enrollment. The combination of PARPis with ARSIs represents a significant strategy with a view to the anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR genes.

Abstract Background Surgical treatment for nasal obstruction caused by nasal valve collapse requires a significant recovery period and risks of complications, while nasal dilators are uncomfortable. Recently, radiofrequency treatment of lateral walls has been used under local anesthesia as an office base surgery. This work aims to assess the efficacy of a new radiofrequency device, the Vivaer™ System (Aerin Medical, Sunnyvale, CA), to treat nasal obstruction through a systematic review and meta-analysis. Methods Two researchers independently reviewed the literature up to December 2021. Studies on patients seeking treatment for nasal obstruction due to nasal valve collapse were included in the analysis. Results Four studies (218 patients) met the inclusion criteria and treated the nasal valve regions bilaterally with the Aerin Medical Vivaer™ System. After the treatment, the NOSE score was reduced at three months postoperatively. Minor adverse events were reported in the included studies, and two showed no complications. None of the studies reported changes in the external appearance of the nose. Conclusion The radiofrequency treatment using the Vivaer device can be useful for treating nasal valve collapse, improving significantly subjective breathing symptom scores. Further studies on a large scale are needed to confirm these results.

This piece outlines the conceptualisation, planning, delivery and staff reflections on the culmination of the pilot year of the ‘Literature across Borders’ project, a collaborative endeavour between Ashoka University (India) and Bath Spa University (UK), facilitated by the Green Literature Festival (India). This piece accompanies a partner article (see this issue) exploring the reflections of eight of the pilot year student participants.

Background: House dust mite (HDM)-induced allergic rhinitis (AR) is a major cause of allergic respiratory disease. The efficacy and safety of the 300 IR HDM sublingual immunotherapy (SLIT) tablet in patients with moderate-to-severe HDM-AR was confirmed in a large, international, phase 3 randomized controlled trials (RCTs). Here, we analyzed the results in the European population. Methods: Data from 91 European centers that participated in the international, double-blind, RCT (EudraCT 2014-004223-46, NCT02443805) with the 300 IR HDM SLIT tablet versus placebo over 12 months were analyzed post hoc. The treatment effect in European adults and adolescents was notably assessed through the European Academy of Allergy and Clinical Immunology (EAACI)-recommended combined symptom and medication score (CSMS0-6, pre-defined endpoint) and the total combined rhinitis score (TCRS0-24, post hoc endpoint, also balanced) during the primary evaluation period (4 weeks at the end of treatment period) using analysis of covariance (ANCOVA). Results: There were 818 patients who comprised the modified full analysis set in Europe. Over the primary period, the differences in CSMS0-6 and TCRS0-24 between the 300 IR and placebo groups were statistically significant (p

Soil is a very fragile ecosystem, often subject to many threats. Wildfires can affect edaphic communities depending on the intensity and seasonality of the fire. Different groups of soil fauna tend to respond differently to this type of disturbance, but the lack of data prevents to fully analyze the impact of fire. Soil microarthropods show a particular sensitivity to disturbances of different nature, making them excellent biological indicators. That is why in recent years many biotic indices to assess soil quality, like QBS-ar (Soil Biological Quality based on arthropods), have been developed. The objective of this study was to evaluate whether there might be a significant difference between areas affected or not by fire in the locality of Andonno (Piedmont, Italy) in terms of QBS-ar values, 18 years after this disturbance, and whether the reforestation intervention is having a positive effect on soil quality. Two sampling sites were selected within the sampling area and in each, six soil samples were taken. Microarthropods were extracted with a Berlese-Tüllgren extractor and soil biological quality was calculated using the QBS-ar index. No significant difference in QBS-ar values were found between the fire burned and unburned areas (p=0.37). The number of biological and euedaphic forms in the two sites was similar. It appears that microarthropod communities manage to recover in a short time, indicating that in the study area soil fauna has shown a fast recovery after extreme events like wildfires.