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Abstract While the COVID-19 outbreak and its complications are still under investigation, post-inflammatory pulmonary fibrosis (PF) has already been described as a long-term sequela of acute respiratory distress syndrome (ARDS) secondary to SARS-CoV2 infection. However, therapeutical strategies for patients with ARDS and PF are still limited and do not significantly extend lifespan. So far, lung transplantation remains the only definitive treatment for end-stage PF. Over the last years, numerous preclinical and clinical studies have shown that allogeneic mesenchymal stromal cells (MSCs) might represent a promising therapeutical approach in several lung disorders, and their potential for ARDS treatment and PF prevention has been investigated during the COVID-19 pandemic. From April 2020 to April 2022, we treated six adult patients with moderate COVID-19-related ARDS in a late proliferative stage with up to two same-dose infusions of third-party allogeneic bone marrow-derived MSCs (BM-MSCs), administered intravenously 15 days apart. No major adverse events were registered. Four patients completed the treatment and reached ICU discharge, while two received only one dose of MSCs due to multiorgan dysfunction syndrome (MODS) and subsequent death. All four survivors showed improved gas exchanges (PaO2/FiO2 ratio > 200), contrary to the others. Furthermore, LDH trends after MSCs significantly differed between survivors and the deceased. Although further investigations and shared protocols are still needed, the safety of MSC therapy has been recurrently shown, and its potential in treating ARDS and preventing PF might represent a new therapeutic strategy.

Acute upper and lower gastrointestinal (GI) bleeding may be a potentially life-threatening event that requires prompt recognition and an early effective management, being responsible for a considerable number of hospital admissions. Methods. We perform a clinical review to summarize the recent international guidelines, helping the physician in clinical practice. Older people are a vulnerable subgroup of patients more prone to developing GI bleeding because of several comorbidities and polypharmacy, especially related to an increased use of antiplatelet and anticoagulant drugs. In addition, older patients may have higher peri-procedural risk that should be evaluated. The recent introduction of reversal strategies may help the management of GI bleeding in this subgroup of patients. In this review, we aimed to (1) summarize the epidemiology and risk factors for upper and lower GI bleeding, (2) describe treatment options with a focus on pharmacodynamics and pharmacokinetics of different proton pump inhibitors, and (3) provide an overview of the clinical management with flowcharts for risk stratification and treatment. In conclusion, GI is common in older patients and an early effective management may be helpful in the reduction of several complications.

This Preliminary Investigation document, on one hand, outlines challenges encountered by SB/DBEs in the process of getting certified, entering into a contract, executing on projects or delivering services, and sustaining or growing their business. On the other hand, it summarizes OCR’s current ongoing efforts that are aiming to expand contracting with SB/DBEs. Along the way it identifies opportunities that warrant more in-depth investigation for OCR to target its programming and resource allocation as it aims to reduce obstacles or otherwise improve the ability of SBs/DBEs to successfully contract with Caltrans.

Abstract Introduction Unintentional dural puncture (UDP) occurs in 0.5–1.5% of labour epidural analgesia cases. To date, little is known about evidence of UDP-related complications. This work aimed to assess the incidence of intrapartum and postpartum complications in parturients who experienced UDP. Methods This is a 10-year retrospective observational study on parturients admitted to our centre who presented UDP. Data collection gathered UDP-related complications during labour and postpartum. All women who displayed UDP received medical therapy and bed rest. An epidural blood patch (EBP) was not used in this population. Once asymptomatic, patients were discharged from the hospital. Results Out of 7718 neuraxial analgesia cases, 97 cases of UDP occurred (1.25%). During labour, complications appeared in a small percentage of analgesia procedures performed, including total spinal anaesthesia (1.0%), extended motor block (3%), hypotension (4.1%), abnormal foetal heart rate (2%), inadequate analgesia (14.4%), and general anaesthesia following neuraxial anaesthesia failure (33.3% of emergency caesarean sections). During the postpartum period, 53.6% of parturients exhibited a postdural puncture headache, 13.4% showed neurological symptoms, and 14.4% required neurological consultation and neuroimaging. No patient developed subdural hematoma or cerebral venous sinus thrombosis; one woman presented posterior reversible encephalopathy syndrome associated with eclampsia. Overall, 82.5% of women experienced an extension of hospital stay. Conclusion Major complications occurred in a small percentage of patients during labour. However, since they represent high-risk maternal and neonatal health events, a dedicated anaesthesiologist and a trained obstetric team are essential. No major neurological complications were registered postpartum, and EBP was not performed. Nevertheless, all patients with UDP were carefully monitored and treated until complete recovery before discharge, leading to an extension of their hospitalization.

Abstract Our bodies are inhabited by trillions of microorganisms. The host immune system constantly interacts with the microbiota in barrier organs, including the intestines. Over decades, numerous studies have shown that our mucosal immune system is dynamically shaped by a variety of microbiota-derived signals. Elucidating the mediators of these interactions is an important step for understanding how the microbiota is linked to mucosal immune homeostasis and gut-associated diseases. Interestingly, the efficacy of cancer immunotherapies that manipulate costimulatory and coinhibitory pathways has been correlated with the gut microbiota. Moreover, adverse effects of these therapies in the gut are linked to dysregulation of the intestinal immune system. These findings suggest that costimulatory pathways in the immune system might serve as a bridge between the host immune system and the gut microbiota. Here, we review mechanisms by which commensal microorganisms signal immune cells and their potential impact on costimulation. We highlight how costimulatory pathways modulate the mucosal immune system through not only classical antigen-presenting cells but also innate lymphocytes, which are highly enriched in barrier organs. Finally, we discuss the adverse effects of immune checkpoint inhibitors in the gut and the possible relationship with the gut microbiota.

Vaccination against SARS-CoV-2 has been demonstrated to be safe during gestation. Nevertheless, there are no robust data investigating the entity of maternal antibodies’ transmission through the placenta to the newborn and the persistence of the antibodies in babies’ serum. The objective of this study is to assess the maternal antibody transmission and kinetics among newborns in the first months of life. Women having received one or two doses of anti-SARS-CoV-2 mRNA-vaccines during pregnancy at any gestational age, and their newborns, were recruited and followed-up over 9 months. Ninety-eight women and 103 babies were included. At birth, we observed a significant positive correlation between maternal and neonatal serum anti-SARS-CoV-2 antibody levels and a significant negative correlation between the time since last dose and antibody levels in mothers with two doses. Over the follow-up, the birth antibody level significantly decreased in time according to the received doses number at 3, 6, and 9 months. During the follow-up, we registered 34 dyad SARS-CoV-2 infection cases. The decreasing trend was slower in the SARS-CoV-2 infection group and among breastfed non-infected babies. Antibodies from maternal anti-SARS-CoV-2 vaccination are efficiently transferred via the placenta and potentially even through breast milk. Among newborns, antibodies show relevant durability in the first months of life.

Oral colon delivery systems based on a dual targeting strategy, harnessing time- and microbiota-dependent release mechanisms, were designed in the form of a drug-containing core, a swellable/biodegradable polysaccharide inner layer and a gastroresistant outer film. High-methoxyl pectin was employed as the functional coating polymer and was applied by spray-coating or powder-layering. Stratification of pectin powder required the use of low-viscosity hydroxypropyl methylcellulose in water solution as the binder. These coatings exhibited rough surfaces and higher thicknesses than the spray-coated ones. Using a finer powder fraction improved the process outcome, coating quality and inherent barrier properties in aqueous fluids. Pulsatile release profiles and reproducible lag phases of the pursued duration were obtained from systems manufactured by both techniques. This performance was confirmed by double-coated systems, provided with a Kollicoat® MAE outer film that yielded resistance in the acidic stage of the test. Moreover, HM pectin-based coatings manufactured by powder-layering, tested in the presence of bacteria from a Crohn’s disease patient, showed earlier release, supporting the role of microbial degradation as a triggering mechanism at the target site. The overall results highlighted viable coating options and in vitro release characteristics, sparking new interest in naturally occurring pectin as a coating agent for oral colon delivery.

AbstractThe use of the term “irrational”, when interpreting ancient and contemporary medical systems, is generally based on a bipolar, perhaps two-party, ideological systematization. This is a perspective behind which there is a reifying ideology that defines medical knowledge based on divination and symbolic practices as “irrational”. Moreover, they are seen as systematized “beliefs”. However, this approach neglects the extent to which rituals permeate all practices, including those of contemporary biomedicine. Even in the case of ancient medicine, concepts of the natural and the spiritual are not, therefore, connoted as a clear watershed between the rational and the irrational in the reductive sense described above. On the contrary, they are conjugated in a manner that coexists within the same medical system. Starting from this interpretative foundation, it is possible to trace practices of rational medicine in the temples of Asclepius, in accordance with the late testimonies of Hippocratic medicine. Consequently, this paper focuses on demonstrating the continuity between temple medicine and “rational medicine” through the communication strategy of the iamata (sanationes) as well as the reports of special patients, such as Aelius Aristides. In addition, the article highlights the political role of writing as a way to regulate the healing not only of the body but also of the civic body. This approach is perfectly consistent with the ancient wisdom and philosophical tradition of overlapping state and body, politics and medicine, lawgivers and physicians.

ABSTRACTSymbiotic microbiota critically contribute to host immune homeostasis in effector cell-specific manner. For exclusion of microbial component, germ-free animals have been the gold standard method. However, total removal of the entire gut microbiota of an animal from birth significantly skews physiological development. On the other hand, removal of gut microbiota from conventional mice using oral antibiotics has its own limitations, especially lack of consistency and the requirement for long-term treatment period. Here, we introduce an improved regimen to quickly remove gut microbiota and to maintain sterility, that is well received by animals without refusal. Rapid and consistent exclusion of resident bacteria in the gut lumen revealed kinetic differences among colonic lymphocyte subsets, which cannot be observed with typical germ-free animal models. Furthermore, the proposed method distinguished the mechanism of microbiota contribution as a direct stimulus to capable effector cells and a homeostatic cue to maintain such cell types.

Four-dimensional printing (4DP) is emerging as an innovative research topic. It involves the use of smart materials for three-dimensional printing (3DP) of items that change their shape after production, in a programmed way over time, when exposed to appropriate external non-mechanical stimuli (moisture, electric or magnetic fields, UV, temperature, pH or ion composition). In the performance of 4D printed devices, time is involved as the 4th dimension. 4D smart structures have been known for many years in the scientific literature, well before the advent of 3D printing, and the concepts of shape evolution as well as self-assembly have been applied to drug delivery at the nano-, micro- and macro-scale levels. The neologism “4DP” was coined by Tibbits, Massachusetts Institute of Technology, in 2013, who also showed the earliest examples of 4D printed objects. Since then, smart materials have often been combined with additive manufacturing, which makes production of complex shapes easy to achieve: going beyond 3DP, 4D printed items are no static objects. Two main categories of raw materials have been employed for 4DP: shape memory polymers (SMPs) and shape morphing hydrogels (SMHs). In principle, all types of 3D printers could be used for 4DP. In this article, examples of systems for use in the biomedical field, such as stents and scaffolds, and in drug delivery are reviewed, with special emphasis on indwelling devices for retention in the urinary bladder and in the stomach.

The present work focused on evaluating the feasibility of fused deposition modeling (FDM) in the development of a dosage form containing Timapiprant (TMP), also known as CHF6532, which is a novel active molecule indicated in the potential treatment of eosinophilic asthma upon oral administration. The resulting product could be an alternative, with potential towards personalization, of immediate release (IR) tablets used in the clinical studies. Formulations based on different polymeric carriers were screened, leading to the identification of a polyvinyl alcohol-based one, which turned out acceptable for versatility in terms of active ingredient content, printability and dissolution performance (i.e. capability to meet the dissolution specification set, envisaging >80% of the drug dissolved within 30 min). Following an in-depth evaluation on the influence of TMP solid state and of the voids volume resulting from printing on dissolution, few prototypes with shapes especially devised for therapy customization were successfully printed and were compliant with the dissolution specification set.

BackgroundWe examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.MethodsSerial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.ResultsLatent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.ConclusionsWe identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.

Evidence has been provided that circulating cancer-associated macrophage-like cell (CAM-L) numbers increase in response to chemotherapy, with an inverse trend compared to circulating tumor cells (CTCs). In the era of evolving cancer immunotherapy, whether CAM-Ls might have a potential role as predictive biomarkers of response has been unexplored. We evaluated whether a serial blood evaluation of CTC to CAM-L ratio might predict response to immune checkpoint inhibitors in a cohort of non-small-cell lung cancer patients. At baseline, CTCs, CAM-Ls, and the CTC/CAM-L ratio significantly correlate with both progression-free survival (PFS) and overall survival (OS). The baseline CTC/CAM-L ratio was significantly different in early progressors (4.28 ± 3.21) compared to long responders (0.42 ± 0.47) (p = 0.001). In patients treated with immune checkpoint inhibitors, a CTC/CAM-L ratio ≤ 0.25 at baseline is associated with better PFS and OS. A baseline CTC/CAM-L ratio ≤ 0.25 is statistically significant to discriminate early progressions from durable response. The results of the present pilot study suggest that CAM-Ls together with CTCs could play an important role in evaluating patients treated with cancer immunotherapy.

Early detection of disease progression is a crucial issue in the management of cancer patients, especially in metastatic settings. Currently, treatment selection mostly relies on criteria based on radiologic evaluations (RECIST). The aim of the present retrospective study is to evaluate the potential inclusion of circulating tumor cells (CTCs) in hybrid criteria. CTC counts from a total of 160 patients with different metastatic tumors were analyzed for this purpose. In our cohort, 73 patients were affected by breast cancer, 69 by colorectal cancer and 18 by prostate cancer. PFS and OS were evaluated according to the corresponding prediction of disease progression by CTCs and RECIST criteria. In breast cancer, CTC-I has an important impact on the progression-free survival (PFS) and overall survival (OS) values. When CTC-I predicted earlier than RECIST-I, the disease progression, the PFS and OS were shorter with respect to the opposite case. In particular, PFS was 11 (5–16) vs. 34 (23–45)—with p < 0.001—and OS was 80 (22–138) vs. 116 (43–189), p = 0.33. The results suggest a promising role of CTCs as complementary information which could significantly improve the clinical outcomes, and they encourage consideration of future trials to evaluate new hybrid criteria, particularly for patients with breast cancer.

How has the diffusion of online communities changed howtheir users construct, view, and define their identity? In thispaper, we choose to approach this issue by considering twoparticular philosophical problems related to personal identity:1) The Characterization Question, namely “which actions, ex-periences, beliefs, values, desires, character traits, and so oncan we attribute to a given person?” 2) “How do self-other re-lations affect the ethical implication of identity construction?”To address them, we adopt a comprehensive framework com-posed of cognitive niches and cognitive niche construction the-ories, and we discuss different philosophical and technologicalnotions. In particular: the Filter Bubble problem, the conceptof affordances, and the Sartrean idea of Bad Faith.

Objective: There is little doubt that there are currently obstacles in measuring the impact of the history of medicine within medical training. Consequently, there is a clear need to support a vision that can historicize Euro-Western medicine, leading to a greater understanding of how the medical world is a distinct form of reality for those who are about to immerse themselves in the study of medicine. Methods: History teaches that changes in medicine are due to the processes inherent to the interaction among individuals, institutions, and society rather than individual facts or individual authors. Results: Therefore, we cannot ignore the fact that the expertise and know-how developed during medical training are the final product of relationships and memories that have a historical life that is based social, economic, and political aspects. Conclusion: Moreover, these relationships and memories have undergone dynamic processes of selection and attribution of meaning, as well as individual and collective sharing, which have also been confronted with archetypes that are still able to influence clinical approaches and medical therapy today.

BackgroundThe term “neo-RAS wild-type” refers to the switch to RAS wild-type disease in plasma circulating tumor DNA (ctDNA) from originally RAS mutant colorectal cancers. Consistently, the hypothesis to re-determine RAS mutational status in ctDNA at disease progression in RAS mutant mCRC opened to a new perspective for clinically-based selection of patients to be treated with EGFR inhibitors. Currently, the genomic landscape of “neo-RAS wild-type” is unknown. This is a prospective study aimed to investigate clinical and genomic features associated with RAS mutation clearance in a large cohort of RAS mutant mCRC patients who converted to RAS wild- type in liquid biopsy at failure of first-line treatments. Secondary aim was to investigate the long term prognostic significance of “true neo-RAS wild- type”.Patients and methods70 patients with stage IV RAS mutant colorectal cancer were prospectively enrolled. Plasma samples were collected at progression from first-line treatment. RAS/BRAF mutations in plasma were assessed by RT-PCR. In RAS/BRAF wild-type samples, ctDNA was used to generate libraries using a 17 genes panel whose alteration has clinical relevance. To investigate the prognostic significance of RAS mutation clearance, test curves for PFS and OS were represented by Kaplan-Meier estimator plot and Log-rank test.ResultsThe most commonly detected actionable mutations in “neo-RAS wild-type” were: PIK3CA (35.7%); RET (11.9%); IDH1 (9.5%); KIT (7%); EGFR (7%); MET (4.7%); ERBB2 (4.7%); FGFR3 (4.7%). Both OS and post-progression survival were longer in patients with “neo-RAS wild-type” compared to those who remained RAS mutant (p

The aim of this study is to analyze the effects of Organizational Learning (OL) and Entrepreneurial Orientation (EO) on the profitability of MSMEs. To this end, field research was conducted on a sample of 1,620 companies located in Argentina (630), Mexico (550), and Ecuador (440). The data collection was carried out between May and September 2020, through a structured questionnaire addressed to the highest level of the company. The results were analyzed and validated using the partial least square (PLS) structural equation modeling (SEM) statistical technique. This work contributes to the development of the literature on dynamic capabilities, social capital theory, and stakeholder theory. Our results reveal that Entrepreneurial Orientation is a determinant variable for generating better Environmental Corporate Social Responsibility (ESCR) practices and is key to increasing the financial profitability of MSMEs. Furthermore, it is found that ESCR is a variable that partially mediates between EO and the Performance of MSMEs.