Early palliative care program in idiopathic pulmonary fibrosis patients favors at-home and hospice deaths, reduces unplanned medical visits, and prolongs survival: A pilot study.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a lethal disease; most patients die in hospitals because palliative care (PC) is not wildly and early available. We aimed to determine the impact of an early PC program in IPF patients on place of death, emergency department (ED) admission, unplanned medical visits and survival before and after its implementation at our clinic. METHODS: IPF patients from our ILD clinic who died between January 1st, 2018 and December 31th, 2023 were included in the analysis. Primary outcomes were location of death, number of ED access and unplanned medical visits; secondary outcomes was survival from diagnosis. RESULTS: A total of 46 decedents between 2018 and 2023 were analysed: (median age 71,5 ± 5,5 years, 89 % male): 26 died before the implementation of the early PC program and 20 after. Through χ2 test, location of death resulted significantly different in the two groups, showing the capacity of early PC to favor at home or in hospice death (p = 0,02); similarly, the number of unplanned visits was significantly lower (p = 0,03). Finally, survival was significantly lower in patients not receiving the early PC program (p = 0,01). CONCLUSION: The availability of an early PC program since the diagnosis significantly reduced both the death rate in hospital settings, favoring dying in hospice or at home, and the number of unplanned medical visits. Furthermore, IPF patients receiving early PC showed a longer survival than those who did not.

Clinical Outcomes according to Timing to Non Invasive Ventilation Initiation in COPD Patients with Acute Respiratory Failure: A Retrospective Cohort Study.

Nighttime and non-working days are characterized by a shortage of dedicated staff and available resources. Previous studies have highlighted that patients admitted during the weekend had higher mortality than patients admitted on weekdays ("weekend effect"). However, most studies have focused on specific conditions and controversial results were reported. We conducted an observational, monocentric, retrospective cohort study, based on data collected prospectively to evaluate the impact of the timing of NIV initiation on clinical outcomes in COPD patients with acute respiratory failure (ARF). A total of 266 patients requiring NIV with a time gap between diagnosis of ARF and NIV initiation <48 h were included. Interestingly, 39% of patients were not acidotic (pH = 7.38 ± 0.09 vs. 7.26 ± 0.05, p = 0.003) at the time of NIV initiation. The rate of NIV failure (need for intubation and/or all-cause in-hospital death) was similar among three different scenarios: "daytime" vs. "nighttime", "working" vs. "non-working days", "nighttime or non-working days" vs. "working days at daytime". Patients starting NIV during nighttime had a longer gap to NIV initiation compared to daytime (219 vs. 115 min respectively, p = 0.01), but this did not influence the NIV outcome. These results suggested that in a training center for NIV management, the failure rate did not increase during the "silent" hours.

COPD Exacerbation: Why It Is Important to Avoid ICU Admission.

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide. Hospitalization due to acute exacerbations of COPD (AECOPD) is a relevant health problem both for its impact on disease outcomes and on health system resources. Severe AECOPD causing acute respiratory failure (ARF) often requires admission to an intensive care unit (ICU) with endotracheal intubation and invasive mechanical ventilation. AECOPD also acts as comorbidity in critically ill patients; this condition is associated with poorer prognoses. The prevalence reported in the literature on ICU admission rates ranges from 2 to 19% for AECOPD requiring hospitalization, with an in-hospital mortality rate of 20-40% and a re-hospitalization rate for a new severe event being 18% of the AECOPD cases admitted to ICUs. The prevalence of AECOPD in ICUs is not properly known due to an underestimation of COPD diagnoses and COPD misclassifications in administrative data. Non-invasive ventilation in acute and chronic respiratory failure may prevent AECOPD, reducing ICU admissions and disease mortality, especially when associated with a life-threating episode of hypercapnic ARF. In this review, we report on up to date evidence from the literature, showing how improving the knowledge and management of AECOPD is still a current research issue and clinical need.

Structural Investigations on Novel Non-Nucleoside Inhibitors of Human Norovirus Polymerase.

Human norovirus is the first cause of foodborne disease worldwide, leading to extensive outbreaks of acute gastroenteritis, and causing around 200,000 children to die annually in developing countries. No specific vaccines or antiviral agents are currently available, with therapeutic options limited to supportive care to prevent dehydration. The infection can become severe and lead to life-threatening complications in young children, the elderly and immunocompromised individuals, leading to a clear need for antiviral agents, to be used as treatments and as prophylactic measures in case of outbreaks. Due to the key role played by the viral RNA-dependent RNA polymerase (RdRp) in the virus life cycle, this enzyme is a promising target for antiviral drug discovery. In previous studies, following in silico investigations, we identified different small-molecule inhibitors of this enzyme. In this study, we rationally modified five identified scaffolds, to further explore structure-activity relationships, and to enhance binding to the RdRp. The newly designed compounds were synthesized according to multiple-step synthetic routes and evaluated for their inhibition of the enzyme in vitro. New inhibitors with low micromolar inhibitory activity of the RdRp were identified, which provide a promising basis for further hit-to-lead optimization.

A new antiviral scaffold for human norovirus identified with computer-aided approaches on the viral polymerase.

Human norovirus is the leading cause of acute gastroenteritis worldwide, affecting every year 685 million people. In about one third of cases, this virus affects children under five years of age, causing each year up to 200,000 child deaths, mainly in the developing countries. Norovirus outbreaks are associated with very significant economic losses, with an estimated societal cost of 60 billion dollars per year. Despite the marked socio-economic consequences associated, no therapeutic options or vaccines are currently available to treat or prevent this infection. One promising target to identify new antiviral agents for norovirus is the viral polymerase, which has a pivotal role for the viral replication and lacks closely homologous structures in the host. Starting from the scaffold of a novel class of norovirus polymerase inhibitors recently discovered in our research group with a computer-aided method, different new chemical modifications were designed and carried out, with the aim to identify improved agents effective against norovirus replication in cell-based assays. While different new inhibitors of the viral polymerase were found, a further computer-aided ligand optimisation approach led to the identification of a new antiviral scaffold for norovirus, which inhibits human norovirus replication at low-micromolar concentrations.

Rational modifications on a benzylidene-acrylohydrazide antiviral scaffold, synthesis and evaluation of bioactivity against Chikungunya virus.

Chikungunya virus is a re-emerging arbovirus transmitted to humans by Aedes mosquitoes, responsible for an acute febrile illness associated with painful and debilitating arthralgia, which can persist for several months or become chronic. Over the past few years, infection with this virus has spread worldwide with a previously unknown virulence. No specific antiviral treatments nor vaccines are currently available against this important pathogen. Starting from the structure of a class of selective anti-CHIKV agents previously identified in our research group, different modifications to this scaffold were rationally designed, and 69 novel small-molecule derivatives were synthesised and evaluated for their inhibition of Chikungunya virus replication in Vero cells. Further structure-activity relationships associated with this class of antiviral agents were elucidated for the original scaffolds, and novel antiviral compounds with EC50 values in the low micromolar range were identified. This work provides the foundation for further investigation of these new structures as antivirals against Chikungunya virus.

Design, synthesis and evaluation against Chikungunya virus of novel small-molecule antiviral agents.

Chikungunya virus is a re-emerging arbovirus transmitted to humans by mosquitoes, responsible for an acute flu-like illness associated with debilitating arthralgia, which can persist for several months or become chronic. In recent years, this viral infection has spread worldwide with a previously unknown virulence. To date, no specific antivirals treatments nor vaccines are available against this important pathogen. Starting from the structures of two antiviral hits previously identified in our research group with in silico techniques, this work describes the design and preparation of 31 novel structural analogues, with which different pharmacophoric features of the two hits have been explored and correlated with the inhibition of Chikungunya virus replication in cells. Structure-activity relationships were elucidated for the original scaffolds, and different novel antiviral compounds with EC50 values in the low micromolar range were identified. This work provides the foundation for further investigation of these promising novel structures as antiviral agents against Chikungunya virus.

An update on small molecules targeting CXCR4 as starting points for the development of anti-cancer therapeutics.

CXCR4 (C-X-C Chemokine Receptor type 4) and its natural ligand SDF-1α (Stromal-Derived-Factor-1α) are involved in a number of physiological and pathological processes including cancer spread and progression. Over the past few years, numerous CXCR4 antagonists have been identified and currently are in different development stages as potential agents for the treatment of several diseases involving the CXCR4/SDF-1α axis. Herein, we focus on small molecules reported in literature between 2013 and 2017, claimed as CXCR4 antagonists and potentially useful in the treatment of cancer and other diseases where this receptor is involved. Most of the compounds resulted from a chemical optimization of previously identified molecules and some of them could represent suitable candidates for the development of advanced anticancer agents.

Rational design and synthesis of novel phenylsulfonyl-benzamides as anti-prostate cancer agents.

Prostate cancer is a major cause of male death worldwide and the identification of new efficient treatments is constantly needed. Different non-steroidal androgen receptor antagonists are approved also in the case of castration-resistant cancer forms. Using a rational approach and molecular modelling studies to modify the structure of antiandrogen drug bicalutamide, a new series of phenylsulfonyl-benzamide derivatives was designed and synthesised. Their antiproliferative activities were evaluated in four different human prostate cancer cell lines and several new compounds showed significantly improved IC50 values in the low µM range. The cytotoxicity profile was also evaluated for the novel structures in the HEK293 cell line.