The impact of armed conflict on the development and global spread of antibiotic resistance: a systematic review.

BACKGROUND: Scant data are available on the link between armed conflicts and the development and spread of antimicrobial resistance. OBJECTIVES: We performed a systematic review with the aim to summarize the available data on the prevalence and features of antibiotic resistance and the causes of antibiotic resistance development during armed conflicts in the 21st century. METHODS: Data sources: PubMed and SCOPUS databases were searched from 1 January 2000 to 30 November 2023. STUDY ELIGIBILITY CRITERIA: Original articles reporting data on armed conflicts and antimicrobial resistance were included in this systematic review. No attempt was made to obtain information from unpublished studies. No language restriction was applied. Methods of data synthesis: Both quantitative and qualitative information were summarized by means of textual descriptions. PARTICIPANTS: Patients or soldiers deployed in armed conflict zones. TESTS: culture-dependent antibiotic sensitivity testing or molecular detection of the genetic determinants of antibiotic resistance after a confirmed diagnosis of bacterial infection. Assessment of risk of bias: To evaluate the quality of the included studies, we adapted the tool recommended by the Joanna Briggs Institute. RESULTS: Thirty-four studies were identified, published between November 2004 and November 2023. The quality of included studies was high and medium in 47% and 53% of the studies, respectively. The included studies reported high infection and colonization rates of multidrug-resistant bacteria. Studies performed during the Eastern Ukraine conflict reported high rates of New Delhi metallo-ß-lactamase producers. DISCUSSION: Our findings confirm that wars lead to a large pool of multidrug-resistant infections that could potentially spread. Infection control in healthcare facilities in conflict zones and proper antimicrobial stewardship are crucial.

Nurses' compliance to standard precautions prior to and during COVID-19.

AIMS: To measure nurses' compliance with standard precautions during the COVID-19 pandemic, compare findings with previous assessments and describe the barriers affecting nurses' compliance. BACKGROUND: Healthcare providers' compliance with standard precautions is still limited worldwide. Implementation of infection control policies in hospitals is needed internationally, especially during a pandemic. Surprisingly, studies exploring nurses' compliance with standard precautions are lacking during COVID-19. METHODS: A multicenter cross-sectional study was adopted in two Italian hospitals. Nurses' compliance with standard precautions was measured through The Compliance with Standard Precautions Scale (Italian version). An open-ended question explored the barriers to nurses' compliance with standard precautions. Reporting, followed the STROBE guidelines. RESULTS: A total of 201 nurses were enrolled in 2020. Nurses' compliance with standard precautions was suboptimal. A statistically significant improvement in the compliance rate with standard precautions was observed between pre- and during COVID-19 assessments. High compliance was found in the appropriate use of surgical masks, gloves and sharps disposal. Nurses perceived personal, structural and organizational barriers to standard precautions adherence. CONCLUSION: Nurses' compliance with standard precautions was not 100%, and different factors impeded nurses to work safely. Our findings provide institutional leaders and educators with the basis for implementing policies to optimize nurse safety, well-being and patient care. IMPLICATIONS FOR NURSING AND HEALTH POLICIES: Nurses have the right to work safely, and when the shortage of personal protective equipment and nurses during an emergency threatens healthcare quality worldwide, policymakers are challenged to act by establishing an effective allocation of resources for consistent compliance with standard precautions. Moreover, nurses should actively engage in the implementation of infection control policies to improve safe behaviours among citizens and students accessing hospitals.

Neutralizing Antibodies against SARS-CoV-2 Beta and Omicron Variants Inhibition Comparison after BNT162b2 mRNA Booster Doses with a New PETIA sVNT Assay.

BACKGROUND: Monitoring antibody response following SARS-CoV-2 vaccination is strategic, and neutralizing antibodies represent the gold standard. The neutralizing response to Beta and Omicron VOCs was evaluated versus the gold standard by a new commercial automated assay. METHODS: Serum samples from 100 healthcare workers from the Fondazione Policlinico Universitario Campus Biomedico and the Pescara Hospital were collected. IgG levels were determined by chemiluminescent immunoassay (Abbott Laboratories, Wiesbaden, Germany) and serum neutralization assay as the gold standard. Moreover, a new commercial immunoassay, the PETIA test Nab (SGM, Rome, Italy), was used for neutralization evaluation. Statistical analysis was performed with R software, version 3.6.0. RESULTS: Anti-SARS-CoV-2 IgG titers decayed during the first ninety days after the vaccine second dose. The following booster dose significantly (p < 0.001) increased IgG levels. A correlation between IgG expression and neutralizing activity modulation was found with a significant increase after the second and the third booster dose (p < 0.05. Compared to the Beta variant of the virus, the Omicron VOC was associated with a significantly larger quantity of IgG antibodies needed to achieve the same degree of neutralization. The best Nab test cutoff for high neutralization titer (≥1:80) was set for both Beta and Omicron variants. CONCLUSION: This study correlates vaccine-induced IgG expression and neutralizing activity using a new PETIA assay, suggesting its usefulness for SARS-CoV2 infection management.

Stereoselective synthesis of 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as PIM kinase inhibitors inspired from marine alkaloids.

We previously demonstrated that natural product-inspired 3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-ones derivatives delivered potent and selective PIM kinases inhibitors however with non-optimal ADME/PK properties and modest oral bioavailability. Herein, we describe a structure-based scaffold decoration and a stereoselective approach to this chemical class. The synthesis, structure-activity relationship studies, chiral analysis, and pharmacokinetic data of compounds from this inhibitor class are presented herein. Compound 20c demonstrated excellent potency on PIM1 and PIM2 with exquisite kinases selectivity and PK properties that efficiently and dose-dependently promoted c-Myc degradation and appear to be promising lead compounds for further development.

Identification of unprecedented ATP-competitive choline kinase inhibitors.

In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.

The opinions and feelings about their educational needs and role of familial caregivers of Parkinson's Disease patients: a qualitative study.

BACKGROUND AND AIM OF THE WORK: In the advanced stages of Parkinson's Disease, patients need complex care and support, especially at home, where they often receive assistance by familial caregivers. However, caregivers may be or feel unable to cope with their role and, despite the needs of caregivers are often assessed in the literature, their opinions and feelings about these needs are not widely explored yet. This study aimed at exploring the opinions and feelings about their educational needs and role of familial caregivers of Parkinson's Disease patients. METHODS: A qualitative study was conducted from October to December 2017 in a polyclinic of central Italy. Fourteen caregivers voluntarily participated in the study; semi-structured face-to-face interviews were conducted, and audio recorded until data saturation. Two investigators reviewed the transcribed notes, created Meaning Units, Sub-categories and finally the Categories with emerged themes. RESULTS: The analysis of the 14 interviews generated three categories: supportiveness of healthcare educational programs; sense of inability to manage caregiver tasks; need for interaction with other familial caregivers. CONCLUSIONS: The caregivers declared their belief that healthcare educational courses can be useful in helping them live and understand the caregiving tasks and expressed their need to share their experiences with other caregivers. In fact, they often they felt abandoned and poorly trained for the patient's management at the home. The clinical practice should allow healthcare professionals to meet the training and emotional needs of caregivers and create a trust relationship with them to make caregivers skilled in caring for patients.

Effectiveness of implementing link nurses and audits and feedback to improve nurses' compliance with standard precautions: A cluster randomized controlled trial.

BACKGROUND: To prevent health care-associated infections, health organizations recommend that health care workers stringently observe standard precautions (SPs). Nevertheless, compliance with SPs is still suboptimal, emphasizing the need for improvement interventions. METHODS: A cluster randomized controlled trial with a pretest-post-test design was conducted with 121 clinical nurses who worked in different wards of a university hospital. The intervention group (n = 61) had 3 infection control link nurses nominated and attended systematic audits and feedback. The control group (n = 60) received only the standard multimodal approach used in the hospital. Pre- and post-test assessment of SPs compliance was performed via the World Health Organization observational hand hygiene form and Compliance with Standard Precaution Scale Italian version. RESULTS: At the post-test, nurses in the intervention group reported significantly increased compliance with hand hygiene, whereas no significant improvement was found in the control group. Nurses in both groups reported significantly increased Compliance with Standard Precaution Scale Italian version scores; however, a higher increase and practical significance was observed in the intervention group. Participants who improved their scores were also compared between groups, showing a significantly greater increase of individual scores in intervention group compared to the control group. CONCLUSIONS: The findings of this study provide significant practical implications for hospitals seeking to improve compliance with SPs among nurses, showing the effectiveness of using infection control link nurses combined with systematic audits and feedback.

Stress-related vulnerability and usefulness of healthcare education in Parkinson's disease: The perception of a group of family caregivers, a cross-sectional study.

Parkinson's Disease is associated with a high assistive complexity, thus generating in caregivers a burden proportional to the intensity of the care provided. This study aims to evaluate whether the stress-related level of caregivers is related to their perception of the need for healthcare education. A cross-sectional study was conducted on 69 family caregivers that completed the Stress-related Vulnerability Scale (SVS scale) with a tool of proposed interventions stratified according to caregivers' need as "nothing", "somewhat", "moderately" and "extremely". A direct association between the SVS scale and the perception of the usefulness of interventions was detected, and significant differences were observed for "Caregivers tele-support group" and "Peer-led support group" interventions, thus suggesting an important role for caregivers' emotional status in considering of training courses. Caregivers are split between low vulnerability, with minimal perception of training need, and high burden state with the acute necessity of support to manage patients.

Experiences of compliance with standard precautions during emergencies: A qualitative study of nurses working in intensive care units.

Aim To explore factors that influence intensive care nurses' experiences of being compliant with standard precautions (SP) during emergencies. BACKGROUND: Intensive care nurses can be exposed to a greater risk of biohazardous exposure during an emergency. The primary strategy to address the complex variety of biological hazards in clinical practice is represented by the implementation of SP guidelines. Previous research has indicated that nurses' compliance rates with SPs are suboptimal, but no study has focused on the factors influencing compliance during an emergency. DESIGN: A descriptive qualitative study was conducted in an Italian university hospital with 19 intensive care nurses who had at least two years of work experience in critical care. The nurses were interviewed in four focus groups and were asked about their experiences of being compliant with SPs during an emergency. Data were analyzed using conventional content analysis. RESULTS: Three themes emerged: conflict, competencies, and context. Conflict was reported regarding the need to save the patient and the need for self-protection through the use of SPs. In particular, nurses had to manage the pressure of limited time. Competencies were identified by nurses' knowledge, attitude, skills, training, and experience. Context was related to the work and organizational conditions during the emergency, including overcrowding. CONCLUSION: To support intensive care nurses' compliance with SPs during emergencies, conflict, competencies, and context should be audited regularly in clinical practice. The findings of this study could inform infection control programs and training that targets intensive care nurses.

The transmission dynamic of Madariaga Virus by bayesian phylogenetic analysis: Molecular surveillance of an emergent pathogen.

Madariaga Virus (MADV) is an emergent Alphavirus of the eastern equine encephalitis virus (EEEV) strain complex causing epizootic epidemics. In this study the genetic diversity and the transmission dynamics of Madariaga virus has been investigated by Bayesian phylogenetics and phylodynamic analysis. A database of 32 sequences of MADV group structural polyprotein were downloaded from GenBank, aligned manually edited by Bioedit Software. ModelTest v. 3.7 was used to select the simplest evolutionary model that adequately fitted the sequence data. Neighbor-joining tree was generated using MEGA7. The phylogenetic signal of the dataset was tested by the likelihood mapping analysis. The Bayesian phylogenetic tree was built using BEAST. Selective pressure analysis revealed one positive selection site. The phylogenetic trees showed two main clusters. In particular, Lineage II showed an epizootic infection in monkeys and Lineage III, including 2 main clusters (IIIa and IIIB), revealing an epizootic infection in humans in Haiti and an epizootic infection in humans in Venezuela during the 2016, respectively. The Bayesian maximum clade credibility tree and the time of the most common recent ancestor estimates, showed that the root of the tree dated back to the year 346 with the probable origin in Brazil. Gene flow analysis revealed viral exchanges between different neighbor countries of South America. In conclusion, Bayesian phylogenetic and phylodynamic represent useful tools to follow the transmission dynamic of emergent pathogens to prevent new epidemics spreading worldwide.

Discovery of Stereospecific PARP-1 Inhibitor Isoindolinone NMS-P515.

Poly(ADP-ribose) polymerase-1 (PARP-1) is an enzyme involved in signaling and repair of DNA single strand breaks. PARP-1 employs NAD+ to modify substrate proteins via the attachment of poly(ADP-ribose) chains. PARP-1 is a well established target in oncology, as testified by the number of marketed drugs (e.g., Lynparza, Rubraca, Zejula, and Talzenna) used for the treatment of ovarian, breast, and prostate tumors. Efforts in investigating an uncharted region of the previously identified isoindolinone carboxamide series delivered (S)-13 (NMS-P515), a potent inhibitor of PARP-1 both in biochemical (K d: 0.016 µM) and cellular (IC50: 0.027 µM) assays. Cocrystal structure allowed explaining NMS-P515 stereospecific inhibition of the target. After having ruled out potential loss of enantiopurity in vitro and in vivo, NMS-P515 was synthesized in an asymmetric fashion. NMS-P515 ADME profile and its antitumor activity in a mouse xenograft cancer model render the compound eligible for further optimization.

Compliance with Standard Precautions among Clinical Nurses: Validity and Reliability of the Italian Version of the Compliance with Standard Precautions Scale (CSPS-It).

BACKGROUND: The compliance with Standard Precautions (SPs) guidelines, as a primary strategy for the prevention of healthcare associated infections, is still suboptimal among healthcare providers. However, no instrument measuring nurses' compliance with SPs is available in Italian. This study aims to assess the validity and reliability of the Compliance with Standard Precaution Scale⁻Italian version (CSPS-It) among clinical nurses. METHODS: The study consisted of two phases: (1) translation and cross-cultural adaptation of the CSPS; (2) validity and reliability evaluation of the CSPS-It. Confirmatory factor analysis (CFA) and hypothesis testing were performed to evaluate the construct validity. Cronbach's alpha, intra-class correlation coefficient of test-retest scores, and item-total correlations were computed to establish reliability. RESULTS: The CSPS-It showed a sound validity and reliability. The unidimensional model tested at CFA yielded acceptable fit indices. The hypothesis testing supported better nurses' compliance based on participation in at least one training course on SPs. CONCLUSIONS: The CSPS-It is a valid and reliable instrument for measuring the compliance with SPs among clinical nurses. This version will allow for the conduction of further studies in favor of progress in this specific field of research. Managers should pay greater attention in monitoring compliance with SPs among clinical nurses.

The effects of a multidisciplinary education course on the burden, health literacy and needs of family caregivers.

Chronic diseases are mostly managed by family caregivers that often face the "caregiver burden". This study aimed to understand whether a multidisciplinary theoretical-practical training course could influence the burden, health literacy and needs of caregivers. Seventy-six familial caregivers were asked to complete the Caregiver Burden Inventory-CBI, Caregiver Needs Assessment-CNA, and Health Literacy Questionnaire-HLQ, before and after the course. A significant decrease in CBI and an increase of CNA were observed. However, a significantly higher rate of CBI decrease and a lower increase of CNA were detected in the neurological compared to the oncological group (p = 0.001). Moreover, the ability of the participants to look for and find health information significantly improved. The course contrasted caregivers' burden, increased their search for health information, and revealed their requiring of training and emotional and social support. Caregiver education plays a pivotal role in the management of chronic patients, enhancing the quality of life of both patients and caregivers.

BRASS score and complex discharge: a pilot study

AIMS: A highly functional continuity of patient care, which is linked to the reduction of the risk of long-term hospitalization, above all for 'at-risk' patients. Research into an objective, reliable instrument for redirecting individual results to organizational aims to extend the entire country, is a fundamental step to move from a reactive assistance approach to a pro-active one. METHODS: An observational and descriptive retrospective study was carried out July - November 2014 in two Italian state hospitals, completing the BRASS Index within 48/72 hours of admission. RESULTS: The study group consisted of 122 inpatients. A correlation presented itself, albeit low (ñ=0.05191), between age and the number of 'revolving door' admissions; a medium correlation (ñ=0.485131) between age and risk band (according to BRASS). CONCLUSIONS: The BRASS Index is straightforward and swift, and can prove a valuable tool in directing nurses' attention to those patients most at risk of prolonged hospitalization.

Discovery of Entrectinib: A New 3-Aminoindazole As a Potent Anaplastic Lymphoma Kinase (ALK), c-ros Oncogene 1 Kinase (ROS1), and Pan-Tropomyosin Receptor Kinases (Pan-TRKs) inhibitor.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase responsible for the development of different tumor types. Despite the remarkable clinical activity of crizotinib (Xalkori), the first ALK inhibitor approved in 2011, the emergence of resistance mutations and of brain metastases frequently causes relapse in patients. Within our ALK drug discovery program, we identified compound 1, a novel 3-aminoindazole active on ALK in biochemical and in cellular assays. Its optimization led to compound 2 (entrectinib), a potent orally available ALK inhibitor active on ALK-dependent cell lines, efficiently penetrant the blood-brain barrier (BBB) in different animal species and highly efficacious in in vivo xenograft models. Moreover, entrectinib resulted to be strictly potent on the closely related tyrosine kinases ROS1 and TRKs recently found constitutively activated in several tumor types. Entrectinib is currently undergoing phase I/II clinical trial for the treatment of patients affected by ALK-, ROS1-, and TRK-positive tumors.

Entrectinib, a Pan-TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications.

Activated ALK and ROS1 tyrosine kinases, resulting from chromosomal rearrangements, occur in a subset of non-small cell lung cancers (NSCLC) as well as other tumor types and their oncogenic relevance as actionable targets has been demonstrated by the efficacy of selective kinase inhibitors such as crizotinib, ceritinib, and alectinib. More recently, low-frequency rearrangements of TRK kinases have been described in NSCLC, colorectal carcinoma, glioblastoma, and Spitzoid melanoma. Entrectinib, whose discovery and preclinical characterization are reported herein, is a novel, potent inhibitor of ALK, ROS1, and, importantly, of TRK family kinases, which shows promise for therapy of tumors bearing oncogenic forms of these proteins. Proliferation profiling against over 200 human tumor cell lines revealed that entrectinib is exquisitely potent in vitro against lines that are dependent on the drug's pharmacologic targets. Oral administration of entrectinib to tumor-bearing mice induced regression in relevant human xenograft tumors, including the TRKA-dependent colorectal carcinoma KM12, ROS1-driven tumors, and several ALK-dependent models of different tissue origins, including a model of brain-localized lung cancer metastasis. Entrectinib is currently showing great promise in phase I/II clinical trials, including the first documented objective responses to a TRK inhibitor in colorectal carcinoma and in NSCLC. The drug is, thus, potentially suited to the therapy of several molecularly defined cancer settings, especially that of TRK-dependent tumors, for which no approved drugs are currently available. Mol Cancer Ther; 15(4); 628-39. ©2016 AACR.

Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy.

The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-(4,4-difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

Novel pyrrole carboxamide inhibitors of JAK2 as potential treatment of myeloproliferative disorders.

Compound 1, a hit from the screening of our chemical collection displaying activity against JAK2, was deconstructed for SAR analysis into three regions, which were explored. A series of compounds was synthesized leading to the identification of the potent and orally bioavailable JAK2 inhibitor 16 (NMS-P830), which showed an encouraging tumour growth inhibition in SET-2 xenograft tumour model, with evidence for JAK2 pathway suppression demonstrated by in vivo pharmacodynamic effects.