Unveiling the Secrets of Acinetobacter baumannii: Resistance, Current Treatments, and Future Innovations.

Acinetobacter baumannii represents a significant concern in nosocomial settings, particularly in critically ill patients who are forced to remain in hospital for extended periods. The challenge of managing and preventing this organism is further compounded by its increasing ability to develop resistance due to its extraordinary genomic plasticity, particularly in response to adverse environmental conditions. Its recognition as a significant public health risk has provided a significant impetus for the identification of new therapeutic approaches and infection control strategies. Indeed, currently used antimicrobial agents are gradually losing their efficacy, neutralized by newer and newer mechanisms of bacterial resistance, especially to carbapenem antibiotics. A deep understanding of the underlying molecular mechanisms is urgently needed to shed light on the properties that allow A. baumannii enormous resilience against standard therapies. Among the most promising alternatives under investigation are the combination sulbactam/durlobactam, cefepime/zidebactam, imipenem/funobactam, xeruborbactam, and the newest molecules such as novel polymyxins or zosurabalpin. Furthermore, the potential of phage therapy, as well as deep learning and artificial intelligence, offer a complementary approach that could be particularly useful in cases where traditional strategies fail. The fight against A. baumannii is not confined to the microcosm of microbiological research or hospital wards; instead, it is a broader public health dilemma that demands a coordinated, global response.

Navigating the path towards successful implementation of the EU HTA Regulation: key takeaways from the 2023 Spring Convention of the European Access Academy.

BACKGROUND: The European Regulation on Health Technology Assessment (EU HTA R), effective since January 2022, aims to harmonize and improve the efficiency of common HTA across Member States (MS), with a phased implementation from January 2025. At "midterms" of the preparation phase for the implementation of the Regulation our aim was to identify and prioritize tangible action points to move forward. METHODS: During the 2023 Spring Convention of the European Access Academy (EAA), participants from different nationalities and stakeholder backgrounds discussed readiness and remaining challenges for the Regulation's implementation and identified and prioritized action points. For this purpose, participants were assigned to four working groups: (i) Health Policy Challenges, (ii) Stakeholder Readiness, (iii) Approach to Uncertainty and (iv) Challenges regarding Methodology. Top four action points for each working group were identified and subsequently ranked by all participants during the final plenary session. RESULTS: Overall "readiness" for the Regulation was perceived as neutral. Prioritized action points included the following: Health Policy, i.e. assess adjustability of MS laws and health policy processes; Stakeholders, i.e. capacity building; Uncertainty, i.e. implement HTA guidelines as living documents; Methodology, i.e. clarify the Population, Intervention, Comparator(s), Outcomes (PICO) identification process. CONCLUSIONS: At "midterms" of the preparation phase, the focus for the months to come is on executing the tangible action points identified at EAA's Spring Convention. All action points centre around three overarching themes: harmonization and standardization, capacity building and collaboration, uncertainty management and robust data. These themes will ultimately determine the success of the EU HTA R in the long run.

A web-based scoping review assessing the influence of smoking and smoking cessation on antidiabetic drug meabolism: implications for medication efficacy.

Currently 1.3 billion individuals globally engage in smoking, leading to significant morbidity and mortality, particularly among diabetic patients. There is urgent need for a better understanding of how smoking influences antidiabetic treatment efficacy. The review underscores the role of cigarette smoke, particularly polycyclic aromatic hydrocarbons (PAHs), in modulating the metabolic pathways of antidiabetic drugs, primarily through the induction of cytochrome P450 (CYP450) enzymes and uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), thus impacting drug pharmacokinetics and therapeutic outcomes. Furthermore, the review addresses the relatively uncharted territory of how smoking cessation influences diabetes treatment, noting that cessation can lead to significant changes in drug metabolism, necessitating dosage adjustments. Special attention is given to the interaction between smoking cessation aids and antidiabetic medications, a critical area for patient safety and effective diabetes management. This scoping review aims to provide healthcare professionals with the knowledge to better support diabetic patients who smoke or are attempting to quit, ensuring tailored and effective treatment strategies. It also identifies gaps in current research, advocating for more studies to fill these voids, thereby enhancing patient care and treatment outcomes for this at-risk population.

Obesity as a Confounding Factor in the Diagnosis of Wilson's Disease: Case Report of Two Siblings with the Same Genotype but Different Clinical Courses.

Wilson's disease (WD) is a biallelic disease-causing variant in the ATP7B gene on chromosome 13q14.3 that results in copper accumulation in many organs, particularly the liver and brain. The phenotypic spectrum is wide and symptoms at onset can be heterogeneous. We describe two Sicilian siblings, a young man and his elder sister, both compound heterozygous for the variants c.1286-2A>G and c.2668G>A (p.Val890Met) in the ATB7B gene. The male patient presented with liver cirrhosis, which quickly progressed to end-stage liver disease (Child-Pugh score = C10), while his sister had moderate steatotic liver disease (SLD). Our findings highlight that SLD may not always be related to obesity in overweight patients, especially when there are other potential risk factors such as a family history of chronic liver disease, or the persistence of high transaminase despite the adoption of adequate dietary and pharmacological intervention. Screening for conditions such as WD could identify patients at risk of developing SLD and avoid delays in diagnosis. Phenotypic variability in WD is considerable; therefore, further studies are needed to identify which WD patients have a greater risk of developing SLD and determine factors that can predict the severity of the disease.

Pharmacological enhancement of cholinergic neurotransmission alleviates neuroinflammation and improves functional outcomes in a triple transgenic mouse model of Alzheimer's disease.

Introduction: Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting the elderly population worldwide. Due to the multifactorial nature of the disease, involving impairment of cholinergic neurotransmission and immune system, previous attempts to find effective treatments have faced challenges. Methods: In such scenario, we attempted to investigate the effects of alpha-glyceryl-phosphoryl-choline (α-GPC), a cholinomimetic molecule, on neuroinflammation and memory outcome in the triple transgenic mouse model of AD (3xTg-AD). Mice were enrolled at 4 months of age, treated orally with α-GPC dissolved in drinking water at a concentration resulting in an average daily dose of 100 mg/kg for 8 months and sacrificed at 12 months of age. Thereafter, inflammatory markers, as well as cognitive parameters, were measured. Results: Chronic α-GPC treatment reduced accumulation of amyloid deposits and led to a substantial re-balance of the inflammatory response of resident innate immune cells, astrocytes and microglia. Specifically, fluorescent immunohistochemistry and Western blot analysis showed that α-GPC contributed to reduction of cortical and hippocampal reactive astrocytes and pro-inflammatory microglia, concurrently increasing the expression of anti-inflammatory molecules. Whereas α-GPC beneficially affect the synaptic marker synaptophysin in the hippocampus. Furthermore, we observed that α-GPC was effective in restoring cognitive dysfunction, as measured by the Novel Object Recognition test, wherein 3xTg-AD mice treated with α-GPC significantly spent more time exploring the novel object compared to 3xTg-AD untreated mice. Discussion: In conclusion, chronic treatment with α-GPC exhibited a significant anti-inflammatory activity and sustained the key function of hippocampal synapses, crucial for the maintenance of a regular cognitive status. In light of our results, we suggest that α-GPC could be exploited as a promising therapeutic approach in early phases of AD.

Taming Microglia in Alzheimer's Disease: Exploring Potential Implications of Choline Alphoscerate via α7 nAChR Modulation.

Alzheimer's disease (AD), marked by cognitive impairment, predominantly affects the brain regions regulated by cholinergic innervation, such as the cerebral cortex and hippocampus. Cholinergic dysfunction, a key contributor to age-related cognitive decline, has spurred investigations into potential therapeutic interventions. We have previously shown that choline alphoscerate (α-GPC), a cholinergic neurotransmission-enhancing agent, protects from Aß-mediated neurotoxicity. Herein, we investigated the effects of α-GPC on the microglial phenotype in response to Aß via modulation of the nicotinic alpha-7 acetylcholine receptor (α7 nAChR). BV2 microglial cells were pre-treated for 1 h with α-GPC and were treated for 24, 48, and 72 h with Aß1-42 and/or α-BTX, a selective α7nAchR antagonist. Fluorescent immunocytochemistry and Western blot analysis showed that α-GPC was able to antagonize Aß-induced inflammatory effects. Of note, α-GPC exerted its anti-inflammatory effect by directly activating the α7nAChR receptor, as suggested by the induction of an increase in [Ca2+]i and Ach-like currents. Considering that cholinergic transmission appears crucial in regulating the inflammatory profiles of glial cells, its modulation emerges as a potential pharmaco-therapeutic target to improve outcomes in inflammatory neurodegenerative disorders, such as AD.

Disease Modifying Strategies in Multiple Sclerosis: New Rays of Hope to Combat Disability?

Multiple sclerosis (MS) is the most prevalent chronic autoimmune inflammatory- demyelinating disorder of the central nervous system (CNS). It usually begins in young adulthood, mainly between the second and fourth decades of life. Usually, the clinical course is characterized by the involvement of multiple CNS functional systems and by different, often overlapping phenotypes. In the last decades, remarkable results have been achieved in the treatment of MS, particularly in the relapsing- remitting (RRMS) form, thus improving the long-term outcome for many patients. As deeper knowledge of MS pathogenesis and respective molecular targets keeps growing, nowadays, several lines of disease-modifying treatments (DMT) are available, an impressive change compared to the relative poverty of options available in the past. Current MS management by DMTs is aimed at reducing relapse frequency, ameliorating symptoms, and preventing clinical disability and progression. Notwithstanding the relevant increase in pharmacological options for the management of RRMS, research is now increasingly pointing to identify new molecules with high efficacy, particularly in progressive forms. Hence, future efforts should be concentrated on achieving a more extensive, if not exhaustive, understanding of the pathogenetic mechanisms underlying this phase of the disease in order to characterize novel molecules for therapeutic intervention. The purpose of this review is to provide a compact overview of the numerous currently approved treatments and future innovative approaches, including neuroprotective treatments as anti-LINGO-1 monoclonal antibody and cell therapies, for effective and safe management of MS, potentially leading to a cure for this disease.

Insight into Risk Factors, Pharmacogenetics/Genomics, and Management of Adverse Drug Reactions in Elderly: A Narrative Review.

The European Medicine Agency (EMA) has defined Adverse Drug Reactions (ADRs) as "a noxious and unintended response to a medicine", not including poisoning, accidental, or intentional overdoses. The ADR occurrence differs based on the approach adopted for defining and detecting them, the characteristics of the population under study, and the research setting. ADRs have a significant impact on morbidity and mortality, particularly among older adults, and represent a financial burden for health services. Between 30% and 60% of ADRs might be predictable and preventable, emerging as a result of inappropriate prescription, drug chemistry inherent toxicity, cell-specific drug toxicity, age- and sex-related anomalies in drug absorption, distribution, metabolism, and elimination (ADME), and drug-drug interactions (DDIs) in combination therapies or when a patient is treated with different drugs for concomitant disorders. This is particularly important in chronic diseases which require long-term treatments. Rapid developments in pharmacogenetics/genomics have improved the understanding of ADRs accompanied by more accurate prescriptions and reduction in unnecessary costs. To alleviate the burden of ADRs, especially in the elderly, interventions focused on pharmaceutical principles, such as medication review and reconciliation, should be integrated into a broader assessment of patients' characteristics, needs, and health priorities. Digital health interventions could offer valuable solutions to assist healthcare professionals in identifying inappropriate prescriptions and promoting patient adherence to pharmacotherapies.

Melatonin or Ramelteon for Delirium Prevention in the Intensive Care Unit: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Melatonin modulates the circadian rhythm and has been studied as a preventive measure against the development of delirium in hospitalized patients. Such an effect may be more evident in patients admitted to the ICU, but findings from the literature are conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether melatonin or ramelteon (melatonin agonist) reduce delirium incidence as compared to a placebo in ICU patients. Secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV) and mortality. Estimates are presented as risk ratio (RR) or mean differences (MD) with 95% confidence interval (CI). Nine RCTs were included, six of them reporting delirium incidence. Neither melatonin nor ramelteon reduced delirium incidence (RR 0.76 (0.54, 1.07), p = 0.12; I2 = 64%), although a sensitivity analysis conducted adding other four studies showed a reduction in the risk of delirium (RR = 0.67 (95%CI 0.48, 0.92), p = 0.01; I2 = 67). Among the secondary outcomes, we found a trend towards a reduction in the duration of MV (MD -2.80 (-6.06, 0.47), p = 0.09; I2 = 94%) but no differences in ICU-LOS (MD -0.26 (95%CI -0.89, 0.37), p = 0.42; I2 = 75%) and mortality (RR = 0.85 (95%CI 0.63, 1.15), p = 0.30; I2 = 0%). Melatonin and ramelteon do not seem to reduce delirium incidence in ICU patients but evidence is weak. More studies are needed to confirm this finding.

TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-ß.

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-ß (Aß) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R-/-). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R-/- mouse embryonic hippocampal cells after treatment with either Aß1-42 or TRAIL. Consistently, stereotaxic injection of Aß1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R-/- mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone Aß1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3ß proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and Aß-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R-/- mice challenged with Aß1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1ß, TNF-α, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aß1-42, providing further evidence on the prominent role played by TRAIL in course of Aß-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

Role of Microglia and Astrocytes in Alzheimer's Disease: From Neuroinflammation to Ca2+ Homeostasis Dysregulation.

Alzheimer's disease (AD) is the most common form of dementia worldwide, with a complex, poorly understood pathogenesis. Cerebral atrophy, amyloid-ß (Aß) plaques, and neurofibrillary tangles represent the main pathological hallmarks of the AD brain. Recently, neuroinflammation has been recognized as a prominent feature of the AD brain and substantial evidence suggests that the inflammatory response modulates disease progression. Additionally, dysregulation of calcium (Ca2+) homeostasis represents another early factor involved in the AD pathogenesis, as intracellular Ca2+ concentration is essential to ensure proper cellular and neuronal functions. Although growing evidence supports the involvement of Ca2+ in the mechanisms of neurodegeneration-related inflammatory processes, scant data are available on its contribution in microglia and astrocytes functioning, both in health and throughout the AD continuum. Nevertheless, AD-related aberrant Ca2+ signalling in astrocytes and microglia is crucially involved in the mechanisms underpinning neuroinflammatory processes that, in turn, impact neuronal Ca2+ homeostasis and brain function. In this light, we attempted to provide an overview of the current understanding of the interactions between the glia cells-mediated inflammatory responses and the molecular mechanisms involved in Ca2+ homeostasis dysregulation in AD.

Oral Fosfomycin Formulation in Bacterial Prostatitis: New Role for an Old Molecule-Brief Literature Review and Clinical Considerations.

Bacterial prostatitis infections are described as infections that are difficult-to-treat, due to prostate anatomic characteristics along with clinical difficulty in terms of diagnosis and management. Furthermore, the emergence of multidrug resistant (MDR) bacteria, such as extended-spectrum beta-lactamase (ESBL) producer Escherichia coli, also representing the main causative pathogen in prostatitis, poses major problems in terms of antibiotic management and favorable clinical outcome. Oral fosfomycin, an antibiotic commonly used for the treatment of uncomplicated urinary tract infections (UTIs), has been recently evaluated for the treatment of bacterial prostatitis due to its favorable pharmacokinetic profile, its activity against MDR gram-positive and gram-negative bacteria, safety profile, and multiple synergic effect with other antibiotics as well as the low resistance rate. This review addresses fosfomycin pharmacokinetics and pharmacodynamics and discusses the latest clinical evidence on its clinical use to treat acute and chronic bacterial prostatitis in hospitalized patients and in outpatients. As described in several reports, oral fosfomycin may represent a valid therapeutic option to treat susceptible germs commonly causing prostatitis, such as E. coli and other Enterobacterales as well as Enterococcus faecium, even as a first-line regimen in particular clinical settings (patients with previous treatment failure, with allergies or outpatients). Stronger data from further studies, including randomized controlled trials, would be helpful to establish the proper dosage and specific indications.

Sarilumab Administration in COVID-19 Patients: Literature Review and Considerations.

Two years have passed since WHO declared a pandemic state for SARS-CoV-2 infection. COVID-19 pathogenesis consists of a first viral phase responsible for early symptoms followed by an inflammatory phase, cytokine-mediated, responsible for late-onset manifestations up to ARDS. The dysregulated immune response has an outstanding role in the progression of pulmonary damage in COVID-19. IL-6, through the induction of pro-inflammatory chemokines and cytokines, plays a key role in the development and maintenance of inflammation, acting as a pioneer of the hyperinflammatory condition and cytokine storm in severe COVID-19. Therefore, drugs targeting both IL-6 and IL-6 receptors have been evaluated in order to blunt the abnormal SARS-CoV-2-induced cytokine release. Sarilumab, a high-affinity anti-IL-6 receptor antibody, may represent a promising weapon to treat the fearsome hyperinflammatory phase by improving the outcome of patients with moderate-to-severe COVID-19 pneumonia. Further prospective and well-designed clinical studies with larger sample sizes and long-term follow-up are needed to assess the efficacy and the safety of this therapeutic approach to achieve improved outcomes in COVID-19.

Intranasal Administration of a TRAIL Neutralizing Monoclonal Antibody Adsorbed in PLGA Nanoparticles and NLC Nanosystems: An In Vivo Study on a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder that progressively compromises cognitive functions. Tumor necrosis factor (TNF)-Related Apoptosis Inducing Ligand (TRAIL), a proinflammatory cytokine belonging to the TNF superfamily, appears to be a key player in the inflammatory/immune orchestra of the AD brain. Despite the ability of an anti-TRAIL monoclonal antibody to reach the brain producing beneficial effects in AD mice, we attempted to develop such a TRAIL-neutralizing monoclonal antibody adsorbed on lipid and polymeric nanocarriers, for intranasal administration, in a valid approach to overcome issues related to both high dose and drug transport across the blood-brain barrier. The two types of nanomedicines produced showed physico-chemical characteristics appropriate for intranasal administration. As confirmed by enzyme-linked immunosorbent assay (ELISA), both nanomedicines were able to form a complex with the antibody with an encapsulation efficiency of ≈99%. After testing in vitro the immunoneutralizing properties of the nanomedicines, the latter were intranasally administered in AD mice. The antibody-nanocarrier complexes were detectable in the brain in substantial amounts at concentrations significantly higher compared to the free form of the anti-TRAIL antibody. These data support the use of nanomedicine as an optimal method for the delivery of the TRAIL neutralizing antibody to the brain through the nose-to-brain route, aiming to improve the biological attributes of anti-TRAIL-based therapy for AD treatment.

Ampicillin plus ceftriaxone therapy against Enterococcus faecalis endocarditis: A case report, guidelines considerations, and literature review.

Enterococcus faecalis infective endocarditis (EFIE) continues to be a very serious disease, showing considerable morbidity and mortality rates which are influenced by the spread of multi-drug resistant strains occurred in the last decades. Although aminoglycosides were considered the treatment of choice of EIFE, in recent years several studies have investigated alternative therapeutic approaches, including combinations of beta-lactams, mainly because of the aminoglycoside-renowned nephrotoxicity and the widespread development of high-level aminoglycosides resistance (HLAR). In this scenario, we reported a case involving a prosthetic valve infective endocarditis caused by an aminoglycoside-resistant E. faecalis strain which was successfully treated with ampicillin plus ceftriaxone despite the presence of artificial heart valve and the patient's severe clinical conditions.

Repurposing Pomalidomide as a Neuroprotective Drug: Efficacy in an Alpha-Synuclein-Based Model of Parkinson's Disease.

Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.

The importance of immune checkpoints in immune monitoring: A future paradigm shift in the treatment of cancer.

The growth and development of cancer are directly correlated to the suppression of the immune system. A major breakthrough in cancer immunotherapy depends on various mechanisms to detect immunosuppressive factors that inhibit anti-tumor immune responses. Immune checkpoints are expressed on many immune cells such as T-cells, regulatory B cells (Bregs), dendritic cells (DCs), natural killer cells (NKs), regulatory T (Tregs), M2-type macrophages, and myeloid-derived suppressor cells (MDSCs). Immune inhibitory molecules, including CTLA-4, TIM-3, TIGIT, PD-1, and LAG-3, normally inhibit immune responses via negatively regulating immune cell signaling pathways to prevent immune injury. However, the up-regulation of inhibitory immune checkpoints during tumor progression on immune cells suppresses anti-tumor immune responses and promotes immune escape in cancer. It has recently been indicated that cancer cells can up-regulate various pathways of the immune checkpoints. Therefore, targeting immune inhibitory molecules through antibodies or miRNAs is a promising therapeutic strategy and shows favorable results. Immune checkpoint inhibitors (ICIs) are introduced as a new immunotherapy strategy that enhance immune cell-induced antitumor responses in many patients. In this review, we highlighted the function of each immune checkpoint on different immune cells and therapeutic strategies aimed at using monoclonal antibodies and miRNAs against inhibitory receptors. We also discussed current challenges and future strategies for maximizing these FDA-approved immunosuppressants' effectiveness and clinical success in cancer treatment.

Immunotherapy of cancer in single-cell RNA sequencing era: A precision medicine perspective.

Immunotherapy has revolutionized cancer treatment and brought new aspects into tumor immunology. Effective immunotherapy will require using the suitable target antigens, optimizing the interaction between the antigenic peptide, the APC, and the T cell, and the simultaneous inhibitor of the negative regulatory process that inhibits immunotherapeutic effects and develop resistance. Tumor heterogeneity and its microenvironment is the leading cause of resistance in patients. Recently by emerging the single-cell RNA sequencing technology and its combination with immunotherapy, now we can specifically evaluate the mechanism of tumors in the face of immunotherapy agents at the single-cell resolution by detecting the transcriptional activity of immune checkpoints, screening neoantigens with high transcription levels, identifying rare cells, and other important processes. This review focuses on scRNA-seq, particularly on its application in cancer immunotherapy.

Intravenous Fosfomycin: A Potential Good Partner for Cefiderocol. Clinical Experience and Considerations.

Multidrug resistant Gram-negative bacteremia represents a therapeutic challenge clinicians have to deal with. This concern becomes more difficult when causing germs are represented by carbapenem resistant Acinetobacter baumannii or difficult-to-treat Pseudomonas aeruginosa. Few antibiotics are available against these cumbersome bacteria, although literature data are not conclusive, especially for Acinetobacter. Cefiderocol could represent a valid antibiotic choice, being a molecule with an innovative mechanism of action capable of overcoming common resistance pathways, whereas intravenous fosfomycin may be an appropriate partner either enhancing cefiderocol activity or avoiding resistance development. Here we report two patients with MDR Gram negative bacteremia who were successfully treated with a cefiderocol/fosfomycin combination.