Is the Hedgehog Pathway Involved in the Pathophysiology of Schizophrenia? A Systematic Review of Current Evidence of Neural Molecular Correlates and Perspectives on Drug Development.

Among the pathophysiological correlates of schizophrenia, recent research suggests a potential role for the Hedgehog (Hh) signalling pathway, which has been traditionally studied in embryonic development and oncology. Its dysregulation may impact brain homeostasis, neuroplasticity, and potential involvement in neural processes. This systematic review provides an overview of the involvement of Hh signalling in the pathophysiology of schizophrenia and antipsychotic responses. We searched the PubMed and Scopus databases to identify peer-reviewed scientific studies focusing on Hh and schizophrenia, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, finally including eight studies, including three articles focused on patients with schizophrenia, two animal models of schizophrenia, two animal embryo studies, and one cellular differentiation study. The Hh pathway is crucial in the development of midbrain dopaminergic neurons, neuroplasticity mechanisms, regulating astrocyte phenotype and function, brain-derived neurotrophic factor expression, brain glutamatergic neural transmission, and responses to antipsychotics. Overall, results indicate an involvement of Hh in the pathophysiology of schizophrenia and antipsychotic responses, although an exiguity of studies characterises the literature. The heterogeneity between animal and human studies is another main limitation. Further research can lead to better comprehension and the development of novel personalised drug treatments and therapeutic interventions.

Opioid Use and Gut Dysbiosis in Cancer Pain Patients.

Opioids are commonly used for the management of severe chronic cancer pain. Their well-known pharmacological effects on the gastrointestinal system, particularly opioid-induced constipation (OIC), are the most common limiting factors in the optimization of analgesia, and have led to the wide use of laxatives and/or peripherally acting mu-opioid receptor antagonists (PAMORAs). A growing interest has been recently recorded in the possible effects of opioid treatment on the gut microbiota. Preclinical and clinical data, as presented in this review, showed that alterations of the gut microbiota play a role in modulating opioid-mediated analgesia and tolerability, including constipation. Moreover, due to the bidirectional crosstalk between gut bacteria and the central nervous system, gut dysbiosis may be crucial in modulating opioid reward and addictive behavior. The microbiota may also modulate pain regulation and tolerance, by activating microglial cells and inducing the release of inflammatory cytokines and chemokines, which sustain neuroinflammation. In the subset of cancer patients, the clinical meaning of opioid-induced gut dysbiosis, particularly its possible interference with the efficacy of chemotherapy and immunotherapy, is still unclear. Gut dysbiosis could be a new target for treatment in cancer patients. Restoring the physiological amount of specific gut bacteria may represent a promising therapeutic option for managing gastrointestinal symptoms and optimizing analgesia for cancer patients using opioids.

Opinion paper on the systematic application of integrated bioinformatic tools to actuate routine precision medicine in poly-treated patients.

Precision Medicine is a reality in selected medical areas, as oncology, or in excellent healthcare structures, but it is still far to reach million patients who could benefit from this medical concept. Here, we sought to highlight how the time is ripe to achieve horizontal delivery to a significant larger audience of patients, represented by the poly-treated patients. Combination therapies are frequent (especially in the elderly, to treat comorbidities) and are related to decreased drug safety and efficacy, disease's exacerbation, additional treatments, hospitalization. But the recent development and validation of bioinformatic tools, aimed to automatic evaluation and optimization of poly-therapies, according to the unique individual characteristics (including genotype), is ready to change the daily approach to pharmacological prescription.

Hard-to-heal peripheral wounds infected with Corynebacterium striatum: a prospective study.

OBJECTIVE: To investigate Corynebacterium striatum as a nosocomial pathogen infecting hard-to-heal peripheral wounds, such as skin wounds, soft tissue abscesses and osteomyelitis. As of 2023, the medical community were alerted against the risk of emerging systemic and central infections; on the other hand literature on peripheral cutaneous regions is still scarce. METHOD: In this study, two groups of patients with similar lesions which were infected were compared: one group with the presence of the coryneform rod, the other without. RESULTS: In total, Corynebacterium striatum was cultured from 62 patients and 131 samples. Corynebacterium striatum infection correlated well with the presence of: foot ulcer; venous leg ulcer; altered ambulation and/or altered foot loading; peripheral vascular and arterial disease; hospitalisation; malignancy; spinal cord injury; and recent administration of antibiotics (p<0.05 for all associations). Patients with Corynebacterium striatum had a lower overall survival rate compared to patients in the non-Corynebacterium striatum group (28.6 versus 31.6 months, respectively; p=0.0285). Multivariate analysis revealed that Corynebacterium striatum infection was an independent factor for poor prognosis (p<0.0001). CONCLUSION: In view of the findings of our study, Corynebacterium striatum appears to be an important opportunistic pathogen infecting peripheral tissues and complicating wound healing. Given its numerous and worrying virulence factors (such as multidrug resistance and biofilm production), particular attention should be given to this pathogen by professional wound care providers in nosocomial and outpatient environments.

Frequencies of Combined Dysfunction of Cytochromes P450 2C9, 2C19, and 2D6 in an Italian Cohort: Suggestions for a More Appropriate Medication Prescribing Process.

Improper drug prescription is a main cause of both drug-related harms (inefficacy and toxicity) and ineffective spending and waste of the healthcare system's resources. Nowadays, strategies to support an improved, informed prescription process may benefit from the adequate use of pharmacogenomic testing. Using next-generation sequencing, we analyzed the genomic profile for three major cytochromes P450 (CYP2C9, CYP2C19, CYP2D6) and studied the frequencies of dysfunctional isozymes (e.g., poor, intermediate, or rapid/ultra-rapid metabolizers) in a cohort of 298 Italian subjects. We found just 14.8% of subjects with a fully normal set of cytochromes, whereas 26.5% of subjects had combined cytochrome dysfunction (more than one isozyme involved). As improper drug prescription is more frequent, and more burdening, in polytreated patients, since drug-drug interactions also cause patient harm, we discuss the potential benefits of a more comprehensive PGX testing approach to support informed drug selection in such patients.

The Impact of Non-Andrological Medications on Semen Characteristics, Oxidative Stress and Inflammatory Parameters.

Background and Objectives: The aim of this study was to evaluate the impact of medications on oxidative stress, inflammatory biomarkers and semen characteristics in males with idiopathic infertility. Materials and Methods: In this observational case-control clinical study, 50 men with idiopathic infertility were enrolled, of whom 38 (the study group) were on pharmacological treatment and 12 made up the control group. The study group was clustered according to the medications (Group A: anti-hypertensive, n = 10; Group B: thyroxine, n = 6; Group C: non-steroidal anti-inflammatory drugs, n = 13; Group D: miscellaneous, n = 6; Group E: lipid-lowering drugs, n = 4). Semen analyses were performed according to WHO 2010 guidelines. Interleukins (IL)-10, IL-1 beta, IL-4, IL-6, Tumor Necrosis Factor- alpha (TNF-alpha) and IL-1 alpha were determined using a solid-phase sandwich immunoassay. The diacron reactive oxygen metabolites, d-ROMs test, was performed by means of a colorimetric determination of reactive oxygen metabolites and measured with a spectrophotometer. Beta-2-microglobulin and cystatin-C were measured with an immunoturbidimetric analyzer. Results: No differences between the study and control groups for age and macroscopic and microscopic semen characteristics were found, nor were any differences found after clustering according to the drug categories. IL-1 alpha and IL-10 were significantly lower in the study group compared with the control group; IL-10 was significantly lower in groups A, B, C and D compared with the control group. Furthermore, a direct correlation between IL-1 alpha, IL-10 and TNF-alpha and leukocytes was found. Conclusions: Despite the sample size limitations, the data suggest a correlation between drug use and activation of the inflammatory response. This could clarify the pathogenic mechanism of action for several pharmacological classes on male infertility.

Predicting Dihydropyrimidine Dehydrogenase Deficiency and Related 5-Fluorouracil Toxicity: Opportunities and Challenges of DPYD Exon Sequencing and the Role of Phenotyping Assays.

Deficiency of dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is associated with severe toxicity induced by the anti-cancer drug 5-Fluorouracil (5-FU). DPYD genotyping of four recommended polymorphisms is widely used to predict toxicity, yet their prediction power is limited. Increasing availability of next generation sequencing (NGS) will allow us to screen rare variants, predicting a larger fraction of DPD deficiencies. Genotype−phenotype correlations were investigated by performing DPYD exon sequencing in 94 patients assessed for DPD deficiency by the 5-FU degradation rate (5-FUDR) assay. Association of common variants with 5-FUDR was analyzed with the SNPStats software. Functional interpretation of rare variants was performed by in-silico analysis (using the HSF system and PredictSNP) and literature review. A total of 23 rare variants and 8 common variants were detected. Among common variants, a significant association was found between homozygosity for the rs72728438 (c.1974+75A>G) and decreased 5-FUDR. Haplotype analysis did not detect significant associations with 5-FUDR. Overall, in our sample cohort, NGS exon sequencing allowed us to explain 42.5% of the total DPD deficiencies. NGS sharply improves prediction of DPD deficiencies, yet a broader collection of genotype−phenotype association data is needed to enable the clinical use of sequencing data.

Accuracy and Cost-Effectivenss of a Novel Method for Alpha Defensins Measurement in the Diagnosis of Periprosthetic Joint Infections.

BACKGROUND: Two methods for detecting synovial fluids alpha defensins are available: the enzyme-linked immunosorbent assay and the lateral flow test. For both, the proper role and accuracy remain uncertain. The purpose of this study was to assess the accuracy of the matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) for alpha defensin detection in synovial fluids of patients with total knee arthroplasty/total hip arthroplasty failures. The hypothesis was that the alpha defensin measurement through MALDI-TOF MS assay could be a high sensitive and specific test for periprosthetic joint infections (PJI) diagnosis as compared with Musculoskeletal Infection Society (MSIS) criteria. METHODS: The study included 138 patients. The 2018 MSIS criteria were used to diagnose PJIs. Synovial fluids were assessed for routinely synovial fluid tests and alpha defensin measurement through MALDI-TOF MS. Sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, receiver operator curves, and area under the curve were calculated. RESULTS: As per the 2018 MSIS criteria, 59 PJIs (43%) and 79 aseptic failures (57%) were diagnosed. The MALDI-TOF MS assay showed an overall accuracy of 94.9%. The sensitivity was 93%, the specificity was 96%, the positive predictive value was 95%, and the negative predictive value was 95%. Receiver operator curves analysis demonstrates an area under the curve of 0.95 (P < .001). CONCLUSION: The MALDI-TOF MS assay showed high sensitivity and specificity for alpha defensin detection in case of total knee arthroplasty/total hip arthroplasty failures. The advantages of the technology, such as the few milliliters of sample needed, the rapidity of obtaining results, and the cost-effectiveness of the procedure could make the MALDI-TOF MS alpha defensin assay a useful and widespread test in clinical practice.

Aberrant mitochondrial bioenergetics in the cerebral cortex of the Fmr1 knockout mouse model of fragile X syndrome.

Impaired energy metabolism may play a role in the pathogenesis of neurodevelopmental disorders including fragile X syndrome (FXS). We checked brain energy status and some aspects of cell bioenergetics, namely the activity of key glycolytic enzymes, glycerol-3-phosphate shuttle and mitochondrial respiratory chain (MRC) complexes, in the cerebral cortex of the Fmr1 knockout (KO) mouse model of FXS. We found that, despite a hyperactivation of MRC complexes, adenosine triphosphate (ATP) production via mitochondrial oxidative phosphorylation (OXPHOS) is compromised, resulting in brain energy impairment in juvenile and late-adult Fmr1 KO mice. Thus, an altered mitochondrial energy metabolism may contribute to neurological impairment in FXS.

Detection of α-defensin in synovial fluids by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry as an innovative and cost-effective assay for improved definition of periprosthetic joint infections.

RATIONALE: Detection of α-defensins in synovial fluid is gaining more and more interest in the field of correct diagnosis of periprosthetic joint infections (PJIs). At present, they can be assessed by a quantitative enzyme-linked immunosorbent assay which is expensive and time-consuming and by a qualitative lateral flow immunoassay which is rapid but quite expensive and whose clinical sensitivity is debated. Thus, developing an alternative rapid, accurate, and low-cost assay for α-defensins is important to make α-defensins actionable as novel key clinical markers. METHODS: Synovial fluid (SF) samples were obtained from 18 patients undergoing revision of primary joint arthroplasty. Of these, eight met the 2013 Musculoskeletal Infection Society (MSIS) criteria for PJIs, the remaining were classified as aseptic failure. Microbiological analysis and Synovasure assays were carried out on all samples. Sample preparation and the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) settings were adjusted to detect human neutrophil peptide (HNP)-1, -2 and -3 and to obtain optimal results in term of sensitivity and stability. RESULTS: MALDI-TOF MS was able to detect HNPs in SF from septic patients. No signals for HNPs were detected in SF from aseptic failure. The limits of detection (LOD) were 2.5 and 1.25 µg/mL for HNP-2 and HNP-1, respectively. The turnaround time of the analysis is 20 min, and SF samples are stable at -20°C for up to 3 days. Assay sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were 100% for all parameters. On the same SF samples, the Synovasure assay showed lower sensitivity specificity, and PPV and NPV of 87.5%, 90%, 87.5% and 90%, respectively. Microbiological analysis of SF confirmed the presence of bacteria only in SF MSIS-positive patients. CONCLUSIONS: The reported MALDI-TOF MS assay was able to detect and differentiate HNPs in SF samples and showed a slightly better diagnostic accuracy than the Synovasure assay.

Optimising migraine treatment: from drug-drug interactions to personalized medicine.

Migraine is the most disabling and expensive chronic disorders, the etiology of which is still not fully known. The neuronal systems, (glutammatergic, dopaminergic, serotoninergic and GABA-ergic) whose functionality is partly attributable to genetically determined factors, has been suggested to play an important role. The treatment of acute attacks and the prophylactic management of chronic forms include the use of different category of drugs, and it is demonstrated that not each subject has the same clinical answer to them. The reason of this is to be searched in different functional capacity and quantity of phase I enzymes (such as different isoforms of CYP P450), phase II enzymes (such as UDP-glucuronosyltransferases), receptors (such as OPRM1 for opioids) and transporters (such as ABCB1) involved in the metabolic destiny of each drug, all of these dictated by DNA and RNA variations. The general picture is further exacerbated by the need for polytherapies, often also to treat comorbidities, which may interfere with the pharmacological action of anti-migraine drugs. Personalized medicine has the objective of setting the optimal therapies in the light of the functional biochemical asset and of the comorbidities of the individual patient, in order to obtain the best clinical response. Novel therapeutic perspectives in migraine includes biotechnological drugs directed against molecules (such as CGRP and its receptor) that cause vasodilatation at the peripheral level of the meningeal blood vessels and reflex stimulation of the parasympathetic system. Drug-drug interactions and the possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale. Drug-drug interactions and their possible competitive metabolic destiny should be studied by the application of pharmacogenomics in large scale.

5-Fluorouracil degradation rate could predict toxicity in stages II-III colorectal cancer patients undergoing adjuvant FOLFOX.

5-Fluorouracil is commonly used for gastrointestinal cancer treatment in an adjuvant setting; however, the toxicity can lead to a reduction, delay, or discontinuation of treatment. We retrospectively investigated the association between the 5-fluorouracil degradation rate (5-FUDR) and genetic polymorphisms of TSER, DPYD, and MHTFR with toxicity in colorectal cancer patients treated with adjuvant FOLFOX. Pretreatment 5-FUDR and MTHFR A1298T or C677T, TSER, and DPYD gene polymorphisms were characterized in stages II-III colorectal cancer patients. Patients were classified into three metabolic classes according to the 5-FUDR value. Association with toxicities was evaluated retrospectively using logistic regression analysis. Overall, 126 patients were selected (35 women, 91 men). Seven patients were poor metabolizers, 116 patients were normal metabolizers and three patients were ultra-rapid metabolizers. The median 5-FUDR was 1.53 ng/ml/10 cells/min (range: 0.42-2.57 ng/ml/10 cells/min). Severe, rate-limiting toxicities (grades 3-4) were encountered in 22.2% of patients. No associations between MTHFR or TSER polymorphisms and toxicity were detected, whereas 5-FUDR showed a statistically significant association with toxicity (P=0.0047). The DPYD heterozygous mutation was detected in only one patient, who showed grade 4 hematological toxicity and a lower 5-FUDR value. The 5-FUDR value seems not to be affected by MTHFR and TSER polymorphisms. Compared with the available pharmacogenomics tests, the pretreatment evaluation of 5-FUDR increases the proportion of identified colorectal patients at high risk for severe toxicity. Thus, it appears to be a suitable pretreatment toxicity biomarker in a subgroup of patients in whom dose-intensity maintenance is the key factor.

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

Osteopontin and galectin-3 predict the risk of ventricular tachycardia and fibrillation in heart failure patients with implantable defibrillators.

BACKGROUND: Myocardial extracellular matrix remodelling provides electrical heterogeneity entailing ventricular tachycardia/fibrillation (VT/VF) in heart failure (HF) patients. Osteopontin (OPN) and Galectin-3 (Gal-3) are fibrosis markers and may reflect the extension of the arrhythmogenic substrate. We assessed whether plasma OPN and Gal-3 predict the risk of sustained VT/VF in a cohort of HF patients with implantable cardioverter-defibrillator (ICD). METHODS: A total of 75 HF patients underwent pre-ICD implantation clinical evaluation and assessment of plasma OPN and Gal-3. The primary endpoint was the time to the occurrence of the first sustained VT/VF. Hazard ratios (HR) were derived from Cox proportional-hazards analysis. RESULTS: Patients with coronary artery disease (CAD) had higher plasma OPN (79.8 ± 44.0 ng/mL vs. 66.0 ± 31.8 ng/mL; P = 0.04). Both Gal-3 (r = -0.38; P = 0.01) and OPN (r = -0.27; p = 0.01) were negatively related to estimated glomerular filtration rate. After 29 ± 17 months, 20 patients (27%) reached the primary endpoint. Patients with VT/VF had higher plasma OPN and Gal-3 (97.4 ± 51.7 ng/mL vs. 65.9 ± 31.3 ng/mL; P = 0.002 and 19.7 ± 8.5 ng/mL vs. 16.2 ± 6.2 ng/mL; P = 0.05). In univariate analysis, OPN (log-OPN, HR: 32.4; 95%CI: 3.9-264.7; P = 0.001) and Gal-3 (HR: 1.05; 95%CI: 1.00-1.11; P = 0.04) predicted sustained VT/VF. In multivariable analysis, both OPN (HR: 41.4; 95%CI: 3.8-441.9; P = 0.002) and Gal-3 (HR: 1.06; 95%CI: 1.00-1.12; P = 0.03) retained their prognostic power after correction for age, sex, history of MI, EF, NYHA class, eGFR, use of ACE-I, and amiodarone. CONCLUSIONS: Plasma OPN and Gal-3 predict sustained VT/VF in HF patients at high risk for SCD. Larger prospective studies should outline the role of these biomarkers in predicting SCD on top of conventional risk stratification.

Low prostate concentration of lycopene is associated with development of prostate cancer in patients with high-grade prostatic intraepithelial neoplasia.

Prostate cancer (PC) is a frequent male malignancy and represents the second most diagnosed cancer in men. Since pre-cancerous lesions, i.e., the high-grade prostatic intraepithelial neoplasia (HGPIN), can be detected years before progression to PC, early diagnosis and chemoprevention are targeted strategies to reduce PC rates. Animal studies have shown that lycopene, a carotenoid contained in tomatoes, is a promising candidate for the chemoprevention of PC. However, its efficacy in humans remains controversial. The present study aimed to investigate the relevance of plasma and prostate concentration of lycopene after a lycopene-enriched diet in patients diagnosed with HGPIN. Thirty-two patients diagnosed with HGPIN were administered a lycopene-enriched diet (20-25 mg/day of lycopene; through 30 g/day of triple concentrated tomato paste) for 6 months. A 6-month follow-up prostate biopsy assessed progression to PC. Patients were classified into three groups according to the histopathological features of the 6-month follow-up biopsy results: prostatitis; HGPIN and PC. PSA and plasma lycopene levels were measured before and after the dietary lycopene supplementation. Prostatic lycopene concentration was only assessed after the supplementation diet. Only prostatic lycopene concentration showed significant differences between the three groups (p = 0.03). Prostatic lycopene concentration below a 1 ng/mg threshold was associated with PC at 6-month follow-up biopsy (p = 0.003). We observed no overall benefits from a 6-month lycopene supplementation, as the rate of HGPIN progression to PC in our population (9/32, 28%) was similar to rates reported in the literature. Baseline PSA levels also showed no significant changes after a lycopene-enriched diet. Our findings point to prostatic lycopene concentration as a promising biomarker of PC. Further prospective longitudinal studies are needed to assess the prognostic role of prostatic lycopene in PC.

PAR level mediates the link between ROS and inflammatory response in patients with type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by disrupted glucose homeostasis and metabolic abnormalities, with oxidative stress and inflammation playing pivotal roles in its pathophysiology. Poly(ADP-ribosyl)ation (PARylation) is a post-translational process involving the addition of ADP-ribose polymers (PAR) to target proteins. While preclinical studies have implicated PARylation in the interplay between oxidative stress and inflammation in T2DM, direct clinical evidence in humans remains limited. This study investigates the relationship between oxidative stress, PARylation, and inflammatory response in T2DM patients. METHODS: This cross-sectional investigation involved 61 T2DM patients and 48 controls. PAR levels were determined in peripheral blood cells (PBMC) by ELISA-based methodologies. Oxidative stress was assessed in plasma and PBMC. In plasma, we monitored reactive oxygen metabolites (d-ROMs) and ferric-reducing antioxidant power. In PBMC, we measured the expression of antioxidant enzymes SOD1, GPX1 and CAT by qPCR. Further, we evaluated the expression of inflammatory mediators such as IL6, TNF-α, CD68 and MCP1 by qPCR in PBMC. RESULTS: T2DM patients exhibited elevated PAR levels in PBMC and increased d-ROMs in plasma. Positive associations were found between PAR levels and d-ROMs, suggesting a link between oxidative stress and altered PAR metabolism. Mediation analysis revealed that d-ROMs mediate the association between HbA1c levels and PAR, indicating oxidative stress as a potential driver of increased PARylation in T2DM. Furthermore, elevated PAR levels were found to be associated with increased expression of pro-inflammatory cytokines IL6 and TNF-α in the PBMC of T2DM patients. CONCLUSIONS: This study highlights that hyperactivation of PARylation is associated with poor glycemic control and the resultant oxidative stress in T2DM. The increase of PAR levels is correlated with the upregulation of key mediators of the inflammatory response. Further research is warranted to validate these findings and explore their clinical implications.

Recognizing and preventing unacknowledged prescribing errors associated with polypharmacy.

BACKGROUND: Prescribing errors put an enormous burden on health and the economy, claiming implementation of effective methods to prevent/reduce them. Polypharmacy regimens (five or more drugs) are highly prone to unacknowledged prescribing errors, since the complex network of drug-drug interactions, guidelines and contraindications is challenging to be adequately evaluated in the prescription phase, especially if different doctors are involved. Clinical decision support systems aimed at polypharmacy evaluation may be crucial to recognize and correct prescribing errors. METHODS: A commercial clinical decision support system (Drug-PIN®) was applied to estimate the frequency of unrecognized prescribing errors in a group of 307 consecutive patients accessing the hospital pre-admission service of the Sant'Andrea Hospital of Rome, Italy, in the period April-June 2023. Drug-PIN® is a two-step system, first scoring the risk (low, moderate or high) associated with a certain therapy-patient pair, then allowing therapy optimization by medications exchanges. We defined prescribing errors as cases where therapy optimization could achieve consistent reduction of the Drug-PIN® calculated risk. RESULTS: Polypharmacy was present in 205 patients, and moderate to high risk for medication harm was predicted by Drug-PIN® in 91 patients (29.6%). In 58 of them (63.7%), Drug-PIN® guided optimization of the therapy could be achieved, with a statistically significant reduction of the calculated therapy-associated risk score. Patients whose therapy cannot be improved have a statistically significant higher number of used drugs. Considering the overall study population, the rate of avoidable prescribing errors was 18.89%. CONCLUSIONS: Results suggest that computer-aided evaluation of medication-associated harm could be a valuable and actionable tool to identify and prevent prescribing errors in polypharmacy. We conducted the study in a Hospital pre-admission setting, which is not representative of the general population but represents a hotspot to intercept fragile population, where a consistent fraction of potentially harmful polypharmacy regimens could be promptly identified and corrected by systematic use of adequate clinical decision support tools.

Seminological, Hormonal and Ultrasonographic Features of Male Factor Infertility Due to Genetic Causes: Results from a Large Monocentric Retrospective Study.

Objectives: Evaluate the prevalence of genetic factors in a large population of infertile subjects and define the seminological, hormonal, and ultrasonographic features for each alteration. Methods: This single-center retrospective study included male partners of infertile couples undergoing genetic investigations due to oligozoospermia or azoospermia evaluated from January 2012 to January 2022. The genetic investigations consist of karyotype, CFTR gene mutations plus variant of the IVS8-5T polymorphic trait, Y chromosome microdeletion, and Next Generation Sequencing panel to analyze genes implicated in congenital hypogonadotropic hypogonadism (CHH). Results: Overall, 15.4% (72/466) of patients received a diagnosis of genetic cause of infertility. Specifically, 23 patients (31.9%) harbor mutations in the CFTR gene, 22 (30.6%) have a 47, XXY karyotype, 14 (19.4%) patients show a Y chromosome microdeletion, 7 (9.7%) have structural chromosomal anomalies, and 6 (8.3%) have CHH. Overall, 80.6% of patients were azoospermic and 19.4% oligozoospermic (sperm concentration 3.5 ± 3.8 million/mL). Almost all patients presented hormonal alterations related to the specific genotype, while the main ultrasound alterations were testicular hypoplasia, calcifications/microcalcifications, and enlarged/hyperechoic epididymis. Conclusions: The prevalence of genetic abnormalities in males of infertile couples was 15.4% in our Center. CFTR gene disease-causing variants resulted in more frequent, with various clinical features, highlighting the complexity and heterogeneity of the presentation. Other investigations are needed to understand if conditions like ring chromosomes and other translocations are related to infertility or are incidental factors.

Gastric Microbiota Gender Differences in Subjects with Healthy Stomachs and Autoimmune Atrophic Gastritis.

Gender differences and microbiota are gaining increasing attention. This study aimed to assess gender differences in gastric bacterial microbiota between subjects with healthy stomachs and those with autoimmune atrophic gastritis. This was a post hoc analysis of 52 subjects undergoing gastroscopy for dyspepsia (57.7% healthy stomach, 42.3% autoimmune atrophic gastritis). Gastric biopsies were obtained for histopathology and genomic DNA extraction. Gastric microbiota were assessed by sequencing the hypervariable regions of the 16SrRNA gene. The bacterial profile at the phylum level was reported as being in relative abundance expressed as 16SrRNA OTUs (>0.5%) and biodiversity calculated as Shannon-diversity index-H. All data were stratified for the female and male gender. Results showed that women with healthy stomachs had a higher gastric bacterial abundance and less microbial diversity compared to men. Likely due to hypochlorhydria and the non-acid intragastric environment, autoimmune atrophic gastritis seems to reset gender differences in gastric bacterial abundance and reduce biodiversity in males, showing a greater extent of dysbiosis in terms of reduced biodiversity in men. Differences between gender on taxa frequency at the phylum and genus level in healthy subjects and autoimmune atrophic gastritis were observed. The impact of these findings on the gender-specific natural history of autoimmune atrophic gastritis remains to be elucidated; in any case, gender differences should deserve attention in gastric microbiota studies.

Machine Learning and Pharmacogenomics at the Time of Precision Psychiatry.

Traditional medicine and biomedical sciences are reaching a turning point because of the constantly growing impact and volume of Big Data. Machine Learning (ML) techniques and related algorithms play a central role as diagnostic, prognostic, and decision-making tools in this field. Another promising area becoming part of everyday clinical practice is personalized therapy and pharmacogenomics. Applying ML to pharmacogenomics opens new frontiers to tailored therapeutical strategies to help clinicians choose drugs with the best response and fewer side effects, operating with genetic information and combining it with the clinical profile. This systematic review aims to draw up the state-of-the-art ML applied to pharmacogenomics in psychiatry. Our research yielded fourteen papers; most were published in the last three years. The sample comprises 9,180 patients diagnosed with mood disorders, psychoses, or autism spectrum disorders. Prediction of drug response and prediction of side effects are the most frequently considered domains with the supervised ML technique, which first requires training and then testing. The random forest is the most used algorithm; it comprises several decision trees, reduces the training set's overfitting, and makes precise predictions. ML proved effective and reliable, especially when genetic and biodemographic information were integrated into the algorithm. Even though ML and pharmacogenomics are not part of everyday clinical practice yet, they will gain a unique role in the next future in improving personalized treatments in psychiatry.