In vitro selection of resistance in Streptococcus pneumoniae at in vivo fluoroquinolone concentrations

Methods: Twenty strains of S. pneumoniae susceptible to fluoroquinolones were used. The frequencies of spontaneous single-step mutations at plasma and epithelial lining fluid (ELF) peak and trough antibiotic concentrations were calculated. Multi-step selection of resistance was evaluated by performing 10 serial subcultures on agar plates containing a linear gradient from peak to trough antimicrobial concentrations, followed by 10 subcultures on antibiotic-free agar. Resistant strains selected after multi-step selection were characterized for DNA mutations by sequencing gyrA, gyrB, parC and parE genes. Results: Levofloxacin and moxifloxacin showed the lowest frequencies of mutations (median <10 211 ) at plasma peak and at ELF concentrations, while medians ranging from 10 28 to 10 26 were observed for ciprofloxacin and prulifloxacin. In a multi-step selection assay, ciprofloxacin and prulifloxacin selected for the highest number of resistant strains (19 and 31, respectively). No selection of resistance was observed for levofloxacin at ELF concentrations and for moxifloxacin at plasma and ELF concentrations. Mutations in parC, parE and gyrA genes were found in ciprofloxacin- and prulifloxacinresistant strains, while only parC mutations were found for levofloxacin. Conclusions: Levofloxacin and moxifloxacin are characterized by a lower propensity to select in vitro for resistance in S. pneumoniae than ciprofloxacin and prulifloxacin, when tested at plasma and lung concentrations

Social cognition in people with schizophrenia: A cluster-analytic approach

Background The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. Method A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. Results We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI &lt;10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. Conclusions If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person

Social cognition in people with schizophrenia: A cluster-analytic approach

Background The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. Method A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. Results We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI <10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. Conclusions If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Vitamin-D-Mangel in der Schweizer Sonnenstube?

In dieser Studie wurden die Prävalenz sowie saisonale Fluktuationen des VitD-Mangels bei Bewohnern des Tessins evaluiert. Klinische Indikatoren zur Erkennung eines VitD-Mangelzustands wurden untersucht (Alter, Geschlecht, Hauptdiagnose, Komorbiditäten, Medikamentenanzahl). Beim Eintreffen auf der Notfallstation des Regionalspitals Bellinzona wurde bei je einer Population älterer internistischer Patienten eine einmalige VitD-Serumspiegelbestimmung im Frühling (n = 58) und im Herbst (n = 49) durchgeführt. Die Prävalenz des VitD-Mangels im Frühling betrug 98 % (Serumspiegelmittelwert 21,4±12,2 nmol/l) versus 63 % im Herbst (Serumspiegelmittelwert 43,7±18,6 nmol/l). Auch nach dem Sommer litten 66 % der Patienten an einem VitD-Mangel. Es konnten keine verlässlichen Indikatoren eruiert werden. Angesichts dieser Ergebnisse und der BAG-Empfehlungen ist eine Prophylaxe mit 800 IE täglich bei allen älteren Schweizern, v.a. im Winter, sinnvoll. Diese Präventionsmassnahme ist kostengünstig, einfach, sicher und effektiv

The performance of levothyroxine tablet is impaired by bariatric surgery

Objective The aim was to evaluate if bariatric surgery can affect the LT4 performance. The endpoints were the following: 1) difference between LT4 daily dose before and 1 year after surgery, 2) difference between LT4 dose per weight before and 1 year after surgery, 3) difference among LT4 preparations. Methods The study period was between January 2018 and May 2022. Inclusion criteria were a) adults undergone bariatric surgery, b) with proven autoimmune hypothyroidism, c) on LT4 therapy before bariatric surgery, d) using any commercialized LT4 preparation. Excluded were patients a) proven to have or suspected for pre-surgical intestinal malabsorption, b) with other potential interfering factors on LT4 absorption; c) with heart, renal, and/or hepatic failure, d) with recent/current infection/inflammation, e) in pregnancy, f) with incomplete data about LT4 therapy. Results According to the selection criteria, 40 patients were included. Both TSH and LT4 daily doses were not significantly different with respect to baseline values. On the contrary, the LT4 dose per weight was significantly increased, especially in RYGB patients. An increased LT4 dose per weight was observed with the reduction of weight. ConclusionOne year after bariatric surgery 1) the daily dose of LT4 remains unchanged, and 2) despite the significant weight reduction, LT4 dose per weight increases. Most data are referred to LT4 tablet and the performance of LT4 caps should be further investigated

The Two pore Potassium Channel THIK-1 Regulates NLRP3 Inflammasome Activation

The NLRP3 (NLR family, pyrin domain containing 3) inflammasome is a multi‐protein complex responsible for the activation of caspase‐1 and the subsequent cleavage and activation of the potent proinflammatory cytokines IL‐1β and IL‐18, and pyroptotic cell death. NLRP3 is implicated as a driver of inflammation in a range of disorders including neurodegenerative diseases, type 2 diabetes, and atherosclerosis. A commonly reported mechanism contributing to NLRP3 inflammasome activation is potassium ion (K(+)) efflux across the plasma membrane. Identification of K(+) channels involved in NLRP3 activation remains incomplete. Here, we investigated the role of the K(+) channel THIK‐1 in NLRP3 activation. Both pharmacological inhibitors and cells from THIK‐1 knockout (KO) mice were used to assess THIK‐1 contribution to macrophage NLRP3 activation in vitro. Pharmacological inhibition of THIK‐1 inhibited caspase‐1 activation and IL‐1β release from mouse bone‐marrow‐derived macrophages (BMDMs), mixed glia, and microglia in response to NLRP3 agonists. Similarly, BMDMs and microglia from THIK‐1 KO mice had reduced NLRP3‐dependent IL‐1β release in response to P2X7 receptor activation with ATP. Overall, these data suggest that THIK‐1 is a regulator of NLRP3 inflammasome activation in response to ATP and identify THIK‐1 as a potential therapeutic target for inflammatory disease

Evaluation of the Performance of ACR TI-RADS Also Considering Those Nodules with No Indication of FNAC: A Single-Center Experience

Background: Several US risk stratification score systems (RSSs) have been developed to standardize a thyroid nodule risk of malignancy. It is still a matter of debate which RSS is the most reliable. The purpose of this study is to evaluate: (1) the concordance between the American College of Radiology TI-RADS (ACR TI-RADS) and fine needle aspiration cytology (FNAC), (2) the cancer rate in the ACR TI-RADS categories, (3) the characteristics of nodules evaluated by FNAC even if not formally indicated according to ACR TI-RADS (‘not indicated FNACs”). Methods: From January 2021 to September 2022, patients attending the Endocrinology Unit of the CTO Hospital of Rome for evaluation of thyroid nodules were included. Results: 830 nodules had negative cytology, belonging to TIR2 and TIR1C. One hundred and thirteen nodules were determined to be suspicious for or consistent with malignancy belonging to TIR3B/TIR4/TIR5. Of this last group, 94% were classified as TR4/TR5 nodules. In total, 87/113 underwent surgery. Among these, 73 had histologically proven cancer, 14 turned out to be benign. “Not indicated FNACs” was 623. Among these, 42 cancers were present. Conclusions: This study confirmed the diagnostic power of ACR TI-RADS. In addition, these data suggest revising the ACR TI-RADS indication to FNAC, especially for TR4

Effects of in-utero exposure to chemotherapy on fetal brain growth

OBJECTIVE: Children exposed to chemotherapy in the prenatal period demonstrate normal neurocognitive development at 3 years but concerns regarding fetal brain growth remain high considering its vulnerability to external stimuli. Our aim was to evaluate the impact of in-utero chemotherapy exposure on brain growth and its effects on neurodevelopmental outcome. METHODS: The protocol was approved by the local ethics committee. Brain regional volumes at term postmenstrual age were measured by MRI in children exposed to in-utero chemotherapy and compared with normal MRI controls. Brain segmentation was performed by Advanced Normalization Tools (ANTs)-based transformations of the Neonatal Brain Atlas (ALBERT). Neurodevelopmental assessment (Bayley-III scales) was performed at 18 months corrected age in both exposed infants and in a group of healthy controls. Multiple linear regressions and false discovery rate correction for multiple comparisons were performed. RESULTS: Twenty-one newborns prenatally exposed to chemotherapy (epirubicin administered in 81% of mothers) were enrolled in the study: the mean gestational age was 36.4±2.4 weeks and the mean birthweight was 2,753±622 g. Brain MRI was performed at mean postmenstrual age of 41.1±1.4 weeks. No statistically significant differences were identified between the children exposed to chemotherapy and controls in both the total (398±55 cm3 vs 427±56 cm3, respectively) and regional brain volumes. Exposed children showed normal Bayley-III scores (cognitive 110.2±14.5, language 99.1±11.3, and motor 102.6±7.3), and no significant correlation was identified between the brain volumes and neurodevelopmental outcome. CONCLUSION: Prenatal exposure to anthracycline/cyclophosphamide-based chemotherapy does not impact fetal brain growth, thus supporting the idea that oncological treatment in pregnant women seems to be feasible and safe for the fetus.status: publishe