Xanthan-based chlorhexidine gel effects in non-surgical periodontal therapy? A meta-analysis.

OBJECTIVE: To carry out a systematic review and meta-analysis of randomized controlled clinical trials (RCTs) and controlled clinical trials (CCTs) comparing scaling and root planing (SRP) or placebo with subgingival application of xanthan-based CHX (chlorhexidine) gel as adjunct to SRP. MATERIALS AND METHODS: The literature search was carried out in PubMed/MEDLINE, EMBASE, and SCOPUS; primary outcomes were probing pocket depth (PPD) reduction and gain in clinical attachment level (CAL). RESULTS: Overall, 15 studies were included. Three studies were judged to be at moderate risk of bias while the remaining 12 were rated at high risk of bias. A significant improvement in PPD reduction (standardized mean difference, SMD, 0.87, 95% CI, 0.41-1.34) and CAL gain (SMD = 0.84, 95% CI, 0.36-1.33) emerged for the SRP + CXH gel compared to the SRP alone group, in the presence of significant high heterogeneity among the studies. CONCLUSIONS: Our systematic review and meta-analysis showed that xanthan-based chlorhexidine gel as adjunct to non-surgical periodontal therapy gives benefit in terms of PPD reduction and CAL gain as compared to non-surgical periodontal therapy only. Since there was high heterogeneity among studies and the quality of the evidence is low, further studies characterized by a better methodology, adequate sample size and longer follow-up are warranted in the next future. REGISTRATION: The protocol of this scoping review was registered in the International Prospective Register of Systematic Reviews (https://www.crd.york.ac.uk/PROSPERO) with ID: CRD42023391589.

The effect of weight gain and metabolic dysfunction-associated steatotic liver disease on liver fibrosis progression and regression in people with HIV.

OBJECTIVE: People with HIV (PWH) have high risk of liver fibrosis. We investigated the effect of weight gain and metabolic dysfunction-associated steatotic liver disease (MASLD) on liver fibrosis dynamics. DESIGN: Multicenter cohort study. METHODS: Fibrosis progression was defined as development of significant fibrosis (liver stiffness measurement [LSM]≥8 kPa), or transition to cirrhosis (LSM≥13 kPa), for those with significant fibrosis at baseline. Fibrosis regression was defined as transition to LSM<8 kPa, or to LSM<13 kPa for those with cirrhosis at baseline. MASLD was defined as hepatic steatosis (controlled attenuation parameter >248 dB/m) with at least one metabolic abnormality. A continuous-time multi-state Markov model was used to describe transitions across fibrosis states. RESULTS: Among 1183 PWH included from three centres (25.2% with viral hepatitis coinfection), baseline prevalence of significant fibrosis and MASLD was 14.4% and 46.8%, respectively. During a median follow-up of 2.5 years (interquartile range 1.9-3.5) the incidence rate of fibrosis progression and regression was 2.8 (95% CI, 2.3-3.4) and 2.2 (95% CI, 1.9-2.6) per 100 person-years, respectively. In Markov model, weight gain increased the odds of fibrosis progression (odds ratio [OR] 3.11, 95% CI 1.59-6.08), whereas weight gain (OR 0.30, 95% CI 0.10-0.84) and male sex (OR 0.32, 95% CI 0.14-0.75) decreased the odds of fibrosis regression. On multivariable Cox regression analysis, predictors of fibrosis progression were weight gain (adjusted hazard ratio [aHR] 3.12, 95% CI 1.41-6.90) and MASLD (aHR 2.72, 95% CI 1.05-7.02). CONCLUSIONS: Fibrosis transitions are driven by metabolic health variables in PWH, independently of viral hepatitis coinfection and antiretroviral class therapy.

The CDK Inhibitor Dinaciclib Improves Cisplatin Response in Nonseminomatous Testicular Cancer: A Preclinical Study.

BACKGROUND: Most patients with testicular germ cell tumors (GCTs) are treated with cisplatin (CP)-based chemotherapy. However, some of them may develop CP resistance and therefore represent a clinical challenge. Cyclin-dependent kinase 5 (CDK5) is involved in chemotherapy resistance in different types of cancer. Here, we investigated the possible role of CDK5 and other CDKs targeted by dinaciclib in nonseminoma cell models (both CP-sensitive and CP-resistant), evaluating the potential of the CDK inhibitor dinaciclib as a single/combined agent for the treatment of advanced/metastatic testicular cancer (TC). METHODS: The effects of dinaciclib and CP on sensitive and resistant NT2/D1 and NCCIT cell viability and proliferation were evaluated using MTT assays and direct count methods. Flow cytometry cell-cycle analysis was performed. The protein expression was assessed via Western blotting. The in vivo experiments were conducted in zebrafish embryos xenografted with TC cells. RESULTS: Among all the CDKs analyzed, CDK5 protein expression was significantly higher in CP-resistant models. Dinaciclib reduced the cell viability and proliferation in each cell model, inducing changes in cell-cycle distribution. In drug combination experiments, dinaciclib enhances the CP effect both in vitro and in the zebrafish model. CONCLUSIONS: Dinaciclib, when combined with CP, could be useful for improving nonseminoma TC response to CP.

Topical Antiseptics in Minimizing Ocular Surface Bacterial Load Before Ophthalmic Surgery: A Randomized Controlled Trial.

PURPOSE: To investigate the reduction of the ocular surface bacterial load induced by 2 commercially available ophthalmic antiseptic formulations, povidone-iodine (PVI) 0.6% and chlorhexidine (CLX) 0.02%, before ocular surgery. DESIGN: Randomized controlled trial. METHODS: Seventy adult patients undergoing intraocular surgery (phacoemulsification) were randomized to receive in the index eye PVI (group A) 4 times a day for 3 days or CLX (group B) 4 times a day for 3 days before surgery. The untreated eye was used as control. A conjunctival swab was taken in both eyes before (T0) and after (T1) therapy. Microbial DNA was quantified with real-time polymerase chain reaction (PCR) analysis. The Mick algorithm was used to compare the abundance of each genus/genera against the distribution of abundances from the reference. At T1, patients filled a questionnaire to evaluate therapy-induced symptoms. Primary outcome was the reduction of bacterial DNA at T1 (microbial load), vs control arm, expressed as mean number of real-time PCR cycle times (CTs). Secondary outcomes were taxonomic composition, differential abundance, and therapy-induced ocular symptoms. RESULTS: The T0-T1 difference in CT was significant in group B, but not in group A (mean [95% CI], 0.99 [0.33] vs 0.26 [0.15], P < .001, and 0.65 [0.3] vs 0.45 [0.41], P = .09, respectively). The taxonomic composition, alpha, and beta diversity remained consistent at all time points in both groups. The rate of patients reporting therapy-induced ocular symptoms and the mean discomfort grade were greater in group A than in group B (97% vs 26% and 4.97±2.48 vs 0.66±1.53, respectively). CONCLUSIONS: Compared with PVI 0.6%, CLX 0.02% induced a greater reduction of ocular surface bacterial load, with no significant alterations of the taxonomic composition. Moreover, CLX was better tolerated than PVI.

Stability of circulating miRNA in saliva: The influence of sample associated pre-analytical variables.

BACKGROUND AND AIMS: Increasing evidence supports the practicability of salivary cell-free (cf) miRNA as liquid biopsy markers in cancers. Its successful translation in the clinical setting requires reproducible approaches for saliva manipulation, in order to control for pre-analytical variables influencing miRNA stability. This study aims to define the optimal conditions to maintain the integrity of saliva during collection, transport and processing with respect to cf-miRNA quantification. MATERIALS AND METHODS: Saliva was collected from 20 healthy subjects and 8 oral cancer patients. Two sampling methods were tested and different storage temperatures and times were evaluated. Salivary expression level of target miRNAs was quantified by qPCR. Comparison between group mean values at specific conditions were performed using paired t-tests. Agreement between measurements was evaluated using a Bland-Altman plot. RESULTS: Different collection methods revealed comparable levels of salivary miR-484 and miR-106b-5p in both subject cohorts. MiRNAs were stable for up to 48 h at 4 °C in saliva supernatant, showing significant alteration after 96 h. Mid-term storage of supernatant at -20 °C decreased miRNA stability significantly compared to standard -80 °C. CONCLUSIONS: Cf-miRNA in saliva were slightly altered by collection methods and storage conditions, both in healthy and in pathological contexts, and remained stable for a period of time compatible with main clinical routine needs.

Electrophysiological neuromuscular alterations and severe fatigue predict long-term muscle weakness in survivors of COVID-19 acute respiratory distress syndrome.

Introduction: Long-term weakness is common in survivors of COVID-19-associated acute respiratory distress syndrome (CARDS). We longitudinally assessed the predictors of muscle weakness in patients evaluated 6 and 12 months after intensive care unit discharge with in-person visits. Methods: Muscle strength was measured by isometric maximal voluntary contraction (MVC) of the tibialis anterior muscle. Candidate predictors of muscle weakness were follow-up time, sex, age, mechanical ventilation duration, use of steroids in the intensive care unit, the compound muscle action potential of the tibialis anterior muscle (CMAP-TA-S100), a 6-min walk test, severe fatigue, depression and anxiety, post-traumatic stress disorder, cognitive assessment, and body mass index. We also compared the clinical tools currently available for the evaluation of muscle strength (handgrip strength and Medical Research Council sum score) and electrical neuromuscular function (simplified peroneal nerve test [PENT]) with more objective and robust measures of force (MVC) and electrophysiological evaluation of the neuromuscular function of the tibialis anterior muscle (CMAP-TA-S100) for their essential role in ankle control. Results: MVC improved at 12 months compared with 6 months. CMAP-TA-S100 (P = 0.016) and the presence of severe fatigue (P = 0.036) were independent predictors of MVC. MVC was strongly associated with handgrip strength, whereas CMAP-TA-S100 was strongly associated with PENT. Discussion: Electrical neuromuscular abnormalities and severe fatigue are independently associated with reduced MVC and can be used to predict the risk of long-term muscle weakness in CARDS survivors.

Bone Mineral Density and Trabecular Bone Score Changes throughout Menopause in Women with HIV.

OBJECTIVE: The objectives of this study were to describe the trajectories of bone mineral density (BMD) and trabecular bone score (TBS) changes throughout pre-menopause (reproductive phase and menopausal transition) and post-menopause (early and late menopause) in women with HIV (WWH) undergoing different antiretroviral therapies (ARTs) and explore the risk factors associated with those changes. METHODS: This was an observational longitudinal retrospective study in WWH with a minimum of two DEXA evaluations comprising BMD and TBS measurements, both in the pre-menopausal and post-menopausal periods. Menopause was determined according to the STRAW+10 criteria, comprising four periods: the reproductive period, menopausal transition, and early- and late-menopausal periods. Mixed-effects models were fitted to estimate the trajectories of the two outcomes (BMD and TBS) over time. Annualized lumbar BMD and TBS absolute and percentage changes were calculated in each STRAW+10 time window. A backward elimination procedure was applied to obtain the final model, including the predictors that affected the trajectories of BMD or TBS over time. RESULTS: A total of 202 WWH, all Caucasian, were included. In detail, 1954 BMD and 195 TBS data were analyzed. The median number of DEXA evaluations per woman was 10 (IQR: 7, 12). The median observation periods per patient were 12.0 years (IQR = 8.9-14.4) for BMD and 6.0 years (IQR: 4.3, 7.9) for TBS. The prevalence of osteopenia (63% vs. 76%; p < 0.001) and osteoporosis (16% vs. 36%; p < 0.001) increased significantly between the pre-menopausal and post-menopausal periods. Both BMD (1.03 (±0.14) vs. 0.92 (±0.12) g/cm2; p < 0.001) and TBS (1.41 (IQR: 1.35, 1.45) vs. 1.32 (IQR: 1.28, 1.39); p < 0.001) decreased significantly between the two periods. The trend in BMD decreased across the four STRAW+10 periods, with a slight attenuation only in the late-menopausal period when compared with the other intervals. The TBS slope did not significantly change throughout menopause. The delta mean values of TBS in WWH were lower between the menopausal transition and reproductive period compared with the difference between menopause and menopausal transition. CONCLUSIONS: Both BMD and TBS significantly decreased over time. The slope of the change in BMD and TBS significantly decreased in the menopausal transition, suggesting that this period should be considered by clinicians as a key time during which to assess bone health and modifiable risk factors in WWH.

The burden of rare variants in DPYS gene is a novel predictor of the risk of developing severe fluoropyrimidine-related toxicity.

BACKGROUND: Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity. METHODS: The coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3-5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework). RESULTS: SKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann-Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity. CONCLUSION: This work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation.

Academic skills in children with cerebral palsy and specific learning disorders.

AIM: To investigate the prevalence and clinical manifestations of reading, writing, and mathematics disorders in children with cerebral palsy (CP). We explored how the clinical profile of these children differed from those with specific learning disorders (SLDs), taking into account several factors, particularly IQ scores, neuropsychological aspects, and the presence of a visual impairment. METHOD: A prospective cross-sectional study was conducted in 42 children with CP (mean age 9 years 8 months; SD = 2 years 2 months) and 60 children with SLDs (mean age 10 years; SD = 1 year 7 months). Clinical characteristics, neuromotor and cognitive profiles, neuropsychological aspects (speech performance, academic skills, visual attention, phonological awareness, working memory), and signs of visual impairment (visual acuity, contrast sensitivity, visual field, oculomotor functions) were assessed. A machine learning approach consisting of a random forest algorithm, where the outcome was the diagnosis and the covariates were the clinical variables collected in the sample, was used for the analyses. RESULTS: About 59% of the children with CP had reading, writing, or mathematics disorders. Children with CP with learning disorders had a low performance IQ, normal phonological awareness, and working memory difficulties, whereas children with SLDs had normal performance IQ, impaired phonological awareness, and mild working memory difficulties. There were no differences in verbal IQ between the two groups. INTERPRETATION: Learning disorders are frequently associated with CP, with different clinical characteristics, compared with SLDs. Assessment of academic skills is mandatory in these children, even if the IQ is normal. At school age, specific interventions to promote academic skills in children with CP could be a major rehabilitative goal.

Ecological monitoring of physical activity, emotions and daily life activities in schizophrenia: the DiAPAson study.

BACKGROUND: Schizophrenia spectrum disorders (SSD) compromise psychosocial functioning, including daily time use, emotional expression and physical activity (PA). OBJECTIVE: We performed a cohort study aimed at investigating: (1) the differences in PA, daily activities and emotions between patients with SSD and healthy controls (HC); (2) the strength of the association between these variables and clinical features among patients with SSD. METHODS: Ninety-nine patients with SSD (53 residential patients, 46 outpatients) and 111 matched HC were assessed for several clinical variables, and levels of functioning by means of standardised clinical measures. Self-reported daily activities and emotions were assessed with a smartphone application for ecological momentary assessment (EMA), and PA levels were assessed with a wearable accelerometer for 7 consecutive days.FindingsPatients with SSD, especially those living in residential facilities, spent more time being sedentary, and self-reported more sedentary and self-care activities, experiencing higher levels of negative emotions compared with HC. Moreover, higher functioning levels among patients were associated with more time spent in moderate-to-vigorous activity. CONCLUSIONS: Sedentary behaviour and negative emotions are particularly critical among patients with SSD and are associated with more impaired clinical outcomes. CLINICAL IMPLICATIONS: Mobile-EMA and wearable sensors are useful for monitoring the daily life of patients with SSD and the level of PA. This population needs to be targeted with specific rehabilitative programmes aimed at improving their commitment to structured daily activities.

Preoperative surgeon evaluation of corneal endothelial status: the Viability Control of Human Endothelial Cells before Keratoplasty (V-CHECK) study protocol.

INTRODUCTION: The success of keratoplasty strongly depends on the health status of the transplanted endothelial cells. Donor corneal tissues are routinely screened for endothelial damage before shipment; however, surgical teams have currently no means of assessing the overall viability of corneal endothelium immediately prior to transplantation. The aim of this study is to validate a preoperative method of evaluating the endothelial health of donor corneal tissues, to assess the proportion of tissues deemed suitable for transplantation by the surgeons and to prospectively record the clinical outcomes of a cohort of patients undergoing keratoplasty in relation to preoperatively defined endothelial viability. METHODS AND ANALYSIS: In this multicentre cohort study, consecutive patients undergoing keratoplasty (perforating keratoplasty, Descemet stripping automated endothelial keratoplasty (DSAEK), ultra-thin DSAEK (UT-DSAEK) or Descemet membrane endothelial keratoplasty) will be enrolled and followed-up for 1 year. Before transplantation, the endothelial viability of the donor corneal tissue will be evaluated preoperatively through trypan blue staining and custom image analysis to estimate the overall percentage of trypan blue-positive areas (TBPAs), a proxy of endothelial damage. Functional and structural outcomes at the end of the follow-up will be correlated with preoperatively assessed TBPA values. ETHICS AND DISSEMINATION: The protocol will be reviewed by the ethical committees of participating centres, with the sponsor centre issuing the final definitive approval. The results will be disseminated on ClinicalTrials.gov, at national and international conferences, by partner patient groups and in open access, peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05847387.

Sarcopenic Obesity Phenotypes in Patients With HIV: Implications for Cardiovascular Prevention and Rehabilitation.

BACKGROUND: We aimed to describe prevalence, incidence, and risk factors for sarcopenic obesity (SO) phenotypes in people living with HIV (PWH) and their association with subclinical cardiovascular disease (CVD). METHODS: Observational, longitudinal study of PWH. A minimum of 1 criterion was necessary to diagnose sarcopenia: weak hand grip (HG), low appendicular skeletal muscle index (ASMI), short physical performance battery (SPPB < 11). Obesity was defined as body mass index (BMI) ≥ 30 kg/m2 or visceral adipose tissue (VAT) ≥ 160 cm2. These variables combined generated 5 SO phenotypes: severe SO: low HG + low ASMI + low SPPB + high BMI; SO1: weak HG + high VAT; SO2: weak HG + high BMI; SO3: low ASMI + high VAT; SO4: low ASMI + high BMI. Subclinical CVD was defined as carotid intima-media thickness (IMT) ≥ 1 mm, presence of carotid plaque, or coronary artery calcification (CAC) score > 10. RESULTS: Among 2379 male PWH 72%, median age was 52 years, median HIV vintage 21 years, and median BMI 24 kg/m2. Two PWH had severe SO. The prevalence of SO1-SO4 was 19.7%, 3.6%, 20.8% and 0.8%, respectively. Incidence of SO1-SO4 was 6.90, 1.2, 5.6, and 0.29 × 100 person-years, respectively. SO1 was associated with risk of IMT ≥ 1, and SO3 with risk of CAC score > 10. CONCLUSIONS: There was a large variability in incidence and prevalence of SO phenotypes. The presence of SO may have important implications for cardiovascular prevention and cardiac rehabilitation of PWH who suffered events.

Interplay between negative symptoms, time spent doing nothing, and negative emotions in patients with schizophrenia spectrum disorders: results from a 37-site study.

This study evaluated the relationship between negative symptoms, daily time use (productive/non-productive activities, PA/NPA), and negative emotions in schizophrenia-spectrum disorders (SSDs): 618 individuals with SSDs (311 residential care patients [RCPs], 307 outpatients) were surveyed about socio-demographic, clinical (BPRS, BNSS) and daily time use (paper-and-pencil Time Use Survey completed twice/week) characteristics. Among them 57 RCPs and 46 outpatients, matched to 112 healthy controls, also underwent ecological monitoring of emotions (8 times/day for a week) through Experience Sampling Method (ESM). RCPs spent significantly less time in PA than outpatients. Patients with more negative symptomatology spent more time in NPA and less in PA compared to patients with milder symptoms. Higher time spent in NPA was associated with negative emotions (p < 0.001 during workdays) even when correcting for BNSS total and antipsychotic polypharmacy (p = 0.002 for workdays, p = 0.006 for Sundays). Future studies are needed to explore in more detail the relationship between negative emotions, negative symptoms, time use, and functioning in individuals with SSDs, providing opportunities for more informed and personalised clinical treatment planning and research into interactions between different motivational, saliency and behavioural aspects in individuals with SSDs.

Feasibility of the pupillary pain index as a guide for depth of analgesia during opioid-sparing anesthesia with continuous infusion of dexmedetomidine.

BACKGROUND: The pupillary dilation reflex (PDR) is an objective indicator of analgesic levels in anesthetized patients. Through measurement of the PDR during increasing tetanic stimulation (10-60 mA), it is possible to obtain the pupillary pain index (PPI), a score that assesses the level of analgesia. OBJECTIVES: The depth of analgesia during opioid-sparing anesthesia (OSA) with continuous infusion of dexmedetomidine in addition to general anesthesia was assessed. DESIGN: Observational prospective feasibility pilot study SETTING: This study was performed in the operating rooms of the Spedali Civili University-affiliated hospital of Brescia, Italy. PATIENTS: Forty-five adults who underwent elective open (5-cm incision) surgery under general anesthesia (78% inhalation anesthesia), from Feb. 18th to Aug. 1st, 2019, were enrolled. Exclusion criteria were as follows: implanted pacemaker or ICD, ophthalmological comorbidities, chronic opioid use, peripheral neuropathy, other adjuvant drugs, epidural analgesia, or locoregional block. MAIN OUTCOME MEASURES: The first aim was to verify the feasibility of applying a study protocol to evaluate the depth of analgesia during intraoperative dexmedetomidine administration using an instrumental pupillary evaluation. The secondary outcome was to evaluate appropriate analgesia, drug dosage, anesthesia depth, heart rate, blood pressure, transient side effects, postoperative nausea and vomiting (PONV), and pain numerical rating scale (NRS) score. RESULTS: Thirty out of 50 patients (60%) treated with dexmedetomidine during the study period were included in the DEX group (8 males, age 42 ± 13 years, BMI 45 ± 8), and 15 other patients were included in the N-DEX group (8 males, age 62 ± 13 years, BMI 26 ± 6). Patients who underwent bariatric, abdominal, or plastic surgery were enrolled. At least 3 pupillary evaluations were taken for each patient. PPI ≤ 3 was observed in 97% of patients in the DEX group and 53% in the N-DEX group. Additionally, the DEX group received less than half the remifentanil dose than the N-DEX group (0.13 ± 0.07 vs 0.3 ± 0.11 mcg kg-1 min-1). The average dose of dexmedetomidine administered was 0.17 ± 0.08 mcg kg-1 h-1. CONCLUSION: The feasibility of applying the protocol was verified. An OSA strategy involving dexmedetomidine may be associated with improved analgesic stability: a randomized controlled trial is necessary to verify this hypothesis. TRIAL REGISTRATION: Trial.gov registration number: NCT05785273.

A weighted quantile sum regression with penalized weights and two indices.

Background: New statistical methodologies were developed in the last decade to face the challenges of estimating the effects of exposure to multiple chemicals. Weighted Quantile Sum (WQS) regression is a recent statistical method that allows estimating a mixture effect associated with a specific health effect and identifying the components that characterize the mixture effect. Objectives: In this study, we propose an extension of WQS regression that estimates two mixture effects of chemicals on a health outcome in the same model through the inclusion of two indices, one in the positive direction and one in the negative direction, with the introduction of a penalization term. Methods: To evaluate the performance of this new model we performed both a simulation study and a real case study where we assessed the effects of nutrients on obesity among adults using the National Health and Nutrition Examination Survey (NHANES) data. Results: The method showed good performance in estimating both the regression parameter and the weights associated with the single elements when the penalized term was set equal to the magnitude of the Akaike information criterion of the unpenalized WQS regression. The two indices further helped to give a better estimate of the parameters [Positive direction Median Error (PME): 0.022; Negative direction Median Error (NME): -0.044] compared to the standard WQS without the penalization term (PME: -0.227; NME: 0.215). In the case study, WQS with two indices was able to find a significant effect of nutrients on obesity in both directions identifying sodium and magnesium as the main actors in the positive and negative association, respectively. Discussion: Through this work, we introduced an extension of WQS regression that improved the accuracy of the parameter estimates when considering a mixture of elements that can have both a protective and a harmful effect on the outcome; and the advantage of adding a penalization term when estimating the weights.

FGF-trapping hampers cancer stem-like cells in uveal melanoma.

BACKGROUND: Cancer stem-like cells (CSCs) are a subpopulation of tumor cells responsible for tumor initiation, metastasis, chemoresistance, and relapse. Recently, CSCs have been identified in Uveal Melanoma (UM), which represents the most common primary tumor of the eye. UM is highly resistant to systemic chemotherapy and effective therapies aimed at improving overall survival of patients are eagerly required. METHODS: Herein, taking advantage from a pan Fibroblast Growth Factor (FGF)-trap molecule, we singled out and analyzed a UM-CSC subset with marked stem-like properties. A hierarchical clustering of gene expression data publicly available on The Cancer Genome Atlas (TCGA) was performed to identify patients' clusters. RESULTS: By disrupting the FGF/FGF receptor (FGFR)-mediated signaling, we unmasked an FGF-sensitive UM population characterized by increased expression of numerous stemness-related transcription factors, enhanced aldehyde dehydrogenase (ALDH) activity, and tumor-sphere formation capacity. Moreover, FGF inhibition deeply affected UM-CSC survival in vivo in a chorioallantoic membrane (CAM) tumor graft assay, resulting in the reduction of tumor growth. At clinical level, hierarchical clustering of TCGA gene expression data revealed a strong correlation between FGFs/FGFRs and stemness-related genes, allowing the identification of three distinct clusters characterized by different clinical outcomes. CONCLUSIONS: Our findings support the evidence that the FGF/FGFR axis represents a master regulator of cancer stemness in primary UM tumors and point to anti-FGF treatments as a novel therapeutic strategy to hit the CSC component in UM.

Shared and distinct abnormalities in sleep-wake patterns and their relationship with the negative symptoms of Schizophrenia Spectrum Disorder patients.

Sleep and rest-activity-rhythm (RAR) abnormalities are commonly reported in schizophrenia spectrum disorder (SSD) patients. However, an in-depth characterization of sleep/RAR alterations in SSD, including patients in different treatment settings, and the relationship between these alterations and SSD clinical features (e.g., negative symptoms) is lacking. SSD (N = 137 altogether, N = 79 residential and N = 58 outpatients) and healthy control (HC) subjects (N = 113) were recruited for the DiAPAson project. Participants wore an ActiGraph for seven consecutive days to monitor habitual sleep-RAR patterns. Sleep/rest duration, activity (i.e., M10, calculated on the 10 most active hours), rhythm fragmentation within days (i.e., intra-daily variability, IV; beta, steepness of rest-active changes), and rhythm regularity across days (i.e., inter-daily stability, IS) were computed in each study participant. Negative symptoms were assessed in SSD patients with the Brief Negative Symptom Scale (BNSS). Both SSD groups showed lower M10 and longer sleep/rest duration vs. HC, while only residential patients had more fragmented and irregular rhythms than HC. Compared to outpatients, residential patients had lower M10 and higher beta, IV and IS. Furthermore, residential patients had worse BNSS scores relative to outpatients, and higher IS contributed to between-group differences in BNSS score severity. Altogether, residentials and outpatients SSD had both shared and unique abnormalities in Sleep/RAR measures vs. HC and relative to one another, which also contributed to the patients' negative symptom severity. Future work will help establish whether improving some of these measures may ameliorate the quality of life and clinical symptoms of SSD patients.

Comprehensive transcriptomic analysis to identify biological and clinical differences in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CC) is a rare and aggressive disease with limited therapeutic options and a poor prognosis. All available public records of cohorts reporting transcriptomic data on intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) were collected with the aim to provide a comprehensive gene expression-based classification with clinical relevance. METHODS: A total of 543 patients with primary tumor tissues profiled by RNAseq and microarray platforms from seven public datasets were used as a discovery set to identify distinct biological subgroups. Group predictors developed on the discovery sets were applied to a single cohort of 131 patients profiled with RNAseq for validation and assessment of clinical relevance leveraging machine learning techniques. RESULTS: By unsupervised clustering analysis of gene expression data we identified both in the ICC and ECC discovery datasets four subgroups characterized by a distinct type of immune infiltrate and signaling pathways. We next developed class predictors using short gene list signatures and identified in an independent dataset subgroups of ICC tumors at different prognosis. CONCLUSIONS: The developed class-predictor allows identification of CC subgroups with specific biological features and clinical behavior at single-sample level. Such results represent the starting point for a complete molecular characterization of CC, including integration of genomics data to develop in clinical practice.

Long-term physical impairments in survivors of COVID-19-associated ARDS compared with classic ARDS: A two-center study.

PURPOSE: This work aimed to compare physical impairment in survivors of classic ARDS compared with COVID-19-associated ARDS (CARDS) survivors. MATERIAL AND METHODS: This is a prospective observational cohort study on 248 patients with CARDS and compared them with a historical cohort of 48 patients with classic ARDS. Physical performance was evaluated at 6 and 12 months after ICU discharge, using the Medical Research Council Scale (MRCss), 6-min walk test (6MWT), handgrip dynamometry (HGD), and fatigue severity score (FSS). We also assessed activities of daily living (ADLs) using the Barthel index. RESULTS: At 6 months, patients with classic ARDS had lower HGD (estimated difference [ED]: 11.71 kg, p < 0.001; ED 31.9% of predicted value, p < 0.001), 6MWT distance (ED: 89.11 m, p < 0.001; ED 12.96% of predicted value, p = 0.032), and more frequent significant fatigue (OR 0.35, p = 0.046). At 12 months, patients with classic ARDS had lower HGD (ED: 9.08 kg, p = 0.0014; ED 25.9% of predicted value, p < 0.001) and no difference in terms of 6MWT and fatigue. At 12 months, patients with classic ARDS improved their MRCss (ED 2.50, p = 0.006) and HGD (ED: 4.13 kg, p = 0.002; ED 9.45% of predicted value, p = 0.005), while those with CARDS did not. Most patients in both groups regained independence in ADLs at 6 months. COVID-19 diagnosis was a significant independent predictor of better HGD (p < 0.0001) and 6MWT performance (p = 0.001), and lower prevalence of fatigue (p = 0.018). CONCLUSIONS: Both classic ARDS and CARDS survivors experienced long-term impairments in physical functioning, confirming that post-intensive care syndrome remains a major legacy of critical illness. Surprisingly, however, persisting disability was more common in survivors of classic ARDS than in CARDS survivors. In fact, muscle strength measured with HGD was reduced in survivors of classic ARDS compared to CARDS patients at both 6 and 12 months. The 6MWT was reduced and fatigue was more common in classic ARDS compared to CARDS at 6 months but differences were no longer significant at 12 months. Most patients in both groups regained independent function in ADLs at 6 months.