Miracle-dz/UniFAR-FTUs huggingface dataset:
(2R,6R)-hydroxynorketamine exerts mGlu2 receptor-dependent antidepressant actions

Significance Despite available medications for depression, currently approved antidepressants take months to exert therapeutic effects, and ∼30% of patients remain treatment resistant. In contrast, a single subanesthetic dose of ketamine exerts rapid (within hours) and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant candidate with limited adverse effects compared with ketamine. Using behavioral, genetic, and pharmacological approaches and EEG measurements, we determined that the mechanism underlying antidepressant-relevant actions of (2R,6R)-HNK converges with metabotropic glutamate receptor subtype 2 (mGlu2) receptor signaling and identified high-frequency EEG oscillations as a marker associated with rapid antidepressant responses. Our data support the use of individually subtherapeutic doses of mGlu2 receptor inhibitors with ketamine or (2R,6R)-HNK in clinical trials for the treatment of depression. Currently approved antidepressant drugs often take months to take full effect, and ∼30% of depressed patients remain treatment resistant. In contrast, ketamine, when administered as a single subanesthetic dose, exerts rapid and sustained antidepressant actions. Preclinical studies indicate that the ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a rapid-acting antidepressant drug candidate with limited dissociation properties and abuse potential. We assessed the role of group II metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) in the antidepressant-relevant actions of (2R,6R)-HNK using behavioral, genetic, and pharmacological approaches as well as cortical quantitative EEG (qEEG) measurements in mice. Both ketamine and (2R,6R)-HNK prevented mGlu2/3 receptor agonist (LY379268)-induced body temperature increases in mice lacking the Grm3, but not Grm2, gene. This action was not replicated by NMDA receptor antagonists or a chemical variant of ketamine that limits metabolism to (2R,6R)-HNK. The antidepressant-relevant behavioral effects and 30- to 80-Hz qEEG oscillation (gamma-range) increases resultant from (2R,6R)-HNK administration were prevented by pretreatment with an mGlu2/3 receptor agonist and absent in mice lacking the Grm2, but not Grm3−/−, gene. Combined subeffective doses of the mGlu2/3 receptor antagonist LY341495 and (2R,6R)-HNK exerted synergistic increases on gamma oscillations and antidepressant-relevant behavioral actions. These findings highlight that (2R,6R)-HNK exerts antidepressant-relevant actions via a mechanism converging with mGlu2 receptor signaling and suggest enhanced cortical gamma oscillations as a marker of target engagement relevant to antidepressant efficacy. Moreover, these results support the use of (2R,6R)-HNK and inhibitors of mGlu2 receptor function in clinical trials for treatment-resistant depression either alone or in combination.
Serum irisin and apelin levels and markers of atherosclerosis in patients with subclinical hypothyroidism

ABSTRACT Objective: In this study, we aimed to evaluate serum irisin and apelin levels in patients with subclinical hypothyroidism (SCH) when they were subclinical hypothyroid and become euthyroid after levothyroxine therapy and association of these adipokines with markers of atherosclerosis such as serum homocysteine levels and carotid intima-media thickness (IMT). Subjects and methods: The study included 160 patients with newly diagnosed subclinical hypothyroidism due to Hashimoto's thyroiditis and 86 euthyroid healty subjects. Serum glucose and lipid profile, insulin, HOMA, TSH, free T3, free T4, anti-thyroperoxidase and anti-thyroglobulin antibodies, homocysteine, apelin and irisin levels were measured in all study subjects. Thyroid and carotid ultrasound examinations were performed. The subclinical hypothyroid group was reevaluated after 12-weeks of levothyroxine therapy when they became euthyroid. Results: Clinical characteristics of the patient and control group were similar. Glucose, insulin and HOMA levels, lipid parameters and free T3 were similar between the two groups. Serum homocystein was higher and apelin was lower in patients with SCH, but irisin levels were similar between the two groups. While thyroid volume was lower, carotid IMT was significantly greater in patients with SCH (pCarotidIMT:0,01). After 12-weeks of levothyroxine therapy, all the studied parameters remained unchanged except, serum freeT4, TSH, homocystein and apelin. While homocystein decreased (p: 0,001), apelin increased significantly (p = 0,049). In multivariate analysis, low apelin levels significantly contributed to carotid IMT (p = 0,041). Conclusions: Apelin-APJ system may play a role in vascular and cardiac dysfunction in patients with SCH and treatment of this condition may improve the risk of cardiovascular disease.
The Therapeutic Potential of MicroRNAs as Orthobiologics for Skeletal Fractures

The repair of a fractured bone is critical to the well‐being of humans. Failure of the repair process to proceed normally can lead to complicated fractures, exemplified by either a delay in union or a complete nonunion. Both of these conditions lead to pain, the possibility of additional surgery, and impairment of life quality. Additionally, work productivity decreases, income is reduced, and treatment costs increase, resulting in financial hardship. Thus, developing effective treatments for these difficult fractures or even accelerating the normal physiological repair process is warranted. Accumulating evidence shows that microRNAs (miRNAs), small noncoding RNAs, can serve as key regulatory molecules of fracture repair. In this review, a brief description of the fracture repair process and miRNA biogenesis is presented, as well as a summary of our current knowledge of the involvement of miRNAs in physiological fracture repair, osteoporotic fractures, and bone defect healing. Further, miRNA polymorphisms associated with fractures, miRNA presence in exosomes, and miRNAs as potential therapeutic orthobiologics are also discussed. This is a timely review as several miRNA‐based therapeutics have recently entered clinical trials for nonskeletal applications and thus it is incumbent upon bone researchers to explore whether miRNAs can become the next class of orthobiologics for the treatment of skeletal fractures.
Reducing the Number of Children Entering Foster Care: Effects of State Earned Income Tax Credits

Foster care caseloads, an indicator of child maltreatment, are increasing. Children living in poverty are significantly more likely to be reported to the child welfare system and are overrepresented in foster care. Thus, it is critical to identify prevention strategies that can stem the flow of foster care entries, particularly among populations at higher risk. We used variations in the adoption and refund status of state-level Earned Income Tax Credit (EITC), a socioeconomic policy intended to reduce poverty, to examine their effect on foster care entry rates. Fixed-effects models, accounting for year- and state-fixed effects, demonstrated that a refundable EITC was associated with an 11% decrease in foster care entries compared to states without a state-level EITC after controlling for child poverty rate, racial/ethnic composition, education, and unemployment. Policies that strengthen economic supports for families may prevent child maltreatment and reduce foster care entries and associated costs.
Assessing students' confidence in interpreting dental radiographs following a blended learning module.

OBJECTIVE This study assessed senior dental hygiene (DH) students' self-reported confidence in interpreting dental radiographs following the introduction of a blended learning (BL) module for radiology interpretation. The assessment of students was conducted five months prior to graduation. METHODS A BL oral radiology module was designed. In order to capture the context, descriptions and differences of students' experience and confidence, a qualitative research approach was selected. Data were captured using a semi-structured interview process and analysed using phenomenographic methods. RESULTS Sixteen students were interviewed. Blinded transcripts were analysed, and the main themes relating to confidence were extracted and arranged into categories. The categories were coded as to how confident (low, medium or high) each of the students felt specific to varying contexts and complexities of radiographic interpretation. CONCLUSION Predominately, the BL model had a positive impact on DH students' confidence in the interpretation of radiographic findings. However, when asked about their level of overall confidence in interpreting dental radiographs, students still did not describe themselves as confident for all potential findings on radiographs at this point in their education. The students highlighted the importance of having patient history details and clinical assessment findings included in the interpretation exercises and expressed a desire to collaborate with other professionals when interpreting radiographs.
Immunization with whole cell but not acellular pertussis vaccines primes CD4 TRM cells that sustain protective immunity against nasal colonization with Bordetella pertussis

ABSTRACT Protective immunity wanes rapidly after immunization of children with acellular pertussis (aP) vaccines and these vaccines do not prevent nasal colonization or transmission of Bordetella pertussis in baboons. In this study, we examined the role of tissue-resident memory T (TRM) cells in persistent protective immunity induced by infection or immunization with aP and whole-cell pertussis (wP) vaccines in mice. Immunization of mice with a wP vaccine protected against lung and nasal colonization, whereas an aP vaccine failed to protect in the nose. IL-17 and IFN-γ-secreting CD69+CD4+ TRM cells were expanded in the lung and nasal tissue after B. pertussis challenge of mice immunized with wP, but not aP vaccines. However, previous infection induced the most persistent protection against nasal colonization and this correlated with potent induction of nasal tissue TRM cells, especially IL-17-secreting TRM cells. Blocking T cell migration to respiratory tissue during immunization with a wP vaccine impaired bacterial clearance, whereas transfer of TRM cells from convalescent or wP-immunized mice conferred protection to naïve mice. Our findings reveal that previous infection or wP vaccination are significantly more effective than aP vaccination in conferring persistent protective immunity against B. pertussis and that this is mediated by respiratory TRM cells.
Differential Item Functioning of the Everyday Cognition (ECog) Scales in Relation to Racial/Ethnic Groups

Abstract Objective: The Everyday Cognition (ECog) scales measure cognitively based across domains of everyday abilities that are affected early in the course of neurodegenerative disorders such as Alzheimer’s disease. However, the degree to which the ECog may be differentially influenced by ethnic/racial background is unknown. This study evaluates measurement invariance of the ECog across non-Hispanic White (NHW), Black, and Hispanic individuals. Methods: Participants included 1177 NHW, 243 Black, and 216 Hispanic older adults from the UC Davis Alzheimer’s Disease Center Cohort who had an ECog. Differential item functioning (DIF) for each ECog domain was evaluated separately for Black and Hispanic participants compared to NHW participants. An iterative multiple group confirmatory factor analysis approach for ordinal scores was used to identify items whose measurement properties differed across groups and to adjust scores for DIF. Adjusted scores were then evaluated to test whether they were more strongly associated with cognitive function (concurrent and longitudinal change in cognition) and brain volumes (measured by brain imaging). Results: Varying levels, patterns, and impacts of DIF were found across domains and groups. However, the impact of DIF was relatively small, and DIF effects on scores generally were less than one-half standard error of measurement. There were no meaningful differences in associations with cognition and brain injury between DIF adjusted and unadjusted scores. Conclusions: Varying patterns of DIF were observed across the Black and Hispanic participants across select ECog domains. Overall, DIF effects were relatively small and did not change the relationship between the ECog and other indicators of disease.
Genotypic and Phenotypic Aspects of Longevity: Results from a Sicilian Survey and Implication for the Prevention and Treatment of Age-related Diseases.

BACKGROUND It is well known that long living individuals are a model of successful ageing and that the identification of both genetic variants and environmental factors that predispose to a long and healthy life is of tremendous interest for translational medicine. METHODS We present the preliminary findings obtained from an ongoing study on longevity conducted on a sample of Sicilian long-lived individuals. RESULTS We review the characteristics of longevity in Sicily, taking into account lifestyle, environment, genetics, hematochemical values, body composition and immunophenotype. In addition, we discuss the possible implications of our data for the prevention and/or treatment of age-related diseases. CONCLUSION As widely discussed in this review, the explanation of the role of genetics and lifestyle in longevity can provide important information on how to develop drugs and/or behaviours that can slow down or delay ageing. Thus, it will be possible to understand, through a "positive biology" approach, how to prevent and/or reduce elderly frailty and disability.
Hepatic blood flow by perfusion computed tomography as an imaging biomarker for patients with gastric cancer

Perfusion computed tomography (PCT) is a less invasive imaging modality that provides information about tissue hemodynamics at the capillary level. The present study aimed to investigate the correlation between hepatic perfusion and gastric cancer progression. A total of 136 patients with gastric adenocarcinoma were evaluated in the present study. Prior to initial treatment, liver PCT was performed across the hepatic hilar plane and the hepatic blood flow (HBF) was measured using the dual-input deconvolution method. HBF was compared with clinicopathological factors, patient prognosis and circulating serum proangiogenic cytokines. The median HBF was 217 ml/min/100 g tissue. Patients with high HBF had larger tumors (43 mm vs. 71, P<0.001) and more advanced tumor-node stages (P<0.001 for both). When both patient groups of operable and inoperable were compared by their respective median HBF values, each high-HBF group had a significantly worse prognosis (P=0.002 and P=0.024), notably in the inoperable group, with <1-year survival. In 17 postoperative recurrent patients, the high-HBF at recurrence group also had a significantly worse postrecurrent prognosis (P=0.019). HBF was an independent prognostic factor (hazard ratio, 2.019; P=0.048) and was strongly associated with serum vascular endothelial growth factor level (R=0.607, P<0.001). HBF was significantly correlated with gastric cancer progression, and is an easily measured imaging biomarker reflecting patient survival.
Does Long‐Term Proton Pump Inhibitor Use Increase Risk of Dementia? Not Really! Results of the Group‐Based Trajectory Analysis

Conflicting data of the potential association between proton pump inhibitors (PPIs) and risk of dementia have been reported. This study aimed to examine the subsequent risk of incident dementia in older adults by categorizing subjects into different trajectories of longitudinal PPI use. A group‐based trajectory modeling was used to identify distinct groups with regard to longitudinal PPI use over 3 years and to further examine the association between the trajectories of PPI use and dementia in a 5‐year follow‐up. Among 10,533 older adults who initiated PPIs, three distinct trajectories of longitudinal PPI use were identified: short‐term (n = 7,406, 70.3%), intermittent (n = 1,528, 14.5%), and long‐term users (n = 1,599, 15.2%). Long‐term (hazard ratio (HR) = 0.99 (95% confidence interval (CI), 0.93–1.17)) and intermittent PPI users (HR = 0.91 (95% CI, 0.76–1.09)) were not associated with an increased risk of incident dementia compared with short‐term users. Regardless of pattern of use, PPIs did not appear to significantly increase the risk of dementia over a mean follow‐up period of 4 years.
The Predictive Value of Personality Traits for Psychological Problems (Stress, Anxiety and Depression): Results from a Large Population Based Study

The current study aimed to determine the prognostic values of personality traits for common psychological problems in a large sample of Iranian adult. In a large sample of healthy people (n = 4763) who lived in Isfahan province; the NEO-FFI was used to assess the personality traits; depression and anxiety were assessed using the “Hospital Anxiety and Depression Scale (HADS)” also stress was measured through Persian validated version of General Health Questionnaire (GHQ-12). Receiver Operating Characteristics Curve (ROC) analysis was used as main statistical method for data analysis. ROC analysis showed neuroticism was the best predictor for all psychological problems with highest area under the curve (AUC) (95% confidence interval) for stress, 0.837 (0.837–0.851), anxiety 0.861 (0.847–0.876) and depression 0.833 (0.820–0.846) (p < .001) and the corresponding cut-off points (sensitivity, specificity), were 21.5 (77%, 66%), 22.5 (81%, 77%) and 20.5 (77%, 74%), respectively . Other personality traits were significant protective factors for being affected with psychological problems (p < .001). Similar findings were observed separately in women and men. The present study showed that the neuroticism is significant risk factor for being affected with three psychological problems while other traits are significant protective factors. Personality traits are useful indices for screening psychological problems and an effective pathway toward prevention in general population.
Different exercise modalities exert opposite acute effects on short-term blood pressure variability in male patients with hypertension

Background The aim of this study was to compare the acute effects produced by a single bout of three different exercise modalities on short-term blood pressure variability. Methods The study enrolled 21 sedentary male patients with hypertension and a mean age of 63 ± 7.2 years. Blood pressure variability was evaluated through ambulatory blood pressure monitoring that was performed twice: during an ordinary daily activity and after an exercise session lasting 60 minutes. Patients were divided into three groups according to the different exercise modality performed during the session: aerobic continuous training, interval training or combined training including aerobic and resistance training. Results Twenty-four-hour systolic blood pressure variability increased in the interval training group, was unchanged in the aerobic continuous training group and decreased in the combined training group (intergroup P = 0.03). Daytime systolic blood pressure variability increased in the interval training and aerobic continuous training groups while it decreased in the combined training group (intergroup P = 0.0006). Twenty-four-hour diastolic blood pressure variability decreased in the aerobic continuous training and combined training groups while it increased in the interval training group (intergroup P = 0.002). Conclusion Different training modalities have similar hypotensive action but exert different acute effects on blood pressure variability. Combined training seems to be the most suitable training modality for sedentary men with hypertension.
Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus

OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors have lately become the recommended treatment in patients with type 2 diabetes and high cardiovascular risk. Patients with posttransplant diabetes mellitus (PTDM) also have high cardiovascular risk. The aim of this study was to investigate the safety and efficacy of empagliflozin in renal transplant recipients with PTDM. RESEARCH DESIGN AND METHODS Forty-nine renal transplant recipients were included in an investigator-initiated, single-center, prospective, double-blind study and randomized to receive either 10 mg empagliflozin or placebo once daily for 24 weeks. Patients transplanted >1 year ago, diagnosed with PTDM, with stable renal function (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2), and with stable immunosuppressive therapy were studied. RESULTS Forty-four renal transplant recipients (22 empagliflozin/22 placebo, 34 males) completed the study. Median (interquartile range) change in glycated hemoglobin (HbA1c) was significantly reduced with empagliflozin compared with placebo: −0.2% (−0.6, −0.1) (−2.0 mmol/mol [−6.5, −1.0]) vs. 0.1% (−0.1, 0.4) (1.0 mmol/mol [−0.75, 3.8]) (P = 0.025). The magnitude of glucose reduction was dependent on GFR and baseline HbA1c. The treatment also resulted in a significant reduction in body weight of −2.5 kg (−4.0, −0.05) compared with an increase of 1.0 kg (0.0, 2.0) in the placebo group (P = 0.014). There were no significant differences between the groups in adverse events, immunosuppressive drug levels, or eGFR. CONCLUSIONS Empagliflozin appeared safe and improved glycemic control in renal transplant recipients with PTDM compared with placebo. A concomitant reduction in body weight was seen.
A panel of colorimetric assays to measure enzymatic activity in the base excision DNA repair pathway

Abstract DNA repair is essential for the maintenance of genomic integrity, and evidence suggest that inter-individual variation in DNA repair efficiency may contribute to disease risk. However, robust assays suitable for quantitative determination of DNA repair capacity in large cohort and clinical trials are needed to evaluate these apparent associations fully. We describe here a set of microplate-based oligonucleotide assays for high-throughput, non-radioactive and quantitative determination of repair enzyme activity at individual steps and over multiple steps of the DNA base excision repair pathway. The assays are highly sensitive: using HepG2 nuclear extract, enzyme activities were quantifiable at concentrations of 0.0002 to 0.181 μg per reaction, depending on the enzyme being measured. Assay coefficients of variation are comparable with other microplate-based assays. The assay format requires no specialist equipment and has the potential to be extended for analysis of a wide range of DNA repair enzyme activities. As such, these assays hold considerable promise for gaining new mechanistic insights into how DNA repair is related to individual genetics, disease status or progression and other environmental factors and investigating whether DNA repair activities can be used a biomarker of disease risk.