Modest Effect Research Articles

Altered longitudinal structural connectome in paediatric mild traumatic brain injury: an Advancing Concussion Assessment in Paediatrics study.

Advanced diffusion-weighted imaging techniques have increased understanding of the neuropathology of paediatric mild traumatic brain injury (i.e. concussion). Most studies have examined discrete white-matter pathways, which may not capture the characteristically subtle, diffuse and heterogenous effects of paediatric concussion on brain microstructure. This study compared the structural connectome of children with concussion to those with mild orthopaedic injury to determine whether network metrics and their trajectories across time post-injury differentiate paediatric concussion from mild traumatic injury more generally. Data were drawn from of a large study of outcomes in paediatric concussion. Children aged 8-16.99 years were recruited from five paediatric emergency departments within 48 h of sustaining a concussion (n = 360; 56% male) or mild orthopaedic injury (n = 196; 62% male). A reliable change score was used to classify children with concussion into two groups: concussion with or without persistent symptoms. Children completed 3 T MRI at post-acute (2-33 days) and/or chronic (3 or 6 months, via random assignment) post-injury follow-ups. Diffusion-weighted images were used to calculate the diffusion tensor, conduct deterministic whole-brain fibre tractography and compute connectivity matrices in native (diffusion) space for 90 supratentorial regions. Weighted adjacency matrices were constructed using average fractional anisotropy and used to calculate global and local (regional) graph theory metrics. Linear mixed effects modelling was performed to compare groups, correcting for multiple comparisons. Groups did not differ in global network metrics. However, the clustering coefficient, betweenness centrality and efficiency of the insula, cingulate, parietal, occipital and subcortical regions differed among groups, with differences moderated by time (days) post-injury, biological sex and age at time of injury. Post-acute differences were minimal, whereas more robust alterations emerged at 3 and especially 6 months in children with concussion with persistent symptoms, albeit differently by sex and age. In the largest neuroimaging study to date, post-acute regional network metrics distinguished concussion from mild orthopaedic injury and predicted symptom recovery 1-month post-injury. Regional network parameters alterations were more robust and widespread at chronic timepoints than post-acutely after concussion. Results suggest that increased regional and local subnetwork segregation (modularity) and inefficiency occurs across time after concussion, emerging after post-concussive symptom resolve in most children. These differences persist up to 6 months after concussion, especially in children who showed persistent symptoms. While prognostic, the small to modest effect size of group differences and the moderating effects of sex likely would preclude effective clinical application in individual patients.

γc receptor antagonist, EQ102, prevents the NK and T cell-mediated responses driven by IL-15 and IL-21

Abstract Synergistic signaling of IL-15 and IL-21 is important in driving pathogenic T and NK cell responses in multiple inflammatory diseases. IL-15 and IL-21 are part of the common gamma chain (γc) cytokine family, which use the shared γc receptor subunit in their signaling complexes. IL-15 and IL-21 each promote cytolytic activity and IFNγ production but can also synergistically enhance the function of other cytotoxic cytokines. Consequently, blockade of IL-15 or IL-21 alone is likely insufficient to improve disease outcome in pathologic environments. EQ102 is a multi-cytokine inhibitor that selectively blocks IL-15 and IL-21 signaling while preserving signaling of other γc family members. Here, we sought to investigate the effect of synergistic signaling from both IL-15 and IL-21 on NK and T cell activities and the ability of EQ102 to inhibit these signals and resultant cellular response. PBMCs from healthy donors or NK-92 cells were incubated with EQ102 for 1 hour and then stimulated with IL-15, IL-21, or in combination. Following stimulation, cellular expression of transcription factors and activation markers were analyzed by flow cytometry. Cell supernatant was assessed for T and NK cell cytokines. IL-15 stimulation increases proliferation of T and NK cells, where IL-21 had a modest effect. However, co-stimulation of IL-15 and IL-21 enhanced proliferation, activation, and upregulation of IFNγ production over single cytokine IL-15 conditions. EQ102 treatment effectively inhibits the IL-15/IL-21 co-stimulatory cytolytic responses of these cell populations. These results suggest that selective blockade of IL-15 and IL-21 by EQ102 inhibits the synergistic signaling that mediates NK and T cell responses in multiple immune disorders. None

Inflammatory bowel disease (IBD)-specific immune cell recruitment and response can be modulated with anti-TNF-α therapies in the human Colon Intestine-Chip

Abstract Objective: Inflammatory bowel disease (IBD) is a complex inflammatory disease, for which few effective therapies exist. The goal of our current work was to show: i) that such a complex, immune cell-driven pathogenesis could be captured on Emulate’s human Colon Intestine-Chips; and ii) that this could be used as a novel human-centric system to support IBD drug development including anti-TNF-α antibodies. Methods: PBMCs were perfused through the vascular (bottom) channel in untreated ‘resting’ or cytokine-‘primed’ Colon Intestine-Chips. Clinically relevant IBD drugs, including anti-TNF-α antibodies (Humira and Cimzia), as well as dexamethasone and AJM300 were administered through the vascular channel during PBMC administration. Total cell recruitment, effluent biomarker secretion (cytokines, calprotectin, C-reactive protein), and barrier function were analyzed for 72 hours. Results: α4β7 +‘gut-tropic’ PBMCs (monocytes, CD4 +, CD8 +, and NK cells) preferentially adhered and transmigrated in a cytokine priming-dependent manner. These PBMCs released clinically relevant IBD cytokines and biomarkers and induced barrier disruption, a hallmark of IBD. Anti-TNF-α antibodies and AJM300 caused reduced PBMC recruitment, inflammatory response and barrier disruption >90%. Dexamethasone had more modest effects, as expected. Conclusion: The human Colon Intestine-Chip can both model complex immune cell-driven IBD and validate effects of clinically relevant IBD drugs. This system could provide predictive validity for pre-clinical development of new IBD drugs.

Indoxyl sulfate influences susceptibility of proximal tubule epithelial cells to gentamicin cytotoxicity

Background: Patients with chronic kidney disease (CKD) are at increased risk of acute kidney injury (AKI) following exposure to nephrotoxic medications such as gentamicin, which can accelerate the progression of CKD. Therefore, there is a critical need to understand the molecular pathogenesis of acute-on-chronic kidney disease. A hallmark of CKD is the systemic bioaccumulation of uremic solutes, such as the tryptophan metabolite indoxyl sulfate (IS). Accumulating evidence suggests that IS has direct effects on the kidneys that contribute to CKD progression, and the objective of this study was to the determine the effect of IS on proximal tubule epithelial cell (PTEC) and test the hypothesis that IS exposure increases susceptibility to gentamicin-induced cytotoxicity. Methods: Cultured immortalized PTECs (HK-2 cells) were treated with IS and gentamicin at varying concentrations, and cell viability was assessed using the Trypan blue and MTT assays. TMT proteomic profiling with IBAQ quantitation and gene set enrichment analysis was used to identify differentially abundant proteins and cellular processes and pathways that are dysregulated by IS exposure and could mediate the cytotoxic effects of IS and influence susceptibility to gentamicin cytotoxicity. Results: Treatment with 100 μM IS had a modest cytotoxic effect (15-20% cell death after 24 hours over multiple experiments). Proteomic profiling of HK-2 cells identified 10,030 proteins, and IS treatment induced changes in the abundance of 60 proteins, including increased expression of kidney injury molecule-1, an established biomarker of PTEC injury, and VCAM-1, a marker of maladaptive repair after AKI. In contrast, expression of mitochondrial complex V ATPase F o subunits C1, C2, and C3 and mitochondrial ribosomal proteins L18 and L50 were down regulated, and GSEA found that there was an overall decrease in mitochondrial translation following IS exposure. These results suggest that IS is directly cytotoxic to PTECs and negatively impacts mitochondrial dynamics and cellular respiration. Pretreatment with IS increased susceptibility of HK-2 cells to 10 mM gentamicin cytotoxicity as assessed by Trypan blue staining (30.1% +/- 6.4% cells stained positive without IS pretreatment vs 46.1 +/- 3.1% with IS pretreatment, p < 0.001), and this effect was confirmed using the MTT assay. Conclusion: IS has direct cytotoxic effects on PTECs and increases their susceptibility to gentamicin cytotoxicity, and systemic bioaccumulation of IS in CKD could therefore predispose to subsequent AKI following nephrotoxic medication exposure. This phenomenon could be mediated IS-induced downregulation of mitochondrial gene translation associated with dysregulated mitochondrial dynamics and impaired cellular respiration. This study was supported by the George M. O'Brien Kidney Translational Core Center at the University of Michigan (subaward of 5P30-DK081943 14). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Overcoming immunotherapy resistance in melanoma defective of IFN-γ signaling

Abstract Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue. Initial efforts from others and us show that ICB resistance can derive from melanoma-intrinsic loss of the IFN-γ signaling, which occurs in ~20.9% of the 287 melanoma cases (CBioPortal), based on the cumulative frequency of damaging mutations of 12 core genes. However, how to overcome this resistance mechanism remains largely unexplored. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1 KO) impacts TILs. Here, we report that IFNγR1 KOmelanomas have reduced infiltration and function of TILs. Combining kinomics, RNA-seq, and proteomics, we unveil that Janus Kinase 1 and 2 (JAK1-2), key downstream kinases in the IFN-γ signaling cascade, are constitutively active, mediated by heightened mTOR. Importantly, mTOR inhibition with Everolimus induces a potent suppression of IFNγR1 KOmelanoma growth, particularly when combined with ICBs, despite its reported modest effects on WT tumors; similarly, targeting JAK1-2 with Ruxolitinib (Ruxo) selectively impedes the growth of IFNγR1 KObut not WT melanomas, revealing effective “targeted” treatments for ICB resistance. Mechanistically, these therapeutics successfully reprogram “cold” TILs in IFNγR1 KOmelanoma to functional effectors (e.g., increased production of TNF), and deleting T cells or using TNF KOmice completely abrogates Ruxo efficacy. Altogether, our results highlight an active role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest therapeutic targets that can be harnessed to bypass ICB resistance of melanomas defective of IFN-γ signaling. Supported by grants from NIH (1R21CA259721-01A1) and from DoD Idea Award (ME210108)

Myopia Control Efficacy and Long-Term Safety of a Novel Orthokeratology Lens (MESOK Study)-A Randomized Controlled Clinical Trial Combining Clinical and Tear Proteomics Data.

Myopia control efficacy and long-term safety of the Breath-O-Correct orthokeratology (OK) lens was evaluated in a 2-year randomized, single vision (SV) spectacle lens-controlled, single-blind clinical trial combining clinical and tear proteomics data. A total of 71 children (43 OK, 9.8 ± 1.3 years; 28 SV, 9.5 ± 1.4 years) completed the 2-year study. Axial length (AL), cycloplegic refraction, clinical safety parameters (best-corrected visual acuity, central cornea thickness, corneal endothelial health, ocular surface disease index), and quantitative tear proteomics were evaluated by masked examiners. Mean 2-year-normalized AL elongations in the OK and SV groups differed significantly (p = 0.03) and were 0.37 ± 0.37 mm and 0.60 ± 0.41 mm, respectively. OK-mediated myopia control efficacy was 37.1%. No significant difference was found in clinical safety parameters of both groups (p > 0.10), except for a thinner central corneal thickness in the OK group (p = 0.01). Proteomics revealed modest OK lens-mediated effects on immune response proteins, including an increased abundance of haptoglobin at 6 and 12 months and a decreased abundance of two proteins (neutrophil defensin 3 and histone 4) at 6 months. The changes were further validated using a high-resolution multiple-reaction monitoring (MRMHR) mass spectrometry. In summary, the Breath-O-Correct OK lens significantly reduced AL elongation in schoolchildren without adverse clinical effects or subclinical inflammatory responses.

Fetal and neonatal dioxin exposure causes sex-specific metabolic alterations in mice.

Epidemiological studies report associations between early-life exposure to persistent organic pollutants (POPs) and impaired metabolic homeostasis in adulthood. We investigated the impact of early-life exposure to low-dose 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or 'dioxin') on the establishment of β-cell area during the perinatal period, as well as β-cell health and glucose homeostasis later in life. Adult female mice were injected with either corn oil (CO; vehicle control) or TCDD (20 ng/kg/day) 2×/week throughout mating, pregnancy, and lactation; offspring were thus indirectly exposed to maternal TCDD in utero and during lactation, with pollutant exposure ending at weaning. All offspring were maintained on chow diet from weaning until 12-17 weeks of age, after which a subset of CO- and TCDD-exposed offspring were transferred to a 45% high fat diet (HFD) as a metabolic stressor for an additional 10 weeks. TCDD significantly upregulated cytochrome P450 1a1 (Cyp1a1) gene expression in offspring pancreas at birth and weaning, indicating that maternal TCDD directly reaches the developing pancreas. TCDD-exposed pups were transiently hypoglycemic at birth and females were born with reduced % β-cell area, which persisted into adulthood. Early-life TCDD exposure had no persistent long-term effects on glucose homeostasis in chow-fed offspring, but when transferred to HFD, TCDD-exposed female offspring had a delayed onset of HFD-induced hyperglycemia, more pronounced HFD-induced hyperinsulinemia, and increase % PCNA+ β-cells compared with CO-exposed female offspring. This study demonstrates that early-life exposure of mice to TCDD has modest effects on metabolic health in chow-fed offspring but alters metabolic adaptability to HFD feeding in females.

Expression of leptin receptor in renal tubules is sparse but implicated in leptin-dependent kidney gene expression and function.

Leptin regulates energy balance via leptin receptors expressed in central and peripheral tissues, but little is known about leptin-sensitive kidney genes and the role of the tubular leptin receptor (Lepr) in response to a high-fat diet (HFD). Quantitative RT-PCR analysis of Lepr splice variants A, B, and C revealed a ratio of ∼100:10:1 in the mouse kidney cortex and medulla, with medullary levels being ∼10 times higher. Leptin replacement in ob/ob mice for 6 days reduced hyperphagia, hyperglycemia, and albuminuria, associated with normalization of kidney mRNA expression of molecular markers of glycolysis, gluconeogenesis, amino acid synthesis, and megalin. Normalization of leptin for 7 h in ob/ob mice did not normalize hyperglycemia or albuminuria. Tubular knockdown of Lepr [Pax8-Lepr knockout (KO)] and in situ hybridization revealed a minor fraction of Lepr mRNA in tubular cells compared with endothelial cells. Nevertheless, Pax8-Lepr KO mice had lower kidney weight. Moreover, while HFD-induced hyperleptinemia, increases in kidney weight and glomerular filtration rate, and a modest blood pressure lowering effect were similar compared with controls, they showed a blunted rise in albuminuria. Use of Pax8-Lepr KO and leptin replacement in ob/ob mice identified acetoacetyl-CoA synthetase and gremlin 1 as tubular Lepr-sensitive genes that are increased and reduced by leptin, respectively. In conclusion, leptin deficiency may increase albuminuria via systemic metabolic effects that impinge on kidney megalin expression, whereas hyperleptinemia may induce albuminuria by direct tubular Lepr effects. Implications of Lepr variants and the novel tubular Lepr/acetoacetyl-CoA synthetase/gremlin 1 axis remain to be determined.NEW & NOTEWORTHY This study provides new insights into kidney gene expression of leptin receptor splice variants, leptin-sensitive kidney gene expression, and the role of the leptin receptor in renal tubular cells for the response to diet-induced hyperleptinemia and obesity including albuminuria.

Idiopathic pulmonary fibrosis and the role of genetics in the era of precision medicine.

Idiopathic pulmonary fibrosis (IPF) is a chronic, rare progressive lung disease, characterized by lung scarring and the irreversible loss of lung function. Two anti-fibrotic drugs, nintedanib and pirfenidone, have been demonstrated to slow down disease progression, although IPF mortality remains a challenge and the patients die after a few years from diagnosis. Rare pathogenic variants in genes that are involved in the surfactant metabolism and telomere maintenance, among others, have a high penetrance and tend to co-segregate with the disease in families. Common recurrent variants in the population with modest effect sizes have been also associated with the disease risk and progression. Genome-wide association studies (GWAS) support at least 23 genetic risk loci, linking the disease pathogenesis with unexpected molecular pathways including cellular adhesion and signaling, wound healing, barrier function, airway clearance, and innate immunity and host defense, besides the surfactant metabolism and telomere biology. As the cost of high-throughput genomic technologies continuously decreases and new technologies and approaches arise, their widespread use by clinicians and researchers is efficiently contributing to a better understanding of the pathogenesis of progressive pulmonary fibrosis. Here we provide an overview of the genetic factors known to be involved in IPF pathogenesis and discuss how they will continue to further advance in this field. We also discuss how genomic technologies could help to further improve IPF diagnosis and prognosis as well as for assessing genetic risk in unaffected relatives. The development and validation of evidence-based guidelines for genetic-based screening of IPF will allow redefining and classifying this disease relying on molecular characteristics and contribute to the implementation of precision medicine approaches.

Adenovirus Encoded Adjuvant (AdEnA) anti-CTLA-4, a novel strategy to improve Adenovirus based vaccines against infectious diseases and cancer.

Virus vectored genetic vaccines (Vvgv) represent a promising approach for eliciting immune protection against infectious diseases and cancer. However, at variance with classical vaccines to date, no adjuvant has been combined with clinically approved genetic vaccines, possibly due to the detrimental effect of the adjuvant-induced innate response on the expression driven by the genetic vaccine vector. We reasoned that a potential novel approach to develop adjuvants for genetic vaccines would be to "synchronize" in time and space the activity of the adjuvant with that of the vaccine. To this aim, we generated an Adenovirus vector encoding a murine anti-CTLA-4 monoclonal antibody (Ad-9D9) as a genetic adjuvant for Adenovirus based vaccines. The co-delivery of Ad-9D9 with an Adeno-based COVID-19 vaccine encoding the Spike protein resulted in stronger cellular and humoral immune responses. In contrast, only a modest adjuvant effect was achieved when combining the vaccine with the same anti-CTLA-4 in its proteinaceous form. Importantly, the administration of the adjuvant vector at different sites of the vaccine vector abrogates the immunostimulatory effect. We showed that the adjuvant activity of Ad-α-CTLA-4 is independent from the vaccine antigen as it improved the immune response and efficacy of an Adenovirus based polyepitope vaccine encoding tumor neoantigens. Our study demonstrated that the combination of Adenovirus Encoded Adjuvant (AdEnA) with an Adeno-encoded antigen vaccine enhances immune responses to viral and tumor antigens, representing a potent approach to develop more effective genetic vaccines.

Educated politicians and government efficiency: Evidence from Norwegian local government

The paper studies the effect of politicians’ education levels on government efficiency. Using data on Norwegian local government, the paper measures efficiency by DEA-productivity indicators and comprehensive indicators of service production. The identification of causal effects exploits close (within-list) elections to design an instrumental variable for council shares with higher education.Consistent with survey data, the estimates show that better-educated politicians induce higher levels of efficiency, particularly for old-age care services. A similar empirical strategy indicates that political experience has small efficiency effects. Educational misrepresentation has modest effects on fiscal allocations and is mostly canceled out by the efficiency gains.

Higher inequality in Latin America: a collateral effect of the pandemic

ABSTRACT This study explores the evolution of inequality in Latin America during the COVID-19 pandemic by using primary data from household and employment surveys collected in 2020. First, we discuss the trends in inequality in the region from 1992 to 2020. Next, we estimate regression models to examine how the changes in demographics and education levels might be correlated with changes in income distribution. Finally, we use a panel regression model with fixed effects for 16 countries in the region to identify how the socioeconomic context might help explain the changes in income inequality. The empirical findings suggest that inequality increased by a statistically significant 2% between 2019 and 2020. We obtained significantly heterogeneous results when disaggregating by gender, urban/rural location, and sector of economic activity. Remittances had a modest effect, while government transfers helped to prevent more significant disparities in half the countries studied. Our estimations show that the decline in employment levels – due to the economic contraction caused by COVID-19— is associated with increases in income inequality that might gradually diminish with the recovery.

The Influence of APOE Genotype, DHA, and Flavanol Intervention on Brain DHA and Lipidomics Profile in Aged Transgenic Mice.

The apolipoprotein E4 (APOE4) genotype is predictive of Alzheimer's disease (AD). The brain is highly enriched with the omega-3 polyunsaturated fatty acid (n3-PUFA), docosahexaenoic acid (DHA). DHA's metabolism is defective in APOE4 carriers. Flavanol intake can play a role in modulating DHA levels. However, the impact of flavanol co-supplementation with fish oil on brain DHA uptake, status and partitioning, and according to APOE genotype is currently unknown. Here, using a humanised APOE3 and APOE4 targeted replacement transgenic mouse model, the interactive influence of cocoa flavanols (FLAV) and APOE genotype on the blood and subcortical brain PUFA status following the supplementation of a high fat (HF) enriched with DHA from fish oil (FO) was investigated. DHA levels increased in the blood (p < 0.001) and brain (p = 0.001) following supplementation. Compared to APOE3, a higher red blood cell (RBC) DHA (p < 0.001) was evident in APOE4 mice following FO and FLAV supplementation. Although FO did not increase the percentage of brain DHA in APOE4, a 17.1% (p < 0.05) and 20.0% (p < 0.001) higher DHA level in the phosphatidylcholine (PC) fraction in the HF FO and HF FO FLAV groups, and a 14.5% (p < 0.05) higher DHA level in the phosphatidylethanolamine (PE) fraction in the HF FO FLAV group was evident in these animals relative to the HF controls. The addition of FLAV (+/- FO) did not significantly increase the percentage of brain DHA in the group as a whole. However, a higher brain: RBC DHA ratio was evident in APOE3 only (p < 0.05) for HF FLAV versus HF. In conclusion, our data shows only modest effects of FLAV on the brain DHA status, which is limited to APOE3.

Progestogen maintenance therapy for prolongation of pregnancy after an episode of preterm labour: A systematic review and meta-analysis.

Evidence for progestogen maintenance therapy after an episode of preterm labour (PTL) is contradictory. To assess effectiveness of progestogen maintenance therapy after an episode of PTL. An electronic search in Central Cochrane, Ovid Embase, Ovid Medline and clinical trial databases was performed. Randomised controlled trials (RCT) investigating women between 16+0 and 37+0 weeks of gestation with an episode of PTL who were treated with progestogen maintenance therapy compared with a control group. Systematic review and meta-analysis were conducted. The primary outcome was latency time in days. Secondary neonatal and maternal outcomes are consistent with the core outcome set for preterm birth studies. Studies were extensively assessed for data trustworthiness (integrity) and risk of bias. Thirteen RCT (1722 women) were included. Progestogen maintenance therapy demonstrated a longer latency time of 4.32 days compared with controls (mean difference [MD] 4.32, 95% CI 0.40-8.24) and neonates were born with a higher birthweight (MD 124.25 g, 95% CI 8.99-239.51). No differences were found for other perinatal outcomes. However, when analysing studies with low risk of bias only (five RCT, 591 women), a significantly longer latency time could not be shown (MD 2.44 days; 95% CI -4.55 to 9.42). Progestogen maintenance therapy after PTL might have a modest effect on prolongation of latency time. When analysing low risk of bias studies only, this effect was not demonstrated. Validation through further research, preferably by an individual patient data meta-analysis is highly recommended.

Independent Effects of HIV and Antiretroviral Therapy on the Oral Microbiome Identified by Multivariate Analyses.

The oral microbiome is an important predictor of health and disease. We recently reported significant yet modest effects of HIV under highly active antiretroviral therapy (ART) on the oral microbiome (bacterial and fungal) in a large cohort of HIV-positive (HIV+) and matched HIV-negative (HIV-) individuals. As it was unclear whether ART added to or masked further effects of HIV on the oral microbiome, the present study aimed to analyze the effects of HIV and ART independently, which also included HIV- subjects on preexposure prophylaxis (PrEP) therapy. Cross-sectional analyses of the effect of HIV devoid of ART (HIV+ ART- versus matched HIV- subjects) showed a significant effect on both the bacteriome and mycobiome (P < 0.024) after controlling for other clinical variables (permutational multivariate analysis of variance [PERMANOVA] of Bray-Curtis dissimilarity). Cross-sectional analyses evaluating the effects of ART (HIV+ ART+ versus HIV+ ART- subjects) revealed a significant effect on the mycobiome (P < 0.007) but not the bacteriome. In parallel longitudinal analyses, ART (before versus after the initiation of ART) had a significant effect on the bacteriome, but not the mycobiome, of HIV+ and HIV- PrEP subjects (P < 0.005 and P < 0.016, respectively). These analyses also revealed significant differences in the oral microbiome and several clinical variables between HIV- PrEP subjects (pre-PrEP) and the HIV-matched HIV- group (P < 0.001). At the species level, a small number of differences in both bacterial and fungal taxa were identified within the effects of HIV and/or ART. We conclude that the effects of HIV and ART on the oral microbiome are similar to those of the clinical variables but collectively are modest overall. IMPORTANCE The oral microbiome can be an important predictor of health and disease. For persons living with HIV (PLWH), HIV and highly active antiretroviral therapy (ART) may have a significant influence on their oral microbiome. We previously reported a significant effect of HIV with ART on both the bacteriome and mycobiome. It was unclear whether ART added to or masked further effects of HIV on the oral microbiome. Hence, it was important to evaluate the effects of HIV and ART independently. For this, multivariate cross-sectional and longitudinal oral microbiome analyses (bacteriome and mycobiome) were conducted within the cohort, including HIV+ ART+ subjects and HIV+ and HIV- (preexposure prophylaxis [PrEP]) subjects before and after the initiation of ART. While we report independent significant effects of HIV and ART on the oral microbiome, we conclude that their influence is similar to that of the clinical variables but collectively modest overall.

A Comprehensive Review on Weight Loss Associated with Anti-Diabetic Medications.

Obesity is a complex metabolic condition that can have a negative impact on one's health and even result in mortality. The management of obesity has been addressed in a number of ways, including lifestyle changes, medication using appetite suppressants and thermogenics, and bariatric surgery for individuals who are severely obese. Liraglutide and semaglutide are two of the five Food and Drug Administration (FDA)-approved anti-obesity drugs that are FDA-approved agents for the treatment of type 2 diabetes mellitus (T2DM) patients. In order to highlight the positive effects of these drugs as anti-obesity treatments, we analyzed the weight loss effects of T2DM agents that have demonstrated weight loss effects in this study by evaluating clinical studies that were published for each agent. Many clinical studies have revealed that some antihyperglycemic medications can help people lose weight, while others either cause weight gain or neutral results. Acarbose has mild weight loss effects and metformin and sodium-dependent glucose cotransporter proteins-2 (SGLT-2) inhibitors have modest weight loss effects; however, some glucagon-like peptide-1 (GLP-1) receptor agonists had the greatest impact on weight loss. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed a neutral or mild weight loss effect. To sum up, some of the GLP-1 agonist drugs show promise as weight-loss treatments.

Prebiotic and Probiotic Modulation of the Microbiota-Gut-Brain Axis in Depression.

Emerging evidence demonstrates that alterations to the gut microbiota can affect mood, suggesting that the microbiota-gut-brain (MGB) axis contributes to the pathogenesis of depression. Many of these pathways overlap with the way in which the gut microbiota are thought to contribute to metabolic disease progression and obesity. In rodents, prebiotics and probiotics have been shown to modulate the composition and function of the gut microbiota. Together with germ-free rodent models, probiotics have provided compelling evidence for a causal relationship between microbes, microbial metabolites, and altered neurochemical signalling and inflammatory pathways in the brain. In humans, probiotic supplementation has demonstrated modest antidepressant effects in individuals with depressive symptoms, though more studies in clinically relevant populations are needed. This review critically discusses the role of the MGB axis in depression pathophysiology, integrating preclinical and clinical evidence, as well as the putative routes of communication between the microbiota-gut interface and the brain. A critical overview of the current approaches to investigating microbiome changes in depression is provided. To effectively translate preclinical breakthroughs in MGB axis research into novel therapies, rigorous placebo-controlled trials alongside a mechanistic and biochemical understanding of prebiotic and probiotic action are required from future research.

Modulating chronic outcomes after pediatric traumatic brain injury: Distinct effects of social and environmental enrichment

Impairments in social and cognitive function are a common consequence of pediatric traumatic brain injury (TBI). Rehabilitation has the potential to promote optimal behavioral recovery. Here, we evaluated whether an enhanced social and/or cognitive environment could improve long-term outcomes in a preclinical model of pediatric TBI. Male C57Bl/6 J mice received a moderately-severe TBI or sham procedure at postnatal day 21. After one week, mice were randomized to different social conditions (minimal socialization, n = 2/cage; or social grouping, n = 6/cage), and housing conditions (standard cage, or environmental enrichment (EE), incorporating sensory, motor, and cognitive stimuli). After 8 weeks, neurobehavioral outcomes were assessed, followed by post-mortem neuropathology. We found that TBI mice exhibited hyperactivity, spatial memory deficits, reduced anxiety-like behavior, and reduced sensorimotor performance compared to age-matched sham controls. Pro-social and sociosexual behaviors were also reduced in TBI mice. EE increased sensorimotor performance, and the duration of sociosexual interactions. Conversely, social housing reduced hyperactivity and altered anxiety-like behavior in TBI mice, and reduced same-sex social investigation. TBI mice showed impaired spatial memory retention, except for TBI mice exposed to both EE and group housing. In the brain, while TBI led to significant regional tissue atrophy, social housing had modest neuroprotective effects on hippocampal volumes, neurogenesis, and oligodendrocyte progenitor numbers. In conclusion, manipulation of the post-injury environment has benefit for chronic behavioral outcomes, but the benefits are specific to the type of enrichment available. This study improves understanding of modifiable factors that may be harnessed to optimize long-term outcomes for survivors of early-life TBI.

Auditing and compliance in public procurement – an empirical assessment

Purpose This study aims to empirically evaluate the effectiveness of government auditing of local authorities’ compliance with the procurement rules. Design/methodology/approach A diff-in-diff approach is used where the measure of compliance is (changes in) the incidence of private litigation under the Public Procurement Act, in audited vs non-audited municipalities. Further, semi-structured interviews were conducted with chief procurement officials. Findings No statistically significant effect is found. While strong effects of audits can be ruled out, the statistical results and the interviews do not, however, contradict a modest but long-lasting effect. Originality/value Few studies have addressed the effect of public procurement auditing on compliance. This study develops an empirical framework and presents empirical results.

Unemployment, workplace socialization, and electoral participation: evidence from Sweden

Abstract How unemployment affects electoral participation is a archetypal question in political sociology and of particular relevance in economic crises; in the 1930s as well as during a pandemic. A frequent argument in the literature is that unemployment leads to political withdrawal as the unemployed have to focus on their economy and other personal matters. Some scholars, on the other hand, reason that unemployment triggers political mobilization through feelings of grievance and a strive to protest against leading politicians. However, existing empirical evidence is mixed and often suffers from limitations in data and research design. To make progress on this difficult empirical question, the present study leverages Swedish register data on turnout, spanning nine elections between 1970 and 2018. This extensive panel dataset enables us to more adequately address the causal status of the relationship by relying on the with-in individual variation in turnout. Our results report significant but modest negative effects of both unemployment in general and of losing a relatively well-paid job (job loss). The effects are driven by the young. We also find that the negative effect is less pronounced for those who have previously worked at a workplace where most colleagues participate, supporting a socialization mechanism.