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Multidisciplinary collaboration to improve neonatal kidney health
No full textThe Neonatal Kidney Collaborative is a multidisciplinary initiative aimed at enhancing neonatal kidney health. By uniting experts and promoting trainees from various fields, the collaborative has developed a strong foundation for research, education, and advocacy efforts that will advance understanding and treatment of kidney issues in newborns
A metabolic shift to the serine pathway induced by lipids fosters epigenetic reprogramming in nontransformed breast cells
No full textLipid metabolism and the serine, one-carbon, glycine (SOG) and methionine pathways are independently and significantly correlated with estrogen receptor-negative breast cancer (ERneg BC). Here, we propose a link between lipid metabolism and ERneg BC through phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in the de novo serine pathway. We demonstrate that the metabolism of the paradigmatic medium-chain fatty acid octanoic acid leads to a metabolic shift toward the SOG and methionine pathways. PHGDH plays a role in both the forward direction, contributing to the production of S-adenosylmethionine, and the reverse direction, generating the oncometabolite 2-hydroxyglutarate, leading to epigenomic reprogramming and phenotypic plasticity. The methionine cycle is closely linked to the transsulfuration pathway. Consequently, we observe that the shift increases the antioxidant glutathione, which mitigates reactive oxygen species (ROS), enabling survival of a subset of cells that have undergone DNA damage. These metabolic changes contribute to several hallmarks of cancer
Sex Differences in Risky Decision-Making Neural Processing and Its Link to Problematic Substance Use in Adolescents at Risk for Substance Use Disorders
No full textIUIBackground: Risky decision-making deficits are associated with substance use risk. However, sex differences in risky decision-making neural processing among adolescents with externalizing disorders (EXT), like ADHD and conduct disorder, have been understudied though EXT youth are at high risk for developing substance use disorders (SUDs), partially due to impaired decision-making. While males with EXT tend to engage in more risky behavior, the neural mechanisms underlying these patterns may differ for EXT females. This dissertation presents two studies exploring 1) sex differences in brain activation during risky decision-making, and 2) how these differences relate to problematic substance use in EXT youth.
Method: The first study included 168 adolescents (81 EXT males, 39 EXT females, 33 control males, 15 control females), who completed the Balloon Analogue Risk Task (BART) during a magnetic resonance imaging (MRI) session. The second study utilized 115 drug-naive EXT adolescents (78 males, 37 females) who also completed the BART during an MRI session and were assessed for problematic substance use during longitudinal follow-up. Statistical analyses compared sex and EXT differences in brain activation during risky decision-making and the associated risk of substance use using Cox proportional hazards models, respectively.
Results: EXT males showed greater activation in the cingulo-opercular network during risky versus safe choice as that choice became riskier (modulated) compared to EXT females and controls. Greater modulated activation in the right nucleus accumbens (NAc) during risky versus safe choice was associated with less problematic substance use in EXT females, but not in EXT males. Greater unmodulated choice phase activation in the NAc in males and in the subgenual anterior cingulate cortex in females were associated with less problematic substance use.
Conclusions: This dissertation highlights significant sex differences in both the neural processing of risky decision-making and its connection to substance use in EXT youth. These findings suggest that proper risk processing in the cingulo-opercular and reward networks may protect against substance use, with distinct patterns in males and females. These results underscore the importance of sex-specific approaches for prevention and intervention in youth at risk for substance misuse
IA-2A positivity increases risk of progression within and across established stages of type 1 diabetes
No full textAims/hypothesis: Accurate understanding of type 1 diabetes risk is critical for optimisation of counselling, monitoring and interventions, yet even within established staging classifications, individual time to clinical disease varies. Previous work has associated IA-2A positivity with increased type 1 diabetes progression but a comprehensive assessment of the impact of screening for IA-2A positivity across the natural history of autoantibody positivity has not been performed. We asked whether IA-2A would consistently be associated with higher risk of progression within and across established stages of type 1 diabetes in a large natural history study.
Methods: Genetic, autoantibody and metabolic data from adult and paediatric autoantibody-negative (n=192) and autoantibody-positive (n=4577) relatives of individuals with type 1 diabetes followed longitudinally in the Type 1 Diabetes TrialNet Pathway to Prevention Study were analysed. Cox regression was used to compare cumulative incidences of clinical diabetes by autoantibody profiles and disease stages.
Results: Compared with IA-2A- individuals, IA-2A+ individuals had higher genetic risk scores and clinical progression risk within single-autoantibody-positive (5.3-fold increased 5 year risk), stage 1 (2.2-fold increased 5 year risk) and stage 2 (1.3-fold increased 5 year risk) type 1 diabetes categories. Individuals with single-autoantibody positivity for IA-2A showed increased metabolic dysfunction and diabetes progression compared with people who were autoantibody negative, those positive for another single autoantibody, and IA-2A- stage 1 individuals. Individuals at highest risk within the single-IA-2A+ category included children (HR 14.2 [95% CI 1.9, 103.1], p=0.009), individuals with IA-2A titres above the median (HR 3.5 [95% CI 1.9, 6.6], p<0.001), individuals with high genetic risk scores (HR 1.4 [95% CI 1.2,1.6], p<0.001) and individuals with HLA DR4-positive status (HR 3.7 [95% CI 1.6, 8.3], p=0.002). When considering all autoantibody-positive individuals, progression risk was similar for euglycaemic IA-2A+ individuals and dysglycaemic IA-2A- individuals.
Conclusions/interpretation: IA-2A positivity is consistently associated with increased progression risk throughout the natural history of type 1 diabetes development. Individuals with single-autoantibody positivity for IA-2A have a greater risk of disease progression than those who meet stage 1 criteria but who are IA-2A-. Approaches to incorporate IA-2A+ status into monitoring strategies for autoantibody-positive individuals should be considered
In-utero therapy for cystic fibrosis: Baby Piper's CF journey
No full textA Plainfield mom was the first Riley patient to take Trikafta while pregnant to help her daughter, who was diagnosed with Cystic Fibrosis before birth. Both are doing well today
From Program Review to Strategic Blueprint: Translating Assessment Insights Into Effective Strategic Planning
No full textIn higher education, time and space to meaningfully reflect and carefully plan is often limited. Translating the findings from program reviews into actionable strategic plans is crucial for maximizing staff time; utilizing institutional resources; and sustaining momentum. The presenters will delve into effective methodologies for bridging the gap between program review processes and the creation of comprehensive strategic plans
Maternal Preconception Omega-6, Omega-3, and Omega-6:Omega-3 Intake and Uterine Artery Indices in Mid-Gestation
No full textObjective: Maternal preconception diet influences pregnancy health and fetal outcomes. We examined the relationship between preconception fatty acid (FA) intake and uterine artery indices in mid-gestation in a large, heterogeneous cohort of nulliparous individuals.
Study design: This is a secondary analysis of the nuMom2b (Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be) study. Dietary ω-6 and ω-3 FA intake was assessed with food frequency questionnaires and uterine artery indices were obtained via Doppler studies in the second trimester. For our primary outcome of pulsatility index (PI) > 1.6, we compared proportions by each dichotomous FA exposure and tested differences with chi-square test.
Results: For PI > 1.6, odds ratio for the unfavorable FA quartile compared with remaining quartiles for the exposures were 0.96 to 1.25, p = 0.157 (ω-6 FA); 0.97 to 1.26, p = 0.124 (ω-3 FA); 0.87 to 1.14, p = 1.00 (ω-6:ω-3 FA ratio).
Conclusion: No significant associations between self-reported maternal preconception ω-6 and ω-3 FA intake and uterine artery Doppler indices measured during the second trimester were observed
Hypokalaemia in patients with type 2 diabetes and chronic kidney disease: the effect of finerenone-a FIDELITY analysis
No full textAims: Hypokalaemia is associated with cardiovascular events and mortality in patients with chronic kidney disease (CKD). This exploratory FIDELITY analysis, a prespecified pooled patient-dataset from FIDELIO-DKD and FIGARO-DKD, investigated the incidence and effect of hypokalaemia in patients with CKD and type 2 diabetes (T2D) treated with finerenone vs. placebo.
Methods and results: Outcomes include the incidence of treatment-emergent hypokalaemia (serum potassium <4.0 or <3.5 mmol/L) and the effect of finerenone on cardiovascular composite outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) and arrhythmia composite outcome (new diagnosis of atrial fibrillation/atrial flutter, hospitalization due to arrhythmia, or sudden cardiac death) by baseline serum potassium subgroups. In the FIDELITY population, treatment-emergent hypokalaemia with serum potassium <4.0 and <3.5 mmol/L occurred in 41.1% and 7.5%, respectively. Hazards of cardiovascular and arrhythmia composite outcomes were higher in patients with baseline serum potassium <4.0 vs. 4.0-4.5 mmol/L [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.02-1.32, P = 0.022 and HR 1.20; 95% CI 1.00-1.44, P = 0.055, respectively]. Finerenone reduced the incidence of hypokalaemia with serum potassium <4.0 mmol/L (HR 0.63; 95% CI 0.60-0.66) and <3.5 mmol/L (HR 0.46; 95% CI 0.40-0.53) vs. placebo. Finerenone lessened the hazard of cardiovascular and arrhythmia events vs. placebo, irrespective of baseline serum potassium.
Conclusion: A substantial proportion of patients with CKD and T2D experienced hypokalaemia, which was associated with an increased hazard of adverse cardiovascular outcomes. Finerenone reduced the incidence of hypokalaemia. Finerenone reduced the hazard of cardiovascular and arrhythmia outcomes irrespective of serum potassium subgroups
Indiana’s Physician Workforce: Supply and Demand Brief
No full textThis brief highlights the Supply and Demand of Indiana's Physician Workforce from 2020-2030