Pregnancy outcomes post-kidney transplantation across 23 years.

BACKGROUND: Pregnancy in kidney transplant recipients has become increasingly common. However, pregnancy carries higher risks to these patients compared to the general population. AIMS: To describe pregnancy outcomes in kidney transplant recipients. MATERIALS AND METHODS: We conducted a single-centre retrospective cohort study of kidney transplant recipients who delivered after 20 weeks gestation at a quaternary hospital in Victoria, Australia, between 2000 and 2022 inclusive. RESULTS: The study included 37 pregnancies from 27 patients, accounting for 38 infants. Over half of recorded pregnancies occurred in the past five years (56.8%, n = 21). There were high rates of pre-existing hypertension (75.7%, n = 28). Pregnancy-induced hypertension and pre-eclampsia were common antenatal complications (21.6%, n = 8 and 48.6%, n = 18 respectively). Soluble fms-like tyrosine kinase-1 / placental growth factor ratios were elevated in all patients who developed severe pre-eclampsia (16.2%, n = 6). The median gestational age at birth was 36.4 weeks (range 20-40.4, Q1 32.9, Q3 37.6) and 59.5% (n = 22) of births were preterm. Unplanned caesarean without labour was the most common mode of birth (35.1%, n = 13). The overall caesarean rate was 62.1% (n = 23). Post-partum haemorrhage complicated over half of pregnancies (56.8%, n = 21). Fifty percent (n = 19) of infants were admitted for neonatal care, in particular neonatal intensive care, and had low birthweights under 2500 g. While there was a transient deterioration in kidney function, there was no graft rejection within one year of birth. CONCLUSIONS: Clinicians should consider the high rates of pre-existing hypertension, preterm birth, and caesarean birth when counselling and managing pregnant kidney transplant recipients.

Stigmatizing attitudes towards mental illness: A cross-sectional survey of Australian medical students.

OBJECTIVES: We aimed to assess the degree of stigmatizing attitudes and psychological distress amongst Australian medical students in order to better understand factors that may impact help-seeking behaviours of students. We hypothesize that sociodemographic factors will not significantly predict stigmatizing attitudes, and increasing levels of psychological distress will be associated with increasing stigma. METHODS: A cross-sectional online survey was distributed to medical students at Western Australian universities and members of the Australian Medical Students' Association. Stigma was scored using the Mental Illness Clinicians' Attitudes (MICA-2) scale. Psychological distress was assessed using the Hospital Anxiety and Depression Scale (HADS). Participants provided information about gender, age, spirituality, financial hardship, treatment for mental illness, and experience in psychiatry. RESULTS: There were 598 responses. The mean (Standard Deviation) MICA-2 score was 36.8 (7.5) out of a maximum of 96, and the mean (SD) HADS depression score was 4.7 (3.7). The mean (SD) HADS anxiety score was 9.3 (4.4). Past or current treatment for a mental illness was associated with lower MICA-2 scores. There was no association between MICA-2 and HADS scores, or sociodemographic factors. CONCLUSIONS: Our results demonstrate relatively low MICA-2 scores and high HADS-A scores overall, with no association between HADS scores and stigma.

Skin Cancer Risk Is Increased by Somatic Mutations Detected Noninvasively in Healthy-Appearing Sun-Exposed Skin.

Skin cancer risk is increased by exposure to ultraviolet radiation (UVR). Because UVR exposure accumulates over time and lighter skin is more susceptible to UVR, age and skin tone are risk factors for skin cancer. However, measurements of somatic mutations in healthy-appearing skin have not been used to calculate skin cancer risk. In this study, we developed a noninvasive test that quantifies somatic mutations in healthy-appearing sun-exposed skin and applied it to a 1038-subject cohort. Somatic mutations were combined with other known skin cancer risk factors to train a model to calculate risk. The final model (DNA-Skin Cancer Assessment of Risk) was trained to predict personal history of skin cancer from age, family history, skin tone, and mutation count. The addition of mutation count significantly improved model performance (OR = 1.3, 95% confidence interval = 1.14-1.48; P = 5.3 × 10-6) and made a more significant contribution than skin tone. Calculations of skin cancer risk matched the known United States population prevalence, indicating that DNA-Skin Cancer Assessment of Risk was well-calibrated. In conclusion, somatic mutations in healthy-appearing sun-exposed skin increase skin cancer risk, and mutations capture risk information that is not accounted for by other risk factors. Clinical utility is supported by the noninvasive nature of skin sample collection through adhesive patches.

Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Impact of a Clinician Incentive Program on Quality Measures Performance in a Medicare Shared Savings Accountable Care Organization.

Financial incentives are often used to encourage and reward clinicians for achieving specific outcomes; however, there is limited data on their effectiveness. This study evaluates the impact of NewYork Quality Care's Clinician Incentive Program on improving quality measure performance over 4 years. Clinicians including primary care physicians and specialists actively opted-in to an incentive program where their quality performance was evaluated and rewarded biannually. Using Medicare Shared Savings Program data extracted for quality measures (2016-2019), this study analyzes quality measure performance between clinicians who opted-in to the program compared to those who did not. Additional analysis was performed comparing primary care clinician and specialist performance. The analysis revealed that clinicians in the incentive program significantly outperform (P < 0.05) clinicians who chose not to join the program in 6 of the 7 quality measures. In addition, the program helped facilitate discussions with clinicians more broadly in population health efforts.

Protein restriction slows the development and progression of Alzheimer's disease in mice.

Over the last decade, it has become evident that dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and we and others have shown that dietary protein restriction (PR) extends the lifespan and healthspan of mice. Here, we examined the effect of PR on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. We found that PR has metabolic benefits for 3xTg mice and non-transgenic controls of both sexes, promoting leanness and glycemic control in 3xTg mice. We found that PR induces sex-specific alterations in circulating metabolites and in the brain lipidome, downregulating sphingolipid subclasses including ceramides, glucosylceramides, and sphingomyelins in 3xTg females. Consumption of a PR diet starting at 6 months of age reduced AD pathology in conjunction with reduced mTORC1 activity, increased autophagy, and had cognitive benefits for 3xTg mice. Finally, PR improved the survival of 3xTg mice. Our results demonstrate that PR slows the progression of AD at molecular and pathological levels, preserves cognition in this mouse model of AD, and suggests that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Trimethylamine N-Oxide Reduces Neurite Density and Plaque Intensity in a Murine Model of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N-oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology. OBJECTIVE: We assessed the direct impact of TMAO on AD progression. METHODS: To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks. Neurite density was assessed through quantitative brain microstructure imaging with neurite orientation dispersion and density imaging magnetic resonance imaging (MRI). Label-free, quantitative proteomics was performed on cortex lysates from TMAO-treated and untreated animals. Amyloid-ß plaques, astrocytes, and microglia were assessed by fluorescent immunohistochemistry and synaptic protein expression was quantified via western blot. RESULTS: Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain. Amyloid-ß plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis revealed that TMAO treatment impacted the expression of 30 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-ß precursor protein processing. TMAO treatment did not alter astrocyte and microglial response nor cortical synaptic protein expression. CONCLUSION: These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density.

Gut microbiome variation modulates the effects of dietary fiber on host metabolism.

BACKGROUND: There is general consensus that consumption of dietary fermentable fiber improves cardiometabolic health, in part by promoting mutualistic microbes and by increasing production of beneficial metabolites in the distal gut. However, human studies have reported variations in the observed benefits among individuals consuming the same fiber. Several factors likely contribute to this variation, including host genetic and gut microbial differences. We hypothesized that gut microbial metabolism of dietary fiber represents an important and differential factor that modulates how dietary fiber impacts the host. RESULTS: We examined genetically identical gnotobiotic mice harboring two distinct complex gut microbial communities and exposed to four isocaloric diets, each containing different fibers: (i) cellulose, (ii) inulin, (iii) pectin, (iv) a mix of 5 fermentable fibers (assorted fiber). Gut microbiome analysis showed that each transplanted community preserved a core of common taxa across diets that differentiated it from the other community, but there were variations in richness and bacterial taxa abundance within each community among the different diet treatments. Host epigenetic, transcriptional, and metabolomic analyses revealed diet-directed differences between animals colonized with the two communities, including variation in amino acids and lipid pathways that were associated with divergent health outcomes. CONCLUSION: This study demonstrates that interindividual variation in the gut microbiome is causally linked to differential effects of dietary fiber on host metabolic phenotypes and suggests that a one-fits-all fiber supplementation approach to promote health is unlikely to elicit consistent effects across individuals. Overall, the presented results underscore the importance of microbe-diet interactions on host metabolism and suggest that gut microbes modulate dietary fiber efficacy. Video abstract.

Vorinostat differentially alters 3D nuclear structure of cancer and non-cancerous esophageal cells.

The histone deacetylase (HDAC) inhibitor vorinostat has received significant attention in recent years as an 'epigenetic' drug used to treat solid tumors. However, its mechanisms of action are not entirely understood, particularly with regard to its interaction with the aberrations in 3D nuclear structure that accompany neoplastic progression. We investigated the impact of vorinostat on human esophageal epithelial cell lines derived from normal, metaplastic (pre-cancerous), and malignant tissue. Using a combination of novel optical computed tomography (CT)-based quantitative 3D absorption microscopy and conventional confocal fluorescence microscopy, we show that subjecting malignant cells to vorinostat preferentially alters their 3D nuclear architecture relative to non-cancerous cells. Optical CT (cell CT) imaging of fixed single cells showed that drug-treated cancer cells exhibit significant alterations in nuclear morphometry. Confocal microscopy revealed that vorinostat caused changes in the distribution of H3K9ac-marked euchromatin and H3K9me3-marked constitutive heterochromatin. Additionally, 3D immuno-FISH showed that drug-induced expression of the DNA repair gene MGMT was accompanied by spatial relocation toward the center of the nucleus in the nuclei of metaplastic but not in non-neoplastic cells. Our data suggest that vorinostat's differential modulation of 3D nuclear architecture in normal and abnormal cells could play a functional role in its anti-cancer action.

Patterns of chlamydia/gonorrhea positivity among voluntarily screened New York City public high school students.

PURPOSE: Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC) are common sexually transmitted infections that disproportionately affect adolescents. Annual screening for CT for sexually active female adolescents is recommended. In 2006, New York City began conducting CT/GC education, screening, and treatment in public high schools. We examine 3-year programmatic outcomes and the relationship between sexual activity, screening, and CT/GC positivity. METHODS: We describe the epidemiology of students who screened and those infected with CT/GC. Univariate, bivariate, and multivariate logistic regression analyses were performed to assess relationships between sex, race/ethnicity, age, sexual activity, and screening status; and the relationship between sexually transmitted infection positivity and sexual activity. RESULTS: Between July 2006 and June 2009, we educated 57,418 students and screened 27,353 (47.6%) for CT/GC; 1,736 (6.3%) students were reported to be infected with either organism. Students who screened positive were more likely to be females (8.9%), report black race (8.3%) and be ≥16 years of age (6.6%-9.7%). Screening rates were 70.6% for students who were sexually active, 27.9% for those who had never had sex, and 47.3% for those who did not respond to the sexual activity question; CT/GC positivity was 7.2%, 1.4%, and 6.1%, respectively. CONCLUSIONS: Black, older adolescent females were most likely to screen positive for CT/GC in this population. A large proportion of students who did not answer the sexual activity question chose to screen for CT/GC and screened positive. School screening programs should offer screening to all students regardless of reported sexual activity. Programs should target females and older adolescents.