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INTRODUCTION: The incidence of Alzheimer's disease (AD) and obesity rise concomitantly. This study examined whether factors affecting metabolism, race/ethnicity, and sex are associated with AD development. METHODS: The analyses included patients ≥ 65 years with AD diagnosis in six University of California hospitals between January 2012 and October 2023. The controls were race/ethnicity, sex, and age matched without dementia. Data analyses used the Cox proportional hazards model and machine learning (ML). RESULTS: Hispanic/Latino and Native Hawaiian/Pacific Islander, but not Black subjects, had increased AD risk compared to White subjects. Non‐infectious hepatitis and alcohol abuse were significant hazards, and alcohol abuse had a greater impact on women than men. While underweight increased AD risk, overweight or obesity reduced risk. ML confirmed the importance of metabolic laboratory tests in predicting AD development. DISCUSSION: The data stress the significance of metabolism in AD development and the need for racial/ethnic‐ and sex‐specific preventive strategies. Highlights: Hispanics/Latinos and Native Hawaiians/Pacific Islanders show increased hazards of Alzheimer's disease (AD) compared to White subjects.Underweight individuals demonstrate a significantly higher hazard ratio for AD compared to those with normal body mass index.The association between obesity and AD hazard differs among racial groups, with elderly Asian subjects showing increased risk compared to White subjects.Alcohol consumption and non‐infectious hepatitis are significant hazards for AD.Machine learning approaches highlight the potential of metabolic panels for AD prediction. [ABSTRACT FROM AUTHOR]

Background: Fragile X–associated tremor/ataxia syndrome is a neurodegenerative disease of late onset developed by carriers of the premutation in the fragile x mental retardation 1 (FMR1) gene. Pathological features of neurodegeneration in fragile X–associated tremor/ataxia syndrome include toxic levels of FMR1 mRNA, ubiquitin‐positive intranuclear inclusions, white matter disease, iron accumulation, and a proinflammatory state. Objective: The objective of this study was to analyze the presence of cerebral microbleeds in the brains of patients with fragile X–associated tremor/ataxia syndrome and investigate plausible causes for cerebral microbleeds in fragile X–associated tremor/ataxia syndrome. Methods: We collected cerebral and cerebellar tissue from 15 fragile X–associated tremor/ataxia syndrome cases and 15 control cases carrying FMR1 normal alleles. We performed hematoxylin and eosin, Perls and Congo red stains, ubiquitin, and amyloid β protein immunostaining. We quantified the number of cerebral microbleeds, amount of iron, presence of amyloid β within the capillaries, and number of endothelial cells containing intranuclear inclusions. We evaluated the relationships between pathological findings using correlation analysis. Results: We found intranuclear inclusions in the endothelial cells of capillaries and an increased number of cerebral microbleeds in the brains of those with fragile X–associated tremor/ataxia syndrome, both of which are indicators of cerebrovascular dysfunction. We also found a suggestive association between the amount of capillaries that contain amyloid β in the cerebral cortex and the rate of disease progression. Conclusion: We propose microangiopathy as a pathologic feature of fragile X–associated tremor/ataxia syndrome. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

The prenatal period is a critical window for the development of autism spectrum disorder (ASD). The relationship between prenatal nutrients and gestational gene expression in mothers of children later diagnosed with ASD or non‐typical development (Non‐TD) is poorly understood. Maternal blood collected prospectively during pregnancy provides insights into the effects of nutrition, particularly one‐carbon metabolites, on gene pathways and neurodevelopment. Genome‐wide transcriptomes were measured with microarrays in 300 maternal blood samples in Markers of Autism Risk in Babies‐Learning Early Signs. Sixteen different one‐carbon metabolites, including folic acid, betaine, 5′‐methyltretrahydrofolate (5‐MeTHF), and dimethylglycine (DMG) were measured. Differential expression analysis and weighted gene correlation network analysis (WGCNA) were used to compare gene expression between children later diagnosed as typical development (TD), Non‐TD and ASD, and to one‐carbon metabolites. Using differential gene expression analysis, six transcripts (TGR‐AS1, SQSTM1, HLA‐C, and RFESD) were associated with child outcomes (ASD, Non‐TD, and TD) with genome‐wide significance. Genes nominally differentially expressed between ASD and TD significantly overlapped with seven high confidence ASD genes. WGCNA identified co‐expressed gene modules significantly correlated with 5‐MeTHF, folic acid, DMG, and betaine. A module enriched in DNA methylation functions showed a suggestive protective association with folic acid/5‐MeTHF concentrations and ASD risk. Maternal plasma betaine and DMG concentrations were associated with a block of co‐expressed genes enriched for adaptive immune, histone modification, and RNA processing functions. These results suggest that the prenatal maternal blood transcriptome is a sensitive indicator of gestational one‐carbon metabolite status and changes relevant to children's later neurodevelopmental outcomes. Lay Summary Pregnancy is a time when maternal nutrition could interact with genetic risk for autism spectrum disorder. Blood samples collected during pregnancy from mothers who had a prior child with autism were examined for gene expression and nutrient metabolites, then compared to the diagnosis of the child at age three. Expression differences in gene pathways related to the immune system and gene regulation were observed for pregnancies of children with autism and non‐typical neurodevelopment and were associated with maternal nutrients. [ABSTRACT FROM AUTHOR]

Aims: Machine learning (ML) binary classification in diagnostic histopathology is an area of intense investigation. Several assumptions, including training image quality/format and the number of training images required, appear to be similar in many studies irrespective of the paucity of supporting evidence. We empirically compared training image file type, training set size, and two common convolutional neural networks (CNNs) using transfer learning (ResNet50 and SqueezeNet). Methods and results: Thirty haematoxylin and eosin (H&E)‐stained slides with carcinoma or normal tissue from three tissue types (breast, colon, and prostate) were photographed, generating 3000 partially overlapping images (1000 per tissue type). These lossless Portable Networks Graphics (PNGs) images were converted to lossy Joint Photographic Experts Group (JPG) images. Tissue type‐specific binary classification ML models were developed by the use of all PNG or JPG images, and repeated with a subset of 500, 200, 100, 50, 30 and 10 images. Eleven models were generated for each tissue type, at each quantity of training images, for each file type, and for each CNN, resulting in 924 models. Internal accuracies and generalisation accuracies were compared. There was no meaningful significant difference in accuracies between PNG and JPG models. Models trained with more images did not invariably perform better. ResNet50 typically outperformed SqueezeNet. Models were generalisable within a tissue type but not across tissue types. Conclusions: Lossy JPG images were not inferior to lossless PNG images in our models. Large numbers of unique H&E‐stained slides were not required for training optimal ML models. This reinforces the need for an evidence‐based approach to best practices for histopathological ML. [ABSTRACT FROM AUTHOR]

In estuary and coastal systems, human demand for freshwater, climate change‐driven precipitation variability, and extreme weather impact salinity levels, reducing connectivity between mesohaline coastal fish populations and potentially contributing to genomic divergence. We examined gill transcriptome responses to salinity in wild‐caught juveniles from two populations of Sacramento splittail (Pogonichthys macrolepidotus), a species of conservation concern that is endemic to the San Francisco Estuary, USA, and the lower reaches of its tributaries. Recent extreme droughts have led to salinities above the tolerance limits for this species, creating a migration barrier between these populations, which potentially contributed to population divergence. We identified transcripts involved in a conserved response to salinity; however, the more salinity‐tolerant San Pablo population had greater transcriptome plasticity (3.6‐fold more transcripts responded than the Central Valley population) and a response consistent with gill remodeling after 168 hr of exposure to elevated salinity. The reorganization of the gill in response to changing osmotic gradients is a process critical for acclimation and would facilitate enhanced salinity tolerance. We detected an upregulation of receptors that control the Wnt (wingless‐type) cell signaling pathway that may be required for an adaptive response to increases in salinity, patterns not observed in the relatively salinity‐sensitive Central Valley population. We detected 62 single nucleotide polymorphisms (SNPs) in coding regions of 26 transcripts that differed between the populations. Eight transcripts that contained SNPs were associated with immune responses, highlighting the importance of diversity in immune gene sequences as a defining characteristic of genomic divergence between these populations. Our data demonstrate that these populations have divergent transcriptomic responses to salinity, which is consistent with observed physiological differences in salinity tolerance. [ABSTRACT FROM AUTHOR]

Abstract: Advances in mass spectrometry‐based proteomics now permit analysis of complex cellular structures. Application to epidermis and its appendages (nail plate, hair shaft) has revealed a wealth of information about their protein profiles. The results confirm known site‐specific differences in levels of certain keratins and add great depth to our knowledge of site specificity of scores of other proteins, thereby connecting anatomy and pathology. An example is the evident overlap in protein profiles of hair shaft and nail plate, helping rationalize their sharing of certain dystrophic syndromes distinct from epidermis. In addition, interindividual differences in protein level are manifest as would be expected. This approach permits characterization of altered profiles as a result of disease, where the magnitude of perturbation can be quantified and monitored during treatment. Proteomic analysis has also clarified the nature of the isopeptide cross‐linked residual insoluble material after vigorous extraction with protein denaturants, nearly intractable to analysis without fragmentation. These structures, including the cross‐linked envelope of epidermal corneocytes, are comprised of hundreds of protein constituents, evidence for strengthening the terminal structure complementary to disulphide bonding. Along with other developing technologies, proteomic analysis is anticipated to find use in disease risk stratification, detection, diagnosis and prognosis after the discovery phase and clinical validation. [ABSTRACT FROM AUTHOR]

Aims There is a lack of data describing the current state of stress urinary incontinence (SUI) procedures in academic centers. Urologists, gynecologists, and urogynecologists perform these operations, but the relative volume each group accounts for is unknown. The purpose of this study was to evaluate the distribution of cases in academic centers between specialties and associated patient characteristics. Methods A hospital consortium database was used to identify patients treated surgically for SUI between 2009 and 2014. Patient and surgeon variables were evaluated. Patient variables (age, region, insurance, race) and surgeon volume were analyzed. Sub-analysis was conducted to determine concomitant prolapse repairs. Results Of the 50,315 stress urinary incontinence procedures performed, 22% were performed by urologists. Overall volume dropped 39% and mean surgeon volumes for all three groups decreased with time. Average median volume for urogynecologists (29/year) differed from both urologists (3/year) and non-urogynecologists (2/year). There was a significant difference in rate of concomitant prolapse repairs performed by urogynecologists (56%), gynecologists (54%), and urologists (26%). Conclusions These data portray the changing pattern of SUI procedure practice in academic centers. Academic urologists are performing less than 25% of SUI procedures, with an overall decline in number of procedures across all specialties. Urogynecologists and gynecologists are performing a significantly higher proportion of concomitant prolapse repairs. Neurourol. Urodynam. 36:394-398, 2017. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background The frequency of alcoholic liver disease (ALD), including alcoholic steatosis, hepatitis, and cirrhosis, varies significantly by ethnicity. Methods With the goal to assess the role of ethnicity in determining the age of onset and severity of ALD and to compare the risk factors for its progression among ethnic groups, we conducted a retrospective chart review of all patients with ALD who were admitted or were followed as outpatients at University of California Davis Medical Center between 2002 and 2010. After excluding HBsAg- and HIV-positive subjects, we reviewed the charts of 791 patients with ALD including 130 with alcoholic fatty liver, 154 with alcoholic hepatitis, and 507 with alcoholic cirrhosis. Results When controlling for all variables in the model, Hispanic patients presented at significantly 4 to 10 years younger ages than White/Caucasian patients, in each of the 3 disease severity categories, and the results were confirmed after excluding HCV Ab-/RNA-positive subjects. There were more obese Hispanic patients than White/Caucasian patients, whereas the proportion of patients with hepatitis C was significantly greater in African American subjects with alcoholic hepatitis, and the proportion of patients with diabetes mellitus was significantly lower in White/Caucasian subjects than in Hispanic subjects with cirrhosis. The proportion of subjects with severe alcoholic hepatitis was similar in Hispanic and White/Caucasian patients, but lower in African American subjects. Conclusions Ethnicity is a major factor affecting the age and severity of presentation of different subtypes of ALD. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis To evaluate the prevalence and unmet need for cleft lip-cleft palate reconstructive surgery by using incidence. Our hypotheses were that the age of presentation to screening clinics will decrease between 2006 and 2012, and the geospatial distribution of cases will expand to a more rural catchment area. Study Design Longitudinal cross-sectional/geospatial distribution study. Methods An online, secure database was created from intake forms for children with cleft lip-cleft palate (N = 604) in Zimbabwe (2006-2012). Univariate analysis was completed. A linear regression model was fitted to test the time trend of a child's age at the time of presentation. Unique patient addresses (n = 411) were matched. Maps presenting cleft diagnosis and presentation year were created with geographic information systems (GIS) software. Results The median age of presentation was greater for isolated cleft palate (4.2 years, n = 106) than isolated cleft lip (1.5 years, n = 251) and cleft lip-cleft palate (2.0 years, n = 175). Cleft lip cases were mostly left sided with equal gender distribution. The overall age of presentation remained stable ( P = .83). The age of children with isolated cleft palate decreased by 0.8 years per surgical trip ( P = .01), suggesting the prevalence of unrepaired cleft palate is decreasing due to local and visiting surgeons. The catchment area extended to a less populous area, but clustered around Harare and Bulawayo. Conclusions This study gives Zimbabwe-specific evidence that supports reports of the persistent burden of disease requiring attention. The GIS software provided data for the primary needs assessment, which will direct communication to healthcare providers and prospective patients outside of the current catchment area. Level of Evidence 3 Laryngoscope, 125:S1-S14, 2015 [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis: The objective of this study was to determine if there are differences in decannulation rates and duration of cannulation between pediatric patients undergoing tracheotomy for different indications. Study Design: Retrospective chart review. Methods: Medical records for pediatric patients (age 0-18 years) undergoing tracheotomy between January 1, 2003, and May 31, 2012, were retrospectively reviewed. Patients were assigned an indication for tracheotomy from five categories: neurological, cardiopulmonary, upper airway obstruction, craniofacial anomalies, and maxillofacial/laryngotracheal trauma. Results: Initial chart review identified 124 patients, 113 for whom complete data was available. Of these patients, the indications for tracheotomy were cardiopulmonary disease in 24 (21.2%), craniofacial anomalies in 12 (10.6%), neurological impairment in 44 (38.9%), traumatic injury in 11 (9.7%), and upper airway obstruction in 22 (19.5%). The time to decannulation was shorter for trauma patients compared to cardiopulmonary (P = 0.044) and neurological patients (P = 0.001). A total of 32 (31.9%) patients were decannulated during the study period, with a higher rate in trauma patients (72.7%) and a lower rate in those with upper airway obstruction (36.4%) than would be expected under homogeneity. Of the 32 patients who were decannulated, 11 (30.6%) were decannulated during the same hospitalization in which the tracheotomy was performed. Conclusion: This study demonstrates a difference in overall decannulation rates and a shorter time to decannulation in children undergoing tracheotomy for maxillofacial and laryngotracheal trauma compared to cardiopulmonary and neurological indications. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by lack of the FMR1 protein, FMRP, a translational repressor. Its absence leads to up-regulation of locally translated proteins involved in synaptic transmission and plasticity, including the matrix metalloproteinase-9 (MMP-9). In the Fmr1 knock-out (KO), a mouse model of FXS, an abnormal elevated expression of MMP-9 in the brain was pharmacologically down-regulated after treatment with the tetracycline derivative minocycline. Moreover, the rescue of immature dendritic spine morphology and a significant improvement of abnormal behavior were associated with down-regulation of MMP-9. Here, we report on high plasma activity of MMP-9 in individuals with FXS. In addition, we investigate MMP-9 changes in patients with FXS who have gone through a minocycline controlled clinical trial and correlate MMP-9 activity to clinical observations. The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background: The costs associated with a contemporary active surveillance strategy compared with immediate treatment for prostate cancer are not well characterized. The purpose of this study is to elucidate the health care costs of an active surveillance paradigm for prostate cancer.Methods: A theoretical cohort of 120,000 men selecting active surveillance for prostate cancer was created. The number of men remaining on active surveillance and those exiting to each of 5 treatments over 5 years were simulated in a Markov model. Estimated total costs after 5 years of active surveillance with subsequent delayed treatment were compared with immediate treatment. Sensitivity analyses were performed to test the effect of various surveillance strategies and attrition rates. Additional analyses to include 10 years of follow-up were performed.Results: The average simulated cost of treatment for 120,000 men initiating active surveillance with 5 years of follow-up and subsequent delayed treatment resulted in per patient cost savings of $16,042 (95% confidence interval [CI], $16,039-$16,046) relative to initial curative treatment. This represents a $1.9 billion dollar savings to the cohort. The strict costs of active surveillance exceeded those of brachytherapy in the ninth year of follow-up. A yearly biopsy within the active surveillance cohort increased costs by 22%, compared with every other year biopsy. At 10 years of follow-up, active surveillance still resulted in a cost benefit; however, the savings were reduced by 38% to $9944 (95% CI, $9941-$9948) per patient relative to initial treatment.Conclusions: These data demonstrate that active surveillance represents a considerable cost savings over immediate treatment for prostate cancer in a theoretical cohort after 5 and 10 years of follow-up. [ABSTRACT FROM AUTHOR]