Leveraging Policy Solutions for Diabetes Disparities: Suggestions for Improving the National Clinical Care Commission Report's Recommendations for Hispanic/Latino Populations.

In the U.S., Hispanic/Latino populations face increased disparities in both the prevalence and management of type 2 diabetes mellitus (T2DM). This article critically examines the multifaceted nature of T2DM disparities among Hispanic/Latino populations in the U.S. and identifies key factors contributing to T2DM prevalence within these communities, including socioeconomic status, cultural influences, and healthcare access. Utilizing a modified expert consensus procedure, we evaluate the ways in which the National Clinical Care Commission (NCCC) recommendations apply to the Hispanic/Latino community as well as propose recommendations for improved efficacy. Through a comprehensive analysis of government-community health initiatives, food security, environmental exposures, and housing inequalities, we emphasize the need for targeted interventions and health policies to effectively address and dismantle these disparities. Overall, while the National Clinical Care Commission's recommendations provide a valuable framework for the implementation of policies pertaining to diabetes management and prevention in the general population, our analysis suggests that recommendations may be strengthened by considering the unique cultural, social, and economic needs of the Hispanic/Latino population moving forward.

Frequency of Treatment Failure of UTIs in Children With Congenital Urinary Tract Anomalies.

OBJECTIVES: Children with certain congenital anomalies of the kidney and urinary tract and neurogenic bladder (CAKUT/NGB) are at higher risk of treatment failure for urinary tract infections (UTIs) than children with normal genitourinary anatomy, but the literature describing treatment and outcomes is limited. The objectives of this study were to describe the rate of treatment failure in children with CAKUT/NGB and compare duration of antibiotics between those with and without treatment failure. METHODS: Multicenter retrospective cohort of children 0 to 17 years old with CAKUT/NGB who presented to the emergency department with fever or hypothermia and were diagnosed with UTI between 2017 and 2018. The outcome of interest was treatment failure, defined as subsequent emergency department visit or hospitalization for UTI because of the same pathogen within 30 days of the index encounter. Descriptive statistics and univariates analyses were used to compare covariates between groups. RESULTS: Of the 2014 patient encounters identified, 482 were included. Twenty-nine (6.0%) of the 482 included encounters had treatment failure. There was no difference in the mean duration of intravenous antibiotics (3.4 ± 2.5 days, 3.5 ± 2.8 days, P = .87) or total antibiotics between children with and without treatment failure (10.2 ± 3.8 days, 10.8 ± 4.0 days, P = .39) Of note, there was a higher rate of bacteremia in children with treatment failure (P = .04). CONCLUSIONS: In children with CAKUT/NGB and UTI, 6.0% of encounters had treatment failure. Duration of antibiotics was not associated with treatment failure. Larger studies are needed to assess whether bacteremia modifies the risk of treatment failure.

Complete chloroplast genome of the marine red alga Rhodochorton tenue (Rhodochortonaceae, Rhodophyta) from San Juan Island, Washington.

We present the complete chloroplast genome sequence of Rhodochorton tenue from San Juan Island, Washington. The chloroplast genome of R. tenue is 192,037 bp in length, contains 244 genes, and is similar in content to Acrochaetium secundatum. Rhodochorton tenue is genetically distinct from Rhodochorton purpureum from the North Atlantic Ocean.

To let go or not to let go: how ParA can impact the release of the chromosomal anchoring in Caulobacter crescentus.

Chromosomal maintenance is vital for the survival of bacteria. In Caulobacter crescentus, chromosome replication initiates at ori and segregation is delayed until the nearby centromere-like region parS is replicated. Our understanding of how this sequence of events is regulated remains limited. The segregation of parS has been shown to involve multiple steps including polar release from anchoring protein PopZ, slow movement and fast ParA-dependent movement to the opposite cell pole. In this study, we demonstrate that ParA's competing attractions from PopZ and from DNA are critical for segregation of parS. Interfering with this balance of attractions-by expressing a variant ParA-R195E unable to bind DNA and thus favoring interactions exclusively between ParA-PopZ-results in cell death. Our data revealed that ParA-R195E's sole interactions with PopZ obstruct PopZ's ability to release the polar anchoring of parS, resulting in cells with multiple parS loci fixed at one cell pole. We show that the inability to separate and segregate multiple parS loci from the pole is specifically dependent on the interaction between ParA and PopZ. Collectively, our results reveal that the initial steps in chromosome segregation are highly regulated.

To let go or not to let go: how ParA can impact the release of the chromosomal anchoring in Caulobacter crescentus.

Chromosomal maintenance is vital for the survival of bacteria. In Caulobacter crescentus, chromosome replication initiates at ori and segregation is delayed until the nearby centromere-like region parS is replicated. Our understanding of how this sequence of events is regulated remains limited. The segregation of parS has been shown to involve multiple steps including polar release from anchoring protein PopZ, slow movement, and fast ParA-dependent movement to opposite cell pole. In this study, we demonstrate that ParA's competing attractions from PopZ and from DNA are critical for segregation of parS. Interfering with this balance of attractions - by expressing a variant ParA-R195E unable to bind DNA and thus favoring interactions exclusively between ParA-PopZ - results in cell death. Our data revealed that ParA-R195E's sole interactions with PopZ obstruct PopZ's ability to release the polar anchoring of parS resulting in cells with multiple parS loci fixed at one cell pole. We show that the inability to separate and segregate multiple parS loci from the pole is specifically dependent on the interaction between ParA and PopZ. Interfering with interactions between PopZ and the partitioning protein ParB, which is the interaction that anchors parS at the cell pole, does not rescue the ability of cells to separate the fixed parS loci when expressing parA-R195E. Thus, ParA and PopZ appear to have a distinct conversation from ParB yet can impact the release of ParB-parS from the anchoring at the cell pole. Collectively, our results reveal that the initial steps in chromosome segregation are highly regulated.

ParA's Impact beyond Chromosome Segregation in Caulobacter crescentus.

Maintaining proper chromosome inheritance after the completion of each cell cycle is paramount for bacterial survival. Mechanistic details remain incomplete for how bacteria manage to retain complete chromosomes after each cell cycle. In this study, we examined the potential roles of the partitioning protein ParA on chromosomal maintenance that go beyond triggering the onset of chromosome segregation in Caulobacter crescentus. Our data revealed that increasing the levels of ParA result in cells with multiple origins of replication in a DnaA-ATP-dependent manner. This ori supernumerary is retained even when expressing variants of ParA that are deficient in promoting chromosome segregation. Our data suggest that in Caulobacter ParA's impact on replication initiation is likely indirect, possibly through the effect of other cell cycle events. Overall, our data provide new insights into the highly interconnected network that drives the forward progression of the bacterial cell cycle. IMPORTANCE The successful generation of a daughter cell containing a complete copy of the chromosome requires the exquisite coordination of major cell cycle events. Any mistake in this coordination can be lethal, making these processes ideal targets for novel antibiotics. In this study, we focused on the coordination between the onset of chromosome replication, and the partitioning protein ParA. We demonstrate that altering the cellular levels of ParA causes cells to accumulate multiple origins of replication in Caulobacter crescentus. Our work provides important insights into the complex regulation involved in the coordination of the bacterial cell cycle.

Identification of gingerenone A as a novel senolytic compound.

Senescent cells accumulate with aging and have been shown to contribute to age-associated diseases and organ dysfunction. Eliminating senescent cells with senolytic drugs has been shown to improve age phenotypes in mouse models and there is some initial evidence that it may improve the health of persons with chronic diseases. In this study, we employed WI-38 human fibroblasts rendered senescent by exposure to ionizing radiation (IR) to screen several plant extracts for their potential senolytic and/or senomorphic activity. Of these, ginger extract (Zingiber officinale Rosc.) selectively caused the death of senescent cells without affecting proliferating cells. Among the major individual components of ginger extract, gingerenone A and 6-shogaol showed promising senolytic properties, with gingerenone A selectively eliminating senescent cells. Similar to the senolytic cocktail dasatinib and quercetin (D+Q), gingerenone A and 6-shogaol elicited an apoptotic program. Additionally, both D+Q and gingerenone A had a pronounced effect on suppressing the senescence-associated secretory phenotype (SASP). Gingerenone A selectively promotes the death of senescent cells with no effect on non-senescent cells and these characteristics strongly support the idea that this natural compound may have therapeutic benefit in diseases characterized by senescent cell accumulation.

Single-Institution Learning Curve for Management of Mega-Fistulae Revision.

BACKGROUND: Mega-fistulae are generalized aneurysmal dilations of a high flow (1500-4000 mL/min) autogenous arteriovenous (AV) access which may result in hemorrhage and/or high-output cardiac failure. Current treatments include ligation, ligation with prosthetic jump graft, and imbrication; however, these may not be suitable for advanced disease, or may result in loss of functioning access, poor cosmesis, or recurrence. We describe our early experience with a technique of complete mega-fistula resection and replacement with an early use prosthetic graft that both maintains existing AV access and eliminates the need for long-term catheter (LTC) placement; including lessons learned. METHODS: A single-center, retrospective review of medical records was conducted from March 2018-February 2021. Outcomes were technical success, LTC use, time to cannulation, and complications. Mega-fistulae were completely resected from the proximal to distal aneurysmal segment, including all pseudoaneurysms, followed by tunneling a prosthetic graft (Propaten later converted to Acuseal; W.L. Gore Assoc.) with an end-to-end anastomosis to the remaining arterial and venous ends of the previous AV access. RESULTS: We had 100% immediate technical success (n=12). Pre-operative long-term catheters were placed in all eight Propaten patients; one was already placed in an Acuseal patient.  Average time to cannulation was six weeks with Propaten and 4.5 days with Acuseal. At 30 days, three Propaten patients developed complications including one instance of skin necrosis, one seroma, and one hematoma. Two Acuseal patients developed complications including one central venous occlusion (CVO) and one graft infection. Of the six patients with long-term follow-up, five continue to use their access, however, two required thrombectomies and central venous angioplasties. One patient required a new contralateral access due to CVO. CONCLUSIONS: Complete mega-fistula resection and replacement with Acuseal graft maintains existing AV access and may eliminate the need for long-term catheter placement. Our early experience with this technique is encouraging, but further follow-up is required to determine the durability of this approach.

A Novel Angiography Scoring System Predicts Improvement After Isolated Common Femoral Endarterectomy With Profundaplasty.

BACKGROUND: Numerous angiography-based peripheral arterial disease classification schemes have been developed to stratify severity of preoperative patient disease, but few studies have correlated angiography-based anatomic classification schemes to postoperative outcomes. This study examined whether a proposed pre-operative angiography scoring system was predictive of outcomes after isolated common femoral endarterectomy with profundaplasty (CFEP). METHODS: A retrospective review was conducted of patients treated with isolated CFEP for claudication and/or rest pain at a single institution from 2016-19. Pre-operative angiograms were assessed quantitatively by 4 blinded surgeons across 3 domains: profunda stenosis, profunda disease length, and outflow disease severity. Table I describes the proposed angiography scoring system. Internal consistency reliability of rater scores was calculated using Cronbach alpha. Outcomes included clinical improvement, further interventions, major amputations, mortality, and mean increase in ankle-brachial index (ABI) at 30 days, and 6 months. McNemar tests, between-group t-tests, Pearson correlations, and linear regression were used. RESULTS: Clinical Outcomes 88% of patients (n = 22) had clinical improvement at 30 days; the remaining 12% of patients (n = 3) required further interventions. One patient (4%) required major amputation between 30 days and 6 months for recurrence of rest pain that had initially resolved after isolated CFEP. There was 0% mortality during the study period. Mean ABI increased by 0.15 ± 0.21 at 30 days, and by 0.06 ± 0.21 at 6 months. Angiography Scoring System Profunda stenosis score was associated with clinical improvement at 6 months (P = 0.04). A profunda stenosis score of ≥2.6 was strongly associated with 6-month clinical improvement (64% of those ≥ 2.6 improved, versus 15% of those <2.6, P = 0.15). Profunda stenosis score was associated with ABI improvement at 30 days (r = 0.73, P = 0.01) and 6 months (r = 0.82, P = 0.007). Profunda disease length score was associated with clinical improvement at 30 days (P = 0.002). 100% of patients with a profunda disease length score of ≥1.5 clinically improved at 30 days, versus 67% of those with <1.5 (P = 0.04). Angiography scores were not found to be associated with further intervention, major amputation, or mortality. Cronbach alpha for profunda stenosis, profunda disease length, and outflow severity scores were 0.90, 0.90, and 0.79, respectively, indicating strong internal consistency. CONCLUSIONS: This institutional angiography scoring system successfully predicts clinical improvement following CFEP.  Higher profunda stenosis and profunda disease length scores were most predictive of operative success within 6 months. Future validation studies will investigate these outcomes in a larger population, and over a longer period.

Faster and less invasive tools to identify patients with ileal colonization by adherent-invasive E. coli in Crohn's disease.

BACKGROUND AND AIMS: The identification of Crohn's disease (CD)-associated adherent and invasive Escherichia coli (AIEC) is time-consuming and requires ileal biopsies. We aimed to identify a faster and less invasive methods to detect ileal colonization by AIEC in CD patients. METHODS: CD patients requiring ileo-colonoscopy were consecutively enrolled in this prospective multicenter study. Samples from saliva, serum, stools, and ileal biopsies of CD patients were collected. RESULTS: Among 102 CD patients, the prevalence of AIEC on ileal biopsies was 24.5%. The abundance and global invasive ability of ileal-associated total E. coli were respectively ten-fold (p = 0.0065) and two-fold (p = 0.0007) higher in AIEC-positive (vs. AIEC-negative), while abundance of total E. coli in the feces was not correlated with AIEC status in the ileum. The best threshold of ileal total E. coli was 60 cfu/biopsy to detect AIEC-positive patients, with high negative predictive value (NPV) (94.1%[80.3-99.3]), while the global invasive ability (>9000 internalized bacteria) was able to detect the presence of AIEC with high positive predictive value (80.0% [55.2-100.0]). Overall, 78.1% of the AIEC + patients were colonized by two or less different AIEC strains. The level of serum anti-total E. coli antibodies (AEcAb) was higher in AIEC-positive patients (p = 0.038) with a very high negative predictive value (96.6% [89.9-100.0]) (p = 0.038) for a cut-off value > 1.9 × 10-3 . CONCLUSIONS: More than two thirds of AIEC-positive CD patients were colonized by two or less AIEC strains. While stools samples are not accurate to screen AIEC status, the AEcAb level appears to be an attractive, rapid and easier biomarker to identify patients with Crohn's disease harboring AIEC.

Increasing URiM Family Medicine Residents at University of Utah Health.

INTRODUCTION: The Department of Family and Preventive Medicine is home for the University of Utah's Family Medicine Residency program. Although Utah's diversity is steadily increasing, the race/ethnic diversity of the program's family medicine residency does not reflect the state's general population. METHODS: From 2017 to 2021, the residency instituted several adjustments to recruitment processes, including modification of an existing screening system to better highlight resiliency in overcoming challenging life experiences; promotion of commitment to diversity during interview days; incorporation of increased participation from diverse faculty and residents on interview days; and addition of outreach from the Office of Health, Equity, Diversity, and Inclusion. Underrepresented in medicine (URiM) applicants were the first to be offered interviews in an identical screening score cohort, and were ranked highest in rank lists in cohorts with identical final rank scores. RESULTS: Over the past five match cycles, Latinx residents have increased from zero to six, and underrepresented Asian residents from zero to two. In the 2021 match cycle, five of 10 incoming residents (50%) are URiM. Overall, URiM residents are now 30%, and residents of color 36%, of a total of 30 residents across all 3 training years. We found that eight URiM interviews were needed for every one URiM match. CONCLUSION: Intentional resident recruitment initiatives can transform racial/ethnic diversity in a family medicine residency program in a short amount of time.

Surviving Under Pressure: The Role of Solvent, Crystal Size, and Morphology During Pelletization of Metal-Organic Frameworks.

As metal-organic frameworks (MOFs) gain traction for applications, such as hydrogen storage, it is essential to form the as-synthesized powder materials into shaped bodies with high packing densities to maximize their volumetric performance. Mechanical compaction, which involves compressing the materials at high pressure, has been reported to yield high monolith density but often results in a significant loss in accessible porosity. Herein, we sought to systematically control (1) crystal size, (2) solvation, and (3) compacting pressure in the pelletization process to achieve high packing density without compromising the porosity that makes MOFs functional. It was determined that solvation is the most critical factor among the three factors examined. Solvation that exceeds the pore volume prevents the framework from collapsing, allowing for porosity to be maintained through pelletization. Higher pelletization pressure results in higher packing density, with extensive loss of porosity being observed at a higher pressure if the solvation is below the pore volume. Lastly, we observed that the morphology and size of the MOF particles result in variation in the highest achievable packing efficiency, but these numbers (75%) are still greater than many existing techniques used to form MOFs. We concluded that the application of pressure through pelletization is a suitable and widely applicable technique for forming high-density MOF-monoliths.

Isolation, Gastroprotective Effects and Untargeted Metabolomics Analysis of Lycium Minutifolium J. Remy (Solanaceae).

Lycium minutifolium J. Remy (Solanaceae) is commonly used as an infusion in traditional medicine to treat stomach pain, meteorism, intestinal disorders, stomach ailments, and other severe problems including prostate cancer and stomach cancer. From the EtOAc extract of L. minutifolium bark five known metabolites were isolated using chromatographic techniques. The gastroprotective effects of the EtOAc fraction and edible infusion extract of the bark were assayed on the hydrochloric acid (HCl)/EtOH induced gastric ulcer model in mice to support the traditional use of the plant. The EtOAc extract and the edible infusion showed gastroprotective effect at dose of 100 mg/kg reducing lesions by 31% and 64%, respectively. The gastroprotective action mechanisms of the edible infusion at a single oral dose of 100 mg/kg were evaluated suggesting that prostaglandins, sulfhydryl groups, and nitric oxide are involved in the mode of gastroprotective action. The UHPLC analysis coupled to high-resolution mass spectrometry of the edible infusion showed the presence of twenty-three compounds. Our results can support the gastroprotective properties of the edible infusion extract, and at least can validate in part, the ethnopharmacological uses of the plant.

Racial disparities in late-stage prostate cancer: a SEER analysis 2005-2015.

INTRODUCTION: To evaluate the impact of prostate cancer screening guidelines on different racial and ethnic populations. MATERIALS AND METHODS: Data was collected from the 2005-2015 Surveillance, Epidemiology, and End Results (SEER) program. Incidence of prostate cancer diagnosis was categorized and analyzed by stage, race/ethnicity, and age group. Appropriate univariate and multivariable statistical analysis was performed. RESULTS: The odds of being diagnosed with regional-stage prostate cancer in 2013-2015 were 1.3 times higher for black men, 1.3 times higher for Asian American/Pacific Islander (AAPI) men, and 1.2 times higher for white men when compared to 2005-2008. The odds of being diagnosed with distant-stage prostate cancer in 2013-2015 were 1.6 times higher for black men, 1.8 times higher for AAPI men, and 2.1 times higher for white men when compared to 2005-2008. In 2005-2008, 2009-2012, and 2013-2015 respectively, the odds of being diagnosed with distant-stage prostate cancer were 1.8 times higher, 1.7 times higher, and 1.4 times higher for black men compared to white men, and 1.5 times higher, 1.5 times higher, and 1.4 times higher for AAPI men compared to white men (all respective p < .001). CONCLUSIONS: The proportion of late-stage prostate cancer has increased significantly in all US males regardless of race and/or ethnicity. From 2013-2015, all men had a higher chance of being diagnosed with regional or distant stage disease compared to years prior. Newly-diagnosed regional-stage disease increased the most over time in AAPI and black men, while distant prostate cancer increased the most over time in white men.

Complete Genome Sequences of Mycobacterium smegmatis Phages NihilNomen and Carlyle, Isolated in Las Vegas, Nevada.

We present the complete genomes of the Mycobacterium smegmatis phages Carlyle and NihilNomen, isolated from soil in Las Vegas, Nevada. The phages were isolated and annotated by undergraduate students enrolled in the Phage Discovery course offered by the School of Life Sciences at the University of Nevada Las Vegas.

EZH2 cooperates with E2F1 to stimulate expression of genes involved in adrenocortical carcinoma aggressiveness.

BACKGROUND: EZH2 is overexpressed and associated with poor prognosis in adrenocortical carcinoma (ACC) and its inhibition reduces growth and aggressiveness of ACC cells in culture. Although EZH2 was identified as the methyltransferase that deposits the repressive H3K27me3 histone mark, it can cooperate with transcription factors to stimulate gene transcription. METHODS: We used bioinformatics approaches on gene expression data from three cohorts of patients and a mouse model of EZH2 ablation, to identify targets and mode of action of EZH2 in ACC. This was followed by ChIP and functional assays to evaluate contribution of identified targets to ACC pathogenesis. RESULTS: We show that EZH2 mostly works as a transcriptional inducer in ACC, through cooperation with the transcription factor E2F1 and identify three positive targets involved in cell cycle regulation and mitosis i.e., RRM2, PTTG1 and ASE1/PRC1. Overexpression of these genes is associated with poor prognosis, suggesting a potential role in acquisition of aggressive ACC features. Pharmacological and siRNA-mediated inhibition of RRM2 blocks cell proliferation, induces apoptosis and inhibits cell migration, suggesting that it may be an interesting target in ACC. CONCLUSIONS: Altogether, these data show an unexpected role of EZH2 and E2F1 in stimulating expression of genes associated with ACC aggressiveness.

Targeted Treatment of Individuals With Psychosis Carrying a Copy Number Variant Containing a Genomic Triplication of the Glycine Decarboxylase Gene.

BACKGROUND: The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS: We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS: Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS: These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

Inhibition of fibronectin polymerization alleviates kidney injury due to ischemia-reperfusion.

Fibrosis is a common feature of chronic kidney disease; however, no clinical therapies effectively target the progression of fibrosis. Inhibition of fibronectin polymerization with the small peptide pUR4 attenuates fibrosis in the liver and heart. Here, we show that pUR4 decreases renal fibrosis and tissue remodeling using a clinically relevant model of kidney injury, unilateral ischemia-reperfusion. This work highlights the benefits of inhibiting matrix polymerization, alone or in conjunction with cell-based therapies, as a novel approach to diminish the maladaptive responses to ischemic kidney injury that lead to chronic renal failure.

A ZNRF3-dependent Wnt/ß-catenin signaling gradient is required for adrenal homeostasis.

Spatiotemporal control of Wnt signaling is essential for the development and homeostasis of many tissues. The transmembrane E3 ubiquitin ligases ZNRF3 (zinc and ring finger 3) and RNF43 (ring finger protein 43) antagonize Wnt signaling by promoting degradation of frizzled receptors. ZNRF3 and RNF43 are frequently inactivated in human cancer, but the molecular and therapeutic implications remain unclear. Here, we demonstrate that adrenocortical-specific loss of ZNRF3, but not RNF43, results in adrenal hyperplasia that depends on Porcupine-mediated Wnt ligand secretion. Furthermore, we discovered a Wnt/ß-catenin signaling gradient in the adrenal cortex that is disrupted upon loss of ZNRF3. Unlike ß-catenin gain-of-function models, which induce high Wnt/ß-catenin activation and expansion of the peripheral cortex, ZNRF3 loss triggers activation of moderate-level Wnt/ß-catenin signaling that drives proliferative expansion of only the histologically and functionally distinct inner cortex. Genetically reducing ß-catenin dosage significantly reverses the ZNRF3-deficient phenotype. Thus, homeostatic maintenance of the adrenal cortex is dependent on varying levels of Wnt/ß-catenin activation, which is regulated by ZNRF3.