Results of a defined surgical protocol for treating pediatric neurogenic bladder incontinence in a single institution.

INTRODUCTION: Incontinent pediatric neurogenic bladder (NB) patients face social ostracization and potential renal deterioration. Reconstructive surgery, after maximal medical therapy, requires a difficult decision-making process. Current literature for NB surgeries is difficult to interpret given definitions of dryness, use of augmentation cystoplasty (AC) and the lack of renal preservation. This study assesses the results of a defined surgical protocol to treat incontinent NB patients, using a new composite outcome measure, which includes upper tracts status and a definition of dryness. MATERIALS AND METHODS: This is a retrospective cohort study assessing 33 consecutive incontinent NB patients (Spina bifida 31, Sacral agenesis- 2) who underwent one of 2 procedures between 2008 and 2021. AC with a Mitrofanoff procedure (MP) was performed in patients who had a high detrusor leak point pressure (DLPP) and significant bladder trabeculations (N = 21, Group 1). Children with a low DLPP and non-trabeculated bladders, underwent a modified Young-Dees-Leadbetter/Mitchell procedure with a 360° autologous rectus fascial sling (BOP) with concomitant AC and MP (N-12, Group 2). Post-operative success was defined using a composite grading of success assessing dryness, upper tract stability and medication use. RESULTS: The mean age at surgery was 11.6 years (SD = 6 years), with 21 in Group 1 and 12 in Group 2. Mean follow-up was 3.25 years, with a minimum 24-month follow-up period. Success rate was 90% in Group 1 and 66% in Group 2. No patient had upper tract deterioration following surgery. Redo-surgical intervention, was required in 38% of Group 1 and 50% of Group 2 patients. These include 3 bladder neck injections in Group 1 and 2 bladder neck closure in Group 2, with a final success rate to 95 % in Group 1 and 83 % in Group 2. DISCUSSION: Achieving dryness and preserving upper tracts is a challenge in incontinent NB patients. Dryness rates achieved in this study is comparable, given complications and redo-surgery. Primary bladder neck closure is a radical intervention, but Group 2 patients, may benefit from an upfront discussion of the pros and cons of a bladder neck closure primarily or as a secondary procedure. CONCLUSIONS: Isolated AC obtains acceptable results for a selected subset of incontinent NB patients with significant bladder trabeculation. For those requiring a BOP, the success rate is relatively lower with the higher rate of potential complications and need for redo-surgery.

The guide-RNA sequence dictates the slicing kinetics and conformational dynamics of the Argonaute silencing complex.

The RNA-induced silencing complex (RISC), which powers RNA interference (RNAi), consists of a guide RNA and an Argonaute protein that slices target RNAs complementary to the guide. We find that, for different guide-RNA sequences, slicing rates of perfectly complementary bound targets can be surprisingly different (>250-fold range), and that faster slicing confers better knockdown in cells. Nucleotide sequence identities at guide-RNA positions 7, 10, and 17 underlie much of this variation in slicing rates. Analysis of one of these determinants implicates a structural distortion at guide nucleotides 6-7 in promoting slicing. Moreover, slicing directed by different guide sequences has an unanticipated, 600-fold range in 3'-mismatch tolerance, attributable to guides with weak (AU-rich) central pairing requiring extensive 3' complementarity (pairing beyond position 16) to more fully populate the slicing-competent conformation. Together, our analyses identify sequence determinants of RISC activity and provide biochemical and conformational rationale for their action.

N-of-1 health optimization: Digital monitoring of biomarker dynamics to gamify adherence to metabolic switching.

The digital health field is experiencing substantial growth due to its potential for sustained and longitudinal deployment. In turn, this may drive improved monitoring and intervention as catalysts for behavioral change compared to traditional point-of-care practices. In particular, the increase in incidence of population health challenges such as diabetes, heart disease, fatty liver disease, and other disorders coupled with rising healthcare costs have emphasized the importance of exploring technical, economics, and implementation considerations, among others in the decentralization of health and healthcare innovations. Both healthy individuals and patients stand to benefit from continued technical advances and studies in these domains. To address these points, this study reports a N-of-1 study comprised of sustained regimens of intermittent fasting, fitness (strength and cardiovascular training), and high protein, low carbohydrate diet and parallel monitoring. These regimens were paired with serial blood ketone, blood glucose (wearable and finger stick) and blood pressure readings, as well as body weight measurements using a collection of devices. Collectively this suite of platforms and approaches were used to monitor metabolic switching from glucose to ketones as energy sources-a process associated with potential cardio- and neuroprotective functions. In addition to longitudinal biomarker dynamics, this work discusses user perspectives on the potential role of harnessing digital devices to these dynamics as potential gamification factors, as well as considerations for the role of biomarker monitoring in health regimen development, user stratification, and potentially informing downstream population-scale studies to address metabolic disease, healthy aging and longevity, among other indications.

p53/MDM2 signaling pathway in aging, senescence and tumorigenesis.

A wealth of evidence has emerged that there is an association between aging, senescence and tumorigenesis. Senescence, a biological process by which cells cease to divide and enter a status of permanent cell cycle arrest, contributes to aging and aging-related diseases, including cancer. Aging populations have the higher incidence of cancer due to a lifetime of exposure to cancer-causing agents, reduction of repairing DNA damage, accumulated genetic mutations, and decreased immune system efficiency. Cancer patients undergoing cytotoxic therapies, such as chemotherapy and radiotherapy, accelerate aging. There is growing evidence that p53/MDM2 (murine double minute 2) axis is critically involved in regulation of aging, senescence and oncogenesis. Therefore, in this review, we describe the functions and mechanisms of p53/MDM2-mediated senescence, aging and carcinogenesis. Moreover, we highlight the small molecular inhibitors, natural compounds and PROTACs (proteolysis targeting chimeras) that target p53/MDM2 pathway to influence aging and cancer. Modification of p53/MDM2 could be a potential strategy for treatment of aging, senescence and tumorigenesis.

The guide RNA sequence dictates the slicing kinetics and conformational dynamics of the Argonaute silencing complex.

The RNA-induced silencing complex (RISC), which powers RNA interference (RNAi), consists of a guide RNA and an Argonaute protein that slices target RNAs complementary to the guide. We find that for different guide-RNA sequences, slicing rates of perfectly complementary, bound targets can be surprisingly different (>250-fold range), and that faster slicing confers better knockdown in cells. Nucleotide sequence identities at guide-RNA positions 7, 10, and 17 underlie much of this variation in slicing rates. Analysis of one of these determinants implicates a structural distortion at guide nucleotides 6-7 in promoting slicing. Moreover, slicing directed by different guide sequences has an unanticipated, 600-fold range in 3'-mismatch tolerance, attributable to guides with weak (AU-rich) central pairing requiring extensive 3' complementarity (pairing beyond position 16) to more fully populate the slicing-competent conformation. Together, our analyses identify sequence determinants of RISC activity and provide biochemical and conformational rationale for their action.

Racial and sociodemographic distribution of colorectal cancer screening in Canada: A cross-sectional study.

OBJECTIVES: To assess the racial and sociodemographic distribution of colorectal cancer (CRC) screening uptake in Canada, identify disparities, and evaluate the potential predictors and barriers to CRC screening. METHODS: Data from the 2017 cycle of the Canadian Community Health Survey (CCHS) were analyzed, focusing on individuals aged 50-74 years. CRC screening participation rates were evaluated at both national and provincial levels and across various sociodemographic characteristics. Multivariable logistic regression models were employed to identify predictors and barriers to CRC screening. RESULTS: Of the 56,950 respondents to the 2017 CCHS, 41.7% (n = 23,727) were between 50 and 74 years of age. The overall CRC screening participation rate was 59.8%, with provinces like Alberta and Manitoba achieving rates of 65.7% and 66.5%, respectively. Significant disparities were observed across socioeconomic, geographical, and racial or ethnic groups. Notably, older adults [AOR 2.41, 95% CI 2.06‒2.83], higher income earners [AOR 1.99, 95% CI 1.77‒2.24], and non-smokers [AOR 1.76, 95% CI 1.55‒2.0] had higher odds of screening, while immigrants and minority ethnic groups, especially South-East Asians [AOR 0.48, 95% CI 0.29‒0.78] and South Asians [AOR 0.65, 95% CI 0.44‒0.95], had lower odds of being up to date with CRC screening. A significant portion of unscreened individuals cited their healthcare provider's perception of the test as unnecessary. CONCLUSION: While there is promising progress in CRC screening participation rates across Canada, significant disparities persist. Addressing these disparities is crucial for public health. Efforts should focus on enhancing public awareness, facilitating accessibility, and ensuring cultural appropriateness of CRC screening initiatives.

RéSUMé: OBJECTIFS: Évaluer la distribution raciale et sociodémographique de la participation au dépistage du cancer colorectal (CCR) au Canada, identifier les disparités et évaluer les potentiels prédicteurs et obstacles au dépistage du CCR. MéTHODES: Les données du cycle 2017 de l'Enquête sur la santé dans les collectivités canadiennes (ESCC) ont été analysées, en se concentrant sur les individus âgés de 50 à 74 ans. Les taux de participation au dépistage du CCR ont été évalués à la fois au niveau national et provincial et selon diverses caractéristiques sociodémographiques. Des modèles de régression logistique multivariée ont été utilisés pour identifier les prédicteurs et les obstacles au dépistage du CCR. RéSULTATS: Sur les 56 950 répondants à l'ESCC 2017, 41,7% (n = 23 727) étaient âgés de 50 à 74 ans. Le taux global de participation au dépistage du CCR était de 59,8%, des provinces comme l'Alberta et le Manitoba atteignant des taux de 65,7% et 66,5% respectivement. Des disparités significatives ont été observées selon les groupes socioéconomiques, géographiques et raciaux ou ethniques. Notamment, les personnes âgées [AOR 2,41, IC 95% 2,06‒2,83], les personnes à revenu élevé [AOR 1,99 IC 95% 1,77‒2,24] et les non-fumeurs [AOR 1,76, IC 95% 1,55‒2,0] avaient des chances plus élevées de dépistage, tandis que les immigrants et les groupes ethniques minoritaires, en particulier les Asiatiques du Sud-Est [AOR 0,48, IC 95% 0,29‒0,78] et les Asiatiques du Sud [AOR 0,65, IC 95% 0,44‒0,95] avaient moins de chances d'être à jour avec le dépistage du CCR. Une part significative des individus non dépistés a cité la perception de leur prestataire de soins de santé selon laquelle le test était inutile. CONCLUSION: Bien qu'il y ait une progression prometteuse des taux de participation au dépistage du CCR au Canada, des disparités significatives persistent. Il est crucial pour la santé publique de s'attaquer à ces disparités. Les efforts devraient se concentrer sur l'amélioration de la sensibilisation du public, la facilitation de l'accessibilité et la garantie de l'adéquation culturelle des initiatives de dépistage du CCR.

Radiation therapy with phenotypic medicine: towards N-of-1 personalization.

In current clinical practice, radiotherapy (RT) is prescribed as a pre-determined total dose divided over daily doses (fractions) given over several weeks. The treatment response is typically assessed months after the end of RT. However, the conventional one-dose-fits-all strategy may not achieve the desired outcome, owing to patient and tumor heterogeneity. Therefore, a treatment strategy that allows for RT dose personalization based on each individual response is preferred. Multiple strategies have been adopted to address this challenge. As an alternative to current known strategies, artificial intelligence (AI)-derived mechanism-independent small data phenotypic medicine (PM) platforms may be utilized for N-of-1 RT personalization. Unlike existing big data approaches, PM does not engage in model refining, training, and validation, and guides treatment by utilizing prospectively collected patient's own small datasets. With PM, clinicians may guide patients' RT dose recommendations using their responses in real-time and potentially avoid over-treatment in good responders and under-treatment in poor responders. In this paper, we discuss the potential of engaging PM to guide clinicians on upfront dose selections and ongoing adaptations during RT, as well as considerations and limitations for implementation. For practicing oncologists, clinical trialists, and researchers, PM can either be implemented as a standalone strategy or in complement with other existing RT personalizations. In addition, PM can either be used for monotherapeutic RT personalization, or in combination with other therapeutics (e.g. chemotherapy, targeted therapy). The potential of N-of-1 RT personalization with drugs will also be presented.

N-of-1 medicine.

ABSTRACT: The fields of precision and personalised medicine have led to promising advances in tailoring treatment to individual patients. Examples include genome/molecular alteration-guided drug selection, single-patient gene therapy design and synergy-based drug combination development, and these approaches can yield substantially diverse recommendations. Therefore, it is important to define each domain and delineate their commonalities and differences in an effort to develop novel clinical trial designs, streamline workflow development, rethink regulatory considerations, create value in healthcare and economics assessments, and other factors. These and other segments are essential to recognise the diversity within these domains to accelerate their respective workflows towards practice-changing healthcare. To emphasise these points, this article elaborates on the concept of digital health and digital medicine-enabled N-of-1 medicine, which individualises combination regimen and dosing using a patient's own data. We will conclude with recommendations for consideration when developing novel workflows based on emerging digital-based platforms.

Clinical correlation and prognostic value of xanthine and inflammatory factors in postpartum depression.

OBJECTIVES: As a common postpartum complication, postpartum depression is an important social and health problem. Postpartum depression causes many changes in relevant indicators, such as inflammatory factors and thyroid hormones. However, the effects of inflammatory factors, thyroid hormones and xanthine on postpartum depression have not yet been fully elucidated. Therefore, it is of great clinical significance to clarify the changes in the key indicators of postpartum depression. MATERIAL AND METHODS: A total of 139 pregnant women were included in this study. Finally, only 56 patients completed the Edinburgh Depression Scale (EPDS) evaluation and blood sample collection. RESULTS: In the current study, 34 (60.7%) patients were normal, 10 (17.9%) women were depressive tendency and 12 (21.4%) women developed depression. Among the serum indexes detected, the expression levels of thyroid function indexes T3, T4 and TSH, and inflammatory factors, such as hs-CRP, IL-1ß, IL-6 and TNF-α, in the EPDS ≥ 9 group were slightly higher than those in the normal group (EPDS < 9). Xanthine levels in the depression group (EPDS ≥ 13) were significantly higher than normal group (EPDS < 9). CONCLUSIONS: Our findings suggest that xanthine levels in patients with postpartum depression were increased significantly, but there were no significant changes in thyroid function and some inflammatory indexes. Therefore, timely detection and intervention of maternal xanthine may help reduce the incidence of postpartum depression.

Improved Productivity with Multilaser Rotary Powder Bed Fusion Additive Manufacturing.

Laser powder bed fusion (LPBF) enables the fabrication of intricate, geometrically complex structures with a sufficiently fine surface finish for many engineering applications with a diversity of available feedstock metals. However, the production rate of LPBF systems is not well suited for mass production in comparison to traditional manufacturing methods. LPBF systems measure their deposition rates in 100's of grams per hour, while other processes measure in kilograms per hour or even in the case of processes such as forming, stamping, and casting, 100's of kilograms per hour. To be widely adopted in industry for mass production, LPBF requires a new scalable architecture that enables many orders of magnitude improvement in deposition rate, while maintaining the geometry freedom of additive manufacturing. This article explores concepts that could achieve as much as four orders of magnitude increase in the production rate through the application of (1) rotary table kinematic arrangements; (2) a dramatic number of simultaneously operating lasers; (3) reductions of laser optic size; (4) improved scanning techniques; and (5) an optimization of toroidal build plate size. To theoretically demonstrate the possibilities of production improvements, a productivity analysis is proposed for synchronous reluctance motors with relevance to the electric vehicle industry, given the recent increase in the diversity of printable soft magnetic alloys. The analysis provides insights into the impact of the architecture and process parameters necessary to optimize rotary powder bed fusion for mass production.

Deciphering roles of protein post-translational modifications in IgA nephropathy progression and potential therapy.

Immunoglobulin A nephropathy (IgAN), one type of glomerulonephritis, displays the accumulation of glycosylated IgA in the mesangium. Studies have demonstrated that both genetics and epigenetics play a pivotal role in the occurrence and progression of IgAN. Post-translational modification (PTM) has been revealed to critically participate in IgAN development and progression because PTM dysregulation results in impaired degradation of proteins that regulate IgAN pathogenesis. A growing number of studies identify that PTMs, including sialylation, o-glycosylation, galactosylation, phosphorylation, ubiquitination and deubiquitination, modulate the initiation and progression of IgAN. Hence, in this review, we discuss the functions and mechanisms of PTMs in regulation of IgAN. Moreover, we outline numerous compounds that govern PTMs and attenuate IgAN progression. Targeting PTMs might be a useful strategy to ameliorate IgAN.

Low-affinity CD8+ T cells provide interclonal help to high-affinity CD8+ T cells to augment alloimmunity.

Following solid organ transplantation, small precursor populations of polyclonal CD8+ T cells specific for any graft-expressed antigen preferentially expand their high-affinity clones. This phenomenon, termed "avidity maturation," results in a larger population of CD8+ T cells with increased sensitivity to alloantigen, posing a greater risk for graft rejection. Using a mouse model of minor-mismatched skin transplantation, coupled with the tracking of 2 skin graft-reactive CD8+ T cell receptor-transgenic tracer populations with high and low affinity for the same peptide-major histocompatibility complex, we explored the conventional paradigm that CD8+ T cell avidity maturation occurs through T cell receptor affinity-based competition for cognate antigen. Our data revealed "interclonal CD8-CD8 help," whereby lower/intermediate affinity clones help drive the preferential expansion of their higher affinity counterparts in an interleukin-2/CD25-dependent manner. Consequently, the CD8-helped high-affinity clones exhibit greater expansion and develop augmented effector functions in the presence of their low-affinity counterparts, correlating with more severe graft damage. Finally, interclonal CD8-CD8 help was suppressed by costimulation blockade treatment. Thus, high-affinity CD8+ T cells can leverage help from low-affinity CD8+ T cells of identical specificity to promote graft rejection. Suppressing provision of interclonal CD8-CD8 help may be important to improve transplant outcomes.

SPLASH: A statistical, reference-free genomic algorithm unifies biological discovery.

Today's genomics workflows typically require alignment to a reference sequence, which limits discovery. We introduce a unifying paradigm, SPLASH (Statistically Primary aLignment Agnostic Sequence Homing), which directly analyzes raw sequencing data, using a statistical test to detect a signature of regulation: sample-specific sequence variation. SPLASH detects many types of variation and can be efficiently run at scale. We show that SPLASH identifies complex mutation patterns in SARS-CoV-2, discovers regulated RNA isoforms at the single-cell level, detects the vast sequence diversity of adaptive immune receptors, and uncovers biology in non-model organisms undocumented in their reference genomes: geographic and seasonal variation and diatom association in eelgrass, an oceanic plant impacted by climate change, and tissue-specific transcripts in octopus. SPLASH is a unifying approach to genomic analysis that enables expansive discovery without metadata or references.

In focus: perplexing increase of urinary stone disease in children, adolescent and young adult women and its economic impact.

Background: Urinary stone disease (USD) historically has affected older men, but studies suggest recent increases in women, leading to a near identical sex incidence ratio. USD incidence has doubled every 10 years, with disproportionate increases amongst children, adolescent, and young adult (AYA) women. USD stone composition in women is frequently apatite (calcium phosphate), which forms in a higher urine pH, low urinary citrate, and an abundance of urinary uric acid, while men produce more calcium oxalate stones. The reasons for this epidemiological trend are unknown. Methods: This perspective presents the extent of USD with data from a Canadian Province and a North American institution, explanations for these findings and offers potential solutions to decrease this trend. We describe the economic impact of USD. Findings: There was a significant increase of 46% in overall surgical interventions for USD in Ontario. The incidence rose from 47.0/100,000 in 2002 to 68.7/100,000 population in 2016. In a single United States institution, the overall USD annual unique patient count rose from 10,612 to 17,706 from 2015 to 2019, and the proportion of women with USD was much higher than expected. In the 10-17-year-old patients, 50.1% were girls; with 57.5% in the 18-34 age group and 53.6% in the 35-44 age group. The roles of obesity, diet, hormones, environmental factors, infections, and antibiotics, as well as the economic impact, are discussed. Interpretation: We confirm the significant increase in USD among women. We offer potential explanations for this sex disparity, including microbiological and pathophysiological aspects. We also outline innovative solutions - that may require steps beyond typical preventive and treatment recommendations.

The emerging role of lncRNAs in osteoarthritis development and potential therapy.

Osteoarthritis impairs the functions of various joints, such as knees, hips, hands and spine, which causes pain, swelling, stiffness and reduced mobility in joints. Multiple factors, including age, joint injuries, obesity, and mechanical stress, could contribute to osteoarthritis development and progression. Evidence has demonstrated that genetics and epigenetics play a critical role in osteoarthritis initiation and progression. Noncoding RNAs (ncRNAs) have been revealed to participate in osteoarthritis development. In this review, we describe the pivotal functions and molecular mechanisms of numerous lncRNAs in osteoarthritis progression. We mention that long noncoding RNAs (lncRNAs) could be biomarkers for osteoarthritis diagnosis, prognosis and therapeutic targets. Moreover, we highlight the several compounds that alleviate osteoarthritis progression in part via targeting lncRNAs. Furthermore, we provide the future perspectives regarding the potential application of lncRNAs in diagnosis, treatment and prognosis of osteoarthritis.

DIVE: a reference-free statistical approach to diversity-generating and mobile genetic element discovery.

Diversity-generating and mobile genetic elements are key to microbial and viral evolution and can result in evolutionary leaps. State-of-the-art algorithms to detect these elements have limitations. Here, we introduce DIVE, a new reference-free approach to overcome these limitations using information contained in sequencing reads alone. We show that DIVE has improved detection power compared to existing reference-based methods using simulations and real data. We use DIVE to rediscover and characterize the activity of known and novel elements and generate new biological hypotheses about the mobilome. Building on DIVE, we develop a reference-free framework capable of de novo discovery of mobile genetic elements.

Reciprocal transmission of activating and inhibitory signals and cell fate in regenerating T cells.

The ability of activated progenitor T cells to self-renew while producing differentiated effector cell descendants may underlie immunological memory and persistent responses to ongoing infection. The nature of stem-like T cells responding to cancer and during treatment with immunotherapy is not clear. The subcellular organization of dividing progenitor CD8+ T cells from mice challenged with syngeneic tumors is examined here. Three-dimensional microscopy reveals an activating hub composed of polarized CD3, CD28, and phosphatidylinositol 3-kinase (PI3K) activity at the putative immunological synapse with an inhibitory hub composed of polarized PD-1 and CD73 at the opposite pole of mitotic blasts. Progenitor T cells from untreated and inhibitory checkpoint blockade-treated mice yield a differentiated TCF1- daughter cell, which inherits the PI3K activation hub, alongside a discordantly fated, self-renewing TCF1+ sister cell. Dynamic organization of opposite activating and inhibitory signaling poles in mitotic lymphocytes may account for the enigmatic durability of specific immunity.