Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know / Complexo da Esclerose Tuberosa e rins: o que os nefrologistas devem saber

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

Resumo O complexo da esclerose tuberosa (CET) é uma doença autossômica dominante caracterizada pelo desenvolvimento de hamartomas no sistema nervoso central, coração, pele, pulmões e rins e outras manifestações, incluindo convulsões, tubérculos corticais, linhas de migração radial, autismo e deficiência cognitiva. A doença está associada a variantes patogênicas nos genes TSC1 ou TSC2, resultando na hiperativação da via mTOR, um importante regulador do crescimento e metabolismo celular. Consequentemente, a hiperativação da via mTOR leva à proliferação anormal do tecido e ao desenvolvimento de tumores sólidos. O envolvimento renal no CET é caracterizado pelo desenvolvimento de lesões císticas, carcinoma de células renais e angiomiolipomas renais, que podem progredir e causar dor, sangramento e perda da função renal. Nos últimos anos, houve uma mudança notável na abordagem terapêutica do CET, especialmente no tratamento das manifestações renais. Os inibidores de mTOR surgiram como a principal opção terapêutica, enquanto intervenções cirúrgicas como nefrectomia e embolização são reservadas principalmente para complicações que não respondem ao tratamento clínico, como hemorragia renal grave. Esta revisão se concentra nas principais características clínicas do CET, nos mecanismos subjacentes ao envolvimento renal, nos recentes avanços na terapia para lesões renais e nas perspectivas futuras.

Optical Coherence Tomography Angiography Retinal Imaging Associations With Burden of Small Vessel Disease and Amyloid Positivity in the Brain.

BACKGROUND: Alzheimer disease (AD) and other dementias are associated with vascular changes and amyloid deposition, which may be reflected as density changes in the retinal capillaries. These changes may can be directly visualized and quantified with optical coherence tomography angiography (OCTA), making OCTA a potential noninvasive preclinical biomarker of small vessel disease and amyloid positivity. Our objective was to investigate the feasibility of retinal imaging metrics as noninvasive biomarkers of small vessel disease and amyloid positivity in the brain. METHODS: We investigated associations between OCTA and neuroimaging and cognitive metrics in 41 participants without dementia from the Mayo Clinic Study of Aging and Alzheimer's Disease Research Center. OCTA metrics included superficial, deep, and full retina capillary density of the fovea, parafovea, and macula as well as the area of the foveal avascular zone (FAZ). Neuroimaging metrics included a high burden of white matter hyperintensity (WMH), presence of cerebral microbleeds (CMB), lacunar infarcts, and amyloid positivity as evidenced on positron emission tomography (PET), whereas cognitive metrics included mini-mental status examination (MMSE) score. We performed generalized estimating equations to account for measurements in each eye while controlling for age and sex to estimate associations between OCTA metrics and neuroimaging and cognitive scores. RESULTS: Associations between OCTA and neuroimaging metrics were restricted to the fovea. OCTA showed decreased capillary density with high burden of WMH in both the superficial (P = 0.003), deep (P = 0.004), and full retina (P = 0.01) in the fovea but not the parafovea or whole macula. Similarly, participants with amyloid PET positivity had significantly decreased capillary density in the superficial fovea (P = 0.027) and deep fovea (P = 0.03) but higher density in the superficial parafovea (P = 0.038). Participants with amyloid PET positivity also had a significantly larger FAZ (P = 0.031), whereas in those with high WMH burden the difference did not reach statistical significance (P = 0.075). There was also a positive association between MMSE and capillary density of the full retina within the fovea (P = 0.037) and in the superficial parafovea (P = 0.046). No associations were found between OCTA metrics and presence of CMB or presence of lacunar infarcts. CONCLUSION: The associations of lower foveal capillary density with cerebral WMH and amyloid positivity suggest that further research is warranted to evaluate for shared mechanisms of disease between small vessel disease and AD pathologies.

Predictors of Delayed Clinical Benefit Following Surgical Treatment for Low Grade Spondylolisthesis.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To investigate what factors predict delayed improvement after surgical treatment of low grade spondylolisthesis. SUMMARY OF BACKGROUND DATA: Lumbar surgery leads to clinical improvement in the majority of patients with low grade spondylolisthesis. Most patients improve rapidly after surgery, but some patients demonstrate a delayed clinical course. METHODS: The Quality and Outcomes Database (QOD) was queried for grade 1 spondylolisthesis patients who underwent surgery who had patient reported outcome measures (PROMs) collected at baseline, 3-, 6- and 12-months, including back and leg pain numeric rating scale (NRS), Oswestry Disability Index (ODI), and EuroQol-5D (EQ-5D). Patients were stratified as "Early responders" reaching MCID at 3 months and maintaining improvement through 12 months and "Delayed responders" not reaching MCID at 3 months but ultimately reaching MCID at 12 months. These two groups were compared with respect to factors which predicted delayed improvement. RESULTS: Of 608 patients enrolled, 436 (72%) met inclusion criteria for this study. Overall, 317 patients (72.7%) reached MCID for ODI at 12 months following surgery. Of these patients, 249 (78.5%) exhibited a rapid clinical improvement trajectory and had achieved ODI MCID threshold by the 3-month postop follow-up. 68 patients (21.4%) showed a delayed trajectory, and had not achieved ODI MCID threshold at 3 months, but did ultimately reach MCID at 12-month follow-up. Factors associated with delayed improvement included impaired preoperative ambulatory status, better baseline back and leg pain scores, and worse 3-month leg pain scores (P<0.01). CONCLUSIONS: The majority of patients undergoing surgery for low grade spondylolisthesis reach ODI MCID threshold rapidly, within the first three months after surgery. Factors associated with a delayed clinical course include impaired preoperative ambulation status, relatively better preoperative back and leg pain, and persistent leg pain at 3 months.

Addressing emerging issues in entomology: 2023 student debates.

The Entomological Society of America (ESA) Student Debates is an annual student competition at the ESA Annual Meeting organized by Student Debates Subcommittee (SDS) members of the ESA Student Affairs Committee. In conjunction with the 2023 ESA Annual Meeting theme, 'Insects and influence: Advancing entomology's impact on people and policy', the theme of this year's student debate was 'Addressing emerging issues in entomology'. With the aid of ESA membership, the SDS selected the following debate topics: (1) Should disclosure of artificial intelligence large language models in scientific writing always be required? and (2) Is it more important to prioritize honey bee or native pollinator health for long-term food security within North America? Four student teams from across the nation, composed of 3-5 student members and a professional advisor, were assigned a topic and stance. Over the course of 5 months, all team members researched and prepared for their assigned topic before debating live with an opposing team at the 2023 ESA Annual Meeting in National Harbor, Maryland. SDS members additionally prepared and presented introductions for each debate topic to provide unbiased backgrounds to the judges and audience for context in assessing teams' arguments. The result was an engaging discussion between our teams, judges, and audience members on emerging issues facing entomology and its impact on people and policy, such as scientific communication and food security, that brought attention to the complexities involved when debating topics concerning insects and influence.

Application of the international criteria for optic neuritis in the Acute Optic Neuritis Network.

OBJECTIVE: The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON). METHODS: We included 160 patients with a first-ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present. RESULTS: According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody-associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%). INTERPRETATION: According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

High-Level Isolation: A Landscape Analysis of Global Capabilities and Opportunities to Advance the Field.

High-level isolation units (HLIUs) have been established by countries to provide safe and optimal medical care for patients with high-consequence infectious diseases. We aimed to identify global high-level isolation capabilities and determine gaps and priorities of global HLIUs, using a multiple method approach that included a systematic review of published and gray literature and a review of Joint External Evaluations and Global Health Security Index reports from 112 countries. A follow-up electronic survey was distributed to identified HLIUs. The landscape analysis found 44 previously designated/self-described HLIUs in 19 countries. An additional 33 countries had potential HLIUs; however, there were not enough details on capabilities to determine if they fit the HLIU definition. An electronic survey was distributed to 36 HLIUs to validate landscape analysis findings and to understand challenges, best practices, and priorities for increased networking with a global HLIU cohort; 31 (86%) HLIUs responded. Responses revealed an additional 30 confirmed HLIUs that were not identified in the landscape analysis. To our knowledge, this was the first mapping and the largest ever survey of global HLIUs. Survey findings identified major gaps in visibility of HLIUs: while our landscape analysis initially identified 44 units, the survey unveiled an additional 30 HLIUs that had not been previously identified or confirmed. The lack of formalized regional or global coordinating organizations exacerbates these visibility gaps. The unique characteristics and capabilities of these facilities, coupled with the likelihood these units serve as core components of national health security plans, provides an opportunity for increased connection and networking to advance the field of high-level isolation and address identified gaps in coordination, build an evidence base for HLIU approaches, and inform HLIU definitions and key components.

Phenotypic and molecular characterization of Streptococcus pneumoniae serotype 3 isolates from blood and respiratory samples in Canada: CANWARD 2007-21.

BACKGROUND: Lower respiratory infections and invasive disease caused by Streptococcus pneumoniae serotype 3 remain major clinical challenges around the world, despite widespread availability of updated vaccines. METHODS: As part of CANWARD, antimicrobial susceptibility testing and serotyping were performed on all S. pneumoniae isolates from 2007 to 2021. A subset of 226/264 (85.6%) serotype 3 isolates were selected for WGS to determine sequence type (ST)/clonal cluster (CC) and correspondence of antimicrobial resistance determinants (erm, mefAE, tetM, cat, folA, folP) with resistance phenotype. RESULTS: Of the 3,039 S. pneumoniae isolates obtained from 2007 to 2021, 8.7% (n = 264) were serotype 3, with 64.0% of respiratory origin and 36.0% from blood. Of 226 sequenced serotype 3 isolates, 184 (81.4%) were ST180 (GPSC12). The proportion of ST8561 (single locus variant of ST180) increased from 7.2% to 16.6% during the study period. An increasing proportion of serotype 3 isolates had phenotypic resistance (P = 0.0007) and genetic resistance determinants (P = 0.004), comparing 2017-21 to 2007-11, largely due to a recently expanded ST180 clade with cat, tetM and mef determinants. CONCLUSIONS: S. pneumoniae serotype 3 from GPSC12 continues to dominate throughout Canada, with an increase in the proportion of ST8561. The proportion of serotype 3 isolates that are phenotypically resistant and with genetic resistance determinants is increasing over time, reflecting a global increase in GPSC12 genotypes with known resistance determinants. Phylogenomic characterization of isolates collected over time and from around the world may facilitate improved treatment and enhanced prevention strategies, including new vaccines with activity against S. pneumoniae serotype 3.

Exploring Radiofrequency Ablation for T1 Papillary Thyroid Cancer in the United States: Mayo Clinic Experience.

OBJECTIVE: To report the efficacy, safety, and feasibility of radiofrequency ablation (RFA) for T1 papillary thyroid carcinoma (PTC) in a large referral center in the United States. PATIENTS AND METHODS: We conducted a retrospective study of 8 patients who underwent RFA for T1 PTC at Mayo Clinic in Rochester Minnesota, between July 1, 2020, and February 28, 2023. The RFA technique and the type of anesthesia are described. Thyroid function, changes in ablated zone, and adverse events were analyzed for up to 24 months after the procedure. RESULTS: Of the 8 patients included in the study, 7 were female and 1 was male with a mean ± SD age of 53±16.4 years. Thyroid status was unaffected in 7 of the 8 patients. The median duration of RFA was 6 minutes (range, 2 to 14.5 minutes) with energy delivered at between 25 and 45 W. The mean ± SD volume of small PTCs was 0.3±0.2 mL, and the mean largest diameter was 9.5±3.3 mm (range, 6 to 15 mm). The mean ± SD ablated volume at 3 to 6 months was larger than the target lesion (0.8±0.7 mL), with a reduction in mean ± SD ablated volume of 0.4±0.4 mL at 7 to 12 months and 0.1±0.06 mL at 13 to 18 months. The ablated zone almost disappeared at 19 to 24 months (0.04±0.04 mL). There were no major adverse events during or after the RFA procedure. CONCLUSION: This is the first reported series of T1 PTC treated with RFA in the United States. Early postablation imaging revealed that the ablated region was larger than the target lesions, followed by a serial decrease in size. Therefore, RFA at centers with such expertise appears to be a safe and effective treatment for small PTCs. Further studies are needed to evaluate its long-term efficacy and the risk of recurrence.

Sacubitril/Valsartan Versus Enalapril in Chronic Chagas Cardiomyopathy: Rationale and Design of the PARACHUTE-HF Trial.

Chronic Chagas cardiomyopathy (CCC) has unique pathogenic and clinical features with worse prognosis than other causes of heart failure (HF), despite the fact that patients with CCC are often younger and have fewer comorbidities. Patients with CCC were not adequately represented in any of the landmark HF studies that support current treatment guidelines. PARACHUTE-HF (Prevention And Reduction of Adverse outcomes in Chagasic Heart failUre Trial Evaluation) is an active-controlled, randomized, phase IV trial designed to evaluate the effect of sacubitril/valsartan 200 mg twice daily vs enalapril 10 mg twice daily added to standard of care treatment for HF. The study aims to enroll approximately 900 patients with CCC and reduced ejection fraction at around 100 sites in Latin America. The primary outcome is a hierarchical composite of time from randomization to cardiovascular death, first HF hospitalization, or relative change from baseline to week 12 in NT-proBNP levels. PARACHUTE-HF will provide new data on the treatment of this high-risk population. (Efficacy and Safety of Sacubitril/Valsartan Compared With Enalapril on Morbidity, Mortality, and NT-proBNP Change in Patients With CCC [PARACHUTE-HF]; NCT04023227).

Rates of Sudden Death After Myocardial Infarction-Insights From the VALIANT and PARADISE-MI Trials.

Importance: Sudden death is a leading cause of death after acute myocardial infarction (AMI). The Prospective ARNi vs ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI (PARADISE-MI) and Valsartan in Acute Myocardial Infarction (VALIANT) trials enrolled patients with pulmonary congestion and/or left ventricular dysfunction after AMI. Whether the prognosis in such patients has changed over time has not been examined. Objective: To compare the rate of sudden death/resuscitated cardiac arrest (RCA) after AMI in the PARADISE-MI and VALIANT trials. Design, Setting, and Participants: This was a secondary analysis of multicenter randomized clinical trials enrolling patients after AMI. In the primary analysis, the VALIANT cohort was restricted to patients with "PARADISE-MI-like" characteristics (eg, at least 1 augmenting risk factor and no history of heart failure). The baseline characteristics of people in both trials were compared. The VALIANT trial enrolled from December 1998 to June 2001, and the PARADISE-MI trial enrolled between December 2016, and March 2020. The median follow-up in the VALIANT and PARADISE-MI trials was 24.7 and 22 months, respectively. People with AMI, complicated by pulmonary congestion and/or left ventricular dysfunction, were included in the analysis. Exposure: Sudden death after AMI. Results: A total of 5661 patients were included in the PARADISE-MI cohort (mean [SD] age, 63.7 [11.5] years; 4298 male [75.9%]), 9617 were included in the VALIANT (PARADISE-MI-like) cohort (mean [SD] age, 66.1 [11.5] years; 6504 male [67.6%]), and 14 703 patients were included in the VALIANT (total) cohort (mean [SD] age, 64.8 [11.8] years; 10 133 male [68.9%]). In the PARADISE-MI-like cohort of the VALIANT trial, 707 of 9617 participants (7.4%) experienced sudden death/RCA. A total of 148 of 5661 people (2.6%) in the PARADISE-MI trial experienced sudden death/RCA. Sudden death rates were highest in the first month after infarction in both trials: 19.3 (95% CI, 16.4-22.6) per 100 person-years in the VALIANT trial and 9.5 (95% CI, 7.0-12.7) per 100 person-years in the PARADISE-MI trial, and these rates declined steadily thereafter. Compared with the VALIANT cohort, people in the PARADISE-MI trial were more often treated with percutaneous coronary intervention for their qualifying AMI and received a ß-blocker, statin, and mineralocorticoid receptor antagonist more frequently. Conclusions and Relevance: After AMI, the risk of sudden death/RCA was highest in the first month, declining rapidly thereafter. Results revealed that compared with counterparts from 20 years ago, the rate of sudden death/RCA in patients with a reduced left ventricular ejection fraction and/or pulmonary congestion was 2- to 3-fold lower in people receiving contemporary management. Interventions to further protect people in the highest risk first month after infarction are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT02924727.

Convergent direct and indirect cortical streams shape avoidance decisions in mice via the midline thalamus.

Current concepts of corticothalamic organization in the mammalian brain are mainly based on sensory systems, with less focus on circuits for higher-order cognitive functions. In sensory systems, first-order thalamic relays are driven by subcortical inputs and modulated by cortical feedback, while higher-order relays receive strong excitatory cortical inputs. The applicability of these principles beyond sensory systems is uncertain. We investigated mouse prefronto-thalamic projections to the midline thalamus, revealing distinct top-down control. Unlike sensory systems, this pathway relies on indirect modulation via the thalamic reticular nucleus (TRN). Specifically, the prelimbic area, which influences emotional and motivated behaviors, impacts instrumental avoidance responses through direct and indirect projections to the paraventricular thalamus. Both pathways promote defensive states, but the indirect pathway via the TRN is essential for organizing avoidance decisions through disinhibition. Our findings highlight intra-thalamic circuit dynamics that integrate cortical cognitive signals and their role in shaping complex behaviors.

Family-centred care interventions for children with chronic conditions: A scoping review.

INTRODUCTION: Children with chronic conditions have greater health care needs than the general paediatric population but may not receive care that centres their needs and preferences as identified by their families. Clinicians and researchers are interested in developing interventions to improve family-centred care need information about the characteristics of existing interventions, their development and the domains of family-centred care that they address. We conducted a scoping review that aimed to identify and characterize recent family-centred interventions designed to improve experiences with care for children with chronic conditions. METHODS: We searched Medline, Embase, PsycInfo and Cochrane databases, and grey literature sources for relevant articles or documents published between 1 January 2019 and 11 August 2020 (databases) or 7-20 October 2020 (grey literature). Primary studies with ≥10 participants, clinical practice guidelines and theoretical articles describing family-centred interventions that aimed to improve experiences with care for children with chronic conditions were eligible. Following citation and full-text screening by two reviewers working independently, we charted data covering study characteristics and interventions from eligible reports and synthesized interventions by domains of family-centred care. RESULTS: Our search identified 2882 citations, from which 63 articles describing 61 unique interventions met the eligibility criteria and were included in this review. The most common study designs were quasiexperimental studies (n = 18), randomized controlled trials (n = 11) and qualitative and mixed-methods studies (n = 9 each). The most frequently addressed domains of family-centred care were communication and information provision (n = 45), family involvement in care (n = 37) and access to care (n = 30). CONCLUSION: This review, which identified 61 unique interventions aimed at improving family-centred care for children with chronic conditions across a range of settings, is a concrete resource for researchers, health care providers and administrators interested in improving care for this high-needs population. PATIENT OR PUBLIC CONTRIBUTION: This study was co-developed with three patient partner co-investigators, all of whom are individuals with lived experiences of rare chronic diseases as parents and/or patients and have prior experience in patient engagement in research (I. J., N. P., M. S.). These patient partner co-investigators contributed to this study at all stages, from conceptualization to dissemination.

Recalcitrant Lateral Epicondylitis: A Systematic Review on Current Nonoperative and Operative Treatment Modalities.

BACKGROUND: Lateral epicondylitis is a common cause of elbow pain that is generally self-limiting. For patients who have persistent symptoms refractory to conservative treatment, there is still no clear consensus on the most favorable treatment modality. The purpose of this systematic review was to synthesize the available literature regarding both nonoperative and operative treatment modalities for recalcitrant lateral epicondylitis (RLE) to provide insight into the efficacy of treatment options. METHODS: A systematic review was performed in accordance with the 2020 Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, where the PubMed, MEDLINE/Ovid, CINAHL, Cochrane, and Scopus databases were queried to identify studies evaluating treatment options for RLE. RESULTS: A total of 27 studies with 1,958 patients were included. Of the reviewed studies, there were a wide variety of treatments including platelet-rich plasma injections, percutaneous tenotomies, and various arthroscopic and open procedures. CONCLUSION: There are a wide variety of treatment modalities available for RLE that have promising efficacy in the short, medium, and long terms. A comprehensive approach combining evidence-based and patient-centered care is critical for effective management of refractory symptoms. LEVEL OF EVIDENCE: Level IV. See Instructions for Authors for a complete description of levels of evidence.

Understanding the physical literacy development of 8- to 12-year-old children living with chronic medical conditions: A comprehensive, mixed methods inquiry.

BACKGROUND: Physical literacy is a concept used to describe the combined physical, affective and cognitive capacities facilitating an active lifestyle. Physical activity participation is essential for children living with chronic medical conditions, but knowledge of physical literacy among this group is scarce. METHODS: An explanatory, sequential mixed methods design was used to comprehensively describe the physical literacies of children with chronic medical conditions (CMCs). Participants were recruited from paediatric cardiology, respirology/cystic fibrosis, neurology, haematology and endocrinology outpatient clinics. All participants completed the Canadian Assessment of Physical Literacy (2nd Edition), and those with higher and lower scores were invited to a semi-structured interview. A deductive-inductive thematic analysis was applied using Margaret Whitehead's conceptualization of physical literacy. RESULTS: Using normative strata, 80.0% of the 99 children assessed (mean age = 9.97 ± 1.3 years, 48% girls) were considered beginning or progressing in their overall physical literacy (mean score = 56.5 ± 13.8/100). Meanwhile, physical literacy informed participants' approach to new, active experiences and may have contributed to a strong sense of self. There was a significant difference between endocrinology and haematology patients on total physical literacy score (p = 0.03) but not domain scores. Participants scored high on motivation/confidence (mean = 22.9 ± 5.0/30) but obtained low physical competence (mean = 11.8 ± 5.6/30) and daily behaviour scores (n = 72, mean = 15.5 ± 7.1/30). Main themes represent salient experiences of children with CMCs within the domains of physical literacy, including their need to evaluate active contexts, self-regulate activity intensity and manage physical limitations. CONCLUSIONS: Children with CMCs can achieve recommended levels of physical literacy without meeting normative standards for physical competence. Participants would benefit from a physical literacy intervention that targets the development of bodily self-regulation skills and risk evaluation in active settings.

Comparison of Costs, Re-Intervention Rates, and Length of Hospital Stay for Three Uterus Sparing Interventions for Uterine Fibroids: A 2-Year Retrospective Claims Analysis.

Purpose: To describe two-year post-operative outcomes, and healthcare utilization of three uterus-sparing interventions used to treat women with intramural and/or subserosal uterine fibroids. Subjects and Methods: This was a post-market, randomized, prospective, multi-center, longitudinal, interventional, and comparative clinical study to evaluate the costs and health outcomes of LAP-RFA vs the standard uterine conserving technologies (myomectomy and UAE) for the treatment of symptomatic uterine fibroids in women who desire uterine conservation. For this RCT study, 54 subjects were randomized on a 1:1 ratio across the three procedures and followed out to two years. Their results were compared to retrospective US insurance claims from the IBM MarketScan® Commercial Database from 2017-2020 for 96,854 women who underwent a uterus-sparing procedure for fibroids. Results: Mean ambulatory surgical center costs and the mean out-patient hospital costs were lowest for LAP-RFA ($13,134 and $14,428) and highest for UAE ($28,214 and $19,131). The total two-year re-intervention rate of any subsequent procedure (AM, LM, LAP-RFA, or UAE) was lowest in AM group (0%) followed by LM (4.2%), LAP-RFA (11%), and UAE (33%). Mean peri-operative reintervention costs and the mean reintervention total costs were $2429 and $5939 for LAP-RFA, $2122 and $8368 for LM, $4410 and $11,942 for AM, and $8113 and $46,692 for UAE subjects. In the RCT study, the average length of hospital stay was significantly less for the LAP-RFA group subjects (8.2 hours) in contrast to both the laparoscopic myomectomy group subjects (16.0 hours) and the abdominal myomectomy group subjects (33.6 hours). Despite the small numbers, two-year reintervention rates followed a similar pattern as the IBM MarketScan data. Conclusion: In comparing these three non-invasive approaches, LAP-RFA was associated with the lowest peri-operative cost, and UAE was associated with the highest peri-operative cost. Further studies are needed to assess the cost, effectiveness, and subject satisfaction with each procedure.

Risk of Serious Adverse Gastrointestinal Events with Potassium Binders in Hospitalized Patients: A National Study.

BACKGROUND: Concerns about serious adverse gastrointestinal (GI) events with sodium polystyrene sulfonate (SPS) led to development of two new potassium binders, patiromer and sodium zirconium cyclosilicate (SZC), for treatment of hyperkalemia. OBJECTIVE: To compare risk of intestinal ischemia/thrombosis or other serious GI events associated with SPS, patiromer, or SZC in hospitalized patients. DESIGN: Retrospective cohort study. PARTICIPANTS: National sample of 3,144,960 veterans hospitalized 2016-2022 in the U.S. Department of Veterans Affairs Healthcare System. MAIN MEASURES: Demographics, comorbidities, medications and outcomes were ascertained from the VA Corporate Data Warehouse. Exposures were SPS, patiromer, SZC. Outcomes were 30-day intestinal ischemia/thrombosis, and a composite of intestinal ischemia/thrombosis, peptic ulcer/perforation or bowel resection/ostomy. KEY RESULTS: Potassium binders were used during 39,270 (1.3%) hospitalizations: SPS = 30,040 (1.0%), patiromer = 3,750 (0.1%), and SZC = 5,520 (0.2%). Intestinal ischemia/thrombosis occurred with 106/30,040 (0.4%) SPS, 12/3750 (0.3%) patiromer and 24/5520 (0.4%) SZC, vs. 6998/3,105,650 (0.2%) without potassium binder. Adjusted odds ratios (aOR) were 1.40 [95% CI, 1.16 to 1.69] with SPS, 1.36 [CI, 0.79 to 2.36] with patiromer, and 1.78 [CI, 1.21 to 2.63] with SZC exposures. Composite GI adverse events occurred with 754/30,040 (2.5%) SPS, 96/3750 (2.6%) patiromer, 2.6% SZC, vs. 144/5520 (2.4%) without binder; aOR were 1.00 [CI, 0.94 to 1.08] with SPS, 1.08 [CI, 0.89 to 1.32] with patiromer, and 1.08 [CI, 0.93 to 1.27] with SZC exposures. No statistical difference in intestinal ischemia/thrombosis between each new agent and SPS was seen (p = 0.274 for SPS vs. SZC; p = 0.916 for SPS vs. patiromer). CONCLUSION: Risk of intestinal ischemia/thrombosis or other serious adverse GI events was low and did not differ across three potassium-binding drugs.

A comparative study of circulating tumor cell isolation and enumeration technologies in lung cancer.

Circulating tumor cells (CTCs) have potential as diagnostic, prognostic, and predictive biomarkers in solid tumors. Despite Food and Drug Administration (FDA) approval of CTC devices in various cancers, the rarity and heterogeneity of CTCs in lung cancer make them technically challenging to isolate and analyze, hindering their clinical integration. Establishing a consensus through comparative analysis of different CTC systems is warranted. This study aimed to evaluate seven different CTC enrichment methods across five technologies using a standardized spike-in protocol: the CellMag™ (EpCAM-dependent enrichment), EasySep™ and RosetteSep™ (blood cell depletion), and the Parsortix® PR1 and the new design Parsortix® Prototype (PP) (size- and deformability-based enrichment). The Parsortix® systems were also evaluated for any differences in recovery rates between cell harvest versus in-cassette staining. Healthy donor blood (5 mL) was spiked with 100 fluorescently labeled EpCAMhigh H1975 cells, processed through each system, and the isolation efficiency was calculated. The CellMag™ had the highest recovery rate (70 ± 14%), followed by Parsortix® PR1 in-cassette staining, while the EasySep™ had the lowest recovery (18 ± 8%). Additional spike-in experiments were performed with EpCAMmoderate A549 and EpCAMlow H1299 cells using the CellMag™ and Parsortix® PR1 in-cassette staining. The recovery rate of CellMag™ significantly reduced to 35 ± 14% with A549 cells and 1 ± 1% with H1299 cells. However, the Parsortix® PR1 in-cassette staining showed cell phenotype-independent and consistent recovery rates among all lung cancer cell lines: H1975 (49 ± 2%), A549 (47 ± 10%), and H1299 (52 ± 10%). Furthermore, we demonstrated that the Parsortix® PR1 in-cassette staining method is capable of isolating heterogeneous single CTCs and cell clusters from patient samples. The Parsortix® PR1 in-cassette staining, capable of isolating different phenotypes of CTCs as either single cells or cell clusters with consistent recovery rates, is considered optimal for CTC enrichment for lung cancer, albeit needing further optimization and validation.

Source-to-tap investigation of the occurrence of nontuberculous mycobacteria in a full-scale chloraminated drinking water system.

Nontuberculous mycobacteria (NTM) in drinking water are a significant public health concern. However, an incomplete understanding of the factors that influence the occurrence of NTM in drinking water limits our ability to characterize risk and prevent infection. This study sought to evaluate the influence of season and water treatment, distribution, and stagnation on NTM in drinking water. Samples were collected source-to-tap in a full-scale, chloraminated drinking water system approximately monthly from December 2019 to November 2020. NTM were characterized using culture-dependent (plate culture with matrix-assisted laser desorption ionization-time-of-flight mass spectrometry [MALDI-TOF MS] isolate analysis) and culture-independent methods (quantitative PCR and genome-resolved metagenomics). Sampling locations included source waters, three locations within the treatment plant, and five buildings receiving water from the distribution system. Building plumbing samples consisted of first draw, 5-min flush, and full flush cold-water samples. As the study took place during the COVID-19 pandemic, the influence of reduced water usage in three of the five buildings was also investigated. The highest NTM densities source-to-tap were found in the summer first draw building water samples (107 gene copies/L), which also had the lowest monochloramine concentrations. Flushing was found to be effective for reducing NTM and restoring disinfectant residuals, though flush times necessary to improve water quality varied by building. Clinically relevant NTM species, including Mycobacterium avium, were recovered via plate culture, with increased occurrence observed in buildings with higher water age. Four of five NTM metagenome-assembled genomes were identified to the species level and matched identified isolates.IMPORTANCENTM infections are increasing in prevalence, difficult to treat, and associated with high morbidity and mortality rates. Our lack of understanding of the factors that influence NTM occurrence in drinking water limits our ability to prevent infections, accurately characterize risk, and focus remediation efforts. In this study, we comprehensively evaluated NTM in a full-scale drinking water system, showing that various steps in treatment and distribution influence NTM presence. Stagnant building water contained the highest NTM densities source-to-tap and was associated with low disinfectant residuals. We illustrated the differences in NTM detection and characterization obtained from culture-based and culture-independent methods, highlighting the complementarity between these approaches. We demonstrated that focusing NTM mitigation efforts in building plumbing systems, which have the highest NTM densities source-to-tap, has potential for immediate positive effects. We also identified steps during treatment that increase NTM levels, which provides beneficial information for utilities seeking to reduce NTM in finished water.

The Effect of Replication Protein A Inhibition and Post-Translational Modification on ATR Kinase Signaling.

The ATR kinase responds to elevated levels of single-stranded DNA (ssDNA) to activate the G2/M checkpoint, regulate origin utilization, preserve fork stability, and allow DNA repair towards ensuring genome integrity. The intrinsic replication stress in cancer cells makes this pathway an attractive therapeutic target. The ssDNA that drives ATR signaling is sensed by the ssDNA-binding protein replication protein A (RPA), which acts as a platform for ATRIP recruitment and subsequent ATR activation by TopBP1. We have developed chemical RPA inhibitors (RPAi) that block RPA-ssDNA interactions, termed RPA-DBi, and RPA protein-protein interactions, termed RPA-PPIi; both activities are required for ATR activation. Here, we employ a biochemically reconstituted ATR kinase signaling pathway and demonstrate that both RPA-DBi and RPA-PPIi abrogate ATR-dependent phosphorylation of downstream target proteins. We demonstrate that RPA post-translational modifications (PTMs) impact ATR kinase activation but do not alter sensitivity to RPAi. Specifically, phosphorylation of RPA32 and TopBP1 stimulate, while RPA70 acetylation has no effect on ATR phosphorylation of target proteins. Collectively, this work reveals the RPAi mechanism of action to inhibit ATR signaling that can be regulated by RPA PTMs and offers insight into the anti-cancer activity of ATR pathway targeted cancer therapeutics.

A Specialized Reference Panel with Structural Variants Integration for Improving Genotype Imputation in Alzheimer's Disease and Related Dementias (ADRD).

We developed an imputation panel for Alzheimer's disease (AD) and related dementias (ADRD) using whole-genome sequencing (WGS) data from the Alzheimer's Disease Sequencing Project (ADSP). Recognizing the significant associations between structural variants (SVs) and AD, and their underrepresentation in existing public reference panels, our panel uniquely integrates single nucleotide variants (SNVs), short insertions and deletions (indels), and SVs. This panel enhances the imputation of disease susceptibility, including rare AD-associated SNVs, indels, and SVs, onto genotype array data, offering a cost-effective alternative to whole-genome sequencing while significantly augmenting statistical power. Notably, we discovered 10 rare indels nominal significant related to AD that are absent in the TOPMed-r2 panel and identified three suggestive significant (p-value < 1E-05) AD-associated SVs in the genes EXOC3L2 and DMPK, were identified. These findings provide new insights into AD genetics and underscore the critical role of imputation panels in advancing our understanding of complex diseases like ADRD.