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.

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.

Discovery of Pyrazolopyrazines as Selective, Potent, and Mutant-Active MET Inhibitors with Intracranial Efficacy.

Mesenchymal-epithelial transition factor (MET) is a receptor tyrosine kinase that serves a critical function in numerous developmental, morphogenic, and proliferative signaling pathways. If dysregulated, MET has been shown to be involved in the development and survival of several cancers, including non-small cell lung cancer (NSCLC), renal cancer, and other epithelial tumors. Currently, the clinical efficacy of FDA approved MET inhibitors is limited by on-target acquired resistance, dose-limiting toxicities, and less than optimal efficacy against brain metastasis. Therefore, there is still an unmet medical need for the development of MET inhibitors to address these issues. Herein we report the application of structure-based design for the discovery and development of a novel class of brain-penetrant MET inhibitors with enhanced activity against clinically relevant mutations and improved selectivity. Compound 13 with a MET D1228N cell line IC50 value of 23 nM showed good efficacy in an intracranial tumor model and increased the median overall survival of the animals to 100% when dosed orally at 100 mg/kg daily for 21 days.

Concomitant Wilms tumor and autosomal dominant polycystic kidney disease.

BACKGROUND: Concomitant Wilms tumor (WT) and autosomal dominant polycystic kidney disease (ADPKD) is exceedingly rare, presenting a diagnostic and technical challenge to pediatric surgical oncologists. The simultaneous workup and management of these disease processes are incompletely described. PROCEDURE: We performed a retrospective analysis of patients treated at our institution with concomitant diagnoses of WT and ADPKD. We also review the literature on the underlying biology and management principles of these conditions. RESULTS: We present three diverse cases of concomitant unilateral WT and ADPKD who underwent nephrectomy. One patient had preoperative imaging consistent with ADPKD with confirmatory testing postoperatively, one was found to have contralateral renal cysts intraoperatively with confirmatory imaging post nephrectomy, and one was diagnosed in childhood post nephrectomy. All patients are alive at last follow-up, and the patient with longest follow-up has progressed to end-stage kidney failure requiring transplantation and dialysis in adulthood. All patients underwent germline testing and were found to have no cancer predisposition syndrome or pathogenic or likely pathogenic variants for WT. CONCLUSION: Concomitant inheritance of ADPKD and development of WT are extremely rare, and manifestations of ADPKD may not present until late childhood or adulthood. ADPKD is not a known predisposing condition for WT. When ADPKD diagnosis is made by family history, imaging, and/or genetic testing before WT diagnosis and treatment, the need for extensive preoperative characterization of cystic kidney lesions in children and increased risk of post-nephrectomy kidney failure warrant further discussion of surgical approach and perioperative management strategies.

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.

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.

Extended-Release Mixed Amphetamine Salts for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cannabis Use Disorder: A Pilot, Randomized Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: To determine if treatment of co-occurring adult ADHD and Cannabis Use Disorder (CUD) with extended-release mixed amphetamine salts (MAS-ER) would be effective at improving ADHD symptoms and promoting abstinence. METHOD: A 12-week randomized, double-blind, two-arm pilot feasibility trial of adults with comorbid ADHD and CUD (n = 28) comparing MAS-ER (80 mg) to placebo. Main outcomes: ADHD: ≥30% symptom reduction, measured by the Adult ADHD Investigator Symptom Rating Scale (AISRS). CUD: Abstinence during last 2 observed weeks of maintenance phase. RESULTS: Overall, medication was well-tolerated. There was no significant difference in ADHD symptom reduction (MAS-ER: 83.3%; placebo: 71.4%; p = .65) or cannabis abstinence (MAS-ER: 15.4%; placebo: 0%; p = .27). MAS-ER group showed a significant decrease in weekly cannabis use days over time compared to placebo (p < .0001). CONCLUSIONS: MAS-ER was generally well-tolerated. The small sample size precluded a determination of MAS-ER's superiority reducing ADHD symptoms or promoting abstinence. Notably, MAS-ER significantly reduced weekly days of use over time.

Drug Screening Using Normal Cell and Cancer Cell Mixture in an Automated 3D Cell Culture System.

Three-dimensional (3D) cell culture creates a more physiologically relevant environment for enhanced drug screening capabilities using microcarriers. An automated 3D system that integrates robotic manipulators, liquid handling systems, sensors, and environment control systems has the capacity to handle multiple samples in parallel, perform repetitive tasks, and provide real-time monitoring and analysis. This chapter describes a potential 3D cell culture drug screening model by combining renal proximal tubule cells as a representative normal cell line with cancer cell lines. This combination is subjected to drug screening to evaluate the drug's efficacy in suppressing cancer cells while minimizing impact on normal cells with the added benefit of having the ability to separate the two cell types by magnetic isolation for high content screens including mass spectrometry-based proteomics. This study presents advancements in 3D cell culture techniques, emphasizing the importance of automation and the potential of microcarriers in drug screening and disease modeling.

Inhibition of muscle sympathetic nerve activity in pre-menopausal women: responses to sudden sensory stimuli predict responses to mental stress.

Muscle sympathetic nerve responses to sudden sensory stimuli have been elucidated in several studies on young healthy men, showing reproducible interindividual differences ranging from varying degrees of inhibition to no significant change, with very few subjects showing significant excitation. These individual response patterns have been shown to predict the neural response to mental stress, and coupled blood pressure responses. The aim of this study was to investigate whether pre-menopausal healthy women show similar neural and blood pressure responses. Muscle sympathetic nerve recordings from the peroneal nerve were performed in 34 healthy women (mean age 27±8 years) during sudden sensory stimuli (electrical stimuli to a finger) and 3 minutes of mental stress (forced arithmetics). After sensory stimuli 18 women showed varying degrees of inhibition of muscle sympathetic nerve activity (burst amplitude mean reduction 60%, range 34 to 100%). The remaining 16 showed no inhibition (mean 5%, range -31 to 28%; one subject exhibiting excitation). During 3 minutes of mental stress the normalized change in burst incidence for muscle sympathetic nerve activity correlated with the percentage change of muscle sympathetic nerve activity induced by the sensory stimulation protocol (r=0.64, p=0.0042). In contrast to men, the neural responses did not predict changes in blood pressure. Thus, pre-menopausal females show a similar range of individual differences in defence-related muscle sympathetic neural responses as men, but no associated differences in blood pressure responses. Whether these patterns are unchanged after menopause remains to be investigated.

Impact of Preoperative Intervertebral Disc Degeneration on Patient-Reported Outcome Measures After Lumbar Fusion.

OBJECTIVE: The Pfirrmann scoring system classifies lumbosacral disc degeneration based on magnetic resonance imaging signal intensity. The relationship between pre-existing disc degeneration and patient-reported outcome measures (PROMs) after one-level lumbar fusion is not well documented. The purpose of this study was to investigate the relationship between the severity of preoperative intervertebral disc degeneration and preoperative and postoperative PROMs in patients undergoing one-level lumbar fusion. METHODS: All adult patients who underwent posterior lumbar decompression and fusion or transforaminal lumbar interbody fusion between 2014 and 2022 were included. Patient demographics and comorbidities were extracted from medical records. Lumbar intervertebral discs on sagittal magnetic resonance imaging T2-weighted images were assessed by 2 independent graders utilizing Pfirrmann criteria. Grades I-III were categorized as low-grade disc degeneration, while IV-V were considered high grade. Multivariable linear regression assessed the impact of disc degeneration on PROMs. RESULTS: A total of 150 patients were included, of which 69 (46%) had low-grade disc degeneration, while 81 (54%) had high-grade degeneration. Patients with high-grade degeneration had increased preoperative visual analog scale (VAS)-Leg scores (6.10 vs. 4.54, P = 0.005) and displayed greater 1-year postoperative improvements in VAS-Back scores (-2.11 vs. -0.66, P = 0.002). Multivariable regression demonstrated Pfirrmann scores as independent predictors for both preoperative VAS-Leg scores (P = 0.004) and postoperative VAS-Back improvement (P = 0.005). CONCLUSIONS: In patients undergoing one-level lumbar fusion, higher Pfirmann scores were associated with increased preoperative leg pain and greater 1-year postoperative improvement in back pain. Further studies into the relationship of preoperative disc degeneration and their impact on postoperative outcomes may help guide clinical decision-making and patient expectations.

Prostate cancer perspective: Africa versus the world.

Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men, with a rising global incidence. Currently, the PCa landscape is vastly different between developed countries and Africa. Of note, owing to various biological, socioeconomic and institutional factors, black African men often present with more advanced disease and suffer greater mortality. This review will focus on the burden of PCa globally and in Africa, compare the state of the disease in Africa with that in more developed regions of the world, and answer the question why it can sometimes look like a 'different' disease compared with developed regions. In addition, we address the racial disparities of PCa.

The impact of Library Size and Scale of Testing on Virtual Screening.

Virtual libraries for ligand discovery have recently increased 10,000-fold, and this is thought to have improved hit rates and potencies from library docking. This idea has not, however, been experimentally tested in direct comparisons of larger-vs-smaller libraries. Meanwhile, though libraries have exploded, the scale of experimental testing has little changed, with often only dozens of high-ranked molecules investigated, making interpretation of hit rates and affinities uncertain. Accordingly, we docked a 1.7 billion molecule virtual library against the model enzyme AmpC ß-lactamase, testing 1,521 new molecules and comparing the results to the same screen with a library of 99 million molecules, where only 44 molecules were tested. Encouragingly, the larger screen outperformed the smaller one: hit rates improved by two-fold, more new scaffolds were discovered, and potency improved. Overall, 50-fold more inhibitors were found, supporting the idea that there are many more compounds to be discovered than are being tested. With so many compounds evaluated, we could ask how the results vary with number tested, sampling smaller sets at random from the 1521. Hit rates and affinities were highly variable when we only sampled dozens of molecules, and it was only when we included several hundred molecules that results converged. As docking scores improved, so too did the likelihood of a molecule binding; hit rates improved steadily with docking score, as did affinities. This also appeared true on reanalysis of large-scale results against the σ2 and dopamine D4 receptors. It may be that as the scale of both the virtual libraries and their testing grows, not only are better ligands found but so too does our ability to rank them.

The Shoeshine Stand and the Renaissance of Primary Care.

Over the past century, family physicians have moved from small independently owned practices, many of them solo, to being employed by large hospital systems, corporate entities, or health systems. Today, almost three-quarters of all physicians are employed and the highest percentage of employed physicians are family physicians.This essay contrasts the elements of independent practice with employed practice as part of what has been lost in the past half century, but what might be regained if physicians demanded more autonomy and control over their practices.

Elf1 promotes transcription-coupled repair in yeast by using its C-terminal domain to bind TFIIH.

Transcription coupled-nucleotide excision repair (TC-NER) removes DNA lesions that block RNA polymerase II (Pol II) transcription. A key step in TC-NER is the recruitment of the TFIIH complex, which initiates DNA unwinding and damage verification; however, the mechanism by which TFIIH is recruited during TC-NER, particularly in yeast, remains unclear. Here, we show that the C-terminal domain (CTD) of elongation factor-1 (Elf1) plays a critical role in TC-NER in yeast by binding TFIIH. Analysis of genome-wide repair of UV-induced cyclobutane pyrimidine dimers (CPDs) using CPD-seq indicates that the Elf1 CTD in yeast is required for efficient TC-NER. We show that the Elf1 CTD binds to the pleckstrin homology (PH) domain of the p62 subunit of TFIIH in vitro, and identify a putative TFIIH-interaction region (TIR) in the Elf1 CTD that is important for PH binding and TC-NER. The Elf1 TIR shows functional, structural, and sequence similarities to a conserved TIR in the mammalian UV sensitivity syndrome A (UVSSA) protein, which recruits TFIIH during TC-NER in mammalian cells. These findings suggest that the Elf1 CTD acts as a functional counterpart to mammalian UVSSA in TC-NER by recruiting TFIIH in response to Pol II stalling at DNA lesions.

Performance of the Open-first Repair Strategy in Type A Aortic Dissection with Mesenteric Malperfusion Syndrome Eligible for Delayed Repair.

OBJECTIVE: For patients with Type A aortic dissection complicated by mesenteric malperfusion syndrome (MMPS), some centers advocate a non-traditional approach based on upfront endovascular intervention and delayed open repair. However, the efficacy of this strategy cannot be understood without first understanding outcomes of the traditional open-first strategy in the same select patient population eligible for delayed repair, applying modern techniques of hybrid aortic surgery. METHODS: Patients with acute Type A aortic dissection and mesenteric malperfusion syndrome were queried from a single institution. Those presenting with aortic rupture, tamponade, or cardiogenic shock (ineligible for delayed repair) were excluded. Patients were managed with immediate open aortic repair. Short-term and long-term outcomes are reported. RESULTS: A total of 1228 patients were treated for acute Type A dissection in the study period, of whom 77 were included in the MMPS cohort. In-hospital mortality was 29%, compared with 39% in an identically selected MMPS population undergoing delayed repair reported previously. Among MMPS patients, 32% underwent additional procedures addressing distal malperfusion in a hybrid operating room during or after open repair. Concomitant proximal malperfusion (coronary, cerebral, or upper extremity) was common in the MMPS cohort, present in 35% of cases. While early mortality was greater in the MMPS cohort compared to all acute Type A dissections, ten-year survival among those discharged alive was similar (65% vs 59%, p=0.18). CONCLUSION: The traditional open-first repair strategy performs equal to or better than the delayed repair strategy for patients with MMPS eligible for delayed repair.

Acute changes in kidney function and outcomes following an acute myocardial infarction: Insights from PARADISE-MI.

AIMS: Pharmacologic blockade of neurohormonal pathways in patients with acute myocardial infarction (MI) can result in acute changes in biomarkers of kidney function. We evaluated the effect of sacubitril/valsartan versus ramipril on initial changes in serum creatinine and the association of these changes with longer-term outcomes among participants in PARADISE-MI. METHODS AND RESULTS: In this randomized, double-blind, active-controlled, event-driven trial, 5661 patients with an acute MI were assigned to receive sacubitril/valsartan or ramipril, with no run-in. The frequency of an initial pre-specified increase in serum creatinine (≥26.5 or ≥44 µmol/L) from baseline to week 1 was compared between arms. Multivariable Cox regression models were fit to examine the association of acute changes in serum creatinine with the primary cardiovascular composite outcome (cardiovascular death, first heart failure hospitalization, or outpatient heart failure), all-cause mortality, and longer-term changes in estimated glomerular filtration rate (eGFR). An initial increase in serum creatinine ≥26.5 µmol/L occurred in 155 of 2604 (6.0%) patients assigned to sacubitril/valsartan and 120 of 2603 (4.6%) patients assigned to ramipril (odds ratio [OR] 1.32; 95% confidence interval [CI] 1.03-1.68). The corresponding numbers for an increase ≥44 µmol/L were 57 (2.2%) and 42 (1.6%), respectively (OR 1.37; 95% CI 0.92-2.05). A higher odds of increased serum creatinine ≥26.5 and ≥44 µmol/L for sacubitril/valsartan versus ramipril appeared to be restricted to patients who had a greater decline in systolic blood pressure over the same period (p-interaction = 0.05 and 0.001, respectively). In multivariable analyses, neither an acute increase in serum creatinine ≥26.5 or ≥44 µmol/L was associated with a higher risk of cardiovascular outcomes, all-cause mortality, or differences in longer-term eGFR slope. Findings were similar across the randomized treatment arms (p-interaction >0.6 for all). CONCLUSIONS: Following acute MI, patients assigned to sacubitril/valsartan had a higher frequency of initial increases in serum creatinine at 1 week, compared with ramipril. In adjusted models, initial increases in serum creatinine with either treatment were not associated with adverse cardiovascular outcomes or changes in longer-term kidney function.