Publications by Year: 2026

BACKGROUND: Timely colonoscopy completion in primary care can prevent diagnostic delays in colorectal cancer. Factors that influence why patients experience timely or delayed colonoscopy completion are unclear. We sought to identify potentially intervenable factors associated with earlier (or later) colonoscopy test completion in primary care.

METHODS: All colonoscopy orders placed by primary care clinicians in two clinics within a single hospital system between January 1 2018 and December 31 2021 were examined for time to completion using the Cox Proportional Hazards Model, where the hazards of completion were adjusted for variables potentially associated with the outcome, including sociodemographic, individual health-related, and care delivery factors.

RESULTS: Among 10,576 colonoscopy tests ordered, 56% were completed within one year and the median time to colonoscopy completion was 230 days, 95% CI [217, 242]. After multivariable adjustment, earlier colonoscopy completion was associated with receiving care at a community health center (HR 1.13, 95% CI [1.03, 1.24]), preferred spoken language other than English (HR 1.23, 95% CI [1.12, 1.34]), male sex (HR 1.09, 95% CI [1.03, 1.14]), Black race (HR 1.08, 95% CI [1.02, 1.16]), any college education (HR 1.07, 95% CI [1.01, 1.14]), a diagnosis of rectal bleeding (HR 1.88, 95% CI [1.69, 2.08]), and documented use of an electronic patient portal (HR 1.19, 95% CI [1.13, 1.26]). Completion occurred later among patients with Medicaid insurance (HR 0.82, 95% CI [0.75, 0.89]), subsidized commercial insurance (HR 0.80, 95% CI [0.69, 0.91]), depression (HR 0.95, 95% CI [0.89, 1.01]), and when ordered by a nurse practitioner (HR 0.77, 95% CI [0.68, 0.88]), resident (HR 0.92, 95% CI [0.85, 0.99]) or during a telehealth appointment (via telephone HR 0.56, 95% CI [0.49, 0.64] and via video HR 0.76, 95% CI [0.63, 0.90]). Results were similar for a sensitivity analysis restricted to patients within a Medicaid Accountable Care Organization (ACO) network.

CONCLUSIONS: Several sociodemographic, clinical, and telehealth factors were associated with time to colonoscopy completion, identifying potential opportunities for targeted care and future research.

BACKGROUND: APOL1 high-risk variants predispose to chronic kidney disease (CKD) in individuals of African genetic ancestry due to podocyte toxicity. As congenital anomalies of the kidney and urinary tract (CAKUT) have variable outcomes potentially driven by podocyte injury, we hypothesize that the outcome of children with CAKUT is influenced by APOL1 risk genotypes.

METHODS: APOL1 risk status was determined in children and adults with CAKUT from African genetic ancestry using DNA microarrays or exome sequencing. Phenotypic information and CKD outcomes at last follow-up were collected. We computed odds ratios (OR) and hazard ratios between APOL1-high risk (HR) vs. low risk (LR) carriers under different models using logistic regression and Cox proportional hazards.

RESULTS: Clinical data were available for 195 patients (median age 15.35 years, [IQR 11.01-19.87]), including 20 (10.3%) carrying APOL1-HR. Under a recessive model, APOL1-HR vs. LR showed no differences in proteinuria or hypertension (OR 0.24, 95% CI 0.04-1.30, p = 0.10 and OR 0.99, 95% CI 0.38-2.54, p = 0.98, respectively), nor in CKD stage ≥ G2 risk (OR 0.71, 95% CI 0.29-1.78, p = 0.47). Median time until kidney failure for APOL1 risk groups was 11.59 years [IQR 7.15-21.47] and 14.35 years ([IQR 9.16-17.20]; p = 0.73) for HR and LR, respectively. Additional exploratory analyses showed comparable outcomes between HR and LR variant carriers.

CONCLUSIONS: This pilot study identified no association between APOL1 risk genotypes and kidney outcomes in patients with CAKUT across genetic models. With APOL1-targeted therapies emerging, large-scale prospective studies are needed to identify individuals with CAKUT who may benefit from these treatment strategies.

Mosaic chromosomal alterations (mCAs) accumulate in the brain tissues and are associated with psychiatric disorders. The association between mCAs in circulating blood and schizophrenia (SCZ) and bipolar disorders (BD) has not been fully evaluated. We detected mCAs from blood samples in 2470 SCZ, 3732 BD, and 177,773 control subjects. The associations between mCAs and SCZ or BD were evaluated using age-adjusted logistic regression models, further evaluated in age subgroups. We analyzed the associations between high cell fraction (CF) mosaic events (CF-mCAs >5% or CF-mCAs >10%) and SCZ or BD in the same way. Furthermore, we assessed the interaction between mCAs and genetic risk scores for SCZ or BD. Autosomal mCAs, especially mosaic loss events, increased in both SCZ and BD (SCZ; OR = 1.78, P = 4.9×10-6, BD; OR = 1.41, P = 0.0025). These associations were highlighted in the young-age subgroup (SCZ; OR = 7.01, P = 1.7×10-16, BD; OR = 4.01, P = 2.9×10-8). In addition, the effect sizes of losses increased in a CF-dependent manner in both SCZ and BD. Loss events with high cell fraction interacted with polygenic risk score in SCZ (P = 0.0098). SCZ or BD were characterized by the presence of a high burden of mosaic losses in blood, especially in young age, suggesting the common somatic pathophysiological mechanisms between these psychiatric diseases. The possible interaction between losses and PRS for SCZ supports the genetic and environmental cross-talk in SCZ.

Candida auris, an increasingly prevalent fungal pathogen, requires both rapid identification and antifungal susceptibility testing to enable proper treatment. This study introduces digital SHERLOCK (dSHERLOCK), a platform that combines CRISPR/Cas nucleic acid detection, single-template quantification and real-time kinetics monitoring. Assays implemented on this platform display excellent sensitivity to C. auris from major clades 1-4, while maintaining specificity when challenged with common environmental and pathogenic fungi. dSHERLOCK detects C. auris within 20 min in minimally processed swab samples and achieves sensitive quantification (1 c.f.u. µl-1) within 40 min. To address antifungal susceptibility testing, we develop assays that detect mutations that are commonly associated with azole and echinocandin multidrug resistance. We use machine learning and real-time monitoring of reaction kinetics to achieve highly accurate simultaneous quantification of mutant and wild-type FKS1 SNP alleles in fungal populations with mixed antifungal susceptibility, which would be misdiagnosed as completely susceptible or resistant under standard reaction conditions. Our platform's use of commercially available materials and common laboratory equipment makes C. auris diagnostics widely deployable in global healthcare settings.

The human metabolome reflects complex metabolic states affected by genetic and environmental factors. However, metabolites associated with type 2 diabetes (T2D) risk and their determinants remain insufficiently characterized. Here we integrated blood metabolomic, genomic and lifestyle data from up to 23,634 initially T2D-free participants from ten cohorts. Of 469 metabolites examined, 235 were associated with incident T2D during up to 26 years of follow-up, including 67 associations not previously reported across bile acid, lipid, carnitine, urea cycle and arginine/proline, glycine and histidine pathways. Further genetic analyses linked these metabolites to signaling pathways and clinical traits central to T2D pathophysiology, including insulin resistance, glucose/insulin response, ectopic fat deposition, energy/lipid regulation and liver function. Lifestyle factors-particularly physical activity, obesity and diet-explained greater variations in T2D-associated versus non-associated metabolites, with specific metabolites revealed as potential mediators. Finally, a 44-metabolite signature improved T2D risk prediction beyond conventional factors. These findings provide a foundation for understanding T2D mechanisms and may inform precision prevention targeting specific metabolic pathways.

Intra-articular RNA therapeutics have shown promise in osteoarthritis (OA); however, maximizing their efficacy requires targeted delivery to degenerating cartilage within focal lesions. As OA progresses, cartilage degeneration worsens, necessitating disease-responsive targeting with enhanced delivery in advanced stages. Here we develop an anionic nanoparticle (NP) strategy for targeting glycosaminoglycan loss, a hallmark of OA's progression that reduces cartilage's negative charge. These NPs selectively diffuse and accumulate into matrix regions inversely correlated with glycosaminoglycan content owing to reduced electrostatic repulsion, a strategy we term 'matrix inverse targeting' (MINT). In a mouse model of OA, intra-articular delivery of luciferase messenger RNA-loaded MINT NPs demonstrated disease-severity-responsive expression. Using this strategy, we delivered ghrelin mRNA, as ghrelin has shown chondroprotection properties previously. Ghrelin mRNA-loaded MINT NPs reduced cartilage degeneration, subchondral bone thickening and nociceptive pain. Our findings highlight the potential of ghrelin mRNA delivery as a disease-modifying therapy for OA and the platform's potential for lesion-targeted RNA delivery responsive to disease severity.

BACKGROUND AND OBJECTIVES: Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders.

METHODS: A retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns.

RESULTS: The study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions.

DISCUSSION: This large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.

OBJECTIVES: Severe aortic stenosis (AS) with a left ventricular ejection fraction (LVEF) of 50% to 54% is associated with worse outcomes than an LVEF greater than or equal to 55%. European guidelines consider aortic valve replacement (AVR) a Class IIa indication for asymptomatic patients with an LVEF of less than 55%, whereas American guidelines recommend AVR when the LVEF is less than 50%. The authors assessed outcomes of AVR vs conservative management in this range where guidelines differ.

METHODS: A registry was created for individuals with severe high-gradient AS (AVA ≤ 1 cm²), an LVEF of 50% to 54%, and a mean gradient greater than or equal to 40 mm Hg from 2000 to 2022 using queries of transthoracic echocardiogram (TTE) reports. Only asymptomatic cases were included; time-zero was defined as the time of the index TTE, and both AVR (considered as a time-dependent covariate) and mortality could occur at any point after. Proportional hazard modeling assessed the AVR-mortality association, with subset analyses for individuals with AVAs of less than 0.9 cm² and less than or equal to 0.75 cm².

RESULTS: Among 693 included individuals, 83 were asymptomatic at their index TTE. Of these, 38 (45.8%) underwent AVR within 2 years. After adjusting for immortal time, individuals with AVR had a trend toward decreased mortality (HR, 0.56; 95% CI, 0.31-1.01; P = .054). Among individuals with AVAs of less than 0.9 cm² and less than or equal to 0.75 cm², AVR was associated with improved survival (HR, 0.42; 95% CI, 0.21-0.84; P less tan .01 and HR, 0.33; 95% CI, 0.15-0.75; P less than .008, respectively).

CONCLUSIONS: AVR within 2 years was associated with improved survival among asymptomatic individuals with high-grade severe AS and an LVEF of 50% to 54%.

PURPOSE: To evaluate the clinical benefit of extended endocrine therapy (eET) after 5 years of adjuvant treatment with luteinizing hormone-releasing hormone agonists (LHRHa) in premenopausal women with node-positive, hormone receptor-positive early breast cancer (eBC).

METHODS: We conducted a cohort study analysis on two prospectively collected data sets (the Young Women's Breast Cancer Study and IEO Breast Cancer Cohort). Eligible patients were diagnosed with eBC at age ≤40 years (between 2005 and 2016), had node-positive, hormone receptor-positive disease, and remained premenopausal after 5 years of adjuvant LHRHa with no evidence of recurrence. The primary end point was invasive breast cancer-free survival (IBCFS), calculated from the sixth year after the initiation of adjuvant endocrine therapy (ET; study baseline), and adjusted through the propensity score (PS) weighting analysis.

RESULTS: A total of 501 patients were included in the analysis: 287 received eET for a median duration of 3.7 years (IQR, 2.3-5.0), including 48% tamoxifen monotherapy and 52% LHRHa plus tamoxifen or aromatase inhibitor. After a median follow-up of 7.3 years from the study baseline, the PS weighted IBCFS rates at 5 years were 85% in the eET group and 78% in the non-eET group (hazard ratio [HR], 0.63 [95% CI, 0.44 to 0.89]; P = .0135). The PS weighted distant recurrence-free survival rates at 5 years were 91% and 83% in the eET and non-eET group, respectively (cause-specific HR, 0.49 [95% CI, 0.31 to 0.79]). In both groups, bone fractures and major cardiovascular events were reported in 1% of patients.

CONCLUSION: In this cohort study analysis, extending ET in premenopausal patients with node-positive eBC after 5 years of LHRHa treatment was associated with a clinically meaningful reduction in both invasive and distant breast cancer recurrences.

HYPOTHESIS: Traumatic neuromas of the facial nerve are rare lesions that can mimic other tumors of the temporal bone and might be consequential to injuries of common otologic surgeries. Literature is scarce in describing these lesions in the temporal bone. The aim of this study is to expand the histologic understanding of these lesions.

BACKGROUND: Traumatic neuromas are benign proliferations of neural structures after total or partial sectioning, representing what seems to be a reparative attempt. In otologic surgeries, the facial nerve and its branch chorda tympani are at risk of iatrogenic injury that can lead to the formation of such neuromas.

METHODS: A descriptive otopathology study of 14 temporal bones taken from 13 human subjects identified to have facial nerve or facial chorda tympani branch traumatic neuromas.

RESULTS: We observed traumatic neuromas more commonly after stapedectomy (n = 9). Other surgeries were mastoidectomy (n = 2), cochlear implantation (n = 2), and temporal bone resection (n = 1). The chorda tympani nerve was more commonly affected than the facial nerve's main trunk. The majority of chorda tympani lesions were found in the iter chordae posterius.

CONCLUSIONS: Surgical intervention can result in neuroma formation. We present a large and detailed description of histologic changes observed in posttraumatic neuromas, adding to the current knowledge of this subject.