Citations

Context.— One objective of the College of American Pathologists/American College of Medical Genetics Cytogenetics Committee is to ensure the accurate detection and clinical interpretation of abnormalities observed by fluorescence in situ hybridization (FISH) analysis when evaluating solid tumor and brain/glioma specimens. Objective.— To report on a 20-year performance summary (2006–2025) of FISH challenges focusing on solid tumor and brain/glioma specimens. Design.— A retrospective review was performed from 2006–2025 to identify FISH challenges specifically addressing solid tumor and brain/glioma specimens. The overall performance of participants was evaluated to identify potential recurring errors. Results.— A total of 54 solid tumor formalin-fixed paraffin-embedded (FFPE) FISH challenges were provided from 2006–2025, including 38 FFPE specimen challenges and 16 educational image challenges (EICs). Of the 38 FFPE specimen challenges, 36 (95%) met the 80% grading consensus threshold. Two of 38 (5%) challenges failed to meet the 80% grading threshold, both involving break-apart probes. Fourteen of 16 (88%) EICs met the 80% “grading” consensus threshold, while 2 (12%) failed, including the misinterpretation of an ALK rearrangement in 1 challenge and the incorrect identification of solid tumors associated with MDM2 amplification in the other challenge. A total of 38 brain/glioma FFPE specimen challenges were provided from 2006–2025 (all involving the deletion status of 1p36 and/or 19q13 regions), and 35 (92%) met the 80% grading consensus threshold. Only 3 (8%) challenges failed to meet the 80% grading threshold. Conclusions.— Overall, this data review demonstrates that clinical cytogenomic laboratories are highly skilled at accurately detecting and interpreting genetic abnormalities by FISH in the setting of FFPE solid tumor and brain/glioma specimens.

Background: Anatomic isthmus 3 (AI 3) is defined as the myocardium between the pulmonary valve annulus and the ventricular septal defect patch that persists after tetralogy of Fallot (ToF) repair. Ventricular tachycardia (VT) propagated through slow conducting AI 3 (SCAI 3) represents a significant cause of morbidity in ToF. There is an unmet need for non-invasive identification of SCAI 3 in patients with ToF. Objectives: To assess whether the anatomic features of AI 3 as derived from cardiac computed tomography (CT) can predict slow conduction velocity during EP study. Methods: This retrospective single-center study included patients with ToF who underwent an electrophysiologic study and had AI 3 width measured from the pre-procedure cardiac CT. All patients underwent programmed ventricular stimulation, and electroanatomic. Logistic regression was performed to assess the relationship between AI 3 width and the presence of SCAI 3. Results: Of 27 consecutive patients with ToF, twelve patients were found to have SCAI 3, and ten patients were found to have SCAI 3 mediated VT. The AI 3 was significantly narrower in patients with SCAI 3 compared to those with normal AI 3 conduction (18.4 +/- 6.6 mm vs. 29.2 +/- 9.0 mm; p = 0.001). An AI 3 width above 21.5 mm carried a negative predictive value of 80.0%. Conclusion: In adults with repaired ToF referred for electrophysiology study, a narrower CT-derived AI 3 width was associated with SCAI 3 identification. AI 3 width measured on a CT obtained before PV replacement could help guide invasive risk stratification.

Background Independent second checks for proton and carbon-ion pencil-beam scanning should assess the planned physical dose, the expected delivery sequence, and the model-dependent relative biological effectiveness (RBE)-weighted dose. Objective The aim of this study was to design, implement, and assess a traceable second-check system that combines delivery-aware Monte Carlo transport with microdosimetric RBE calculation for both particle species. Methods The system receives Digital Imaging and Communications in Medicine (DICOM) planning data, converts the discrete spot sequence into a predicted delivery sequence for dose-driven continuous scanning (DDCS), generates weighted particle histories, and performs independent TOPAS/Geant4 transport. It scores physical dose, dose-averaged linear energy transfer (LETd), and voxel-level microdosimetric quantities. For both beam types, the scored lineal-energy distribution is represented using abridged microdosimetry distribution methodology (AMDM) and processed with the Mayo Clinic Florida microdosimetric kinetic model (MCF MKM). The proton branch additionally produces a fixed-RBE-weighted dose using RBE = 1.1. No fixed-RBE model is used for carbon ions. Proton assessment included component tests, single-energy source, transport, and scoring checks at 70.0, 170.2, and 229.1 MeV, patient-level evaluations using de-identified plans, and operational timing. Carbon-ion assessment used a pre-existing Monte Carlo dataset to evaluate component-level handling and visualization of AMDM descriptors, the MCF MKM RBE factor, and RBE-weighted dose. Results The integrated workflow completed plan receiving, delivery-sequence generation, particle transport, physical and biological dose calculation, comparison, and report generation. The proton case for which detailed quantitative end-to-end results were reported was classified as REVIEW REQUIRED because not all dosimetric comparison criteria were met. A pre-existing carbon-ion dataset was used to verify the component-level handling and separate presentation of physical dose, AMDM descriptors, RBE factor, and RBE-weighted dose. Predicted DDCS timing and the stationary-versus-moving irradiation components were not benchmarked against machine logs or measurements. Conclusion A common delivery-aware platform was implemented to support independent physical dose and microdosimetric RBE-weighted dose assessment for proton and carbon-ion treatments while retaining beam-specific dose conventions and biological model information. Further local commissioning and multicase validation are required before clinical use.

Background: Acute kidney injury (AKI) is a common complication of COVID-19-associated acute respiratory distress syndrome (ARDS), yet the impact of extracorporeal membrane oxygenation (ECMO) on outcomes in this high-risk population remains unclear. Methods: We performed a retrospective, survey-weighted study using the National Inpatient Sample (NIS) database from 2020–2022 to compare outcomes among adults hospitalized with COVID-19-associated ARDS and AKI managed with invasive mechanical ventilation (IMV) alone versus IMV and ECMO. The primary outcome was in-hospital mortality, while secondary outcomes included renal replacement therapy (RRT), complications, hospital length of stay (LOS), and healthcare utilization. Results: Among 198,395 hospitalizations with COVID-19 ARDS complicated by AKI, 4730 received IMV and ECMO. ECMO use was not associated with statistically significantly lower adjusted in-hospital mortality (adjusted odds ratio [aOR] 0.96, 95% CI 0.81–1.12). However, ECMO was associated with greater odds of RRT, intracranial hemorrhage, disseminated intravascular coagulation, cardiogenic shock, vasopressor use, tracheostomy, acute liver failure, deep vein thrombosis, ischemic stroke and ICU-acquired weakness. ECMO was also associated with longer LOS and higher hospitalization charges. Conclusions: Among hospitalizations with COVID-19-associated ARDS and AKI, ECMO was not associated with statistically significantly lower adjusted in-hospital mortality but was associated with markedly higher complication burden, longer hospitalization, and substantially greater healthcare resource utilization.

Abstract Background Spinal cord stimulation (SCS) is an important modality for treating chronic pain in patients who have failed conservative therapy and a substantial portion of the population rely on fee-for-service Medicare or Medicaid for coverage. We aimed to determine physician professional fee reimbursement rates and the ratio of Medicaid to Medicare professional fee reimbursement (MMI) for three common Current Procedural Terminology (CPT) codes related to SCS therapy (63650, 63685, and 63655) across states. Secondarily, we explored trends in utilization and reimbursement of these procedures by Medicare at the national level between 2013 and 2023. Methods Medicaid professional fee reimbursement data were extracted from publicly available fee schedules where available for individual states, while Medicare reimbursement data were extracted from the Centers for Medicare and Medicaid Services (CMS) Physician Fee Schedule. Baseline and wage-adjusted MMI values were calculated for each state. Results Medicaid reimbursed 11.5–21.0% less than Medicare across the evaluated CPT codes after wage adjustment, with differences of 11.8% for CPT 63650 (facility), 18.0% for CPT 63650 (non-facility), 11.5% for CPT 63685 (facility), and 21.0% for CPT 63655 (facility). Medicaid MMI values ranged from 0.397–1.87 across codes and settings. State-level Medicaid professional fee reimbursement varied substantially, ranging from $194.52–$639.38 for CPT 63650 (facility), $978.72–$2,781.65 for CPT 63650 (non-facility), $160.82–$558.00 for CPT 63685 (facility), and $375.97–$1,045.15 for CPT 63655 (facility); Medicare reimbursement was substantially less variable. From 2013–2023, Medicare utilization, rendering providers, beneficiaries, and standardized payments generally increased, although trends varied by CPT code and site of service. Conclusions Medicare physician professional fee reimbursement largely exceeds Medicaid physician professional fee reimbursement for three of the most common SCS procedural codes, suggesting potential access barriers to chronic pain procedures. Medicaid reimbursement shows considerable variation across states and among procedural codes, suggesting substantial interstate heterogeneity in Medicaid rate-setting that may reflect differences in state policy priorities or other factors not analyzed in this study.

BACKGROUND: The impact of life-course blood pressure (BP) trajectories on later-life focal left ventricular (LV) fibrosis by late gadolinium enhancement (LGE) remains elusive. METHODS: MyoFit46 prospectively recruited ≈500 participants from a 1946 birth cohort for a cardiovascular magnetic resonance scan at 77 years, assessing LV LGE calculated using the 3-SD method or 5-SD method. Systolic BP (SBP) and diastolic BP were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, annual rates of BP change (steepness) and area under the BP trajectory (cumulative burden) for each age interval were calculated using mixed-effects models. Associations between life-course BPs and LGE were tested using generalized linear models, adjusted for antihypertensives, demographics, lifestyle, and comorbidities. Time-to-event associations between LGE and incident major adverse cardiovascular event (hospitalizations for coronary artery disease, stroke, heart failure, and atrial/ventricular arrhythmias; n=29) were also evaluated. RESULTS: Among 472 participants (54% male), each 10 mm Hg greater individual SBPs at 36 to 69 years were associated with 6% to 11% greater LV LGE calculated using the 3-SD method (all P ≤0.033), whereas each 10 mm Hg sustained greater SBPs on any age interval from 36 to 69 associated with 16% to 24% greater LGE calculated using the 3-SD method at 77(all P ≤0.005), independent of SBP at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, and 53 to 63 was associated with 6% to 12% greater LGE calculated using the 3-SD method at 77 years. LGE presence was associated with greater major adverse cardiovascular event rates (hazard ratio, 2.5 [95% CI, 1.2–5.2]). CONCLUSIONS: Higher life-course BPs, cumulative burden, and steeper increases were associated with greater older-age LV LGE, which was linked to incident major adverse cardiovascular events. BP trajectories, beyond single-point BP measurements, warrant further investigation as tools to guide BP management strategies.

Importance Effective interventions are needed to support the cocreation of diabetes care plans that are sensible, desirable, and feasible for the people living with diabetes (ie, care that fits). Objective To investigate whether an agenda-setting kit (ASK) added to usual primary care improves fit of care and glycemic control in adults with type 2 diabetes (T2D). Design, Setting, and Participants This single-center, clinician-level cluster randomized clinical trial was conducted from February 16, 2023, to July 26, 2024, with a 6-month follow-up, at a federally qualified health center in New Haven, Connecticut. Eligible clinicians were primary care physicians, nurse practitioners, and physician assistants who prescribed medication to treat patients with T2D. Eligible patients were English- or Spanish-speaking adults aged 18 years or older with T2D and hemoglobin (Hb) A 1c level greater than 8%. Patients were excluded if their clinician determined that an HbA 1c level 8% or lower was inconsistent with goals of care. Data were analyzed from November 7, 2024, to August 13, 2026. Intervention Clinicians were randomized 1:1 to the ASK plus usual primary care group (intervention group) or usual primary care only (control group). The ASK intervention consisted of 14 conversation cards about life with diabetes and its treatment. Prior to the clinical encounter, patients were asked to select 0 to 3 cards they wanted to prioritize for discussion. Main Outcomes and Measures The primary outcome was the 6-month change from baseline in illness intrusiveness measured with the Illness Intrusiveness Ratings Scale (IIRS; range: 13-91, with higher scores indicating greater intrusiveness) and HbA 1c level. Secondary outcomes included changes in treatment burden measured with the Treatment Burden Questionnaire (TBQ; range: 0-150, with higher scores indicating greater burden), diabetes distress measured with the 17-Item Diabetes Distress Scale (DDS-17; scores: indicate little or no distress [<2.0], moderate distress [2.0-2.9], and high distress [≥3.0]), and visit satisfaction. Results Eleven clinicians (6 [54.5%] female) were included in the trial along with 143 of their patients. The mean (SD) patient age was 56 (12) years; 87 participants (60.8%) were female and 88 (61.5%) reported Spanish as their primary language. Six-month survey data were available for 65 of 74 patients (87.8%) in the intervention group and 58 of 69 (84.0%) in the control group; data on HbA 1c level were available for 71 (95.9%) and 65 (94.2%), respectively. At 6 months, mean (SD) IIRS scores were 32.1 (15.1) and 37.1 (18.7) in the intervention and control groups (adjusted mean difference, −3.9; 95% CI, −10.4 to 2.6). The mean (SD) HbA 1c levels were 8.8% (1.8) in the intervention group and 9.1% (1.8) in the control group (adjusted mean difference, −0.2%; 95% CI, −0.9% to 0.5%). Mean (SD) TBQ scores in the intervention and control groups were 41.2 (44.8) and 46.8 (44.4) (adjusted mean difference, 1.0; 95% CI, −16.6 to 18.6), and mean (SD) DDS-17 scores were 2.0 (1.0) and 2.3 (1.0) (adjusted mean difference, −0.1; 95% CI, −0.4 to 0.2). Clinician-reported satisfaction was greater in the intervention group; patient satisfaction did not differ between groups. Conclusions and Relevance In this cluster randomized clinical trial of adults with T2D, use of the ASK with usual primary care was associated with greater clinician satisfaction but not with improvements in patients’ fit of care or glycemic control over 6 months. Larger studies should evaluate interventions that not only identify patients’ priorities and treatment burdens but also better support clinicians in addressing them. Trial Registration ClinicalTrials.gov Identifier: NCT05553912

Background: Subtotal colectomy (STC) with end ileostomy (EI) is usually the first surgical stage for patients with ulcerative colitis (UC) who fail medical treatment, most often with biological agents. Is there a difference in surgical outcome after failure of one or two biologicals vs. three or four? Methods: A retrospective study of all patients who underwent STC with EI for UC (5-2018 to 1-2022). After excluding emergent cases, the elective cohort was divided into patients who failed 1–2 biologicals (group 1–2) vs. patients who failed 3–4 biologicals (group 3–4), and surgical outcomes were compared. Data collected included patients’ demographics, preoperative clinical manifestations, and operative and postoperative outcomes. Results: Ninety-eight patients underwent STC for UC, and of them, 53 were elective. Thirty patients failed 1–2 biologics (group 1–2), and 23 failed 3–4 biologics (group 3–4). The groups were similar in average age (37.6 ± 11 vs. 32.7 ± 10), BMI (26.7 ± 6 vs. 27.7 ± 7), number of years with UC (9.5 ± 9 vs. 9 ± 8), rate of steroid dependence (20 (67%) vs. 13 (57%)) but differed in sex; there were 25 (83%) males in group 1–2, and 8 (35%) in group 3–4 (p < 0.01). The operative approaches were similar, as was the operative time (217 ± 74 vs. 210 ± 79 min). The length of hospital stay was 3.2 ± 1 days for group 1–2 and 5 ± 6 days for group 3–4 (p = 0.14). Postoperative complications were seen in 10 patients (33%) vs. 7 patients (30%) (p = 0.82), and of them, two (7%) and two (9%) (p = 0.82) had Venous thromboembolism (VTE), respectively. Only 20 patients (67%) in group 1–2 and 16 patients (70%) in group 3–4 (p = 0.82) progressed to a second stage of an Ileoanal pouch (IPAA) at 11.1 ± 4 and 9.2 ± 2 months, respectively. The overall average follow-up time was 41.1 months. Conclusions: Ulcerative Colitis patients who fail 3–4 biological agents and choose to go to elective STC with EI have very similar surgical outcomes compared to patients who choose elective surgery after failing only 1–2 biological agents in the same time span of known disease. UC patients with severe colitis and poor quality of life who fail two lines of biological agents may be better off electing surgical treatment than failing more biologics and then going to surgery. On the other hand, patients who try 3–4 biologics may expect no worse surgical outcomes than after 1–2 biologics.

Chronic liver disease represents a substantial global health burden, yet effective anti-fibrotic therapies remain elusive, largely due to an incomplete understanding of extracellular matrix (ECM) remodeling. While historical research prioritized the role of matrix metalloproteinase (MMP) deficiency in fibrogenesis, clinical outcomes indicate that broad-spectrum MMP modulation is paradoxically ineffective. This review synthesizes current evidence to demonstrate that hepatic fibrosis is driven by a complex regulatory imbalance wherein tissue inhibitors of metalloproteinases (TIMPs) sustain a pathological microenvironment. We highlight that TIMPs facilitate fibrogenesis through two primary mechanisms: the inhibition of MMP-mediated ECM degradation and the suppression of apoptosis in activated hepatic stellate cells (HSCs), a process exacerbated by mechanotransduction-driven feedback loops. Importantly, we address the functional redundancy within the TIMP family, as evidenced by the progression of fibrosis in TIMP-1-deficient models, which challenges traditional linear regulatory paradigms. Ultimately, we propose that the future of fibrosis treatment necessitates a shift from broad-spectrum enzyme modulation toward precision molecular strategies, including small-molecule inhibition, antisense oligonucleotides, and epigenetic reprogramming aimed at restoring the physiological MMP/TIMP equilibrium within the fibrotic niche.