Citations

Background: Quantitative neuromorphometric analysis of the peripheral nerve is paramount to nerve regeneration research. However, this technique relies upon accurate segmentation and determination of myelin and axonal area. Manual histologic analysis methods are time-consuming and subject to error and bias. The authors demonstrate and validate a user-friendly method relying on open-source machine-learning software and requiring no coding knowledge. Methods: Nineteen rat facial nerve segments were fixed, osmicated, embedded in epoxy, sectioned, and stained with toluidine blue. Whole nerve cross-sections were scanned at 20×. Images were preprocessed in ImageJ to measure fascicular area and remove background. Images were imported into Ilastik, and the pixel classification module was used to segment myelin and axons. A novel CellProfiler pipeline was used with Otsu 2-threshold processing to segment and quantify individual axon and myelin objects from segmentations. Axon counts and g-ratio of nerve samples were acquired manually and using this technique to compare between methods. Results: Analysis of an entire nerve cross-section can be completed with this method in less than 5 minutes. Bland-Altman plot and intraclass correlation coefficient demonstrated reliability between axon counts performed manually and with this protocol. There was no significant difference in accuracy in determining g-ratio compared with manual techniques (P < 0.05). Conclusions: The protocol presented here demonstrates a novel and accurate means of segmenting and analyzing histologic nerve cross-sections. This method decreases both user time and potential bias, enables analysis of an entire nerve versus random sampling, and uses only open-source software freely accessible to researchers.

Purpose: To update the epidemiological patterns of facial nerve palsy (FNP) in Olmsted County, Minnesota. Methods: A retrospective chart review using the Rochester Epidemiology Project database was conducted. Patients aged ≥18 years receiving a diagnosis of FNP within the Rochester Epidemiology Project database from the years 2000 to 2010 were included in the study. Data collected included age, gender, cause of FNP, degree of paralysis, medical and/or surgical management, and outcomes. Overall incidence rates were determined using gender-specific population figures for Olmsted County. Incidence trends were compared with previous Rochester Epidemiology Project studies. Results: The most common cause for FNP was Bell palsy (70.3% of cases). The overall incidence rate for Bell palsy in Olmsted County from 2000 to 2010 was 39.9 (95% CI, 36.1–43.7) per 100,000 person-years. This is an absolute increase of 14.9 per 100,000 person-years and a 60% relative increase in Bell palsy compared with a previous study performed at Mayo Clinic using the Rochester Epidemiology Project database population data from 1968 to 1982. Patients were infrequently evaluated by an ophthalmologist (8.4% of cases), and surgical intervention to address ophthalmic sequelae was rare (1.7% of cases). Conclusions: The incidence of Bell palsy has increased dramatically over previous studies, which has occurred in the setting of declining herpes simplex virus type 1 seropositivity trends and increasing herpes zoster incidence in the United States. Few patients with FNP are referred to ophthalmologists, which may represent a gap in care for both acute and long-term ophthalmic sequelae.

Targeted therapies have changed the treatment landscape of non-small-cell lung cancer and led to improved patient survival across all stages of lung cancer. Newer advances in common and novel oncogenic drivers continue to occur at vigorous speed, making it challenging to stay up to date with the rapidly evolving field. In this article, we review the emerging perspectives in the treatment of actionable targets in lung cancer. We focus on the development of newer KRAS-directed therapies, particularly on non-G12C mutations, pan-RAS inhibitors, and RAS-GTP inhibitors. We also describe the current standard of care for EGFR- and ALK-altered NSCLC and dive into the novel treatments expected to be in the clinic soon. A similar approach is taken toward MET, HER2, RET, ROS1, and FGFR alterations as emerging targets in non-small-cell lung cancer. Finally, we conclude this review with the current body of evidence for targeting TROP-2 as a novel target, potentially of importance in post-targeted therapy scenarios.

Lipoprotein(a) [Lp(a)] is a well-established causal risk factor for cardiovascular diseases (CVDs), as reported by multiple Mendelian randomization studies and large epidemiological studies. When elevated Lp(a) is combined with other risk factors, most notably elevated low-density lipoprotein cholesterol (LDL-C), a synergistic atherogenic effect has been reported. However, the current literature is conflicting regarding how Lp(a) interacts in the context of controlled LDL-C levels (e.g., <70 mg/dL) and whether reducing LDL-C can modify the atherogenic effect of Lp(a). In some studies, elevated Lp(a) was still significantly associated with a higher risk of cardiovascular events, despite controlled levels of LDL-C. In contrast, multiple studies have reported attenuation of the cardiovascular risk mediated by elevated Lp(a) with lower LDL-C levels. Moreover, the relationship between Lp(a) and triglycerides, high-density lipoprotein, and very low-density lipoprotein remains unclear. In this literature review, we summarize and discuss the current evidence regarding the interactions between Lp(a) and other lipid molecules, how they contribute to the pathogenesis of CVD, and future perspectives, particularly in the current era where promising targeted Lp(a)-lowering therapies are under development.

BACKGROUND: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards. METHODS: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4–6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively. RESULTS: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%–88%) with a body mass index (BMI) <35 kg/m 2 , decreasing to 67% (95% CI, 58%–77%) with a BMI ≥35 kg/m 2 . A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m 2 (97% [95% CI, 95%–99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m 2 (86% [95% CI, 79%–93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%–95%] and 86% [95% CI, 80%–93%] with a BMI <35 kg/m 2 ; 80% [95% CI, 74%–87%] and 84% [95% CI, 74%–93%] with a BMI ≥35 kg/m 2 ). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%–72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%–91%) with a BMI <35 kg/m 2 (87% [95% CI, 80%–94%] and 90% [95% CI, 81%–99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m 2 (93% [95% CI, 81%–100%] and 100% in validation cohorts). With a BMI ≥35 kg/m 2 , lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%–100%]; 93% [95% CI, 81%–100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%–98%; specificity of ≥500 pg/mL, 82%–89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts. CONCLUSIONS: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.

Ankle brachial index (ABI) can be unreliable in patients with non-compressible vessels. Our aim is to determine the feasibility of toe brachial index (TBI) and reporting criteria in a large population. We evaluated Doppler waveforms and segmental pressures in 26,719 limbs. TBI was obtained in 92.7%, mean TBI = 0.61 ± 0.25. TBI was obtained in 82%of limbs with unobtainable ABI. In hemodynamically normal subgroup (defined as those with normal ankle-brachial indices at rest and after exercise) the mean TBI was 0.84 ± 0.14. In severe PAD subgroup (defined as ABI < 0.5 and monophasic waveforms) the mean TBI was 0.16 ± 0.12. Limbs with a diagnosis of a PAD (ABI ≤ 0.9) had a TBI <0.8 in 99.5% of the cases, and <0.6 in 90% of the cases. A TBI of 0.8 had a negative predictive value for PAD of 0.99. A TBI cutoff of 0.6 had a positive predictive value for PAD of 0.95. Based on these results we propose defining normal TBI above 0.8, borderline between 0.8 and 0.61, abnormal TBI ≤ 0.6 and severe PAD as TBI ≤ 0.2. In conclusion TBI can be reliably measured in patients with PAD and offer valuable information when diagnosing PAD. We present our diagnostic criteria based on clinical data.

Abstract Background Adult onset medulloblastoma (aMB) is a rare tumor with limited available evidence. We present a large multi-institutional retrospective cohort of aMB patients treated in the modern era, with an emphasis on understanding the role of chemotherapy at initial diagnosis. Methods We included 267 consecutive patients with aMB treated at 7 different institutions from 2000-present, controlling for chemotherapy regimen and cycles received. Results Treatment factors were highly intercorrelated with one another and with treating institution. Concurrent chemotherapy was not associated with overall survival (OS). Adjuvant chemotherapy was associated with OS on univariable analyses (HR = 0.55, P = .029) and on multivariable analysis when adjusting for risk status (HR 0.55, P = .026) but not when also adjusting for treating institution. Proton craniospinal irradiation was associated with improved survival on univariable (HR = 0.50, P = .019) and multivariable analysis adjusting for risk status (HR = 0.51, P = .024) but not when treating institution was also considered. On subgroup analysis, adjuvant chemotherapy was associated with improved survival in M0 (HR = 0.55, P = .043) but not M1 disease, in patients with subtotal resection (HR = 0.43, P = .048) but not those with GTR. Similarly, progression-free survival was improved with chemotherapy in patients with M0 (HR = 0.57, P = .032) but not M1 disease, and in patients with subtotal (HR = 0.50, P = .054) but not gross total resection. Conclusions There was no benefit of concurrent chemotherapy. Adjuvant chemotherapy was associated with improved overall survival and this effect was driven by select subgroups, specifically those with M0 disease and those with residual tumor. We could not confirm that these associations are independent of the treating institution.