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Purpose: HERALD/EPOC1806 was conducted as a multicenter phase II trial assessing trastuzumab deruxtecan (T-DXd) therapy for patients with human epidermal growth factor receptor 2 ( HER2 )-amplified progressive stage solid tumors detected by cell-free DNA (cfDNA) testing., Patients and Methods: Patients exhibited advanced solid tumors with HER2 amplification that was identified via next-generation sequencing of cfDNA testing, without the requirement for immunohistochemical HER2 testing. The studied group was administered T-DXd at 5.4 mg/kg once every 3 weeks until onset of disease progression or intolerable toxicity., Results: Overall, 4,734 patients underwent cfDNA testing from December 2019 to January 2022, and 252 demonstrated HER2 amplification. Finally, the study included 62 patients with 16 cancer types with a median baseline plasma HER2 copy number (CN) of 8.55 (range, 2.4-73.9). Confirmed overall response rate (ORR) by investigator assessment was 56.5% (95% CI, 43.3 to 69.0), thus showing a value beyond the 5% threshold. Responses were evaluated for 13 cancer types, including KRAS -mutant colorectal (1/3), PIK3CA -mutant endometrial (5/6), and tissue HER2-negative gastric (1/2) cancers. Plasma HER2 CN above versus below the baseline median value did not differ for impact response; however, clearance of HER2 amplification in cfDNA on cycle 2 day 1 had higher response values compared with persistence. Median progression-free survival and response duration were 7.0 (95% CI, 4.9 to 9.7) and 8.8 (95% CI, 5.8 to 11.2) months, respectively, with the majority of complications being mild to moderate. Interstitial lung diseases were identified in 16 (26%) patients, including 14 patients with grade 1 disease, one patient with grade 2 disease, and one patient with grade 3 disease., Conclusion: T-DXd treatment demonstrated high ORR with durable response in patients with advanced HER2 -amplified solid tumors determined with cfDNA testing.

Objective: The intention of this tutorial video is to illustrate the methods of examining the forelimb and neck of a horse in order to identify abnormalities that may be associated with lameness or disease., Animal: A 16-year-old quarter horse gelding was used for examination., Methods: The horse was examined for abnormalities by means of physical examination., Results: The examination of the forelimb and neck of the horse was successfully completed., Clinical Relevance: This examination technique is required to identify abnormalities in the equine forelimb and can be utilized during a lameness examination.

Goals: Despite the proliferation of over 45 000 smartphone mobile health applications (MHAs), as far as we know, there is no MHA for those living with rare diseases such as Bladder Exstrophy-Epispadias-Cloacal Exstrophy complex (BEEC). We hypothesized that an MHA could provide similar "on-demand" information and connectivity within health communities for patients with BEEC as they do for more common diseases. Thus, our primary goal was to create an MHA for patients and families affected by BEEC to provide them with important information about the condition and a format for them to connect with other affected patients and families. A secondary goal was to develop an adaptable MHA template for other rare diseases in the future., Methods: We began our app development by examining existing common-disease MHAs for thematic structure. We conducted an extensive literature search of PubMed and Google scholar for MHA development and existing MHAs related to BEEC, utilizing these search terms: mobile health applications, rare diseases, bladder exstrophy, and online health communities. Our app development team began with our clinical multidisciplinary team of pediatric urologists; a child psychiatrist; a patient/family mental health therapist; and a certified nurse practitioner. We hired a website engineer and a production team. All clinical members have extensive experience caring for children and families affected by BEEC. Additionally, clinical team members compiled lists of themes deemed relevant from these reviews and themes gleaned from their clinical experience that appear with some frequency or urgency and from the myriad of themes discussed within the literature for MHAs., Results: We found no existing rare disease MHAs in the literature or our search of app stores online. However, we derived basic app categories from existing MHA formats and the thematic content of all sources reviewed. These categories aligned with the groupings of our lists of clinical themes. Thus, we could subsume diverse themes within a broad categorical format: for example, child development (as "Psychological Development" in the app) or various clinical care options (as "Treatment"). This app structure became nine sections, as shown in. This format allows diverse information to be retrieved efficiently from broader categories. This app is being offered to affected families, healthcare providers, and individuals unrelated to where care is offered., Conclusion: "We the BE" is the first MHA developed for a rare disease, BEEC. It has been published in a downloadable format for the general public at no cost. Further research is required to determine its efficacy for the BEEC community members; preliminary, unsolicited feedback from multiple users has been positive., Competing Interests: Conflicts of interest We have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The clinical utility of plasma tumor mutational burden (pTMB) requires further validation. Herein, the pTMB and genetic alterations were investigated as predictive biomarkers for anti-PD-1 monotherapy outcome in metastatic non-small cell lung cancer (NSCLC)., Methods: The GuardantOMNI panel (Guardant Health) was used to identify pTMB and genetic alterations. Data from 99 patients with metastatic NSCLC treated with pembrolizumab or nivolumab in first-, second-, or third-line settings between June 2016 and December 2020 were collected. Associations between pTMB and clinical benefit rate (CBR, stable disease ⩾6 months or partial response), progression-free survival (PFS), and overall survival (OS) were assessed., Results: Median pTMB in 84 patients was 10.8 mutations/megabase (mut/Mb). Histological analyses revealed that 61 and 36% of the patients had adenocarcinomas and squamous NSCLC, respectively. Most patients were treated with nivolumab (74%) and most anti-PD-1 agents were administered as second-line treatment (70%). The median follow-up duration was of 10.9 months (range, 0.2-40.7). Patients with high pTMB (⩾19 mut/Mb) had a higher CBR (69%) compared with low pTMB patients (33%; p  = 0.01). ARID1A ( p  = 0.007) and either ERBB2 or KIT mutations ( p  = 0.012) were positive and negative determinants, respectively, for clinical benefit. Multivariate analysis further showed that high pTMB was an independent predictive biomarker for both PFS [hazard ratio (HR) = 0.44, 95% confidence interval (CI): 0.22-0.88, p  = 0.02] and OS (HR = 0.37, 95% CI: 0.18-0.76, p  = 0.007)., Conclusion: High pTMB (⩾19 mut/Mb) is significantly associated with CBR in patients with NSCLC treated with anti-PD-1 agents., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2022.)

Background: Patients with ALK-rearranged non-small cell lung cancer (ALK+ NSCLC) inevitably acquire resistance to ALK inhibitors. Longitudinal monitoring of cell-free plasma DNA (cfDNA) next-generation sequencing (NGS) could predict the response and resistance to tyrosine kinase inhibitor (TKI) therapy in ALK+ NSCLC., Methods: Patients with ALK+ NSCLC determined by standard tissue testing and planned to undergo TKI therapy were prospectively recruited. Plasma was collected at pretreatment, 2 months-post therapy, and at progression for cfDNA-NGS analysis, Guardant 360., Results: Among 92 patients enrolled, circulating tumor DNA (ctDNA) was detected in 69 baseline samples (75%): 43 ALK fusions (62.3%) and two ALK mutations without fusion (2.8%). Two patients showed ALK-resistance mutations after ceritinib; G1202R, and co-occurring G1202R and T1151R. Eight patients developed ALK resistance mutations after crizotinib therapy; L1196M (n = 5), G1269A (n = 1), G1202R (n = 1), and co-occurring F1174L, G1202R, and G1269A (n = 1). Absence of ctDNA at baseline was significantly associated with longer progression-free survival (PFS; median 36.1 vs. 11.4 months, p = 0.0049) and overall survival (OS; not reached vs. 29.3 months, p = 0.0200). ctDNA clearance at 2 months (n = 29) was associated with significantly longer PFS (25.4 vs. 11.6 months, p = 0.0012) and OS (not reached vs. 26.1 months, p = 0.0307) than those without clearance (n = 22). Patients with co-occurring TP53 alterations and ALK fusions at baseline (n = 16) showed significantly shorter PFS (7.28 vs. 13.0 months, p = 0.0307) than those without TP53 alterations (n = 25)., Conclusions: cfDNA-NGS facilitates detection of ALK fusions and resistance mutations, assessment of prognosis, and monitoring dynamic changes of genomic alterations in ALK+ NSCLC treated with ALK-TKI., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline BRCA2 mutation with acquired resistance to olaparib related to biallelic BRCA2 reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline BRCA2 mutations. Within the germline BRCA2 -positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.

Histologically normal tissue adjacent to the tumor (NAT) is commonly used as a control in cancer studies. However, little is known about the transcriptomic profile of NAT, how it is influenced by the tumor, and how the profile compares with non-tumor-bearing tissues. Here, we integrate data from the Genotype-Tissue Expression project and The Cancer Genome Atlas to comprehensively analyze the transcriptomes of healthy, NAT, and tumor tissues in 6506 samples across eight tissues and corresponding tumor types. Our analysis shows that NAT presents a unique intermediate state between healthy and tumor. Differential gene expression and protein-protein interaction analyses reveal altered pathways shared among NATs across tissue types. We characterize a set of 18 genes that are specifically activated in NATs. By applying pathway and tissue composition analyses, we suggest a pan-cancer mechanism of pro-inflammatory signals from the tumor stimulates an inflammatory response in the adjacent endothelium.

Rationale: Thousands of mutations across >50 genes have been implicated in inherited cardiomyopathies. However, options for sequencing this rapidly evolving gene set are limited because many sequencing services and off-the-shelf kits suffer from slow turnaround, inefficient capture of genomic DNA, and high cost. Furthermore, customization of these assays to cover emerging targets that suit individual needs is often expensive and time consuming., Objective: We sought to develop a custom high throughput, clinical-grade next-generation sequencing assay for detecting cardiac disease gene mutations with improved accuracy, flexibility, turnaround, and cost., Methods and Results: We used double-stranded probes (complementary long padlock probes), an inexpensive and customizable capture technology, to efficiently capture and amplify the entire coding region and flanking intronic and regulatory sequences of 88 genes and 40 microRNAs associated with inherited cardiomyopathies, congenital heart disease, and cardiac development. Multiplexing 11 samples per sequencing run resulted in a mean base pair coverage of 420, of which 97% had >20× coverage and >99% were concordant with known heterozygous single nucleotide polymorphisms. The assay correctly detected germline variants in 24 individuals and revealed several polymorphic regions in miR-499. Total run time was 3 days at an approximate cost of $100 per sample., Conclusions: Accurate, high-throughput detection of mutations across numerous cardiac genes is achievable with complementary long padlock probe technology. Moreover, this format allows facile insertion of additional probes as more cardiomyopathy and congenital heart disease genes are discovered, giving researchers a powerful new tool for DNA mutation detection and discovery., (© 2015 American Heart Association, Inc.)

The exact nature of the immune response elicited by autologous-induced pluripotent stem cell (iPSC) progeny is still not well understood. Here we show in murine models that autologous iPSC-derived endothelial cells (iECs) elicit an immune response that resembles the one against a comparable somatic cell, the aortic endothelial cell (AEC). These cells exhibit long-term survival in vivo and prompt a tolerogenic immune response characterized by elevated IL-10 expression. In contrast, undifferentiated iPSCs elicit a very different immune response with high lymphocytic infiltration and elevated IFN-γ, granzyme-B and perforin intragraft. Furthermore, the clonal structure of infiltrating T cells from iEC grafts is statistically indistinguishable from that of AECs, but is different from that of undifferentiated iPSC grafts. Taken together, our results indicate that the differentiation of iPSCs results in a loss of immunogenicity and leads to the induction of tolerance, despite expected antigen expression differences between iPSC-derived versus original somatic cells.

Background and Aim of the Study: Aortic aneurysm size is known to portend a higher likelihood of aortic complications in patients with connective tissue disorders (CTD), but other objective tools are needed to determine which patients are at greatest risk of dissection, especially those which reflect the structural integrity and strength of the aortic wall., Methods: The aortic wall pathology was evaluated in CTD patients with and without acute aortic dissection to identify parameters that affect the risk of dissection. A retrospective review was performed of aneurysm pathology from patients with Marfan syndrome (MFS; n = 53) without dissection undergoing prophylactic aortic root surgery, and acute type A aortic dissection patients (AAAoD; n = 16). Patients without a cardiovascular cause of death (n = 19) served as controls. The minimal aortic medial wall thickness was measured, and medial myxoid degeneration (MMD) and the degree of elastin loss and fragmentation were graded., Results: The mean minimal aortic wall thickness was 1,625 +/- 364 microm in controls, and 703 +/- 256 microm and 438 +/- 322 microm for MFS and AAAoD patients, respectively. Aortic root diameters did not correlate with aortic wall thickness. A comparison of aortic medial thickness showed that the media was significantly thinner among acute dissection patients than either elective surgical patients (p = 0.02) or controls (p < 0.001). Aortic size, degree of MMD, and elastin loss did not vary significantly between CTD patients., Conclusion: A diminished aortic wall medial thickness may be linked to aortic dissection. High-resolution imaging techniques in the future may lead to the morphological assessment of aortic medial wall thickness in vivo becoming a reality which, in theory, could provide a more refined risk prognostication for acute aortic dissection.

Rationale: Human embryonic stem cell (hESC) derivatives are attractive candidates for therapeutic use. The engraftment and survival of hESC derivatives as xenografts or allografts require effective immunosuppression to prevent immune cell infiltration and graft destruction., Objective: To test the hypothesis that a short-course, dual-agent regimen of two costimulation-adhesion blockade agents can induce better engraftment of hESC derivatives compared to current immunosuppressive agents., Methods and Results: We transduced hESCs with a double fusion reporter gene construct expressing firefly luciferase (Fluc) and enhanced green fluorescent protein, and differentiated these cells to endothelial cells (hESC-ECs). Reporter gene expression enabled longitudinal assessment of cell engraftment by bioluminescence imaging. Costimulation-adhesion therapy resulted in superior hESC-EC and mouse EC engraftment compared to cyclosporine therapy in a hind limb model. Costimulation-adhesion therapy also promoted robust hESC-EC and hESC-derived cardiomyocyte survival in an ischemic myocardial injury model. Improved hESC-EC engraftment had a cardioprotective effect after myocardial injury, as assessed by magnetic resonance imaging. Mechanistically, costimulation-adhesion therapy is associated with systemic and intragraft upregulation of T-cell immunoglobulin and mucin domain 3 (TIM3) and a reduced proinflammatory cytokine profile., Conclusions: Costimulation-adhesion therapy is a superior alternative to current clinical immunosuppressive strategies for preventing the post-transplant rejection of hESC derivatives. By extending the window for cellular engraftment, costimulation-adhesion therapy enhances functional preservation following ischemic injury. This regimen may function through a TIM3-dependent mechanism., (© AlphaMed Press.)

A finite difference method was used to simulate the electric fields induced in the model by a gradient wire pattern. The pattern simulated corresponded to a design used to perform peripheral nerves stimulation experiments. The size (187.8, 169.02, and 150.24 cm tall) and position (brain and neck mode) of the model, relative to the magnet, as well as the voxel dimensions (3, 6, and 9 mm) of the model were varied to assess the effect on the simulation. The locations of stimulation reported from an experiment were classified according to nerve branch and compared with the peak-simulated electric fields. Model size and location affected the magnitude of the electric field, but not the position. Model resolution affected the location of the peak field. For the smallest resolution investigated, the nerves affected by the locations of peak stimulations in the model correlated to the frequency of stimulation in experiments. Although adequate resolution is required in order to assess the electric fields induced by gradient coil operation, the simulation of electric fields may be useful in evaluating gradient coil design prior to construction., (Copyright © 2012 Wiley Periodicals, Inc.)

Introduction: Endometriosis of the lung and the diaphragm is rare. Patients may present with symptoms such as shortness of breath, chest pain, and shoulder pain or they may be asymptomatic. Of note, there have been few reports of bilateral catamenial disease, and no reports, to our knowledge, of bilateral pathology proven pulmonary parenchymal endometriosis., Case: A 43-year-old with stage IV endometriosis and large leiomyoma underwent a laparoscopic hysterectomy and treatment of endometrial lesions in 2005. In March and April of 2011, she presented with bilateral pneumothoraces. She subsequently underwent video-assisted thoracoscopy as well as resection and fulguration of bilateral lung and diaphragmatic endometriosis. Pathology confirmed endometrial implants in the lung parenchyma bilaterally., Conclusion: Catamenial pneumothorax is the most common presentation of thoracic endometriosis. However, bilateral catamenial pneumothoraces are rare. To the best of our knowledge, this case reflects the first report of pathology proven bilateral lung and diaphragm endometriosis.

Objective: High altitude headache (HAH) is the most common neurological complaint at altitude and the defining component of acute mountain sickness (AMS). However, there is a paucity of literature concerning its prevention. Toward this end, we initiated a prospective, double-blind, randomized, placebo-controlled trial in the Nepal Himalaya designed to compare the effectiveness of ibuprofen and acetazolamide for the prevention of HAH., Methods: Three hundred forty-three healthy western trekkers were recruited at altitudes of 4280 m and 4358 m and assigned to receive ibuprofen 600 mg, acetazolamide 85 mg, or placebo 3 times daily before continued ascent to 4928 m. Outcome measures included headache incidence and severity, AMS incidence and severity on the Lake Louise AMS Questionnaire (LLQ), and visual analog scale (VAS)., Results: Two hundred sixty-five of 343 subjects completed the trial. HAH incidence was similar when treated with acetazolamide (27.1%) or ibuprofen (27.5%; P = .95), and both agents were significantly more effective than placebo (45.3%; P = .01). AMS incidence was similar when treated with acetazolamide (18.8%) or ibuprofen (13.7%; P = .34), and both agents were significantly more effective than placebo (28.6%; P = .03). In fully compliant participants, moderate or severe headache incidence was similar when treated with acetazolamide (3.8%) or ibuprofen (4.7%; P = .79), and both agents were significantly more effective than placebo (13.5%; P = .03)., Conclusions: Ibuprofen and acetazolamide were similarly effective in preventing HAH. Ibuprofen was similar to acetazolamide in preventing symptoms of AMS, an interesting finding that implies a potentially new approach to prevention of cerebral forms of acute altitude illness., (Copyright 2010 Wilderness Medical Society. Published by Elsevier Inc. All rights reserved.)

Finite mixture models are helpful for uncovering heterogeneity due to hidden structure. Quantitative genetics issues of continuous characters having a finite mixture of Gaussian components as statistical distribution are explored in this article. The partition of variance in a mixture, the covariance between relatives under the supposition of an additive genetic model, and the offspring-parent regression are derived. Formulas for assessing the effect of mass selection operating on a mixture are given. Expressions for the genetic and phenotypic correlations between mixture and Gaussian traits and between two mixture traits are presented. It is found that, if there is heterogeneity in a population at the genetic or environmental level, then genetic parameters based on theory treating distributions as homogeneous can lead to misleading interpretations. Some peculiarities of mixture characters are: heritability depends on the mean values of the component distributions, the offspring-parent regression is nonlinear, and genetic or phenotypic correlations cannot be interpreted devoid of the mixture proportions and of the parameters of the distributions mixed.

The bending stiffness of superelastic nickel-titanium archwires is influenced by alterations in mouth temperature. The activation and deactivation phases of a load-deflection loop of superelastic wires have different stress-magnitudes. This investigation compared the effect of short-term cooling or heating on the bending force exerted by nickel-titanium archwires. Two rectangular superelastic and one conventional nickel titanium wire were tested in bending at 37 degrees C. The specimens were tested during the activation phase and during the deactivation phase. The wires were kept at constant strain and the bending force was measured continually while the activated specimens were subjected to cold (10 degrees C) or hot (80 degrees C) water. The test situation simulates a patient's archwire that is subjected to cold or hot drinks or food during a meal. The conventional nickel-titanium wire was marginally affected by brief cooling or heating, regardless of activation phase. In contrast, the superelastic wires were strongly affected by short-term application of cold or hot water. When tested in activation phase, the effect of heating was transient whereas the wires continued to exert sub-baseline bending forces after short-term application of cold water. When tested in deactivation phase, the effect of cooling was transient whereas the wires exerted supra-baseline bending forces after a short-term application of hot water. The effect of short-term temperature changes on the bending stiffness of superelastic nickel titanium archwires is dependent upon the bending phase. Cooling induced transient effects on a wire in its deactivation phase, but prolonged effects when the wire was tested in the activation phase. In contrast, the effect of short-term heating was transient when the wire was tested in the activation phase, but prolonged when the wire was tested in the deactivation phase.

Background: Alterations in mouth temperature may lead to changes in the force exerted by an activated superelastic wire. It has been assumed that variations in archwire stiffness associated with short-term cooling or heating are transient. This investigation studied the effect of short-term cooling or heating on the bending force exerted by nickel-titanium archwire., Material and Methods: Six rectangular superelastic wires and one conventional nickel-titanium wire were tested in bending at 37 degrees C. The test specimens were deflected 0.5 mm, and the bending force was measured continually. The activated specimens were subjected to cold (10 degrees C) or hot (80 degrees C) water under constant deflection, simulating an inserted archwire that is subjected to cold or hot drinks or food during a meal., Results: The conventional nickel-titanium wire was marginally affected by brief cooling or heating. In contrast, some of the superelastic wires were strongly affected by short-time application of cold or hot water. Whereas the effect of brief heating disappeared quickly, some wires continued to exert sub-baseline bending forces (up to 32% less) after short-time application of cold water and showed little or no tendencies toward increase even after 30 minutes of postexposure restitution (up to 43% less)., Conclusions: Short-term exposures to hot liquid increased the bending force exerted for a given deflection transiently. The effect of short-term exposures to cold liquid was not always transient; the bending force remained sub-baseline for a number of the thermosensitive wires tested for a prolonged time.