Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD. METHODS: In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions. FINDINGS: We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions. INTERPRETATION: The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD. FUNDING: The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.

Lymph node ratio is a more robust predictor of overall survival than N stage in stage III colorectal adenocarcinoma.

BACKGROUND: Lymph node ratio (LNR) may offer superior prognostic stratification in colorectal adenocarcinoma compared with N stage. However, candidate cutoff ratios require validation. We aimed to study the prognostic significance of LNR and its optimal cutoff ratio. METHODS: We reviewed the pathology records of all patients with stage III colorectal adenocarcinoma who were managed at the King Hussein Cancer Center between January 2014 and December 2019. We then studied the clinical characteristics of the patients, correlates of lymph node count, prognostic significance of positive lymph nodes, and value of sampling additional lymph nodes. RESULTS: Among 226 included patients, 94.2% had ≥ 12 lymph nodes sampled, while 5.8% had < 12 sampled lymph nodes. The median number of lymph nodes sampled varied according to tumor site, neoadjuvant therapy, and the grossing pathologist's level of training. According to the TNM system, 142 cases were N1 (62.8%) and 84 were N2 (37.2%). Survival distributions differed according to LNR at 10% (p = 0.022), and 16% (p < 0.001), but not the N stage (p = 0.065). Adjusted Cox-regression analyses demonstrated that both N stage and LNR at 10% and 16% predicted overall survival (p = 0.044, p = 0.010, and p = 0.001, respectively). CONCLUSIONS: LNR is a robust predictor of overall survival in patients with stage III colorectal adenocarcinoma. At a cutoff ratio of 0.10 and 0.16, LNR offers better prognostic stratification in comparison with N stage and is less susceptible to variation introduced by the number of lymph nodes sampled, which is influenced both by clinical variables and grossing technique.

Improvement of the photoelectric dye sensitized solar cell performance using Fe/S-TiO2 nanoparticles as photoanode electrode.

A sulfur nanoparticles-incorporated iron-doped titanium oxide (Fe/TiO2) with different ratio was successfully synthesized by photolysis method and utilized as effective photoanode in dye sensitized solar cell (DSSC) application with N719 dye. The photolysis method was contained the irradiation of the Fe, S and Ti mixture solution with 15 W source irradiation, and then calcined the formed precipitate. The DSSCs fabricated with Fe/S-TiO2 photoanode appeared an improved solar-to-electrical energy conversion efficiency of 6.46, which more than pure TiO2 (3.43) below full sunlight illumination (1.5 G). The impact of Fe content on the total efficiency was also inspected and the Fe content with 6% S-TiO2 was found 5 wt%. Due to the improved the efficiency of solar cell conversion of Fe/S-TiO2 nanocomposite, it should be deemed as a potential photoanode for DSSCs with high performance.

Estimating the environmental impacts of global lithium-ion battery supply chain: A temporal, geographical, and technological perspective.

A sustainable low-carbon transition via electric vehicles will require a comprehensive understanding of lithium-ion batteries' global supply chain environmental impacts. Here, we analyze the cradle-to-gate energy use and greenhouse gas emissions of current and future nickel-manganese-cobalt and lithium-iron-phosphate battery technologies. We consider existing battery supply chains and future electricity grid decarbonization prospects for countries involved in material mining and battery production. Currently, around two-thirds of the total global emissions associated with battery production are highly concentrated in three countries as follows: China (45%), Indonesia (13%), and Australia (9%). On a unit basis, projected electricity grid decarbonization could reduce emissions of future battery production by up to 38% by 2050. An aggressive electric vehicle uptake scenario could result in cumulative emissions of 8.1 GtCO2eq by 2050 due to the manufacturing of nickel-based chemistries. However, a switch to lithium iron phosphate-based chemistry could enable emission savings of about 1.5 GtCO2eq. Secondary materials, via recycling, can help reduce primary supply requirements and alleviate the environmental burdens associated with the extraction and processing of materials from primary sources, where direct recycling offers the lowest impacts, followed by hydrometallurgical and pyrometallurgical, reducing greenhouse gas emissions by 61, 51, and 17%, respectively. This study can inform global and regional clean energy strategies to boost technology innovations, decarbonize the electricity grid, and optimize the global supply chain toward a net-zero future.

Platelet Delta (δ)-Storage Pool Deficiency: A Case Series and Review of the Literature.

Hereditary platelet delta (δ)-storage pool deficiency is a rare condition in which there are fewer dense granules in platelets disrupting primary hemostasis. It can cause a mild-moderate bleeding tendency with normal coagulation studies; hence, it is an underdiagnosed diagnostic challenge. The authors present three patients with hereditary platelet delta (δ)-storage pool deficiency who had heavy menstrual bleeding, excessive bleeding following surgery, mucocutaneous bleeding, and a bleeding score greater than or equal to 6. These cases reveal the susceptibility of underdiagnosing platelet disorders and the significance of utilizing a bleeding assessment tool to help guide further workup with transmission electron microscopy to visualize the fewer dense granules in platelets. Although bleeding is typically moderate, it can be severe in certain scenarios, like after mucosal surgeries, and can lead to death, highlighting the importance of the condition's recognition and prophylactic treatment.

Acquired Factor X Deficiency without Amyloidosis Presenting with Massive Hematuria: A Case Report and Review of the Literature.

Acquired factor X deficiency is a rare diagnosis, especially without the association of other co-existing conditions such as amyloidosis. The authors report the case of a 34-year-old male with severe frank hematuria found to have markedly prolonged prothrombin time and activated partial thromboplastin time. A mixing study showed correction utilizing normal plasma and a coagulation panel testing revealed decreased factor X activity. The patient was treated with multiple blood transfusions, fresh frozen plasma, high-dose pulse steroids, and rituximab. The patient's condition improved during his 21-day hospital stay and was followed up every 2 weeks for 3 months. The patient's factor X level recovered after two weeks of discharge with no other hemorrhagic episodes.

Pathological Complete Response of Metastatic Clear Cell Renal Carcinoma with Pembrolizumab and Axitinib: A Case Report and Review of Literature.

The role of cytoreductive nephrectomy has become unclear since the introduction of immunotherapy which is now the backbone of the treatment for metastatic renal cell carcinoma. Different combinations are used based on the prognosis. Achieving a complete response would be ideal and includes radiographic disappearance of lesions. However, there have been a few reported cases of pathological complete response with persistent radiographic evidence of cancer. The authors report a case of pathological complete response despite persistent radiographic evidence of residual disease in a patient with metastatic renal cell carcinoma treated with pembrolizumab and axitinib. The patient subsequently underwent cytoreductive nephrectomy after the 13th dose of pembrolizumab. The resected mass consisted of scar tissue with no viable tumor cells seen on pathology but only scar tissue. This case reveals that persistent radiographic evidence of the tumor may be explained by scar tissue, challenging the role of cytoreductive nephrectomy in the era of immunotherapy.

Modulation of Kinase Activities In Vitro by Hepatitis C Virus Protease NS3/NS4A Mediated-Cleavage of Key Immune Modulator Kinases.

Hepatitis C Virus NS3/NS4A, a serine protease complex, has been found to interact with many host proteins and cause various adverse effects on cellular function and immune response. For example, the cleavage of important immune factors by NS3/NS4A has been suggested as a mechanism for the hepatitis C virus to evade innate immunity. The spectrum of susceptible substrates for NS3/NS4A cleavage certainly includes important immune modulator kinases such as IKKα, IKKß, IKKε, and TBK1, as demonstrated in this paper. We show that the kinase activities of these four host kinases were transformed in unexpected ways by NS3/NS4A. Treatment with NS3/NS4A caused a significant reduction in the kinase activities of both IKKα and IKKß, suggesting that HCV might use its NS3/NS4A protease activity to deactivate the NF-κB-associated innate immune responses. In contrast, the kinase activities of both IKKε and TBK1 were enhanced after NS3/NS4A treatment, and more strikingly, the enhancement was more than 10-fold within 20 min of treatment. Our mass spectroscopic results suggested that the cleavage after Cys89 in the kinase domain of IKKε by NS3/NS4A led to their higher kinase activities, and three potential mechanisms were discussed. The observed kinase activity enhancement might facilitate the activation of both IKKε- and TBK1-dependent cellular antiviral pathways, likely contributing to spontaneous clearance of the virus and observed acute HCV infection. After longer than 20 min cleavage, both IKKε- and TBK1 gradually lost their kinase activities and the relevant antiviral pathways were expected to be inactivated, facilitating the establishment of chronic HCV infection.

Circumferential Bone Fusion in Adult Spinal Deformity via Combination of Oblique Lateral Interbody Fusion and Grade 2 Posterior Column Osteotomy.

STUDY DESIGN: Retrospective study. OBJECTIVES: The combination of oblique lateral interbody fusion (OLIF) with grade 2 posterior column osteotomy (PCO) is an effective treatment for adult spinal deformity. However, grade 2 PCO may lead to pseudoarthrosis because it involves complete removal of the bilateral posterior facet joints. The main study objective was to determine the achievement rate of anterior and posterolateral fusion resulting in circumferential fusion in patients who underwent combined OLIF and grade 2 PCO. METHODS: This retrospective study included consecutive patients who underwent OLIF and grade 2 PCO. The group comprised a long fusion group, with fusion from the thoracic level to the ilium, and a short fusion group, with fusion within the lumbar region. The OLIF with percutaneous pedicle screw insertion group was also used for reference. The Brantigan-Steffee-Fraser classification was used to assess interbody fusion and Lenke classification for assessment of posterolateral fusion. RESULTS: Sixty-six patients with 109 lumbar levels were included in the study. We observed 100% anterior fusion in all 3 groups. The fusion rate for posterolateral fusion between the OLIF-grade 2 PCO group was 97%, with very low (3%) non-circumferential fusion (pseudoarthrosis only at the osteotomy site). In most cases, solid posterolateral fusions (Lenke A) occurred within 24 months. CONCLUSIONS: The combination of OLIF and grade 2 PCO resulted in circumferential fusion for most (97%) of the cases within 24 months. OLIF and grade 2 PCO are considered a good combination treatment to achieve sufficient lumbar lordosis and solid bone fusion.

Circulating fibrillin fragment concentrations in patients with and without aortic pathology.

Objective: Fragments of fibrillin-1 and fibrillin-2 will be detectable in the plasma of patients with aortic dissections and aneurysms. We sought to determine whether the plasma fibrillin fragment levels (PFFLs) differ between patients with thoracic aortic pathology and those presenting with nonaortic chest pain. Methods: PFFLs were measured in patients with thoracic aortic aneurysm (n = 27) or dissection (n = 28). For comparison, patients without aortic pathology who had presented to the emergency department with acute chest pain (n = 281) were categorized into three groups according to the cause of the chest pain: ischemic cardiac chest pain; nonischemic cardiac chest pain; and noncardiac chest pain. The PFFLs were measured using a sandwich enzyme-linked immunosorbent assay. Results: Fibrillin-1 fragments were detectable in all patients and were lowest in the ischemic cardiac chest pain group. Age, sex, and the presence of hypertension were associated with differences in fibrillin-1 fragment levels. Fibrillin-2 fragments were detected more often in the thoracic aneurysm and dissection groups than in the emergency department chest pain group (P < .0001). Patients with aortic dissection demonstrated a trend toward increased detectability (P = .051) and concentrations (P = .06) of fibrillin-2 fragments compared with patients with aortic aneurysms. Analysis of specific antibody pairs identified fibrillin-1 B15-HRP26 and fibrillin-2 B205-HRP143 as the most informative in distinguishing between the emergency department and aortic pathology groups. Conclusions: Patients with thoracic aortic dissections demonstrated elevated plasma fibrillin-2 fragment levels (B205-HRP143) compared with patients presenting with ischemic or nonischemic cardiac chest pain and increased fibrillin-1 levels (B15-HRP26) compared with patients with ischemic cardiac chest pain. Investigation of fibrillin-1 and fibrillin-2 fragment generation might lead to diagnostic, therapeutic, and prognostic advances for patients with thoracic aortic dissection.

Implementation of a Morphological Filter for Removing Spikes from the Epileptic Brain Signals to Improve Identification Ripples.

Epilepsy is a very common disease affecting at least 1% of the population, comprising a number of over 50 million people. As many patients suffer from the drug-resistant version, the number of potential treatment methods is very small. However, since not only the treatment of epilepsy, but also its proper diagnosis or observation of brain signals from recordings are important research areas, in this paper, we address this very problem by developing a reliable technique for removing spikes and sharp transients from the baseline of the brain signal using a morphological filter. This allows much more precise identification of the so-called epileptic zone, which can then be resected, which is one of the methods of epilepsy treatment. We used eight patients with 5 KHz data set and depended upon the Staba 2002 algorithm as a reference to detect the ripples. We found that the average sensitivity and false detection rate of our technique are significant, and they are ∼94% and ∼14%, respectively.

Pre-endoscopy Symptoms and Age, But Not Esophageal Biopsy Number Are Associated With Post-endoscopy Adverse Events.

Esophagogastroduodenoscopy (EGD) is a frequently utilized investigative tool in the management of gastrointestinal conditions in children. Biopsies obtained during EGD may pose risk for post-operative adverse events (AEs), and further understanding of risk is imperative to provide informed consent to families and safe patient care. In particular, the impact of biopsy number and location on the development of AEs has not been studied in pediatric patients. We prospectively assessed for AEs by telephone survey 3-7 days after 209 EGDs performed on patients ages 1-21 years over a 1-year period. Demographic, endoscopic, and histologic data were collected. The most common symptoms reported were throat pain (61%), chest pain (26%), and dysphagia (26%). Binary regression models identified age and pre-operative symptoms as factors that influenced the likelihood of post-operative morbidity. Multiple biopsies from 3 different locations of the esophagus did not impact the risk of post-operative AEs.

Frequency equation and semi-empirical mechanical coupling strength of microcantilevers in an array.

A characteristic equation for the frequencies of the T-shaped and overhang-shaped cantilevers is derived for the first time. We show that there are optimum values of the overhang lengths and widths that maximize the frequency and the number of maxima is corresponding to the mode number. The frequency of higher-order modes could be tuned by changing the overhang dimensions. Especially, a semi-empirical formula for the coupling strength κ between cantilevers in an array is proposed where the strength presents a cubic decrease with the overhang width ξ and a linear increase with the overhang length η , κ = η / ξ 3 . There is a very good agreement between the proposed formula and the values obtained in recent experiments by other researchers.

Electrifying passenger road transport in India requires near-term electricity grid decarbonisation.

Battery-electric vehicles (BEV) have emerged as a favoured technology solution to mitigate transport greenhouse gas (GHG) emissions in many non-Annex 1 countries, including India. GHG mitigation potentials of electric 4-wheelers in India depend critically on when and where they are charged: 40% reduction in the north-eastern states and more than 15% increase in the eastern/western regions today, with higher overall GHGs emitted when charged overnight and in the summer. Self-charging gasoline-electric hybrids can lead to 33% GHG reductions, though they haven't been fully considered a mitigation option in India. Electric 2-wheelers can already enable a 20% reduction in GHG emissions given their small battery size and superior efficiency. India's electrification plan demands up to 125GWh of annual battery capacities by 2030, nearly 10% of projected worldwide productions. India requires a phased electrification with a near-term focus on 2-wheelers and a clear trajectory to phase-out coal-power for an organised mobility transition.

Reliability and responsiveness of endoscopic disease activity assessment in eosinophilic esophagitis.

BACKGROUND AND AIMS: Endoscopic outcomes have become important measures of eosinophilic esophagitis (EoE) disease activity, including as an endpoint in randomized controlled trials (RCTs). We evaluated the operating properties of endoscopic measures for use in EoE RCTs. METHODS: Modified Research and Development/University of California Los Angeles appropriateness methods and a panel of 15 international EoE experts identified endoscopic items and definitions with face validity that were used in a 2-round voting process to define simplified (all items graded as absent or present) and expanded versions (additional grades for edema, furrows, and/or exudates) of the EoE Endoscopic Reference Score (EREFS). Inter- and intrarater reliability of these instruments (expressed as intraclass correlation coefficients [ICC]) were evaluated using paired endoscopy video assessments of 2 blinded central readers in patients before and after 8 weeks of proton pump inhibitors, swallowed topical corticosteroids, or dietary elimination. Responsiveness was measured using the standardized effect size (SES). RESULTS: The appropriateness of 41 statements relevant to EoE endoscopic activity (endoscopic items, item definitions and grading, and other considerations relevant for endoscopy) was considered. The original and expanded EREFS demonstrated moderate-to-substantial inter-rater reliability (ICCs of .472-.736 and .469-.763, respectively) and moderate-to-almost perfect intrarater reliability (ICCs of .580-.828 and .581-.828, respectively). Strictures were least reliably assessed (ICC, .072-.385). The original EREFS was highly responsive (SES, 1.126 [95% confidence interval {CI}, .757-1.534]), although both expanded versions of EREFS, scored based on worst affected area, were numerically most responsive to treatment (expanded furrows: SES, 1.229 [95% CI, .858-1.643]; all items expanded: SES, 1.252 [95% CI, .880-1.667]). The EREFS and its modifications were not more reliably scored by segment and also not more responsive when proximal and distal EREFSs were summed. CONCLUSIONS: EREFS and its modifications were reliable and responsive, and the original or expanded versions of the EREFS may be preferred in RCTs. Disease activity scored based on the worst affected area optimizes reliability and responsiveness.

A Novel Model of Tobacco Smoke-Mediated Aortic Injury.

OBJECTIVE: Tobacco smoke exposure is a major risk factor for aortic aneurysm development. However, the initial aortic response to tobacco smoke, preceding aneurysm formation, is not well understood. We sought to create a model to determine the effect of solubilized tobacco smoke (STS) on the thoracic and abdominal aorta of mice as well as on cultured human aortic smooth muscle cells (HASMCs). METHODS: Tobacco smoke was solubilized and delivered to mice via implanted osmotic minipumps. Twenty male C57BL/6 mice received STS or vehicle infusion. The descending thoracic, suprarenal abdominal, and infrarenal abdominal segments of the aorta were assessed for elastic lamellar damage, smooth muscle cell phenotype, and infiltration of inflammatory cells. Cultured HASMCs grown in media containing STS were compared to cells grown in standard media in order to verify our in vivo findings. RESULTS: Tobacco smoke solution caused significantly more breaks in the elastic lamellae of the thoracic and abdominal aorta compared to control solution (P< .0001) without inciting an inflammatory infiltrate. Elastin breaks occurred more frequently in the abdominal aorta than the thoracic aorta (P < .01). Exposure to STS-induced aortic microdissections and downregulation of α-smooth muscle actin (α-SMA) by vascular smooth muscle cells (VSMCs). Treatment of cultured HASMCs with STS confirmed the decrease in α-SMA expression. CONCLUSION: Delivery of STS via osmotic minipumps appears to be a promising model for investigating the early aortic response to tobacco smoke exposure. The initial effect of tobacco smoke exposure on the aorta is elastic lamellar damage and downregulation of (α-SMA) expression by VSMCs. Elastic lamellar damage occurs more frequently in the abdominal aorta than the thoracic aorta and does not seem to be mediated by the presence of macrophages or other inflammatory cells.

A Single-Food Milk Elimination Diet Is Effective for Treatment of Eosinophilic Esophagitis in Children.

BACKGROUND & AIMS: Cow's milk protein (CMP) is the most common trigger of inflammation in children and adults with eosinophilic esophagitis (EoE). We sought to assess the clinical, endoscopic, and histologic efficacy of dietary elimination of all CMP-containing foods in EoE. METHODS: We performed a prospective observational study in children with EoE treated with the 1-food elimination diet (1FED), excluding all CMP. Children and their caretakers were educated by a registered dietitian regarding dietary elimination of all CMP-containing foods, with substitutions to meet nutritional needs for optimal growth and development, and daily meal planning. Upper endoscopy with biopsies was performed after 8 to 12 weeks of treatment. The primary end point was histologic remission, defined as fewer than 15 eosinophils per high-power field. Secondary end points were symptomatic, endoscopic, and quality-of-life (QOL) improvements. RESULTS: Forty-one children (76% male; ages, 9 ± 4 years; 88% white) underwent 1FED education and post-treatment endoscopy with biopsies. Histologic remission occurred in 21 (51%) children, with a decrease in peak eosinophils per high-power field from a median of 50 (interquartile range, 35-70) to a median of 1 (interquartile range, 0-6; P < .0001). Endoscopic abnormalities improved in 24 (59%) patients, while symptoms improved in 25 (61%). Improved symptoms included chest pain, dysphagia, and pocketing/spitting out food. Parents perceived worse QOL, while children perceived improved QOL with the 1FED. CONCLUSIONS: One-food elimination of CMP-containing foods from the diet induced histologic remission in more than 50% of children with EoE and led to significant improvement in symptoms and endoscopic abnormalities. The ease of implementation and adherence supports the 1FED as first-line dietary treatment.

Development of a core outcome set for therapeutic studies in eosinophilic esophagitis (COREOS).

BACKGROUND: End points used to determine treatment efficacy in eosinophilic esophagitis (EoE) have evolved over time. With multiple novel therapies in development for EoE, harmonization of outcomes measures will facilitate evidence synthesis and appraisal when comparing different treatments. OBJECTIVE: We sought to develop a core outcome set (COS) for controlled and observational studies of pharmacologic and diet interventions in adult and pediatric patients with EoE. METHODS: Candidate outcomes were generated from systematic literature reviews and patient engagement interviews and surveys. Consensus was established using an iterative Delphi process, with items voted on using a 9-point Likert scale and with feedback from other participants to allow score refinement. Consensus meetings were held to ratify the outcome domains of importance and the core outcome measures. Stakeholders were recruited internationally and included adult and pediatric gastroenterologists, allergists, dieticians, pathologists, psychologists, researchers, and methodologists. RESULTS: The COS consists of 4 outcome domains for controlled and observational studies: histopathology, endoscopy, patient-reported symptoms, and EoE-specific quality of life. A total of 69 stakeholders (response rate 95.8%) prioritized 42 outcomes in a 2-round Delphi process, and the final ratification meeting generated consensus on 33 outcome measures. These included measurement of the peak eosinophil count, Eosinophilic Esophagitis Histology Scoring System, Eosinophilic Esophagitis Endoscopic Reference Score, and patient-reported measures of dysphagia and quality of life. CONCLUSIONS: This interdisciplinary collaboration involving global stakeholders has produced a COS that can be applied to adult and pediatric studies of pharmacologic and diet therapies for EoE and will facilitate meaningful treatment comparisons and improve the quality of data synthesis.

Defining the Patchy Landscape of Esophageal Eosinophilia in Children With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a patchy disease of the esophagus with significant variability in intraepithelial eosinophilia. Three biopsies each from distal and proximal esophagus are recommended for identification of active EoE. Recent work suggests 3 biopsy sites are more optimal. We sought to evaluate 2-site vs 3-site esophageal biopsy combinations for utility to identify active EoE. METHODS: We prospectively obtained 3-site esophageal biopsies based on rigorous endoscopic measurements of the proximal, mid, and distal esophagus and gastroesophageal junction. Biopsies were reviewed by a pathologist, and those with at least 15 eosinophils per high-power field were considered active EoE. The sensitivity of one or more sites to identify active EoE was determined, and endoscopic measurements were correlated to height and age. RESULTS: Five hundred ninety-six endoscopies were performed in 217 patients; of these, 304 endoscopies in 167 patients had active EoE. Among the initial esophagogastroduodenoscopies with active EoE, distal biopsies had greater than 80% sensitivity, whereas mid and proximal biopsies had sensitivity of 65% and 62%, respectively, and distal + proximal biopsies had the highest diagnostic sensitivity for a 2-site combination. Among the 304 endoscopies with active EoE, 9 had focal eosinophilia restricted to the mid esophagus, and 8 were restricted to the proximal esophagus. For patients with multiple endoscopies with active EoE, nearly one fourth had reduced sites with eosinophilia at the second time point. Endoscopic measurements strongly correlated with height and age. CONCLUSIONS: This study supports endoscopic measurement-guided 3-site biopsies for optimal disease assessment of active EoE in children.

Development of a flexure-based nano-actuator for high-frequency high-resolution directional sensing with atomic force microscopy.

Scanning probe microscopies typically rely on the high-precision positioning of a nanoscale probe in order to gain local information about the properties of a sample. At a given location, the probe is used to interrogate a minute region of the sample, often relying on dynamical sensing for improved accuracy. This is the case for most force-based measurements in atomic force microscopy (AFM) where sensing occurs with a tip oscillating vertically, typically in the kHz to MHz frequency regime. While this approach is ideal for many applications, restricting dynamical sensing to only one direction (vertical) can become a serious limitation when aiming to quantify the properties of inherently three-dimensional systems, such as a liquid near a wall. Here, we present the design, fabrication, and calibration of a miniature high-speed scanner able to apply controlled fast and directional in-plane vibrations with sub-nanometer precision. The scanner has a resonance frequency of ∼35 kHz and is used in conjunction with a traditional AFM to augment the measurement capabilities. We illustrate its capabilities at a solid-liquid interface where we use it to quantify the preferred lateral flow direction of the liquid around every sample location. The AFM can simultaneously acquire high-resolution images of the interface, which can be superimposed with the directional measurements. Examples of sub-nanometer measurements conducted with the new scanner are also presented.