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Objective: Visceral branch artery dissection (VBAD) is uncommon and may occur with or without an associated aortic dissection (AD). We hypothesized that isolated VBAD would have a more benign clinical course than those with concurrent AD and compared survival outcomes stratified based on aortic involvement., Methods: VBAD over a 5-year period were identified using International Classification of Diseases codes. Data related to patient demographics, comorbid conditions, clinical presentation, management (including procedural interventions), and survival were obtained from medical records. Anatomic imaging studies were reviewed to characterize anatomy, including the presence or absence of concurrent AD. Overall survival and intervention-free survival were evaluated using Kaplan-Meier and Cox proportional hazards models., Results: A total of 299 VBAD were identified, 174 of which were isolated VBAD and 125 were associated with concurrent AD. Seventy-one percent of patients were men, 77% were White, and 85% were non-Hispanic. The mean age was 61.1 ± 14.4 years. The mean follow-up was 53.2 ± 50.0 months. The estimated overall survival was 88.2% and the estimated overall intervention-free survival was 55.6% at 12 months. Isolated VBAD had better overall survival than those with concurrent AD (69.2% vs 32.4%; P < .001). Concurrent AD was also associated with inferior intervention-free survival (57.5% vs 7.3%; P < .001). Acute presentation was associated with decreased intervention-free survival (86.1% vs 13.4%; P < .001). Acute presentation was also associated with decreased overall survival in patients with isolated VBAD (60.8% vs 80.0% at 180 months; P < .001) and inferior intervention-free survival (48.4% vs 69.5% at 180 months; P < .001) in the subgroup of patients with isolated VBAD. Multivariable Cox models identified that age (hazard ratio [HR]: 1.05, standard deviation [SD]: 0.02; P = .001) was associated with inferior survival and renal dissections (HR: 3.08, SD: 0.99; P = .001) or mesenteric and renal dissections (HR: 3.39, SD: 1.44; P = .004) were associated with inferior intervention-free survival., Conclusions: Isolated VBAD has superior overall and intervention-free survival to those associated with concurrent AD. The absence vs presence of aortic involvement is useful for risk stratification and may support tailored approaches to the frequency of imaging surveillance., Competing Interests: Disclosures None., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation., Methods: This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility., Findings: Between May 10, 2020, and Jan 13, 2021, 202 patients were enrolled in the study and randomly assigned to ravulizumab plus BSC or BSC. 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group). The ravulizumab plus BSC group comprised 96 (71%) men and 39 (29%) women with a mean age of 63·2 years (SD 13·23); the BSC group comprised 43 (65%) men and 23 (35%) women with a mean age of 63·5 years (12·40). Most patients (113 [84%] of 135 in the ravulizumab plus BSC group and 53 [80%] of 66 in the BSC group) were on invasive mechanical ventilation at baseline. Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC (Mantel-Haenszel analysis: risk difference -0·0205; 95% CI -0·1703 to 0·1293; one-sided p=0·61). In the safety population, 113 (89%) of 127 patients in the ravulizumab plus BSC group and 56 (84%) of 67 in the BSC group had a treatment-emergent adverse event. Of these events, infections and infestations (73 [57%] vs 24 [36%] patients) and vascular disorders (39 [31%] vs 12 [18%]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group. Five patients had serious adverse events considered to be related to ravulizumab. These events were bacteraemia, thrombocytopenia, oesophageal haemorrhage, cryptococcal pneumonia, and pyrexia (in one patient each)., Interpretation: Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients., Funding: Alexion, AstraZeneca Rare Disease., Competing Interests: Declaration of interests DA received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease and is co-inventor on pending patent WO2021211940A1. SJP has received funding for this study, grants or contracts, consulting fees, and honoraria and travel expenses for lectures, advisory boards, and conference attendance from Alexion, AstraZeneca Rare Disease (all paid to institution). SJP also receives royalties from a patent (US-9891219-B). HSK received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; grants or contracts (paid to institution) from the US National Institutes of Health, the US Department of Defense, the Children's Discovery Institute, and the Longer Life Foundation; consulting fees (personal) from Indemic and Guidepoint; honoraria (personal) from the University of Pittsburgh; support for attending meetings or travel (personal) from the American Thoracic Society; and has participated in an unpaid capacity in advocacy groups, boards, or committees for the American Thoracic Society and the American Society of Clinical Investigation. HSK also has stock in Moderna. BWP received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; consulting fees (personal) from Philips; and royalties and stock options from Ambient Clinical Analytics, of which he is a member of the board. BWP is also co-inventor on a patent (held by Ambient Clinical Analytics) for the presentation of critical clinical information. MRK received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease. JLS received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease. CAP received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; and is Chair of the Senhwa Biosciences data safety monitoring board for a COVID-19 clinical trial. PC received funding (paid to institution) for this study, honoraria (personal) for teaching lectures and participation in advisory boards, and payment for expert testimony (personal) from Alexion, AstraZeneca Rare Disease. TF received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease. DD and SK are employees of Alexion, AstraZeneca Rare Disease, own stock in AstraZeneca, and are co-inventors on pending patent WO2021211940A1. KS and SM are employees of Alexion, AstraZeneca Rare Disease and own stock in AstraZeneca. AK received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; consulting fees (personal) from Regeneron, Samsung, Silence Therapeutics, and Novo Nordisk; and honoraria or support for attending meetings or travel (personal) from Alexion, AstraZeneca Rare Disease, Amgen, Sobi, Celgene (a subsidiary of BMS), Biocryst, Pfizer, Roche, Novartis, and Janssen., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Patient-reported outcomes (PRO) have been increasingly emphasized for peripheral artery disease (PAD). Patient-defined treatment goals and expectations, however, are poorly understood and might not be achievable or aligned with guidelines or clinical outcomes. We evaluated the patient-reported treatment goals among patients with claudication and the associations between patient characteristics, goals, and PAD-specific PRO scores., Methods: Patients with a diagnosis of claudication were prospectively recruited. Patient-defined treatment goals and outcomes related to walking distance, duration, and speed were quantified using multiple-choice survey items. Free-text items were used to identify activities other than walking distance, duration, or speed associated with symptoms and treatment goals. The peripheral artery disease quality of life and walking impairment questionnaire instruments were included as PRO. The treatment goal categories were compared with the PRO percentile scores using 95% confidence intervals (CIs), categorical tests, and logistic regression models. Associations between the patient characteristics and PRO were evaluated using linear and ordinal logistic regression models., Results: A total of 150 patients meeting the inclusion criteria were included in the present study. Of these 150 patients, 144 (96%) viewed the entire survey. Their mean age was 70.0 ± 11.3 years, and 32.9% were women. Most of the respondents had self-reported their race as White (n = 135), followed by Black (n = 3), Asian (n = 2), Native American (n = 2), and other/unknown (n = 2). Two participants self-reported Hispanic ethnicity. The primary treatment goals were an increased walking distance or duration without stopping (62.0%), the ability to perform a specific activity or task (23.0%), an increased walking speed (8.0%), or other/none of the above (7.0%). The specific activities associated with symptoms or goals included outdoor recreation (38.5%), labor-related tasks (30.7%), sports (26.9%), climbing stairs (23.1%), uphill walking (19.2%), and shopping (6%). Among the patients choosing an increased walking distance and duration as the primary goals, 64% had indicated that a distance of ≥0.5 mile (2640 ft) and 59% had indicated a duration of ≥30 minutes would be a minimum increase consistent with meaningful improvement. Increasing age was associated with lower odds of a distance improvement goal of ≥0.5 mile (odds ratio [OR], 0.68 per 5 years; 95% CI, 0.51-0.92; P = .012) or duration improvement goal of ≥30 minutes (OR, 0.76 per 5 years; 95% CI, 0.58-0.99; P = .047). Patient characteristics associated with PAD Quality of Life percentile scores included age, ankle brachial index, and gender. Ankle brachial index was the only patient characteristic associated with the walking impairment questionnaire percentile scores., Conclusions: Patients define treatment goals according to their desired activities and expectations, which may influence their goals and perceived outcomes. Patients' expectations of minimum increases in walking distance and duration consistent with meaningful improvement exceeded reported minimum important difference criteria for many patients and would not be captured using common clinic-based walking tests. Patient age was associated with both treatment goals and PRO scores, and the related floor and ceiling effects could influence sensitivity to PRO changes for younger and older patients, respectively. Heterogeneity in treatment goals supports consideration of tailored decision-making and outcomes informed by patient characteristics and perspectives., (Copyright © 2022 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Introduction: This pooled analysis of nine phase I and II trastuzumab deruxtecan (T-DXd) monotherapy studies described drug-related interstitial lung disease (ILD)/pneumonitis in patients treated with T-DXd., Methods: Patients who received T-DXd across nine studies were included. Investigator-assessed ILD/pneumonitis events were retrospectively reviewed by an independent adjudication committee; events adjudicated as drug-related ILD/pneumonitis are summarized., Results: The analysis included 1150 patients (breast cancer, 44.3%; gastric cancer, 25.6%; lung cancer, 17.7%; colorectal cancer, 9.3%; other cancer, 3.0%). Median treatment duration was 5.8 (range, 0.7-56.3) months, with a median of 4 (range, 1-27) prior lines of therapy. The overall incidence of adjudicated drug-related ILD/pneumonitis was 15.4% (grade 5, 2.2%). Most patients with ILD/pneumonitis experienced low-grade events (grade 1 or 2, 77.4%); 87.0% had their first event within 12 months [median, 5.4 (range, <0.1-46.8) months] of their first dose of T-DXd. Based on data review, adjudicated ILD/pneumonitis onset occurred earlier than identified by investigators for 53.2% of events [median difference in onset date, 43 (range, 1-499) days]. Stepwise Cox regression identified several baseline factors potentially associated with increased risk of adjudicated drug-related ILD/pneumonitis: age <65 years, enrollment in Japan, T-DXd dose >6.4 mg/kg, oxygen saturation <95%, moderate/severe renal impairment, presence of lung comorbidities, and time since initial diagnosis >4 years., Conclusions: In this pooled analysis of heavily treated patients, the incidence of ILD/pneumonitis was 15.4%, with most being low grade and occurring in the first 12 months of treatment. The benefit-risk of T-DXd treatment is positive; however, some patients may be at increased risk of developing ILD/pneumonitis, and further investigation is needed to confirm ILD/pneumonitis risk factors. Close monitoring and proactive management of ILD/pneumonitis are warranted for all., Competing Interests: Disclosure All authors received nonfinancial support (assistance with manuscript preparation) from ArticulateScience, LLC, funded by AstraZeneca. Additional disclosures are as follows: CAP reports personal fees from Daiichi Sankyo, AstraZeneca, and Voluntis, outside of the submitted work. SM reports consulting or advisory roles for Daiichi Sankyo, MacroGenics, and AstraZeneca; speakers bureau involvement with Genentech, Daiichi Sankyo, AstraZeneca, and Seagen; travel fees from Genentech and Daiichi Sankyo; honoraria from Novartis; and research funding from Roche/Genentech, Novartis, Seagen, Synta, and Daiichi Sankyo. HI reports grants from Daiichi Sankyo, Novartis, AstraZeneca, Pfizer, Eli Lilly Japan, Chugai, Eisai, Kyowa Kirin, Merck Sharp & Dohme (MSD), GSK, Nippon Kayaku, and Bayer; and personal fees from Daiichi Sankyo, Novartis, AstraZeneca, Pfizer, Eli Lilly Japan, Chugai, Eisai, and Kyowa Kirin. ST reports grants and personal fees from Daiichi Sankyo, Eisai, Novartis, Taiho, MSD, Chugai, Bayer, and AstraZeneca. EFS reports consulting or advisory roles for Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol Myers Squibb, Merck KGaA, MSD Oncology, Takeda, and Bayer; and research funding from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca, and Bristol Myers Squibb. SS reports personal fees from Amgen, Roche/Genentech, Bayer, Bristol Myers Squibb, Daiichi Sankyo, Merck KGaA, Seagen, Checkmab, and AstraZeneca. DYC reports personal fees from Novartis, Pfizer, Eli Lilly, Roche, AstraZeneca, Sanofi, Amgen, and Daiichi Sankyo; and travel fees from Pfizer, Daiichi Sankyo, and Eisai. EM and NS are employees of AstraZeneca and may own stock or stock options in that company. AQ, JS, and CT are employees of Daiichi Sankyo and may own stock or stock options in that company. DRC reports personal fees from Daiichi Sankyo., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: To report the clinical and radiological outcomes after medial femoral trochlear (MFT) osteochondral graft for the salvage of proximal scaphoid fractures with a minimum 2-year follow-up., Methods: A retrospective review was performed of patients with comminuted fractures of the proximal scaphoid treated by excision of the proximal pole and replacement with free vascularized MFT osteochondral graft. Demographic data, objective and radiographic measurements, and patient-reported outcome measures of the upper limb and knee were collected. Pain was assessed by completion of a visual analog scale (VAS)., Results: Between February 2014 and May 2015, 12 MFT osteochondral grafts were performed. Eight patients were available for follow-up at a mean of 34 months (range, 28-39 months). The mean range of wrist flexion was 31° (range, 15°-60°), extension was 34° (range, 5°-60°), radial deviation was 9° (range, 0°-20°), ulnar deviation was 28° (range, 10°-45°) and grip strength was 42 kg (range, 25-53 kg). The median wrist pain, as measured by VAS, was 0.7 (mean, 1.3; range, 0-6). The average follow-up scapholunate, radiolunate, and radioscaphoid angles were 58.9° (range, 44°-93°), 12.9° (range, 0°-30°), and 46.0° (range, 35°-63°), respectively. The mean Disabilities of the Arm, Shoulder, and Hand (DASH) score was 13.9 (range, 3-43) and Patient Rated Wrist Evaluation (PRWE) score was 22.4 (range, 2-68). The mean postoperative Oxford Knee Score was 42 (range, 14-48). One patient suffered notable knee pain at 37-month follow-up. One patient suffered notable pain on the radial side of the wrist and underwent scaphoid excision and 4-corner arthrodesis., Conclusions: Replacement of the fragmented proximal scaphoid by MFT graft is an alternative to other salvage options and most patients can expect pain relief and acceptable wrist motion. These results need to be balanced against the potential for donor-site morbidity., Type of Study/level of Evidence: Therapeutic V., (Copyright © 2021 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

The term interstitial lung abnormalities refers to specific CT findings that are potentially compatible with interstitial lung disease in patients without clinical suspicion of the disease. Interstitial lung abnormalities are increasingly recognised as a common feature on CT of the lung in older individuals, occurring in 4-9% of smokers and 2-7% of non-smokers. Identification of interstitial lung abnormalities will increase with implementation of lung cancer screening, along with increased use of CT for other diagnostic purposes. These abnormalities are associated with radiological progression, increased mortality, and the risk of complications from medical interventions, such as chemotherapy and surgery. Management requires distinguishing interstitial lung abnormalities that represent clinically significant interstitial lung disease from those that are subclinical. In particular, it is important to identify the subpleural fibrotic subtype, which is more likely to progress and to be associated with mortality. This multidisciplinary Position Paper by the Fleischner Society addresses important issues regarding interstitial lung abnormalities, including standardisation of the definition and terminology; predisposing risk factors; clinical outcomes; options for initial evaluation, monitoring, and management; the role of quantitative evaluation; and future research needs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic., Methods: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario., Results: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non-small-cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non-small-cell lung cancer., Conclusions: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care., (Copyright © 2020 American College of Chest Physicians, published by Elsevier Inc; RSNA; and The American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Background: The risks from potential exposure to coronavirus disease 2019 (COVID-19), and resource reallocation that has occurred to combat the pandemic, have altered the balance of benefits and harms that informed current (pre-COVID-19) guideline recommendations for lung cancer screening and lung nodule evaluation. Consensus statements were developed to guide clinicians managing lung cancer screening programs and patients with lung nodules during the COVID-19 pandemic., Methods: An expert panel of 24 members, including pulmonologists (n = 17), thoracic radiologists (n = 5), and thoracic surgeons (n = 2), was formed. The panel was provided with an overview of current evidence, summarized by recent guidelines related to lung cancer screening and lung nodule evaluation. The panel was convened by video teleconference to discuss and then vote on statements related to 12 common clinical scenarios. A predefined threshold of 70% of panel members voting agree or strongly agree was used to determine if there was a consensus for each statement. Items that may influence decisions were listed as notes to be considered for each scenario., Results: Twelve statements related to baseline and annual lung cancer screening (n = 2), surveillance of a previously detected lung nodule (n = 5), evaluation of intermediate and high-risk lung nodules (n = 4), and management of clinical stage I non-small cell lung cancer (n = 1) were developed and modified. All 12 statements were confirmed as consensus statements according to the voting results. The consensus statements provide guidance about situations in which it was believed to be appropriate to delay screening, defer surveillance imaging of lung nodules, and minimize nonurgent interventions during the evaluation of lung nodules and stage I non-small cell lung cancer., Conclusions: There was consensus that during the COVID-19 pandemic, it is appropriate to defer enrollment in lung cancer screening and modify the evaluation of lung nodules due to the added risks from potential exposure and the need for resource reallocation. There are multiple local, regional, and patient-related factors that should be considered when applying these statements to individual patient care., (Copyright © 2020 The American College of Chest Physicians, published by Elsevier Inc; RSNA; and The American College of Radiology, Published by Elsevier Inc. Published by Elsevier Inc. All rights reserved.)

Dramatic progress in targeted therapy and immunotherapy has been changing clinical practices in lung cancer. With the accumulation of clinical practice, it has become clear that pre-existing interstitial pneumonia (IP) could be a risk factor for drug-induced lung injury, which has enhanced awareness regarding the difficulty in treating lung cancer with comorbid IP. Unfortunately, there is only low-grade evidence in the field of lung cancer with comorbid IP, because almost all clinical trials exclude such patients. There have been very few specialized clinical trials for patients with lung cancer and underlying IPs thus far. Therefore, it is necessary to treat such cases empirically or to give up on the treatment itself. Considering these circumstances, establishing how to treat lung cancer with comorbid IP is an urgent issue. This paper is a summary of the official statement reported by the Diffuse Lung Disease/Thoracic Oncology Assembly and the Japanese Respiratory Society (JRS) in 2017, which attempts to approach lung cancer with comorbid IP systematically., (Copyright © 2019 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

Correct expression of the mitochondrially-encoded genes is critical for the production of the components of the oxidative phosphorylation machinery. Post-transcriptional modifications of mitochondrial transcripts have been emerging as an important regulatory feature of mitochondrial gene expression. Here we review the current knowledge on how the mammalian mitochondrial epitranscriptome participates in regulating mitochondrial homeostasis. In particular, we focus on the latest breakthroughs made towards understanding the roles of the modified nucleotides in mitochondrially-encoded ribosomal and transfer RNAs, the enzymes responsible for introducing these modifications and on recent transcriptome-wide studies reporting modifications to mitochondrial messenger RNAs. This article is part of a Special Issue entitled: mRNA modifications in gene expression control edited by Dr. Matthias Soller and Dr. Rupert Fray., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Trypsin modulating oostatic factor, a decapaptide isolated from the ovaries of A. aegypti, is the physiological factor that terminates the trypsin biosynthesis after the blood meal. Earlier results obtained from feeding mosquito larvae and injecting female mosquitoes with TMOF show that trypsin biosynthesis and egg development are inhibited, indicating that TMOF traverses the gut epithelial cells and modulates trypsin biosynthesis, making it a potential larvacidal peptide hormone. Therefore, TMOF and TMOF green fluorescent protein (GFP) fusion protein with a trypsin cleavage site, allowing TMOF release in the larval gut, were expressed in S. cerevisiae cells that were transformed using homologous recombination at ura3-52 with an engineered plasmid (pYDB2) carrying tmfA and gfp-tmfA and a strong galactose promoter (P GAL 1 ). Southern blot analyses showed that each cell incorporated a single tmfA or gfp-tmfA. Western blot analyses of cells that were fermented up to 48h showed that the engineered S. cerevisiae cells synthesized both TMOF and GFP-TMOF and heat treatment did not affect the recombinant proteins. Engineered S. cerevisiae (3×10 8 cells) that were fermented for 4h produced (2.1±0.2μg±S.E.M) of TMOF. Feeding the engineered cells producing TMOF and GFP-TMOF to larval mosquito caused high mortalities (66±12% and 83±8%, respectively). S. cerevisiae cells transfected with pYEX-BX carrying gfp-tmfA and (DPAR) 4 or transformed by homologous recombination of pYDB2-gfp-tmfA carrying a heat shock promoter (P HP ) were ineffective. Engineered heat treated yeast cells are consumed by mosquito larvae, and could be used to control mosquitoes., (Published by Elsevier Ltd.)

Background: The rates of resection of nonmalignant lung nodules suspected preoperatively to be lung cancer vary widely and are reported to be as high as 40%. We determined the impact of the frequent use of computed tomography (CT)-guided fine needle aspiration (FNA) on the resection rate of nonmalignant nodules and frequency of resections of benign disease among patients undergoing evaluation for lung cancer resection operation in an academic medical center., Methods: Eligible patients underwent CT-guided FNA, surgical resection, or both during the 12-month period between July 2013 and July 2014 for known or suspected first primary resectable stage I-III lung cancer. Patient data were extracted from the electronic medical records., Results: One hundred ninety-seven patients underwent surgical resection; among them the overall resection rate of nonmalignant lesions was 13.1% (26/197). For those with preoperative FNA, the rate was 7.9% (11/139), and for those with no biopsy, the rate was 25.9% (15/58) (p = 0.001). The sensitivity and specificity of FNA biopsy were 96% and 98%, respectively. The false-negative rate was 3.9% (5/128)., Conclusions: The resection rate of nonmalignant nodules was significantly lower for patients with preoperative CT-guided FNA biopsy than in those without. The diagnostic accuracy of FNA in these patients at moderate to high risk for lung cancer is higher than that of positron emission tomography, with a low rate of adverse events. These findings suggest that the frequent use of preoperative diagnostic confirmation by FNA results in a low rate of nonmalignant resection., (Copyright © 2017 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

This article proposes codes for the primary tumor categories of adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and a uniform way to measure tumor size in part-solid tumors for the eighth edition of the tumor, node, and metastasis classification of lung cancer. In 2011, new entities of AIS, MIA, and lepidic predominant adenocarcinoma were defined, and they were later incorporated into the 2015 World Health Organization classification of lung cancer. To fit these entities into the T component of the staging system, the Tis category is proposed for AIS, with Tis (AIS) specified if it is to be distinguished from squamous cell carcinoma in situ (SCIS), which is to be designated Tis (SCIS). We also propose that MIA be classified as T1mi. Furthermore, the use of the invasive size for T descriptor size follows a recommendation made in three editions of the Union for International Cancer Control tumor, node, and metastasis supplement since 2003. For tumor size, the greatest dimension should be reported both clinically and pathologically. In nonmucinous lung adenocarcinomas, the computed tomography (CT) findings of ground glass versus solid opacities tend to correspond respectively to lepidic versus invasive patterns seen pathologically. However, this correlation is not absolute; so when CT features suggest nonmucinous AIS, MIA, and lepidic predominant adenocarcinoma, the suspected diagnosis and clinical staging should be regarded as a preliminary assessment that is subject to revision after pathologic evaluation of resected specimens. The ability to predict invasive versus noninvasive size on the basis of solid versus ground glass components is not applicable to mucinous AIS, MIA, or invasive mucinous adenocarcinomas because they generally show solid nodules or consolidation on CT., (Copyright © 2016 International Association for the Study of Lung Cancer. All rights reserved.)

Background: Limited resection and stereotactic body radiotherapy (SBRT) have emerged as treatment options for older patients with early-stage non-small-cell lung cancer (NSCLC), who are not good candidates for lobectomy., Methods: We used the Surveillance, Epidemiology and End Results-Medicare registry to identify patients older than 65 years with stage I to II NSCLC and negative lymph nodes treated with SBRT versus limited resection. We fitted a propensity score model predicting the use of SBRT and compared adjusted overall survival of patients treated with SBRT versus limited resection. Secondary analyses stratified the sample by type of limited resection (wedge versus segmentectomy), age (≤75 versus >75 years), and tumor size (<3 versus ≥3 cm). We also compared rates of surgical complications and SBRT-related toxicity in the two groups., Results: We identified 2243 patients of which 362 (16%) patients received SBRT. SBRT-treated patients were older, had higher comorbidity scores, and had larger tumors (p < 0.001 for all comparisons). Adjusted analyses showed no differences in survival (hazard ratio [HR], 1.19; 95% confidence interval [CI], 0.97-1.47) among patients treated with SBRT versus limited resection. Although survival of patients who underwent SBRT versus wedge resection was not different (HR, 1.22; 95% CI, 0.98-1.52), SBRT was associated with worse outcomes when compared with segmentectomy (HR, 1.55; 95% CI, 1.18-2.03). Adverse events were most often respiratory and more frequent in the patients treated with limited resection (28% versus 14%, p < 0.001)., Conclusion: SBRT is better tolerated and associated with similar survival when compared with wedge resection but not with segmentectomy in older patients with node-negative NSCLC.

Lung cancer screening with a low-dose chest CT scan can result in more benefit than harm when performed in settings committed to developing and maintaining high-quality programs. This project aimed to identify the components of screening that should be a part of all lung cancer screening programs. To do so, committees with expertise in lung cancer screening were assembled by the Thoracic Oncology Network of the American College of Chest Physicians (CHEST) and the Thoracic Oncology Assembly of the American Thoracic Society (ATS). Lung cancer program components were derived from evidence-based reviews of lung cancer screening and supplemented by expert opinion. This statement was developed and modified based on iterative feedback of the committees. Nine essential components of a lung cancer screening program were identified. Within these components 21 Policy Statements were developed and translated into criteria that could be used to assess the qualification of a program as a screening facility. Two additional Policy Statements related to the need for multisociety governance of lung cancer screening were developed. High-quality lung cancer screening programs can be developed within the presented framework of nine essential program components outlined by our committees. The statement was developed, reviewed, and formally approved by the leadership of CHEST and the ATS. It was subsequently endorsed by the American Association of Throacic Surgery, American Cancer Society, and the American Society of Preventive Oncology.

Diaprepes abbreviatus is an important pest that causes extensive damage to citrus in the USA. Analysis of an expressed sequence tag (EST) library from the digestive tract of larvae and adult D. abbreviatus identified cathepsins as major putative digestive enzymes. One class, sharing amino acid sequence identity with cathepsin L's, was the most abundant in the EST dataset representing 14.4% and 3.6% of the total sequences in feeding larvae and adults, respectively. The predominant cathepsin (Da-CTSL1) among this class was further studied. Three dimensional modeling of the protein sequence showed that the mature Da-CTSL1 protein folds into an expected cathepsin L structure producing a substrate binding pocket with appropriate positioning of conserved amino acid residues. A full-length cDNA was obtained and the proCTSL1 encoding sequence was expressed in Rosetta™ Escherichia coli cells engineered to express tRNAs specific for eukaryotic codon usage. The Da-CTSL1 was expressed as a fusion protein with GST and His6 tags and purified in the presence of 1% Triton X-100 by Ni-NTA affinity and size exclusion chromatography. Recombinant mature Da-CTSL1 (23 KDa) exhibits optimal activity at pH 8, rather than at acidic pH that was shown of all previously characterized cathepsins L. Substrate specificity supports the hypothesis that Da-CTSL1 is a unique basic cathepsin L and protease inhibitor studies also suggest unique activity, unlike other characterized acidic cathepsin Ls. This paper describes for the first time a prokaryotic expression system for the production of a functional eukaryotic cathepsin L1 from larval gut of D. abbreviatus., (Published by Elsevier Ltd.)

RNA interference (RNAi) is a powerful approach for elucidating gene functions in a variety of organisms, including mosquitoes and many other insects. Little has been done, however, to harness this approach in order to control adult and larval mosquitoes. Juvenile hormone (JH) plays a pivotal role in the control of reproduction in adults and metamorphism in larval mosquitoes. This report describes an approach to control Aedes aegypti using RNAi against JH acid methyl transferase (AeaJHAMT), the ultimate enzyme in the biosynthetic pathway of JH III that converts JH acid III (JHA III) into JH III. In female A. aegypti that were injected or fed jmtA dsRNA targeting the AeaJHAMT gene (jmtA) transcript, egg development was inhibited in 50% of the treated females. In mosquito larvae that were fed transgenic Pichia pastoris cells expressing long hair pin (LHP) RNA, adult eclosion was delayed by 3 weeks causing high mortality. Northern blot analyses and qPCR studies show that jmtA dsRNA causes inhibition of jmtA transcript in adults and larvae, which is consistent with the observed inhibition of egg maturation and larval development. Taken together, these results suggest that jmtA LHP RNA expressed in heat inactivated genetically modified P. pastoris cells could be used to control mosquito populations in the marsh., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

We report on the cloning, sequencing, characterization, 3D modeling and docking of Aedes aegypti juvenile hormone acid methyl transferase (AeaJHAMT), the enzyme that converts juvenile hormone acid (JHA) into juvenile hormone (JH). Purified recombinant AeaJHAMT was extensively characterized for enzymatic activity and the Michaelis Menten kinetic parameters Km, Vmax, k(cat) (turn over number) and k(cat)/Km (catalytic efficiency) using JHA and its analogues as substrates. AeaJHAMT methylates JHA III 5-fold faster than farnesoic acid (FA). Significant differences in lower methyl transferase (MT) activities towards the cis/trans/trans, cis/trans/cis and the trans/cis/cis isomers of JHA I (1.32, 4.71 and 156-fold, respectively) indicate that substrate chirality is important for proper alignment at the catalytic cavity and for efficient methyl transfer by S-adenosyl methionine (SAM). Our 3D model shows a potential binding site below the main catalytic cavity for JHA analogues causing conformational change and steric hindrance in the transfer of the methyl group to JHA III. These, in silico, observations were corroborated by, in vitro, studies showing that several JHA analogues are potent inhibitors of AeaJHAMT. In vitro, and in vivo studies using [(3)H-methyl]SAM show that the enzyme is present and active throughout the adult life stage of A. aegypti. Tissue specific expressions of the JHAMT gene of A. aegypti (jmtA) transcript during the life cycle of A. aegypti show that AeaJHAMT is a constitutive enzyme and jmtA transcript is expressed in the corpora allata (CA), and the ovary before and after the blood meal. These results indicate that JH III can be synthesized from JHA III by the mosquito ovary, suggesting that ovarian JH III may play an important physiological role in ovarian development and reproduction. Incubating AeaJHAMT with highly pure synthetic substrates indicates that JHA III is the enzyme's preferred substrate, suggesting that AeaJHAMT is the ultimate enzyme in the biosynthetic pathway of JH III., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics.

Surface runoff water is an important non-point source of fecal pollution to downstream water; however, there is a lack of systematic studies on the microbial quality of surface runoff water from watersheds with mixed land uses. In this study water samples from 12 surface runoff holding water bodies (SRW), which collected runoff from various patterns of land use within the St. Lucie watershed along the southeastern coastline of Florida, were collected monthly for 22 months. The concentration of fecal indicator bacteria (FIB) and frequency of detection of Salmonella and host specific markers (HF183, CF128, CF193, and HS-esp) were determined, and their associations with land use, rainfall, and water physico-chemical parameters were investigated. Higher FIB concentrations were observed from urban land and cattle ranch sites. Within the same primary land use pattern, different sub-patterns did not have the same level of FIB: golf communities contributed less to fecal pollution than residential areas, and plant nursery sites contained relative higher FIB concentrations than other agricultural sites. Salmonella, CF128, and CF193 markers were more frequently detected from the cattle ranch sites. In contrast the frequency of detecting human specific markers (HF183 and HS-esp) was much higher in residential sites. Rainfall positively affected the concentration of FIB and occurrence of Salmonella, possibly by providing more inputs or mobilizing the sources from sediments. Water temperature, dissolved organic carbon (DOC), and nutrient levels were positively correlated with FIB concentrations and occurrence in SRW, possibly by promoting their growth and survival. This study indicated the need for site specific mitigation strategies to improve SRW and downstream water quality., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Minority patients in the United States present with later stages of lung cancer and have poorer outcomes. Cultural factors, such as beliefs regarding lung cancer and discrimination experiences, may underlie this disparity., Methods: Patients with a new diagnosis of lung cancer were recruited from four medical centers in New York City. A survey, using validated items, was conducted on the minority (black and Hispanic) and nonminority patients about their beliefs regarding lung cancer, fatalism, and medical mistrust. Univariate and logistic regression analyses were used to compare beliefs among minorities and nonminorities and to assess the association of these factors with late-stage (III and IV) presentation., Results: Of the 357 lung cancer patients, 40% were black or Hispanic. Minorities were more likely to be diagnosed with advanced-stage lung cancer (53% versus 38%, p = 0.01). Although beliefs about lung cancer etiology, symptoms, and treatment were similar between groups (p > 0.05), fatalistic views and medical mistrust were more common among minorities and among late-stage lung cancer patients (p < 0.05, for all comparisons). Adjusting for age, sex, education, and insurance, minorities had increased odds of advanced-stage lung cancer (odds ratio: 1.79; 95% confidence interval, 1.04-3.08). After controlling for fatalism and medical mistrust, the association between minority status and advanced stage at diagnosis was attenuated and no longer statistically significant (odds ratio: 1.56; 95% confidence interval, 0.84-2.87)., Conclusions: Fatalism and medical mistrust are more common among minorities and may partially explain the disparities in cancer stage at diagnosis. Addressing these factors may contribute to reducing disparities in lung cancer diagnosis and outcomes.

Background: Disparities in lung cancer treatment and palliative care are well documented. However,the mechanisms underlying these disparities are not fully understood. In this study, we evaluated racial and ethnic differences in beliefs and attitudes about lung cancer treatment and palliative care among patients receiving a new diagnosis of lung cancer., Methods: Patients were recruited from four medical centers in New York City and surveyed about their beliefs regarding lung cancer care, including disease-directed treatments, palliative and end-of-life care, and fatalistic and spiritual beliefs. We used univariate and multiple regression analyses to compare the distribution of beliefs among minority (black and Hispanic) and nonminority patients., Results: Of the 335 patients, 21% were black, 20% were Hispanic, and 59% were nonminority. Beliefs about chemotherapy and radiotherapy were similar across the three groups ( P > .05),whereas black patients were more likely to believe that surgery might cause lung cancer to spread( P =.008). Fatalistic beliefs potentially affecting cancer treatment were more common among both minority groups ( P ≤ .02). No signifi cant differences were found in attitudes toward clinician communication about cancer prognosis ( P > .05). However, both blacks and Hispanics were more likely to have misconceptions about advance directives and hospice care ( P ≤ .02)., Conclusions: Similarities and differences in beliefs about disease-directed treatment were observed between minority and nonminority patients with lung cancer. Minority patients hold more fatalistic views about the disease and misperceptions about advance care planning and hospice care. Further research is needed to assess the impact of these beliefs on decisions about lung cancer care and patient outcomes.

Background: Integration of palliative care with standard oncologic care improves quality of life and survival of lung cancer patients. We surveyed physicians to identify factors influencing their decisions for referral to palliative care., Methods: We provided a self-administered questionnaire to physicians caring for lung cancer patients at five medical centers. The questionnaire asked about practices and views with respect to palliative care referral. We used multiple regression analysis to identify predictors of low referral rates (<25%)., Results: Of 155 physicians who returned survey responses, 75 (48%) reported referring <25% of patients for palliative care consultation. Multivariate analysis, controlling for provider characteristics, found that low referral rates were associated with physicians' concerns that palliative care referral would alarm patients and families [odds ratio (OR) 0.45, 95% confidence interval (CI) 0.21-0.98], while the belief that palliative care specialists have more time to discuss complex issues (OR 3.07, 95% CI 1.56-6.02) was associated with higher rates of referral., Conclusions: Although palliative care consultation is increasingly available and recommended throughout the trajectory of lung cancer, our data indicate it is underutilized. Understanding factors influencing decisions to refer can be used to improve integration of palliative care as part of lung cancer management.

Inequality between and within populations has origins in adverse early experiences. Developmental neuroscience shows how early biological and psychosocial experiences affect brain development. We previously identified inadequate cognitive stimulation, stunting, iodine deficiency, and iron-deficiency anaemia as key risks that prevent millions of young children from attaining their developmental potential. Recent research emphasises the importance of these risks, strengthens the evidence for other risk factors including intrauterine growth restriction, malaria, lead exposure, HIV infection, maternal depression, institutionalisation, and exposure to societal violence, and identifies protective factors such as breastfeeding and maternal education. Evidence on risks resulting from prenatal maternal nutrition, maternal stress, and families affected with HIV is emerging. Interventions are urgently needed to reduce children's risk exposure and to promote development in affected children. Our goal is to provide information to help the setting of priorities for early child development programmes and policies to benefit the world's poorest children and reduce persistent inequalities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Introduction: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies., Methods: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach., Results: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with ≤ 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life-threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized., Conclusions: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules.

The histologic distinction between bronchioloalveolar carcinoma and other adenocarcinomas is tissue invasion. The clinical importance of lung adenocarcinoma invasion is supported by several recent studies indicating that the risk of death in nonmucinous bronchioloalveolar carcinoma is significantly lower than that of pure invasive tumors and in tumors with greater than 0.5 cm of fibrosis or linear invasion. Using microarray gene expression profiling of human tumors, dysregulation of transforming growth factor-beta signaling was identified as an important mediator of tumor invasion. Subsequent studies showed that the CC chemokine regulated on activation, normal T cell expressed, and presumably secreted was up-regulated in invasive tumors and was required for invasion in cells with repressed levels of the transforming growth factor-beta type II receptor. Taken together, these studies illustrate how information gained from global expression profiling of tumors can be used to identify key pathways and genes mediating tumor growth, invasion, and metastasis.

Cigarette smoking is a major source of oxidative stress. Protein carbonyls have been used as a biomarker of oxidative stress because of the relative stability of carbonylated proteins and the high protein concentration in blood. Increased levels of carbonyl groups have been found in serum proteins of smokers compared to nonsmokers. However, neither the dose effect of current cigarette smoke nor other predictors of oxidative stress have been studied. Hence, we used an Enzyme-Linked Immunosorbent Assay (ELISA) to evaluate plasma protein carbonyls in smokers recruited in the Early Lung Cancer Action Project (ELCAP) program. The lung cancer screening program enrolled current and former smokers age 60 years and over without a prior cancer diagnosis. A total of 542 participants (282 men and 260 women) completed a baseline questionnaire and provided blood samples for the biomarker study. Protein oxidation was measured by derivatization of the carbonyl groups with 2,4-dinitrophenylhydrazine (DNPH) and ELISA quantitation of the DNPH group. Current smoking status was confirmed with urinary cotinine. The mean (+/-S.D.) protein carbonyl level was 17.9+/-2.9 nmol carbonyl/ml plasma. Protein carbonyls did not differ significantly by gender. Carbonyl levels were higher among current than former smokers, but these differences did not attain statistical significance, nor did differences by urine cotinine levels, pack-years, pack/day among current smokers, and smoking duration. In a multiple regression analysis, higher protein carbonyl levels were independently associated with increasing age (0.59 nmol/ml increase per 10 years, 95% CI 0.14, 1.05, p=0.01), African-American vs. white race/ethnicity, (1.30 nmol/ml, 95% CI 0.4, 2.19, p=0.008), and lower educational attainment (0.75 nmol/ml, 95% CI 0.12, 1.38, p=0.02). Although we found no significant difference between current vs. past cigarette smoking and protein carbonyls in this older group of smokers, associations were found for age, ethnicity, and educational attainment. Our results indicate that the measurement of plasma carbonyls by this ELISA technique is still an easy and suitable method for studies of diseases related to oxidative stress.

Stunting is associated with deficits in cognition and school achievement from early childhood to late adolescence; however, there has been little investigation of emotional and behavioral outcomes. The objective of this study was to determine whether linear growth retardation (stunting) in early childhood is associated with poorer psychological functioning in late adolescence. The study was a prospective cohort study of stunted and nonstunted children. Participants were identified at age 9-24 mo by a survey of poor neighborhoods in Kingston, Jamaica, and a 2-y intervention trial of supplementation and stimulation was conducted in the stunted children. Psychological functioning was assessed at age 17 y in 103 of 129 stunted children enrolled and 64 of 84 nonstunted participants. Anxiety, depressive symptoms, self-esteem, and antisocial behavior were reported by participants using interviewer-administered questionnaires and attention deficit, hyperactivity, and oppositional behavior were reported by parent interviews. The stunted participants reported significantly more anxiety (regression coefficient = 3.03; 95% CI = 0.99, 5.08) and depressive symptoms (0.37; 95% CI = 0.01, 0.72) and lower self-esteem (-1.67; 95% CI = -0.38, -2.97) than nonstunted participants and were reported by their parents to be more hyperactive (1.29; 95% CI = 0.12, 2.46). Effect sizes were 0.4-0.5 SD. Participants who received stimulation in early childhood differed from the nonstunted group in hyperactivity only. Children stunted before age 2 y thus have poorer emotional and behavioral outcomes in late adolescence. The findings expand the range of disadvantages associated with early stunting, which affects 151 million children <5 y old in developing countries.

The palatal groove is a developmental anomaly that predisposes the tooth involved to a severe periodontal defect. When further complicated by pulp necrosis, these grooves often present a diagnostic and treatment planning challenge that requires an interdisciplinary treatment approach. This case report describes the successful collaborative management of a maxillary lateral incisor with an extensive palatal groove using a combination of nonsurgical endodontic therapy, odontoplasty, and periodontal regenerative techniques.

Growth retardation affects about a third of children younger than age 5 years in developing countries and is associated with poor development. Previously, we did a trial of nutritional supplementation and psychosocial stimulation in stunted children aged 9-24 months. Non-stunted children were also assessed. Both types of intervention improved development. We now present the effects of early interventions on cognition and education in 103 of the 129 stunted children and compare them with 64 of the 84 non-stunted children now aged 17-18 years. We recorded no significant effects of nutritional supplementation. Compared with no intervention, stimulation resulted in higher full scale IQ scores (coefficient 0.38, 95% CI 0.06-0.71, p=0.02) and higher scores on the verbal subscale (0.37, 0.07-0.68, p=0.02), Peabody picture vocabulary test (7.84, 0.73-14.95, p=0.03), verbal analogies (0.26, 0.03-0.49, p=0.03), and reading tests (4.73, 1.31-8.14, p=0.007, and 2.7, 1.12-4.37, p=0.001). Overall, stunted non-stimulated participants had significantly poorer scores than the non-stunted group on 11 of 12 cognitive and educational tests. Stunting in early childhood is associated with cognitive and educational deficits in late adolescence, which are reduced by stimulation at a young age.

Background: Undernourished children have poor levels of development that benefit from stimulation. Zinc deficiency is prevalent in undernourished children and may contribute to their poor development., Objective: We assessed the effects of zinc supplementation and psychosocial stimulation given together or separately on the psychomotor development of undernourished children., Design: This was a randomized controlled trial with 4 groups: stimulation alone, zinc supplementation alone, both interventions, and control (routine care only). Subjects were 114 children aged 9-30 mo and below -1.5 z scores of the National Center for Health Statistics weight-for-age references who were recruited from 18 health clinics. Clinics were randomly assigned to receive stimulation or not; individual children were randomly assigned to receive zinc or placebo. The stimulation program comprised weekly home visits during which play was demonstrated and maternal-child interactions were encouraged. The supplementation was 10 mg Zn as sulfate daily or placebo. Development (assessed by use of the Griffiths Mental Development Scales), length, and weight were measured at baseline and 6 mo later. Weekly morbidity histories were taken., Results: Significant interactions were found between zinc supplementation and stimulation. Zinc benefited the developmental quotient only in children who received stimulation, and benefits from zinc to hand and eye coordination were greater in stimulated children. Zinc supplementation alone improved hand and eye coordination, and stimulation alone benefited the developmental quotient, hearing and speech, and performance. Zinc supplementation also reduced diarrheal morbidity but did not significantly improve growth., Conclusion: Zinc supplementation benefits development in undernourished children, and the benefits are enhanced if stimulation is also provided.

It is estimated that 11% of births in developing counties are term low-birth-weight (LBW); however, there is limited information on the development of these infants. Our objectives were to determine the effect of psychosocial intervention on the development of LBW infants and to compare term LBW and normal-birth-weight (NBW) infants. Term LBW (n = 140) and NBW infants (n = 94) were enrolled from the main maternity hospital in Kingston, Jamaica. The LBW infants were randomly assigned to control or intervention comprising weekly home visits from birth to 8 wk and from 7 to 24 mo of age. Development was assessed at 15 and 24 mo with the Griffiths Scales. The intervention benefited the infants' developmental quotient (DQ, P < 0.05) and performance subscale at 15 mo (P < 0.02), the hand and eye (P < 0.05) and performance subscales (P < 0.02) at 24 mo, and home environment at 12 mo. The effect of the intervention on development was mediated in part by the improvement in the home environment. The control LBW infants had significantly lower scores than the NBW in DQ and several subscales, whereas there were no significant differences between the NBW and the LBW infants after intervention. In conclusion, term LBW was associated with developmental delays, which were reduced with psychosocial intervention.

Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histological types. These paradigms suggest lung tumor cell ontogeny is determined by consequences of gene expression that recapitulate events important in embryonic lung development. Using oligonucleotide microarrays, we acquired gene profiles from 32 microdissected non-small-cell lung tumors. We determined the 100 top-ranked marker genes for adenocarcinoma, squamous cell, large cell, and carcinoid using nearest neighbor analysis. Results were validated by immunostaining for 11 selected proteins using a tissue microarray representing 80 tumors. Gene expression data of lung development were accessed from a publicly available dataset generated with the murine Mu11k genome microarray. Self-organized mapping identified two temporally distinct clusters of murine orthologues. Supervised clustering of lung development data showed large-cell carcinoma gene orthologues were in a cluster expressed in pseudoglandular and canalicular stages whereas adenocarcinoma homologues were predominantly in a cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large-cell genes (E2F3, MYBL2, HDAC2, CDK4, PCNA) are expressed in the nucleus and are associated with cell cycle and proliferation. In contrast, adenocarcinoma genes are associated with lung-specific transcription pathways (SFTPB, TTF-1), cell adhesion, and signal transduction. In sum, non-small-cell lung tumors histology gene profiles suggest mechanisms relevant to ontogeny and clinical course. Adenocarcinoma genes are associated with differentiation and glandular formation whereas large-cell genes are associated with proliferation and differentiation arrest. The identification of developmentally regulated pathways active in tumorigenesis provides insights into lung carcinogenesis and suggests early steps may differ according to the eventual tumor morphology.

Wilms' tumor (WT) has been considered a prototype for arrested cellular differentiation in cancer, but previous studies have relied on selected markers. We have now performed an unbiased survey of gene expression in WTs using oligonucleotide microarrays. Statistical criteria identified 357 genes as differentially expressed between WTs and fetal kidneys. This set contained 124 matches to genes on a microarray used by Stuart and colleagues (Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci USA 2001, 98:5649-5654) to establish genes with stage-specific expression in the developing rat kidney. Mapping between the two data sets showed that WTs systematically overexpressed genes corresponding to the earliest stage of metanephric development, and underexpressed genes corresponding to later stages. Automated clustering identified a smaller group of 27 genes that were highly expressed in WTs compared to fetal kidney and heterologous tumor and normal tissues. This signature set was enriched in genes encoding transcription factors. Four of these, PAX2, EYA1, HBF2, and HOXA11, are essential for cell survival and proliferation in early metanephric development, whereas others, including SIX1, MOX1, and SALL2, are predicted to act at this stage. SIX1 and SALL2 proteins were expressed in the condensing mesenchyme in normal human fetal kidneys, but were absent (SIX1) or reduced (SALL2) in cells at other developmental stages. These data imply that the blastema in WTs has progressed to the committed stage in the mesenchymal-epithelial transition, where it is partially arrested in differentiation. The WT-signature set also contained the Wnt receptor FZD7, the tumor antigen PRAME, the imprinted gene NNAT and the metastasis-associated transcription factor E1AF.

Hunger during school may prevent children in developing countries from benefiting from education. Although many countries have implemented school feeding programs, few programs have been rigorously evaluated. We conducted a randomized, controlled trial of giving breakfast to undernourished and adequately nourished children. The undernourished group comprised 407 children in grades 2-5 in 16 rural Jamaican schools (weights-for-age < or = -1 SD of the National Center for Health Statistics references) and the adequately nourished group comprised 407 children matched for school and class (weights-for-age >-1 SD). Both groups were stratified by class and school, then randomly assigned to breakfast or control groups. After the initial measurements, breakfast was provided every school day for 1 school year. Children in the control group were given one-quarter of an orange and the same amount of attention as children in the breakfast group. All children had their heights and weights measured and were given the Wide Range Achievement Test before and after the intervention. School attendance was taken from the schools' registers. Compared with the control group, height, weight, and attendance improved significantly in the breakfast group. Both groups made poor progress in Wide Range Achievement Test scores. Younger children in the breakfast group improved in arithmetic. There was no effect of nutritional group on the response to breakfast. In conclusion, the provision of a school breakfast produced small benefits in children's nutritional status, school attendance, and achievement. Greater improvements may occur in more undernourished populations; however, the massive problem of poor achievement levels requires integrated programs including health and educational inputs as well as school meals.

Trapping properties of a panel of monoclonal antibodies (Mabs) raised against citrus tristeza virus (CTV) were analyzed in an indirect double-antibody sandwich ELISA (I-DAS-ELISA). These antibodies had been previously assigned by serological specificity into five groups (I to V). Mabs from group V, which are directed to conformational epitopes, trapped significant amounts of virus antigen from CTV-infected plant tissue at IgG concentration above 10 ng/ml. Mabs from groups I to IV, which are directed to linear, continuous epitopes, performed poorly as coating antibodies, even at a 1 microgram/ml concentration of the IgG's, indicating that the respective linear epitopes were inaccessible. However, when Mabs from groups I to IV were combined with a small amount of Mabs from group V, a substantial increase in trapping of the CTV antigen was recorded. In this 'two antibody-binding assay' previously cryptic, linear epitopes of the CTV CP apparently became accessible to the Mabs from groups I to IV. Modulation of the antigenic reactivity of the CTV CP was also recorded upon binding of the Mabs directed to the conformational epitopes in solution. Induced exposure of the linear epitopes of the CTV CP was revealed in 'two antibody-binding assays' with pairwise combinations of different mouse Mabs and several rabbit and chicken polyclonal antisera with different serological specificities, including antisera to bacterially expressed CP fragments. This mixed coating in I-DAS-ELISA resulted in substantially increased efficiency of the virus antigen trapping by antisera produced against bacterially expressed protein fragments and an increased sensitivity of the CTV detection after optimization of the ratio between conformational and linear antibodies.

It is not known whether nutritional supplementation in early childhood has long-term benefits on stunted children's mental development. We followed up 127 7-8-y old children who had been stunted in early childhood and received supplementation, stimulation, or both. At 9-24 mo of age, the children had been randomly assigned to four treatment groups: nutritional supplementation, stimulation, both treatments, and control. After 2 y, supplementation and stimulation had independent benefits on the children's development and the effects were additive. The group receiving both treatments caught up to a matched group of 32 nonstunted children. Four years after the end of the 2-y intervention 97% of the children were given a battery of cognitive function, school achievement, and fine motor tests. An additional 52 nonstunted children were included. Factor analyses of the test scores produced three factors: general cognitive, perceptual-motor, and memory. One, the perceptual-motor factor, showed a significant benefit from stimulation, and supplementation benefited only those children whose mothers had higher verbal intelligence quotients. However, each intervention group had higher scores than the control subjects on more tests than would be expected by chance (supplemented and both groups on 14 of 15 tests, P = 0.002; stimulated group in 13 of 15 tests, P = 0.01), suggesting a very small global benefit. There was no longer an additive effect of combined treatments at the end of the intervention. The stunted control group had significantly lower scores than the nonstunted children on most tests. Stunted children's heights and head circumferences on enrollment significantly predicted intelligence quotient at follow-up.

We have used a preperitoneal suprahepatic location for pacemaker generator placement in pediatric patients requiring permanent pacemakers with epicardial leads. The technique is rapid, simple, and safe, and cosmesis is excellent, making this approach particularly advantageous in the younger infant and neonate.

The long-term benefits of early childhood supplementation and the extent to which catch-up growth occurs following linear growth retardation remain controversial. Stunted children (height-for-age < -2 SD of NCHS references, n = 122) recruited from a survey of poor neighborhoods in Kingston, Jamaica, participated in a 2-yr randomized, controlled trial of supplementation beginning at ages 9-24 mo. A group of 32 non-stunted children from the same neighborhoods was also followed. Four years after the intervention ended, when children were 7 to 8 y old, there were no effects of supplementation on any anthropometric measure. From the end of the trial until follow-up, the children who had been supplemented gained 1.2 cm less (P < 0.05) than the non-supplemented children, approximately the same amount as they had gained during the trial compared with the non-supplemented children. After adjustment for regression to the mean, the height-for-age of stunted children (supplemented and non-supplemented combined) increased from enrollment to follow-up by 0.31 Z-score (95% CI 0.17, 0.46). The height-for-age of the non-stunted children also increased (0.96 Z-score; 95% CI 0.70, 1.22). Our results suggest that some catch-up growth is possible even when children remain in poor environments. Long-term benefits of supplementation to growth may not be achieved when intervention begins after age 12 mo in children who have already become undernourished.

Children aged 9-24 mo were recruited by a survey of poor areas of Kingston, Jamaica. Stunted children were randomly assigned to supplementation or not. Weekly morbidity histories were taken for 2 y. Separate multiple regressions on each symptom for weight or length gain in 2-mo intervals showed significant reductions in weight gain with coughing, apathy, anorexia, diarrhea, and fever, ranging from -2.1 to -16.8 g/d ill. Apathy and diarrhea reduced gains in length (-0.26 and -0.20 mm/d ill). Significant reductions in linear growth with lower respiratory-tract infections (-0.16 mm/d ill) occurred only in nonsupplemented children. Growth over 4-mo intervals was reduced if diarrhea occurred in the first 2 mo of the interval but there were no long-term effects of apathy, fever, or anorexia. Some of the effects of morbidity on growth were therefore transient and morbidity is unlikely to be a major cause of growth retardation in this population.