Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker testing: A National Lung Cancer Roundtable best-practice guide.

Advances in biomarker-driven therapies for patients with nonsmall cell lung cancer (NSCLC) both provide opportunities to improve the treatment (and thus outcomes) for patients and pose new challenges for equitable care delivery. Over the last decade, the continuing development of new biomarker-driven therapies and evolving indications for their use have intensified the importance of interdisciplinary communication and coordination for patients with or suspected to have lung cancer. Multidisciplinary teams are challenged with completing comprehensive and timely biomarker testing and navigating the constantly evolving evidence base for a complex and time-sensitive disease. This guide provides context for the current state of comprehensive biomarker testing for NSCLC, reviews how biomarker testing integrates within the diagnostic continuum for patients, and illustrates best practices and common pitfalls that influence the success and timeliness of biomarker testing using a series of case scenarios.

Assessment of Advanced Diagnostic Bronchoscopy Outcomes for Peripheral Lung Lesions: A Delphi Consensus Definition of Diagnostic Yield and Recommendations for Patient-centered Study Designs. An Official American Thoracic Society/American College of Chest Physicians Research Statement.

Background: Advanced diagnostic bronchoscopy targeting the lung periphery has developed at an accelerated pace over the last two decades, whereas evidence to support introduction of innovative technologies has been variable and deficient. A major gap relates to variable reporting of diagnostic yield, in addition to limited comparative studies. Objectives: To develop a research framework to standardize the evaluation of advanced diagnostic bronchoscopy techniques for peripheral lung lesions. Specifically, we aimed for consensus on a robust definition of diagnostic yield, and we propose potential study designs at various stages of technology development. Methods: Panel members were selected for their diverse expertise. Workgroup meetings were conducted in virtual or hybrid format. The cochairs subsequently developed summary statements, with voting proceeding according to a modified Delphi process. The statement was cosponsored by the American Thoracic Society and the American College of Chest Physicians. Results: Consensus was reached on 15 statements on the definition of diagnostic outcomes and study designs. A strict definition of diagnostic yield should be used, and studies should be reported according to the STARD (Standards for Reporting Diagnostic Accuracy Studies) guidelines. Clinical or radiographic follow-up may be incorporated into the reference standard definition but should not be used to calculate diagnostic yield from the procedural encounter. Methodologically robust comparative studies, with incorporation of patient-reported outcomes, are needed to adequately assess and validate minimally invasive diagnostic technologies targeting the lung periphery. Conclusions: This American Thoracic Society/American College of Chest Physicians statement aims to provide a research framework that allows greater standardization of device validation efforts through clearly defined diagnostic outcomes and robust study designs. High-quality studies, both industry and publicly funded, can support subsequent health economic analyses and guide implementation decisions in various healthcare settings.

Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Cancer-related Fatigue in Lung Cancer: A Research Agenda: An Official American Thoracic Society Research Statement.

Background: Fatigue is the most common symptom among cancer survivors. Cancer-related fatigue (CRF) may occur at any point in the cancer care continuum. Multiple factors contribute to CRF development and severity, including cancer type, treatments, presence of other symptoms, comorbidities, and medication side effects. Clinically, increasing physical activity, enhancing sleep quality, and recognizing sleep disorders are integral to managing CRF. Unfortunately, CRF is infrequently recognized, evaluated, or treated in lung cancer survivors despite more frequent and severe symptoms than in other cancers. Therefore, increased awareness and understanding of CRF are needed to improve health-related quality of life in lung cancer survivors. Objectives: 1) To identify and prioritize knowledge and research gaps and 2) to develop and prioritize research questions to evaluate mechanistic, diagnostic, and therapeutic approaches to CRF among lung cancer survivors. Methods: We convened a multidisciplinary panel to review the available literature on CRF, focusing on the impacts of physical activity, rehabilitation, and sleep disturbances in lung cancer. We used a three-round modified Delphi process to prioritize research questions. Results: This statement identifies knowledge gaps in the 1) detection and diagnostic evaluation of CRF in lung cancer survivors; 2) timing, goals, and implementation of physical activity and rehabilitation; and 3) evaluation and treatment of sleep disturbances and disorders to reduce CRF. Finally, we present the panel's initial 32 research questions and seven final prioritized questions. Conclusions: This statement offers a prioritized research agenda to 1) advance clinical and research efforts and 2) increase awareness of CRF in lung cancer survivors.

Research Priorities for Interventions to Address Health Disparities in Lung Nodule Management: An Official American Thoracic Society Research Statement.

Background: Lung nodules are common incidental findings, and timely evaluation is critical to ensure diagnosis of localized-stage and potentially curable lung cancers. Rates of guideline-concordant lung nodule evaluation are low, and the risk of delayed evaluation is higher for minoritized groups. Objectives: To summarize the existing evidence, identify knowledge gaps, and prioritize research questions related to interventions to reduce disparities in lung nodule evaluation. Methods: A multidisciplinary committee was convened to review the evidence and identify key knowledge gaps in four domains: 1) research methodology, 2) patient-level interventions, 3) clinician-level interventions, and 4) health system-level interventions. A modified Delphi approach was used to identify research priorities. Results: Key knowledge gaps included 1) a lack of standardized approaches to identify factors associated with lung nodule management disparities, 2) limited data evaluating the role of social determinants of health on disparities in lung nodule management, 3) a lack of certainty regarding the optimal strategy to improve patient-clinician communication and information transmission and/or retention, and 4) a paucity of information on the impact of patient navigators and culturally trained multidisciplinary teams. Conclusions: This statement outlines a research agenda intended to stimulate high-impact studies of interventions to mitigate disparities in lung nodule evaluation. Research questions were prioritized around the following domains: 1) need for methodologic guidelines for conducting research related to disparities in nodule management, 2) evaluating how social determinants of health influence lung nodule evaluation, 3) studying approaches to improve patient-clinician communication, and 4) evaluating the utility of patient navigators and culturally enriched multidisciplinary teams to reduce disparities.

Increasing Uptake of Lung Cancer Screening Among Emergency Department Patients: A Pilot Study.

BACKGROUND: Lung cancer is the leading cause of cancer death in the United States. Lung cancer screening (LCS) decreases lung cancer mortality. Emergency department (ED) patients are at disproportionately high risk for lung cancer. The ED, therefore, is an optimal environment for interventions to promote LCS. OBJECTIVES: Demonstrate the operational feasibility of identifying ED patients in need of LCS, referring them to LCS services, deploying a text message intervention to promote LCS, and conducting follow-up to determine LCS uptake. METHODS: We conducted a randomized clinical trial to determine the feasibility and provide estimates of the preliminary efficacies of 1) basic referral for LCS and 2) basic referral plus a text messaging intervention, grounded in behavioral change theory, to promote uptake of LCS among ED patients. Participants aged 50 to 80, identified as eligible for LCS, were randomized to study arms and followed up at 150 days to assess interval LCS uptake (primary outcome), barriers to screening, and perceptions of the study interventions. RESULTS: A total of 303 patients were surveyed, with 198 identified as eligible for LCS and subsequently randomized. Results indicated that 24% of participants with follow-up data received LCS (11% of the total randomized sample). Rates of screening at follow-up were similar across study arms. The intervention significantly improved normative perceptions of LCS (p = 0.015; Cohen's d = 0.45). CONCLUSION: This pilot study demonstrates the feasibility of ED-based interventions to increase uptake of LCS among ED patients. A scalable ED-based intervention that increases LCS uptake could reduce lung cancer mortality.

The quality of teaching behaviors in learning environments of DHH students.

Classrooms are complex learning environments, with instruction, climate, and teacher-student interactions playing important roles in students' academic progress. To investigate the learning environments of deaf and hard-of-hearing (DHH) students, we developed a new observational tool called the Quality of the Learning Environment-DHH rating scale (QLE-DHH) and rated 98 teachers of DHH students being educated in a range of classroom environments. The present study sought to (1) determine if the items on the QLE-DHH are good indicators of theoretically meaningful dimensions of classroom quality; (2) determine to what extent these dimensions predicted language and reading outcomes of DHH students; and (3) examine how teachers of DHH students were rated on the indicators of classroom quality. The findings suggested that the QLE-DHH has excellent structural validity. Ratings predicted student reading outcomes. Finally, the QLE-DHH was able to capture teachers' strengths and skills in need of improvement. The QLE-DHH appears to hold promise for use in both research and teacher preparation programs.

Characteristics of Persons Screened for Lung Cancer in the United States : A Cohort Study.

BACKGROUND: Lung cancer screening (LCS) with low-dose computed tomography (LDCT) was recommended by the U.S. Preventive Services Task Force (USPSTF) in 2013, making approximately 8 million Americans eligible for screening. The demographic characteristics and adherence of persons screened in the United States have not been reported at the population level. OBJECTIVE: To define sociodemographic characteristics and adherence among persons screened and entered into the American College of Radiology's Lung Cancer Screening Registry (LCSR). DESIGN: Cohort study. SETTING: United States, 2015 to 2019. PARTICIPANTS: Persons receiving a baseline LDCT for LCS from 3625 facilities reporting to the LCSR. MEASUREMENTS: Age, sex, and smoking status distributions (percentages) were computed among persons who were screened and among respondents in the 2015 National Health Interview Survey (NHIS) who were eligible for screening. The prevalence between the LCSR and the NHIS was compared with prevalence ratios (PRs) and 95% CIs. Adherence to annual screening was defined as having a follow-up test within 11 to 15 months of an initial LDCT. RESULTS: Among 1 159 092 persons who were screened, 90.8% (n = 1 052 591) met the USPSTF eligibility criteria. Compared with adults from the NHIS who met the criteria (n = 1257), screening recipients in the LCSR were older (34.7% vs. 44.8% were aged 65 to 74 years; PR, 1.29 [95% CI, 1.20 to 1.39]), more likely to be female (41.8% vs. 48.1%; PR, 1.15 [CI, 1.08 to 1.23]), and more likely to currently smoke (52.3% vs. 61.4%; PR, 1.17 [CI, 1.11 to 1.23]). Only 22.3% had a repeated annual LDCT. If follow-up was extended to 24 months and more than 24 months, 34.3% and 40.3% were adherent, respectively. LIMITATIONS: Underreporting of LCS and missing data may skew demographic characteristics of persons reported to be screened. Underreporting of adherence may result in underestimates of follow-up. CONCLUSION: Approximately 91% of persons who had LCS met USPSTF eligibility criteria. In addition to continuing to target all eligible adults, men, those who formerly smoked, and younger eligible patients may be less likely to be screened. Adherence to annual follow-up screening was poor, potentially limiting screening effectiveness. PRIMARY FUNDING SOURCE: None.

The impact of Hurricane Maria on individuals living with non-communicable disease in Puerto Rico: the experience of 10 communities.

BACKGROUND: Coinciding with the rising non-communicable disease (NCD) prevalence worldwide is the increasing frequency and severity of natural hazards. Protecting populations with NCDs against natural hazards is ever more pressing given their increased risk of morbidity and mortality in disaster contexts. This investigation examined Hurricane Maria's impacts across ten lower SES municipalities in Puerto Rico with varying community characteristics and hurricane impacts to understand experiences of supporting individuals with NCD management in the six-month period following the hurricane. METHODS: We conducted 40 qualitative interviews with mayors, first responders, faith leaders, community leaders, and municipal employees from 10 municipalities in Puerto Rico. Using QSR NVivo software, we deductively and inductively coded interview transcripts and undertook thematic analysis to characterize community-level hurricane impact and consequences for NCD management, and to identify convergent and divergent themes. RESULTS: Damages to infrastructure, including healthcare facilities and roadways, complicated the provision of timely health care for NCDs, patient transport, and pharmaceutical/medical supply chain continuity. Lengthy power outages at both healthcare facilities and private residences were barriers to healthcare service delivery, use of medical equipment, and storage of prescription medications with refrigeration, and led to a widespread mental health crisis. Cascading failures such as fuel shortages further compounded these challenges. The consequences of these impacts included the reported exacerbation of health conditions and loss of life among NCD patients. CONCLUSIONS: Study findings identify contributors to morbidity and mortality among individuals with NCDs following Hurricane Maria. With the growing frequency of catastrophic disasters from natural hazards, the experiences of communities that endured these impacts offer important lessons regarding policies and practices to better support community disaster resilience and address the evolving preparedness needs of NCD patients.

An alternate approach to simulate the dynamics of perturbed liquid drops.

Liquid drops when subjected to external periodic perturbations can execute polygonal oscillations. In this work, a simple model is presented that demonstrates these oscillations and their characteristic properties. The model consists of a spring-mass network such that masses are analogous to liquid molecules and the springs correspond to intermolecular links. Neo-Hookean springs are considered to represent these intermolecular links. The restoring force of a neo-Hookean spring depends nonlinearly on its length such that the force of a compressed spring is much higher than the force of the spring elongated by the same amount. This is analogous to the incompressibility of liquids, making these springs suitable to simulate the polygonal oscillations. It is shown that this spring-mass network can imitate most of the characteristic features of experimentally reported polygonal oscillations. Additionally, it is shown that the network can execute certain dynamics, which so far have not been observed in a perturbed liquid drop. The characteristics of dynamics that are observed in the perturbed network are polygonal oscillations, rotation of network, numerical relations (rational and irrational) between the frequencies of polygonal oscillations and the forcing signal, and that the shape of the polygons depends on the parameters of perturbation.

Independent-noise provoked spiking, synchronized via coupling.

We report experimental and numerical evidence of synchronized spiking phenomena provoked by the interaction of two bidirectionally coupled electrochemical systems subjected to independent stochastic input signals. To this end, the anodic potentials of two such systems were diffusively coupled. The corresponding anodic currents of these systems exhibited excitable fixed point behavior in the vicinity of a homoclinic bifurcation. Following this, the anodic potentials were perturbed by independent noise signals. The invoked oscillatory dynamics are analyzed using normalized variance and cross-correlation coefficient. By systematically varying the coupling strength between the systems and the level of external noise, regions exhibiting synchronized spiking behavior were identified.

Sleep Problems Are Related to a Worse Quality of Life and a Greater Non-Motor Symptoms Burden in Parkinson's Disease.

INTRODUCTION: The aim of the present study was to examine the frequency of self-reported sleep problems and their associated factors in a large cohort of PD patients. METHODS: PD patients and controls, recruited from 35 centers of Spain from the COPPADIS cohort were included in this cross-sectional study. Sleep problems were assessed by the Spanish version of the Parkinson's disease Sleep Scale version 1 (PDSS-1). An overall score below 82 or a score below 5 on at least 1 item was defined as sleep problems. RESULTS: The frequency of sleep problems was nearly double in PD patients compared to controls: 65.8% (448/681) vs 33.5% (65/206) (p < 0.0001). Mean total PDSS score was lower in PD patients than controls: 114.9 ± 28.8 vs 132.8 ± 16.3 (p < 0.0001). Quality of life (QoL) was worse in PD patients with sleep problems compared to those without: PDQ-39SI, 19.3 ± 14 vs 13 ± 11.6 (p < 0.0001); EUROHIS-QoL8, 3.7 ± 0.5 vs 3.9 ± 0.5 (p < 0.0001). Non-motor symptoms burden (NMSS; OR = 1.029; 95%CI 1.015-1.043; p < 0.0001) and impulse control behaviors (QUIP-RS; OR = 1.054; 95%CI 1.009-1.101; p = 0.018) were associated with sleep problems after adjustment for age, gender, disease duration, daily equivalent levodopa dose, H&Y, UPDRS-III, UPDRS-IV, PD-CRS, BDI-II, NPI, VAS-Pain, VAFS, FOGQ, and total number of non-antiparkinsonian treatments. CONCLUSION: Sleep problems were frequent in PD patients and were related to both a worse QoL and a greater non-motor symptoms burden in PD. These findings call for increased awareness of sleep problems in PD patients.

Mood in Parkinson's disease: From early- to late-stage disease.

BACKGROUND: Although depression is known to be frequent in Parkinson's disease (PD), it is unclear how mood can change and/or impact on patient's quality of life (QoL) over time. Our aim was to analyze the frequency of depression, mood related factors and the contribution of mood to a patient's QoL perception in regard to disease duration. METHODS: PD patients recruited from the COPPADIS cohort from January 2016 to November 2017 were included in this cross-sectional study. Three groups were defined: <5 years (Group A); from 5 to <10 years (Group B); ≥10 years (Group C). Analysis with well-planned linear regression models was conducted to determine how different factors contribute to mood (Beck Depression Inventory-II [BDI-II] as dependent variable), to health-related QoL (39-item Parkinson's Disease Questionnaire [PDQ-39SI] as dependent variable) and to global QoL (European Health Interview Survey - Quality of Life Eight-Item Index [EUROHIS-QOL8] as dependent variable). RESULTS: Six hundred and sixty-three PD patients (62.6 ± 8.9 years old, 59.6% males) were included: Group A, 50.1% (n = 332); Group B, 33.3% (n = 221) and Group C, 16.6% (n = 110). There were no differences between the three groups in terms of the frequency of depressive symptoms nor the frequency of depression type (major vs. minor vs. subthreshold) (p = 0.729). However, the unique percent variance of PDQ-39SI and EUROHIS-QOL8 explained by BDI-II total score was 2 (23.7%) and threefold (26.9%), respectively, in Group C compared to the other two groups. EUROHIS-QOL8 total score provided the highest unique contribution to mood (16.8%). CONCLUSIONS: Although depression-type frequency does not appear to change over time in PD; the contribution of mood on QoL perception is greater in patients with longer disease duration.

Addressing Disparities in Lung Cancer Screening Eligibility and Healthcare Access. An Official American Thoracic Society Statement.

Background: There are well-documented disparities in lung cancer outcomes across populations. Lung cancer screening (LCS) has the potential to reduce lung cancer mortality, but for this benefit to be realized by all high-risk groups, there must be careful attention to ensuring equitable access to this lifesaving preventive health measure.Objectives: To outline current knowledge on disparities in eligibility criteria for, access to, and implementation of LCS, and to develop an official American Thoracic Society statement to propose strategies to optimize current screening guidelines and resource allocation for equitable LCS implementation and dissemination.Methods: A multidisciplinary panel with expertise in LCS, implementation science, primary care, pulmonology, health behavior, smoking cessation, epidemiology, and disparities research was convened. Participants reviewed available literature on historical disparities in cancer screening and emerging evidence of disparities in LCS.Results: Existing LCS guidelines do not consider racial, ethnic, socioeconomic, and sex-based differences in smoking behaviors or lung cancer risk. Multiple barriers, including access to screening and cost, further contribute to the inequities in implementation and dissemination of LCS.Conclusions: This statement identifies the impact of LCS eligibility criteria on vulnerable populations who are at increased risk of lung cancer but do not meet eligibility criteria for screening, as well as multiple barriers that contribute to disparities in LCS implementation. Strategies to improve the selection and dissemination of LCS in vulnerable groups are described.

Explicit and Contextual Vocabulary Intervention: Effects on Word and Definition Learning.

Two single-case studies examined the effects of a vocabulary intervention on K-second grade Deaf or Hard-of-Hearing (DHH) children's vocabulary learning. The intervention consisted of (a) explicit instruction that included fast mapping, and drill and practice games and (b) in-context activities that included book reading, conceptual activities, and conversation. Study 1 compared the effectiveness of in-context alone and explicit+in-context instruction for four DHH children. This multiple baseline across content study showed that children learned more words rapidly in the explicit + in-context condition. Study 2 examined the effects of the explicit+in-context intervention on five DHH children's word and definition learning and use of new words in spontaneous communication. A multiple baseline study across participants showed that all children learned the targeted vocabulary, improved expression of definitions, and used target words in spontaneous language. We discuss the value of explicit and in-context instruction on breadth and depth of vocabulary learning.

Non-motor symptom burden is strongly correlated to motor complications in patients with Parkinson's disease.

BACKGROUND AND PURPOSE: The objective of this study was to analyze the relationship between motor complications and non-motor symptom (NMS) burden in a population of patients with Parkinson's disease (PD) and also in a subgroup of patients with early PD. METHODS: Patients with PD from the COPPADIS cohort were included in this cross-sectional study. NMS burden was defined according to the Non-Motor Symptoms Scale (NMSS) total score. Unified Parkinson's Disease Rating Scale (UPDRS) part IV was used to establish motor complication types and their severity. Patients with ≤5 years of symptoms from onset were included as patients with early PD. RESULTS: Of 690 patients with PD (62.6 ± 8.9 years old, 60.1% males), 33.9% and 18.1% presented motor fluctuations and dyskinesia, respectively. The NMS total score was higher in patients with motor fluctuations (59.2 ± 43.1 vs. 38.3 ± 33.1; P < 0.0001) and dyskinesia (63.5 ± 40.7 vs. 41.4 ± 36.3; P < 0.0001). In a multiple linear regression model and after adjustment for age, sex, disease duration, Hoehn & Yahr stage, UPDRS-III score and levodopa equivalent daily dose, UPDRS-IV score was significantly related to a higher NMSS total score (ß = 0.27; 95% confidence intervals, 2.81-5.61; P < 0.0001), as it was in a logistic regression model on dichotomous NMSS total score (≤40, mild or moderate vs. >40, severe or very severe) (odds ratio, 1.31; 95% confidence intervals, 1.17-1.47; P < 0.0001). In the subgroup of patients with early PD (n = 396; mean disease duration 2.7 ± 1.5 years), motor fluctuations were frequent (18.1%) and similar results were obtained. CONCLUSIONS: Motor complications were frequent and were associated with a greater NMS burden in patients with PD even during the first 5 years of disease duration.

Knowledge Gaps and Research Priorities in Immune Checkpoint Inhibitor-related Pneumonitis. An Official American Thoracic Society Research Statement.

Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized cancer care but are associated with unique adverse events, including potentially life-threatening pneumonitis. The diagnosis of ICI-pneumonitis is increasing; however, the biological mechanisms, clinical and radiologic features, and the diagnosis and management have not been well defined.Objectives: To summarize evidence, identify knowledge and research gaps, and prioritize topics and propose methods for future research on ICI-pneumonitis.Methods: A multidisciplinary group of international clinical researchers reviewed available data on ICI-pneumonitis to develop and refine research questions pertaining to ICI-pneumonitis.Results: This statement identifies gaps in knowledge and develops potential research questions to further expand knowledge regarding risk, biologic mechanisms, clinical and radiologic presentation, and management of ICI-pneumonitis.Conclusions: Gaps in knowledge of the basic biological mechanisms of ICI-pneumonitis, coupled with a precipitous increase in the use of ICIs alone or combined with other therapies, highlight the importance in triaging research priorities for ICI-pneumonitis.

Pre- and postnatal heat stress abatement affects dairy calf thermoregulation and performance.

Prenatal heat stress during late gestation exerts long-term effects on growth and productivity of the dairy calf. Further, direct exposure to heat stress during the preweaning period impairs calf thermoregulation and performance. We examined the effects of heat stress abatement during the prenatal period, postnatal period, or both on calf performance. We hypothesized that calves exposed to pre- and postnatal heat stress abatement would perform most optimally in terms of thermoregulation, growth, and health responses when compared with calves that are heat-stressed at any time in the pre- or postnatal periods. Holstein calves born to heat-stressed (HT) or cooled (CL) dams during late gestation (44 ± 5 d; prenatal HT or CL) were exposed to heat stress or cooling postnatally for 56 d (postnatal HT or CL), resulting in 4 treatments: HT-HT, HT-CL, CL-HT, and CL-CL; n = 12/treatment. Calves were administered 4 L of pooled colostrum and after 2 d of age allotted 10 L/d milk replacer and up to 3 kg/d concentrate in automatic feeder group pens (n = 6/pen). Postnatal cooling was achieved by 2 fans (average wind speed 2 m/s). Thermoregulatory responses (respiration rate and heart rate; rectal, body, and skin temperature), feed intake, growth parameters including average daily gain and medication events were recorded, and blood samples were collected weekly. Thermoregulatory responses were lower in postnatal CL calves compared with postnatal HT. In the afternoon, HT-HT calves had the highest respiration rate and rectal temperature, HT-CL calves had the lowest respiration rate, and CL-HT calves had the lowest heart rate compared with the other treatment groups. Prenatal CL calves weighed more at birth and weaning with a tendency for greater average daily gain compared with prenatal HT calves, whereas postnatal CL calves had increased milk replacer and concentrate intake and a tendency for reduced fever, infection, and total medication events relative to postnatal HT. Prenatal HT calves were esophageal tube fed more often than prenatal CL. Blood hematocrit and 24-h serum IgG concentration were greater in prenatal CL calves relative to prenatal HT. Prenatal heat stress abatement improves weight gain, hematocrit, and immunoglobulin transfer, whereas postnatal heat stress abatement modulates thermoregulatory responses, feed intake, and calf health. This study is the first to characterize the combined effects of pre- and postnatal heat stress or active cooling on the dairy calf.

Explosive synchronization in temporal networks: A comparative study.

We present a comparative study on Explosive Synchronization (ES) in temporal networks consisting of phase oscillators. The temporal nature of the networks is modeled with two configurations: (1) oscillators are allowed to move in a closed two-dimensional box such that they couple with their neighbors and (2) oscillators are static and they randomly switch their coupling partners. Configuration (1) is further studied under two possible scenarios: in the first case, oscillators couple to fixed numbers of neighbors, while, in the other case, they couple to all oscillators lying in their circle of vision. Under these circumstances, we monitor the degrees of temporal networks, velocities, and radius of circle of vision of the oscillators and the probability of forming connections in order to study and compare the critical values of the coupling required to induce ES in the population of phase oscillators.

Thiol/disulfide exchange occurs in rotavirus structural proteins during contact with intestinal villus cell surface.

Protein disulfide isomerase (PDI) is an enzyme that catalyzes disulfide bond reduction or formation and rearrangements of disulfide bridges, and also functions as a chaperone. During entry of some of the viruses PDI participates in thiol-disulfide exchange. Previous reports show that rotavirus entry is interfered by impermeant thiol/disulfide exchange inhibitors and antibodies against PDI. Our objective was to assess the interaction between PDI and triple-layered particles (TLPs) from rotavirus strains ECwt and RRV and from a human rotavirus isolate (HI) during the early steps of virus entry in a system of isolated small intestinal villi. Purified soluble PDI was incubated with either isolated intestinal villi or cell membrane-enriched fractions in the presence or absence of thiol/disulfide inhibitors such as bacitracin, DTNB or N- ethylmaleimide followed by the assessment of the PDI interactions with TLPs and rotavirus structural proteins in terms of their redox state changes. Soluble and membrane-bound PDI was found to interact with TLPs from all the rotaviruses assayed and also with the isolated structural proteins represented by the recombinant rVP5* (a tryptic cleavage product of VP4), rVP6 and the native VP7. PDI interaction with TLPs and rotavirus structural proteins was decreased by the presence of thiol/disulfide exchange inhibitors. Interactions of cell membrane-enriched fractions with TLPs produced rearrangements in the disulfide bridges of rotavirus structural proteins. We conclude that PDI interacts with rotavirus virions through redox reactions that could facilitate the rotavirus entry into the host cell. Keywords: cell surface PDI; thiol-disulfide exchange; rotavirus TLPs; virus entry; bacitracin; DTNB.