The role of response adapted therapy in the era of novel agents.

The optimal treatment of classic Hodgkin Lymphoma (cHL) requires an individualized approach, with therapy guided by pretreatment clinical risk stratification and interim response assessment with positron emission tomography (PET). The overall goal is to achieve high cure rates while minimizing acute toxicity and late therapy-related effects. Interim PET-adapted strategies (iPET) were initially developed with traditional chemotherapy, reducing intensity after interim complete response and escalating treatment for patients with iPET+ disease. Recently, novel agents including brentuximab vedotin and the checkpoint inhibitor immunotherapies (CPIs) pembrolizumab and nivolumab have been adopted into the front-line treatment of cHL, and PET-adapted approaches may be relevant for these drugs as well. In this review we discuss response-adapted strategies utilizing novel agents, consider challenges including indeterminate radiographic findings with CPIs, and address emerging techniques for response assessment including new PET-based imaging metrics and the role of circulating tumor DNA.

Syntax-like Structures in Maternal Contact Calls of Chestnut-Crowned Babblers (Pomatostomus ruficeps).

The combination of meaning-bearing units (e.g., words) into higher-order structures (e.g., compound words and phrases) is integral to human language. Despite this central role of syntax in language, little is known about its evolutionary progression. Comparative data using animal communication systems offer potential insights, but only a handful of species have been identified to combine meaningful calls together into larger signals. We investigated a candidate for syntax-like structure in the highly social chestnut-crowned babbler (Pomatostomus ruficeps). Using a combination of behavioral observations, acoustic analyses, and playback experiments, we test whether the form and function of maternal contact calls is modified by combining the core "piping" elements of such calls with at least one other call element or call. Results from the acoustic analyses (236 analysed calls from 10 individuals) suggested that piping call elements can be flexibly initiated with either "peow" elements from middle-distance contact calls or adult "begging" calls to form "peow-pipe" and "beg-pipe" calls. Behavioral responses to playbacks (20 trials to 7 groups) of natural peow-pipe and beg-pipe calls were comparable to those of artificially generated versions of each call using peow elements and begging calls from other contexts. Furthermore, responses to playbacks (34 trials to 7 groups) of the three forms of maternal contact calls (piping alone, peow-pipe, beg-pipe) differed. Together these data suggest that meaning encoded in piping calls is modified by combining such calls with begging calls or peow elements used in other contexts and so provide rare empirical evidence for syntactic-like structuring in a nonhuman animal.

Monitoring iohexol and its transformation products as evidence of reclaimed water irrigation input to contiguous waterbodies.

Irrigation with reclaimed water alleviates water supply shortages, but excess application often results in impairment of contiguous waterbodies. This project investigated the potential use of iohexol, an iodinated contrast media used in medical imaging, together with its bio- and phototransformation products as unique reconnaissance markers of reclaimed water irrigation intrusion at three golf courses within the state of Florida. Inter-facility iohexol concentrations measured in reclaimed waters ranged over ~2 orders of magnitude while observed intra-facility seasonal differences were ≤1 order of magnitude. A ~50 % reduction in iohexol was observed post-disinfection for reclaimed water facilities utilizing UV light while none was observed with use of chlorine. Iohexol biotransformation products were observed to decline or shift to lower molecular weight compounds when exposed to UV light but not during disinfection using chlorine. Iohexol biotransformation products were observed in most of the samples but were more prevalent in samples collected during the dry season. Much fewer iohexol phototransformation products were observed in chlorinated reclaimed water, and they were only observed in UV light irradiated reclaimed water when the pre-disinfectant iohexol concentration was ≥5000 ng/L or from solar exposure of reclaimed water spiked with 10 µM of iohexol. For the Hillsborough golf course overlaying an aquifer, the groundwater did not contain iohexol or phototransformation products but did contain biotransformation products. It is not known if these biotransformation products are from active or historical intrusion. The additional presence of sucralose in the aquifer suggests that intrusion has occurred within the past 3 years. This study demonstrates three crucial points in attempting to utilize iohexol to denote reclaimed water intrusion from irrigation overapplication: (1) interpretable results are obtained when iohexol concentrations in the reclaimed water employed for irrigation are ≥1000 ng/L, with higher concentrations in the range of ≥5000 ng/L better able to meet analytical sensitivity requirements after further dilution or degradation in the environment; (2) it is beneficial to assess iohexol transformation products in tandem with iohexol monitoring to account for environmental transformations of iohexol during storage and transport to the receiving water of concern; and (3) inclusion of monitoring for sucralose, an artificial sweetener ubiquitous in wastewater sources that is comparatively stable in the environment, can aid in interpretating whether reclaimed water intrusion based on identification of iohexol and transformation products in the receiving water is attributable to historic or ongoing irrigation overapplications.

The Florida Geriatric Head Trauma CT Clinical Decision Rule.

BACKGROUND: Several clinical decision rules have been devised to guide head computed tomography (CT) use in patients with minor head injuries, but none have been validated in patients 65 years or older. We aimed to derive and validate a head injury clinical decision rule for older adults. METHODS: We conducted a secondary analysis of an existing dataset of consecutive emergency department (ED) patients >65 years old with blunt head trauma. The main predictive outcomes were significant intracranial injury and Need for Neurosurgical Intervention on CT. The secondary outcomes also considered in the model development and validation were All Injuries and All Intracranial Injuries. Predictor variables were identified using multiple variable logistic regression, and clinical decision rule models were developed in a split-sample derivation cohort and then tested in an independent validation cohort. RESULTS: Of 5776 patients, 233 (4.0%) had significant intracranial injury and an additional 104 (1.8%) met CT criteria for Need for Neurosurgical Intervention. The best performing model, the Florida Geriatric Head Trauma CT Clinical Decision Rule, assigns points based on several clinical variables. If the points totaled 25 or more, a CT scan is indicated. The included predictors were arrival via Emergency Medical Services (+30 points), Glasgow Coma Scale (GCS) <15 (+20 points), GCS <14 (+50 points), antiplatelet medications (+17 points), loss of consciousness (+16 points), signs of basilar skull fracture (+50 points), and headache (+20 points). Utilizing this clinical decision rule in the validation cohort, a point total ≥25 had a sensitivity and specificity of 100.0% (95% CI: 96.0-100) and 12.3% (95% CI: 10.9-13.8), respectively, for significant intracranial injury and Need for Neurosurgical Intervention. CONCLUSIONS: The Florida Geriatric Head Trauma CT Clinical Decision Rule has the potential to reduce unnecessary CT scans in older adults, without compromising safe emergency medicine practice.

A CFD study on the effect of portable air cleaner placement on airborne infection control in a classroom.

The utilization of portable air cleaners (PACs) is a recommended supplemental approach to help remove airborne pathogens and mitigate disease transmission in learning environments. To improve PAC effectiveness, science-based information is needed to optimize their implementation strategies such as the deployment location, height, and number of PACs. In this study, we developed a Computational Fluid Dynamics (CFD) model to assess how PACs perform in occupied classrooms equipped with displacement and mixing ventilation systems. The results show that PACs with a flow rate of 2.6 h-1 reduce the mean aerosol intake of all students by up to 66%. A key benefit of using PACs is to facilitate air mixing and movement in indoor environments with inadequate ventilation, thereby effectively reducing high aerosol concentrations near the infector. Furthermore, our results highlight the impact of PAC location on its performance. PACs achieve the best effectiveness when placed closed to the infector (within a distance <3 m). In the absence of knowing who is infected, deploying a PAC at the center of the room is recommended. Moreover, adjusting PAC flow discharge height to the breathing height of occupants (e.g., 0.9-1.2 m for seated people) can enhance their effectiveness in spaces with poor air mixing.

Amino acids biosynthesis in root hair development: a mini-review.

Metabolic factors are essential for developmental biology of an organism. In plants, roots fulfill important functions, in part due to the development of specific epidermal cells, called hair cells that form root hairs (RHs) responsible for water and mineral uptake. RH development consists in (a) patterning processes involved in formation of hair and non-hair cells developed from trichoblasts and atrichoblasts; (b) RH initiation; and (c) apical (tip) growth of the RH. Here we review how these processes depend on pools of different amino acids and what is known about RH phenotypes of mutants disrupted in amino acid biosynthesis. This analysis shows that some amino acids, particularly aromatic ones, are required for RH apical (tip) growth, and that not much is known about the role of amino acids at earlier stages of RH formation. We also address the role of amino acids in rhizosphere, inhibitory and stimulating effects of amino acids on RH growth, amino acids as N source in plant nutrition, and amino acid transporters and their expression in the RHs. Amino acids form conjugates with auxin, a hormone essential for RH growth, and respective genes are overviewed. Finally, we outline missing links and envision some perspectives in the field.

Membrane HIV-1 envelope glycoproteins stabilized more strongly in a pretriggered conformation than natural virus Envs.

The pretriggered conformation of the human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer ((gp120/gp41)3) is targeted by virus entry inhibitors and broadly neutralizing antibodies (bNAbs). The lability of pretriggered Env has hindered its characterization. Here, we produce membrane Env variants progressively stabilized in pretriggered conformations, in some cases to a degree beyond that found in natural HIV-1 strains. Pretriggered Env stability correlated with stronger trimer subunit association, increased virus sensitivity to bNAb neutralization, and decreased capacity to mediate cell-cell fusion and virus entry. For some highly stabilized Env mutants, after virus-host cell engagement, the normally inaccessible gp120 V3 region on an Env intermediate became targetable by otherwise poorly neutralizing antibodies. Thus, evolutionary pressure on HIV-1 Env to maintain trimer integrity, responsiveness to the CD4 receptor, and resistance to antibodies modulates pretriggered Env stability. The strongly stabilized pretriggered membrane Envs reported here will facilitate further characterization of this functionally important conformation.

Evolution of Telehealth Program to Meet Current Needs of Post-Acute and Long-Term Care Communities.

This article describes a telehealth program initially created to reduce transfers to acute care from the nursing home and its evolution into a robust program that includes Behavioral Health, a Medical Director program, and telenursing.

The effectiveness of social prescribing in the management of long-term conditions in community-based adults: A systematic review and meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the effectiveness of social prescribing interventions in the management of long-term conditions in adults. DATA SOURCES: Eleven electronic databases were searched for randomised and quasi-randomised controlled trials. REVIEW METHODS: Outcomes of interest were quality of life, physical activity, psychological well-being and disease-specific measures. Bias was assessed with the Cochrane Risk of Bias 2 tool. A narrative synthesis and meta-analysis were performed. RESULTS: Twelve studies (n = 3566) were included in this review. Social prescribing interventions were heterogeneous and the most common risks of bias were poor blinding and high attrition. Social prescribing interventions designed to target specific long-term conditions i.e., cancer and diabetes demonstrated significant improvements in quality of life (n = 2 studies) and disease-specific psychological outcomes respectively (n = 3 studies). There was some evidence for improvement in physical activity (n = 2 studies) but most changes were within group only (n = 4 studies). Social prescribing interventions did not demonstrate any significant changes in general psychological well-being. CONCLUSION: Social prescribing interventions demonstrated some improvements across a range of outcomes although the quality of evidence remains poor.

Improving symptom management for survivors of young adult cancer: rationale and study protocol for a pilot randomized controlled trial.

BACKGROUND: Young adult (YA) cancer survivors are a growing, yet underserved population who often face significant and long-lasting cancer-related physical (e.g., pain, fatigue) and emotional (e.g., psychological distress) symptoms. Post-treatment symptoms can persist, disrupting YA's abilities to complete goals consistent with their developmental stage (e.g., completing their education, achieving autonomy and independence, building their careers, establishing peer and romantic relationships, building their families). While symptom management has been identified as a significant issue in YA's transitions to survivorship, the symptom management needs of this population largely go unmet. METHODS: We developed an eight-session, group-based behavioral intervention that is delivered using videoconferencing to address the unique symptom management needs of YA cancer survivors. The intervention was developed in conjunction with YA survivors, leading to the novel combination of traditional behavioral symptom coping strategies, home-based physical activity, strategies from contemporary cognitive-behavioral approaches (e.g., those derived from acceptance and commitment therapy, strategies to foster self-compassion), concepts from meaning centered psychotherapy, and behavioral strategies to improve communication and health care engagement. Participants receive printed intervention materials and access to a study-specific mobile application, both of which are used throughout the program. Herein, we report on a pilot study that is in progress. Recruitment has been completed. YA cancer survivors were recruited in cohorts of n = 10 or n = 11 (n = 61) and randomized to the intervention or waitlist control arms. All participants completed a baseline assessment and four additional assessments over 1 year, with each involving a battery of self-report measures. DISCUSSION: The primary objective is to evaluate intervention feasibility and acceptability. As a secondary objective, we will examine patterns of change in intervention targets (i.e., pain, fatigue, emotional distress, symptom interference). Changes from baseline among intervention targets will be estimated for each patient and compared between arms using unadjusted statistical testing. Unadjusted and adjusted multilevel modeling will be used to estimate the effect of the intervention on changes in intervention targets. Interaction models will be used to compare the trajectory of change over time between arms. We expect that this pilot trial will inform our future approach to identify, recruit, and retain participants and provide preliminary data to support a larger, fully powered randomized controlled trial evaluating the intervention. TRIAL REGISTRATION: NCT04035447 at clinicaltrials.gov; registered July 29, 2019.

Physical modeling of nucleosome clustering in euchromatin resulting from interactions between epigenetic reader proteins.

Euchromatin is an accessible phase of genetic material containing genes that encode proteins with increased expression levels. The structure of euchromatin in vitro has been described as a 30-nm fiber formed from ordered nucleosome arrays. However, recent advances in microscopy have revealed an in vivo euchromatin architecture that is much more disordered, characterized by variable-length linker DNA and sporadic nucleosome clusters. In this work, we develop a theoretical model to elucidate factors contributing to the disordered in vivo architecture of euchromatin. We begin by developing a 1D model of nucleosome positioning that captures the interactions between bound epigenetic reader proteins to predict the distribution of DNA linker lengths between adjacent nucleosomes. We then use the predicted linker lengths to construct 3D chromatin configurations consistent with the physical properties of DNA within the nucleosome array, and we evaluate the distribution of nucleosome cluster sizes in those configurations. Our model reproduces experimental cluster-size distributions, which are dramatically influenced by the local pattern of epigenetic marks and the concentration of reader proteins. Based on our model, we attribute the disordered arrangement of euchromatin to the heterogeneous binding of reader proteins and subsequent short-range interactions between bound reader proteins on adjacent nucleosomes. By replicating experimental results with our physics-based model, we propose a mechanism for euchromatin organization in the nucleus that impacts gene regulation and the maintenance of epigenetic marks.

Predictors and Impact of Prolonged Vasoplegia After Continuous-Flow Left Ventricular Assist Device Implantation.

Background: Vasoplegia after cardiac surgery is associated with adverse outcomes. However, the clinical effects of vasoplegia and the significance of its duration after continuous-flow left ventricular assist device (CF-LVAD) implantation are less known. Objectives: This study aimed to identify predictors of and outcomes from transient vs prolonged vasoplegia after CF-LVAD implantation. Methods: The study was a retrospective review of consecutive patients who underwent CF-LVAD implantation between January 1, 2005, and December 31, 2017. Vasoplegia was defined as the presence of all of the following: mean arterial pressure ≤65 mm Hg, vasopressor (epinephrine, norepinephrine, vasopressin, or dopamine) use for >6 hours within the first 24 hours postoperatively, cardiac index ≥2.2 L/min/m2 and systemic vascular resistance <800 dyne/s/cm5, and vasodilatory shock not attributable to other causes. Prolonged vasoplegia was defined as that lasting 12 to 24 hours; transient vasoplegia was that lasting 6 to <12 hours. Patient characteristics, outcomes, and risk factors were analyzed. Results: Of the 600 patients who underwent CF-LVAD implantation during the study period, 182 (30.3%) developed vasoplegia. Mean patient age was similar between the vasoplegia and no-vasoplegia groups. Prolonged vasoplegia (n = 78; 13.0%), compared with transient vasoplegia (n = 104; 17.3%), was associated with greater 30-day mortality (16.7% vs 5.8%; P = 0.02). Risk factors for prolonged vasoplegia included preoperative dialysis and elevated body mass index. Conclusions: Compared with vasoplegia overall, prolonged vasoplegia was associated with worse survival after CF-LVAD implantation. Treatment to avoid or minimize progression to prolonged vasoplegia may be warranted.

Neighbourhood inequities in the availability of retailers selling tobacco products: a systematic review.

OBJECTIVE: To examine inequities in tobacco retailer availability by neighbourhood-level socioeconomic, racial/ethnic and same-sex couple composition. DATA SOURCES: We conducted a 10 November 2022 search of PubMed, PsycINFO, Global Health, LILACS, Embase, ABI/Inform, CINAHL, Business Source Complete, Web of Science and Scopus. STUDY SELECTION: We included records from Organisation for Economic Co-operation and Development member countries that tested associations of area-level measures of tobacco retailer availability and neighbourhood-level sociodemographic characteristics. Two coders reviewed the full text of eligible records (n=58), including 41 records and 205 effect sizes for synthesis. DATA EXTRACTION: We used dual independent screening of titles, abstracts and full texts. One author abstracted and a second author confirmed the study design, location, unit of analysis, sample size, retailer data source, availability measure, statistical approach, sociodemographic characteristic and unadjusted effect sizes. DATA SYNTHESIS: Of the 124 effect sizes related to socioeconomic inequities (60.5% of all effect sizes), 101 (81.5%) indicated evidence of inequities. Of 205 effect sizes, 69 (33.7%) tested associations between retailer availability and neighbourhood composition of racially and ethnically minoritised people, and 57/69 (82.6%) documented inequities. Tobacco availability was greater in neighbourhoods with more Black, Hispanic/Latine and Asian residents (82.8%, 90.3% and 40.0% of effect sizes, respectively). Two effect sizes found greater availability with more same-sex households. CONCLUSIONS: There are stark inequities in tobacco retailer availability. Moving beyond documenting inequities to partnering with communities to design, implement, and evaluate interventions that reduce and eliminate inequities in retail availability is needed to promote an equitable retail environment. PROSPERO REGISTRATION NUMBER: CRD42019124984.

Characterization of an expanded set of assays for immunomodulatory proteins using targeted mass spectrometry.

Immunotherapies are revolutionizing cancer care, but many patients do not achieve durable responses and immune-related adverse events are difficult to predict. Quantifying the hundreds of proteins involved in cancer immunity has the potential to provide biomarkers to monitor and predict tumor response. We previously developed robust, multiplexed quantitative assays for immunomodulatory proteins using targeted mass spectrometry, providing measurements that can be performed reproducibly and harmonized across laboratories. Here, we expand upon those efforts in presenting data from a multiplexed immuno-oncology (IO)-3 assay panel targeting 43 peptides representing 39 immune- and inflammation-related proteins. A suite of novel monoclonal antibodies was generated as assay reagents, and the fully characterized antibodies are made available as a resource to the community. The publicly available dataset contains complete characterization of the assay performance, as well as the mass spectrometer parameters and reagent information necessary for implementation of the assay. Quantification of the proteins will provide benefit to correlative studies in clinical trials, identification of new biomarkers, and improve understanding of the immune response in cancer.

Obstetric outcomes of women with congenital uterine anomalies in the United States.

BACKGROUND: Due to the rarity, congenital uterine anomaly type-specific evaluation of pregnant women has been relatively understudied. OBJECTIVE: To describe national-level obstetric outcomes in women with congenital uterine anomalies. STUDY DESIGN: This cross-sectional study queried the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample. Pregnant women with diagnosis of congenital uterine anomalies who had hospital delivery between 2016 and 2019 were examined. The World Health Organization's International Classification of Disease, 10th revision coding was used to delineate type of congenital uterine anomaly, diagnoses, and procedures performed during the index admission. Primary outcomes included pregnancy outcome, which was classified as full-term live birth, preterm live birth, abortion/stillbirth, or ectopic pregnancy. Secondary outcomes included obstetric comorbidities and severe maternal mortality, which were compared between different subtypes of congenital uterine anomalies with multivariable logistic regression model. RESULTS: A total of 50,180 pregnant women with congenital uterine anomalies were identified. Bicornuate was the most common subtype (73.5%), followed by arcuate (13.5%) and unicornuate (10.0%). 70.6% of women with congenital uterine anomalies had a full-term live birth, 26.8% had a preterm live birth, 2.1% had an abortion or stillbirth, and 0.4% had an ectopic pregnancy. 61.8% of preterm births occurred between 33 and 36 weeks, 16.9% between 30 and 32 weeks, and 21.3% at <30 weeks. There were 1,440 (2.9%) periviable births. The preterm (34.5%) and periviable (6.9%) birth rates were highest in the uterine didelphys group. Overall, two-thirds (65.7%) of patients with congenital uterine anomalies were delivered via cesarean section. When compared to arcuate uterus, risk of severe maternal morbidity in septate uterus (4.8% vs 2.6%, adjusted-odds ratio [aOR] 2.60, 95% confidence interval [CI] 1.49-4.52) was increased, including hemorrhage (14.5% vs 7.7%, aOR 2.16, 95% CI 1.51-3.07). This was followed by uterine didelphys (4.2% vs 2.6%, aOR 1.75, 95% CI 1.24-2.47), unicornuate uterus (3.8% vs 2.6%, aOR 1.61, 95% CI 1.29-2.01), and bicornuate uterus (3.0% vs 2.6%, aOR 1.23, 95% CI 1.04-1.47). CONCLUSION: While the majority of patients with congenital uterine anomalies result in full-term viable deliveries, each subtype of congenital uterine anomalies confers different obstetric risks. Uterine didelphys was associated with the highest risk of preterm birth, while septate uterus was associated with the highest risk of severe maternal morbidity. While this hospital delivery dataset likely overrepresents bicornuate uteri, this populational data may help inform patients with congenital anomalies considering pregnancy.

Two-year evaluation of Legionella in an aging residential building: Assessment of multiple potable water remediation approaches.

Legionella is an opportunistic waterborne pathogen that is difficult to eradicate in colonized drinking water pipes. Legionella control is further challenged by aging water infrastructure and lack of evidence-based guidance for building treatment. This study assessed multiple premise water remediation approaches designed to reduce Legionella pneumophila within a residential building located in an aging, urban drinking water system over a two-year period. Samples (n = 745) were collected from hot and cold-water lines and quantified via most probable number culture. Building-level treatment approaches included three single heat shocks, three single chemical shocks, and continuous low-level chemical disinfection in the potable water system. The building was highly colonized with L. pneumophila with 71 % L. pneumophila positivity. Single heat shocks had a statistically significant L. pneumophila reduction one day post treatment but no significant L. pneumophila reduction at one week, two weeks, and four weeks post treatment. The first two chemical shocks resulted in statistically significant L. pneumophila reduction at two days and four weeks post treatment, but there was a significant L. pneumophila increase at four weeks following the third chemical shock. Continuous low-level chemical disinfection resulted in statistically significant L. pneumophila reduction at ten weeks post treatment implementation. This demonstrates that in a building highly colonized with L. pneumophila, sustained remediation is best achieved using continuous low-level chemical treatment.

Retailers' Compliance with Federal Age of Cigarette Sales Policies -- Pitt County, North Carolina, January-March 2022.

BACKGROUND: Tobacco use remains a leading cause of preventable morbidity and premature mortality. In December 2019, the federal age of sale for tobacco products increased from 18 to 21 years of age. This study aimed to evaluate the implementation of federal tobacco 21 policies in Pitt County, North Carolina (NC), by conducting multiple purchase attempts for cigarettes. METHOD: Stores in Pitt County that sold cigarettes were randomly sampled and visited by up to six different underage (18-20) buyers who attempted to buy cigarettes from January-March 2022. Buyers made a total of 217 cigarette purchase attempts from 49 Pitt County retailers. Analyses were conducted using SPSS Complex Samples (v.28/Macintosh) and estimate retailer prevalence of requesting identification (ID) and selling to underage buyers across multiple purchase attempts. RESULTS: On average, retailers failed to request ID in 15.4% of purchase attempts (95% CI: 9.4%-21.3%) and sold to an underage buyer 34.2% of the time (95% CI: 27.0-41.4%). Additionally, 75.5% (95% CI: 63.4%-84.6%) of retailers sold to an underage buyer at least once. LIMITATIONS: This study is limited to a single county in NC and to underage buyers aged 18 to 20. CONCLUSION: There is widespread non-compliance with federal age of sale policies for tobacco products in Pitt County, NC. State enforcement is warranted, and NC's youth access law should be amended to match the federal age of sale. Changes to the law should allow research involving underage purchases.