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Tupanviruses, members of the family Mimiviridae , infect phagocytic cells. Particle uncoating begins inside the phagosome, with capsid opening via the stargate. The mechanism through which this opening takes place is unknown. Once phagocytized, metal ion flux control and ROS are induced to inactivate foreign particles, including viruses. Here, we studied the effect of iron ions, copper ions, and H 2 O 2 on Tupanvirus particles. Such treatments induced stargate opening in vitro , as observed by different microscopy techniques. Metal-treated viruses were found to be non-infectious, leading to the hypothesis that stargate opening likely resulted in the release of the viral seed, which is required for infection initiation. To the best of our knowledge, this is the first description of a giant virus capsid morphological change induced by transition metals and H 2 O 2 , which may be important to describe new virulence factors and capsid uncoating mechanisms., Competing Interests: The authors declare no conflict of interest.

Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution of microglia to pain progression, we take advantage of a temporally controlled transgenic approach to transiently deplete microglia. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion. We find that repopulated mouse spinal cord microglia are morphologically distinct from control microglia and exhibit a unique transcriptome. Repopulated microglia from males and females express overlapping networks of genes related to phagocytosis and response to stress. We intersect the identified mouse genes with a single-nuclei microglial dataset from human spinal cord to identify human-relevant genes that may ultimately promote pain resolution after injury. This work presents a comprehensive approach to gene discovery in pain and provides datasets for the development of future microglial-targeted therapeutics., Competing Interests: Declaration of interests The authors declare that they have no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Many temperate phages encode prophage-expressed functions that interfere with superinfection of the host bacterium by external phages. Salmonella phage P22 has four such systems that are expressed from the prophage in a lysogen that are encoded by the c2 (repressor), gtrABC , sieA , and sieB genes. Here we report that the P22-encoded SieA protein is necessary and sufficient for exclusion by the SieA system and that it is an inner membrane protein that blocks DNA injection by P22 and its relatives, but has no effect on infection by other tailed phage types. The P22 virion injects its DNA through the host cell membranes and periplasm via a conduit assembled from three "ejection proteins" after their release from the virion. Phage P22 mutants that overcome the SieA block were isolated, and they have amino acid changes in the C-terminal regions of the gene 16 and 20 encoded ejection proteins. Three different single-amino acid changes in these proteins are required to obtain nearly full resistance to SieA. Hybrid P22 phages that have phage HK620 ejection protein genes are also partially resistant to SieA. There are three sequence types of extant phage-encoded SieA proteins that are less than 30% identical to one another, yet comparison of two of these types found no differences in phage target specificity. Our data strongly suggest a model in which the inner membrane protein SieA interferes with the assembly or function of the periplasmic gp20 and membrane-bound gp16 DNA delivery conduit.IMPORTANCEThe ongoing evolutionary battle between bacteria and the viruses that infect them is a critical feature of bacterial ecology on Earth. Viruses can kill bacteria by infecting them. However, when their chromosomes are integrated into a bacterial genome as a prophage, viruses can also protect the host bacterium by expressing genes whose products defend against infection by other viruses. This defense property is called "superinfection exclusion." A significant fraction of bacteria harbor prophages that encode such protective systems, and there are many different molecular strategies by which superinfection exclusion is mediated. This report is the first to describe the mechanism by which bacteriophage P22 SieA superinfection exclusion protein protects its host bacterium from infection by other P22-like phages. The P22 prophage-encoded inner membrane SieA protein prevents infection by blocking transport of superinfecting phage DNA across the inner membrane during injection., Competing Interests: The authors declare no conflict of interest.

The rhizosphere is the region of soil directly influenced by plant roots. The microbial community in the rhizosphere includes fungi, protists, and bacteria: all play significant roles in plant health. The beneficial bacterium Sinorhizobium meliloti infects growing root hairs on nitrogen-starved leguminous plants. Infection leads to the formation of a root nodule, where S. meliloti converts atmospheric nitrogen to ammonia, a bioavailable form. In soil, S. meliloti is often found in biofilms and travels slowly along the roots, leaving developing root hairs at the growing root tips uninfected. Soil protists are an important component of the rhizosphere system, able to travel quickly along roots and water films, who prey on soil bacteria and have been known to egest undigested phagosomes. We show that a soil protist, Colpoda sp., can transport S. meliloti down Medicago truncatula roots. Using model soil microcosms, we directly observed fluorescently labeled S. meliloti along M. truncatula roots and tracked the displacement of the fluorescence signal over time. Two weeks after co-inoculation, this signal extended 52 mm farther down plant roots when Colpoda sp. was also present versus treatments that contained bacteria but not protists. Direct counts also showed protists are required for viable bacteria to reach the deeper sections of our microcosms. Facilitating bacterial transport may be an important mechanism whereby soil protists promote plant health. IMPORTANCE Soil protists are an important part of the microbial community in the rhizosphere. Plants grown with protists fare better than plants grown without protists. Mechanisms through which protists support plant health include nutrient cycling, alteration of the bacterial community through selective feeding, and consumption of plant pathogens. Here, we provide data in support of an additional mechanism: protists act as transport vehicles for bacteria in soil. We show that protist-facilitated transport can deliver plant-beneficial bacteria to the growing tips of roots that may otherwise be sparsely inhabited with bacteria originating from a seed-associated inoculum. By co-inoculating Medicago truncatula roots with both S. meliloti, a nitrogen-fixing legume symbiont, and Colpoda sp., a ciliated protist, we show substantial and statistically significant transport with depth and breadth of bacteria-associated fluorescence as well as transport of viable bacteria. Co-inoculation with shelf-stable encysted soil protists may be employed as a sustainable agriculture biotechnology to better distribute beneficial bacteria and enhance the performance of inoculants.

The Black pediatric population is one that has been historically underserved and continues to have unmet needs. Factors including lack of diversity in orthopaedic studies and in historical standards, such as bone age, may inadvertently lead to inferior care. There are certain conditions in this population for which the practicing orthopaedic surgeon should have a higher degree of suspicion, including slipped capital femoral epiphysis, Blount disease, and postaxial polydactyly. Systemic diseases with higher rates in this population have orthopaedic manifestations, including sickle cell disease, vitamin D deficiency, and obesity. Racial discrepancies in access to prenatal care can have orthopaedic consequences for babies, especially cerebral palsy and myelodysplasia. Racial discrepancy exists in evaluation for nonaccidental trauma. Increased awareness of these issues better prepares practitioners to provide equitable care., (Copyright © 2022 by the American Academy of Orthopaedic Surgeons.)

Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex in situ hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H6 ).

Dysgonomonas species are facultative heterotrophs capable of growth on lignocellulose-derived polysaccharides. Dysgonomonas species harbor myriad genes involved in glycan modification and are well suited to the lignocellulose-rich conditions within the termite hindgut. Here, we report draft genome sequences for Dysgonomonas sp. strains GY75 and GY617, isolated from the hindgut of Reticulitermes flavipes ., (Copyright © 2021 Bridges and Gage.)

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is commonly experienced by children receiving neurotoxic chemotherapy. No validated pediatric CIPN patient-reported outcome (PRO) measures exist. Purpose: To test sensitivity, internal consistency reliability, content and convergent validity, and feasibility of the Pediatric Chemotherapy-Induced Neuropathy (P-CIN), an electronic PRO measure for assessing CIPN in children who received neurotoxic chemotherapy. Method: Five experts evaluated content validity of the 14-item P-CIN. Children 5 to 17 years old with CIPN ( N = 79) completed the P-CIN via tablet computer; a subset ( n = 26) also underwent neurological examinations using the Pediatric-Modified Total Neuropathy Score. Following preliminary analyses, one item was deleted and three others modified. The revised P-CIN was retested with patients ( n = 6) who also completed the Bruininks-Oseretsky Test of Motor Proficiency motor function assessment. Means, item response ranges, standard deviations, content validity indexes, Cronbach's alphas, and correlation coefficients were calculated. Results: Mean participant age was 11.25 ( SD = 4.0) years. Most had acute leukemia (62.5%) and received vincristine (98.7%). Content validity index coefficients ranged from .80 to 1.0 ( p = .05). For 9 of 14 items, responses ranged from 0 to 4 or 5; response ranges for toe numbness, pick up a coin, and three of four pain items were 0 to 3. After deleting one item, Cronbach's alpha coefficient was .83. P-CIN scores were strongly associated with Pediatric-Modified Total Neuropathy Score ( r = .52, p < .01) and Bruininks-Oseretsky Test of Motor Proficiency ( r = -.83, p = .04) scores. Sixty-eight percent of children 6 to 17 years old completed P-CIN independently. Discussion: Preliminary evidence suggests that the 13-item P-CIN is internally consistent, is valid, and can be completed independently by children ≥ 6 years. However, we recommend additional testing.

Microorganisms play a vital role in shaping the soil environment and enhancing plant growth by interacting with plant root systems. Because of the vast diversity of cell types involved, combined with dynamic and spatial heterogeneity, identifying the causal contribution of a defined factor, such as a microbial exopolysaccharide (EPS), remains elusive. Synthetic approaches that enable orthogonal control of microbial pathways are a promising means to dissect such complexity. Here we report the implementation of a synthetic, light-activated, transcriptional control platform using the blue-light responsive DNA binding protein EL222 in the nitrogen fixing soil bacterium Sinorhizobium meliloti . By fine-tuning the system, we successfully achieved optical control of an EPS production pathway without significant basal expression under noninducing (dark) conditions. Optical control of EPS recapitulated important behaviors such as a mucoid plate phenotype and formation of structured biofilms, enabling spatial control of biofilm structures in S. meliloti . The successful implementation of optically controlled gene expression in S. meliloti enables systematic investigation of how genotype and microenvironmental factors together shape phenotype in situ .

Members of Dysgonomonas are Gram-stain-negative, non-motile, facultatively anaerobic coccobacilli originally described in relation to their isolation from stool and wounds of human patients (CDC group DF-3). More recently, Dysgonomonas have been found to be widely distributed in terrestrial environments and are particularly enriched in insect systems. Their prevalence in xylophagous insects such as termites and wood-feeding cockroaches, as well as in soil-fed microbial fuel cells, elicit interest in lignocellulose degradation and biofuel production, respectively. Their occurrence in mosquito and fruit fly have implications relating to symbiosis, host immunology and developmental biology. Additionally, their presence in termite, mosquito and nematode present novel opportunities for pest and vector control. Currently, the absolute growth requirements of Dysgonomonas are unknown, and they are commonly cultured under anaerobic conditions on complex media containing blood, peptones, tryptones, and yeast, plant or meat extracts. Restrictive and undefined culturing conditions preclude physiological and genetic studies, and thus further understanding of their metabolic potential. Here we describe the requirements for growth of termite-derived Dysgonomonas isolates and create parallel complex, defined and minimal media that permit vigorous and reliable aerobic growth. Furthermore, we show that these media can be used to easily enrich for Dysgonomonas isolates from densely-colonized and microbially-diverse environmental samples., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dysgonomonas spp. are facultative heterotrophs which colonize diverse environments, including the hindgut of the lower termite Reticulitermes flavipes Dysgonomonas genomes are enriched for genes involving oligo- and polysaccharide utilization, enabling modification of a wide array of complex glycans. Here, we report draft genome sequences for Dysgonomonas sp. strains BGC7 and HGC4., (Copyright © 2021 Bridges et al.)

Background: Microdeletions of the MEF2C gene are linked to a syndromic form of autism termed MEF2C haploinsufficiency syndrome (MCHS). MEF2C hypofunction in neurons is presumed to underlie most of the symptoms of MCHS. However, it is unclear in which cell populations MEF2C functions to regulate neurotypical development., Methods: Multiple biochemical, molecular, electrophysiological, behavioral, and transgenic mouse approaches were used to characterize MCHS-relevant synaptic, behavioral, and gene expression changes in mouse models of MCHS., Results: We showed that MCHS-associated missense mutations cluster in the conserved DNA binding domain and disrupt MEF2C DNA binding. DNA binding-deficient global Mef2c heterozygous mice (Mef2c-Het) displayed numerous MCHS-related behaviors, including autism-related behaviors, changes in cortical gene expression, and deficits in cortical excitatory synaptic transmission. We detected hundreds of dysregulated genes in Mef2c-Het cortex, including significant enrichments of autism risk and excitatory neuron genes. In addition, we observed an enrichment of upregulated microglial genes, but this was not due to neuroinflammation in the Mef2c-Het cortex. Importantly, conditional Mef2c heterozygosity in forebrain excitatory neurons reproduced a subset of the Mef2c-Het phenotypes, while conditional Mef2c heterozygosity in microglia reproduced social deficits and repetitive behavior., Conclusions: Taken together, our findings show that mutations found in individuals with MCHS disrupt the DNA-binding function of MEF2C, and DNA binding-deficient Mef2c global heterozygous mice display numerous MCHS-related phenotypes, including excitatory neuron and microglia gene expression changes. Our findings suggest that MEF2C regulates typical brain development and function through multiple cell types, including excitatory neuronal and neuroimmune populations., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Childhood trauma has been linked to neuropathic pain in noncancer populations, but its relationship with cancer treatment-related neuropathic pain is unknown., Objective: This secondary data analysis of a prospective, longitudinal, observational study aimed to explore the relationship of childhood trauma experience with pain severity, pain interference, and neuropathic symptom severity (NSS) 12 months after surgery in women receiving treatment for stage 0 to III breast cancer., Methods: Women (N = 44) recruited from a comprehensive cancer center self-reported childhood trauma experience, pain severity, pain interference, NSS, co-occurring symptoms, and pain beliefs via questionnaires. Descriptive statistics were used to describe childhood trauma experience. Linear regression was used to model childhood trauma and other predictors on pain variables 12 months after surgery., Results: Childhood trauma predicted pain severity and pain interference 12 months after surgery (P < .05), as did baseline pain severities and helplessness-pain catastrophizing. Age predicted only NSS. Together, the best models predicted 31.6% to 40.9% of the variance in pain severities at 12 months (P < .001)., Conclusions: Childhood trauma exposure was a significant predictor of pain 12 months after breast cancer surgery and adjuvant treatment. Younger and helplessness-pain catastrophizing women are also at risk. Research is needed to identify preventive neuropathic pain interventions for high-risk women., Implications for Practice: Women receiving breast cancer treatment should proactively be assessed for childhood trauma history, possibly by using discreet previsit questionnaires. Childhood trauma survivors may be at high risk for poor pain outcomes and may benefit from tailored pain interventions.

In children who receive neurotoxic chemotherapy, peripheral neurotoxicity occurs frequently, necessitates dose reduction or treatment cessation, and affects function and long-term quality of life. No treatments exist for peripheral neurotoxicity and few assessment measures are specific to children. We did a systematic review to analyse the published literature concerning the evaluation of assessment measures for paediatric chemotherapy-induced peripheral neurotoxicity. We searched PubMed, CINAHL, PsycINFO, and Embase on Nov 7-8, 2018; of 1409 articles, seven met the inclusion criteria. A total of 335 children (excluding ten healthy controls) were enrolled in the seven studies and the sample sizes ranged from 17 to 86 individuals. 276 (82%) of the 335 children were actively undergoing chemotherapy treatment. Most studies did not comprehensively evaluate the psychometric properties of assessment measures for chemotherapy-induced peripheral neurotoxicity. By use of a narrative analysis that combined approaches from the Joanna Briggs Institute (Adelaide, SA, Australia) and the quality of diagnostic accuracy studies assessment method (known as QUADAS), only one study was deemed high quality. We identified two variants of the Total Neuropathy Score, two grading scales, two semi-objective tests, one patient-reported outcome, and several mobility measures. The National Cancer Institute Common Terminology Criteria for Adverse Events and the Balis grading scales showed lower sensitivity and specificity than the items of the Total Neuropathy Score. Although there is insufficient evidence to support the use of most approaches to assess chemotherapy-induced peripheral neurotoxicity in children, two variants of the Total Neuropathy Score, the pediatric-modified Total Neuropathy Score and the Total Neuropathy Score-pediatric vincristine, are promising but require further testing. Other approaches are less sensitive or less feasible. A patient-reported outcome measure for chemotherapy-induced peripheral neurotoxicity in children is needed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To describe the known predictors and pathophysiological mechanisms of chronic painful chemotherapy-induced peripheral neuropathy (CIPN) in cancer survivors and the challenges in assessing and managing it., Data Sources: PubMed/Medline, CINAHL, Scopus, and PsycINFO., Conclusion: The research on chronic painful CIPN is limited. Additional research is needed to identify the predictors and pathophysiological mechanisms of chronic painful CIPN to inform the development of assessment tools and management options for this painful and possibly debilitating condition., Implications for Nursing Practice: Recognition of the predictors of chronic painful CIPN and proactive CIPN assessment and palliative management are important steps in reducing its impact on physical function and quality of life., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: No criterion-standard patient-reported outcome measure of chemotherapy-induced peripheral neuropathy (CIPN) exists., Objectives: The aims of this study were to reevaluate the sensitivity, reliability, and validity of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN (QLQ-CIPN20) measure and suggest possible revisions that could strengthen it., Methods: Cross-sectional QLQ-CIPN20 data from 8 European countries (n = 271) were pooled with data from 4 North American multisite CIPN intervention trials (n = 884). The combined sample (N = 1155) included patients with varied cancer diagnoses who had received neurotoxic chemotherapy. Item score ranges, Cronbach's α, and exploratory factor analysis were used to evaluate sensitivity, internal consistency, and structural validity., Results: Individual item mean scores ranged from 1.21 to 2.34 (SD range, 0.55-1.17). All item scores encompassed the entire 1 to 4 range. We recommend that 4 items be removed because of low item-item score correlations (r < 0.30). On the basis of the remaining 16 items, 88% of the variance was explained by 2 factors whose Cronbach's α coefficients were .90 and .85. However, items lacked conceptual alignment with previously published factor structures., Conclusion: Using a large, diverse sample of European and North American participants, the reduced 16-item QLQ-CIPN20 is sensitive and internally consistent. However, factor analysis results revealed an unstable factor structure., Implications for Practice: The use of a reliable, valid, and sensitive criterion-standard QLQ-CIPN20 variant in clinical practice settings could improve function, quality of life, and CIPN symptom control by facilitating patient reporting and thereby clinician awareness of this underrecognized consequence of cancer therapy.

Purpose: Many survivors of breast cancer experience an array of chronic symptoms, including pain, insomnia, and fatigue. Few effective therapies have been identified. Behavioral management programs to address similar symptom clusters in other chronic conditions have been effective. The objective of this study was to determine the effect of an Internet-based lifestyle and behavioral self-management program on cancer-related symptoms., Patients and Methods: Women with stage 0 to 3 breast cancer who reported insomnia, pain, or fatigue as their primary symptom of concern during the 7 days before enrollment were enrolled. Local therapies and/or chemotherapy were completed at least 3 months before enrollment. Patients were assessed at baseline and after 8 weeks, and they completed the Patient-Reported Outcomes Measurement Information System (PROMIS)-29 Profile and Patient Global Impression of Change (PGIC) questionnaire electronically. Change in each of the eight symptom domains was assessed., Results: Fifty patients enrolled. In the 45 patients with both baseline and 8-week PROMIS data, statistically significant improvements in anxiety, sleep, fatigue, activity level, and pain severity were reported. Of the 35 patients who responded to the PGIC, 62.9% reported improvement in their primary symptom. Those who reported fatigue as their primary symptom reported greatest overall benefit in multiple symptom improvement, including improvements in fatigue, anxiety, pain severity, pain interference, and participation in social activities., Conclusions: These findings suggest that this lifestyle and behavioral management program may improve multiple symptoms in breast cancer survivors when delivered via the Internet. Randomized studies are warranted to evaluate the efficacy of the online intervention compared with standard symptom management approaches and to identify patients most likely to benefit.

Objectives: To explore associations between quantitative sensory testing (QST) and pretreatment pain, physical, and psychological characteristics in women with breast cancer., Sample & Setting: 41 women with treatment-naive stage 0-III breast cancer at the University of Michigan Comprehensive Cancer Center in Ann Arbor., Methods & Variables: Participants completed self-report surveys and QST within the month before breast surgery. Pressure pain thresholds (PPTs) were measured bilaterally at each trapezius with a manual QST algometer. PPT values were split, yielding low, moderate, and high pain sensitivity subgroups. Subgroup self-reported characteristics were compared using Spearman's correlation, chi-square, and one-way analysis of variance., Results: Lower PPT (higher sensitivity) was associated with higher levels of pain interference and maladaptive pain cognitions. The high-sensitivity group reported higher pain severities, interference, and catastrophizing and lower belief in internal locus of pain control than the low-sensitivity group., Implications for Nursing: Individualized interventions for maladaptive pain cognitions before surgery may reduce pain sensitivity and the severity of chronic pain developed after surgery.

Purpose: To test a reduced version-CIPN15-of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy scale (QLQ-CIPN20) to establish a possible gold-standard patient-reported outcome measure for chemotherapy-induced peripheral neuropathy (CIPN)., Methods: Using a prospective, longitudinal, case-control design, patients (n = 121) receiving neurotoxic chemotherapy completed the CIPN15 at baseline and 12 weeks and underwent objective neurological assessment using the 5-item Total Neuropathy Score-Clinical (TNSc). Healthy controls (n = 30) completed the CIPN15 once. Structural validity was evaluated using factor analysis. Because a stable factor structure was not found, a sum score was used to evaluate measures of the CIPN15's psychometric properties-reliability, validity, sensitivity, and responsiveness-as follows: internal consistency via Cronbach's α and item-item correlations; test-retest reliability via correlation between 2 CIPN15 scores from each patient; concurrent validity via correlation between CIPN15 and 5-item TNSc scores; contrasting group validity via comparison of CIPN15 scores from patients and healthy controls; sensitivity via descriptive statistics (means, standard deviation, ranges); and responsiveness via Cohen's d effect size., Results: Most patients received single agent oxaliplatin (33.7%), paclitaxel (21.2%), or more than 1 neurotoxic drug concurrently (29.8%). Factor analysis revealed no stable factor structure. Cronbach's α for the CIPN15 sum score was 0.91 (confidence interval [CI] = 0.89-0.93). Test-retest reliability was demonstrated based on strong correlations between the 2 scores obtained at the 12-week time point ( r = 0.86; CI = 0.80-0.90). The CIPN15 and 5-item TNSc items reflecting symptoms (not signs) were moderately correlated ( r range 0.57-0.72): concurrent validity. Statistically significant differences were found between patient and healthy control CIPN15 mean scores ( P < .0001): contrasting group validity. All items encompassed the full score range but the CIPN15 linearly converted sum score did not: sensitivity. The CIPN15 was responsive based on a Cohen's d of 0.52 (CI = 0.25-0.79)., Conclusion: The sum-scored CIPN15 is reliable, valid, sensitive, and responsive when used to assess taxane- and platinum-induced CIPN.

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine-induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1-18 years who received vincristine at one of four academic children's hospitals. VIPN assessments were obtained using the Total Neuropathy Score-Pediatric Vincristine (TNS©-PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©-Five (PNPS©-5). Of children who provided a full TNS©-PV score, 85/109 (78%) developed VIPN (TNS©-PV ≥4). Mean TNS©-PV, grading scale, and pain scores were low. CTCAE©-derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8-12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2-3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe., (© 2015 Peripheral Nerve Society.)

Cancer treatment-related chronic neuropathic pain (NP) is a pervasive and distressing problem that negatively influences function and quality of life for countless cancer survivors. It occurs because of cancer treatment-induced damage to peripheral and central nervous system structures. NP becomes chronic when pain signal transmission persists, eventually sensitizing neurons in the dorsal horn and other pain-processing regions in the central nervous system. Frequently overlooked, NP due to cancer treatment has been understudied. Consequently, only a few pharmacologic interventions have been shown to be effective based on the results of randomized controlled trials. Future research designed to explore pathophysiologic mechanisms and effective mechanism-targeted interventions is sorely needed.

Purpose: In this review, we discuss the plight of Alice, a patient with advanced nonsmall cell lung cancer (NSCLC) who struggles with taxane-related peripheral neuropathy (PN). Using this unique point of view helps us to appreciate the implications of PN on daily activities as well as the difficulty in decision-making regarding continuation of treatment. In addition, published reports of phase 3 trials are reviewed to identify the incidence and severity of chemotherapy-induced PN as well as the assessment tools used in these studies., Methods: A literature review spanning the years 1998-2012 was performed. Phase 3 studies and a meta-analysis of taxane-based therapy in advanced NSCLC were selected for review for their findings regarding the incidence and severity of chemotherapy-induced PN., Results: In total, 16 phase 3 studies and 1 meta-analysis were reviewed. Use of grading scales and PN assessment tools was inconsistent across the studies, and some studies did not report PN at all., Conclusions: The true incidence and severity of chemotherapy-induced PN in clinical trials may be masked by nonstandardized reporting; thus, a more standardized approach to grading, assessing, and reporting PN in clinical trials is greatly needed to allow for appropriate comparisons across studies. Understanding chemotherapy-induced PN from the patient's perspective as well as the development of PN at the clinical trial level will help health care providers anticipate the development of PN and improve their ability to manage it.

Many habitats may be exposed to multiple chemical contaminants, particularly in agricultural areas where fertilizer and pesticide use are common; however, the singular and interactive effects of contaminants are not well understood. The objective of our study was to examine how realistic, sublethal environmental levels of ammonium nitrate fertilizer (0, 10, 20 mg/L and ammonium chloride control) and the common insecticide carbaryl (0 or 2.5 mg/L) individually and interactively affect the development, size, and survival of green frog (Rana clamitans) tadpoles. We reared tadpoles for 95 d in outdoor 1,000-L polyethylene ponds. We found that the combination of carbaryl and nitrate had a negative effect on development and mass of tadpoles compared to the positive effect that either contaminant had alone. Presence of carbaryl was generally associated with short-term increases in algal resources, including ponds exposed to both carbaryl and nitrate. However, with exposure to nitrate and carbaryl, tadpole mass and development were not positively affected as with one chemical stressor alone. The combination of these sublethal contaminants may reduce the ability of amphibians to benefit from food-rich environments or have metabolic costs. Our study demonstrates the importance of considering multiple stressors when evaluating population-level responses.

Assessment of contaminant impacts to federally identified endangered, threatened and candidate, and state-identified endangered species (collectively referred to as "listed" species) requires understanding of a species' sensitivities to particular chemicals. The most direct approach would be to determine the sensitivity of a listed species to a particular contaminant or perturbation. An indirect approach for aquatic species would be application of toxicity data obtained from standard test procedures and species commonly used in laboratory toxicity tests. Common test species (fathead minnow, Pimephales promelas; sheepshead minnow, Cyprinodon variegatus; and rainbow trout, Oncorhynchus mykiss) and 17 listed or closely related species were tested in acute 96-hour water exposures with five chemicals (carbaryl, copper, 4-nonylphenol, pentachlorophenol, and permethrin) representing a broad range of toxic modes of action. No single species was the most sensitive to all chemicals. For the three standard test species evaluated, the rainbow trout was more sensitive than either the fathead minnow or sheepshead minnow and was equal to or more sensitive than listed and related species 81% of the time. To estimate an LC50 for a listed species, a factor of 0.63 can be applied to the geometric mean LC50 of rainbow trout toxicity data, and more conservative factors can be determined using variance estimates (0.46 based on 1 SD of the mean and 0.33 based on 2 SD of the mean). Additionally, a low- or no-acute effect concentration can be estimated by multiplying the respective LC50 by a factor of approximately 0.56, which supports the United States Environmental Protection Agency approach of multiplying the final acute value by 0.5 (division by 2). When captive or locally abundant populations of listed fish are available, consideration should be given to direct testing. When direct toxicity testing cannot be performed, approaches for developing protective measures using common test species toxicity data are available.

The majority of studies on pesticide impacts have evaluated the effects of single exposures. However, multiple exposures to a pesticide may be more prevalent. The objective of our study was to determine how multiple exposures versus single exposure at different times during development affected survival to metamorphosis, tadpole survival, tadpole mass, and tadpole developmental stage of green frog (Rana clamitans) tadpoles reared at low and high density in outdoor cattle tank ponds. Tadpoles were exposed to carbaryl zero, one, two, or three times at 14-d intervals. We applied single doses of carbaryl at one of three times, specifically during early, mid, or late development. Overall, we found that multiple exposures had a greater impact than single exposures during development. More individuals reached metamorphosis in ponds exposed to multiple doses of carbaryl compared with controls, indicating that the presence of carbaryl stimulated metamorphosis. The presence of carbaryl in the aquatic environment also resulted in more developed tadpoles compared with controls. Tadpoles in control ponds did not reach metamorphosis and were less developed than individuals exposed to carbaryl; this effect indicates that, under ideal conditions, green frogs could overwinter in ponds so that greater size could be attained before metamorphosis in the following spring or summer. Our study demonstrated the importance of including realistic application procedures when evaluating the effects of a pesticide and that multiple exposures to a short-lived pesticide are more likely to affect an amphibian population.

Our objective was to determine how green frogs (Rana clamitans) are affected by multiple exposures to a sublethal level of the carbamate insecticide, carbaryl, in outdoor ponds. Tadpoles were added to 1,000-l ponds at a low or high density which were exposed to carbaryl 0, 1, 2, or 3 times. Length of the larval period, mass, developmental stage, tadpole survival, and proportion metamorphosed were used to determine treatment effects. The frequency of dosing affected the proportion of green frogs that reached metamorphosis and the developmental stage of tadpoles. Generally, exposure to carbaryl increased rates of metamorphosis and development. The effect of the frequency of carbaryl exposure on development varied with the density treatment; the majority of metamorphs and the most developed tadpoles came from high-density ponds exposed to carbaryl 3 times. This interaction suggests that exposure to carbaryl later in the larval period stimulated metamorphosis, directly or indirectly, under high-density conditions. Our study indicates that exposure to a contaminant can lead to early initiation of metamorphosis and that natural biotic factors can mediate the effects of a contaminant in the environment.

One of the major unanswered questions in the study of global amphibian declines is why only some species or populations suffer declines. A possible explanation is that species and populations vary in the genetic basis of their tolerance to environmental stress such as chemical contamination. The presence of genetic variation in tolerance to chemicals and in fitness traits of amphibians is essential for persistence of species populations through survival and successful reproduction in contaminated environments. We tested for the presence of genetic variation in the tolerance of amphibian larvae to the insecticide carbaryl using gray treefrog tadpoles (Hyla versicolor). We also assessed whether tolerance of tadpoles is negatively associated with larval performance traits directly related to adult fitness, thereby providing a test of the "cost of tolerance" hypothesis. Our results demonstrate significant variation in tolerance of tadpoles to the insecticide carbaryl within a single population of the gray treefrog, Hyla versicolor. Our half-sibship design indicates that variation among sires explains a significant amount of the variation in chemical tolerance thereby suggesting a heritability genetic basis. Our results also indicate the presence of a fitness tradeoff with tolerance to the chemical carbaryl being negatively correlated, or traded off, with survival of tadpoles reared in the field in the absence of the chemical. Knowledge of genetic tradeoffs with chemical tolerance under realistic environmental conditions will be important for predicting the rate of adaptation and potential for persistence of species. Finally, the partitioning of environmental and genetic variation in tolerance to chemicals is critical to identifying which species are most susceptible, the amount of genetic variance present, the potential for adaptation to contaminants, and the presence of fitness tradeoffs. Such information is necessary to clearly understand the persistence of populations, and ultimately, the processes leading to species declines.

Amphibian larvae are commonly exposed to low levels of pesticides during their development. Chronic studies generally examine the effects of long-term exposure, but they often disregard the importance of the individual life stage at which tadpoles are exposed. I determined the point during development at which carbaryl effects are manifested by exposing southern leopard frog tadpoles (Rana sphenocephala) to the pesticide carbaryl at five different times during development. Metamorphs exposed throughout the tadpole stage and throughout development (egg, embryo, tadpole) experienced significant mortality at all chemical levels. Although the length of the larval period was the same for all experimental groups, metamorphs exposed during the egg stage were smaller than their corresponding controls, independent of whether they were exposed at any other stage. Nearly 18% of individuals exposed to carbaryl during development exhibited some type of developmental deformity (including both visceral and limb malformities), compared to a single deformed (< 1%) control tadpole, demonstrating that a chemical hypothesis for amphibian deformities remains viable. Because exposure to nonpersistent chemicals may last for only a short period of time, it is important to examine the long-term effects that short-term exposure has on larval amphibians and the existence of any sensitive life stage. Any delay in metamorphosis or decrease in size at metamorphosis can impact demographic processes of the population, potentially leading to declines or local extinction.