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Abstract Background A number of infant pain measures have been developed over the past 15 years incorporating behavioural and physiologic indicators; however, no reliable or valid measure exists for infants who are at risk for neurological impairments (NI). The objective of this study was to establish consensus about which behavioural, physiologic and contextual indicators best characterize pain in infants at high, moderate and low levels of risk for NI. Methods A 39- item, self-administered electronic survey that included infant physiologic, behavioral and contextual pain indicators was used in a two round Delphi consensus exercise. Fourteen pediatric pain experts were polled individually and anonymously on the importance and usefulness of the pain indicators for the 3 differing levels of risk for NI. Results The strength of agreement between expert raters was moderate in Round 1 and fair in Round 2. In general, pain indicators with the highest concordance for all three groups were brow bulge, facial grimace, eye squeeze, and inconsolability. Increased heart rate from baseline in the moderate and severe groups demonstrated high concordance. In the severe risk group, fluctuations in heart rate and reduced oxygen saturation were also highly rated. Conclusion These data constitute the first step in contributing to the development and validation of a pain measure for infants at risk for NI. In future research, we will integrate these findings with the opinions of (a) health care providers about the importance and usefulness of infant pain indicators and (b) the pain responses of infants at mild, moderate and high risk for NI.

Background: Thoracic spine height is cited as a crucial outcome measure in the treatment of early-onset scoliosis (EOS) because of its reported relationship to pulmonary function tests (PFTs). An 18-cm threshold has been proposed, although this single parameter might be overly simplistic for cases of different etiologies and deformity magnitude. We aimed to reevaluate pulmonary function in patients undergoing corrective surgery, assessing the role of residual scoliosis as well as spine elongation., Methods: Patients undergoing EOS correction with a minimum of 5 years of follow-up since initial treatment were evaluated. Standard spirometry (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1]) was correlated to deformity magnitude and T1-T12 height. Patients were compared by age at first surgery (<5 or ≥5 years), final thoracic height (≤18 or >18 cm), and percentage of predicted pulmonary function (<60% or ≥60%)., Results: Twenty-nine patients (15 congenital, 11 syndromic, and 3 idiopathic cases) were tested at a mean of 8.5 years following initial surgery. Twenty-two patients (mean initial age, 4.8 years) had growth-sparing instrumentation, and 7 patients (age, 5.1 years) had definitive fusion performed. Age at initial surgery was not associated with a difference in PFT results at the time of follow-up, and both age groups had ominously low percentages of predicted pulmonary-function volumes (50% to 55%). Only 18 of the 29 patients achieved a T1-T12 height of >18 cm. Those with a thoracic height of ≤18 cm had similar percentage-of-predicted spirometry results at the time of follow-up as those with greater thoracic height, possibly because of increased deformity correction. Only 14 of 29 patients had spirometry of ≥60% of predicted volume at the time of follow-up. These 14 had slightly smaller curves and slightly greater T1-T12 heights but significantly better spirometry results than the 15 subjects with <60% of predicted volume. For those with a T1-T12 height of ≤18 cm, the residual Cobb angle negatively correlated with spirometry results. In those with a final T1-T12 height of >18 cm, spirometry did correlate with thoracic height, especially when residual deformity was ≥60°., Conclusions: Regardless of thoracic height of ≤18 or >18 cm, with residual curves of >50 o , pulmonary function was ominously low in fully half of the patients, raising doubt about the value of this threshold as an EOS outcome parameter., Level of Evidence: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A348)., (Copyright © 2021 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

While the expansion of anthropogenic noise studies in aquatic habitats has produced conservation-based results for a range of taxa, relatively little attention has been paid to the potential impacts on stream fishes. Recent work has shown responses to road noise in single species of stream fish; however, assemblage-wide effects of anthropogenic noise pollution have not yet been investigated. By examining five metrics of disturbance across four ecologically and evolutionarily disparate species of stream fishes, a series of laboratory experiments aimed to describe the effects of and species susceptibility to anthropogenic noise playback. Each species studied represented a unique combination of hearing sensitivity and water column position. Physiological and behavioral metrics were compared across the presence and absence of rail-noise noise playback in four target species. Through repeated subsampling, the temporal dynamics of cortisol secretion in response to noise in two target species were additionally described. Rail-noise playback had no statistically significant effect on blood glucose or water-borne cortisol levels, with the exception of decreased cortisol in noise-exposed largescale stoneroller ( Campostoma oligolepis ). Time-course cortisol experiments revealed rapid secretion and showed minimal effects of noise at most observation points. The presence of noise produced significant changes in ventilation rate and swimming parameters in a portion of the four species observed representing the most conserved responses. Overall, effects of noise were observed in species contrary to what would be hypothesized based on theoretical hearing sensitivity and water column position demonstrating that predicting susceptibility to this type of stressor cannot be accomplished based off these course considerations alone. More importantly, we show that anthropogenic noise can disrupt a variety of behavioral and physiological processes in certain taxa and should be further investigated via measures of fitness in the wild., (© The Author(s) 2020. Published by Oxford University Press and the Society for Experimental Biology.)

Background: This study assessed the outcomes, at skeletal maturity, for 34 patients in whom congenital pseudarthrosis of the tibia (CPT) had been treated with intramedullary (IM) rod fixation., Methods: The results in skeletally mature patients in whom type-4 CPT had been treated with an IM rod at an average of 11.9 years earlier were reviewed. The rod procedures varied according to whether both the tibia and the fibula were resected and both bones (type A) or just the tibia (type B) were fixed with an IM rod or whether only the tibia was resected and the fibula received no surgery (type C). Outcome grading ranged from unequivocal union with brace-free function (grade 1) to a functional limb with residual angulation or cortical defects (grade 2) to a severely impaired extremity with insufficient union or refracture (grade 3)., Results: Thirty-four patients were evaluated at a mean age of 16.9 years, a mean of 11.9 years after their initial surgical procedure. Seventeen patients had a grade-1 result; 11 patients, grade 2; and 6, grade 3. Thus, 82% (28) of the 34 patients had a functional extremity at maturity. All patients with a final grade-3 outcome eventually requested amputation. The final outcomes were not affected by the age at the initial fracture or surgery, the presence of neurofibromatosis-1, or cross-ankle fixation. A total of 58 IM rod procedures were performed in the 34 patients. Twenty-four (73%) of the 33 type-A procedures produced grade-1 or 2 outcomes, as did 14 (88%) of the 16 type-B procedures. Of the 9 type-C procedures, none produced a grade-1 result and 4 produced a grade-2 outcome. The results of types A and B combined were superior to those of type-C procedures (p = 0.03). Refracture occurred in 13 of 33 patients with initial stability/union after rod fixation, with 3 of those fractures remaining ununited at the latest follow-up. A dystrophic fibula had no effect on the eventual achievement of a grade-1 or 2 outcome., Conclusions: This review, in which all patients had reached skeletal maturity, documents functional (grade-1 or 2) outcomes in 82% of cases of IM rod fixation for CPT. This finding was almost identical to the result in our earlier report and confirms the long-term value of permanent IM rod fixation in maintaining union and function in patients with CPT. Procedures not addressing the fibula produced inferior results. Although 13 patients had a refracture following initial union, only 3 of these fractures failed to heal with additional treatment., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Background: Software applications (apps) could potentially promote exercise adherence. However, it is unclear whether adolescents with painful hyperkyphosis will use an app designed for a home exercise program. The purpose of this study is to assess factors regarding adherence to an app-based home exercise program in adolescents with hyperkyphosis and back pain who were provided a one-time exercise treatment., Methods: Twenty-one participants were instructed in a one-time exercise treatment and asked to complete a home exercise program 3 times a week for 6 months using an app called PT PAL. At a 6-month follow-up, 14 participants completed a survey assessing factors related to their experiences using the app and their treatment engagement., Results: Although most participants did not use the app, they reported performing their exercises a few times per week. The adolescent participants considered the app to be more of a barrier than a supportive measure for promoting exercise adherence. Most participants still reported bothersome back pain., Conclusions: Although adherence to the 6-month app-based home exercise program was not successful, adolescents still viewed technology support such as text reminders as a potential solution., Trial Registration: ClinicalTrials.gov Identifier: NCT03212664. Registered 11 July 2017. Retrospectively registered., Competing Interests: This study was approved by the Institutional Review Board of the primary investigator’s affiliated institute and registered with ClinicalTrials.gov. Prior to data collection, each adolescent participant’s assent and caregiver’s consent to participate in the study were obtained.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Noise pollution from anthropogenic sources is an increasingly problematic challenge faced by many taxa, including fishes. Recent studies demonstrate that road traffic noise propagates effectively from bridge crossings into surrounding freshwater ecosystems; yet, its effect on the stress response and auditory function of freshwater stream fishes is unexamined. The blacktail shiner (Cyprinella venusta) was used as a model to investigate the degree to which traffic noise impacts stress and hearing in exposed fishes. Fish were exposed to an underwater recording of traffic noise played at approximately 140 dB re 1 μPa. Waterborne cortisol samples were collected and quantified using enzyme immunoassay (EIA). Auditory thresholds were assessed in control and traffic exposed groups by measuring auditory evoked potentials (AEPs). After acute exposure to traffic noise, fish exhibited a significant elevation in cortisol levels. Individuals exposed to 2 hours of traffic noise playback had elevated hearing thresholds at 300 and 400 Hz, corresponding to the most sensitive bandwidth for this species.

Chicken eggs are the main source of human Salmonella enterica serovar Enteritidis infection. S. Enteritidis infects the oviduct and ovary of the chicken leading to infection of developing eggs. Therefore, control in poultry production is a major public health priority. Vaccination of hens has proved successful in control strategies in United Kingdom leading to a 70% drop in human cases since introduced. However, as hens reach sexual maturity they become immunosuppressed and it has been postulated this leads to increased susceptibility to Salmonella infection. In this study we define the changes to the systemic and reproductive tract-associated immune system of hens throughout sexual development by flow cytometry and histology and determine changes in susceptibility to experimental S. Enteritidis challenge in naive and vaccinated hens. Changes to both systemic and local immune systems occur in chickens at sexual development around 140 days of age. The population of several leukocyte classes drop, with the greatest fall in CD4+ lymphocyte numbers. Within the developing reproductive tract there an organised structure of lymphocytic aggregates with γδ-T lymphocytes associated with the mucosa. At point-of-lay, this organised structure disappears and only scattered lymphocytes remain. Protection against Salmonella challenge is significantly reduced in vaccinated birds at point-of-lay, coinciding with the drop in CD4+ lymphocytes. Susceptibility to reproductive tract infection by Salmonella increased in vaccinated and naïve animals at 140 and 148 days of age. We hypothesise that the drop in γδ-T lymphocytes in the tract leads to decreased innate protection of the mucosa to infection. These findings indicate that systemic and local changes to the immune system increase the susceptibility of hens to S. Enteritidis infection. The loss of protective immunity in vaccinated birds demonstrates that Salmonella control should not rely on vaccination alone, but as part of an integrated control strategy including biosecurity and improved animal welfare.

When skin is compromised, a cascade of signals initiates the rapid repair of the epidermis to prevent fluid loss and provide defense against invading microbes. During this response, keratinocytes produce host defense peptides (HDPs) that have antimicrobial activity against a diverse set of pathogens. Using nonviral vectors we have genetically modified the novel, nontumorigenic, pathogen-free human keratinocyte progenitor cell line (NIKS) to express the human cathelicidin HDP in a tissue-specific manner. NIKS skin tissue that expresses elevated levels of cathelicidin possesses key histological features of normal epidermis and displays enhanced antimicrobial activity against bacteria in vitro. Moreover, in an in vivo infected burn wound model, this tissue results in a two log reduction in a clinical isolate of multidrug-resistant Acinetobacter baumannii. Taken together, these results suggest that this genetically engineered human tissue could be applied to burns and ulcers to counteract bacterial contamination and prevent infection.

Purpose: Two common treatment options for congenital pseudarthrosis of the tibia (CPT) are intramedullary fixation following resection/shortening of the pseudarthrosis site and reconstruction with an Ilizarov external fixator following resection. We present in detail a narrative of two cases with similar degrees of tibial dysplasia associated with NF-1 treated using these different methods and followed to completion., Methods: Technical issues and details of the treatment methods from case reports are discussed in depth. The eventual profoundly different outcomes are correlated to the technical variations used., Results: Treatment with the Charnley-Williams rodding method and aggressive bone grafting supplemented by rh-BMP2 resulted in a normal functioning limb at maturity, while treatment with first, an ineffective version of IM rodding, followed by two sessions of bone transport using an Ilizarov fixator failed to gain useful union and eventually resulted in amputation., Conclusions: Technical details, heretofore inadequately reviewed in the literature, are crucial to the success of either of these commonly utilized treatment methods for CPT.

Background: Affymetrix GeneChips are a popular platform for performing whole-genome experiments on the transcriptome. There are a range of different calibration steps, and users are presented with choices of different background subtractions, normalisations and expression measures. We wished to establish which of the calibration steps resulted in the biggest uncertainty in the sets of genes reported to be differentially expressed., Results: Our results indicate that the sets of genes identified as being most significantly differentially expressed, as estimated by the z-score of fold change, is relatively insensitive to the choice of background subtraction and normalisation. However, the contents of the gene list are most sensitive to the choice of expression measure. This is irrespective of whether the experiment uses a rat, mouse or human chip and whether the chip definition is made using probe mappings from Unigene, RefSeq, Entrez Gene or the original Affymetrix definitions. It is also irrespective of whether both Present and Absent, or just Present, Calls from the MAS5 algorithm are used to filter genelists, and this conclusion holds for genes of differing intensities. We also reach the same conclusion after assigning genes to be differentially expressed using t-statistics, although this approach results in a large amount of false positives in the sets of genes identified due to the small numbers of replicates typically used in microarray experiments., Conclusion: The major calibration uncertainty that biologists need to consider when analysing Affymetrix data is how their multiple probe values are condensed into one expression measure.

Background: A gene for Larsen syndrome was recently described, and mutations were reported in five cases., Objective: To test whether mutations in this gene, FLNB, could explain the disease in our independent collection of sporadic and dominant Larsen syndrome cases; and to test whether mutations occurred in a non-random pattern., Results: Missense mutations were found in each of five cases. Four of the five were new; one was reported in a sporadic case in the original Larsen syndrome study of five cases. All mutations from the two studies were compiled. Clustered mutations were observed within three filamin B protein domains: the calponin homology 2 domain, repeat 14, and repeat 15. This suggested that as few as five (of the total of 46) coding exons of FLNB could be screened to detect Larsen syndrome mutations. Four of these exons were screened in a sixth (sporadic) case and a previously reported G1691S substitution mutation detected., Conclusions: Mutations in FLNB may be responsible for all cases of Larsen syndrome. They appear to occur in specific functional domains of the filamin B protein. This should simplify diagnostic screening of the FLNB gene. Analyses in larger patient series are warranted to quantify this. The study confirmed the extreme variability in clinical presentation and the presence of unaffected carriers. A molecular screen would be valuable for diagnosis and genetic counselling.

We recently developed a nonshivering human model for severe hypothermia by using meperidine to inhibit shivering in mildly hypothermic subjects. This thermal model was used to evaluate warming techniques. On three occasions, eight subjects were immersed for approximately 25 min in 9 degrees C water. Meperidine (1.5 mg/kg) was injected before the subjects exited the water. Subjects were then removed, insulated, and rewarmed in an ambient temperature of -20 degrees C with either 1) spontaneous rewarming (control), 2) inhalation rewarming with saturated air at approximately 43 degrees C, or 3) forced-air warming. Additional meperidine (to a maximum cumulative dose of 2.5 mg/kg) was given to maintain shivering inhibition. The core temperature afterdrop was 30-40% less during forced-air warming (0.9 degree C) than during control (1.4 degrees C) and inhalation rewarming (1.2 degrees C) (P < 0.05). Rewarming rate was 6- to 10-fold greater during forced-air warming (2.40 degrees C/h) than during control (0.41 degree C/h) and inhalation rewarming (0.23 degree C/h) (P < 0.05). In nonshivering hypothermic subjects, forced-air warming provided a rewarming advantage, but inhalation rewarming did not.

During severe hypothermia, shivering is absent. To simulate severe hypothermia, shivering in eight mildly hypothermic subjects was inhibited with meperidine (1.5 mg/kg). Subjects were cooled twice (meperidine and control trials) in 8 degrees C water to a core temperature of 35.9 +/- 0.5 (SD) degrees C, dried, and then placed in sleeping bags. Meperidine caused a 3.2-fold increase in core temperature afterdrop (1.1 +/- 0.6 vs. 0.4 +/- 0.2 degree C), a 4.3-fold increase in afterdrop duration (89.4 +/- 31.4 vs. 20.9 +/- 5.7 min), and a 37% decrease in rewarming rate (1.2 +/- 0.5 vs. 1.9 +/- 0.9 degrees C/h). Meperidine inhibited overt shivering. Oxygen consumption, minute ventilation, and heart rate decreased after meperidine injection but subsequently returned toward preinjection values after 45 min postimmersion. This was likely due to the increased thermoregulatory drive with the greater afterdrop and the short half-life of meperidine. These results demonstrate the effectiveness of shivering heat production in attenuating the postcooling afterdrop of core temperature and potentiating core rewarming. The meperidine protocol may be valuable for comparing the efficacy of various hypothermia rewarming methods in the absence of shivering.

A description of the typical emotional reactions experienced by parents of children with chronic conditions is presented. Nursing strategies are given to facilitate parental adjustment to the child's condition. An emphasis is made on the normalization of experiencing intense emotions. Also addressed are the presentations of problematic parental reactions to the child's diagnosis requiring referral to mental health professionals.