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Chloé ML Peters,1 Paul Lodder,2,3 Jolanda de Vries,2,4 Stijn L Steunenberg,1 Eelco J Veen,1 Hans GW de Groot,1 Gwan H Ho,1 Lijckle van der Laan1,5 1Department of Surgery, Amphia Hospital, Breda, The Netherlands; 2Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands; 3Department of Methodology and Statistics, Tilburg University, Tilburg, The Netherlands; 4Department of Medical Psychology, Elisabeth-TweeSteden Hospital Tilburg University, Tilburg, The Netherlands; 5Department of Cardiovascular Science, UZ Leuven - University Hospitals, Leuven, BelgiumCorrespondence: Lijckle van der LaanAmphia Hospital, Molengracht 21, Breda, CK 4818, the NetherlandsTel +31 76 595 5000Email lvanderlaan@amphia.nlPurpose: In elderly patients with chronic limb-threatening ischemia (CLTI), there is little scientific understanding of the long-term changes of quality of life (QoL) and health status (HS) after treatment. The primary goal of this study was to provide long-term QoL and HS results for elderly CLTI patients after therapy. Treatments consisted of endovascular revascularization, surgical revascularization, or conservative treatment. Furthermore, the aim of this study was to identify the distinctive trajectories of QoL and HS.Patients and Methods: CLTI patients aged ≥ 70 years were included in a prospective observational cohort study with a two-year follow-up. The WHOQOL-BREF was used to asses QoL. The 12-Item Short Form Health Survey was used to measure HS. The QoL and HS scores were compared to the scores in the general elderly Dutch population. Latent class trajectory analysis was used.Results: A total of 195 patients were included in this study. After two years, in all treatment groups patients showed significantly higher physical QoL score compared to baseline and there was no significant difference with the corresponding values in the elderly Dutch population. In the latent class trajectory analysis, there were no overlapping risk factors for poorer QoL or HS.Conclusion: This study shows that QoL levels in surviving elderly CLTI patients in the long-term do not differ from the corresponding values for elderly in the general population. There were no disparities in sociodemographic, clinical and treatment characteristics associated with poorer QoL and HS. This study was carried out to encourage further analysis of the influence of biopsychosocial characteristics on QoL and HS in elderly CLTI patients.Keywords: quality of life, health status, peripheral arterial disease, frail elderly, chronic limb-threatening ischemia

Chloé ML Peters,1 Jolanda de Vries,2,3 Eelco J Veen,1 Hans GW de Groot,1 Gwan H Ho,1 Paul Lodder,2,4 Stijn L Steunenberg,1 Lijckle van der Laan11Department of Surgery, Amphia Hospital, Breda, The Netherlands; 2Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands; 3Department of Medical Psychology, Elisabeth-Tweesteden Hospital (ETZ), Tilburg, The Netherlands; 4Department of Methodology and Statistics, Tilburg University, Tilburg, The NetherlandsPurpose: Despite high amputation rates, data on patient-reported outcomes is scarce in the elderly population with critical limb ischemia. The aim of this study was to provide mortality rates and long-term changes of the following patient-reported outcomes in elderly critical limb ischemia amputees: quality of life (QoL), health status (HS), and symptoms of depression.Patients and methods: In this prospective observational cohort study, amputated critical limb ischemia patients ≥70 years were included. The follow-up period was two years. Within the follow-up period patients completed the following questionnaires: the World Health Organization Quality Of Life -abbreviated version of the WHOQOL 100 (WHOQOL-BREF), the 12-Item Short Form Health Survey, and the Center for Epidemiological Studies Depression Scale.Results : A total of 49 elderly patients with critical limb ischemia had undergone major limb amputation within two years after inclusion. In these patients, the one-year mortality rate was 39% and the two-year mortality rate was 55%. The physical QoL was the only domain of the WHOQOL-BREF that improved significantly across time after amputation (p≤0.001). In the long-term, there was no difference in the ability to enjoy life (p=0.380) or the satisfaction in performing daily living activities (p=0.231) compared to the scores of the general elderly population. After amputation, the physical HS domain (p≤0.001) and the mental HS domain (p=0.002) improved. In the first year, amputees experienced less symptoms of depression (p=0.004).Conclusion: Elderly critical limb ischemia amputees are a fragile population with high mortality rates. Their QoL and HS increased after major limb amputation as compared to the baseline situation and they experienced less symptoms of depression. Moreover, our results show that, in the long-term, major limb amputation in the elderly patients with critical limb ischemia shows an acceptable QoL, which, in some aspects, is comparable to the QoL of their peers. These results can improve the shared-decision making process that does not delay the timing of major limb amputation.Keywords: amputation, critical limb ischemia, frail elderly, health status, quality of life

Abstract: Aim of the study: Pu-erh (or pu’er) tea tasting is a social practice that emphasizes shared sensory experience, wellbeing, and alertness. The present study examines how variable production and preparation practices of pu-erh tea affect drinkers’ perceptions, phytochemical profiles, and anti-oxidant activity. Materials and methods: One hundred semi-structured interviews were conducted in Yunnan Province to understand the cultural and environmental context of pu-erh tea tasting. The gong fu cha dao (‘way of tea’ with ‘effort,’ ‘work,’ or ‘skill’) method of brewing tea through multiple infusions was employed to evaluate green and black pu-erh samples from smallholder agro-forests and terrace plantations. Ranking interviews, High Performance Liquid Chromatography (HPLC), and the 1-1-diphenyl-2-picrylhydrazyl (DPPH) assay were conducted to characterize color and taste profiles, Total Catechin Content (TCC), Total Methylxanthine Content (TMC), and free radical scavenging capacity (IC50). Results: Significant variation was found among pu-erh samples based on: (1) agro-ecosystem mode of production by TCC (P <0.0001) and TMC (P <0.0265), (2) processing method for TCC (P <0.0001), TMC (P <0.0027), and free radical scavenging capacity (P <0.0001), (3) infusion sequence for TMC (P <0.0013), (4) taste rankings for TCC (P <0.0001), TMC (P <0.0001), and IC50 (P <0.0059) and, (5) color rankings for TMC (P <0.0009) and IC50 (P <0.0001). Samples rated as bitter and bitter-sweet contained the greatest TCC and free radical scavenging capacity. Conclusions: This research demonstrated that production environment, processing methods, and infusion sequence in preparing tea are related to the phytochemical profile, free radical scavenging activity, and flavor of tea. Findings contribute to the ethnomedical literature by supporting previous studies that have hypothesized that the taste of plants, particularly bitterness, may guide societies in the search for medicinal plants and beneficial phytochemicals. [ABSTRACT FROM AUTHOR]

Background: Female sex workers (FSW) have a higher burden of sexually transmitted infections (STI), including Neisseria gonorrhoeae (NG), than the non-sex worker population, mainly due to social vulnerability and work-related factors. This large study evaluated the anatomical site distribution of NG, and specifically the occurrence of single-site pharyngeal NG, among FSW visiting Dutch STI clinics in the Netherlands., Methods: Coded STI clinic consultations from FSW attending any Dutch STI clinic between 2016 and 2021, in which tests were performed on all three anatomical sites, according to the Dutch testing policy for FSW, were included in analyses (n = 22,304). To compare the anatomical site distribution of NG among FSW with women in general, 15,494 consultations from women who were tested on three anatomical sites in clinics that performed standard testing at three anatomical sites were used. Descriptive statistics were used to compare the anatomical site distribution of NG and occurrence of single-site pharyngeal NG among FSW and universally tested women., Results: NG was diagnosed among 3.5% (782/22,034) among FSW and 1.7% (271/15,494) among universally tested women (p < 0.001). Pharyngeal NG was diagnosed among 2.3% among FSW, versus 0.8% among universally tested women (p < 0.001). Single-site pharyngeal NG was diagnosed in 19.9% (156/782) of all NG infections, compared to 14.8% (40/271) of NG infections among universally tested women., Conclusion: The substantial proportion pharyngeal NG and single-site pharyngeal NG among FSW, confirms the relevance of pharyngeal testing among this key population for optimal patient management, also in the context of the potential role of pharyngeal NG in antimicrobial resistance., Competing Interests: Potential conflicts of interest: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Sexually Transmitted Diseases Association.)

Although the role of peripheral nerves in cancer progression has been appreciated, little is known regarding cancer/sensory nerve crosstalk and its contribution to bone metastasis and associated pain. In this study, we revealed that the cancer/sensory nerve crosstalk plays a crucial role in bone metastatic progression. We found that (i) periosteal sensory nerves expressing calcitonin gene-related peptide (CGRP) are enriched in mice with bone metastasis; (ii) cancer patients with bone metastasis have elevated CGRP serum levels; (iii) bone metastatic patient tumor samples express elevated calcitonin receptor-like receptor (CRLR, a CGRP receptor component); (iv) higher CRLR levels in cancer patients are negatively correlated with recurrence-free survival; (v) CGRP induces cancer cell proliferation through the CRLR/p38/HSP27 pathway; and (vi) blocking sensory neuron-derived CGRP reduces cancer cell proliferation in vitro and bone metastatic progression in vivo. This suggests that CGRP-expressing sensory nerves are involved in bone metastatic progression and that the CGRP/CRLR axis may serve as a potential therapeutic target for bone metastasis., (© 2024 Park et al.)

Stereotactic Body Radiation Therapy for lung tumors near the chest wall often causes significant chest wall pain (CWP), negatively impacting patients' quality of life. The mechanisms behind SBRT-induced CWP remain unclear and may involve multiple factors. We investigated the potential crosstalk between radiation-activated osteoclasts and sensory neurons, focusing on osteoclast-derived factors in CWP. Using the murine pre-osteoclast cell line Raw264.7, we induced differentiation with RANKL, followed by 10Gy gamma-irradiation. Conditioned media from these irradiated osteoclasts was used to treat sensory neuronal cultures from mouse dorsal root ganglia. Neuronal cultures were also directly exposed to 10Gy radiation, with and without osteoclast co-culture. Analysis of osteoclast markers and pain-associated neuropeptides was conducted using RT-qPCR and histochemical staining. Osteoclast differentiation and activity were inhibited using Osteoprotegerin and risedronate. Results showed that high-dose radiation significantly increased osteoclast size, resorption pit size, and activity biomarkers. Neurons treated with CM from irradiated osteoclasts showed increased expression of pain-associated neuropeptides CGRP and Substance P, which was mitigated by osteoprotegerin and risedronate. This study suggests that high-dose radiation enhances osteoclast activity, upregulating pain-associated neuropeptides in sensory neurons, and that inhibitors like osteoprotegerin and risedronate may offer therapeutic strategies for managing radiation-induced pain., Competing Interests: Declarations CONFLICT OF INTEREST The authors have no conflicts of interest to declare

The increase in social media mental health (MH) campaigns provides an opportunity to improve awareness and attitudes toward MH. However, racial disparities remain in these social media campaigns. Black youth who participated in MH social media campaigns reported lower levels of improvement in stigma and help-seeking than their White peers. We employed a youth participatory action research (YPAR) process to expand on a previous community-wide MH social media campaign (A. Thompson et al., 2021), focusing on a Central Midwest community. We studied Black adolescents' perceptions of MH stigma and help-seeking to determine essential features of a culturally responsive MH social media campaign for Black youth. With a lead youth-research collaborator, the research team designed the following two-staged study. The first stage consisted of four semistructured focus group interviews (FGIs) ( N = 20), analyzed by using a rapid analysis strategy to obtain results for the development of the campaign. In the second stage, using YPAR's iterative and action-based process, five youth researchers collaborated with the research team on the campaign's design. Following the two stages, the researcher's thematic analysis resulted in three themes: (a) broadening horizons for campaign designers and MH professionals; (b) considering mistrust of schools and school personnel; and (c) diverse experiences, sustainability, and accessibility in a campaign. Findings indicated that while culturally responsive social media campaigns to promote MH can be designed, mistrust of adults in schools is likely to hinder the impact of such campaigns. Implications for school psychology practice and research are discussed. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Background. Many occupational therapists make home modification recommendations; however, it is unknown if sustainability considerations (i.e., economic, social, and environmental) are contemplated during this process. Purpose. To understand occupational therapists' perceptions regarding the sustainability of home modifications. Method. This study adopted a qualitative description approach. Researchers utilized semistructured interviews as the primary means of data collection. Findings. The ten female occupational therapists interviewed had three or more years of experience working with home modifications. The analysis identified three themes: It's not easy being green: environmental sustainability, stretching a dollar: financial inequities, and barriers and benefits in the home modification process. Implications. Findings suggest OTs have a varied and a general understanding of how to implement sustainability concepts in their practice. There is also a need to make access to home modifications more equitable. Further research is needed to build a more robust understanding of how OT recommended home modifications can contribute to sustainability.

Background: Prolonged fetal exposure to hyperglycemia may increase the risk of developing abnormal glucose metabolism and type-2 diabetes during childhood, adolescence, and adulthood; however, the mechanisms by which gestational diabetes mellitus (GDM) predisposes offspring to metabolic disorders remain unknown., Aim: To quantify the nerve axons, macrophages, and vasculature in the pancreas from adult offspring born from mouse dams with GDM., Methods: GDM was induced by i.p. administration of streptozotocin (STZ) in ICR mouse dams. At 12 wk old, fasting blood glucose levels were determined in offspring. At 15 wk old, female offspring born from dams with and without GDM were sacrificed and pancreata were processed for immunohistochemistry. We quantified the density of sensory [calcitonin gene-related peptide (CGRP)] and tyrosine hydroxylase (TH) axons, blood vessels (endomucin), and macro-phages (CD68) in the splenic pancreas using confocal microscopy., Results: Offspring mice born from STZ-treated dams had similar body weight and blood glucose values compared to offspring born from vehicle-treated dams. However, the density of CGRP + and TH + axons, endomucin + blood vessels, and CD68 + macrophages in the exocrine pancreas was significantly greater in offspring from mothers with GDM vs control offspring. Likewise, the microvasculature in the islets was significantly greater, but not the number of macrophages within the islets of offspring born from dams with GDM compared to control mice., Conclusion: GDM induces neuronal, vascular, and inflammatory changes in the pancreas of adult progeny, which may partially explain the higher propensity for offspring of mothers with GDM to develop metabolic diseases., Competing Interests: Conflict-of-interest statement: The authors declare no conflicts of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Abstract: Nearly 40 yr ago, Professor Dempsey delivered the 1985 ACSM Joseph B. Wolffe Memorial Lecture titled: "Is the lung built for exercise?" Since then, much experimental work has been directed at enhancing our understanding of the functional capacity of the respiratory system by applying complex methodologies to the study of exercise. This review summarizes a symposium entitled: "Revisiting 'Is the lung built for exercise?'" presented at the 2022 American College of Sports Medicine annual meeting, highlighting the progress made in the last three-plus decades and acknowledging new research questions that have arisen. We have chosen to subdivide our topic into four areas of active study: (i) the adaptability of lung structure to exercise training, (ii) the utilization of airway imaging to better understand how airway anatomy relates to exercising lung mechanics, (iii) measurement techniques of pulmonary gas exchange and their importance, and (iv) the interactions of the respiratory and cardiovascular system during exercise. Each of the four sections highlights gaps in our knowledge of the exercising lung. Addressing these areas that would benefit from further study will help us comprehend the intricacies of the lung that allow it to meet and adapt to the acute and chronic demands of exercise in health, aging, and disease., (Copyright © 2023 by the American College of Sports Medicine.)

Cancer-induced bone pain (CIBP) is the most common and devastating symptom of bone metastatic cancer that substantially disrupts patients' quality of life. Currently, there are few effective analgesic treatments for CIBP other than opioids which come with severe side effects. In order to better understand the factors and mechanisms responsible for CIBP it is essential to have clinically relevant animal models that mirror pain-related symptoms and disease progression observed in patients with bone metastatic cancer. In the current study, we characterize a syngeneic mouse model of prostate cancer induced bone pain. We transfected a prostate cancer cell line (RM1) with green fluorescent protein (GFP) and luciferase reporters in order to visualize tumor growth longitudinally in vivo and to assess the relationship between sensory neurons and tumor cells within the bone microenvironment. Following intra-femoral injection of the RM1 prostate cancer cell line into male C57BL/6 mice, we observed a progressive increase in spontaneous guarding of the inoculated limb between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. Daily running wheel performance was evaluated as a measure of functional impairment and potentially movement evoked pain. We observed a progressive reduction in the distance traveled and percentage of time at optimal velocity between 12 and 21 days post inoculation in tumor bearing compared to sham operated mice. We utilized histological, radiographic and μCT analysis to examine tumor induced bone remodeling and observed osteolytic lesions as well as extra-periosteal aberrant bone formation in the tumor bearing femur, similar to clinical findings in patients with bone metastatic prostate cancer. Within the tumor bearing femur, we observed reorganization of blood vessels, macrophage and nerve fibers within the intramedullary space and periosteum adjacent to tumor cells. Tumor bearing mice displayed significant increases in the injury marker ATF3 and upregulation of the neuropeptides SP and CGRP in the ipsilateral DRG as well as increased measures of central sensitization and glial activation in the ipsilateral spinal cord. This immunocompetent mouse model will be useful when combined with cell type selective transgenic mice to examine tumor, immune cell and sensory neuron interactions in the bone microenvironment and their role in pain and disease progression associated with bone metastatic prostate cancer., 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., (© 2023 The Authors.)

The purpose of the study was to characterize exercise induced arterial hypoxemia (EIAH) in female masters athletes (FMA). We hypothesized that FMA would experience EIAH during treadmill running. Eight FMA (48-57 years) completed pulmonary function testing and an incremental exercise test until exhaustion (V̇O 2 max⁡ = 45.7 ± 6.5, range:35-54 ml/kg/min). On a separate day, the participants were instrumented with a radial arterial catheter and an esophageal temperature probe. Participants performed three to four constant load exercise tests at 60-70 %, 75 %, 90 %, 95 %, and 100 % of maximal oxygen uptake while sampling arterial blood and recording esophageal temperature. We found that FMA decrease their partial pressure of oxygen (86.0 ± 7.6, range:73-108 mmHg), arterial saturation (96.2 ± 1.2, range:93-98 %), and widen their alveolar to arterial oxygen difference (23.2 ± 8.8, range:5-42 mmHg) during all exercise intensities however, with variability in terms of severity and pattern. Our findings suggest that FMA experience EIAH however aerobic fitness appears unrelated to occurrence or severity (r = 0.13, p = 0.756)., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: This project assessed vaccine hesitancy among staff and incarcerated adults in one rural medium-security prison in the Midwestern United States and identified differences in hesitancy across sociodemographic and work-related variables., Methods: 610 prison staff and people incarcerated completed a cross-sectional survey in May 2021. The vaccine hesitancy scale (VHS) identified perceived risk and confidence in vaccination. A single item assessed whether people typically follow public health protocols in the prison. A combination of analyses was utilized, including ANOVA, Chi-Square, and Pearson's correlation., Results: Vaccine hesitancy was moderate to high for both populations. Incarcerated people had more confidence in vaccination than staff; differences did not reach statistical significance. Incarcerated people had statistically significantly higher perceptions of risk compared to staff. Both populations reported doing their best to follow public health protocols. For both populations, vaccine hesitancy varied by education and veteran status. Among staff, hesitancy varied by gender and political beliefs. For people incarcerated, it varied by pre-incarceration income and visit frequency., Conclusions: Results support the need for public health policy and procedural interventions to reduce hesitancy towards vaccination in correctional settings., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kelli E. Canada reports financial support was provided by Urban Institute., (© 2023 The Author(s).)

Two groups of mice were exposed to stimulus discrimination training and testing under different motivational conditions to study interactions between motivating operations (MOs) during initial discrimination training and MOs when performance is tested following training. One group received all discrimination training sessions under 24-h food deprivation while the other received all sessions under 0-h food deprivation. The number of responses allowed during discrimination training sessions was limited such that the two groups experienced the same number of response-outcome contingencies. The groups then received two post-discrimination training tests: one conducted under 24-h food deprivation and the other conducted under 0-h food deprivation. Results indicated no difference between groups in terms of discrimination ratio. However, subjects trained under 24-h deprivation made more responses in the 24-h test, while subjects trained under 0-h deprivation made more responses in the 0-h test. These results are discussed in terms of motivational state-dependent learning., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Rationale: It is unclear whether the frequency and mechanisms of expiratory flow limitation (EFL) during exercise differ between males and females., Purpose: This study aimed to determine which factors predispose individuals to EFL during exercise and whether these factors differ based on sex. We hypothesized that i) EFL frequency would be similar in males and females and ii) in females, EFL would be associated with indices of low ventilatory capacity, whereas in males, EFL would be associated with indices of high ventilatory demand., Methods: Data from n = 126 healthy adults (20-45 y, n = 60 males, n = 66 females) with a wide range of cardiorespiratory fitness (81%-182% predicted maximal oxygen uptake) were included in the study. Participants performed spirometry and an incremental cycle exercise test to exhaustion. Standard cardiorespiratory variables were assessed throughout exercise. The tidal flow-volume overlap method was used to assess EFL based on a minimum threshold of 5% overlap between the tidal and the maximum expiratory flow-volume curves. Predictors of EFL during exercise were determined via multiple logistical regression using anthropometric, pulmonary function, and peak exercise data., Results: During exercise, EFL occurred in 49% of participants and was similar between the sexes (females = 45%, males = 53%; P = 0.48). In males, low forced expired flow between 25% and 75% of forced vital capacity and high slope ratio as well as low end-expiratory lung volume, high breathing frequency, and high relative tidal volume at peak exercise were associated with EFL ( P < 0.001; Nagelkerke R2 = 0.73). In females, high slope ratio, high breathing frequency, and tidal volume at peak exercise were associated with EFL ( P < 0.001; Nagelkerke R2 = 0.61)., Conclusions: Despite sex differences in respiratory system morphology, the frequency and the predictors of EFL during exercise do not substantially differ between the sexes., (Copyright © 2022 by the American College of Sports Medicine.)

Optical coherence tomography (OCT) is an imaging methodology that can be used to assess human airways. OCT avoids the harmful effects of ionizing radiation and has a high spatial resolution making it well suited for imaging the structure of small airways. Analysis of OCT airway images has typically been performed manually by tracing the airway with a relatively high coefficient of variation. The purpose of this study was to develop an analysis tool to reduce the inter- and intra-observer reproducibility of OCT and improve the ability to detect differences in airways. OCT images from healthy, young human volunteers were used to develop and test the OCT software. Measurement software was developed to allow the conversion of the original image into a grayscale image and was followed by an enhancement operation to brighten the image, and contour measurement. A total of 140 OCT images, 70 small (<2 mm) and 70 medium (2-4 mm) sized airways were analyzed. The inter- and intraobserver reproducibility of airway measurements ranged for strong to very strong in the small-sized airways. For medium-sized airways the reproducibility was considered moderate. Bland-Altman bias was low between observers and observations for all measures. The minimal detectable differences in the airway measurements with our semi-automated software were lower relative to manual tracing in medium-sized airways. Our software improves the ability to perform quantitative OCT analysis and may help to quantify the extent of airway remodelling in respiratory disease or elite athletes in future studies., (© 2022 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Cervical spinal cord injury (C-SCI) negatively impacts cardiac and respiratory function. As the heart and lungs are linked via the pulmonary circuit these systems are interdependent. Here, we utilized inspiratory and expiratory loading to assess whether augmenting the respiratory pump improves left-ventricular (LV) filling and output in individuals with motor-complete C-SCI. We hypothesized LV end-diastolic volume (LVEDV) would increase and decrease with inspiratory and expiratory loading, respectively. Participants (C-SCI: 7M/1F, 35 ± 7 years; able-bodied: 7M/1F, 32 ± 6 years) were assessed under five conditions during 45° head-up tilt; unloaded, inspiratory loading with -10 and -20 cmH 2 O oesophageal pressure (P oes ) on inspiration, and expiratory loading with +10 and +20 cmH 2 O P oes on expiration. An oesophageal balloon catheter monitored P oes , and LV structure and function were assessed by echocardiography. In C-SCI only, (1) +20 cmH 2 O reduced LVEDV vs. unloaded (81 ± 15 vs. 88 ± 11 ml, P = 0.006); (2) heart rate was higher during +20 cmH 2 O compared to unloaded (P = 0.001) and +10 cmH 2 O (P = 0.002); (3) cardiac output was higher during +20 cmH 2 O than unloaded (P = 0.002); and (4) end-expiratory lung volume was higher during +20 cmH 2 O vs. unloaded (63 ± 10 vs. 55 ± 13% total lung capacity, P = 0.003) but was unaffected by inspiratory loading. In both groups, -10 and -20 cmH 2 O had no significant effect on LVEDV. These findings suggest greater expiratory positive pressure acutely impairs LV filling in C-SCI, potentially via impaired venous return, mediastinal constraint and/or direct ventricular interaction subsequent to dynamic hyperinflation. Inspiratory loading did not significantly improve LV function in C-SCI and neither inspiratory nor expiratory loading affected cardiac function or lung volumes in able-bodied participants. KEY POINTS: Cervical spinal cord injury (C-SCI) alters both the cardiac and the respiratory system, but little is known about how these systems interact following injury. Here, we manipulated inspiratory or expiratory intrathoracic pressure (ITP) to mechanistically test the role of the respiratory pump in circulatory function in highly trained individuals with C-SCI and an able-bodied reference group. In individuals with C-SCI, greater ITP during expiratory loading caused dynamic hyperinflation that was associated with impaired left-ventricular filling. More negative ITP during inspiratory loading did not significantly alter left-ventricular volumes in either group. Interventions that prevent dynamic hyperinflation and/or enhance the ability to generate expiratory pressures may help preserve left-ventricular filling in individuals with C-SCI., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Disruption of endogenous pain control mechanisms including descending pain inhibition has been linked to several forms of pain including chronic pain after traumatic brain injury (TBI). The locus coeruleus (LC) is the principal noradrenergic (NA) nucleus participating in descending pain inhibition. We therefore hypothesized that selectively stimulating LC neurons would reduce nociception after TBI. All experiments used a well-characterized rat lateral fluid percussion model of TBI. NA neurons were stimulated by administering clozapine N-oxide (CNO) to rats selectively expressing a designer receptor exclusively activated by designer drug (DREADD) viral construct in their LC's. Mechanical nociceptive thresholds were measured using von Frey fibers. The efficacy of diffuse noxious inhibitory control (DNIC), a critical endogenous pain control mechanism, was assessed using the hindpaw administration of capsaicin. Immunohistochemical analyses demonstrated the selective expression of the DREADD construct in LC neurons after stereotactic injection. During the 1st week after TBI, when rats demonstrated hindlimb (HL) nociceptive sensitization, CNO administration provided transient anti-allodynia in DREADD-expressing rats but not in rats injected with control virus. Seven weeks after TBI we observed a complete loss of DNIC in response to capsaicin. However, CNO administration largely restored DNIC in TBI DREADD-expressing rats but not those injected with control virus. Unexpectedly, the effects of LC activation in the DREADD-expressing rats were blocked by the α-1 adrenergic receptor antagonist prazosin, but not the α-2 adrenergic receptor antagonist atipamezole. These results suggest that directly stimulating the LC after TBI can reduce both early and late manifestations of dysfunctional endogenous pain regulation. Clinical approaches to activating descending pain circuits may reduce suffering in those with pain after TBI.

Acute respiratory distress syndrome (ARDS) is a lung injury characterized by noncardiogenic pulmonary edema and hypoxic respiratory failure. The purpose of this study was to investigate the effects of therapeutic hypothermia on short-term experimental ARDS. Twenty adult female Yorkshire pigs were divided into four groups (n = 5 each): normothermic control (C), normothermic injured (I), hypothermic control (HC), and hypothermic injured (HI). Acute respiratory distress syndrome was induced experimentally via intrapulmonary injection of oleic acid. Target core temperature was achieved in the HI group within 1 h of injury induction. Cardiorespiratory, histologic, cytokine, and metabolomic data were collected on all animals prior to and following injury/sham. All data were collected for approximately 12 h from the beginning of the study until euthanasia. Therapeutic hypothermia reduced injury in the HI compared to the I group (histological injury score = 0.51 ± 0.18 vs. 0.76 ± 0.06; p = 0.02) with no change in gas exchange. All groups expressed distinct phenotypes, with a reduction in pro-inflammatory metabolites, an increase in anti-inflammatory metabolites, and a reduction in inflammatory cytokines observed in the HI group compared to the I group. Changes to respiratory system mechanics in the injured groups were due to increases in lung elastance (E) and resistance (R) (ΔE from pre-injury = 46 ± 14 cmH 2 O L -1 , p < 0.0001; ΔR from pre-injury: 3 ± 2 cmH 2 O L -1  s - , p = 0.30) rather than changes to the chest wall (ΔE from pre-injury: 0.7 ± 1.6 cmH 2 O L -1 , p = 0.99; ΔR from pre-injury: 0.6 ± 0.1 cmH 2 O L -1  s - , p = 0.01). Both control groups had no change in respiratory mechanics. In conclusion, therapeutic hypothermia can reduce markers of injury and inflammation associated with experimentally induced short-term ARDS., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Despite accumulating evidence in rodents, the functional role of neuromedin B (NMB) in regulating somatosensory systems in primate spinal cord is unknown. We aimed to compare the expression patterns of NMB and its receptor (NMBR) and the behavioral effects of intrathecal (i.t.) NMB with gastrin-releasing peptide (GRP) on itch or pain in non-human primates (NHPs). We used six adult rhesus monkeys. The mRNA or protein expressions of NMB, GRP, and their receptors were evaluated by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, or in situ hybridization. We determined the behavioral effects of NMB or GRP via acute thermal nociception, capsaicin-induced thermal allodynia, and itch scratching response assays. NMB expression levels were greater than those of GRP in the dorsal root ganglia and spinal dorsal horn. Conversely, NMBR expression was significantly lower than GRP receptor (GRPR). I.t. NMB elicited only mild scratching responses, whereas GRP caused robust scratching responses. GRP- and NMB-elicited scratching responses were attenuated by GRPR (RC-3095) and NMBR (PD168368) antagonists, respectively. Moreover, i.t. NMB and GRP did not induce thermal hypersensitivity and GRPR and NMBR antagonists did not affect peripherally elicited thermal allodynia. Consistently, NMBR expression was low in both itch- and pain-responsive neurons in the spinal dorsal horn. Spinal NMB-NMBR system plays a minimal functional role in the neurotransmission of itch and pain in primates. Unlike the functional significance of the GRP-GRPR system in itch, drugs targeting the spinal NMB-NMBR system may not effectively alleviate non-NMBR-mediated itch., (Copyright © 2022. Published by Elsevier Inc.)

Many types of solid tumors metastasize to the bone, where it causes significant morbidity and mortality in patients with advanced disease. Bone metastases are not only incurable but also affect bone health which impairs patients' quality of life. In order to understand the mechanisms and develop effective treatments for bone-metastatic disease, it is first necessary to develop animal models that permit the assessment of tumor growth in the bone and progressive structural changes of the bone simultaneously. Longitudinal analysis of bone tumor progression is generally performed by bioluminescent imaging; however, this method is not able to assess progressive structural changes of the bone. Here, we describe a simple method for assessment of bone lesions using a scoring system that takes into account disease burden and bone destruction using longitudinal radiographs., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

Music and metronomes differentially impact movement performance. The current experiment presented metronome and drum beats in simple and complex rhythms before goal-directed reaching movements, while also quantifying enjoyment. Auditory conditions were completed with and without visual feedback and were blocked and counterbalanced. There were no differences between simple and complex rhythms, indicating that rhythmic information alone is sufficient to benefit performance. The drum elicited shorter movement times and higher peak velocities, without an increase in spatial variability. Reaction times were moderately correlated with ratings of enjoyment. These data provide evidence that the source of an auditory stimulus impacts movement performance of a goal-directed reaching task. Results are contextualized within models of goal-directed reaching to elucidate mechanisms contributing to performance improvements.

We examined the relationship between the work of breathing (W b ) during exercise and in vivo measures of airway size in healthy females and males. We hypothesized that sex differences in airway luminal area would explain the larger resistive W b during exercise in females. Healthy participants ( n = 11 females and n = 11 males; 19-30 yr) completed a cycle exercise test to exhaustion where W b was assessed using an esophageal balloon catheter. On a separate day, each participant underwent a bronchoscopy procedure for optical coherence tomography measures of seven airways. In vivo measures of luminal area were made for the fourth to eighth airway generations. A composite index of airway size was calculated as the sum of the luminal area for each generation, and the total area was calculated based on Weibel's model. We found that index of airway size (males: 37.4 ± 6.3 mm 2 vs. females: 27.5 ± 7.4 mm 2 ) and airway area calculated based on Weibel's model (males: 2,274 ± 557 mm 2 vs. females: 1,594 ± 389 mm 2 ) were significantly larger in males (both P = 0.003). When minute ventilation was greater than ∼60 L·min -1 , the resistive W b was higher in females. At the highest equivalent flow achieved by all subjects, resistance to inspired flow was larger in females and significantly associated with two measures of airway size in all subjects: index of airway size ( r = 0.524, P = 0.012) and Weibel area ( r = 0.525, P = 0.012). Our findings suggest that innate sex differences in luminal area result in a greater resistive W b during exercise in females compared with males. NEW & NOTEWORTHY We hypothesized that the higher resistive work of breathing in females compared with males during high-intensity exercise is due to smaller airways. In vivo measures of the fourth to eighth airway generations made using optical coherence tomography show that females tend to have smaller airway luminal areas of the fourth to sixth airway generations. Sex differences in airway luminal area result in a greater resistive work of breathing during exercise in females compared with males.

Rhythmic auditory stimuli presented before a goal-directed movement have been found to improve temporal and spatial movement outcomes. However, little is known about the mechanisms mediating these benefits. The present experiment used three types of auditory stimuli to probe how improved scaling of movement parameters, temporal preparation and an external focus of attention may contribute to changes in movement performance. Three types of auditory stimuli were presented for 1200 ms before movement initiation; three metronome beats (RAS), a tone that stayed the same (tone-same), a tone that increased in pitch (tone-change) and a no sound control, were presented with and without visual feedback for a total of eight experimental conditions. The sound was presented before a visual go-signal, and participants were instructed to reach quickly and accurately to one of two targets randomly identified in left and right hemispace. Twenty-two young adults completed 24 trials per blocked condition in a counterbalanced order. Movements were captured with an Optotrak 3D Investigator, and a 4(sound) by 2(vision) repeated measures ANOVA was used to analyze dependant variables. All auditory conditions had shorter reaction times than no sound. Tone-same and tone-change conditions had shorter movement times and higher peak velocities, with no change in trajectory variability or endpoint error. Therefore, rhythmic and non-rhythmic auditory stimuli impacted movement performance differently. Based on the pattern of results we propose multiple mechanisms impact movement planning processes when rhythmic auditory stimuli are present., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

How to optimize practice through scheduling of different task components or skills is a question that has received a lot of attention in motor learning research. Consistently, schedules with high variability in the order that skills are practiced elicit better learning outcomes than schedules with low variability. Another idea is that learners should seek to reduce the uncertainty of practice outcomes, by avoiding well-learned, low error components in acquisition. To test this idea, we used a target exclusion method to prevent learners from returning to task components with low error and studied how individuals given choice over practice choose to allocate time to components of varying difficulty. In a multi-target adaptation paradigm, we compared exclusion with no exclusion methods in random-schedule, self-control and yoked, matched-schedule groups (6 groups total). To manipulate uncertainty, we excluded targets from practice once participants attained a criterion error score (mean < 5 o ) from the last 5 trials to the same target. Contrary to our predictions, groups that practiced without target exclusion were more accurate in retention compared to exclusion groups; irrespective of practice schedule. Self-control groups adopted uncertainty-based practice, spending more time at difficult targets and less time at easier targets. However, there were no group differences in error, based on schedule-type (random, self-control and yoked). In conclusion, target exclusion was not an effective method for learning and did not support the efficacy of uncertainty-based practice for learning novel skills. There were benefits from keeping easier/low error skills in practice for later retention. These benefits did not appear to be related to the increased switching between skills, but could be related to increased task engagement and more optimal challenge associated with practice on a range of target difficulties, rather than the most difficult., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rationale: The pathophysiology of interstitial lung disease (ILD) impacts body composition, whereby ILD severity is linked to lower lean mass., Objectives: To determine i) if pectoralis muscle area (PMA) is a surrogate for whole-body lean mass in ILD, ii) whether PMA is associated with ILD severity, and iii) if the longitudinal change in PMA is associated with pulmonary function and mortality in ILD., Methods: Patients with ILD (n = 164) were analyzed retrospectively. PMA was quantified from a chest computed tomography scan. Peripheral oxygen saturation (SpO 2 ), 6-min walk distance (6MWD), and pulmonary function were obtained as part of routine clinical care. Dyspnea and quality of life were assessed using the UCSD Shortness of Breath Questionnaire and European Quality of Life 5 Dimensions questionnaire, respectively., Results: PMA was associated with whole-body lean mass (p < 0.001). After adjusting for age, sex, height, body mass, and prednisone status, PMA was associated with %-predicted forced vital capacity (FVC), %-predicted diffusion capacity (DL CO ), resting and exertional SpO 2 , and dyspnea (all p < 0.05), but not forced expiratory volume in 1 s (FEV 1 ), FEV 1 /FVC, 6MWD, or quality of life (all p > 0.05). The annual negative PMA slope was associated with annual negative slopes in FVC, FEV 1 , and DL CO (all p < 0.05), but not FEV 1 /FVC (p = 0.46). Annual slope in PMA was associated with all-cause mortality (hazard ratio = -0.80, 95% CI:0.889-0.959; p < 0.001)., Conclusion: In patients with ILD, PMA is a suitable surrogate for whole-body lean mass. A lower PMA is associated with indices of ILD severity, which supports the notion that ILD progression may involve sarcopenia., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Abnormal outgrowth of sensory nerves is one of the important contributors to pain associated with cancer and its treatments. Primary neuronal cultures derived from dorsal root ganglia (DRG) have been widely used to study pain-associated signal transduction and electrical activity of sensory nerves. However, there are only a few studies using primary DRG neuronal culture to investigate neurite outgrowth alterations due to underlying cancer-related factors and chemotherapeutic agents. In this study, primary DRG sensory neurons derived from mouse, non-human primate, and human were established in serum and growth factor-free conditions. A bovine serum albumin gradient centrifugation method improved the separation of sensory neurons from satellite cells. The purified DRG neurons were able to maintain their heterogeneous subpopulations, and displayed an increase in neurite growth when exposed to cancer-derived conditioned medium, while they showed a reduction in neurite length when treated with a neurotoxic chemotherapeutic agent. Additionally, a semi-automated quantification method was developed to measure neurite length in an accurate and time-efficient manner. Finally, these exogenous factors altered the gene expression patterns of murine primary sensory neurons, which are related to nerve growth, and neuro-inflammatory pain and nociceptor development. Together, the primary DRG neuronal culture in combination with a semi-automated quantification method can be a useful tool for further understanding the impact of exogenous factors on the growth of sensory nerve fibers and gene expression changes in sensory neurons., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Airway luminal area (A i ) influences respiratory mechanics during dynamic exercise; however, previous studies have investigated the relationship between airway anatomy and physiological function in different groups of individuals. The purpose of this study was to determine the effect of A i on respiratory mechanics by making in vivo measures of airway dimensions and work of breathing (Wb) in the same individuals. Healthy participants (3F/2M; 23-45 years) completed a cycle exercise test to exhaustion. During exercise, Wb was assessed using an esophageal balloon catheter, while simultaneously assessing minute ventilation ( V ˙ E ). On a separate day, subjects underwent a bronchoscopy procedure to capture optical coherence tomography (OCT) measures of three airways in the right lung. Each participant's Wb- V ˙ E data were fit to a non-linear regression equation (Wb = a V ˙ E 3  + b V ˙ E 2 ) that partitions Wb into its turbulent resistive (a) and viscoelastic (b) components. Measures of A i and luminal diameter were made for the 4th-6th airway generations. A composite index of airway size was calculated as the sum of the A i for each generation and the total area of the 4th-6th generation was calculated based on Weibel's model. Constant a was significantly correlated to the Weibel model total airway area (r = -0.94, p = 0.017) and index of airway size (r = -0.929, p = 0.023), whereas constant b was not associated with either measure (both p > 0.05). We found that individuals who had the smallest A i had the highest resistive Wb and our findings provide the basis for further study of the relationship between airway size and respiratory mechanics during exercise., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Beta 2 adrenergic receptor (β2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of β2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the β2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of β2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined β2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of β2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of β2-AR agonists to models of surgical injury.

New Findings: What is the central question of this study? How does sternocleidomastoid blood flow change in response to increasing ventilation and whole-body exercise intensity? What is the main finding and its importance? Sternocleidomastoid blood flow increased with increasing ventilation. For a given ventilation, sternocleidomastoid blood flow was lower during whole-body exercise compared to resting hyperpnoea. These findings suggest that locomotor muscle work exerts an effect on respiratory muscle blood flow that can be observed in the sternocleidomastoid., Abstract: Respiratory muscle work influences the distribution of blood flow during exercise. Most studies have focused on blood flow to the locomotor musculature rather than the respiratory muscles, owing to the complex anatomical arrangement of respiratory muscles. The purpose of this study was to examine how accessory respiratory (i.e. sternocleidomastoid, and muscles in the intercostal space) muscle blood flow changes in response to locomotor muscle work. Seven men performed 5 min bouts of constant load cycling exercise trials at 30%, 60% and 90% of peak work rate in a randomized order, followed by 5 min bouts of voluntary hyperpnoea (VH) matching the ventilation achieved during each exercise (EX) trial. Blood-flow index (BFI) of the vastus lateralis, sternocleidomastoid (SCM) and seventh intercostal space (IC) were estimated using near-infrared spectroscopy and indocyanine green and expressed relative to resting levels. BFI SCM was greater during VH compared to EX (P = 0.002) and increased with increasing exercise intensity (P = 0.036). BFI SCM reached 493 ± 219% and 301 ± 215% rest during VH and EX at 90% peak work rate, respectively. BFI IC increased to 242 ± 178% and 210 ± 117% rest at 30% peak work rate during VH and EX, respectively. No statistically significant differences in BFI IC were observed with increased work rate during VH or EX (both P > 0.05). Moreover, there was no observed difference in BFI IC between conditions (P > 0.05). BFI SCM was lower for a given minute ventilation during EX compared to VH, suggesting that accessory respiratory muscle blood flow is influenced by whole-body exercise., (© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society.)

Swimmers have a high prevalence of exercise-induced bronchoconstriction (EIB), which may be associated with repeated exposure to chlorinated pool water. The eucapnic voluntary hyperpnea (EVH) test is used to diagnose EIB; however, it fails to replicate the environmental conditions experienced by swimmers. The relationship between the composition of the EVH inspired gas and the development of EIB from swim exercise remains unclear., Purpose: This study aimed to compare the bronchoconstrictive effect of a chlorinated inspirate EVH test and swim test to a laboratory-based EVH test in swimmers., Methods: Fifteen collegiate swimmers (n = 5 male, n = 10 female; 21 ± 2 yr) completed 3 d of testing in pseudorandom order; a standard EVH test (EVHL), a pool air EVH test (EVHCl), and a swimming test (Swim). Spirometry was measured at baseline, and 3, 5, 10, 15, and 20 min after each test., Results: EVHL elicited a forced expired volume in 1 s (FEV1) fall index of -9.7% ± 6.4% compared with -6.6% ± 9.2% and -3.0% ± 7.5% after EVHCl and Swim, respectively (P < 0.05). Using Bland-Altman analysis, we found good agreement between EVHL and EVHCl (bias = -2.8, r = 0.79; P < 0.05) with poor agreement between EVHL and Swim (bias = -6.7, r = 0.20) and between EVHCl and Swim (bias = -3.9, r = 0.50; both P < 0.05). Forced expired flow between 25% and 75% lung volume and peak expired flow were significantly reduced by the EVHL compared with the EVHCl and Swim tests (P < 0.05)., Conclusions: EVHL elicits a greater forced expired volume in 1-s fall index compared with EVHCl and Swim. The unique aquatic environment of swimmers potentially protects against bronchoconstriction and should be considered in the determination of EIB.

Rhythmic auditory stimuli (RAS) have been proposed to improve motor performance in populations with and without sensorimotor impairments. However, the reasons for the reported benefits are poorly understood. One idea is that RAS may supplement intrinsic feedback when other sensory input is diminished. The current experiment tested this idea by removing vision during a goal-directed reaching task. We hypothesized that any improvements in movement performance due to the RAS would be greater when vision was removed. Twenty-two typically developing adults performed reaching movements to one of two targets with RAS presented before movement initiation, after movement initiation, both before and after movement initiation, and no sound, all with and without vision. Dependent variables were analyzed using a 2 vision by 2 sound-before by 2 sound-during repeated measures ANOVA. Conditions where the metronome was heard before movement initiation yielded shorter and less variable reaction times compared when there was no sound before the movement. The RAS heard before and during the movement independently impacted spatial aspects of the movement. Sound before movement initiation resulted in smaller endpoint error, primarily in the anterior-posterior axis. Sound during the movement resulted in smaller endpoint error, primarily in the mediolateral axis. In no-vision blocks, inclusion of RAS resulted in improved endpoint performance, indicating that RAS supplemented the motor system. The present results strengthen our understanding of sensory integration underlying reaching performance by demonstrating that sound heard before and during a reaching movement can improve motor performance by supplementing the motor system when vision is unavailable., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Background: Our study aim was to evaluate neuromuscular ultrasound (NMUS) for the assessment of taxane chemotherapy-induced peripheral neuropathy (CIPN), the dose-limiting toxicity of this agent., Methods: This cross-sectional study of breast cancer patients with taxane CIPN measured nerve cross-sectional area (CSA) by NMUS and compared with healthy historical controls. Correlations were determined between CSA and symptom scale, nerve conduction studies, and intraepidermal nerve fiber density (IENFD)., Results: A total of 20 participants reported moderate CIPN symptoms at a median of 3.8 months following the last taxane dose. Sural nerve CSA was 1.2 mm 2 smaller than healthy controls (P ≤ .01). Older age and time since taxane were associated with smaller sural nerve CSA. For each 1 mm 2 decrease in sural nerve CSA, distal IENFD decreased by 2.1 nerve/mm (R 2 0.30; P = .04)., Conclusions: These data support a sensory predominant taxane neuropathy or neuronopathy and warrant future research on longitudinal NMUS assessment of CIPN., (© 2020 Wiley Periodicals, Inc.)

Adult survivors of very preterm (≤32 wk gestational age) birth without (PRE) and with bronchopulmonary dysplasia (BPD) have variable degrees of airflow obstruction at rest. Assessment of the shape of the maximal expiratory flow-volume (MEFV) curve in PRE and BPD may provide information concerning their unique pattern of airflow obstruction. The purposes of the present study were to 1 ) quantitatively assess the shape of the MEFV curve in PRE, BPD, and healthy adults born at full-term (CON), 2 ) identify where along the MEFV curve differences in shape existed between groups, and 3 ) determine the association between an index of MEFV curve shape and characteristics of preterm birth (i.e., gestational age, mass at birth, duration of oxygen therapy) in PRE and BPD. To do so, we calculated the average slope ratio (SR) throughout the effort-independent portion of the MEFV curve and at increments of 5% of forced vital capacity (FVC) between 20 and 80% of FVC in PRE ( n = 19), BPD ( n = 25), and CON ( n = 20). We found that average SR was significantly higher in PRE (1.34 ± 0.35) and BPD (1.33 ± 0.45) compared with CON (1.03 ± 0.22; both P < 0.05) but similar between PRE and BPD ( P = 0.99). Differences in SR between groups occurred early in expiration (i.e., 20-30% of FVC). There was no association between SR and characteristics of preterm birth in PRE and BPD groups (all P > 0.05). The mechanism(s) of increased SR during early expiration in PRE/BPD relative to CON is unknown but may be due to differences in the structural and mechanical properties of the airways.

Key Points: The female diaphragm fatigues at a slower rate compared to that of males, with blunted cardiovascular consequences (i.e. inspiratory muscle metaboreflex). It is unclear if these findings are a function of relative or absolute diaphragmatic work. We asked if sex differences in diaphragm fatigue and the inspiratory muscle metaboreflex persisted during inspiratory loading performed at equal absolute intensities. We found that matching men and women for absolute diaphragmatic work resulted in an equal degree of diaphragm fatigue, despite women performing significantly greater work relative to body mass. Metabolite-induced reflex influences in sympathetic outflow originating from the diaphragm are attenuated in women, with potential implications for blood flow distribution during exercise., Abstract: In response to inspiratory pressure-threshold loading (PTL), women have greater inspiratory muscle endurance time, slower rate of diaphragm fatigue development, and a blunted pressor response compared to men. It is unclear if these differences are due to discrepancies in absolute diaphragm force output. We tested the hypothesis that following inspirations performed at equal absolute intensities, females would develop a similar level of diaphragm fatigue and an attenuated cardiovascular response relative to men. Healthy young men (n = 8, age = 24 ± 3 years) and women (n = 8, age = 23 ± 3 years) performed PTL whilst targeting a transdiaphragmatic pressure (P di ) of 92 cmH 2 O for 5 min. Diaphragm fatigue was assessed via twitch P di (P di,tw ) using cervical magnetic stimulation. Heart rate (HR) and mean arterial blood pressure were monitored continuously. During PTL, the absolute amount of diaphragm work was not different between men (13,399 ± 2019 cmH 2 O s) and women (12,986 ± 1846 cmH 2 O s; P > 0.05); however, women performed the PTL task at a higher relative P ¯ di /P di,max . Following inspiratory PTL, the magnitude of reduction in P di,tw was similar between men (-27.1 ± 7.2%) and women (-23.8 ± 13.8%; P > 0.05). There were significant increases in HR over time (P < 0.05), but this did not differ on the basis of sex (P > 0.05). Mean arterial blood pressure increased significantly over time in both men and women (P < 0.05); however, the rate of change was higher in men (6.24 ± 2.54 mmHg min -1 ) than in women (4.15 ± 2.52 mmHg min -1 ) (P < 0.05). We conclude that the female diaphragm is protected against severe fatigue when inspiratory work is excessive and as a result does not evoke overt sympathoexcitation., (© 2019 The Authors. The Journal of Physiology © 2019 The Physiological Society.)

The thorax undergoes unique conditions while swimming. Hydrostatic pressure from water immersion places an external load on the thorax and increases airway resistance, and the horizontal body position results in central venous engorgement and an associated reduction in lung compliance. The aforementioned factors likely increase the work of breathing (Wb); however, this hypothesis remains untested., Purpose: This study aimed to compare Wb during freestyle swimming relative to cycling and to characterize the differences in the cardiorespiratory responses to swimming relative to cycling in the same individuals., Methods: Eight collegiate swimmers (four men and four women, age = 22 ± 2 yr) performed an incremental swim test while tethered to a resistance apparatus. On a separate day, subjects performed an incremental cycle test. During swimming and cycling, metabolic and ventilatory parameters were measured using a customized metabolic cart, and inspired Wb was quantified using an esophageal balloon catheter., Results: Swimming and cycling elicited statistically similar levels of peak oxygen uptake (3.87 ± 0.92 vs 4.20 ± 0.83 L·min, P = 0.143). However, peak minute ventilation (V˙E) (118 ± 3 vs 154 ± 25 L·min) and heart rate (164 ± 19 vs 183 ± 8 bpm) were significantly lower during swimming relative to cycling (both P < 0.05). Inspired Wb was higher at a V˙E of 50 L·min (+27 ± 16 J·min), 75 L·min (+56 ± 23 J·min), and 100 L·min (+53 ± 22 J·min) during swimming compared with cycling (all P < 0.05). Periods of interbreath apnea were observed while swimming (duration = 0.13-2.07 s)., Conclusion: We interpret our findings to mean that the horizontal body position and hydrostatic pressure on the chest wall requires swimmers to generate greater inspiratory pressures to sustain adequate V˙E during exercise.

Background: The internal validity of long-term studies is significantly affected by the high loss to follow-up in the spine surgery population (>20%). Phone and email-based administration of patient-reported outcomes instruments is a less cumbersome approach for increasing response rates and assessment frequency while potentially decreasing follow-up burden on patients and physicians., Purpose: This study sought to validate simultaneous administration of the Neck Disability Index (NDI) and Japanese Orthopedic Association (JOA) questionnaires in patients with either cervical myelopathy and/or radiculopathy., Study Design/setting: This is a single-center, randomized crossover phone and email validation of legacy outcome measures for cervical myelopathy and/or radiculopathy patients., Patient Sample: The study included nonsurgical along with pre- and postsurgical cervical myelopathy and/or radiculopathy patients presenting to a tertiary spine care center., Outcome Measures: NDI and JOA., Methods: Two-hundred and six patients (mean age: 58.5 years) were randomized in a 1:4 ratio to either email completion of the NDI and JOA before or after in-office completion, or to phone completion before or after in-office completion. An interval of 1 to 4 weeks was established between the administration of questionnaires. The difference between written in-office and corresponding email and phone versions was assessed with a paired t test. Homogeneity was assessed using intraclass correlation coefficients. Test-retest reliabilities were independently examined for postoperative patients (n=145). Recall bias was assessed in postoperative patients by calculating intraclass correlation coefficients for those with days between assessments lesser than the mean and for those greater. Differences in response rates between phone and email versions were assessed with McNemar's and Cochran-Mantel-Haenszel tests., Results: There was no significant difference between email and in-office versions (n=85) of the NDI (p=.17, Mean Paired Difference=1.34) and JOA (p=.64, Mean Paired Difference=0.11). No significant difference was seen between phone followed by in-office administration (n=32) of the NDI (p=.88, Mean Paired Difference=0.22) and JOA (p=.38, Mean Paired Difference=-0.22), nor between in-office administration followed by phone (n=44) for the NDI (p=.10, Mean Paired Difference=2.79) and JOA (p=.37, Mean Paired Difference=0.27). Intraclass coefficients (ICCs) of the email versions of the NDI and JOA were 0.88 and 0.78, respectively; of the phone-before-office versions of the NDI and JOA were 0.91 and 0.82; of the office-before-phone versions were 0.86 and 0.78. Similarly, strong intraclass correlation coefficients indicative of a lack of recall bias were found for "In-Office" and external assessments completed by postsurgical patients with days between assessments lesser and greater than the mean (ICC range 0.63-0.92). No significant difference was seen in completion rates between email and in-office questionnaire completion (p=.13) and phone-before-office and in-office questionnaire completion (p=.31). However, a significant difference was found in completion rates for phone-after-office questionnaires (p<.001)., Conclusions: Administration of the NDI and JOA over phone and email in patients with cervical myelopathy or radiculopathy is valid with strong test-retest reliability and internal consistency. Phone and email administration of the NDI and JOA can reduce nonresponse rates and decrease the burden of follow-up and data acquisition. Follow-up phone reminders increase the response rate for administration of these patient-reported outcomes (PROs) via email., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Two experiments examined interactions between the effects of food and water motivating operations (MOs) on the food- and water-reinforced operant behavior of mice. In Experiment 1, mice responded for sucrose pellets and then water reinforcement under four different MOs: food deprivation, water deprivation, concurrent food and water deprivation, and no deprivation. The most responding for pellets occurred under food deprivation and the most responding for water occurred under water deprivation. Concurrent food and water deprivation decreased responding for both reinforcers. Nevertheless, water deprivation alone increased pellet-reinforced responding and food deprivation alone likewise increased water-reinforced responding relative to no deprivation. Experiment 2 demonstrated that presession food during concurrent food and water deprivation increased in-session responding for water relative to sessions where no presession food was provided. Conversely, presession water during concurrent food and water deprivation did not increase in-session responding for pellets. These results suggest that a) the reinforcing value of a single stimulus can be affected by multiple MOs, b) a single MO can affect the reinforcing value of multiple stimuli, and c) reinforcing events can also function as MOs. We consider implications for theory and practice and suggest strategies for further basic research on MOs., (© 2019 Society for the Experimental Analysis of Behavior.)

Key Points: The perceived intensity of exertional breathlessness (i.e. dyspnoea) is higher in older women than in older men, possibly as a result of sex-differences in respiratory system morphology. During exercise at a given absolute intensity or minute ventilation, older women have a greater degree of mechanical ventilatory constraint (i.e. work of breathing and expiratory flow limitation) than their male counterparts, which may lead to a greater perceived intensity of dyspnoea. Using a single-blind randomized study design, we experimentally manipulated the magnitude of mechanical ventilatory constraint during moderate-intensity exercise at ventilatory threshold in healthy older men and women. We found that changes in the magnitude of mechanical ventilatory constraint within the physiological range had no effect on dyspnoea in healthy older adults. When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea., Abstract: We aimed to determine the effect of manipulating mechanical ventilatory constraint during submaximal exercise on dyspnoea in older men and women. Eighteen healthy subjects (aged 60-80 years; nine men and nine women) completed two days of testing. On day 1, subjects were assessed for pulmonary function and performed a maximal incremental cycle exercise test. On day 2, subjects performed three 6-min bouts of cycling at ventilatory threshold, in a single-blind randomized manner, while breathing: (i) normoxic helium-oxygen (HEL) to reduce the work of breathing (W b ) and alleviate expiratory flow limitation (EFL); (ii) through an inspiratory resistance (RES) of ∼5 cmH 2 O L -1  s -1 to increase W b ; and (iii) ambient air as a control (CON). Oesophageal pressure, diaphragm electromyography, and sensory responses (category-ratio 10 Borg scale) were monitored throughout exercise. During the HEL condition, there was a significant decrease in W b (men: -21 ± 6%, women: -17 ± 10%) relative to CON (both P < 0.01). Moreover, if EFL was present during CON (four men and five women), it was alleviated during HEL. Conversely, during the RES condition, W b (men: 42 ± 19%, women: 50 ± 16%) significantly increased relative to CON (both P < 0.01). There was no main effect of sex on W b (P = 0.59). Across conditions, women reported significantly higher dyspnoea intensity than men (2.9 ± 0.9 vs. 1.9 ± 0.8 Borg scale units, P < 0.05). Despite significant differences in the degree of mechanical ventilatory constraint between conditions, the intensity of dyspnoea was unaffected, independent of sex (P = 0.46). When older men and women perform moderate intensity exercise, mechanical ventilatory constraint does not contribute significantly to the sensation of dyspnoea., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Background: Given that diabetes-associated complications are closely associated with neuroinflammation, it is imperative to study potential changes in neuroinflammatory modulators in the central nervous system of diabetic primates., Methods: The mRNA levels of pro- and anti-inflammatory cytokines, toll-like receptors (TLRs), growth factors, and cannabinoid receptors were compared in the spinal dorsal horn (SDH) and thalamus of naturally occurring type 2 diabetic monkeys and an age-matched control group using reverse transcription and quantitative real-time polymerase chain reaction., Results: In the SDH of diabetic monkeys, mRNA levels of proinflammatory cytokines (i.e. interleukin [IL]-1β and tumor necrosis factor [TNF] α), TLR1, and TLR2 were increased, whereas mRNA levels of IL-10, an anti-inflammatory cytokine, were decreased. No changes were observed in the mRNA levels of growth factors and cannabinoid receptors. In line with the mRNA data, TNFα immunoreactivity was significantly increased in diabetic monkeys. Moreover, mRNA expression levels of IL-1β, TNFα, TLR1, and TLR2 in the SDH were positively correlated with plasma glucose concentrations in all monkeys., Conclusions: Several ligands and receptors involved in neuroinflammation are simultaneously dysregulated in the spinal cord of diabetic monkeys. This primate disease model will facilitate the design of novel treatment approaches to ameliorate neuroinflammation-driven adverse effects in diabetic patients., (© 2018 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Recovery from pain after surgery is faster after cesarean delivery than after other abdominal procedures. The authors hypothesized that recovery in rats after surgery could be reversed by antagonism of spinal oxytocin or vasopressin receptors, that there may be a sex difference, and that spinal oxytocin innervation could change after surgery., Methods: Male and female rats underwent partial spinal nerve ligation surgery. Effects of nonselective and selective oxytocin and vasopressin 1A receptor antagonists on mechanical hypersensitivity during partial recovery were assessed (n = 8 to 14/group). Oxytocin immunoreactivity in the dorsal horn of the spinal cord (n = 7 to 8/group) and messenger RNA (mRNA) expression for oxytocin-binding receptors in dorsal root ganglia and spinal cord (n = 8/group) were measured., Results: Intrathecal injection of oxytocin and vasopressin receptor antagonists were similarly effective at reducing withdrawal threshold (in all experiments from 22 [19, 26] median [first quartile, third quartile]) g to 8.3 [6.4, 12] g after injection) in both sexes, while having no or minimal effects in animals without surgery. Oxytocin fiber immunoreactivity was 3- to 5-fold greater in lumbar than other regions of the spinal cord and was increased more than 2-fold in lumbar cord ipsilateral to surgery. Injury was also associated with a 6.5-fold increase in oxytocin receptor and a 2-fold increase in vasopressin 1A receptor messenger RNA expression in the L4 dorsal root ganglion ipsilateral to surgery., Conclusions: These findings suggest that the capacity for oxytocin signaling in the spinal cord increases after surgery and that spinal oxytocin signaling plays ongoing roles in both sexes in recovery from mechanical hypersensitivity after surgery with known nerve injury.

Psychosocial factors such as anxiety, depression and catastrophizing, commonly associated with established chronic pain, also may be associated with an increased risk of chronic postsurgical pain (CPSP) when present preoperatively. We used a repeat social defeat (RSD) paradigm to induce psychosocial stress in rodents prior to incisional surgery of the paw. Mixed effects growth curve models were utilized to examine resolution of mechanical hypersensitivity in rats for four weeks following surgery. Eight days following surgery, immunohistochemistry was conducted to examine glial activation as well as evoked neuronal activation in the spinal cord. Here we document that RSD resulted in reduced weight gain and increased depressive symptoms prior to surgery. Rats exposed to RSD displayed delayed resolution of mechanical hypersensitivity in the ipsilateral paw following surgery compared to non-defeated rats. Prior exposure to RSD significantly increased microglial activation and neuronal sensitization (pERK-IR) within the ipsilateral spinal cord. In conclusion, we found that chronic social stress alters the neurobiological response to surgical injury, resulting in slowed recovery. This model maybe useful for future interventional studies examining the mechanistic interactions between depression and risk of CPSP., (Published by Elsevier Ltd.)

Background Context: Recombinant human bone morphogenetic protein 2 (rhBMP-2) plays a pivotal role in complex spine surgery. Despite its limited approval, the off-label use of rhBMP-2 is prevalent, particularly in transforaminal lumbar interbody fusions (TLIFs)., Purpose: To determine the effectiveness and safety of rhBMP-2 use in TLIF procedures versus autograft., Study Design: Retrospective cohort study., Patient Sample: Patients older than 18 years undergoing spine surgery for lumbar degenerative spine disease at a single academic institution., Outcome Measures: Clinical outcome was determined according to patient records. Radiographic outcome was determined according to plain X-rays and computed tomography (CT)., Methods: A retrospective study from 1997 to 2014 was conducted on 191 adults undergoing anterior-posterior instrumented spinal fusion with TLIF at a single academic institution. Patient data were gathered from operative notes, follow-up clinic notes, and imaging studies to determine complications and fusion rates. One hundred eighty-seven patients fit the criteria, which included patients with a minimum of one TLIF, and had a minimum 2-year radiographic and clinical follow-up. Patients were further classified into a BMP group (n=83) or non-BMP group (n=104). Three logistic regression models were run using rhBMP-2 exposure as the independent variable. The respective outcome variables were TLIF-related complications (radiculitis, seroma, osteolysis, and ectopic bone), surgical complications, and all complications., Results: Bone morphogenetic protein (n=83) and non-BMP (n=104) groups had similar baseline demographics (sex, diabetes, pre-existing cancer). On average, the BMP and non-BMP groups were similarly aged (51.9 vs. 47.9 years, p>.05), but the BMP group had a shorter follow-up time (3.03 vs. 4.06 years; p<.001) and fewer smokers (8 vs. 21 patients; p<.048). The fusion rate for the BMP and non-BMP groups was 92.7% and 92.3%, respectively. The pseudoarthrosis rate was 7.5% (14 of 187 patients). Radiculitis was observed in seven patients in the BMP group (8.4%) and two patients in the non-BMP group (1.9%). Seroma was observed in two patients in the BMP group (2.4%) and none in the non-BMP group. No deep infections were observed in the BMP group, and in one patient in the non-BMP group (0.96%). Although patients exposed to BMP were at a significantlygreater risk of developing radiculitis and seroma (odds ratio [OR]=4.53, confidence interval [CI]=1.42-14.5), BMP exposure was not a significant predictor of surgical complications (OR=0.32, CI=0.10-1.00) or overall complications (OR=1.11, CI=0.53-2.34). The outcome of TLIF-related complications was too rare and the confidence interval too wide for practical significance of the first model., Conclusion: Evidence supports the hypothesis that off-label use of rhBMP-2 in TLIF procedures is relatively effective for achieving bone fusion at rates similar to patients receiving autograft. Patients exhibited similar complication rates between the two groups, with the BMP group exhibiting slightly higher rates of radiculitis and seroma., (Copyright © 2017 Elsevier Inc. All rights reserved.)