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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

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.)

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.)

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).)

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.)

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.)

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.

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.)

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.

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.

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.)

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.

Adeno-associated virus (AAV) is frequently used to manipulate gene expression in the sensory nervous system for the study of pain mechanisms. Although some serotypes of AAV are known to have nerve tropism, whether AAV can distribute to sensory nerves that innervate the bone or skeletal tissue has not been shown. This information is crucial, since bone pain, including cancer-induced bone pain, is an area of high importance in pain biology. In this study, we found that AAVrh10 transduces neurons in the spinal cord and dorsal root ganglia of immunodeficient mice with higher efficacy than AAV2, 5, 6, 8, and 9 when injected intrathecally. Additionally, AAVrh10 has tropism towards sensory neurons in skeletal tissue, such as bone marrow and periosteum, while it occasionally reaches the sensory nerve fibers in the mouse footpad. Moreover, AAVrh10 has higher tropic affinity to large myelinated and small peptidergic sensory neurons that innervate bone, compared to small non-peptidergic sensory neurons that rarely innervate bone. Taken together, these results suggest that AAVrh10 is a useful gene delivery vector to target the sensory nerves innervating bone. This finding may lead to a greater understanding of the molecular mechanisms of chronic bone pain and cancer-induced bone pain.

New Findings: What is the central question of this study? Does manipulation of the work of breathing during high-intensity exercise alter respiratory and locomotor muscle blood flow? What is the main finding and its importance? We found that when the work of breathing was reduced during exercise, respiratory muscle blood flow decreased, while locomotor muscle blood flow increased. Conversely, when the work of breathing was increased, respiratory muscle blood flow increased, while locomotor muscle blood flow decreased. Our findings support the theory of a competitive relationship between locomotor and respiratory muscles during intense exercise. Manipulation of the work of breathing (WOB) during near-maximal exercise influences leg blood flow, but the effects on respiratory muscle blood flow are equivocal. We sought to assess leg and respiratory muscle blood flow simultaneously during intense exercise while manipulating WOB. Our hypotheses were as follows: (i) increasing the WOB would increase respiratory muscle blood flow and decrease leg blood flow; and (ii) decreasing the WOB would decrease respiratory muscle blood flow and increase leg blood flow. Eight healthy subjects (n = 5 men, n = 3 women) performed a maximal cycle test (day 1) and a series of constant-load exercise trials at 90% of peak work rate (day 2). On day 2, WOB was assessed with oesophageal balloon catheters and was increased (via resistors), decreased (via proportional assist ventilation) or unchanged (control) during the trials. Blood flow was assessed using near-infrared spectroscopy optodes placed over quadriceps and the sternocleidomastoid muscles, coupled with a venous Indocyanine Green dye injection. Changes in WOB were significantly and positively related to changes in respiratory muscle blood flow (r = 0.73), whereby increasing the WOB increased blood flow. Conversely, changes in WOB were significantly and inversely related to changes in locomotor blood flow (r = 0.57), whereby decreasing the WOB increased locomotor blood flow. Oxygen uptake was not different during the control and resistor trials (3.8 ± 0.9 versus 3.7 ± 0.8 l min -1 , P > 0.05), but was lower on the proportional assist ventilator trial (3.4 ± 0.7 l min -1 , P < 0.05) compared with control. Our findings support the concept that respiratory muscle work significantly influences the distribution of blood flow to both respiratory and locomotor muscles., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

New Findings: What is the central question of this study? This study is the first to measure objectively both inspiratory and expiratory muscle fatigue after inspiratory resistive loading to determine whether the expiratory muscles are activated to the point of fatigue when specifically loading the inspiratory muscles. What is the main finding and its importance? The absence of abdominal muscle fatigue suggests that future studies attempting to understand the neural and circulatory consequences of diaphragm fatigue can use inspiratory resistive loading without considering the confounding effects of abdominal muscle fatigue. Expiratory resistive loading elicits inspiratory as well as expiratory muscle fatigue, suggesting parallel coactivation of the inspiratory muscles during expiration. It is unknown whether the expiratory muscles are likewise coactivated to the point of fatigue during inspiratory resistive loading (IRL). The purpose of this study was to determine whether IRL elicits expiratory as well as inspiratory muscle fatigue. Healthy male subjects (n = 9) underwent isocapnic IRL (60% maximal inspiratory pressure, 15 breaths min -1 , 0.7 inspiratory duty cycle) to task failure. Abdominal and diaphragm contractile function was assessed at baseline and at 3, 15 and 30 min post-IRL by measuring gastric twitch pressure (P ga,tw ) and transdiaphragmatic twitch pressure (P di,tw ) in response to potentiated magnetic stimulation of the thoracic and phrenic nerves, respectively. Fatigue was defined as a significant reduction from baseline in P ga,tw or P di,tw . Throughout IRL, there was a time-dependent increase in cardiac frequency and mean arterial blood pressure, suggesting activation of the respiratory muscle metaboreflex. The P di,tw was significantly lower than baseline (34.3 ± 9.6 cmH 2 O) at 3 (23.2 ± 5.7 cmH 2 O, P < 0.001), 15 (24.2 ± 5.1 cmH 2 O, P < 0.001) and 30 min post-IRL (26.3 ± 6.0 cmH 2 O, P < 0.001). The P ga,tw was not significantly different from baseline (37.6 ± 17.1 cmH 2 O) at 3 (36.5 ± 14.6 cmH 2 O), 15 (33.7 ± 12.4 cmH 2 O) and 30 min post-IRL (32.9 ± 11.3 cmH 2 O). Inspiratory resistive loading elicits objective evidence of diaphragm, but not abdominal, muscle fatigue. Agonist-antagonist interactions for the respiratory muscles appear to be more important during expiratory versus inspiratory loading., (© 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.)

Key Points: High work of breathing and exercise-induced arterial hypoxaemia (EIAH) can decrease O 2 delivery and exacerbate exercise-induced quadriceps fatigue in healthy men. Women have a higher work of breathing during exercise, dedicate a greater fraction of whole-body V̇O2 towards their respiratory muscles and develop EIAH. Despite a greater reduction in men's work of breathing, the attenuation of quadriceps fatigue was similar between the sexes. The degree of EIAH was similar between sexes, and regardless of sex, those who developed the greatest hypoxaemia during exercise demonstrated the most attenuation of quadriceps fatigue. Based on our previous finding that women have a greater relative oxygen cost of breathing, women appear to be especially susceptible to work of breathing-related changes in quadriceps muscle fatigue., Abstract: Reducing the work of breathing or eliminating exercise-induced arterial hypoxaemia (EIAH) during exercise decreases the severity of quadriceps fatigue in men. Women have a greater work of breathing during exercise, dedicate a greater fraction of whole-body V̇O2 towards their respiratory muscles, and demonstrate EIAH, suggesting women may be especially susceptible to quadriceps fatigue. Healthy subjects (8 male, 8 female) completed three constant load exercise tests over 4 days. During the first (control) test, subjects exercised at ∼85% of maximum while arterial blood gases and work of breathing were assessed. Subsequent constant load exercise tests were iso-time and iso-work rate, but with EIAH prevented by inspiring hyperoxic gas or work of breathing reduced via a proportional assist ventilator (PAV). Quadriceps fatigue was assessed by measuring force in response to femoral nerve stimulation. For both sexes, quadriceps force was equally reduced after the control trial (-27 ± 2% baseline) and was attenuated with hyperoxia and PAV (-18 ± 1 and -17 ± 2% baseline, P < 0.01, respectively), with no sex difference. EIAH was similar between the sexes, and regardless of sex, subjects with the lowest oxyhaemoglobin saturation during the control test had the greatest quadriceps fatigue attenuation with hyperoxia (r 2  = 0.79, P < 0.0001). For the PAV trial, despite reducing the work of breathing to a greater degree in men (men: 60 ± 5, women: 75 ± 6% control, P < 0.05), the attenuation of quadriceps fatigue was similar between the sexes (36 ± 4 vs. 37 ± 7%). Owing to a greater relative V̇O2 of the respiratory muscles in women, less of a change in work of breathing is needed to reduce quadriceps fatigue., (© 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.)

Study Design: Multicenter retrospective case series and review of the literature., Objective: To determine the rate of esophageal perforations following anterior cervical spine surgery., Methods: As part of an AOSpine series on rare complications, a retrospective cohort study was conducted among 21 high-volume surgical centers to identify esophageal perforations following anterior cervical spine surgery. Staff at each center abstracted data from patients' charts and created case report forms for each event identified. Case report forms were then sent to the AOSpine North America Clinical Research Network Methodological Core for data processing and analysis., Results: The records of 9591 patients who underwent anterior cervical spine surgery were reviewed. Two (0.02%) were found to have esophageal perforations following anterior cervical spine surgery. Both cases were detected and treated in the acute postoperative period. One patient was successfully treated with primary repair and debridement. One patient underwent multiple debridement attempts and expired., Conclusions: Esophageal perforation following anterior cervical spine surgery is a relatively rare occurrence. Prompt recognition and treatment of these injuries is critical to minimizing morbidity and mortality., Competing Interests: Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Stuart H. Hershman reports grants from AOSpine North America during the conduct of the study; William A. Kunkle reports grants from AOSpine North America during the conduct of the study; Michael P. Kelly reports grants from AOSpine North America during the conduct of the study; Wilson Z. Ray reports grants from NIH/NINDs, grants from Department of Defense, grants from DARPA, other from Depuy/Synthes, other from Ulrich, other from Harvest Technologies, outside the submitted work; David B. Bumpass reports grants from AOSpine North America during the conduct of the study, grants from North American Spine Society, personal fees from Doximity, personal fees from Gerson Lehrman Group, outside the submitted work; Jeffrey L. Gum reports grants from AOSpine North America during the conduct of the study, personal fees from Medtronic, Alphatec, Stryker, LifeSpine, Acuity, Pacira, PAKmed, Gerson Lehrman Group, personal fees from OREF, AOSpine, personal fees from Acuity, other from Medtronic, personal fees from MiMedx, Pacira Pharmaceuticals, Alphatec, grants from Fischer Owen Fund, nonfinancial support from American Journal of Orthopaedics, nonfinancial support from American Journal of Orthopaedics, The Spine Journal, outside the submitted work; Colleen M. Peters reports grants from AOSpine North America during the conduct of the study; Wellington K. Hsu reports grants from AOSpine North America during the conduct of the study, personal fees from Medtronic, personal fees from Stryker, personal fees from Bacterin, personal fees from Graftys, personal fees from Ceramtec, personal fees from Relievant, personal fees from Bioventus, personal fees from Globus, personal fees from SpineSmith, outside the submitted work; Bradford L. Currier reports grants from AOSpine North America during the conduct of the study, personal fees from DePuy Spine, personal fees from Stryker Spine, personal fees from Zimmer Spine, other from Zimmer Spine, other from Tenex, other from Spinology, other from LSRS, other from AOSNA, outside the submitted work; Robert E. Isaacs reports grants from AOSpine North America during the conduct of the study, grants and personal fees from NuVasive, Inc., personal fees from Association for Collaborative Spine research, outside the submitted work; Justin S. Smith reports grants from AOSpine North America during the conduct of the study, personal fees from Biomet, personal fees from Nuvasive, personal fees from Cerapedics, personal fees from K2M, personal fees and other from DePuy, personal fees from Medtronic, outside the submitted work; Christopher Shaffrey reports grants from AOSpine North America during the conduct of the study, personal fees from Biomet, personal fees from Medtronic, from Nuvasive, personal fees from K2M, personal fees from Stryker, outside the submitted work; and Editorial Board Spine, Spinal Deformity and Neurosurgery; Sara E. Thompson reports grants from AOSpine North America during the conduct of the study; Jeffrey C. Wang reports grants from AOSpine North America during the conduct of the study; Elizabeth L. Lord reports grants from AOSpine North America during the conduct of the study; Zorica Buser reports grants from AOSpine North America during the conduct of the study; Michael G. Fehlings reports grants from AOSpine North America during the conduct of the study; Thomas E. Mroz reports other from AOSpine during the conduct of the study, personal fees from Stryker, personal fees from Ceramtec, other from Pearl Diver, outside the submitted work; and K. Daniel Riew reports personal fees from AOSpine International, other from Global Spine Journal, other from Spine Journal, other from Neurosurgery, personal fees from Multiple Entities for defense, plaintiff, grants from AOSpine, grants from Cerapedics, grants from Medtronic, personal fees from AOSpine, personal fees from NASS, personal fees from Biomet, personal fees from Medtronic, nonfinancial support from Broadwater, outside the submitted work; Jacob M. Buchowski reports grants from AOSpine North America during the conduct of the study; personal fees from Advance Medical, personal fees from DePuy, personal fees from CoreLink, Inc., personal fees from Globus Medical, Inc., personal fees from K2M, Inc., personal fees from Medtronic, Inc., personal fees from Stryker, Inc., personal fees from Broadwater/Vertical Health, personal fees from DePuy Synthes, personal fees from Globus Medical, Inc., personal fees from Orthofix, personal fees from Stryker, Inc., personal fees from Wolters Kluwer Health, Inc., personal fees from Globus Medical, Inc., outside the submitted work; and AO Foundation (parent organization to AO Spine). AO FOUNDATION is a non for profit organization. “Other”, “Teaching”, “Not for Profit Organization” Weerasak Singhatanadgige reports grants from AOSpine North America during the conduct of the study; Jin Young Kim Dr. Kim reports grants from AOSpine North America, during the conduct of the study; Zachary A. Smith Dr. Smith reports grants from AOSpine North America, during the conduct of the study; Ahmad Nassr reports grants from AOSpine North America during the conduct of the study; Ra'Kerry K. Rahman reports grants from AOSpine North America during the conduct of the study; in addition, Dr. Rahman has a patent Deformity System & Pedicle Screws pending; Paul M. Arnold reports grants from AOSpine North America during the conduct of the study; other from Z-Plasty, other from Medtronic Sofamore Danek, other from Stryker Spine, other from FzioMed, other from AOSpine North America, other from Life Spine, other from Integra Life, other from Spine Wave, other from MIEMS, other from Cerapedics, other from AOSpine North America, outside the submitted work.

The aim of the present study was to determine whether lung volume recruitment (LVR) acutely increases respiratory system compliance ( C rs ) in individuals with severe respiratory muscle weakness (RMW). Individuals with RMW resulting from neuromuscular disease or quadriplegia (n=12) and healthy controls (n=12) underwent pulmonary function testing and the measurement of C rs at baseline, immediately after, 1 h after and 2 h after a single standardised session of LVR. The LVR session involved 10 consecutive supramaximal lung inflations with a manual resuscitation bag to the highest tolerable mouth pressure or a maximum of 50 cmH 2 O. Each LVR inflation was followed by brief breath-hold and a maximal expiration to residual volume. At baseline, individuals with RMW had lower C rs than controls (37±5 cmH 2 O versus 109±10 mL·cmH 2 O -1 , p<0.001). Immediately after LVR, C rs increased by 39.5±9.8% to 50±7 mL·cmH 2 O -1 in individuals with RMW (p<0.05), while no significant change occurred in controls (p=0.23). At 1 h and 2 h post-treatment, there were no within-group differences in C rs compared to baseline (all p>0.05). LVR had no significant effect on measures of pulmonary function at any time point in either group (all p>0.05). During inflations, mean arterial pressure decreased significantly relative to baseline by 10.4±2.8 mmHg and 17.3±3.0 mmHg in individuals with RMW and controls, respectively (both p<0.05). LVR acutely increases C rs in individuals with RMW. However, the high airway pressures during inflations cause reductions in mean arterial pressure that should be considered when applying this technique.

Neuroinflammation is a pathological condition that underlies diabetes and affects sensory processing. Given the high prevalence of pain in diabetic patients and crosstalk between chemokines and opioids, it is pivotal to know whether neuroinflammation-associated mediators are dysregulated in the central nervous system of diabetic primates. Therefore, the aim of this study was to investigate whether mRNA expression levels of glial markers, chemokines, and opioid receptors are altered in the spinal cord and thalamus of naturally occurring type 2 diabetic monkeys (n=7) compared with age-matched non-diabetic monkeys (n=6). By using RT-qPCR, we found that mRNA expression levels of both GFAP and IBA1 were up-regulated in the spinal dorsal horn (SDH) of diabetic monkeys compared with non-diabetic monkeys. Among all chemokines, expression levels of three chemokine ligand-receptor systems, i.e., CCL2-CCR2, CCL3-CCR1/5, and CCL4-CCR5, were up-regulated in the SDH of diabetic monkeys. Moreover, in the SDH, seven additional chemokine receptors, i.e., CCR4, CCR6, CCR8, CCR10, CXCR3, CXCR5, and CXCR6, were also up-regulated in diabetic monkeys. In contrast, expression levels of MOP, KOP, and DOP, but not NOP receptors, were down-regulated in the SDH of diabetic monkeys, and the thalamus had fewer changes in the glial markers, chemokines and opioids. These findings indicate that neuroinflammation, manifested as glial activation and simultaneous up-regulation of multiple chemokine ligands and receptors, seems to be permanent in type 2 diabetic monkeys. As chemokines and opioids are important pain modulators, this first-in-primate study provides a translational bridge for determining the functional efficacy of spinal drugs targeting their signaling cascades., (Copyright © 2016 Elsevier B.V. All rights reserved.)

B-type natriuretic peptide (BNP)-natriuretic peptide receptor A (NPRA) and gastrin-releasing peptide (GRP)-GRP receptor (GRPR) systems contribute to spinal processing of itch. However, pharmacological and anatomic evidence of these two spinal ligand-receptor systems are still not clear. The aim of this study was to determine the spinal functions of BNP-NPRA and GRP-GRPR systems for regulating scratching activities in mice by using pharmacological and immunohistochemical approaches. Our results showed that intrathecal administration of BNP (0.3-3 nmol) dose dependently elicited scratching responses, which could be blocked by the NPRA antagonist (Arg6,β-cyclohexyl-Ala8,D-Tic16,Arg17,Cys18)-atrial natriuretic factor(6-18) amide (A71915). However, A71915 had no effect on intrathecal GRP-induced scratching. In contrast, pretreatment with a GRPR antagonist (D-Tpi6,Leu13ψ(CH2-NH)-Leu14)bombesin(6-14) (RC-3095) inhibited BNP-induced scratching. Immunostaining revealed that NPRA proteins colocalize with GRP, but not GRPR, in the superficial area of dorsal horn, whereas BNP proteins do not colocalize with either GRP or GRPR in the dorsal horn. Intradermal administration of ligands including endothelin-1, U-46619, bovine adrenal medulla 8-22, and Ser-Leu-Ile-Gly-Arg-Leu-NH2 (SLIGRL) increased scratching bouts at different levels of magnitude. Pretreatment with intrathecal A71915 did not affect scratching responses elicited by all four pruritogens, whereas pretreatment with RC-3095 only inhibited SLIGRL-induced scratching. Interestingly, immunostaining showed that RC-3095, but not A71915, inhibited SLIGRL-elicited c-Fos activation in the spinal dorsal horn, which was in line with behavioral outcomes. These findings demonstrate that: 1) BNP-NPRA system may function upstream of the GRP-GRPR system to regulate itch in the mouse spinal cord, and 2) both NPRA and GRPR antagonists may have antipruritic efficacy against centrally, but not peripherally, elicited itch., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)

Unlabelled: Results of clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain after surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine β-hydroxylase conjugated to saporin (DβH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and nonevoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DβH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DβH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days after incision compared with immunoglobulin G-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 μg/d) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity after surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system might be important to speed recovery from pain after surgery., Perspective: Endogenous descending spinal noradrenergic activation promotes resolution of incision-induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Background: Patients with neuropathic pain show reduced endogenous analgesia induced by a conditioned noxious stimulus. Here, the authors tested whether peripheral nerve injury impairs descending noradrenergic inhibition from the locus coeruleus (LC) after L5-L6 spinal nerve ligation (SNL) in rats., Methods: A subdermal injection of capsaicin was used to examine noxious stimulation-induced analgesia (NSIA), evoked LC glutamate and spinal noradrenaline release, and evoked LC neuronal activity in normal and SNL rats. The authors also examined the role of presynaptic metabotropic glutamate receptors or the astroglial glutamate transporter-1 (GLT-1)., Results: SNL increased basal extracellular glutamate concentration in the LC (170.1%; 95% CI, 44.7 to 295.5; n = 15) and basal spinal cord noradrenaline release (252.1%; 95% CI, 113.6 to 391.3; n = 15), which was associated with an increased tonic LC neuronal activity and a down-regulation of GLT-1 in the LC. SNL reduced NSIA (-77.6%; 95% CI, -116.4 to -38.8; n = 14) and capsaicin evoked release of glutamate in the LC (-36.2%; 95% CI, -49.3 to -23.2; n = 8) and noradrenaline in the spinal cord (-38.8%; 95% CI, -45.1 to -32.5; n = 8). Capsaicin-evoked LC neuronal activation was masked in SNL rats. Removing autoinhibition of glutamatergic terminals by metabotropic glutamate receptor blockade or increasing GLT-1 expression by histone deacetylase inhibition restored NSIA in SNL rats. SNL-induced impairment of NSIA was mimicked in normal rats by knockdown of GLT-1 in the LC., Conclusions: These results suggest that increased extracellular glutamate in the LC consequent to down-regulation of GLT-1 contributes to LC dysfunction and impaired pain-evoked endogenous analgesia after nerve injury.

Background: Chronic postsurgical pain, a significant public health problem, occurs in 10 to 50% of patients undergoing major surgery. Acute pain induces endogenous analgesia termed conditioned pain modulation (CPM), and the strength of CPM preoperatively predicts the likelihood of chronic postsurgical pain. The relation between CPM and recovery from surgery has not been examined in preclinical models., Methods: CPM was assessed in individual rats and correlated with each animal's time course of recovery of hypersensitivity after partial spinal nerve ligation. The role of descending noradrenergic pathways in the spinal cord to mechanisms of CPM and recovery was tested using idazoxan to block noradrenergic receptors or antidopamine β-hydroxylase-conjugated saporin to ablate these pathways. Behavioral hypersensitivity, static weight bearing, and spinal glial activation were measured after partial spinal nerve ligation., Results: The strength of CPM varied over two-fold between individuals and was directly correlated with the slope of recovery from hypersensitivity after surgery (P < 0.0001; r = 0.660). CPM induced the release of norepinephrine in the spinal cord and was partially blocked by intrathecal idazoxan or dopamine β-hydroxylase-saporin. Dopamine β-hydroxylase-saporin also slowed recovery and enhanced spinal glial activation after partial spinal nerve ligation surgery. Ongoing activation of these pathways was critical to sustained recovery because intrathecal dopamine β-hydroxylase-saporin given 7 weeks after recovery reinstituted hypersensitivity, while having no effect in animals without previous surgery., Conclusion: Collectively, these studies provide a clear back-translation from clinical observations of CPM and chronic postsurgical pain and suggest that the ability to engage ongoing descending endogenous noradrenergic signaling may be critical in determining time course of recovery from hypersensitivity after surgery.

Background: Long-lasting, sensory-specific peripheral nerve blockade would advance perioperative analgesia. Perineural injection of a combination of transient receptor potential vanilloid 1 channel agonists and lidocaine or its hydrophilic derivative, QX-314, produces prolonged sensory or nociceptor-selective nerve block in rodents. In this study, the authors tested the efficacy of these combinations in peripheral nerve block after incisional surgery in rats., Methods: The authors administered perisciatic lidocaine (2%), QX-314 (0.2%) followed by dilute capsaicin (0.05%, 10 min later), or vehicle in rats and the duration of motor and sensory block to thermal and mechanical stimuli assessed in normal animals and those after incisional surgery to the hind paw. Other animals receiving these injections were evaluated 7 weeks later by behavior and histology for potential neurotoxicity., Results: Perineural injection of the combination not only attenuated mechanical hypersensitivity for 72 h after incision but also resulted in delayed onset mechanical hypersensitivity several weeks later, accompanied by degeneration of central terminals of isolectin B4 (nonpeptidergic) and calcitonin gene-related peptide-containing (peptidergic) afferents in the ipsilateral spinal cord. Dorsal root ganglia ipsilateral to injection of the combination showed increased expression of activating transcription factor-3 and satellite cell activation., Conclusions: Combined administration of local anesthetics with the transient receptor potential vanilloid 1 agonist capsaicin induced a near complete blockade of incision-induced hypersensitivity for several days. However, the same combination induced delayed mechanical hypersensitivity and neurotoxicity in naïve rats. Combination of these drugs in these concentrations is likely to result in neurotoxicity, and the safety of other concentrations warrants further study.

Background: Excessive prescribing of antibiotics in patients with lower respiratory tract infections (LRTIs) is common in the general population. Due to communication difficulties, it is hypothesised that prescriptions are even more commonplace in the primary care of individuals with intellectual disabilities. Point-of-care C-reactive protein (POC-CRP) testing might lead to more efficient prescribing of antibiotics., Aim: To evaluate the effect of POC-CRP testing on antibiotic prescriptions for LRTIs by physicians specialising in the care of individuals with intellectual disabilities., Design and Setting: A prospective case-control study in four care centres for individuals with intellectual disabilities in The Netherlands., Method: Between 27 October 2010 and 27 October 2011, a prospective efficiency study was performed with a base population of 1472 individuals. This population consisted of 882 individuals in whom POC-CRP tests were used and a control group (n = 590) in whom no POC-CRP test was performed., Results: Of the 48 patients in the control group who were diagnosed as having an LRTI, 43 (90%) received antibiotics, compared with 59 out of the 144 patients (41%) in the case group (OR = 12.0; 95% CI = 4.1-35.3). No significant differences in outcome were found between both groups during a follow-up period of 1 month., Conclusion: This study shows that the use of POC-CRP testing in patients with intellectual disabilities and LRTIs can lead to a significant reduction in antibiotic prescriptions, with no significant differences in outcome during follow-up.

Unlabelled: The present study examined the role of endogenous noradrenaline on glial and neuronal plasticity in the spinal cord in rats after peripheral nerve injury. An intrathecal injection of dopamine-β-hydroxylase antibody conjugated to saporin (DβH-saporin) completely depleted noradrenergic axons in the spinal cord and also reduced noradrenergic neurons in the locus coeruleus (A6) and A5 noradrenergic nucleus in the brainstem and noradrenergic axons in the paraventricular nucleus of the hypothalamus. DβH-saporin treatment itself did not alter mechanical withdrawal threshold, but enhanced mechanical hypersensitivity and intrathecal clonidine analgesia after L5-L6 spinal nerve ligation. In the spinal dorsal horn of spinal nerve ligation rats, DβH-saporin treatment increased choline acetyltransferase immunoreactivity as well as immunoreactivity in microglia of ionized calcium binding adaptor molecule 1[IBA1] and in astrocytes of glial fibrillary acidic protein, and brain-derived nerve growth factor content. DβH-saporin treatment did not, however, alter the fractional release of acetylcholine from terminals by dexmedetomidine after nerve injury. These results suggest that endogenous tone of noradrenergic fibers is not necessary for the plasticity of α2-adrenoceptor analgesia and glial activation after nerve injury, but might play an inhibitory role on glial activation., Perspective: This study demonstrates that endogenous noradrenaline modulates plasticity of glia and cholinergic neurons in the spinal cord after peripheral nerve injury and hence influences the pathophysiology of spinal cord changes associated with neuropathic pain., (Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Social work's weak presence in the field of corrections is peculiar, given that those involved in the criminal andjuvenile justice systems are undeniably among the vulnerable and oppressed populations that the profession has traditionally served. The field of juvenile probation shares roots with the profession of social work but lacks a strong connection to it today. Traditional explanations focus on the reluctance of social workers to engage clients in coercive environments, but historical analysis suggests that this account tells only part of the story. An examination of social work's origins shows that issues involving gender stereotyping and the failure of theory help explain social workers' diminished role in juvenile probation. In recent decades, changes in attitudes regarding gender and working with coerced clients, as well as evidence of effective interventions, suggest that social workers may be ready to reengage meaningfully with juvenile probation and other corrections work. This article outlines steps in professional education and workforce development that would move the profession toward reintegrating social work into the corrections field.

Objectives: to evaluate specialist geriatric input and medication review in patients in high-dependency continuing care., Design: prospective, randomised, controlled trial., Setting: two residential continuing care hospitals., Participants: two hundred and twenty-five permanent patients., Intervention: patients were randomised to either specialist geriatric input or regular input. The specialist group had a medical assessment by a geriatrician and medication review by a multidisciplinary expert panel. Regular input consisted of review as required by a medical officer attached to each ward. Reassessment occurred after 6 months., Results: one hundred and ten patients were randomised to specialist input and 115 to regular input. These were comparable for age, gender, dependency levels and cognition. After 6 months, the total number of medications per patient per day fell from 11.64 to 11.09 in the specialist group (P = 0.0364) and increased from 11.07 to 11.5 in the regular group (P = 0.094). There was no significant difference in mortality or frequency of acute hospital transfers (11 versus 6 in the specialist versus regular group, P = 0.213)., Conclusion: specialist geriatric assessment and medication review in hospital continuing care resulted in a reduction in medication use, but at a significant cost. No benefits in hard clinical outcomes were demonstrated. However, qualitative benefits and lower costs may become evident over longer periods.

Background: Neural glial signaling in the spinal cord may underlie pain and sensitization after peripheral injury. The authors test the role of a glial activator, the chemokine (C-C motif) ligand 2 (CCL2), on mechanical hypersensitivity after plantar incision in a rat model of postoperative pain., Methods: Twenty-four hours after hind paw incision, rats were intrathecally administered an anti-CCL2 neutralizing antibody (3 and 10 microg) or control immunoglobulin G (10 microg). Mechanical hypersensitivity was assessed acutely and for several days after administration of anti-CCL2 antibody using von Frey filaments. Immunohistochemical analysis was conducted on spinal cord sections to examine the effects of treatment on measures of microglial activation, including levels of ionized calcium-binding adaptor molecule 1 and phosphorylated p38 mitogen-activated protein kinase., Results: Neutralization of spinal CCL2 acutely reversed mechanical hypersensitivity within 30 min in a dose-dependent manner. A single administration also produced a sustained decrease in mechanical hypersensitivity 48 and 72 h after incision. Anti-CCL2 antibody reduced microglial activation as measured by the levels of ionized calcium-binding adaptor molecule 1 immunoreactivity and the number of microglia containing phosphorylated p38 mitogen-activated protein kinase 48 h after incision but not within 30 min of administration., Conclusions: These results provide evidence that CCL2 contributes to the maintenance of mechanical hypersensitivity after plantar incision and establish a role for neural glial signaling in postoperative pain. The long-term effects of anti-CCL2 treatment correlate with reduced microglial activation. Spinal blockade of CCL2 may serve as a useful therapy for the treatment of certain aspects of postoperative pain.

Unlabelled: A closed femur fracture pain model was developed in the C57BL/6J mouse. One day after fracture, a monoclonal antibody raised against nerve growth factor (anti-NGF) was delivered intraperitoneally and resulted in a reduction in fracture pain-related behaviors of approximately 50%. Anti-NGF therapy did not interfere with bone healing as assessed by mechanical testing and histomorphometric analysis., Introduction: Current therapies to treat skeletal fracture pain are limited. This is because of the side effect profile of available analgesics and the scarcity of animal models that can be used to understand the mechanisms that drive this pain. Whereas previous studies have shown that mineralized bone, marrow, and periosteum are innervated by sensory and sympathetic fibers, it is not understood how skeletal pain is generated and maintained even in common conditions such as osteoarthritis, low back pain, or fracture., Materials and Methods: In this study, we characterized the pain-related behaviors after a closed femur fracture in the C57BL/6J mouse. Additionally, we assessed the effect of a monoclonal antibody that binds to and sequesters nerve growth factor (anti-NGF) on pain-related behaviors and bone healing (mechanical properties and histomorphometric analysis) after fracture., Results: Administration of anti-NGF therapy (10 mg/kg, days 1, 6, and 11 after fracture) resulted in a reduction of fracture pain-related behaviors of approximately 50%. Attenuation of fracture pain was evident as early as 24 h after the initial dosing and remained efficacious throughout the course of fracture pain. Anti-NGF therapy did not modify biomechanical properties of the femur or histomorphometric indices of bone healing., Conclusions: These findings suggest that therapies that target NGF or its cognate receptor(s) may be effective in attenuating nonmalignant fracture pain without interfering with bone healing.

Maintaining crop diversity on farms where cultivars can evolve is a conservation goal, but few tools are available to assess the long-term maintenance of genetic diversity on farms. One important issue for on-farm conservation is gene flow from crops with a narrow genetic base into related populations that are genetically diverse. In a case study of avocado (Persea americana var. americana) in one of its centers of diversity (San Jerónimo, Costa Rica), we used 10 DNA microsatellite markers in a parentage analysis to estimate gene flow from commercialized varieties into a traditional crop population. Five commercialized genotypes comprised nearly 40% of orchard trees, but they contributed only about 14.5% of the gametes to the youngest cohort of trees. Although commercialized varieties and the diverse population were often planted on the same farm, planting patterns appeared to keep the two types of trees separated on small scales, possibly explaining the limited gene flow. In a simulation that combined gene flow estimates, crop biology, and graft tree management, loss of allelic diversity was less than 10% over 150 yr, and selection was effective in retaining desirable alleles in the diverse subpopulation. Simulations also showed that, in addition to gene flow, managing the genetic makeup and life history traits of the invasive commercialized varieties could have a significant impact on genetic diversity in the target population. The results support the feasibility of on-farm crop conservation, but simulations also showed that higher levels of gene flow could lead to severe losses of genetic diversity even if farmers continue to plant diverse varieties.