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Abstract: Anti-gravity treadmill training is a therapeutic option to help recovering runners return to activity after injury. This current concept paper provides a synopsis of the latest evidence of the biomechanical and metabolic changes that occur with body weight support (BWS) treadmill training, effects of antigravity treadmill training on clinical outcomes and clinical case studies in injured runners. Literature searches identified studies with descriptive, experimental and interventional designs and case studies that examined acute and chronic use of antigravity treadmills in runners and relevant populations. Laboratory-based studies were included to provide technical considerations for rehabilitation programming. Antigravity treadmills use causes reductions in cadence, ground reaction forces (GRF), GRF impulses, knee and ankle range of motion, and vertical stiffness, with elevations in stride duration, flight time, ground contact time, and plantarflexion. Antigravity treadmills appear useful across a spectrum of injuries in runners, including postsurgical repair of osteochondral defect, stress reactions (medial tibia, pelvis), and lumbar disc herniation. Runners may preserve aerobic fitness, muscle activation patterns, and muscle mass during recovery compared to traditional rehabilitation protocols. Technical considerations for accurate loading include treadmill frame adjustment to appropriate height to ensure accuracy of level of BWS while running, and monitoring for fast cadence to ensure impact loading rates remain low. Speed or grade can be increased to maintain metabolic demand and fitness while minimizing bone and tissue loading. Monitoring for symptom provocation will guide protocol adjustments to BWS and prescriptions. Once able to run pain-free (sustained or interval) >95% BWS for >30 min, the runner is likely ready to safely transition to ground running. Antigravity treadmill training can be considered when available to facilitate smooth transition back to ground running in a conditioned state.

Abstract: This current concept, narrative review provides the latest integrated evidence of the musculoskeletal injuries involved with trail running and therapeutic strategies to prevent injury and promote safe participation. Running activities that comprise any form of off-road running (trail running, orienteering, short-long distance, different terrain, and climate) are relevant to this review. Literature searches were conducted to 1) identify types and mechanisms of acute and chronic/overuse musculoskeletal injuries in trail runners, 2) injury prevention techniques most relevant to running trails, 3) safe methods of participation and rehabilitation timelines in the sport. The majority of acute and chronic trail running-related musculoskeletal injuries in trail running occur in the lower leg, primarily in the knee and ankle. More than 70% are due to overuse, and ankle sprains are the most common acute injury. Key mechanisms underlying injury and injury progression include inadequate neuromotor control-balance-coordination, running through fatigue, and abnormal kinematics on variable terrain. Complete kinetic chain prehabilitation programs consisting of dynamic flexibility, neuromotor strength and balance, and plyometrics exercise can foster stable, controlled movement on trails. Patient education about early musculoskeletal pain symptoms and training adjustment can help prevent injury from progressing to serious overuse injuries. Real-time adjustments to cadence, step length, and knee flexion on the trail may also mitigate impact-related risk for injury. After injury occurs, rehabilitation will involve similar exercise components, but it will also incorporate rest and active rest based on the type of injury. Multicomponent prehabilitation can help prevent musculoskeletal injuries in trail runners through movement control and fatigue resistance.

Leiomyomas, the most common benign neoplasms of the female reproductive tract, currently have limited medical treatment options. Drugs targeting estrogen/progesterone signaling are used, but side effects and limited efficacy in many cases are major limitation of their clinical use. Previous studies from our laboratory and others demonstrated that 2-methoxyestradiol (2-ME) is promising treatment for uterine fibroids. However, its poor bioavailability and rapid degradation hinder its development for clinical use. The objective of this study is to evaluate the in vivo effect of biodegradable and biocompatible 2-ME-loaded polymeric nanoparticles in a patient-derived leiomyoma xenograft mouse model. PEGylated poly(lactide-co-glycolide) (PEG-PLGA) nanoparticles loaded with 2-ME were prepared by nanoprecipitation. Female 6-week age immunodeficient NOG (NOD/Shi-scid/IL-2Rγ null ) mice were used. Estrogen-progesterone pellets were implanted subcutaneously. Five days later, patient-derived human fibroid tumors were xenografted bilaterally subcutaneously. Engrafted mice were treated with 2-ME-loaded or blank (control) PEGylated nanoparticles. Nanoparticles were injected intraperitoneally and after 28 days of treatment, tumor volume was measured by caliper following hair removal, and tumors were removed and weighed. Up to 99.1% encapsulation efficiency was achieved, and the in vitro release profile showed minimal burst release, thus confirming the high encapsulation efficiency. In vivo administration of the 2-ME-loaded nanoparticles led to 51% growth inhibition of xenografted tumors compared to controls (P < 0.01). Thus, 2-ME-loaded nanoparticles may represent a novel approach for the treatment of uterine fibroids., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to report., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Recombinant adeno-associated (rAAV) vector-based gene therapy has been the focus of intense research driven by the safety profile and several recent clinical breakthroughs. As of April 2021, there are two rAAV-based gene therapies approved and more than two-hundred active clinical trials (approximately thirty in Phase III). However, the expected increase in demand for rAAV vectors still poses several challenges. Discussed herein are key aspects related to R&D needs and Chemistry, Manufacturing and Control (CMC) efforts required to attend this growing demand. Authors provide their perspective on strategic topics for rAAV-based therapies success: scalability and productivity; improved safety; increased process understanding combined with development of orthogonal bioanalytics that are able to identify, monitor and control Critical Quality Attributes (CQAs) during bioprocessing., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Chronic pelvic pain affects 2-24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology., Methods: We performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18-50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16-17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13-16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762., Findings: Participants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13-16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was -1·4 (SD 2·3) in the gabapentin group and -1·2 (SD 2·1) in the placebo group (adjusted mean difference -0·20 [97·5% CI -0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was -1·1 (SD 2·0) in the gabapentin group and -0·9 (SD 1·8) in the placebo group (adjusted mean difference -0·18 [97·5% CI -0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group., Interpretation: This study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology., Funding: National Institute for Health Research., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Tumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer. Conversely, fibroblast activation was impaired in mice with a fibroblast-specific deletion of cellular communication network 2 (Ccn2), associated with reduced expression of α-smooth muscle actin and Sox2. Multipotent Sox2-expressing skin-derived precursor (SKP) spheroids were cultured from murine back skin. Using lineage tracing and flow cytometry, approximately 40% of SKPs were found to be derived from type I collagen-lineage cells and acquired multipotency in culture. Inhibition of mechanotransduction pathways prevented myofibroblast differentiation of SKPs and expression of Ccn2. In SKPs deleted for Ccn2, differentiation into a myofibroblast, but not an adipocyte or neuronal phenotype, was also impaired. In human melanoma, CCN2 expression was associated with a profibrotic integrin alpha (ITGA) 11-expressing subset of CAFs that negatively associated with survival. These results suggest that synthetic dermal fibroblasts are plastic, and that CCN2 is required for the differentiation of dermal progenitor cells into a myofibroblast/CAF phenotype and is, therefore, a therapeutic target in melanoma., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Metastatic melanoma is highly fatal. Within the tumor microenvironment, the role of cancer-associated fibroblasts (CAFs) in melanoma metastasis and progression is relatively understudied. The matricellular protein CCN2 (formerly termed connective tissue growth factor, CTGF) is overexpressed, in a fashion independent of BRAF mutational status, by CAFs in melanoma. Herein, we find, in human melanoma patients, that CCN2 expression negatively correlates with survival and positively correlates with expression of neovascularization markers. To assess the role of CAFs in melanoma progression, we used C57BL/6 mice expressing a tamoxifen-dependent cre recombinase expressed under the control of a fibroblast-specific promoter/enhancer (COL1A2) to delete CCN2 postnatally in fibroblasts. Mice deleted or not for CCN2 in fibroblasts were injected subcutaneously with B16-F10 melanoma cells. Loss of CCN2 in CAFs resulted in reduced CAF activation, as detected by staining with anti-α-smooth muscle actin antibodies, and reduced tumor-induced neovascularization, as detected by micro-computed tomography (micro-CT) and staining with anti-CD31 antibodies. CCN2-deficient B16(F10) cells were defective in a tubule formation/vasculogenic mimicry assay in vitro. Mice deleted for CCN2 in CAFs also showed impaired vasculogenic mimicry of subcutaneously-injected B16-F10 cells in vivo. Our results provide new insights into the cross-talk among different cell types in the tumor microenvironment and suggest CAFs play a heretofore unappreciated role by being essential for tumor neovascularization via the production of CCN2. Our data are consistent with the hypothesis that activated CAFs are essential for melanoma metastasis and that, due to its role in this process, CCN2 is a therapeutic target for melanoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

To better anticipate potential impacts of climate change, diverse information about the future is required, including climate, society and economy, and adaptation and mitigation. To address this need, a global RCP (Representative Concentration Pathways), SSP (Shared Socio-economic Pathways), and SPA (Shared climate Policy Assumptions) (RCP-SSP-SPA) scenario framework has been developed by the Intergovernmental Panel on Climate Change Fifth Assessment Report (IPCC-AR5). Application of this full global framework at sub-national scales introduces two key challenges: added complexity in capturing the multiple dimensions of change, and issues of scale. Perhaps for this reason, there are few such applications of this new framework. Here, we present an integrated multi-scale hybrid scenario approach that combines both expert-based and participatory methods. The framework has been developed and applied within the DECCMA 1 project with the purpose of exploring migration and adaptation in three deltas across West Africa and South Asia: (i) the Volta delta (Ghana), (ii) the Mahanadi delta (India), and (iii) the Ganges-Brahmaputra-Meghna (GBM) delta (Bangladesh/India). Using a climate scenario that encompasses a wide range of impacts (RCP8.5) combined with three SSP-based socio-economic scenarios (SSP2, SSP3, SSP5), we generate highly divergent and challenging scenario contexts across multiple scales against which robustness of the human and natural systems within the deltas are tested. In addition, we consider four distinct adaptation policy trajectories: Minimum intervention, Economic capacity expansion, System efficiency enhancement, and System restructuring, which describe alternative future bundles of adaptation actions/measures under different socio-economic trajectories. The paper highlights the importance of multi-scale (combined top-down and bottom-up) and participatory (joint expert-stakeholder) scenario methods for addressing uncertainty in adaptation decision-making. The framework facilitates improved integrated assessments of the potential impacts and plausible adaptation policy choices (including migration) under uncertain future changing conditions. The concept, methods, and processes presented are transferable to other sub-national socio-ecological settings with multi-scale challenges., (Copyright © 2018. Published by Elsevier B.V.)

Deltas are precarious environments experiencing significant biophysical, and socio-economic changes with the ebb and flow of seasons (including with floods and drought), with infrastructural developments (such as dikes and polders), with the movement of people, and as a result of climate and environmental variability and change. Decisions are being taken about the future of deltas and about the provision of adaptation investment to enable people and the environment to respond to the changing climate and related changes. The paper presents a framework to identify options for, and trade-offs between, long term adaptation strategies in deltas. Using a three step process, we: (1) identify current policy-led adaptations actions in deltas by conducting literature searches on current observable adaptations, potential transformational adaptations and government policy; (2) develop narratives of future adaptation policy directions that take into account investment cost of adaptation and the extent to which significant policy change/political effort is required; and (3) explore trade-offs that occur within each policy direction using a subjective weighting process developed during a collaborative expert workshop. We conclude that the process of developing policy directions for adaptation can assist policy makers in scoping the spectrum of options that exist, while enabling them to consider their own willingness to make significant policy changes within the delta and to initiate transformative change., (Copyright © 2018. Published by Elsevier B.V.)

Although pain is one of the main symptoms women with endometriosis present with, there is poor correlation between symptom severity and disease burden and the underlying biological mechanisms by which pain arises are still only poorly understood. We briefly review the neurobiology of pain before considering mechanisms that may be specifically relevant in the context of endometriosis. The role of pelvic factors such as new nerve fibre growth, peritoneal fluid and inflammation is explored with a particular focus on studies where these factors have been associated with pain symptoms rather than just being compared between women with endometriosis and disease-free controls. We then consider the role of the central nervous system and associated systems, including the stress axis and psychological factors, in the modulation of pain. The potential for changes in these systems to be a cause and/or a consequence of the pain and how they might explain some of the known associations between endometriosis and other somatic symptoms is discussed. The chapter concludes by considering the implications of these mechanisms on treatment strategies for these women., (Copyright © 2018. Published by Elsevier Ltd.)

The technique of cryosurgery has been used to control local recurrence in a variety of benign and malignant bone tumors. Early studies revealed significant complication rates (25%) that included fracture, infection, and soft tissue injury. Our method of cryosurgery has yielded excellent tumor control with improved complication rates. The objective of this study is to determine the characteristics of postoperative complications after pouring liquid nitrogen into curettaged bone defects, and to review our current indications and surgical technique in bone tumor management. We reviewed charts in over 200 patients who received cryoablation for bone tumors from 1994 to 2015. Imaging studies were evaluated in all patients diagnosed with a complication. All patients receiving cryotherapy had soft tissue management intraoperatively that included warm saline directed to the structures. Liquid nitrogen was poured into the bone defect and in some cases, additional spraying with a cryogun into the defect was performed. The majority of cryotherapy was used in cases of active or aggressive benign tumors. Our low complication rate of 2.34% included 1 post-operative fracture, 3 infection, and 1 paraesthesia. Bone graft or cementation was used in the majority of patients, all of which fully incorporated. Cryoablation is an excellent from of adjuvant therapy for active and aggressive benign tumors and may be used in malignant tumors as well. Soft tissue protection is critical to avoid skin necrosis and wound breakdown. We recommend the use of cryotherapy in active and aggressive bone tumors as an adjuvant treatment prior to bone grafting or cementation.

Objective: Uterine leiomyomas represent a common gynecologic problem with no satisfactory long-term medical treatment. The purpose of this study is to examine the effects of simvastatin on uterine leiomyoma, both in vitro and in vivo., Study Design: This is a laboratory-based experimental study. For in vitro studies, we used human and rat leiomyoma cells. For in vivo studies, we used immunodeficient mice supplemented with estrogen/progesterone pellets xenografted with human leiomyoma tissue explant., Results: For in vitro studies, cells were treated with different concentrations of simvastatin for 48 hours. Simvastatin induced dose-dependent apoptosis in leiomyoma cells as measured by a fluorometric caspase-3 activity assay, and inhibited proliferation as demonstrated by an (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay (both were significant at 5 and 10 μM). In addition, simvastatin decreased Akt signaling pathway phosphorylation as examined using Western blot analysis. For in vivo studies, animals were treated for 28 days with simvastatin (20 μg/gm body weight/day) vs vehicle control. The treatment inhibited tumor growth as measured weekly using calipers and/ or ultrasound (P < .01). Finally, simvastatin decreased expression of the proliferation marker Ki67 in xenograft tumor tissue as examined by immunohistochemistry (P = .02)., Conclusion: Simvastatin can be a promising treatment for uterine leiomyoma. Further studies, including pharmacokinetic and drug delivery studies, are required., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: To quantify and model drivers of community pharmacists' self-reported levels of occupational satisfaction and stress and to identify key segments for possible intervention by the profession., Design: Descriptive nonexperimental study., Setting: United States during January to February 2012., Participants: 303 independent and community chain pharmacists., Intervention: Online survey instrument of previously validated occupational stress and satisfaction attribute batteries., Results: Participants reported a high level of dissatisfaction with current employment, with more than 50% stating that they were considering quitting their jobs. Dissatisfaction was higher among those with a doctor of pharmacy degree and those employed in community chains. Occupational stress and satisfaction were highly correlated with the intention to search for a new position. Approximately 20% of respondents felt that stress from their employment adversely affected their mental health and well-being, physical health, quality of the work, or relationships with family and friends., Conclusion: Substantive levels of occupational dissatisfaction and stress exist among pharmacists currently in community practice. These negative attributes are associated with a damaging promotion of community practice-a marker of a negative trajectory in sustaining this practice environment. The results of this study have implications for the health care industry, commercial pharmacy vendors, independent pharmacies, the profession, and academic training institutions as they prepare the pharmacy workforce of the future for potentially dissatisfying and stressful work environments.

Inhibition of calcium oxalate monohydrate (COM) formation and initiation of the dihydrate (COD) phase by osteopontin (OPN) have been proposed to play an important role in preventing kidney stone formation. We have studied the roles of OPN phosphate and carboxylate groups in the modulation of calcium oxalate (CaOx) crystallization using synthetic peptides corresponding to residues 65-80, 129-144, 220-235 and 273-288 of rat OPN. We investigated the effects of these peptides (0-20 μg/ml) on COM and COD formation by correlating qualitative and quantitative microscopic data with the physicochemical characteristics of the peptides used. In general, highly acidic/hydrophilic peptides strongly inhibit COM and promote COD formation. However, OPN129-144, which is basic, and OPN273-288, which is only slightly acidic, also induced COD precipitation. It is likely that inhibition of nucleation and/or growth of COM by OPN peptides maintains a high supersaturation, thereby allowing formation of the more-soluble dihydrate polymorph. In addition, growth of COD from the substrate in <100>/<110> directions suggests that highly acidic OPN peptides may nucleate crystals from the Ca(2+)-rich {100}/{110} faces. At higher peptide concentrations, however, peptides containing either phosphates or contiguous carboxylates inhibit COD, whereas peptides containing both promote COD formation further., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Allogeneic hematopoietic cell transplantation led to the discovery of the allogeneic GVL effect, which remains the most convincing evidence that immune cells can cure cancer in humans. However, despite its great paradigmatic and clinical relevance, induction of GVL by conventional allogeneic hematopoietic cell transplantation remains a quite rudimentary form of leukemia immunotherapy. It is toxic and its efficacy is far from optimal. It is therefore sobering that since the discovery of the GVL effect 3 decades ago, the way GVL is induced and manipulated has practically not changed. Preclinical and clinical studies suggest that injection of T cells primed against a single Ag present on neoplastic cells could enhance the GVL effect without causing any GVHD. We therefore contend that Ag-targeted adoptive T-cell immunotherapy represents the future of leukemia immunotherapy, and we discuss the specific strategies that ought to be evaluated to reach this goal. Differences between these strategies hinge on 2 key elements: the nature of the target Ag and the type of Ag receptor expressed on T cells.

Tyrosyl-tRNA synthetase (TyrRS) has been studied extensively by mutational and structural analyses to elucidate its catalytic mechanism. TyrRS has the HIGH and KMSKS motifs that catalyze the amino acid activation with ATP. In the present study, the crystal structures of the Escherichia coli TyrRS catalytic domain, in complexes with l-tyrosine and a l-tyrosyladenylate analogue, Tyr-AMS, were solved at 2.0A and 2.7A resolution, respectively. In the Tyr-AMS-bound structure, the 2'-OH group and adenine ring of the Tyr-AMS are strictly recognized by hydrogen bonds. This manner of hydrogen-bond recognition is conserved among the class I synthetases. Moreover, a comparison between the two structures revealed that the KMSKS loop is rearranged in response to adenine moiety binding and hydrogen-bond formation, and the KMSKS loop adopts the more compact ("semi-open") form, rather than the flexible, open form. The HIGH motif initially recognizes the gamma-phosphate, and then the alpha and gamma-phosphates of ATP, with a slight rearrangement of the residues. The other residues around the substrate also accommodate the Tyr-AMS. This induced-fit form presents a novel "snapshot" of the amino acid activation step in the aminoacylation reaction by TyrRS. The present structures and the T.thermophilus TyrRS ATP-free and bound structures revealed that the extensive induced-fit conformational changes of the KMSKS loop and the local conformational changes within the substrate binding site form the basis for driving the amino acid activation step: the KMSKS loop adopts the open form, transiently shifts to the semi-open conformation according to the adenosyl moiety binding, and finally assumes the rigid ATP-bound, closed form. After the amino acid activation, the KMSKS loop adopts the semi-open form again to accept the CCA end of tRNA for the aminoacyl transfer reaction.