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PURPOSE: Prostate cancer is the most common cancer among men in the United States. The majority of prostate cancer treatment occurs in the ambulatory setting, and patients and their caregivers take on significant responsibility for monitoring and managing treatment and disease-related toxicity. Digital health coaching has shown promise as a tool to positively influence outcomes. We completed a single-arm pilot study to assess the feasibility of digital health coaching in men with prostate cancer. METHODS: Men with a history of prostate cancer requiring treatment in the past 2 years were eligible for inclusion. Participants engaged in a 12-week health coaching program, consisting of a combination of at least one telephone call and up to four digital nudges (defined as content delivered via text, e-mail, or app on the basis of the participant's preference) per week. Prostate cancer–specific content addressed one of the following topics each week: fatigue, pain management, healthy eating, exercise, managing incontinence, sexual health, managing stress and anxiety, financial toxicity, goal setting during treatment, managing side effects, communicating with the health care team, and medication adherence. Services were provided at no cost to the participant. RESULTS: A hundred patients were consented for the study, and 88 enrolled. The feasibility threshold of 60% was met with 63 of the 88 enrolled individuals completing the 3-month program (proportion = 71.6%; 90% CI, 62.6 to 79.4; P = .016). CONCLUSION: Digital health coaching for men with prostate cancer is feasible. These findings support further evaluation of digital health coaching for men with prostate cancer in larger randomized controlled trials.

The isolation of intact single cells from frozen tissue is a challenge due to the mechanical and physical stress inflicted upon the cell during the freeze-thaw process. Ruptured cells release ambient RNA into the cell suspension, which can become encapsulated into droplets during droplet based single cell RNA-seq library preparation methods. The presence of ambient RNA in droplets has been suggested to impact data quality, however there have been limited reports on single cell RNA-seq data from frozen tissue. Here, we compare the results of single cell RNA-seq derived from disaggregated cells from frozen brain tissue with single nuclei RNA-seq derived from purified nuclei of identical tissue using the 10X Genomics Chromium 3’gene expression assay. Our results indicated that presence of ambient RNA in the cell suspension resulted in single cell RNA-seq data with a 25-fold lower gene count, a 5-fold lower UMI count per cell and a 2-fold lower fraction of reads per cell compared with single nuclei RNA-seq data. Cell clustering with the single cell RNA-seq data was unable to resolve the heterogeneity of brain cell types. Our conclusion is that nuclei from frozen tissue are the superior substrate for single cell transcriptome analysis.

In the United Kingdom (UK), orthopaedic trauma surgeons utilise evidence-based practice through distillation of high-quality primary research, interrogation of registries and implementation of evidence-based guidelines. Concurrent with this ambition of providing exemplar care based on robust patient centred research, there has evolved a culture of remuneration ‘by results’. Therefore, there is a drive for excellence combined with a system of collation and validation of data input as well as remuneration where care excels. There are several organisations involved in each stage of this process, the output of which has much that is pertinent to the globally similar consequences of physical injury. However, their relevance and impact within the UK is magnified as they are written against the backdrop of a unified healthcare system. In this article, we will describe the roles of the different organisations guiding and regulating trauma practice across the UK and discuss how the interplay of these impacts on clinical care.

Background Patients with cancer constitute a large and increasing segment of patients who receive unscheduled hospital-based care due to treatment-related symptoms and disease progression. The initial hospital-based touchpoint for these unscheduled hospitalizations is often the emergency department. Traditional models of emergency department and inpatient hospital-based care are saturated and incapable of scaling to accommodate the future, increased needs projected for this population. New models of care are necessary to address this gap. Acute home-based care is a promising tool potentially providing patient-centric, efficient care to eligible patients. Methods We applied Porter’s Five Forces framework that addresses the bargaining power of buyers and suppliers, threat of substitutes and new entrants, and industry rivalries plus the sixth force of regulation to clarify the factors that will promote or challenge the adoption of a home-based cancer care referral model before or following emergency department visits. Exploring this framework provides insights into the complexities of scaling an acute home-based cancer care model and highlights ways for health systems including hospitals, emergency departments, physician groups, and individual emergency physicians and oncologists to optimize their roles in this emerging model of care. Results We found that current workforce shortages, as well as workflow, infrastructure, and regulatory complexities, pose major challenges that unless carefully addressed may restrict the growth of acute home-based cancer care. Additional uncertainties persist around appropriate payment models and the competitive landscape. Key promoting factors include the recognized need in the cancer community and among payers for new models to decrease unscheduled hospitalizations and emergency department visits as well as the uptake of home-based and technology-enabled solutions during the COVID-19 pandemic. A better understanding of these forces helps to clarify the risks and opportunities as new entrants build their programs. Conclusions Acute home-based cancer care is a promising tool to complement traditional outpatient clinics, emergency departments, and inpatient hospital-based models of cancer care. New technologies and policies increasingly enable a broader scope of cancer care in the home setting.

Background: The pathological mechanism of cellular dysfunction and death in Huntington’s disease (HD) is not well defined. Our transgenic HD sheep model (OVT73) was generated to investigate these mechanisms and for therapeutic testing. One particular cohort of animals has undergone focused investigation resulting in a large interrelated multi-omic dataset, with statistically significant changes observed comparing OVT73 and control ‘omic’ profiles and reported in literature. Objective: Here we make this dataset publicly available for the advancement of HD pathogenic mechanism discovery. Methods: To enable investigation in a user-friendly format, we integrated seven multi-omic datasets from a cohort of 5-year-old OVT73 (n = 6) and control (n = 6) sheep into a single database utilising the programming language R. It includes high-throughput transcriptomic, metabolomic and proteomic data from blood, brain, and other tissues. Results: We present the ‘multi-omic’ HD sheep database as a queryable web-based platform that can be used by the wider HD research community (https://hdsheep.cer.auckland.ac.nz/). The database is supported with a suite of simple automated statistical analysis functions for rapid exploratory analyses. We present examples of its use that validates the integrity relative to results previously reported. The data may also be downloaded for user determined analysis. Conclusion: We propose the use of this online database as a hypothesis generator and method to confirm/refute findings made from patient samples and alternate model systems, to expand our understanding of HD pathogenesis. Importantly, additional tissue samples are available for further investigation of this cohort.

Our aim was to evaluate the safety of transplanting kidneys from HCV-infected donors in HCV-uninfected recipients. Data collected from 53 recipients in a single center, observational study included donor and recipient characteristics, liver and kidney graft function, new infections and de novo donor-specific antibodies and renal histology. Treatment with a direct-acting antiviral regimen was initiated when HCV RNA was detected. The mean ± SD age of recipients was 53 ± 11 years, 34% were female, 19% and 79% of recipients were white and African American, respectively. The median and interquartile range (IQR) time between transplant and treatment initiation was 76 (IQR: 68-88) days. All 53 recipients became viremic (genotype: 1a [N = 34], 1b [N = 1], 2 [N = 3], and 3 [N = 15]). The majority (81%) of recipients did not experience clinically significant increases (>3 times higher than upper limit of the normal value) in aminotransferase levels and their HCV RNA levels were in the 5 to 6 log range. One patient developed fibrosing cholestatic hepatitis with complete resolution. All recipients completed antiviral treatment and 100% were HCV RNA-negative and achieved 12-week sustained virologic response. The estimated GFRs at end of treatment and 12-week posttreatment were 67 ± 21 mL/min/1.73 m2 and 67 ± 17 mL/min/1.73 m2 , respectively. Four recipients developed acute rejection. Kidney transplantation from HCV-infected donors to HCV-negative recipients should be considered in all eligible patients.

In this paper, documentary and artistic pairings of nineteenth-century survey photographs with rephotographs from the 1970s-2000s of identical views of western U.S. sites are read within divergent temporal and historiographical paradigms about historical and geological change. Viewed and interpreted within the legacy of American technocratic “progress” and of debates about the “old” and “new” western histories, this juxtaposed work across a century speaks to shifts in historians’ paradigms about the meaning of western expansion, from optimism to tragedy, and to whether geologic and human history are continuous or discontinuous. The ecological rupture of the Anthropocene returns us to nineteenth-century debates, which in part motivated survey photographs, about whether changes in geological and life forms are gradual or catastrophic—or some uneasy combination of the two. What haunts these photographs today is both a lost ideological past and a precarious, humanly viable future that the Anthropocene exposes.

Key Points Question How do medical oncologists perceive telehealth video visits for cancer care? Findings In this qualitative study, in which 29 medical oncology health professionals were interviewed prior to the coronavirus disease 2019 (COVID-19) pandemic, the barriers to and benefits of telehealth video visits were elucidated. Although oncologists disagreed on the scope of a virtual physical examination and the financial impact of video visits, most recognized the benefit of eliminating travel and the challenge of delivering serious or bad news. Meaning Differing opinions of medical oncology health professionals regarding the barriers to and benefits of telehealth video visits provide insight into the challenges that limit telehealth quality as well as its expansion potential., This qualitative study surveyed physicians and other health professionals working in oncology to determine the perceived advantages and disadvantages of telehealth video visits in cancer care., Importance Telehealth has emerged as a means of improving access and reducing cost for medical oncology care; however, use by specialists prior to the coronavirus disease 2019 (COVID-19) pandemic still remained low. Medical oncology professionals’ perceptions of telehealth for cancer care are largely unknown, but are critical to telehealth utilization and expansion efforts. Objective To identify medical oncology health professionals’ perceptions of the barriers to and benefits of telehealth video visits. Design, Setting, and Participants This qualitative study used interviews conducted from October 30, 2019, to March 5, 2020, of medical oncology health professionals at the Thomas Jefferson University Hospital, an urban academic health system in the US with a cancer center. All medical oncology physicians, physicians assistants, and nurse practitioners at the hospital were eligible to participate. A combination of volunteer and convenience sampling was used, resulting in the participation of 29 medical oncology health professionals, including 20 physicians and 9 advanced practice professionals, in semistructured interviews. Main Outcomes and Measures Medical oncology health professionals’ perceptions of barriers to and benefits of telehealth video visits as experienced by patients receiving cancer treatment. Results Of the 29 participants, 15 (52%) were women and 22 (76%) were White, with a mean (SD) age of 48.5 (12.0) years. Respondents’ perceptions were organized using the 4 domains of the National Quality Forum framework: clinical effectiveness, patient experience, access to care, and financial impact. Respondents disagreed on the clinical effectiveness and potential limitations of the virtual physical examination, as well as on the financial impact on patients. Respondents also largely recognized the convenience and improved access to care enabled by telehealth for patients. However, many reported concern regarding the health professional–patient relationship and their limited ability to comfort patients in a virtual setting. Conclusions and Relevance Medical oncology health professionals shared conflicting opinions regarding the barriers to and benefits of telehealth in regard to clinical effectiveness, patient experience, access to care, and financial impact. Understanding oncologists’ perceptions of telehealth elucidates potential barriers that need to be further investigated or improved for telehealth expansion and continued utilization; further research is ongoing to assess current perceptions of health professionals and patients given the rapid expansion of telehealth during the COVID-19 pandemic.

In the United Kingdom (UK), orthopaedic trauma surgeons utilise evidence-based practice through distillation of high-quality primary research, interrogation of registries and implementation of evidence-based guidelines. Concurrent with this ambition of providing exemplar care based on robust patient centred research, there has evolved a culture of remuneration 'by results'. Therefore, there is a drive for excellence combined with a system of collation and validation of data input as well as remuneration where care excels. There are several organisations involved in each stage of this process, the output of which has much that is pertinent to the globally similar consequences of physical injury. However, their relevance and impact within the UK is magnified as they are written against the backdrop of a unified healthcare system. In this article, we will describe the roles of the different organisations guiding and regulating trauma practice across the UK and discuss how the interplay of these impacts on clinical care.

Background The DGAT1 gene encodes an enzyme responsible for catalysing the terminal reaction in mammary triglyceride synthesis, and underpins a well-known pleiotropic quantitative trait locus (QTL) with a large influence on milk composition phenotypes. Since first described over 15 years ago, a protein-coding variant K232A has been assumed as the causative variant underlying these effects, following in-vitro studies that demonstrated differing levels of triglyceride synthesis between the two protein isoforms. Results We used a large RNAseq dataset to re-examine the underlying mechanisms of this large milk production QTL, and hereby report novel expression-based functions of the chr14 g.1802265AA > GC variant that encodes the DGAT1 K232A substitution. Using expression QTL (eQTL) mapping, we demonstrate a highly-significant mammary eQTL for DGAT1, where the K232A mutation appears as one of the top associated variants for this effect. By conducting in vitro expression and splicing experiments in bovine mammary cell culture, we further show modulation of splicing efficiency by this mutation, likely through disruption of an exon splice enhancer as a consequence of the allele encoding the 232A variant. Conclusions The relative contributions of the enzymatic and transcription-based mechanisms now attributed to K232A remain unclear; however, these results suggest that transcriptional impacts contribute to the diversity of lactation effects observed at the DGAT1 locus.

Background Microglia play critical roles in the brain during homeostasis and pathological conditions. Understanding the molecular events underpinning microglial functions and activation states will further enable us to target these cells for the treatment of neurological disorders. The transcription factor PU.1 is critical in the development of myeloid cells and a major regulator of microglial gene expression. In the brain, PU.1 is specifically expressed in microglia and recent evidence from genome-wide association studies suggests that reductions in PU.1 contribute to a delayed onset of Alzheimer’s disease (AD), possibly through limiting neuroinflammatory responses. Methods To investigate how PU.1 contributes to immune activation in human microglia, microarray analysis was performed on primary human mixed glial cultures subjected to siRNA-mediated knockdown of PU.1. Microarray hits were confirmed by qRT-PCR and immunocytochemistry in both mixed glial cultures and isolated microglia following PU.1 knockdown. To identify attenuators of PU.1 expression in microglia, high throughput drug screening was undertaken using a compound library containing FDA-approved drugs. NanoString and immunohistochemistry was utilised to investigate the expression of PU.1 itself and PU.1-regulated mediators in primary human brain tissue derived from neurologically normal and clinically and pathologically confirmed cases of AD. Results Bioinformatic analysis of gene expression upon PU.1 silencing in mixed glial cultures revealed a network of modified AD-associated microglial genes involved in the innate and adaptive immune systems, particularly those involved in antigen presentation and phagocytosis. These gene changes were confirmed using isolated microglial cultures. Utilising high throughput screening of FDA-approved compounds in mixed glial cultures we identified the histone deacetylase inhibitor vorinostat as an effective attenuator of PU.1 expression in human microglia. Further characterisation of vorinostat in isolated microglial cultures revealed gene and protein changes partially recapitulating those seen following siRNA-mediated PU.1 knockdown. Lastly, we demonstrate that several of these PU.1-regulated genes are expressed by microglia in the human AD brain in situ. Conclusions Collectively, these results suggest that attenuating PU.1 may be a valid therapeutic approach to limit microglial-mediated inflammatory responses in AD and demonstrate utility of vorinostat for this purpose. Electronic supplementary material The online version of this article (10.1186/s13024-018-0277-1) contains supplementary material, which is available to authorized users.

Objective Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to have anti-proliferative, anti-angiogenic, and proapoptotic effects, leading to interest in their use as cancer therapeutics. Pioglitazone, a U.S. Food and Drug Administration-approved type II diabetes medication and PPARγ agonist, may have a role in adjuvant head-and-neck squamous cell carcinoma treatment or prevention. Therefore, the purpose of this study was: 1) to treat oral cavity cancer cells with the PPARγ activator, pioglitazone, to analyze gene expression changes; and 2) to compare those changes with our preexisting genomic data for development of hypothesis-driven additional basic and clinical studies. Study Design Prospective in vitro. Methods We utilized microarray technology, as well as OCPlus (Bioconductor open source software) and Ingenuity Pathway Analysis (Qiagen, Redwood City, CA), to analyze differential gene expression in tumor and pioglitazone-treated tumor cells on a genome-wide level to demonstrate the feasibility of such an approach and determine appropriate sample size for future investigations. Results We found that approximately 35 samples are required to adequately power future studies. We next discovered that pioglitazone significantly affects Inducible T-Cell Costimulator (iCOS)-Ligand for the T-cell-specific cell surface receptor ICOS (iCOSL) and type II diabetes mellitus pathways as a putative anti-cancer mechanism. Conclusion Genome-wide analysis is possible for the exploration of differential pathway modulation and rapid hypothesis generation. Both inflammation and type II diabetes pathways were significantly altered and therefore might provide unique hypothesis-driven pharmacodynamic parameters for future in vitro or in vivo studies utilizing thiazolidinediones. These techniques could be applied to microarray or other high throughput data from a variety of hypothesis-generating research scenarios in otolaryngology (e.g., middle ear proteomics, sinus microbiome studies). Level of Evidence NA. Laryngoscope, 2016

Milking cows once daily (1×) is a management practice occasionally used during mid/late lactation in pasture-based systems. It has been postulated that 1× milking will reduce dry matter intake (DMI) and increase body condition score (BCS) gain; however, this has not been quantified. Lactating, pregnant Holstein-Friesian dairy cows (n=52) were allocated to either 1× or twice-daily (2×) milking in mid-January (summer, 175d in milk). To obtain accurate DMI measurements, cows underwent 4 periods in a Calan gate indoor feeding facility, interspersed with grazing outdoors. Milk production, body weight (BW), and BCS were recorded 2 wk before treatment start (-2 wk) and weekly thereafter. Blood variables were recorded at -2 wk and weekly when indoors. Liver was biopsied at -2, 2, and 10 wk, and hepatic gene expression measured using quantitative PCR. Milking cows 1× tended to lower DMI (17.8 vs. 18.2 kg of dry matter), but increased BCS gain (0.36 vs. 0.13 BCS units) and BW (546 vs. 533 kg) at wk 12 relative to 2×. The greater BCS and BW of cows milked 1× compared with 2× were reflected in lower plasma concentrations of nonesterified fatty acids and lower transcription of genes involved in the oxidation of fatty acids, indicating reduced release and processing of fatty acids. Cows milked 1× produced 20% less milk, and although milk fat and protein concentrations were increased relative to cows milked 2×, yields of fat and protein were 14 and 17% less, respectively. The reduction in milk production with 1× milking (14.1 vs. 16.8 kg/cow per d energy-corrected milk) was accompanied by increases in blood concentrations of glucose and insulin, with a concurrent decrease in the transcription of the insulin receptor and gluconeogenic genes. These results indicate a coordinated response to reduce glucose production due to decreased mammary demand. Expression of 2 genes linked to inflammation and adipokine signaling was reduced in cows milked 1× and may indicate a lower inflammatory state in the liver of cows milked 1× in late lactation. No effect was found of milking frequency during late lactation on milk production in the subsequent lactation. In summary, although 1× milking tended to reduce DMI and increase BCS in late lactation, these effects were lower than what is commonly supposed in pasture-based dairy systems. The modest BCS gains need to be considered with the reduced milk production when adopting 1× milking as a management strategy.

Because of its high yield and the ability of cows to graze it in situ, fodder beet (FB) has become a popular crop in grazing systems, particularly for nonlactating cows. Due to its high sugar content, however, the transition to FB must be managed carefully to avoid rumen acidosis and associated metabolic dysfunction. The initial consumption of FB reduces ruminal pH; however, it is unclear whether this affects liver metabolism and results in systemic inflammation, as has been reported during subacute ruminal acidosis from high-grain diets. We used a quantitative case study approach to undertake additional measurements on a project demonstrating the effects of FB on urinary nitrogen excretion. The objective of our component, therefore, was to determine whether the inclusion of high rates of FB in the diet of nonlactating cows changed indicators of hepatic metabolism relative to a standard diet for nonlactating grazing cows. During the nonlactating period, multiparous, pregnant Holstein-Friesian cows were randomly assigned (n = 15 per treatment) to either pasture (8 kg of DM/cow per day) with corn silage (4 kg of DM/cow per day; PA) or transitioning onto an FB diet (8 kg of DM/cow per day) with pasture silage (4 kg of DM/cow per day; BT) over 14 d. Blood was sampled and the liver was biopsied during the adaptation period and after 7 d of full diet allocation. The hepatic expression of genes involved in peroxisomal oxidation was increased in cows adapting to FB, whereas the expression of genes involved in mitochondrial oxidation was increased when cows were on their full allocation of FB. These results indicate changes to fatty acid metabolism with FB consumption. Expression of 2 genes involved in the unfolded protein response was greater during the adaptation period in cows consuming FB, potentially reflecting negative effects of transitioning onto the FB diet on hepatic metabolism. Interestingly, expression of genes involved in the methionine cycle was increased in the BT cows. We hypothesize that this is a result of FB betaine absorption, although it is unclear to what extent betaine escapes ruminal degradation. While on the full diet allocation, there were lower serum concentrations of markers of hepatic stress in BT cows and no difference in expression of genes involved in oxidative stress compared with pasture-fed cows. However, there was an increase in plasma haptoglobin concentrations, indicative of an acute inflammatory response in BT cows. From this case study, we conclude that the results indicate no negative effects of the FB diet on liver metabolism and, possibly, positive effects on hepatic function. It appears, therefore, that the transition of nonlactating cows onto an FB diet can be managed to minimize the negative effects of the high sugar intake. Further research on the amount of betaine that escapes ruminal degradation in cows consuming FB would be of value to better understand whether betaine reduces liver damage in dairy cows consuming FB.

We present evidence for the presymptomatic dysregulation of urea metabolism in Huntington’s disease (HD). We identified increased levels of a urea transporter transcript and other osmotic regulators in the striatum of our prodromal sheep model of HD and a concomitant increase in striatal and cerebellar urea. Elevated urea was also detected in brain tissue from postmortem HD cases, including cases with low-level cell loss, implying that increased brain urea in HD is not just a product of end-stage cachexia. Disruption of urea metabolism is known to cause neurologic impairment and could initiate neurodegeneration and the symptoms of HD. Our findings suggest that lowering brain levels of urea and/or ammonia would be a worthwhile therapeutic target in HD.

Objectives: There has been significant research on provider attribution for quality and cost. Low-value care is an area of heightened focus, with little of the focus being on measurement; a key methodological decision is how to attribute delivered services and procedures. We illustrate the difference in relative and absolute physician- and panel-attributed services and procedures using overuse in cervical cancer screening.Study Design: A retrospective, cross-sectional study in an integrated health care system.Methods: We used 2013 physician-level data from Group Health Cooperative to calculate two utilization attributions: (1) panel attribution with the procedure assigned to the physician’s predetermined panel, regardless of who performed the procedure; and (2) physician attribution with the procedure assigned to the performing physician. We calculated the percentage of low-value cervical cancer screening tests and ranked physicians within the clinic using the two utilization attribution methods.Results: The percentage of low-value cervical cancer screening varied substantially between physician and panel attributions. Across the whole delivery system, median panel- and physician-attributed percentages were 15 percent and 10 percent, respectively. Among sampled clinics, panel-attributed percentages ranged between 10 percent and 17 percent, and physician-attributed percentages ranged between 9 percent and 13 percent. Within a clinic, median panel-attributed screening percentage was 17 percent (range 0 percent–27 percent) and physician-attributed percentage was 11 percent (range 0 percent–24 percent); physician rank varied by attribution method.Conclusions: The attribution method is an important methodological decision when developing low-value care measures since measures may ultimately have an impact on national benchmarking and quality scores. Cross-organizational dialogue and transparency in low-value care measurement will become increasingly important for all stakeholders.

Integration of exogenous DNA into a host genome represents an important route to generate animal and cellular models for exploration into human disease and therapeutic development. In most models, little is known concerning structural integrity of the transgene, precise site of integration, or its impact on the host genome. We previously used whole-genome and targeted sequencing approaches to reconstruct transgene structure and integration sites in models of Huntington’s disease, revealing complex structural rearrangements that can result from transgenesis. Here, we demonstrate in the R6/2 mouse, a widely used Huntington’s disease model, that integration of a rearranged transgene with coincident deletion of 5,444 bp of host genome within the gene Gm12695 has striking molecular consequences. Gm12695, the function of which is unknown, is normally expressed at negligible levels in mouse brain, but transgene integration has resulted in cortical expression of a partial fragment (exons 8–11) 3’ to the transgene integration site in R6/2. This transcript shows significant expression among the extensive network of differentially expressed genes associated with this model, including synaptic transmission, cell signalling and transcription. These data illustrate the value of sequence-level resolution of transgene insertions and transcription analysis to inform phenotypic characterization of transgenic models utilized in therapeutic research.

Atypical fractures of the femur (AFF) are defined as atraumatic or low-trauma fractures located in the subtrochanteric region or femoral shaft, and have characteristic clinical and radiological features.[1][1] The use of bisphosphonates and denosumab, both anti-resorptives, is associated with a

Huntington’s disease (HD) is a dominantly inherited, progressive neurodegenerative disorder caused by a CAG repeat expansion within exon 1 of HTT, encoding huntingtin. There are no therapies that can delay the progression of this devastating disease. One feature of HD that may play a critical role in its pathogenesis is metabolic disruption. Consequently, we undertook a comparative study of metabolites in our transgenic sheep model of HD (OVT73). This model does not display overt symptoms of HD but has circadian rhythm alterations and molecular changes characteristic of the early phase disease. Quantitative metabolite profiles were generated from the motor cortex, hippocampus, cerebellum and liver tissue of 5 year old transgenic sheep and matched controls by gas chromatography-mass spectrometry. Differentially abundant metabolites were evident in the cerebellum and liver. There was striking tissue-specificity, with predominantly amino acids affected in the transgenic cerebellum and fatty acids in the transgenic liver, which together may indicate a hyper-metabolic state. Furthermore, there were more strong pair-wise correlations of metabolite abundance in transgenic than in wild-type cerebellum and liver, suggesting altered metabolic constraints. Together these differences indicate a metabolic disruption in the sheep model of HD and could provide insight into the presymptomatic human disease.

This article presents a unified clinical theory that links established facts about the physiology of bone and homeostasis, with those involved in the healing of fractures and the development of nonunion. The key to this theory is the concept that the tissue that forms in and around a fracture should be considered a specific functional entity. This ‘bone-healing unit’ produces a physiological response to its biological and mechanical environment, which leads to the normal healing of bone. This tissue responds to mechanical forces and functions according to Wolff’s law, Perren’s strain theory and Frost’s concept of the “mechanostat”. In response to the local mechanical environment, the bone-healing unit normally changes with time, producing different tissues that can tolerate various levels of strain. The normal result is the formation of bone that bridges the fracture – healing by callus. Nonunion occurs when the bone-healing unit fails either due to mechanical or biological problems or a combination of both. In clinical practice, the majority of nonunions are due to mechanical problems with instability, resulting in too much strain at the fracture site. In most nonunions, there is an intact bone-healing unit. We suggest that this maintains its biological potential to heal, but fails to function due to the mechanical conditions. The theory predicts the healing pattern of multifragmentary fractures and the observed morphological characteristics of different nonunions. It suggests that the majority of nonunions will heal if the correct mechanical environment is produced by surgery, without the need for biological adjuncts such as autologous bone graft. Cite this article: Bone Joint J 2016;98-B:884–91.