Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of ...particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions.
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•PPM1D is mutated in ∼20% of patients with therapy-related AML or MDS•PPM1D mutations are associated with prior exposure to specific DNA-damaging agents•Mutant PPM1D confers a survival advantage after cisplatin-induced stress•PPM1D mutants lack an advantage under bone marrow transplantation stress
Cytotoxic chemotherapies put patients at risk for future hematopoietic malignancies. Goodell and colleagues show that PPM1D mutations confer a survival advantage onto hematopoietic clones by rendering them resistant to DNA-damaging agents such as cisplatin. Selective pressures will be specific to different mutations and should be considered in choice of chemotherapy.
BACKGROUND:In the past 2 decades, overdoses and deaths from prescription opioids have reached epidemic proportions in the United States. The widespread use of opioids complicates management of the ...orthopaedic surgery patient in the acute and chronic settings. Orthopaedic surgeons are some of the top prescribers of opioids in the complex setting of chronic use, abuse, and diversion.
METHODS:The literature regarding the basic science of pharmacologic options for pain management (e.g., opioids and nonsteroidal anti-inflammatory drugs), the impact of strategies on bone and soft-tissue healing, and pain relief are summarized as they relate to the management of orthopaedic injuries and conditions. Additionally, a section on designing solutions to address the current opioid crisis is presented.
RESULTS:The mechanism of action of different classes of analgesic medications is discussed, as well as the basic scientific evidence regarding the impact of narcotic and nonnarcotic analgesic medications on bone-healing and on other organ systems. Differences between pain and nociception, various treatment strategies, and clinical comparisons of the effectiveness of various analgesics compared with opioids are summarized. Finally, options for addressing the opioid crisis, including the description of a large system-wide intervention to impact prescriber behavior at the point of care using health-information solutions, are presented.
CONCLUSIONS:Orthopaedic leaders, armed with information and strategies, can help lead the way to solutions to the opioid epidemic in their respective communities, institutions, and subspecialty societies. Through leadership and education, orthopaedic surgeons can help shape the solution for this critical public health issue.
Volumetric muscle loss Grogan, Brian F; Hsu, Joseph R
Journal of the American Academy of Orthopaedic Surgeons,
01/2011, Letnik:
19 Suppl 1
Journal Article
Recenzirano
Odprti dostop
Prevention of infection, as well as bone covering and healing, is paramount in the management of limb injury with associated muscle injury. Volumetric muscle loss (VML) is the traumatic or surgical ...loss of skeletal muscle with resultant functional impairment. No standardized evaluation protocol exists for the characterization and quantification of VML. Clinical photographs and video recordings, range of motion measurements, manual muscle strength testing, and isokinetic muscle function testing may prove to be useful in documenting VML. Current treatment options include functional free muscle transfer and the use of advanced bracing designs. Advances in powered bracing and regenerative medicine may one day provide additional therapeutic options. Further research on VML is warranted.
Antibiotic-coated implants are increasing in prevalence in the treatment of fracture-related infections. Coated plates may be desirable in certain anatomic locations or to augment nail fixation. We ...describe a simple, reproducible technique for the fabrication of antibiotic-coated plates and our initial results of a small case series.
The COVID-19 pandemic has presented challenges to healthcare systems, including the cancellation and then staged resumption of elective procedures. The orthopaedic trauma community has continued to ...provide care to patients with acute musculoskeletal injuries that cannot be delayed in all scenarios. This article summarizes and provides relevant information (orthopaedic trauma service, outpatient fracture clinic, inpatient surgery) to the practicing orthopaedic traumatologist on maximizing outcomes while limiting exposure during the pandemic.
LEVEL OF EVIDENCE:Therapeutic Level V. See Instructions for Authors for a complete description of levels of evidence.
Breast cancer arising in young women is correlated with inferior survival and higher incidence of negative clinicopathologic features. The biology driving this aggressive disease has yet to be ...defined.
Clinically annotated, microarray data from 784 early-stage breast cancers were identified, and prospectively defined, age-specific cohorts (young: </= 45 years, n = 200; older: >/= 65 years, n = 211) were compared by prognosis, clinicopathologic variables, mRNA expression values, single-gene analysis, and gene set enrichment analysis (GSEA). Univariate and multivariate analyses were performed.
Using clinicopathologic variables, young women illustrated lower estrogen receptor (ER) positivity (immunohistochemistry IHC, P = .027), larger tumors (P = .012), higher human epidermal growth factor receptor 2 (HER-2) overexpression (IHC, P = .075), lymph node positivity (P = .008), higher grade tumors (P < .0001), and trends toward inferior disease-free survival (DFS; hazard ratio = 1.32; P = .094). Using genomic expression analysis, tumors arising in young women had significantly lower ERalpha mRNA (P < .0001), ERbeta (P = .02), and progesterone receptor (PR) expression (P < .0001), but higher HER-2 (P < .0001) and epidermal growth factor receptor (EGFR) expression (P < .0001). Exploratory analysis (GSEA) revealed 367 biologically relevant gene sets significantly distinguishing breast tumors arising in young women. Combining clinicopathologic and genomic variables among tumors arising in young women demonstrated that younger age and lower ERbeta and higher EGFR mRNA expression were significant predictors of inferior DFS.
This large-scale genomic analysis illustrates that breast cancer arising in young women is a unique biologic entity driven by unifying oncogenic signaling pathways, is characterized by less hormone sensitivity and higher HER-2/EGFR expression, and warrants further study to offer this poor-prognosis group of women better preventative and therapeutic options.
PURPOSE:We aimed to produce comprehensive guidelines and recommendations that can be utilized by orthopaedic practices as well as other specialties to improve the management of acute pain following ...musculoskeletal injury.
METHODS:A panel of 15 members with expertise in orthopaedic trauma, pain management, or both was convened to review the literature and develop recommendations on acute musculoskeletal pain management. The methods described by the Grading of Recommendations Assessment, Development, and Evaluation Working Group were applied to each recommendation. The guideline was submitted to the Orthopaedic Trauma Association (OTA) for review and was approved on October 16, 2018.
RESULTS:We present evidence-based best practice recommendations and pain medication recommendations with the hope that they can be utilized by orthopaedic practices as well as other specialties to improve the management of acute pain following musculoskeletal injury. Recommendations are presented regarding pain management, cognitive strategies, physical strategies, strategies for patients on long term opioids at presentation, and system implementation strategies. We recommend the use of multimodal analgesia, prescribing the lowest effective immediate-release opioid for the shortest period possible, and considering regional anesthesia. We also recommend connecting patients to psychosocial interventions as indicated and considering anxiety reduction strategies such as aromatherapy. Finally, we also recommend physical strategies including ice, elevation, and transcutaneous electrical stimulation. Prescribing for patients on long term opioids at presentation should be limited to one prescriber. Both pain and sedation should be assessed regularly for inpatients with short, validated tools. Finally, the group supports querying the relevant regional and state prescription drug monitoring program, development of clinical decision support, opioid education efforts for prescribers and patients, and implementing a department or organization pain medication prescribing strategy or policy.
CONCLUSIONS:Balancing comfort and patient safety following acute musculoskeletal injury is possible when utilizing a true multimodal approach including cognitive, physical, and pharmaceutical strategies. In this guideline, we attempt to provide practical, evidence-based guidance for clinicians in both the operative and non-operative settings to address acute pain from musculoskeletal injury. We also organized and graded the evidence to both support recommendations and identify gap areas for future research.
Inflammatory bowel disease (IBD) is associated with a loss of intestinal barrier function and dysregulated immune responses. It has been shown that short chain fatty acids (SCFAs) are protective in ...IBD and that GPR43 mediates the protective effects of SCFAs. In this study, we investigated the effects of SCFAs in comparison to highly specific GPR43 agonists on human intestinal epithelial and immune cells. Our results confirm that SCFAs are enhancers of barrier function in intestinal epithelial cells. Additionally, SCFAs also displayed potent immunoregulatory properties based upon the ability to inhibit LPS-induced cytokine production in PBMC, and human T cell proliferation and cytokine production. Unexpectedly, and in contrast to the current belief, specific GPR43 agonists failed to exhibit similar barrier enhancing and anti-inflammatory properties. These findings demonstrate that SCFA possess broad protective functions in IBD and agonizing GPR43 alone is unlikely to be beneficial in patients.
Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) ...as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
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•Fab-dimerized glycan-reactive (FDG) natural antibodies (Abs) are prevalent in primates•Fab-dimerization can occur independent of VH domain-swapping•Precursor FDG natural Abs acquire neutralization breadth in retroviral infection•FDG Abs recognize a quaternary epitope in the S2 subunit of SARS-CoV-2 spike
Structural and functional analyses identify a category of glycan-reactive antibodies in macaques and humans that are marked by the dimerization of the antigen-binding fragment. These antibodies are involved in HIV neutralization and also recognize the S2 protein of SARS-CoV-2.
Orthopaedic trauma patients have high rates of psychiatric disorders, which put them at risk for worse outcomes after injury and surgery, including worse pain. Mental health conditions, such as ...depression and anxiety, can affect the perception of pain. Pain can also exacerbate or contribute to the development of mental illness after injury. Interventions to address both mental health and pain among orthopaedic trauma patients are critical. Balancing safety and comfort amid a drug overdose epidemic is challenging, and many clinicians do not feel comfortable addressing mental health or have the resources necessary. We reviewed the literature on the complex relationship between pain and mental health and presented examples of scalable and accessible interventions that can be implemented to promote the health and recovery of our patients. Interventions described include screening for depression in the orthopaedic trauma clinic and the emergency department or inpatient setting during injury and using a comprehensive and evidence-based multimodal pain management regimen that blends pharmacologic alternatives to opioids and physical and cognitive strategies to manage pain.
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