Medial malleolar fractures: current treatment concepts.

The medial malleolus, once believed to be the primary stabilizer of the ankle, has been the topic of conflicting clinical and biomechanical data for many decades. Despite the relevant surgical anatomy being understood for almost 40 years, the optimal treatment of medial malleolar fractures remains unclear, whether the injury occurs in isolation or as part of an unstable bi- or trimalleolar fracture configuration. Traditional teaching recommends open reduction and fixation of medial malleolar fractures that are part of an unstable injury. However, there is recent evidence to suggest that nonoperative management of well-reduced fractures may result in equivalent outcomes, but without the morbidity associated with surgery. This review gives an update on the relevant anatomy and classification systems for medial malleolar fractures and an overview of the current literature regarding their management, including surgical approaches and the choice of implants. Cite this article: Bone Joint J 2019;101-B:512-521.

Discharged but not dissatisfied: outcomes and satisfaction of patients discharged from the Edinburgh Trauma Triage Clinic.

Aims: The Edinburgh Trauma Triage Clinic (TTC) streamlines outpatient care through consultant-led 'virtual' triage of referrals and the direct discharge of minor fractures from the Emergency Department. We compared the patient outcomes for simple fractures of the radial head, little finger metacarpal, and fifth metatarsal before and after the implementation of the TTC. Patients and Methods: A total of 628 patients who had sustained these injuries over a one-year period were identified. There were 337 patients in the pre-TTC group and 289 in the post-TTC group. The Disabilities of the Arm, Shoulder and Hand Score (QuickDASH) or Foot and Ankle Disability Index (FADI), EuroQol-5D (EQ-5D), visual analogue scale (VAS) pain score, satisfaction rates, and return to work/sport were assessed six months post-injury. The development of late complications was excluded by an electronic record evaluation at three years post-injury. A cost analysis was performed. Results: Outcomes were as good or better post-TTC, compared with pre-TTC scores. At three years, the pre-TTC group required a total of 496 fracture clinic appointments compared with 61 in the post-TTC group. Mean cost per patient was nearly fourfold less after the commencement of the TTC. Conclusion: Management of minor fractures through the Edinburgh TTC results in clinical outcomes that are comparable with the previous system of routine face-to-face consultation. Outpatient workload for these injures was reduced by 88%. Cite this article: Bone Joint J 2018;100-B:959-65.

The evolution of fracture clinic design : the activity and safety of the Edinburgh Trauma Triage Clinic, with one-year follow-up.

AIMS: Fracture clinics are often characterised by the referral of large numbers of unselected patients with minor injuries not requiring investigation or intervention, long waiting times and recurrent unnecessary reviews. Our experience had been of an unsustainable system and we implemented a 'Trauma Triage Clinic' (TTC) in order to rationalise and regulate access to our fracture service. The British Orthopaedic Association's guidelines have required a prospective evaluation of this change of practice, and we report our experience and results. PATIENTS AND METHODS: We review the management of all 12 069 patients referred to our service in the calendar year 2014, with a minimum of one year follow-up during the calendar year 2015. RESULTS: Following the successful introduction of the TTC, only 2836 patients (23.5%) who would previously have been reviewed in the general fracture clinic were brought back to such a clinic to be seen by a surgeon. An additional 2366 patients (19.6%) were brought back to a sub-specialist injury-specific clinic. Another 2776 patients (23%) with relatively predictable injuries were reviewed by a nurse practitioner according to an established protocol or specific consultant instructions. A further 3222 patients (26.7%) were discharged from the service without attending the clinic. No significant errors or omissions occurred with the introduction of the TTC. CONCLUSION: We have found that our TTC allows large numbers of referrals to be reviewed and triaged safely and effectively, to the benefit and satisfaction of patients, consultants, trainees, staff and the organisation. This paper provides the first large-scale review of the instigation of a TTC, and its effect, acceptability and safety. Cite this article: Bone Joint J 2017;99-B:503-7.

Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia.

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.

A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia.

Acute myeloid leukemia (AML) is hypothesized to be sustained by self-renewing leukemia stem cells (LSCs). Recently, gene expression signatures (GES) from functionally defined AML LSC populations were reported, and expression of a 'core enriched' (CE) GES, representing 44 genes activated in LCSs, conferred shorter survival in cytogenetically normal (CN) AML. The prognostic impact of the CE GES in the context of other molecular markers, including gene mutations and microRNA (miR) expression alterations, is unknown and its clinical utility is unclear. We studied associations of the CE GES with known molecular prognosticators, miR expression profiles, and outcomes in 364 well-characterized CN-AML patients. A high CE score (CE(high)) associated with FLT3-internal tandem duplication, WT1 and RUNX1 mutations, wild-type CEBPA and TET2, and high ERG, BAALC and miR-155 expression. CE(high) patients had a lower complete remission (CR) rate (P=0.003) and shorter disease-free (DFS, P<0.001) and overall survival (OS, P<0.001) than CE(low) patients. These associations persisted in multivariable analyses adjusting for other prognosticators (CR, P=0.02; DFS, P<0.001; and OS, P<0.001). CE(high) status was accompanied by a characteristic miR expression signature. Fifteen miRs were upregulated in both younger and older CE(high) patients, including miRs relevant for stem cell function. Our results support the clinical relevance of LSCs and improve risk stratification in AML.

Indole-3-carbinol and diindolylmethane induce apoptosis of human cervical cancer cells and in murine HPV16-transgenic preneoplastic cervical epithelium.

Dietary indole-3-carbinol (I3C) has clinical benefits for both cervical cancer and laryngeal papillomatosis, and causes apoptosis of breast cancer cells in vitro. We asked whether I3C and its major acid-catalyzed condensation product diindolylmethane (DIM), which is produced in the stomach after consumption of cruciferous vegetables, could induce apoptosis of cervical cancer cell lines. We also asked whether this effect could be observed in vivo. In vitro, both I3C and DIM caused accumulation of DNA strand breaks in three cervical cancer cell lines. Induction of apoptosis was confirmed by nuclear morphology, nucleosome leakage, altered cytoplasmic membrane permeability and caspase 3 activation. Neither I3C nor DIM caused apoptotic changes in normal human keratinocytes. In C33A cervical cancer cells, DIM was more potent than I3C [dose at which the number of viable cells was 50% of that in untreated cultures (LD(50)) = 50-60 micromol/L for DIM and 200 micromol/L for I3C in a mitochondrial function assay] and faster acting. Furthermore, I3C reduced Bcl-2 protein in a time- and dose-dependent manner. In HPV16-transgenic mice, which develop cervical cancer after chronic estradiol exposure, apoptotic cells were detected in cervical epithelium by TdT-mediated dUTP nick-end labeling staining and by immunohistochemical staining of active caspase 3 only in mice exposed to 17beta-estradiol (E2) and fed I3C. Rare apoptotic cells were also observed by hematoxylin and eosin staining in the spinous layer of the cervical epithelium in both control and transgenic mice. Estradiol reduced the percentage of these late-stage apoptotic cells in the cervical epithelium of transgenic, E2-treated mice, but this reduction was prevented by I3C. These data confirm the proapoptotic action of I3C on transformed cells in vitro, extend the observations to cervical cancer cells and to DIM and show for the first time that dietary I3C results in increased apoptosis in target tissues in vivo.

Successful non-surgical treatment of disseminated polymicrobial fungal infection in a patient with pancytopenia and graft-versus-host disease.

Invasive fungal infections after bone marrow transplantation have an extremely poor prognosis. Surgical excision in combination with antifungal therapy is considered necessary for treatment, especially for central nervous system (CNS) infection. We describe successful medical management with lipid complex amphotericin B (ABLC) and itraconazole, without surgical excision, of disseminated fungal infection involving the lungs and CNS in a patient with pancytopenia and graft-versus-host disease.

Treatment of human papillomavirus gynecologic infections.

The future holds promise for better prevention and treatment of HPV infections. Currently, therapeutic options for HPV infections are limited, expensive, and often ineffective. Recent advances in understanding the basic virology and natural history of HPV infection have identified hitherto unsuspected approaches to therapy and have suggested novel pharmacologic and other types of interventions. An important area for future research is the need for detailed information about the mechanisms that trigger latent HPV and induce wart formation or promote malignant transformation. Conversely, we also need to know more about mechanisms that keep the virus in check (latent) in many HPV-infected persons.

Efficacy and safety of oral granisetron versus i.v. granisetron in patients undergoing peripheral blood progenitor cell and bone marrow transplantation.

This randomized, controlled, double-blind pilot study assessed the efficacy and safety of oral versus i.v. granisetron, both in combination with non-5-HT3 antiemetics, in preventing emesis caused by high-dose chemotherapy. Fifty-one patients who underwent peripheral blood progenitor cell transplantation (PBPCT) or bone marrow transplantation (BMT) were evaluated. Efficacy was assessed by the number of emetic episodes during the worst 24 h period. A complete response (CR) was defined as no vomiting, partial response (PR) as less than three emetic episodes and failure as three or more emetic episodes. Patients who received oral granisetron experienced significantly (p<0.0008) fewer emetic episodes than those who received i.v. granisetron; however, the number of emetic episodes over the worst 24 h was similar between the oral and i.v. granisetron groups (13 and 15, respectively), as were the overall response rates (CR+PR, 54.5 and 41.4%, respectively). Both dosage forms were well tolerated. Based on these findings, further comparative studies of oral granisetron are warranted in patients undergoing PBPCT or BMT.

The role of community review in evaluating the risks of human genetic variation research.

The practicality and moral value of community review of human genetic research has become a focus of debate. Examples from two Native American communities are used to address four aspects of that debate: (1) the value of community review in larger, geographically dispersed populations; (2) the identification of culturally specific risks; (3) the potential conflict between individual and group assessments of research-related risks; and (4) the confusion of social categories with biological categories. Our experiences working with these two communities suggest that: (1) successful community review may require the involvement of private social units (e.g., families); (2) culturally specific implications of genetic research may be identifiable only by community members and are of valid concern in their moral universes; (3) community concerns can be incorporated into existing review mechanisms without necessarily giving communities the power to veto research proposals; and (4) the conflation of social and biological categories presents recruitment problems for genetic studies. These conclusions argue for the use of community review to identify and minimize research-related risks posed by genetic studies. Community review also can assist in facilitating participant recruitment and retention, as well as in developing partnerships between researchers and communities.

Marrow and stem cell transplantation in Oklahoma: fifteen years of experience and results.

From September 1982 to August 1997, 767 bone marrow or peripheral blood stem cell transplants have been performed at the Health Sciences Center in Oklahoma. Five hundred and two (502) autologous transplants (AutoTX) preceded by high-dose myeloablative therapy were performed for breast cancer (BC, 36%), non-Hodgkin's lymphomas (NHL, 24%), Hodgkin's disease (HD, 10%), acute myeloid leukemia (AML, 8%), testicular cancer (TC, 4%), multiple myeloma (MM, 2%) and other malignancies (16%). Two hundred and sixty-five (265) allogeneic marrow transplants (AlloTX) (related, unrelated) were carried out in chronic myeloid leukemia (CML, 30%), AML (23%), acute lymphoid leukemia (ALL, 14%), myelodysplastic syndrome (MDS, 9%), severe aplastic anemia (SAA, 8%), and other diseases (14%). Compared between 1980s to 1990s, 100-day mortality rates have decreased from 28% to 5% for AutoTX and from 40% to 25% for AlloTX. In the AutoTX setting, major changes included the routine use of growth factors post-transplant and the switch from bone marrow to growth factor-mobilized peripheral blood as a source of stem cells over the last five years. In the AlloTX setting, improvements in recognition and control of cytomegalovirus and Candida organisms, the selective use of growth factors and screened blood products, and better selection of unrelated donors using DNA-based techniques of HLA-matching have contributed to reduce early mortality from infection and primary graft failure. The five-year survival outcomes are comparable to those reported in registry data from the International Bone Marrow Transplant Registry (IBMTR) and the National Marrow Donor Program (NMDP).

A model agreement for genetic research in socially identifiable populations.

Genetic research increasingly focuses on population-specific human genetic diversity. However, the naming of a human population in public databases and scientific publications entails collective risks for its members. Those collective risks can be evaluated and protections can be put in place by the establishment of a dialogue with the subject population, before a research study is initiated. Here we describe an agreement to undertake genetic research with a Native American tribe. We identified the culturally appropriate public and private social units within which community members are accustomed to make decisions about health. We then engaged those units in a process of communal discourse. In their discourses about our proposed study, community members expressed most concern about culturally specific implications. We also found that, in this population, private social units were more influential in communal decision making than were public authorities. An agreement was reached that defined the scope of research, provided options for naming the population in publications (including anonymity), and addressed the distribution of royalties from intellectual property, the future use of archival samples, and specific cultural concerns. We found that informed consent by individuals could not fully address these collective issues. This approach may serve as a general model for the undertaking of population-specific genetic studies.

Communal discourse as a supplement to informed consent for genetic research.

Genetic technologies present unique problems for the practice of informed consent. They provide information that may affect a study participant's family or kindred, which may be identifiable as an ethnic or locally isolated population. That information may be used to construct adverse perceptions of such identifiable populations, including non-participants who may not have been informed of or consented to the analyses. To address collective implications of genetic research, we describe a process that can supplement individual consent. Our approach engages pre-existing social units in discourses about proposed research. Communal discourses can influence individuals' decisions to participate in research studies.

Genetic screening of targeted subpopulations: the role of communal discourse in evaluating sociocultural implications.

Targeting socially identifiable subpopulations for genetic screening entails the risk of stigmatizing them. The potential for such harm should be considered before programs are initiated. There is an emerging consensus that targeted subpopulations should be actively involved in evaluating these risks. A process of communal discourse engages the community in discussions that reflect both public and private sociocultural contexts in which individual decisions about screening will be made. This allows the subpopulation to address the collective implications of testing in a culturally appropriate way. Communal discourse was used to evaluate the collective implications of genetic testing in two Native American communities. We found that private social units were more influential than public units in reaching communal consensus, that local sociocultural issues were of more concern than were general issues such as employment and insurance discrimination, and that heterogeneity within a subpopulation may be just as significant a consideration in designing a targeted screening program as diversity between subpopulations. Heterogeneity is constructed by using a dichotomy between community-specific and biomedical health representations and practices. How genetic screening is socially constructed using a community's existing dichotomy may be central to its success.

Autoantibodies that stabilize the molecular interaction of Ku antigen with DNA-dependent protein kinase catalytic subunit.

DNA-dependent protein kinase (DNA-PK) consists of a DNA binding subunit (Ku autoantigen), and a catalytic subunit (DNA-PKcs). In the present study, human autoantibodies that recognize novel antigenic determinants of DNA-PK were identified. One type of autoantibody stabilized the interaction of DNA-PKcs with Ku and recognized the DNA-PKcs -Ku complex, but not bio-chemically purified DNA-PKcs. Another type recognized purified DNA-PKcs. Autoantibodies to Ku (p70/p80 heterodimer), 'stabilizing' antibodies, and antibodies to DNA-PKcs comprise a linked autoantibody set, since antibodies recognizing purified DNA-PKcs were strongly associated with stabilizing antibodies, whereas stabilizing antibodies were strongly associated with anti-Ku. This hierarchical pattern of autoantibodies specific for components of DNA-PK (anti-Ku > stabilizing antibodies > anti-DNA-PKcs) may have implications for the pathogenesis of autoimmunity to DNA-PK and other chromatin particles. The data raise the possibility that altered antigen processing and/or stabilization of the DNA-PKcs-Ku complex due to autoantibody binding could play a role in spreading autoimmunity from Ku to the weakly associated antigen DNA-PKcs.

Human DNA-activated protein kinase (DNA-PK) is homologous to phosphatidylinositol kinases.

DNA-activated protein kinase (DNA-PK) is a serine/threonine protein kinase that interacts with a DNA end-binding heterodimeric protein, Ku, and is activated by double-stranded DNA. Genomic clones that contain the DNA-PK gene complement the murine scid defect, indicating that DNA-PK affects double-strand break repair and V(D)J recombination. Here we describe the cDNA sequence of the region that corresponds to about 100 kDa of C-terminal sequence of this large (> p350 kDa) protein. This region contains a kinase domain that has strong homology to phosphatidylinositol kinases.