Comparison of 3 Dynamic External Fixation Devices for Proximal Interphalangeal Joint Dorsal Fracture-Dislocations in a Cadaver Model.

PURPOSE: Several improvised dynamic external fixation devices are used for treating unstable dorsal proximal interphalangeal (PIP) joint fracture-dislocations. We compared the effectiveness of 3 constructs for simulated dorsal PIP joint fracture-dislocations in a cadaver model. METHODS: We tested 30 digits from 10 fresh-frozen, thawed cadaver hands. We aimed to remove the palmar 50% of the base of each digit's middle phalanx (P2), simulating an unstable dorsal PIP joint fracture-dislocation. Each PIP joint was then stabilized via external fixation with either a pins-and-rubber-bands construct, pins-only construct, or tuberculin syringe-pins construct. We allocated 10 digits per fixation group. The finger tendons were secured to a computer-controlled stepper motor-driven linear actuator. Via this mechanism, all PIP joints were taken through 1,400 cycles of flexion-extension. With the PIP joint in neutral extension, we measured the P2 dorsal translation at baseline, after fixator stabilization, and after the motion protocol. RESULTS: The actual mean P2 palmar defect created was 48% of the base. All PIP joints were unstable after creating the defect, with a mean initial P2 dorsal displacement of 3.7 mm. After application of the fixators, all PIP joint dislocations were reduced. The median residual P2 dorsal displacements were 0.0 mm for the pins-rubber bands group, 0.1 mm for the pins-only group, and 0.5 mm for the syringe-pins group. There were no cases of PIP joint redislocation after flexion-extension cycling, and the median dorsal P2 displacements were 0.0 mm for the pins-rubber bands group; 0.0 mm for the pins-only group; and 0.5 mm for the syringe-pins group. CONCLUSIONS: All 3 external fixators restored PIP joint stability following simulated dorsal fracture-dislocation, with all reductions maintained after motion testing. The syringe-pins construct had significantly greater median residual P2 dorsal displacement after the initial reduction and motion testing, which is of unclear clinical importance. CLINICAL RELEVANCE: This study informs surgeon decision-making when considering dynamic external fixator options for dorsal PIP joint fracture-dislocations.

Exogenous ubiquitin attenuates hypoxia/reoxygenation-induced cardiac myocyte apoptosis via the involvement of CXCR4 and modulation of mitochondrial homeostasis.

Exogenous ubiquitin (UB) plays a protective role in ß-adrenergic receptor-stimulated and ischemia/reperfusion (I/R)-induced myocardial remodeling. Here, we report that UB treatment inhibits hypoxia/reoxygenation (H/R)-induced apoptosis in adult rat ventricular myocytes (ARVMs). The activation of Akt was elevated, whereas the activation of glycogen synthase kinase-3ß was reduced in UB-treated cells post-H/R. The level of oxidative stress was lower, whereas the number of ARVMs with polarized mitochondria was significantly greater in the UB-treated samples. ARVMs express CXCR4 with majority of CXCR4 localized in the membrane fraction. CXCR4 antagonism using AMD3100, and siRNA-mediated knockdown of CXCR4 negated the protective effects of UB. Two mutated UB proteins (unable to bind CXCR4) had no effect on H/R-induced apoptosis, activation of Akt and GSK-3ß, or oxidative stress. UB treatment enhanced mitochondrial biogenesis, and inhibition of mitochondrial fission using mdivi1 inhibited H/R-induced apoptosis. Ex vivo, UB treatment significantly decreased infarct size and improved functional recovery of the heart following global I/R. Activation of caspase-9, a key player of the mitochondrial death pathway, was significantly lower in UB-treated hearts post-I/R. UB, most likely acting via CXCR4, plays a protective role in H/R-induced myocyte apoptosis and myocardial I/R injury via modulation of mitochondrial homeostasis and the mitochondrial death pathway of apoptosis.

Exogenous ubiquitin reduces inflammatory response and preserves myocardial function 3 days post-ischemia-reperfusion injury.

ß-Adrenergic receptor (ß-AR) stimulation increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases ß-AR-stimulated myocyte apoptosis and myocardial fibrosis. Here, we hypothesized that exogenous UB modulates the inflammatory response, thereby playing a protective role in cardiac remodeling after ischemia-reperfusion (I/R) injury. C57BL/6 mice infused with vehicle or UB (1 µg·g-1·h-1) were subjected to myocardial I/R injury. Functional and biochemical parameters of the heart were examined 3 days post-I/R. Heart weight-to-body weight ratios were similarly increased in I/R and UB + I/R groups. The area at risk and infarct size were significantly lower in UB + I/R versus I/R groups. Measurement of heart function using echocardiography revealed that I/R decreases percent fractional shortening and percent ejection fraction. However, the decrease in fractional shortening and ejection fraction was significantly lower in the UB + I/R group. The UB + I/R group displayed a significant decrease in inflammatory infiltrates, neutrophils, and macrophages versus the I/R group. Neutrophil activity was significantly lower in the UB + I/R group. Analysis of the concentration of a panel of 23 cytokines/chemokines in the serum using a Bio-Plex assay revealed a significantly lower concentration of IL-12 subunit p40 in the UB + I/R versus I/R group. The concentration of monocyte chemotactic protein-1 was lower, whereas the concentration of macrophage inflammatory protein-1α was significantly higher, in the UB+I/R group versus the sham group. Expression of matrix metalloproteinase (MMP)-2 and activity of MMP-9 were higher in the UB + I/R group versus the I/R group. Levels of ubiquitinated proteins and tissue inhibitor of metalloproteinase 2 expression were increased to a similar extent in both I/R groups. Thus, exogenous UB plays a protective role in myocardial remodeling post-I/R with effects on cardiac function, area at risk/infarct size, the inflammatory response, levels of serum cytokines/chemokines, and MMP expression and activity. NEW & NOTEWORTHY Stimulation of ß-adrenergic receptors increases extracellular levels of ubiquitin (UB) in myocytes, and exogenous UB decreases ß-adrenergic receptor-stimulated myocyte apoptosis and myocardial fibrosis. Here, we provide evidence that exogenous UB decreases the inflammatory response and preserves heart function 3 days after myocardial ischemia-reperfusion injury. Further identification of the molecular events involved in the anti-inflammatory role of exogenous UB may provide therapeutic targets for patients with ischemic heart disease.

Ataxia telangiectasia-mutated kinase deficiency exacerbates left ventricular dysfunction and remodeling late after myocardial infarction.

Ataxia telangiectasia-mutated kinase (ATM), a cell cycle checkpoint protein, is activated in response to DNA damage and oxidative stress. We have previously shown that ATM deficiency is associated with increased apoptosis and fibrosis and attenuation of cardiac dysfunction early (1-7 days) following myocardial infarction (MI). Here, we tested the hypothesis that enhanced fibrosis and apoptosis, as observed early post-MI during ATM deficiency, exacerbate cardiac dysfunction and remodeling in ATM-deficient mice late post-MI. MIs were induced in wild-type (WT) and ATM heterozygous knockout (hKO) mice by ligation of the left anterior descending artery. Left ventricular (LV) structural and functional parameters were assessed by echocardiography 14 and 28 days post-MI, whereas biochemical parameters were measured 28 days post-MI. hKO-MI mice exhibited exacerbated LV dysfunction as observed by increased LV end-systolic volume and decreased percent fractional shortening and ejection fraction. Infarct size and thickness were not different between the two genotypes. Myocyte cross-sectional area was greater in hKO-MI group. The hKO-MI group exhibited increased fibrosis in the noninfarct and higher expression of α-smooth muscle actin (myofibroblast marker) in the infarct region. Apoptosis and activation of GSK-3ß (proapoptotic kinase) were significantly lower in the infarct region of hKO-MI group. Matrix metalloproteinase 2 (MMP-2) expression was not different between the two genotypes. However, MMP-9 expression was significantly lower in the noninfarct region of hKO-MI group. Thus ATM deficiency exacerbates cardiac remodeling late post-MI with effects on cardiac function, fibrosis, apoptosis, and myocyte hypertrophy.

Osteopontin stimulates apoptosis in adult cardiac myocytes via the involvement of CD44 receptors, mitochondrial death pathway, and endoplasmic reticulum stress.

Increased osteopontin (OPN) expression associates with increased myocyte apoptosis and myocardial dysfunction. The objective of this study was to identify the receptor for OPN and get insight into the mechanism by which OPN induces cardiac myocyte apoptosis. Adult rat ventricular myocytes (ARVMs) and transgenic mice expressing OPN in a myocyte-specific manner were used for in vitro and in vivo studies. Treatment with purified OPN (20 nM) protein or adenoviral-mediated OPN expression induced apoptosis in ARVMs. OPN co-immunoprecipitated with CD44 receptors, not with ß1 or ß3 integrins. Proximity ligation assay confirmed interaction of OPN with CD44 receptors. Neutralizing anti-CD44 antibodies inhibited OPN-stimulated apoptosis. OPN activated JNKs and increased expression of Bax and levels of cytosolic cytochrome c, suggesting involvement of mitochondrial death pathway. OPN increased endoplasmic reticulum (ER) stress, as evidenced by increased expression of Gadd153 and activation of caspase-12. Inhibition of JNKs using SP600125 or ER stress using salubrinal or caspase-12 inhibitor significantly reduced OPN-stimulated apoptosis. Expression of OPN in adult mouse heart in myocyte-specific manner associated with decreased left ventricular function and increased myocyte apoptosis. In the heart, OPN expression increased JNKs and caspase-12 activities, and expression of Bax and Gadd153. Thus, OPN, acting via CD44 receptors, induces apoptosis in myocytes via the involvement of mitochondrial death pathway and ER stress.

Extracellular ubiquitin increases expression of angiogenic molecules and stimulates angiogenesis in cardiac microvascular endothelial cells.

Extracellular Ub is an immune modulator that plays a role in suppression of inflammation, organ injury, myocyte apoptosis, and fibrosis. The purpose of this study was to investigate the effects of extracellular Ub on the process of cardiac angiogenesis. CMECs and aortic tissue were isolated from rats to measure changes in angiogenic protein levels and to assess angiogenic responses to extracellular Ub. In CMECs, extracellular Ub increased protein levels of VEGF-A and MMP-2, known angiogenesis regulators. CMECs demonstrated enhanced rearrangement of fibrillar actin and migration in response to Ub treatment. Ub-treated CMECs demonstrated an increase in tube network formation which was inhibited by the CXCR4 receptor antagonist, AMD3100. Methylated Ub, unable to form polyubiquitin chains, enhanced tube network formation. Aortic ring sprouting assays demonstrated that Ub increases microvessel sprouting in the Matrigel. The results of our study suggest a novel role for extracellular Ub in cardiac angiogenesis, providing evidence that extracellular Ub, at least in part acting via the CXCR4 receptor, has the potential to facilitate the process of angiogenesis in myocardial endothelial cells.

Biochanin A reduces pancreatic cancer survival and progression.

Pancreatic cancer has dismally low mean survival rates worldwide. Only a few chemotherapeutic agents including gemcitabine have been shown to improve the survival of pancreatic cancer patients. Biochanin A, an isoflavone, is known to exert an anticancer effect on various cancer types. In this study, we examined the anticancer properties of biochanin A on pancreatic cancer cells. The effect of biochanin A on cellular survival, apoptosis, and proliferation was analyzed using MTT, flow cytometry, and colony formation assay. The effect of biochanin A on pancreatic cancer's mitogenic signaling was determined using western blot analysis. Migration assay and zymography were used to determine biochanin A's effect on pancreatic cancer progression. Biochanin A induced dose-dependent toxicity on pancreatic cancer cells (Panc1 and AsPC-1). It reduced colony formation ability of Panc1 cells and induced dose-dependent apoptosis. Activation of Akt and MAPK was inhibited. Furthermore, the migratory and invasive potential of the cancer cells was also reduced. The results suggest that biochanin A is effective in reducing pancreatic cancer cell survival by inhibiting their proliferation and inducing apoptosis. It affects mitogenic, migratory, and invasive processes involved in cancer progression. These findings may lead to novel approaches to treat pancreatic cancer using isoflavones in combination with other therapeutic drugs.

Positive surgical margins: rate, contributing factors and impact on further treatment: findings from the Prostate Cancer Registry.

OBJECTIVE: To describe the characteristics of patients with and without positive surgical margins (PSMs) and to analyse the impact of PSMs on secondary cancer treatment after radical prostatectomy (RP), with short-term follow-up. PATIENTS AND METHODS: We analysed data from 2385 consecutive patients treated using RP, who were notified to the Prostate Cancer Registry by 37 hospitals in Victoria, Australia between August 2008 and February 2012. Independent and multivariate models were constructed to predict the likelihood of PSMs. Independent and multivariate predictors of secondary treatment after RP in the initial 12 months after diagnosis were also assessed. RESULTS: Data on PSM status were collected for 2219/2385 (93%) patients. In total 592/2175 (27.2%) RPs resulted in PSMs; 102/534 (19.1%) in the low-risk group, 317/1218 (26.0%) in the intermediate-risk group, 153/387 (39.5%) in the high-risk group, and 9/11 (81.8%) in the very-high-risk disease group of patients. Patients having surgery in a hospital where <10 RPs occur each year were significantly more likely to have a PSM (incidence rate ratio [IRR] 1.44, 95% confidence interval [CI] 1.07-1.93) and those in the intermediate-, high- or very-high-risk groups (IRR 1.34, 95% CI 1.09-1.65, P = 0.007, IRR 1.96, 95% CI 1.57-2.45, P < 0.001 and IRR 3.81, 95% CI 2.60-5.60, P < 0.001, respectively) were significantly more likely to have a PSM than those in the low-risk group (IRR 2.50, 95% CI 1.23-5.11, P = 0.012). Patients with PSMs were significantly less likely to have been treated at a private hospital than a public hospital (IRR 0.76, 95% CI 0.63-0.93, P = 0.006) or to have undergone robot-assisted RP (IRR 0.69, 95% CI 0.55-0.87; P = 0.002) than open RP. Of the 2182 patients who underwent RP in the initial 12 months after diagnosis, 1987 (91.1%) received no subsequent treatment, 123 (5.6%) received radiotherapy, 47 (2.1%) received androgen deprivation therapy (ADT) and 23 (1.1%) received a combination of radiotherapy and ADT. Two patients (0.1%) received chemotherapy combined with another treatment. At a multivariate level, predictors of additional treatment after RP in the initial 12 months included having a PSM compared with a negative surgical margin (odds ratio [OR] 5.61, 95% CI 3.82-8.22, P < 0.001); pT3 compared with pT2 disease (OR 4.72, 95% CI 2.69-8.23, P < 0.001); and having high- or very-high-risk disease compared with low-risk disease (OR 4.36, 95% CI 2.24-8.50, P < 0.001 and OR 4.50, 95% CI 1.34-15.17, P = 0.015, respectively). Patient age, hospital location and hospital type were not associated with secondary treatment. Patients undergoing robot-assisted RP were significantly less likely to receive additional treatment than those receiving open RP (OR 0.59, 95% CI 0.39-0.88, P = 0.010). CONCLUSIONS: These data indicate an important association between hospital status and PSMs, with patients who underwent RP in private hospitals less likely than those in public hospitals to have a PSM. Patients treated in lower-volume hospitals were more likely to have a PSM and less likely to receive additional treatment after surgery in the initial 12 months, and robot-assisted RP was associated with fewer PSMs than was open RP in this non-randomized observational study. PSM status and pathological T3 disease are both important and independent predictors of secondary cancer treatment for patients undergoing RP. A robot-assisted RP approach appears to decrease the likelihood of subsequent treatment, when compared with the open approach.

Revision Distal Biceps Tendon Repair Using Original Intramedullary Buttons.

There are several techniques used for tendon fixation in distal biceps tendon repair. Intramedullary unicortical button fixation has the advantage of high biomechanical strength, minimal proximal radial bone removal, and low risk of injury to the posterior interosseous nerve. One disadvantage in revision surgery is retained implants in the medullary canal. This article describes a novel technique for revision distal biceps repair initially fixed with intramedullary unicortical buttons, using the original implants.

Surgical and Patient-Centered Outcomes of Open versus Arthroscopic Ganglion Cyst Excision: A Systematic Review.

Introduction As the popularity of wrist arthroscopy grows, it continues to prove useful in the treatment of ganglion cysts. Previous studies comparing an arthroscopic technique to traditional open excision have demonstrated generally equivalent results regarding complications and cyst recurrence. However, this systematic review compares the two treatment methods not only regarding cyst recurrence but also regarding patient-centered outcomes. Additionally, new studies in the available literature may allow for further analysis. Methods This systematic review identified 23 articles published between 2000 and 2021 that met inclusion criteria. Articles were assessed for quality, and reported cyst recurrence rates, patient satisfaction, patients' preoperative and postoperative pain, and complications associated with either open or arthroscopic excisions were pooled into open excision and arthroscopic excision groups for analysis. Results In total, 23 studies accounted for 1,670 cases. Pooled data for patient-centered outcomes indicated a significantly higher patient satisfaction rate (89.2 vs 85.6%, p < 0.001) and higher reported pain relief (69.5 vs. 66.7%, p = 0.011) associated with arthroscopic excision versus open excision. Recurrence rates were also significantly lower for the arthroscopic excision group (9.4 vs. 11.2%, p < 0.001). Overall, the complication rate was significantly lower for arthroscopic excision (7.5 vs. 10.7%, p < 0.001), but the complication profile distinctly differed between the two methods. Conclusions Both arthroscopic and open excision of dorsal wrist ganglions are viable treatment options. However, the results of this meta-analysis suggest benefits associated with the arthroscopic technique in both patient-centered outcomes and in traditional, surgical outcomes. This may prove advantageous as wrist arthroscopy becomes more common.

Individuality and stability of the koala (Phascolarctos cinereus) faecal microbiota through time.

Gut microbiota studies often rely on a single sample taken per individual, representing a snapshot in time. However, we know that gut microbiota composition in many animals exhibits intra-individual variation over the course of days to months. Such temporal variations can be a confounding factor in studies seeking to compare the gut microbiota of different wild populations, or to assess the impact of medical/veterinary interventions. To date, little is known about the variability of the koala (Phascolarctos cinereus) gut microbiota through time. Here, we characterise the gut microbiota from faecal samples collected at eight timepoints over a month for a captive population of South Australian koalas (n individuals = 7), and monthly over 7 months for a wild population of New South Wales koalas (n individuals = 5). Using 16S rRNA gene sequencing, we found that microbial diversity was stable over the course of days to months. Each koala had a distinct faecal microbiota composition which in the captive koalas was stable across days. The wild koalas showed more variation across months, although each individual still maintained a distinct microbial composition. Per koala, an average of 57 (±16) amplicon sequence variants (ASVs) were detected across all time points; these ASVs accounted for an average of 97% (±1.9%) of the faecal microbial community per koala. The koala faecal microbiota exhibits stability over the course of days to months. Such knowledge will be useful for future studies comparing koala populations and developing microbiota interventions for this regionally endangered marsupial.

Exogenous ubiquitin modulates chronic ß-adrenergic receptor-stimulated myocardial remodeling: role in Akt activity and matrix metalloproteinase expression.

ß-Adrenergic receptor (ß-AR) stimulation increases extracellular ubiquitin (UB) levels, and extracellular UB inhibits ß-AR-stimulated apoptosis in adult cardiac myocytes. This study investigates the role of exogenous UB in chronic ß-AR-stimulated myocardial remodeling. l-Isoproterenol (ISO; 400 µg·kg(-1)·h(-1)) was infused in mice in the presence or absence of UB (1 µg·g(-1)·h(-1)). Left ventricular (LV) structural and functional remodeling was studied 7 days after infusion. UB infusion enhanced serum UB levels. In most parts, UB alone had no effect on morphometric or functional parameters. Heart weight-to-body weight ratios were increased to a similar extent in the ISO and UB + ISO groups. Echocardiographic analyses showed increased percent fractional shortening, ejection fraction, and LV circumferential stress and fiber-shortening velocity in the ISO group. These parameters were significantly lower in UB + ISO vs. ISO. Isovolumic contraction and relaxation times and ejection time were significantly lower in ISO vs. UB + ISO. The increase in the number of TUNEL-positive myocytes and fibrosis was significantly higher in ISO vs. UB + ISO. Activation of Akt was higher, whereas activation of GSK-3ß and JNKs was lower in UB + ISO vs ISO. Expression of MMP-2, MMP-9, and TIMP-2 was higher in UB + ISO vs ISO. In isolated cardiac fibroblasts, UB enhanced expression of MMP-2 and TIMP-2 in the presence of ISO. Neutralizing UB antibodies negated the effects of UB on MMP-2 expression, whereas recombinant UB enhanced MMP-2 expression. UB activated Akt, and inhibition of Akt inhibited UB + ISO-mediated increases in MMP-2 expression. Thus, exogenous UB plays an important role in ß-AR-stimulated myocardial remodeling with effects on LV function, fibrosis, and myocyte apoptosis.

Surgeon perceptions and patient outcomes regarding proximal ulna fixation: a multicenter experience.

BACKGROUND: Our objective was to determine surgeon- and patient-based perceptions concerning proximal ulna fixation, including rates of implant removal and overall satisfaction. METHODS: Orthopedic surgeons were surveyed about surgical experience managing proximal ulna fractures and their perception regarding implant removal/revision. A retrospective chart review identified all patients who underwent fixation for proximal ulna fractures and osteotomies between January 2004 and December 2008. RESULTS: In total, 583 surgeons responded to the survey (80%). Of these, 67% believed that their implant removal rate was the same as other surgeons whereas 31% believed that their rate was lower. Seventy-one percent believed that patients required hardware removal less than 30% of the time. Ninety-eight percent believed that they were the same surgeons to remove the implant. In total, 138 consecutive patients were surveyed about their proximal ulna implant. Plating was performed in 80 (58%), and tension banding was performed in 55 (40%). The overall rate of implant removal was 64.5% (89 of 138) at 18.8 months. A second surgeon performed the removal in 68 patients (76%). Of the 49 patients without implant removal, 11 (22%) reported satisfaction with the implant and 19 (39%) reported a functional impairment because of the implant. If guaranteed a safe surgery, 36 (73%) would have the implant removed. CONCLUSION: Surgeons underestimate the rates of proximal ulna implant removal and patient dissatisfaction. Because 76% of the implant removals were performed by a second surgeon, in sharp contrast to the surgeon-perceived rate of 2%, we challenge surgeons to become more aware of this problem in their practices.

Ecosystem restoration is integral to humanity's recovery from COVID-19.

COVID-19 has devastated global communities and economies. The pandemic has exposed socioeconomic disparities and weaknesses in health systems worldwide. Long-term health effects and economic recovery are major concerns. Ecosystem restoration-ie, the repair of ecosystems that have been degraded-relates directly to tackling the health and socioeconomic burdens of COVID-19, because stable and resilient ecosystems are fundamental determinants of health and socioeconomic stability. Here, we use COVID-19 as a case study, showing how ecosystem restoration can reduce the risk of infection and adverse sequelae and have an integral role in humanity's recovery from COVID-19. The next decade will be crucial for humanity's recovery from COVID-19 and for ecosystem repair. Indeed, in the absence of effective, large-scale restoration, 95% of the Earth's land could be degraded by 2050. The UN Decade on Ecosystem Restoration (2021-30) declaration reflects the growing urgency and scale at which we should repair ecosystems. Importantly, ecosystem restoration could also help to combat the health and socioeconomic issues that are associated with COVID-19, yet it is poorly integrated into current responses to the disease. Ecosystem restoration can be a core public health intervention and assist in COVID-19 recovery if it is closely integrated with socioeconomic, health, and environmental policies.

Structural basis for the inhibition of RNase H activity of HIV-1 reverse transcriptase by RNase H active site-directed inhibitors.

HIV/AIDS continues to be a menace to public health. Several drugs currently on the market have successfully improved the ability to manage the viral burden in infected patients. However, new drugs are needed to combat the rapid emergence of mutated forms of the virus that are resistant to existing therapies. Currently, approved drugs target three of the four major enzyme activities encoded by the virus that are critical to the HIV life cycle. Although a number of inhibitors of HIV RNase H activity have been reported, few inhibit by directly engaging the RNase H active site. Here, we describe structures of naphthyridinone-containing inhibitors bound to the RNase H active site. This class of compounds binds to the active site via two metal ions that are coordinated by catalytic site residues, D443, E478, D498, and D549. The directionality of the naphthyridinone pharmacophore is restricted by the ordering of D549 and H539 in the RNase H domain. In addition, one of the naphthyridinone-based compounds was found to bind at a second site close to the polymerase active site and non-nucleoside/nucleotide inhibitor sites in a metal-independent manner. Further characterization, using fluorescence-based thermal denaturation and a crystal structure of the isolated RNase H domain reveals that this compound can also bind the RNase H site and retains the metal-dependent binding mode of this class of molecules. These structures provide a means for structurally guided design of novel RNase H inhibitors.

Indications and limits of postoperative radiotherapy for skin malignancies.

PURPOSE OF REVIEW: To provide a summary of the current evidence, with a focus on recent publications, pertaining to indications for postoperative radiation therapy for cutaneous squamous-cell carcinoma (cSCC), basal-cell carcinoma, Merkel-cell carcinoma and melanoma of the head and neck. RECENT FINDINGS: Meta-analyses in cSCC and Merkel-cell carcinoma have shown an association between postoperative radiation therapy and overall survival. Prospective phase III data in head and neck cSCC has shown excellent locoregional control following surgery and postoperative radiation therapy. The addition of concurrent cytotoxic chemotherapy to postoperative radiation therapy has not improved outcomes in either of these two entities. Postoperative immune checkpoint inhibition or combined BRAF and MEK blockade in stage-III melanoma improves progression-free survival whereas postoperative radiation therapy does not. SUMMARY: Further improvement in outcomes with high-risk cSCC and Merkel-cell carcinoma might be achieved with concurrent or sequential immune checkpoint inhibition and postoperative radiation therapy. Postoperative radiation therapy for cutaneous melanoma should be reserved for patients in whom novel systemic therapies are not a treatment option.

Risk Factors for Distal Radius Osteotomy Nonunion.

BACKGROUND: Osteotomy-site nonunion after distal radius corrective osteotomy is a detrimental complication. This retrospective study aims to identify patient and surgical factors associated with nonunion risk to help mitigate this. The authors hypothesize that patient factors and potentially modifiable surgical factors are contributory. METHODS: Thirty-three patients who underwent corrective osteotomy of the distal radius for prior fracture malunion were identified. Radiographs and patient records were reviewed for demographics, comorbidities, nutritional status, plate position, angle and length of osteotomy correction, and graft used. The primary study outcome was osteotomy nonunion. Descriptive and bivariate statistics were used to identify covariates relevant to nonunion. Backward, stepwise logistic regression was applied to investigate the multivariate effects on outcome, and regression analysis was adjusted for confounders. RESULTS: Seven patients (21 percent) experienced nonunion after initial corrective osteotomy. Risk factors associated with nonunion included correction length of osteotomy of 5 mm or greater and prior treatment with open reduction and internal fixation. Autograft use was protective against nonunion. History of osteoporosis showed a trend toward increased risk. Angle of osteotomy correction, nutritional deficit, age, diabetes, smoking status, and obesity were not identified as risk factors by the multivariate model. CONCLUSIONS: Distraction length at the osteotomy site, graft selection, and prior internal fixation were significant risk factors for distal radius osteotomy nonunion, but other factors traditionally associated with nonunion did not appear to impact risk. The authors recommend using autograft bone augmentation, particularly when distracting the osteotomy beyond 5 mm or after prior internal fixation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Characterization of traumatized muscle-derived multipotent progenitor cells from low-energy trauma.

BACKGROUND: Multipotent progenitor cells have been harvested from different human tissues, including the bone marrow, adipose tissue, and umbilical cord blood. Previously, we identified a population of mesenchymal progenitor cells (MPCs) isolated from the traumatized muscle of patients undergoing reconstructive surgery following a war-related blast injury. These cells demonstrated the ability to differentiate into multiple mesenchymal lineages. While distal radius fractures from a civilian setting have a much lower injury mechanism (low-energy trauma), we hypothesized that debrided traumatized muscle near the fracture site would contain multipotent progenitor cells with the ability to differentiate and regenerate the injured tissue. METHODS: The traumatized muscle was debrided from the pronator quadratus in patients undergoing open reduction and internal fixation for a distal radius fracture at the Walter Reed National Military Medical Center. Using a previously described protocol for the isolation of MPCs from war-related extremity injuries, cells were harvested from the low-energy traumatized muscle samples and expanded in culture. Isolated cells were characterized by flow cytometry and q-RT-PCRs and induced to adipogenic, osteogenic, and chondrogenic differentiation. Downstream analyses consisted of lineage-specific staining and q-RT-PCR. RESULTS: Cells isolated from low-energy traumatized muscle samples were CD73+, CD90+, and CD105+ that are the characteristic of adult human mesenchymal stem cells. These cells expressed high levels of the stem cell markers OCT4 and NANOG 1-day after isolation, which was dramatically reduced over-time in monolayer culture. Following induction, lineage-specific markers were demonstrated by each specific staining and confirmed by gene expression analysis, demonstrating the ability of these cells to differentiate into adipogenic, osteogenic, and chondrogenic lineages. CONCLUSIONS: Adult multipotent progenitor cells are an essential component for the success of regenerative medicine efforts. While MPCs have been isolated and characterized from severely traumatized muscle from high-energy injuries, here, we report that cells with similar characteristics and multipotential capacity have been isolated from the tissue that was exposed to low-energy, community trauma.

The importance of smoking status at diagnosis in human papillomavirus-associated oropharyngeal cancer.

BACKGROUND: Smoking status at point of diagnosis is not used in defining risk groups for human papillomavirus (HPV)-associated oropharyngeal cancer (OPC) despite its prognostic value in head and neck cancer. METHODS: Retrospective analysis of consecutive patients treated with chemoradiotherapy between January 2005 and July 2017 was performed with multivariable analysis to explore the impact of smoking status at diagnosis (current/former/never) on overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS). RESULTS: Median follow-up was 61 months. Four hundred and four patients were included. Current smokers had inferior OS versus never and former smokers [adjusted HR 2.37 (95% CI 1.26-4.45, p < 0.01) and 2.58 (95% CI 1.40-4.73, p < 0.01), respectively] and inferior PFS versus never smokers [adjusted HR 1.83 (95% CI 1.00-3.35, p = 0.04)]. Smoking status did not predict for CSS. CONCLUSION: Detailed smoking behavior should be considered in refining risk groups in HPV-associated OPC treated with radiotherapy and in future trial design eligibility and stratification.