Porous Metal Augments Have Comparable Outcomes to Other Constructs for Severe Acetabular Bone Loss at Mid-Term Follow-up.

BACKGROUND: Acetabular reconstruction options in the setting of severe bone loss remain limited, with few comparative studies published to date. The purpose of this study was to compare the outcomes of revision total hip arthroplasty (THA) for severe bone loss using porous metal augments to cup cage and triflange prostheses. METHODS: We reviewed a consecutive series of 180 patients who had Paprosky 3A or 3B acetabular defects and underwent revision THA. Patients treated with porous augments (n = 141) were compared with those who received cup cages or triflange constructs (n = 39). Failure of the acetabular construct was defined as undergoing acetabular revision surgery or radiographic evidence of loosening. RESULTS: There was no difference in acetabular component survivorship in patients undergoing revision THA with porous augments or a cage or triflange prosthesis (92.2 versus 87.2%, P = .470) at a mean follow-up of 6.6 ± 3.4 years. Overall, survivorship free from any revision surgery was comparable between the 2 groups (78.7 versus 79.5%, P = .720). There was also no difference in dislocation (5.7 versus 10.3%, P = .309) or periprosthetic joint infection rates (7.8 versus 10.3%, P = .623). In a subgroup analysis of patients who had pelvic discontinuity (n = 47), survivorship free from any revision surgery was comparable between the 2 groups (79.5 versus 72.2%, P = .543). CONCLUSIONS: Porous metal augments in the setting of severe acetabular bone loss demonstrated excellent survivorship at intermediate-term (mean 6.6 years follow-up, even in cases of pelvic discontinuity, with comparable outcomes to cup cages and triflanges. Instability and infection remain major causes of failure in this patient population, and long-term follow-up is needed.

Finding the Optimal Screening Test for Periprosthetic Joint Infection: A Prospective Study.

BACKGROUND: No single test has demonstrated absolute accuracy in the diagnosis of periprosthetic joint infection (PJI). Serological markers are often used as screening tools to avoid unnecessary joint aspiration in cases with a low probability of infection. This study aimed to determine the utility of standard-of-care serological tests as a screening tool for PJI in patients undergoing revision arthroplasty. METHODS: This prospective study enrolled 502 patients undergoing revision hip or knee arthroplasty between May 2017 and August 2021. A PJI was defined using a modified definition of the 2018 International Consensus Meeting criteria. Plasma D-dimer, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and fibrinogen were measured preoperatively. There were 82 patients undergoing reimplantation who were excluded. Additionally, 8 patients who had an inconclusive International Consensus Meeting score were also excluded. Of the 412 included patients, 317 (76.9%) underwent revision for aseptic failure, and 95 (23.1%) had PJI. Receiver operating characteristic curves were used to assess the diagnostic utility of each serological test. A pairwise comparison with Bonferroni correction was performed to determine whether the differences in areas under the curve (AUCs) between the tests were significant. Additional analyses were performed to find the threshold for each test that offered 100% sensitivity, allowing it to be the optimal screening test. RESULTS: All 4 serological markers, D-dimer (AUC 0.860, sensitivity 81.3%, specificity 81.7%), CRP (AUC 0.862, sensitivity 90.4%, specificity 70.0%), ESR (AUC 0.833, sensitivity 73.9%, specificity 85.2%), and fibrinogen (AUC 0.798, sensitivity 74.7%, specificity 75.4%), demonstrated comparable accuracy for the diagnosis of PJI (all P > .05). When maximizing sensitivity to 100%, D-dimer demonstrated the highest specificity (AUC 0.860, specificity 40.2%), outperforming ESR (AUC 0.833, specificity 3.3%), fibrinogen (AUC 0.798, specificity 2.3%), and CRP (AUC 0.862, specificity 0%). A plasma D-dimer level of ≥ 244 ng/mL was identified as the optimal cutoff for use as a screening test. CONCLUSIONS: Although plasma D-dimer demonstrated similar diagnostic accuracy as CRP, ESR, and fibrinogen, it outperformed all 3 aforementioned serological markers when used as a screening test for PJI. LEVEL OF EVIDENCE: Level II.

Self- reported oral health and oral health- related quality of life among patients with diabetes mellitus in a tertiary health facility.

BACKGROUND: Considering the inter-relationship between Diabetes Mellitus (DM) and oral tissues, assessment of oral health status in relation to glycemic control might be informative about the disease condition, which might be pivotal to appropriate management and ultimately improve life satisfaction. This study therefore aimed to assess the pattern of self-reported diabetes related oral conditions and oral health-related quality of life (OHRQoL) among patients with DM at the University College Hospital (UCH), Ibadan, Nigeria. MATERIALS AND METHODS: A cross- sectional study using an interviewer administered questionnaire was conducted among in- and out- patients being managed for DM by the Endocrinology unit of the hospital. Data collected included bio-data, medical history, self-reported oral conditions and dental service utilisation. The impact of oral health related quality of life was measured using OHIP-14. Oral examination was done to assess oral mucosal lesions and their oral hygiene status. Data was analysed using SPSS 21. RESULTS: Eighty-four patients with diabetes consisting 23 (27%) in-patients and 61 (63%) out-patients were enrolled. Males were 26(31%) and females 58(69%); their ages ranged from 22 to 88 years with a mean of 60.9 ± 12.8 years. Most (67%) of the participants had one or more self-reported oral complaints, dryness (20.4%) being the most common and bad breath (4.6%) as the least reported. Poor glycemic level was found to be higher among the in-patients (82%) with random blood glucose > 200 mg/dL during admission, compared to the out-patient participants (51%) who had fasting plasma glucose > 110 mg/dL. Their oral hygiene status was assessed using simplified oral hygiene index and documented as fair (65%), poor (25%) and good (10%). About two-thirds (61%) had ever visited a dentist, majorly due to toothache. Only the pain (21.9%) and physical disability (26.3%) components of OHIP-14 were mainly found to affect the participants' OHRQOL. CONCLUSIONS: This study found high rate of self- reported DM related oral conditions notably oral dryness, and periodontal diseases particularly as teeth mobility and spontaneous exfoliation. Nonetheless, most of the study participants had fair OHRQoL while its physical pain, functional limitation and psychological disability components were most reported.

Myofibroblast-specific inhibition of the Rho kinase-MRTF-SRF pathway using nanotechnology for the prevention of pulmonary fibrosis.

Pulmonary fibrosis is characterized by the accumulation of myofibroblasts in the lung and progressive tissue scarring. Fibroblasts exist across a spectrum of states, from quiescence in health to activated myofibroblasts in the setting of injury. Highly activated myofibroblasts have a critical role in the establishment of fibrosis as the predominant source of type 1 collagen and profibrotic mediators. Myofibroblasts are also highly contractile cells and can alter lung biomechanical properties through tissue contraction. Inhibiting signaling pathways involved in myofibroblast activation could therefore have significant therapeutic value. One of the ways myofibroblast activation occurs is through activation of the Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF) pathway, which signals through intracellular actin polymerization. However, concerns surrounding the pleiotropic and ubiquitous nature of these signaling pathways have limited the translation of inhibitory drugs. Herein, we demonstrate a novel therapeutic antifibrotic strategy using myofibroblast-targeted nanoparticles containing a MTRF/SRF pathway inhibitor (CCG-1423), which has been shown to block myofibroblast activation in vitro. Myofibroblasts were preferentially targeted via the angiotensin 2 receptor, which has been shown to be selectively upregulated in animal and human studies. These nanoparticles were nontoxic and accumulated in lung myofibroblasts in the bleomycin-induced mouse model of pulmonary fibrosis, reducing the number of these activated cells and their production of profibrotic mediators. Ultimately, in a murine model of lung fibrosis, a single injection of these drugs containing targeted nanoagents reduced fibrosis as compared with control mice. This approach has the potential to deliver personalized therapy by precisely targeting signaling pathways in a cell-specific manner, allowing increased efficacy with reduced deleterious off-target effects.

Screening for Inhibitors of YAP Nuclear Localization Identifies Aurora Kinase A as a Modulator of Lung Fibrosis.

Idiopathic pulmonary fibrosis is a progressive lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. We previously identified HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors (statins) as YAP inhibitors based on a high-throughput small-molecule screen in primary human lung fibroblasts. Here we report that several Aurora kinase inhibitors were also identified from the top hits of this screen. MK-5108, a highly selective inhibitor for AURKA (Aurora kinase A), induced YAP phosphorylation and cytoplasmic retention and significantly reduced profibrotic gene expression in human lung fibroblasts. The inhibitory effect on YAP nuclear translocation and profibrotic gene expression is specific to inhibition of AURKA, but not Aurora kinase B or C, and is independent of the Hippo pathway kinases LATS1 and LATS2 (Large Tumor Suppressor 1 and 2). Further characterization of the effects of MK-5108 demonstrate that it inhibits YAP nuclear localization indirectly via effects on actin polymerization and TGFß (Transforming Growth Factor ß) signaling. In addition, MK-5108 treatment reduced lung collagen deposition in the bleomycin mouse model of pulmonary fibrosis. Our results reveal a novel role for AURKA in YAP-mediated profibrotic activity in fibroblasts and highlight the potential of small-molecule screens for YAP inhibitors for identification of novel agents with antifibrotic activity.

Endothelial-Specific Loss of Sphingosine-1-Phosphate Receptor 1 Increases Vascular Permeability and Exacerbates Bleomycin-induced Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease which leads to significant morbidity and mortality from respiratory failure. The two drugs currently approved for clinical use slow the rate of decline in lung function but have not been shown to halt disease progression or reverse established fibrosis. Thus, new therapeutic targets are needed. Endothelial injury and the resultant vascular permeability are critical components in the response to tissue injury and are present in patients with IPF. However, it remains unclear how vascular permeability affects lung repair and fibrosis following injury. Lipid mediators such as sphingosine-1-phosphate (S1P) are known to regulate multiple homeostatic processes in the lung including vascular permeability. We demonstrate that endothelial cell-(EC) specific deletion of the S1P receptor 1 (S1PR1) in mice (EC-S1pr1-/-) results in increased lung vascular permeability at baseline. Following a low-dose intratracheal bleomycin challenge, EC-S1pr1-/- mice had increased and persistent vascular permeability compared with wild-type mice, which was strongly correlated with the amount and localization of resulting pulmonary fibrosis. EC-S1pr1-/- mice also had increased immune cell infiltration and activation of the coagulation cascade within the lung. However, increased circulating S1P ligand in ApoM-overexpressing mice was insufficient to protect against bleomycin-induced pulmonary fibrosis. Overall, these data demonstrate that endothelial cell S1PR1 controls vascular permeability in the lung, is associated with changes in immune cell infiltration and extravascular coagulation, and modulates the fibrotic response to lung injury.

Requirement of Complement C6 for Intact Innate Immune Responses in Mice.

Over the first days of polymicrobial sepsis, there is robust activation of the innate immune system, causing the appearance of proinflammatory cytokines and chemokines, along with the appearance of extracellular histones, which are highly proinflammatory and prothrombotic. In the current study, we studied different innate immune responses in mice with knockout (KO) of complement protein 6 (C6). Polymorphonuclear neutrophils (PMNs) from these KO mice had defective innate immune responses, including defective expression of surface adhesion molecules, generation of superoxide anion, and appearance of reactive oxygen species and histone release after activation of PMNs, along with defective phagocytosis. In addition, in C6-/- mice, the NLRP3 inflammasome was defective both in PMNs and in macrophages. When these KO mice were subjected to polymicrobial sepsis, their survival was improved, associated with reduced levels in the plasma of proinflammatory cytokines and chemokines and lower levels of histones in plasma. In addition, sepsis-induced cardiac dysfunction was attenuated in these KO mice. In a model of acute lung injury induced by LPS, C6-/- mice showed reduced PMN buildup and less lung epithelial/endothelial cell dysfunction (edema and hemorrhage). These data indicate that C6-/- mice have reduced innate immune responses that result in less organ injury and improved survival after polymicrobial sepsis.

Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.

Polymicrobial sepsis in mice causes myocardial dysfunction after generation of the complement anaphylatoxin, complement component 5a (C5a). C5a interacts with its receptors on cardiomyocytes (CMs), resulting in redox imbalance and cardiac dysfunction that can be functionally measured and quantitated using Doppler echocardiography. In this report we have evaluated activation of MAPKs and Akt in CMs exposed to C5a in vitro and after cecal ligation and puncture (CLP) in vivo In both cases, C5a in vitro caused activation (phosphorylation) of MAPKs and Akt in CMs, which required availability of both C5a receptors. Using immunofluorescence technology, activation of MAPKs and Akt occurred in left ventricular (LV) CMs, requiring both C5a receptors, C5aR1 and -2. Use of a water-soluble p38 inhibitor curtailed activation in vivo of MAPKs and Akt in LV CMs as well as the appearance of cytokines and histones in plasma from CLP mice. When mouse macrophages were exposed in vitro to LPS, activation of MAPKs and Akt also occurred. The copresence of the p38 inhibitor blocked these activation responses. Finally, the presence of the p38 inhibitor in CLP mice reduced the development of cardiac dysfunction. These data suggest that polymicrobial sepsis causes cardiac dysfunction that appears to be linked to activation of MAPKs and Akt in heart.-Fattahi, F., Kalbitz, M., Malan, E. A., Abe, E., Jajou, L., Huber-Lang, M. S., Bosmann, M., Russell, M. W., Zetoune, F. S., Ward, P. A. Complement-induced activation of MAPKs and Akt during sepsis: role in cardiac dysfunction.

Serum and Synovial Markers in the Diagnosis of Periprosthetic Joint Infection of the Hip, Knee, and Shoulder: An Algorithmic Approach.

➤ No single test has demonstrated absolute accuracy for the diagnosis of periprosthetic joint infection (PJI).➤ Physicians rely on a combination of serological tests, synovial markers, and clinical findings plus clinical judgment to help to guide preoperative decision-making.➤ Several organizations have proposed criteria for the diagnosis of hip or knee PJI on which we now rely.➤ Given that shoulder arthroplasty has only recently become popular, it is possible that a shoulder-specific definition of PJI will be introduced in the coming years.➤ Although a number of serum and synovial markers have demonstrated high accuracy for the diagnosis of PJI of the hip and knee, further research is needed in order to identify markers that may be more suitable for the diagnosis of shoulder PJI and for the potential development and identification of specific serological tests as screening tools for PJI.

Relationship between CD4+ count, serum inflammatory cytokines, and oral melanotic hyperpigmentation in newly diagnosed HIV-seropositive patients: a nested case-control study.

OBJECTIVE: Oral melanotic hyperpigmentation (OMH) in patients with human immunodeficiency virus (HIV) infection has been attributed to the use of antifungal or antiretroviral drugs, as well as HIV-induced cytokine dysregulation. This research aimed to determine the relationship between immunosuppression and cytokine dysregulation in newly diagnosed HIV-seropositive subjects with OMH. STUDY DESIGN: The study was conducted among newly diagnosed HIV-seropositive patients at the Infectious Disease Clinic, Ibadan, Nigeria. The cases were patients with OMH matched for age and sex with control subjects without OMH. CD4+ count and cytokine levels (interleukin-6 and tumor necrosis factor-α) were compared between the cases and control subjects. SPSS version 21 software was used for data analysis. RESULTS: Seventy newly diagnosed HIV-seropositive patients were studied, which comprised of 35 cases and 35 control subjects. The median CD4+ counts for cases and control subjects were 174 cells/mm3 (interquartile range [IQR], 57-250) and 324 cells/mm3 (IQR, 107-424), respectively. Severe immunosuppression (CD4+ count, ≤200 cells/mm3) was found in over half of the study participants, being more prevalent among the cases than among the control group (P = .019). Serum cytokine levels did not significantly vary between the cases and control subjects. CONCLUSIONS: There was a significant association between HIV-OMH and severe immunosuppression in the newly diagnosed HIV-seropositive patients.

Soluble Suppression of Tumorigenicity-2 Associates With Ventilator Dependence in Coronavirus Disease 2019 Respiratory Failure.

OBJECTIVES: We hypothesize that elevated soluble suppression of tumorigenicity-2 concentrations, a marker of pulmonary epithelial injury, reflect ongoing lung injury in acute hypoxemic respiratory failure due to coronavirus disease 2019 and associate with continued ventilator dependence. DESIGN: We associated serial plasma soluble suppression of tumorigenicity-2 levels and markers of systemic inflammation including d-dimer, C-reactive protein, and erythrocyte sedimentation rate with 30-day mortality and ventilator dependence. SETTING: Adult medical ICUs and general medicine wards at an academic teaching hospital in Boston, MA. PATIENTS: Adult patients with severe acute respiratory syndrome coronavirus 2 infection and acute hypoxemic respiratory failure admitted to the ICU (n = 72) and non-ICU patients managed with supplemental oxygen (n = 77). INTERVENTIONS: Observational study from April 25 to June 25, 2020. MEASUREMENTS AND MAIN RESULTS: ICU patients had a higher baseline body mass index and median soluble suppression of tumorigenicity-2, d-dimer, and C-reactive protein concentrations compared with non-ICU patients. Among ICU patients, elevated baseline modified Sequential Organ Failure Assessment score and log (soluble suppression of tumorigenicity-2) were associated with 30-day mortality, whereas initial Pao2/Fio2 and markers of systemic inflammation were similar between groups. Only log (soluble suppression of tumorigenicity-2) associated with ventilator dependence over time, with the last measured log (soluble suppression of tumorigenicity-2) concentration obtained on ICU day 11.5 (interquartile range [7-17]) higher in patients who required reintubation or tracheostomy placement compared with patients who were successfully extubated (2.10 [1.89-2.26] vs 1.87 ng/mL [1.72-2.13 ng/mL]; p = 0.03). Last measured systemic inflammatory markers, modified Sequential Organ Failure Assessment score, and Pao2/Fio2 were not different between patients who were successfully extubated compared with those with continued ventilator dependence. CONCLUSIONS: Plasma soluble suppression of tumorigenicity-2 is a biomarker readily measured in blood that can provide dynamic information about the degree of a patient's lung injury and real-time assessment of the likelihood of extubation success. Measures of systemic inflammation, illness severity, and oxygenation did not associate with ventilator outcomes.

Harmful Roles of TLR3 and TLR9 in Cardiac Dysfunction Developing during Polymicrobial Sepsis.

We determined the roles of TLR3 and TLR9 in adverse events of polymicrobial sepsis, with a focus on development of septic cardiomyopathy, progression of which we have recently shown to be complement- and histones-dependent. So Wt, TLR3-knocked out (K.O.), and TLR9-K.O. mice were subjected to polymicrobial sepsis following cecal ligation and puncture (CLP). In the absence of either TLR3 or TLR9, the intensity of echocardiogram (Echo)-Doppler dysfunction during development of cardiomyopathy was substantially reduced in the K.O. mice. Based on our prior studies emphasizing the adverse effects of plasma C5a and histones in the cardiomyopathy of sepsis, in TLR3- and TLR9-K.O. mice, there were striking reductions in plasma levels of C5a and histones as well as reduced levels of cytokines in plasma and heart tissue after CLP. Since we know that histones cause cardiac dysfunction, rat cardiomyocytes (CMs) were exposed in vitro to the histones (purified from calf thymus), which caused bleb formation on the surfaces of CMs, suggesting histones may perturb the cell membrane of CMs. In vitro, exposure of CMs to the histones for 3 hours caused lactate dehydrogenase release from CMs. These data indicate that sepsis-induced cardiac dysfunction requires presence of TLR3 and TLR9 and may be linked to histone-induced damage of CMs.

Oral and dental lesions in HIV infected Nigerian children.

INTRODUCTION: Oral diseases in the HIV infected children though commonly encountered are under researched and often overlooked by physicians in developing countries. The aim of this study is to document the types and frequency of oral lesions in HIV infected children and examine the effects of management with HAART on their rates. METHODS: A cross sectional study designed to identify the oral lesions in consecutive HIV infected children and their distribution at a Paediatric Anti-retroviral clinic. Information on oral disease and clinical features of the subjects were obtained by history and clinical examination and laboratory investigations by the pediatricians and dental surgeons. RESULTS: The 58 children studied consisted of 34 boys and 24 girls with their ages ranging from 3 months to 13 years. Thirty seven (63.8%) of the 58 children had oral diseases. Enamel hypoplasia, candidiasis, caries, angular chelitis, and herpes labialis were the most common oral lesions found in the patients. Oral soft tissue lesions were less frequently encountered among children on HAART. Statistical significance was recorded among those infected with candidiasis. More than 60% of the children diagnosed with oral disease had no knowledge of the state of their oral health before the study. CONCLUSION: Oral diseases are very common amongst the children studied. Awareness of oral disease among the children and their caregivers is low. Administration of HAART may have a preventive effect on the development of oral soft tissue disease. There is a need to integrate dental care into the paediatric HIV care programs.