The aim of this study was to determine both the incidence of, and the reoperation rate for, postoperative periprosthetic femoral fracture (POPFF) after total hip arthroplasty (THA) with either a ...collared cementless (CC) femoral component or a cemented polished taper-slip (PTS) femoral component.
We performed a retrospective review of a consecutive series of 11,018 THAs over a ten-year period. All POPFFs were identified using regional radiograph archiving and electronic care systems.
A total of 11,018 THAs were implanted: 4,952 CC femoral components and 6,066 cemented PTS femoral components. Between groups, age, sex, and BMI did not differ. Overall, 91 patients (0.8%) sustained a POPFF. For all patients with a POPFF, 16.5% (15/91) were managed conservatively, 67.0% (61/91) underwent open reduction and internal fixation (ORIF), and 16.5% (15/91) underwent revision. The CC group had a lower POPFF rate compared to the PTS group (0.7% (36/4,952) vs 0.9% (55/6,066); p = 0.345). Fewer POPFFs in the CC group required surgery (0.4% (22/4,952) vs 0.9% (54/6,066); p = 0.005). Fewer POPFFs required surgery in males with a CC than males with a PTS (0.3% (7/2,121) vs 1.3% (36/2,674); p < 0.001).
Male patients with a PTS femoral component were five times more likely to have a reoperation for POPFF. Female patients had the same incidence of reoperation with either component type. Of those having a reoperation, 80.3% (61/76) had an ORIF, which could greatly mask the size of this problem in many registries.
Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL ...inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
Mutations in receptor tyrosine kinase (RTK) growth factor receptors (epidermal growth factor receptor, platelet-derived growth factor receptor, MET and ERBB2), which result in downstream activation ...of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral replication-competent avian leukosis virus long terminal repeat, splice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in Ink4a/Arf(lox/lox) mice in vivo. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.
Kidney failure is frequently observed during and after COVID-19, but it remains elusive whether this is a direct effect of the virus. Here, we report that SARS-CoV-2 directly infects kidney cells and ...is associated with increased tubule-interstitial kidney fibrosis in patient autopsy samples. To study direct effects of the virus on the kidney independent of systemic effects of COVID-19, we infected human-induced pluripotent stem-cell-derived kidney organoids with SARS-CoV-2. Single-cell RNA sequencing indicated injury and dedifferentiation of infected cells with activation of profibrotic signaling pathways. Importantly, SARS-CoV-2 infection also led to increased collagen 1 protein expression in organoids. A SARS-CoV-2 protease inhibitor was able to ameliorate the infection of kidney cells by SARS-CoV-2. Our results suggest that SARS-CoV-2 can directly infect kidney cells and induce cell injury with subsequent fibrosis. These data could explain both acute kidney injury in COVID-19 patients and the development of chronic kidney disease in long COVID.
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•COVID-19 patients present tubulo-interstitial kidney fibrosis compared with controls•SARS-CoV-2 infection stimulates profibrotic signaling in human kidney organoids•SARS-CoV-2 infection can be inhibited by a protease blocker in human kidney organoids
Jansen, Reimer, Nagai, et al. report that SARS-CoV-2 infects kidney cells and is associated with kidney fibrosis in patients. Using single-cell transcriptomics of infected kidney organoids, they show that SARS-CoV-2 causes kidney injury and stimulates profibrotic signaling. Viral infection in organoids was inhibited by a recently developed protease blocker.
This investigation compares the outcomes of proximal interphalangeal (PIP) arthroplasty in patients older than and younger than 60 years.
Overall, 299 consecutive, primary PIP arthroplasties were ...performed over a 14-year period, including 126 arthroplasties performed in patients younger than 60 years. In younger patients group, a higher rate of posttraumatic and inflammatory arthritis was observed.
In patients younger than 60 years, 32 (25%) revision surgeries occurred. Risk of revision surgery was associated with younger age. The 10-year implant survival rate was 72% for the patients younger than 60 years versus 86% for those older than 60 years. Silicone implants decreased the risk of revision surgery, although it was increased in posttraumatic arthritis. The most common complication in young patients was dislocation (n = 21). At a mean follow-up of 6.4 years, pain levels had significantly improved in patients younger than 60 years, and PIP range of motion and pinch strength were maintained. However, older patients had improved PIP motion compared with younger patients.
Younger age leads higher revision rates after PIP arthroplasty, particularly in the posttraumatic setting.
Therapeutic, level III.
The familial hypercholesterolemias (FH) are a group of genetic defects resulting in severe elevations of blood cholesterol levels and increased risk of premature coronary heart disease. FH is among ...the most commonly occurring congenital metabolic disorders. FH is a treatable disease. Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more. Even greater target LDL cholesterol reductions may be necessary for FH patients who have other CHD risk factors. Despite the prevalence of this disease and the availability of effective treatment options, FH is both underdiagnosed and undertreated, particularly among children. Deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of the public and of healthcare practitioners. This document provides recommendations for the screening, diagnosis and treatment of FH in pediatric and adult patients developed by the National Lipid Association Expert Panel on Familial Hypercholesterolemia. This report goes beyond previously published guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their elevated risk for CHD.
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For understanding material performance under dynamic loading, there is significant interest in the strain rate dependence of material response and in the degree to which high-rate ...response depends on initial material state. Experimental tests at high strain rates (>103/s) often use measurement of shape change to infer flow strength behavior. Given stress and strain heterogeneities, inferences about flow strength behavior from those observations are facilitated by comparisons with advanced simulations. A new plate impact-based experimental test is described, consisting of in situ X-ray imaging to observe the closure of a cylindrical hole during the passage of a pressure pulse of controlled amplitude and duration. With the goal of providing unique data regarding plastic response at high strain rates, the closure of the hole is measured through time using multi-frame imaging. A first set of experiments on copper examines the role of starting microstructure on material flow behavior. The experimental observations are compared with predictions from direct numerical simulations using the Preston-Tonks-Wallace (PTW) and the Mechanical Threshold Stress (MTS) flow strength models. The quantitative utility of the overall approach is demonstrated in that the results provide information about MTS model parameters associated with high-rate hardening behavior, with the parameters having been unconstrained by quasi-static experimental data.
Pain commonly coexists with depression, but its impact on treatment outcomes has not been well studied. Therefore, we prospectively evaluated the impact of comorbid pain on depression treatment ...response and health-related quality of life.
We analyzed data from the ARTIST study, a randomized controlled trial with naturalistic follow-up conducted in 37 primary care clinics. Participants were 573 clinically depressed patients randomized to one of three selective serotonin reuptake inhibitor (SSRI) antidepressants: fluoxetine, paroxetine, or sertraline. Depression as assessed by the Symptom Checklist-20 (SCL-20) was the primary outcome. Secondary outcomes included pain and health-related quality of life.
Pain was reported by more than two thirds of depressed patients at baseline, with the severity of pain mild in 25% of patients, moderate in 30%, and severe in 14%. After 3 months of antidepressant therapy, 24% of patients had a poor depression treatment response (ie, SCL-20 >1.3). Multivariate odds ratios for poor treatment response were 1.5 (95% confidence interval, 0.8-3.2) for mild pain, 2.0 (1.1-4.0) for moderate pain, and 4.1 (1.9-8.8) for severe pain compared with those without pain. Increasing pain severity also had an adverse impact on outcomes in multiple domains of health-related quality of life.
Pain is present in two thirds of depressed primary care patients begun on antidepressant therapy, and the severity of pain is a strong predictor of poor depression and health-related quality of life outcomes at 3 months. Better recognition, assessment, and treatment of comorbid pain may enhance outcomes of depression therapy.
The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In a prospective biopsy-stratified clinical trial, we combined detailed ...molecular profiling and drug screening in newly established patient-derived models in vitro and in vivo. We identified in vitro sensitivity to MEK inhibitors in DIPGs harboring MAPK pathway alterations, but treatment of patient-derived xenograft models and a patient at relapse failed to elicit a significant response. We generated trametinib-resistant clones in a BRAFG469V model through continuous drug exposure and identified acquired mutations in MEK1/2 with sustained pathway upregulation. These cells showed hallmarks of mesenchymal transition and expression signatures overlapping with inherently trametinib-insensitive patient-derived cells, predicting sensitivity to dasatinib. Combined trametinib and dasatinib showed highly synergistic effects in vitro and on ex vivo brain slices. We highlight the MAPK pathway as a therapeutic target in DIPG and show the importance of parallel resistance modeling and combinatorial treatments for meaningful clinical translation.
We report alterations in the MAPK pathway in DIPGs to confer initial sensitivity to targeted MEK inhibition. We further identify for the first time the mechanism of resistance to single-agent targeted therapy in these tumors and suggest a novel combinatorial treatment strategy to overcome it in the clinic. This article is highlighted in the In This Issue feature, p. 587.
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