Anterior cruciate ligament graft size is an important consideration when planning the length of the tibial tunnel. In general, longer grafts require longer tunnels to accommodate the graft. Ideally, ...the tibial bone plug should be flush with the tibial cortex after graft passage and femoral fixation. Alternatively, allograft bone-patellar tendon-bone grafts can be selected based on their lengths to assure an ideal fit in the tibial tunnel. However, there are increased risks of allograft failure in young patients that anterior cruciate ligament surgeons should recognize.
Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small ...proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug treatment, resulting in disease recurrence/persistence. Using a single-cell assay to track individual cells that exit a drug-induced senescence-like state, we show that cells exhibit asynchronous exit from a senescent-like state, and display different rates of proliferation. Escaped cells retain sensitivity to drug treatment, but display inter-clonal variability. We also find heterogeneity in gene expression with some of the escaped clones retaining senescence-associated gene expression. Senescent leukemia cells exhibit changes in gene expression that affect metabolism and senescence-associated secretory phenotype (SASP)-related genes. Herein, we generate a senescence gene signature and show that this signature is a prognostic marker of worse overall survival in AML and multiple other cancers. A portion of senescent leukemia cells depend on lysosome activity; chloroquine, an inhibitor of lysosome activity, promotes senolysis of some senescent leukemia cells. Our study indicates that the serious risks associated with the use of erythropoietin-stimulating agents (ESAs) in anemic cancer patients may be attributed to their ability to promote drug-tolerant cancer cells through the senescence program.
Background
Increased contact stresses after meniscectomy have led to an increased focus on meniscal preservation strategies to prevent articular cartilage degeneration. Platelet-rich plasma (PRP) has ...received attention as a promising strategy to help induce healing and has been shown to do so both in vitro and in vivo. Although PRP has been used in clinical practice for some time, to date, few clinical studies support its use in meniscal repair.
Questions/purposes
We sought to (1) evaluate whether PRP augmentation at the time of index meniscal repair decreases the likelihood that subsequent meniscectomy will be performed; (2) determine if PRP augmentation in arthroscopic meniscus repair influenced functional outcome measures; and (3) examine whether PRP augmentation altered clinical and patient-reported outcomes.
Methods
Between 2008 and 2011, three surgeons performed 35 isolated arthroscopic meniscus repairs. Of those, 15 (43%) were augmented with PRP, and 20 (57%) were performed without PRP augmentation. During the study period, PRP was used for patients with meniscus tears in the setting of no ACL reconstruction. Complete followup at a minimum of 2 years (mean, 4 years; range, 2–6 years) was available on 11 (73%) of the PRP-augmented knees and 15 (75%) of the nonaugmented knees. Clinical outcome measures including the International Knee Documentation Committee (IKDC) score, Tegner Lysholm Knee Scoring Scale, and return to work and sports/activities survey tools were completed in person, over the phone, or through the mail. Range of motion data were collected from electronic patient charts in chart review. With the numbers available, a post hoc power calculation demonstrated that we would have expected to be able to discern a difference using IKDC if we treated 153 patients with PRP and 219 without PRP assuming an alpha rate of 5% and power exceeding 80%. Using the Lysholm score as an outcome measure, post hoc power estimate was 0.523 and effect size was −1.1 (−2.1 to −0.05) requiring 12 patients treated with PRP and 17 without to find statistically significant differences at p = 0.05 and power = 80%.
Results
There was no difference in the proportion of patients who underwent reoperation in the PRP group (27% four of 15) compared with the non-PRP group (25% five of 20; p = 0.89). Functional outcome measures were not different between the two groups based on the measures used (mean IKDC score, 69; SD, 26 with PRP and 76; SD, 17 without PRP; p = 0.288; mean, Tegner Lysholm Knee Scoring Scale, 66, SD, 32 with PRP and 89; SD, 10 without PRP; p = 0.065). With the numbers available there was no difference in the proportion of patients who returned to work in the PRP group (100% six of six) compared with the non-PRP group (100% nine of nine) or in the patients who returned to their regular sports/activities in the PRP group (71% five of seven) compared with the non-PRP group (78% seven of nine; p = 0.75).
Conclusions
Patients who sustain meniscus injuries should be counseled at the time of injury about the outcomes after meniscus repair. With our limited study group, outcomes after meniscus repair with and without PRP appear similar in terms of reoperation rate. However, given the lack of power and nature of the study, modest size differences in outcome may not have been detected. Future larger prospective studies are needed to definitively determine whether PRP should be used with meniscal repair. Additionally, studies are needed to determine if PRP and other biologics may benefit complex tear types.
Level of Evidence
Level III, therapeutic study.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Background: There is increasing evidence in humans and in experimental animals for a relationship between exposure to specific environmental chemicals and perturbations in levels of critically ...important thyroid hormones (THs). Identification and proper interpretation of these relationships are required for accurate assessment of risk to public health. Objectives: We review the role of TH in nervous system development and specific outcomes in adults, the impact of xenobiotics on thyroid signaling, the relationship between adverse outcomes of thyroid disruption and upstream causal biomarkers, and the societal implications of perturbations in thyroid signaling by xenobiotic chemicals. Data sources: We drew on an extensive body of epidemiologic, toxicologic, and mechanistic studies. Data synthesis: THs are critical for normal nervous system development, and decreased maternal TH levels are associated with adverse neuropsychological development in children. In adult humans, increased thyroid-stimulating hormone is associated with increased blood pressure and poorer blood lipid profiles, both risk factors for cardiovascular disease and death. These effects of thyroid suppression are observed even within the "normal" range for the population. Environmental chemicals may affect thyroid homeostasis by a number of mechanisms, and multiple chemicals have been identified that interfere with thyroid function by each of the identified mechanisms. Conclusions: Individuals are potentially vulnerable to adverse effects as a consequence of exposure to thyroid-disrupting chemicals. Any degree of thyroid disruption that affects TH levels on a population basis should be considered a biomarker of adverse outcomes, which may have important societal outcomes.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Background: Disruption of fundamental biologic processes and associated signaling events may result in clinically significant alterations in lung development. Objectives: We reviewed evidence on the ...impact of environmental chemicals on lung development and key signaling events in lung morphogenesis, and the relevance of potential outcomes to public health and regulatory science. Data sources: We evaluated the peer-reviewed literature on developmental lung biology and toxicology, mechanistic studies, and supporting epidemiology. Data synthesis: Lung function in infancy predicts pulmonary function throughout life. In utero and early postnatal exposures influence both childhood and adult lung structure and function and may predispose individuals to chronic obstructive lung disease and other disorders. The nutritional and endogenous chemical environment affects development of the lung and can result in altered function in the adult. Studies now suggest that similar adverse impacts may occur in animals and humans after exposure to environmentally relevant doses of certain xenobiotics during critical windows in early life. Potential mechanisms include interference with highly conserved factors in developmental processes such as gene regulation, molecular signaling, and growth factors involved in branching morphogenesis and alveolarization. Conclusions: Assessment of environmental chemical impacts on the lung requires studies that evaluate specific alterations in structure or function—end points not regularly assessed in standard toxicity tests. Identifying effects on important signaling events may inform protocols of developmental toxicology studies. Such knowledge may enable policies promoting true primary prevention of lung diseases. Evidence of relevant signaling disruption in the absence of adequate developmental toxicology data should influence the size of the uncertainty factors used in risk assessments.
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BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Summary Background At present, diagnosis of Ebola virus disease requires transport of venepuncture blood to field biocontainment laboratories for testing by real-time RT-PCR, resulting in delays that ...complicate patient care and infection control efforts. Therefore, an urgent need exists for a point-of-care rapid diagnostic test for this disease. In this Article, we report the results of a field validation of the Corgenix ReEBOV Antigen Rapid Test kit. Methods We performed the rapid diagnostic test on fingerstick blood samples from 106 individuals with suspected Ebola virus disease presenting at two clinical centres in Sierra Leone. Adults and children who were able to provide verbal consent or assent were included; we excluded patients with haemodynamic instability and those who were unable to cooperate with fingerstick or venous blood draw. Two independent readers scored each rapid diagnostic test, with any disagreements resolved by a third. We compared point-of-care rapid diagnostic test results with clinical real-time RT-PCR results (RealStar Filovirus Screen RT-PCR kit 1·0; altona Diagnostics GmbH, Hamburg, Germany) for venepuncture plasma samples tested in a Public Health England field reference laboratory (Port Loko, Sierra Leone). Separately, we performed the rapid diagnostic test (on whole blood) and real-time RT-PCR (on plasma) on 284 specimens in the reference laboratory, which were submitted to the laboratory for testing from many clinical sites in Sierra Leone, including our two clinical centres. Findings In point-of-care testing, all 28 patients who tested positive for Ebola virus disease by RT-PCR were also positive by fingerstick rapid diagnostic test (sensitivity 100% 95% CI 87·7–100), and 71 of 77 patients who tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92·2% 95% CI 83·8–97·1). In laboratory testing, all 45 specimens that tested positive by RT-PCR were also positive by the rapid diagnostic test (sensitivity 100% 95% CI 92·1–100), and 214 of 232 specimens that tested negative by RT-PCR were also negative by the rapid diagnostic test (specificity 92·2% 88·0–95·3). The two independent readers agreed about 95·2% of point-of-care and 98·6% of reference laboratory rapid diagnostic test results. Cycle threshold values ranged from 15·9 to 26·3 (mean 22·6 SD 2·6) for the PCR-positive point-of-care cohort and from 17·5 to 26·3 (mean 21·5 2·7) for the reference laboratory cohort. Six of 16 banked plasma samples from rapid diagnostic test-positive and altona-negative patients were positive by an alternative real-time RT-PCR assay (the Trombley assay); three (17%) of 18 samples from individuals who were negative by both the rapid diagnostic test and altona test were also positive by Trombley. Interpretation The ReEBOV rapid diagnostic test had 100% sensitivity and 92% specificity in both point-of-care and reference laboratory testing in this population (maximum cycle threshold 26·3). With two independent readers, the test detected all patients who were positive for Ebola virus by altona real-time RT-PCR; however, this benchmark itself had imperfect sensitivity. Funding Abundance Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Evidence is growing on the adverse neurodevelopmental effects of exposure to combustion-related air pollution. Project TENDR (Targeting Environmental Neurodevelopmental Risks), a unique collaboration ...of leading scientists, health professionals, and children's and environmental health advocates, has identified combustion-related air pollutants as critical targets for action to protect healthy brain development. We present policy recommendations for maintaining and strengthening federal environmental health protections, advancing state and local actions, and supporting scientific research to inform effective strategies for reducing children's exposures to combustion-related air pollution. Such actions not only would improve children's neurological development but also would have the important co-benefit of climate change mitigation and further improvements in other health conditions.
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CEKLJ, DOBA, FSPLJ, IZUM, KILJ, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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