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Background Laboratory studies are routinely performed as a part of the preoperative workup for a total knee arthroplasty (TKA). The ramifications of abnormal preoperative platelet counts remain uncharacterized in large, multicenter patient populations. Methods Patients who underwent elective primary TKA were identified in the 2011-2015 National Surgical Quality Improvement Program database. Risk of 30-day postoperative complications was calculated as a function of preoperative platelet counts. Patients were characterized as having a normal platelet count, abnormally low platelet count, and abnormally high platelet count based on relative risk calculations. Univariate and multivariate analyses were performed to associate abnormal platelet counts with patient demographics, operative variables, 30-day postoperative complications, and readmissions. Results In total, 140,073 patients who underwent elective TKA were identified. Using the relative risk threshold of 1.5 for any adverse event, abnormally low and abnormally high platelet count thresholds were set at ≤116,000/mL and ≥492,000/mL, respectively. Multivariate analyses revealed low platelet counts to be associated with higher rates of any, major, and minor adverse events and longer length of stay. Analogously, high platelet counts were associated with higher rates of any and minor adverse events and longer length of stay. Conclusion The present study employed a large patient sample size and showed that elective TKA patients with abnormally high, as well as low, platelet counts are at increased risk of postoperative adverse outcomes. Focused attention needs to be paid to TKA patients with preoperative abnormal platelet counts for optimization and postoperative care. Level of Evidence Level III, retrospective comparative study.

Introduction: Postoperative delirium is common for patients with hip fracture. Predictors of postoperative delirium and its association with preexisting dementia and adverse postoperative outcomes in a geriatric hip fracture population were assessed. Methods: Patients with hip fracture aged 60 years and older were identified in the 2016 and 2017 National Surgical Quality Improvement Program Procedure Targeted Databases. Independent risk factors of postoperative delirium were identified. Associations with mortality, readmission, and revision surgery were evaluated using moderation and mediation analysis. Results: Of 18,754 patients with hip fracture, 30.2% had preoperative dementia, 18.8% had postoperative delirium, and 8.3% had both preoperative dementia and postoperative delirium. Independent predictors of postoperative delirium were as follows: older age, male sex, higher American Society of Anesthesiologists score, dependent functional status, nongeneral anesthesia, preoperative diabetes, bleeding disorder, and preoperative dementia. Preoperative dementia and postoperative delirium each had an independent correlation with 30-day mortality (odds ratios = 2.06 and 1.92, respectively, with P < 0.001 for both). However, when both were present, those with preoperative dementia and postoperative delirium had an even higher odds of mortality based on moderation analysis (odds ratio = 2.25, P < 0.001). Readmissions and reoperations were significantly correlated with postoperative delirium, but not with preoperative dementia. The combination of preoperative dementia and postoperative delirium, however, did have compounding effects. Furthermore, a significant proportion of the total effect of preoperative dementia on mortality and readmission was accounted for by the development of postoperative delirium based on mediation analysis (medeff: 7%, P < 0.001 and medeff: 35%, P < 0.001). Discussion: Postoperative delirium is a potentially preventable postoperative adverse outcome that was seen in 18.8% of 18,754 patients with hip fracture. Those with preoperative dementia seem to be a particularly at-risk subpopulation. Quality improvement initiatives to minimize postoperative delirium in this hip fracture population should be considered and optimized.

Geriatric femoral neck fracture is a common injury for which hemiarthroplasty (HA) or total hip arthroplasty (THA) may be considered in select patients. As prior database studies comparing these have not used propensity matching, which is a robust statistical method of controlling for potentially confounding variables, unmatched and matched methodologies are contrasted in the present study.Patients aged ≥70 years who underwent HA or THA for hip fractures were identified from the 2012-2015 National Surgical Quality Improvement database. Propensity score 1:1 matching was performed. Differences in rates of 30-day postoperative adverse outcomes were compared using multivariate logistic regression for unmatched and matched cohorts.In total, 15,558 patients (14,403 HA and 1155 THA) were evaluated. Although multivariate outcomes for the unmatched populations were different for blood transfusion, mortality, minor adverse events, major adverse events, and reoperation, multivariate outcomes for matched populations only differed for blood transfusion (odds ratio 0.6 for HA vs THA, P.001). Of note, although readmissions were similar for the two groups, patients undergoing THA had a 5.4% greater rate of perioperative readmission due to dislocation.Geriatric patients undergoing HA and THA for hip fracture were compared with and without propensity matching. Once matching was performed, the only differences in outcomes between the two groups were a lower transfusion rate among the HA group and a greater readmission rate due to dislocation among the THA group. This suggests that either procedure can be safely considered if found to be advantageous from a longer-term outcome perspective.Level III, retrospective comparative study.

The future of cancer treatment is promising. Although marred by years of plateau in outcomes, new avenues have been identified that are poised to change how we treat cancer. Molecular targeted therapy or targeted therapy is one of these methods. Molecular targeted therapy involves identifying specific pathways or markers that allow cancer cells to flourish. Once identified, specific molecules can be used to block proliferative pathways, thereby negatively impacting tumor growth. Targeting specific pathways that prolong the survival of the cancer cell can lead to a decreased cancer burden, and improved patient outcomes. This article reviews the tenets of molecular targeted therapy, common pathways, target acquisition for drug development, and the pathways that have been elucidated in musculoskeletal tumors.

The prevalence of dialysis-dependent patients is growing, and an increasing number of these patients are being considered for total knee arthroplasty (TKA). Studies assessing the preoperative risk associated with TKA in this population are limited to institutional cohorts with small sample sizes or national inpatient databases that lack follow-up data.The 2006-2015 National Surgical Quality Improvement Program databases were queried for adult patients undergoing elective TKA. Differences in 30-day any/severe/minor adverse event, need for reoperation, readmission, and mortality were compared for dialysis-dependent and nondialysis TKA patients using risk-adjusted logistic regression. To account for the smaller number of dialysis patients and variations in study populations, coarsened exact matching was used. The proportion of adverse events that occurred before vs after discharge was also assessed.In total, 250 dialysis-dependent patients and 163,560 nondialysis patients met inclusion criteria. After controlling for patient demographics (age, sex, body mass index, functional status) and overall health (American Society of Anesthesiologists class), matched analysis revealed dialysis-dependent patients to be significantly more likely to experience any adverse event (odds ratio = 2.01; 95% confidence interval [CI], 1.34-3.02; P = .001), severe adverse event (odds ratio = 2.49; 95% CI, 1.61-3.84; P.001), reoperation (odds ratio = 2.38; 95% CI, 1.19-4.75; P = .014), readmission (odds ratio = 2.32; 95% CI, 1.47-3.66; P = .001), and mortality (odds ratio = 6.71; 95% CI, 2.99-22.50; P = .002). The majority of adverse outcomes occurred postdischarge.Independent of patient demographics and overall health (American Society of Anesthesiologists), patients undergoing dialysis before TKA are significantly more likely to experience 30-day adverse outcomes than matched nondialysis cohorts. Preoperative evaluation of bone health status and management of medical treatment are warranted in this fragile population. Cautious surgical planning, patient counseling, and heightened surveillance are necessitated throughout their perioperative period and postoperative recovery plans may need to be different from nondialysis counterparts. Furthermore, hospitals and physicians must take these increased risks into account when working on bundle payment reimbursement strategies and resource allocation.3.

The objective of this article is to review large database comparisons of total hip arthroplasty (THA) to hemiarthroplasty (HA) for geriatric hip fracture patients. This article followed a systematic review of the literature using published studies identified via PubMed as the data source. A literature search was done iteratively with a systematic use of variations of key search terms. The initial search identified 490 references. Of the 490, 15 full-text papers were reviewed. Ultimately, nine papers were included in the review. Five of the included studies utilized the National Surgical Quality Improvement Program database, one utilized Hospital Episode Statistics, one utilized The National Hospital Discharge Survey, one utilized Swedish Nation Hip Fracture/Arthroplasty Register, and the last utilized the ENCLAVE system of the Centers for Medicare & Medicaid Services. These all included data ranging from 2005 to 2013 and included at least 1,000 patients. Clinical postoperative outcomes of THA and HA were grouped and compared among the nine studies. The studies used multivariable analysis to make comparisons, and it is of note that HA is much more common than THA in this patient population. Primary outcome variables evaluated included major/minor complications, mortality, length of stay, postoperative transfusion, readmission, dislocation, and revision. Overall, major and minor adverse events (or a combination of the two) were lower for THA than for HA patients, and postoperative transfusions were more common for THA patients. Mortality was significantly less for THA patients by 3% to 4%. Length of stay was lower for THA patients. Dislocation rates were higher for THA patients at 30 days, 18 months, 24 months, and 4 years by odds ratios of three to five times. One study found THA patients more likely to undergo reoperation. In select geriatric patients with femoral neck fractures, THA and HA may be appropriately considered. For those patients, studies suggest that THA may be associated with fewer postoperative challenges than HA; however, postoperative transfusion and dislocation rates were noted to be higher for THA patients.

Large cohort studies evaluating cardiac complications in patients undergoing spine surgery are lacking. The purpose of this study was to determine the incidence, timing, risk factors, and effect of cardiac complications in spine surgery by using a national database, the American College of Surgeons National Surgical Quality Improvement Program.Patients who underwent spine surgery in the 2005 to 2012 National Surgical Quality Improvement Program database were identified. The primary outcome was an occurrence of cardiac arrest or myocardial infarction during the operation or the 30-day postoperative period. Risk factors for development of cardiac complications were identified using multivariate regression. The postoperative length of stay, 30-day readmission, and mortality were compared between patients who did and did not experience a cardiac complication.A total of 30,339 patients who underwent spine surgery were identified. The incidence of cardiac complications was 0.34% (95% confidence interval [CI], 0.27% to 0.40%). Of the cases in which a cardiac complication developed, 30% were diagnosed after discharge. Risk factors for the development of cardiac complications were greater age (most notably ≥80 years, relative risk [RR] = 5.53; 95% CI = 2.28 to 13.43; P0.001), insulin-dependent diabetes (RR = 2.58; 95% CI = 1.51 to 4.41; P = 0.002), preoperative anemia (RR = 2.46; 95% CI = 1.62 to 3.76; P0.001), and history of cardiac disorders and treatments (RR = 1.88; 95% CI = 1.16 to 3.07; P = 0.011). Development of a cardiac complication before discharge was associated with a greater length of stay (7.9 versus 2.6 days; P0.001), and a cardiac complication after discharge was associated with increased 30-day readmission (RR = 12.32; 95% CI = 8.17 to 18.59; P0.001). Development of a cardiac complication any time during the operation or 30-day postoperative period was associated with increased mortality (RR = 113.83; 95% CI = 58.72 to 220.68; P0.001).Perioperative cardiac complications were diagnosed in approximately 1 in 300 patients undergoing spine surgery. High-risk patients should be medically optimized and closely monitored through the perioperative period.Level III.

Author(s): Conca Dioguardi, Carola; Uslu, Bahar; Haynes, Monique; Kurus, Meltem; Gul, Mehmet; Miao, De-Qiang; De Santis, Lucia; Ferrari, Maurizio; Bellone, Stefania; Santin, Alessandro; Giulivi, Cecilia; Hoffman, Gloria; Usdin, Karen; Johnson, Joshua | Abstract: Study hypothesisWe hypothesized that the mitochondria of granulosa cells (GC) and/or oocytes might be abnormal in a mouse model of fragile X premutation (FXPM).Study findingMice heterozygous and homozygous for the FXPM have increased death (atresia) of large ovarian follicles, fewer corpora lutea with a gene dosage effect manifesting in decreased litter size(s). Furthermore, granulosa cells (GC) and oocytes of FXPM mice have decreased mitochondrial content, structurally abnormal mitochondria, and reduced expression of critical mitochondrial genes. Because this mouse allele produces the mutant Fragile X mental retardation 1 (Fmr1) transcript and reduced levels of wild-type (WT) Fmr1 protein (FMRP), but does not produce a Repeat Associated Non-ATG Translation (RAN)-translation product, our data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary.What is known alreadyMitochondrial dysfunction has been detected in somatic cells of human and mouse FX PM carriers and mitochondria are essential for oogenesis and ovarian follicle development, FX-associated primary ovarian insufficiency (FXPOI) is seen in women with FXPM alleles. These alleles have 55-200 CGG repeats in the 5' UTR of an X-linked gene known as FMR1. The molecular basis of the pathology seen in this disorder is unclear but is thought to involve either some deleterious consequence of overexpression of RNA with long CGG-repeat tracts or of the generation of a repeat-associated non-AUG translation (RAN translation) product that is toxic.Study design, samples/materials, methodsAnalysis of ovarian function in a knock-in FXPM mouse model carrying 130 CGG repeats was performed as follows on WT, PM/+, and PM/PM genotypes. Histomorphometric assessment of follicle and corpora lutea numbers in ovaries from 8-month-old mice was executed, along with litter size analysis. Mitochondrial DNA copy number was quantified in oocytes and GC using quantitative PCR, and cumulus granulosa mitochondrial content was measured by flow cytometric analysis after staining of cells with Mitotracker dye. Transmission electron micrographs were prepared of GC within small growing follicles and mitochondrial architecture was compared. Quantitative RT-PCR analysis of key genes involved in mitochondrial structure and recycling was performed.Main results and the role of chanceA defect was found in follicle survival at the large antral stage in PM/+ and PM/PM mice. Litter size was significantly decreased in PM/PM mice, and corpora lutea were significantly reduced in mice of both mutant genotypes. Mitochondrial DNA copy number was significantly decreased in GC and metaphase II eggs in mutants. Flow cytometric analysis revealed that PM/+ and PM/PM animals lack the cumulus GC that harbor the greatest mitochondrial content as found in wild-type animals. Electron microscopic evaluation of GC of small growing follicles revealed mitochondrial structural abnormalities, including disorganized and vacuolar cristae. Finally, aberrant mitochondrial gene expression was detected. Mitofusin 2 (Mfn2) and Optic atrophy 1 (Opa1), genes involved in mitochondrial fusion and structure, respectively, were significantly decreased in whole ovaries of both mutant genotypes. Mitochondrial fission factor 1 (Mff1) was significantly decreased in PM/+ and PM/PM GC and eggs compared with wild-type controls.Limitations, reasons for cautionData from the mouse model used for these studies should be viewed with some caution when considering parallels to the human FXPOI condition.Wider implications of the findingsOur data lend support to the idea that Fmr1 mRNA with large numbers of CGG-repeats is intrinsically deleterious in the ovary. FXPM disease states, including FXPOI, may share mitochondrial dysfunction as a common underlying mechanism.Large scale dataNot applicable.Study funding and competing interestsStudies were supported by NIH R21 071873 (J.J./G.H), The Albert McKern Fund for Perinatal Research (J.J.), NIH Intramural Funds (K.U.), and a TUBITAK Research Fellowship Award (B.U.). No conflict(s) of interest or competing interest(s) are noted.

BackgroundPostoperative stroke is a rare but potentially devastating complication following total hip arthroplasty (THA) and total knee arthroplasty (TKA). The purpose of the current study was to determine the incidence, independent risk factors, and timing of stroke following THA and TKA utilizing the National Surgical Quality Improvement (NSQIP) database.MethodsPatients who underwent elective primary THA and TKA were identified in the 2005-2016 NSQIP database. Thirty-day postoperative strokes were identified, timing was characterized, and an incidence curve was created. Multivariate analyses determined the independent predictors of these strokes.ResultsOf 333,117 patients identified, 286 (0.09%) experienced a stroke. Given that THA vs TKA was not a univariate predictor of stroke, the two procedures were considered together. The majority (65%) of strokes occurred before discharge. Of the strokes observed, 25% occurred by postoperative day one, 50% by postoperative day two, and 75% by postoperative day nine. Independent risk factors for postoperative stroke were: age (60-69 years old odds ratio [OR] = 4.2; 70-79 years old OR = 8.1; ≤80 years old OR = 16.1), higher American Society of Anesthesiologists (ASA) score (ASA≥3 OR = 1.7), and smoking [OR = 1.6).ConclusionThe incidence of stroke after THA/TKA was low at 0.09%, with the majority occurring prior to discharge and half occurring by postoperative day two. Patients who were older, sicker, or who were smokers were at greater risk of postoperative stroke. These findings can be used to council patients and to optimize patient care.Level of evidenceLevel III, Retrospective comparative study.

Background A standard histomorphometric approach has been used for nearly 40 years that identifies atretic (e.g., dying) follicles by counting the number of pyknotic granulosa cells (GC) in the largest follicle cross-section. This method holds that if one pyknotic granulosa nucleus is seen in the largest cross section of a primary follicle, or three pyknotic cells are found in a larger follicle, it should be categorized as atretic. Many studies have used these criteria to estimate the fraction of atretic follicles that result from genetic manipulation or environmental insult. During an analysis of follicle development in a mouse model of Fragile X premutation, we asked whether these ‘historical’ criteria could correctly identify follicles that were not growing (and could thus confirmed to be dying). Methods Reasoning that the fraction of mitotic GC reveals whether the GC population was increasing at the time of sample fixation, we compared the number of pyknotic nuclei to the number of mitotic figures in follicles within a set of age-matched ovaries. Results We found that, by itself, pyknotic nuclei quantification resulted in high numbers of false positives (improperly categorized as atretic) and false negatives (improperly categorized intact). For preantral follicles, scoring mitotic and pyknotic GC nuclei allowed rapid, accurate identification of non-growing follicles with 98% accuracy. This method most often required the evaluation of one follicle section, and at most two serial follicle sections to correctly categorize follicle status. For antral follicles, we show that a rapid evaluation of follicle shape reveals which are intact and likely to survive to ovulation. Conclusions Combined, these improved, non-arbitrary methods will greatly improve our ability to estimate the fractions of growing/intact and non-growing/atretic follicles in mouse ovaries.