Periprosthetic fractures are osteoporotic fractures: missed opportunities for osteoporosis diagnosis.

Joint replacement surgery is common in older adults, leading to increasing periprosthetic fracture (PPFx) occurrence. We reviewed all PPFx seen over a 4-year period at an academic hospital. Clinical osteoporosis could be diagnosed based on existing data in 104 (67%) at the time of PPFx. Periprosthetic fractures are generally osteoporosis-related. PURPOSE: Periprosthetic fractures (PPFx) cause morbidity, mortality, and cost. This study's purpose was to describe osteoporosis-related data available at the time of PPFx. METHODS: The electronic medical record (EMR) of PPFx patients seen over 4 years in a university orthopedic practice were reviewed. Demographic data and osteoporosis relevant parameters were collected. Prior DXA studies were reviewed, and L1 Hounsfield unit (HU) measurements were performed on CT scans obtained within 2 years before PPFx. Clinical osteoporosis was defined as prior diagnosis, prescribed osteoporosis treatment, T-score ≤ - 2.5, HU ≤ 100, or prior fracture. RESULTS: Records of 156 PPFx patients (115 F/41 M), mean (SD) age 75.4 (11.9), were reviewed. Almost all 153/156 (98%) of these fractures were femoral. Falls caused 139 (89%); 12 (8%) were spontaneous. Mean time post-arthroplasty was 7.9 (6.3) years. Prior fragility fracture(s) occurred in 72 (46%); 14 were PPFx. Osteoporosis was previously diagnosed in 45 (29%) and medications prescribed in 41 (26%). Prior to PPFx, DXA data were available in 62, mean (SD) lowest T-score was - 1.9 (0.9) and was ≤ - 2.5 in 19. CT data were available in 46; mean (SD) L1 HU was 79.0 (29.4) and was ≤ 100 in 35. Based on existing data, clinical osteoporosis could have been diagnosed in 104 (67%) at the time of PPFx. CONCLUSION: Periprosthetic fractures are osteoporosis-related. They occur in older adults, often female, and result from falls; BMD, when assessed, is low. Data available at the time of PPFx often allows osteoporosis diagnosis; this should prompt evaluation and pharmacologic treatment consideration.

Epigenetic repression of Wnt receptors in AD: a role for Sirtuin2-induced H4K16ac deacetylation of Frizzled1 and Frizzled7 promoters.

Growing evidence supports a role for deficient Wnt signalling in Alzheimer's disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-ß-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology.

Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at 16q11.2 and MAPT H1 loci.

Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

Compartment Syndrome in Operatively Managed Pediatric Monteggia Fractures and Equivalents.

BACKGROUND: Acute compartment syndrome (ACS) is not commonly associated with pediatric Monteggia fractures or Monteggia equivalents (MF/ME). The aims of this study were: (1) To document a rate of ACS among children with operatively managed MF/ME, comparing this to the rate of ACS in classically associated Type 3 supracondylar humerus (T3-SCH) fractures at the same institution; (2) To determine which patients with MF/ME are at highest risk for ACS. METHODS: Children ages 2 to 12 with MF/ME requiring operative management at an academic institution over a 14-year period were identified. The Monteggia fractures were characterized using the Bado classification; equivalent injuries were identified according to established criteria. Similarly, all patients with T3-SCH fractures managed over the same period were identified. Record review included demographic, procedural, and radiographic variables. Statistical analysis compared the rates of ACS in both groups and determined risk factors associated with developing ACS in patients with MF/ME. RESULTS: The rate of ACS in MF/ME was 9 of the 59 (15.3%), which was significantly higher than the rate of ACS in T3-SCH fractures 2 of the 230 (0.9%) (P=0.001). Comparing MF/ME with ACS to those without; there was no difference in sex (P=1.00), Bado Type (P=0.683), or Monteggia fracture versus equivalent (P=0.704). MF/ME with preoperative vascular deficits (22.2%) and those undergoing intramedullary fixation of the radius were more likely to develop ACS (P=0.021 and 0.015, respectively), and there was a trend toward higher rates of ACS among MF/ME with preoperative neurological deficits (P=0.064). CONCLUSIONS: Patients with operatively managed MF/ME had a significantly higher rate of ACS compared with patients with T3-SCH fractures. With no predisposition based on Bado classification or Monteggia fracture versus equivalent, all operatively managed MF/ME appear to be at risk for ACS. Patients with preoperative neurovascular deficits and those undergoing intramedullary radial fixation develop ACS at higher rates. Careful assessment of the forearm for signs and symptoms of ACS both before and after fixation is critical. LEVEL OF EVIDENCE: Level III-retrospective case control.

New approaches for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent chronic neurodegenerative disease. Current approved therapies are symptomatic treatments having some effect on cognitive function. Therapies that target ß-amyloid (Aß) have been the focus of efforts to develop a disease modification treatment for AD but these approaches have failed to show any clinical benefit so far. Beyond the 'Aß hypothesis', there are a number of newer approaches to treat AD with neuroinflammation emerging as a very active area of research based on risk gene analysis. This short review will summarize approved drug therapies, recent clinical trials and new approaches for the treatment of AD.

Orthopaedic injuries from snowmobile accidents: a multi-centre analysis of demographics, injury patterns, and outcomes.

PURPOSE: More than 2 million people in North America use snowmobiles, resulting in an estimated 200 fatalities and 14,000 injuries annually. The purpose of this study is to document the demographics, orthopaedic injury patterns, and short-term outcomes of patients with snowmobile-related injuries. MATERIALS AND METHODS: A retrospective review was performed at two regional trauma centres in a region where snowmobile use is prevalent. Patients who sustained snowmobile-related injuries over a 12-year period were identified from the hospitals' trauma registries using E-codes (E820-E820.9). Patient demographics were recorded, as were injury characteristics including rates of substance use, open fractures, Injury Severity Score (ISS), Abbreviated Injury Score (AIS) for the extremities, and mortality. Rates of inpatient surgery, as well as hospital and ICU length of stay (LOS), were also recorded. RESULTS: We identified 528 patients with snowmobile-related injuries. Average age was 37 years, and 418 patients (79%) were male. Eighty-eight per cent of all patients with snowmobile injuries were admitted to the hospital with an average LOS of 5.7 days. Among those admitted to the hospital, average ISS was 12.3, and 28% of these patients had ISS > 15. A total of 261 patients (56%) suffered extremity injuries (including 163 upper and 173 lower extremity fractures) with an average extremity AIS of 2.4. There were 700 total fractures (1.5 per patient), and 9% of all fractures were open. A total of 208 patients (45%) suffered head injuries, and 132 patients (28%) sustained vertebral column fractures. A total of 201 patients (43%) required inpatient surgery, and eight patients (1.7%) sustained fatal injuries. CONCLUSIONS: We present a detailed multi-centre analysis of orthopaedic injury patterns and outcomes resulting from snowmobile-related injuries. Patients injured while snowmobiling share similar injury patterns with patients injured in motorcycle and other high-energy motor vehicle accidents.

Management of Femoral Defects Greater Than 5 cm Following Open Femur Fractures: A 12-Year Retrospective Review.

This study sought to evaluate the outcomes of patients with osseous defects exceeding 5 cm following open femur fractures. Size of the osseous defect, method of internal fixation (plate vs. intramedullary nail), patient demographics, medical comorbidities, and surgical complications were collected. Twenty-seven of the 832 open femur fracture patients had osseous defects exceeding 5 cm. Mean osseous defect size was 8 cm, and each patient had an average of four operations including initial debridement. Average time from injury to bone grafting was 123.7 days. The overall complication rate was 48.1% (n = 13). The most common complications were infection (26.0%, n = 7) and nonunion (41.0%, n = 11). Smoking, diabetes, ASA score, and defect size did not independently increase the risk of a complication. Management of open femur fractures with osseous defects greater than 5 cm is associated with high complication rate, driven primarily by infection and nonunion. (Journal of Surgical Orthopaedic Advances 27(3):203-208, 2018).

Damage Control Plating in Open Tibial Shaft Fractures: A Cheaper and Equally Effective Alternative to Spanning External Fixation.

The purpose of this study was to evaluate damage control plating (DCP) as an alternative to external fixation (EF) in the provisional stabilization of open tibial shaft fractures. Through retrospective analysis, the study found 445 patients who underwent operative fixation for tibial shaft fractures from 2008 to 2012. Twenty patients received DCP or EF before intramedullary nailing with a minimum follow-up of 3 months. Charts and radiographs were reviewed for postoperative complications. Hospital charges were reviewed for implant costs. Nine patients (45%) with DCP and 11 patients (55%) with EF were analyzed. There was no significant difference in the complication rates. The mean implant cost of DCP was $1028, whereas mean EF construct cost was $4204. Therefore, DCP resulted in significant cost savings with no difference in complication rates, making it a valuable alternative to EF for the provisional stabilization of open tibial shaft fractures.

Risk factors for adverse cardiac events in hip fracture patients: an analysis of NSQIP data.

PURPOSE: Cardiovascular complications constitute morbidity and mortality for hip fracture patients. Relatively little data exist exploring risk factors for post-operative complications. Using the American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database, we identified significant risk factors associated with adverse cardiac events in hip fracture patients and provide recommendations for practising orthopaedists. METHODS: A cohort of 27,441 patients with hip fractures from 2006 to 2013 was identified using Current Procedural Terminology codes. Cardiac complications were defined as cardiac arrests or myocardial infarctions occurring within 30 days after surgery. Bivariate analysis was run on over 30 patient and surgical factors to determine significant associations with cardiac events. Multivariate logistical analysis was then performed to determine risk factors most predictive for cardiac events. RESULTS: Of the 27,441 hip fracture patients, 594 (2.2%) had cardiac complications within 30 days post-operatively. There was no significant association with respect to type of hip fracture surgery and adverse cardiac event rates (p = 0.545). After multivariate analysis, dialysis use (OR: 2.22, p = 0.026), and histories of peripheral vascular disease (OR: 2.11, p = 0.016), stroke (OR: 1.83, p = 0.009), COPD (OR: 1.69, p = 0.014), and cardiac disease (OR: 1.55, p = 0.017) were significantly predictive of post-operative cardiac events in all hip fracture patients. CONCLUSION: Orthopaedic trauma surgeons should be aware of cardiac disease history and atherosclerotic conditions (PVD, stroke) in risk stratifying patients to prevent cardiac complications. Our recommendations to reduce cardiac events include simple pre-operative lab-work to full-fledged cardiac work-up and referrals to specific medicine disciplines based on the specific risk factors present.

Characterizing human stem cell-derived sensory neurons at the single-cell level reveals their ion channel expression and utility in pain research.

The generation of human sensory neurons by directed differentiation of pluripotent stem cells opens new opportunities for investigating the biology of pain. The inability to generate this cell type has meant that up until now their study has been reliant on the use of rodent models. Here, we use a combination of population and single-cell techniques to perform a detailed molecular, electrophysiological, and pharmacological phenotyping of sensory neurons derived from human embryonic stem cells. We describe the evolution of cell populations over 6 weeks of directed differentiation; a process that results in the generation of a largely homogeneous population of neurons that are both molecularly and functionally comparable to human sensory neurons derived from mature dorsal root ganglia. This work opens the prospect of using pluripotent stem-cell-derived sensory neurons to study human neuronal physiology and as in vitro models for drug discovery in pain and sensory disorders.

Regional anaesthesia for hip fracture surgery is associated with significantly more peri-operative complications compared with general anaesthesia.

INTRODUCTION: Although several studies have advocated the use of regional versus general anaesthesia as a means of reducing peri-operative complications from hip fracture surgery, the ideal method of anaesthesia remains controversial. Our purpose was to investigate the association between anaesthesia type and peri-operative complications in hip fracture surgery. METHODS: From the 2005-2011 ACS-NSQIP database, all patients with operatively treated hip fractures were identified using CPT codes, and fifteen peri-operative complications were recorded and categorized as either minor or major. Rates of minor, major, and total complications by anaesthesia type were compared using chi-square and Fischer's exact tests. A multivariate model was used to determine odds of minor, major, and total complications between anaesthesia types. Multivariate analysis was then repeated after combining patients who received regional nerve blocks or spinal anaesthesia. RESULTS: A total of 7,764 hip fracture patients were included in our analysis. Spinal anaesthesia had the highest total complication rate (19.6%), followed by general (17.9%) and regional nerve blocks (12.6%). Multivariate analysis demonstrated that spinal anaesthesia was associated with significantly greater odds of minor complications and total complications compared with general anaesthesia. After combining the regional nerve block and spinal anaesthesia groups, multivariate analysis again showed significantly greater odds of minor and total complications with regional versus general anaesthesia. CONCLUSIONS: Using a large multi-centre database, we demonstrate that regional anaesthesia was associated with significantly greater odds of minor and total peri-operative complications compared with general anaesthesia. Our results challenge the notion that regional anaesthesia is the preferred method of anaesthesia for hip fractures in the elderly.

What factors influence follow-up in orthopedic trauma surgery?

BACKGROUND: Among surgical patients, follow-up visits are essential for monitoring post-operative recovery and determining ongoing treatment plans. Non-adherence to clinic follow-up appointments has been associated with poorer outcomes in many different patient populations. We sought to identify factors associated with non-attendance at follow-up appointments for orthopedic trauma patients. MATERIALS AND METHODS: A retrospective chart review at a level I trauma center identified 2,165 patients who underwent orthopedic trauma surgery from 2008 to 2009. Demographic data including age, sex, race, tobacco use, American Society of Anesthesiologist (ASA) score, insurance status, distance from the hospital, and follow-up time were collected. Injury characteristics including fracture type, anatomic location of the operation, length of hospital stay, living situation and employment status were recorded. Attendance at the first scheduled follow-up visit was recorded. Multivariable log-binomial regression analyses were used with statistical significance maintained at p < 0.05. RESULTS: Of the 2,165 patients included in the analysis, 1,449 (66.9 %) attended their first scheduled post-operative clinic visit. 33.1 % (717) were not compliant with keeping their first clinic appointment after surgery. Patients who used tobacco, lived more than 100 miles from the clinic site, did not have private insurance, had an ASA score >2, or had a fracture of the hip or pelvis were significantly less likely to follow-up. Age, sex, and race were not significantly associated with failure to follow-up. DISCUSSION: Follow-up appointments are essential for preventing complications among orthopedic trauma patients. By identifying patients at risk of failure to follow-up, orthopedic surgeons can appropriately design and implement long-term treatment plans specifically targeted for high-risk patients.

Open fractures: evidence-based best practices.

Open fracture management is a common challenge to orthopaedic trauma surgeons and a burdensome condition to the patient, health care, and entire society. Fracture-related infection (FRI) is the leading morbid complication to avoid during open fracture management because it leads to sepsis, nonunion, limb loss, and overall very poor region-specific and general functional outcomes. This review, based on a symposium presented at the 2022 OTA International Trauma Care Forum, provides a practical and evidence-based summary on key strategies to prevent FRI in open fractures, which can be grouped as optimizing host factors, antimicrobial prophylaxis, surgical site management (skin preparation, debridement, and wound irrigation), provision of skeletal stability, and soft-tissue coverage. When it is applicable, strategies are differentiated between optimal resource and resource-limited settings.

The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function - Insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation.

Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.

Does Topical Vancomycin Powder Use in Fracture Surgery Change Bacteriology and Antibiotic Susceptibilities? An Analysis of the VANCO Trial.

OBJECTIVE: To determine whether intrawound vancomycin changes the bacteriology of surgical site infection pathogens and investigate the emergence of antibiotic-resistant pathogens. DESIGN: Secondary analysis of phase III, prospective, randomized clinical trial. SETTING: Thirty-six US trauma centers. PATIENT SELECTION CRITERIA: Patients who became infected after fixation of tibial plateau or pilon fracture. OUTCOME MEASURES AND COMPARISONS: Pathogen types and bacterial susceptibilities as determined from routine clinical culture in the operating room. RESULTS: Seventy-four patients were studied who were 67.5% male with a mean age of 48.6 years. A lower proportion of gram-positive cocci was observed in the vancomycin powder compared with the standard-of-care group (3.7% vs. 8.0%, P = 0.01). Methicillin-resistant Staphylococcus aureus infection incidence was comparable in both the vancomycin powder and the standard-of-care groups, but rates of methicillin-susceptible S. aureus infections were lower in the treatment group (1.4% vs. 4.8%, P = 0.01). The incidence of coagulase-negative Staphylococci and gram-negative rod infections were similar in both groups. There was no significant difference in susceptibilities between groups in rates of vancomycin-resistant enterococcus. CONCLUSIONS: Topical vancomycin powder decreases the likelihood of gram-positive infections consistent with the biologic activity of vancomycin. Fewer methicillin-susceptible S. aureus and coagulase-negative Staphylococci infections were observed in the group treated with vancomycin powder. An effect of vancomycin powder on methicillin-resistant S. aureus infection risk was not detected given the low incidence in both the intrawound vancomycin and the standard-of-care groups. There was no emergence of gram-negative rod infections or increased resistance patterns observed. Use of topical vancomycin powder does not seem to produce infections in these patients with greater antibiotic resistance than would have occurred without its use. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Directing differentiation of human embryonic stem cells toward anterior neural ectoderm using small molecules.

Based on knowledge of early embryo development, where anterior neural ectoderm (ANE) development is regulated by native inhibitors of bone morphogenic protein (BMP) and Nodal/Activin signaling, most published protocols of human embryonic stem cell differentiation to ANE have demonstrated a crucial role for Smad signaling in neural induction. The drawbacks of such protocols include the use of an embryoid body culture step and use of polypeptide secreted factors that are both expensive and, when considering clinical applications, have significant challenges in terms of good manufacturing practices compliancy. The use of small molecules to direct differentiation of pluripotent stem cells toward a specified lineage represents a powerful approach to generate specific cell types for further understanding of biological function, for understanding disease processes, for use in drug discovery, and finally for use in regenerative medicine. We therefore aimed to find controlled and reproducible animal-component-free differentiation conditions that would use only small molecules. Here, we demonstrate that pluripotent stem cells can be reproducibly and efficiently differentiated to PAX6(+) (a marker of neuroectoderm) and OCT4(-) (a marker of pluripotent stem cells) cells with the use of potent small inhibitors of the BMP and Activin/Nodal pathways, and in animal-component-free conditions, replacing the frequently used Noggin and SB431542. We also show by transcript analysis, both at the population level and for the first time at the single-cell level, that differentiated cells express genes characteristic for the development of ANE, in particular for the development of the future forebrain.

Republication of "A Novel Casting Technique for Tongue-Type Calcaneus Fractures With Soft Tissue Compromise".

Displaced calcaneal fractures encompass a spectrum of fracture patterns, many of which are associated with soft tissue complications. Displaced tongue-type calcaneal fractures often cause pressure on the posterior heel skin, particularly when treatment is delayed. Resultant partial- or full-thickness skin necrosis presents significant challenges to the treating surgeon. In this article, the authors report on a case of full-thickness skin necrosis associated with a displaced tongue-type calcaneus fracture. The authors describe the use of a specialized heel window casting technique, which eliminates posterior heel pressure and greatly facilitates soft tissue surveillance and local wound care. The article also reviews the literature on soft tissue complications associated with displaced calcaneus fractures.

Pelvic ring injuries: recent advances in diagnosis and treatment.

Pelvic ring injuries typically occur from high-energy trauma and are often associated with multisystem injuries. Prompt diagnosis of pelvic ring injuries is essential, and timely initial management is critical in the early resuscitation of polytraumatized patients. Definitive management of pelvic ring injuries continues to be a topic of much debate in the trauma community. Recent studies continue to inform our understanding of static and dynamic pelvic ring stability. Furthermore, literature investigating radiographic and clinical outcomes after nonoperative and operative management will help guide trauma surgeons select the most appropriate treatment of patients with these injuries.

Microglial Expression of the Wnt Signaling Modulator DKK2 Differs between Human Alzheimer's Disease Brains and Mouse Neurodegeneration Models.

Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer's disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2+ microglia preferentially accumulated close to ßAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglial DKK2 upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.

Mortality Rates After Nonoperative Geriatric Hip Fracture Treatment: A Matched Cohort Analysis.

OBJECTIVE: To compare the mortality rate between geriatric patients with hip fracture treated nonoperatively and a matched cohort treated operatively. DESIGN: Retrospective Observational Matched Cohort Study. SETTING: Academic Level 1 Trauma Center. PATIENTS: Geriatric patients who sustained femoral neck and intertrochanteric/peritrochanteric fractures, excluding isolated greater trochanteric fractures. All patients older than 65 years with hip fractures over a 10-year period were identified. Operative patients were matched at a 2:1 ratio, when possible, to nonoperative patients based on Charlson Comorbidity Index and American Society of Anesthesiologists score. INTERVENTION: Nonoperative treatment or operative treatment (femoral neck fractures: cannulated screw fixation or hemiarthroplasty; intertrochanteric/peritrochanteric fractures: sliding hip screw or cephalomedullary nail fixation; or proximal femoral locking plate). MAIN OUTCOMES: Mortality calculated at 30 and 90 days, and 1-year after injury. Mortality was compared between groups using logistic regression while controlling for age, CVA/TIA, and dementia. RESULTS: Seven hundred seventy-two patients (171 nonoperative and 601 operative) were initially identified. After applying the matching algorithm, 128 nonoperative and 239 operative patients were included in the analysis. There were no significant differences in age, sex, Charlson Comorbidity Index, or American Society of Anesthesiologists score between the cohorts. Nonoperative patients had a significantly higher 1-year mortality rate than operative patients [46.1% vs. 18.0%, Odds Ratio (95% confidence interval): 3.85 (2.34-6.41), P < 0.001]. CONCLUSIONS: Geriatric patients with hip fracture treated nonoperatively had a 1-year mortality rate of 46.1%, more than double the rate among operative patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.