More Similar than Different: Memory, Executive Functions, Cortical Thickness, and Glucose Metabolism in Biomarker-Positive Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia.

Background: Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD) are typically associated with very different clinical and neuroanatomical presentations; however, there is increasing recognition of similarities. Objective: To examine memory and executive functions, as well as cortical thickness, and glucose metabolism in AD and bvFTD signature brain regions. Methods: We compared differences in a group of biomarker-defined participants with Alzheimer's disease and a group of clinically diagnosed participants with bvFTD. These groups were also contrasted with healthy controls (HC). Results: As expected, memory functions were generally more impaired in AD, followed by bvFTD, and both clinical groups performed more poorly than the HC group. Executive function measures were similar in AD compared to bvFTD for motor sequencing and go/no-go, but bvFTD had more difficulty with a set shifting task. Participants with AD showed thinner cortex and lower glucose metabolism in the angular gyrus compared to bvFTD. Participants with bvFTD had thinner cortex in the insula and temporal pole relative to AD and healthy controls, but otherwise the two clinical groups were similar for other frontal and temporal signature regions. Conclusions: Overall, the results of this study highlight more similarities than differences between AD and bvFTD in terms of cognitive functions, cortical thickness, and glucose metabolism. Further research is needed to better understand the mechanisms mediating this overlap and how these relationships evolve longitudinally.

Surface-based correlates of cognition along the Alzheimer's continuum in a memory clinic population.

Composite cognitive measures in large-scale studies with biomarker data for amyloid and tau have been widely used to characterize Alzheimer's disease (AD). However, little is known about how the findings from these studies translate to memory clinic populations without biomarker data, using single measures of cognition. Additionally, most studies have utilized voxel-based morphometry or limited surface-based morphometry such as cortical thickness, to measure the neurodegeneration associated with cognitive deficits. In this study, we aimed to replicate and extend the biomarker, composite study relationships using expanded surface-based morphometry and single measures of cognition in a memory clinic population. We examined 271 clinically diagnosed symptomatic individuals with mild cognitive impairment (N = 93) and Alzheimer's disease dementia (N = 178), as well as healthy controls (N = 29). Surface-based morphometry measures included cortical thickness, sulcal depth, and gyrification index within the "signature areas" of Alzheimer's disease. The cognitive variables pertained to hallmark features of Alzheimer's disease including verbal learning, verbal memory retention, and language, as well as executive function. The results demonstrated that verbal learning, language, and executive function correlated with the cortical thickness of the temporal, frontal, and parietal areas. Verbal memory retention was correlated to the thickness of temporal regions and gyrification of the inferior temporal gyrus. Language was related to the temporal regions and the supramarginal gyrus' sulcal depth and gyrification index. Executive function was correlated with the medial temporal gyrus and supramarginal gyrus sulcal depth, and the gyrification index of temporal regions and supramarginal gyrus, but not with the frontal areas. Predictions of each of these cognitive measures were dependent on a combination of structures and each of the morphometry measurements, and often included medial temporal gyrus thickness and sulcal depth. Overall, the results demonstrated that the relationships between cortical thinning and cognition are widespread and can be observed using single measures of cognition in a clinically diagnosed AD population. The utility of sulcal depth and gyrification index measures may be more focal to certain brain areas and cognitive measures. The relative importance of temporal, frontal, and parietal regions in verbal learning, language, and executive function, but not verbal memory retention, was replicated in this clinic cohort.

Body Mass Index (BMI) Cutoffs and Racial, Ethnic, Sex, or Age Disparities in Patients Treated With Total Ankle Arthroplasty.

Background: The rising prevalence of obesity among American adults has disproportionately affected Black adults and women. Furthermore, body mass index (BMI) has historically been used as a relative contraindication to many total joint arthroplasty (TJA) procedures, including total ankle arthroplasty. The purpose of this study was to investigate potential disparities in patient eligibility for total ankle arthroplasty based on race, ethnicity, sex, and age by applying commonly used BMI cutoffs to the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database. Methods: Patients in the ACS-NSQIP database who underwent TAA from 2011 to 2020 were retrospectively reviewed in a cross-sectional analysis. BMI cutoffs of <50, <45, <40, and <35 were then applied. The eligibility rate for TAA was examined for each BMI cutoff, and findings were stratified by race, ethnicity, sex, and age. Independent t tests, chi-squared tests, and Fisher exact tests were performed to compare differences at an α = 0.05. Results: A total of 1215 of 1865 TAA patients (65.1%) were included after applying the exclusion criteria. Black patients had disproportionately lower rates of eligibility at the most stringent BMI cutoff of <35 (P = .004). Hispanic patients had generally lower rates of eligibility across all BMI cutoffs. In contrast, Asian American and Pacific Islander patients had higher rates of eligibility at the BMI cutoffs of <35 (P = .033) and <40 (P = .039), and White non-Hispanic patients had higher rates of eligibility across all BMI cutoffs. Females had lower eligibility rates across all BMI cutoffs. Ineligible patients were also younger compared to eligible patients across all BMI cutoffs. Conclusion: Stringent BMI cutoffs may disproportionately disqualify Black, female, and younger patients from receiving total ankle arthroplasty. Level of Evidence: Level III, retrospective cross-sectional study.

Non-emergent Conditions of the Ankle, Hindfoot, and Midfoot in Elderly Patients Are as Mobility Limiting as Congestive Heart Failure.

BACKGROUND: Mobility limitations are well linked to increased morbidity and mortality. Older patients with chronic pathologies of the foot and ankle can suffer from significant mobility limitations; however, the magnitude of limitation experienced by this cohort is not well characterized. Conversely, the effects of congestive heart failure (CHF) on patient mobility are routinely assessed via the New York Heart Association (NYHA) classification. New York Heart Association classification is determined by a patient's physical activity limitation and is strongly correlated to functional status. We hypothesized that non-emergent conditions of the foot and ankle would be as mobility limiting as CHF. METHODS: Life-Space Mobility Assessments (LSAs) were prospectively collected from orthopaedic patients at their preoperative visits and from CHF patients at a cardiology clinic. Patients over the age of 50 years were included in this study. Congestive heart failure patients NYHA class II or greater were included. The non-emergent foot and ankle cohort included Achilles tendonitis, ankle joint cartilage defects, ankle arthritis, subtalar arthritis, and midfoot arthritis. Patient demographics and LSA scores were analyzed using Mann-Whitney U and chi-squared tests. RESULTS: A total of 96 elderly, non-emergent foot and ankle operative patients and 45 CHF patients met inclusion criteria. All medical comorbidities, except smoking status, were significantly more prevalent in the CHF cohort. No statistical difference was observed between CHF and preoperative foot and ankle LSA scores (56.1 vs 62.4, P = .320). Life-Space Mobility Assessment scores in the foot and ankle cohort were significantly improved relative to CHF patients, at 6-month and 1-year postoperative visits (P = .028, P < .0001, respectively). CONCLUSION: Non-emergent ankle, hindfoot, and midfoot pathology is associated with similar mobility limitation to that of NYHA class II and III CHF. Older patients undergoing elective foot and ankle procedures exceeded the mobility of CHF patients at 6 months post-operation, and the mobility gains persisted at 1-year post-operation. LEVELS OF EVIDENCE: Level II: Prospective cohort study.

The Rise of Total Ankle Arthroplasty Use: A Database Analysis Describing Case Volumes and Incidence Trends in the United States Between 2009 and 2019.

BACKGROUND: Ankle arthrodesis has been the mainstay treatment for end-stage ankle arthritis. The popularity of total ankle arthroplasty (TAA) has been on the rise due to improved implant design and postoperative outcomes. The purpose of this study was to describe the basic epidemiology and trends of annual procedure volumes and incidence in the general American population as well as in different population subgroups from 2009 to 2019. We hypothesize that the incidence of TAA has significantly risen while the median length of hospital stay has decreased nationwide. METHODS: The IBM MarketScan database was queried for patients who underwent TAA from January 2009 to December 2019 based on Current Procedural Terminology coding. Population estimates from the US Census Bureau were used to calculate the annual incidence of TAA. Procedural volume and incidence were calculated for annual sums, gender, age subgroups, inpatient and outpatient TAA, as well as in four statistical geographic regions in the United States. Median length of hospital stay was calculated and trended annually for inpatient TAA. RESULTS: A total of 41,060 primary TAAs were identified in the database from 2009 to 2019, in which 52.5% were performed in males. Annual volumes increased by 136.1%, from 2180 to 5147 procedures nationwide. Incidence reported per 100 000 population increased by 120.8%. Both inpatient and outpatient procedures have increased, by 242.5% and 86.6%, respectively. Median length of hospital stay decreased from 3 days in 2009 to 1 day in 2019 and did not differ between genders. Growth in incidence was demonstrated in males and females above the age of 54 years with the largest growth in annual incidence found between 65 and 74 years. Incidence rose in the South and West of the United States by 111.8% and 136.5%, respectively. CONCLUSION: We found that annual volumes and incidence rates of primary TAA has increased between 2009 and 2019. Although both inpatient and outpatient surgery have become more frequent, inpatient volumes and incidence have increased almost 3 times more than those of outpatient surgery. Length of hospital stay decreased over the study years. When adjusted for the same study period, the cumulative annual growth rates of TAA were found to be 2 times greater than total knee arthroplasty and 3.6 times greater than total hip arthroplasty. LEVEL OF EVIDENCE: Level III, retrospective database review.

Effect of Obesity on Patient-Perceived Outcomes After First Metatarsophalangeal Joint Arthrodesis.

BACKGROUND: While first metatarsophalangeal joint (MTPJ) arthrodesis is a common and effective procedure, there is a paucity of studies examining obesity's effect on outcomes of 1st MTPJ arthrodesis. This study's purpose was to evaluate patient-reported outcomes following 1st MTPJ arthrodesis in obese versus non-obese patients. METHODS: A retrospective cohort study of 94 patients undergoing first MTPJ fusion over the age of 18 with a diagnosis of hallux valgus or hallux rigidus was performed. Surgical and postoperative outcomes were examined preoperatively and at 6 and 12 months follow-up via Visual Analog Pain scale (VAS), and Short Form 36 (SF-36) surveys, and data were stratified into 2 patient groups: BMI < 30 (n = 62, mean age 63.9 ± 9.1 and ≥ 30 (n = 32, mean age 61.9 ± 8.4). RESULTS: Average overall VAS and SF-36 physical component scores improved significantly at 6 months (P < .001, .006) and 1 year postoperative visits (P < .001, .007) with no differences in survey scores, outcomes, or complications between weight groups. CONCLUSION: Our study showed first MTPJ fusion improves short-term pain and physical quality-of-life in arthritic obese and non-obese patients without differences in nonunion, complications, or patient-reported measures. LEVEL OF EVIDENCE: Level III, Prognostic, Case-Control Study.

Preoperative Depression is Associated With Increased Complications Following Ankle Fracture Surgery.

BACKGROUND: The effects of preoperative depression following ankle fracture surgery remains unknown. The purpose of this study is to investigate the relationship between preoperative depression and outcomes following ankle fracture surgery. METHODS: This retrospective study used the Truven MarketScan database to identify patients who underwent ankle fracture surgery from January 2009 to December 2018. Patients with and without a diagnosis of preoperative depression were identified based on International Classification of Diseases (ICD) codes. Chi-squared and multivariate analyses were performed to determine the association between preoperative depression and postoperative complications following ankle fracture surgery. RESULTS: In total, 107,897 patients were identified for analysis, 13,981 of whom were diagnosed with depression (13%). Preoperative depression was associated with the increased odds for postoperative infection (odds ratio [OR]: 1.33, confidence interval [CI]: 1.20-1.46), wound complications (OR: 1.13, CI: 1.00-1.28), pain-related postoperative emergency department visits (OR: 1.58, CI: 1.30-19.1), 30-day and 90-day readmissions (OR: 1.08, CI: 1.03-1.21 and OR: 1.13, CI: 1.07-1.18), sepsis (OR: 1.39, CI: 1.12-1.72), and postoperative development of complex regional pain syndrome (OR: 1.46, CI: 1.18-1.81). CONCLUSION: Preoperative depression is associated with increased complications following ankle fracture surgery. Further studies are warranted to investigate the degree to which depression is a modifiable risk factor. LEVEL OF EVIDENCE: 3.

What Is the Interrater and Intrarater Reliability of the Lawrence and Botte Classification System of Fifth Metatarsal Base Fractures?

BACKGROUND: Fractures of the proximal fifth metatarsal are common, and often they are classified using a three-part scale first proposed by Lawrence and Botte. A clear consensus on prognosis and treatment for these fractures is lacking, particularly for fractures in the middle classification, Zone 2; the reliability of the classification scheme itself may be partly at fault for this. The intra- and interrater reliability of the classification itself has never been established, and it remains unclear whether the three-part classification of fifth metatarsal fractures can be applied consistently enough to guide treatment. QUESTIONS/PURPOSES: When used by experienced orthopaedic surgeons, (1) What is the overall interrater reliability of the three-part Lawrence and Botte classification of fifth metatarsal base fractures? (2) What is the overall intrarater reliability of the three-part Lawrence and Botte classification of fifth metatarsal base fractures? (3) What are these same metrics for the individual transitions within the classification (Zone 1-2 and Zone 2-3)? METHODS: Thirty sets of initial presentation radiographs representing an equal number of fractures originally diagnosed by treating clinicians as Zone 1, Zone 2, and Zone 3 were evaluated and classified by three orthopaedic surgeons specializing in foot and ankle surgery and eight foot and ankle fellows to determine interrater reliability. Two weeks later, the same set of radiographs were reevaluated in random order to determine intrarater reliability. Kappa values for interrater and intrarater reliability were calculated. Additionally, the individual transitions between zones were separately analyzed by calculating kappa values for a hypothetical two-part classification based on each transition. RESULTS: The three-part Lawrence and Botte classification of fifth metatarsal fractures demonstrated an overall interrater agreement of κ = 0.66 (observed agreement 77% versus chance agreement 33%). Intrarater reliability for the 11 surgeons ranged from κ = 0.60 to κ = 0.90. A two-part scheme divided by the transition between Zone 1 and Zone 2 demonstrated an interrater agreement of κ = 0.83, and a two-part scheme divided by the transition between Zone 2 and Zone 3 demonstrated a much lower interrater reliability of κ = 0.66. CONCLUSION: The three-part Lawrence and Botte classification system demonstrated a concerningly low level of interrater reliability with an observed agreement of 77% compared with a chance agreement of 33%. The primary source of concern is the assessment of the interface between Zone 2 and Zone 3, which proved much less reliable than that between Zone 1 and Zone 2. This suggests that previous studies of isolated Zone 1 fractures likely contain a homogeneous fracture cohort, whereas studies of Zone 2 or Zone 3 fractures are likely to include a mixture of fracture types. In practice, the consensus treatment of fifth metatarsal fractures differs based on whether they represent a more proximal, avulsive injury or a more distal injury from indirect trauma. Our data suggest that the Lawrence and Botte classification should be abandoned. Further work should focus on developing a new classification scheme that demonstrates improved interobserver reliability and more directly corresponds to this treatment paradigm. LEVEL OF EVIDENCE: Level III, diagnostic study.

Is Arthrodesis Sufficient in the Setting of Complex, Severe and Rigid Progressive Collapsing Foot Deformities?

Arthrodesis of the hindfoot is typically used for the correction of severe and arthritic progressive collapsing foot deformity. Concomitant bony or soft tissue procedures may be helpful in patients with congenital abnormalities including the ball-and-socket ankle or congenital vertical talus. Dysplasia of the hindfoot bones may be more common than previously recognized, and corrective procedures or alterations in technique may need to be performed during hindfoot arthrodesis to account for bony deformity. Intraarticular osteotomies, extraarticular osteotomies, tendon lengthening, and tendon transfer procedures may be used in specific instances to aid in deformity correction and improve overall function.

Radiographic Outcomes of Cotton Osteotomy in Treatment of Adult-Acquired Flatfoot Deformity.

BACKGROUND: We investigated the long-term radiographic outcomes of the Cotton osteotomy performed at our institution by the 2 senior authors in conjunction with other reconstruction procedures to correct adult-acquired flatfoot deformity (AAFD). METHODS: We retrospectively studied patients who underwent Cotton osteotomy between 2005 and 2010 with minimum 4-year follow-up. Radiographic assessment was made on weightbearing radiographs taken at 4 different time intervals: preoperative, early (first postoperative full weightbearing), intermediate (between 1 and 4 years postoperatively), and final (over 4 years postoperatively). RESULTS: Nineteen patients were included. Final follow-up was 8.6 ± 2.6 years. The lateral talus-first metatarsal angle improved significantly from preoperative to early radiographs (n = 15; mean change: 30 degrees, 95% CI, 21.6-38.7; P < .0001). A significant loss of correction was observed between intermediate and final radiographs (n = 11; mean change: 17 degrees, 95% CI, 8.1-26.4; P < .0001). Of 14 patients with early radiographs, 8 lost >50% of the correction initially achieved. Medial column height decreased by 3.0 mm (95% CI, 1.80-7.90; P = .35) between early radiographs and final follow-up. DISCUSSION: This is the longest reported radiographic follow-up of the Cotton osteotomy performed to address forefoot varus deformity as part of AAFD. The Cotton osteotomy achieved radiographic correction of the medial longitudinal arch at early follow-up, but approximately half of the patients had lost over 50% of that correction at final follow-up. The lengthened angular shape of the cuneiform did not collapse, implying that further collapse occurred through the medial column joints. LEVEL OF EVIDENCE: Level IV, case series.

Risk Factors for Complications Associated With Minimally Invasive Medial Displacement Calcaneal Osteotomy.

BACKGROUND: Few studies have reported the outcomes following minimally invasive medial displacement calcaneal osteotomy (MDCO) for correction of pes planovalgus deformities. METHODS: Charts were retrospectively reviewed for consecutive patients who underwent minimally invasive MDCO procedures by a single surgeon from 2013 to 2019 with more than 3 months of follow-up. A total of 160 consecutive patients who underwent 189 minimally invasive MDCO procedures were included in the study. Median follow-up was 12 months (interquartile range, 7-25 months). RESULTS: Osteotomy healing complications were present in 7% of cases during the 6-year study period. A 12-month case cluster of osteotomy healing complications was observed. Healing complication rates were 28% during the cluster and 0.7% outside of the cluster. No definitive cause was found for the case cluster, although heat osteonecrosis from the burr was suspected to be involved. Osteotomy healing complications were significantly associated with higher American Society of Anesthesiologists (ASA) classification, female sex, current tobacco use, and higher body mass index (BMI). Healing complications were not associated with osteotomy technique or fixation type. Other complications included wound dehiscence (3%), surgical site infection (2%), transient nerve symptoms (6%), and persistent nerve symptoms (2%). Nerve symptoms were significantly associated with an increased number of concomitant procedures. CONCLUSION: Patients with higher ASA classification, current tobacco use, and higher BMI were at higher risk for osteotomy healing complications after minimally invasive MDCO procedures. Patients were also more likely to develop nerve complications with more extensive surgical procedures. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Load to Failure and Stiffness of Interference Screw vs Pulvertaft Weave for Distal Fixation in Peroneal Allograft Reconstruction.

BACKGROUND: Allograft reconstruction of the peroneal tendons is an option for treatment of major tears of 1 or both peroneal tendons. No consensus on a superior distal fixation method has been reported. The purpose of the study was to compare load to failure and stiffness of a Pulvertaft weave (PTW) through a residual tendon stump to direct-to-bone interference screw (IS) fixation. METHODS: Fifteen pairs of long leg cadaver specimens were used. All grafts were secured proximally to the peroneus brevis myotendinous junction via a PTW technique. Distally, the tendons were either sutured to the peroneus brevis stump via PTW or secured to the base of the fifth metatarsal via IS. Stiffness (slope of force/displacement) was measured for the intact tendon and after reconstruction, and finally each specimen was loaded to failure. RESULTS: Mean load to failure was significantly higher in the PTW group compared with the IS group (373.6 ± 265.5 N vs 150.1 ± 93.1 N; P = .01). The PTW and IS groups had significantly lower stiffness compared with the intact specimens (P < .001). There was no statistical significance in stiffness between the 2 techniques (P = .96). CONCLUSION: The PTW technique yielded higher load to failure in comparison to IS. There was no difference in overall construct stiffness between both techniques. Both constructs demonstrated 19% decrease in stiffness compared to the intact state. CLINICAL RELEVANCE: The PTW and IS constructs were biomechanically similar, and these results suggest that both should be moderately overtensioned to compensate for an inherent decreased initial stiffness.

Risk factors for hardware removal following operative treatment of middle- and distal-third clavicular fractures.

BACKGROUND: The incidence of hardware removal (HWR) after operative fixation of clavicular fractures varies widely. Risk factors related to HWR remain incompletely understood. The aim of this study was to evaluate the incidence of and risk factors for HWR after plate fixation of middle- and distal-third clavicular fractures. We hypothesized that (1) the total HWR incidence would be <20%, (2) the HWR incidence of operatively treated distal- and middle-third clavicular fractures would not be statistically different, and (3) symptomatic implants would be the most common HWR indication. METHODS: We performed a multi-hospital retrospective study of skeletally mature patients who underwent plate fixation of middle- and distal-third clavicular fractures from November 2008 to November 2018. Data included patient demographic characteristics, mechanism of injury, operative records, hardware-related symptoms, subsequent HWR, and complications. RESULTS: A total of 103 patients (aged 16-75 years, 76.7% male patients) were included. Of the patients, 87 (84.5%) underwent plate fixation for midshaft clavicular fractures and 16 (15.5%) underwent plate fixation for distal-third clavicular fractures. HWR was performed in 13 patients (12.6%). A significantly higher percentage of HWR procedures were performed for distal clavicular fractures (50%) than for middle-third clavicular fractures (4.9%, P < .0001). An initial high-energy mechanism of injury was associated with HWR (P = .0025). The most common indication for HWR was symptomatic hardware (69.2%). The overall complication rate was 14.5%. CONCLUSION: The overall incidence of clavicular HWR was 12.6%. A distal fracture location was associated with a significantly higher incidence of HWR. An initial high-energy mechanism of injury was a significant risk factor for HWR. The primary indication for HWR was symptomatic hardware.

Jones Fracture in the Nonathletic Population.

Fractures of the proximal fifth metatarsal are common injuries with a unique history. Treatment of these fractures is controversial partly because of confusion regarding fracture subtype nomenclature. Today "Jones fracture" refers to proximal fifth metatarsal fracture in zones 2 or 3. Zone 2 fractures are acute injuries, and their optimal treatment is unclear. Zone 3 fractures commonly occur in the presence of a chronic stress reaction. Because of poor healing potential, zone 3 fractures typically require operative treatment. Zone 1 fractures have excellent healing potential and may be treated nonoperatively with a weightbearing as tolerated protocol.

Early Experience and Results Using Patient-Reported Outcomes Measurement Information System Scores in Primary Total Hip and Knee Arthroplasty.

BACKGROUND: Our study determined if preoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores could predict achieving minimum clinically important differences (MCIDs) in postoperative PROMIS scores after primary total hip and knee arthroplasty. METHODS: Ninety-three patients were administered the PROMIS Depression, Pain Interference, and Physical Function domains at their preoperative appointment and 6-week follow-up visit. MCIDs were drawn from existing literature for the PROMIS domains. RESULTS: The MCID was achieved in 74% of patients for Pain Interference, 34% for Physical Function, and 24% for Depression. Our model could predict with 90% specificity which patients would meet MCID if their preop PROMIS Pain score was above 38, Physical Function score less than 19, or Depression score above 22. CONCLUSION: Preoperative PROMIS Pain Interference, Physical Function, and Depression scores can predict achieving MCID in postoperative PROMIS scores.

All-trans Retinoic Acid Augments Autophagy during Intracellular Bacterial Infection.

Vitamin A deficiency strongly predicts the risk of developing tuberculosis (TB) in individuals exposed to Mycobacterium tuberculosis (Mtb). The burden of antibiotic-resistant TB is increasing globally; therefore, there is an urgent need to develop host-directed adjunctive therapies to treat TB. Alveolar macrophages, the niche cell for Mtb, metabolize vitamin A to all-trans retinoic acid (atRA), which influences host immune responses. We sought to determine the mechanistic effects of atRA on the host immune response to intracellular bacterial infection in primary human and murine macrophages. In this study, atRA promoted autophagy resulting in a reduced bacterial burden in human macrophages infected with Mtb and Bordetella pertussis, but not bacillus Calmette-Guérin (BCG). Autophagy is induced by cytosolic sensing of double-stranded DNA via the STING/TBK1/IRF3 axis; however, BCG is known to evade cytosolic DNA sensors. atRA enhanced colocalization of Mtb, but not BCG, with autophagic vesicles and acidified lysosomes. This enhancement was inhibited by blocking TBK1. Our data indicate that atRA augments the autophagy of intracellular bacteria that trigger cytosolic DNA-sensing pathways but does not affect bacteria that evade these sensors. The finding that BCG evades the beneficial effects of atRA has implications for vaccine design and global health nutritional supplementation strategies. The ability of atRA to promote autophagy and aid bacterial clearance of Mtb and B. pertussis highlights a potential role for atRA as a host-directed adjunctive therapy.

Cigarette smoking impairs human pulmonary immunity to Mycobacterium tuberculosis.

RATIONALE: Cigarette smoking is linked to important aspects of tuberculosis, such as susceptibility to infection, disease reactivation, mortality, transmission, and persistent infectiousness. The mechanistic basis for this remains poorly understood. OBJECTIVES: To compare the functional impairment seen in human alveolar macrophages (AM) from nonsmokers, smokers, and ex-smokers after infection with Mycobacterium tuberculosis (Mtb). METHODS: AM were acquired at bronchoscopy, and number and viability from smoking donors were compared with nonsmoking donors. AM were challenged in vitro with Mtb and intracellular bacterial viability was measured. Cytokine secretion was measured 24 hours postinfection by ELISA. Previously we determined the frequency of CD4(+)FoxP3(+) T cells in the presence or absence of allogeneic AM, and data were reanalyzed to separate the patient subjects according to smoking status. MEASUREMENTS AND MAIN RESULTS: There were significantly more AM from smokers compared with nonsmokers or ex-smokers (P < 0.01). AM from smokers could not control intracellular Mtb growth. Nonsmokers' AM generated significantly more tumor necrosis factor (TNF)-α, IFN-γ, and IL-1ß after Mtb infection compared with uninfected AM (P < 0.05). However, Mtb-infected AM from smokers did not secrete significantly more TNF-α, IFN-γ, and IL-1ß compared with uninfected smokers' AM. AM taken from ex-smokers also failed to secrete significantly increased TNF-α, IFN-γ, and IL-1ß after Mtb infection. Both smokers' and nonsmokers' AM induced FoxP3(+) T regulatory cell phenotype responses in allogeneic admixed T cells (>4.8 fold; P < 0.05). Even after Mtb infection, AM continued to drive this regulatory phenotype. CONCLUSIONS: In smokers, the pulmonary compartment has a number of macrophage-specific immune impairments that provide some mechanistic explanations whereby cigarette smoking renders a patient susceptible to tuberculosis infection and disease.

Injury type and emergency department management of orthopaedic patients influences follow-up rates.

BACKGROUND: Orthopaedic clinic follow-up is required to ensure optimal management and outcome for many patients who present to the emergency department (ED) with an orthopaedic injury. While several studies have shown that demographic variables influence patient follow-up after discharge from the ED, the objective of this study was to examine orthopaedic-related and other factors associated with the failure to return for orthopaedic outpatient management, so-called "no-show," after an ED visit. METHODS: A chart review was conducted at a large academic public hospital. Four hundred and sixty-four consecutive adult patients who received an orthopaedic consult in the ED with subsequent referral to the orthopaedic clinic from January through June, 2011, were included. With use of chi-square and Mann-Whitney univariate tests, data regarding injury type and management were analyzed for association with no-show. Variables with p < 0.25 were included in a multivariate stepwise forward logistic regression analysis. RESULTS: The overall no-show rate was 26.1%. Logistic regression modeling revealed significant differences in no-show rates based on cause of injury (odds ratio [OR] 7.51; 95% confidence interval [CI], 2.27 to 25.1), with assault victims having the highest no-show rate. Anatomic region of injury significantly influenced no-show rates (OR 6.61; 95% CI, 1.45 to 30.5), with patients with a spine or back complaint having the highest no-show rate. Follow-up rates were influenced by the orthopaedic resident provider consulted (OR 10.8; 95% CI, 4.11 to 31.1), and this was not related to level of training (p = 0.25). The type of bracing applied influenced the no-show rate (OR 2.46; 95% CI, 1.58 to 3.96), and the easier it was to remove the brace (splint), the worse the follow-up (p = 0.0001). Several demographic variables were also predictive of clinic nonattendance, including morbid obesity (OR 15.0; 95% CI, 4.83 to 51.6) and current tobacco use (OR 5.56; 95% CI, 2.19 to 15.4). CONCLUSIONS: This study supports previous evidence of high no-show rates with scheduled orthopaedic follow-up among patients treated in the ED. The data highlight distinct orthopaedic-related factors associated with nonattendance. These findings are useful in identifying patients at high risk for no-show to scheduled orthopaedic follow-up appointments and may influence disposition and management decisions for these patients.

Outcomes in the management of adult soft tissue sarcomas.

Adult soft tissue sarcomas (STSs) are heterogeneous neoplasms that account for 11,410 new diagnoses and 4,390 deaths per year. This article summarizes recent NCCN guidelines for diagnosis and management of STSs of the extremities and retroperitoneum, as well as gastrointestinal stromal tumors (GIST). AJCC staging and recently reported NCDB data regarding outcomes are reviewed. Currently accepted STS prognostic variables are presented, as are future directions regarding the utility of molecular prognosticators and nomograms.