Assessing Bias in Cognitive Testing for Older Adults with Sensory Impairment: An Analysis of Differential Item Functioning in the Baltimore Longitudinal Study on Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

OBJECTIVES: Vision and hearing impairments affect 55% of people aged 60+ years and are associated with lower cognitive test performance; however, tests rely on vision, hearing, or both. We hypothesized that scores on tests that depend on vision or hearing are different among those with vision or hearing impairments, respectively, controlling for underlying cognition. METHODS: Leveraging cross-sectional data from the Baltimore Longitudinal Study of Aging (BLSA) and the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS), we used item response theory to test for differential item functioning (DIF) by vision impairment (better eye presenting visual acuity worse than 20/40) and hearing impairment (better ear .5-4 kHz pure-tone average > 25 decibels). RESULTS: We identified DIF by vision impairment for tests whose administrations do not rely on vision [e.g., Delayed Word Recall both in ARIC-NCS: .50 logit difference between impaired and unimpaired (p = .04) and in BLSA: .62 logits (p = .02)] and DIF by hearing impairment for tests whose administrations do not rely on hearing [Digit Symbol Substitution test in BLSA: 1.25 logits (p = .001) and Incidental Learning test in ARIC-NCS: .35 logits (p = .001)]. However, no individuals had differences between unadjusted and DIF-adjusted measures of greater than the standard error of measurement. CONCLUSIONS: DIF by sensory impairment in cognitive tests was independent of administration characteristics, which could indicate that elevated cognitive load among persons with sensory impairment plays a larger role in test performance than previously acknowledged. While these results were unexpected, neither of these samples are nationally representative and each has unique selection factors; thus, replication is critical.

The effect of missing data and imputation on the detection of bias in cognitive testing using differential item functioning methods.

BACKGROUND: Item response theory (IRT) methods for addressing differential item functioning (DIF) can detect group differences in responses to individual items (e.g., bias). IRT and DIF-detection methods have been used increasingly often to identify bias in cognitive test performance by characteristics (DIF grouping variables) such as hearing impairment, race, and educational attainment. Previous analyses have not considered the effect of missing data on inferences, although levels of missing cognitive data can be substantial in epidemiologic studies. METHODS: We used data from Visit 6 (2016-2017) of the Atherosclerosis Risk in Communities Neurocognitive Study (N = 3,580) to explicate the effect of artificially imposed missing data patterns and imputation on DIF detection. RESULTS: When missing data was imposed among individuals in a specific DIF group but was unrelated to cognitive test performance, there was no systematic error. However, when missing data was related to cognitive test performance and DIF group membership, there was systematic error in DIF detection. Given this missing data pattern, the median DIF detection error associated with 10%, 30%, and 50% missingness was -0.03, -0.08, and -0.14 standard deviation (SD) units without imputation, but this decreased to -0.02, -0.04, and -0.08 SD units with multiple imputation. CONCLUSIONS: Incorrect inferences in DIF testing have downstream consequences for the use of cognitive tests in research. It is therefore crucial to consider the effect and reasons behind missing data when evaluating bias in cognitive testing.

Empirical Treatment of Uncomplicated Septic Olecranon Bursitis Without Aspiration.

PURPOSE: Although aspiration of septic olecranon bursitis is recommended in the literature, no high-level evidence exists to support this practice. The purpose of this study was to retrospectively compare the results of traditional bursal aspiration (TBA) with empirical management without aspiration (EM). We hypothesized that EM of uncomplicated septic olecranon bursitis results in resolution, with fewer chronic draining sinuses and less progression to bursectomy. METHODS: We performed a retrospective review of all cases of septic olecranon bursitis seen by the orthopedic surgery department at a single tertiary referral center over a 5-year period. Cases were manually reviewed to determine patient demographics, management, and treatment results. The primary outcome was success of nonsurgical management versus requirement for surgical bursectomy. RESULTS: Thirty cases of uncomplicated septic olecranon bursitis were identified within the study period. Eleven patients were initially managed with TBA (performed by an emergency or primary care physician prior to orthopedic consultation), resulting in 11 positive cultures. Only 1 of these prompted a change of antibiotic management, and despite this information, 5 patients required a second course of antibiotics for incomplete resolution. Eight of the TBA cases went on to bursectomy. Nineteen patients underwent EM. Sixteen of these cases resolved with a single course of empirical antibiotics, and 3 (16%) cases required a second antibiotic course. One patient had a recurrence of symptoms 2 months after resolution with a single course of empirical antibiotics. This resolved with a second course of oral antibiotics. No patients who underwent EM went on to require bursectomy. The number needed to harm when aspiration was performed was 1.46. CONCLUSIONS: We found EM of uncomplicated septic olecranon bursitis to be effective. Although 1 recurrence did occur in the EM group, no other complications occurred. Empirical management without aspiration may be considered in cases of uncomplicated septic olecranon bursitis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

No difference in torque load to failure between split anconeus fascia transfer and autograft palmaris longus tendon for reconstruction of the lateral ulnar collateral ligament.

Background: The split anconeus fascia transfer (SAFT) is an option for reconstruction of the lateral ulnar collateral ligament (LUCL) in chronic posterolateral rotatory instability (PLRI) of the elbow with potential advantages of using only local tissue within the surgical exposure and not requiring ulnar fixation. This study aimed to assess SAFT strength compared to a traditional free graft reconstruction in a PLRI biomechanical model. Methods: To measure biomechanical strength, eight cadaveric upper extremity pairs were utilized. Within each pair, one specimen was randomly assigned to LUCL reconstruction with autograft palmaris longus and the other to SAFT reconstruction. Torque load to failure was assessed on a load frame with the elbow in 30 degrees of flexion, 5 degrees of valgus, and 25 N axial load as the elbow was brought into external rotation. Torque load to failure was compared between the two reconstruction techniques. Results: No difference was found in the torque load to failure between SAFT specimens compared to palmaris longus autograft specimens (mean 14.6 ± 4.4 Nm vs. mean 11.3 ± 3.9 Nm; P = .16). Discussion: In this biomechanical study, the SAFT LUCL reconstruction provided torque load to failure similar to that of the traditional technique. These findings suggest that the SAFT technique warrants continued study as a biomechanically sound option for LUCL reconstruction in the setting of elbow PLRI.

Correlation of stress radiographs to injuries associated with lateral ankle instability.

BACKGROUND: Stress radiographs have demonstrated superior efficacy in the evaluation of ankle instability. AIM: To determine if there is a degree of instability evidenced by stress radiographs that is associated with pathology concomitant with ankle ligamentous instability. METHODS: A retrospective review of 87 consecutive patients aged 18-74 who had stress radiographs performed at a single institution between 2014 and 2020 was performed. These manual radiographic stress views were then correlated with magnetic resonance imaging and operative findings. RESULTS: A statistically significant association was determined for the mean and median stress radiographic values and the presence of peroneal pathology (P = 0.008 for tendonitis and P = 0.020 for peroneal tendon tears). A significant inverse relationship was found between the presence of an osteochondral defect and increasing degrees of instability (P = 0.043). CONCLUSION: Although valuable in the clinical evaluation of ankle instability, stress radiographs are not an independent predictor of conditions associated with ankle instability.

Carpal Tunnel Syndrome in Military Aviators.

INTRODUCTION: The incidence of carpal tunnel syndrome (CTS) is increased in occupations exposed to repetitive motion, poor wrist posture, and vibration exposure. While all pilots are exposed to these factors, helicopter pilots are especially exposed to vibration. The study is to identify the incidence and risk factors for CTS in military aviators. MATERIALS AND METHODS: Clearance was obtained from Tripler Army Medical Center IRB. The Defense Medical Epidemiological Database was queried for all new cases of CTS from 2006 to 2015. Incidence rates (IRs) were determined for helicopter pilots, fixed-wing pilots, and nonpilot officers. Poisson regression analysis was used to calculate adjusted IR in order to control for demographic factors. Race was also taken into account, where pilots would classify themselves into a white or non-white race, defined by each individual. Race was assessed in the study to see if there were any differences in IR of CTS between white and non-white pilots. RESULTS: We identified 7,398 new cases of CTS among 2,319,352 person-years within the study period. Increasing age, female gender, and non-white race were significantly correlated with higher IR. Fixed-wing pilots demonstrated significantly lower adjusted IR than nonpilot officers in each age group. Helicopter pilots demonstrated higher IR than fixed-wing pilots in each age group. Helicopter pilots had lower incidence of CTS early in their career compared to nonpilot officers, but by age 40+, their IR ratio was significantly higher (1.21). CONCLUSION: Analysis of the database indicates that fixed-wing pilot status is a protective factor against development of CTS among U.S. military officers. In contrast, helicopter pilots were found to be at an increased rate of CTS than their fixed-wing counterparts. Their incidence is comparable to their nonpilot officer peers early in their career, but is significantly increased at the senior level. Increasing age and female gender are risk factors in the military officer population as expected. Non-white race was found to increase risk in the military population, in contrast to reports of the civilian population.

A Preligamentous Variant of the Thenar Motor Branch of the Median Nerve.

We report a rare variant of the thenar motor branch (TMB) of the median nerve. A preligamentous TMB was discovered during revision carpal tunnel release in a 49-year-old man. The prevalence and characteristics of TMB variations are discussed. The literature describing iatrogenic injury to the TMB variants, surgical treatment, and preoperative screening tools is reviewed. Recognition of anatomic variants of the TMB is essential considering notable consequences of iatrogenic injury.

Anatomic Double Bundle Posterior Cruciate Ligament Reconstruction Using an Internal Splint.

Techniques for reconstruction of posterior cruciate ligament (PCL) tears are rapidly evolving. One problem with current techniques is that laxity may develop early in the postoperative period, leading to relapsed posterior translation of the tibia. Therefore, maintaining tibial reduction during graft incorporation is a target for improvement. We describe using an internal splint to optimize the 4-tunnel, double-bundle allograft PCL reconstruction.

Milestones in the development and implementation of FRET-based sensors of intracellular signals: A biological perspective of the history of FRET.

FÓ§rster resonance energy transfer (FRET) has been described for more than a century. FRET has become a mainstay for the study of protein localization in living cells and tissues. It has also become widely used in the fields that comprise cellular signaling. FRET-based probes have been developed to monitor second messenger signals, the phosphorylation state of peptides and proteins, and subsequent cellular responses. Here, we discuss the milestones that led to FRET becoming a widely used tool for the study of biological systems: the theoretical description of FRET, the insight to use FRET as a molecular ruler, and the isolation and genetic modification of green fluorescent protein (GFP). Each of these milestones were critical to the development of a myriad of FRET-based probes and reporters in common use today. FRET-probes offer a unique opportunity to interrogate second messenger signals and subsequent protein phosphorylation - and perhaps the most effective approach for study of cAMP/PKA pathways. As such, FRET probes are widely used in the study of intracellular signaling pathways. Yet, somehow, the potential of FRET-based probes to provide windows through which we can visualize complex cellular signaling systems has not been fully reached. Hence we conclude by discussing the technical challenges to be overcome if FRET-based probes are to live up to their potential for the study of complex signaling networks.

Early vs Delayed Weightbearing After Microfracture of Osteochondral Lesions of the Talus: A Prospective Randomized Trial.

BACKGROUND: Osteochondral lesions of the talus (OLTs) are common injuries in young, active patients. Microfracture is an effective treatment for lesions less than 150 mm2 in size. Most commonly employed postoperative protocols involve delaying weightbearing for 6 to 8 weeks (DWB), though one study suggests that early weightbearing (EWB) may not be detrimental to patient outcomes. The goal of this research is to compare outcomes following EWB and DWB protocols after microfracture for OLTs. METHODS: We performed a prospective, randomized, multicenter clinical trial of subjects with unilateral, primary, unifocal OLTs treated with microfracture. Thirty-eight subjects were randomized into EWB (18 subjects) and DWB (20 subjects) at their first postsurgical visit. The EWB group began unrestricted WB at that time, whereas the DWB group were instructed to remain strictly nonweightbearing for an additional 4 weeks. Primary outcome measures were the American Academy of Orthopaedic Surgery (AAOS) Foot and Ankle score and numeric rating scale (NRS) pain score. RESULTS: The EWB group demonstrated significant improvement in AAOS Foot and Ankle Questionnaire scores at the 6-week follow-up appointment as compared to the DWB group (83.1 ± 13.5 vs 68.7 ± 15.8, P = .017). Following this point, there were no significant differences in AAOS scores between groups. At no point were NRS pain scores significantly different between the groups. CONCLUSIONS: EWB after microfracture for OLTs was associated with improved AAOS scores in the short term. Thereafter and through 2 years' follow-up, no statistically significant differences were seen between EWB and DWB groups. LEVEL OF EVIDENCE: Level II, prospective randomized trial.

Lumbar Disc Herniation in Military Helicopter Pilots vs. Matched Controls.

INTRODUCTION: Lumbar disc herniation (LDH) is a common injury among active duty service members resulting in missed duty hours and limited duty status. Little is known about the current burden of disease and risk factors for LDH among military rotary wing aviators. METHODS: A query was made using the Defense Medical Epidemiology Database (DMED), including patient encounters for the U.S. Military from 2006-2015 using the ICD-9 code for LDH. Incidence rates were calculated for patients with the occupation of helicopter pilot and stratified by age, gender, and branch of service, then compared to matched controls using a Poisson regression analysis. Then, data from a 17-yr period were examined for long term trends. RESULTS: We identified 1218 cases of LDH among 141,383 person-years among helicopter pilots, yielding a 1.22-fold higher incidence rate compared to controls. Significant risk factors identified after Poisson regression analysis were age greater than 30 yr old and Army service branch affiliation. Male gender was not found to be a significant risk factor. Long term data revealed a 2.6-fold increased incidence of LDH among helicopter pilots since 1997. DISCUSSION: We identified significant increased risk of LDH in rotary wing pilots as compared to their nonpilot peers. Among rotary wing pilots, the incidence of this condition has increased, with both increasing pilot age and Army branch affiliation identified as risk factors. This information will allow targeted prevention strategies and further investigation to potential aircraft-specific causes of increased risk in Army pilots.Knox JB, Deal JB Jr, Knox JA. Lumbar disc herniation in military helicopter pilots vs. matched controls. Aerosp Med Hum Perform. 2018; 89(5):442-445.

Platelet-Rich Plasma for Primary Treatment of Partial Ulnar Collateral Ligament Tears: MRI Correlation With Results.

BACKGROUND: Jobe revolutionized the treatment of medial ulnar collateral ligament (MUCL) tears with his reconstruction technique. However, not all MUCL injuries require operative management; Rettig showed that 42% of MUCL injuries respond to conservative management. This was improved by Podesta, who showed that augmentation of nonoperative management with platelet-rich plasma (PRP) and magnetic resonance imaging (MRI) for detecting partial MUCL tears resulted in significantly higher success rates. Their series used a single injection of leukocyte-rich PRP. However, to our knowledge, no study has established optimal dosing and composition of PRP for augmentation of soft tissue healing. We present a series of patients with partial MUCL tears of the elbow treated with a series of 2 leukocyte-rich PRP injections, bracing, physical therapy, and a structured return-to-throwing protocol. HYPOTHESIS: Nonoperative management of acute or subacute partial MUCL tears of the elbow with a formal treatment protocol will allow the injured ligament to heal without surgery and will permit a rapid return to sport. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Patients with symptomatic MUCL instability and magnetic resonance arthrography demonstrating grade 2 MUCL tears at the proximal or distal aspect were treated with varus-loading elbow bracing, activity restriction, and physical therapy, supplemented by 2 injections of PRP. The injections were separated by 2 weeks. Two weeks after the second injection, a repeat examination and magnetic resonance arthrogram were obtained to evaluate the response to treatment. RESULTS: A total of 25 athletes (23 baseball athletes, 2 softball athletes [1 participant also danced]) underwent PRP injections and guided rehabilitation. Of these patients, 23 were diagnosed with primary grade 2 injuries of the MUCL; 22 patients with primary injuries (96%) demonstrated stability of the MUCL after treatment and returned to play at the same or higher level of competition without further intervention. Repeat MRI demonstrated reconstitution of the ligament in all patients, although 2 patients demonstrated only partial reconstitution. Patients were released to play at 6 weeks; due to vagaries of sports seasons, the mean time to return to competitive play was 82 days. Two of the 25 patients had undergone prior surgery (1 MUCL reconstruction and 1 repair). These patients remained unstable and symptomatic on examination after this treatment regimen, did not show complete reconstitution of the ligament on subsequent MRI, and required MUCL reconstruction. CONCLUSION: Ouf of 23 primary injury patients who received PRP injections and nonoperative measures, 22 (96%) were able to return to play and demonstrated reconstitution of the MUCL on MRI. Two of the 3 patients for whom PRP therapy failed had undergone previous MUCL surgery. We conclude that a 2-injection regimen of leukocyte-rich PRP is a safe and effective treatment for partial MUCL tears, but it appears to be less effective in patients with previous surgery for MUCL repair or reconstruction.

Design of thymidylate synthase inhibitors using protein crystal structures: the synthesis and biological evaluation of a novel class of 5-substituted quinazolinones.

The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-resolution ternary crystal complex of Escherichia coli TS, 5'-fluorodeoxyuridylate (5-FdUMP) and a classical glutamate-containing folic acid analog. A preliminary ternary crystal structure of a novel compound was successfully solved. Upon analysis of this initial complex, further structural elaborations were made, and a series of active 5-(arylthio)quinazolinones was developed. The synthetic strategy was based on the displacement of a halogen at the 5-position of a quinazolinone by various aryl thioanions. The compounds were tested for inhibition of purified E. coli and/or human TS, and were assayed for cytotoxicity against three tumor cell lines in vitro. Significant thymidine protection effects were observed with several of the inhibitors, indicating that TS was the intracellular locus of activity.

Synthesis and biological evaluation of novel 2,6-diaminobenz[cd]indole inhibitors of thymidylate synthase using the protein structure as a guide.

The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.

Crystal-structure-based design and synthesis of benz[cd]indole-containing inhibitors of thymidylate synthase.

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benz[cd]indole-containing inhibitors of thymidylate synthase (TS) are described. The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region. Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM. Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells. The inhibitors were synthesized from substituted 6-aminobenz[cd]indol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion. The 2,6-diaminobenz[cd]indoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.

Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase.

Six new diphenyl sulfoxide and five new diphenyl sulfones were designed, synthesized, and tested for their inhibition of human and Escherichia coli thymidylate synthase (TS) and of the growth of cells in tissue culture. The best sulfoxide inhibitor of human TS was 3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4- (phenylsulfinyl)-N-(prop-2-ynyl)-aniline (7c) that had a Ki of 27 nM. No sulfone improved on TS inhibition by the previously reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2- ynylamino)phenyl phenyl sulfone (Ki = 12 nM). Nevertheless, one sulfone, 4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)-N-(prop-2-ynyl)aniline, was selected, on the basis of its inhibition of both TS and cell growth, for antitumor testing; it gave a 61% increase in life span to mice bearing the thymidino kinase-deficient L5178Y (TK-) lymphoma. A crystal structure of N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-((2- methylphenyl)sulfinyl)-N-(prop-2-ynyl)aniline complexed with E. coli TS was solved and revealed selective binding of one sulfoxide enantiomer. AMBER calculations showed that the enantioselection was due to asymmetric electrostatic effects at the mouth of the active site. In contrast, a similar crystal structure of the sulfoxide 7c, along with AMBER calculations, indicated that both enantiomers bound, but with different affinities. The side chain of Phe176 shifted in order to structurally accommodate the chlorine of the more weakly bound enantiomer.

Unusual manifestations of arsenic intoxication.

A patient with arsenic intoxication is reported, who presented with a variety of gastrointestinal and neurologic disturbances including unilateral facial nerve palsy and acute symptomatic pancreatitis, neither of which have been previously described as sequelae of arsenic poisoning. The patient also suffered hematologic, dermatologic, and cardiopulmonary complications. A review of the literature about this interesting problem is also presented.

Gastroesophageal fundoplication improves symptoms in refractory asthma.

Gastroesophageal (GE) reflux has been etiologically linked to a number of pulmonary diseases. Subclinical pulmonary aspiration from nocturnal GE reflux has been proposed as a cause of asthma. A patient with severe asthma, refractory to conventional medical therapy, is presented. The asthma was presumed to be secondary to gastroesophageal reflux and indeed the patient became asymptomatic following a Nissen fundoplication procedure. This case report documents that surgical correction of GE reflux may be an appropriate therapeutic maneuver in asthmatics who subclinically aspirate as a consequence of GE reflux.

Renal disease, epidermal necrosis, and epithelial cell antibodies.

OBJECTIVE: To describe the association between epithelial cell IgM, which has previously been associated with an increased incidence of loss of renal graft in children, with a novel cutaneous eruption and unexplained native renal disease. DESIGN: Observational study on children with epithelial cell antibody presenting with unexplained renal or skin disease. SETTING: General paediatric department and regional paediatric nephrology unit. PATIENTS: Six children (five girls, one boy), who presented to the unit in 1989-90. RESULTS: Three children, two of whom had a history of a hyperpigmented rash, presented with hypertension, proteinuria, and impaired renal function. Renal biopsy specimens from two of these children showed severe arteriolar endothelial cell swelling with arteriolar occlusion. These children fully recovered after treatment with antihypertensive drugs. The third child developed end stage renal failure and required dialysis. Three other children presented with an unusual cutaneous eruption but no evidence of renal disease. Histology of the skin lesions showed acute epidermal necrosis and features consistent with a viral infection. CONCLUSIONS: The aetiology and pathogenesis of the epithelial cell antibody are unknown. These cases indicate that it may have a role in native kidney disease and focal epidermal necrosis. Clinical and histological features suggest that the antibody may be associated with a viral infection.