Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm.

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 shown to preferentially elevate the nicotinamide adenine dinucleotide (NAD+) metabolome compared to other vitamin B3 forms (nicotinic acid and nicotinamide). Although daily requirements of vitamin B3 are typically met through the diet, recent studies have shown that additional supplementation with NR may be an effective method to counter the age-related decline in NAD+ levels as NR bypasses the rate-limiting step in NAD+ biosynthesis. Furthermore, pharmaceutical applications of NR for age-related disorders have been proposed. In this study, the safety of a high-purity, nature-identical, synthetic NR (NR-E), manufactured under the guidelines of good manufacturing practices for dietary supplements (21 CFR 111) as well as for drugs (21 CFR 210), was investigated in a 90-day oral toxicity study in Sprague Dawley rats at 300, 500, and 1,200 mg/kg/d. There were no mortality or clinical observations attributable to the test substance at any dose. A small but statistically significant decrease in body weight was observed at day 92 in the 1,200 mg/kg/d NR-treated male rats only. In contrast to a previously published safety assessment using a different synthetic NR (NIAGEN), whose no-observed-adverse-effect-level (NOAEL) was reported to be 300 mg/kg/d, there were no adverse changes in clinical pathology parameters and no notable macroscopic or microscopic findings or treatment-related effects at similar doses. In the current study, the NOAEL for systemic toxicity of NR-E in Sprague-Dawley rats was conservatively determined to be 500 mg/kg/d for males (solely based on body weight) and 1,200 mg/kg/d for females.

Republication of "Cross-Sectional Assessment of Orthopedic Foot and Ankle Patient Knowledge".

Background: Individuals with limited health literacy often struggle in effectively communicating with their physicians and may lack the skills needed to make informed health decisions. It is therefore important that providers have insight into patients' baseline medical knowledge, as this can help physicians customize their approach to, and conversations with, each patient. As such, this study evaluated the foot and ankle-specific knowledge of patients seeking care for various foot and ankle ailments. Methods: An unvalidated survey developed by our study group was distributed to 206 patients, assessing their knowledge of foot and ankle anatomy, terminology, conditions, treatment, and perioperative issues. Performance was evaluated as a function of participants' demographic factors. Results: Participants performed significantly worse on the conditions and treatment questions as compared to the anatomy, terminology, and perioperative considerations subsections. Significantly better performance correlated with education (≥college), visit type (preoperative evaluation), a current or previous health care occupation, and prior orthopedic surgeon evaluation. Conclusions: Patients' knowledge of foot and ankle anatomy, terminology, conditions, treatment, and perioperative issues correlates with certain patient characteristics and demographics. With enhanced insight into the risk factors for limited knowledge, education campaigns can be designed to target those most in need.

Republication of "The Utilization of Internet Resources by Foot and Ankle Patients".

Background: It is critical for patients seeking foot and ankle care to have access to quality online resources, as the treatment of their conditions may involve the use of a variety of diagnostic and therapeutic modalities with which they are unfamiliar. This study was performed to enhance our understanding of if and why patients use Internet-based educational materials, to identify trends in utilization, and to delineate the patient-perceived attributes of quality resources. Methods: Questionnaires were distributed to 150 adult foot and ankle patients. The questionnaire consisted of demographic and Internet utilization questions. Statistical analysis was performed to determine the frequency of responses for each question and the relationship between demographics and Internet usage. Results: Younger patients were more likely to use the Internet (P= .006). However, there were no other significant differences in demographic attributes between patients who did (76%) and did not (24%) utilize the Internet (P <.05). Of the participants who didn't search the Internet about their condition, the most commonly cited reason was they preferred to receive information directly from their physician (47%). Among Internet users, most found the quality of resources to be good or very good (75%). However, many patients were unsure of the specific websites they accessed (66%) and if materials were AOFAS sponsored (18%). When asked about the attributes of a reliable website, patients felt that physician and/or medical society endorsement were most important (52% and 46%, respectively). Conclusion: Although physician and medical society endorsement positively shape patients' opinions of online education materials, patients often struggle in remembering the site they visited and if it was sponsored by a certain society. Despite this, patients are generally satisfied with online foot and ankle education resources. Future works must assess whether patient and physician perceptions of quality Internet resources are correlated. Level of Evidence: Level IV, case series.

Laser-Induced Maculopathy and Outcomes After Treatment With Corticosteroids and Lutein.

This case report presents treatment outcomes for a patient with accidental laser-induced retinal injury. A 30-year-old man was evaluated for a sudden decrease of vision and metamorphopsia in his left eye after staring at a laser in a nightclub five days before presentation. Eye examination showed left visual acuity of 6/18-2 unaided, which improved to 6/12-2 on the pinhole test. Dilated fundoscopy showed a yellow-orange foveolar lesion in the left eye. Optic coherence tomography (OCT) showed an alteration of foveal anatomy predominantly involving the outer retinal layers, hyper-reflective vertical bands, and large cystoid change at the inner retina. Foveolar thickness was increased to 397 µ. Treatment was initiated with oral corticosteroids (prednisolone 0.5 mg/kg/day). At the one-week follow-up, left visual acuity improved to 6/12+2. Hardly any cystic changes were noted, with fewer hyper-reflective bands and less disruption at the outer layer. Treatment with prednisolone was continued and lutein capsules (20 mg/day) were added. At three weeks, the patient reported a return to normal vision, with left visual acuity of 6/6-2 unaided. On OCT, near-complete restoration of the macular structure was visualized. Although these results show positive clinical outcomes with combined oral corticosteroids and lutein over a short time for a typical case of laser-induced maculopathy, further review is recommended to determine the ideal treatment regimen.

Correlation of Clinical Evaluation and Radiographic Hindfoot Alignment in Stage II Adult-Acquired Flatfoot Deformity.

BACKGROUND: Previous work has demonstrated that the amount of radiographic hindfoot correction required at the time of adult-acquired flatfoot deformity (AAFD) operative treatment can be predicted by the amount of radiographic deformity present before surgery. Successful outcomes after reconstruction are closely correlated with hindfoot valgus correction. However, it is not clear if differences exist between clinical and radiographic assessment of hindfoot valgus. The purpose of this study was to evaluate the correlation between radiographic and clinical evaluation of hindfoot alignment in patients with stage II AAFD. METHODS: Twenty-nine patients (30 feet) with stage II AAFD, 17 men and 12 women, mean age of 51 (range, 20-71) years, were prospectively recruited. In a controlled and standardized fashion, bilateral weightbearing radiographic hindfoot alignment views were taken. Radiographic parameters were measured by 2 blinded and independent readers: hindfoot alignment angle (HAA) and hindfoot moment arm (HMA). Clinical photographs of hindfoot alignment were taken in 3 different vertical camera angulations (0, 20, and 40 degrees). Pictures were assessed by the same readers for standing tibiocalcaneal angle (STCA) and resting calcaneal stance position (RCSP). Intra- and interobserver reliability were assessed by Pearson/Spearman's and intraclass correlation coefficient (ICC), respectively. Relationship between clinical and radiographic hindfoot alignment was evaluated by a linear regression model. Comparison between the different angles (RCSP, STCA, and HAA) was performed using the Wilcoxon rank-sum test. P values of less than .05 were considered significant. RESULTS: We found overall almost perfect intraobserver (range, 0.91-0.99) and interobserver reliability (range, 0.74-0.98) for all measures. Mean value and confidence interval (CI) for RCSP and STCA were 10.8 degrees (CI, 10.1-11.5) and 12.6 degrees (CI, 11.7-13.4), respectively. The position of the camera did not influence readings of clinical alignment ( P > .05). The mean HMA was 18.7 mm (CI, 16.3-21.1 mm), and the mean HAA was 23.5 degrees (CI, 21.1-26.0). Clinical and radiographic hindfoot alignment were found to significantly correlate ( P < .05). However, the radiographic HAA demonstrated increased valgus compared to both clinical alignment measurements, with a mean difference of 12.8 degrees from the RCSP (CI, 11.0-14.5, P < .0001) and 11.0 degrees from the STCA (CI, 9.2-12.8, P < .0001). CONCLUSION: We found significant correlation between radiographic and clinical hindfoot alignment in patients with stage II AAFD. However, radiographic measurements of HAA demonstrated significantly more pronounced valgus alignment than the clinical evaluation. The results of our study suggest that clinical evaluation of hindfoot alignment in patients with AAFD potentially underestimates the bony valgus deformity. One should consider these findings when using clinical evaluation in the treatment algorithm of flatfoot patients. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Comparative Outcomes Between Step-Cut Lengthening Calcaneal Osteotomy vs Traditional Evans Osteotomy for Stage IIB Adult-Acquired Flatfoot Deformity.

BACKGROUND: The forefoot abduction component of the flexible adult-acquired flatfoot can be addressed with lengthening of the anterior process of the calcaneus. We hypothesized that the step-cut lengthening calcaneal osteotomy (SLCO) would decrease the incidence of nonunion, lead to improvement in clinical outcome scores, and have a faster time to healing compared with the traditional Evans osteotomy. METHODS: We retrospectively reviewed 111 patients (143 total feet: 65 Evans, 78 SLCO) undergoing stage IIB reconstruction followed clinically for at least 2 years. Preoperative and postoperative radiographs were analyzed for the amount of deformity correction. Computed tomography (CT) was used to analyze osteotomy healing. The Foot and Ankle Outcome Scores (FAOS) and lateral pain surveys were used to assess clinical outcomes. Mann-Whitney U tests were used to assess nonnormally distributed data while χ2 and Fisher exact tests were used to analyze categorical variables (α = 0.05 significant). RESULTS: The Evans group used a larger graft size ( P < .001) and returned more often for hardware removal ( P = .038) than the SLCO group. SLCO union occurred at a mean of 8.77 weeks ( P < .001), which was significantly lower compared with the Evans group ( P = .02). The SLCO group also had fewer nonunions ( P = .016). FAOS scores improved equivalently between the 2 groups. Lateral column pain, ability to exercise, and ambulation distance were similar between groups. CONCLUSION: Following SLCO, patients had faster healing times and fewer nonunions, similar outcomes scores, and equivalent correction of deformity. SLCO is a viable technique for lateral column lengthening. LEVEL OF EVIDENCE: Level III, retrospective cohort study.

Patient Factors Associated With Higher Expectations From Foot and Ankle Surgery.

BACKGROUND: Few authors have investigated patients' expectations from foot and ankle surgery. In this study, we aimed to examine relationships between patients' preoperative expectations and their demographic and clinical characteristics. We hypothesized that patients with more disability and those with anxiety or depressive symptoms would have greater expectations. METHODS: All adult patients scheduled for elective foot or ankle surgery by 1 of 6 orthopaedic foot and ankle surgeons were screened for inclusion over 8 months. Preoperatively, all patients completed the Hospital for Special Surgery Foot & Ankle Surgery Expectations Survey in addition to the Foot & Ankle Outcome Score (FAOS), Short Form (SF)-12, Patient Health Questionnaire (PHQ)-8, Generalized Anxiety Disorder 7-item scale (GAD-7), and pain visual analog scale (VAS). The expectations survey contained 23 expectations categories, each with 5 answer choices ranging from "I do not have this expectation" to "complete improvement" expected. It was scored from 0 to 100, with higher scores indicating more expectations. Differences in expectations relating to numerous patient demographic and clinical variables were assessed. In total, 352 patients with an average age of 55 ± 15 (range, 18-86) years were enrolled. RESULTS: Expectations scores were not related to age ( P = .36). On average, women expected to achieve complete improvement more often than men ( P = .011). Variables that were significantly associated with higher expectations scores ( P < .05) included nonwhite race, use of a cane or other assistive device, and greater medical comorbidity. Worse function and quality of life (as assessed by all FAOS subscales and the SF-12 physical and mental components), more depressive and anxiety symptoms, and higher pain VAS scores were associated with higher expectations scores and more expectations ( P < .01 for all). CONCLUSIONS: The results of this study may help inform surgeons' preoperative discussions with their patients regarding realistic expectations from surgery. Generally, patients with worse function and more disability had higher expectations from surgery. Addressing these patients' expectations preoperatively may help improve their ultimate satisfaction with surgery. LEVEL OF EVIDENCE: Level II, cross sectional study.

Measuring Joint Flexibility in Hallux Rigidus Using a Novel Flexibility Jig.

BACKGROUND: The flexibility of the first metatarsophalangeal (MTP) joint in patients with hallux rigidus (HR) has not been studied. Compared to measuring range of motion alone, measures of joint flexibility provide additional information that may prove useful in the assessment of HR. The purpose of this study was to assess the flexibility of the hallux MTP joint in patients with HR compared to controls using a novel flexibility device. METHODS: Fifteen patients with Coughlin stage II or III HR and 20 healthy controls were recruited prospectively. Using a custom flexibility jig, each of 2 raters performed a series of seated and standing tests on each subject. Dorsiflexion angle and applied torque were plotted against each other to generate 5 different parameters of flexibility. Differences between (1) HR patients and controls and (2) the sitting and standing testing positions were assessed with t tests. Intrarater test-retest reliability, remove-replace reliability, and interrater reliability were assessed with intraclass correlation coefficients (ICCs). RESULTS: Patients in the HR group were older than patients in the control group ( P < .001) and had lower maximum dorsiflexion ( P < .001). HR patients were less flexible as measured by 3 of the 5 flexibility parameters: early flexibility (first 25% of motion; P = .027), laxity angle ( P < .001), and torque angle ( P = .002). After controlling for age, only laxity angle differed significantly between HR patients and controls ( P < .001). Generally, patients were more flexible when seated compared to standing, with this effect being more marked in HR patients. All parameters had good or excellent intra- and interrater reliability (ICC ≥ 0.60). CONCLUSIONS: Hallux MTP joint flexibility was reliably assessed in HR patients using a flexibility device. Patients with HR had decreased flexibility of the hallux MTP joint compared to control patients. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Development of an Expectations Survey for Patients Undergoing Foot and Ankle Surgery.

BACKGROUND: Many authors have reported on patient satisfaction from foot and ankle surgery, but rarely on expectations, which may vary widely between patients and strongly affect satisfaction. In this study, we aimed to develop a patient-derived survey on expectations from foot and ankle surgery. METHODS: We developed and tested our survey using a 3-phase process. Patients with a wide spectrum of foot and ankle diagnoses were enrolled. In phase 1, patients were interviewed preoperatively with open-ended questions about their expectations from surgery. Major concepts were grouped into categories that were used to form a draft survey. In phase 2, the survey was administered to preoperative patients on 2 occasions to establish test-retest reliability. In phase 3, the final survey items were selected based on weighted kappa values for response concordance and clinical relevance. RESULTS: In phase 1, 94 preoperative patients volunteered 655 expectations. Twenty-nine representative categories were discerned by qualitative analysis and became the draft survey. In phase 2, another 60 patients completed the draft survey twice preoperatively. In phase 3, 23 items were retained for the final survey. For retained items, the average weighted kappa value was 0.54. An overall score was calculated based on the amount of improvement expected for each item on the survey and ranged from zero to 100, with higher scores indicating more expectations. For patients in phase 2, mean scores for both administrations were 65 and 66 and approximated normal distributions. The intraclass correlation coefficient between scores was 0.78. CONCLUSION: We developed a patient-derived survey specific to foot and ankle surgery that is valid, reliable, applicable to diverse diagnoses, and includes physical and psychological expectations. The survey generates an overall score that is easy to calculate and interpret, and thus offers a practical and comprehensive way to record patients' expectations. We believe this survey may be used preoperatively by surgeons to help guide patients' expectations and facilitate shared decision making. LEVEL OF EVIDENCE: Level II, cross-sectional study.

Effect of glutaraldehyde fixation on the frictional response of immature bovine articular cartilage explants.

This study examined functional properties and biocompatibility of glutaraldehyde-fixed bovine articular cartilage over several weeks of incubation at body temperature to investigate its potential use as a resurfacing material in joint arthroplasty. In the first experiment, treated cartilage disks were fixed using 0.02, 0.20 and 0.60% glutaraldehyde for 24h then incubated, along with an untreated control group, in saline for up to 28d at 37°C. Both the equilibrium compressive and tensile moduli increased nearly twofold in treated samples compared to day 0 control, and remained at that level from day 1 to 28; the equilibrium friction coefficient against glass rose nearly twofold immediately after fixation (day 1) but returned to control values after day 7. Live explants co-cultured with fixed explants showed no quantitative difference in cell viability over 28d. In general, no significant differences were observed between 0.20 and 0.60% groups, so 0.20% was deemed sufficient for complete fixation. In the second experiment, cartilage-on-cartilage frictional measurements were performed under a migrating contact configuration. In the treated group, one explant was fixed using 0.20% glutaraldehyde while the apposing explant was left untreated; in the control group both explants were left untreated. From day 1 to 28, the treated group exhibited either no significant difference or slightly lower friction coefficient than the untreated group. These results suggest that a properly titrated glutaraldehyde treatment can reproduce the desired functional properties of native articular cartilage and maintain these properties for at least 28d at body temperature.

Isolated retinal cotton wool spot after coronary angiography.

Visual symptoms after coronary angiography are rarely encountered and mostly related to contrast induced transient cortical blindness or retinal artery occlusions. We report an intriguing case of a 50-year-old woman, who presented with vision deterioration in her right eye 12 h after coronary angiography for cardiac palpitation. Fundoscopy and optical coherence tomography scan revealed an isolated parafoveal cotton wool spot in her right eye that has totally resolved 6 weeks after initial presentation. This is the first case report of this rare post coronary angiography complication.

Central nervous system tuberculosis presenting as branch retinal vein occlusion.

Branch retinal vein occlusion (BRVO) associated with ocular tuberculosis (TB) is a rare presentation of retinal vasculitis but it can also present in the absence of active uveitis. We present a 39-year-old patient with BRVO who slowly developed bilateral papilloedema due to TB in the central nervous system. To our knowledge, this is the first case of systemic central nervous system TB confirmed by biopsy presenting as a branch retinal vein occlusion and shows the importance of extensive causative investigation of BRVO, especially for young patients.

Giant cell arteritis presenting as choroidal infarction.

Background. Giant cell arteritis (GCA) is a systemic granulomatous vasculitis that affects large- and medium-sized arteries of the head and neck. Ocular manifestations of GCA usually are anterior ischaemic optic neuropathy (AION) or retinal vessel occlusion. Case Report. We report an interesting case of a 70-year-old man who presented with sudden vision loss and choroidal infarction in his left eye. Thorough clinical and paraclinical evaluation revealed an underlying GCA, the treatment of which prevented further vision loss and systemic complications. Conclusion. This is an unusual presentation of choroidal infarction associated with CGA and emphasizes the need of thorough systemic evaluation in patients with choroidal infarction.

Structural features associated with the binding of glutamine-containing peptides to Factor XIII.

Activated Factor XIII a2 catalyzes the formation of intermolecular gamma-glutamyl- epsilon -lysyl cross-links in the fibrin network. Solution NMR studies were carried out to characterize, the structural features associated with the binding of glutamine-containing peptides to Factor XIII. A coupled uv/vis kinetic assay demonstrated that K9 peptide (1-10), alpha2-antiplasmin (1-15), and alpha2-antiplasmin (1-15 Q4N) all function as glutamine-containing substrates for activated Factor XIII a2. 2D TOCSY spectra of the peptides exhibit upfield chemical shifts for the glutamine protons in the presence of Factor XIII. These results indicate that the reactive peptide glutamines are encountering a distinctive environment within the Factor XIII active site. 1D proton line-broadening and 2D transferred-NOESY studies reveal that the glutamines and residues located C-terminally come in direct contact with the enzyme and adopt an extended conformation. Substrates with sequences similar to alpha2-antiplasmin (1-15) are proposed to bind both at the catalytic site and at a neighboring apolar region.