The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo.

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue and has transformed neural imaging, but applying this technique in vivo can be limited by the mechanical and optical constraints of conventional objectives. Short working distance objectives can collide with compact surgical windows or other instrumentation and preclude imaging. Here we present an ultra-long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a more than 4 mm2 field of view with submicrometer lateral resolution and is compatible with commonly used multiphoton imaging systems. A novel mechanical design, wider than typical microscope objectives, enabled this combination of specifications. We share the full optical prescription, and report performance including in vivo two-photon and three-photon imaging in an array of species and preparations, including nonhuman primates. The Cousa objective can enable a range of experiments in neuroscience and beyond.

Characterizing utilization patterns and reoperation risk factors of interspinous process devices: analysis of a national claims database.

INTRODUCTION: Interspinous process devices (IPDs) were developed as minimally invasive alternatives to open decompression surgery for spinal stenosis. However, given high treatment failure and reoperation rates, there has been minimal adoption by spine surgeons. This study leveraged a national claims database to characterize national IPD usage patterns and postoperative outcomes after IPD implantation. METHOD: Using the PearlDiver database, we identified all patients who underwent 1- or 2-level IPD implantation between 2010 and 2018. Univariate and multivariable logistic regression was performed to identify predictors of the number of IPD levels implanted and reoperation up to 3 years after the index surgery. Right-censored Kaplan-Meier curves were plotted for duration of reoperation-free survival and compared with log-rank tests. RESULTS: Patients (n = 4865) received 1-level (n = 3246) or 2-level (n = 1619) IPDs. Patients who were older (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.01-1.03, P < .001), male (aOR 1.31, 95% CI 116-1.50, P < .001), and obese (aOR 1.19, 95% CI 1.05-1.36, P < .01) were significantly more likely to receive a 2-level IPD than to receive a 1-level IPD. The 3-year reoperation rate was 9.3% of patients when mortality was accounted for during the follow-up period. Older age decreased (aOR 0.97, 95% CI 0.97-0.99, P = .0039) likelihood of reoperation, whereas 1-level IPD (aOR 1.37, 95% CI 1.01-1.89, P = .048), Charlson Comorbidity Index (aOR 1.07, 95% CI 1.01-1.14, P = .018), and performing concomitant open decompression increased the likelihood of reoperation (aOR 1.68, 95% CI 1.35-2.09, P = .0014). CONCLUSION: Compared with 1-level IPDs, 2-level IPDs were implanted more frequently in older, male, and obese patients. The 3-year reoperation rate was 9.3%. Concomitant open decompression with IPD placement was identified as a significant risk factor for subsequent reoperation and warrants future investigation.

The Multiplicative Effects of Individual Risk Factors in the Development of Osteonecrosis of the Femoral Head.

BACKGROUND: While individual risk factors, including chronic corticosteroid use, alcohol abuse, and smoking, are implicated in osteonecrosis of the femoral head (ONFH), the degree to which multiple risk factors increase risk is unknown. This study aimed to: (1) identify the demographic characteristics of patients who have ONFH; (2) quantify the effects of individual risk factors on ONFH development; (3) quantify the effects of combined risk factors on ONFH development; and (4) determine the prognostic implications of combined risk factors on ONFH development. METHODS: This was a retrospective cohort study. A national insurance database was used to study a population of 2,612,383 adult patients who had a 10-year follow-up period. There were 10,233 patients identified who had a diagnosis of ONFH. We identified patients who had chronic corticosteroid use, tobacco use, and/or alcohol abuse and assessed the risk of developing ONFH over a 10-year period. Patients who had individual and multiple risk factors were grouped for comparison, and Chi-square analyses were performed. RESULTS: Higher proportions of patients who had each individual risk factor developed ONFH compared to proportions of patients who did not have risk factors. Patients who had combined risk factors were at greater risk of developing ONFH compared to patients who had no risk factors and those who had single risk factors. Combined risk factors demonstrated multiplicative effects on the development of ONFH: tobacco-alcohol risk ratio (RR) 5.25, corticosteroid-alcohol RR 10.20, tobacco-corticosteroid RR 8.69, and corticosteroid-tobacco-alcohol RR 12.54. Patients who had combined risk factors developed ONFH at younger ages than those who had single risk factors. Kaplan-Meier curve analyses demonstrated worse 10-year hip survival in the setting of combined risk factors. CONCLUSIONS: Combined risk factors have a multiplicative effect on the risk of developing of atraumatic ONFH. Orthopaedic surgeons may care for at-risk individuals through modulation of risk factors. LEVEL OF EVIDENCE: Retrospective Cohort Study, Level III.

Fibromyalgia Increases Post-operative Healthcare Utilization Following total Hip Arthroplasty.

BACKGROUND: Preoperative factors can complicate the postoperative course and increase health care utilization following total hip arthroplasty (THA). Fibromyalgia is not generally recognized as a modifiable risk factor prior to THA. The aim of this investigation was to assess the effect of fibromyalgia on postoperative health care utilization following THA. METHODS: Patients who underwent primary THA from 2018 to 2019 were identified from a large national database using Current Procedural Terminology and International Classification of Diseases, tenth revision (International Classification of Diseases-10) codes. Patient demographics, age, sex, and preoperative opioid use were collected. Analysis compared patients who did and did not have fibromyalgia for postoperative health care utilization metrics; lengths of stay (LOS), 90-day postoperative opioid usages, dislocations, and emergency room visits. Independent t-tests were used to compare LOS and rates of ongoing opioid use. Logistic regression analyses with adjusted odds ratios evaluated the risk of dislocation and emergency room visit after adjusting for demographic characteristics and comorbidities. RESULTS: Compared to those who did not have fibromyalgia, patients who had fibromyalgia experienced longer LOS (P < .0001), increased odds of opioid use 90 days postoperatively (P < .0001) as well as increased odds of hip dislocation (P < .0001) and presentation to the emergency room (P < .0001). Patients who had fibromyalgia were also more likely to be "frequent flyers" with ≥5 emergency room visits after THA (P < .0001). CONCLUSIONS: Fibromyalgia can complicate postoperative care following THA with increased LOS, higher rates of opioid use, and increased odds of dislocation and emergency room visits. As focus shifts to preoperative optimization and risk stratification, more attention should be placed on fibromyalgia prior to THA.

It is the Opioids Not the Spine Surgeon; Dislocation After Total Hip Arthroplasty is Associated With Opioid Use in Patients Who Have Prior Lumbar Spine Fusion.

BACKGROUND: Patients who have prior lumbar spine fusion (LSF) have an increased risk for dislocation after total hip arthroplasty (THA). These patients also have elevated rates of opioid use. We aimed to evaluate the associated risk of dislocation after THA in patients who have prior LSF comparing those who have opioid use to those who do not. METHODS: This was a retrospective review using a large national database of 246,617 primary and 34,083 revision THA cases from 2012 to 2019. There were 1,903 primary THA and 288 revision THA cases identified with LSF prior to THA. Postoperative hip dislocation was our primary outcome variable and patients were stratified to use or nonuse of opioid at THA. Demographic data including age, sex, and obesity were collected. Multivariate analyses evaluated association of opioid use and dislocation after adjusting for demographics. RESULTS: There was increased odds of dislocation for opioid use at THA for both primary (adjusted Odds Ratio [aOR] = 2.29, 95% Confidence Interval [CI] 1.46 to 3.57, P < .0003) and revision THA (aOR = 1.92, 95% CI 1.62 to 3.08, P < .0003), in patients who have prior LSF. Prior LSF without opioid use was associated with increased odds of dislocation (aOR = 1.38, 95% CI 1.01 to 1.88, P = .04), but this was lower than the associated risk of opioid use without LSF (aOR 1.72, 95% CI 1.63 to 1.81, P < .001). CONCLUSION: Increased odds of dislocation were noted with opioid use at time of THA in patients who have prior LSF. Associated risk of dislocation was higher for opioid use than prior LSF. This suggests that dislocation risk is multifactorial and we should look to strategies to reduce opioid use prior to THA.

Acoustic Change Complex and Visually Reinforced Infant Speech Discrimination Measures of Vowel Contrast Detection.

OBJECTIVES: To measure the effect of stimulus rate and vowel change direction on the acoustic change complex (ACC) latencies and amplitudes and compare ACC metrics to behavioral measures of vowel contrast detection for infants tested under the age of 1 year. We tested the hypothesis that the direction of spectral energy shift from a vowel change would result in differences in the ACC, owing to the sensitivity of cortical neurons to the direction of frequency change. We evaluated the effect of the stimulus rate (1/s versus 2/s) on the infants' ACC. We evaluated the ACC amplitude ratio's sensitivity (proportion of ACCs present for each change trial) and compared it to perceptual responses obtained using a visually reinforced infant speech discrimination paradigm (VRISD). This report provides normative data from infants for the ACC toward the ultimate goal of developing a clinically useful index of neural capacity for vowel discrimination. DESIGN: Twenty-nine infants, nine females, 4.0 to 11.8 months of age, participated. All participants were born at full term and passed their newborn hearing screens. None had risk factors for hearing or neurologic impairment. Cortical auditory evoked potentials were obtained in response to synthesized vowel tokens /a/, /i/, /o/, and /u/ presented at a rate of 1- or 2/s in an oddball stimulus paradigm with a 25% probability of the deviant stimulus. All combinations of vowel tokens were tested at the two rates. The ACC was obtained in response to the deviant stimulus. The infants were also tested for vowel contrast detection using a VRISD paradigm with the same combinations of vowel tokens used for the ACC. The mean age at the time of the ACC test was 5.4 months, while the mean age at the behavioral test was 6.8 months. RESULTS: Variations in ACC amplitude and latency occurred as a function of the initial vowel token and the contrast token. However, the hypothesis that the direction of vowel (spectral) change would result in significantly larger change responses for high-to-low spectral changes was not supported. The contrasts with /a/ as the leading vowel of the contrast pair resulted in the largest ACC amplitudes than other conditions. Significant differences in the ACC presence and amplitude were observed as a function of rate, with 2/s resulting in ACCs with the largest amplitude ratios. Latency effects of vowel contrast and rate were present, but not systematic. The ACC amplitude ratio's sensitivity for detecting a vowel contrast was greater for the 2/s rate than the 1/s rate. For an amplitude ratio criterion of ≥1.5, the sensitivity was 93% for ACC component P2-N2 at 2/s, whereas at 1/s sensitivity was 70%. VRISD tests of vowel-contrast detection had a 71% hit and a 21% false-positive rate. Many infants who could not reach performance criteria for VRISD had ACC amplitude ratios of ≥2.0. CONCLUSIONS: The ACC for vowel contrasts presented at a rate of 2/s is a robust index of vowel-contrast detection when obtained in typically developing infants under the age of 1 year. The ACC is present in over 90% of infants tested at this rate when an amplitude ratio criterion of ≥1.5 is used to define a response. The amplitude ratio appears to be a sensitive metric for the difference between a control and contrast condition. The ACC can be obtained in infants who do not yet exhibit valid behavioral responses for vowel change contrasts and may be useful for estimating neural capacity for discriminating these sounds.

Utility of upright radiographs in traumatic thoracolumbar fracture management.

BACKGROUND: It is common practice to use a combination approach of computed tomography (CT) scan followed by upright radiographs when assessing traumatic thoracolumbar (TL) vertebral fractures. The purpose of this study was to determine the clinical utility of upright spine radiographs in the setting of traumatic TL fracture management. Our null hypothesis is that upright TL radiographs rarely change management of acute vertebral fractures. METHODS: A retrospective study was performed on patients with an initial plan of non-operative management for a TL fracture between January 2014 and June 2020 at a single Level 1 trauma center. Patients were followed from time of initial consult to either conversion to surgery (operative) or last available outpatient follow up imaging (non-operative). Lateral kyphotic angle of the fractured vertebra and anterior vertebral body height% loss on initial CT, first upright radiograph, and endpoint upright radiograph imaging were measured. Measurements were compared between and within operative and non-operative groups using t-tests and Mann-Whitney U tests when appropriate. P-values ≤ 0.05 were considered statistically significant. RESULTS: The study included 70 patients with an average age of 54 years and 37 (52.9%) were women. Six (8.6%) of 70 patients had a change from non-operative to operative management based on upright radiographs. The mean (standard deviation) change in degrees of kyphosis from CT scan to first X-ray was 4.6 (7.0) in the non-operative group and 11.5 (8.1) in the operative group (P = 0.03). Delta degrees of kyphosis from CT scan to endpoint X-ray was 6.4 (9.0) and 16.2 (6.2) in the non-operative and operative groups, respectively (P = 0.01). In the operative group, mean degrees of kyphosis increased from 1.6 (7.6) in initial CT to 13.1 (8.9) in first X-ray (P = 0.02). First X-ray mean anterior body height% loss was 37.5 (17.6) and 53.2 (16.1) in the non-operative and operative groups, respectively (P = 0.04). CONCLUSIONS: Upright radiographs are useful in guiding traumatic vertebral fracture management decisions. Larger studies are needed to determine the degree of change in kyphosis between CT and first standing radiograph that is suggestive of operative management. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: Not applicable.

Strategies for Therapeutic Amelioration of Aberrant Plasma Zn2+ Handling in Thrombotic Disease: Targeting Fatty Acid/Serum Albumin-Mediated Effects.

The initiation, maintenance and regulation of blood coagulation is inexorably linked to the actions of Zn2+ in blood plasma. Zn2+ interacts with a variety of haemostatic proteins in the bloodstream including fibrinogen, histidine-rich glycoprotein (HRG) and high molecular weight kininogen (HMWK) to regulate haemostasis. The availability of Zn2+ to bind such proteins is controlled by human serum albumin (HSA), which binds 70-85% of plasma Zn2+ under basal conditions. HSA also binds and transports non-esterified fatty acids (NEFAs). Upon NEFA binding, there is a change in the structure of HSA which leads to a reduction in its affinity for Zn2+. This enables other plasma proteins to better compete for binding of Zn2+. In diseases where elevated plasma NEFA concentrations are a feature, such as obesity and diabetes, there is a concurrent increase in hypercoagulability. Evidence indicates that NEFA-induced perturbation of Zn2+-binding by HSA may contribute to the thrombotic complications frequently observed in these pathophysiological conditions. This review highlights potential interventions, both pharmaceutical and non-pharmaceutical that may be employed to combat this dysregulation. Lifestyle and dietary changes have been shown to reduce plasma NEFA concentrations. Furthermore, drugs that influence NEFA levels such as statins and fibrates may be useful in this context. In severely obese patients, more invasive therapies such as bariatric surgery may be useful. Finally, other potential treatments such as chelation therapies, use of cholesteryl transfer protein (CETP) inhibitors, lipase inhibitors, fatty acid inhibitors and other treatments are highlighted, which with additional research and appropriate clinical trials, could prove useful in the treatment and management of thrombotic disease through amelioration of plasma Zn2+ dysregulation in high-risk individuals.

Comparison of two cortical measures of binaural hearing acuity.

OBJECTIVE: Multiple studies have demonstrated binaural hearing deficits in the aging and those with hearing loss. Consequently, there is great interest in developing efficient clinical tests of binaural hearing acuity to improve diagnostic assessments and to assist clinicians when fitting binaural hearing aids and/or cochlear implants. DESIGN: Two cortical measures of interaural phase difference sensitivity, the acoustic change complex (ACC) and interaural phase modulation following response (IPM-FR), were compared on three metrics using five different stimulus interaural phase differences (IPDs; 0°, ±22.5°, ±45°, ±67.5° and ±90°). These metrics were scalp topography, time-to-detect, and input-output characteristics. STUDY SAMPLE: Ten young, normal-hearing listeners. RESULTS: Scalp topography qualitatively differed between ACC and IPM-FR. The IPM-FR demonstrated better time-to-detect performance on smaller (±22.5° and ±45°) but not larger (67.5°, and ±90°) IPDs. Input-output characteristics of each response were similar. CONCLUSIONS: The IPM-FR may be a faster and more efficient tool for assessing neural sensitivity to subtle IPD changes. However, the ACC may be useful for research or clinical questions concerned with the topographic representation of binaural cues.

Degradation of Transcriptional Repressor ATF4 during Long-Term Synaptic Plasticity.

Maintenance of long-term synaptic plasticity requires gene expression mediated by cAMP-responsive element binding protein (CREB). Gene expression driven by CREB can commence only if the inhibition by a transcriptional repressor activating transcription factor 4 (ATF4; also known as CREB2) is relieved. Previous research showed that the removal of ATF4 occurs through ubiquitin-proteasome-mediated proteolysis. Using chemically induced hippocampal long-term potentiation (cLTP) as a model system, we investigate the mechanisms that control ATF4 degradation. We observed that ATF4 phosphorylated at serine-219 increases upon induction of cLTP and decreases about 30 min thereafter. Proteasome inhibitor ß-lactone prevents the decrease in ATF4. We found that the phosphorylation of ATF4 is mediated by cAMP-dependent protein kinase. Our initial experiments towards the identification of the ligase that mediates ubiquitination of ATF4 revealed a possible role for ß-transducin repeat containing protein (ß-TrCP). Regulation of ATF4 degradation is likely to be a mechanism for determining the threshold for gene expression underlying maintenance of long-term synaptic plasticity and by extension, long-term memory.