Faculty Bibliography

OBJECTIVES/OBJECTIVE:The authors report no conflict of interest.To determine if short-term immobilization with a rigid long arm plaster elbow splint after surgery of the arm, elbow, or forearm results in superior outcomes compared with a soft dressing with early motion. DESIGN/METHODS:Prospective Randomized Control Trial. SETTING/METHODS:Academic Medical Center. PATIENT SELECTION CRITERIA/UNASSIGNED:Patients undergoing operative treatment for a mid-diaphysis or distal humerus, elbow, or forearm fracture were consented and randomized according to the study protocol for postoperative application of a rigid elbow splint (10-14 days in a plaster Sugar Tong Splint for forearm fracture or a Long Arm plaster Splint for 10-14 for all others) or soft dressing and allowing immediate free range of elbow and wrist motion (range of motion [ROM]). OUTCOME MEASURES AND COMPARISONS/UNASSIGNED:Self-reported pain (visual analog score or VAS), Healthscale (0-100, 100 denoting excellent health), and physical function (EuroQol 5 Dimension or EQ-5D) surveyed on postoperative days 1-5 and 14 were compared between groups. Patient-reported pain score (0-10, 10 denoting highest satisfaction) at week 6, time to fracture union, ultimate disabilities of the arm, shoulder, and hand score, and elbow ROM were also collected for analysis. Incidence of complications were assessed. RESULTS:Hundred patients (38 men to 62 women with a mean age of 55.7 years) were included. Over the first 5 days and again at postop day 14, the splint cohort reported a higher "Healthscale" from 0 to 100 than the nonsplint group on all study days ( P = 0.041). There was no difference in reported pain between the 2 study groups over the same interval ( P = 0.161 and 0.338 for least and worst pain, respectively), and both groups reported similar rates of treatment satisfaction ( P = 0.30). Physical function ( P = 0.67) and rates of wound problems ( P = 0.27) were similar. Additionally, the mean time to fracture healing was similar for the splint and control groups (4.6 ± 2.8 vs. 4.0 ± 2.2 months, P = 0.34). Ultimate elbow ROM was similar between the study groups ( P = 0.48, P = 0.49, P = 0.61, and P = 0.51 for elbow extension, flexion, pronation, and supination, respectively). CONCLUSIONS:Free range of elbow motion without splinting produced similar results compared with elbow immobilization after surgical intervention for a fracture to the humerus, elbow, and forearm. There was no difference in patient-reported pain outcomes, wound problems, or elbow ROM. Immobilized patients reported slightly higher "healthscale" ratings than nonsplinted patients and, however, reported similar rates of satisfaction. Both treatment strategies are acceptable after upper extremity fracture surgery. LEVEL OF EVIDENCE/METHODS:Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

PURPOSE/UNASSIGNED:This study sought to examine the utilization of bone health evaluations in geriatric hip fracture patients and identify risk factors for the development of future fragility fractures. MATERIALS AND METHODS/UNASSIGNED:A consecutive series of patients ≥55 years who underwent surgical management of a hip fracture between September 2015 and July 2019 were identified. Chart review was performed to evaluate post-injury follow-up, performance of a bone health evaluation, and use of osteoporosis-related diagnostic and pharmacologic treatment. RESULTS/UNASSIGNED:A total of 832 patients were included. The mean age of the patients was 81.2±9.9 years. Approximately 21% of patients underwent a comprehensive bone health evaluation. Of this cohort, 64.7% were started on pharmacologic therapy, and 73 patients underwent bone mineral density testing. Following discharge from the hospital, 70.3% of the patients followed-up on an outpatient basis with 95.7% seeing orthopedic surgery for post-fracture care. Overall, 102 patients (12.3%) sustained additional fragility fractures within two years, and 31 of these patients (3.7%) sustained a second hip fracture. There was no difference in the rate of second hip fractures or other additional fragility fractures based on the use of osteoporosis medications. CONCLUSION/UNASSIGNED:Management of osteoporosis in geriatric hip fracture patients could be improved. Outpatient follow-up post-hip fracture is almost 70%, yet a minority of patients were started on osteoporosis medications and many sustained additional fragility fractures. The findings of this study indicate that orthopedic surgeons have an opportunity to lead the charge in treatment of osteoporosis in the post-fracture setting.

OBJECTIVES/OBJECTIVE:The objective of this study was to ascertain outcome differences after fixation of unstable rotational ankle fractures allowed to weight-bear 2 weeks postoperatively compared with 6 weeks. DESIGN/METHODS:Prospective case-control study. SETTING/METHODS:Academic medical center; Level 1 trauma center. PATIENT SELECTION CRITERIA/UNASSIGNED:Patients with unstable ankle fractures (OTA/AO:44A-C) undergoing open reduction internal fixation (ORIF) were enrolled. Patients requiring trans-syndesmotic fixation were excluded. Two surgeons allowed weight-bearing at 2 weeks postoperatively (early weight-bearing [EWB] cohort). Two other surgeons instructed standard non-weight-bearing until 6 weeks postoperatively (non-weight-bearing cohort). OUTCOME MEASURES AND COMPARISONS/UNASSIGNED:The main outcome measures included the Olerud-Molander questionnaire, the SF-36 questionnaire, and visual analog scale at 6 weeks, 3 months, 6 months, and 12 months postoperatively and complications, return to work, range of ankle motion, and reoperations at 12 months were compared between the 2 cohorts. RESULTS:One hundred seven patients were included. The 2 cohorts did not differ in demographics or preinjury scores ( P > 0.05). Six weeks postoperatively, EWB patients had improved functional outcomes as measured by the Olerud-Molander and SF-36 questionnaires. Early weight-bearing patients also had better visual analog scale scores (standardized mean difference -0.98, 95% confidence interval [CI] -1.27 to -0.70, P < 0.05) and a greater proportion returning to full capacity work at 6 weeks (odds ratio = 3.42, 95% CI, 1.08-13.07, P < 0.05). One year postoperatively, EWB patients had improved pain measured by SF-36 (standardized mean difference 6.25, 95% CI, 5.59-6.92, P < 0.01) and visual analog scale scores (standardized mean difference -0.05, 95% CI, -0.32 to 0.23, P < 0.01). There were no differences in complications or reoperation at 12 months ( P > 0.05). CONCLUSIONS:EWB patients had improved early function, final pain scores, and earlier return to work, without an increased complication rate compared with those kept non-weight-bearing for 6 weeks. LEVEL OF EVIDENCE/METHODS:Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

IMPORTANCE/UNASSIGNED:Current measures of alopecia areata (AA) severity, such as the Severity of Alopecia Tool score, do not adequately capture overall disease impact. OBJECTIVE/UNASSIGNED:To explore factors associated with AA severity beyond scalp hair loss, and to support the development of the Alopecia Areata Severity and Morbidity Index (ASAMI). EVIDENCE REVIEW/UNASSIGNED:A total of 74 hair and scalp disorder specialists from multiple continents were invited to participate in an eDelphi project consisting of 3 survey rounds. The first 2 sessions took place via a text-based web application following the Delphi study design. The final round took place virtually among participants via video conferencing software on April 30, 2022. FINDINGS/UNASSIGNED:Of all invited experts, 64 completed the first survey round (global representation: Africa [4.7%], Asia [9.4%], Australia [14.1%], Europe [43.8%], North America [23.4%], and South America [4.7%]; health care setting: public [20.3%], private [28.1%], and both [51.6%]). A total of 58 specialists completed the second round, and 42 participated in the final video conference meeting. Overall, consensus was achieved in 96 of 107 questions. Several factors, independent of the Severity of Alopecia Tool score, were identified as potentially worsening AA severity outcomes. These factors included a disease duration of 12 months or more, 3 or more relapses, inadequate response to topical or systemic treatments, rapid disease progression, difficulty in cosmetically concealing hair loss, facial hair involvement (eyebrows, eyelashes, and/or beard), nail involvement, impaired quality of life, and a history of anxiety, depression, or suicidal ideation due to or exacerbated by AA. Consensus was reached that the Alopecia Areata Investigator Global Assessment scale adequately classified the severity of scalp hair loss. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This eDelphi survey study, with consensus among global experts, identified various determinants of AA severity, encompassing not only scalp hair loss but also other outcomes. These findings are expected to facilitate the development of a multicomponent severity tool that endeavors to competently measure various disease impact. The findings are also anticipated to aid in identifying candidates for current and emerging systemic treatments. Future research must incorporate the perspectives of patients and the public to assign weight to the domains recognized in this project as associated with AA severity.

A wooden house frame consists of many different lumber pieces, but because of the regularity of these building blocks, the structure can be designed using straightforward geometrical principles. The design of multicomponent protein assemblies, in comparison, has been much more complex, largely owing to the irregular shapes of protein structures¹. Here we describe extendable linear, curved and angled protein building blocks, as well as inter-block interactions, that conform to specified geometric standards; assemblies designed using these blocks inherit their extendability and regular interaction surfaces, enabling them to be expanded or contracted by varying the number of modules, and reinforced with secondary struts. Using X-ray crystallography and electron microscopy, we validate nanomaterial designs ranging from simple polygonal and circular oligomers that can be concentrically nested, up to large polyhedral nanocages and unbounded straight 'train track' assemblies with reconfigurable sizes and geometries that can be readily blueprinted. Because of the complexity of protein structures and sequence-structure relationships, it has not previously been possible to build up large protein assemblies by deliberate placement of protein backbones onto a blank three-dimensional canvas; the simplicity and geometric regularity of our design platform now enables construction of protein nanomaterials according to 'back of an envelope' architectural blueprints.

PURPOSE/OBJECTIVE:Roux-en-Y gastric bypass (RYGB) leads to the improvement of many obesity-associated conditions. The degree to which post-operative macronutrient composition contributes to metabolic improvement after RYGB is understudied. METHODS:A mouse model of RYGB was used to examine the effects of diet on the post-operative outcomes of RYGB. Obese mice underwent either Sham or RYGB surgery and were administered either chow or HFD and then monitored for an additional 8 weeks. RESULTS:After RYGB, reductions to body weight, fat mass, and lean mass were similar regardless of diet. RYGB and HFD were independently detrimental to bone mineral density and plasma vitamin D levels. Independent of surgery, HFD accelerated hematopoietic stem and progenitor cell proliferation and differentiation and exhibited greater myeloid lineage commitment. Independent of diet, systemic iron deficiency was present after RYGB. In both Sham and RYGB groups, HFD increased energy expenditure. RYGB increased fecal energy loss, and HFD after RYGB increased fecal lipid content. RYGB lowered fasting glucose and liver glycogen levels but HFD had an opposing effect. Indices of insulin sensitivity improved independent of diet. HFD impaired improvements to dyslipidemia, NAFLD, and fibrosis. CONCLUSION/CONCLUSIONS:Post-operative diet plays a significant role in determining the degree to which RYGB reverses obesity-induced metabolic abnormalities such as hyperglycemia, dyslipidemia, and NAFLD. Diet composition may be targeted in order to assist in the treatment of post-RYGB bone mineral density loss and vitamin D deficiency as well as to reverse myeloid lineage commitment. HFD after RYGB continues to pose a significant multidimensional health risk.

Astrocytes are a heterogeneous population of central nervous system glial cells that respond to pathological insults and injury by undergoing a transformation called "reactivity." Reactive astrocytes exhibit distinct and context-dependent cellular, molecular, and functional state changes that can either support or disturb tissue homeostasis. We recently identified a reactive astrocyte sub-state defined by interferon-responsive genes like Igtp, Ifit3, Mx1, and others, called interferon-responsive reactive astrocytes (IRRAs). To further this transcriptomic definition of IRRAs, we wanted to define the proteomic changes that occur in this reactive sub-state. We induced IRRAs in immunopanned rodent astrocytes and human iPSC-differentiated astrocytes using TNF, IL1α, C1Q, and IFNβ and characterized their proteomic profile (both cellular and secreted) using unbiased quantitative proteomics. We identified 2335 unique cellular proteins, including IFIT2/3, IFITM3, OASL1/2, MX1/2/3, and STAT1. We also report that rodent and human IRRAs secrete PAI1, a serine protease inhibitor which may influence reactive states and functions of nearby cells. Finally, we evaluated how IRRAs are distinct from neurotoxic reactive astrocytes (NRAs). While NRAs are described by expression of the complement protein C3, it was not upregulated in IRRAs. Instead, we found ~90 proteins unique to IRRAs not identified in NRAs, including OAS1A, IFIT3, and MX1. Interferon signaling in astrocytes is critical for the antiviral immune response and for regulating synaptic plasticity and glutamate transport mechanisms. How IRRAs contribute to these functions is unknown. This study provides the basis for future experiments to define the functional roles of IRRAs in the context of neurodegenerative disorders.

Microsporidia are eukaryotic, obligate intracellular parasites that infect a wide range of hosts, leading to health and economic burdens worldwide. Microsporidia use an unusual invasion organelle called the polar tube (PT), which is ejected from a dormant spore at ultra-fast speeds, to infect host cells. The mechanics of PT ejection are impressive. Anncaliia algerae microsporidia spores (3-4 μm in size) shoot out a 100-nm-wide PT at a speed of 300 μm/s, creating a shear rate of 3000 s^-1. The infectious cargo, which contains two nuclei, is shot through this narrow tube for a distance of ∼60-140 μm (Jaroenlak et al, 2020) and into the host cell. Considering the large hydraulic resistance in an extremely thin tube and the low-Reynolds-number nature of the process, it is not known how microsporidia can achieve this ultrafast event. In this study, we use Serial Block-Face Scanning Electron Microscopy to capture 3-dimensional snapshots of A. algerae spores in different states of the PT ejection process. Grounded in these data, we propose a theoretical framework starting with a systematic exploration of possible topological connectivity amongst organelles, and assess the energy requirements of the resulting models. We perform PT firing experiments in media of varying viscosity, and use the results to rank our proposed hypotheses based on their predicted energy requirement. We also present a possible mechanism for cargo translocation, and quantitatively compare our predictions to experimental observations. Our study provides a comprehensive biophysical analysis of the energy dissipation of microsporidian infection process and demonstrates the extreme limits of cellular hydraulics.

The ongoing transmission of influenza A viruses (IAV) for the past century continues to be a burden to humans. IAV binds terminal sialic acids (SA) of sugar molecules present within the upper respiratory tract (URT) in order to successfully infect hosts. The two most common SA structures that are important for IAV infection are those with α2,3- and α2,6-linkages. While mice were once considered to be an unsuitable system for studying IAV transmission due to their lack of α2,6-SA in the trachea, we have successfully demonstrated that IAV transmission in infant mice is remarkably efficient. This finding led us to re-evaluate the SA composition of the URT of mice using in situ immunofluorescence and examine its in vivo contribution to transmission for the first time. We demonstrate that mice express both α2,3- and α2,6-SA in the URT and that the difference in expression between infants and adults contributes to the variable transmission efficiencies observed. Furthermore, selectively blocking α2,3-SA or α2,6-SA within the URT of infant mice using lectins was necessary but insufficient at inhibiting transmission, and simultaneous blockade of both receptors was crucial in achieving the desired inhibitory effect. By employing a broadly acting neuraminidase to indiscriminately remove both SA moieties in vivo, we effectively suppressed viral shedding and halted the transmission of different strains of influenza viruses. These results emphasize the utility of the infant mouse model for studying IAV transmission and strongly indicate that broadly targeting host SA is an effective approach that inhibits IAV contagion.IMPORTANCEInfluenza virus transmission studies have historically focused on viral mutations that alter hemagglutinin binding to sialic acid (SA) receptors in vitro. However, SA binding preference does not fully account for the complexities of influenza A virus transmission in humans. Our previous findings reveal that viruses that are known to bind α2,6-SA in vitro have different transmission kinetics in vivo, suggesting that diverse SA interactions may occur during their life cycle. In this study, we examine the role of host SA on viral replication, shedding, and transmission in vivo. We highlight the critical role of SA presence during virus shedding, such that attachment to SA during virion egress is equally important as detachment from SA during virion release. These insights support the potential of broadly acting neuraminidases as therapeutic agents capable of restraining viral transmission in vivo. Our study unveils intricate virus-host interactions during shedding, highlighting the necessity to develop innovative strategies to effectively target transmission.