Faculty Bibliography

Much is known about molecular mechanisms by which animals detect pathogenic microbes, but how animals sense beneficial microbes remains poorly understood. The roundworm Caenorhabditis elegans is a microbivore that must distinguish nutritive microbes from pathogens. We characterized a neural circuit used by C. elegans to rapidly discriminate between nutritive bacteria and pathogens. Distinct sensory neuron populations responded to chemical cues from nutritive Escherichia coli and pathogenic Enterococcus faecalis, and these neural signals are decoded by downstream AIB interneurons. The polyamine metabolites cadaverine, putrescine, and spermidine produced by E. coli activate this neural circuit and elicit positive chemotaxis. Our study shows how polyamine odorants can be sensed by animals as proxies for microbe identity and suggests that, hence, polyamines might have widespread roles brokering host-microbe interactions.

RNA polymerase II (RNA Pol II) can backtrack during transcription elongation, exposing the 3' end of nascent RNA. Nascent RNA sequencing can approximate the location of backtracking events that are quickly resolved; however, the extent and genome-wide distribution of more persistent backtracking are unknown. Consequently, we developed a method to directly sequence the extruded, "backtracked" 3' RNA. Our data show that RNA Pol II slides backward more than 20 nt in human cells and can persist in this backtracked state. Persistent backtracking mainly occurs where RNA Pol II pauses near promoters and intron-exon junctions and is enriched in genes involved in translation, replication, and development, where gene expression is decreased if these events are unresolved. Histone genes are highly prone to persistent backtracking, and the resolution of such events is likely required for timely expression during cell division. These results demonstrate that persistent backtracking can potentially affect diverse gene expression programs.

Alopecia is traditionally classified into scarring and nonscarring subtypes, with etiopathologies ranging from androgen-mediated to immuno-inflammatory. Over 50% of men and almost 50% of women will experience some form of hair loss in their lifetime. Given this prevalence and the psychosocial significance of hair, understanding the pathophysiology and comorbidities of different types of hair loss is imperative. Other proinflammatory dermatologic disorders, such as psoriasis, are recognised to have systemic manifestations including an increased risk of cardiovascular (CV) disease, and are now considered CV risk-enhancing conditions. With increased recognition of the importance of systemic inflammation in promoting atherosclerosis, high prevalence, and improved treatment strategies, there is increased interest in establishing whether a similar association between alopecia and cardiovascular disease (CVD) exists. In this manuscript, we aim to review the current literature regarding CV risk in androgenic alopecia (AGA) and alopecia areata (AA). Additionally, we review the literature for cicatricial alopecias and highlight the need for more research into their potential associations with CV risk. Evidence from the identified AGA publications suggests an association of AGA with CV risk factors including hypertension, dyslipidemia, and insulin resistance, as well as with coronary artery disease. For AA, most of the identified studies found an association between AA and CV risk, though the relationships were not always statistically significant. Research on cicatricial alopecias and CV risk is limited and often contradictory. There is great need for more studies regarding the association between various types of alopecia and the development of CVD, and potential mechanisms. Particularly needed are more studies of cicatricial alopecias and potential associated CV risk. While some literature suggests that patients with alopecia have an increased risk of CVD, the lack of concrete evidence represents a notable gap in our current understanding.

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 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.

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.

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.

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.

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.