The impact of race and ethnicity on diffuse large B-cell lymphoma outcomes within the veterans health administration (VHA).

We performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. The 3178 patients who met inclusion criteria were predominantly male (97%) and white (75%). Median age of diagnosis for Black patients was 63 years vs 69 years for the entire cohort (p < 0.001). However, patients in each race/ethnicity subgroup presented with similar rates of stage I/II and III/IV disease, IPI score, cell of origin and HIT status. Outcomes analysis revealed similar treatment, response rates, median overall survival, and 1-, 3-, and 5-year survival across all subgroups. Hispanic patients had a 21% lower risk of death (HR = 0.79) than white patients, and Black patients had no significant difference in survival (HR = 0.98). This large retrospective study shows that when standard of care therapy is given within an equal access system, short-term treatment and survival outcomes are the same for all races.

Durvalumab Treatment Patterns for Patients with Unresectable Stage III Non-Small Cell Lung Cancer in the Veterans Health Administration (VHA): A Nationwide, Real-World Study.

BACKGROUND: Durvalumab is approved for the treatment of adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This real-world study describes patient characteristics and durvalumab treatment patterns (number of doses and therapy duration; treatment initiation delays, interruptions, discontinuations, and associated reasons) among VHA-treated patients. METHODS: This was a retrospective cohort study of adults with unresectable stage III NSCLC receiving durvalumab at the VHA between 1 January 2017 and 30 June 2020. Patient characteristics and treatment patterns were presented descriptively. RESULTS: A total of 935 patients were included (median age: 69 years; 95% males; 21% Blacks; 46% current smokers; 16% ECOG performance scores ≥ 2; 50% squamous histology). Durvalumab initiation was delayed in 39% of patients (n = 367). Among the 200 patients with recorded reasons, delays were mainly due to physician preference (20%) and CRT toxicity (11%). Overall, patients received a median (interquartile range) of 16 (7-24) doses of durvalumab over 9.0 (2.9-11.8) months. Treatment interruptions were experienced by 19% of patients (n = 180), with toxicity (7.8%) and social reasons (2.6%) being the most cited reasons. Early discontinuation occurred in 59% of patients (n = 551), largely due to disease progression (24.2%) and toxicity (18.2%). CONCLUSIONS: These real-world analyses corroborate PACIFIC study results in terms of the main reasons for treatment discontinuation in a VHA population with worse prognostic factors, including older age, predominantly male sex, and poorer performance score. One of the main reasons for durvalumab initiation delays, treatment interruptions, or discontinuations was due to toxicities. Patients could benefit from improved strategies to prevent, identify, and manage CRT and durvalumab toxicities timely and effectively.

Health Equity in Patients Receiving Durvalumab for Unresectable Stage III Non-Small Cell Lung Cancer in the US Veterans Health Administration.

BACKGROUND: Real-world evidence is limited regarding the relationship between race and use of durvalumab, an immunotherapy approved for use in adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This study aimed to evaluate if durvalumab treatment patterns differed by race in patients with unresectable stage III NSCLC in a Veterans Health Administration (VHA) population. MATERIALS AND METHODS: This was a retrospective analysis of White and Black adults with unresectable stage III NSCLC treated with durvalumab presenting to any VHA facility in the US from January 1, 2017, to June 30, 2020. Data captured included baseline characteristics and durvalumab treatment patterns, including treatment initiation delay (TID), interruption (TI), and discontinuation (TD); defined as CRT completion to durvalumab initiation greater than 42 days, greater than 28 days between durvalumab infusions, and more than 28 days from the last durvalumab dose with no new durvalumab restarts, respectively. The number of doses, duration of therapy, and adverse events were also collected. RESULTS: A total of 924 patients were included in this study (White = 726; Black = 198). Race was not a significant factor in a multivariate logistic regression model for TID (OR, 1.39; 95% CI, 0.81-2.37), TI (OR, 1.58; 95% CI, 0.90-2.76), or TD (OR, 0.84; 95% CI, 0.50-1.38). There were also no significant differences in median (interquartile range [IQR]) number of doses (White: 15 [7-24], Black: 18 [7-25]; P = .25) or median (IQR) duration of therapy (White: 8.7 months [2.9-11.8], Black: 9.8 months [3.6-12.0]; P = .08), although Black patients were less likely to experience an immune-related adverse event (28% vs. 36%, P = .03) and less likely to experience pneumonitis (7% vs. 14%, P < .01). CONCLUSION: Race was not found to be linked with TID, TI, or TD in this real-world study of patients with unresectable stage III NSCLC treated with durvalumab at the VHA.

Prospective evaluation of the prevalence of non-alcoholic fatty liver disease and steatohepatitis in a large middle-aged US cohort.

BACKGROUND & AIMS: Large prospective studies to establish the prevalence of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), are lacking. We prospectively assessed the prevalence and severity of NAFLD/NASH in a cohort of asymptomatic middle-aged Americans attending a colonoscopy class at a gastroenterology clinic. METHODS: Screening for NAFLD was performed using magnetic resonance (MR)-based LiverMultiScan® proton density fat fraction (LMS-PDFF). MR exams also included corrected T1 and elastography for liver stiffness measurement (LSM). FibroScan® was also used to measure LSM. Participants with predetermined abnormal imaging parameters were offered a liver biopsy. Biopsies were read in a blinded fashion with results based on the consensus by 2 expert pathologists. The prevalence of NAFLD was determined by PDFF ≥5% or by histological diagnosis of NAFLD (if biopsy data were available). The prevalence of NASH was defined by biopsy. RESULTS: Of 835 participants, 664 met the inclusion and exclusion criteria. The mean age was 56 ± 6.4 years, 50% were male, the mean BMI was 30.48 ± 5.46 kg/m2, and 52% were obese. The prevalence of NAFLD was 38% (95% CI 34-41%) and the prevalence of NASH was 14% (95% CI 12-17%). While no patient had cirrhosis on biopsy, significant fibrosis (F ≥2) was present in 5.9% (95% CI 4-8%) and bridging fibrosis in 1.6% (95% CI 1-3%). In a multivariable analysis, factors associated with the presence of NASH were race, obesity, and diabetes. CONCLUSION: Using state-of-the-art liver imaging modalities and reference biopsy, this study establishes an overall prevalence of NAFLD of 38% and NASH by biopsy of 14% in this cohort of asymptomatic middle-aged US adults. LAY SUMMARY: There are no prospective studies to determine how common is nonalcoholic steatohepatitis (NASH), the severe form of non-alcoholic fatty liver disease (NAFLD). In a large number of asymptomatic middle-aged Americans, we used a combination of state-of-the-art liver imaging methods and liver biopsy to prospectively determine the prevalence of NAFLD and NASH. NAFLD was diagnosed in 38%, NASH in 14%, and significant liver fibrosis in 6% of asymptomatic middle-aged Americans.

Feasibility of a paediatric radiology escape room for undergraduate education.

OBJECTIVES: To develop a paediatric radiology themed escape room session for undergraduate education and secondly, to determine participant satisfaction and improvement in knowledge. METHODS: A paediatric radiology escape room with accompanying tutorial was developed around key learning objectives set within the RCR and ESR undergraduate curriculum. Students were recruited from two different universities and undertook the escape room themed teaching. An 8-question single best answer (SBA) test was completed before, immediately after and at 2 weeks post-teaching to determine participant improvement and retention of knowledge. The general feedback was also collected. RESULTS: The escape room sessions were held three times, for 19 students (6-7 students per session). All groups completed the escape room in ≤ 20 min. Students enjoyed the experience, assigning an average satisfaction score of 9.4/10 (range 7-10). The majority (17/19, 89.5%) preferred this method of teaching to a lecture-based tutorial alone, although all said they found the tutorial component useful. For the SBA test, there was an average increase in 3.6 marks (range 1-6 marks) per participant between before and after the escape room. This improved knowledge was mostly sustained after 2 weeks, with an average increase of 3.4 marks difference (range 1 to 6) per participant compared to before the teaching. CONCLUSIONS: A paediatric radiology themed escape room is a feasible teaching method, enjoyed by participants and associated with an increase in radiological knowledge. Further work with larger sample size and direct comparison with other traditional teaching methods is required.

Utility and variability of three non-invasive liver fibrosis imaging modalities to evaluate efficacy of GR-MD-02 in subjects with NASH and bridging fibrosis during a phase-2 randomized clinical trial.

BACKGROUND: Given the worldwide prevalence of NAFLD and NASH, there is a need to develop treatments to slow or reverse disease progression. GR-MD-02 (galactoarabino-rhamnogalaturonate) has been shown to reduce hepatic fibrosis in animal studies, and lower serum biomarkers of NASH fibrogenesis in humans. The primary aim of this study was to determine the difference between four-months of treatment with GR-MD-02 or placebo in liver inflammation and fibrosis as measured by iron-corrected T1 (cT1) mapping, a non-invasive magnetic resonance imaging (MRI) biomarker that correlates with the extent of hepatic fibro-inflammatory disease. The secondary aims were to determine change in liver stiffness as measured by magnetic resonance elastography (MRE) and shear-wave ultrasonic elastography (LSM), and to explore test-retest repeatability of the three biomarkers. MATERIALS AND METHODS: Thirty subjects (13 females, 46-71 years) with NASH and advanced fibrosis were recruited. Subjects were randomized to receive 8 mg.kg-1 GR-MD-02 (via IV infusion) or placebo, administered biweekly over a 16-week period. Therapeutic efficacy was examined using cT1, MRE, and LSM. Statistical analyses on group differences in the biomarkers were performed using robust ANCOVA models adjusting for baseline measurement and additional covariates. RESULTS: There was no significant difference in cT1 (p = 0.16) between GR-MD-02 and placebo groups following a 16-week intervention. There was also no significant difference in liver stiffness, measured by MRE (p = 0.80) or LSM (p = 0.63), between groups. Examination of repeatability of the cT1, MRE and LSM revealed coefficient of variations of 3.1%, 11% and 40% respectively. CONCLUSIONS: 8 mg.kg-1 of GR-MD-02 had no significant effect on non-invasive biomarkers of liver inflammation or fibrosis over a 4-month period. Histological confirmation was not available in this study. The high reproducibility of the primary outcome measure suggests that cT1 could be utilized for monitoring longitudinal change in patients with NASH.

Moving beyond sex: Assessing the impact of gender identity on human papillomavirus vaccine recommendations and uptake among a national sample of rural-residing LGBT young adults.

BACKGROUND: While national human papillomavirus (HPV) vaccination estimates exist by sex, little is known about HPV vaccination rates by gender identity. METHODS: We conducted a self-administered, anonymous online cross-sectional survey, with recruitment through Facebook ads, of lesbian, gay, bisexual, and transgender individuals in rural areas of the US. We compared HPV vaccine recommendation and uptake by self-reported sex assigned at birth and current gender identity. RESULTS: Six hundred sixty respondents were age eligible for HPV vaccination: 84% reported gender identity aligned with their sex assigned at birth, while 10% reported gender identity the differed from their sex assigned at birth; an additional 6% reported non-binary gender identity. Only 14% of male sex assigned at birth and 44% of female sex assigned at birth received HPV vaccine, similar to estimates by current gender identity. Transgender respondents' HPV vaccination experience mirrored that of cisgender respondents with regard to sex assigned at birth. CONCLUSIONS: Providers may base HPV vaccine recommendations on individuals' sex assigned at birth, which may impact transgender individuals' vaccine coverage. Future HPV vaccine uptake studies should account for gender identity. With sex-specific catch-up HPV vaccination recommendations, the role of gender identity on provider recommendation and reimbursement needs to be addressed.

Evaluation of a Powered Ankle-Foot Prosthesis during Slope Ascent Gait.

Passive prosthetic feet lack active plantarflexion and push-off power resulting in gait deviations and compensations by individuals with transtibial amputation (TTA) during slope ascent. We sought to determine the effect of active ankle plantarflexion and push-off power provided by a powered prosthetic ankle-foot (PWR) on lower extremity compensations in individuals with unilateral TTA as they walked up a slope. We hypothesized that increased ankle plantarflexion and push-off power would reduce compensations commonly observed with a passive, energy-storing-returning prosthetic ankle-foot (ESR). We compared the temporal spatial, kinematic, and kinetic measures of ten individuals with TTA (age: 30.2 ± 5.3 yrs) to matched abled-bodied (AB) individuals during 5° slope ascent. The TTA group walked with an ESR and separately with a PWR. The PWR produced significantly greater prosthetic ankle plantarflexion and push-off power generation compared to an ESR and more closely matched AB values. The PWR functioned similar to a passive ESR device when transitioning onto the prosthetic limb due to limited prosthetic dorsiflexion, which resulted in similar deviations and compensations. In contrast, when transitioning off the prosthetic limb, increased ankle plantarflexion and push-off power provided by the PWR contributed to decreased intact limb knee extensor power production, lessening demand on the intact limb knee.

Whole-body angular momentum during sloped walking using passive and powered lower-limb prostheses.

Sloped walking requires altered strategies for maintaining dynamic balance relative to level-ground walking, as evidenced by changes in sagittal-plane whole-body angular momentum (H) in able-bodied individuals. The ankle plantarflexor muscles are critical for regulating H, and functional loss of these muscles from transtibial amputation affects this regulation. However, it is unclear if a powered prosthesis, which more closely emulates intact ankle function than a passive energy-storage-and-return prosthesis, affects H differently during sloped walking. Therefore, our purpose was to investigate H in individuals with unilateral transtibial amputation when using powered and passive prostheses. Overall, the range of H was greater in people with a transtibial amputation relative to able-bodied individuals. On a -10° decline, individuals with amputation did not decrease H as much as able-bodied individuals, and had reduced prosthetic limb braking ground reaction forces and knee power absorption. On a +10° incline, individuals with amputation had a greater relative increase of H than able-bodied individuals, a more anterior placement of the prosthetic foot, and higher peak hip power generation. The powered prosthesis condition resulted in a smaller range of H during prosthetic stance relative to the passive condition, although it was still larger than able-bodied individuals. Our results suggest that prosthetic ankle power generation may help regulate dynamic balance during prosthetic stance, but alone is not sufficient for restoring H to that of able-bodied individuals on slopes. Contributions of knee extensor muscles and the biarticular gastrocnemius in regulating H on slopes should be further investigated.

Stair ascent and descent biomechanical adaptations while using a custom ankle-foot orthosis.

The ability to navigate stairs step-over-step is an important functional outcome following severe lower leg injury and is difficult for many patients. Ankle-foot orthoses, such as the Intrepid Dynamic Exoskeletal Orthosis (IDEO), are often prescribed to improve function. This study compared stair climbing mechanics between IDEO users and able-bodied control participants. Thirteen IDEO users who sustained severe lower leg injury and 13 controls underwent biomechanical gait analysis. Participants ascended and descended a 16-step instrumented staircase without handrail use at a controlled cadence of 80 steps/min. Peak joint angles, moments, powers, and ground reaction forces, and integrated mechanical work were calculated. Independent t-tests with Bonferroni-Holm corrections were used to compare controls to IDEO and sound limbs. Reduced ankle range of motion on the IDEO limb resulted in compensatory strategies while ascending or descending stairs. During ascent, IDEO users had greater bilateral hip power during pull-up (p<0.007) to compensate for the IDEO limb׳s reduced ankle dorsiflexion (p<0.001) and knee extensor moment (p=0.001) while it was leading, and reduced ankle plantarflexor power while it was trailing (p<0.001). During stair descent, when the IDEO limb had was trailing, it had less ankle dorsiflexion during controlled lowering (p<0.001), resulting in greater vertical ground reaction force (p=0.005) and greater ankle and knee power absorption (p<0.001). Reduced IDEO limb ankle power absorption during weight acceptance (p<0.001) resulted in a large knee extensor moment (p<0.001) on the trailing sound limb to lower the body. Despite gait deviations, IDEO users were able to climb stairs step-over-step unassisted.

Step-to-step transition work during level and inclined walking using passive and powered ankle-foot prostheses.

BACKGROUND: Individuals with leg amputations who use passive prostheses have greater metabolic demands than non-amputees likely due to limited net positive work compared to a biological ankle. New powered ankle-foot prostheses can perform net positive mechanical work to aid push-off capabilities, which may reduce metabolic demands. OBJECTIVES: Compare step-to-step transition work and metabolic demand during level and inclined walking using passive and powered ankle-foot prostheses. STUDY DESIGN: Repeated measures. METHODS: Six individuals with transtibial amputation and six able-bodied controls walked at a standardized speed across level ground and up a 5° incline. Calculated measures included mechanical work during step-to-step transitions from the trailing prosthetic to leading intact limb, steady state metabolic rate, and ankle joint kinetics and kinematics. RESULTS: The powered prosthesis generated 63% greater trailing limb step-to-step transition work than the passive during level walking only (p = 0.004). Metabolic rate was lower with the powered prosthesis during level (p = 0.006) but not inclined walking (p = 0.281). The powered prosthesis increased ankle power compared to the passive, to the extent that power was normalized to controls during inclined walking and greater than controls during level walking. CONCLUSION: The powered prosthesis improved ankle power, metabolic rate, and step-to-step transition work on level ground, with few negative consequences on inclines. These results may be used to guide the development and use of actively powered prosthetic devices in high-functioning individuals. CLINICAL RELEVANCE: Overall, powered devices offer biomechanical and metabolic benefits over passive energy storage and return designs on level ground and perform as well as a passive model on inclines. The lower metabolic demand when using the powered device may delay fatigue for individuals with transtibial amputation when walking over level ground.

Sound limb loading in individuals with unilateral transfemoral amputation across a range of walking velocities.

BACKGROUND: Individuals with unilateral transfemoral amputation demonstrate significantly increased rates of osteoarthritis in their sound knee. This increased risk is likely the result of altered knee mechanical loading and gait compensations resulting from limited function in the prosthetic limb. Altered knee loading as calculated using loading rates and peak external knee adduction moments and impulses have been associated with both the development and progression of knee osteoarthritis in other populations. The purpose of this study was to determine if young individuals with transfemoral amputation demonstrate biomechanical indicators of increased knee osteoarthritis risk. METHODS: Fourteen young male Service Members with unilateral transfemoral amputation and 14 able-bodied service members underwent biomechanical gait analysis at three standardized walking velocities. A two-way ANOVA (group × speed) with unpaired comparisons with Bonferroni-Holm post-hoc corrections assessed statistical significance and effect sizes (d) were calculated. FINDINGS: Normalized peak external knee adduction moments and impulses were 25.7% (P < 0.014, d > 0.994) and 27.1% (P < 0.012, d > 1.019) lower, respectively, in individuals with trans-femoral amputation than controls when averaged across speeds, and effect sizes were large. External knee flexor moments were not, however, different between groups and effect sizes were generally small (P > 0.380, d < 0.338). Maximal loading rates were significantly greater in individuals with amputation and effect sizes were large (P < 0.001, d > 1.644). INTERPRETATION: Individuals with transfemoral amputation did not demonstrate biomechanical risk factors for high medial compartment knee joint loads, but the increased loading rates could place the sound knee at greater risk for cartilage or other tissue damage, even if not localized to the medial compartment.

Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis.

Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically.

Does a microprocessor-controlled prosthetic knee affect stair ascent strategies in persons with transfemoral amputation?

BACKGROUND: Stair ascent can be difficult for individuals with transfemoral amputation because of the loss of knee function. Most individuals with transfemoral amputation use either a step-to-step (nonreciprocal, advancing one stair at a time) or skip-step strategy (nonreciprocal, advancing two stairs at a time), rather than a step-over-step (reciprocal) strategy, because step-to-step and skip-step allow the leading intact limb to do the majority of work. A new microprocessor-controlled knee (Ottobock X2(®)) uses flexion/extension resistance to allow step-over-step stair ascent. QUESTIONS/PURPOSES: We compared self-selected stair ascent strategies between conventional and X2(®) prosthetic knees, examined between-limb differences, and differentiated stair ascent mechanics between X2(®) users and individuals without amputation. We also determined which factors are associated with differences in knee position during initial contact and swing within X2(®) users. METHODS: Fourteen individuals with transfemoral amputation participated in stair ascent sessions while using conventional and X2(®) knees. Ten individuals without amputation also completed a stair ascent session. Lower-extremity stair ascent joint angles, moment, and powers and ground reaction forces were calculated using inverse dynamics during self-selected strategy and cadence and controlled cadence using a step-over-step strategy. RESULTS: One individual with amputation self-selected a step-over-step strategy while using a conventional knee, while 10 individuals self-selected a step-over-step strategy while using X2(®) knees. Individuals with amputation used greater prosthetic knee flexion during initial contact (32.5°, p = 0.003) and swing (68.2°, p = 0.001) with higher intersubject variability while using X2(®) knees compared to conventional knees (initial contact: 1.6°, swing: 6.2°). The increased prosthetic knee flexion while using X2(®) knees normalized knee kinematics to individuals without amputation during swing (88.4°, p = 0.179) but not during initial contact (65.7°, p = 0.002). Prosthetic knee flexion during initial contact and swing were positively correlated with prosthetic limb hip power during pull-up (r = 0.641, p = 0.046) and push-up/early swing (r = 0.993, p < 0.001), respectively. CONCLUSIONS: Participants with transfemoral amputation were more likely to self-select a step-over-step strategy similar to individuals without amputation while using X2(®) knees than conventional prostheses. Additionally, the increased prosthetic knee flexion used with X2(®) knees placed large power demands on the hip during pull-up and push-up/early swing. A modified strategy that uses less knee flexion can be used to allow step-over-step ascent in individuals with less hip strength.

The suprascapular nerve and its articular branch to the acromioclavicular joint: an anatomic study.

HYPOTHESIS: The suprascapular nerve and its articular branch innervate the acromioclavicular (AC) joint. Documenting the detailed anatomy of this innervation in the AC joint, including the pertinent surgical and anatomic relationships of the suprascapular nerve and its branches to the AC joint, will aid in the prevention of injury and the reduction of risk of denervation during shoulder surgery. MATERIALS AND METHODS: Twelve shoulders from 6 embalmed human cadavers were bilaterally dissected to study the course of the suprascapular nerve and its motor and sensory branches. RESULTS: The sensory branch runs superiorly to the supraspinatus muscle towards the AC joint. The average distance from the supraglenoid tubercle to the nerve at the coracoid base was 15 mm. The average distance from the coracoclavicular ligaments to the nerve at the coracoid base was 6 mm. The average distance from the spinoglenoid notch to the sensory branch at the suprascapular notch was 22 mm. The average length of the sensory branch was 30 mm. In half of the specimen shoulders, the suprascapular artery accompanied the nerve at the suprascapular notch under the transverse scapular ligament. DISCUSSION: The innervation of the AC joint by the suprascapular nerve has been described, along with pertinent distances to anatomic landmarks. The sensory branch of the suprascapular nerve, which passed through the scapular notch inferior to the transverse scapular ligament, was found in 100% of the study specimens. CONCLUSION: The sensory branch of the suprascapular nerve runs superiorly to the supraspinatus muscle towards the AC joint. The detailed information can be used to help decrease the risk of nerve injury during shoulder surgery and to aid in effectively diagnosing and treating AC joint-related disorders.

The neuroplasticity-associated arc gene is a direct transcriptional target of early growth response (Egr) transcription factors.

Early growth response (Egr) transcription factors (Egr1 to Egr4) are synaptic activity-inducible immediate early genes (IEGs) that regulate some aspects of synaptic plasticity-related to learning and memory, yet the target genes regulated by them are unknown. In particular, Egr1 is essential for persistence of late-phase long-term potentiation (L-LTP), for hippocampus-dependent long-term memory formation, and for reconsolidation of previously established memories. Here, we show that Egr1 and Egr3 directly regulate the plasticity-associated activity-regulated cytoskeletal-related (Arc) gene, a synaptic activity-induced effector molecule which is also required for L-LTP and hippocampus-dependent learning and memory processing. Moreover, Egr1-deficient and Egr3-deficient mice lack Arc protein in a subpopulation of neurons, while mice lacking both Egr1 and Egr3 lack Arc in all neurons. Thus, Egr1 and Egr3 can indirectly modulate synaptic plasticity by directly regulating Arc and the plasticity mechanisms it mediates in recently activated synapses.

Transcriptional regulation of myotube fate specification and intrafusal muscle fiber morphogenesis.

Vertebrate muscle spindle stretch receptors are important for limb position sensation (proprioception) and stretch reflexes. The structurally complex stretch receptor arises from a single myotube, which is transformed into multiple intrafusal muscle fibers by sensory axon-dependent signal transduction that alters gene expression in the contacted myotubes. The sensory-derived signal transduction pathways that specify the fate of myotubes are very poorly understood. The zinc finger transcription factor, early growth response gene 3 (Egr3), is selectively expressed in sensory axon-contacted myotubes, and it is required for normal intrafusal muscle fiber differentiation and spindle development. Here, we show that overexpression of Egr3 in primary myotubes in vitro leads to the expression of a particular repertoire of genes, some of which we demonstrate are also regulated by Egr3 in developing intrafusal muscle fibers within spindles. Thus, our results identify a network of genes that are regulated by Egr3 and are involved in intrafusal muscle fiber differentiation. Moreover, we show that Egr3 mediates myotube fate specification that is induced by sensory innervation because skeletal myotubes that express Egr3 independent of other sensory axon regulation are transformed into muscle fibers with structural and molecular similarities to intrafusal muscle fibers. Hence, Egr3 is a target gene that is regulated by sensory innervation and that mediates gene expression involved in myotube fate specification and intrafusal muscle fiber morphogenesis.

Glial cell-line derived neurotrophic factor-dependent fusimotor neuron survival during development.

Glial cell-line derived neurotrophic factor (GDNF) is a potent survival factor for motor neurons. Previous studies have shown that some motor neurons depend upon GDNF during development but this GDNF-dependent motor neuron subpopulation has not been characterized. We examined GDNF expression patterns in muscle and the impact of altered GDNF expression on the development of subtypes of motor neurons. In GDNF hemizygous mice, motor neuron innervation to muscle spindle stretch receptors (fusimotor neuron innervation) was decreased, whereas in transgenic mice that overexpress GDNF in muscle, fusimotor innervation to muscle spindles was increased. Facial motor neurons, which do not contain fusimotor neurons, were not changed in number when GDNF was over expressed by facial muscles during their development. Taken together, these data indicate that fusimotor neurons depend upon GDNF for survival during development. Since the fraction of cervical and lumbar motor neurons lost in GDNF-deficient mice at birth closely approximates the size of the fusimotor neuron pool, these data suggest that motor neuron loss in GDNF-deficient mice may be primarily of fusimotor neuron origin.