Efficacy and safety of bendamustine for lymphodepletion before lisocabtagene maraleucel.

Bendamustine has been retrospectively shown to be an effective and safe lymphodepletion regimen prior to the anti-CD19 chimeric antigen receptor T cell (CART) products tisagenlecleucel and axicabtagene ciloleucel, as well as the anti-BCMA CART products idecabtagene vicleucel and ciltacabtagene autoleucel. However, bendamustine as lymphodepletion prior to lisocabtagene maraleucel (liso-cel), a 4-1BB co-stimulated, fixed CD4:CD8 ratio anti-CD19 CART product, has not been described yet. Thus, we studied a cohort of sequentially-treated patients with large B-cell lymphomas who received bendamustine lymphodepletion before liso-cel at the University of Pennsylvania between 5/2021 and 12/2023 (n = 31). Patients were evaluated for toxicities and responses. Of note, 7 patients (22.6%) would have dnot met the inclusion criteria for the registrational liso-cel clinical trials, mostly due to older age. Overall and complete response rates were 76.9% and 73.1%, respectively. At a median follow-up of 6.3 months, the 6-month progression-free and overall survival were 59.9% and 91.1%, respectively. Rates of cytokine-release syndrome (CRS) and neurotoxicity (ICANS) of any grade were 9.7% and 9.7%, respectively, with no grade ≥ 3 events. No infections were reported during the first 30 days following liso-cel infusion. Neutropenia ≥ grade 3 was observed in 29.0% of patients; thrombocytopenia ≥ grade 3 occurred in 9.7%. In conclusion, bendamustine lymphodepletion before liso-cel appears to be a strategy that can drive tumor responses while ensuring a mild toxicity profile.

Inhibition of Estradiol Signaling in the Basolateral Amygdala Impairs Extinction Memory Recall for Heroin-Conditioned Cues in a Sex-Specific Manner.

INTRODUCTION: Relapse is a major treatment barrier for opioid use disorder. Environmental cues become associated with the rewarding effects of opioids and can precipitate relapse, even after numerous unreinforced cue presentations, due to deficits in extinction memory recall (EMR). Estradiol (E2) modulates EMR of fear-related cues, but it is unknown whether E2 impacts EMR of reward cues and what brain region(s) are responsible for E2s effects. Here, we hypothesize that inhibition of E2 signaling in the basolateral amygdala (BLA) will impair EMR of a heroin-associated cue in both male and female rats. METHODS: We pharmacologically manipulated E2 signaling to characterize the role of E2 in the BLA on heroin-cue EMR. Following heroin self-administration, during which a light/tone cue was co-presented with each heroin infusion, rats underwent cued extinction to extinguish the conditioned association between the light/tone and heroin. During extinction, E2 signaling in the BLA was blocked by an aromatase inhibitor or specific estrogen receptor (ER) antagonists. The next day, subjects underwent a cued test to assess heroin-cue EMR. RESULTS: In both experiments, females took more heroin than males (mg/kg) and had higher operant responding during cued extinction. Inhibition of E2 synthesis in the BLA impaired heroin-cue EMR in both sexes. Notably, E2s actions are mediated by different ER mechanisms, ERα in males but ERß in females. CONCLUSIONS: This study is the first to demonstrate a behavioral role for centrally-produced E2 in the BLA and that E2 also impacts EMR of reward-associated stimuli in both sexes.

Bendamustine lymphodepletion before axicabtagene ciloleucel is safe and associates with reduced inflammatory cytokines.

ABSTRACT: Lymphodepletion (LD) is an integral component of chimeric antigen receptor T-cell (CART) immunotherapies. In this study, we compared the safety and efficacy of bendamustine (Benda) to standard fludarabine/cyclophosphamide (Flu/Cy) LD before CD19-directed, CD28-costimulated CART axicabtagene ciloleucel (axi-cel) for patients with large B-cell lymphoma (LBCL) and follicular lymphoma (FL). We analyzed 59 patients diagnosed with LBCL (n = 48) and FL (n = 11) consecutively treated with axi-cel at the University of Pennsylvania. We also analyzed serum samples for cytokine levels and metabolomic changes before and after LD. Flu/Cy and Benda demonstrated similar efficacy, with complete remission rates of 51.4% and 50.0% (P = .981), respectively, and similar progression-free and overall survivals. Any-grade cytokine-release syndrome occurred in 91.9% of patients receiving Flu/Cy vs 72.7% of patients receiving Benda (P = .048); any-grade neurotoxicity after Flu/Cy occurred in 45.9% of patients and after Benda in 18.2% of patients (P = .031). In addition, Flu/Cy was associated with a higher incidence of grade ≥3 neutropenia (100% vs 54.5%; P < .001), infections (78.4% vs 27.3%; P < .001), and neutropenic fever (78.4% vs 13.6%; P < .001). These results were confirmed both in patients with LBCL and those with FL. Mechanistically, patients with Flu/Cy had a greater increase in inflammatory cytokines associated with neurotoxicity and reduced levels of metabolites critical for redox balance and biosynthesis. This study suggests that Benda LD may be a safe alternative to Flu/Cy for CD28-based CART CD19-directed immunotherapy with similar efficacy and reduced toxicities. Benda is associated with reduced levels of inflammatory cytokines and increased anabolic metabolites.

Structural and functional interactions between the EF hand domain and S2-S3 loop in the type-1 ryanodine receptor ion channel.

Previous cryo-electron micrographs suggested that the skeletal muscle Ca2+ release channel, ryanodine receptor (RyR)1, is regulated by intricate interactions between the EF hand Ca2+ binding domain and the cytosolic loop (S2-S3 loop). However, the precise molecular details of these interactions and functional consequences of the interactions remain elusive. Here, we used molecular dynamics simulations to explore the specific amino acid pairs involved in hydrogen bond interactions within the EF hand-S2-S3 loop interface. Our simulations unveiled two key interactions: (1) K4101 (EF hand) with D4730 (S2-S3 loop) and (2) E4075, Q4078, and D4079 (EF hand) with R4736 (S2-S3 loop). To probe the functional significance of these interactions, we constructed mutant RyR1 complementary DNAs and expressed them in HEK293 cells for [3H]ryanodine binding assays. Our results demonstrated that mutations in the EF hand, specifically K4101E and K4101M, resulted in reduced affinities for Ca2+/Mg2+-dependent inhibitions. Interestingly, the K4101E mutation increased the affinity for Ca2+-dependent activation. Conversely, mutations in the S2-S3 loop, D4730K and D4730N, did not significantly change the affinities for Ca2+/Mg2+-dependent inhibitions. Our previous finding that skeletal disease-associated RyR1 mutations, R4736Q and R4736W, impaired Ca2+-dependent inhibition, is consistent with the current results. In silico mutagenesis analysis aligned with our functional data, indicating altered hydrogen bonding patterns upon mutations. Taken together, our findings emphasize the critical role of the EF hand-S2-S3 loop interaction in Ca2+/Mg2+-dependent inhibition of RyR1 and provide insights into potential therapeutic strategies targeting this domain interaction for the treatment of skeletal myopathies.

Perirhinal to prefrontal circuit in methamphetamine induced recognition memory deficits.

Return to methamphetamine (meth) use is part of an overarching addictive disorder hallmarked by cognitive sequela and cortical dysfunction in individuals who use meth chronically. In rats, long access meth self-administration produces object recognition memory deficits due to drug-induced plasticity within the perirhinal cortex (PRH). PRH projections are numerous and include the medial prefrontal cortex (mPFC). To evaluate the role of the PRH-mPFC reciprocal circuit in novel object recognition memory, a rgAAV encoding GFP-tagged Cre recombinase was infused into the PRH or the mPFC and rats were tested for recognition memory. On test day, one group explored both familiar and novel objects. A second group explored only familiar objects. GFP and Fos expression were visualized in the mPFC or PRH. During exploration, PRH neurons receiving input from the mPFC were equally activated by exploration of novel and familiar objects. In contrast, PRH neurons that provide input to the mPFC were disproportionately activated by novel objects. Further, the percent of Fos + cells in the PRH positively correlated with recognition memory. As such, the flow of communication appears to be from the PRH to the mPFC. In agreement with this proposed directionality, chemogenetic inhibition of the PRH-mPFC circuit impaired object recognition memory, whereas chemogenetic activation in animals with a history of long access meth self-administration reversed the meth-induced recognition memory deficit. This finding informs future work aimed at understanding the role of the PRH, mPFC, and their connectivity in meth associated memory deficits. These data suggest a more complex circuitry governing recognition memory than previously indicated with anatomical or lesion studies.

Social solidarity, social infrastructure, and community food access.

This study examines the case of community resource mobilization within the context of a farmers market incentive program in Washington D.C., USA to illustrate the ways in which providing opportunities for people impacted by food inequities to develop and lead programming can help to promote food access. Through an analysis of interviews with 36 participants in the Produce Plus program, some of whom also served as paid staff and volunteers with the program, this study examines the ways that group-level social interactions among program participants helped to ensure the program was accessible and accountable to the primarily Black communities that it serves. Specifically, we explore a particular set of social interactions, which we collectively term social solidarity, as a community-level form of social infrastructure that program volunteers and participants mobilized to support access to fresh, local food in their communities. We also examine the elements of the Produce Plus program that contributed to the flow of social solidarity within the program, providing insight into the ways in which the structure of food access programs can serve as a social conduit to facilitate or hinder the mobilization of community cultural resources like social solidarity.

Matrix metalloproteinase activity during methamphetamine cued relapse.

Relapse to drug seeking involves transient synaptic remodelling that occurs in response to drug-associated cues. This remodelling includes activation of matrix metalloproteinases (MMPs) to initiate catalytic signalling in the extracellular matrix in the nucleus accumbens core (NAcore). We hypothesized that MMP activity would be increased in the NAcore during cue-induced methamphetamine (meth) seeking in a rat model of meth use and relapse. Male and female rats had indwelling jugular catheters and bilateral intracranial cannula targeting the NAcore surgically implanted. Following recovery, rats underwent meth or saline self-administration (6 h/day for 15 days) in which active lever responding was paired with a light + tone stimulus complex, followed by home cage abstinence. Testing occurred after 7 or 30 days of abstinence. On test day, rats were microinjected with a fluorescein isothiocyanate (FITC)-quenched gelatin substrate that fluoresces following cleavage by MMP-2,9, allowing for the quantification of gelatinase activity during cued-relapse testing. MMP-2,9 activity was significantly increased in the NAcore by meth cues presentation after 7 and 30 days of abstinence, indicating that remodelling by MMPs occurs during presentation of meth associated cues. Surprisingly, although cue-induced seeking increased between Days 7 and 30, MMP-2,9 activity did not increase. These findings indicate that although MMP activation is elicited during meth cue-induced seeking, MMP activation did not parallel the meth seeking that occurs during extended drug abstinence.

EBV-positive PCNSL in older patients: incidence, characteristics, tumor pathology, and outcomes across a large multicenter cohort.

The objective of this multicenter retrospective study was to examine the incidence, patient characteristics, pathology, and outcomes associated with Epstein-Barr virus (EBV)-related CNS lymphoma (CNSL) in older patients. Among 309 CNSL patients aged ≥60, 11.7% had EBV + tumors of which 72.2% were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD). Younger age, SOT or autoimmune disease, and immunosuppressive treatment correlated highly with EBV-positivity. EBV + tumors were associated with absent C-MYC and BCL6 expression. EBV + PTLD was more likely to be associated with the absence of CD5 expression. EBV + non-PTLD had better median OS (not reached) compared to EBV + PTLD (10.8 months) and EBV-negative patients (43 months). Multivariable Cox regression analysis showed that age, performance status, and PTLD were negative predictors of OS. EBV status and immunosuppressive treatment were not correlated with OS. Our findings merit further investigation of EBV + PCNSL tumors and EBV-directed therapies.

Older patients with primary central nervous system lymphoma: Survival and prognostication across 20 U.S. cancer centers.

There is a paucity of large-scale data delineating outcomes and prognostication of older patients with primary central nervous system lymphoma (PCNSL). We retrospectively analyzed 539 newly-diagnosed PCNSL patients ages ≥60 years across 20 U.S. academic centers. The median age was 70 years (range 60-88); at least one geriatric syndrome was present in 46%; the median Cumulative Index Ratings Scale-Geriatrics (CIRS-G) score was 6 (range, 0-27); and 36% had impairment in activities of daily living (ADL). The most common induction regimens were high-dose methotrexate (HD-MTX) ± rituximab; methotrexate, temozolomide, rituximab (MTR); and rituximab, methotrexate, procarbazine, vincristine (R-MPV). Overall, 70% of patients achieved remission, with 14% undergoing consolidative autologous stem cell transplant (ASCT) and 24% receiving maintenance. With 58-month median follow-up, median progression-free survival (PFS) and overall survival (OS) were 17 months (95% CI 13-22 months) and 43 months (95% CI 31-56 months), respectively. Three-year PFS and OS were highest with MTR (55% and 74%, respectively). With single-agent methotrexate ± rituximab, 3-year PFS and OS were 30% (p = .0002) and 47% (p = .0072). On multivariate analysis, increasing age at diagnosis and Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS; age, hypoalbuminemia, higher CIRS-G score, and ECOG PS adversely affected OS. Among patients receiving maintenance, 3-year PFS was 65% versus 45% without maintenance (p = 0.02), with 3-year OS of 84% versus 61%, respectively (p = .0003). Altogether, outcomes in older PCNSL patients appeared optimized with HD-MTX combination induction regimens and maintenance therapy. Furthermore, several prognostic factors, including geriatric measures, were associated with inferior outcomes.

Primary Repair versus Reverse End-to-Side Coaptation by Anterior Interosseous Nerve Transfer in Proximal Ulnar Nerve Injuries.

BACKGROUND: Proximal ulnar nerve lacerations are challenging to treat because of the complex integration of sensory and motor function in the hand. The purpose of this study was to compare primary repair and primary repair plus anterior interosseous nerve (AIN) reverse end-to-side (RETS) coaptation in the setting of proximal ulnar nerve injuries. METHODS: A prospective cohort study was performed of all patients at a single, academic, level I trauma center from 2014 to 2018 presenting with isolated complete ulnar nerve lacerations. Patients underwent either primary repair (PR) only or primary repair and AIN RETS (PR + RETS). Data collected included demographic information; quick Disabilities of the Arm, Shoulder and Hand questionnaire score; Medical Research Council score; grip and pinch strength; and visual analogue scale pain scores at 6 and 12 months postoperatively. RESULTS: Sixty patients were included in the study: 28 in the PR group and 32 in the RETS + PR group. There was no difference in demographic variables or location of injury between the two groups. Average quick Disabilities of the Arm, Shoulder and Hand questionnaire scores for the PR and PR + RETS groups were 65 ± 6 and 36 ± 4 at 6 months and 46 ± 4 and 24 ± 3 at 12 months postoperatively, respectively, and were significantly lower in the PR + RETS group at both points. Average grip and pinch strength were significantly greater for the PR + RETS group at 6 and 12 months. CONCLUSION: This study demonstrated that primary repair of proximal ulnar nerve injuries plus AIN RETS coaptation yielded superior strength and improved upper extremity function when compared with PR alone. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

NPAS4 in the medial prefrontal cortex mediates chronic social defeat stress-induced anhedonia-like behavior and reductions in excitatory synapses.

Chronic stress can produce reward system deficits (i.e., anhedonia) and other common symptoms associated with depressive disorders, as well as neural circuit hypofunction in the medial prefrontal cortex (mPFC). However, the molecular mechanisms by which chronic stress promotes depressive-like behavior and hypofrontality remain unclear. We show here that the neuronal activity-regulated transcription factor, NPAS4, in the mPFC is regulated by chronic social defeat stress (CSDS), and it is required in this brain region for CSDS-induced changes in sucrose preference and natural reward motivation in the mice. Interestingly, NPAS4 is not required for CSDS-induced social avoidance or anxiety-like behavior. We also find that mPFC NPAS4 is required for CSDS-induced reductions in pyramidal neuron dendritic spine density, excitatory synaptic transmission, and presynaptic function, revealing a relationship between perturbation in excitatory synaptic transmission and the expression of anhedonia-like behavior in the mice. Finally, analysis of the mice mPFC tissues revealed that NPAS4 regulates the expression of numerous genes linked to glutamatergic synapses and ribosomal function, the expression of upregulated genes in CSDS-susceptible animals, and differentially expressed genes in postmortem human brains of patients with common neuropsychiatric disorders, including depression. Together, our findings position NPAS4 as a key mediator of chronic stress-induced hypofrontal states and anhedonia-like behavior.

Paraventricular Nucleus of the Hypothalamus Oxytocin and Incubation of Heroin Seeking.

INTRODUCTION: There are numerous pharmacologic treatments for opioid use disorder (OUD), but none that directly target the underlying addictive effects of opioids. Oxytocin, a peptide hormone produced in the paraventricular nucleus (PVN) of the hypothalamus, has been investigated as a potential therapeutic for OUD. Promising preclinical and clinical results have been reported, but the brain region(s) and mechanism(s) by which oxytocin impacts reward processes remain undetermined. METHODS: Here, we assess peripherally administered oxytocin's impacts on cued reinstatement of heroin seeking following forced abstinence and its effects on neuronal activation in the PVN and key projection regions. We also examine how designer receptors exclusively activated by designer drug (DREADD)-mediated activation or inhibition of oxytocinergic PVN neurons alters cued heroin seeking and social interaction. RESULTS: As predicted, peripheral oxytocin administration successfully decreased cued heroin seeking on days 1 and 30 of abstinence. Oxytocin administration also led to increased neuronal activity within the PVN and the central amygdala (CeA). Activation of oxytocinergic PVN neurons with an excitatory (Gq) DREADD did not impact cued reinstatement or social interaction. In contrast, suppression with an inhibitory (Gi) DREADD reduced heroin seeking on abstinence day 30 and decreased time spent interacting with a novel conspecific. DISCUSSION: These findings reinforce oxytocin's therapeutic potential for OUD, the basis for which may be driven in part by increased PVN-CeA circuit activity. Our results also suggest that oxytocin has distinct signaling and/or other mechanisms of action to produce these effects, as inhibition, but not activation, of oxytocinergic PVN neurons did not recapitulate the suppression in heroin seeking.

Primary Repair of Upper Extremity Peripheral Nerve Injuries: An NSQIP Analysis From 2010 to 2016.

BACKGROUND: To identify the rate of 30-day complications after primary repair of upper extremity peripheral nerve injuries, associated diagnoses, and postoperative complication rate. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was reviewed from 2010 to 2016. Current Procedural Terminology codes consistent with primary nerve repair of the upper extremity were identified and included in the analysis. Patient demographics, comorbidities, type of procedure (elective/emergent), wound class, operative time, and 30-day complications were recorded. Patients with isolated upper extremity nerve injuries (isolated) were compared with those with peripheral nerve injuries in addition to bone, tendon, or soft tissue injuries (multiple). RESULTS: In all, 785 patients were identified as having upper extremity nerve repairs (0.16%). Of them, 64% were men and 36% were women; the average patient age was 40 years. The most common indication for surgery was injury to the digits (54% of cases). Thirty-day adverse events occurred in 3% of all cases. Isolated nerve injury occurred in 43% of patients, whereas 57% had additional injuries. The multiple injury group had a significantly higher complication rate compared with the isolated group (1% vs 4.5%) (P = .007). Repair of tendon at forearm or wrist was the most common concurrent procedure performed. CONCLUSIONS: Thirty-day complications among upper extremity peripheral nerve injuries are low, accounting for 3% of cases. Return to the operating room accounted for nearly half of all complications. Patients in the multiple injury group accounted for more than half of these and had a significantly higher complication rate compared with patients with isolated nerve injuries.

Negative pressure wound therapy on complex extremity wounds requiring coverage with a meshed bilayer wound matrix: a retrospective analysis.

OBJECTIVE: The treatment of complex extremity wounds is technically challenging. In this 5-year retrospective review, we compared the use of Integra Meshed Bilayer Wound Matrix (IMBWM; Integra LifeSciences, US) followed by a split-thickness skin graft (STSG) combined with negative pressure wound therapy (NPWT) versus IMBWM followed by STSG alone for the management of these wounds. METHOD: Data from patients undergoing management using IMBWM for a complex extremity wound coverage were collected. RESULTS: Among the 109 patients studied, the wounds of 62 patients were managed using IMBWM and NPWT, and 47 were managed using IMBWM alone. The most common aetiology of these injuries was trauma. Wound size and location were similar for each group, ranging in size from 2-30cm2 and being primarily on the forearm, followed by the leg and arm. There was a significantly greater take of the IMBWM+STSG with NPWT (96.8%) compared to without NPWT (85.1%, p=0.03). There were significantly fewer reapplications of the dermal matrix required in the NPWT group (3.2%) versus the non-NPWT group (14.9%, p=0.03). There were significantly fewer postoperative complications, prior to STSG, in the NPWT group (3.2%) versus the non-NPWT group (14.9%, p=0.03). CONCLUSION: The combination of IMBWM with NPWT leads to a higher success rate, and can reduce the number of dermal matrix reapplications and postoperative complications, in the setting of complex extremity wounds. The use of IMBWM in combination with NPWT has the potential to improve both surgical procedures and patient outcomes in this setting.

Medical Management of Septic Arthritis of the Sternoclavicular Joint With Extended-Spectrum Beta-Lactamase-Producing Escherichia coli: A Case Report.

The sternoclavicular joint (SCJ) is an uncommon location for septic arthritis to occur in. Due to the rarity of the condition and the nonspecific symptoms, SCJ septic arthritis can be missed or mislabeled as osteoarthritis or muscle strain. Accurate history and physical examination is crucial for recognizing this condition. With the potential life-threatening complications that may ensue, SCJ septic arthritis has traditionally been managed surgically. This ranges from simple incision and drainage to resection of the joint. However, in cases where there is not enough fluid for incision and drainage, a trial of medical management with antibiotics can be attempted. We herein describe a case of a 58-year-old male who presented with nonspecific anterior chest wall and neck pain. Chest X-ray and ultrasound of the anterior chest wall was normal; however, magnetic resonance imaging (MRI) of the chest showed a small effusion without other complications. His blood cultures grew extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli, rendering this as his hematogenous source of septic arthritis. The ESBL was from a left-sided obstructing kidney stone that resulted in pyelonephritis, which was confirmed via computed tomography of the abdomen. His effusion was too minimal to drain; therefore, he was managed medically with intravenous (IV) antibiotics along with a left ureteral stent placement, and he had a full recovery. This case represents the ability for SCJ septic arthritis to be managed medically with IV antibiotics, especially when the diagnosis is caught early without complications. The role of MRI is indispensable for coming to the diagnosis, as it is capable of detecting complications that ultimately dictate management. Additionally, this case highlights the unique microorganism, ESBL-producing E. coli causing the SCJ septic arthritis, a finding that has been rarely reported in the literature as the majority of microorganisms that have been previously documented are either Staphylococcus aureus or Pseudomonas aeruginosa.

Validity of Using the Scratch Collapse Test in the Lower Extremities.

BACKGROUND: The scratch collapse test is a provocative test that has been successfully used for peripheral neuropathies. The elbow is the main testing site, but there may be times when use of the upper extremities is contraindicated. This study sought to determine the sensitivity of using the scratch collapse test on the lower extremity for upper extremity neuropathies. METHODS: One hundred patients with an electromyographically confirmed diagnosis of carpal tunnel or cubital tunnel syndrome were prospectively enrolled. As a control, the scratch collapse test was conducted normally using the elbow as a testing site. After a baseline was established, the test was repeated using eversion of the foot and ankle against an inversion force. RESULTS: Of the 100 study patients, 89 had a positive scratch collapse test on the upper extremity and 84 had a positive test on the lower extremity. In the 51 patients with carpal tunnel syndrome, 45 had a positive test on the upper extremity (sensitivity, 88.2 percent; 95 percent CI, 76.13 to 95.56 percent), and 42 had a positive test of the lower extremity (sensitivity, 82.35 percent; 95 percent CI, 69.13 to 91.60 percent). In the 49 patients with cubital tunnel syndrome, 44 had a positive test on the upper extremity (sensitivity, 89.8 percent; 95 percent CI, 77.77 to 96.6 percent), and 42 had a positive test on the lower extremity (sensitivity, 85.7 percent; 95 percent CI, 72.76 to 94.06 percent). CONCLUSION: There were no statistically significant differences in the sensitivities of the scratch collapse test on the upper or lower extremities, suggesting that the lower extremity could serve as an alternative site for the scratch collapse test. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II.

Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice.

Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.

Posterior approach to the elbow for insertion of the internal joint stabilizer.

Management of unstable injuries was revolutionized by the Internal Joint Stabilizer (IJS). When compared to long-term immobilization, transarticular pinning, and hinge external fixation, the IJS results in decreased complications and improved clinical outcomes. Historically, the IJS was applied via a lateral approach; however, this limited intraoperative visualization and, in some cases, resulted in increased operative times. This technical report describes a posterior approach, for IJS application. The posterior approach involves an 8- to 10-cm incision over the posterior elbow through the deep fascia before identifying the olecranon and lateral capitellum, then proceeding with IJS application through manufacturer instructions. The ulnar and radial nerves must be identified as they could be damaged in this approach. Using the posterior approach at our institution, we have noticed a possible decrease in operative times and an increase in intraoperative visualization of the elbow without a subsequent increase in complications.

Publication Trends of Residents Accepted for Shoulder and Elbow Fellowships.

This study aims to evaluate the research productivity trends in orthopaedic residents who were selected for shoulder and elbow fellowships from 2010 to 2019. We hypothesize that residents matching into orthopaedic shoulder and elbow fellowships are increasing both their publication number and publication quality from 2010 to 2019. Fellows of orthopaedic shoulder and elbow programs from 2010 to 2019 were identified through publicly accessible information on fellowship programs. Each fellow's publication data during their residency was collected via publicly available search engines, and analyzed to include: fellowship year, residency years, fellowship program and location, total publications, number of publications in high-impact general orthopaedic and shoulder and elbow journals, and authorship position. A total of 176 orthopaedic shoulder and elbow fellows from 17 different programs were identified and included in the study. The fellows produced a total of 668 publications, published 172 articles in high impact journals, and had first authorship on 49% of the studies. On average, there were 3.8 publications per fellow per year from 2010 to 2019. There were 5.7 publications produced per fellow in 2018-2019, compared to just 2.92 publications per fellow in 2010-2011. Overall, there was an increasing trend in publications, publications in high impact journals, and first authorship publications per applicant matching into shoulder and elbow fellowship from 2010 to 2019. (Journal of Surgical Orthopaedic Advances 31(4):205-208, 2022).

Complex Interactions Between Sex and Stress on Heroin Seeking.

Rationale: Stress plays a dual role in substance use disorders as a precursor to drug intake and a relapse precipitant. With heroin use at epidemic proportions in the United States, understanding interactions between stress disorders and opioid use disorder is vital and will aid in treatment of these frequently comorbid conditions. Objectives: Here, we combine assays of stress and contingent heroin self-administration (SA) to study behavioral adaptations in response to stress and heroin associated cues in male and female rats. Methods: Rats underwent acute restraint stress paired with an odor stimulus and heroin SA for subsequent analysis of stress and heroin cue reactivity. Lofexidine was administered during heroin SA and reinstatement testing to evaluate its therapeutic potential. Rats also underwent tests on the elevated plus maze, locomotor activity in a novel environment, and object recognition memory following stress and/or heroin. Results: A history of stress and heroin resulted in disrupted behavior on multiple levels. Stress rats avoided the stress conditioned stimulus and reinstated heroin seeking in response to it, with males reinstating to a greater extent than females. Lofexidine decreased heroin intake, reinstatement, and motor activity. Previous heroin exposure increased time spent in the closed arms of an elevated plus maze, activity in a round novel field, and resulted in object recognition memory deficits. Discussion: These studies report that a history of stress and heroin results in maladaptive coping strategies and suggests a need for future studies seeking to understand circuits recruited in this pathology and eventually help develop therapeutic approaches.