Elevated risk of recurrence and retreatment for silent pituitary adenomas.

PURPOSE: Pituitary adenomas are the most common tumor of the pituitary gland and comprise nearly 15% of all intracranial masses. These tumors are stratified into functional or silent categories based on their pattern of hormone expression and secretion. Preliminary evidence supports differential clinical outcomes between some functional pituitary adenoma (FPA) subtypes and silent pituitary adenoma (SPA) subtypes. METHODS: We collected and analyzed the medical records of all patients undergoing resection of SPAs or FPAs from a single high-volume neurosurgeon between 2007 and 2018 at Brigham and Women's Hospital. Descriptive statistics and the Mantel-Cox log-rank test were used to identify differences in outcomes between these cohorts, and multivariate logistic regression was used to identify predictors of radiographic recurrence for SPAs. RESULTS: Our cohort included 88 SPAs and 200 FPAs. The majority of patients in both cohorts were female (48.9% of SPAs and 63.5% of FPAs). SPAs were larger in median diameter than FPAs (2.1 cm vs. 1.2 cm, p < 0.001). The most frequent subtypes of SPA were gonadotrophs (55.7%) and corticotrophs (30.7%). Gross total resection (GTR) was achieved in 70.1% of SPA resections and 86.0% of FPA resections (p < 0.001). SPAs had a higher likelihood of recurring (hazard ratio [HR] 3.2, 95% confidence interval [95%CI] 1.6-7.2) and a higher likelihood of requiring retreatment for recurrence (HR 2.5; 95%CI 1.0-6.1). Subset analyses revealed that recurrence and retreatment were more both likely for subtotally resected SPAs than subtotally resected FPAs, but this pattern was not observed in SPAs and FPAs after GTR. Among SPAs, recurrence was associated with STR (odds ratio [OR] 9.3; 95%CI 1.4-64.0) and younger age (OR 0.92 per year; 95%CI 0.88-0.98) in multivariable analysis. Of SPAs that recurred, 12 of 19 (63.2%) were retreated with repeat surgery (n = 11) or radiosurgery (n = 1), while the remainder were observed (n = 7).There were similar rates of recurrence across different SPA subtypes. CONCLUSION: Patients undergoing resection of SPAs should be closely monitored for disease recurrence through more frequent clinical follow-up and diagnostic imaging than other adenomas, particularly among patients with STR and younger patients. Several patients can be observed after radiographic recurrence, and the decision to retreat should be individualized. Longitudinal clinical follow-up of SPAs, including an assessment of symptoms, endocrine function, and imaging remains critical.

The relationship between expressive suppression, therapeutic bond, and treatment outcomes of a positive affect intervention for adults with anxiety and/or depression.

Expressive suppression (ES; reducing emotional expression) is linked with reduced social connectedness in individuals with anxiety or depression. One implication is that people who use ES may have difficulty establishing a bond with their therapist which may impede clinical improvement. We examined this hypothesis in 33 adults with clinically elevated anxiety or depression receiving treatment focused on enhancing positive thoughts, emotions, and behaviors. At baseline, participants rated ES for positive and negative emotions during a standardized conversation task designed to generate connectedness. They also rated measures of early (session 3) perceived therapeutic bond and treatment outcomes (i.e. positive affect and social connectedness). ES of positive (r = -.39, p = .018), but not negative (r = .06, p = .747), emotions was negatively associated with therapeutic bond. Therapeutic bond mediated the relationship between greater ES of positive emotions during affiliation and lower post-treatment positive affect, 95% bias-corrected bootstrap confidence interval [-0.021, -0.000], adjusted for pre-treatment positive affect, as well as lower post-treatment social connectedness [-0.397, -0.015]; however, the indirect effect was not significant when accounting for pre-treatment social connectedness (p > .05). ES of positive emotions may be an important factor in the development of therapeutic bond and therefore treatment outcomes for individuals with anxiety or depression.

Baseline executive functioning moderates treatment-related changes in quality of life in veterans with posttraumatic stress disorder and comorbid traumatic brain injury.

Posttraumatic stress disorder (PTSD) treatment has been associated with improvement in quality of life (QOL); however, little is known about factors that moderate treatment-related changes in QOL, particularly cognitive factors. Executive functioning (EF) is important for success across all aspects of everyday life and predicts better psychological and physical health. EF is important to QOL, but more work is needed to better understand the association between EF and QOL improvements following interventions. We hypothesized that poorer baseline EF would be associated with less improvement in overall life satisfaction and satisfaction with health following PTSD treatment. U.S. veterans who served after the September 11, 2001 terrorist attacks (post 9-11; N = 80) with PTSD and a history of mild-to-moderate traumatic brain injury were randomized to standard cognitive processing therapy (CPT) or CPT combined with cognitive rehabilitation (SMART-CPT). Multilevel modeling was used to examine whether baseline EF performance was associated with changes in QOL scores from pretreatment to follow-up across both groups. Results indicated that poorer baseline performance on EF tests of working memory and inhibition were associated with less treatment-related improvements in general life satisfaction and satisfaction with health, rs = .26-.36. Treatment condition did not moderate any results. Future research should examine whether implementing EF-focused techniques before and/or concurrently with CPT for individuals with poorer baseline working memory and inhibition enhances QOL treatment gains, particularly in terms of general life and health-related satisfaction.

Endoscopic Versus Open Carpal Tunnel Surgery: Risk Factors and Rates of Revision Surgery.

PURPOSE: The purpose of our study was to compare the 1-year revision surgery rates and outcomes of open versus endoscopic carpal tunnel release. Our hypothesis was that, compared to open release, endoscopic carpal tunnel release was an independent risk factor for revision surgery within 1-year. METHODS: This was a retrospective cohort study of 4338 patients undergoing isolated endoscopic or open carpal tunnel release. Demographic data, medical comorbidities, surgical approach, need for revision surgery, hand dominance, history of prior injection, and Patient Reported Outcomes Measurement Information System upper extremity (UE), pain interference (PI) and physical function scores were analyzed. Multivariable analysis was used to identify the risk factors for revision surgery within one year of the index procedure. RESULTS: In total, 3280 patients (76%) underwent open and 1058 (24%) underwent endoscopic carpal tunnel release. Within one year of the index procedure, 45 patients required revision carpal tunnel release. The average time to revision was 143 days. The rate of revision carpal tunnel release in the open group was 0.71% compared to 2.08% in the endoscopic group. Multivariable analysis demonstrated that endoscopic surgery, male sex, cubital tunnel syndrome, tobacco use, and diabetes were associated independently with revision surgery. CONCLUSIONS: In this study, we found that endoscopic carpal tunnel release was associated independently with a 2.96 times greater likelihood of requiring revision carpal tunnel release within one year, compared to open carpal tunnel release. Male sex, concurrent cubital tunnel syndrome, tobacco use, and diabetes also were associated independently with greater risk of needing revision carpal tunnel release within one year. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

Teaching through the screen: a toolbox for creating a virtual neurosurgical subinternship program.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic disrupted the landscape of traditional neurosurgical subinternships, ramifications of which persist to this day. The outright cancellation of in-person subinternships in 2020 presented not only a challenge to both applicants and programs, but also an opportunity to establish an effective and efficient platform for virtual neurosurgical training. To address this need, the authors designed and trialed a novel virtual neurosurgical subinternship (Virtual Sub-I). METHODS: The weeklong, case-based Virtual Sub-I program combined flipped-classroom and active learning approaches. Students worked in small groups to discuss neurosurgical cases. Faculty and residents offered personalized mentorship sessions to participants. Surveys were used to assess students' experience with the authors' subinternship program, consistent with level 1 of the Kirkpatrick model. RESULTS: A total of 132 students applied from both international and American medical schools. The final cohort comprised 27 students, of whom 8 (30%) were female and 19 (70%) were male. Students characterized the subinternship as "interactive," "educational," and "engaging." One hundred percent of survey respondents were "very likely" to recommend the Virtual Sub-I to their peers. Faculty involved in the Virtual Sub-I stated that the program allowed them to determine the fit of participating medical students for their neurosurgery residency program, and that information gathered from the Virtual Sub-I had the potential to influence their ranking decisions. CONCLUSIONS: The Virtual Sub-I recapitulates the educational and interpersonal benefits of the traditional subinternship experience and can serve as a prototype for future virtual surgical education endeavors. Furthermore, the Virtual Sub-I presents a more equitable platform for introducing medical students across the undergraduate medical education spectrum to neurosurgical education and mentorship.

Self-efficacy and coping style in Iraq and Afghanistan-era veterans with and without mild traumatic brain injury and posttraumatic stress disorder.

OBJECTIVE: To examine self-efficacy and coping style in combat-exposed Veterans with and without mild traumatic brain injury (mTBI) history and posttraumatic stress disorder (PTSD). METHODS: Veterans (N = 81) were categorized into four groups: comorbid mTBI and PTSD (n = 23), PTSD-only (n = 16), mTBI-only (n = 25), and combat-exposed controls (n = 17). Outcomes included the Self-Efficacy for Symptom Management Scale and the Brief Coping Orientation to Problems Experienced. RESULTS: Significant group effects were found on self-efficacy and coping style, even when adjusting for total mTBIs and psychiatric comorbidities. Post-hoc analyses revealed that the comorbid and PTSD-only groups generally had lower self-efficacy than the mTBI-only and control groups and that the PTSD-only group used less action-focused coping than the mTBI-only and control groups. CONCLUSION: Our results suggest that self-efficacy and coping style vary as a function of mTBI history and PTSD status and that it may be important to integrate these malleable factors into interventions for this population.

Psychological Symptoms and Rates of Performance Validity Improve Following Trauma-Focused Treatment in Veterans with PTSD and History of Mild-to-Moderate TBI.

OBJECTIVE: Iraq and Afghanistan Veterans with posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) history have high rates of performance validity test (PVT) failure. The study aimed to determine whether those with scores in the invalid versus valid range on PVTs show similar benefit from psychotherapy and if psychotherapy improves PVT performance. METHOD: Veterans (N = 100) with PTSD, mild-to-moderate TBI history, and cognitive complaints underwent neuropsychological testing at baseline, post-treatment, and 3-month post-treatment. Veterans were randomly assigned to cognitive processing therapy (CPT) or a novel hybrid intervention integrating CPT with TBI psychoeducation and cognitive rehabilitation strategies from Cognitive Symptom Management and Rehabilitation Therapy (CogSMART). Performance below standard cutoffs on any PVT trial across three different PVT measures was considered invalid (PVT-Fail), whereas performance above cutoffs on all measures was considered valid (PVT-Pass). RESULTS: Although both PVT groups exhibited clinically significant improvement in PTSD symptoms, the PVT-Pass group demonstrated greater symptom reduction than the PVT-Fail group. Measures of post-concussive and depressive symptoms improved to a similar degree across groups. Treatment condition did not moderate these results. Rate of valid test performance increased from baseline to follow-up across conditions, with a stronger effect in the SMART-CPT compared to CPT condition. CONCLUSION: Both PVT groups experienced improved psychological symptoms following treatment. Veterans who failed PVTs at baseline demonstrated better test engagement following treatment, resulting in higher rates of valid PVTs at follow-up. Veterans with invalid PVTs should be enrolled in trauma-focused treatment and may benefit from neuropsychological assessment after, rather than before, treatment.

The diagnosis and management of primary and iatrogenic soft tissue sarcomas of the sella.

PURPOSE: Soft tissue sarcoma (STS) of the sella is exceptionally rare. We conducted a case series, literature review, and nationwide analysis of primary and iatrogenic (radiation-associated) STS of the sella to define the clinical course of this entity. METHODS: This study employed a multi-institutional retrospective case review, literature review, and nationwide analysis using the National Cancer Database (NCDB). RESULTS: We report five patients who were diagnosed at three institutions with malignant STS of the sella. All patients presented with symptoms related to mass effect in the sellar region. All tumors extended to the suprasellar space, with the majority displaying extension into the cavernous sinus. All patients underwent an operation via a transsphenoidal approach with a goal of maximal safe tumor resection in four patients and biopsy for 1 patient. Histopathologic evaluation demonstrated STS in all patients. Post-operative adjuvant radiotherapy and chemotherapy were given to 2 and 1 out of 4 patients with known post-operative clinical course, respectively. The 1-year and 5-year overall survival rates were 100% (5/5) and 25% (1/4). Twenty-two additional reports of primary, non-iatrogenic STS of the sella were identified in the literature. Including the three cases from our series, treatment included resection in all cases, and adjuvant radiotherapy and chemotherapy were utilized in 50% (12/24) and 17% (4/24) of cases, respectively. The national prevalence of malignant STS is estimated to be 0.01% among all pituitary and sellar tumors within the NCDB. CONCLUSIONS: We report the prevalence and survival rates of STS of the sella. Multimodal therapy, including maximal safe resection, chemotherapy, and radiotherapy are necessary to optimize outcomes for this uncommon pathology.

The Role of Pain Catastrophizing in Cognitive Functioning Among Veterans With a History of Mild Traumatic Brain Injury.

OBJECTIVE: To determine the role of pain catastrophizing (PC) in neuropsychological functioning in veterans with a history of mild traumatic brain injury (TBI). PARTICIPANTS: Thirty-nine Iraq and Afghanistan combat veterans evaluated in the post-acute phase following mild TBI. METHODS: Participants underwent psychiatric and TBI clinical interviews, neuropsychological tests, and self-report assessments of PC, pain intensity, depression, and posttraumatic stress disorder symptoms. Cognitive functioning composite scores of executive functioning, processing speed, and learning and memory were created. Composites were entered as dependent variables into separate linear regressions to examine relations with PC. RESULTS: Greater PC was associated with worse executive functioning and processing speed even when controlling for confounding variables. CONCLUSIONS: One's interpretation of pain, in addition to pain intensity, has implications for cognitive functioning. Future research is encouraged to determine whether adaptive pain coping mechanisms improve cognitive functioning or, alternatively, whether cognitive rehabilitation strategies reduce PC.

Pilot investigation of a novel white matter imaging technique in Veterans with and without history of mild traumatic brain injury.

OBJECTIVE: The objective of this study is to assess utility of in vivo myelin imaging in combat Veterans with and without history of mild traumatic brain injury (mTBI). We hypothesized that those with history of mTBI would have lower myelin water fraction (MWF), a marker of myelin integrity and content, than those without, and lower MWF would be associated with worse speeded attention/processing speed. RESEARCH DESIGN: Combat Veterans (N = 70) with (n = 42) and without history of mTBI (n = 28) underwent neuroimaging including a novel myelin-sensitive magnetic resonance imaging technique (multicomponent-driven equilibrium single-pulse observation of T1/T2; mcDESPOT) and comprehensive neuropsychological assessment. RESULTS: There were no group differences in MWF using a region-of-interest approach. An exploratory analysis applying limited spatial constraints, however, revealed significantly more 'potholes' (clusters of low MWF) in Veterans with history of mTBI compared to those without. Lower MWF across several ROIs was associated with worse performance on a speeded attention task across groups. CONCLUSION: Veterans in the post-acute period following mTBI showed limited and spatially heterogeneous MWF changes and myelin integrity was significantly related to processing speed. This preliminary evidence for usefulness of mcDESPOT in combat Veterans with history of mTBI warrants future research to determine mcDESPOT's relative utility compared to techniques such as diffusion tensor imaging.

Positive and negative affect change following psychotherapeutic treatment for anxiety-related disorders: A systematic review and meta-analysis.

BACKGROUND: Anxiety-related disorders feature elevated negative affect (NA), and in some cases, diminished positive affect (PA). It remains unclear how well extant psychotherapies for anxiety-related disorders improve PA versus NA. METHODS: We systematically searched the Cochrane Central Register of Controlled Trials, PubMed, PsychInfo, and Web of Science databases. Records included studies involving (1) patients with a principal or co-principal diagnosis of at least one anxiety-related disorder (i.e., generalized anxiety, social anxiety, panic, agoraphobia, health anxiety, specific phobia, obsessive-compulsive disorder, or posttraumatic stress disorder), and (2) pre- and post-treatment PA and NA scores or a change index between pre- and post-treatment PA and NA scores. Effect sizes were calculated for meta-analyses. RESULTS: Fourteen studies with 1001 adults with an anxiety-related disorder were included. Psychotherapeutic interventions included cognitive behavioral, present-centered, and imagery-based approaches. Treatments reduced NA (g = -0.90; 95%CI [-1.19, -0.61]) to a greater extent than they improved PA (g = 0.27; 95%CI [0.05, 0.59]), Z = -5.26, p < .001. The limited number of studies available precluded analyses of the relationship between changes in affect and symptoms. LIMITATIONS: Results should be considered with caution given the small number and heterogeneity of included studies. CONCLUSIONS: Current psychotherapeutic interventions for anxiety-related disorders may not improve PA and NA to comparable levels.

Differential Time-To-Promotion Trajectories Among Female and Male Neurosurgeons Contribute to Gender Disparities in Academic Rank Achievement.

OBJECTIVE: Despite the increasing representation of females in neurosurgical training, the fraction of female to male neurosurgeons decreases dramatically as faculty rank (Assistant, Associate, or Full Professor) increases. To assess this discrepancy, we quantified self-reported time-to-promotion trajectories for female and male neurosurgeons holding academic appointments. METHODS: In this cross-sectional institutional review board (IRB)-approved study, 147 female and 84 male neurosurgeons currently holding faculty positions in the US were contacted via email and invited to complete an anonymous, standardized survey. Respondents provided the calendar year of postgraduate training completion, promotion to different faculty ranks, geographic region of current practice (Western, Midwest, Southern, Northeast), and practice subspecialty. RESULTS: The response rate was 44.2% for females and 59.5% for males, with 114 participants included (65 female, 49 male). On average, female neurosurgeons required 25% longer to become an Associate Professor (P = 0.017), 34% longer to become a Full Professor (P = 0.004), 37% longer for promotion from Assistant to Associate Professor (P < 0.001), and 32% longer from Assistant to Full Professor (P = 0.012). Promotion timelines did not vary by region or specialty among male and female cohorts. Linear regressions revealed that female neurosurgeons with more recent training completion experienced shorter time-to-promotion to Associate and Full Professor compared to females of earlier generations (P = 0.005 and 0.001, respectively), while male timelines remained stable. CONCLUSIONS: This study identifies a significant delay in time-to-promotion for female neurosurgeons compared to their male counterparts. Investigation and standardization of promotion timelines are necessary to ensure meaningful representation gains from the increased number of women entering neurosurgical training.

Recruitment in Appalachian, Rural and Older Adult Populations in an Artificial Intelligence World: Study Using Human-Mediated Follow-Up.

BACKGROUND: Participant recruitment in rural and hard-to-reach (HTR) populations can present unique challenges. These challenges are further exacerbated by the need for low-cost recruiting, which often leads to use of web-based recruitment methods (eg, email, social media). Despite these challenges, recruitment strategy statistics that support effective enrollment strategies for underserved and HTR populations are underreported. This study highlights how a recruitment strategy that uses email in combination with follow-up, mostly phone calls and email reminders, produced a higher-than-expected enrollment rate that includes a diversity of participants from rural, Appalachian populations in older age brackets and reports recruitment and demographic statistics within a subset of HTR populations. OBJECTIVE: This study aims to provide evidence that a recruitment strategy that uses a combination of email, telephonic, and follow-up recruitment strategies increases recruitment rates in various HTR populations, specifically in rural, older, and Appalachian populations. METHODS: We evaluated the overall enrollment rate of 1 recruitment arm of a larger study that aims to understand the relationship between genetics and substance use disorders. We evaluated the enrolled population's characteristics to determine recruitment success of a combined email and follow-up recruitment strategy, and the enrollment rate of HTR populations. These characteristics included (1) enrollment rate before versus after follow-up; (2) zip code and county of enrollee to determine rural or urban and Appalachian status; (3) age to verify recruitment in all eligible age brackets; and (4) sex distribution among age brackets and rural or urban status. RESULTS: The email and follow-up arm of the study had a 17.4% enrollment rate. Of the enrolled participants, 76.3% (4602/6030) lived in rural counties and 23.7% (1428/6030) lived in urban counties in Pennsylvania. In addition, of patients enrolled, 98.7% (5956/6030) were from Appalachian counties and 1.3% (76/6030) were from non-Appalachian counties. Patients from rural Appalachia made up 76.2% (4603/6030) of the total rural population. Enrolled patients represented all eligible age brackets from ages 20 to 75 years, with the 60-70 years age bracket having the most enrollees. Females made up 72.5% (4371/6030) of the enrolled population and males made up 27.5% (1659/6030) of the population. CONCLUSIONS: Results indicate that a web-based recruitment method with participant follow-up, such as a phone call and email follow-up, increases enrollment numbers more than web-based methods alone for rural, Appalachian, and older populations. Adding a humanizing component, such as a live person phone call, may be a key element needed to establish trust and encourage patients from underserved and rural areas to enroll in studies via web-based recruitment methods. Supporting statistics on this recruitment strategy should help researchers identify whether this strategy may be useful in future studies and HTR populations.

Ultra-high frequency repetitive TMS at subthreshold intensity induces suprathreshold motor response via temporal summation.

Objective.The transcranial magnetic stimulation (TMS) coil induces an electric field that diminishes rapidly upon entering the brain. This presents a challenge in achieving focal stimulation of a deep brain structure. Neuronal elements, including axons, dendrites, and cell bodies, exhibit specific time constants. When exposed to repetitive TMS pulses at a high frequency, there is a cumulative effect on neuronal membrane potentials, resulting in temporal summation. This study aims to determine whether TMS pulse train at high-frequency and subthreshold intensity could induce a suprathreshold response.Approach.As a proof of concept, we developed a TMS machine in-house that could consistently output pulses up to 250 Hz, and performed experiments on 22 awake rats to test whether temporal summation was detectable under pulse trains at 100, 166, or 250 Hz.Main results.Results revealed that TMS pulses at 55% maximum stimulator output (MSO, peak dI/dt= 68.5 A/µs at 100% MSO, pulse width = 48µs) did not induce motor responses with either single pulses or pulse trains. Similarly, a single TMS pulse at 65% MSO failed to evoke a motor response in rats; however, a train of TMS pulses at frequencies of 166 and 250 Hz, but not at 100 Hz, successfully triggered motor responses and MEP signals, suggesting a temporal summation effect dependent on both pulse intensities and pulse train frequencies.Significance.We propose that the temporal summation effect can be leveraged to design the next-generation focal TMS system: by sequentially driving multiple coils at high-frequency and subthreshold intensity, areas with the most significant overlapping E-fields undergo maximal temporal summation effects, resulting in a suprathreshold response.

On the Difficulty Predicting Word Recognition Performance After Cochlear Implantation.

HYPOTHESIS: Preimplantation word scores cannot reliably predict postimplantation outcomes. BACKGROUND: To date, there is no model based on preoperative data that can reliably predict the postoperative outcomes of cochlear implantation in the postlingually deafened adult patient. METHODS: In a group of 228 patients who received a cochlear implant between 2002 and 2021, we tested the predictive power of nine variables (age, etiology, sex, laterality of implantation, preimplantation thresholds and word scores, as well as the design, insertion approach, and angular insertion depth of the electrode array) on postimplantation outcomes. Results of multivariable linear regression analyses were then interpreted in light of data obtained from histopathological analyses of human temporal bones. RESULTS: Age and etiology were the only significant predictors of postimplantation outcomes. In agreement with many investigations, preimplantation word scores failed to significantly predict postimplantation outcomes. Analysis of temporal bone histopathology suggests that neuronal survival must fall below 40% before word scores in quiet begin to drop. Scores fall steeply with further neurodegeneration, such that only 20% survival can support acoustically driven word scores of 50%. Because almost all cochlear implant implantees have at least 20% of their spiral ganglion neurons (SGNs) surviving, it is expected that most cochlear implant users on average should improve to at least 50% word recognition score, as we observed, even if their preimplantation score was near zero as a result of widespread hair cell damage and the fact that ~50% of their SGNs have likely lost their peripheral axons. These "disconnected" SGNs would not contribute to acoustic hearing but likely remain electrically excitable. CONCLUSION: The relationship between preimplantation word scores and data describing the survival of SGNs in humans can explain why preimplantation word scores obtained in unaided conditions fail to predict postimplantation outcomes.

Primary Closure of External Fixator Pin Sites Is Safe After Orthopaedic Trauma Surgery.

OBJECTIVES: To determine if rates of pin site infection and surgical site infection among patients managed with primary closure after external fixator removal were similar to those allowed to heal secondarily. DESIGN: Retrospective cohort. SETTING: Urban/Suburban Academic Level I Trauma Center. PATIENT SELECTION CRITERIA: Patients who had received a lower extremity external fixator for provisional management before definitive fixation of lower extremity fractures were included with pin site wounds closed primarily or allowed to heal by secondary intention. OUTCOME MEASURES AND COMPARISONS: The rate of pin tract infection and surgical site infection following primary closure of external fixator pin sites relative to patients whose pin sites were allowed to heal through secondary intention. RESULTS: In total, 256 patients were evaluated: 143 patients (406 pin sites) in the primary closure group and 113 patients (340 in sites) in the secondary closure group. The average age was 49 ± 16 years. Sixty-five percent of included patients were male. There was no difference in pin tract infections between cohorts (primary = 0.5%, secondary = 1.5%, P = 0.26). External fixator duration in the primary closure group was 11.5 ± 8.4 days and 13.0 ± 8.1 days in the secondary closure group (P = 0.15). There was a greater rate of surgical site infections in the secondary intention cohort (15.9% vs. 7.7%, P = 0.047). CONCLUSIONS: There was no difference in pin site infection rate after primary pin site closure relative to patients who were allowed to heal through secondary intention. Furthermore, there was a lower rate of surgical site infection after primary closure. These results challenge the dogma of secondary closure for ex fix pin sites, suggesting that debridement and primary closure is a safe option for management of external fixator pin sites and may impart benefit in decreasing infection risk. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Cell states and neighborhoods in distinct clinical stages of primary and metastatic esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a highly lethal cancer of the upper gastrointestinal tract with rising incidence in western populations. To decipher EAC disease progression and therapeutic response, we performed multiomic analyses of a cohort of primary and metastatic EAC tumors, incorporating single-nuclei transcriptomic and chromatin accessibility sequencing, along with spatial profiling. We identified tumor microenvironmental features previously described to associate with therapy response. We identified five malignant cell programs, including undifferentiated, intermediate, differentiated, epithelial-to-mesenchymal transition, and cycling programs, which were associated with differential epigenetic plasticity and clinical outcomes, and for which we inferred candidate transcription factor regulons. Furthermore, we revealed diverse spatial localizations of malignant cells expressing their associated transcriptional programs and predicted their significant interactions with microenvironmental cell types. We validated our findings in three external single-cell RNA-seq and three bulk RNA-seq studies. Altogether, our findings advance the understanding of EAC heterogeneity, disease progression, and therapeutic response.

Contemporary Prognostic Signatures and Refined Risk Stratification of Gliomas: An Analysis of 4,400 Tumors.

BACKGROUND: With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received. METHODS: We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival. RESULTS: 4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received. CONCLUSIONS: By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations.

GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant.

Diffuse hemispheric gliomas, H3G34R/V-mutant (DHG-H3G34), are lethal brain tumors lacking targeted therapies. They originate from interneuronal precursors; however, leveraging this origin for therapeutic insights remains unexplored. Here, we delineate a cellular hierarchy along the interneuron lineage development continuum, revealing that DHG-H3G34 mirror spatial patterns of progenitor streams surrounding interneuron nests, as seen during human brain development. Integrating these findings with genome-wide CRISPR-Cas9 screens identifies genes upregulated in interneuron lineage progenitors as major dependencies. Among these, CDK6 emerges as a targetable vulnerability: DHG-H3G34 tumor cells show enhanced sensitivity to CDK4/6 inhibitors and a CDK6-specific degrader, promoting a shift toward more mature interneuron-like states, reducing tumor growth, and prolonging xenograft survival. Notably, a patient with progressive DHG-H3G34 treated with a CDK4/6 inhibitor achieved 17 months of stable disease. This study underscores interneuronal progenitor-like states, organized in characteristic niches, as a distinct vulnerability in DHG-H3G34, highlighting CDK6 as a promising clinically actionable target.

Examining affective reactivity as a link between suicidality and social disconnection.

The link between suicidality and social disconnection is well-established. We explored possible mechanisms that may account for this link using a positive and negative valence systems framework in a clinical sample with and without suicidality (i.e., suicidal ideation and/or behaviors in the past month). Participants (N = 228) interacted with a trained confederate during a controlled conversation task designed to generate social affiliation. Participant-rated positive affect (PA) and negative affect (NA) were collected during the task (baseline, anticipation, post). Participant-rated desire for future interaction was collected after the task. We tested if (1) groups with (n = 82) and without (n = 146) suicidality differed in affect during the task and (2) whether affect accounted for the link between suicidality and desire for future interaction. Results revealed that groups differed in PA, but not NA, throughout the task. Participants with suicidality reported no significant changes in PA over the task (ps > .05); and, experienced less PA at post-task compared to those without (p = .003, d = 0.38) whereas participants without suicidality reported increased PA at post-task compared to baseline and anticipation of the task, ps < .001. Mediation analysis suggested blunted post-task PA accounted for the relationship between suicidality and less desire for future interaction, 95%CI [-2.59,-0.51]. Diminished PA reactivity during social affiliation opportunities may help explain the link between suicidality and social disconnection. Preliminary findings highlight PA as a potential mechanistic target for improving social connection for individuals at risk for suicide, though prospective and experimental research is needed.