Health Disparities in the Neurosurgical Care of Patients with Trigeminal Neuralgia.

INTRODUCTION: There has been limited investigation into how social determinants of health (SDOH) impact treatment outcomes in patients with trigeminal neuralgia (TN). We aimed to investigate how SDOH may alter the course of clinical care for patients with TN. METHODS: The electronic medical record was queried for patients with a diagnosis of TN co-managed by neurosurgeons and other facial pain specialists at our medical center. Area Deprivation Index (ADI) served as a proxy for socioeconomic status. Multivariable linear regression models were performed using RStudio to assess the impact of social determinants on the time to neurosurgical referral and surgical intervention. RESULTS: 229 patients (mean age 50 years, 74% female) were included. 135 (60%) patients underwent a neurosurgical procedure after referral, the most common being microvascular decompression (n=84, 62%) (Table 1). Most of the patients were white (76.3%) and insured by Medicare (51.8%), followed by private insurance (38.6%). Age and sex were significant predictors of time to neurosurgical referral after symptom onset, as older patients (p<0.01, Figure 3) and females (p=0.02) tended to have a greater delay between symptom onset and specialist referral. Race, socioeconomic status, and insurance status were not significantly associated with time-to-referral or time-to-treatment. DISCUSSION: This study found that older and female patients with TN had a longer time from symptom onset to specialist referral. Based on these data, there is no association between race, socioeconomic status, and insurance status with time-to-referral or time-to-treatment in patients with TN.

Treating Benzodiazepine Withdrawal in a Bridge Clinic.

BACKGROUND: Benzodiazepine-involved overdose deaths are rising, driven by increasing use of nonprescribed benzodiazepine pills. For patients who wish to stop nonprescribed benzodiazepine use, rapid inpatient tapers are typically the only option to treat benzodiazepine withdrawal. Substance use disorder bridge clinics can provide the high-touch care needed to manage outpatient benzodiazepine tapers in patients at high risk due to other substance use disorders. OBJECTIVE: Describe the implementation and short-term outcomes of an outpatient benzodiazepine taper protocol to treat benzodiazepine withdrawal in a substance use disorder bridge clinic. METHODS: The clinical team developed a 4- to 6-week intensive outpatient taper protocol using diazepam. Patients with benzodiazepine use disorder were eligible if they had benzodiazepine withdrawal, lacked a prescriber, wanted to stop benzodiazepines completely, and agreed to daily visits. For patients who initiated a taper between April 2021 and December 2022, we evaluated the proportion of patients who completed a taper (i.e., tapered to a last prescribed dose of diazepam 10 mg/d or less); likelihood of remaining on the taper over time; and seizure, overdose, or death documented at the study institution during or within 1 month of taper completion or discontinuation. Other secondary outcomes included HIV testing and prevention, hepatitis C testing, and referrals to recovery coaching or psychiatry. RESULTS: Fifty-four patients initiated a total of 60 benzodiazepine tapers. The population was mostly male (61%) and non-Hispanic White (85%). Nearly all patients had opioid use disorder (96%), and most (80%) were taking methadone or buprenorphine for opioid use disorder before starting the taper. Patients reported using multiple substances in addition to benzodiazepines, most commonly fentanyl (75%), followed by cocaine (41%) and methamphetamine (21%). Fourteen patients (23%) completed a taper with a median duration of 34 days (IQR 27.8-43.5). Most tapers were stopped when the patient was lost to follow-up (57%), or the team recommended inpatient care (18%). Two patients had a seizure, and 4 had a presumed opioid-involved overdose during or within 1 month after the last taper visit, all individuals who did not complete a taper. No deaths occurred during or within 1 month of taper completion or discontinuation. Challenges included frequent loss to follow-up in the setting of other unstable substance use. Patients received other high-priority care during the taper including HIV testing (32%), PrEP initiation (6.7%), hepatitis C testing (30%), and referrals to recovery coaches (18%) and psychiatry (6.7%). CONCLUSIONS: Managing benzodiazepine withdrawal with a 4- to 6-week intensive outpatient taper in patients with benzodiazepine and opioid use disorders is challenging. More work is needed to refine patient selection, balance safety risks with feasibility, and study long-term, patient-centered outcomes.

Health net-outcome objectives and approaches for spatial planning and development: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to review the body of knowledge on net gain and no net loss (net-outcome) objectives and approaches applicable to health in spatial planning and development policies and practice. INTRODUCTION: There is an established body of academic and gray literature addressing environmental net-outcome objectives, such as biodiversity net gain, in spatial planning policies and practice. A "health net gain" objective has recently been proposed as a driver for health protection and the realization of health. Such an objective and approach are yet to be scoped and defined. INCLUSION CRITERIA: This review will consider sources in the scientific and gray literature that describe health net-outcome objectives that can be implemented in spatial planning and development policies and practice. Source contexts will not be limited to specific countries, geographical areas, or settings. All types of evidence will be considered. METHODS: This review will follow the JBI methodology for scoping reviews. Databases to be searched include PsycINFO (APA), Embase, HMIC Health Management Information Consortium, MEDLINE (Ovid), Scopus, and selected databases from the ProQuest Social Science Premium Collection. Sources of gray literature to be searched include ProQuest Dissertations and Theses, TRIP Pro, and BASE. No language or date restrictions will be applied. Two independent reviewers will retrieve and review full-text studies and extract data. The results will be presented in tabular or diagrammatic format with a narrative summary. REVIEW REGISTRATION: Open Science Framework https://osf.io/4dbcm.

Predictors of Durable Remission After Successful Surgery for Cushing Disease: Results From the Multicenter RAPID Registry.

BACKGROUND AND OBJECTIVE: Cushing disease (CD) affects mortality and quality of life along with limited long-term remission, underscoring the need to better identify recurrence risk. The identification of surgical or imaging predictors for CD remission after transsphenoidal surgery has yielded some inconsistent results and has been limited by single-center, single-surgeon, or meta-analyses studies. We sought to evaluate the multicenter Registry of Adenomas of the Pituitary and Related Disorders (RAPID) database of academic US pituitary centers to assess whether robust nonhormonal recurrence predictors could be elucidated. METHODS: Patients with treated CD from 2011 to 2023 were included. The perioperative and long-term characteristics of CD patients with and without recurrence were assessed using univariable and multivariable analyses. RESULTS: Of 383 patients with CD from 26 surgeons achieving postoperative remission, 288 (75.2%) maintained remission at last follow-up while 95 (24.8%) showed recurrence (median time to recurrence 9.99 ± 1.34 years). Patients with recurrence required longer postoperative hospital stays (5 ± 3 vs 4 ± 2 days, P = .002), had larger average tumor volumes (1.76 ± 2.53 cm3 vs 0.49 ± 1.17 cm3, P = .0001), and more often previously failed prior treatment (31.1% vs 14.9%, P = .001) mostly being prior surgery. Multivariable hazard prediction models for tumor recurrence found younger age (odds ratio [OR] = 0.95, P = .002) and Knosp grade of 0 (OR = 0.09, reference Knosp grade 4, P = .03) to be protective against recurrence. Comparison of Knosp grade 0 to 2 vs 3 to 4 showed that lower grades had reduced risk of recurrence (OR = 0.27, P = .04). Other factors such as length of stay, surgeon experience, prior tumor treatment, and Knosp grades 1, 2, or 3 failed to reach levels of statistical significance in multivariable analysis. CONCLUSION: This multicenter study centers suggests that the strongest predictors of recurrence include tumor size/invasion and age. This insight can help with patient counseling and prognostication. Long-term follow-up is necessary for patients, and early treatment of small tumors may improve outcomes.

The annotation of GBA1 has been concealed by its protein-coding pseudogene GBAP1.

Mutations in GBA1 cause Gaucher disease and are the most important genetic risk factor for Parkinson's disease. However, analysis of transcription at this locus is complicated by its highly homologous pseudogene, GBAP1. We show that >50% of short RNA-sequencing reads mapping to GBA1 also map to GBAP1. Thus, we used long-read RNA sequencing in the human brain, which allowed us to accurately quantify expression from both GBA1 and GBAP1. We discovered significant differences in expression compared to short-read data and identify currently unannotated transcripts of both GBA1 and GBAP1. These included protein-coding transcripts from both genes that were translated in human brain, but without the known lysosomal function-yet accounting for almost a third of transcription. Analyzing brain-specific cell types using long-read and single-nucleus RNA sequencing revealed region-specific variations in transcript expression. Overall, these findings suggest nonlysosomal roles for GBA1 and GBAP1 with implications for our understanding of the role of GBA1 in health and disease.

Long-Term Outcomes of Surgery and Radiation Treatment for Adult Patients with Craniopharyngioma.

OBJECTIVE: Treatment of craniopharyngioma typically entails gross total resection (GTR) or subtotal resection with adjuvant radiation (STR-RT). We analyzed outcomes in adults with craniopharyngioma undergoing GTR versus STR-RT. METHODS: This retrospective study enrolled 115 patients with craniopharyngioma in 5 institutions. Patients with STR received postoperative RT with stereotactic radiosurgery or fractionated radiation therapy per institutional preference and ability to spare optic structures. RESULTS: Median age was 44 years (range, 19-79 years). GTR was performed in 34 patients and STR-RT was performed in 81 patients with median follow-up of 78.9 months (range, 1-268 months). For GTR, local control was 90.5% at 2 years, 87.2% at 3 years, and 71.9% at 5 years. For STR-RT, local control was 93.6% at 2 years, 90.3% at 3 years, and 88.4% at 5 years. At 5 years following resection, there was no difference in local control (P = 0.08). Differences in rates of visual deterioration or panhypopituitarism were not observed between GTR and STR-RT groups. There was no difference in local control in adamantinomatous and papillary craniopharyngioma regardless of treatment. Additionally, worse local control was found in patients receiving STR-RT who were underdosed with fractionated radiation therapy (P = 0.03) or stereotactic radiosurgery (P = 0.04). CONCLUSIONS: Good long-term control was achieved in adults with craniopharyngioma who underwent STR-RT or GTR with no significant difference in local control. First-line treatment for craniopharyngioma should continue to be maximal safe resection followed by RT as needed to balance optimal local control with long-term morbidity.

Unlocking the distinctive enzymatic functions of the early plant biomass deconstructive genes in a brown rot fungus by cell-free protein expression.

Saprotrophic fungi that cause brown rot of woody biomass evolved a distinctive mechanism that relies on reactive oxygen species (ROS) to kick-start lignocellulosic polymers' deconstruction. These ROS agents are generated at incipient decay stages through a series of redox relays that shuttle electrons from fungus's central metabolism to extracellular Fenton chemistry. A list of genes has been suggested encoding the enzyme catalysts of the redox processes involved in ROS's function. However, navigating the functions of the encoded enzymes has been challenging due to the lack of a rapid method for protein synthesis. Here, we employed cell-free expression system to synthesize four redox or degradative enzymes, which were identified, by transcriptomic data, as conserved players of the ROS oxidation phase across brown rot fungal species. All four enzymes were successfully expressed and showed activities that enable confident assignment of function, namely, benzoquinone reductase (BQR), ferric reductase, α-L-arabinofuranosidase (ABF), and heme-thiolate peroxidase (HTP). Detailed analysis of their catalytic features within the context of brown rot environments allowed us to interpret their roles during ROS-driven wood decomposition. Specifically, we validated the functions of BQR as the driver redox enzyme of Fenton cycles and reconstructed its interactions with the co-occurring HTP or laccase and ABF. Taken together, this research demonstrated that the cell-free expression platform is adequate for synthesizing functional fungal enzymes and provided an alternative route for the rapid characterization of fungal proteins, escalating our understanding of the distinctive biocatalyst system for plant biomass conversion.IMPORTANCEBrown rot fungi are efficient wood decomposers in nature, and their unique degradative systems harbor untapped catalysts pursued by the biorefinery and bioremediation industries. While the use of "omics" platforms has recently uncovered the key "oxidative-hydrolytic" mechanisms that allow these fungi to attack lignocellulose, individual protein characterization is lagging behind due to the lack of a robust method for rapid synthesis of crucial fungal enzymes. This work delves into the studies of biochemical functions of brown rot enzymes using a rapid, cell-free expression platform, which allowed the successful depictions of enzymes' catalytic features, their interactions with Fenton chemistry, and their roles played during the incipient stage of brown rot when fungus sets off the reactive oxygen species for oxidative degradation. We expect this research could illuminate cell-free protein expression system's use to fulfill the increasing need for functional studies of fungal enzymes, advancing the discoveries of novel biomass-converting catalysts.

Mitotic gene regulation by the N-MYC-WDR5-PDPK1 nexus.

BACKGROUND: During mitosis the cell depends on proper attachment and segregation of replicated chromosomes to generate two identical progeny. In cancers defined by overexpression or dysregulation of the MYC oncogene this process becomes impaired, leading to genomic instability and tumor evolution. Recently it was discovered that the chromatin regulator WDR5-a critical MYC cofactor-regulates expression of genes needed in mitosis through a direct interaction with the master kinase PDPK1. However, whether PDPK1 and WDR5 contribute to similar mitotic gene regulation in MYC-overexpressing cancers remains unclear. Therefore, to characterize the influence of WDR5 and PDPK1 on mitotic gene expression in cells with high MYC levels, we performed a comparative transcriptomic analysis in neuroblastoma cell lines defined by MYCN-amplification, which results in high cellular levels of the N-MYC protein. RESULTS: Using RNA-seq analysis, we identify the genes regulated by N-MYC and PDPK1 in multiple engineered CHP-134 neuroblastoma cell lines and compare them to previously published gene expression data collected in CHP-134 cells following inhibition of WDR5. We find that as expected N-MYC regulates a multitude of genes, including those related to mitosis, but that PDPK1 regulates specific sets of genes involved in development, signaling, and mitosis. Analysis of N-MYC- and PDPK1-regulated genes reveals a small group of commonly controlled genes associated with spindle pole formation and chromosome segregation, which overlap with genes that are also regulated by WDR5. We also find that N-MYC physically interacts with PDPK1 through the WDR5-PDPK1 interaction suggesting regulation of mitotic gene expression may be achieved through a N-MYC-WDR5-PDPK1 nexus. CONCLUSIONS: Overall, we identify a small group of genes highly enriched within functional gene categories related to mitotic processes that are commonly regulated by N-MYC, WDR5, and PDPK1 and suggest that a tripartite interaction between the three regulators may be responsible for setting the level of mitotic gene regulation in N-MYC amplified cell lines. This study provides a foundation for future studies to determine the exact mechanism by which N-MYC, WDR5, and PDPK1 converge on cell cycle related processes.

Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy.

RAS oncogenes (collectively NRAS, HRAS and especially KRAS) are among the most frequently mutated genes in cancer, with common driver mutations occurring at codons 12, 13 and 611. Small molecule inhibitors of the KRAS(G12C) oncoprotein have demonstrated clinical efficacy in patients with multiple cancer types and have led to regulatory approvals for the treatment of non-small cell lung cancer2,3. Nevertheless, KRASG12C mutations account for only around 15% of KRAS-mutated cancers4,5, and there are no approved KRAS inhibitors for the majority of patients with tumours containing other common KRAS mutations. Here we describe RMC-7977, a reversible, tri-complex RAS inhibitor with broad-spectrum activity for the active state of both mutant and wild-type KRAS, NRAS and HRAS variants (a RAS(ON) multi-selective inhibitor). Preclinically, RMC-7977 demonstrated potent activity against RAS-addicted tumours carrying various RAS genotypes, particularly against cancer models with KRAS codon 12 mutations (KRASG12X). Treatment with RMC-7977 led to tumour regression and was well tolerated in diverse RAS-addicted preclinical cancer models. Additionally, RMC-7977 inhibited the growth of KRASG12C cancer models that are resistant to KRAS(G12C) inhibitors owing to restoration of RAS pathway signalling. Thus, RAS(ON) multi-selective inhibitors can target multiple oncogenic and wild-type RAS isoforms and have the potential to treat a wide range of RAS-addicted cancers with high unmet clinical need. A related RAS(ON) multi-selective inhibitor, RMC-6236, is currently under clinical evaluation in patients with KRAS-mutant solid tumours (ClinicalTrials.gov identifier: NCT05379985).

Predictors of Subjective Olfactory Dysfunction and Sinonasal Quality-of-Life After Endoscopic Transsphenoidal Pituitary Surgery.

BACKGROUND: This is the largest study in North America investigating olfactory outcomes after pituitary surgery to date. OBJECTIVE: Characterize factors associated with subjective olfactory dysfunction (OD) and worsened sinonasal quality-of-life (QOL) after endoscopic TSA. METHODS: Patients undergoing primary TSA for secreting and non-secreting pituitary adenomas between 2017 and 2021 with pre- and post-operative SNOT-22 scores were included. Subjective OD was determined by the smell/taste dysfunction question on the SNOT-22 (smell-SNOT). RESULTS: 159 patients with pre- and post-operative SNOT-22 scores were included. Average total SNOT-22 scores worsened from pre-operative (16.91 ± 16.91) to POM1 (25.15 ± 20.83, P < .001), with no difference from pre-operative (16.40 ± 15.88) to POM6 (16.27 ± 17.92, P = .936) or pre-operative (13.63 ± 13.54) to POM12 (12.60 ± 16.45, P = .651). Average smell-SNOT scores worsened from pre-operative (0.40 ± 1.27) to POM1 (2.09 ± 2.01, P < .001), and pre-operative (0.46 ± 1.29) to POM6 (1.13 ± 2.45, P = .002), with no difference from pre-operative (0.40 ± 1.07) to POM12 (0.71 ± 1.32, P = .100). Female gender had a 0.9-point (95% CI 0.1 to 1.6) P = .021, increase in smell-SNOT at POM1, resolving by POM6 (0.1 [-0.9 to 1.1], P = .800) and POM12 (0.0 [-1.0 to 0.9], P = .942). Septoplasty with tunnel approach had a 1.1 [0.2 to 2.0] out of 5-point (P = .023) increase in smell-SNOT at POM1, resolving by POM6 (0.2 [-1.1 to 1.6], P = .764) and POM12 (0.4 [-0.9 to 1.6], P = .567). Female gender had a 9.5 (4.0 to 15.1)-point (P = .001) increase in SNOT-22 scores at POM1, resolving by POM6 (3.4 [-3.0 to 9.8], P = .292) and POM12 (6.4 [-5.4 to 18.2], P = .276). Intra-operative CSF leak had an 8.6 [2.1 to 15.1]-point (P = .009) increase in SNOT-22 scores at POM1, resolving by POM6 (5.4 [-1.7 to 12.5], P = .135), and POM12 (1.1 [-12.9 to 15.1], P = .873). CONCLUSION: Changes in subjective olfaction and sinonasal QOL after TSA may be associated with gender, operative approach, and intra-operative CSF leak, resolving 6-12 months post-operatively.

Translational and Therapeutic Evaluation of RAS-GTP Inhibition by RMC-6236 in RAS-Driven Cancers.

RAS-driven cancers comprise up to 30% of human cancers. RMC-6236 is a RAS(ON) multi-selective noncovalent inhibitor of the active, GTP-bound state of both mutant and wild-type variants of canonical RAS isoforms with broad therapeutic potential for the aforementioned unmet medical need. RMC-6236 exhibited potent anticancer activity across RAS-addicted cell lines, particularly those harboring mutations at codon 12 of KRAS. Notably, oral administration of RMC-6236 was tolerated in vivo and drove profound tumor regressions across multiple tumor types in a mouse clinical trial with KRASG12X xenograft models. Translational PK/efficacy and PK/PD modeling predicted that daily doses of 100 mg and 300 mg would achieve tumor control and objective responses, respectively, in patients with RAS-driven tumors. Consistent with this, we describe here objective responses in two patients (at 300 mg daily) with advanced KRASG12X lung and pancreatic adenocarcinoma, respectively, demonstrating the initial activity of RMC-6236 in an ongoing phase I/Ib clinical trial (NCT05379985). SIGNIFICANCE: The discovery of RMC-6236 enables the first-ever therapeutic evaluation of targeted and concurrent inhibition of canonical mutant and wild-type RAS-GTP in RAS-driven cancers. We demonstrate that broad-spectrum RAS-GTP inhibition is tolerable at exposures that induce profound tumor regressions in preclinical models of, and in patients with, such tumors. This article is featured in Selected Articles from This Issue, p. 897.

Super-Enhancer Dysregulation in Rhabdoid Tumor Cells Is Regulated by the SWI/SNF ATPase BRG1.

Mutations in the SWI/SNF chromatin remodeling complex occur in ~20% of cancers. In rhabdoid tumors defined by loss of the SWI/SNF subunit SMARCB1, dysregulation of enhancer-mediated gene expression is pivotal in driving oncogenesis. Enhancer dysregulation in this setting is tied to retention of the SWI/SNF ATPase BRG1-which becomes essential in the absence of SMARCB1-but precisely how BRG1 contributes to this process remains unknown. To characterize how BRG1 participates in chromatin remodeling and gene expression in SMARCB1-deficient cells, we performed a genome-wide characterization of the impact of BRG1 depletion in multiple rhabdoid tumor cell lines. We find that although BRG1-regulated open chromatin sites are distinct at the locus level, the biological characteristics of the loci are very similar, converging on a set of thematically related genes and pointing to the involvement of the AP-1 transcription factor. The open chromatin sites regulated by BRG1 colocalize with histone-marked enhancers and intriguingly include almost all super-enhancers, revealing that BRG1 plays a critical role in maintaining super-enhancer function in this setting. These studies can explain the essentiality of BRG1 to rhabdoid tumor cell identity and survival and implicate the involvement of AP-1 as a critical downstream effector of rhabdoid tumor cell transcriptional programs.

Evaluation of in vitro treatments against the causative agent of Diadema antillarum scuticociliatosis (DaSc).

In the 1980s, a mass die-off of the long-spined sea urchin Diadema antillarum occurred on Florida and Caribbean coral reefs. D. antillarum populations largely did not recover, and in 2022, remaining populations experienced another mass mortality event. A ciliate most similar to Philaster apodigitiformis was identified as the causative agent of the 2022 event, which was named D. antillarum scuticociliatosis (DaSc). Here, we investigated possible treatments for this pathogen. We tested the efficacy of 10 compounds at final concentrations of 100, 50, 25, 12.5, 6.25, and 3.13 µM, or a 10-fold serial dilution series, against ciliates cultured from an infected D. antillarum specimen. Of the tested compounds, 8 induced 100% ciliate mortality at some dose after 24 h. The most effective (defined as those requiring the lowest dose to induce 100% ciliate mortality) were quinacrine and tomatine (both effective at 12.5 µM), followed by furaltadone and plumbagin (25 µM), bithionol sulfoxide and 2'4' dihydroxychalcone (50 µM), and oxyclozanide and carnidazole (100 µM). Toltrazuril and a commercially available anticiliate product containing naphthoquinones were not effective at any dose tested. Shortened (15 min) time trials were performed using ciliate cultures reared in natural seawater to better reflect natural environmental conditions, and revealed that 2 of the compounds (quinacrine and tomatine) induced 100% ciliate mortality at 100 µM, with tomatine also effective at 50 µM. This study identified several treatments effective against the causative agent of DaSc in vitro, but their toxicity and utility in vivo remain unknown.

Can the implementation of net gain requirements in England's planning system be applied to health?

This Personal View considers the relationship between spatial planning and health and the potential benefits of requiring health net gain from land use decisions and new developments. We explore how a health net gain objective could be applied in spatial planning policy and practice to improve people's health and wellbeing, using England's implementation of a biodiversity net gain objective as a model. This Personal View emphasises the need for a systems approach to the definition and strategic coordination of health gains, recognising the breadth of health determinants and inter-related economic, environmental, and social policy objectives. By considering the potential application of a net gain principle to health in spatial planning, we offer valuable insights into how the spatial planning system could be used to build the conditions of health creation. A road map is provided for exploration of health net gain in other national contexts in support of the operationalisation of global urban health initiatives.

Multicenter Registry of Adenomas of the Pituitary and Related Disorders: Initial Description of Cushing Disease Cohort, Surgical Outcomes, and Surgeon Characteristics.

BACKGROUND AND OBJECTIVES: To address the lack of a multicenter pituitary surgery research consortium in the United States, we established the Registry of Adenomas of the Pituitary and Related Disorders (RAPID). The goals of RAPID are to examine surgical outcomes, improve patient care, disseminate best practices, and facilitate multicenter surgery research at scale. Our initial focus is Cushing disease (CD). This study aims to describe the current RAPID patient cohort, explore surgical outcomes, and lay the foundation for future studies addressing the limitations of previous studies. METHODS: Prospectively and retrospectively obtained data from participating sites were aggregated using a cloud-based registry and analyzed retrospectively. Standard preoperative variables and outcome measures included length of stay, unplanned readmission, and remission. RESULTS: By July 2023, 528 patients with CD had been treated by 26 neurosurgeons with varying levels of experience at 9 academic pituitary centers. No surgeon treated more than 81 of 528 (15.3%) patients. The mean ± SD patient age was 43.8 ± 13.9 years, and most patients were female (82.2%, 433/527). The mean tumor diameter was 0.8 ± 2.7 cm. Most patients (76.6%, 354/462) had no prior treatment. The most common pathology was corticotroph tumor (76.8%, 381/496). The mean length of stay was 3.8 ± 2.5 days. The most common discharge destination was home (97.2%, 513/528). Two patients (0.4%, 2/528) died perioperatively. A total of 57 patients (11.0%, 57/519) required an unplanned hospital readmission within 90 days of surgery. The median actuarial disease-free survival after index surgery was 8.5 years. CONCLUSION: This study examined an evolving multicenter collaboration on patient outcomes after surgery for CD. Our results provide novel insights on surgical outcomes not possible in prior single-center studies or with national administrative data sets. This collaboration will power future studies to better advance the standard of care for patients with CD.

Human languages with greater information density have higher communication speed but lower conversation breadth.

Human languages vary widely in how they encode information within circumscribed semantic domains (for example, time, space, colour, human body parts and activities), but little is known about the global structure of semantic information and nothing about its relation to human communication. We first show that across a sample of ~1,000 languages, there is broad variation in how densely languages encode information into words. Second, we show that this language information density is associated with a denser configuration of semantic information. Finally, we trace the relationship between language information density and patterns of communication, showing that informationally denser languages tend towards faster communication but conceptually narrower conversations or expositions within which topics are discussed at greater depth. These results highlight an important source of variation across the human communicative channel, revealing that the structure of language shapes the nature and texture of human engagement, with consequences for human behaviour across levels of society.

Novel Uses of Methadone Under the "72-Hour Rule" to Facilitate Transitions of Care and Low-Dose Buprenorphine Induction in an Outpatient Bridge Clinic.

BACKGROUND: Federal regulations restrict methadone for opioid use disorder (OUD) treatment to licensed opioid treatment programs (OTPs). However, providers in other settings can administer methadone for opioid withdrawal under the "72-hour rule" while linking to further care. Prior work has demonstrated that methadone initiation in a low-barrier bridge clinic is associated with high OTP linkage and 1-month retention rates. We describe 2 other novel applications of the 72-hour rule in which methadone withdrawal management facilitated linkage to inpatient hospitalization and outpatient buprenorphine induction. CASE PRESENTATIONS: Patient 1 was a 46-year-old woman with OUD complicated by serious injection-related infections. Severe opioid withdrawal limited her ability to tolerate emergency department wait times and receive inpatient care. We administered methadone for opioid withdrawal in an outpatient bridge clinic immediately before emergency department referral; this enabled hospital admission for intravenous antibiotics and anticoagulation. Patient 2 was a 36-year-old man with OUD desiring buprenorphine treatment. He had been unable to complete traditional buprenorphine induction without experiencing precipitated withdrawal. Thus, we recommended a low-dose buprenorphine induction overlapping with a full opioid agonist. Given the patient's preference to stop using fentanyl immediately, he received 72 hours of methadone for withdrawal treatment during the induction phase and successfully transitioned to buprenorphine without significant concomitant fentanyl use. CONCLUSION: In addition to facilitating OTP linkage, on-demand 72-hour methadone administration for opioid withdrawal can reduce barriers to acute medical care and buprenorphine treatment.

Transglobal spread of an ecologically relevant sea urchin parasite.

Mass mortality of the dominant coral reef herbivore Diadema antillarum in the Caribbean in the early 1980s contributed to a persistent phase shift from coral- to algal-dominated reefs. In 2022, a scuticociliate most closely related to Philaster apodigitiformis caused further mass mortality of D. antillarum across the Caribbean, leading to >95% mortality at affected sites. Mortality was also reported in the related species Diadema setosum in the Mediterranean in 2022, though the causative agent of the Mediterranean outbreak has not yet been determined. In April 2023, mass mortality of Diadema setosum occurred along the Sultanate of Oman's coastline. Urchins displayed signs compatible with scuticociliatosis including abnormal behavior, drooping and loss of spines, followed by tissue necrosis and death. Here we report the detection of an 18S rRNA gene sequence in abnormal urchins from Muscat, Oman, that is identical to the Philaster strain responsible for D. antillarum mass mortality in the Caribbean. We also show that scuticociliatosis signs can be elicited in Diadema setosum by experimental challenge with the cultivated Philaster strain associated with Caribbean scuticociliatosis. These results demonstrate the Philaster sp. associated with D. antillarum mass mortality has rapidly spread to geographically distant coral reefs, compelling global-scale awareness and monitoring for this devastating condition through field surveys, microscopy, and molecular microbiological approaches, and prompting investigation of long-range transmission mechanisms.

Disrupted routines anticipate musical exploration.

Understanding and predicting the emergence and evolution of cultural tastes manifested in consumption patterns is of central interest to social scientists, analysts of culture, and purveyors of content. Prior research suggests that taste preferences relate to personality traits, values, shifts in mood, and immigration destination. Understanding everyday patterns of listening and the function music plays in life has remained elusive, however, despite speculation that musical nostalgia may compensate for local disruption. Using more than one hundred million streams of four million songs by tens of thousands of international listeners from a global music service, we show that breaches in personal routine are systematically associated with personal musical exploration. As people visited new cities and countries, their preferences diversified, converging toward their travel destinations. As people experienced the very different disruptions associated with COVID-19 lockdowns, their preferences diversified further. Personal explorations did not tend to veer toward the global listening average, but away from it, toward distinctive regional musical content. Exposure to novel music explored during periods of routine disruption showed a persistent influence on listeners' future consumption patterns. Across all of these settings, musical preference reflected rather than compensated for life's surprises, leaving a lasting legacy on tastes. We explore the relationship between these findings and global patterns of behavior and cultural consumption.

A strategic approach for efficient cryo-EM grid optimization using design of experiments.

In recent years, cryo-electron microscopy (cryo-EM) has become a practical and effective method of determining structures at previously unattainable resolutions due to advances in detection, automation, and data processing. However, sample preparation remains a major bottleneck in the cryo-EM workflow. Even after the arduous process of biochemical sample optimization, it often takes several iterations of grid vitrification and screening to determine the optimal grid freezing parameters that yield suitable ice thickness and particle distribution for data collection. Since a high-quality sample is imperative for high-resolution structure determination, grid optimization is a vital step. For researchers who rely on cryo-EM facilities for grid screening, each iteration of this optimization process may delay research progress by a matter of months. Therefore, a more strategic and efficient approach should be taken to ensure that the grid optimization process can be completed in as few iterations as possible. Here, we present an implementation of Design of Experiments (DOE) to expedite and strategize the grid optimization process. A Fractional Factorial Design (FFD) guides the determination of a limited set of experimental conditions which can model the full parameter space of interest. Grids are frozen with these conditions and screened for particle distribution and ice thickness. Quantitative scores are assigned to each of these grid characteristics based on a qualitative rubric. Input conditions and response scores are used to generate a least-squares regression model of the parameter space in JMP, which is used to determine the conditions which should, in theory, yield optimal grids. Upon testing this approach on apoferritin and L-glutamate dehydrogenase on both the Vitrobot Mark IV and the Leica GP2 plunge freezers, the resulting grid conditions reliably yielded grids with high-quality ice and particle distribution that were suitable for collecting large overnight datasets on a Krios. We conclude that a DOE-based approach is a cost-effective and time-saving tool for cryo-EM grid preparation.