Examining whether young adults differ in their endorsement and subjective evaluation of alcohol consequences by age, drinking frequency, and current undergraduate status.

OBJECTIVE: There is considerable variability in how young adults (YAs) perceive drinking-related consequences, and some researcher-identified "negative" consequences are viewed by YAs as neutral or even somewhat positive. Little is known about individual difference factors that may influence subjective evaluations of alcohol consequences. METHOD: We tested whether endorsement and subjective evaluation ('extremely negative' to 'extremely positive') of 24 alcohol-related "negative" consequences differed by age (18-20, 21-27), past 3-month drinking frequency (3x/month or less, weekly or more), and current undergraduate status (4-year undergraduate, non-student). YAs were recruited for a longitudinal ecological momentary assessment study on cognitions and alcohol use. Participants in the analytic sample (N=640; 48.1% White non-Hispanic/Latinx, 50.0% female, mean age=22.2 years, SD=2.3) reported past 3-month drinking. Past 3-month drinking frequency, negative consequences (total and item-level), and subjective evaluations of consequences were assessed cross-sectionally. RESULTS: Compared to YAs 18-20, YAs 21+ experienced fewer total consequences, were significantly less likely to endorse experiencing physical/behavioral consequences, and rated these consequences more negatively if they were endorsed. YAs who drank weekly or more reported experiencing more consequences and were significantly more likely to experience all 24 consequences in comparison to YAs who drank 3x/month or less. Subjective evaluation ratings did not significantly differ by drinking frequency. There were few differences between 4-year undergraduate and non-undergraduates; non-undergraduates rated several health/responsibility-related consequences more negatively. CONCLUSIONS: Findings highlight the importance of identifying individual difference factors that contribute to subjective evaluation ratings, and may be useful for tailoring brief, personalized alcohol interventions for YAs.

Endoscopic Endonasal Approach to the Ventral Petroclival Fissure: Anatomical Findings and Surgical Techniques.

Objective The endoscopic endonasal approach has emerged as an excellent option for the treatment of lesions involving the petroclival fissure (PCF). Here, we investigate the surgical anatomy of the ventral PCF and its application in endoscopic endonasal surgery. Methods Sixteen head specimens were used to investigate the anatomical features of PCF and relevant technical nuances in translacerum, extreme medial, and contralateral transmaxillary (CTM) approaches. Two representative endoscopic endonasal surgeries involving the PCF were selected to illustrate the clinical application. Results From the endoscopic endonasal view, the ventral PCF is presented as a lazy L sign, which is divided into two distinct segments: (1) upper (or petrosphenoidal) segment, which extends vertically from the foramen lacerum inferiorly to the junction of the petrosal process of sphenoid bone and petrous apex superiorly, and (2) lower (or petroclival) segment, which extends inferolaterally from the foramen lacerum to the ventral jugular foramen. Approaching both segments of the ventral PCF first requires full exposure of the foramen lacerum, followed either by exposure of the anterior wall of cavernous sinus and paraclival internal carotid artery for upper segment access, or transection of pterygosphenoidal fissure and Eustachian tube mobilization for lower segment access. Combined with a CTM approach, the lateral extension of the surgical access can be improved for both upper and lower segment PCF approaches. Conclusion This study provides a detailed investigation of the microsurgical anatomy of the ventral part of PCF, relevant surgical approaches, and technical nuances that may facilitate its safe exposure intraoperatively.

Molecular Characterization and Functional Analysis of a Schistosoma mansoni Serine Protease Inhibitor, Smserpin-p46.

Serine protease inhibitors are a superfamily of proteins that regulate various physiological processes including fibrinolysis, inflammation and immune responses. In parasite systems, serpins are believed to play important roles in parasite colonization, inhibition of host immune serine proteases and penetration of defensive barriers. However, serpins are less well characterized in schistosomes. In this study, a Schistosoma mansoni serpin (Smserpin-p46) containing a 1360 base pair open reading frame, was cloned, expressed and functionally characterized. Bioinformatics analysis revealed that Smserpin-p46 contains the key residues, structural domains and motifs characteristic of inhibitory serpins. Gene expression profiling demonstrated stage-specific expression of Smserpin-p46 with the highest expression in adult male worms. Recombinant Smserpin-p46 (rSmserpin-p46) inhibited both human neutrophil cathepsin G and elastase, key serine proteases involved in NETosis, a program for the formation of neutrophil extracellular traps. Using specific rabbit antiserum, Smserpin-p46 was detected in soluble worm antigen preparation and was localized to the adult worm tegument. Cumulatively, the expression of Smserpin-p46 on the parasite tegument and its ability to inhibit proteases involved in NETosis highlights the importance of this serpin in parasite-host interactions and encourages its further investigation as a candidate vaccine antigen for the control of schistosomiasis.

Early Graft Loss With Suspected Seventh-Day Syndrome Following Pediatric Liver Transplantation.

INTRODUCTION: Allograft dysfunction within the first week posttransplant is an uncommon but known complication following liver transplantation. Seventh-Day Syndrome (7DS) is a rare complication of allograft dysfunction following liver transplantation characterized by the rapid clinical deterioration of a formerly well-functioning allograft within the first week posttransplant. The etiology of 7DS is unknown, and treatment options remain limited. While cases of graft survival have been reported, the risk of mortality remains exceedingly high without urgent retransplantation. METHODS: Patient data was retrospectively analyzed and a literature review performed. RESULTS: We present a unique case of split liver transplantation into two pediatric recipients in which one recipient developed rapidly progressive graft failure approximately 1 week postoperatively requiring urgent retransplantation while the other recipient had an unremarkable postoperative course. Upon clinical manifestation of progressive graft failure, the patient was treated with thymoglobulin, rituximab, intravenous immunoglobulin, and plasmapheresis. Despite this, the patient's clinical status continued to decline and she underwent retransplantation 11 days following her initial liver transplant. CONCLUSION: Seventh-Day Syndrome is a rare complication following liver transplantation that is associated with a high risk of morbidity and mortality. Our case adds to the limited literature on 7DS in children and is the first to report a comparative posttransplant clinical course in two recipients who received split grafts from the same donor.

Integrated Safety and Efficacy Analyses of Phase 3 Trials of a Microbiome Therapeutic for Recurrent CDI.

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI. OBJECTIVE, DESIGN, AND PATIENTS: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities. METHODS: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24. RESULTS: TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6-13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression. CONCLUSIONS: VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.

Crisis prediction among tele-mental health patients: A large language model and expert clinician comparison.

BACKGROUND: Due to recent advances in artificial intelligence (AI), large language models (LLMs) have emerged as a powerful tool for a variety of language related tasks, including sentiment analysis, and summarization of provider-patient interactions. However, there is limited research on these models in the area of crisis prediction. OBJECTIVE: This study aimed to evaluate the performance of LLMs, specifically OpenAI's GPT-4, in predicting current and future mental health crisis episodes using patient provided information at intake among users of a national telemental health platform. METHODS: De-identified patient provided data was pulled from specific intake questions of the Brightside telehealth platform, including the chief complaint, for 140 patients who indicated suicidal ideation (SI), and another 120 patients who later indicated SI with a plan during the course of treatment. Similar data was pulled for 200 randomly selected patients treated during the same time period who never endorsed SI. Six senior Brightside clinicians (three psychologists and three psychiatrists) were shown patients' self-reported chief complaint and self-reported suicide attempt history but were blinded to the future course of treatment and other reported symptoms including SI. They were asked a simple yes/no question regarding their prediction of endorsement of SI with plan along with their confidence level about the prediction. GPT-4 was provided similar information and asked to answer the same questions, enabling us to directly compare the performance of AI and clinicians. RESULTS: Overall, clinicians' average precision (0.698) was higher than GPT-4 (0.596) in identifying SI with plan at intake (n=140) vs. no SI (n=200) when using chief complaint alone, while sensitivity was higher for GPT-4 (0.621) than clinicians' average (0.529). The addition of suicide attempt history increased clinicians' average sensitivity (0.590) and precision (0.765), while increasing GPT-4 sensitivity (0.590) but decreasing GPT-4 precision (0.544). Performance decreased comparatively when predicting future SI with plan (n=120) vs no SI (n=200) with chief complaint only for clinicians (average sensitivity=0.399; average precision=0.594) and GPT-4 (sensitivity=0.458; precision=0.482). The addition of suicide attempt history increased performance comparatively for clinicians (average sensitivity=0.457; average precision=0.687) and GPT-4 (sensitivity=0.742; precision=0.476). CONCLUSIONS: GPT-4 with a simple prompt design produced results on some metrics that approached that of a trained clinician. Additional work must be done before such a model could be piloted in a clinical setting. The model should undergo safety checks for bias given evidence that LLMs can perpetuate the biases of the underlying data they are trained upon. We believe that LLMs hold promise to augment identification of higher risk patients at intake and potentially deliver more timely care to patients.

An Allergic Reaction in Contrast-enhanced Ultrasound Lymphography for Lymphovenous Bypass Surgery.

Lymphedema following oncologic intervention can cause significant lifelong morbidity for patients in whom conservative management fails. The associated swelling, discomfort, pain, and recurrent cellulitis greatly diminish quality of life. Surgical procedures, including suction-assisted lipectomy, lymphovenous anastomosis (LVA), and vascularized lymph node transfers, show effectiveness in both volume reduction in affected extremities and symptom relief. However, the success of procedures like LVA is dependent on effective preoperative lymphatic mapping to identify suitable vessels for anastomosis. Traditional superficial lymphatic mapping uses near infrared fluorescence indocyanine green (ICG) imaging. Moreover, recent advances in contrast-enhanced ultrasound (CEUS) lymphography increased lymphovenous bypass target identification for LVA in the extremities.7 CEUS lymphography uses microbubbles as a contrast-enhancing agent injected intradermally into the affected extremity with subsequent identification of superficial collecting lymphatic vessels using ultrasound. Although a recent report noted an uptick in severe and critical adverse drug reactions to an ultrasound contrast agent injected intravenously in stress echocardiography, adverse drug reactions associated with ultrasound contrast-enhancing agents in body ultrasound are rare. The safety profile and potential complications from CEUS lymphography in the lymphedema population have yet to be fully characterized. In this case report, the authors present the first cutaneous adverse drug event following a secondary exposure to the contrast used for CEUS imaging. Mechanisms and justifications for an immune-mediated process are explored, and a review of similar manifestations in other related contrast applications is discussed.

Estimating substance use disparities across intersectional social positions using machine learning: An application of group-lasso interaction network.

OBJECTIVE: An aim of quantitative intersectional research is to model the joint impact of multiple social positions on health risk behaviors. Although moderated multiple regression is frequently used to pursue intersectional research hypotheses, such parametric approaches may produce unreliable effect estimates due to data sparsity and high dimensionality. Machine learning provides viable alternatives, offering greater flexibility in evaluating many candidate interactions amid sparse data conditions, yet remains rarely employed. This study introduces group-lasso interaction network (glinternet), a novel machine learning approach involving hierarchical regularization, to assess intersectional differences in substance use prevalence. METHOD: Utilizing variable selection and parameter stabilization functionality for main and interaction effects, glinternet was employed to examine two-way interactions between three primary social positions (gender, sexual orientation, and race) predicting heavy episodic drinking, cannabis use, and cigarette use prevalence. Analyses were conducted using the All of Us Research Program (N = 283,403), a national sample with high representation from populations historically underrepresented in biomedical research. Results were replicated using holdout cross-validation and compared against logistic regression estimates. RESULTS: Glinternet prevalence estimates were more stable across discovery and replication samples relative to logistic regression, particularly among sparsely represented groups. Prevalence estimates for cigarette and cannabis use were elevated among sexual minority and White cisgender women compared to heterosexual and non-White women, respectively. CONCLUSIONS: Glinternet may improve upon traditional moderated multiple regression methods for pursuing intersectional hypotheses by improving model parsimony and parameter stability, providing novel means for quantifying health disparities among intersectional social positions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Granuloma annulare and possible relation to purified protein derivative administration: a case report.

BACKGROUND: Granuloma annulare is a noninfectious inflammatory granulomatous skin disease characterized by an erythematous or skin colored annulare plaque. The diagnosis of granuloma annulare may be challenging owing to its diverse morphology. In such cases, a correlation between the clinical findings and histologic findings are necessary. CASE PRESENTATION: We report a case of granuloma annulare after purified protein derivative administration. A 56-year-old Caucasian female patient complained of mildly pruritic rashes which started on both arms and lower extremities, and eventually spread to both thighs, the left popliteal region, left upper back, and the right abdominal area. About 6 weeks prior to the eruption of the rashes, the patient had been given a purified protein derivative tuberculin skin test. Biopsy specimens revealed dermal histiocytes palisading around areas of mucin and degenerated collagen, confirming granuloma annulare. After treatment with 0.1% topical triamcinolone acetanide and 500 mg oral metronidazole, the patient's lesions resolved. DISCUSSION: Relatively little is known about granuloma annulare's exact etiology. Granuloma annulare has four variations presenting as either localized, generalized, subcutaneous, or perforating and patch granuloma annulare. The clinical prognosis for granuloma annulare varies according to clinical subtypes. Proposed causal mechanisms of subcutaneous granuloma annulare include physical trauma, infections, immunizations, insect bites, diabetes mellitus, and alterations in the cell-mediated immune responses. The disease likely has an inflammatory component. Clinically, granuloma annulare may be confused with many other skin diseases. CONCLUSION: This case of subcutaneous granuloma annulare was reported since it is a rare dermatologic pathological condition that can be confused with other skin rash disorders. Although it is a benign self-limited disease, definitive diagnosis is important to rule out other pathologies with similar clinical appearances, such as cancer or human immunodeficiency virus (HIV) infection. Diagnostic confirmation is best made through skin biopsy.

Endoscopic Endonasal Resection of a Thyroid-Stimulating Hormone-Secreting Pituitary Adenoma With Invasion of the Medial Wall of the Cavernous Sinus.

Thyroid-stimulating hormone-secreting adenomas (TSH-oma) are exceptionally rare.1 The primary treatment is surgical resection with radiation and pharmacotherapy postoperatively if subtotal resection, especially with cavernous sinus invasion.2 We present the case of a 29-year-old man with TSH-oma with cavernous sinus medial wall invasion. This is the first documented case with selective resection of the cavernous sinus medial wall to achieve a complete resection and biochemical remission in TSH-oma through endoscopic endonasal approach. The patient had elevated TSH and thyroid hormones with symptoms of weight loss, palpitations, excess sweating, and decreased endurance. MRI revealed a 1.3 × 2.1 × 1.2 cm contrast-enhancing sellar mass with rightward pituitary gland displacement without evidence of cavernous sinus invasion (Knosp 2). The patient consented to procedure/publication. No institutional review board approval needed per institution. We performed standard resection of the firm sellar tumor portion and noted that there was tumor invasion into the left cavernous sinus medial wall dura. The bony opening was expanded to expose the anterior wall of the cavernous sinus, which was opened to identify the cavernous internal carotid artery and the medial wall attachments. The thickened medial wall was completely resected. We achieved a complete tumor resection, and the patient's TSH and thyroid hormone dropped to a desired threshold.3 Tumor stained for GATA3 and PIT1, characterizing the TSH-oma.4,5 Understanding cavernous sinus vascular and ligamentous anatomy allows for safe separation of invaded medial wall dura from the cavernous internal carotid artery,6 allowing for a more complete tumor resection, improving surgical cure rates, and sparing the patient from future radiation and pharmacotherapy.

Daily-Level Associations between Situational Familiarity with Location and People and Use of Alcohol-related Protective Behavioral Strategy Among Adolescents and Young Adults.

OBJECTIVE: Despite protective behavioral strategies (PBS) being an important part of alcohol prevention programs, utilization of PBS is sub-optimal, and research is needed to determine factors associated with use and non-use of PBS. The present study examined daily-level associations between situational familiarity (i.e., familiarity with locations and people) and the use of alcohol-related PBS among adolescents and young adults. METHOD: Participants (analysis N = 564, 55.1% females, 45.2% White, Non-Hispanic, ages 15 to 25, mean = 21.07 years [SD = 2.79]) were part of a longitudinal ecological momentary assessment burst study on cognitions and alcohol use. Mixed effects Poisson models were used to analyze data for engagement in PBS (i.e., serious harm reduction, stopping/limiting, and manner of drinking PBS). RESULTS: Within-person results indicated when participants had elevated (i.e., higher than their own average) familiarity with their location, they were less likely to use serious harm reduction PBS (Rate ratio [RR] = 0.94, p < 0.001) and stopping/limiting PBS (RR = 0.95, p < 0.001). Results showed that on drinking days with elevated familiarity with people, individuals were more likely to use serious harm reduction PBS (RR = 1.03, p = 0.01). There were no significant daily-level associations between familiarity with people or location and manner of drinking PBS. CONCLUSION: The study suggests PBS use, particularly for serious harm reduction and stopping/limiting strategies, varies among adolescents and young adults based on familiarity with location and people. Alcohol prevention interventions, including just-in-time interventions, should consider how to promote PBS use particularly in familiar locations and with less familiar people.

Supramarginal resection of skull base chordomas: proof of concept and preliminary outcomes.

OBJECTIVE: The mainstay of treatment for skull base chordoma (SBC) is maximal safe resection followed by radiotherapy. However, even after gross-total resection (GTR), the recurrence rate is high due to microscopic disease in the resection margins. Therefore, supramarginal resection (SMR) could be beneficial, as has been shown for sacral chordoma. The paradigm of postoperative radiation therapy for every patient has also begun to change, as molecular profiling has shown variability in the risk of recurrence. The aim of this study was to present the concept of SMR applied to SBC, along with an individualized decision for postoperative radiation therapy. METHODS: This is a retrospective analysis of all SBCs operated on by the senior author between 2018 and 2023. SMR was defined as negative histological margins of bone and/or dura mater, along with evidence of bone resection beyond the tumor margins in the craniocaudal and lateral planes on postoperative imaging. Tumors were classified into 3 molecular recurrence risk groups (group A, low risk; group B, intermediate risk; and group C, high risk). Postoperative radiation therapy was indicated in group C tumors, in group B chordomas without SMR, or in cases of patient preference. RESULTS: Twenty-two cases of SBC fulfilled the inclusion criteria. SMR was achieved in 12 (55%) cases, with a mean (range) amount of bone resection beyond the tumor margins of 10 (2-20) mm (+40%) in the craniocaudal axis and 6 (1-15) mm (+31%) in the lateral plane. GTR and near-total resection were each achieved in 5 (23%) cases. Three (19%) tumors were classified as group A, 12 (75%) as group B, and 1 (6%) as group C. Although nonsignificant due to the small sample size, the trends showed that patients in the SMR group had smaller tumor volumes (13.9 vs 19.6 cm3, p = 0.35), fewer previous treatments (33% vs 60% of patients, p = 0.39), and less use of postoperative radiotherapy (25% vs 60%, p = 0.19) compared to patients in the non-SMR group. There were no significant differences in postoperative CSF leak (0% vs 10%, p = 0.45), persistent cranial nerve palsy (8% vs 20%, p = 0.57), and tumor recurrence (8% vs 10%, p = 0.99; mean follow-up 15 months) rates between the SMR and non-SMR groups. CONCLUSIONS: In select cases, SMR of SBC appears to be feasible and safe. Larger cohorts and longer follow-up evaluations are necessary to explore the benefit of SMR and individualized postoperative radiation therapy on progression-free survival.

SARS-CoV-2 recombinant spike ferritin nanoparticle vaccine adjuvanted with Army Liposome Formulation containing monophosphoryl lipid A and QS-21: a phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial.

BACKGROUND: A self-assembling SARS-CoV-2 WA-1 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) has shown protective efficacy in animal challenge models. This trial aims to assess the safety and immunogenicity of SpFN/ALFQ in a first-in-human clinical trial. METHODS: In this phase 1, randomised, double-blind, placebo-controlled, first-in-human clinical trial, adults were randomly assigned (5:5:2) to receive 25 µg or 50 µg of SpFN/ALFQ or saline placebo intramuscularly at day 1 and day 29, with an optional open-label third vaccination at day 181. Enrolment and randomisation occurred sequentially by group; randomisation was done by an interactive web-based randomisation system and only designated unmasked study personnel had access to the randomisation code. Adults were required to be seronegative and unvaccinated for inclusion. Local and systemic reactogenicity, adverse events, binding and neutralising antibodies, and antigen-specific T-cell responses were quantified. For safety analyses, exact 95% Clopper-Pearson CIs for the probability of any incidence of an unsolicited adverse event was computed for each group. For immunogenicity results, CIs for binary variables were computed using the exact Clopper-Pearson methodology, while CIs for geometric mean titres were based on 10 000 empirical bootstrap samples. Post-hoc, paired one-sample t tests were used to assess the increase in mean log-10 neutralising antibody titres between day 29 and day 43 (after the second vaccination) for the primary SARS-CoV-2 targets of interest. This trial is registered at ClinicalTrials.gov, NCT04784767, and is closed to new participants. FINDINGS: Between April 7, and June 29, 2021, 29 participants were enrolled in the study. 20 individuals were assigned to receive 25 µg SpFN/ALFQ, four to 50 µg SpFN/ALFQ, and five to placebo. Neutralising antibody responses peaked at day 43, 2 weeks after the second dose. Neutralisation activity against multiple omicron subvariants decayed more slowly than against the D614G or beta variants until 5 months after second vaccination for both dose groups. CD4+ T-cell responses were elicited 4 weeks after the first dose and were boosted after a second dose of SpFN/ALFQ for both dose groups. Neutralising antibody titres against early omicron subvariants and clade 1 sarbecoviruses were detectable after two immunisations and peaked after the third immunisation for both dose groups. Neutralising antibody titres against XBB.1.5 were detected after three vaccinations. Passive IgG transfer from vaccinated volunteers into Syrian golden hamsters controlled replication of SARS-CoV-1 after challenge. INTERPRETATION: SpFN/ALFQ was well tolerated and elicited robust and durable binding antibody and neutralising antibody titres against a broad panel of SARS-CoV-2 variants and other sarbecoviruses. FUNDING: US Department of Defense, Defense Health Agency.

Increased genetic risk for ß-cell failure is associated with ß-cell function decline in people with prediabetes.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (ß-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher ß-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the ß-cell cluster pPS had worsening in measures of ß-cell function.

Homologous recombination deficiency should be tested for in patients with advanced stage high-grade serous ovarian cancer aged 70 years and over.

OBJECTIVE: Due to limited data on homologous recombination deficiency (HRD) in older patients (≥ 70 years) with advanced stage high grade serous ovarian cancer (HGSC), we aimed to determine the rates of HRD at diagnosis in this age group. METHODS: From the Phase 3 trial VELIA the frequency of HRD and BRCA1/2 pathogenic variants (PVs) was compared between younger (< 70 years) and older participants. HRD and somatic(s) BRCA1/2 pathogenic variants (PVs) were determined at diagnosis using Myriad myChoice® CDx and germline(g) BRCA1/2 PVs using Myriad BRACAnalysis CDx®. HRD was defined if a BRCA PV was present, or the genomic instability score (GIS) met threshold (GIS ≥ 33 & ≥ 42 analyzed). RESULTS: Of 1140 participants, 21% were ≥ 70 years. In total, 26% (n = 298) had a BRCA1/2 PV and HRD, 29% (n = 329) were HRD/BRCA wild-type, 33% (n = 372) non-HRD, and 12% HR-status unknown (n = 141). HRD rates were higher in younger participants, 59% (n = 476/802), compared to 40% (n = 78/197) of older participants (GIS ≥ 42) [p < 0.001]; similar rates demonstrated with GIS ≥ 33, 66% vs 48% [p < 0.001]. gBRCA PVs observed in 24% younger vs 8% of older participants (p < 0.001); sBRCA in 8% vs 10% (p = 0.2559), and HRD (GIS ≥ 42) not due to gBRCA was 35% vs 31% (p = 0.36). CONCLUSIONS: HRD frequency was similar in participants aged < 70 and ≥ 70 years (35% vs 31%) when the contribution of gBRCA was excluded; rates of sBRCA PVs were also similar (8% v 10%), thus underscoring the importance of HRD and BRCA testing at diagnosis in older patients with advanced HGSC given the therapeutic implications.

Is the 21st birthday a turning point for alcohol and cannabis use? A monthly study of young adults.

BACKGROUND: An important life-course event with respect to alcohol and cannabis use is turning 21 years of age, which may be associated with increases in use of these substances due to celebrations during the month and easier access to them on and following this birthday. We examined the trajectories of alcohol and cannabis use behaviors in the months leading up to, during, and following the 21st birthday month. We also examined whether the use trajectories vary by college status and baseline levels of use. METHODS: We used data from 203 young adults recruited from the Greater Seattle region who turned 21 during the course of the study. Surveys were administered each month for 24 consecutive months. Measures included the typical number of drinks per week for the past month, the frequency of heavy episodic drinking, the number of cannabis use days, and any simultaneous alcohol and cannabis use. Multilevel spline models were run that estimated linear slopes over time at four intervals: (1) up to 1 month before the 21st birthday month; (2) from 1 month before to the month of the 21st birthday; (3) from the 21st birthday month to 1 month following; and (4) from 1 month following the 21st birthday month through all following months. RESULTS: Alcohol use, generally, and simultaneous alcohol and cannabis use showed sharp increases from the month before the 21st birthday month to the 21st birthday month and decreases following the 21st birthday month. For cannabis use, there were significant increases in the months leading up to the 21st birthday and no other significant changes during other time intervals. Patterns differed by baseline substance use and college status. CONCLUSIONS: Findings from the current study have implications for the timing and personalization of prevention and intervention efforts. Event-specific 21st birthday interventions may benefit from incorporating content targeting specific hazardous drinking behaviors in the month prior to the 21st birthday.

A Radiological Clip Design Using Ultrasound Identification to Improve Localization.

OBJECTIVE: We demonstrate the use of ultrasound to receive an acoustic signal transmitted from a radiological clip designed from a custom circuit. This signal encodes an identification number and is localized and identified wirelessly by the ultrasound imaging system. METHODS: We designed and constructed the test platform with a Teensy 4.0 microcontroller core to detect ultrasonic imaging pulses received by a transducer embedded in a phantom, which acted as the radiological clip. Ultrasound identification (USID) signals were generated and transmitted as a result. The phantom and clip were imaged using an ultrasonic array (Philips L7-4) connected to a Verasonics™ Vantage 128 system operating in pulse inversion (PI) mode. Cross-correlations were performed to localize and identify the code sequences in the PI images. RESULTS: USID signals were detected and visualized on B-mode images of the phantoms with up to sub-millimeter localization accuracy. The average detection rate across 30,400 frames of ultrasound data was 98.1%. CONCLUSION: The USID clip produced identifiable, distinguishable, and localizable signals when imaged. SIGNIFICANCE: Radiological clips are used to mark breast cancer being treated by neoadjuvant chemotherapy (NAC) via implant in or near treated lesions. As NAC progresses, available marking clips can lose visibility in ultrasound, the imaging modality of choice for monitoring NAC-treated lesions. By transmitting an active signal, more accurate and reliable ultrasound localization of these clips could be achieved and multiple clips with different ID values could be imaged in the same field of view.

Endoscopic endonasal pituitary sacrifice for select tumors with retrochiasmatic and/or retrosellar extension: surgical anatomy, operative technique, and case series.

OBJECTIVE: Tumors located in the retrochiasmatic region with extension to the third ventricle might be difficult to access when the pituitary-chiasmatic corridor is narrow. Similarly, tumor extension into the interpeduncular and retrosellar space poses a major surgical challenge. Pituitary transposition techniques have been developed to gain additional access. However, when preoperative pituitary function is already impaired or the risk of postoperative panhypopituitarism (PH) is considered to be particularly high, removal of the pituitary gland (PG) might be the preferred option to increase the working corridor. The aim of this study was to describe the relevant surgical anatomy, operative steps, and clinical experience with the endoscopic endonasal pituitary sacrifice (EEPS) and transsellar approach. METHODS: This study comprised anatomical dissections to highlight the relevant surgical steps and a retrospective case series reporting clinical characteristics, indications, and outcomes of patients who underwent EEPS. The surgical technique is as follows: both lateral opticocarotid recesses are exposed laterally, the limbus sphenoidale superiorly, and the sellar floor inferiorly. After opening the dura, the PG is detached circumferentially and mobilized off the medial walls of the cavernous sinuses. The descending branches of the superior hypophyseal artery are coagulated, and the stalk is transected. After removal of the PG, drilling of the dorsum sellae and bilateral posterior clinoidectomies are performed to gain access to the hypothalamic region, interpeduncular, and prepontine cisterns. RESULTS: From 2018 to 2023, 11 patients underwent EEPS. The cohort comprised mostly tuberoinfundibular craniopharyngiomas (n = 8, 73%). Seven (64%) patients had partial or complete anterior PG dysfunction preoperatively, while 4 (36%) had preoperative diabetes insipidus. Because of the specific tumor configuration, the chance of preserving endocrine function was estimated to be very low in patients with intact function. The main reasons for pituitary sacrifice were impaired visibility and surgical accessibility to the retrochiasmatic and retrosellar spaces. Gross-total tumor resection was achieved in 10 (91%) patients and near-total resection in 1 (9%) patient. Two (18%) patients experienced a postoperative CSF leak, requiring surgical revision. CONCLUSIONS: When preoperative pituitary function is already impaired or the risk for postoperative PH is considered particularly high, the EEPS and transsellar approach appears to be a feasible surgical option to improve visibility and accessibility to the retrochiasmatic hypothalamic and retrosellar spaces, thus increasing tumor resectability.

Mutant IDH inhibitors induce lineage differentiation in IDH-mutant oligodendroglioma.

A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.