Lateral compartment of the cavernous sinus from the endoscopic endonasal approach: anatomical considerations and surgical relevance to adenoma surgery.

OBJECTIVE: The cavernous sinus (CS) has 4 compartments: superior, inferior, posterior, and lateral. Among these, the lateral compartment is the most common location for residual tumor, given the risk of neurovascular injury. The authors' study aimed to delineate the anatomical landmarks in this area and illustrate the technical nuances of the lateral transcavernous approach. METHODS: Twenty-two colored silicone-injected specimens were dissected via an endoscopic endonasal approach to the lateral compartment of the CS. The anatomical landmarks and the internal carotid artery (ICA) mobilization technique were investigated. Two illustrative cases are provided. RESULTS: The lateral compartment of the CS is bounded by the carotid-oculomotor membrane (COM) and optic strut as the roof and the petrolingual ligament and lingual process as the floor. It is divided into 2 asymmetrical subcompartments: the upper, larger subcompartment, located superior to the abducens nerve, accommodates the lateral parasellar ligament (LPL), inferolateral trunk (ILT), and branches of the tentorial artery; and the lower, smaller subcompartment, inferior to the abducens nerve, accommodates only the sympathetic nerve branches as they join the abducens nerve. The LPL is a well-defined ligamentous band and was identified in 38 (86%) hemispheres with 2 distinct configurations: 1) robust LPL (59%), with highly compacted ligamentous bands tightly adherent to the ICA; and 2) dispersed LPL (27%), with less compaction and adherence to ICA. The main attachment of the LPL to the cavernous ICA was most commonly observed at the horizontal ICA segment (55%), followed by the anterior (18%) and posterior (14%) genua. The ILT, as the main vessel in the lateral compartment, was identified in 41 (93%) hemispheres and originated from the horizontal ICA segment (80%) or the anterior genu (14%), from either the lateral (52%) or inferior (41%) aspect of the cross-section of the ICA. In 64% of hemispheres, the LPL wrapped the ILT, abducens nerve, and sympathetic nerve to form a broad and firm neurovascular-ligamental complex. Transection of the LPL, ILT, and COM enables medial ICA mobilization and enhances access to the lateral compartment of the CS, potentially increasing the exposure width by 6 ± 1 mm. CONCLUSIONS: This study provides valuable insights into the anatomical intricacies of the lateral compartment of the CS and underscores the potential benefits of the endoscopic endonasal lateral transcavernous approach. Further clinical applications are essential for validating these findings and optimizing surgical outcomes.

Safety and immunogenicity of a next-generation live-attenuated yellow fever vaccine produced in a Vero cell line in the USA: a phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial.

BACKGROUND: Recent outbreaks between 2015-17 and production delays have led to a yellow fever vaccine shortage. Therefore, there is an urgent need for new yellow fever vaccines with improved production scalability. A next-generation live-attenuated yellow fever vaccine candidate (vYF), produced in a Vero cell line has shown similar immunogenicity to licensed yellow fever vaccines in preclinical studies. In this study, we aimed to report the safety and immunogenicity of vYF in human clinical trial participants. METHODS: In this first in-human, phase 1 randomised, observer-blind, active-controlled, dose-ranging clinical trial conducted at a single centre in the USA (Walter Reed Army Institute of Research, Silver Spring, MD, USA), 72 healthy adults (aged 18-60 years), without a known history of flavivirus infection or vaccination were randomly assigned (1:1:1:1) using interactive response technology to receive one dose of either vYF at 4, 5 or 6 Log CCID50 or the licensed YF-VAX (18 individuals per group). The primary outcomes were safety, neutralising antibody (NAb) titres through D180 post-vaccination in the per-protocol analysis set (comprised of yellow fever-naive participants who received their intended vaccine and provided a valid post-vaccination blood sample), and occurrence, and level of yellow fever viraemia in each vaccine group through D14 post-vaccination. FINDINGS: All vYF doses had a safety and tolerability profile similar to YF-VAX. The most frequently reported solicited injection site reactions (vYF groups vs YF-VAX group) were pain (22% [12 of 54 participants, 95% CI 12-36] vs 28% [five of 18 participants, 10-54]), and erythema (13% [seven of 54 participants, 5-25] vs 39% [seven of 18 participants, 17-64]), with headache (32% [17 of 54 participants, 20-46] vs 44% [eight of 18 participants, 22-69]) and malaise (26% [14 of 54 participants, 15-40] vs 33% [six of 18 participants, 13-59]) as the most frequently reported solicited systemic reactions. One grade 3 solicited reaction (erythema) reported in the YF-VAX group resolved spontaneously. No serious unsolicited adverse events or deaths were reported. Viraemia was transiently detected in 50 participants between D4 and D10 in all groups and was observed in more participants or for a longer time in the vYF 6 Log CCID50 and YF-VAX groups. All yellow fever-naive vaccine recipients across the study groups seroconverted yielding four-fold increase from baseline in yellow fever NAb titres measured by yellow fever microneutralisation assay by D28 and were seroprotected with yellow fever NAb titres of at least 10 [1/dil]). Overall, 100% (18 of 18 participants, 95% CI 82-100), 89% (16 participants, 65-99), 100% (18 participants, 82-100), and 94% (17 participants, 73-100) of participants in the vYF 4 Log, vYF 5 Log, vYF 6 Log CCID50 groups, and YF-VAX group, respectively, remained seroprotected through D180. INTERPRETATION: vYF has a similar safety and immunogenicity profile to YF-VAX. In general, the vYF 5 Log CCID50 dose appeared to show optimal viraemia, safety, and immunogenicity, and was chosen for subsequent development. FUNDING: Sanofi.

Simultaneous use of alcohol and cannabis and attenuated age-related declines in alcohol and cannabis use disorder symptoms across young adulthood.

Most young adults naturally mature out of high-risk substance use patterns, but it is important to identify factors that may impede normative declines. Use of alcohol and cannabis simultaneously (i.e., simultaneous alcohol and marijuana/cannabis [SAM]) is cross-sectionally associated with alcohol and cannabis concerns, and SAM use increases acute risks at the daily level. However, less is known about long-term risks of SAM use and, specifically, how SAM use relates to maturing out of alcohol and cannabis use. Using four consecutive years of survey data from young adults who reported SAM use (N=409; 1636 responses; aged 18-25 at baseline), we first estimated age-related changes in symptoms of alcohol and cannabis use disorder (AUD/CUD) using multilevel growth modeling. Findings supported a maturing out process, as both AUD and CUD symptom severity significantly declined across young adulthood, on average (4 % and 5 % per year respectively, with significant acceleration). Cross-level interactions tested whether participants' mean SAM use frequency across all four timepoints moderated age-related trajectories in AUD/CUD symptom severity. Significant interactions indicated that, relative to less-frequent SAM use, participants with more frequent SAM use showed less steep declines in AUD (1 % decrease per year vs. 6 % per year) and CUD symptoms (0 % decrease per year vs. 7 % per year); thus, SAM frequency was associated with slower/delayed maturing out of hazardous alcohol and cannabis use. Findings highlight that SAM use may be a correlate or risk-factor for prolonged high-risk substance use during young adulthood that relates to deviations from maturing out processes.

Randomized Feasibility Study Evaluating Multiple FDA-approved Microbubbles for CEUS Lymphography.

Prior studies on contrast-enhanced ultrasound (CEUS) lymphography for preoperative mapping before lymphaticovenous anastomosis surgery in patients with extremity lymphedema have been limited to using only Lumason and Sonazoid as microbubble contrast agents. The purpose of this study was to determine the feasibility of using two other Food & Drug Administration-approved microbubble agents, Optison and Definity, for imaging lymphatic vessels in the upper extremities. Nine female adults with unilateral upper extremity lymphedema anticipating lymphaticovenous anastomosis surgery underwent CEUS lymphography of the unaffected upper extremity randomized to either Lumason, Definity, or Optison. Lymphatic vessels were visualized in all but one case when undilated Definity was used. In the eight upper extremities where lymphatic vessels were visualized, an average of eight intradermal injections of microbubbles were performed in the extremity. Lymphatic vessels could be identified in 57% (36 of 63) of the injections. The effective dilution for each of the microbubble agents is provided. This was the first successful demonstration of lymphatic vessel visualization using either Definity or Optison. Broadening the range of available microbubble agents for CEUS lymphography could improve accessibility to the procedure and provide potentially safer alternatives.

Negative urgency as a state-level process.

OBJECTIVE: Test whether global self-reports of urgency moderated the within-person associations of affect and impulsive behaviors. BACKGROUND: Negative urgency is a personality trait that is a risk factor for a range of psychopathology. Although it is assumed that global self-reports of urgency measure individual tendencies to act more impulsively in the face of negative emotions, evidence from ecological momentary assessment studies is mixed. METHOD: In this Registered Report, we used ecological momentary assessment data from a large sample of young adults (n = 496, age 18-22, 5 surveys per day for 40 days). RESULTS: All forms of momentary impulsivity were impaired in moments when people reported more intense negative emotions, but global self-reports of urgency did not explain individual differences in this association. Moreover, averaged affective states, rather than specific dimensions, affective circumplex, or appraisals, best predicted impulsive states. CONCLUSIONS: Results suggest that face-valid interpretations of global self-report of urgency are inaccurate, and it may be important to understand how some people come to understand themselves as high on urgency rather than assuming that people's self-reports of their motivations are accurate. Momentary experiences of emotions globally impact multiple weakly to moderately associated impulsive behaviors, and future research should seek to understand both when and for whom these associations are strongest.

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.

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.

Large Language Models Versus Expert Clinicians in Crisis Prediction Among Telemental Health Patients: Comparative Study.

BACKGROUND: Due to recent advances in artificial intelligence, 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 generative pretrained transformer 4 (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: Deidentified patient-provided data were 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 were pulled for 200 randomly selected patients, treated during the same time period, who never endorsed SI. In total, 6 senior Brightside clinicians (3 psychologists and 3 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 or no question regarding their prediction of endorsement of SI with plan, along with their confidence level about the prediction. GPT-4 was provided with similar information and asked to answer the same questions, enabling us to directly compare the performance of artificial intelligence and clinicians. RESULTS: Overall, the clinicians' average precision (0.7) was higher than that of GPT-4 (0.6) in identifying the SI with plan at intake (n=140) versus no SI (n=200) when using the chief complaint alone, while sensitivity was higher for the GPT-4 (0.62) than the clinicians' average (0.53). The addition of suicide attempt history increased the clinicians' average sensitivity (0.59) and precision (0.77) while increasing the GPT-4 sensitivity (0.59) but decreasing the GPT-4 precision (0.54). Performance decreased comparatively when predicting future SI with plan (n=120) versus no SI (n=200) with a chief complaint only for the clinicians (average sensitivity=0.4; average precision=0.59) and the GPT-4 (sensitivity=0.46; precision=0.48). The addition of suicide attempt history increased performance comparatively for the clinicians (average sensitivity=0.46; average precision=0.69) and the GPT-4 (sensitivity=0.74; precision=0.48). CONCLUSIONS: GPT-4, with a simple prompt design, produced results on some metrics that approached those of a trained clinician. Additional work must be done before such a model can 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 on which they are trained. We believe that LLMs hold promise for augmenting the identification of higher-risk patients at intake and potentially delivering more timely care to patients.

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.

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.

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.

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.

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).

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.

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 association of T2D pPS with 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 with general linear models and Cox regression with adjustment 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 1-year follow-up with adjustment for baseline measures (effect per pPS SD -0.04, P = 9.6 × 10-7, and -8.45 µU/mg, P = 5.6 × 10-6, respectively) and with increased diabetes incidence with adjustment for BMI at nominal significance (hazard ratio 1.10 per SD, P = 0.035). The liver/lipid pPS was associated with reduced 1-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.

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.