Large-scale neurophysiology and single-cell profiling in human neuroscience.

Advances in large-scale single-unit human neurophysiology, single-cell RNA sequencing, spatial transcriptomics and long-term ex vivo tissue culture of surgically resected human brain tissue have provided an unprecedented opportunity to study human neuroscience. In this Perspective, we describe the development of these paradigms, including Neuropixels and recent brain-cell atlas efforts, and discuss how their convergence will further investigations into the cellular underpinnings of network-level activity in the human brain. Specifically, we introduce a workflow in which functionally mapped samples of human brain tissue resected during awake brain surgery can be cultured ex vivo for multi-modal cellular and functional profiling. We then explore how advances in human neuroscience will affect clinical practice, and conclude by discussing societal and ethical implications to consider. Potential findings from the field of human neuroscience will be vast, ranging from insights into human neurodiversity and evolution to providing cell-type-specific access to study and manipulate diseased circuits in pathology. This Perspective aims to provide a unifying framework for the field of human neuroscience as we welcome an exciting era for understanding the functional cytoarchitecture of the human brain.

Re-evaluating the Role of Partnership-Related Perceptions in Women's Preferences for Men with Masculine Face Shapes.

Many researchers have proposed that women perceive men with masculine face shapes to be less suitable as parents and long-term partners than men with feminine face shapes, causing women to find masculine men more attractive for short-term than long-term relationships. However, recent work shows that results obtained using the type of experimentally manipulated stimuli that were employed in studies presenting evidence for these claims are not necessarily observed when natural (i.e., unmanipulated) face stimuli were used to suggest that the evidence for these claims may need to be revaluated. Consequently, we tested for possible relationships between ratings of natural male faces for parenting- and relationship-related traits and shape masculinity (Study 1) and also tested whether women's preferences for shape masculinity were stronger when natural male faces were rated for short-term relationships than when natural male faces were rated for long-term relationships (Studies 2 and 3). We saw no evidence for either of these predictions, instead finding that men with more attractive faces were perceived to be better parents and better long-term partners. Thus, our findings do not support the widely held view that masculine men are more attractive for short-term relationships because they are perceived to be unlikely to invest time and effort in their romantic partners and offspring.

Time-varying brentuximab vedotin pharmacokinetics and weight-based dosing in paediatric patients despite lower exposure in those aged 2 to <6 and 6-11 years.

AIMS: We studied the pharmacokinetics and exposure-response relationships of the brentuximab vedotin (BV) antibody-drug conjugate (ADC) and unconjugated monomethyl auristatin E in haematologic malignancies. METHODS: This population pharmacokinetic analysis included data from five adult and three paediatric studies. Exposures in virtual adult and paediatric populations following BV 1.8 mg/kg (maximum 180 mg) intravenously every 3 weeks were simulated. Clinical endpoints included overall response rate, grade ≥2 peripheral neuropathy (PN) and grade ≥3 neutropenia. RESULTS: BV ADC exhibited linear pharmacokinetics, well-described by a three-compartment model, with body weight being the only significant covariate for exposure. Monomethyl auristatin E exhibited time-varying formation rate. Simulated steady-state BV ADC exposures in patients aged 12 to <18 years were similar to those of adult patients, but 23%-38% lower in patients aged 2 to <12 years. Despite lower exposure, clinical activity was observed with BV 1.8 mg/kg every 3 weeks in those aged 2 to <12 years (overall response rate: 2 to <12 years, 60%; 12 to <18 years, 43%). In adult, but not paediatric patients, increased BV ADC exposures were associated with grade ≥2 PN and grade ≥3 neutropenia occurrence. CONCLUSIONS: BV pharmacokinetics in adult and paediatric patients were consistent. BV ADC exposures were lower in patients aged 2 to <12 years vs. ≥12 years, but no apparent clinically relevant differences in efficacy, grade ≥2 PN or grade ≥3 neutropenia were observed. These data support body weight-based dosing of BV in patients irrespective of age; thus, dose adjustment in those 2 to <12 years does not appear warranted.

Postdissection aortic aneurysm sac enlargement after fenestrated and branched endovascular aortic aneurysm repair.

OBJECTIVES: Aneurysm sac changes after fenestrated-branched endovascular aneurysm repair (FBEVAR) for postdissection thoracoabdominal aortic aneurysms (PD-TAAs) are poorly understood. Partial thrombosis of the false lumen and endoleaks may impair sac regression. To characterize sac changes after FBEVAR for PD-TAAs, this study examined midterm results and predictors for sac enlargement. METHODS: FBEVARs performed for PD-TAAs in 10 physician-sponsored investigational device exemption studies from 2008 to 2023 were analyzed. The maximum aortic aneurysm diameter was compared between the 30-day computed tomography angiogram and follow-up imaging studies. Aneurysm sac enlargement was defined as an increase in diameter of ≥5 mm. Kaplan-Meier curves and Cox regression were used to evaluate sac enlargement and midterm FBEVAR outcomes. RESULTS: Among 3296 FBEVARs, 290 patients (72.4% male; median age, 68.4 years) were treated for PD-TAAs. Most aneurysms treated were extent II (72%) and III (12%). Mean aneurysm diameter was 66.5 ± 11.2 mm. Mortality at 30 days was 1.4%. At a mean follow-up of 2.9 ± 1.9 years, at least one follow-up imaging study revealed sac enlargement in 43 patients (15%), sac regression in 115 patients (40%), and neither enlargement nor regression in 137 (47%); 5 (2%) demonstrated both expansion and regression during follow-up. Freedom from aneurysm sac enlargement was 93%, 82%, and 80% at 1, 3, and 5 years, respectively. Overall, endoleaks were detected in 27 patients (63%) with sac enlargement and 143 patients (58%) without enlargement (P = .54). Sac enlargement was significantly more frequent among older patients (mean age at the index procedure, 70.2 ± 8.9 years vs 66.5 ± 11 years; P = .04) and those with type II endoleaks at 1 year (74% vs 52%; P = .031). Cox regression revealed age >70 years at baseline (hazard ratio [HR], 2.146; 95% confidence interval [CI], 1.167-3.944; P = .010) and presence of type II endoleak at 1 year (HR, 2.25; 95% CI, 1.07-4.79; P = .032) were independent predictors of sac enlargement. Patient survival was 92%, 81%, and 68% at 1, 3, and 5 years, respectively. Cumulative target vessel instability was 7%, and aneurysm-related mortality was 2% at 5 years. At least 42% of patients required secondary interventions. Sac enlargement did not affect patient survival. CONCLUSIONS: Aneurysm sac enlargement occurs in 15% of patients after FBEVAR for PD-TAAs. Elderly patients (>70 years at baseline) and those with type II endoleaks at 1 year may need closer monitoring and secondary interventions to prevent sac enlargement. Despite sac enlargement in some patients, aneurysm-related mortality at 5 years remains low and overall survival was not associated with sac enlargement.

The Association Between Task Complexity and Cortical Language Mapping Accuracy.

BACKGROUND AND OBJECTIVES: Direct cortical stimulation (DCS) mapping enables the identification of functional language regions within and around gliomas before tumor resection. Intraoperative mapping is required because glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but has decreased ability to encode information for complex tasks. It is unknown whether task complexity influenced DCS mapping results. We aim to understand correlations between audiovisual picture naming (PN) task complexity and DCS error rate. We also asked what functional and oncological factors might be associated with higher rates of erroneous responses. METHODS: We retrospectively reviewed intraoperative PN and word reading (WR) task performance during awake DCS language mapping for resection of dominant hemisphere World Health Organization grade 2 to 4 gliomas. The complexity of word tested in PN/WR tasks, patient characteristics, and tumor characteristics were compared between correct and incorrect trials. RESULTS: Between 2017 and 2021, 74 patients met inclusion criteria. At median 18.6 months of follow-up, 73.0% were alive and 52.7% remained recurrence-free. A total of 2643 PN and 978 WR trials were analyzed. A greater number of syllables in PN was associated with a higher DCS error rate (P = .001). Multivariate logistic regression found that each additional syllable in PN tasks independently increased odds of error by 2.40 (P < .001). Older age was also an independent correlate of higher error rate (P < .043). World Health Organization grade did not correlate with error rate (P = .866). More severe language impairment before surgery correlated with worse performance on more complex intraoperative tasks (P < .001). A higher error rate on PN testing did not correlate with lower extent of glioma resection (P = .949). CONCLUSION: Word complexity, quantified by the number of syllables, is associated with higher error rates for intraoperative PN tasks but does not affect extent of resection.

No evidence that averaging voices influences attractiveness.

Vocal attractiveness influences important social outcomes. While most research on the acoustic parameters that influence vocal attractiveness has focused on the possible roles of sexually dimorphic characteristics of voices, such as fundamental frequency (i.e., pitch) and formant frequencies (i.e., a correlate of body size), other work has reported that increasing vocal averageness increases attractiveness. Here we investigated the roles these three characteristics play in judgments of the attractiveness of male and female voices. In Study 1, we found that increasing vocal averageness significantly decreased distinctiveness ratings, demonstrating that participants could detect manipulations of vocal averageness in this stimulus set and using this testing paradigm. However, in Study 2, we found no evidence that increasing averageness significantly increased attractiveness ratings of voices. In Study 3, we found that fundamental frequency was negatively correlated with male vocal attractiveness and positively correlated with female vocal attractiveness. By contrast with these results for fundamental frequency, vocal attractiveness and formant frequencies were not significantly correlated. Collectively, our results suggest that averageness may not necessarily significantly increase attractiveness judgments of voices and are consistent with previous work reporting significant associations between attractiveness and voice pitch.

Performance of an Electronic Medical Record-based 'Syphilis Flag' in Identifying at-risk Patients in an Emergency Department.

BACKGROUND: The United States (US) has seen a > 40% increase in syphilis cases since 2017. Early disease identification and treatment are crucial. This review sought to identify emergency department (ED) patients at risk for syphilis. METHODS: A 30-day retrospective review was conducted of visits to a single ED. Patient visits were assessed for pre-determined syphilis 'flags' to include history of sexually transmitted infection (STI), current chief complaint (CC) or reason for visit (RFV) keyword(s) suggestive of potential STI, or positive pregnancy test. Flagged charts were assessed for STI testing results within six-months of ED visit. Data was analyzed using chi-square. RESULTS: There were 5537 total patient encounters, resulting in 455 flagged visits from 408 (8.4%) unique individuals, majority female (282, 69.1%; p < .001)), Black (251, 61.5%; p < .001), aged 15-44 (308, 75.5%; p < .001). Chief complaint was the most frequent flag (65.3%) followed by RFV (37.4%), prior STI (31.0%), and pregnancy (12.3%). Syphilis testing data was available for 120 flagged patents; 29 (24.2%) screened positive, including 11 (2.7% of total flagged cohort) with evidence for active infection. Among those, majority were Black (90.9%), male (72.7%), aged 25 to 34 (63.6%); nine (81.8%) had concomitant HIV; in active infection, prior STI flag was most common (72.7%), followed by CC (54.5%) and RFV (45.5%). CONCLUSION: This review demonstrates the performance of an EMR-based 'syphilis risk flag' screener applied to ED patients. Sex- and race-based discrepancies exist in flag rates, which may be reflective of sex- and race-based epidemiologic discrepancies in STI incidence.

Knowledge of head and neck cancer among medical students in the UK.

Head and neck cancer (HNC) refers to malignancies found in mucosal surfaces anywhere from the paranasal sinuses to the larynx, including the various glands and cavities. Between the years 2016 and 2018, there were about 3900 new cases every year in women and 8600 in men, making it the thirteenth most common cancer in women and fourth most common in men. The aim of our study was to evaluate the amount and type of teaching United Kingdom (UK) medical students receive on HNC, and to assess their current knowledge of these cancers. An online survey distributed via university representatives was responded to by 311 final year medical students from 25 medical schools across the UK. Regarding HNC teaching, 72 students (23.2%) reported receiving no teaching at their medical school. Of the 239 who reported receiving teaching, 169 (54.3%) received it in the format of a non-interactive, large group lecture. A total of 271 respondents (87.1%) believed that medical students at their university would benefit from more teaching on HNC. Based on our sample, there appears to be an overall dissatisfaction and lack of confidence surrounding HNC in the undergraduate curriculum. With its increasing prevalence in the UK, it is vital that red-flag symptoms and referral criteria are understood by the future medical workforce.

Ketamine Use in the Intubation of Critically Ill Children with Neurological Indications: A Multicenter Retrospective Analysis.

BACKGROUND: Ketamine has traditionally been avoided for tracheal intubations (TIs) in patients with acute neurological conditions. We evaluate its current usage pattern in these patients and any associated adverse events. METHODS: We conducted a retrospective observational cohort study of critically ill children undergoing TI for neurological indications in 53 international pediatric intensive care units and emergency departments. We screened all intubations from 2014 to 2020 entered into the multicenter National Emergency Airway Registry for Children (NEAR4KIDS) registry database. Patients were included if they were under the age of 18 years and underwent TI for a primary neurological indication. Usage patterns and reported periprocedural composite adverse outcomes (hypoxemia < 80%, hypotension/hypertension, cardiac arrest, and dysrhythmia) were noted. RESULTS: Of 21,562 TIs, 2,073 (9.6%) were performed for a primary neurological indication, including 190 for traumatic brain injury/trauma. Patients received ketamine in 495 TIs (23.9%), which increased from 10% in 2014 to 41% in 2020 (p < 0.001). Ketamine use was associated with a coindication of respiratory failure, difficult airway history, and use of vagolytic agents, apneic oxygenation, and video laryngoscopy. Composite adverse outcomes were reported in 289 (13.9%) Tis and were more common in the ketamine group (17.0% vs. 13.0%, p = 0.026). After adjusting for location, patient age and codiagnoses, the presence of respiratory failure and shock, difficult airway history, provider demographics, intubating device, and the use of apneic oxygenation, vagolytic agents, and neuromuscular blockade, ketamine use was not significantly associated with increased composite adverse outcomes (adjusted odds ratio 1.34, 95% confidence interval CI 0.99-1.81, p = 0.057). This paucity of association remained even when only neurotrauma intubations were considered (10.6% vs. 7.7%, p = 0.528). CONCLUSIONS: This retrospective cohort study did not demonstrate an association between procedural ketamine use and increased risk of peri-intubation hypoxemia and hemodynamic instability in patients intubated for neurological indications.

Creation of Novel Sensitive Probe Substrate and Moderate Inhibitor Models for a Comprehensive Prediction of CYP2C8 Interactions for Tucatinib.

A physiologically-based pharmacokinetic (PBPK) model was developed to simulate plasma concentrations of tucatinib (TUKYSA®) after single-dose or multiple-dose administration of 300 mg b.i.d. orally. This PBPK model was subsequently applied to support evaluation of drug-drug interaction (DDI) risk as a perpetrator resulting from tucatinib inhibition of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was also applied to support evaluation of DDI risk as a victim resulting from co-administration with CYP3A4 or CYP2C8 inhibitors, or a CYP3A4 inducer. After refinement with clinical DDI data, the final PBPK model was able to recover the clinically observed single and multiple-dose plasma concentrations for tucatinib when tucatinib was administered as a single agent in healthy subjects. In addition, the final model was able to recover clinically observed plasma concentrations of tucatinib when administered in combination with itraconazole, rifampin, or gemfibrozil as well as clinically observed plasma concentrations of probe substrates of CYP3A4, CYP2C8, CYP2C9, P-gp, or MATE1/2-K. The PBPK model was then applied to prospectively predict the potential perpetrator or victim DDIs with other substrates, inducers, or inhibitors. To simulate a potential interaction with a moderate CYP2C8 inhibitor, two novel PBPK models representing a moderate CYP2C8 inhibitor and a sensitive CYP2C8 substrate were developed based on the existing PBPK models for gemfibrozil and rosiglitazone, respectively. The simulated population geometric mean area under the curve ratio of tucatinib with a moderate CYP2C8 inhibitor ranged from 1.98- to 3.08-fold, and based on these results, no dose modifications were proposed for moderate CYP2C8 inhibitors for the tucatinib label.

Tracheal Intubation by Advanced Practice Registered Nurses in Pediatric Critical Care: Retrospective Study From the National Emergency Airway for Children Registry (2015-2019).

OBJECTIVES: To describe tracheal intubation (TI) practice by Advanced Practice Registered Nurses (APRNs) in North American PICUs, including rates of TI-associated events (TIAEs) from 2015 to 2019. DESIGN/SETTING: Retrospective study using the National Emergency Airway Registry for Children with all TIs performed in PICU and pediatric cardiac ICU between January 2015 and December 2019. The primary outcome was first attempt TI success rate. Secondary outcomes were TIAEs, severe TIAEs, and hypoxemia. SUBJECTS: Critically ill children requiring TI in a PICU or pediatric cardiac ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 11,012 TIs, APRNs performed 1,626 (14.7%). Overall, TI by APRNs, compared with other clinicians, occurred less frequently in patients with known difficult airway (11.1% vs. 14.3%; p < 0.001), but more frequently in infants younger than 1 year old (55.9% vs. 44.4%; p < 0.0001), and in patients with cardiac disease (26.3% vs. 15.9%; p < 0.0001).There was lower odds of success in first attempt TI for APRNs vs. other clinicians (adjusted odds ratio, 0.70; 95% CI, 0.62-0.79). We failed to identify a difference in rates of TIAE, severe TIAE, and oxygen desaturation events for TIs by APRNs compared with other clinicians. The TI first attempt success rate improved with APRN experience (< 1 yr: 54.2%, 1-5 yr: 59.4%, 6-10 yr: 67.6%, > 10 yr: 63.1%; p = 0.021). CONCLUSIONS: TI performed by APRNs was associated with lower odds of first attempt success when compared with other ICU clinicians although there was no appreciable difference in procedural adverse events. There appears to be a positive relationship between experience and success rates. These data suggest there is an ongoing need for opportunities to build on TI competency with APRNs.

Women's Preferences for Masculinity in Male Faces Are Predicted by Material Scarcity, But Not Time or Psychological Scarcity.

Facial femininity in men is purportedly used as a cue by women as a signal of parental quality and willingness to provide resources. Accordingly, in contexts where choosing a partner that will provide resources is more beneficial (e.g., when resources are scarce), women have shown an increase preference for facial femininity in male faces. However, domains of scarcity often covary, and it is, therefore, unclear whether these contextual shifts in facial masculinity/femininity preferences are specific to material scarcity (as implied by previous theory), or due to an unrelated domain of scarcity (e.g., time or psychological scarcity). Here, a sample of 823 women completed the Perceived Scarcity Scale, which measures three separate domains of scarcity: material scarcity, time scarcity, and psychological scarcity. Participants also rated the attractiveness of 42 male faces, which were measured on objective sexual dimorphism and perceived masculinity. Consistent with theory, material scarcity, and not time or psychological scarcity, was associated with a decreased preference for objective sexual dimorphism (i.e., an increased preference for facial femininity). This study provides evidence that women use sexual dimorphism as a cue to material resource provisioning potential when assessing men as a mate.

The importance of face-shape masculinity for perceptions of male dominance depends on study design.

Dominance perceptions play an important role in social interactions. Although many researchers have proposed that shape masculinity is an important facial cue for dominance perceptions, evidence for this claim has come almost exclusively from studies that assessed perceptions of experimentally manipulated faces using forced-choice paradigms. Consequently, we investigated the role of masculine shape characteristics in perceptions of men's facial dominance (1) when shape-manipulated stimuli were presented in a forced-choice paradigm and (2) when unmanipulated face images were rated for dominance and shape masculinity was measured from face images. Although we observed large effects of masculinity on dominance perceptions when we used the forced-choice method (Cohen's ds = 2.51 and 3.28), the effect of masculinity on dominance perceptions was considerably smaller when unmanipulated face images were rated and shape masculinity measured from face images (Cohen's ds = 0.44 and 0.62). This pattern was observed when faces were rated separately for physical dominance, social dominance, and masculinity, and was seen for two different sets of stimuli. Collectively, these results suggest that shape masculinity may not be a particularly important cue for dominance perceptions when faces vary simultaneously on multiple dimensions, as is the case during everyday social interactions.

No evidence that sociosexual orientation moderates effects of conception probability on women's preferences for male facial masculinity.

Although many researchers have proposed that women will show stronger preferences for male facial masculinity when conception probability is high, empirical tests of this hypothesis have produced mixed results. One possible explanation for these inconsistent findings is that effects of conception probability on women's preferences for facial masculinity are moderated by additional factors not typically considered in these empirical tests. One such potential moderator is individual differences in women's openness to uncommitted sexual relationships (i.e., individual differences in women's sociosexual orientation); women who are more open to uncommitted sexual relationships might show stronger positive effects of conception probability on masculinity preferences, as their sexuality is more overt and sexual attitudes and behaviours are more diversified. Consequently, we analysed data from three independent samples (N = 2304, N = 483, and N = 339) to assess whether sociosexual orientation moderates the hypothesised positive effect of conception probability on women's facial masculinity preferences. Analyses showed no evidence that higher conception probability increased preferences for facial masculinity or that sociosexual orientation moderated the effect of conception probability on women's preferences for facial masculinity. While it remains possible that factors other than sociosexual orientation moderate effects of conception probability on masculinity preferences, our null results suggest that the mixed results for the effects of conception probability on facial masculinity preferences in previous studies are unlikely to be a consequence of failing to consider the moderating role of sociosexual orientation.

Facial Attractiveness, but not Facial Masculinity, is Used as a Cue to Paternal Involvement in Fathers.

Purpose: Facial femininity in men is purportedly used as a cue by women as a signal of paternal involvement. However, evidence for this claim is questionable. Previous findings have shown that paternal involvement is linked to testosterone, but have not investigated facial masculinity directly, while other studies have found that facial masculinity is negatively associated with perceptions of paternal involvement but do not assess the accuracy of this judgement. Here, we assess whether facial masculinity in men is used as a cue to paternal involvement, and whether this cue is accurate. Methods: We collected facial photographs of 259 men (156 of which were fathers) who also completed self-report measures of paternal involvement. Facial images were then rated by a separate group of raters on facial masculinity, attractiveness, and perceived paternal involvement. Shape sexual dimorphism was also calculated from the images using geometric morphometrics. Results: We found that facial masculinity was not associated with perceptions of paternal involvement, nor was it related with self-reported paternal involvement. Interestingly, facial attractiveness was negatively associated with perceptions of paternal involvement, and we found partial evidence that facial attractiveness was also negatively associated with self-reported paternal involvement. Conclusion: These findings challenge the hypothesis that sexual dimorphism is used as a cue to paternal involvement, and perhaps indicate that facial attractiveness is more important for this judgement instead. Supplementary Information: The online version contains supplementary material available at 10.1007/s40750-023-00217-y.

Glioblastoma remodelling of human neural circuits decreases survival.

Gliomas synaptically integrate into neural circuits1,2. Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8. Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain. Site-directed biopsies from regions within the tumour that exhibit high functional connectivity between the tumour and the rest of the brain are enriched for a glioblastoma subpopulation that exhibits a distinct synaptogenic and neuronotrophic phenotype. Tumour cells from functionally connected regions secrete the synaptogenic factor thrombospondin-1, which contributes to the differential neuron-glioma interactions observed in functionally connected tumour regions compared with tumour regions with less functional connectivity. Pharmacological inhibition of thrombospondin-1 using the FDA-approved drug gabapentin decreases glioblastoma proliferation. The degree of functional connectivity between glioblastoma and the normal brain negatively affects both patient survival and performance in language tasks. These data demonstrate that high-grade gliomas functionally remodel neural circuits in the human brain, which both promotes tumour progression and impairs cognition.

Tumor Dynamic Model-Based Decision Support for Phase Ib/II Combination Studies: A Retrospective Assessment Based on Resampling of the Phase III Study IMpower150.

PURPOSE: Model-based tumor growth inhibition (TGI) metrics are increasingly incorporated into go/no-go decisions in early clinical studies. To apply this methodology to new investigational combinations requires independent evaluation of TGI metrics in recently completed Phase III trials of effective immunotherapy. PATIENTS AND METHODS: Data were extracted from IMpower150, a positive, randomized, Phase III study of first-line therapy in 1,202 patients with non-small cell lung cancer. We resampled baseline characteristics and longitudinal sum of longest diameters of tumor lesions of patients from both arms, atezolizumab+ bevacizumab+chemotherapy (ABCP) versus BCP, to mimic Phase Ib/II studies of 15 to 40 patients/arm with 6 to 24 weeks follow-up. TGI metrics were estimated using a bi-exponential TGI model. Effect sizes were calculated as TGI metrics geometric mean ratio (GMR), objective response rate (ORR) difference (d), and progression-free survival (PFS), hazard ratio (HR) between arms. Correct and incorrect go decisions were evaluated as the probability to achieve desired effect sizes in ABCP versus BCP and BCP versus BCP, respectively, across 500 replicated subsamples for each design. RESULTS: For 40 patients/24 weeks follow-up, correct go decisions based on probability tumor growth rate (KG) GMR <0.90, dORR >0.10, and PFS HR <0.70 were 83%, 69%, and 58% with incorrect go decision rates of 4%, 12%, and 11%, respectively. For other designs, the ranking did not change with TGI metrics consistently overperforming RECIST endpoints. The predicted overall survival (OS) HR was around 0.80 in most of the scenarios investigated. CONCLUSIONS: Model-based estimate of KG GMR is an exploratory endpoint that informs early clinical decisions for combination studies.

Modern intracranial electroencephalography for epilepsy localization with combined subdural grid and depth electrodes with low and improved hemorrhagic complication rates.

OBJECTIVE: Recent trends have moved from subdural grid electrocorticography (ECoG) recordings toward stereo-electroencephalography (SEEG) depth electrodes for intracranial localization of seizures, in part because of perceived morbidity from subdural grid and strip electrodes. For invasive epilepsy monitoring, the authors describe the outcomes of a hybrid approach, whereby patients receive a combination of subdural grids, strips, and frameless stereotactic depth electrode implantations through a craniotomy. Evolution of surgical techniques was employed to reduce complications. In this study, the authors review the surgical hemorrhage and functional outcomes of this hybrid approach. METHODS: A retrospective review was performed of consecutive patients who underwent hybrid implantation from July 2012 to May 2022 at an academic epilepsy center by a single surgeon. Outcomes included hemorrhagic and nonhemorrhagic complications, neurological deficits, length of monitoring, and number of electrodes. RESULTS: A total of 137 consecutive procedures were performed; 113 procedures included both subdural and depth electrodes. The number of depth electrodes and electrode contacts did not increase the risk of hemorrhage. A mean of 1.9 ± 0.8 grid, 4.9 ± 2.1 strip, and 3.0 ± 1.9 depth electrodes were implanted, for a mean of 125.1 ± 32 electrode contacts per patient. The overall incidence of hematomas over the study period was 5.1% (7 patients) and decreased significantly with experience and the introduction of new surgical techniques. The incidence of hematomas in the last 4 years of the study period was 0% (55 patients). Symptomatic hematomas were all delayed and extra-axial. These patients required surgical evacuation, and there were no cases of hematoma recurrence. All neurological deficits related to hematomas were temporary and were resolved at hospital discharge. There were 2 nonhemorrhagic complications. The mean duration of monitoring was 7.3 ± 3.2 days. Seizures were localized in 95% of patients, with 77% of patients eventually undergoing resection and 17% undergoing responsive neurostimulation device implantation. CONCLUSIONS: In the authors' institutional experience, craniotomy-based subdural and depth electrode implantation was associated with low hemorrhage rates and no permanent morbidity. The rate of hemorrhage can be nearly eliminated with surgical experience and specific techniques. The decision to use subdural electrodes or SEEG should be tailored to the patient's unique pathology and surgeon experience.

The Pharmacokinetics and Safety of Tucatinib in Volunteers with Hepatic Impairment.

BACKGROUND AND OBJECTIVE: Tucatinib, a highly selective tyrosine kinase inhibitor of the human epidermal growth factor receptor 2 (HER2) approved for HER2-positive metastatic breast cancer, is cleared by hepatic metabolism and subsequent biliary excretion. Liver disease can alter drug disposition and pharmacokinetics (PK). The objective of this study is to characterize PK and safety of tucatinib in volunteers with hepatic impairment. METHODS: This Phase 1 study compared the PK and safety of a single 300-mg oral dose of tucatinib in volunteers with mild, moderate, and severe hepatic impairment (Child-Pugh A/B/C) to healthy volunteers matched for sex, age, and body mass index. Pharmacokinetic parameters were determined for tucatinib and its predominant metabolite ONT-993. RESULTS: Compared with healthy volunteers, tucatinib exposure was similar in volunteers with mild impairment and increased in those with moderate or severe impairment without reaching statistical significance. Respective fold increases in geometric mean ratios for AUC0-t and AUC0-∞ were 1.13 and 1.15 in moderate impairment, and 1.43 and 1.61 in severe impairment compared with healthy volunteers. Three treatment-emergent adverse events (nausea, dermatitis, and increased transaminases) were reported in three volunteers and showed no obvious association with hepatic impairment status. CONCLUSION: The 1.61-fold geometric mean ratio AUC0-∞ increase in volunteers with severe hepatic impairment supports the recommendation in the tucatinib prescribing information to reduce the dose from 300 mg twice daily to 200 mg twice daily in patients with severe impairment; no dose adjustment is recommended for patients with mild or moderate hepatic impairment. This trial (NCT03722823) was registered on October 29, 2018.