The use of oral benzodiazepines for patient anxiety associated with Mohs micrographic surgery: An Australian survey.

A survey of Mohs surgery specialists in Australia showed diazepam was the preferred agent and felt to be the safest oral benzodiazepine for perioperative anxiolysis.

Subjective Probability Increases Across Communication Chains: Introducing the Probability Escalation Effect.

A severity effect has previously been documented, whereby numerical translations of verbal probability expressions are higher for severe outcomes than for non-severe outcomes. Recent work has additionally shown the same effect in the opposite direction (translating numerical probabilities into words). Here, we aimed to test whether these effects lead to an escalation of subjective probabilities across a communication chain. In four 'communication chain' studies, participants at each communication stage either translated a verbal probability expression into a number, or a number into a verbal expression (where the probability to be translated was yoked to a previous participant). Across these four studies, we found a general Probability Escalation Effect, whereby subjective probabilities increased with subsequent communications for severe, non-severe and positive events. Having ruled out some alternative explanations, we propose that the most likely explanation is in terms of communications directing attention towards an event's occurrence. Probability estimates of focal outcomes increase across communication stages.

Severity influences categorical likelihood communications: A case study with Southeast Asian weather forecasters.

Risk assessments are common in multiple domains, from finance to medicine. They require evaluating an event's potential severity and likelihood. We investigate the possible dependence of likelihood and severity within the domain of impact-based weather forecasting (IBF), following predictions derived from considering asymmetric loss functions. In a collaboration between UK psychologists and partners from four meteorological organisations in Southeast Asia, we conducted two studies (N = 363) eliciting weather warnings from forecasters. Forecasters provided warnings denoting higher likelihoods for high severity impacts than low severity impacts, despite these impacts being described as having the same explicit numerical likelihood of occurrence. This 'Severity effect' is pervasive, and we find it can have a continued influence even for an updated forecast. It is additionally observed when translating warnings made on a risk matrix to numerical probabilities.

Magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor in a patient with von Willebrand disease: perioperative optimization for patients with coagulopathies. Illustrative case.

BACKGROUND: Essential tremor (ET) is one of the most common movement disorders worldwide. In medically refractory ET, deep brain stimulation (DBS) of the ventral intermediate nucleus of the thalamus is the current standard of care. However, DBS carries an inherent 2% to 3% risk of hemorrhage, a risk that can be much higher in patients with concomitant coagulopathy. Magnetic resonance imaging-guided focused ultrasound (MRgFUS) thalamotomy is a surgical alternative that is highly effective in treating ET, with no reports of intracranial hemorrhage to date. OBSERVATIONS: This is the first documented case of successful MRgFUS thalamotomy in a patient with von Willebrand disease (VWD). A 60-year-old left-handed male had medically refractory ET, VWD type 2B, and a family history of clinically significant hemorrhage after DBS. He underwent right-sided MRgFUS thalamotomy and received a perioperative course of VONVENDI (recombinant von Willebrand factor) to ensure appropriate hemostasis. Postprocedure imaging confirmed a focal lesion in the right thalamus without evidence of hemorrhage. The patient reported 90% improvement of his left-hand tremor and significant improvement in his quality of life without obvious side effects. LESSONS: MRgFUS thalamotomy with peri- and postoperative hematological management is a promising alternative to DBS for patients with underlying coagulopathies.

Exploring open science practices in behavioural public policy research.

In their book 'Nudge: Improving Decisions About Health, Wealth and Happiness', Thaler & Sunstein (2009) argue that choice architectures are promising public policy interventions. This research programme motivated the creation of 'nudge units', government agencies which aim to apply insights from behavioural science to improve public policy. We closely examine a meta-analysis of the evidence gathered by two of the largest and most influential nudge units (DellaVigna & Linos (2022 Econometrica 90, 81-116 (doi:10.3982/ECTA18709))) and use statistical techniques to detect reporting biases. Our analysis shows evidence suggestive of selective reporting. We additionally evaluate the public pre-analysis plans from one of the two nudge units (Office of Evaluation Sciences). We identify several instances of excellent practice; however, we also find that the analysis plans and reporting often lack sufficient detail to evaluate (unintentional) reporting biases. We highlight several improvements that would enhance the effectiveness of the pre-analysis plans and reports as a means to combat reporting biases. Our findings and suggestions can further improve the evidence base for policy decisions.

The gene expression profile and cell of origin of canine peripheral T-cell lymphoma.

BACKGROUND: Peripheral T-cell lymphoma (PTCL) refers to a heterogenous group of T-cell neoplasms with poor treatment responses and survival times. Canine PTCL clinically and immunophenotypically resembles the most common human subtype, PTCL-not otherwise specified (PTCL-NOS), leading to interest in this canine disease as a naturally occurring model for human PTCL. Gene expression profiling in human PTCL-NOS has helped characterize this ambiguous diagnosis into distinct subtypes, but similar gene expression profiling in canine PTCL is lacking. METHODS: Bulk RNA-sequencing was performed on tumor samples from 33 dogs with either CD4+ (26/33), CD8+ (4/33), or CD4-CD8- (3/33) PTCL as diagnosed by flow cytometry, and sorted CD4+ and CD8+ lymphocytes from healthy control dogs. Following normalization of RNA-seq data, we performed differential gene expression and unsupervised clustering methods. Gene set enrichment analysis was performed to determine the enrichment of canine CD4+ PTCL for human PTCL-NOS, oncogenic pathways, and various stages of T-cell development gene signatures. We utilized gene set variation analysis to evaluate individual canine CD4+ PTCLs for various human and murine T-cell and thymocyte gene signatures. Cultured canine PTCL cells were treated with a pan-PI3K inhibitor, and cell survival and proliferation were compared to DMSO-treated controls. Expression of GATA3 and phosphorylated AKT was validated by immunohistochemistry. RESULTS: While the canine CD4+ PTCL phenotype exhibited a consistent gene expression profile, the expression profiles of CD8+ and CD4-CD8- canine PTCLs were more heterogeneous. Canine CD4+ PTCL had increased expression of GATA3, upregulation of its target genes, enrichment for PI3K/AKT/mTOR signaling, and downregulation of PTEN, features consistent with the more aggressive GATA3-PTCL subtype of human PTCL-NOS. In vitro assays validated the reliance of canine CD4+ PTCL cells on PI3K/AKT/mTOR signaling for survival and proliferation. Canine CD4+ PTCL was enriched for thymic precursor gene signatures, exhibited increased expression of markers of immaturity (CD34, KIT, DNTT, and CCR9), and downregulated genes associated with the T-cell receptor, MHC class II associated genes (DLA-DQA1, DLA-DRA, HLA-DQB1, and HLA-DQB2), and CD25. CONCLUSIONS: Canine CD4+ PTCL most closely resembled the GATA3-PTCL subtype of PTCL-NOS and may originate from an earlier stage of T-cell development than the more conventionally posited mature T-helper cell origin.

A disaster medicine course for Canadian medical students: first implementation of a large-scale mass-casualty simulation.

Mass-casualty incidents have a significant global impact. Despite calls for improved disaster-preparedness training, most medical curriculums do not include formal disaster-medicine education. In 2021, the Medical Council of Canada introduced new disaster-medicine learning objectives. This article presents a mass-casualty-incident course for 3rd-year Canadian medical students. The course includes lectures, and a large-scale simulation of an explosion scene, field triage zone, and simulated emergency department (ED). The simulation incorporated "Dark-team-member" facilitators and 17 live actor and 8 mannequin patients with moulage. Pre-/post-event evaluation data was collected. One-hundred and twenty medical students participated in the course. Confidence in managing a real mass-casualty incident, on a scale from 1 to 10 (no-confidence to completely confident) significantly improved based on a Mann-Whitney U test, p < 0.05. Few formal medical student mass-casualty-incident courses exist. Combining "Dark-team-members" with live actors, imbedding clinician facilitators with medical students, and having a simulation with a continuous disaster scene to the ED are unique to this course. The methodology is presented for future replication.

RéSUMé: Les incidents faisant de nombreuses victimes ont un impact mondial significatif. Malgré les appels à l'amélioration de la formation à la préparation aux catastrophes, la plupart des cursus médicaux n'incluent pas de formation formelle à la médecine des catastrophes. En 2021, le Conseil médical du Canada a introduit de nouveaux objectifs d'apprentissage en médecine de catastrophe. Cet article présente un cours sur les accidents de masse destiné aux étudiants en médecine canadiens de troisième année. Le cours comprend des cours magistraux et une simulation à grande échelle d'une scène d'explosion, d'une zone de triage sur le terrain et d'un service d'urgence (SU) simulé. La simulation comprenait des facilitateurs "Dark-team-member" et 17 acteurs réels et 8 patients mannequins avec moulage. Des données d'évaluation avant/après l'événement ont été collectées. Cent vingt étudiants en médecine ont participé au cours. La confiance dans la gestion d'un véritable incident de masse, sur une échelle de 1 à 10 (aucune confiance à une confiance totale), s'est améliorée de manière significative d'après un test U de Mann-Whitney p<0,05. Il existe peu de cours formels sur les accidents de masse à l'intention des étudiants en médecine. La combinaison de " Dark-team-member " avec des acteurs en chair et en os, l'intégration d'animateurs cliniciens avec des étudiants en médecine et la simulation d'une scène de catastrophe continue au service des urgences sont des éléments uniques de ce cours. La méthodologie est présentée pour être reproduite à l'avenir.

A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer.

PURPOSE: To report the safety and efficacy of ipatasertib (AKT inhibitor) combined with rucaparib (PARP inhibitor) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with second-generation androgen receptor inhibitors. PATIENTS AND METHODS: In this two-part phase Ib trial (NCT03840200), patients with advanced prostate, breast, or ovarian cancer received ipatasertib (300 or 400 mg daily) plus rucaparib (400 or 600 mg twice daily) to assess safety and identify a recommended phase II dose (RP2D). A part 1 dose-escalation phase was followed by a part 2 dose-expansion phase in which only patients with mCRPC received the RP2D. The primary efficacy endpoint was prostate-specific antigen (PSA) response (≥50% reduction) in patients with mCRPC. Patients were not selected on the basis of tumor mutational status. RESULTS: Fifty-one patients were enrolled (part 1 = 21; part 2 = 30). Ipatasertib 400 mg daily plus rucaparib 400 mg twice daily was the selected RP2D, received by 37 patients with mCRPC. Grade 3/4 adverse events occurred in 46% (17/37) of patients, with one grade 4 adverse event (anemia, deemed related to rucaparib) and no deaths. Adverse events leading to treatment modification occurred in 70% (26/37). The PSA response rate was 26% (9/35), and the objective response rate per Response Criteria in Solid Tumors (RECIST) 1.1 was 10% (2/21). Median radiographic progression-free survival per Prostate Cancer Working Group 3 criteria was 5.8 months [95% confidence interval (CI), 4.0-8.1], and median overall survival was 13.3 months (95% CI, 10.9-not evaluable). CONCLUSIONS: Ipatasertib plus rucaparib was manageable with dose modification but did not demonstrate synergistic or additive antitumor activity in previously treated patients with mCRPC.

Safety Profile of Ipatasertib Plus Abiraterone vs Placebo Plus Abiraterone in Metastatic Castration-resistant Prostate Cancer.

PURPOSE: Adding ipatasertib to abiraterone and prednisone/prednisolone significantly improved radiographic progression-free survival for patients with metastatic castration-resistant prostate cancer (mCRPC) with PTEN-loss tumours by immunohistochemistry in the IPATential150 trial (NCT03072238). Here we characterise the safety of these agents in subpopulations and assess manageability of key adverse events (AEs). MATERIALS AND METHODS: In this randomised, double-blind, phase 3 trial, patients with previously untreated asymptomatic or mildly symptomatic mCRPC were randomised 1:1 to receive ipatasertib-abiraterone or placebo-abiraterone (all with prednisone/prednisolone). AEs were analysed, focusing on key AEs of diarrhoea, hyperglycaemia, rash and transaminase increased. RESULTS: 1097 patients received study medication and were assessed for safety (47% with PTEN-loss tumours by immunohistochemistry and 20% were Asian). Ipatasertib was associated with increased Grade 3/4 AEs and AEs leading to treatment discontinuation vs placebo. The rate of discontinuation of ipatasertib was 18% in patients with PTEN-loss and 21% overall. The frequencies of all-grade, Grade 3/4 and serious AEs were similar between the PTEN-loss and overall populations. Diarrhoea, hyperglycaemia, rash and transaminase elevation were more frequent in ipatasertib-treated patients, appearing rapidly after treatment initiation (median onset: 8-43 days for ipatasertib arm and 56-104 days for placebo). The ipatasertib discontinuation rate was 32% and 18% in Asian and non-Asian patients, respectively, despite similar baseline characteristics and Grade 3/4 AE frequencies between groups. CONCLUSIONS: Ipatasertib plus abiraterone had an overall tolerable safety profile consistent with known toxicities. More AEs leading to drug discontinuation were observed with ipatasertib than placebo, but incidence would likely be lessened with prophylactic measures.

An online randomised controlled trial of prognosticating imminent death in advanced cancer patients: Clinicians give greater weight to advice from a prognostic algorithm than from another clinician with a different profession.

BACKGROUND: A second opinion or a prognostic algorithm may increase prognostic accuracy. This study assessed the level to which clinicians integrate advice perceived to be coming from another clinician or a prognostic algorithm into their prognostic estimates, and how participant characteristics and nature of advice received affect this. METHODS: An online double-blind randomised controlled trial was conducted. Palliative doctors, nurses and other types of healthcare professionals were randomised into study arms differing by perceived source of advice (algorithm or another clinician). In fact, the advice was the same in both arms (emanating from the PiPS-B14 prognostic model). Each participant reviewed five patient summaries. For each summary, participants: (1) provided an initial probability estimate of two-week survival (0% 'certain death'-100% 'certain survival'); (2) received advice (another estimate); (3) provided a final estimate. Weight of Advice (WOA) was calculated for each summary (0 '100% advice discounting' - 1 '0% discounting') and multilevel linear regression analyses were conducted. CLINICAL TRIAL REGISTRATION NUMBER: NCT04568629. RESULTS: A total of 283 clinicians were included in the analysis. Clinicians integrated advice from the algorithm more than advice from another clinician (WOA difference = -0.12 [95% CI -0.18, -0.07], p < 0.001). There was no interaction between study arm and participant profession, years of palliative care or overall experience. Advice of intermediate strength (75%) was given a lower WOA (0.31) than advice received at either the 50% (WOA 0.40) or 90% level (WOA 0.43). The overall interaction between strength of advice and study arm on WOA was significant (p < 0.001). CONCLUSION: Clinicians adjusted their prognostic estimates more when advice was perceived to come from a prognostic algorithm than from another clinician. Research is needed to understand how clinicians make prognostic decisions and how algorithms are used in clinical practice.

Dietary inclusion of nitrite-containing frankfurter exacerbates colorectal cancer pathology and alters metabolism in APCmin mice.

Colorectal cancer (CRC) is the second most prevelant malignancy in Europe and diet is an important modifiable risk factor. Processed meat consumption, including meats with preservative salts such as sodium nitrite, have been implicated in CRC pathogenesis. This study investigated how the CRC pathology and metabolic status of adenomatous polyposis coli (APC) multiple intestinal neoplasia (min) mice was perturbed following 8 weeks of pork meat consumption. Dietary inclusions (15%) of either nitrite-free pork, nitrite-free sausage, or nitrite-containing sausage (frankfurter) were compared against a parallel control group (100% chow). Comprehensive studies investigated: gastrointestinal tract histology (tumours), aberrant crypt foci (ACF), mucin deplin foci (MDF), lipid peroxidation (urine and serum), faecal microbiota, and serum metabolomics (599 metabolites). After 8 weeks mice consuming the frankfurter diet had 53% more (P = 0.014) gastrointestinal tumours than control, although ACF and MDF did not differ. Urine and serum lipid peroxidation markers were 59% (P = 0.001) and 108% (P = 0.001) higher, respectively in the frankfurter group. Gut dysbiosis was evident in these mice with comparably fewer Bacteriodes and more Firmicutes. Fasting serum levels of trimethylamine N-oxide (TMAO) and numerous triglycerides were elevated. Various serum phosphotidylcholine species were decreased. These results demonstrate that nitrite-containing sausages may exaccerbate the development of CRC pathology in APCMin mice to a greater extent than nitrite-free sausages, and this is associated with greater lipid peroxidation, wide-ranging metabolic alternation and gut dysbiosis.

Drug-Drug Interaction Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Ipatasertib in Combination with Darolutamide in Patients with Advanced Prostate Cancer.

Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC0-24 h,ss and Cmax,ss exposures was observed (~8% and ~21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs.

PTEN Protein Phosphatase Activity Is Not Required for Tumour Suppression in the Mouse Prostate.

Loss PTEN function is one of the most common events driving aggressive prostate cancers and biochemically, PTEN is a lipid phosphatase which opposes the activation of the oncogenic PI3K-AKT signalling network. However, PTEN also has additional potential mechanisms of action, including protein phosphatase activity. Using a mutant enzyme, PTEN Y138L, which selectively lacks protein phosphatase activity, we characterised genetically modified mice lacking either the full function of PTEN in the prostate gland or only lacking protein phosphatase activity. The phenotypes of mice carrying a single allele of either wild-type Pten or PtenY138L in the prostate were similar, with common prostatic intraepithelial neoplasia (PIN) and similar gene expression profiles. However, the latter group, lacking PTEN protein phosphatase activity additionally showed lymphocyte infiltration around PIN and an increased immune cell gene expression signature. Prostate adenocarcinoma, elevated proliferation and AKT activation were only frequently observed when PTEN was fully deleted. We also identify a common gene expression signature of PTEN loss conserved in other studies (including Nkx3.1, Tnf and Cd44). We provide further insight into tumour development in the prostate driven by loss of PTEN function and show that PTEN protein phosphatase activity is not required for tumour suppression.

Contrast reversal of the iris and sclera increases the face sensitive N170.

Previous research has demonstrated that reversing the contrast of the eye region, which includes the eyebrows, affects the N170 ERP. To selectively assess the impact of just the eyes, the present study evaluated the N170 in response to reversing contrast polarity of just the iris and sclera in upright and inverted face stimuli. Contrast reversal of the eyes increased the amplitude of the N170 for upright faces, but not for inverted faces, suggesting that the contrast of eyes is an important contributor to the N170 ERP.

An appropriate verbal probability lexicon for communicating surgical risks is unlikely to exist.

Effective risk communication about medical procedures is critical to ethical shared decision-making. Here, we explore the potential for development of an evidence-based lexicon for verbal communication of surgical risk. We found that Ear, Nose and Throat (ENT) surgeons expressed a preference for communicating such risks using verbal probability expressions (VPEs; e.g., "high risk"). However, there was considerable heterogeneity in the expressions they reported using (Study 1). Study 2 compared ENT surgeons' and laypeople's (i.e., potential patients) interpretations of the ten most frequent VPEs listed in Study 1. While both groups displayed considerable variability in interpretations, lay participants demonstrated more, as well as providing systematically higher interpretations than those of surgeons. Study 3 found that lay participants were typically unable to provide unique VPEs to differentiate between the ranges of (low) probabilities required. Taken together, these results add to arguments that reliance on VPEs for surgical risk communication is ill-advised. Not only are there systematic interpretational differences between surgeons and potential patients, but the coarse granularity of VPEs raises severe challenges for developing an appropriate evidence-based lexicon for surgical risk communication. We caution against the use of VPEs in any risk context characterized by low, but very different, probabilities. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Atypical multiple myeloma in 3 young dogs.

Three dogs under 12 months old were diagnosed with atypical multiple myeloma (MM), having an aggressive multifocal anaplastic round cell sarcoma in bone marrow, viscera, and/or peripheral blood, which were confirmed by cytology and immunohistochemistry to be of plasma cell origin. The intramedullary sarcomas caused myelophthisis, osteolysis, and hypercalcemia. Complete or free light chain monoclonal gammopathy in the serum and/or urine was demonstrated by protein electrophoresis and immunofixation. The polymerase chain reaction for antigen receptor rearrangement assay performed on 2 cases identified a clonally rearranged immunoglobulin gene. Neoplastic cells lacked expression of CD45, CD3, CD18, CD21, CD34, and MHCII by flow cytometry. Immunohistochemistry revealed MUM1 immunoreactivity of the neoplastic cells. Combining all data, the diagnosis was MM. An aggressive form of MM in young dogs should be a differential diagnosis for patients with an immunoglobulin-productive, B cell-clonal, CD45-negative, MUM1-positive discrete cell neoplasm arising from the bone marrow.

Plausibility matters: A challenge to Gilbert's "Spinozan" account of belief formation.

Most of the claims we encounter in real life can be assigned some degree of plausibility, even if they are new to us. On Gilbert's (1991) influential account of belief formation, whereby understanding a sentence implies representing it as true, all new propositions are initially accepted, before any assessment of their veracity. As a result, plausibility cannot have any role in initial belief formation on this account. In order to isolate belief formation experimentally, Gilbert, Krull, and Malone (1990) employed a dual-task design: if a secondary task disrupts participants' evaluation of novel claims presented to them, then the initial encoding should be all there is, and if that initial encoding consistently renders claims 'true' (even where participants were told in the learning phase that the claims they had seen were false), then Gilbert's account is confirmed. In this pre-registered study, we replicate one of Gilbert et al.'s (1990) seminal studies ("The Hopi Language Experiment") while additionally introducing a plausibility variable. Our results show that Gilbert's 'truth bias' does not hold for implausible statements - instead, initial encoding seemingly renders implausible statements 'false'. As alternative explanations of this finding that would be compatible with Gilbert's account can be ruled out, it questions Gilbert's account.

Optimism where there is none: Asymmetric belief updating observed with valence-neutral life events.

How people update their beliefs when faced with new information is integral to everyday life. A sizeable body of literature suggests that people's belief updating is optimistically biased, such that their beliefs are updated more in response to good news than bad news. However, recent research demonstrates that findings previously interpreted as evidence of optimistic belief updating may be the result of flaws in experimental design, rather than motivated reasoning. In light of this controversy, we conduct three pre-registered variations of the standard belief updating paradigm (combined N = 300) in which we test for asymmetric belief updating with neutral, non-valenced stimuli using analytic approaches found in previous research. We find evidence of seemingly biased belief updating with neutral stimuli - results that cannot be attributed to a motivational, valence-based, optimism account - and further show that there is uninterpretable variability across samples and analytic techniques. Jointly, these results serve to highlight the methodological flaws in current optimistic belief updating research.

Pharmacokinetics of Ipatasertib in Subjects With Hepatic Impairment Using 2 Methods of Classification of Hepatic Function.

Ipatasertib is a highly selective small-molecule pan-Akt inhibitor in clinical development. Ipatasertib is predominantly eliminated by the liver, and therefore, the effect of hepatic impairment on ipatasertib pharmacokinetics (PK) was evaluated. In this phase 1 open-label, parallel group study, the PK of ipatasertib were evaluated in subjects with hepatic impairment based on both the Child-Pugh and the National Cancer Institute Organ Dysfunction Working Group classification for hepatic impairment. A single dose of ipatasertib at 100 mg was administered and the PK was characterized in healthy subjects with normal hepatic function or mild, moderate, and severe hepatic impairment. Based on Child-Pugh classification, subjects with moderate and severe hepatic impairment had an ≈2- and 3-fold increase in systemic exposure (area under the plasma concentration-time curve from time 0 to infinity [AUC0-∞ ]) to ipatasertib, respectively, compared to subjects with normal hepatic function. Systemic exposure (AUC0-∞ ) to ipatasertib in subjects with mild hepatic impairment was comparable to that in subjects with normal hepatic function. In accordance with reduced clearance capacity, subjects with mild to severe hepatic impairment showed lower systemic exposure (AUC0-∞ ) of ipatasertib metabolite M1 (G-037720). Overall results were comparable between Child-Pugh and National Cancer Institute Organ Dysfunction Working Group classification criteria. Based on the results from this study, no dosage adjustment is required for ipatasertib when treating patients with mild hepatic impairment, whereas a dose reduction would be recommended for subjects with moderate or severe hepatic impairment. Based on real-world data analysis, ≈2% of the intended patient population is expected to need a modified dose due to moderate or severe hepatic impairment.