Surrogate endpoints are increasingly being used in the pivotal trials of cancer drugs to underpin (conditional) regulatory approval. We examined the relationship between the use of surrogate measures in pivotal trials underpinning cancer drug approvals by the European Medicines Agency (EMA) between 2017 and 2022 and health technology assessment (HTA) recommendations made by the National Centre for Pharmacoeconomics in Ireland (NCPE).

A previously published methodology was used to identify cancer drug indications that received (conditional) marketing authorization between 2017 and 2022, inclusive. EMA-approved cancer drugs were categorized using the following benefit categories, based on pivotal trial endpoints: overall survival (OS), progression-free survival (PFS), disease response (DR), and single-arm trials (SATs). The NCPE website was searched to identify indications that had undergone, at least, a rapid review (RR) assessment. The NCPE recommendation for each assessment was recorded. Additional data including the incremental quality-adjusted life years (QALY) gain reported in cost-effectiveness analyses were extracted for indications that had undergone a full HTA.

One hundred and eight cancer drug indications were identified, comprising 68 cancer drugs. In 2017, OS, PFS, and SAT benefit underpinned equal proportions of approvals (28.6% each). In 2022, SAT underpinned the largest proportion of approvals (53.6%). As of June 2023, 77 indications (71.3%) had undergone at least a RR assessment; 31 indications had completed a full HTA appraisal. All of the indications underpinned by SAT evidence (n=7) received a conditional negative recommendation. Indications with SAT evidence had a mean incremental QALY gain of 1.88 (standard deviation [SD] 1.20), whereas indications with an OS benefit had a mean incremental QALY gain of 0.81 (SD 0.36).

The proportion of cancer drug indications receiving regulatory approval on the basis of SAT evidence, where no direct comparative evidence is available, is increasing. This results in additional uncertainty in the comparative benefit of cancer drugs supported by SAT evidence. The study is limited by the sample size of HTA appraisals included. Further in-depth analysis of factors influencing NCPE recommendations is needed.

Society of Thoracic Surgeons Congenital Heart Surgery Database is the largest congenital heart surgery database worldwide but does not provide information beyond primary episode of care. Linkage to hospital electronic health records would capture complications and comorbidities along with long-term outcomes for patients with CHD surgeries. The current study explores linkage success between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health record data in North Carolina and Georgia.

The Society of Thoracic Surgeons Congenital Heart Surgery Database was linked to hospital electronic health records from four North Carolina congenital heart surgery using indirect identifiers like date of birth, sex, admission, and discharge dates, from 2008 to 2013. Indirect linkage was performed at the admissions level and compared to two other linkages using a “direct identifier,” medical record number: (1) linkage between Society of Thoracic Surgeons Congenital Heart Surgery Database and electronic health records from a subset of patients from one North Carolina institution and (2) linkage between Society of Thoracic Surgeons data from two Georgia facilities and Georgia’s CHD repository, which also uses direct identifiers for linkage.

Indirect identifiers successfully linked 79% (3692/4685) of Society of Thoracic Surgeons Congenital Heart Surgery Database admissions across four North Carolina hospitals. Direct linkage techniques successfully matched Society of Thoracic Surgeons Congenital Heart Surgery Database to 90.2% of electronic health records from the North Carolina subsample. Linkage between Society of Thoracic Surgeons and Georgia’s CHD repository was 99.5% (7,544/7,585).

Linkage methodology was successfully demonstrated between surgical data and hospital-based electronic health records in North Carolina and Georgia, uniting granular procedural details with clinical, developmental, and economic data. Indirect identifiers linked most patients, consistent with similar linkages in adult populations. Future directions include applying these linkage techniques with other data sources and exploring long-term outcomes in linked populations.

The frequent prescribing of psychotropics and high prevalence of polypharmacy among older adults with intellectual disabilities require close monitoring.

To describe change in prevalence, predictors and health outcomes of psychotropic use during the four waves (2009/2010, 2013/2014, 2016/2017, 2019/2020) of the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA).

Eligible participants were adults (≥40 years) with intellectual disabilities who participated in all four waves of IDS-TILDA and who reported medication use for the entire period. Differences between groups were tested using Cochran's Q test for binary variables and the McNemar–Bowker test for variables with more than two categories. Generalised estimating equation models were used to assess associations between psychotropic use, participants’ characteristics and health outcomes.

Across waves (433 participants) there were no significant differences in prevalence of psychotropic use (61.2–64.2%) and psychotropic polypharmacy (42.7–38.3%). Antipsychotics were the most used subgroup, without significant change in prevalence between waves (47.6–44.6%). A significant decrease was observed for anxiolytics (26.8–17.6%; P < 0.001) and hypnotics/sedatives (14.1–9.0%; P < 0.05). A significant increase was recorded for antidepressants (28.6–35.8%; P < 0.001) and mood-stabilising agents (11.5–14.6%; P < 0.05). Psychotropic polypharmacy (≥2 psychotropics) was significantly associated with moderate to total dependence in performing activities of daily living over the 10-year period (OR = 1.80, 95% CI 1.21–2.69; P < 0.05).

The study indicates an increase in usage of some classes of psychotropic, a reduction in others and no change in the relatively high rate of antipsychotic use over 10 years in a cohort of older adults with intellectual disabilities and consequent risk of psychotropic polypharmacy and medication-related harm.

Metacognition is defined as the ability to observe, monitor, and make judgments about one’s own cognitive status. Judgments of learning (JOLs) and retrospective confidence judgments (RCJs) are two elements of metacognition related to memory, or metamemory. JOLs refer to one’s assumptions of their memory performance prior to completing a memory task, while RCJs describe one’s subjective assessment of their memory performance after they have completed the task. Traumatic brain injury (TBI) is known to negatively impact general metacognitive functioning. However, the nuanced effects of TBI on constituent metacognitive subprocesses like JOLs and RCJs remain unclear. This study aimed to characterize patterns of brain activity that occur when individuals with TBI render JOLs and RCJs during a meta-memory task. Differences between JOL- and RCJ-related patterns of activation were also explored.

20 participants with moderate-to-severe TBI completed a metacognition task while undergoing functional magnetic resonance imaging (fMRI). Participants were first exposed to target slides with a set of polygons placed in specific locations, then asked to identify the target slides within a set of distractors. Before identifying the target slides, participants rated how well they believed they would remember the polygons’ shape and location (JOL). After answering, they rated how confident they were that the answer they provided was correct (RCJ). First-level time series analyses of fMRI data were conducted for each participant using FSL FEAT. Higher-level random effects modeling was then performed to assess average activation across all participants. Finally, contrasts were applied to examine and compare JOL- and RCJ-specific patterns of activation.

JOLs were associated with activation of the left frontal gyri, bilateral anterior cingulate, left insula, and right putamen (p < 0.01). RCJs were associated with activation of the bilateral frontal gyri, bilateral posterior and anterior cingulate, left insula, right putamen, and left thalamus (p < 0.01). Compared to RCJs, JOLs demonstrated greater left insula activation (p < 0.01). Compared to JOLs, RCJs demonstrated greater activation of the left superior frontal gyrus, bilateral middle frontal gyrus, and bilateral anterior cingulate (p < 0.01).

The areas of activation found in this study were consistent with structures previously identified in the broader metacognition literature. Overall, RCJs produced activity in a greater number of regions that was more bilaterally distributed compared to JOLs. Moreover, several regions that were active during both metacognitive subprocesses tended to be even more active during RCJs. A hypothesis for this observation suggests that, unlike JOLs, the additional involvement of reflecting on one’s immediate memory of completing the task during RCJs may require greater recruitment of resources compared to JOLs. Importantly, these findings suggest that, while different metacognitive subprocesses may recruit similar brain circuitry, some subprocesses may require more potent and widespread activation of this circuitry than others. As such, subprocesses with greater activational needs and complexity, such as RCJs, may be more susceptible to damage caused by TBI. Future research should aim to compare patterns of activation associated with certain metacognitive subprocesses between survivors of TBI and healthy controls.

The Functional Assessment of Cancer Therapy-Cognitive scale (FACT-Cog) is one of the most frequently used patient-reported outcome (PRO) measures of cancer-related cognitive impairment (CRCI) and of CRCI-related impact on quality of life (QOL). Previous studies using the FACT-Cog found that >75% of women with breast cancer (BCa) experience CRCI. Distress tolerance (DT) is a complex construct that encompasses both the perceived capacity (i.e., cognitive appraisal) and the behavioral act of withstanding uncomfortable/aversive/negative emotional or physical experiences. Low DT is associated with psychopathology and executive dysfunction. We previously found that women with BCa with better DT skills reported less CRCI on the FACT-Cog. However, this relationship has not been tested using a performance-based cognitive measure. Therefore, the aims of this study were to: (1) assess the relationship between the FACT-Cog and the Telephone Interview for Cognitive Status (TICS), a performance-based cognitive measure; and (2) test whether the association between DT and CRCI (using the FACT-Cog) was replicated with the TICS.

Participants completed the Distress Tolerance Scale (DTS), the FACT-Cog, and the TICS after undergoing BCa surgery and prior to starting adjuvant therapy [101 women, age >50 years, M(SD)= 61.15(7.76), 43% White Non-Hispanic, 34.4% White Hispanic, 10.8% Black, with nonmetastatic BCa, 55.4% lumpectomy, 36.6% mastectomy; median 29 days post-surgery].

Although there was a significant correlation between the TICS total score and the FACT-CogQOL subscale (r = 0.347, p < 0.001), the TICS total score was not correlated with scores on the FACT-Cog perceived cognitive impairment (CogPCI), perceived cognitive abilities (CogPCA), or comments from others (CogOth) subscales. However, the TICS memory item, a 10-word list immediate recall task, had a weak statistically significant correlation with CogPCI (r = 0.237, p < 0.032), CogOth (r = 0.223, p < 0.044), and CogPCA (r = 0.233, p < 0.036). Next, the sample was divided based on the participant’s score on TICS memory item (i.e., < vs. > sample mean of 5.09). Results of independent samples t-tests demonstrated significant differences in mean scores for CogPCI, f(80) = -2.09, p = 0.04, Mdt = -7.65, Cohen’s d = 0.483, and CogQOL, f(80) = -2.57, p = 0.01, Mditt = -2.38, Cohen’s d = 0.593. A hierarchical linear regression found that DTS subscale and total scores did not significantly predict performance on the TICS. However, DTS continued to be a significant predictor of poorer FACT-Cog PCI scores while controlling for TICS scores.

We found a weak relationship between self-reported cognitive impairment and objective cognitive performance (TICS). However, greater self-reported PCI and its impact on QOL was found in participants who scored below the sample mean on a recall task from the TICS. Although perceived ability to tolerate distress continued to predict self-reported PCI on the FACT-Cog, it did not predict overall performance on the TICS. Therefore, responses on the FACT-Cog may be more representative of an individual’s ability to tolerate distress related to perceived CRCI than actual overall cognitive ability or impairment.

The process of metacognitive monitoring refers to one’s ability to incorporate rapid in-the-moment self-assessments of their cognitive performance. An area of interest within this literature concerns metacognitive accuracy (MA), or the extent to which an individual can discern when their own judgments are incorrect/correct. Much of the work in this area has either focused on school-aged samples or clinical samples, with findings of impairment in metacognitive processes associated with traumatic brain injury, Schizophrenia, cerebrovascular accidents, and Alzheimer’s disease. Notably, decreased working memory and executive functioning are frequently reported in samples with low MA, suggesting a possible reliance on basic cognitive resources in the facilitation of metacognitive processes. Thus, the goal of this investigation was to elucidate potential relationships between individual domains of cognition and higher-order MA. We hypothesized that performance on measures of working memory and executive function would be positively associated with measures of MA.

Data from 87 undergraduate students who volunteered in research for class credit were used. All participants completed a computerized metamemory task where six lists of 12 words each paired with varying point values were first presented to the participants. After each list, participants were instructed to score as many points as possible by recalling words they could remember. After a brief delay, participants completed a recognition task using the words presented earlier and provided a retrospective confidence judgement (RCJ) following each item. A metric for MA, meta d', was calculated using signal-detection theory analysis from the reported RCJs and recognition task performance. Participants also completed neuropsychological tests of attention (Trails A), working memory (WM; Backward Digits), executive function (EF; Trails B), mental flexibility (MF; Trails B/A Ratio), and processing speed (Symbol Digit Modalities). A sequential multiple regression was performed with meta d’ serving as the criterion, with education, age, and performance on neuropsychological measures entered as predictors.

The model indicated that a moderate percentage of the variability (R2 = .201) in metacognitive accuracy could be attributed to the combination of predictors in the model (F (7,79) = 2.843, p = .011). Examination of the regression coefficients indicated that only measures of attention (ß = .638, p = .01), MF (ß = .473, p = .041), and WM ß = .244, p = .024) were significantly related to MA after controlling for all other variables in the model.

The model suggests that working memory, attention, and mental flexibility increased in a linear fashion as MA increased. Our hypotheses were partially supported, while working memory predicted MA, its contribution to the overall model was the smallest among the significant predictors. While executive function was not a significant contributor to the model, MF (a component of EF) was. The largest contributor to the model was attention, which supports prior findings in the literature. This outcome would suggest that while separate from EF, metacognitive processes in neurotypical students may rely on other, more basic cognitive processes. These results may prove beneficial in guiding the development of rehabilitative interventions for MA in clinical samples.

Metacognition refers to one’s ability to make online, in-the-moment judgments regarding their own cognitive performance, and has significant implications for one’s abilities to function in daily life. It has been documented that individuals with TBI often present with metacognitive deficits, and are slower than neurotypical peers in making such judgments. Preliminary attempts have been made to determine how neural contributions to metacognitive functioning differ after injury. Studies thus far have found unique roles of prefrontal gray matter volume and inter-network connectivity in metacognitive functioning after injury, but functional activation directly associated with metacognitive processing has yet to be investigated. This event-related functional magnetic resonance imaging (fMRI) study aimed to document differences in functional activation between adults with TBI and neurotypical peers when completing metacognitive confidence judgments.

16 adults with moderate to severe TBI and 10 healthy adults (HCs) completed a metacognitive task while in the fMRI scanner. All participants were exposed to target slides with polygons arranged in various positions, then asked to identify the target slide from a group including 3 other distractor slides. Following each response, participants provided a metacognitive retrospective confidence judgment (RCJ) by rating their confidence that the answer they provided was correct. Meta d', a signal-detection based metric of metacognitive accuracy, was calculated. FSL FEAT was used for processing and analysis of the imaging data. Contrasts were created to model activation that was greater when RCJs were made compared to target recognition, mixed effects modeling was then used to investigate group differences. Cluster based thresholding set to z>2.3, p<0.01 was used for multiple comparisons correction.

Healthy controls performed significantly better on the target identification task (p<0.01), and were faster at making RCJs (p=0.03). Individuals with TBI had greater meta d’ scores (p=0.03). Significant activation beyond what was present during target recognition (RCJ>recognition) was found in left supramarginal gyrus, left posterior cingulate, and left cerebellum when individuals with TBI made RCJs, while HCs showed significant activation in the left precuneus, and bilateral superior temporal gyri. Individuals with TBI demonstrated more activation in the lateral occipital cortex bilaterally and the left cerebellum than HCs when completing RCJs. HCs presented with more activation in the left supramarginal gyrus than the TBI group when making RCJs.

The areas of activation present in both the TBI and HC groups are consistent with previous imaging findings from studies of healthy samples. Interestingly, two structures previously implicated in self-directed cognition and consciousness, the posterior cingulate and precuneus, were differentially activated by the groups. The lack of a common network between the two groups suggests that survivors may rely on separate neural substrates to facilitate metacognition after injury. The TBI group was found to recruit more functional areas when completing the RCJs. These findings, paired with the behavioral data indicating metacognitive performance differences, suggests that neural recruitment may occur after injury to allow for survivors to engage in making metacognitive judgments. Future qualitative investigations of the metacognitive judgments are needed to determine the compensatory nature of this postinjury recruitment.