The Persistent Paradox of Rapid Eye Movement Sleep (REMS): Brain Waves and Dreaming.

The original conceptualization of REM sleep as paradoxical sleep was based on its EEG resembling wakefulness and its association with dreaming. Over time, the concept of paradox was expanded to include various associations with REM sleep, such as dream exclusivity, high recall, and pathophysiology. However, none of these associations are unique to REM sleep; they can also occur in other sleep states. Today, after more than fifty years of focused research, two aspects of REMS clearly retain paradoxical exclusivity. Despite the persistent contention that the EEG of human REMS consists of wake-like, low-voltage, non-synchronous electrical discharges, REMS is based on and defined by the intracranial electrical presence of 5-8 Hz. theta, which has always been the marker of REMS in other animals. The wake-like EEG used to define REMS on human polysomnography is secondary to a generalized absence of electrophysiological waveforms because the strong waves of intracranial theta do not propagate to scalp electrodes placed outside the skull. It is a persistent paradox that the theta frequency is restricted to a cyclical intracranial dynamic that does not extend beyond the lining of the brain. REMS has a persistent association with narratively long and salient dream reports. However, the extension of this finding to equate REMS with dreaming led to a foundational error in neuroscientific logic. Major theories and clinical approaches were built upon this belief despite clear evidence that dreaming is reported throughout sleep in definingly different physiologic and phenomenological forms. Few studies have addressed the differences between the dreams reported from the different stages of sleep so that today, the most paradoxical aspect of REMS dreaming may be how little the state has actually been studied. An assessment of the differences in dreaming between sleep stages could provide valuable insights into how dreaming relates to the underlying brain activity and physiological processes occurring during each stage. The brain waves and dreams of REMS persist as being paradoxically unique and different from waking and the other states of sleep consciousness.

Mutagenic Azido Impurities in Drug Substances: A Perspective.

Contamination of drug products and substances containing impurities is a significant concern in the pharmaceutical industry because it may impact the quality and safety of medicinal products. Special attention is required when mutagenic impurities are present in pharmaceuticals, as they may pose a risk of carcinogenicity to humans. Therefore, controlling potential mutagenic impurities in active pharmaceutical ingredients to an acceptable safety limit is mandatory to ensure patient safety. As per the International Council for Harmonization (ICH) M7 (R2)3 Guideline, mutagenic impurities are those compounds or materials that induce point mutations. In 2018, the sartan class of drugs was recalled due to the presence of N-nitrosamine impurities, which are potential mutagens. In addition to the primary impurities being detected, this class of products, especially losartan, irbesartan and valsartan, have been identified as having organic azido contaminants, which are again highly reactive toward DNA, leading to an increased risk of cancer. These azido impurities form during the preparation of the tetrazole moiety via the reaction of a nitrile intermediate with sodium azide. Given that this is a newly raised issue in the pharmaceutical world, it should be noteworthy to review the related literature. Thus, this review article critically accounts for (i) the toxicity of azido impurities and the proposed mechanism of mutagenicity, (ii) the regulatory perspective, and (iii) the sources and control strategies used during the preparation of drug substances and (iv) future perspectives.

Lattice radiotherapy in inflammatory breast cancer: report of a first case treated with curative aim.

Inflammatory breast cancer (IBC) is a rare, aggressive form of breast cancer characterized by poor prognosis. The treatment requires a multidisciplinary approach, with neoadjuvant chemotherapy, surgery, and radiation therapy (RT). Particularly, high doses of conventional RT have been historically delivered in the adjuvant setting after chemotherapy and mastectomy or as radical treatment in patients ineligible for surgery. Here, we report the case of a 49-year-old woman patient with IBC unsuitable for surgery and treated with a combination of lattice RT and fractionated external beam RT concurrent with trastuzumab, with a curative aim. One year after RT, the patient showed a complete response and tolerable toxicities. This is the first reported case of a not-operable IBC patient treated with this particular kind of RT.

Sex-Specific Differences in Serum Kallikrein-8 (KLK8): An Exploratory Study.

Background: There are indications for sex-specific differences regarding the association between kallikrein-8 (KLK8) and cognitive impairment in early stages of Alzheimer's disease for which KLK8 may be an early blood-based biomarker. These may be due to different levels of sex hormones. To correctly interpret KLK8 blood concentrations, sex-specific analyses are needed. Objective: The aim of our exploratory study was to investigate sex-specific differences in blood-based KLK8 in participants of the population-based Heinz Nixdorf Recall study with different cognitive status and the association between KLK8 and sex hormones. Methods: In 290 participants (45% women, 69.7±7.4 years (mean±SD)) we investigated sex-specific serum KLK8 differences between cognitively unimpaired (CU, 43%) and cognitively impaired (CI) participants and the association between KLK8 and dehydroepiandrosteronsulfate (DHEAS), estradiol and testosterone, using adjusted multiple linear regression. Results: The mean±SD KLK8 was similar for CU men (808.1±729.6 pg/ml) and women (795.9±577.7 pg/ml); adjusted mean-difference [95%-CI]: -95.3 [-324.1;133.5] pg/ml. KLK8 was lower in CI women (783.5±498.7 pg/ml) than men (1048.4±829 pg/ml); -261 [-493.1; -29] pg/ml. In men but not women, there was a weak indication for a positive slope between estradiol (11.9 [-0.4;24.3] pg/ml) and DHEAS (1.4 [-0.5;3.3] pg/ml) with KLK8, while testosterone had no impact. Conclusions: The results suggested a different role for KLK8 in the development of cognitive impairment in men and women, potentially influenced by sex hormones. To use blood KLK8 as an early biomarker, further research on hormonal regulation of KLK8 expression is needed as a part of the investigation of the KLK8 involvement in cognitive impairment and Alzheimer's disease pathology.

Forward versus backward recall: Modality testing.

OBJECTIVES: One of the most frequently applied paradigms in the clinical and experimental fields for assessing working memory is the simple span task, composed of forward and backward recall conditions. However, the utility of the simple span measures and their relation to working memory modalities has yet to be elucidated. The current study aimed to address which of the span measures is more sensitive to the differentiation between forward and backward recall in the tactile, verbal, and visuo-spatial modalities, and to test if working memory modalities differ in the disparity between the two conditions. METHODS: 134 healthy young adults performed the Tactual, Digit, and Visuo-spatial Span tasks, producing Total Correct scores and Longest Sequence score measures. RESULTS: There was an interaction effect for condition and modality type, showing better performance for the forward compared to the backward recall in both measures. However, the effect size of the Longest Sequence score was significantly higher than the Total Correct score in all tasks. Furthermore, the Visuo-spatial Span exhibited a larger difference between forward and backward recall compared to the Digit and Tactual Span, whereas no difference was found between the latter two. CONCLUSIONS: Forward and backward recall are distinguished in all three modalities, and the Longest Sequence score is more sensitive to differentiate between storage and manipulation components of working memory than the Total Correct score. Additionally, the cognitive demand imposed by manipulation compared to storage is the greatest in the visuo-spatial modality.

The influence of emotion on temporal context models.

Temporal context models (TCMs) have been influential in understanding episodic memory and its neural underpinnings. Recently, TCMs have been extended to explain emotional memory effects, one of the most clinically important findings in the field of memory research. This review covers recent advances in hypotheses for the neural representation of spatiotemporal context through the lens of TCMs, including their ability to explain the influence of emotion on episodic and temporal memory. In recent years, simplifying assumptions of "classical" TCMs - with exponential trace decay and the mechanism by which temporal context is recovered - have become increasingly clear. The review also outlines how recent advances could be incorporated into a future TCM, beyond classical assumptions, to integrate emotional modulation.

The Role of Prefrontal Ensembles in Memory Across Time: Time-Dependent Transformations of Prefrontal Memory Ensembles.

The medial prefrontal cortex (mPFC) plays a critical role in recalling recent and remote fearful memories. Modern neuroscience techniques, such as projection-specific circuit manipulation and activity-dependent labeling, have illuminated how mPFC memory ensembles are reorganized over time. This chapter discusses the implications of new findings for traditional theories of memory, such as the systems consolidation theory and theories of memory engrams. It also examines the specific contributions of mPFC subregions, like the prelimbic and infralimbic cortices, in fear memory, highlighting how their distinct connections influence memory recall. Further, it elaborates on the cellular and molecular changes within the mPFC that support memory persistence and how these are influenced by interactions with the hippocampus. Ultimately, this chapter provides insights into how lasting memories are dynamically encoded in prefrontal circuits, arguing for a key role of memory ensembles that extend beyond strict definitions of the engram.

Exploring the relationship between marital quality and cognitive function: A systematic review.

Cognitive function is an important indicator of healthy aging as it is central to maintaining functional independence, performing job-related tasks, decision-making, and improving quality of life. Therefore, researchers seek to identify biopsychosocial factors that can help preserve cognitive function in aging individuals. One such factor is the maintenance of good quality marital relationships. Research has consistently shown that married individuals fare better in terms of both physical and psychological health compared to their unmarried counterparts. However, being married is not universally beneficial - the quality of a marriage is also important to consider. To explore the issue further, we conducted a systematic review to examine the association between marital quality and cognitive function. PubMed, PsycINFO, and Scopus were searched for eligible articles examining any measure of marital quality and any cognitive outcome from the inception of each database to January 9th, 2024. Following two levels of citation screening by two independent reviewers, we included 15 articles representing 11 unique studies. Data were synthesized narratively following the Synthesis without Meta-Analysis guidelines and a risk of bias assessment was conducted using the Joanna Briggs Institute checklist. Most articles had a low risk of bias. Although some findings suggested more positive marital quality was associated with improved cognitive function, the results were not uniformly positive; some results were inverse or null, depending upon factors such as differences in study designs and measures of marital quality or cognition. This review is the first attempt to synthesize the literature on this topic. Our findings highlight that any examination of marital status and cognition should also consider contextual factors such as marital quality.

Application of the Japanese Verbal Learning Test to Patients With Alzheimer's Disease in the Early Stage.

INTRODUCTION: This study aimed to investigate the mechanism of memory function in the context of explicit memory in early-stage Alzheimer's disease (AD) using the short-form Japanese Verbal Learning Test (JVLT-9). METHODS: Participants were 20 patients with early-stage AD and a control group of 23 healthy older adults (normal controls: NC), each of whom was administered the JVLT-9, which is a verbal list learning task used to assess explicit memory comprehensively. Between-group differences for each score were investigated using the Mann-Whitney U test. A two-way analysis of variance (ANOVA) was performed for the number of correct recalls by group (AD/NC) × JVLT-9 task. In addition, the AD group was divided into a CDR 0.5 group and a CDR 1.0 group, and it was performed as a group (CDR 0.5/1.0) × JVLT-9 task two-way ANOVA. RESULTS: The results demonstrated that the AD group had lower immediate recall, learning rate, semantic clustering, and recognition discrimination and significantly higher intrusion errors compared to the NC group. Further, JVLT-9 recall and recognition rates were found to be lower with higher CDR (an index of dementia severity). CONCLUSION: These results are largely consistent with the features of explicit memory in AD reported in the English version, confirming the clinical utility of the JVLT-9 as a test of explicit memory function.

If Engrams Are the Answer, What Is the Question?

Engram labelling and manipulation methodologies are now a staple of contemporary neuroscientific practice, giving the impression that the physical basis of engrams has been discovered. Despite enormous progress, engrams have not been clearly identified, and it is unclear what they should look like. There is an epistemic bias in engram neuroscience toward characterizing biological changes while neglecting the development of theory. However, the tools of engram biology are exciting precisely because they are not just an incremental step forward in understanding the mechanisms of plasticity and learning but because they can be leveraged to inform theory on one of the fundamental mysteries in neuroscience-how and in what format the brain stores information. We do not propose such a theory here, as we first require an appreciation for what is lacking. We outline a selection of issues in four sections from theoretical biology and philosophy that engram biology and systems neuroscience generally should engage with in order to construct useful future theoretical frameworks. Specifically, what is it that engrams are supposed to explain? How do the different building blocks of the brain-wide engram come together? What exactly are these component parts? And what information do they carry, if they carry anything at all? Asking these questions is not purely the privilege of philosophy but a key to informing scientific hypotheses that make the most of the experimental tools at our disposal. The risk for not engaging with these issues is high. Without a theory of what engrams are, what they do, and the wider computational processes they fit into, we may never know when they have been found.

Influence of a 2-week transcutaneous auricular vagus nerve stimulation on memory: findings from a randomized placebo controlled trial in non-clinical adults.

PURPOSE: Memory plays an essential role in daily life and is one of the first functions to deteriorate in cognitive impairment and dementia. Transcutaneous vagus nerve stimulation (tVNS) is a promising therapeutic method; however, its ability to enhance memory is underexplored, especially considering long-term stimulation. We aimed to investigate the effect of a 2-week course of auricular tVNS (taVNS) on memory in a non-clinical population. METHODS: This single-blind randomized placebo-wait-list controlled trial recruited 76 participants (30 men; mean age 48.32 years) and randomized them into four groups: early active/sham taVNS and late active/sham taVNS. Participation in the study lasted 4 weeks; early groups underwent 2 weeks intervention immediately following the first study site visit (days 0-13) and late groups 2 weeks after the first study site visit (days 14-27). Active and sham taVNS included 2 weeks of daily 4-h neurostimulation at the tragus or earlobe, respectively. To assess memory, we used the Rey Auditory Verbal Learning Test. RESULTS: Two weeks of active taVNS, but not sham taVNS, improved immediate recall and short-term memory score both in early and late groups. Furthermore, the improvements persisted over subsequent follow-up in early active taVNS. Importantly, the effect of active taVNS was superior to sham for immediate recall in both early and late groups. There were no statistical differences in delayed recall. CONCLUSION: Our findings suggest that taVNS has potential to improve memory, particularly immediate recall, and may be an effective method in preventing memory loss and mitigating cognitive aging.

Exercise and Fear and Safety Learning.

Fear conditioning paradigms have been studied for over 100 years and are of great interest to the behavioral and clinical sciences given that several safety learning processes (e.g., extinction learning and recall) are thought to be fundamental to the success of exposure-based therapies for anxiety and related disorders. This chapter provides an overview of preclinical and clinical investigations that examined the effects of exercise on initial fear acquisition, fear extinction learning and consolidation, and return of fear outcomes. This chapter highlights the collective body of evidence suggesting that exercise administered after extinction learning enhances the consolidation and subsequent recall of extinction memories to a greater extent than exercise administered prior to extinction learning. This suggests that the addition of exercise after exposure therapy sessions may improve treatment outcomes for people with anxiety and related disorders. Potential mechanisms are discussed in addition to suggestions for future research to improve our understanding of the effects of exercise on fear conditioning and extinction outcomes.

Storytelling changes the content and perceived value of event memories.

Memories are not only stored for personal recall, but also to communicate knowledge to others in service of adaptive decision-making. Prior research shows that goals to share information can change which content is communicated in memory as well as the linguistic style embedded in this communication. Yet, little is known as to how communication-related alterations in memory narration drive differences of value processing in listeners. Here, we test how memory communication alters multi-featural recall for complex events and the downstream consequence on value estimations in naïve listeners. Participants recalled a memory of playing an exploratory videogame at a 24-h delay under instructions to either share (i.e., social condition) or recall (i.e., control condition) their memory. Sharing goals systematically altered the content and linguistic style of recall, such that narrators from the social condition were biased towards recall of non-episodic details and communicated their memories with more clout, less formality, and less authenticity. Across two independent samples of naïve listeners, these features differentially influenced value estimations of the video game. We found that greater clout was associated with greater enjoyment while listening to memories (hedonic value), and that greater inclusion of non-episodic details resulted in greater willingness to purchase the video game (motivational drive). These findings indicate that sharing an experience as a story can change the content and linguistic tone of memory recall, which in turn shape perceived value in naïve listeners.

A review of the peak-end rule in mental health contexts.

The peak-end rule, a memory heuristic in which the most emotionally salient part of an experience (i.e., peak) and conclusion of an experience (i.e., end) are weighted more heavily in summary evaluations, has been understudied in mental health contexts. The recent growth of intensive longitudinal methods has provided new opportunities for examining the peak-end rule in the retrospective recall of mental health symptoms, including measures often used in measurement-based care initiatives. Additionally, principles of the peak-end rule have significant potential to be applied to exposure-based therapy procedures. Additional research is needed to better understand the contexts in which, and persons for whom, the peak-end rule presents a greater risk of bias, to ultimately improve assessment strategies and clinical care.

Effectiveness of Catch-Up Vaccination Interventions Versus Standard or Usual Care Procedures in Increasing Adherence to Recommended Vaccinations Among Different Age Groups: Systematic Review and Meta-Analysis of Randomized Controlled Trials and Before-After Studies.

BACKGROUND: To address the global challenge of vaccine hesitancy, the Strategic Advisory Group of Experts on Immunization strongly promotes vaccination reminder and recall interventions. Coupled with the new opportunities presented by scientific advancements, these measures are crucial for successfully immunizing target population groups. OBJECTIVE: This systematic review and meta-analysis aims to assess the effectiveness of various interventions in increasing vaccination coverage compared with standard or usual care. The review will cover all vaccinations recommended for different age groups. METHODS: In February 2022, 2 databases were consulted, retrieving 1850 studies. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, 79 manuscripts were included after the assessment phase. These comprised 46 trials/randomized controlled trials (RCTs) and 33 before-after studies. A meta-analysis using a random-effects model was performed with STATA software (version 14.1.2). The selected outcome was the risk ratio (RR) of vaccination coverage improvement effectiveness. Additionally, meta-regression analyses were conducted for the included manuscripts. RESULTS: The analyses showed an overall efficacy of RR 1.22 (95% CI 1.19-1.26) for RCTs and RR 1.70 (95% CI 1.54-1.87) for before-after studies when considering all interventions cumulatively. Subgroup analyses identified multicomponent interventions (RR 1.58, 95% CI 1.36-1.85) and recall clinical interventions (RR 1.24, 95% CI 1.17-1.32) as the most effective in increasing vaccination coverage for RCTs. By contrast, educational interventions (RR 2.13, 95% CI 1.60-2.83) and multicomponent interventions (RR 1.61, 95% CI 1.43-1.82) achieved the highest increases for before-after studies. Meta-regression analyses indicated that the middle-aged adult population was associated with a higher increase in vaccination coverage (RCT: coefficient 0.54, 95% CI 0.12-0.95; before-after: coefficient 1.27, 95% CI 0.70-1.84). CONCLUSIONS: Community, family, and health care-based multidimensional interventions, as well as education-based catch-up strategies, effectively improve vaccination coverage. Therefore, their systematic implementation is highly relevant for targeting undervaccinated population groups. This approach aligns with national vaccination schedules and aims to eliminate or eradicate vaccine-preventable diseases.

Minimum Dietary Diversity for Women: Partitioning Misclassifications by Proxy Data Collection Methods using Weighed Food Records as the Reference in Ethiopia.

Background: Nonquantitative list-based or open 24-h recalls (24-HRs) have been shown to overestimate the prevalence of Minimum Dietary Diversity for Women (MDD-W), as compared with direct quantitative observations. However, the main sources of error are unknown. Objectives: To assess the measurement agreement of proxy data collection methods for MDD-W, as compared with weighed food records (WFRs). Methods: Applying a noninferiority design, data were collected from 431 nonpregnant females in Ethiopia. MDD-W estimates from both proxy data collection methods were compared with the WFR prevalence by McNemar's chi-square tests, Cohen's Kappa, and receiver operator characteristic analyses. Ten-point food group diversity scores (FGDS) were compared by Bland-Altman plots, Wilcoxon matched-pairs tests, and weighted Kappa. Food group misclassifications were partitioned into errors related to respondent biases or the questionnaire development. Results: List-based and open 24-HRs overreported MDD-W by 8 and 4 percentage points, respectively, as compared with WFR (objective MDD-W prevalence: 8%). Furthermore, list-based 24-HRs overestimated FGDS by 0.4 points (limits of agreement [LOA]: -1.1, 2.0), whereas open 24-HRs led to a 0.3 point (LOA: -1.2, 1.7) overestimate. Food groups most likely to be misreported using proxy data collection methods were "pulses," "nuts and seeds," "dairy products," and "other fruits." Underreporting of consumption occurred among <4% of females for all food groups. Furthermore, respondent biases were the predominant cause of food group overreporting, except for the "pulses" and "other vegetables" food groups, where food items incorrectly included on the food list were the main source of errors. Conclusions: Food group consumption misclassifications by proxy data collection methods were mainly attributable to females overreporting consumption because of respondent biases or the criterion for foods to be counted, rather than the suboptimal development of the food list in Ethiopia. To obtain precise and accurate MDD-W estimates at the (sub)national level, rigorous context-specific food list development, questionnaire pilot testing, and enumerator training are recommended to mitigate identified biases.

Insights from EEG analysis of evoked memory recalls using deep learning for emotion charting.

Affect recognition in a real-world, less constrained environment is the principal prerequisite of the industrial-level usefulness of this technology. Monitoring the psychological profile using smart, wearable electroencephalogram (EEG) sensors during daily activities without external stimuli, such as memory-induced emotions, is a challenging research gap in emotion recognition. This paper proposed a deep learning framework for improved memory-induced emotion recognition leveraging a combination of 1D-CNN and LSTM as feature extractors integrated with an Extreme Learning Machine (ELM) classifier. The proposed deep learning architecture, combined with the EEG preprocessing, such as the removal of the average baseline signal from each sample and extraction of EEG rhythms (delta, theta, alpha, beta, and gamma), aims to capture repetitive and continuous patterns for memory-induced emotion recognition, underexplored with deep learning techniques. This work has analyzed EEG signals using a wearable, ultra-mobile sports cap while recalling autobiographical emotional memories evoked by affect-denoting words, with self-annotation on the scale of valence and arousal. With extensive experimentation using the same dataset, the proposed framework empirically outperforms existing techniques for the emerging area of memory-induced emotion recognition with an accuracy of 65.6%. The EEG rhythms analysis, such as delta, theta, alpha, beta, and gamma, achieved 65.5%, 52.1%, 65.1%, 64.6%, and 65.0% accuracies for classification with four quadrants of valence and arousal. These results underscore the significant advancement achieved by our proposed method for the real-world environment of memory-induced emotion recognition.

Comparisons and correlations of 1-month recall vs 24-hour recall in patient-reported outcomes of an exploratory, phase 2b, randomized, double-blind, placebo-controlled clinical trial of sildenafil cream, 3.6% for the treatment of female sexual arousal disorder.

BACKGROUND: Efficacy assessments in clinical trials of treatments for female sexual arousal disorder (FSAD) and other female sexual dysfunction (FSD) diagnoses rely on various patient-reported outcomes (PROs). AIMS: We sought to compare 1-month recall PRO measures among participants enrolled in a clinical trial who provided these data without (test population) vs with (control population) use of an at-home, 24-hour recall electronic diary (eDiary), capturing similar data. METHODS: Preplanned subset analysis as performed during a phase 2b, exploratory, randomized, placebo-controlled, double-blind study of sildenafil cream, 3.6% (sildenafil cream) among healthy premenopausal women with FSAD. Preliminary product efficacy was assessed via 1-month recall and 24-hour recall questionnaires. A subset of the participants, the Evaluation of Recall Subset [ERS] provided PROs via the 1-month recall instruments but did not provide data via the 24-hour recall eDiary. OUTCOMES: Responses to the 1-month recall instruments were compared among ERS (test) vs non-ERS (control) participants. Among the non-ERS population, correlations between 1-month and 24-hour recall endpoints were calculated. RESULTS: There were no significant differences in the study co-primary 1-month recall efficacy endpoints, the Arousal Sensation (AS) domain of the 28-item Sexual Function Questionnaire (SFQ28) and the Female Sexual Distress Scale - Desire, Arousal, Orgasm question 14, among ERS vs non-ERS participants during the initial 1-month no-drug run-in period or the 1-month single-blind placebo run-in period (P values > .47). Scores on these 1-month recall PROs continued to be similar after randomization for sildenafil cream (P values > .30) and placebo cream (P values > .20) assigned ERS and non-ERS participants during the 3-month double-blind dosing period. There were strong correlations between the SFQ28 AS and eDiary AS scores during the no-drug run-in (R = 0.79, P < .01) and the single-blind run-in (R = 0.73 P < .001). During the double-blind dosing period, the SFQ28 AS score continued to be highly correlated with the eDiary AS score among sildenafil cream users (R = 0.83; P < .001) and placebo cream users (R = 0.8; 2 P < .001). CLINICAL IMPLICATIONS: There was no evidence that 1-month recall PRO instruments introduce recall bias; assessing arousal sensations with 24-hour vs 1-month PRO instruments is similar and either method could be used to assess efficacy depending on study objectives. STRENGTHS AND LIMITATIONS: This preplanned subset analysis compared efficacy of PROs based on recall duration. While the subset was preplanned, the study was powered to detect significant differences in the primary efficacy objectives, not among this subset analyses. CONCLUSION: These data will be used in planning future efficacy assessments of sildenafil cream for FSAD. CLINICAL TRIAL REGISTRATION: This clinical trial was registered with ClinicalTrials.gov, NCT04948151.

Statistical Analysis of Self-Reported Health Conditions in Cohort Studies: Handling of Missing Onset Age.

OBJECTIVE: This paper discusses methodological challenges in epidemiological association analysis of a time-to-event outcome and hypothesized risk factors, where age/time at the onset of the outcome may be missing in some cases, a condition commonly encountered when the outcome is self-reported. STUDY DESIGN AND SETTING: A cohort study with long-term follow-up for outcome ascer- tainment such as the Childhood Cancer Survivor Study (CCSS), a large cohort study of 5-year survivors of childhood cancer diagnosed in 1970-1999 in which occurrences and age at onset of various chronic health conditions (CHCs) are self-reported in surveys. Simple methods for handling missing onset age and their potential bias in the exposure-outcome association infer- ence are discussed. The interval-censored method is discussed as a remedy for handling this problem. The finite sample performance of these approaches is compared through Monte Carlo simulations. Examples from the CCSS include four CHCs (diabetes, myocardial infarction, osteoporosis/osteopenia, and growth hormone deficiency). RESULTS: The interval-censored method is usable in practice using the standard statisti- cal software. The simulation study showed that the regression coefficient estimates from the 'Interval censored' method consistently displayed reduced bias and, in most cases, smaller stan- dard deviations, resulting in smaller mean square errors, compared to those from the simple approaches, regardless of the proportion of subjects with an event of interest, the proportion of missing onset age, and the sample size. CONCLUSION: The interval-censored method is a statistically valid and practical approach to the association analysis of self-reported time-to-event data when onset age may be missing. While the simpler approaches that force such data into complete data may enable the standard analytic methods to be applicable, there is considerable loss in both accuracy and precision relative to the interval-censored method.

Temporal organization of narrative recall is present but attenuated in adults with hippocampal amnesia.

Studies of the impact of brain injury on memory processes often focus on the quantity and episodic richness of those recollections. Here, we argue that the organization of one's recollections offers critical insights into the impact of brain injury on functional memory. It is well-established in studies of word list memory that free recall of unrelated words exhibits a clear temporal organization. This temporal contiguity effect refers to the fact that the order in which word lists are recalled reflects the original presentation order. Little is known, however, about the organization of recall for semantically rich materials, nor how recall organization is impacted by hippocampal damage and memory impairment. The present research is the first study, to our knowledge, of temporal organization in semantically rich narratives in three groups: (1) Adults with bilateral hippocampal damage and severe declarative memory impairment, (2) adults with bilateral ventromedial prefrontal cortex (vmPFC) damage and no memory impairment, and (3) demographically matched non-brain-injured comparison participants. We find that although the narrative recall of adults with bilateral hippocampal damage reflected the temporal order in which those narratives were experienced above chance levels, their temporal contiguity effect was significantly attenuated relative to comparison groups. In contrast, individuals with vmPFC damage did not differ from non-brain-injured comparison participants in temporal contiguity. This pattern of group differences yields insights into the cognitive and neural systems that support the use of temporal organization in recall. These data provide evidence that the retrieval of temporal context in narrative recall is hippocampal-dependent, whereas damage to the vmPFC does not impair the temporal organization of narrative recall. This evidence of limited but demonstrable organization of memory in participants with hippocampal damage and amnesia speaks to the power of narrative structures in supporting meaningfully organized recall despite memory impairment.