Best Practices for the Electronic Implementation and Migration of Patient-Reported Outcome Measures.

While the use of electronic methods to collect patient-reported outcome data in clinical trials continues to increase, it remains the case that many patient-reported outcome measures (PROMs) have originally been developed and validated on paper. Careful consideration during the move from paper PROMs to electronic format is required to preserve the integrity of the measure and ensure a "faithful migration." Relevant literature has long called out the importance of following migration best practices during this process; nevertheless, such best practices are distributed across multiple documents. This article consolidates and builds upon existing electronic PROM implementation best practice recommendations to provide a comprehensive, up-to-date, single point of reference. It reflects the current consensus based on the significant advances in technology capabilities and knowledge gleaned from the growing evidence base on electronic migration and implementation, to balance the need for maintaining the integrity of the measure while optimizing respondent usability. It also specifies whether the practice is rooted in evidence or expert consensus, to enable those using these best practices to make informed and considered decisions when conducting migration.

Vasopressin and oxytocin receptor systems in the brain: Sex differences and sex-specific regulation of social behavior.

The neuropeptides vasopressin (VP) and oxytocin (OT) and their receptors in the brain are involved in the regulation of various social behaviors and have emerged as drug targets for the treatment of social dysfunction in several sex-biased neuropsychiatric disorders. Sex differences in the VP and OT systems may therefore be implicated in sex-specific regulation of healthy as well as impaired social behaviors. We begin this review by highlighting the sex differences, or lack of sex differences, in VP and OT synthesis in the brain. We then discuss the evidence showing the presence or absence of sex differences in VP and OT receptors in rodents and humans, as well as showing new data of sexually dimorphic V1a receptor binding in the rat brain. Importantly, we find that there is lack of comprehensive analysis of sex differences in these systems in common laboratory species, and we find that, when sex differences are present, they are highly brain region- and species-specific. Interestingly, VP system parameters (VP and V1aR) are typically higher in males, while sex differences in the OT system are not always in the same direction, often showing higher OT expression in females, but higher OT receptor expression in males. Furthermore, VP and OT receptor systems show distinct and largely non-overlapping expression in the rodent brain, which may cause these receptors to have either complementary or opposing functional roles in the sex-specific regulation of social behavior. Though still in need of further research, we close by discussing how manipulations of the VP and OT systems have given important insights into the involvement of these neuropeptide systems in the sex-specific regulation of social behavior in rodents and humans.

Sex differences in oxytocin receptor binding in forebrain regions: correlations with social interest in brain region- and sex- specific ways.

Social interest reflects the motivation to approach a conspecific for the assessment of social cues and is measured in rats by the amount of time spent investigating conspecifics. Virgin female rats show lower social interest towards unfamiliar juvenile conspecifics than virgin male rats. We hypothesized that the neuropeptide oxytocin (OT) may modulate sex differences in social interest because of the involvement of OT in pro-social behaviors. We determined whether there are sex differences in OT system parameters in the brain and whether these parameters would correlate with social interest. We also determined whether estrus phase or maternal experience would alter low social interest and whether this would correlate with changes in OT system parameters. Our results show that regardless of estrus phase, females have significantly lower OT receptor (OTR) binding densities than males in the majority of forebrain regions analyzed, including the nucleus accumbens, caudate putamen, lateral septum, bed nucleus of the stria terminalis, medial amygdala, and ventromedial hypothalamus. Interestingly, male social interest correlated positively with OTR binding densities in the medial amygdala, while female social interest correlated negatively with OTR binding densities in the central amygdala. Proestrus/estrus females showed similar social interest to non-estrus females despite increased OTR binding densities in several forebrain areas. Maternal experience had no immediate or long-lasting effects on social interest or OT brain parameters except for higher OTR binding in the medial amygdala in primiparous females. Together, these findings demonstrate that there are robust sex differences in OTR binding densities in multiple forebrain regions of rats and that OTR binding densities correlate with social interest in brain region- and sex-specific ways.

Preferences for Use and Design of Electronic Patient-Reported Outcomes in Patients with Chronic Obstructive Pulmonary Disease.

OBJECTIVES: Collection of patient-reported outcome (PRO) measures is critical to fully understand chronic obstructive pulmonary disease (COPD) management and progression, as the impact on health-related quality of life is not well understood by objective measures alone. Electronic PROs (ePROs) are increasingly used because of their advantages over paper data collection, including elimination of transcription errors, increased accuracy and data quality, real-time data reporting, and increased compliance. The objective of this study was to characterize how patients with COPD prefer to use various types of technology to report disease symptoms, and their preferences for ePRO design and display. METHODS: The sample consisted of subjects with COPD (N = 103) who completed in-person surveys on their ePRO preferences. RESULTS: The majority of subjects prefer to use a form of electronic media over paper to report their disease symptoms. Of these electronic methods, subjects most often prefer to use a smartphone provided by their physician. Subjects were also interested in ePRO features, such as knowing estimated PRO completion time at the outset, tracking their progress in real time as they complete a questionnaire, seeing the data that they report in order to track their health status, being encouraged to complete their diary if they fall behind by positive messaging, and being thanked for their completion of a daily diary. CONCLUSIONS: Investigators should consider including these preferences when designing ePRO assessments. Incorporating patient preferences for ePRO design can ultimately help reduce patient burden and increase engagement, compliance, and improve data quality.

Sex differences in tobacco smokers: Executive control network and frontostriatal connectivity.

BACKGROUND: Women experience greater difficulty quitting smoking than men, which may be explained by sex differences in brain circuitry underlying cognitive control. Prior work has linked reduced interhemispheric executive control network (ECN) coupling with poor executive function, shorter time to relapse, and greater substance use. Lower structural connectivity between a key ECN hub, the dorsolateral prefrontal cortex (DLPFC), and the dorsal striatum (DS) also contributes to less efficient cognitive control recruitment, and reduced intrahemispheric connectivity between these regions has been associated with smoking relapse. Therefore, sex differences were probed by evaluating interhemispheric ECN and intrahemispheric DLPFC-DS connectivity. To assess the potential sex by nicotine interaction, a pilot sample of non-smokers was evaluated following acute nicotine and placebo administration. METHODS: Thirty-five smokers (19 women) completed one resting state functional magnetic resonance imaging scan. Seventeen non-smokers (8 women) were scanned twice using a repeated measures design where they received 2 and 0 mg nicotine. RESULTS: In smokers, women had less interhemispheric ECN and DLPFC-DS coupling than men. In non-smokers, there was a drug x sex interaction where women, relative to men, had weaker ECN coupling following nicotine but not placebo administration. CONCLUSIONS: The current work indicates that nicotine-dependent women, versus men, have weaker connectivity in brain networks critically implicated in cognitive control. How these connectivity differences contribute to the behavioral aspects of smoking requires more testing. However, building on the literature, it is likely these deficits in functional connectivity contribute to the lower abstinence rates noted in women relative to men.

Mechanisms for improving diabetes patient-provider communication through optimal use of e-clinical technologies.

Purpose: Effective health care and patient adherence to their prescribed regimens relies on successful communication between patients and their providers. This study examined mechanisms for optimizing patient-physician communication in subjects with type 2 diabetes, with a focus on optimizing the incorporation of e-clinical technology to improve engagement and communication. Methods: A total of 105 subjects with type 2 diabetes participating in a large US mode equivalency study were surveyed independently of this trial. In addition to demographic information, each subject was queried on their familiarity with and preference for e-clinical technologies. Survey questions focused on mobile technology use, perceptions, and preferences for improving communication and interactions with health care providers. Results: Subjects were diverse in age, sex, education, and ethnicity. Forty nine percent owned a smartphone, and 64% had a computer at home. Most subjects (81%) were interested in using electronic methods (eg, app on a smartphone, email, or text messages) to interact more with physicians between visits. The majority of subjects were interested in using technology to help manage their type 2 diabetes, including 62% favoring communicating with their health-care providers via email and a considerable fraction interested in using smartphones to be provided medication reminders (56%), clinical visit scheduling (55%), and text messaging (49%). Conclusion: Subjects are interested in using electronic methods to increase communication with their physicians and manage their type 2 diabetes. Health-care providers should consider engaging patients with e-clinical technology to increase patient-physician communication and for the ultimate goal of improved health care.

Oestrogen and androgen receptor activation contribute to the masculinisation of oxytocin receptors in the bed nucleus of the stria terminalis of rats.

Oxytocin (OT) often regulates social behaviours in sex-specific ways, and this may be a result of sex differences in the brain OT system. Adult male rats show higher OT receptor (OTR) binding in the posterior bed nucleus of the stria terminalis (pBNST) than adult female rats. In the present study, we investigated the mechanisms that lead to this sex difference. First, we found that male rats have higher OTR mRNA expression in the pBNST than females at postnatal day (P) 35 and P60, which demonstrates the presence of the sex difference in OTR binding density at message level. Second, the sex difference in OTR binding density in the pBNST was absent at P0 and P3, but was present by P5. Third, systemic administration of the oestrogen receptor (ER) antagonist fulvestrant at P0 and P1 dose-dependently reduced OTR binding density in the pBNST of 5-week-old male rats, but did not eliminate the sex difference in OTR binding density. Fourth, pBNST-OTR binding density was lower in androgen receptor (AR) deficient genetic male rats compared to wild-type males, but higher compared to wild-type females. Finally, systemic administration of the histone deacetylase inhibitor valproic acid at P0 and P1 did not alter pBNST-OTR binding density in 5-week-old male and female rats. Interestingly, neonatal ER antagonism, AR deficiency, and neonatal valproic acid treatment each eliminated the sex difference in pBNST size. Overall, we demonstrate a role for neonatal ER and AR activation in setting up the sex difference in OTR binding density in the pBNST, which may underlie sexual differentiation of the pBNST and social behaviour.

Sex differences in default mode and dorsal attention network engagement.

Focusing on sex differences is necessary to fully understand basic neurobiological processes such as the engagement of large-scale brain networks involved in attention. Prior work suggests that women show enhanced attention during tasks of reward/punishment relative to men. Yet, sex differences in the engagement of neural networks sub serving internal and external focus has been unexplored in regard to reward and punishment. Using data from a large sample (n = 190) of healthy participants from the Human Connectome Project, we investigated sex differences in default mode network (DMN), dorsal attention network (DAN), and frontal parietal network (FPN) activation during exposure to reward and punishment. To determine if sex differences are specific to valenced stimuli, we analyzed network activation during working memory. Results indicate that, relative to men, women have increased suppression of the DMN and greater activation of the DAN during exposure to reward and punishment. Given the relative roles of these networks in internal (DMN) and external (DAN) attention, this pattern of activation suggests that women have enhanced external attention to reward and punishment. In contrast, there were no sex differences in network activation during working memory, indicating that this sex difference is specific to the processing of reward and punishment. These findings suggest a neurobiological explanation for prior work showing women have greater sensitivity to reward/punishment and are more prone to psychiatric disorders characterized by enhanced attention to such stimuli. Furthermore, given the large sample from the Human Connectome Project, the current findings provide general implications for the study of sex as a biological variable in investigation of reward processes.

Sex differences in neural activation following different routes of oxytocin administration in awake adult rats.

The neuropeptide oxytocin (OT) regulates social behavior in sex-specific ways across species. OT has promising effects on alleviating social deficits in sex-biased neuropsychiatric disorders. However little is known about potential sexually dimorphic effects of OT on brain function. Using the rat as a model organism, we determined whether OT administered centrally or peripherally induces sex differences in brain activation. Functional magnetic resonance imaging was used to examine blood oxygen level-dependent (BOLD) signal intensity changes in the brains of awake rats during the 20min following intracerebroventricular (ICV; 1µg/5µl) or intraperitoneal (IP; 0.1mg/kg) OT administration as compared to baseline. ICV OT induced sex differences in BOLD activation in 26 out of 172 brain regions analyzed, with 20 regions showing a greater volume of activation in males (most notably the nucleus accumbens and insular cortex), and 6 regions showing a greater volume of activation in females (including the lateral and central amygdala). IP OT also elicited sex differences in BOLD activation with a greater volume of activation in males, but this activation was found in different and fewer (10) brain regions compared to ICV OT. In conclusion, exogenous OT modulates neural activation differently in male versus female rats with the pattern and magnitude, but not the direction, of sex differences depending on the route of administration. These findings highlight the need to include both sexes in basic and clinical studies to fully understand the role of OT on brain function.

Multi-site exploration of sex differences in brain reactivity to smoking cues: Consensus across sites and methodologies.

BACKGROUND: Biological sex influences cigarette smoking behavior. More men than women smoke, but women have a harder time quitting. Sex differences in smoking cue (SC) reactivity may underlie such behavioral differences. However, the influence of sex on brain reactivity to SCs has yielded inconsistent findings suggesting the need for continued study. Here, we investigated the effect of sex on SC reactivity across two sites using different imaging modalities and SC stimulus types. METHODS: Pseudo-continuous arterial spin-labeled (pCASL) perfusion functional magnetic resonance imaging (fMRI) was used to assess brain responses to SC versus non-SC videos in 40 smokers (23 females) at the University of Pennsylvania. BOLD fMRI was used to assess brain responses to SC versus non-SC still images in 32 smokers (18 females) at McLean Hospital. Brain reactivity to SCs was compared between men and women and was correlated with SC-induced craving. RESULTS: In both cohorts, males showed higher SC versus non-SC reactivity compared to females in reward-related brain regions (i.e., ventral striatum/ventral pallidum, ventral medial prefrontal cortex). Brain activation during SC versus non-SC exposure correlated positively with SC-induced subjective craving in males, but not females. CONCLUSIONS: The current work provides much needed replication and validation of sex differences in SC-reactivity. These findings also add to a body of literature showing that men have greater reward-related brain activation to drug cues across drug classes. Such sex differences confirm the need to consider sex not only when evaluating SC-reactivity but when examining nicotine dependence etiology and treatment.

Role of the oxytocin system in amygdala subregions in the regulation of social interest in male and female rats.

We previously found that oxytocin (OT) receptor (OTR) binding density in the medial amygdala (MeA) correlated positively with social interest (i.e., the motivation to investigate a conspecific) in male rats, while OTR binding density in the central amygdala (CeA) correlated negatively with social interest in female rats. Here, we determined the causal involvement of OTR in the MeA and CeA in the sex-specific regulation of social interest in adult rats by injecting an OTR antagonist (5ng/0.5µl/side) or OT (100pg/0.5µl/side) before the social interest test (4-min same-sex juvenile exposure). OTR blockade in the CeA decreased social interest in males but not females, while all other treatments had no behavioral effect. To further explore the sex-specific involvement of the OT system in the CeA in social interest, we used in vivo microdialysis to determine possible sex differences in endogenous OT release in the CeA during social interest. Interestingly, males and females showed similar levels of extracellular OT release at baseline and during social interest, suggesting that factors other than local OT release mediate the sex-specific role of CeA-OTR in social interest. Moreover, we found a positive correlation between CeA-OT release and social investigation time in females. This was further reflected by reduced CeA-OT release during social interest in females that expressed low compared to high social interest. We discuss the possibility that this reduction in OT release may be a consequence, rather than a cause, of exposure to a social stimulus. Overall, our findings show for the first time that extracellular OT release in the CeA is similar between males and females and that OTR in the CeA plays a causal role in the regulation of social interest toward juvenile conspecifics in males.

Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition.

Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 µl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 µl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition.

Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context.

We recently demonstrated that vasopressin (AVP) in the lateral septum modulates social play behavior differently in male and female juvenile rats. However, the extent to which different social contexts (i.e., exposure to an unfamiliar play partner in different environments) affect the regulation of social play remains largely unknown. Given that AVP and the closely related neuropeptide oxytocin (OXT) modulate social behavior as well as anxiety-like behavior, we hypothesized that these neuropeptides may regulate social play behavior differently in novel (novel cage) as opposed to familiar (home cage) social environments. Administration of the specific AVP V1a receptor (V1aR) antagonist (CH2)5Tyr(Me(2))AVP into the lateral septum enhanced home cage social play behavior in males but reduced it in females, confirming our previous findings. These effects were context-specific because V1aR blockade did not alter novel cage social play behavior in either sex. Furthermore, social play in females was reduced by AVP in the novel cage and by OXT in the home cage. Additionally, females administered the specific OXT receptor antagonist desGly-NH2,d(CH2)5-[Tyr(Me)(2),Thr(4)]OVT showed less social play in the novel as compared to the home cage. AVP enhanced anxiety-related behavior in males (tested on the elevated plus-maze), but failed to do so in females, suggesting that exogenous AVP alters social play and anxiety-related behavior via distinct and sex-specific mechanisms. Moreover, none of the other drug treatments that altered social play had an effect on anxiety, suggesting that these drug-induced behavioral alterations are relatively specific to social behavior. Overall, we showed that AVP and OXT systems in the lateral septum modulate social play in juvenile rats in neuropeptide-, sex- and social context-specific ways. These findings underscore the importance of considering not only sex, but also social context, in how AVP and OXT modulate social behavior.