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Understanding how Bipolar Disorder (BD) affects employment is limited by cross-sectional or short-term longitudinal designs. The aims for this study are to examine condition-related and other clinical predictors of longitudinal employment status and stability in those with BD compared to healthy controls (HC).Participants were 358 individuals with BD and HC who were enrolled in the Heinz C. Prechter Longitudinal Study of BD. Participants completed self-report measurements of employment, symptoms, health, personality, life events, and neuropsychological tests at study enrollment, yearly and/or every two months. Repeated measures logistic regression was used to predict employment status and stability.Those with BD were less likely to be employed than HC. Significant predictors of unemployment in BD include having BD type I, younger age, less years with BD, higher depression, worse processing speed, and worse mental and physical health. Of those with BD, 64 % demonstrated greater employment instability compared to 37 % of HC. History of psychosis, worse memory, physical health, and greater disruption of negative life events significantly predicted employment instability.The limitations of this study include the generalizability of this sample, a large reliance of self-report measures, and a lack of employment-related factors such as job-type, functioning, performance, and satisfaction. Lastly, the effects of medication, treatment adherence, and treatment optimization were not assessed in this study.These findings highlight that different aspects of BD are important for being employed versus maintaining stable employment. These findings indicate the need for more effective treatment strategies beyond symptom management.

Objective:Assessing performance validity is imperative in both clinical and research contexts as data interpretation presupposes adequate participation from examinees. Performance validity tests (PVTs) are utilized to identify instances in which results cannot be interpreted at face value. This study explored the hit rates for two frequently used PVTs in a research sample of individuals with and without histories of bipolar disorder (BD).Method:As part of an ongoing longitudinal study of individuals with BD, we examined the performance of 736 individuals with BD and 255 individuals with no history of mental health disorder on the Test of Memory Malingering (TOMM) and the California Verbal Learning Test forced choice trial (CVLT-FC) at three time points.Results:Undiagnosed individuals demonstrated 100% pass rate on PVTs and individuals with BD passed over 98% of the time. A mixed effects model adjusting for relevant demographic variables revealed no significant difference in TOMM scores between the groups, a = .07, SE = .07, p = .31. On the CVLT-FC, no clinically significant differences were observed (ps < .001).Conclusions:Perfect PVT scores were obtained by the majority of individuals, with no differences in failure rates between groups. The tests have approximately >98% specificity in BD and 100% specificity among non-diagnosed individuals. Further, nearly 90% of individuals with BD obtained perfect scores on both measures, a trend observed at each time point.

Background Individuals with bipolar disorder (BD) show different personality profiles compared to non-psychiatric populations, but little is known about the temporal stability of personality traits over time, and if changes in mood state drive changes in personality. Methods Participants were 533 BD and 185 healthy controls (HC) who completed the NEO-Personality Inventory-Revised (NEO-PI-R) and clinician-administered measures of mood at baseline. One-hundred-eighty BD and 79 HC completed the measures at 5-year follow-up and 60 BD and 16 HC completed the measures at 10-year follow-up. The above measures and demographic information, but not other clinical status indicators the BD illness, were used in analyses. Results The BD group has higher Neuroticism (N)/N facets and lower Extraversion (E)/E facets and Consciousness (C)/C facets compared to HC. Significant mean-level changes existed within groups but were small in magnitude, and groups showed similar moderate-to-high rank-order stability. Change in (N)/N facets shows an association with change in depression, but changes in all other NEO-PI-R scores are not associated with changes in mood. Personality traits are clinically stable in part of our bipolar sample using clinically relevant interpretation of changes in T scores; however, some BD subjects did show more reliable changes in personality traits than the healthy controls. Limitations Reliance on self-report measurement and not all our participants completed the 5- and 10-year follow-up personality assessment who were eligible to do so. Conclusions Mean-level and rank-order personality scores show only modest changes, so most personality changes over time are not systematic. Observed changes in personality traits are not explained by changes in mood with the exception of Neuroticism, suggesting other factors influence changes in personality.

Cognitive functioning in bipolar disorder is heterogeneous with evidence for multiple subgroups. However, cognitive subgroup change patterns over time remains unknown. While prior work suggests minimal differences in cognitive functioning patterns over time between those with bipolar disorder and controls, group-based analyses may obscure unique subgroup-based changes.Participants diagnosed with bipolar disorder (I, II, NOS; n = 568) and unaffected controls (n = 234) completed baseline, one- and five-year neuropsychological assessments. Data reduction techniques were used to limit the number of neuropsychological variables. Bipolar disorder participant baseline neuropsychological data were entered into hierarchical cluster analyses and resultant clusters were entered in multilevel models, which tested for differences in baseline and longitudinal cognitive changes in cognition among the cluster groups and with controls.Results were consistent with bipolar disorder participants forming three subgroups with high (n = 209), mid (n = 259), and low (n = 100) cognition. These groups were associated with unique clinical characteristics. Multilevel models demonstrated that over a five-year period, the low group improved, relative to the high and mid groups, and with controls, in auditory memory. Over the five-year period, the mid group, in comparison with the high group, improved in visual memory; additionally, the high group remained stable, in comparison with a slight decline in the control group, in inhibitory control.These results demonstrate that cognition-based subgroups of bipolar disorder participants have minimal differences in their longitudinal course in relation to each other and with unaffected controls.

Horseracing is among the most popular and increasingly lucrative industry sports in the nation. The average jockey must control a thoroughbred horse 10 times their weight that may act unpredictably whether at rest or full gallop resulting in falls, kicks, or even biting injuries. Despite the risks, jockeys do not have access to the same quality of medical care that is standard in similarly profitable sports organizations. Beyond the mental and physical demands of training and performance endured by any professional athlete, jockeys are confronted with health challenges unique to their sport. In this review of the literature, we aim to educate sports medicine physicians regarding the underlying causes of injuries, describe injury management, and make recommendations for appropriate preventive strategies. Overall, there is a void of literature, and so our authors offer expert opinion and encourage others to get involved in making this a safer sport.

The objective of this study was to determine the effects of prepartum negative dietary cation-anion difference diet (DCAD) fed at two dietary Ca inclusion rates on postpartum uterine health and ovulation dynamics of multiparous Holstein cows (n = 76). Treatments began at 28 days before expected calving until parturition and were: CON: DCAD = +6 mEq/100g of DM with low dietary Ca (46.2 ± 15.2 g Ca/d; 0.4% DM; n = 26); ND: DCAD = -24 mEq/100g of DM with low dietary Ca (44.1 ± 16.1 Ca/d; 0.4% DM; n = 24); NDCA: DCAD = -24 mEq/100g of DM with high dietary Ca (226.6 ± 96.0 g Ca/d; 2.0% DM; n = 26). Vaginal discharge was evaluated through the fresh period via Metricheck (MC) for presence of purulent material. Polymorphonuclear (PMN) cell concentration in the uterus was evaluated at 15 and 30 days relative to calving (DRC). Endometrial tissue was harvested at 30 DRC for glandular morphology, presence of tight-junctions and adheren-junctions proteins, as well as assessment of superoxide dismutase (SOD) and glutathione peroxidase (GPX) activity. Blood plasma and serum samples were harvested in the prepartum and postpartum phase and were assessed for concentrations of lipopolysaccharide binding protein (LBP), serum amyloid A (SAA), and haptoglobin (HP). Ovarian dynamics were assessed through the fresh period until first timed artificial insemination (TAI). Cows fed CON had a lower MC score (P = 0.06) than the average of cows fed ND and cows fed NDCA. Cows fed ND had a higher MC score than cows fed NDCA. Cows fed NDCA had greater uterine gland epithelial height (P = 0.02) than cows fed ND. Cows fed NDCA also had a greater number of epithelial cells per gland (P = 0.05) than cows fed ND. Cows fed NDCA had greater intensity of occludin expression (P = 0.15) than cows fed ND. Cows fed NDCA had increased activity of SOD (P = 0.05) and decreased activity of GPX (P 0.001) than cows fed ND. Cows fed ND had higher plasma HP concentrations than cows fed NDCA in the prepartum (P = 0.01) and post-partum (P = 0.03) periods. Cows fed ND and NDCA had lower (P = 0.01) postpartum plasma HP concentration than cows fed CON. In conclusion, cows fed NDCA had an improved uterine environment most likely due to alleviation of oxidative stress, an enhanced immune response to parturition and uterine discharge comparable to cows fed CON.

Objective The increase in smartphone usage has enabled the possibility of more accessible ways to conduct neuropsychological evaluations. The objective of this study was to determine the feasibility of using smartphone typing dynamics with mood scores to supplement cognitive assessment through trail making tests. Methods Using a custom‐built keyboard, naturalistic keypress dynamics were unobtrusively recorded in individuals with bipolar disorder (n = 11) and nonbipolar controls (n = 8) on an Android smartphone. Keypresses were matched to digital trail making tests part B (dTMT‐B) administered daily in two periods and weekly mood assessments. Following comparison of dTMT‐Bs to the pencil‐and‐paper equivalent, longitudinal mixed‐effects models were used to analyze daily dTMT‐B performance as a function of typing and mood. Results Comparison of the first dTMT‐B to paper TMT‐B showed adequate reliability (intraclass correlations = 0.74). In our model, we observed that participants who typed slower took longer to complete dTMT‐B (b = 0.189, p < .001). This trend was also seen in individual fluctuations in typing speed and dTMT‐B performance (b = 0.032, p = .004). Moreover, participants who were more depressed completed the dTMT‐B slower than less depressed participants (b = 0.189, p < .001). A practice effect was observed for the dTMT‐Bs. Conclusion Typing speed in combination with depression scores has the potential to infer aspects of cognition (visual attention, processing speed, and task switching) in people's natural environment to complement formal in‐person neuropsychological assessments that commonly include the trail making test., This study explored the feasibility of using smartphone typing dynamics with mood scores to supplement cognitive assessment through trail making tests. Naturalistic keypress dynamics were unobtrusively collected from individuals with bipolar disorder and nonbipolar controls using a custom‐built keyboard and compared to serial administrations of the trail making test part B. Typing speed in combination with depression scores significantly predicted trail making test time and may have the potential to be used to assess cognition in real time to complement in‐person assessments.

BACKGROUND Life Goals is an evidence-based self-management intervention that assists individuals with bipolar disorder (BD) by aligning BD symptom coping strategies with their personal goals. The intervention can be availed via in-person and telephonic sessions, and it has been recently developed as an individualized, customizable mobile app. OBJECTIVE We examined the feasibility, usability, and acceptability of the Life Goals self-management app among individuals diagnosed with BD who used the app for up to 6 months. METHODS A total of 28 individuals with BD used the Life Goals app on their personal smartphone for 6 months. They completed key clinical outcome measurements of functioning, disability, and psychiatric symptoms at baseline, 3 months, and 6 months, in addition to a poststudy survey about usability and satisfaction. RESULTS Participants used the app for a median of 25 times (IQR 13-65.75), and for a longer time during the first 3 months of the study. The modules on depression and anxiety were the most frequently used, accounting for 35% and 22% of total usage, respectively. Overall, the study participants found the app useful (15/25, 60%) and easy to use (18/25, 72%), and they reported that the screen displayed the material adequately (22/25, 88%). However, less than half of the participants found the app helpful in managing their health (10/25, 40%) or in making progress on their wellness goals (9/25, 36%). Clinical outcomes showed a trend for improvements in mental and physical health and mania-related well-being. CONCLUSIONS The Life Goals app showed feasibility of use among individuals with BD. Higher user engagement was observed in the initial 3 months with users interested more frequently in the mood modules than other wellness modules. Participants reported acceptability with the ease of app use and satisfaction with the app user interface, but the app showed low success in encouraging self-management within this small sample. The Life Goals app is a mobile health technology that can provide individuals with serious mental illness with more flexible access to evidence-based treatments.

Bovine mastitis costs the US dairy industry $2 billion, an average of $200 per cow annually. Mastitis is currently diagnosed based on macroscopic alteration of milk or with a somatic cells count (SCC), which are non-specific markers of infection. Cows that have milk samples with no macroscopic alteration (i.e. clots) with more than 200,000 SCC per mL are classified as experiencing subclinical mastitis. Here, we demonstrate a novel cytometric fingerprinting and machine learning (CFML) toolchain as a label-free, objective, high-throughput microbiological milk quality evaluation method for routine mastitis screening. Milk samples were collected from each quarter of the udder from paired 20 milking Holstein cows. Cytometric fingerprints were immediately obtained along with simultaneous pathological analysis. Cytometric fingerprints largely resembled SCC and unique somatic cytometric fingerprints were observed in response to bacterial pathogens distinct from algal and fungal. To demonstrate applications of machine learning in reducing human intervention in future on-farm automated mastitis screening systems, we trained multiple machine learning models on cytometric fingerprints. Tested classifiers were found to be efficient, scalable and robust in classifying specific pathogen, identifying the lactation stage and pathogen intensity with 99.27%, 100%, and 100% accuracies respectively. Our findings indicate that CFML is sensitive to milk samples from cows experiencing subclinical mastitis spanning distinct types and levels of infections. The use of CFML is hence recommended for rapid, high-throughput mastitis typing. This would assist in the use of data-driven monitoring approaches leading to proper and judicious use of antibiotics in animal agriculture.

Previous studies demonstrate that many men have insecurities about the size of their penises, often resulting in low sexual self-esteem and sexual problems. In the present study, mean self-reported erect penis length by 130 sexually experienced college men (6.62 inches) was greater than found in previous studies in which researchers took measurements. This suggests that many of the men embellished their responses. Only 26.9% of the sexually experienced men self-reported penis lengths of less than 6 inches, while 30.8% self-reported lengths of 7 inches or more (with 10% self-reporting 8 inches or more). The correlation with Marlowe-Crowne social desirability scores was +.257 (p < .01), indicating that men with a high level of social desirability were more likely than others to self-report having a large penis.

Background Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. Methods The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. Results A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. Conclusions In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy. publishedVersion

Background Individuals with bipolar I disorder (BD-I) experience both poor sleep and neuropsychological dysfunction relative to non-psychiatric populations, which limits functional recovery. Poor sleep adversely affects learning, memory, and executive functioning in healthy individuals; however, little is known about the role of poor sleep in neuropsychological functioning in BD-I. We tested whether sleep disturbance was greater in BD-I than healthy control participants (HC), and compared the effect of sleep quality on learning, memory, and executive functioning between BD-I and HC. Methods Participants with BD-I (N=250) and HC (N=206) completed the Pittsburgh Sleep Quality Index, neuropsychological testing, and clinician-administered mood measures as part of a naturalistic study of bipolar disorder. We examined effects of both diagnosis and sleep quality on neuropsychological functioning. Results Relative to HC, BD-I showed poorer sleep quality and neuropsychological functioning in verbal learning, verbal and visual memory, processing speed, psychomotor speed, inhibitory control, and selective attention (7/9 domains). Poor sleep quality was associated with poorer verbal learning, verbal fluency, processing speed, and interference control (4/9). Effects of poor sleep on neuropsychological functioning did not differ between BD-I and HC. Limitations The assessment of sleep quality using a self-report measure and the effects of medications/sleeping aids (given the naturalistic study design) should be considered when interpreting results. Conclusions Those with BD-I experiencing poor sleep may also be more vulnerable to verbal learning and executive functioning impairments. The findings of poor sleep in relation to poorer neuropsychological functioning have implications for assessment and treatment of sleep disturbance in BD-I.

Horseracing is among the most popular and increasingly lucrative industry sports in the nation. The average jockey must control a thoroughbred horse 10 times their weight that may act unpredictably whether at rest or full gallop resulting in falls, kicks, or even biting injuries. Despite the risks, jockeys do not have access to the same quality of medical care that is standard in similarly profitable sports organizations. Beyond the mental and physical demands of training and performance endured by any professional athlete, jockeys are confronted with health challenges unique to their sport. In this review of the literature, we aim to educate sports medicine physicians regarding the underlying causes of injuries, describe injury management, and make recommendations for appropriate preventive strategies. Overall, there is a void of literature, and so our authors offer expert opinion and encourage others to get involved in making this a safer sport.

BACKGROUND There is considerable scientific interest in finding new and innovative ways to capture rapid fluctuations in functioning within individuals with bipolar disorder (BD), a severe, recurrent mental disorder associated with frequent shifts in symptoms and functioning. The use of smartphones can provide valid and real-world tools for use in measurement-based care and could be used to inform more personalized treatment options for this group, which can improve standard of care. OBJECTIVE We examined the feasibility and usability of a smartphone to capture daily fluctuations in mood within BD and to relate daily self-rated mood to smartphone use behaviors indicative of psychomotor activity or symptoms of the illness. METHODS Participants were 26 individuals with BD and 12 healthy control individuals who were recruited from the Prechter Longitudinal Study of BD. All were given a smartphone with a custom-built app and prompted twice a day to complete questions of mood for 28 days. The app automatically and unobtrusively collected phone usage data. A poststudy satisfaction survey was also completed. RESULTS Our sample showed a very high adherence rate to the daily momentary assessments (91% of the 58 prompts completed). Multivariate mixed effect models showed that an increase in rapid thoughts over time was associated with a decrease in outgoing text messages (β=–.02; P=.04), and an increase in impulsivity self-ratings was related to a decrease in total call duration (β=–.29; P=.02). Participants generally reported positive experiences using the smartphone and completing daily prompts. CONCLUSIONS Use of mobile technology shows promise as a way to collect important clinical information that can be used to inform treatment decision making and monitor outcomes in a manner that is not overly burdensome to the patient or providers, highlighting its potential use in measurement-based care.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1–5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p

Background : Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. Methods : In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18–65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. Results : Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. Limitations : Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. Conclusions : Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders.

Trait markers, or intermediate phenotypes linking different units of analysis (self-report, performance) from the Research Domain Criteria (RDoC) matrix across populations is a necessary step in identifying at-risk individuals. In the current study, 150 healthy controls (HC) and 456 individuals with bipolar disorder (BD) Type I or II, NOS (not otherwise specified) or Schizoaffective BD completed self-report neuropsychological tests of inhibitory control (IC) and executive functioning. Bifactor analyses were used to examine the factor structure of these measures and to evaluate for invariance across groups. Bifactor analyses found modest convergence of items from neuropsychological tests and self-report measures of IC among HC and BD. The factor scores showed evidence of a general IC construct (i.e., subdomain) across measures. Importantly, invariance testing indicated that the same construct was measured equally well across groups. Groups differed on the general factor for three of the four scales. Convergence on a general IC factor and invariance across diagnosis supports the use of combined dimensional measures to identify clinical risk and highlights how prospective RDoC studies might integrate units of analysis.

Introduction Studying remitted Major Depressive Disorder (rMDD) facilitates a better understanding of neural mechanisms for risk, given that confounding effects of active symptoms are removed. Disrupted functional connectivity has been reported in multiple networks in MDD. However, no study to date of rMDD has specifically examined connectivity of the ventral striatum (VS), a region highly implicated in reward and motivation. We investigated functional connectivity of the VS in individuals with and without a history of MDD, and in relation to affective personality traits. Methods Forty-two individuals with rMDD and 28 healthy controls across two sites completed resting-state fMRI and the Behavioral Inhibition System/Behavioral Activation System Scale. Voxel-wise, whole-brain comparisons were conducted across and between groups for four seeds: left and right inferior VS (VSi), left and right superior VS (VSs). Results VSs connectivity to temporal and subcortical regions including the putamen and amygdala was positive and greater in HCs compared to rMDD individuals. Across groups, VSi connectivity was positively correlated with trait reward-responsiveness in somatomotor regions. Across groups, VSs connectivity was positively correlated with trait drive, particularly in the putamen, parahippocampal, and inferior temporal gyrus, and was negatively associated with trait behavioral inhibition in the anterior cingulate, frontal gyri, and insula. Limitations Limitations include scanning at two sites and using multiple comparisons. Discussion Group connectivity differences emerged from the VSs rather than VSi. VSs showed associations with trait drive and behavioral inhibition, whereas VSi corrrelated with reward-responsiveness. Depression history and affective traits contribute meaningful and specific information about VS connectivity in understanding risk for MDD.

Diagnostic inaccuracies have been reported in Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) using clinical data alone. The [11C]-PiB PET scan offers a new method of identifying AD based on the detection of amyloid deposits. Our study investigated whether there was an agreement between neuropsychological and behavioral data and PiB findings in the diagnosis of FTD. Participants were 32 patients diagnosed with suspected FTD by clinical consensus. All participants underwent neuropsychological testing and PiB imaging. In addition, caregivers completed behavioral ratings of participants’ memory, frontal behaviors, and mood. Seventeen participants were classified as PiB positive (+). Results of MANOVA and subsequent ANOVA analyses showed a significant difference on memory performance between the PiB− and PiB+ groups, with the PiB− group performing better than the PiB+ group. There were no significant differences between the groups on cognitive or behavioral measures of executive/frontal impairment, mood. Both groups showed similar severity of dementia. These findings provide evidence for the utility of the [11C]-PiB PET scan in distinguishing between AD and FTD, with evaluation of memory at clinical diagnosis serving as a valuable indicator of the absence of FTD and consideration for an AD diagnosis. Our results would support the concern that patients who may present with primary behavioral or executive dysfunction may not necessarily have FTD, particularly if memory deficits are evident.

Objectives Cognitive dysfunction is a key feature of bipolar disorder (BD). However, not much is known about its temporal stability, as some studies have demonstrated a neurodegenerative model in BD while others have shown no change in cognitive functioning over time. Building upon our prior work, which examined the natural course of executive functioning, the current study aimed to investigate the natural course of memory, emotion processing, and fine motor dexterity over a 5-year period in BD and healthy control (HC) samples. Methods Using a 5-year longitudinal cohort, 90 individuals with BD and 17 HCs were administered a battery of neuropsychological tests at study baseline and at 1 and 5 years after study entry that captured four areas of cognitive performance: visual memory, auditory memory, emotion processing, and fine motor dexterity. Results Latent growth curve modeling showed no group differences in the slopes of any of the cognitive factors between the BD and HC groups. Age at baseline was negatively associated with visual memory, emotion processing, and fine motor dexterity. Education level was positively associated with auditory and visual memory and fine motor. Female gender was negatively associated with emotion processing. Conclusions Extending our prior work on longitudinal evaluation of executive functioning, individuals with BD show similar linear change in other areas of cognitive functioning including memory, emotion processing, and fine motor dexterity as compared to unaffected HCs. Age, education, and gender may have some differential effects on cognitive changes.

Although there is a common clinical assumption that bipolar disorder with psychotic features reflects greater severity than bipolar disorder without psychosis, the existing empirical literature is mixed. This study investigated the phenomenology of psychosis as well as demographic, clinical, functional, and neuropsychological features in a large, cross-sectional sample of participants with bipolar disorder divided by history of psychosis.In a large single study, 168 affective-only bipolar disorder (BP-A) participants and 213 bipolar disorder with a history of psychosis (BP-P) participants completed a comprehensive clinical diagnostic interview and neuropsychological testing. t tests, chi-square tests, and Bayes factors were used to investigate group differences or lack thereof.The prevalence of psychosis in this sample (53%) was similar to published reports. Nearly half of BP-P participants experienced grandiose delusions, and relatively few endorsed "first-rank" hallucinations of running commentary or two or more voices conversing. There were no demographic or neuropsychological differences between groups. BP-A participants experienced greater chronicity of affective symptoms and a greater degree of rapid cycling than BP-P participants; there were no other clinical differences between groups.Overall, these results contradict the conventional notion that bipolar disorder with psychotic features represents a more severe illness than bipolar disorder without a history of psychosis. The presence of psychosis does not appear to be associated with poorer clinical/functional outcome or suggest a greater degree of neuropsychological impairment; conversely, the absence of psychosis was associated with affective chronicity and rapid cycling. Nosological and treatment implications are discussed.

OBJECTIVES. Current literature highlights several negative sequelae for caregivers of individuals with Mild Cognitive Impairment (MCI), but little is known regarding the effect that caring for an individual with MCI has on health-related quality of life (HRQOL). The primary purpose of this paper was to identify the most important aspects of HRQOL related to caring for an individual with MCI. METHODS. Six focus groups were conducted with caregivers of individuals with MCI (n=32). Focus group discussions were transcribed verbatim, and a qualitative frequency analysis approach was used to analyze the data. RESULTS. Qualitative frequency analysis revealed that caregivers of individuals with MCI most frequently discussed their social health, including changes in their social roles and an increased need for social support (51.2% of the total discussion). This was followed by mental health concerns (37.9%) centering on anger, frustration, and a need for patience in the caregiving role, as well as caregiver-specific anxiety. Other discussion topics included physical health (10.0%), and the impact that stress and burden have on medical heath, and caregivers’ cognitive health (0.9%) including memory problems in relation to caregiver strain, sleep disruption, and cognitive fatigue. CONCLUSIONS. Findings illustrate the multiple domains of HRQOL that are affected in individuals providing care for someone with MCI. Moreover, findings highlight the need for extending support services to MCI caregivers, a group that is generally overlooked and are typically not offered support services due to the “less severe” nature of an MCI diagnosis.

Bipolar Disorder (BD) is characterized by impairments in psychosocial functioning with occupational disability being one of the most significant. Depression and neurocognitive deficits are features of BD most commonly associated with poor occupational functioning (OF). Few studies have examined these features over an extended period of time focusing on distinct aspects of work functioning.This longitudinal study included 273 adults with bipolar I disorder (N=173), bipolar II disorder (N=69), and bipolar not otherwise specified (N=31). The participants underwent an annual clinical assessment, neuropsychological testing, and work functioning measures over 5 years. We employed multilevel modeling (MLM) to determine which demographic, clinical, and neurocognitive characteristics influence 4 aspects of work functioning (work attendance, conflict, enjoyment, performance) over this 5-year period.Work functioning was measured using a self-report measure, which may be confounded by responder bias and is not tailored for distinct occupations. Due to insufficient power, medication use was not accounted for and our sample may not generalize to the broader BD population.Using MLM, those with higher levels of depression and greater cognitive flexibility deficits were more likely to experience poorer work attendance (p0.01), lower quality of work (p0.01), and reduced satisfaction from work (p0.001). These occupational hardships persisted over the 5-year period.This study emphasizes the need for interventions that specifically focus on the treatment of depressive symptoms and neurocognitive deficits within the context of work functioning, particularly attendance at work, to enable BD patients to live more productive, financially secure, and satisfying lives.

Deficits in cognitive flexibility, a difficulty altering thoughts and behavioral responses in a changing environment, are found in individuals with bipolar disorder (BD) and are associated with poor social and work functioning. However, the current literature is inconsistent in clarifying the long-term nature of these deficits for those with BD. We administered a common task of cognitive flexibility, the Wisconsin Card Sorting Task (WCST) and accounted for demographics, clinical, and cognitive features of BD, to determine the state versus trait characteristics of these deficits.The Wisconsin Card Sorting Test (WCST) was administered to 154 adults with BD and 95 healthy controls twice, one year apart.The main findings show that cognitive inflexibility is a trait feature of BD, independent of clinical features, that may modestly worsen over time due to the presence of certain demographic, cognitive, and functional features of the disorder. In addition, improvements in WCST performance over an extended period of time in both those with and those without already existing cognitive flexibility deficits indicate potential practice effects.These findings suggest that the implementation of early interventions before the illness progresses could potentially prevent further cognitive impairment, mitigate functional outcomes, and improve the quality of life of the individual with BD.

Objective Our aim was to study within-person variability in mood, cognition, energy, and impulsivity measured in an Ecological Momentary Assessment paradigm in bipolar disorder by using modern statistical techniques. Exploratory analyses tested the relationship between bipolar disorder symptoms and hours of sleep, and levels of pain, social and task-based stress. We report an analysis of data from a two-arm, parallel group study (bipolar disorder group N = 10 and healthy control group N = 10, with 70% completion rate of 14-day surveys). Surveys of bipolar disorder symptoms, social stressors and sleep hours were completed on a smartphone at unexpected times in an Ecological Momentary Assessment paradigm twice a day. Multi-level models adjusted for potential subject heterogeneity were adopted to test the difference between the bipolar disorder and health control groups. Results Within-person variability of mood, energy, speed of thoughts, impulsivity, pain and perception of skill of tasks was significantly higher in the bipolar disorder group compared to health controls. Elevated bipolar disorder symptom domains in the evening were associated with reduced sleep time that night. Stressors were associated with worsening of bipolar disorder symptoms. Detection of symptoms when an individual is experiencing difficulty allows personalized, focused interventions.

Two studies evaluated the effects of renal and hepatic impairment on pharmacokinetics and safety of rivipansel (NCT02813798, NCT02871570). A single intravenous 840-mg rivipansel dose was administered to subjects with renal impairment or normal renal function in study 1005 and subjects with moderate hepatic impairment or normal hepatic function in study 1006. Plasma (both studies) and urine (study 1005) samples were collected for 96 hours postdose. All subjects in studies 1005 (n = 28) and 1006 (n = 16) completed all study procedures. Rivipansel exposure (AUCinf ) was 47%, 124%, and 437% higher and total clearance 30%, 57%, and 82% lower in the mild, moderate, and severe renal impairment groups, respectively, than in the normal renal function group. Overall rivipansel exposure was 20% lower and total clearance 31% higher in the moderate hepatic impairment group than in the normal hepatic function group. Ten treatment-emergent adverse events occurred in studies 1005 and 1006; no event was considered treatment related. As expected, clearance of rivipansel decreased with increasing renal impairment. The difference observed between rivipansel pharmacokinetics in subjects with moderate hepatic impairment and subjects with normal hepatic function was not considered clinically significant. Single doses of rivipansel were well tolerated in subjects with either renal or hepatic impairment.

Background Individuals with mood disorders experience a higher rate of obesity than the general population, putting them at risk for poorer outcomes. The relationship between obesity and a core feature of the mood disorders, neurocognition, is less understood. We examined the interaction of obesity as indexed by body mass index (BMI) and working memory performance in a large sample of individuals with bipolar disorder (BD), major depressive disorder (MDD), and healthy controls (HC). Methods Participants with BD (n = 133), MDD (n = 78), and HC (n = 113) (age range 18–40) completed a spatial working memory (SWM) task that included three-graded increases in the number of target locations. Participants were subdivided by BMI classification into six diagnostic-BMI (BMI groups: Normal Weight, Overweight/Obese) subgroups. Performance on the task was indexed by number of errors within each difficulty level. Results The number of errors, across all groups, increased with task difficulty. There was an interaction between errors and diagnostic-BMI group. Post-hoc analyses indicated that while the Normal Weight-BD group did not differ in performance from the other groups, the Overweight/Obese-BD group performed significantly worse than HC groups. Limitations Metabolic effects of psychotropic medications due to the naturalistic nature of the study, younger age of the MDD sample, and utilizing self-reported indicators of obesity may limit generalizability. Conclusions Individuals with BD with increased metabolic burden exhibit increased working memory errors than non-psychiatric controls who also have increased metabolic burden. Future work could address prevention and amelioration of such difficulties to reduce associated functional morbidity.

Memory difficulties are consistently reported in Major Depressive Disorder (MDD). Nonetheless, it has not been thoroughly investigated as to whether these deficits persist during remission from MDD. A group of 32 healthy young adults with no history of a mood disorder (

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patients, we measured circadian rhythms in fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-R patients were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD. © 2018. This is the authors’ accepted and refereed manuscript to the article. Locked until 16.5.2019 due to copyright restrictions.

Background Government regulations mandate appropriate vehicular restraints for children under 4 years of age. Patients treated for infantile developmental dysplasia of the hip (DDH) with spica casts often require special accommodations. Previous work suggests that car seat loaner programs may help achieve these goals while avoiding the need for costly ambulance transportation. The purpose of this study was to evaluate our center's experience with postdischarge transportation in a large population of DDH infants and identify future threats to our program. Methods We performed a retrospective review of patients 4 years or younger of age who underwent closed or open reduction for DDH at our center between 2011 and 2018. Only the initial surgery of staged procedures was included. Patient demographic factors were recorded, as were procedure type, final restraint used for postdischarge transportation, and any potential discharge delays secondary to transportation issues. Costs were compared amongst transportation options. Results Our cohort consisted of 130 patients (mean age, 1.4±0.9 y; 98 females) treated for DDH. In total 41 children (31.5%) underwent closed reduction procedures, whereas 89 patients (68.5%) underwent open reductions. After reduction, 62 (47.7%) received 2-legged spica casts and 68 (52.3%) received 1.5-legged casts. The most common restraint was a hospital-loaned Hippo car seat (73, 55.8%) followed by family-owned car seats (27, 20.8%). Eight patients (6.2%) experienced delays in discharge while waiting for adequate restraints, 6 patients (4.6%) were transported by ambulance, and 4 patients (3.1%) left against medical advice with inadequate restraints. Conclusions Following surgical treatment of DDH, over 50% of patients with a spica cast were discharged using our center's car seat loaner program. However, availability and cost can present barriers for patients, with 4.6% of patients still being transported home by ambulance and 3.1% with inadequate restraints against medical advice. Costs of car seats are significant both for patients' families intending to purchase them, as well as for hospitals maintaining loaner programs and replacing used/lost seats. Moving forward, the recent cessation of production of the most common "spica car seat" threatens the longevity of existing loaner programs and calls renewed attention to the issue of safe transportation in-spica from providers and car-seat manufacturers alike. Level of evidence Level III.

Conjugated estrogens/bazedoxifene reduces vasomotor symptoms and prevents postmenopausal bone loss without stimulating the breast and endometrium. We analyzed changes in bone mineral density (BMD) and bone markers using pooled data from two phase-3 trials.Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 and SMART-5 were randomized, double-blind, placebo- and active-controlled studies conducted in postmenopausal nonhysterectomized women. BMD and turnover marker data were pooled for women given conjugated estrogens (0.45 or 0.625 mg) plus bazedoxifene 20 mg or placebo over 12 months. Sensitivity analyses were conducted using baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, race, and geographic region.There were 1,172 women, mean age 54.9 years, mean 6.21 years since menopause, mean lumbar spine, and total hip T scores -1.05 and -0.58; 58.8% had a Fracture Risk Assessment Tool score less than 5% indicating low fracture risk. At 12 months, adjusted differences (vs placebo) in BMD change in the groups taking conjugated estrogens 0.45 or 0.625 mg plus bazedoxifene 20 mg were 2.3% and 2.4% for lumbar spine, 1.4% and 1.5% for total hip, and 1.1% and 1.5% for femoral neck (all P 0.001 vs placebo). These increases were unrelated to baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, or geographic region. Both doses reduced bone turnover markers (P 0.001).Conjugated estrogens/bazedoxifene significantly improved BMD and turnover in a large population of younger postmenopausal women at low fracture risk and is a promising therapy for preventing postmenopausal bone loss.

Objective Executive Functioning (EF) deficits in bipolar disorder (BD) are commonly present regardless of mood state and therefore are considered core features of the illness. However, very little is known about the temporal stability of these deficits. We examined the natural course of EF over a five year period in BD and healthy control (HC) samples. Method Using a 5-year longitudinal cohort, 91 individuals with BD and 17 HC were administered a battery of neuropsychological tests that captured four main areas of EF: Processing Speed with Interference Resolution, Verbal Fluency with Processing Speed, Inhibitory Control, and Conceptual Reasoning and Set Shifting. Evaluations occurred at study entry, one, and five years later. Results Latent Growth Curve Modeling demonstrated that the BD group performed significantly worse in all EF areas than the HC group. Changes in EF from baseline to 5-year follow-up were similar across both diagnostic groups. Older age at baseline, above and beyond education and diagnosis, was associated with worse initial performance in EF. Being of older age was associated with greater decline in Processing Speed with Interference Resolution, and Verbal Fluency with Processing Speed. Higher education was marginally associated with a smaller declining slope for Processing Speed with Interference Resolution. Conclusions Executive functioning deficits in BD persist over time, and in the context of normative age-related decline, may place individuals at greater risk for cognitive disability as the disease progresses. Age and having a BD diagnosis together, however, do not accelerate executive functioning decline over time.

BackgroundRecent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes.MethodResting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted.ResultsYoung adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN.ConclusionsThis is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Superoxide dismutases (SODs) utilize a ping-pong mechanism in which a redox-active metal cycles between oxidized and reduced forms that differ by one electron to catalyze the disproportionation of superoxide to dioxygen and hydrogen peroxide. Nickel-dependent SOD (NiSOD) is a unique biological solution for controlling superoxide levels. This enzyme relies on the use of cysteinate ligands to bring the Ni(III/II) redox couple into the range required for catalysis (∼300 mV vs. NHE). The use of cysteine thiolates, which are not found in any other SOD, is a curious choice because of their well-known oxidation by peroxide and dioxygen. The NiSOD active site cysteinate ligands are resistant to oxidation, and prior studies of synthetic and computational models point to the backbone N-donors in the active site (the N-terminal amine and the amide N atom of Cys2) as being involved in stabilizing the cysteines to oxidation. To test the role of the backbone N-donors, we have constructed a variant of NiSOD wherein an alanine residue was added to the N-terminus (Ala0-NiSOD), effectively altering the amine ligand to an amide. X-ray absorption, electronic absorption, and magnetic circular dichroism (MCD) spectroscopic analyses of as-isolated Ala0-NiSOD coupled with density functional theory (DFT) geometry optimized models that were evaluated on the basis of the spectroscopic data within the framework of DFT and time-dependent DFT computations are consistent with a diamagnetic Ni(II) site with two cysteinate, one His1 amide, and one Cys2 amidate ligands. The variant protein is catalytically inactive, has an altered electronic absorption spectrum associated with the nickel site, and is sensitive to oxidation. Mass spectrometric analysis of the protein exposed to air shows the presence of a mixture of oxidation products, the principal ones being a disulfide, a bis-sulfenate, and a bis-sulfinate derived from the active site cysteine ligands. Details of the electronic structure of the Ni(III) site available from the DFT calculations point to subtle changes in the unpaired spin density on the S-donors as being responsible for the altered sensitivity of Ala0-NiSOD to O

OBJECTIVE To evaluate the effects of mood and anxiety symptoms in relation to personality dimensions and clinical features such as trauma and substance use on suicidal behaviors in a longitudinal sample of individuals with bipolar illness (BP) and healthy controls (HC). METHODS Mood, personality, and clinical features were assessed in 151 individuals with BP I and 119 HC. Clinical data were collected at baseline and at 2-year follow-up. Personality traits were measured using the NEO PI-R. RESULTS In bivariate analyses, personality measures were significantly different between BP and HC, and between BP based on suicide attempt history. However, in regression analyses, baseline measures of depression, mania, anxiety, trauma, education, and age of BP onset correlated with personality domains, while a history of suicide attempts did not. Logistic regressions showed that prospective depression or mania, and a pattern of mixed mood features and chronicity of illness, along with two Neuroticism facet scores (N4-Self-Consciousness and N6-Vulnerability) were predictive of suicide ideation (SI) in the 2-year follow-up period. CONCLUSIONS While dimensions of personality, trauma, and substance use clearly correlated with suicidal behaviors in BP, in multivariate models emerging mood symptoms were the most robust predictors of suicidality. These results reinforce the importance and attributable role of mood and anxiety symptoms in evaluating suicidal risk.

Bipolar disorder (BD) is characterized by recurrent mood episodes and profound impairments in psychosocial functioning. Occupational disability is one of the most problematic impairments for individuals with BD due to high rates of unemployment and work impairments. Current evidence indicates that social stressors at work-such as social isolation, conflict with others, and stigmas-are common experiences for employed individuals with BD. Yet, few studies have examined the relationship between social stressors at work and overall occupational functioning, instead focusing on individual clinical features of the disorder.This cross-sectional study employed logistic and linear regressions to determine which demographic variables, mood symptoms, and social aspects of the work environment (exclusion, conflict, social support, stigma) were associated with work status (working vs. not working) and work functioning for individuals with bipolar disorder I and II.Greater stigma and exclusion at work (By examining two distinct measures of work outcomes (work status and work functioning) within the same group of participants, this study provides a unique insight, revealing that predictors of occupational functioning vary based on the specific measure of work outcomes used. This study also emphasizes the need for treatments that address the clinical features of BD and intervene in the work environment to improve functioning and prevent unemployment among individuals with BD.

Aim Impairment in neuropsychological functioning is common in major depressive disorder (MDD), but it is not clear to what degree these deficits are related to risk (e.g. trait), scar, burden or state effects of MDD. The objective of this study was to use neuropsychological measures, with factor scores in verbal fluency, processing speed, attention, set-shifting and cognitive control in a unique population of young, remitted, unmedicated, early course individuals with a history of MDD in hopes of identifying putative trait markers of MDD. Methods Youth aged 18–23 in remission from MDD (rMDD; n = 62) and healthy controls (HC; n = 43) were assessed with neuropsychological tests at two time points. These were from four domains of executive functioning, consistent with previous literature as impaired in MDD: verbal fluency and processing speed, conceptual reasoning and set-shifting, processing speed with interference resolution, and cognitive control. Results rMDD youth performed comparably to HCs on verbal fluency and processing speed, processing speed with interference resolution, and conceptual reasoning and set-shifting, reliably over time. Individuals with rMDD demonstrated relative decrements in cognitive control at Time 1, with greater stability than HC participants. Conclusion MDD may be characterized by regulatory difficulties that do not pertain specifically to active mood state or fluctuations in symptoms. Deficient cognitive control may represent a trait vulnerability or early course scar of MDD that may prove a viable target for secondary prevention or early remediation.

Crystal structures of nickel-dependent superoxide dismutases (NiSODs) reveal the presence of a H-bonding network formed between the NH group of the apical imidazole ligand from His1 and the Glu17 carboxylate from a neighboring subunit in the hexameric enzyme. This interaction is supported by another intrasubunit H-bond between Glu17 and Arg47. In this study, four mutant NiSOD proteins were produced to experimentally evaluate the roles of this H-bonding network and compare the results with prior predictions from density functional theory calculations. The X-ray crystal structure of H1A-NiSOD, which lacks the apical ligand entirely, reveals that in the absence of the Glu17-His1 H-bond, the active site is disordered. Characterization of this variant using X-ray absorption spectroscopy (XAS) shows that Ni(II) is bound in the expected N2S2 planar coordination site. Despite these structural perturbations, the H1A-NiSOD variant retains 4% of wild-type (WT) NiSOD activity. Three other mutations were designed to preserve the apical imidazole ligand but perturb the H-bonding network: R47A-NiSOD, which lacks the intramolecular H-bonding interaction; E17R/R47A-NiSOD, which retains the intramolecular H-bond but lacks the intermolecular Glu17-His1 H-bond; and E17A/R47A-NiSOD, which lacks both H-bonding interactions. These variants were characterized by a combination of techniques, including XAS to probe the nickel site structure, kinetic studies employing pulse-radiolytic production of superoxide, and electron paramagnetic resonance to assess the Ni redox activity. The results indicate that in addition to the roles in redox tuning suggested on the basis of previous computational studies, the Glu17-His1 H-bond plays an important structural role in the proper folding of the "Ni-hook" motif that is a critical feature of the active site.

In the 1780s a poem detailed the yearly argument between Mr. and Mrs. Jerkin, a ''man of consequence'' and ''a charming housewife.'' The dispute surged from trivial squabble to violent abuse over whether Mr. Jerkin brought home a starling or a thrush from one of his hunting excursions. Neither spouse relents until Mr. Jerkin introduces violence: '' The lie again, and then the blow. / Blows carry strong and quick conviction, / And marr the power of contradiction.'' After the violence, ''Peace soon ensu'd and all was well'' until a year later, when Mrs. Jerkin comments on their happiness and regrets the past disagreement. '' This is a charming life,'' she declares, ''No tumults now, no blows, no strife; / What fools we were this day last year?'' Mrs. Jerkin remembers, ''Lord! How you beat me then, my dear.'' After they express sorrow that they fought over such a small matter, the original fight starts again as the couple recollect its origins and renew their original positions. ''Again the lie, again the blows.'' The pattern of love and hate the couple engage in year after year is summed up at the end of the poem with their mutual refrain: '' You dog, you bitch, my dear, my darling.'' No particular lament from the poet rebukes Mr. Jerkin's inability to control his rage. Mrs. Jerkin's vanity and ''spirit of contradiction,'' however, are well established in the beginning of the poem, as the poet claims she demands to be called ''Mistress Jerkin.'' In addition, ''She had a vast contempt for spouse'' for being too ''countrified.'' Only the inane argument, Mr. Jerkin's unrefined manner, and Mrs. Jerkin's argumentativeness explain the escalation of the fight.The poem intends to be humorous, given the absurd origins of the fight, but significant truths about early Americans' beliefs and practices lie in the subtext. Some readers saw the couple's insistence on maintaining their stances and arguing over the ''silliest things in life'' as funny, and part of this humor stemmed from their recognition of petty squabbles in their own marital lives. Small disagreements, according to the poet, often turn to the ''bitterest hate . . . words come first; and after, blows.''1 The poem validated violence against women in marriage even as it exposed the foolishness of the Jerkins and the senseless battles of married couples. In other ways, '' The Spirit of Contradiction'' was an increasingly anachronistic rendering of abusive relationships within marriage. More progressive readers would have viewed the escalation into marital violence as a backward response to a marital dispute. In the modern age, society aimed for companionate marriages and increasingly sentimentalized women's roles in the family, and it came to see violence as a retrograde response to conflict.Unlike Mrs. Jerkin, not all women suffered ''blows'' in silence, and some women's ''spirit of contradiction'' led them to protest the abuse they experienced in marriage. Women detailed the violence they experienced in suits against their husbands for breaches of the peace and in divorce petitions. Between 1800 and 1820 in Boston, records of 363 separate cases exist in which wives testified about spousal abuse to justices of the peace (JPs) to force their husbands to make a bond ensuring they would not assault them. Women increasingly made use of this tool over the twenty years examined. Between 1800 and 1804, the average rate of reports was 5.2 cases per year, and from 1816 to 1820, the rate was 39 per year, which is a rise in the number of suits beyond population growth. Numbers of divorces began rising as early as the 1770s and continued through the 1820s. Over the twelveyear period between 1787 and 1799, for example, 21 suits involving cruelty as a causal factor occurred. In contrast, Nancy Cott found 42 cases of divorce involving cruelty over the nearly hundred-year period from 1692 to 1786.2 Women were placing pressure on the judicial system to respond to wife abuse, and their actions changed the government's perception and handling of abuse cases. …

Major depressive disorder (MDD) is characterized by dysfunction in cognitive and emotional systems. However, the neural network correlates of cognitive control (cold cognition) and emotion processing (hot cognition) during the remitted state of MDD (rMDD) remain unclear and not fully probed, which has important implications for identifying intermediate phenotypes of depression risk.43 young adults with rMDD and 33 healthy controls (HCs) underwent fMRI while completing separate tasks of cold cognition (Parametric Go/No-Go test) and hot cognition (Facial Emotion Processing Test). Two 2 group (rMDD, HC) × 2 event (sad/fearful faces, correct rejections) factorial models of activation were calculated in SPM8. Functional activation was evaluated in the salience and emotional network (SEN) and the cognitive control network (CCN), including hypothesized interaction between group and task within the CCN.Individuals with rMDD demonstrated greater spatial extent of suprathreshold activation within the SEN during sad faces relative to HCs. There were several regions within the CCN in which HCs showed greater activation than rMDD during correct rejections of lures, whereas individuals with rMDD showed greater activation than HCs during sad or fearful faces.Results were not directly compared with active MDD.These results provide evidence of deficient CCN engagement during cognitive control in rMDD (dysfunctional cold cognition). Elevated SEN activation during sad faces could represent heightened salience of negative emotional faces in rMDD; elevated CCN activation during emotional faces in rMDD could represent compensatory regulatory control. These group differences may represent vulnerability factors, scars of prior depressive episodes, or processes maintaining wellness.