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Objective: We prospectively evaluated how well combinations of signs and symptoms can identify individuals in the prodromal phase of Parkinson's disease (PD)., Methods: The study comprised 6,108 men who underwent repeated assessments of key prodromal features and were prospectively followed for the development of PD. Two composite measures of prodromal PD were evaluated: (i) the co-occurrence of constipation, probable rapid eye movement (REM) sleep behavior disorder (pRBD), and hyposmia, and (ii) the probability of prodromal PD based on the Movement Disorders Society (MDS) research criteria. We also examined the progression and heterogeneity of the prodromal PD phase., Results: One hundred three individuals were newly diagnosed with PD over an average follow-up of 3.4 years. Men with constipation, pRBD, and hyposmia had a 23-fold higher risk of receiving a PD diagnosis in the subsequent 3 years, compared with men without these features (risk ratio [RR] = 23.35, 95% confidence interval [CI] = 10.62-51.33). The risk of PD was 21-fold higher in men with a probability of prodromal PD ≥ 0.8 compared with those with a probability < 0.2 (RR = 21.96, 95% CI = 11.17-43.17). Both the co-occurrence of the 3 non-motor features and an MDS-based probability ≥ 0.8 had comparable predictive values, and both were stronger predictors of PD than any of the features individually. We identified 2 prodromal PD subtypes where RBD and visual color impairment were key discriminators., Interpretation: Our study demonstrates that combinations of key signs and symptoms strongly predict future clinically manifest PD. These measures may be integrated into screening strategies to identify individuals who could be targeted for enrollment into PD prevention trials. ANN NEUROL 2024., (© 2024 American Neurological Association.)

Objective: Management of cervical high-grade squamous intraepithelial lesions (HSILs), the immediate precursor of cervical cancer, consists largely of surgical treatment for women at higher risk for progression to cancer. The authors' objective was to describe the occurrence of cervical HSIL in the United States and various outcomes for women who received surgical treatment., Methods: From a US commercial health insurer, a cohort of adult women with cervical HSIL diagnoses receiving surgical treatment within 3 months of diagnosis between January 2008 and September 2018 was identified. This cohort was followed for several outcomes, including cervical HSIL recurrence, human papillomavirus clearance, preterm birth, infection, and bleeding., Results: The incidence rate of cervical HSIL declined from 2.34 (95% CI = 2.30-2.39) cases per 1,000 person-years in 2008 to 1.39 (95% CI = 1.35-1.43) cases per 1,000 person-years in 2014, remaining near that level through 2018. Among 65,527 women with cervical HSIL, 47,067 (72%) received surgical treatment within 3 months of diagnosis. Among the women receiving surgical treatment, cervical HSIL recurred in 6% of surgically treated women, whereas 45% of surgically treated women underwent subsequent virological testing that indicated human papillomavirus clearance. Preterm birth was observed in 5.9% by 5 years follow-up and bleeding and infection each at 2.2% by 7 days follow-up., Conclusions: From 2008 through 2018, the incidence of diagnosed cervical HSIL decreased for several years before stabilizing. Surgical treatment of HSIL may be beneficial in removing the precancerous lesion, but cervical HSIL may recur, and the surgery is associated with complications including preterm birth, infection, and bleeding., (Copyright © 2023, ASCCP.)

Objective: Previous research has reported hyperresponsivity in the amygdala and hyporesponsivity in ventral portions of the medial prefrontal cortex to threat-related stimuli in posttraumatic stress disorder (PTSD). Whether such findings generalize to more ambiguous stimuli and whether such brain activation abnormalities reflect familial vulnerabilities, trauma-exposure, or acquired characteristics of PTSD remain unclear. In this study, we measured brain responses to emotionally ambiguous stimuli (i.e., surprised facial expressions) in identical twin pairs discordant for trauma exposure to elucidate the origin of brain activation abnormalities., Methods: Participants with PTSD (n = 12) and their trauma-unexposed identical cotwins (n = 12), as well as trauma-exposed participants without PTSD (n = 15) and their trauma-unexposed identical cotwins (n = 15), passively viewed surprised and neutral facial expressions during functional magnetic resonance imaging (fMRI). Afterward, participants labeled and rated each facial expression on valence and arousal., Results: Amygdala activation to Surprised and Neutral facial expressions (versus Fixation) was greater in the participants with PTSD and their trauma-unexposed identical cotwins without PTSD, compared to the control twin pairs. In contrast, medial frontal gyrus (MFG) activation to Surprised facial expressions (versus Fixation) was diminished in the PTSD group relative to the other three groups., Conclusions: Amygdala hyperresponsivity to emotionally ambiguous facial expressions may be a familial vulnerability factor that increases the likelihood of developing PTSD after experiencing a traumatic event. In contrast, MFG hyporesponsivity may be an acquired characteristic of the disorder., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Significant progress has been made in expanding our understanding of prodromal Parkinson disease (PD), particularly for recognition of early motor and nonmotor signs and symptoms. Although identification of these prodromal features may improve our understanding of the earliest stages of PD, they are individually insufficient for early disease detection and enrollment of participants in prevention trials in most cases because of low sensitivity, specificity, and positive predictive value. Composite cohorts, composed of individuals with multiple co-occurring prodromal features, are an important resource for conducting prodromal PD research and eventual prevention trials because they are more representative of the population at risk for PD, allow investigators to evaluate the efficacy of an intervention across individuals with varying prodromal feature patterns, are able to produce larger sample sizes, and capture individuals at different stages of prodromal PD. A key challenge in identifying individuals with prodromal disease for composite cohorts and prevention trial participation is that we know little about the natural history of prodromal PD. To move toward prevention trials, it is critical that we better understand common prodromal feature patterns and be able to predict the probability of progression and phenoconversion. Ongoing research in cohort studies and administrative databases is beginning to address these questions, but further longitudinal analyses in a large population-based sample are necessary to provide a convincing and definitive strategy for identifying individuals to be enrolled in a prevention trial., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Subtle cognitive deficits can occur during the prodromal phase of Parkinson's disease (PD), commonly in conjunction with hyposmia. However, little is known about the association between cognitive function and other features suggestive of prodromal PD. We evaluated the association of non-motor prodromal PD features, including hyposmia, constipation and probable REM sleep behaviour disorder (pRBD), with objective measures of cognitive function and self-reported cognitive decline., Methods: The study population comprised 804 men who responded to a telephone cognitive interview in 2016-2017. Participants included 680 individuals with hyposmia, of whom 45 had confirmed PD, and 124 men without hyposmia. Among these men, we evaluated objective cognitive function and subjective cognitive decline to determine whether the presence of non-motor features of prodromal PD was associated with cognitive functioning. Analyses were adjusted for age, physical activity, body mass index, smoking status and coffee consumption., Results: Individuals with non-motor features of prodromal PD had worse objective and subjective cognitive performance relative to men without non-motor features. Cognitive impairment was particularly prevalent among individuals with concurrent hyposmia, pRBD and constipation (multivariate-adjusted OR=3.80; 95% CI 1.52 to 9.47 for objective poor cognitive function; OR=8.71; 95% CI 3.18 to 23.83 for subjective cognitive decline). As expected, both objective (OR=7.91) and subjective (OR=17.42) cognitive impairment were also more common among men with confirmed PD., Conclusions: Our study suggests that cognition is commonly affected in individuals with non-motor prodromal PD features, particularly when multiple of these features are present., Competing Interests: Competing interests: MF received a scholarship from Fundación México en Harvard, A. C; KCH reports no disclosures; SM reports no disclosures; XG received research grants from the National Institutes of Health, outside of this work; AA received a research grant from the Department of Defense related to this work. He has also received research grants from the National Institutes of Health, the Michael J. Fox Foundation, and the National Multiple Sclerosis Society, outside of this work; MS served on the scientific advisory board for CBD Solutions (foundation), has served as a consultant for New Beta Innovation (company) and Harvard University, and is funded by NIH grants NS090259, NS098746, U13NS103523, Department of Defense W81XWH-11-1-0150, the Michael J. Fox Foundation, the Parkinson’s Alliance, the Parkinson’s Foundation, Target ALS Foundation; JHK has received research grants from the National Institutes of Health outside of this work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-motor symptoms are common in Parkinson's disease (PD) and some, including hyposmia, constipation, and REM sleep behavior disorder, often precede the clinical diagnosis., Objective: To assess the relation between combinations of non-motor features and presence of PD among women., Methods: A nested case-control study was conducted among women in the Nurses' Health Study. Women were eligible if they responded to screening questions for constipation and probable REM sleep behavior disorder (pRBD) on a 2012 questionnaire and were under age 85 on January 1, 2012. 87 women with confirmed PD and 14,170 women without PD agreed to participate and completed in 2015 the Brief Smell Identification Test to assess hyposmia, as well as a questionnaire to assess parkinsonism and other non-motor PD features, including depressive symptoms, excessive daytime sleepiness, impaired color vision, and body pain., Results: In age-adjusted logistic models, each non-motor feature was significantly associated with PD, and the odds of PD increased exponentially with the number of features. Women with constipation, pRBD, and hyposmia had an age-adjusted OR for PD of 211 (95% CI 84.2-529) compared to women with none of these features. The odds of having PD rose further with the presence of additional non-motor signs. Comparing women with at least 6 of the 7 features assessed in this study to women with one or none, the age-adjusted OR for PD was 356 (95% CI 113-1126)., Conclusion: Results suggest that these non-motor features could be useful in discriminating PD patients from controls in women, and since they often appear during the prodromal period of PD, their combinations may prove useful for identifying populations at high risk of developing PD.

Objective: To assess the relationship between diet pattern and prodromal Parkinson disease (PD) features., Methods: These analyses include 47,679 participants from the Nurses' Health Study and the Health Professionals Follow-up Study. Since 1986, both cohorts have collected dietary information every 4 years and calculated scores for adherence to different diet patterns, including the alternate Mediterranean diet (aMED) and the Alternative Healthy Eating Index (AHEI). In 2012, participants responded to questions regarding constipation and probable REM sleep behavior disorder. For a subset of 17,400 respondents to the 2012 questionnaire, 5 additional prodromal features of PD were assessed in 2014 to 2015. We used multinomial logistic regression to estimate the association between baseline (1986) diet pattern score quintiles and number of prodromal features (0, 1, 2, or ≥3) in 2012 to 2015. Additional analyses investigated the association between long-term adherence to these dietary patterns over 20 years and prodromal features suggestive of PD., Results: In a comparison of extreme aMED diet quintiles, the odds ratio for ≥3 vs 0 features was 0.82 (95% confidence interval [CI] 0.68-1.00, false discovery rate [FDR]-adjusted p trend = 0.03) at baseline and 0.67 (95% CI 0.54-0.83, FDR- p trend < 0.001) for long-term diet; results were equally strong for the association with AHEI scores. Higher adherence to these diets was inversely associated with individual features, including constipation, excessive daytime sleepiness, and depression., Conclusions: The inverse association between these diet patterns and prodromal PD features is consistent with previous findings and suggests that adherence to a healthy diet may reduce the occurrence of nonmotor symptoms that often precede PD diagnosis., (© 2020 American Academy of Neurology.)

Background: Although there is evidence of shared dysregulated pathways between diabetes and Parkinson's disease, epidemiologic research on an association between the two diseases has produced inconsistent results., Objective: We aimed to assess whether known metabolomic markers of insulin resistance and diabetes are also associated with Parkinson's disease development., Methods: We conducted a nested case-control study among Nurses' Health Study and Health Professionals Follow-up Study participants who had provided blood samples up to twenty years prior to Parkinson's diagnosis. Cases were matched to risk-set sampled controls by age, sex, fasting status, and time of blood collection. Participants provided covariate information via regularly collected cohort questionnaires. We used conditional logistic regression models to assess whether plasma levels of branched chain amino acids, acylcarnitines, glutamate, or glutamine were associated with incident development of Parkinson's disease., Results: A total of 349 case-control pairs were included in this analysis. In the primary analyses, none of the metabolites of interest were associated with Parkinson's disease development. In investigations of the association between each metabolite and Parkinson's disease at different time intervals prior to diagnosis, some metabolites showed marginally significant association but, after correction for multiple testing, only C18 : 2 acylcarnitine was significantly associated with Parkinson's disease among subjects for whom blood was collected less than 60 months prior to case diagnosis., Conclusions: Plasma levels of diabetes-related metabolites did not contribute to predict risk of Parkinson's disease. Further investigation of the relationship between pre-diagnostic levels of diabetes-related metabolites and Parkinson's disease in other populations is needed to confirm these findings.

Objective: To investigate the relationship between physical activity and prodromal features of Parkinson disease that often precede the clinical diagnosis., Methods: Included are participants in 2 well-established cohorts: the Nurses' Health Study and the Health Professionals Follow-up Study. Physical activity was assessed using validated questionnaires at baseline (1986) and every 2 years until 2008. Prodromal features (e.g., constipation, hyposmia, and probable REM sleep behavior disorder [pRBD]) were assessed in 2012-2014., Results: The multivariable-adjusted odds ratio (OR) for having ≥3 prodromal features vs none comparing the highest to the lowest quintile were 0.65 (95% confidence interval [CI] 0.53-0.79; p trend = 0.0006) for baseline physical activity and 0.52 (95% CI 0.35-0.76; p trend = 0.009) for cumulative average physical activity. Considering each feature independently, baseline physical activity was associated with lower odds of constipation (OR 0.78, 95% CI 0.73-0.83; p trend < 0.0001), excessive daytime sleepiness (OR 0.72, 95% CI 0.60-0.86; p trend = 0.002), depressive symptoms (OR 0.82, 95% CI 0.69-0.97; p trend = 0.13), and bodily pain (OR 0.81, 95% CI 0.68-0.96; p trend = 0.03). Similar or stronger associations were observed for cumulative average physical activity, which, in addition, was associated with pRBD (OR 0.85, 95% CI 0.77-0.95; p trend = 0.02). In contrast, neither hyposmia nor impaired color vision was associated with physical activity. Early life physical activity was associated with constipation and, in men only, with the co-occurrence of ≥3 features., Conclusions: The reduced prevalence of prodromal features associated with Parkinson disease in older individuals who were more physically active in midlife and beyond is consistent with the hypothesis that high levels of physical activity may reduce risk of Parkinson disease., (© 2019 American Academy of Neurology.)

Objective: To examine the interaction between APOE genotypes and both treated and untreated hypertension on cognitive function in an updated analysis of Nurses' Health Study (NHS) data., Design: At baseline (1995-2001) and 3 biennial follow-up assessments over ~6 years, cognitive function was assessed., Setting and Participants: 8300 NHS participants aged 70+ years underwent a cognitive battery, which comprised 6 tests including the Telephone Interview for Cognitive Status (TICS) and tests of verbal memory, category fluency, and working memory., Measures: We estimated the mean differences in average cognitive scores across up to 4 assessments using multiple linear regression. We also tested for interaction between APOE e4 allele carrier status and hypertension overall, as well as for apparently untreated and treated hypertension., Results: We confirmed that, compared with those with APOE e3/3 genotype, APOE e4 allele carriers scored lower by 0.55 units on the average TICS score (95%CI:-0.67,-0.43). We also observed a significantly worse average TICS score among women with untreated hypertension compared with women without hypertension (difference = -0.23, 95%CI:-0.37,-0.09), while no significant difference was observed for women with treated hypertension. Significant interaction was detected between the APOE e4 allele and untreated hypertension (p-int = 0.02 for the TICS; p-int = 0.045 for global score), but not with treated hypertension. Specifically, compared with normotensive women with the APOE e3/3 genotype, APOE e4 allele carriers with treated hypertension scored lower by 0.50 units (95%CI:-0.69,-0.31); however, the APOE e4 allele carriers with untreated hypertension scored lower by 1.02 units on the TICS score (95%CI:-1.29, -0.76). This interaction of APOE e4 and untreated hypertension was also consistently observed for the global score., Conclusions: Women with hypertension and at least one APOE e4 allele had worse average cognitive function compared with women without hypertension with the e3/3 genotype; this difference was amplified among APOE e4 allele carriers with untreated hypertension., Competing Interests: Dr. Gary Curhan reports grants and personal fees from Allena Pharmaceuticals, personal fees from Shire, royalties for his work as an author and section editor from UpToDate, and personal fees from RenalGuard, outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have completed the ICMJE uniform disclosure form and declare: no support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

Background: Several non-motor features may individually contribute to identify prodromal Parkinson's disease (PD), but little is known on how they interact., Methods: We conducted a case-control study nested within the Health Professionals Follow-up Study in a large cohort of men age 40-75 at recruitment in 1986. Cases (n=120) had confirmed PD, were<85 in January 2012, returned a 2012 questionnaire with questions on probable rapid eye movement sleep behaviour disorder (RBD) and constipation sent to all cohort participants and completed in 2014 the Brief Smell Identification Test and a questionnaire assessing parkinsonism and other non-motor PD features (including depressive symptoms, excessive daytime sleepiness, impaired colour vision and body pain). Controls (n=6479) met the same criteria as cases, except for the PD diagnosis., Results: Concurrent constipation, probable RBD and hyposmia were present in 29.3% of cases and 1.1% of controls, yielding an age-adjusted OR of 160(95%CI 72.8to353) for three features versus none. The odds of PD increased exponentially with additional non-motor features (OR for 6-7 features versus none: 1325; 95%CI333to5279). Among men without PD, the number of non-motor features was associated with odds of parkinsonism (OR for 6-7 features versus none: 89; 95%CI21.2to375). We estimated that in a population with a prodromal PD prevalence of 2%, concurrent constipation, probable RBD and hyposmia would have a maximum sensitivity of 29% and a positive predictive value (PPV) of 35%. The PPV could increase up to 70% by including additional features, but with sharply decreased sensitivity., Conclusions: Concurrent constipation, probable RBD and hyposmia are strongly associated with PD. Because these features often precede motor symptoms and their co-occurrence could provide an efficient method for early PD identification., Competing Interests: Competing interest: XG has served on committees of the Sleep Research Society, American Academy of Sleep Medicine, and Parkinson Study Group and received funding from the NIH/NINDS. MAS served on the scientific advisory board for CBD Solutions (foundation), has served as a consultant for New Beta Innovation (company) and Harvard University and is funded by NIH grants NS090259, NS098746, U13NS103523, Department of Defense W81XWH-11-1-0150, the Michael J. Fox Foundation, the Parkinson’s Alliance, the Parkinson’s Foundation and Target ALS Foundation. AA received a research grant from the Department of Defense related to this work. He has also received research grants from the National Institutes of Health, the Michael J. Fox Foundation and the National Multiple Sclerosis Society, outside of this work., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Previous studies regarding the association between restless legs syndrome (RLS) and Parkinson's disease (PD) have produced contradictory results. However, the time frame between them has varied across these studies, and also, the longitudinal trajectroy of RLS symptoms has not been considered., Objective: To investigate if transient or continuous/recurrent RLS identified by questionnaire are associated with the premotor symptoms of PD., Methods: The study population comprised 16,636 men in the Health Professional Follow-Up Study, who answered questions regarding RLS symptoms in both 2002 and 2008, and were not diagnosed with PD. Outcomes were self-reported constipation, possible REM sleep behavior disorder (pRBD) in 2012 and smell identification test score in 2014., Results: RLS was associated with increased odds of constipation, but only continuous/recurrent RLS status was associated with higher odds of having pRBD. RLS was not significantly associated with olfactory scores., Conclusion: In this large-scale longitudinal study, we found moderate associations between the presence of RLS and increased odds of having constipation and pRBD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Prior work on appendectomy and PD has produced mixed results. In this study we examined whether history of self-reported appendectomy was related to risk of incident Parkinson's disease in the Nurses' Health Study and the Health Professionals Follow-up Study., Methods: We used the Cox proportional hazards model to estimate the hazard ratio of Parkinson's disease associated with self-report of appendectomy in men and women. Among women, we estimated the hazard ratio of Parkinson's disease associated with appendectomy for appendicitis and incidental appendectomy., Results: In pooled analyses, self-report of any appendectomy was not related to Parkinson's disease risk: the hazard ratio of Parkinson's disease comparing participants who reported any appendectomy with those who did not was 1.08 (95% confidence interval, 0.94-1.23). In women, appendectomy for appendicitis, but not incidental appendectomy, was associated with a modestly elevated risk of Parkinson's disease (hazard ratio, 1.23 [95% confidence interval, 1.00-1.50])., Conclusions: Overall, this study suggests limited to no association between appendectomy and Parkinson's disease risk. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Introduction: Higher urate concentrations have been associated with a lower risk of developing Parkinson's disease (PD) and with slower rates of clinical decline in PD patients. Whether these associations reflect a neuroprotective effect of urate is unclear. Our objective was to assess whether genetic variants that modify circulating urate levels are also associated with altered PD risk., Methods: Participants were from three large ongoing cohort studies: the Nurses' Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Cancer Prevention Study II Nutrition Cohort (CPS-IIN). We examined associations between single nucleotide polymorphisms (SNPs) in SLC2A9 and other genes involved in urate transport and PD risk using conditional logistic regression among 1451 cases and 3135 matched controls. We assessed associations between SNPs and plasma urate levels in a subset of 1174 control participants with linear regression models., Results: We found the expected associations between SNPs in SLC2A9 and plasma urate levels among men and women; however, SNPs in other genes tended not to be associated with urate. Each SNP in SLC2A9 explained less than 7% of the variance in plasma urate. We did not find significant associations between the SNPs in SLC2A9 and PD risk among men or women., Conclusion: Our results do not support an association between genetic variants associated with circulating urate levels and risk of PD, but larger investigations are needed to determine whether the modest genetic effects on blood urate contribute to predict PD risk., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To prospectively examine how selected lifestyle factors and family history of Parkinson disease (PD) combine to determine overall PD risk., Methods: We derived risk scores among 69,968 women in the Nurses' Health Study (NHS) (1984-2012) and 45,830 men in the Health Professionals Follow-up Study (HPFS) (1986-2012). Risk scores were computed for each individual based on the following factors previously associated with PD risk: total caffeine intake, smoking, physical activity, and family history of PD for the NHS, and additionally total flavonoid intake and dietary urate index for the HPFS. Hazard ratios were estimated using Cox proportional hazards models. In addition, we performed tests of interactions on both the multiplicative and additive scale between pairs of risk factors., Results: We documented 1,117 incident PD cases during follow-up. The adjusted hazard ratios comparing individuals in the highest category of the reduced risk score to those in the lowest category were 0.33 (95% confidence interval: 0.21, 0.49; p trend < 0.0001) in the NHS and 0.18 (95% confidence interval: 0.10, 0.32; p trend < 0.0001) in the HPFS. Results were similar when applying the risk scores computed by summing the predictors weighted by the log of their individual effect sizes on PD risk in these cohorts. Additive interaction was present between no family history of PD and caffeine in men and between caffeine and physical activity in women., Conclusions: Our results suggest that known protective factors for PD tend to have additive or superadditive effects, so that PD risk is very low in individuals with multiple protective risk factors., (© 2018 American Academy of Neurology.)

Background: Previous research has shown relatively diminished medial prefrontal cortex activation and heightened psychophysiological responses during the recollection of personal events in post-traumatic stress disorder (PTSD), but the origin of these abnormalities is unknown. Twin studies provide the opportunity to determine whether such abnormalities reflect familial vulnerabilities, result from trauma exposure, or are acquired characteristics of PTSD., Methods: In this case-control twin study, 26 male identical twin pairs (12 PTSD; 14 non-PTSD) discordant for PTSD and combat exposure recalled and imagined trauma-unrelated stressful and neutral life events using a standard script-driven imagery paradigm during functional magnetic resonance imaging and concurrent skin conductance measurement., Results: Diminished activation in the medial prefrontal cortex during Stressful v. Neutral script-driven imagery was observed in the individuals with PTSD, relative to other groups., Conclusions: Diminished medial prefrontal cortex activation during Stressful v. Neutral script-driven imagery may be an acquired characteristic of PTSD. If replicated, this finding could be used prospectively to inform diagnosis and the assessment of treatment response.

Background: Caffeine intake has been inversely associated with Parkinson's disease (PD) risk. This relationship may be modified by polymorphisms of glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A) and cytochrome P450 1A2 (CYP1A2), but the results of previous studies have been inconsistent., Method: We examined the interaction of caffeine intake with GRIN2A-rs4998386 and CYP1A2-rs762551 polymorphisms in influencing PD risk among 829 incident cases of PD and 2,754 matched controls selected among participants in the following 3 large prospective ongoing cohorts: the Nurses' Health Study, the Health Professionals' Follow-up Study, and the Cancer Prevention Study II Nutrition Cohort. Matching factors included cohort, birth year, source of DNA, date of DNA collection, and race. Relative risks and 95% confidence intervals were estimated using conditional logistic models. Interactions were tested both on the multiplicative scale and on the additive scale., Results: Overall, caffeine intake was associated with a lower PD risk (adjusted relative risk for highest versus lowest tertile = 0.70; 95% confidence interval, 0.57-0.86; p < .001). In analyses stratified by the GRIN2A-rs4998386 genotype, the multivariable-adjusted relative risk of PD comparing the highest to the lowest tertile of caffeine was 0.69 (95% confidence interval, 0.55-0.88; p < .01) among individuals homozygous for the C allele, and 0.85 (95% confidence interval, 0.55-1.32; p = .47; p RERI  = .43) among carriers for the T allele. Interactions between caffeine and GRIN2A were not significant in either the multiplicative or additive scales. We also did not observe significant interactions for CYP1A2-rs762551 and incident PD risk., Conclusion: Our findings do not support the hypothesis of an interaction between the GRIN2A-rs4998386 or CYP1A2-rs762551 polymorphism and caffeine intake in determining PD risk. © 2018 International Parkinson and Movement Disorder Society., (© 2018 International Parkinson and Movement Disorder Society.)

Objective: To prospectively examine the association between commonly consumed dairy products and the risk of Parkinson disease (PD) in women and men., Methods: Analyses were based on data from 2 large prospective cohort studies, the Nurses' Health Study (n = 80,736) and the Health Professionals Follow-up Study (n = 48,610), with a total of 26 and 24 years of follow-up, respectively. Both US-based studies were conducted via mailed biennial questionnaires. Dietary intake was assessed with food frequency questionnaires administered repeatedly over the follow-up period. Incident cases of PD (n = 1,036) were identified via questionnaires and subsequently confirmed by reviewing medical records. We also conducted a meta-analysis to combine our study with 3 previously published prospective studies on total milk intake and PD risk and 1 study on total dairy intake and PD risk., Results: While total dairy intake was not significantly associated with PD risk in our cohorts, intake of low-fat dairy foods was associated with PD risk. The pooled, multivariable-adjusted hazard ratio (HR) comparing people who consumed at least 3 servings of low-fat dairy per day to those who consumed none was 1.34 (95% confidence interval [CI] 1.01-1.79, p trend = 0.04). This association appeared to be driven by an increased risk of PD associated with skim and low-fat milk (HR 1.39, 95% CI 1.12-1.73, p trend <0.01). Results were similar in women and men ( p for heterogeneity >0.05). In the meta-analysis, the pooled relative risk comparing extreme categories of total milk intake was 1.56 (95% CI 1.30-1.88), and the association between total dairy and PD became significant (HR 1.27, 95% CI 1.04-1.55)., Conclusions: Frequent consumption of dairy products appears to be associated with a modest increased risk of PD in women and men., (© 2017 American Academy of Neurology.)

Background: Caffeine intake has been associated with a lower risk of Parkinson's disease (PD). This association is robust in men, but inconsistent in women due to a possible interaction with post-menopausal hormone (PMH) use., Objective: To (1) evaluate the association between caffeine intake and PD risk and (2) assess potential effect modification of the association by PMH use among women., Methods: We examined associations between caffeine intake and incident PD risk in the Nurses' Health Study (NHS) (N = 121,701 women) and the Health Professionals Follow-up Study (HPFS) (N = 51,529 men). Dietary data on coffee and caffeine from other sources were collected every four years using a validated semi-quantitative food frequency questionnaire for both cohorts. Information on lifestyle and incident PD diagnosis was updated biennially and PD diagnoses were confirmed by medical record review. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards models., Results: We documented a total of 1,219 PD cases over the follow-up period. The multivariable-adjusted HR comparing the highest to lowest quintile of caffeine intake was 0.50 (95% CI: 0.37, 0.68; Ptrend<0.0001) in the HPFS. Among women, there was a suggestion of an interaction between coffee intake and PMH use (P = 0.08). In the pooled analyses combining men and women who have never used PMH, the risk of PD was lower as coffee intake increased (Ptrend<0.001)., Conclusions: Our results support previous findings that increased caffeine intake may be associated with a decreased PD risk in men and women who have never used PMH.

Introduction: Oxidative stress is proposed to be one of the potential mechanisms leading to neurodegeneration in Parkinson's disease. However, previous epidemiologic studies investigating associations between antioxidant vitamins, such as vitamins E and C and carotenoids, and PD risk have produced inconsistent results., Objective: The objective of this work was to prospectively examine associations between intakes of antioxidant vitamins, including vitamins E and C and carotenoids, and PD risk., Methods: Cases were identified in two large cohorts: the Nurses' Health Study and the Health Professionals Follow-up Study. Cohort members completed semiquantitative food frequency questionnaires every 4 years., Results: A total of 1036 PD cases were identified. Dietary intakes of vitamin E and carotenoids were not associated with PD risk; the multivariable-adjusted relative risk comparing extreme intake quintiles were 0.93 (95% confidence interval: 0.75-1.14) and 0.97 (95% confidence interval: 0.69-1.37), respectively. Dietary vitamin C intake was significantly associated with reduced PD risk (relative risk: 0.81; 95% confidence interval: 0.65-1.01; p trend , 0.01); however, this result was not significant in a 4-year lag analysis. For vitamins E and C, intake from foods and supplements combined were also unrelated to PD risk., Conclusions: Our results do not support the hypothesis that intake of antioxidant vitamins reduces the risk of PD. © 2016 International Parkinson and Movement Disorder Society., (© 2016 International Parkinson and Movement Disorder Society.)

Objectives: First, to document a broad range of functional outcomes of bilateral implantation for young children through young adults at a postoperative point at which stable outcomes could be expected. Second, to evaluate the relationship between functional outcomes and age at bilateral implantation and time between implants., Design: A study-specific questionnaire was administered to parents in an interview 3.5 years or more after sequential (n = 50) or simultaneous (n = 7) implants were received by their child. Median age at bilateral implantation was 4.1 years (range 0.7 to 19.8) and time between implants was 2.7 years (range 0.0 to 16.7)., Results: On the basis of parent report, 72% of the sequentially implanted children and young adults found it easy/only "a bit difficult" to adapt to the second implant, and were "happily wearing both implants together most of the time" by 6 months or before; 26% had not adapted, with both implants not worn most of the time or worn as a parental requirement. Seventy-two percent of sequentially implanted children and young adults had a positive attitude toward the second implant, including 9 whose early postoperative attitude was negative or neutral. The majority of children and young adults preferred bilateral implants (70%) and used the two full time (72%), while around half demonstrated similar performance with each implant alone. The proportion of nonusers or very minimal users of the second implant was just 9%. Eighty-eight percent of parents reported superior performance with bilateral versus a unilateral implant (n = 40), or that only bilateral implants were worn (n = 10) so performance could not be compared. The most commonly identified areas of superiority were localization, less need for repetition, and increased responsiveness. In balancing risks and costs with benefits, most parents (86%) considered the second implant worthwhile. Regarding the relationship between outcomes and demographic factors, the group achieving similar performance with each implant alone was younger at bilateral implantation and had less time between implants, and the group bilaterally implanted before 3.5 years of age (who also had less than 2 years between implants) had a higher proportion of positive outcomes on all functional outcome measures., Conclusion: Overall, the results indicate primarily positive functional outcomes for children and young adults receiving bilateral implants at all ages, including when the delay between implants is long. The results are important for evidence-based preoperative counseling, which helps families to make informed decisions and develop appropriate expectations. The results are also important for the development of clinical management practices that support and encourage the minority of recipients who have difficulty adapting to bilateral implants or achieving full-time use.

Background: Coinfection with human immunodeficiency virus (HIV) may modify the risk of transmitting tuberculosis. Some previous investigations suggest that patients coinfected with HIV and tuberculosis are less likely to transmit infection, whereas others do not support this conclusion. Here, we estimated the relative risk of tuberculosis transmission from coinfected patients compared to HIV-negative patients with tuberculosis., Methods: Between September 2009 and August 2012, we identified and enrolled 4841 household contacts of 1608 patients with drug-sensitive tuberculosis in Lima, Peru. We assessed the HIV status and CD4 counts of index patients, as well as other risk factors for infection specific to the index patient, the household, and the exposed individuals. Contacts underwent tuberculin skin testing to determine tuberculosis infection status., Results: After adjusting for covariates, we found that household contacts of HIV-infected tuberculosis patients with a CD4 count ≤250 cells/µL were less likely to be infected with tuberculosis (risk ratio = 0.49 [95% confidence interval, .24-.96]) than the contacts of HIV-negative tuberculosis patients. No children younger than 15 years who were exposed to HIV-positive patients with a CD4 count ≤250 cells/µL were infected with tuberculosis, compared to 22% of those exposed to non-HIV-infected patients. There was no significant difference in the risk of infection between contacts of HIV-infected index patients with CD4 counts >250 cells/µL and contacts of index patients who were not HIV-infected., Conclusions: We found a reduced risk of tuberculosis infection among the household contacts of patients with active tuberculosis who had advanced HIV-related immunosuppression, suggesting reduced transmission from these index patients.

Objectives: To compare the listening effort expended by adolescents and young adults using implants versus their peers with normal hearing when these two groups are achieving similar speech perception scores. The study also aimed to compare listening effort expended by adolescents and young adults with bilateral cochlear implants when using two implants versus one., Methods: Eight participants with bilateral cochlear implants and eight with normal hearing aged 10-22 years were included. Using a dual-task paradigm, participants repeated consonant-nucleus-consonant (CNC) words presented in noise and performed a visual matching task. Signal-to-noise ratios were set individually to ensure the word perception task was challenging but manageable for all. Reduced performance on the visual task in the dual-task condition relative to the single-task condition was indicative of the effort expended on the listening task., Results: The cochlear implant group, when using bilateral implants, expended similar levels of listening effort to the normal hearing group when the two groups were achieving similar speech perception scores. For three individuals with cochlear implants, and the group, listening effort was significantly reduced with bilateral compared to unilateral implants., Discussion: The similar amount of listening effort expended by the two groups indicated that a higher signal-to-noise ratio overcame limitations in the auditory information received or processed by the participants with implants. This study is the first to objectively compare listening effort using two versus one cochlear implant. The results provide objective evidence that reduced listening effort is a benefit that some individuals gain from bilateral cochlear implants.

Background: Previous research suggests that individuals with posttraumatic stress disorder (PTSD) preferentially attend to trauma-related emotional stimuli and have difficulty completing unrelated concurrent tasks. Compared to trauma-exposed control groups, individuals with PTSD also exhibit lower rostral anterior cingulate cortex (rACC) activation during tasks involving interference from trauma-related stimuli. However, it is not clear whether relatively diminished rACC activation in PTSD also occurs during interference tasks involving trauma-unrelated emotional stimuli. The present study employed functional magnetic resonance imaging (fMRI) and an interference task that involves emotional facial expressions and elicits rACC activation in healthy participants., Findings: While performing a trauma-unrelated emotional interference task, participants with PTSD (n=17) showed less rACC activation than trauma-exposed non-PTSD (TENP; n=18) participants. In the PTSD group, rACC activation was negatively correlated with the severity of re-experiencing symptoms. The two groups did not significantly differ on behavioral measures (i.e., response times and error rates)., Conclusions: These findings suggest that relatively diminished rACC activation in PTSD can be observed in interference tasks involving trauma-unrelated emotional stimuli, indicating a more general functional brain abnormality in this disorder. Future neuroimaging studies need not employ trauma-related stimuli in order to detect rACC abnormalities in PTSD.

Objective: To classify adaptation difficulties, or lack thereof, experienced by a clinical population of young bilateral cochlear implant recipients., Method: Forty-six of the first 48 children sequentially or simultaneously implanted at ≤3.5 years at the Melbourne Clinic participated. Classification into categories was based on daily use of both implants at 2 months post-switch-on, with follow-up information obtained at 12 months., Results: The 37 Category 1 children wore both implants full time at 2 months, and 35 still did so at 12 months. The two Category 2 children used both implants 4 hours daily at 2 months, but achieved full-time use within 12 months. The five Category 3 children used both implants for ≤1 hour, with only three achieving full-time use within 12 months. The two Category 4 children did not use two implants at 2 months, and one still did not wear both implants at 12 months. There were weak/modest but significant relationships between category and each of time between implants and age at bilateral implantation., Discussion: Ninety-five percent of simultaneously and 70% of sequentially implanted children demonstrated full-time use within 2 months, and nearly all continued to do so at 12 months. Full-time use maximizes opportunities to develop listening skills. Monitoring device use is necessary for all children, especially when significant change occurs. For those experiencing difficulty in adapting, bilateral implant use usually increased over 12 months. Pre-operative counselling must include discussion of possible adaptation difficulties and raise the potential negative influence of age at bilateral implantation and time between implants.

Objective: Neuroimaging studies have revealed functional abnormalities in the anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal of this study was to determine whether hyperresponsivity of the dorsal anterior cingulate in PTSD is an acquired characteristic or a familial risk factor., Method: Using a case-control twin design, the authors studied combat-exposed veterans with PTSD (N=12) and their identical combat-unexposed co-twins (N=12), as well as combat-exposed veterans without PTSD (N=14) and their identical combat-unexposed co-twins (N=14). Participants underwent functional MRI during completion of the Multi-Source Interference Task, which reliably activates the dorsal anterior cingulate., Results: Combat-exposed veterans with PTSD and their unexposed co-twins had significantly greater activation in the dorsal anterior cingulate and tended to have larger response time difference scores, as compared to combat-exposed veterans without PTSD and their co-twins. Dorsal anterior cingulate activation in the exposed twins was positively correlated with their PTSD symptom severity. Dorsal anterior cingulate activation in the unexposed twins was positively correlated with their combat-exposed co-twins' PTSD symptom severity, but not with depression or alcohol use severity in the combat-exposed co-twins., Conclusions: Hyperresponsivity in the dorsal anterior cingulate appears to be a familial risk factor for the development of PTSD following psychological trauma.

Post-traumatic stress disorder (PTSD) is a significant problem that can affect individuals who have been exposed to a traumatic event or events, such as combat, violent crime or childhood abuse. Over the past several years, neuroimaging studies of PTSD have focused on elucidating the brain circuits that mediate this disorder. In this article, we will briefly introduce some of the methods used in functional neuroimaging studies of PTSD. We will then review functional neuroimaging studies that have reported significant findings in the amygdala, medial prefrontal cortex, hippocampus and insula. Finally, we will suggest future directions for research.

Background: Posttraumatic stress disorder (PTSD) is marked by intrusive, chronic, and distressing memories of highly emotional events. Previous research has highlighted the role of the amygdala and its interactions with the hippocampus in mediating the effect of enhanced memory for emotional information in healthy individuals. As the functional integrity of these regions may be compromised in PTSD, the current study examined the neural correlates of emotional memory in PTSD., Methods: We used functional magnetic resonance imaging and an event-related subsequent memory recognition paradigm to study amygdala and hippocampus activation in 18 individuals with PTSD and 18 trauma-exposed non-PTSD control participants., Results: Memory enhancement for negative, relative to neutral, pictures was found across all subjects, without significant differences between groups. Relative to the trauma-exposed non-PTSD group, the PTSD group showed exaggerated amygdala activation during the encoding of negative versus neutral pictures. This effect was even more pronounced when the analysis included data from only pictures that were subsequently remembered 1 week later. In the PTSD group, degree of amygdala activation during the encoding of negative versus neutral pictures was positively correlated with hippocampal activation and current PTSD symptom severity. The PTSD group also showed exaggerated hippocampal activation in response to negative pictures that were remembered versus forgotten. Finally, hippocampal activation associated with the successful encoding of negative relative to neutral pictures was significantly greater in the PTSD group., Conclusions: Exaggerated amygdala activation during the encoding of emotionally negative stimuli in PTSD is related to symptom severity and to hippocampal activation., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This study aimed to determine if adolescents/young adults gained additional perceptual benefit from sequential bilateral cochlear implants within 12 months, and to document adaptation to the second implant. Assessments comprised a pediatric version of The Speech, Spatial and Qualities of Hearing Scale (SSQ), anecdotal reports of device use and daily listening, and the Adaptive Spondee Discrimination Test (AdSpon). All nine participants achieved full-time use of, a preference for, and superior daily listening with, bilateral implants. Eight participants were comfortable using the second implant alone, and two achieved similar daily listening with either implant alone. SSQ ratings were higher post-operatively for the majority of participants. AdSpon performance was superior bilaterally for five participants with noise ipsilateral to the first implant, but not contralateral. Unilateral performance with either implant was similar for one participant. A second implant may provide additional benefit up to 19 years of age, even with congenital hearing loss and >16 years between implants. Families and clinicians should understand the aspects of second-implant candidacy and post-operative use that are unique to adolescents/young adults.

For children to gain maximum benefit from a second, bilateral cochlear implant clinicians need to be aware of the special needs of the family and child, and to adapt their clinical management appropriately. This article describes how the situation of the family considering a second implant is different, and how the decision to be made differs from that for a first implant. The information specific to sequential implants that should be provided so families can make an informed decision is reviewed. Programming issues unique to sequential bilateral cochlear implants are discussed. Finally, information is provided on how children may respond post-operatively, and what can be done to promote bilateral device use and the development of listening skills with the new implant., (Copyright 2008 John Wiley & Sons, Ltd.)

This study was performed to determine the degree of shrinkage over time in nipple projection after reconstruction. Nipple-areolar reconstruction was performed using the modified Anton-Hartrampf technique, and pigmentation was achieved with tattooing. This study looked at 28 consecutive patients with nipple reconstruction performed at The Milton S. Hershey Medical Center of the Penn State Geisinger Health Systems between September 1989 and November 1993. Two patients were lost to follow-up and 3 patients died of breast cancer. Thus, 23 patients and a total of 32 nipples were investigated. Initial measurements of nipple projection were taken 2 weeks postoperatively. Patients were followed an average of 38.7 months (range, 11-66 months). Ten patients (18 nipples) had tissue expansion and implantation for breast mound reconstruction. Thirteen patients (14 nipples) had autologous breast mound reconstruction. The mean decrease in projection of the tissue expansion and implantation group was 76.7+/-9.7%. The mean decrease in projection of the autologous reconstruction group was 64.3+/-12.1%. The mean decrease in projection for the entire group was 71.3+/-21.9%. Comparison between the two groups using a two-sample t-test showed p = 0.0047. The authors concluded that there is a significant reduction in nipple projection over time using the modified Anton-Hartrampf technique regardless of the type of breast mound reconstruction. In addition, their results also indicated that nipple projection on the breast mound reconstructed with an autologous musculocutaneous flap technique achieved a better long-term outcome. This study is potentially helpful in planning the initial size of the reconstructed nipple papule to match the opposite normal nipple. Additional studies need to be performed on other types of nipple-areolar reconstruction.

The cyclops flap is a little-known but not forgotten alternative in chest-wall reconstruction for women. Female patients having a large, pendulous breast with a contralateral adjacent defect may be reconstructed by this technique. The flap derives its name from the repositioning of the remaining nipple to the center of the chest. The design of the flap is described. By knowing the width and length of the defect, the surgeon can design incisions on the remaining breast tissue that will allow the flap to advance easily, reliably filling the defect. The flap is an axial-pattern flap nourished by the lateral thoracic artery and the variable external mammary artery. This arterial inflow will serve the medial portion of the flap. The operation is straightforward and predictable. In using this design scheme three times in the last two years, there have been no complications. There is little discomfort after surgery. Occasionally, patients will benefit from this reconstructive option.

Imaging of breast implants has assumed more importance in medicine than ever before. Radiologists and surgeons alike have struggled to accurately identify folds in prostheses, rupture of prostheses, and migration of gel. Here we present two patients with an unusual presentation of masses within the gel of ruptured silicone gel-containing prostheses. In one instance, the mass was an organized hematoma. In the other, two round, calcified masses were found that we presume are hematomas that have become calcified over time. Radiologists and surgeons identifying spherical or ovoid masses seemingly within gel breast prostheses should entertain the possibility that the mass represents an organized hematoma and that the implant is ruptured.

Study Objective: To identify the physical properties of the materials most easily located in subcutaneous tissue through the use of conventional ultrasound., Methods: High-resolution real-time sonography was performed by a credentialed sonographer on a chicken breast impregnated with five objects-a metal paper clip, a wooden toothpick, a plastic coffee stirrer, a shard of glass, and an 18-gauge needle. Transducer frequencies ranging from 3.5 to 7.5 MHz with linear, curvilinear, and sector-scanning formats were used. All images were interpreted by a staff attending radiologist with other study authors present. The chicken breast was then subjected to radiography for comparison., Results: Wood yielded the strongest acoustic shadow; plastic had the next-best acoustic shadowing. The 7.5-MHz probe yielded its best resolution at shallow depths, whereas the 5-MHz probe was best at greater depths., Conclusion: We conclude that ultrasonography is an excellent technique for the localization and retrieval of nonradiopaque foreign objects in the superficial subcutaneous tissue. It should be given consideration for use in the removal of nonradiopaque superficial foreign objects when conventional radiographic techniques are not effective.

Obesity is a heterogeneous family of disorders with several overlapping contributory causes. It markedly increases morbidity and mortality from many different diseases, and affected patients are the targets of severe, negative social pressures. Physicians traditionally have been unsuccessful in treating obesity. The usual physician's office approach to obese persons is to conduct a good history and physical examination and then prescribe a 4200-J diet sheet and monthly or biomonthly office visits. This approach usually produces mild and ephemeral weight loss. Some patients quickly become disillusioned and manifest as appointment "no-shows." The doctor often bemoans the lack of will power of his or her ex-patient. Such patients and their physicians would be better served by referral to a professional weight management program, in which a coordinated team approach has proven effective and persistent in body weight control. "He that putteth his trust in the Lord shall be made fat."

The repair of a ventral hernia in an obese patient presents an interesting clinical challenge. We retrospectively reviewed the charts of 55 patients who, over a 12-year period from 1983 to 1995, concomitantly underwent both ventral herniorrhaphy and panniculectomy or abdominoplasty. In six of 55 patients, the hernia was recurrent. Forty-six patients had primary abdominal wall hernias or diastasis recti. Nineteen of 55 patients had weight greater than 200 lbs. This last subset of patients had a significantly higher incidence of complications, such as seroma, cellulitis, and persistent wound drainage. In our 55 patients, we experienced only two hernia recurrences (3.6%) during an average patient follow-up of 53 weeks. From this experience, we believe that simultaneous ventral hernia repair and panniculectomy is a safe and efficacious approach to these two problems so commonly found in the obese patient. Patients with a preoperative weight greater than 200 lbs can be expected to have a greater risk of wound complications. In all cases, the wounds eventually healed with no long-term sequelae.