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Abstract The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is an observer-reported outcome measure that has been widely used in interventional studies to assess changes in hyperphagic behaviors in individuals with Prader-Willi syndrome (PWS). However, HQ-CT scores in the wider PWS population and the general population have not been reported. Here we report HQ-CT scores from more than 400 individuals with PWS and 600 typical individuals, aged 5–26. Overall, HQ-CT scores were significantly higher in those with PWS compared to typically developing individuals at all ages evaluated. In addition, while HQ-CT scores in the typically developing population decreased with age, scores increased with age in PWS. To further understand the variability of HQ-CT scores in the PWS population, semi-structured interviews were conducted with caregivers of a small subset of adults with PWS who had unexpectedly low HQ-CT scores. These caregivers reported that strict adherence to a food routine, food security measures and supervised food preparation reduced the frequency and intensity of hyperphagic behaviors measured by HQ-CT. Thus, hyperphagic behaviors are captured by the HQ-CT for most individuals with PWS, but for some individuals residing in settings with highly structured food routines, HQ-CT scores may not fully reflect the extent of PWS-associated hyperphagia.

Abstract Long interspersed element 1 (LINE-1) open reading frame 1 protein (ORF1p) expression is a common feature of many cancer types, including high-grade serous ovarian carcinoma (HGSOC). Here, we report that ORF1p is not only expressed but also released by ovarian cancer and primary tumor cells. Immuno-multiple reaction monitoring-mass spectrometry assays showed that released ORF1p is confidently detectable in conditioned media, ascites, and patients’ plasma, implicating ORF1p as a potential biomarker. Interestingly, ORF1p expression is detectable in fallopian tube (FT) epithelial precursors of HGSOC but not in benign FT, suggesting that ORF1p expression in an early event in HGSOC development. Finally, treatment of FT cells with DNA methyltransferase inhibitors led to robust expression and release of ORF1p, validating the regulatory role of DNA methylation in LINE-1 repression in non-tumorigenic tissue.

Abstract Introduction Prader–Willi syndrome (PWS) is a rare, genetic, neurodevelopmental syndrome associated with hyperphagia and early onset obesity, growth and sex hormone insufficiencies, mild-to-moderate intellectual disability, and behavioral challenges such as compulsivity, anxiety, skin picking, social skills deficits and temper outbursts. Given high rates of psychiatric comorbidity and potential risk factors for suicide in PWS, this study sought a first estimate of the prevalence of suicidal ideation (SI) and attempts (SA) in the PWS population and any characteristics associated with suicidality in this population. Methods Using the Global Prader-Willi Syndrome Registry, we included all participants who had answered a question about SI. We examined the most recent data from the surveys about social, economic, and demographic factors, genetic subtype, and psychiatric symptoms and treatments. A chi-square analysis was used to compare registry participants who reported SI to those without reported SI. Results From 750 included survey respondents, 94 (12.5%) endorsed some history of SI. Of these, 25 (26.6%) also reported a history of SA, with an average age of 16.25 years at their first attempt. Those with a history of SI were predominantly male and adult age, and had higher rates of aggression and psychiatric comorbidities, therapies, and medications. Conclusions This study indicates that the rate of SI and SA in PWS is comparable to the general population, and that suicide attempts in PWS typically begin in middle-teenage years. Despite unique challenges, individuals with PWS and their caregivers should be included in screens and psychoeducation for suicide and mental health concerns.

Abstract Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org ) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC “Behavior Outcomes Working Group” sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive–compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS.

Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models.

BackgroundNatural language processing (NLP) offers significantly faster variable extraction compared to traditional human extraction but cannot interpret complicated notes as well as humans can. Thus, we hypothesized that an “NLP-assisted” extraction system, which uses humans for complicated notes and NLP for uncomplicated notes, could produce faster extraction without compromising accuracy. ObjectiveThe aim of this study was to develop and pilot an NLP-assisted extraction system to leverage the strengths of both human and NLP extraction of prostate cancer Gleason scores. MethodsWe collected all available clinical and pathology notes for prostate cancer patients in an unselected academic biobank cohort. We developed an NLP system to extract prostate cancer Gleason scores from both clinical and pathology notes. Next, we designed and implemented the NLP-assisted extraction system algorithm to categorize notes into “uncomplicated” and “complicated” notes. Uncomplicated notes were assigned to NLP extraction and complicated notes were assigned to human extraction. We randomly reviewed 200 patients to assess the accuracy and speed of our NLP-assisted extraction system and compared it to NLP extraction alone and human extraction alone. ResultsOf the 2051 patients in our cohort, the NLP system extracted a prostate surgery Gleason score from 1147 (55.92%) patients and a prostate biopsy Gleason score from 1624 (79.18%) patients. Our NLP-assisted extraction system had an overall accuracy rate of 98.7%, which was similar to the accuracy of human extraction alone (97.5%; P=.17) and significantly higher than the accuracy of NLP extraction alone (95.3%; P

ObjectivesPrader-Willi syndrome (PWS) is a rare genetic disorder characterized by maladaptive behaviors, amongst which hyperphagia is a life-long concern for individuals with PWS and their caregivers. The current study examined the contribution of hyperphagia and other factors to caregiver burden across lifespan, in 204 caregivers of individuals with PWS living in the US, using the Zarit Burden Interview (ZBI) and the hyperphagia questionnaire (HQ-CT).ResultsWe found a strong relationship between ZBI and HQ-CT especially in individuals with PWS older than 4 y and showed that HQ-CT scores of individuals with PWS is positively correlated with ZBI scores of their caregivers. The weight status of individuals with PWS was not associated with HQ-CT and ZBI scores, except for obese individuals who had significantly higher HQ-CT scores when compared to normal weight PWS individuals. We looked at PWS symptoms and care-related issues that impacted individuals and caregivers the most. We found that care-related tasks had the biggest negative impact on caregivers of children aged 0-4 y, whereas anxiety, temper tantrums, and oppositional behaviors of older individuals with PWS had the biggest impact on their caregivers concomitant with their high caregiver burden. Finally, we assessed the variability of HQ-CT and ZBI over 6 months in a subgroup of 83 participants. Overall, neither measure differed between 6 months and baseline. Most individual's absolute HQ-CT score changes were between 0-2 units, whereas absolute ZBI score changes were between 0-6 points. Changes in the caregiver's or individual's life had little or no effect on HQ-CT and ZBI scores.ConclusionsThis study demonstrates a relationship between hyperphagia and caregiver burden and sheds light on predominant symptoms in children and adolescents that likely underly PWS caregiver burden. The stability and relationship between HQ-CT and ZBI support ZBI as an additional outcome measure in PWS clinical trials.

It has previously been proposed that high-grade serous ovarian carcinoma (HGSOC) may originate from the fallopian tube. Here, the authors analyze genetic aberrances in fallopian tube lesions, ovarian cancers, and metastases from HGSOC patients and establish the evolutionary origins of HGSOC in the fallopian tube.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long- term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact.Caregivers participating in this study were predominantly mothers, 30-59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregiver`s children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption.Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We identified the ZBI as a good predictor of that impact. Our findings draw attention to the critical unmet need for support for caregivers of individuals with PWS.

Children younger than 5 are at greatest risk for unintentional poisonings. Children in low-income situations are particularly vulnerable for exposures to potential poisons. Focus groups were conducted at a Women, Infants, and Children (WIC) program located in a large urban public hospital in New York City to gain information from low-income parents of young children about real and perceived barriers to calling the local poison control center, resources for poison prevention messages, and ideas about public awareness campaigns. All focus group members were low-income parents of young children. Most participants reported that they would call 911 in the event of a poisoning due to child welfare and self-efficacy issues. Health education theory using the social-cognitive theory provides a framework for developing future poison prevention programs to address identified issues with parents of young children. [ABSTRACT FROM AUTHOR]