Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy: A Systematic Review and Individual Patient Data Meta-Analysis.

PURPOSE: After risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO. METHODS: Unpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study. RESULTS: From 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P < .001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO. CONCLUSION: BRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events.

Patients' perspective on supposedly patient-relevant process and outcome parameters: a cross-sectional survey within the 'PRO patients study'.

BACKGROUND: To be able to make informed choices based on their individual preferences, patients need to be adequately informed about treatment options and their potential outcomes. This implies that studies measure the effects of care based on parameters that are relevant to patients. In a previous scoping review, we found a wide variety of supposedly patient-relevant parameters that equally addressed processes and outcomes of care. We were unable to identify a consistent understanding of patient relevance and therefore aimed to develop an empirically based concept including a generic set of patient-relevant parameters. As a first step we evaluated the process and outcome parameters identified in the scoping review from the patients' perspective. METHODS: We conducted a cross-sectional survey among German general practice patients. Ten research practices of Witten/Herdecke University supported the study. During a two-week period in the fall of 2020, patients willing to participate self-administered a short questionnaire. It evaluated the relevance of the 32 parameters identified in the scoping review on a 5-point Likert scale and offered a free-text field for additional parameters. These free-text answers were inductively categorized by two researchers. Quantitative data were analyzed using descriptive statistics. Bivariate analyses were performed to determine whether there are any correlations between rating a parameter as highly relevant and patients' characteristics. RESULTS: Data from 299 patients were eligible for analysis. All outcomes except 'sexuality' and 'frequency of healthcare service utilization' were rated important. 'Confidence in therapy' was rated most important, followed by 'prevention of comorbidity' and 'mobility'. Relevance ratings of five parameters were associated with patients' age and gender, but not with their chronic status. The free-text analysis revealed 15 additional parameters, 12 of which addressed processes of care, i.e., 'enough time in physician consultation'. CONCLUSION: Patients attach great value to parameters addressing processes of care. It appears as though the way in which patients experience the care process is not less relevant than what comes of it. Relevance ratings were not associated with chronic status, but few parameters were gender- and age-related. TRIAL REGISTRATION: Core Outcome Measures in Effectiveness Trials Initiative, registration number: 1685.

Ubiquitin-Independent Disassembly by a p97 AAA-ATPase Complex Drives PP1 Holoenzyme Formation.

The functional diversity of protein phosphatase-1 (PP1), with its countless substrates, relies on the ordered assembly of alternative PP1 holoenzymes. Here, we show that newly synthesized PP1 is first held by its partners SDS22 and inhibitor-3 (I3) in an inactive complex, which needs to be disassembled by the p97 AAA-ATPase to promote exchange to substrate specifiers. Unlike p97-mediated degradative processes that require the Ufd1-Npl4 ubiquitin adapters, p97 is targeted to PP1 by p37 and related adapter proteins. Reconstitution with purified components revealed direct interaction of the p37 SEP domain with I3 without the need for ubiquitination, and ATP-driven pulling of I3 into the central channel of the p97 hexamer, which triggers dissociation of I3 and SDS22. Thus, we establish regulatory ubiquitin-independent protein complex disassembly as part of the functional arsenal of p97 and define an unanticipated essential step in PP1 biogenesis that illustrates the molecular challenges of ordered subunit exchange.

AP-SWATH Reveals Direct Involvement of VCP/p97 in Integrated Stress Response Signaling Through Facilitating CReP/PPP1R15B Degradation.

The ubiquitin-directed AAA-ATPase VCP/p97 facilitates degradation of damaged or misfolded proteins in diverse cellular stress response pathways. Resolving the complexity of its interactions with partner and substrate proteins and understanding its links to stress signaling is therefore a major challenge. Here, we used affinity-purification SWATH mass spectrometry (AP-SWATH) to identify proteins that specifically interact with the substrate-trapping mutant, p97-E578Q. AP-SWATH identified differential interactions over a large detection range from abundant p97 cofactors to pathway-specific partners and individual ligases such as RNF185 and MUL1 that were trapped in p97-E578Q complexes. In addition, we identified various substrate proteins and candidates including the PP1 regulator CReP/PPP1R15B that dephosphorylates eIF2α and thus counteracts attenuation of translation by stress-kinases. We provide evidence that p97 with its Ufd1-Npl4 adapter ensures rapid constitutive turnover and balanced levels of CReP in unperturbed cells. Moreover, we show that p97-mediated degradation, together with a reduction in CReP synthesis, is essential for timely stress-induced reduction of CReP levels and, consequently, for robust eIF2α phosphorylation to enforce the stress response. Thus, our results demonstrate that p97 not only facilitates bulk degradation of misfolded proteins upon stress, but also directly modulates the integrated stress response at the level of signaling.

Parkinson's disease sleep scale--validation of the revised version PDSS-2.

BACKGROUND: The previous Parkinson's disease sleep scale (PDSS) is a 15-item visual analogue scale that assesses the profile of nocturnal disturbances in Parkinson's disease (PD) patients. OBJECTIVE: To extend the scale so that it becomes a frequency measure scale with five categories and encompasses unmet needs such as restless legs syndrome, akinesia, pain, and sleep apnea. METHODS: For validation of the PDSS-2, PD patients' ratings and investigators' interviews were compared to ratings from a semistructured interview with a caregiver/partner, and to related scales. PDSS-2 was repeated for test-retest-reliability after 1-3 days. RESULTS: A total of 113 PD patients showed a mean (SD) total score of 16.5 (±8.9) (range: 2-40) indicating mild to moderate sleep disturbances. PDSS-2 item-total correlation for proving internal consistency was satisfactory (correlations >0.30). From a factor analysis, three subscales were derived: (1) "motor problems at night," (2) "PD symptoms at night" and (3) "disturbed sleep." The alpha coefficient for the total score was 0.73, for subscales 0.47 to 0.66. The test-retest-reliability intra-class-coefficient for the total score was 0.80, with 0.69 and 0.77 within the subscales. For discriminative validity, significant differences were found in the PDSS-2 total score depending on CGI and Hoehn and Yahr severity levels. A comparison between caregivers' and patients' ratings was carried out. CONCLUSION: The PDSS-2, with an extended spectrum of nocturnal disabilities and easier use for patients, is a reliable, valid, precise, and potentially treatment-responsive tool for measuring sleep disorders in PD.