Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis

Phosphorus is an essential nutrient taken up by organisms in the form of inorganic phosphate (Pi). Eukaryotes have evolved sophisticated Pi sensing and signaling cascades, enabling them to stably maintain cellular Pi concentrations. Pi homeostasis is regulated by inositol pyrophosphate signaling molecules (PP-InsPs), which are sensed by SPX domain-containing proteins. In plants, PP-InsP-bound SPX receptors inactivate Myb coiled-coil (MYB-CC) Pi starvation response transcription factors (PHRs) by an unknown mechanism. Here we report that a InsP8–SPX complex targets the plant-unique CC domain of PHRs. Crystal structures of the CC domain reveal an unusual four-stranded anti-parallel arrangement. Interface mutations in the CC domain yield monomeric PHR1, which is no longer able to bind DNA with high affinity. Mutation of conserved basic residues located at the surface of the CC domain disrupt interaction with the SPX receptor in vitro and in planta, resulting in constitutive Pi starvation responses. Together, our findings suggest that InsP8 regulates plant Pi homeostasis by controlling the oligomeric state and hence the promoter binding capability of PHRs via their SPX receptors

Understanding older patients' willingness to have medications deprescribed in primary care: a protocol for a cross-sectional survey study in nine European countries.

INTRODUCTION To reduce inappropriate polypharmacy, deprescribing should be part of patients' regular care. Yet deprescribing is difficult to implement, as shown in several studies. Understanding patients' attitudes towards deprescribing at the individual and country level may reveal effective ways to involve older adults in decisions about medications and help to implement deprescribing in primary care settings. In this study we aim to investigate older adults' perceptions and views on deprescribing in different European countries. Specific objectives are to investigate the patients' willingness to have medications deprescribed by medication type and to have herbal or dietary supplements reduced or stopped, the role of the Patient Typology (on medication perspectives), and the impact of the patient-GP relationship in these decisions. METHODS AND ANALYSIS This cross-sectional survey study has two parts: Part A and Part B. Data collection for Part A will take place in nine countries, in which per country 10 GPs will recruit 10 older patients (≥65 years old) each (n = 900). Part B will be conducted in Switzerland only, in which an additional 35 GPs will recruit five patients each and respond to a questionnaire themselves, with questions about the patients' medications, their willingness to deprescribe those, and their patient-provider relationship. For both Part A and part B, a questionnaire will be used to assess the willingness of older patients with polypharmacy to have medications deprescribed and other relevant information. For Part B, this same questionnaire will have additional questions on the use of herbal and dietary supplements. DISCUSSION The international study design will allow comparisons of patient perspectives on deprescribing from different countries. We will collect information about willingness to have medications deprescribed by medication type and regarding herbal and dietary supplements, which adds important information to the literature on patients' preferences. In addition, GPs in Switzerland will also be surveyed, allowing us to compare GPs' and patients' views and preferences on stopping or reducing specific medications. Our findings will help to understand patients' attitudes towards deprescribing, contributing to improvements in the design and implementation of deprescribing interventions that are better tailored to patients' preferences

Chronic thromboembolic pulmonary hypertension and impairment after pulmonary embolism: the FOCUS study

AIMS: To systematically assess late outcomes of acute pulmonary embolism (PE) and to investigate the clinical implications of post-PE impairment (PPEI) fulfilling prospectively defined criteria. METHODS AND RESULTS: A prospective multicentre observational cohort study was conducted in 17 large-volume centres across Germany. Adult consecutive patients with confirmed acute symptomatic PE were followed with a standardized assessment plan and pre-defined visits at 3, 12, and 24 months. The co-primary outcomes were (i) diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH), and (ii) PPEI, a combination of persistent or worsening clinical, functional, biochemical, and imaging parameters during follow-up. A total of 1017 patients (45% women, median age 64 years) were included in the primary analysis. They were followed for a median duration of 732 days after PE diagnosis. The CTEPH was diagnosed in 16 (1.6%) patients, after a median of 129 days; the estimated 2-year cumulative incidence was 2.3% (1.2-4.4%). Overall, 880 patients were evaluable for PPEI; the 2-year cumulative incidence was 16.0% (95% confidence interval 12.8-20.8%). The PPEI helped to identify 15 of the 16 patients diagnosed with CTEPH during follow-up (hazard ratio for CTEPH vs. no CTEPH 393; 95% confidence interval 73-2119). Patients with PPEI had a higher risk of re-hospitalization and death as well as worse quality of life compared with those without PPEI. CONCLUSION: In this prospective study, the cumulative 2-year incidence of CTEPH was 2.3%, but PPEI diagnosed by standardized criteria was frequent. Our findings support systematic follow-up of patients after acute PE and may help to optimize guideline recommendations and algorithms for post-PE care

Proteomic-based stratification of intermediate-risk prostate cancer patients

Gleason grading is an important prognostic indicator for prostate adenocarcinoma and is crucial for patient treatment decisions. However, intermediate-risk patients diagnosed in the Gleason grade group (GG) 2 and GG3 can harbour either aggressive or non-aggressive disease, resulting in under- or overtreatment of a significant number of patients. Here, we performed proteomic, differential expression, machine learning, and survival analyses for 1,348 matched tumour and benign sample runs from 278 patients. Three proteins (F5, TMEM126B, and EARS2) were identified as candidate biomarkers in patients with biochemical recurrence. Multivariate Cox regression yielded 18 proteins, from which a risk score was constructed to dichotomize prostate cancer patients into low- and high-risk groups. This 18-protein signature is prognostic for the risk of biochemical recurrence and completely independent of the intermediate GG. Our results suggest that markers generated by computational proteomic profiling have the potential for clinical applications including integration into prostate cancer management

Teaching residents to put patients first: creation and evaluation of a comprehensive curriculum in patient-centered communication

Abstract Background Patient-centered communication is essential for successful patient encounters and positive patient outcomes. Therefore, training residents how to communicate well is one of the key responsibilities of residency programs. However, many residents, especially international medical graduates, continue to struggle with communication barriers. Methods All residents and faculty from a small community teaching hospital participated in a three-year, multidimensional patient-centered communication curriculum including communication training with lectures, experiential learning, communication skills practice, and reflection in the areas of linguistics, physician-patient communication, cultural & linguistically appropriate care, and professionalism. We evaluated the program through a multipronged outcomes assessment, including self-assessment, scores on the Calgary-Cambridge Scale during Objective Structured Clinical Examination (OSCE), a survey to measure the hidden curriculum, English Communication Assessment Profile (E-CAP),, the Maslach Burnout-Inventory (MBI), and residents’ evaluation of faculty communication. Results Sixty-two residents and ten faculty members completed the three-year curriculum. We saw no significant changes in the MBI or hidden curriculum survey. Communication skills as measured by Calgary Cambridge Score, E-CAP, and resident communication improved significantly (average Calgary-Cambridge Scale scores from 70% at baseline to 78% at follow-up (p-value < 0.001), paired t-test score from 68% at baseline to 81% at follow-up (p-value < 0.004), average E-CAP score from 73 to 77% (p-value < 0.001)). Faculty communication and teaching as rated by residents also showed significant improvement in four out of six domains (learning climate (p < 0.001), patient-centered care (p = 0.01), evaluation (p = 0.03), and self-directed learning (p = 0.03)). Conclusion Implementing a multidimensional curriculum in patient-centered communication led to modest improvements in patient-centered communication, improved language skills, and improved communication skills among residents and faculty

Lifestyle medicine curriculum for a preventive medicine residency program: implementation and outcomes

Background: The vast majority of the healthcare problems burdening our society today are caused by disease-promoting lifestyles (e.g., physical inactivity and unhealthy eating). Physicians report poor training and lack of confidence in counseling patients on lifestyle changes. Objective: To evaluate a new curriculum and rotation in lifestyle medicine for preventive medicine residents. Methods: Training included didactics (six sessions/year), distance learning, educational conferences, and newly developed lifestyle medicine rotations at the Institute of Lifestyle Medicine, the Yale-Griffin Prevention Research Center, and the Integrative Medicine Center. We used a number of tools to assess residents’ progress including Objective Structured Clinical Examinations (OSCEs), self-assessments, and logs of personal health habits. Results: A total of 20 residents participated in the lifestyle medicine training between 2010 and 2013. There was a 15% increase in residents’ discussions of lifestyle issues with their patients based on their baseline and follow-up surveys. The performance of preventive medicine residents on OSCEs increased each year they were in the program (average OSCE score: PGY1 73%, PGY2 83%, PGY3 87%, and PGY4 91%, p=0.01). Our internal medicine and preliminary residents served as a control, since they did participate in didactics but not in lifestyle medicine rotations. Internal medicine and preliminary residents who completed the same OSCEs had a slightly lower average score (76%) compared with plural for resident, preventive medicine residents (80%). However, this difference did not reach statistical significance (p=0.11). Conclusion: Incorporating the lifestyle medicine curriculum is feasible for preventive medicine training allowing residents to improve their health behavior change discussions with patients as well as their own personal health habits

Inferring clonal composition from multiple tumor biopsies

Knowledge about the clonal evolution of a tumor can help to interpret the function of its genetic alterations by identifying initiating events and events that contribute to the selective advantage of proliferative, metastatic, and drug-resistant subclones. Clonal evolution can be reconstructed from estimates of the relative abundance (frequency) of subclone-specific alterations in tumor biopsies, which, in turn, inform on its composition. However, estimating these frequencies is complicated by the high genetic instability that characterizes many cancers. Models for genetic instability suggest that copy number alterations (CNAs) can influence mutation-frequency estimates and thus impede efforts to reconstruct tumor phylogenies. Our analysis suggested that accurate mutation frequency estimates require accounting for CNAs-a challenging endeavour using the genetic profile of a single tumor biopsy. Instead, we propose an optimization algorithm, Chimæra, to account for the effects of CNAs using profiles of multiple biopsies per tumor. Analyses of simulated data and tumor profiles suggested that Chimæra estimates are consistently more accurate than those of previously proposed methods and resulted in improved phylogeny reconstructions and subclone characterizations. Our analyses inferred recurrent initiating mutations in hepatocellular carcinomas, resolved the clonal composition of Wilms' tumors, and characterized the acquisition of mutations in drug-resistant prostate cancers

Significance and Costs of Complex Biopsychosocial Health Care Needs in Elderly People: Results of a Population-Based Study

Objective: To improve health care for the elderly, a consideration of biopsychosocial health care needs may be of particular importance-especially because of the prevalence of multiple conditions, mental disorders, and social challenges facing elderly people. The aim of the study was to investigate significance and costs of biopsychosocial health care needs in elderly people. Methods: Data were derived from the 8-year follow-up of the ESTHER study-a German epidemiological study in the elderly population. A total of 3124 participants aged 57 to 84 years were visited at home by trained medical doctors. Biopsychosocial health care needs were assessed using the INTERMED for the Elderly (IM-E) interview. Health-related quality of life (HRQOL) was measured by the 12-Item Short-Form Health Survey, and psychosomatic burden was measured by the Patient Health Questionnaire. Results: The IM-E correlated with decreased mental (mental component score: r = -0.38, p <.0001) and physical HRQOL (physical component score: r = -0.45, p <.0001), increased depression severity (r = 0.53, p <.0001), and costs (R = 0.41, p <.0001). The proportion of the participants who had an IM-E score of at least 21 was 8.2%; according to previous studies, they were classified as complex patients (having complex biopsychosocial health care needs). Complex patients showed a highly reduced HRQOL compared with participants without complex health care needs (mental component score: 37.0 [10.8] versus 48.7 [8.8]; physical component score: 33.0 [9.1] versus 41.6 [9.5]). Mean health care costs per 3 months of complex patients were strongly increased (1651.1 (sic) [3192.2] versus 764.5 (sic) [1868.4]). Conclusions: Complex biopsychosocial health care needs are strongly associated with adverse health outcomes in elderly people. It should be evaluated if interdisciplinary treatment plans would improve the health outcomes for complex patients