Centriole signaling restricts hepatocyte ploidy to maintain liver integrity.

Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome-P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease.

Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer.

Genomic instability is a hallmark of cancer, and has a central role in the initiation and development of breast cancer1,2. The success of poly-ADP ribose polymerase inhibitors in the treatment of breast cancers that are deficient in homologous recombination exemplifies the utility of synthetically lethal genetic interactions in the treatment of breast cancers that are driven by genomic instability3. Given that defects in homologous recombination are present in only a subset of breast cancers, there is a need to identify additional driver mechanisms for genomic instability and targeted strategies to exploit these defects in the treatment of cancer. Here we show that centrosome depletion induces synthetic lethality in cancer cells that contain the 17q23 amplicon, a recurrent copy number aberration that defines about 9% of all primary breast cancer tumours and is associated with high levels of genomic instability4-6. Specifically, inhibition of polo-like kinase 4 (PLK4) using small molecules leads to centrosome depletion, which triggers mitotic catastrophe in cells that exhibit amplicon-directed overexpression of TRIM37. To explain this effect, we identify TRIM37 as a negative regulator of centrosomal pericentriolar material. In 17q23-amplified cells that lack centrosomes, increased levels of TRIM37 block the formation of foci that comprise pericentriolar material-these foci are structures with a microtubule-nucleating capacity that are required for successful cell division in the absence of centrosomes. Finally, we find that the overexpression of TRIM37 causes genomic instability by delaying centrosome maturation and separation at mitotic entry, and thereby increases the frequency of mitotic errors. Collectively, these findings highlight TRIM37-dependent genomic instability as a putative driver event in 17q23-amplified breast cancer and provide a rationale for the use of centrosome-targeting therapeutic agents in treating these cancers.

ANKRD26 recruits PIDD1 to centriolar distal appendages to activate the PIDDosome following centrosome amplification.

Centriole copy number is tightly maintained by the once-per-cycle duplication of these organelles. Centrioles constitute the core of centrosomes, which organize the microtubule cytoskeleton and form the poles of the mitotic spindle. Centrosome amplification is frequently observed in tumors, where it promotes aneuploidy and contributes to invasive phenotypes. In non-transformed cells, centrosome amplification triggers PIDDosome activation as a protective response to inhibit cell proliferation, but how extra centrosomes activate the PIDDosome remains unclear. Using a genome-wide screen, we identify centriole distal appendages as critical for PIDDosome activation in cells with extra centrosomes. The distal appendage protein ANKRD26 is found to interact with and recruit the PIDDosome component PIDD1 to centriole distal appendages, and this interaction is required for PIDDosome activation following centrosome amplification. Furthermore, a recurrent ANKRD26 mutation found in human tumors disrupts PIDD1 localization and PIDDosome activation in cells with extra centrosomes. Our data support a model in which ANKRD26 initiates a centriole-derived signal to limit cell proliferation in response to centrosome amplification.

Risk stratification models for predicting preventable hospitalization in commercially insured late middle-aged adults with depression.

BACKGROUND: A significant number of late middle-aged adults with depression have a high illness burden resulting from chronic conditions which put them at high risk of hospitalization. Many late middle-aged adults are covered by commercial health insurance, but such insurance claims have not been used to identify the risk of hospitalization in individuals with depression. In the present study, we developed and validated a non-proprietary model to identify late middle-aged adults with depression at risk for hospitalization, using machine learning methods. METHODS: This retrospective cohort study involved 71,682 commercially insured older adults aged 55-64 years diagnosed with depression. National health insurance claims were used to capture demographics, health care utilization, and health status during the base year. Health status was captured using 70 chronic health conditions, and 46 mental health conditions. The outcomes were 1- and 2-year preventable hospitalization. For each of our two outcomes, we evaluated seven modelling approaches: four prediction models utilized logistic regression with different combinations of predictors to evaluate the relative contribution of each group of variables, and three prediction models utilized machine learning approaches - logistic regression with LASSO penalty, random forests (RF), and gradient boosting machine (GBM). RESULTS: Our predictive model for 1-year hospitalization achieved an AUC of 0.803, with a sensitivity of 72% and a specificity of 76% under the optimum threshold of 0.463, and our predictive model for 2-year hospitalization achieved an AUC of 0.793, with a sensitivity of 76% and a specificity of 71% under the optimum threshold of 0.452. For predicting both 1-year and 2-year risk of preventable hospitalization, our best performing models utilized the machine learning approach of logistic regression with LASSO penalty which outperformed more black-box machine learning models like RF and GBM. CONCLUSIONS: Our study demonstrates the feasibility of identifying depressed middle-aged adults at higher risk of future hospitalization due to burden of chronic illnesses using basic demographic information and diagnosis codes recorded in health insurance claims. Identifying this population may assist health care planners in developing effective screening strategies and management approaches and in efficient allocation of public healthcare resources as this population transitions to publicly funded healthcare programs, e.g., Medicare in the US.

The identification of clusters of risk factors and their association with hospitalizations or emergency department visits in home health care.

AIMS: To identify clusters of risk factors in home health care and determine if the clusters are associated with hospitalizations or emergency department visits. DESIGN: A retrospective cohort study. METHODS: This study included 61,454 patients pertaining to 79,079 episodes receiving home health care between 2015 and 2017 from one of the largest home health care organizations in the United States. Potential risk factors were extracted from structured data and unstructured clinical notes analysed by natural language processing. A K-means cluster analysis was conducted. Kaplan-Meier analysis was conducted to identify the association between clusters and hospitalizations or emergency department visits during home health care. RESULTS: A total of 11.6% of home health episodes resulted in hospitalizations or emergency department visits. Risk factors formed three clusters. Cluster 1 is characterized by a combination of risk factors related to "impaired physical comfort with pain," defined as situations where patients may experience increased pain. Cluster 2 is characterized by "high comorbidity burden" defined as multiple comorbidities or other risks for hospitalization (e.g., prior falls). Cluster 3 is characterized by "impaired cognitive/psychological and skin integrity" including dementia or skin ulcer. Compared to Cluster 1, the risk of hospitalizations or emergency department visits increased by 1.95 times for Cluster 2 and by 2.12 times for Cluster 3 (all p < .001). CONCLUSION: Risk factors were clustered into three types describing distinct characteristics for hospitalizations or emergency department visits. Different combinations of risk factors affected the likelihood of these negative outcomes. IMPACT: Cluster-based risk prediction models could be integrated into early warning systems to identify patients at risk for hospitalizations or emergency department visits leading to more timely, patient-centred care, ultimately preventing these events. PATIENT OR PUBLIC CONTRIBUTION: There was no involvement of patients in developing the research question, determining the outcome measures, or implementing the study.

Gender Typicality, Pressure to Conform to Gender Norms, and Anti-Fat and Appearance Stereotypes in Girls.

This mixed-methods study investigated the relation among gender identity (i.e., self-perceived gender similarity to girls and boys; self-perceived parental and peer pressure to conform to gender norms) and stereotyping about weight (i.e., anti-fat stereotypes), weight change, and appearance in 83 girls ages 6-9 (Mage = 7.60 years, SD = .85; 65% White, 16% Mixed/Other, 11% Black, 8% Latina) in the U.S. Stereotypes about weight change were assessed with open-ended responses (i.e., qualitatively), and the rest of the constructs were assessed with closed-ended responses (i.e., quantitatively). There was a positive association between pressure from parents to conform to gender norms and appearance stereotypes, and between pressure from peers and negative stereotypes about the fat and thin figures. Girls who were more gender typical, or more similar to girls, were more likely to endorse appearance stereotypes. There was no significant relation among stereotypes about weight change and gender identity. Many girls deemed the fat figure as unattractive, physically restrained, unhealthy, and likely to be bullied and believed that the fat figure should change back to look like a thinner figure. Most girls were aware that exercising, eating healthy, and dietary restriction can lead to weight loss and that food consumption and lack of exercise can lead to weight gain. Findings suggest that certain aspects of weight (anti-fat) and appearance stereotypes are closely linked to gender identity in girls, whereas other aspects of weight stereotypes (e.g., stereotypes about weight change) are so pervasive that they are common in most girls, regardless of their gender identity.

Treatment Adequacy and Adherence as Predictors of Depression Response in Primary Care.

OBJECTIVE: Primary care is the de facto mental health system in the United States where physicians treat large numbers of depressed older adults with antidepressant medication. This study aimed to examine whether antidepressant dosage adequacy and patient adherence are associated with depression response among middle-aged and older adults prescribed with antidepressants by their primary care provider. DESIGN: A secondary analysis was conducted on a sample drawn from a randomized controlled trial comparing Treatment as Usual to Treatment Initiation Program, an adherence intervention. Treatment Initiation Program improved adherence but not depression compared to Treatment as Usual (Sirey et al., 2017). For this analysis, we examined dosing adequacy and adherence at 6 and 12 weeks as predictors of depression response in both groups at 12 and 24 weeks. SETTING: Primary care practices. PARTICIPANTS: One hundred eighty-seven older adults with depression prescribed an antidepressant for depression by their primary care provider. MEASUREMENTS: Depression response was defined as 50% reduction on the Hamilton Rating Scale for Depression. Adherence was defined as taking 80% of doses at follow-up interviews (6 and 12 weeks). Patient-reported dosage and duration of antidepressant therapy was collected using the Composite Antidepressant Score (adequacy score of >3) at follow-up. RESULTS: Greater adherence, but not receipt of adequate dosage, was associated with higher likelihood of treatment response at both 12 (Odds ratio (OR) = 2.63; 95% Confidence Interval (CI), 1.19-5.84) and 24 weeks (OR = 3.09; 95% CI, 1.46-6.55). CONCLUSION: As physicians prescribe antidepressants to the diverse group of adults seen in primary care, special attention to patients' views and approach to adherence may improve depression outcomes.

People with intellectual disabilities' experiences of psychological therapy: A systematic review and meta-ethnography.

The effectiveness of a range of psychological models adapted for use with people with intellectual disabilities has been well documented. A number of studies have used qualitative methods to examine people with intellectual disabilities' experiences of these adapted interventions. Such research is important for identifying service users' views on the helpful and challenging aspects of psychological interventions to ensure that they meet the needs of people with intellectual disabilities. To consolidate this research, a systematic review using a meta-ethnographic approach was undertaken. A systematic search identified 16 relevant studies. These studies were reviewed, critically appraised and key themes were extracted. Five key concepts were identified: adapting to therapy, the therapeutic environment, group dynamics, the therapeutic relationship and the impact of therapy on life. The need for further consideration of power differentials within the therapeutic relationship and further adaptations to ensure accessibility of therapy for people with intellectual disabilities is discussed.

Association networks in a matched case-control design - Co-occurrence patterns of preexisting chronic medical conditions in patients with major depression versus their matched controls.

OBJECTIVE: We present a method for comparing association networks in a matched case-control design, which provides a high-level comparison of co-occurrence patterns of features after adjusting for confounding factors. We demonstrate this approach by examining the differential distribution of chronic medical conditions in patients with major depressive disorder (MDD) compared to the distribution of these conditions in their matched controls. MATERIALS AND METHODS: Newly diagnosed MDD patients were matched to controls based on their demographic characteristics, socioeconomic status, place of residence, and healthcare service utilization in the Korean National Health Insurance Service's National Sample Cohort. Differences in the networks of chronic medical conditions in newly diagnosed MDD cases treated with antidepressants, and their matched controls, were prioritized with a permutation test accounting for the false discovery rate. Sensitivity analyses for the associations between prioritized pairs of chronic medical conditions and new MDD diagnosis were performed with regression modeling. RESULTS: By comparing the association networks of chronic medical conditions in newly diagnosed depression patients and their matched controls, five pairs of such conditions were prioritized among 105 possible pairs after controlling the false discovery rate at 5%. In sensitivity analyses using regression modeling, four out of the five prioritized pairs were statistically significant for the interaction terms. CONCLUSION: Association networks in a matched case-control design can provide a high-level comparison of comorbid features after adjusting for confounding factors, thereby supplementing traditional clinical study approaches. We demonstrate the differential co-occurrence pattern of chronic medical conditions in patients with MDD and prioritize the chronic conditions that have statistically significant interactions in regression models for depression.

Addressing the Health and Wellness Needs of Vulnerable Rockaway Residents in the Wake of Hurricane Sandy: Findings From a Health Coaching and Community Health Worker Program.

OBJECTIVES: To describe the design and participants of a program that employed health coaches and community health workers to address the social, health, and long-term disaster recovery needs of Rockaway residents roughly 2 years after Hurricane Sandy made landfall. DESIGN: Baseline and exit questionnaires, containing demographic, health, and health care utilization measures, were administered to participants at the start and end of the program. Enrollment and encounter information was captured in program administrative records. Descriptive statistics were used to summarize participant characteristics, personal goals, referrals to local organizations and agencies, and outcomes. Qualitative analyses were used to identify recurring themes in challenges faced by participants and barriers to health and wellness. RESULTS: The program served 732 community residents, of whom 455 (62%) completed baseline and exit questionnaires. Participants were directly and/or indirectly impacted by Hurricane Sandy through property damage, closures of health care facilities, limited employment opportunities, and trouble securing affordable housing. Furthermore, many participants faced considerable adversities and struggled to manage chronic health conditions. Personal goals set by participants included locating health care and other resources (44%), weight management and healthy eating (35%), and self-management of chronic conditions (24%). Health coaches and community health workers engaged participants an average of 4 times-providing counseling and referrals to local organizations and services, including medical and dental services (29%), city-issued identification cards (27%), and health insurance and other entitlements (23%). Comparisons of baseline and exit surveys indicated significant improvements in self-reported health, health care utilization, and confidence managing health issues. No significant improvement was observed in the use of preventive health care services. CONCLUSIONS: The program represents a model for engaging vulnerable populations and addressing social and economic barriers to health and wellness during the long-term disaster recovery phase. Health coaches and community health workers may be instrumental in helping to address the health and wellness needs of vulnerable residents living in disaster-affected areas.

Factors Associated with Length of Stay in Psychiatric Inpatient Services in London, UK.

The purpose of this research was to identify factors associated with lengthy stays in psychiatric hospital in a UK mental health trust. A multiple regression using a multiple imputation method to deal with missing data was performed on inpatient admissions data over a four-year period for 7653 individuals. Factors associated with a longer length of stay included gender (being male), ethnicity (being Asian/Asian British, Black/Black British, or having a mixed background compared to being White/White British), accommodation status (being homeless, or in accommodation with support), primary diagnostic group of psychosis (F20-29), and number of care coordinators. Marital status was not found to be associated with length of stay in this sample. Length of stay is likely to be multifactorially determined, and more similar studies examining factors associated with length of hospital stay are needed to understand the operation of psychiatric services.

An evaluation of the effectiveness of psychological therapy in reducing general psychological distress for adults with autism spectrum conditions and comorbid mental health problems.

OBJECTIVE: To investigate the effectiveness of psychological therapy in reducing psychological distress for adults with autism spectrum conditions (ASC) and co-morbid mental health conditions in routine clinical practice. To explore the effect of individual characteristics and service factors on change in general distress. METHOD: In a specialist psychological therapies service for adults with ASC, the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) self-report questionnaire of psychological distress is completed by clients at start and end of therapy. Change over time and reliable and clinical change was assessed for 81 of a total of 122 clients (66.4%). Factors which may influence change over time were explored using available clinical information. RESULTS: Overall, there was a significant reduction in CORE-OM score during therapy with a small effect size. Most clients showed an improvement in psychological distress over therapy (75.4% improved, with 36.9% of these showing reliable changes). Significant and comparable reductions from pre-therapy to post-therapy were seen across the sample, showing that individual differences did not mediate therapy effectiveness. CORE-OM scores mediate the association between age of ASD diagnosis and hours of therapeutic input required, with greater age at diagnosis and higher distress associated with longer therapy duration. CONCLUSIONS: Our preliminary findings suggest that psychological therapy may be effective in reducing general distress for clients with ASC and co-morbid mental health conditions and should be routinely offered. Individuals who are diagnosed with ASD in adulthood are likely to require a longer course of therapy when their general distress scores are high.

Rapid and frequent psychiatric readmissions: associated factors.

OBJECTIVE: This article aims to examine the impact of clinical and demographic factors on both rapid readmission (being readmitted within 30 d) and frequent readmission (experiencing three or more admissions) in a London mental health trust. METHODS: A four-year study period with a sample of 7648 inpatients were examined with chi-square or Mann-Whitney U tests, and binary logistic regressions to assess the associations and possible predictors of rapid (readmitted within 30 d) and frequent (admitted at least three times) readmission. RESULTS: Frequent admitters were more likely to be unemployed, have more care-coordinators, be living in accommodation with support, be Black or Black British, and to have certain diagnoses. Binary logistic regression revealed that our variables of interest explained between 36.1 and 60.9% of the variation in number of readmissions (±3 admissions), and between 3.7 and 4.2% of the variation in time to readmission (±30 d). CONCLUSIONS: Identifying factors that are associated with rehospitalisation and understanding their importance is necessary to reduce the risk of readmission. This study suggests that particular demographic, clinical and treatment factors require consideration to tackle the seemingly wide range of factors that could be affecting readmission to inpatient services.

Statistical approaches for identifying heavy users of inpatient mental health services.

BACKGROUND: A lack of consensus exists concerning how to identify "heavy users" of inpatient mental health services. AIM: To identify a statistical approach that captures, in a clinically meaningful way, "heavy" users of inpatient services using number of admissions and total time spent in hospital. METHODS: "Simple" statistical methods (e.g. top 2%) and data driven methods (e.g. the Poisson mixture distribution) were applied to admissions made to adult acute services of a London mental health trust. RESULTS: The Poisson mixture distribution distinguished "frequent users" of inpatient services, defined as having 4 + admissions in the study period. It also distinguished "high users" of inpatient services, defined as having 52 + occupied bed days. Together "frequent" and "high" users were classified as "heavy users". CONCLUSIONS: Data driven criteria such as the Poisson mixture distribution can identify "heavy" users of inpatient services. The needs of this group require particular attention.

The Impact of Nurses on Neglected Tropical Disease Management.

Although Neglected Tropical Diseases (NTDs) are largely endemic in the developing nations of Africa, Asia, and South and Central America, they are reemerging with increasing frequency in developed countries. Their diagnosis, treatment, and control are an increasing public health concern that requires a different awareness by health care providers. Neglected tropical diseases (NTDs) are chronic infectious diseases which disproportionately burden poor, rural, and marginalized populations with significant mortality and high morbidity (disability, disfigurement, impaired childhood growth and cognitive development, increased vulnerability to coinfection) that reinforces their poverty. What can we learn from the nurses in developing countries already battling NTD's that could be useful in the developed world? This article provides an overview of distribution, pathophysiology, symptoms, and management of 13 NTDs, with particular attention to the role of nurses in delivering cost-effective integrated interventions. Case studies of schistosomiasis, Chagas disease, and leishmaniasis address recognition and treatment of infected individuals in developed nations where NTD infection is limited primarily to immigrants and travelers.

CD1 molecules: Beyond antigen presentation.

CD1 molecules are well known for their role in binding and presenting lipid antigens to mediate the activation of CD1-restricted T cells. However, much less appreciated is the fact that CD1 molecules can have additional "unconventional" roles which impact the activation and functions of CD1-expressing cells, ultimately controlling tissue homeostasis as well as the progression of inflammatory and infectious diseases. Some of these roles are mediated by so-called reverse signalling, by which crosslinking of CD1 molecules at the cell surface initiates intracellular signalling. On the other hand, CD1 molecules can also control metabolic and inflammatory pathways in CD1-expressing cells through cell-intrinsic mechanisms independent of CD1 ligation. Here, we review the evidence for "unconventional" functions of CD1 molecules and the outcomes of such roles for health and disease.

Evaluating Health Literacy in Families of Injured Children: A Prospective Observational Cohort Study at a Level One Pediatric Trauma Center.

BACKGROUND: Low health literacy (HL) has been associated with poor health outcomes in children. Optimal recovery after pediatric injury requires caregiver participation in complicated rehabilitative and medical aftercare. We aimed to quantify HL among guardians of injured children and identify factors associated with low HL of guardians. METHODS: A prospective observational cohort study was conducted to evaluate the HL using the Newest Vital Sign™ of guardians of injured children (≤18 years) admitted to a level 1 pediatric trauma center. Patient and guardian characteristics were compared across levels of HL using univariate statistics. We conducted multivariable logistic regression to identify factors independently-associated with low HL. RESULTS: A sample of 95 guardian-child dyads were enrolled. The majority of guardians had low HL (n = 52, 55%), followed by moderate HL (n = 36, 38%) and high HL (n = 7, 7%). Many families received public benefits (n = 47, 49%) and 12 guardians (13%) had both housing and employment insecurity. Guardians with low HL were significantly more likely to have insecure housing and not have completed any college. CONCLUSION: The majority of injured children had a primary guardian with low HL. Pediatric trauma centers should consider screening for low HL to ensure that families have adequate post-discharge support. LEVEL OF EVIDENCE: Level 3.

Benchmarking Pediatric Trauma Care in Mixed Trauma Centers: Adult Risk-Adjusted Mortality Is Not a Reliable Indicator of Pediatric Outcomes.

BACKGROUND: Trauma center benchmarking has become standard practice for assessing quality. The American College of Surgeons adult trauma center verification standards do not specifically require participation in a pediatric-specific benchmarking program. Centers that treat adults and children may therefore rely solely on adult benchmarking metrics as a surrogate for pediatric quality. This study assessed discordance between adult and pediatric mortality within mixed trauma centers to determine the need to independently report pediatric-specific quality metrics. STUDY DESIGN: A cohort of trauma centers (n = 493, including 347 adult-only, 44 pediatric-only, and 102 mixed) that participated in the American College of Surgeons TQIP in 2017 to 2018 was analyzed. Center-specific observed-to-expected mortality estimates were calculated using TQIP adult inclusion criteria for 449 centers treating adults (16 to 65 years) and using TQIP pediatric inclusion criteria for 146 centers treating children (0 to 15 years). We then correlated risk-adjusted mortality estimates for pediatric and adult patients within mixed centers and evaluated concordance of their outlier status between adults and children. RESULTS: The cohort included 394,075 adults and 97,698 children. Unadjusted mortality was 6.1% in adults and 1.2% in children. Mortality estimates had only moderate correlation ( r = 0.41) between adult and pediatric cohorts within individual mixed centers. Mortality outlier status for adult and pediatric cohorts was discordant in 31% (32 of 102) of mixed centers (weighted Kappa statistic 0.06 [-0.11 to 0.22]), with 78% (23 of 32) of discordant centers having higher odds of mortality for children than for adults (6 centers with average adult mortality and high pediatric mortality and 17 centers with low adult mortality and average pediatric mortality, p < 0.01). CONCLUSIONS: Adult mortality is not a reliable surrogate for pediatric mortality in mixed trauma centers. Incorporation of pediatric-specific benchmarks should be required for centers that admit children.