Building the Infrastructure to Integrate Social Care in a Safety Net Health System.

A recent National Academies report recommended that health systems invest in new infrastructure to integrate social and medical care. Although many health systems routinely screen patients for social concerns, few health systems achieve the recommended model of integration. In this critical case study in an urban safety net health system, we describe the human capital, operational redesign, and financial investment needed to implement the National Academy recommendations. Using data from this case study, we estimate that other health systems seeking to build and maintain this infrastructure would need to invest $1 million to $3 million per year. While health systems with robust existing resources may be able to bootstrap short-term funding to initiate this work, we conclude that long-term investments by insurers and other payers will be necessary for most health systems to achieve the recommended integration of medical and social care. Researchers seeking to test whether integrating social and medical care leads to better patient and population outcomes require access to health systems and communities who have already invested in this model infrastructure. (Am J Public Health. 2024;114(6):619-625. https://doi.org/10.2105/AJPH.2024.307602).

Effect of modernized collaborative care for depression on depressive symptoms and cardiovascular disease risk biomarkers: eIMPACT randomized controlled trial.

Although depression is a risk and prognostic factor for cardiovascular disease (CVD), clinical trials treating depression in patients with CVD have not demonstrated cardiovascular benefits. We proposed a novel explanation for the null results for CVD-related outcomes: the late timing of depression treatment in the natural history of CVD. Our objective was to determine whether successful depression treatment before, versus after, clinical CVD onset reduces CVD risk in depression. We conducted a single-center, parallel-group, assessor-blinded randomized controlled trial. Primary care patients with depression and elevated CVD risk from a safety net healthcare system (N = 216, Mage = 59 years, 78% female, 50% Black, 46% with income <$10,000/year) were randomized to 12 months of the eIMPACT intervention (modernized collaborative care involving internet cognitive-behavioral therapy [CBT], telephonic CBT, and/or select antidepressants) or usual primary care for depression (primary care providers supported by embedded behavioral health clinicians and psychiatrists). Outcomes were depressive symptoms and CVD risk biomarkers at 12 months. Intervention participants, versus usual care participants, exhibited moderate-to-large (Hedges' g = -0.65, p < 0.01) improvements in depressive symptoms. Clinical response data yielded similar results - 43% of intervention participants, versus 17% of usual care participants, had a ≥ 50% reduction in depressive symptoms (OR = 3.73, 95% CI: 1.93-7.21, p < 0.01). However, no treatment group differences were observed for the CVD risk biomarkers - i.e., brachial flow-mediated dilation, high-frequency heart rate variability, interleukin-6, high-sensitivity C-reactive protein, ß-thromboglobulin, and platelet factor 4 (Hedges' gs = -0.23 to 0.02, ps ≥ 0.09). Our modernized collaborative care intervention - which harnessed technology to maximize access and minimize resources - produced clinically meaningful improvements in depressive symptoms. However, successful depression treatment did not lower CVD risk biomarkers. Our findings indicate that depression treatment alone may not be sufficient to reduce the excess CVD risk of people with depression and that alternative approaches are needed. In addition, our effective intervention highlights the utility of eHealth interventions and centralized, remote treatment delivery in safety net clinical settings and could inform contemporary integrated care approaches. Trial Registration:ClinicalTrials.gov Identifier: NCT02458690.

Complex Transitions from Skilled Nursing Facility to Home: Patient and Caregiver Perspectives.

BACKGROUND: Patients who undergo the complex series of transitions from the hospital to a skilled nursing facility (SNF) back to home represent a unique patient population with multiple comorbidities and impaired functional abilities. The needs and outcomes of patients who are discharged from the hospital to SNF before returning home are understudied in care transitions scholarship. OBJECTIVE: To study the patient and caregiver challenges and perspectives on transitions from the hospital to the SNF and back to home. DESIGN: Between 48 h and 1 week after discharge from the SNF, semi-structured interviews were performed with a convenience sample of patients and caregivers in their homes. Within 1 to 2 weeks after the baseline interview, follow-up interviews were performed over the phone. PARTICIPANTS: A total of 39 interviewees comprised older adults undergoing the series of transitions from hospital to skilled nursing facility to home and their informal caregivers. MAIN MEASURES: A constructionist, grounded-theory approach was used to code the interviews, identify major themes and subthemes, and develop a theoretical model explaining the outcomes of the SNF to home transition. KEY RESULTS: The mean age of the patients was 76.6 years and 64.8 years for the caregivers. Four major themes were identified: comforts of home, information needs, post-SNF care, and independence. Patients noted an extended time away from home and were motivated to return to and remain in the home. Information needs were variably met and affected post-SNF care, including medication management, appointments, and therapy gains and setbacks. Interviewees identified independent function at home as the most important outcome of the transition home. CONCLUSIONS: Post-SNF in home support is needed rapidly after discharge from the SNF to prevent adverse outcomes. In-home support needs to be highly individualized based on a patient's and caregiver's unique situation and needs.

Factors Associated with Physician Moral Distress Caring for Hospitalized Elderly Patients Needing a Surrogate Decision-maker: a Prospective Study.

BACKGROUND: When working with surrogate decision-makers, physicians often encounter ethical challenges that may cause moral distress which can have negative consequences for physicians. OBJECTIVE: To determine frequency of and factors associated with physicians' moral distress caring for patients requiring a surrogate. DESIGN: Prospective survey. PARTICIPANTS: Physicians (n = 154) caring for patients aged 65 years and older and their surrogate decision-makers (n = 362 patient/surrogate dyads). Patients were admitted to medicine or medical intensive care services, lacked decisional capacity and had an identified surrogate. MAIN MEASURES: Moral distress thermometer. KEY RESULTS: Physicians experienced moral distress in the care of 152 of 362 patients (42.0%). In analyses adjusted for physician, patient, and surrogate characteristics, physician/surrogate discordance in preferences for the plan of care was not significantly associated with moral distress. Physicians were more likely to experience moral distress when caring for older patients (1.06, 1.02-1.10), and facing a decision about life-sustaining treatment (3.58, 1.54-8.32). Physicians were less likely to experience moral distress when caring for patients residing in a nursing home (0.40, 0.23-0.69), patients who previously discussed care preferences (0.56, 0.35-0.90), and higher surrogate ratings of emotional support from clinicians (0.94, 0.89-0.99). Physicians' internal discordance when they prefer a more comfort-focused plan than the patient is receiving was associated with significantly higher moral distress (2.22, 1.33-3.70) after adjusting for patient, surrogate, and physician characteristics. CONCLUSIONS: Physician moral distress occurs more frequently when the physician is male, the patient is older or requires decisions about life-sustaining treatments. These findings may help target interventions to support physicians. Prior discussions about patient wishes is associated with lower distress and may be a target for patient-centered interventions.

Development and Feasibility of SymTrak, aMulti-domain Tool for Monitoring Symptoms of Older Adults in Primary Care.

BACKGROUND: A clinically practical, brief, user-friendly, multi-domain self-report and caregiver-report tool is needed for tracking actionable symptoms in primary care for elderly patients with multiple chronic conditions (MCCs). OBJECTIVE: Develop and assess usability, administration time, and internal reliability of SymTrak. DESIGN AND PARTICIPANTS: Phase I: legacy instruments, content validity, analyses of existing data, focus groups (physicians, nurses, patients, informal caregivers), and Think Aloud interviews (patients, caregivers) were used to develop SymTrak. Phase II (pilot feasibility study): 81 (27 patient-caregiver dyads, 27 patients without an identified caregiver) participants were self-administered SymTrak in clinic. MAIN MEASURES: SymTrak and demographic questions. KEY RESULTS: Consistent themes emerged from phase I focus groups. Ambiguous wording was corrected with Think Aloud feedback. In phase II, patients and caregivers preferred circling words instead of numbers for item response options. SymTrak self-administration completion time in clinic was brief; mean was 2.4, 3.0, and 3.3 min for the finalized circlingwords version, respectively, for caregivers, dyadic patients, and patients without a caregiver; and the maximum was 6.2 min for any participant. Usability questionnaire ratings were high. Cronbach's alpha for the SymTrak 23-item total score was 0.86, 0.79, and 0.81 for caregivers, dyadic patients, and patients without a caregiver, respectively. CONCLUSIONS: SymTrak demonstrates content validity, positive qualitative findings, high perceived usability, brief self-administered completion time, and good internal reliability.

Reliability and Validity of SymTrak, a Multi-Domain Tool for Monitoring Symptoms of Older Adults with Multiple Chronic Conditions.

BACKGROUND: A reliable and valid clinically practical multi-domain self-report and caregiver-report tool is needed for tracking actionable symptoms in primary care for elderly patients with multiple chronic conditions (MCCs). OBJECTIVE: Assess internal consistency reliability, test-retest reliability, construct validity, and sensitivity to change for SymTrak. DESIGN AND PARTICIPANTS: Among 600 (200 patient-caregiver dyads, 200 patients without an identified caregiver) participants, SymTrak was telephone interviewer-administered at baseline and 3-month follow-up, and at 24 h post-baseline for assessing test-retest reliability in a random subsample of 180 (60 dyads, 60 individual patients) participants. MAIN MEASURES: Demographic questions, SymTrak, Health Utility Index Mark 3 (HUI3). KEY RESULTS: Exploratory factor analysis indicated a single dominant dimension for SymTrak items for both patients and caregivers. Coefficient alpha and 24-h test-retest reliability, respectively, were high for the 23-item SymTrak total score for both patient-reported (0.85; 0.87) and caregiver-reported (0.86; 0.91) scores. Construct validity was supported by monotone decreasing relationships between the mean of SymTrak total scores across the poor-to-excellent categories of physical and emotional general health, and by high correlations with HUI3 overall utility score, even after adjusting for demographic covariates (standardized linear regression coefficient = - 0.84 for patients; - 0.70 for caregivers). Three-month change in the SymTrak total score was sensitive to detecting criterion standard 3-month reliable change categories (Improved, Stable, Declined) in HUI3-based health-related quality of life, especially for caregiver-reported scores. CONCLUSIONS: SymTrak demonstrates good internal consistency and test-retest reliability, construct validity, and sensitivity to change over a 3-month period, supporting its use for monitoring symptoms for older adults with MCCs.

Communication Quality Predicts Psychological Well-Being and Satisfaction in Family Surrogates of Hospitalized Older Adults: An Observational Study.

BACKGROUND: Many hospitalized older adults require family surrogates to make decisions, but surrogates may perceive that the quality of medical decisions is low and may have poor psychological outcomes after the patient's hospitalization. OBJECTIVE: To determine the relationship between communication quality and high-quality medical decisions, psychological well-being, and satisfaction for surrogates of hospitalized older adults. DESIGN: Observational study at three hospitals in a Midwest metropolitan area. PARTICIPANTS: Hospitalized older adults (65+ years) admitted to medicine and medical intensive care units who were unable to make medical decisions, and their family surrogates. Among 799 eligible dyads, 364 (45.6%) completed the study. MAIN MEASURES: Communication was assessed during hospitalization using the information and emotional support subscales of the Family Inpatient Communication Survey. Decision quality was assessed with the Decisional Conflict Scale. Outcomes assessed at baseline and 4-6 weeks post-discharge included anxiety (Generalized Anxiety Disorder-7), depression (Patient Health Questionnaire-9), post-traumatic stress (Impact of Event Scale-Revised), and satisfaction (Hospital Consumer Assessment of Healthcare Providers and Systems). KEY RESULTS: The mean patient age was 81.9 years (SD 8.32); 62% were women, and 28% African American. Among surrogates, 67% were adult children. Six to eight weeks post-discharge, 22.6% of surrogates reported anxiety (11.3% moderate-severe anxiety); 29% reported depression, (14.0% moderate-severe), and 14.6% had high levels of post-traumatic stress. Emotional support was associated with lower odds of anxiety (adjusted odds ratio [AOR] = 0.65, 95% CI 0.50, 0.85) and depression (AOR = 0.80, 95% CI 0.65, 0.99) at follow-up. In multivariable linear regression, emotional support was associated with lower post-traumatic stress (ß = -0.30, p = 0.003) and higher decision quality (ß = -0.44, p < 0.0001). Information was associated with higher post-traumatic stress (ß = 0.23, p = 0.022) but also higher satisfaction (ß = 0.61, p < 0.001). CONCLUSIONS: Emotional support of hospital surrogates is consistently associated with better psychological outcomes and decision quality, suggesting an opportunity to improve decision making and well-being.

Antihypertensive Medication and Dementia Risk in Older Adult African Americans with Hypertension: A Prospective Cohort Study.

BACKGROUND: African Americans are especially at risk of hypertension and dementia. Antihypertensive medications reduce the risk of cardiovascular events, but may also reduce the risk of dementia. OBJECTIVE: To assess the longitudinal effects of antihypertensive medications and blood pressure on the onset of incident dementia in a cohort of African Americans. DESIGN: Prospective cohort. PARTICIPANTS: 1236 community-dwelling patients from an inner-city public health care system, aged 65 years and older, with a history of hypertension but no history of dementia, and who had at least three primary care visits and a prescription filled for any medication. MAIN MEASURES: Blood pressure was the average of three seated measurements. Dementia was diagnosed using a two-stage design, with a screening evaluation every 2 to 3 years followed by a comprehensive in-home clinical evaluation for those with a positive screen. Laboratory, inpatient and outpatient encounter data, coded diagnoses and procedures, and medication records were derived from a health information exchange. KEY RESULTS: Of the 1236 hypertensive participants without dementia at baseline, 114 (9%) developed incident dementia during follow-up. Individuals prescribed any antihypertensive medication (n = 816) were found to have a significantly reduced risk of dementia (HR = 0.57, 95% CI 0.37-0.88, p = 0.0114) compared to untreated hypertensive participants (n = 420). When this analysis was repeated including a variable indicating suboptimally treated blood pressure (> 140 mmHg systolic or >90 mmHg diastolic), the effect of antihypertensive medication was no longer statistically significant (HR = 0.65, 95% CI 0.32-1.30, p = 0.2217). CONCLUSIONS: Control of blood pressure in older adult African American patients with hypertension is a key intervention for preventing dementia, with similar benefits from most of the commonly available antihypertensive medications.

Targeting Functional Decline in Alzheimer Disease: A Randomized Trial.

BACKGROUND: Alzheimer disease results in progressive functional decline, leading to loss of independence. OBJECTIVE: To determine whether collaborative care plus 2 years of home-based occupational therapy delays functional decline. DESIGN: Randomized, controlled clinical trial. (ClinicalTrials.gov: NCT01314950). SETTING: Urban public health system. PATIENTS: 180 community-dwelling participants with Alzheimer disease and their informal caregivers. INTERVENTION: All participants received collaborative care for dementia. Patients in the intervention group also received in-home occupational therapy delivered in 24 sessions over 2 years. MEASUREMENTS: The primary outcome measure was the Alzheimer's Disease Cooperative Study Group Activities of Daily Living Scale (ADCS ADL); performance-based measures included the Short Physical Performance Battery (SPPB) and Short Portable Sarcopenia Measure (SPSM). RESULTS: At baseline, clinical characteristics did not differ significantly between groups; the mean Mini-Mental State Examination score for both groups was 19 (SD, 7). The intervention group received a median of 18 home visits from the study occupational therapists. In both groups, ADCS ADL scores declined over 24 months. At the primary end point of 24 months, ADCS ADL scores did not differ between groups (mean difference, 2.34 [95% CI, -5.27 to 9.96]). We also could not definitively demonstrate between-group differences in mean SPPB or SPSM values. LIMITATION: The results of this trial are indeterminate and do not rule out potential clinically important effects of the intervention. CONCLUSION: The authors could not definitively demonstrate whether the addition of 2 years of in-home occupational therapy to a collaborative care management model slowed the rate of functional decline among persons with Alzheimer disease. This trial underscores the burden undertaken by caregivers as they provide care for family members with Alzheimer disease and the difficulty in slowing functional decline. PRIMARY FUNDING SOURCE: National Institute on Aging.

Home is where the future is: The BrightFocus Foundation consensus panel on dementia care.

INTRODUCTION: A national consensus panel was convened to develop recommendations on future directions for home-based dementia care (HBDC). METHODS: The panel summarized advantages and challenges of shifting to HBDC as the nexus of care and developed consensus-based recommendations. RESULTS: The panel developed five core recommendations: (1) HBDC should be considered the nexus of new dementia models, from diagnosis to end of life in dementia; (2) new payment models are needed to support HBDC and reward integration of care; (3) a diverse new workforce that spans the care continuum should be prepared urgently; (4) new technologies to promote communication, monitoring/safety, and symptoms management must be tested, integrated, and deployed; and (5) targeted dissemination efforts for HBDC must be employed. DISCUSSION: HBDC represents a promising paradigm shift to improve care for those living with dementia and their family caregivers: these recommendations provide a framework to chart a course forward for HBDC.

Categorizing Health Outcomes and Efficacy of mHealth Apps for Persons With Cognitive Impairment: A Systematic Review.

BACKGROUND: Use of mobile health (mHealth) apps is growing at an exponential rate in the United States and around the world. Mild cognitive impairment (MCI), Alzheimer disease, and related dementias are a global health problem. Numerous mHealth interventions exist for this population, yet the effect of these interventions on health has not been systematically described. OBJECTIVE: The aim of this study is to catalog the types of health outcomes used to measure effectiveness of mHealth interventions and assess which mHealth interventions have been shown to improve the health of persons with MCI, Alzheimer disease, and dementia. METHODS: We searched 13 databases, including Ovid MEDLINE, PubMed, EMBASE, the full Cochrane Library, CINAHL, PsycINFO, Ei Compendex, IEEE Xplore, Applied Science & Technology Source, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar from inception through May 2017 for mHealth studies involving persons with cognitive impairment that were evaluated using at least one quantitative health outcome. Proceedings of the Annual ACM Conferences on Human Factors in Computing Systems, the ACM User Interface Software and Technology Symposium, and the IEEE International Symposium on Wearable Computers were searched in the ACM Digital Library from 2012 to 2016. A hand search of JMIR Publications journals was also completed in July 2017. RESULTS: After removal of duplicates, our initial search returned 3955 records. Of these articles, 24 met final inclusion criteria as studies involving mHealth interventions that measured at least one quantitative health outcome for persons with MCI, Alzheimer disease, and dementia. Common quantitative health outcomes included cognition, function, mood, and quality of life. We found that 21.2% (101/476) of the fully reviewed articles were excluded because of a lack of health outcomes. The health outcomes selected were observed to be inconsistent between studies. For those studies with quantitative health outcomes, more than half (58%) reported postintervention improvements in outcomes. CONCLUSIONS: Results showed that many mHealth app interventions targeting those with cognitive impairment lack quantitative health outcomes as a part of their evaluation process and that there is a lack of consensus as to which outcomes to use. The majority of mHealth app interventions that incorporated health outcomes into their evaluation noted improvements in the health of persons with MCI, Alzheimer disease, and dementia. However, these studies were of low quality, leading to a grade C level of evidence. Clarification of the benefits of mHealth interventions for people with cognitive impairment requires more randomized controlled trials, larger numbers of participants, and trial designs that minimize bias. TRIAL REGISTRATION: PROSPERO Registration: PROSPERO 2016:CRD42016033846; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID=CRD42016033846 (Archived by WebCite at http://www.webcitation.org/6sjjwnv1M).

Depression and Anxiety Screens as Predictors of 8-Year Incidence of Myocardial Infarction and Stroke in Primary Care Patients.

OBJECTIVE: Because depression and anxiety are typically studied in isolation, our purpose was to examine the relative importance of these overlapping emotional factors in predicting incident cardiovascular disease (CVD). METHODS: We examined depression and anxiety screens, and their individual items, as predictors of incident hard CVD events, myocardial infarction, and stroke for 8 years in a diverse sample of 2041 older primary care patients initially free of CVD. At baseline, participants completed self-report depression and anxiety screens. Data regarding CVD events were obtained from an electronic medical record system and the Centers for Medicare and Medicaid Services analytic files. RESULTS: During follow-up, 683 (33%) experienced a CVD event. Cox proportional hazards models-adjusted for demographic and CVD risk factors-revealed that a positive anxiety screen, but not a positive depression screen, was associated with an increased risk of a hard CVD event in separate models (Years 0-3: anxiety hazard ratio [HR] = 1.54, 95% confidence interval [CI] = 1.21-1.96, p < .001; Years 3+: anxiety HR = 0.99, CI = 0.81-1.21), p = .93; depression HR = 1.10, CI = 0.88-1.36, p = .41), as well as when entered into the same model (Years 0-3: anxiety HR = 1.53, CI = 1.20-1.95, p < .001; Years 3+: anxiety HR = 0.99, CI = 0.80-1.21, p = .99; depression HR = 1.03, CI = 0.82-1.29, p = .82). Analyses examining individual items and secondary outcomes showed that the anxiety-CVD association was largely driven by the feeling anxious item and the myocardial infarction outcome. CONCLUSIONS: Anxiety, especially feeling anxious, is a unique risk factor for CVD events in older adults, independent of conventional risk factors and depression. Anxiety deserves increased attention as a potential factor relevant to CVD risk stratification and a potential target of CVD primary prevention efforts.

Emergency Department Use Among Older Adults With Dementia.

Although persons with dementia are frequently hospitalized, relatively little is known about the health profile, patterns of health care use, and mortality rates for patients with dementia who access care in the emergency department (ED). We linked data from our hospital system with Medicare and Medicaid claims, Minimum Data Set, and Outcome and Assessment Information Set data to evaluate 175,652 ED visits made by 10,354 individuals with dementia and 15,020 individuals without dementia over 11 years. Survival rates after ED visits and associated charges were examined. Patients with dementia visited the ED more frequently, were hospitalized more often than patients without dementia, and had an increased odds of returning to the ED within 30 days of an index ED visit compared with persons who never had a dementia diagnosis (odds ratio, 2.29; P<0.001). Survival rates differed significantly between patients by dementia status (P<0.001). Mean Medicare payments for ED services were significantly higher among patients with dementia. These results show that older adults with dementia are frequent ED visitors who have greater comorbidity, incur higher charges, are admitted to hospitals at higher rates, return to EDs at higher rates, and have higher mortality after an ED visit than patients without dementia.

Antidepressant Use in the Elderly Is Associated With an Increased Risk of Dementia.

A retrospective cohort study was conducted including 3688 patients age 60 years or older without dementia enrolled in a depression screening study in primary care clinics. Information on antidepressant use and incident dementia during follow-up was retrieved from electronic medical records. The Cox proportional hazard models were used to compare the risk for incident dementia among 5 participant groups: selective serotonin re-uptake inhibitors (SSRI) only, non-SSRI only (non-SSRI), mixed group of SSRI and non-SSRI, not on antidepressants but depressed, and not on antidepressants and not depressed. SSRI and non-SSRI users had significantly higher dementia risk than the nondepressed nonusers (hazard ratio [HR]=1.83, P=0.0025 for SSRI users and HR=1.50, P=0.004 for non-SSRI users). In addition, SSRIs users had significantly higher dementia risk than non-users with severe depression (HR=2.26, P=0.0005). Future research is needed to confirm our results in other populations and to explore potential mechanism underlying the observed association.

Correlation Between Caregiver Reports of Physical Function and Performance-based Measures in a Cohort of Older Adults With Alzheimer Disease.

The objectives of this report are to determine the association between performance-based measures of physical function with caregiver reports of physical function in older adults with Alzheimer disease (AD) and to examine whether those associations vary by the level of patients' cognitive functioning. Subjects included 180 patient-caregiver dyads who are enrolled in a clinical trial testing the impact of an occupational therapy intervention plus guideline-level care to delay functional decline among older adults with AD. The primary caregiver-reported measure is the Alzheimer's Disease Cooperative Study Group Activities of Daily Living Inventory (ADCS-ADL). Performance-based measures include the Short Physical Performance Battery and the Short Portable Sarcopenia Measure. Analysis of covariance (ANCOVA) models were used to determine the associations of each physical performance measure with ADCS-ADL, adjusting for cognition function and other covariates. We found significant correlations between caregiver reports and observed performance-based measures across all levels of cognitive function, with patients in the lowest cognitive group showing the highest correlation. These findings support the use of proxy reports to assess physical function among older adults with AD.

Chronic DLL4 blockade induces vascular neoplasms.

Delta-like 4 (DLL4)-mediated Notch signalling has emerged as an attractive target for cancer therapy. However, the potential side effects of blocking this pathway remain uncertain. Here we show that chronic DLL4 blockade causes pathological activation of endothelial cells, disrupts normal organ homeostasis and induces vascular tumours, raising important safety concerns.

Therapeutic antibody targeting of individual Notch receptors.

The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.

National Institutes of Health Pathways to Prevention Workshop: the role of opioids in the treatment of chronic pain.

This National Institutes of Health (NIH) Pathways to Prevention Workshop was cosponsored by the NIH Office of Disease Prevention (ODP), the NIH Pain Consortium, the National Institute on Drug Abuse, and the National Institute of Neurological Disorders and Stroke. A multidisciplinary working group developed the workshop agenda, and an evidence-based practice center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the workshop discussion. During the 1.5-day workshop, invited experts discussed the body of evidence, and attendees had opportunities to provide comments during open discussion periods. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the ODP Web site for 2 weeks for public comment. This article is an abridged version of the panel's full report, which is available at https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/opioids-chronic-pain/workshop-resources#final report.

Sex and Race Differences in the Relationship between Obesity and C-Reactive Protein.

C-reactive protein (CRP) is a risk factor for cardiovascular disease and mortality; it is known to be positively associated with obesity but there is some evidence that this association differs by race or sex. We used nationally representative data of adults aged >50 years to investigate sex and race modifiers of the associations between obesity and CRP in non-Hispanic White males (n=3,517) and females (n=4,658), and non-Hispanic Black males (n=464) and females (n=826). Using multiple linear regression models with the natural logarithm of CRP as the dependent variable, we sequentially included body mass index (BMI), a body shape index (ABSI), and socioeconomic, health and health behavior covariates in the model. The association between BMI and CRP was significantly stronger in females than males. Obese White females had mean CRP values slightly above 3 mg/liter (vs 2 for White males) and Black females had mean CRP values >4 mg/liter (vs 3 for Black males). More than 50% of Black females in the United States have obesity. Continued research into racial and sex differences in the relationship between obesity, inflammation, and health risks may ultimately lead to more personalized weight loss recommendations.

Hospice use among nursing home and non-nursing home patients.

BACKGROUND: For nursing home patients, hospice use and associated costs have grown dramatically. A better understanding of hospice in all care settings, especially how patients move across settings, is needed to inform debates about appropriateness of use and potential policy reform. OBJECTIVE: Our aim was to describe characteristics and utilization of hospice among nursing home and non-nursing home patients. DESIGN AND PARTICIPANTS: Medicare, Medicaid and Minimum Data Set data, 1999-2008, were merged for 3,771 hospice patients aged 65 years and above from a safety net health system. Patients were classified into four groups who received hospice: 1) only in nursing homes; 2) outside of nursing homes; 3) crossover patients utilizing hospice in both settings; and 4) "near-transition" patients who received hospice within 30 days of a nursing home stay. MAIN MEASURES: Differences in demographics, hospice diagnoses and length of stay, utilization and costs are presented with descriptive statistics. KEY RESULTS: Nursing home hospice patients were older, and more likely to be women and to have dementia (p < 0.0001). Nearly one-third (32.3 %) of crossover patients had hospice stays > 6 months, compared with the other groups (16 % of nursing home hospice only, 10.7 % of non-nursing home hospice and 7.6 % of those with near transitions) (p < 0.0001). Overall, 27.7 % of patients had a hospice stay <1 week, but there were marked differences between groups-48 % of near-transition patients vs. 7.4 % of crossover patients had these short hospice stays (p < 0.0001). Crossover and near-transition hospice patients had higher costs to Medicare compared to other groups (p < 0.05). CONCLUSIONS: Dichotomizing hospice users only into nursing home vs. non-nursing home patients is difficult, due to transitions across settings. Hospice patients with transitions accrue higher costs. The impact of changes to the hospice benefit on patients who live or move through nursing homes near the end of life should be carefully considered.