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Katherine Possin and colleagues report on the implementation, development, and early findings of the Care Ecosystem, an adaptive, personalized, and scalable dementia care program.Katherine Possin and colleagues report on the implementation, development, and early findings of the Care Ecosystem, an adaptive, personalized, and scalable dementia care program.

Introduction Informal caregiving is an essential element of health‐care delivery. Little data describes how caregivers structure care recipients’ lives and impact their functional status. Methods We performed observational studies of community dwelling persons with dementia (PWD) to measure functional status by simultaneous assessment of physical activity (PA) and lifespace (LS). We present data from two caregiver/care‐recipient dyads representing higher and average degrees of caregiver involvement. Results We acquired >42,800 (subject 1); >41,300 (subject 2) PA data points and >154,500 (subject 1); >119,700 (subject 2) LS data points over 15 months of near continuous observation. PA and LS patterns provided insights into the caregiver's role in structuring the PWD's day‐to‐day function and change in function over time. Discussion We show that device‐enabled functional monitoring (FM) can successfully gather and display data at resolutions required for dementia care studies. Objective quantification of individual caregiver/care‐recipient dyads provides opportunities to implement patient‐centered care.

The purpose of this qualitative study was to explore the meanings that childfree African American and Hispanic women place on motherhood and to better understand what impact these meanings may or may not have on the changing demographic of minority women who do not have children. This study used qualitative interviews and the method of phenomenology to elicit descriptions from a sample of African American and Hispanic women who do not have children. Specifically, the goal of this study was to explore how African American and Hispanic childfree women conceptualize their understanding of motherhood and to understand how these conceptualizations may impact their view of motherhood or becoming a mother. Data were collected from 17 in-depth interviews (n = 8 African American childfree women; n = 9 Hispanic childfree women) and then analyzed using phenomenological procedures. From this study six themes emerged: (1) Strong mother influence—Minority childfree women had a mother figure in their lives that shaped the requirements they felt women should fulfill in the motherhood role. (2) Familial Caregiving—Minority women without children experienced caring for children primarily within their own families or through kinship ties and neighbors that were connected to their family of origin. (3) Purposefully Not Ready—The meanings attributed to the role of motherhood by minority women in this study directly affected their decisions to become mothers themselves. (4) Motherhood is Hard Work—Minority childfree women participating in this study framed their desire to have children in part to their perception that the tasks and duties ascribed to motherhood are labor intensive. (5) Rules, Tradition, and \"The Way it Should Be\"—A collective notion of the importance of creating \"rules\" for children and abiding by \"tradition\" is the fifth theme in this study. Women that were interviewed also discussed the importance of raising children in a nuclear family consisting of a two parent household. Statements within this theme related to the insights that the women had regarding how children should be parented. (6) Understood Judgment—The data revealed that African American and Hispanic women experience criticism and judgment within their families and communities for not becoming a mother. Minority women within this study also indicated that criticism was expected and did not affect their desire to have children.

Background This study examined the relationship among enacted weight stigma, weight self-stigma, and multiple health outcomes. Weight stigma, a stressor experienced across all body sizes, may contribute to poorer physical health outcomes by activating the nervous and endocrine system or by triggering counterproductive health behaviors like lower physical activity, maladaptive eating patterns, and delayed health care, as well as provider bias that may cause a medical concern to be discounted. While associations of weight stigma with mental health issues are well documented, less is known about its association with physical health. Methods We enrolled 3821 adults who completed an online survey assessing enacted weight stigma, weight self-stigma, multiple self-reported physical health outcomes, healthcare utilization, and selected health behaviors. Results After controlling for BMI, health care delay or avoidance, sedentary behavior, and selected demographic characteristics, enacted weight stigma, significantly increased the odds of six physical health problems including hypertension (OR 1.36; CI 1.08, 1.72), hyperglycemia (OR 1.73; CI 1.29, 2.31), thyroid disorder, (OR 1.65; CI 1.27, 2.13), any arthritis (OR 1.70; CI 1.27, 2.26), non-arthritic chronic pain (OR 1.76; CI 1.4, 2.29), and infertility (OR 1.53; CI 1.14, 2.05). Weight self-stigma significantly increased the odds for three physical health problems including hypertension (OR 1.43; CI 1.16, 1.76), hyperglycemia (OR 1.37; CI 1.03, 1.81), and non-arthritic chronic pain (OR 1.5; CI 1.2,1.87). Enacted stigma was associated with more than a four-fold increase in odds of believing that a medical concern was disregarded by a health care provider. Conclusions In this study, enacted stigma and weight self-stigma were independently associated with heightened risk for multiple physical health problems, as well as, believing health concerns were discounted by providers. Reducing weight stigma may be an important component of managing multiple physical health conditions.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system 1 . Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis 2 , 3 . However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes. Here, to address these challenges, we developed focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. We applied FIND-seq to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in multiple sclerosis and experimental autoimmune encephalomyelitis 4 . Using FIND-seq in combination with conditional-knockout mice, in vivo CRISPR–Cas9-driven genetic perturbation studies and bulk and single-cell RNA sequencing analyses of samples from mouse experimental autoimmune encephalomyelitis and humans with multiple sclerosis, we identified a new role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, we used FIND-seq to identify a therapeutically targetable mechanism that limits XBP1-driven pathogenic astrocyte responses. FIND-seq enables the investigation of previously inaccessible cells, including rare cell subsets defined by unique gene expression signatures or other nucleic acid markers. The pathogenic function of XBP1-expressing astrocytes in experimental autoimmune encephalomyelitis and multiple sclerosis have been studied using FIND-seq, a new method combining microfluidics cytometry, PCR-based detection of nucleic acids and cell sorting for in-depth single-cell transcriptomics analyses of rare cells.

Early-stage breast cancers resistant to neoadjuvant therapy (NAT), characterized by high residual cancer burden (RCB) after treatment, have an increased risk of metastatic recurrence. Here, we show that circulating tumor DNA (ctDNA) detected using a tumor-informed test (1) can improve risk stratification of patients with NAT-resistant tumors (RCB-II/RCB-III) and (2) predict response to NAT. Stratification using ctDNA status at pretreatment or post-NAT and ctDNA dynamics identified NAT-resistant tumors with a significantly decreased risk of metastatic recurrence. ctDNA clearance as early as week 3 across receptor subtypes predicted favorable responses to NAT, including immunotherapies. Interestingly, less than a fifth of patients with NAT-resistant tumors were ctDNA-positive post-NAT. Serial mutation profiling of NAT-resistant tumors revealed that patient-specific ctDNA assay variants remained detectable over time, including in tumors of patients ctDNA-negative post-NAT. Refining risk stratification for NAT-resistant tumors using ctDNA and understanding ctDNA shedding in these tumors could guide treatment decisions to prevent or delay metastatic recurrence. The metastatic potential of patients following breast cancer neoadjuvant therapy is highly variable. Here, the authors demonstrated the predictive and prognostic value of ctDNA in 723 patients with high-risk early-stage breast cancer using serial analysis.

Background Moving from sitting to standing is a common activity of daily living. The five-repetition sit-to-stand test (5STS) is a test of lower limb function that measures the fastest time taken to stand five times from a chair with arms folded. The 5STS has been validated in healthy community-dwelling adults, but data in chronic obstructive pulmonary disease (COPD) populations are lacking. Aims To determine the reliability, validity and responsiveness of the 5STS in patients with COPD. Methods Test-retest and interobserver reliability of the 5STS was measured in 50 patients with COPD. To address construct validity we collected data on the 5STS, exercise capacity (incremental shuttle walk (ISW)), lower limb strength (quadriceps maximum voluntary contraction (QMVC)), health status (St George's Respiratory Questionnaire (SGRQ)) and composite mortality indices (Age Dyspnoea Obstruction index (ADO), BODE index (iBODE)). Responsiveness was determined by measuring 5STS before and after outpatient pulmonary rehabilitation (PR) in 239 patients. Minimum clinically important difference (MCID) was estimated using anchor-based methods. Results Test-retest and interobserver intraclass correlation coefficients were 0.97 and 0.99, respectively. 5STS time correlated significantly with ISW, QMVC, SGRQ, ADO and iBODE (r=−0.59, −0.38, 0.35, 0.42 and 0.46, respectively; all p<0.001). Median (25th, 75th centiles) 5STS time decreased with PR (Pre: 14.1 (11.5, 21.3) vs Post: 12.4 (10.2, 16.3) s; p<0.001). Using different anchors, a conservative estimate for the MCID was 1.7 s. Conclusions The 5STS is reliable, valid and responsive in patients with COPD with an estimated MCID of 1.7 s. It is a practical functional outcome measure suitable for use in most healthcare settings.

Stem cell therapies are limited by poor cell survival and engraftment. A hurdle to the use of materials for cell delivery is the lack of understanding of material properties that govern transplanted stem cell functionality. Here, we show that synthetic hydrogels presenting integrin-specific peptides enhance the survival, persistence, and osteo-reparative functions of human bone marrow-derived mesenchymal stem cells (hMSCs) transplanted in murine bone defects. Integrin-specific hydrogels regulate hMSC adhesion, paracrine signaling, and osteoblastic differentiation in vitro. Hydrogels presenting GFOGER, a peptide targeting α2β1 integrin, prolong hMSC survival and engraftment in a segmental bone defect and result in improved bone repair compared to other peptides. Integrin-specific hydrogels have diverse pleiotropic effects on hMSC reparative activities, modulating in vitro cytokine secretion and in vivo gene expression for effectors associated with inflammation, vascularization, and bone formation. These results demonstrate that integrin-specific hydrogels improve tissue healing by directing hMSC survival, engraftment, and reparative activities. Mesenchymal stromal cells enhance bone and cartilage repair, but are limited by poor survival and retention after transplantation. Here, the authors show that synthetic hydrogels presenting integrin-specific peptides enhance the survival and persistence of human mesenchymal stromal cells after transplant, as well as bone repair.

Sexual debut, or first intercourse, predicts problem behaviors such as substance use. This association could reflect a direct effect of debut itself, general developmental trends, or the fact that some youth are more predisposed to a wide array of problem behaviors (e.g., risky sex, substance use). Understanding the association between sexual debut and substance use thus requires methods that can distinguish between these various accounts. In this study the association between sexual debut and substance use was investigated in a longitudinal sample of Mexican-origin youth (N = 674) assessed annually from 5th (Mage = 10.86 years, SD = 0.51) through 12th grade (Mage = 17.69 years, SD = 0.48). The longitudinal aspect of the data allowed the direct effect of sexual debut on substance use to be tested while accounting for long-term trends in substance use, and stable individual differences in those trends based on early risk and debut timing. Substance use increased over time, and early risk and debut were consistently associated with more substance use. Sexual debut also modestly predicted an increase in substance use after accounting for these effects, however. Taken together, results provide some evidence consistent with each of the potential explanations for the association between sexual debut and substance use across adolescence.

Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Comprehensive Cancer Center of Wake Forest Baptist Medical Center.