Frailty as an Effect Modifier in Randomized Controlled Trials: A Systematic Review.

BACKGROUND: The effect of clinical interventions may vary by patients' frailty status. Understanding treatment effect heterogeneity by frailty could lead to frailty-guided treatment strategies and reduce overtreatment and undertreatment. This systematic review aimed to examine the effect modification by frailty in randomized controlled trials (RCTs) that evaluate pharmacological, non-pharmacological, and multicomponent interventions. METHODS: We searched PubMed, Web of Science, EMBASE, and ClinicalTrial.gov, from their inception to 8 December 2023. Two reviewers independently extracted trial data and examined the study quality with senior authors. RESULTS: Sixty-one RCTs that evaluated the interaction between frailty and treatment effects in older adults were included. Frailty was evaluated using different tools such as the deficit accumulation frailty index, frailty phenotype, and other methods. The effect of several pharmacological interventions (e.g., edoxaban, sacubitril/valsartan, prasugrel, and chemotherapy) varied according to the degree of frailty, whereas other treatments (e.g., antihypertensives, vaccinations, osteoporosis medications, and androgen medications) demonstrated consistent benefits across different frailty levels. Some non-pharmacological interventions had greater benefits in patients with higher (e.g., chair yoga, functional walking, physical rehabilitation, and higher dose exercise program) or lower (e.g., intensive lifestyle intervention, psychosocial intervention) levels of frailty, while others (e.g., resistance-type exercise training, moderate-intensive physical activity, walking and nutrition or walking) produced similar intervention effects. Specific combined interventions (e.g., hospital-based disease management programs) demonstrated inconsistent effects across different frailty levels. DISCUSSION: The efficacy of clinical interventions often varied by frailty levels, suggesting that frailty is an important factor to consider in recommending clinical interventions in older adults. REGISTRATION: PROSPERO registration number CRD42021283051.

Comparison of serial amnioinfusion strategies for isolated early-onset fetal renal anhydramnios.

Introduction The optimal protocol for serial amnioinfusions to maintain amniotic fluid in pregnancies with early onset-fetal renal anhydramnios before 22 weeks is not known. We compared the performance of two different approaches. Methods A secondary analysis was conducted of serial amnioinfusions performed by a single center during the external pilot and feasibility phases of the Renal Agenesis Fetal Therapy (RAFT) trial. During the external pilot, higher amnioinfusion volumes were given less frequently; in the feasibility study, smaller volume amnioinfusions were administered more frequently. Procedural details, complications, and obstetric outcomes were compared between the two groups using Pearson's chi-squared or Fisher's Exact tests for categorical variables and Student's t-tests or Wilcoxon Rank-Sum tests for continuous variables. The adjusted association between procedural details and chorioamniotic separation was obtained through a multivariate repeated measure logistic regression model. Results Eleven participants underwent 159 amnioinfusions (external pilot: three patients, 21 amnioinfusions; feasibility: eight patients, 138 amnioinfusions). External pilot participants had fewer amnioinfusions (7 vs. 19.5 in the feasibility group, p = 0.04), larger amnioinfusion volume (750 vs. 500 mL, p < 0.01), and longer interval between amnioinfusions (6 [4-7] vs. 4 [3-5] days, p < 0.01). In the external pilot, chorioamniotic separation was more common (28.6% vs. 5.8%, p < 0.01), preterm prelabor rupture of membranes (PPROM) occurred sooner after amnioinfusion initiation (28 ± 21.5 vs. 75.6 ± 24.1 days, p = 0.03), and duration of maintained amniotic fluid between first and last amnioinfusion was shorter (38 ± 17.3 vs. 71 ± 19 days, p=0.03), compared to the feasibility group. While delivery gestational age was similar (35.1 ± 1.7 vs. 33.8 ± 1.5 weeks, p=0.21), feasibility participants maintained amniotic fluid longer. Conclusion Small volume serial amnioinfusions performed more frequently maintain normal amniotic fluid volume longer because of delayed occurrence of PPROM.

Exceptional responses to PARP inhibitors in patients with metastatic breast cancer in oncologic crisis.

PURPOSE: Cancers deficient in homologous recombination DNA repair, such as those with BRCA1 or BRCA2 (BRCA1/2) mutations rely on a pathway mediated by the enzyme poly(adenosine diphosphate-ribose) polymerase (PARP). PARP inhibitors (PARPi's) have demonstrated efficacy in treating patients with germline (g)BRCA1/2, somatic (s)BRCA1/2, and gPALB2 mutations in clinical trials. However, patients with a poor performance status (PS) and those with severe organ impairment are often excluded from clinical trials and cancer-directed treatment. METHODS: We report the cases of two patients with metastatic breast cancer who had poor PS, significant visceral disease, and gPALB2 and sBRCA mutations, who derived significant clinical benefit from treatment with PARP inhibition. RESULTS: Patient A had germline testing demonstrating a heterozygous PALB2 pathogenic mutation (c.3323delA) and a BRCA2 variant of unknown significance (c.9353T>C), and tumor sequencing revealed PALB2 (c.228_229del and c.3323del) and ESR1 (c.1610A>C) mutations. Patient B was negative for pathologic BRCA mutations upon germline testing, but tumor sequencing demonstrated somatic BRCA2 copy number loss and a PIK3CA mutation (c.1633G>A). Treatment with PARPi's in these two patients with an initial PS of 3-4 and significant visceral disease resulted in prolonged clinical benefit. CONCLUSION: Patients with a poor PS, such as those described here, may still have meaningful clinical responses to cancer treatments targeting oncogenic drivers. More studies evaluating PARPi's beyond gBRCA1/2 mutations and in sub-optimal PS would help identify patients who may benefit from these therapies.

Older cancer survivors living with financial hardship in China: A qualitative study of family perspectives.

OBJECTIVE: Financial hardship among older cancer survivors has not been well-studied, despite its debilitating effects on their health and well-being. The purpose of this study was to describe the lived experiences of Chinese older cancer survivors who have experienced financial hardship following a cancer diagnosis. METHODS: A qualitative study was conducted. Data was collected using in-depth interviews with 21 older cancer survivors (aged ≥ 60) with financial hardship and 20 family caregivers in Shandong Province, China between August 2020 and January 2021. Data were analyzed using Colaizzi's phenomenological method. RESULTS: Four main themes emerged: (1) older survivors have insufficient ability to address cancer-related costs; (2) financial transfers from adult children to older parents became prevalent after a cancer diagnosis; (3) cancer-related financial worries and stress extended into children's families; (4) coping and adjustment strategies were used by the extended family. Traditional Confucian culture and the Chinese health care system considerably impacted the interpretation of financial hardship. CONCLUSION: Both older cancer survivors and their adult children experienced financial distress impacted by filial piety in China. Strategies adapted to Confucian family values and the health care system are needed to address cancer-related financial hardships.

A nationally representative study of aerobic activity and strength training in older cancer survivors and their psychological distress and sleep difficulties.

OBJECTIVE: To examine the prevalence of different levels of aerobic activity and strength training in older cancer survivors and their associations with psychological distress and sleep difficulties. METHODS: We used cross-sectional data from the 2016-2018 National Health Interview Survey on 3,425 survivors aged ≥ 65 years. Individuals were classified into active, insufficiently active, and inactive categories, and by whether they reported strength training at least twice per week. The outcome variables were self-reported psychological distress, trouble falling asleep, trouble staying asleep, and trouble waking up feeling rested. Multivariate logistic models were used to calculate the odds ratios (ORs) and the 95% confidence intervals (CIs). RESULTS: Only 35.2% of older survivors reached the recommended aerobic activity guidelines, and 12% had strength training at least twice per week. A total of 626 (18.3%) reported at least moderate psychological distress, and 1,137 (33.2%) had trouble staying asleep. For survivors who reported strength training less than two times per week, being insufficiently active or inactive was associated with worse psychological distress (OR 1.52, 95% CI 1.17-1.97; OR 1.30, 95% CI 1.02-1.64) and more sleep difficulties (OR ranging from 1.33 to 2.07). Among active survivors, strength training two or more times per week was associated with more trouble staying asleep (OR 1.67, 95% CI 1.06-2.58). CONCLUSIONS: Most older cancer survivors did not meet the recommended physical activity guidelines and suffered from psychological distress and sleep difficulties. Additional research may be needed to examine the effects of frequent muscle strength training on sleep quality.

Challenges faced by Chinese community nurses when providing home-based hospice and palliative care: a descriptive qualitative study.

BACKGROUND: Hospital facilities in China are experiencing increased strain on existing systems and medical resources, necessitating the use of home-based hospice and palliative care (HBHPC). HBHPC primarily relies on community nurses and related medical personnel. Understanding the challenges that community nurses face when providing this form of care is urgently needed to optimize the design and delivery of HBHPC. Our study aimed to gain insight into community nurses' challenges when providing HBHPC for patients. METHODS: We performed a descriptive qualitative study using a phenomenology approach. Purposive sampling was used to recruit 13 nurses from two community health service centers in Jinan, Shandong Province, China. A thematic analysis was applied to identify themes from the transcribed data. RESULTS: Three major themes emerged: 1) Community nurses' inadequate self-preparation for providing HBHPC; 2) Patients and their families' non-collaboration in HBHPC; 3) Community health service career disadvantages. Many negative experiences can be attributed to institutional barriers. CONCLUSION: Community nurses faced multifaceted challenges in home care settings. This study could provide a framework for guiding the improvement of interventional variables in the provision of HBHPC. Future research should involve developing effective methods of improving community nurses' job motivation and community health service institutions' incentive systems, as well as increasing advocacy around HBHPC.

The experiences of clinical nurses coping with patient death in the context of rising hospital deaths in China: a qualitative study.

BACKGROUND: Chinese clinical nurses are increasingly confronting patient death, as the proportion of hospital deaths is growing. Witnessing patient suffering and death is stressful, and failure to cope with this challenge may result in decreased well-being of nurses and impediment of the provision of "good death" care for patients and their families. To our knowledge, few studies have specifically explored clinical nurses' experiences coping with patient death in mainland China.  OBJECTIVE: We aimed to explore nurses' experiences coping with patient death in China in order to support frontline clinical nurses effectively and guide the government in improving hospice care policy. METHODS: Clinical nurses were recruited using purposive and snowball sampling between June 2020 and August 2020. We gathered experiences of clinical nurses who have coped with patient death using face-to-face, semi-structured, in-depth interviews. Audio recordings were transcribed verbatim and analyzed using thematic analysis. RESULTS: Three thematic categories were generated from data analysis. The first was "negative emotions from contextual challenges." This category involved grief over deaths of younger persons, pity for deaths without family, and dread related to coping with patient death on night duty. The second category was "awareness of mortality on its own." Subthemes included the ideas that death means that everything stops being and good living is important because we all die and disappear. The third category was "coping style." This category included focusing on treating dying patients, recording the signs and symptoms, and responding to changes in the patient's condition. It also involved subthemes such as avoiding talk about death due to the grief associated with dying and death, and seeking help from colleagues. CONCLUSIONS: Clinical nurses' emotional experiences are shaped by intense Chinese filial love, charity, and cultural attitudes towards death. Reasonable nurse scheduling to ensure patient and staff safety is a major priority. "Good death" decisions based on Chinese ethical and moral beliefs must be embedded throughout hospital care.

Staphylococcus epidermidis protease EcpA can be a deleterious component of the skin microbiome in atopic dermatitis.

BACKGROUND: Staphylococcus aureus and Staphylococcus epidermidis are the most abundant bacteria found on the skin of patients with atopic dermatitis (AD). S aureus is known to exacerbate AD, whereas S epidermidis has been considered a beneficial commensal organism. OBJECTIVE: In this study, we hypothesized that S epidermidis could promote skin damage in AD by the production of a protease that damages the epidermal barrier. METHODS: The protease activity of S epidermidis isolates was compared with that of other staphylococcal species. The capacity of S epidermidis to degrade the barrier and induce inflammation was examined by using human keratinocyte tissue culture and mouse models. Skin swabs from atopic and healthy adult subjects were analyzed for the presence of S epidermidis genomic DNA and mRNA. RESULTS: S epidermidis strains were observed to produce strong cysteine protease activity when grown at high density. The enzyme responsible for this activity was identified as EcpA, a cysteine protease under quorum sensing control. EcpA was shown to degrade desmoglein-1 and LL-37 in vitro, disrupt the physical barrier, and induce skin inflammation in mice. The abundance of S epidermidis and expression of ecpA mRNA were increased on the skin of some patients with AD, and this correlated with disease severity. Another commensal skin bacterial species, Staphylococcus hominis, can inhibit EcpA production by S epidermidis. CONCLUSION: S epidermidis has commonly been regarded as a beneficial skin microbe, whereas S aureus has been considered deleterious. This study suggests that the overabundance of S epidermidis found on some atopic patients can act similarly to S aureus and damage the skin by expression of a cysteine protease.

Overall survival in patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer treated with a cyclin-dependent kinase 4/6 inhibitor plus fulvestrant: a US Food and Drug Administration pooled analysis.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. METHODS: In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0-1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. FINDINGS: Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68-0·88), with a median follow-up of 43·7 months (IQR 37·8-47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52-1·07), with a median follow-up of 39·4 months (IQR 37·0-42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9-not estimable) in the CDKI group and was 45·7 months (95% CI 41·7-not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67-0·89), with a median follow-up of 45·1 months (95% CI 39·2-48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. INTERPRETATION: The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. FUNDING: None.

Benefit-Risk Summary of Nivolumab for the Treatment of Patients with Unresectable Advanced, Recurrent, or Metastatic Esophageal Squamous Cell Carcinoma After Prior Fluoropyrimidine- and Platinum-Based Chemotherapy.

On June 10, 2020, the U.S. Food and Drug Administration (FDA) approved nivolumab (OPDIVO; Bristol Myers Squibb, New York, NY) for the treatment of patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy. Approval was based on the results of a single, randomized, active-control study (ATTRACTION-3) that randomized patients to receive nivolumab or investigator's choice of taxane chemotherapy (docetaxel or paclitaxel). The study demonstrated a significant improvement in overall survival (OS; hazard ratio = 0.77; 95% confidence interval: 0.62-0.96; p = .0189) with an estimated median OS of 10.9 months in the nivolumab arm compared with 8.4 months in the chemotherapy arm. Overall, fewer patients in the nivolumab arm experienced treatment-emergent adverse events (TEAEs) of any grade, grade 3-4 TEAEs, and serious adverse events compared with the control arm. The safety profile of nivolumab in patients with ESCC was generally similar to the known safety profile of nivolumab in other cancer types with the following exception: esophageal fistula was identified as a new, clinically significant risk in patients with ESCC treated with nivolumab. Additionally, the incidence of pneumonitis was higher in the ESCC population than in patients with other cancer types who are treated with nivolumab. This article summarizes the FDA review of the data supporting the approval of nivolumab for the treatment of ESCC. IMPLICATIONS FOR PRACTICE: The approval of nivolumab for the treatment of adult patients with unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy was based on an overall survival (OS) benefit from a randomized, open-label, active-controlled study called ATTRACTION-3. Prior to this study, no drug or combination regimen had demonstrated an OS benefit in a randomized study for patients with ESCC after prior fluoropyrimidine- and platinum-based chemotherapy.

Aiding shared decision making in lung cancer screening: two decision tools.

BACKGROUND: Shared decision making (SDM) preceding lung cancer screening is important for populations that are underrepresented in lung cancer screening trials. Current evidence-based guidelines; however, do not address personal risk and outcomes in underrepresented populations. This study compared two SDM decision aids (Option Grids and Shouldiscreen.com) for SDM efficacy, decision regret and knowledge. METHODS: We conducted a prospective trial of lung cancer screening patients (N = 237) randomized to SDM with Option Grids or Shouldiscreen.com. To evaluate the SDM process after lung cancer screening, patients answered two questionnaires: CollaboRATE and Decision Regret. Patients also completed a questionnaire to test their knowledge of lung cancer screening. RESULTS: Patients were predominantly African American (61.6%), though multiple races, varying education levels and equal genders were represented. Patients in both Option Grids and Shouldiscreen.com groups reported favorable SDM experiences (P = 0.60) and equivalent knowledge about lung cancer screening (P = 0.43). Patients using Shouldiscreen.com had less knowledge regarding the potential complications of subsequent testing (P = 0.02). Shouldiscreen.com patients had increased regret regarding their decision to pursue screening (P = 0.02). CONCLUSIONS: Option Grids and Shouldiscreen.com both facilitated a meaningful SDM process. However, Option Grids patients experienced decreased decision regret and enhanced knowledge of the potential complications of screening.

A qualitative study of home health care experiences among Chinese homebound adults.

BACKGROUND: Home health care services (HHC) are emerging in China to meet increased healthcare needs among the homebound population, but there is a lack of research examining the efficiency and effectiveness of this new care model. This study aimed to investigate care recipients' experiences with HHC and areas for improvement in China. METHODS: This research was a qualitative study based on semi-structured interviews. Qualitative data were collected from homebound adults living in Jinan, Zhangqiu, and Shanghai, China. A sample of 17 homebound participants aged 45 or older (mean age = 76) who have received home-based health care were recruited. Conceptual content analysis and Colaizzi's method was used to generate qualitative codes and identify themes. RESULTS: The evaluations of participants' experiences with HHC yielded both positive and negative aspects. Positive experiences included: 1) the healthcare delivery method was convenient for homebound older adults; 2) health problems could be detected in a timely manner because clinicians visited regularly; 3) home care providers had better bedside manners and technical skills than did hospital-based providers; 4) medical insurance typically covered the cost of home care services. Areas that could potentially be improved included: 1) the scope of HHC services was too limited to meet all the needs of homebound older adults; 2) the visit time was too short; 3) healthcare providers' technical skills varied greatly. CONCLUSIONS: Findings from this study suggested that the HHC model benefited Chinese older adults-primarily homebound adults-in terms of convenience and affordability. There are opportunities to expand the scope of home health care services and improve the quality of care. Policymakers should consider providing more resources and incentives to enhance HHC in China. Educational programs may be created to train more HHC providers and improve their technical skills.

Skin Cancer Incidence in Organ Transplant Recipients Referred for Benign Skin Conditions.

BACKGROUND: Solid organ transplant recipients (SOTRs) are at ∼100-fold increased risk for developing skin cancers compared with the general population, with increased morbidity and mortality. These patients are closely followed by dermatology; however, it is unclear how referral reasons from nondermatologic providers affect care in these patients. OBJECTIVE: This study examines the reason SOTRs are referred to dermatologic care by nondermatologic providers as a potential predictor of nonmelanoma skin cancer (NMSC) outcomes. MATERIALS AND METHODS: A retrospective case-control study was conducted with the records of 353 adult SOTRs referred to a specialized transplant dermatology clinic within an academic tertiary care center between 2007 and mid-2012. RESULTS: Eighty-one patients were diagnosed with 491 total premalignant and malignant skin lesions. A considerable proportion of patients diagnosed with NMSC were referred for benign skin conditions such as rash or acne. CONCLUSION: These results indicate that some SOTRs referred to dermatology for benign skin disorders are incidentally diagnosed with cutaneous malignancies; this is concerning given that referrals for benign skin conditions may delay appropriate care for cutaneous malignancies and preventative care. Better risk stratification, improved interdisciplinary collaboration, and prompt referrals for dermatologic care are needed in the care of SOTRs.

CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis.

BACKGROUND: Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. METHODS: We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. FINDINGS: The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9-25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8-13·3 months; HR 0·59, 95% CI 0·54-0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3-29·1) versus 14·9 months (14·0-16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0-13·3 months; HR 0·55, 95% CI 0·49-0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8-23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42-0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5-7·3 months; HR 0·56, 95% CI 0·49-0·64). INTERPRETATION: Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. FUNDING: None.

High-Cost Patients and Preventable Spending: A Population-Based Study.

BACKGROUND: Although high-cost (HC) patients make up a small proportion of patients, they account for most health system costs. However, little is known about HC patients with cancer or whether some of their care could potentially be prevented. This analysis sought to characterize HC patients with cancer and quantify the costs of preventable acute care (emergency department visits and inpatient hospitalizations). METHODS: This analysis examined a population-based sample of all HC patients in Ontario in 2013. HC patients were defined as those above the 90th percentile of the cost distribution; all other patients were defined as non-high-cost (NHC). Patients with cancer were identified through the Ontario Cancer Registry. Sociodemographic and clinical characteristics were examined and the costs of preventable acute care for both groups by category of visit/condition were estimated using validated algorithms. RESULTS: Compared with NHC patients with cancer (n=369,422), HC patients with cancer (n=187,770) were older (mean age 70 vs 65 years), more likely to live in low-income neighborhoods (19% vs 16%), sicker, and more likely to live in long-term care homes (8% vs 0%). Although most patients from both cohorts tended to be diagnosed with breast, prostate, or colorectal cancer, those with multiple myeloma or pancreatic or liver cancers were overrepresented among the HC group. Moreover, HC patients were more likely to have advanced cancer at diagnosis and be in the initial or terminal phase of treatment compared with NHC patients. Among HC patients with cancer, 9% of spending stemmed from potentially preventable/avoidable acute care, whereas for NHC patients, this spending was approximately 30%. CONCLUSIONS: HC patients with cancer are a unique subpopulation. Given the type of care they receive, there seems to be limited scope to prevent acute care spending among this patient group. To reduce costs, other strategies, such as making hospital care more efficient and generating less costly encounters involving chemotherapy, should be explored.

A qualitative study of health-care experiences and challenges faced by ageing homebound adults.

BACKGROUND: The ageing of the global population is associated with an increasing prevalence of chronic diseases and functional impairments, resulting in a greater proportion of homebound individuals. OBJECTIVE: To examine the health-care experiences of older homebound adults who have not previously received home-based primary care (HBPC). To explore their impressions of this method of care. DESIGN: Cross-sectional qualitative study using semi-structured interviews. SETTING AND PARTICIPANTS: 18 older homebound individuals in Central Virginia. RESULTS: Our findings revealed that homebound individuals faced significant health challenges, including pain resulting from various comorbidities. They felt that their mobility was restricted by their physical conditions and transportation challenges. These were major barriers to social outings and health-care access. Participants left their homes infrequently and typically with assistance. Regarding office-based care, participants were concerned about long wait times and making timely appointments. Some thought that HBPC would be convenient and could result in better quality care; however, others believed that the structure of the health-care system and its focus on efficiency would not permit routine HBPC. DISCUSSION AND CONCLUSIONS: Older homebound adults in this study faced high burdens of disease, a lack of mobility and difficulty accessing quality health care. Our observations may help researchers and clinicians better understand the health-care experiences and personal opinions of older homebound individuals, informing the development of effective and empathetic home-based care. Participant responses illuminated a need for education about HBPC. We must improve health-care delivery and develop comprehensive, patient-centered HBPC to meet the needs of homebound individuals.

A physician-initiated intervention to increase colorectal cancer screening in Chinese patients.

BACKGROUND: Among Chinese American individuals, only approximately 42% of cases of colorectal cancer (CRC) are diagnosed at an early stage, possibly because these patients are less likely than non-Hispanic white individuals to undergo CRC screening. METHODS: Primary care physicians (PCPs) were recruited from a local independent practice association serving Chinese Americans and randomized into early-intervention and delayed-intervention groups. PCPs in the early-intervention group received continuing medical education (CME), and their patients received an intervention mailer, consisting of a letter with the PCP's recommendation, a bilingual educational booklet, and a fecal occult blood test (FOBT) kit in year 1. PCPs in the delayed-intervention group received no CME, and their patients received the mailers in year 2. RESULTS: A total of 20 PCPs were assigned to the early-intervention and 22 PCPs to the delayed-intervention group. A total of 3120 patients of these participating PCPs who had undergone CRC screening that was due during the study period were included. A total of 915 mailers were sent in year 1 and 830 mailers were sent in year 2. FOBT screening rates increased from 26.7% at baseline to 58.5% in year 1 in the early-intervention group versus 19.6% at baseline to 22.2% in year 1 in the delayed-intervention group (P<.0001). The overall effect size of the mailer intervention with or without CME was estimated as a difference of 26.6 percentage points (95% confidence interval, 22.0-31.2 percentage points) from baseline compared with usual care. The intervention was found to have no impact on rates of colonoscopy or sigmoidoscopy. CONCLUSIONS: The results of the current pilot study demonstrated that a mailer including educational materials and FOBT kits can increase CRC screening rates with or without CME for the PCPs. Cancer 2018;124:1568-75. © 2018 American Cancer Society.

mTORC2 in Thymic Epithelial Cells Controls Thymopoiesis and T Cell Development.

Thymic epithelial cells (TECs) play important roles in T cell generation. Mechanisms that control TEC development and function are still not well defined. The mammalian or mechanistic target of rapamycin complex (mTORC)2 signals to regulate cell survival, nutrient uptake, and metabolism. We report in the present study that mice with TEC-specific ablation of Rictor, a critical and unique adaptor molecule in mTORC2, display thymic atrophy, which accompanies decreased TEC numbers in the medulla. Moreover, generation of multiple T cell lineages, including conventional TCRαß T cells, regulatory T cells, invariant NKT cells, and TCRγδ T cells, was reduced in TEC-specific Rictor-deficient mice. Our data demonstrate that mTORC2 in TECs is important for normal thymopoiesis and efficient T cell generation.

The Relation between Food Insecurity and Mental Health Care Service Utilization in Ontario.

OBJECTIVE: To determine the relationship between household food insecurity status over a 12-month period and adults' use of publicly funded health care services in Ontario for mental health reasons during this period. METHODS: Data for 80,942 Ontario residents, 18 to 64 years old, who participated in the Canadian Community Health Survey in 2005, 2007-2008, 2009-2010, or 2011-2012 were linked to administrative health care data to determine individuals' hospitalizations, emergency department visits, and visits to psychiatrists and primary care physicians for mental health reasons. Household food insecurity over the past 12 months was assessed using the Household Food Security Survey Module. Logistic regression models were used to estimate the odds of mental health service utilization in the past 12 months by household food insecurity status, adjusting for sociodemographic factors and prior use of mental health services. RESULTS: In our fully adjusted models, in comparison to food-secure individuals, the odds of any mental health care service utilization over the past 12 months were 1.15 (95% confidence interval [CI], 1.04 to 1.29) for marginally food-insecure individuals, 1.39 (95% CI, 1.19 to 1.42) for moderately food-insecure individuals, and 1.50 (95% CI, 1.35 to 1.68) for severely food-insecure individuals. A similar pattern persisted across individual types of services, with odds of utilization highest with severe food insecurity. CONCLUSIONS: Household food insecurity status is a robust predictor of mental health service utilization among working-age adults in Ontario. Policy interventions are required to address the underlying causes of food insecurity and the particular vulnerability of individuals with mental illness.