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Background: Anticoagulant drugs are a valuable tool for minimizing thrombotic risks in at-risk patients. The purpose of this study is to conduct a literature review highlighting the management of these drugs during daily clinical dental practice. Materials and Methods: We limited our search to English-language papers published between 1 January 1989, and 7 March 2024, in PubMed, Scopus and Web of Science that were relevant to our topic. In the search approach, the Boolean keywords "anticoagulant AND dentistry" were used. Results: Twenty-five clinical trials were included for final review from 623 articles obtained from the databases Web of Science (83), PubMed (382), and Scopus (158), eliminating duplicates and 79 off-topic items, resulting in 419 articles after removing 315 entries and confirming eligibility. Overall, these studies support the use of local hemostatic measures to manage the risk of bleeding in patients on anticoagulant therapy undergoing dental procedures and highlight the importance of greater education and collaboration among healthcare professionals. Conclusions: Research and clinical investigation have improved understanding and management of dental procedures in patients undergoing anticoagulant or antiplatelet therapy. Hemostatic agents, clinical protocols, risk factors, and continuous education are essential for navigating the complexities of anticoagulant therapy, ensuring optimal outcomes and enhancing patient well-being. [ABSTRACT FROM AUTHOR]

Background: Therapeutic ceiling of care is the maximum level of care deemed appropiate to offer to a patient based on their clinical profile and therefore their potential to derive benefit, within the context of the availability of resources. To our knowledge, there are no models to predict ceiling of care decisions in COVID-19 patients or other acute illnesses. We aimed to develop and validate a clinical prediction model to predict ceiling of care decisions using information readily available at the point of hospital admission. Methods: We studied a cohort of adult COVID-19 patients who were hospitalized in 5 centres of Catalonia between 2020 and 2021. All patients had microbiologically proven SARS-CoV-2 infection at the time of hospitalization. Their therapeutic ceiling of care was assessed at hospital admission. Comorbidities collected at hospital admission, age and sex were considered as potential factors for predicting ceiling of care. A logistic regression model was used to predict the ceiling of care. The final model was validated internally and externally using a cohort obtained from the Leeds Teaching Hospitals NHS Trust. The TRIPOD Checklist for Prediction Model Development and Validation from the EQUATOR Network has been followed to report the model. Results: A total of 5813 patients were included in the development cohort, of whom 31.5% were assigned a ceiling of care at the point of hospital admission. A model including age, COVID-19 wave, chronic kidney disease, dementia, dyslipidaemia, heart failure, metastasis, peripheral vascular disease, chronic obstructive pulmonary disease, and stroke or transient ischaemic attack had excellent discrimination and calibration. Subgroup analysis by sex, age group, and relevant comorbidities showed excellent figures for calibration and discrimination. External validation on the Leeds Teaching Hospitals cohort also showed good performance. Conclusions: Ceiling of care can be predicted with great accuracy from a patient's clinical information available at the point of hospital admission. Cohorts without information on ceiling of care could use our model to estimate the probability of ceiling of care. In future pandemics, during emergency situations or when dealing with frail patients, where time-sensitive decisions about the use of life-prolonging treatments are required, this model, combined with clinical expertise, could be valuable. However, future work is needed to evaluate the use of this prediction tool outside COVID-19. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine neoplasms (NENs) are occurring more frequently worldwide. Data from the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed that female patients have better survival with neuroendocrine neoplasms. This study used the U.S. cancer database (Surveillance, Epidemiology, and End Results Program (SEER)) to validate and compare these findings. Sixty-months survival for NENs were calculated for both male and female patients from NCRAS and SEER. The findings from NCRAS were confirmed by the findings from SEER that females survive more than males with NENs, mainly with lung and stomach NENs. The reason behind this is unclear and remains unexplained. Background: Neuroendocrine neoplasms (NENs) are increasing in incidence globally. Previous analysis of the UK cancer database (National Cancer Registration and Analysis Service (NCRAS)) showed a notable female survival advantage in most tumour sites. This study aims to compare NCRAS to the Surveillance, Epidemiology, and End Results Program (SEER) to validate these results using the same statistical methods. Methods: A total of 14,834 and 108,399 patients with NENs were extracted from NCRAS and SEER, respectively. Sixty-months survival for both males and females for each anatomical site of NENs were calculated using restricted mean survival time (RMST) and Kaplan–Meier Survival estimates. The sixty-month RMST female survival advantage (FSA) was calculated. Results: FSA was similar in NCRAS and SEER. The highest FSA occurred in lung and stomach NENs. Conclusions: The data from SEER confirm the findings published by NCRAS. Female survival advantage remains unexplained. [ABSTRACT FROM AUTHOR]

Recognizing the pivotal role of circadian rhythm in the human aging process and its scalability through wearables, we introduce CosinorAge, a digital biomarker of aging developed from wearable-derived circadian rhythmicity from 80,000 midlife and older adults in the UK and US. A one-year increase in CosinorAge corresponded to 8–12% higher all-cause and cause-specific mortality risks and 3–14% increased prospective incidences of age-related diseases. CosinorAge also captured a non-linear decline in resilience and physical functioning, evidenced by an 8–33% reduction in self-rated health and a 3–23% decline in health-related quality of life score, adjusting for covariates and multiple testing. The associations were robust in sensitivity analyses and external validation using an independent cohort from a disparate geographical region using a different wearable device. Moreover, we illustrated a heterogeneous impact of circadian parameters associated with biological aging, with young (<45 years) and fast agers experiencing a substantially delayed acrophase with a 25-minute difference in peak timing compared to slow agers, diminishing to a 7-minute difference in older adults (>65 years). We demonstrated a significant enhancement in the predictive performance when integrating circadian rhythmicity in the estimation of biological aging over physical activity. Our findings underscore CosinorAge's potential as a scalable, economic, and digital solution for promoting healthy longevity, elucidating the critical and multifaceted circadian rhythmicity in aging processes. Consequently, our research contributes to advancing preventive measures in digital medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: This study addresses the challenge of interpreting the efficacy of immunotherapy in biliary tract cancer (BTC) in terms of overall survival (OS). Traditional methods often rely on the proportional hazard assumption, which may not hold in this context. Instead, we performed a meta-analysis of available phase 3 trials using restricted median survival time (RMST) to measure temporal benefits, providing a clearer picture of the real effects of immunotherapy-based regimens. By incorporating anti-PD-1/anti-PD-L1 agents, our analysis confirmed improvements in estimated mean OS and progression-free survival (PFS) at 24 months, as indicated by RMST, of 1.21 (95% CI: 0.49–1.93) and 1.31 (95% CI: 0.66–1.96) months, respectively. This approach not only offers a more nuanced understanding of clinical benefits, but also aids healthcare providers and patients in making informed decisions about treatment options, emphasizing a methodology that can adapt to the complexities of data. Background: For biliary tract cancer (BTC), the addition of immunotherapy (durvalumab or pembrolizumab) to gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in phase 3 clinical trials (RCTs). However, the interpretation and magnitude of the treatment effect is challenging because OS Kaplan–Meier curves violate the proportional hazards (PH) assumption. Analysis using restricted mean survival time (RMST) allows quantification of the benefits in the absence of PH. This systematic review and meta-analysis aims to assess the benefit of immunotherapy-based regimens for OS at 24 months using RMST analysis. Methods: A systematic review was conducted using studies published up to 8 November 2023. Only phase 3 RCTs evaluating the use of anti-PD-1/PD-L1 combined with GemCis and reporting OS were included. KM curves for OS were digitized, and the data were reconstructed. A meta-analysis for OS by RMST at 24 months was performed. Results: A total of 1754 participants from the TOPAZ-1 and KEYNOTE-966 trials were included. In TOPAZ-1, RMSTs at 24 months were 13.52 (7.92) and 12.21 (7.22) months with GemCis plus durvalumab and GemCis alone, respectively. In KEYNOTE-966, RMSTs at 24 months were 13.60 (7.76) and 12.45 (7.73) months with GemCis plus pembrolizumab and GemCis alone, respectively. Immunotherapy-based regimens showed a mean OS difference at 24 months by an RMST of 1.21 months [(95% CI: 0.49–1.93), p < 0.001, I2 = 0%]. Conclusions: Immunotherapy-based regimens improve OS in advanced BTC. Given this magnitude of benefit, it is essential to weigh up individual patient factors, preferences, and potential risks. RMST analysis provides valuable information to patients and physicians, facilitating decision-making in a value-based medical environment. [ABSTRACT FROM AUTHOR]

Simple Summary: Goals-of-care discussions, by promoting mutual understanding between patients and clinicians, supporting decision making and facilitating care planning, have been found to reduce acute care use and cost of care downstream. However, it is not known if goals-of-care discussions have an immediate impact on the cost of the same hospital stay. In this real-world study, we examined the hospitalization cost before and after the implementation of a goals-of-care program. We found that the overall cost in unselected medical patients did not differ significantly before and after program implementation; however, the cost of hospitalization decreased significantly among ICU patients by 17% after program implementation. This study highlights the potential value-based benefit of goals-of-care programs for patients who have serious illnesses. The impact of goals-of-care programs on acute hospitalization costs is unclear. We compared the hospitalization cost in an 8-month period before implementation of a multimodal interdisciplinary goals-of-care program (1 May 2019 to 31 December 2019) to an 8-month period after program implementation (1 May 2020 to 31 December 2020). Propensity score weighting was used to adjust for differences in potential covariates. The primary outcome was total direct cost during the hospital stay for each index hospitalization. This analysis included 6977 patients in 2019 and 5964 patients in 2020. The total direct cost decreased by 3% in 2020 but was not statistically significant (ratio 0.97, 95% CI 0.92, 1.03). Under individual categories, there was a significant decrease in medical oncology (ratio 0.58, 95% CI 0.50, 0.68) and pharmacy costs (ratio 0.86, 95% CI 0.79, 0.96), and an increase in room and board (ratio 1.06, 95% CI 1.01, 1.10). In subgroup analysis, ICU patients had a significant reduction in total direct cost after program implementation (ratio 0.83, 95% CI 0.72, 0.94). After accounting for the length of ICU admission, we found that the total direct cost per hospital day was no longer different between 2019 and 2020 (ratio 0.986, 95% CI 0.92, 1.05), suggesting that shorter ICU admissions likely explained much of the observed cost savings. This study provides real-world data on how "in-the-moment" GOC conversations may contribute to reduced hospitalization costs among ICU patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In a comprehensive analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and the CLL13 trials, we assessed the impact of first-line treatments with targeted agents (TAs), or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT), on overall survival (OS) compared to age- and sex-matched individuals in the general population. TAs demonstrated a higher 5-year restricted mean survival time (RMST) (58.1 months; 95% CI: 57.4 to 58.8) compared to CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Moreover, the comparison with age- and gender-matched general populations (AGMGP) suggested that TAs may mitigate CLL's impact on OS during the first five years post-treatment initiation. In contrast, CLL patients treated with FCR exhibited sustained OS differences compared to both the Italian and US AGMGP cohorts. These results support TAs as the preferred first-line treatment for younger/fit CLL patients but imply the need for a careful interpretation due to variations in patient selection criteria and clinical profiles across trials. Longer follow-up is essential to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. To assess the impact of first-line treatment with targeted agents (TAs) or fludarabine, cyclophosphamide, and rituximab (FCR)-based chemo-immunotherapy (CIT) on overall survival (OS) compared to age- and sex-matched individuals in the general population, we conducted an aggregated analysis of phase 3 clinical trials, including the two FLAIR sub-studies, ECOG1912, and CLL13 trials. The restricted mean survival time (RMST), an alternative measure in outcome analyses capturing OS changes over the entire history of the disease, was used to minimize biases associated with the short follow-up time of trials. Patients treated with TAs demonstrated a higher 5-year RMST (58.1 months; 95% CI: 57.4 to 58.8) compared to those treated with CIT (5-year RMST, 56.9 months; 95% CI: 56.7–58.2). Furthermore, the OS comparison of treatment groups with the AGMGP suggests that TAs may mitigate the impact of CLL on OS during the first five years post-treatment initiation. In summary, the 5-year RMST difference was −0.4 months (95% CI: −0.8 to 0.2; p = 0.10) when comparing CLL patients treated with TAs to the Italian age- and gender-matched general population (AGMGP). A similar trend was observed when CLL patients treated with TAs were compared to the US AGMGP (5-year RMST difference, 0.3 months; 95% CI: −0.1 to 0.9; p = 0.12). In contrast, CLL patients treated with FCR exhibited sustained OS differences when compared to both the Italian cohort (5-year RMST difference: −1.6 months; 95% CI: −2.4 to −0.9; p < 0.0001) and the US AGMGP cohort (5-year RMST difference: −0.9 months; 95% CI: −1.7 to −0.2; p = 0.015). Although these results support TAs as the preferred first-line treatment for younger CLL patients, it is crucial to acknowledge that variations in patient selection criteria and clinical profiles across clinical trials necessitate a cautious interpretation of these findings that should be viewed as directional and hypothesis-generating. A longer follow-up is needed to assess the survival improvement of younger CLL patients treated with TAs relative to the AGMGP. [ABSTRACT FROM AUTHOR]

Purpose: The Aging and Cognitive Health Evaluation in Elders (ACHIEVE) study is a randomized clinical trial designed to determine the effects of a bestpractice hearing intervention versus a successful aging health education control intervention on cognitive decline among community-dwelling older adults with untreated mild-to-moderate hearing loss. We describe the baseline audiologic characteristics of the ACHIEVE participants. Method: Participants aged 70-84 years (N = 977; Mage = 76.8) were enrolled at four U.S. sites through two recruitment routes: (a) an ongoing longitudinal study and (b) de novo through the community. Participants underwent diagnostic evaluation including otoscopy, tympanometry, pure-tone and speech audiometry, speech-in-noise testing, and provided self-reported hearing abilities. Baseline characteristics are reported as frequencies (percentages) for categorical variables or medians (interquartiles, Q1-Q3) for continuous variables. Between-groups comparisons were conducted using chi-square tests for categorical variables or Kruskal--Wallis test for continuous variables. Spearman correlations assessed relationships between measured hearing function and self-reported hearing handicap. Results: The median four-frequency pure-tone average of the better ear was 39 dB HL, and the median speech-in-noise performance was a 6-dB SNR loss, indicating mild speech-in-noise difficulty. No clinically meaningful differences were found across sites. Significant differences in subjective measures were found for recruitment route. Expected correlations between hearing measurements and self-reported handicap were found. Conclusions: The extensive baseline audiologic characteristics reported here will inform future analyses examining associations between hearing loss and cognitive decline. The final ACHIEVE data set will be publicly available for use among the scientific community. [ABSTRACT FROM AUTHOR]

Simple Summary: Drugs that help the immune system attack cancer, known as immunotherapy, benefit only a small fraction of patients with cancer that has spread distant from the primary organ. Thus, markers that indicate immunotherapy failure are needed. Overall changes to DNA structure that lead to the gain or loss of extra copies of genes are known as copy number alteration (CNA) burden. In this study, we obtained data on CNA burden, clinical information, and overall tumor mutations, known as tumor mutational burden (TMB), for 1661 patients. These patients were all treated with immunotherapy and had their cancer specimens analyzed by an approved clinical test called MSK-IMPACT. We report that CNA burden could predict those patients who do not benefit from immunotherapy. Additionally, tumors with high CNA but low TMB could identify those with the worst survival. This work can better match patients to their most effective treatment of immunotherapy or other therapies. Immune checkpoint blockade (ICB) benefits only a subset of advanced cancer patients, and predictive biomarkers for immunotherapy response are needed. Recently, copy number alteration (CNA) burden has been proposed to predict ICB resistance. We assessed this finding using the publicly accessible data for 1661 ICB-treated patients whose tumors were profiled by MSK-IMPACT, an approved targeted assay in clinical care. We tested the hypothesis that the continuous increase in CNA burden is associated with poor overall survival following ICB. In addition, we hypothesized that the combinatorial biomarkers of tumor mutational burden (TMB) and CNA burden would better stratify patients for immune status and ICB response. Of the 1661 cases, 79% (n = 1307) were treated with anti PD-1/PD-L1 and the remaining 21% (n = 354) with anti CTLA-4 or the combination of both. In a multivariate analysis, increase in CNA burden was associated with poor overall survival [HR = 1.52, 95% CI (1.01–2.30), p = 0.04]. The combination of biomarkers TMB and CNA burden stratified patients into four clinically distinct subsets among which "LowTMB/HighCNA" showed the worst survival (p < 0.0001). The four patient subsets had unique CNA profiles and enriched pathways, which could predict transcriptional and phenotypic effects related to immune signaling and CD8+ T-cell abundance in the tumor microenvironment. CNA burden was associated with poor overall survival in patients receiving ICB and could improve patient stratification when incorporated with TMB. These findings may guide patient selection for immunotherapy or alternative strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: In clinical practice, human epidermal growth factor receptor (HER2)-negative tumors include triple-negative or luminal breast cancer. HER2-negative breast cancer can be further characterized by immunohistochemical (IHC) and in situ hybridization (ISH) scores into HER2 IHC0 or HER2-low (IHC 1+, 2+/ISH−. Interest in HER2-low tumors has increased as data show the efficacy of HER2-targeted therapies in this subgroup. While several studies have examined treatment variations in the overall breast cancer population, there is limited information on the real-world treatment patterns among patients with HER2 (IHC0/-low) metastatic or recurrent breast cancer. Our study addresses this gap by analyzing treatment and outcomes by HER2 status and found that outcomes were similar in the HER2 IHC0 and -low groups. Our findings add value to the general understanding of the clinical differences between HER2 IHC0/-low and de novo/recurrent disease and have important implications for new effective treatment strategies designed for varying levels of HER2 expression. Improved understanding of the biological heterogeneity of breast cancer (BC) has facilitated the development of more effective and personalized approaches to treatment. This study describes real-world evidence on treatment patterns and outcomes for a population-based cohort of patients with human epidermal growth factor receptor (HER2) IHC0 and -low BC with de novo or recurrent disease from Alberta, Canada. Patients 18+ years old diagnosed with HER2 IHC0/-low, de novo/recurrent BC from 2010 to 2019 were identified using Alberta's cancer registry. Analyses of these patients' existing electronic medical records and administrative claims data were conducted to examine patient characteristics, treatment patterns, and survival outcomes. A total of 3413 patients were included in the study, of which 72.10% initiated first line hormonal and non-hormonal systemic therapy. The 1-year overall survival (OS) was 81.09% [95% CI, 79.52–82.69]. Recurrent patients had a higher OS compared to de novo patients: 54.30 months [95% CI, 47.80–61.90] vs. 31.5 months [95% CI, 28.40–35.90], respectively. Median OS was 43.4 months [95% CI, 40.70–47.10] and 35.80 months [95% CI, 29.00–41.70] among patients with HER2-low and HER2 IHC0 cancer, respectively. The study results provide real-world evidence regarding the clinical outcomes of HER2 IHC0/-low and de novo/recurrent disease. [ABSTRACT FROM AUTHOR]

Background: Amyloid beta (Ab) plaque density was examined in the amygdala of rhesus macaques, to elucidate the influence of age, diet and hormonal environment. Methods: Luminex technology was used to measure cerebrospinal fluid (CSF) concentrations of Ab40 and Ab42 across three decades, while immunohistochemistry was used to examine Ab plaque density in the amygdala. Results: Ab40 was found to be the predominant isoform of Ab in the CSF, but neither Ab40 or Ab42 concentrations showed an age-related change, and the ratio of Ab42 to Ab40 showed only a marginal increase. Significantly fewer Ab plaques were detected in the amygdala of old ovariectomized animals if they received estradiol HRT (p < 0.001); similar results were obtained regardless of whether they had been maintained on a regular monkey chow for ~48 months or on a high-fat, high-sugar, Western-style diet for ~30 months. Conclusion: The results demonstrate that HRT involving estrogen can reduce Ab plaque load in a cognitive brain region of aged non-human primates. The results from this translational animal model may therefore have clinical relevance to the treatment of AD in post-menopausal women, whether used alone, or as a supplement to current pharmacological and monoclonal antibody-based interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. Developing liquid biopsies that aid in the detection and monitoring of recurrent CRC may improve clinical management and patient outcomes. In this study, we investigated a serially sampled blood assay of methylated DNA markers (MDMs) in combination with carcinoembryonic antigen as a clinical tool to surveil and monitor recurrent cancer in a prospective cohort of patients who completed curative-intent therapy for CRC. We demonstrated that the MDMs detected recurrent CRC before the clinical or radiographic detection of recurrence. In a small number of patients, we further showed that the MDMs may correlate with the tumor burden. These data highlight the importance of incorporating epigenetic signatures into liquid biopsies and support further research to validate the correlations of circulating tumor DNA with the tumor burden. Background: Radiographic surveillance of colorectal cancer (CRC) after curative-intent therapy is costly and unreliable. Methylated DNA markers (MDMs) detected primary CRC and metastatic recurrence with high sensitivity and specificity in cross-sectional studies. This study evaluated using serial MDMs to detect recurrence and monitor the treatment response to anti-cancer therapies. Methods: A nested case-control study was drawn from a prospective cohort of patients with CRC who completed curative-intent therapy for CRC of all stages. Plasma MDMs were assayed vis target enrichment long-probe quantitative-amplified signal assays, normalized to B3GALT6, and analyzed in combination with serum carcinoembryonic antigen to yield an MDM score. Clinical information, including treatment and radiographic measurements of the tumor burden, were longitudinally collected. Results: Of the 35 patients, 18 had recurrence and 17 had no evidence of disease during the study period. The MDM score was positive in 16 out of 18 patients who recurred and only 2 of the 17 patients without recurrence. The MDM score detected recurrence in 12 patients preceding clinical or radiographic detection of recurrent CRC by a median of 106 days (range 90–232 days). Conclusions: Plasma MDMs can detect recurrent CRC prior to radiographic detection; this tumor-agnostic liquid biopsy approach may assist cancer surveillance and monitoring. [ABSTRACT FROM AUTHOR]

Simple Summary: Several risk prediction tools have been developed to better stratify women according to their risk of developing breast cancer (BC) and inform prevention and early detection strategies. Many recent versions of these tools now incorporate a polygenic risk score (PRS) that uses the aggregated effect of common genetic variants, also known as single nucleotide polymorphisms (SNP), as a reliable predictor to estimate BC risk. However, the characteristics of each tool in terms of PRS development, population, and risk factors included vary considerably, which may affect their predictive performance and limit their use in public health practices. Thus, this systematic review characterizes BC risk prediction tools incorporating a PRS and explores the factors that can influence their ability to predict a woman's risk of developing BC during her lifetime. Single nucleotide polymorphisms (SNPs) in the form of a polygenic risk score (PRS) have emerged as a promising factor that could improve the predictive performance of breast cancer (BC) risk prediction tools. This study aims to appraise and critically assess the current evidence on these tools. Studies were identified using Medline, EMBASE and the Cochrane Library up to November 2022 and were included if they described the development and/ or validation of a BC risk prediction model using a PRS for women of the general population and if they reported a measure of predictive performance. We identified 37 articles, of which 29 combined genetic and non-genetic risk factors using seven different risk prediction tools. Most models (55.0%) were developed on populations from European ancestry and performed better than those developed on populations from other ancestry groups. Regardless of the number of SNPs in each PRS, models combining a PRS with genetic and non-genetic risk factors generally had better discriminatory accuracy (AUC from 0.52 to 0.77) than those using a PRS alone (AUC from 0.48 to 0.68). The overall risk of bias was considered low in most studies. BC risk prediction tools combining a PRS with genetic and non-genetic risk factors provided better discriminative accuracy than either used alone. Further studies are needed to cross-compare their clinical utility and readiness for implementation in public health practices. [ABSTRACT FROM AUTHOR]

We examined the role of receptor profiles and other prognostic factors in survival outcomes after stereotactic radiosurgery (SRS) for brain metastases in breast cancer patients, to help improve selection of candidates for SRS. We included 149 consecutive patients who received SRS between 2012 and 2019 at the University Hospital of Copenhagen, Rigshospitalet, Denmark. Overall survival (OS) following SRS was determined through the Kaplan–Meier method, while CNS progression-free survival (CNS-PFS) was determined through competing risk analysis. Prognostic factors for both OS and CNS-PFS were evaluated through uni- and multivariate Cox regression and Fine-Gray models, respectively. The proportional hazards assumptions were tested through Schoenfeld residuals, and non-proportionality was accounted for by the inclusion of time-dependent variables. Median OS was 14.8 months for the entire cohort and was as follows for the four receptor profiles: 33.3 months for ER+/HER2+ (ER: estrogen receptor, HER2: human epidermal growth factor receptor 2), 11.0 months for ER+/HER2−, 17.7 months for ER−/HER2+, and 5.3 months for ER−/HER2−. In the multivariate model, the ER−/HER2− receptor profile (hazard ratio (HR): 2.00, 95% confidence interval (CI): 1.09–3.67) and the presence of extracranial visceral metastases (HR: 2.90, 95% CI: 1.53–5.50) were associated with worse OS. The ER+/HER2+ receptor profile (HR: 0.43, 95% CI: 0.19–0.96) and 5+ lines of treatment (HR: 0.40, 95% CI: 0.20–0.82) were both associated with improved OS. For CNS-PFS, 5+ lines of treatment (sub-distributional hazard ratio (SHR): 2.88, 95% CI: 1.06–7.81) was associated with worse CNS-PFS, while extracranial visceral metastases (SHR: 0.54, 95% CI: 0.30–0.97) was associated with reduced risk of CNS progression – which is primarily due to patients with extracranial metastases dying before developing new CNS progression. Extracranial visceral disease and the ER−/HER2− receptor profile were associated with poor survival outcomes following SRS. [ABSTRACT FROM AUTHOR]

Hereditary breast and ovarian cancer (HBOC) follows an autosomal dominant inheritance pattern of cancer susceptibility genes. The risk of developing this disease is primarily associated with germline mutations in the BRCA1 and BRCA2 genes. The advent of massive genetic sequencing technologies has expanded the mutational spectrum of this hereditary syndrome, thereby increasing the number of variants of uncertain clinical significance (VUS) detected by genetic testing. A prevalence study of HBOC was performed within 2,928 families from the Region of Murcia, in southeastern Spain. Genetic testing enabled the identification of recurrent pathogenic variants and founder mutations, which were mainly related to the BRCA1 and BRCA2 genes. VUS testing was performed using a prioritization algorithm designed by our working group. Variants c.68_69del, c.212+1G>A, and c.5123C>A were detected in 30 % of BRCA1 carriers, whereas exon 2 deletion concurrent with c.3264dupT, c.3455T>G and c.9117G>A variants were found in 30 % of BRCA2 carriers. A total of 16 VUS (15 %) were prioritized. The genotype-phenotype correlation observed in our study is consistent with the scientific literature. Furthermore, the founder effect of c.1918C>T (BRCA1) and c.8251_8254del (ATM) was verified in the Murcian population, whereas exon 2 deletion (BRCA2) was proven to be a Spanish founder mutation. Our algorithm enabled us to prioritize potentially pathogenic VUS that required further testing to determine their clinical significance and potential role in HBOC. [ABSTRACT FROM AUTHOR]

Simple Summary: Depression and cognitive problems are common in breast cancer survivorship and reduce quality of life. Depression, a risk factor for cognitive decline, is often accompanied by elevated inflammation and a "leaky gut", which can also impact cognitive function. This study assessed whether depression in tandem with either elevated inflammation or intestinal permeability predicted poorer subjective or objective cognitive function among breast cancer survivors. In secondary analyses of data from 613 survivors with 1015 total study visits, we found that depression combined with either heightened inflammation or intestinal permeability enhanced subjective cognitive complaints, especially focus problems. On neuropsychological tests, depressed survivors performed worse regardless of inflammation or intestinal permeability. These findings suggest that survivors with depression accompanied by immune dysregulation may be more aware of depression-related cognitive deficits compared to other depressed survivors. About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression—another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein—a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239–246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression. [ABSTRACT FROM AUTHOR]

Aims To determine whether fully automated artificial intelligence-based global circumferential strain (GCS) assessed during vasodilator stress cardiovascular (CV) magnetic resonance (CMR) can provide incremental prognostic value. Methods and results Between 2016 and 2018, a longitudinal study included all consecutive patients with abnormal stress CMR defined by the presence of inducible ischaemia and/or late gadolinium enhancement. Control subjects with normal stress CMR were selected using a propensity score-matching. Stress-GCS was assessed using a fully automatic machine-learning algorithm based on featured-tracking imaging from short-axis cine images. The primary outcome was the occurrence of major adverse clinical events (MACE) defined as CV mortality or nonfatal myocardial infarction. Cox regressions evaluated the association between stress-GCS and the primary outcome after adjustment for traditional prognosticators. In 2152 patients [66 ± 12 years, 77% men, 1:1 matched patients (1076 with normal and 1076 with abnormal CMR)], stress-GCS was associated with MACE [median follow-up 5.2 (4.8–5.5) years] after adjustment for risk factors in the propensity-matched population [adjusted hazard ratio (HR), 1.12 (95% CI, 1.06–1.18)], and patients with normal CMR [adjusted HR, 1.35 (95% CI, 1.19–1.53), both P < 0.001], but not in patients with abnormal CMR (P = 0.058). In patients with normal CMR, an increased stress-GCS showed the best improvement in model discrimination and reclassification above traditional and stress CMR findings (C-statistic improvement: 0.14; NRI = 0.430; IDI = 0.089, all P < 0.001; LR-test P < 0.001). Conclusion Stress-GCS is not a predictor of MACE in patients with ischaemia, but has an incremental prognostic value in those with a normal CMR although the absolute event rate remains low. [ABSTRACT FROM AUTHOR]

Background: Inequitable access to personalized breast cancer screening and prevention may compound racial and ethnic disparities in outcomes. The Breast Cancer Personalized Risk Assessment, Education and Prevention (B-PREP) program, located within the Brigham and Women's Hospital (BWH) Comprehensive Breast Health Center (BHC), provides care to patients at high risk for developing breast cancer. We sought to characterize the differences between BWH primary care patients referred specifically to B-PREP for risk evaluation and those referred to the BHC for benign breast conditions. Through interviews with primary care clinicians, we sought to explore contributors to potentially inequitable B-PREP referral patterns. Methods: We used electronic health record data and the B-PREP clinical database to identify patients referred by primary care clinicians to the BHC or B-PREP between 2017 and 2020. We examined associations with likelihood of referral to B-PREP for risk assessment. Semi-structured interviews were conducted with nine primary care clinicians from six clinics to explore referral patterns. Results: Of 1789 patients, 78.0% were referred for benign breast conditions, and 21.5% for risk assessment. In multivariable analyses, Black individuals were less likely to be referred for risk than for benign conditions (OR 0.38, 95% CI:0.23–0.63) as were those with Medicaid/Medicare (OR 0.72, 95% CI:0.53–0.98; OR 0.52, 95% CI:0.27–0.99) and those whose preferred language was not English (OR 0.26, 95% CI:0.12–0.57). Interviewed clinicians described inconsistent approaches to risk assessment and variable B-PREP awareness. Conclusions: In this single-site evaluation, among individuals referred by primary care clinicians for specialized breast care, Black, publicly-insured patients, and those whose preferred language was not English were less likely to be referred for risk assessment. Larger studies are needed to confirm these findings. Interventions to standardize breast cancer risk assessment in primary care may improve equity. [ABSTRACT FROM AUTHOR]

Background: Post-acute care outcomes for patients with cancer <65 with multiple payers are largely unknown. Objective: Describe the population and outcomes of younger adults discharged to skilled nursing facility (SNF) and those discharged home or with home health care six months following hospitalization. Design: Descriptive cohort analysis. Setting/Subjects: Using a linkage between the Colorado All Payers Claims Database and the Colorado Central Cancer Registry, we studied patients <65 with stage III or IV advanced cancer between 2012 and 2017. Measurements: Receipt of cancer treatment, 30-day readmission, death, and hospice use. Groups of interest were compared by patient demographics and disease characteristics using chi-square tests. Logistic regression was used to describe unadjusted and adjusted outcome rates among discharge setting. Kaplan-Meier method was used to estimate survival by discharge destination. Results: Three percent of patients were discharged to SNF, 79.0% to home, and 18.0% to home health care. SNF discharges were less likely to receive cancer treatment. Among decedents, 39.0%, 51.0%, and 58.0% of SNF, home, and home health care discharges received hospice, respectively. Patients with Medicaid were more likely to be discharged to an SNF. Black/Hispanic patients were more likely to have Medicaid and received less radiation and hospice care, irrespective of discharge location. Those who were discharged to SNF were more likely to receive radiation compared to White patients. Conclusions: Younger patients with cancer discharged to SNF were unlikely to receive cancer treatment and hospice care before death. Racial disparities exist in cancer treatment receipt and hospice use warranting further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Lynch syndrome accounts for 2–3% of all CRC cases. This retroactive and prospective study aimed to estimate the prevalence of Lynch syndrome and describe disease-causing variants in mismatch repair genes in a diagnostic setting and in the Estonian general population. For that, ten years (2012–2022) of data was gathered. In addition, a pilot study for estimating the improvement of Lynch syndrome diagnostics by raising the age limit of mismatch repair gene immunohistochemistry was conducted. We estimated the birth prevalence of LS in Estonia at 1:8638 (95% CI: 1:9859–7588) or 11.58 (95% CI: 10.14–13.18) for 100,000 LBs between 1930 and 2003. The prevalence of Lynch syndrome has increased approximately six-fold in ten years. Due to the improvement of awareness in families and patients sharing information with their family members, the latter receives the diagnosis eight years earlier when most individuals are still healthy, illustrating the benefit of genetic testing and therefore an opportunity for prevention. Furthermore, the pilot study proved to be beneficial. Background: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2–3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population. Methods: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes. Results: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859–7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group. Conclusion: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years (p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment-related symptoms such as fatigue, depression, and disruptions in sleep and physical activity are common and distressing in gynecologic cancer patients. The aim of our study was to examine whether higher levels of inflammation are associated with worse symptomatology, and if these associations are stronger for patients with gynecologic cancer (n = 121) than age-matched women without a cancer history (i.e., controls; n = 105). Elevated levels of C-reactive protein were associated with depression and disrupted physical activity, but there were no other significant associations between inflammation and treatment-related symptoms. Findings suggest that inflammation may not play a significant role in the development of fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity. Previous research suggests that inflammation triggers cancer-treatment-related symptoms (i.e., fatigue, depression, and disruptions in sleep and physical activity), but evidence is mixed. This study examined relationships between inflammatory biomarkers and symptoms in patients with gynecologic cancer compared to age-matched women with no cancer history (i.e., controls). Patients (n = 121) completed assessments before chemotherapy cycles 1, 3, and 6, and 6 and 12 months later. Controls (n = 105) completed assessments at similar timepoints. Changes in inflammation and symptomatology were evaluated using random-effects mixed models, and cross-sectional differences between patients and controls in inflammatory biomarkers and symptoms were evaluated using least squares means. Associations among inflammatory biomarkers and symptoms were evaluated using random-effects fluctuation mixed models. The results indicated that compared to controls, patients typically have higher inflammatory biomarkers (i.e., TNF-alpha, TNFR1, TNFR2, CRP, IL-1ra) and worse fatigue, depression, and sleep (ps < 0.05). Patients reported lower levels of baseline physical activity (p = 0.02) that became more similar to controls over time. Significant associations were observed between CRP, depression, and physical activity (ps < 0.05), but not between inflammation and other symptoms. The results suggest that inflammation may not play a significant role in fatigue or sleep disturbance among gynecologic cancer patients but may contribute to depression and physical inactivity. [ABSTRACT FROM AUTHOR]

Aims We investigated the prevalence and clinical value of assessing multi-organ congestion by ultrasound in heart failure (HF) outpatients. Methods and results Ultrasound congestion was defined as inferior vena cava of ≥21 mm, highest tertile of lung B-lines, or discontinuous renal venous flow. Associations with clinical characteristics and prognosis were explored. We enrolled 310 HF patients [median age: 77 years, median NT-proBNP: 1037 ng/L, 51% with a left ventricular ejection fraction (LVEF) <50%], and 101 patients without HF. There were no clinical signs of congestion in 224 (72%) patients with HF, of whom 95 (42%) had at least one sign of congestion by ultrasound (P < 0.0001). HF patients with ≥2 ultrasound signs were older, and had greater neurohormonal activation, lower urinary sodium concentration, and larger left atria despite similar LVEF. During a median follow-up of 13 (interquartile range: 6–15) months, 77 patients (19%) died or were hospitalized for HF. HF patients without ultrasound evidence of congestion had a similar outcome to patients without HF [reference; hazard ratio (HR) 1.02, 95% confidence interval (CI) 0.86–1.35], while those with ≥2 ultrasound signs had the worst outcome (HR 26.7, 95% CI 12.4–63.6), even after adjusting for multiple clinical variables and NT-proBNP. Adding multi-organ assessment of congestion by ultrasound to a clinical model, including NT-proBNP, provided a net reclassification improvement of 28% (P = 0.03). Conclusion Simultaneous assessment of pulmonary, venous, and kidney congestion by ultrasound is feasible, fast, and identifies a high prevalence of sub-clinical congestion associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Instrumental variable analysis (IVA) has been widely used in many fields, including health care, to determine the comparative effectiveness of a treatment, intervention, or policy. However, its application in pediatric end-of-life care research has been limited. This article provides a brief overview of IVA and its assumptions. It illustrates the use of IVA by investigating the comparative effectiveness of concurrent versus standard hospice care for reducing 1-day hospice enrollments. Concurrent hospice care is a relatively recent type of care enabled by the Affordable Care Act in 2010 for children enrolled in the Medicaid program and allows for receiving life-prolonging medical treatment concurrently with hospice care. The IVA was conducted using observational data from 18,152 pediatric patients enrolled in hospice between 2011 and 2013. The results indicated that enrollment in concurrent hospice care reduced 1-day enrollment by 19.3%. [ABSTRACT FROM AUTHOR]

Background: While communication plays an important role in medicine, it also often represents a challenge when the topic at hand is the prognosis of a high-risk condition. When it comes to pediatric oncology, the challenge becomes even greater for physicians who have to adapt their discourse to both the child and their family. Methods: Following the PRISMA guidelines, an advanced search on PubMed, Scopus and the Cochrane Library was performed, from 1 January 2017 to 31 October 2022. Demographic data for caregivers, pediatric patients and physicians were extracted, as well as diagnosis, prognosis, presence at discussion, emotional states and impact on life, trust, decision roles, communication quality and other outcomes. Results: A total of 21 articles were analyzed. Most studies (17) focused on caregivers, while only seven and five studies were focused on children and physicians, respectively. Most parents reported high trust in their physicians (73.01%), taking the leading role in decision making (48%), moderate distress levels (46.68%), a strong desire for more information (78.64%), receiving high-quality information (56.71%) and communication (52.73%). Most children were not present at discussions (63.98%); however, their desire to know more was expressed in three studies. Moreover, only two studies observed children being involved in decision making. Most physicians had less than 20 years of experience (55.02%) and reported the use of both words and statistics (47.3%) as a communication method. Conclusions: Communication research is focused more on caregivers, yet children may understand more than they seem capable of and want to be included in the conversation. More studies should focus on and quantify the opinions of children and their physicians. In order to improve the quality of communication, healthcare workers should receive professional training. [ABSTRACT FROM AUTHOR]

Objective: Elevated cortisol levels have been frequently reported in Alzheimer's disease (AD) and linked to brain atrophy, especially of the hippocampus. Besides, high cortisol levels have been shown to impair memory performance and increase the risk of developing AD in healthy individuals. We investigated the associations between serum cortisol levels, hippocampal volume, gray matter volume and memory performance in healthy aging and AD. Methods: In our cross-sectional study, we analyzed the relationships between morning serum cortisol levels, verbal memory performance, hippocampal volume, and whole-brain voxel-wise gray matter volume in an independent sample of 29 healthy seniors (HS) and 29 patients along the spectrum of biomarker-based AD. Results: Cortisol levels were significantly elevated in patients with AD as compared to HS, and higher cortisol levels were correlated with worse memory performance in AD. Furthermore, higher cortisol levels were significantly associated with smaller left hippocampal volumes in HS and indirectly negatively correlated to memory function through hippocampal volume. Higher cortisol levels were further related to lower gray matter volume in the hippocampus and temporal and parietal areas in the left hemisphere in both groups. The strength of this association was similar in HS and AD. Conclusion: In AD, cortisol levels are elevated and associated with worse memory performance. Furthermore, in healthy seniors, higher cortisol levels show a detrimental relationship with brain regions typically affected by AD. Thus, increased cortisol levels seem to be indirectly linked to worse memory function even in otherwise healthy individuals. Cortisol may therefore not only serve as a biomarker of increased risk for AD, but maybe even more importantly, as an early target for preventive and therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Although the tumor cell-intrinsic cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment in colorectal cancer (CRC), its impact on the infiltration of immune cells and clinical outcomes in patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC has not been thoroughly investigated. In this study, we examine the expression pattern of cGAS-STING in tumor cells and its effect on the infiltrations of CD8+ and CD4+ T cells, as well as clinical outcomes including survival and recurrence in patients with pMMR/MSS CRC. Our current findings may offer novel insights and therapeutic strategies for patients with pMMR/MSS CRC. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway plays a crucial role in activating immune cells in the tumor microenvironment, thereby contributing to a more favorable response to immune checkpoint inhibitors (ICI) in colorectal cancer (CRC). However, the impact of the expression of cGAS-STING in tumor cells on the infiltration of CD8+ T cells and clinical outcomes in mismatch repair proficient/microsatellite stable (pMMR/MSS) CRC remains largely unknown. Our findings reveal that 56.8% of all pMMR CRC cases were cGAS-negative/STING-negative expressions (cGAS−/STING−) in tumor cells, whereas only 9.9% of all pMMR CRC showed cGAS-positive/STING-positive expression (cGAS+/STING+) in tumor cells. The frequency of cGAS+/STING+ cases was reduced in the advanced stages of pMMR/MSS CRC, and histone methylation might be involved in the down-regulation of STING expression in tumor cells. Since the expression level of cGAS-STING in tumor cells has been associated with the infiltration of CD8+ and/or CD4+ T cells and the frequency of recurrence in pMMR/MSS CRC, decreased expression of cGAS-STING in tumor cells might lead to poor immune cell infiltration and worse prognosis in most pMMR/MSS CRC patients. Our current findings provide a novel insight for the treatment of patients with pMMR/MSS CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancers in the urinary bladder and kidney are common in men and rarer in women. Cigarette smoking is a shared risk factor for both of these cancers. Some 50 years ago, survival in these cancers was low, and it was worse for kidney than bladder cancer. In the present study, we could show improvement in survival for these cancers in the Nordic countries, and similar improvements have also been observed in other countries. Kidney cancer survival improved remarkably well, as 50 years ago, only 20–30% of the patients survived 5 years, but currently, some 75% survive 5 years. In male bladder cancer, 5-year survival is still somewhat better than survival in kidney cancer, but female kidney cancer survival has caught up with that of bladder cancer. The reasons for this positive development for both of these cancers is earlier diagnosis as patients with blood in urine are readily taken for examinations. Additionally, treatment has become more efficient, and continuously new medications are being introduced. Kidney and bladder cancers share etiology and relatively good recent survival, but long-term studies are rare. We analyzed survival for these cancers in Denmark, Finland, Norway (NO), and Sweden (SE) over a 50-year period (1971–2020). Relative 1- and 5-year survival data were obtained from the NORDCAN database, and we additionally calculated conditional 5/1-year survival. In 2016–2020, 5-year survivals for male kidney (79.0%) and bladder (81.6%) cancers were best in SE. For female kidney cancer, NO survival reached 80.0%, and for bladder cancer, SE survival reached 76.1%. The magnitude of 5-year survival improvements during the 50-year period in kidney cancer was over 40% units; for bladder cancer, the improvement was over 20% units. Survival in bladder cancer was worse for women than for men, particularly in year 1. In both cancers, deaths in the first year were approximately as many as in the subsequent 4 years. We could document an impressive development for kidney cancer with tripled male and doubled female 5-year survival in 50 years. Additionally, for bladder cancer, a steady improvement was recorded. The current challenges are to curb early mortality and target treatment to reduce long-term mortality. [ABSTRACT FROM AUTHOR]

Background: Developmental researchers often use a multi-informant approach to measure adolescent behaviour and adjustment, but informant discrepancies are common. In general population samples, it is often found that parents report more positive and less negative outcomes than adolescents themselves. This study aimed to investigate factors associated with informant discrepancy, including adolescent sex, and parental level of psychological distress and education. Methods: Informant discrepancy on the Strengths and Difficulties Questionnaire was investigated using a Latent Difference Score (LDS) approach, which estimates the true difference between parent and adolescent reports in a structural equation model. The sample were parent-adolescent dyads from the seventh wave of the UK Millennium Cohort Study (N = 6947, 49.3% female, aged 17 years). Results: Parents reported lower levels of difficulties (emotion symptoms, peer problems, conduct problems), and higher levels of pro-social behaviour than adolescents themselves. Conditional effects were found, as discrepancy was greater amongst parent-daughter dyads for emotion and peer problems, and greater amongst parent-son dyads for conduct problems and pro-social behaviour. Parent-adolescent discrepancy was also greater generally if parents had a lower level of psychological distress or a higher level of education. Conclusions: In a large general population sample from the UK, it was found that adolescents tended to report more negative and less positive outcomes than parents reported about them. Conditional effects were found at the parent and adolescent level suggesting that specific informant biases are likely to impact the measurement of adolescent behaviour and adjustment across reporters. [ABSTRACT FROM AUTHOR]

Background: Frailty assessment is an important marker of the older adult's fitness for cancer treatment independent of age. Pretreatment geriatric assessment (GA) is associated with improved mortality and morbidity outcomes but must occur in a time sensitive manner to be useful for cancer treatment decision making. Unfortunately, time, resources and other constraints make GA difficult to perform in busy oncology clinics. We developed the Cancer and Aging Interdisciplinary Team (CAIT) clinic model to provide timely GA and treatment recommendations independent of patient's physical location. Methods: The interdisciplinary CAIT clinic model was developed utilizing the surge in telemedicine during the COVID‐19 pandemic. The core team consists of the patient's oncologist, geriatrician, registered nurse, pharmacist, and registered dietitian. The clinic's format is flexible, and the various assessments can be asynchronous. Patients choose the service method—in person, remotely, or hybrid. Based on GA outcomes, the geriatrician provides recommendations and arrange interventions. An assessment summary including life expectancy estimates and chemotoxicity risk calculator scores is conveyed to and discussed with the treating oncologist. Physician and patient satisfaction were assessed. Results: Between May 2021 and June 2022, 50 patients from multiple physical locations were evaluated in the CAIT clinic. Sixty‐eight percent was 80 years of age or older (range 67–99). All the evaluations were hybrid. The median days between receiving a referral and having the appointment was 8. GA detected multiple unidentified impairments. About half of the patients (52%) went on to receive chemotherapy (24% standard dose, 28% with dose modifications). The rest received radiation (20%), immune (12%) or hormonal (4%) therapies, 2% underwent surgery, 2% chose alternative medicine, 8% were placed under observation, and 6% enrolled in hospice care. Feedback was extremely positive. Conclusions: The successful development of the CAIT clinic model provides strong support for the potential dissemination across services and institutions. [ABSTRACT FROM AUTHOR]

Objectives: To understand the magnitude of risk of health events, such as cardiovascular diseases (CVD), related to poor oral health, both relative and absolute risk measures should be reported. Our aim was to investigate the extent to which absolute and relative measures of risk are reported in longitudinal studies that assess the association between oral health indicators (OHIs) and CVD. Methods: A systematic search of longitudinal studies investigating the association of any OHI with CVD was carried out using the Embase, Medline and Cochrane library databases. The search covered each database from its inception date to August 2021. Data about reporting relative and absolute risks of the relationship between CVD and OHI from the abstract were extracted. If the relative risk for OHIs and CVD was reported in the abstract, then the underlying absolute risks were searched from the full text, and it was assessed whether it was similarly adjusted for confounding than was the relative risk in the abstract. Results: One hundred‐six articles were included. From these, 85 (80%) studies reported the association of OHIs and CVD with one or more relative risks in the abstract. Of those 85 studies, the underlying absolute risks were accessible or calculable from the abstract or full text of 60 studies. However, of these 60 studies, in only 10 (12%), the underlying absolute risks were similarly adjusted, as were the relative risks in the abstract. The absolute risks of CVD by OHIs were rarely reported without corresponding relative risks in the abstract (n = 2, 2%). Median absolute risk difference in the CVD risk between exposure levels to which the first relative risk in the abstract referred was 1.8% (interquartile range 0.6–4.6, n = 63). Conclusions: Focusing on relative risks over absolute risks was a common practice in literature. Reporting similarly adjusted underlying absolute risks of relative risks was rare in most studies, despite those being helpful for comprehending the magnitude of CVD‐risk increase related to poor oral health. Current reporting practices could lead to an overinterpretation of risk increase of CVD related to poor oral health. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer-related fatigue (CRF) is a common somatic discomfort in gynecological cancer patients; however, it is usually overlooked by physicians. We aimed to explore the prevalence of CRF's and the clinical characteristics of gynecological cancer patients. The results showed that 77.9% of patients had received related CRF management. A five-item predictive model was developed from the identified risk factors contributing to CRF. The risk factors included (1) diagnosis of endometrial/cervical cancer, (2) International Federation of Gynecology and Obstetrics (FIGO) stage >1, (3) Eastern Cooperative Oncology Group (ECOG) status score ≥1, (4) inadequate treatment response, and (5) having received cancer treatment in the past 1 week. The predictive model may help physicians more promptly identify high-risk patients in clinical practice. Cancer-related fatigue (CRF) is the most common somatic discomfort in patients with gynecological cancers. CRF is often overlooked; however, it can impair the patients' quality of life considerably. This cross-sectional study aimed to identify the clinical characteristics of CRF in gynecological cancer patients. Questionnaires and the International Classification of Diseases 10th Revision (ICD-10) criteria were used to identify CRF. The enrolled patients were further categorized according to the amount of fatigue-related management received. Of the enrolled 190 patients, 40.0% had endometrial cancer, 28.9% had cervical cancer, and 31.1% had ovarian cancer. On the basis of the ICD-10 diagnostic criteria, 42.6% had non-cancer-related fatigue, 10% had CRF, and 51% had BFI-T questionnaire-based fatigue. Moreover, 77.9% of the study cohort had ever received fatigue-related management. Further analysis showed that patients with endometrial/cervical cancer, International Federation of Gynecology and Obstetrics stage >1, Eastern Cooperative Oncology Group performance status score ≥1, inadequate cancer treatment response, and receiving cancer treatment in the past week had a higher probability of receiving more fatigue-related management. The five-item predictive model developed from these factors may help physicians recognize patients seeking more fatigue-related management more efficiently. This is important as they may suffer from a more profound CRF. [ABSTRACT FROM AUTHOR]

Simple Summary: Goals-of-care discussions can help patients to understand their illness and to share their values and treatment preferences with their clinicians. Here, we compared the impact of an institution-wide goals-of-care program on intensive care unit (ICU) mortality between patients with hematologic malignancies and solid tumors. We found that patients with blood cancers had improved goals-of-care documentation, but no change in ICU mortality; in contrast, patients with solid tumors had lesser improvement in goals-of-care documentation, but significantly lower ICU mortality. These findings highlight the need to overcome other barriers to improve care for patients with hematologic malignancies. We recently reported that an interdisciplinary multicomponent goals-of-care (myGOC) program was associated with an improvement in goals-of-care (GOC) documentation and hospital outcomes; however, it is unclear if the benefit was uniform between patients with hematologic malignancies and solid tumors. In this retrospective cohort study, we compared the change in hospital outcomes and GOC documentation before and after myGOC program implementation between patients with hematologic malignancies and solid tumors. We examined the change in outcomes in consecutive medical inpatients before (May 2019–December 2019) and after (May 2020–December 2020) implementation of the myGOC program. The primary outcome was intensive care unit (ICU) mortality. Secondary outcomes included GOC documentation. In total, 5036 (43.4%) patients with hematologic malignancies and 6563 (56.6%) with solid tumors were included. Patients with hematologic malignancies had no significant change in ICU mortality between 2019 and 2020 (26.4% vs. 28.3%), while patients with solid tumors had a significant reduction (32.6% vs. 18.8%) with a significant between-group difference (OR 2.29, 95% CI 1.35, 3.88; p = 0.004). GOC documentation improved significantly in both groups, with greater changes observed in the hematologic group. Despite greater GOC documentation in the hematologic group, ICU mortality only improved in patients with solid tumors. [ABSTRACT FROM AUTHOR]

Purpose: Most parents of children with cancer desire honest prognostic communication, yet oncologists often avoid clear prognostic disclosure. This study explored differences between oncologists' private assessments of prognosis and their prognostic communication with patients and parents. Patients and Methods: In this prospective, longitudinal, mixed-methods study, we audio-recorded serial disease reevaluation conversations between children with advancing cancer, parents, and primary oncologists and separately surveyed and interviewed oncologists at disease progression time points. At time points when oncologists privately described curability as ≤10%, content analysis was used to compare prognostic language in recorded dialogue with private responses about prognosis. Results: Of 33 enrolled patient–parent dyads, 17 patients with high-risk cancer under the care of 6 primary oncologists experienced disease progression during the study period. In 95% of oncologist interviews at disease progression time points, oncologists either predicted curability to be ≤10% or incurable. In most interviews (82%), oncologists stated unequivocally that chances of cure were ≤10%, yet did not communicate these low odds during recorded discussions at the same time point. Analysis revealed three distinct communication patterns through which oncologists softened prognostic disclosure to patients and families: (1) space-holding for hope of cure: statements acknowledging difficult prognosis yet leaving room for possibility of cure; (2) vague warning: statements implying that cancer may progress without offering specifics; and (3) data without interpretation: statements describing disease progression findings in detail without explaining what this meant for the patient's future life or survival. Conclusion: Pediatric oncologists often temper their assessment of poor prognosis when speaking with patients and families. Future work should explore serious conversation guides and other clinical interventions aimed at encouraging person-centered prognostic disclosure for patients with advancing cancer and their families. [ABSTRACT FROM AUTHOR]

Simple Summary: The major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and the beta-2 microglobulin (B2M) genes, play a key role in neoantigens presentation to the immune system. We analyzed allelic imbalance (AI) of the respective chromosomal regions by multiplex PCRs using microsatellite markers in biopsies of 158 patients with gastric/gastroesophageal adenocarcinoma before neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx) for an association with clinical outcome of the patients. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed interesting differences. Of note, AI at markers of the HLA region was associated with a decreased survival only in responding but not in non-responding patients. No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant CTx. We aimed to determine the clinical and prognostic relevance of allelic imbalance (AI) of the major histocompatibility complex (MHC) class I genes, encompassing the human leukocyte antigen (HLA) class I and beta-2 microglobulin (B2M) genes, in the context of neoadjuvant platinum/fluoropyrimidine chemotherapy (CTx). Biopsies before CTx were studied in 158 patients with adenocarcinoma of the stomach or gastroesophageal junction. The response was histopathologically evaluated. AI was detected by multiplex PCRs analysis of four or five microsatellite markers in HLA and B2M regions, respectively. AI with no marker was significantly associated with response or survival. However, subgroup analysis revealed differences. AI at marker D6S265, close to the HLA-A gene, was associated with an obvious increased risk in responding (HR, 3.62; 95% CI, 0.96–13.68, p = 0.058) but not in non-responding patients (HR, 0.92; 95% CI, 0.51–1.65, p = 0.773). Markers D6S273 and D6S2872 showed similar results. The interaction between AI at D6S265 and response to CTx was significant in a multivariable analysis (p = 0.010). No associations were observed for B2M markers. Our results underline the importance of intact neoantigen presentation specifically for responding patients and may help explain an unexpectedly poor survival of a patient despite significant tumor regression after neoadjuvant platinum/fluoropyrimidine CTx. [ABSTRACT FROM AUTHOR]

Simple Summary: This work determines the predictive value of the consensus Immunoscore in 1885 patients with AJCC/UICC-TNM stage I-II Colon Cancer (CC) from North American, European, and Asian care centers. Herein, we demonstrate that the immunity of early-stage CC patients, more than cancer cell-associated parameters, predicts outcome for stage I/II patients. Similar results were found for high-risk patients defined based on parameters such as the grade of differentiation, T4 stage, venous emboli, lymphatic invasion or perineural invasion (VELIPI). Within these pathological risk subgroups, the consensus Immunoscore accurately identifies early-stage CC patients with different clinical outcome, without treatment bias. Thus, the Immunoscore reliably diagnoses low immune cell infiltrated patients at risk of relapse, that would benefit from a more frequent and detailed medical monitoring. The Immunoscore is a patient classification method that can guide treatment decisions, through the quantification of CD3+ and cytotoxic CD8+ T-lymphocytes densities within the tumor and its invasive margin. Background: The prognostic value of Immunoscore was evaluated in Stage II/III colon cancer (CC) patients, but it remains unclear in Stage I/II, and in early-stage subgroups at risk. An international Society for Immunotherapy of Cancer (SITC) study evaluated the pre-defined consensus Immunoscore in tumors from 1885 AJCC/UICC-TNM Stage I/II CC patients from Canada/USA (Cohort 1) and Europe/Asia (Cohort 2). METHODS: Digital-pathology is used to quantify the densities of CD3+ and CD8+ T-lymphocyte in the center of tumor (CT) and the invasive margin (IM). The time to recurrence (TTR) was the primary endpoint. Secondary endpoints were disease-free survival (DFS), overall survival (OS), prognosis in Stage I, Stage II, Stage II-high-risk, and microsatellite-stable (MSS) patients. RESULTS: High-Immunoscore presented with the lowest risk of recurrence in both cohorts. In Stage I/II, recurrence-free rates at 5 years were 78.4% (95%-CI, 74.4–82.6), 88.1% (95%-CI, 85.7–90.4), 93.4% (95%-CI, 91.1–95.8) in low, intermediate and high Immunoscore, respectively (HR (Hi vs. Lo) = 0.27 (95%-CI, 0.18–0.41); p < 0.0001). In Cox multivariable analysis, the association of Immunoscore to outcome was independent (TTR: HR (Hi vs. Lo) = 0.29, (95%-CI, 0.17–0.50); p < 0.0001) of the patient's gender, T-stage, sidedness, and microsatellite instability-status (MSI). A significant association of Immunoscore with survival was found for Stage II, high-risk Stage II, T4N0 and MSS patients. The Immunoscore also showed significant association with TTR in Stage-I (HR (Hi vs. Lo) = 0.07 (95%-CI, 0.01–0.61); P = 0.016). The Immunoscore had the strongest (69.5%) contribution χ2 for influencing survival. Patients with a high Immunoscore had prolonged TTR in T4N0 tumors even for patients not receiving chemotherapy, and the Immunoscore remained the only significant parameter in multivariable analysis. CONCLUSION: In early CC, low Immunoscore reliably identifies patients at risk of relapse for whom a more intensive surveillance program or adjuvant treatment should be considered. [ABSTRACT FROM AUTHOR]

Simple Summary: Short, dysfunctional telomeres represent the genetic biomarkers of cancer. Studies in early-stage non-small-cell lung cancer (NSCLC) have shown that telomere length and telomerase levels are correlated with survival. In patients with advanced NSCLC, telomere status has not yet been investigated, and its clinical significance remains unknown. We studied telomere length and the expression of telomerase and shelterin genes in a cohort of 79 patients with advanced NSCLC, and evaluated these parameters as potential prognostic and predictive factors. Telomere shortening, high levels of telomerase and aberrant expression of shelterin genes TRF2, RAP1 and TIN2 were significantly correlated with shorter survival. Furthermore, a worse response to immunotherapy was observed in patients with shorter telomeres. The determination of telomere parameters in advanced NSCLC could be useful for individualized treatment decisions. Telomere length appears to correlate with survival in early non-small-cell lung cancer (NSCLC), but the prognostic impact of telomere status in advanced NSCLC remains undetermined. Our purpose was to evaluate telomere parameters as prognostic and predictive biomarkers in advanced NSCLC. In 79 biopsies obtained before treatment, we analyzed the telomere length and expression of TERT and shelterin complex genes (TRF1, TRF2, POT1, TPP1, RAP1, and TIN2), using quantitative PCR. Non-responders to first-line chemotherapy were characterized by shorter telomeres and low RAP1 expression (p = 0.0035 and p = 0.0069), and tended to show higher TERT levels (p = 0.058). In multivariate analysis, short telomeres were associated with reduced event-free (EFS, p = 0.0023) and overall survival (OS, p = 0.00041). TERT and TRF2 overexpression correlated with poor EFS (p = 0.0069 and p = 0.00041) and OS (p = 0.0051 and p = 0.007). Low RAP1 and TIN2 expression-levels were linked to reduced EFS (p = 0.00032 and p = 0.0069) and OS (p = 0.000051 and p = 0.02). Short telomeres were also associated with decreased survival after nivolumab therapy (p = 0.097). Evaluation of telomere status in advanced NSCLC emerges as a useful biomarker that allows for the selection of patient groups with different clinical evolutions, to establish personalized treatment. [ABSTRACT FROM AUTHOR]

A holistic concept based on traditional Persian medicine (TPM) describes a headache with a gastrointestinal (GI) origin (gastric-headache). Although the neurological manifestations of this headache are similar to those of other headaches, its etiology is different. Considering its simultaneous effects on the brain and GI system, a formulation was designed based on this concept. This study aimed to determine the safety and efficacy of the designed formulation on migraine headache (MH) associated with functional dyspepsia (FD). A total of 75 diagnosed cases of MH patients with concurrent FD were randomly divided equally into 3 groups: (i) the polyherbal formulation, sodium valproate (VPA), and amitriptyline group, (ii) VPA, amitriptyline, and polyherbal formulation placebo group, and (iii) the polyherbal formulation and VPA placebo group. The primary outcomes, including frequency, duration, and severity of MH attacks, were measured at baseline and weeks 4, 8, and 12. However, secondary outcomes, including the Headache Impact Test 6 (HIT-6) Questionnaire and Parkman's score, were evaluated at baseline and end of treatment. The frequency, duration, and severity of migraine (P < 0.001 for all cases), HIT-6 (P < 0.001 for all cases), and FD (P < 0.001 for all cases) scores at the end of treatment showed a significant decrease in the 3 groups compared to the baseline. However, the differences in those variables between the 3 groups were not significant at the end of the study. The polyherbal formulation alone may improve the symptoms of migraine patients and other groups. This effect could be due to improving digestion and FD in migraine patients. [ABSTRACT FROM AUTHOR]

Background: Left ventricular remodeling (LVR) is common and associated with adverse outcome after ST‐elevation myocardial infarction (STEMI). We aimed to investigate the association between left atrial (LA) mechanical function using speckle tracking imaging and early LVR at follow‐up in STEMI patients. Methods: Baseline 3D thoracic echocardiograms were performed within 48 h following admission and at a median follow‐up of 7 months after STEMI. A > 20% increase in the left ventricular (LV) end‐diastolic volume compared to baseline at follow‐up was defined as LVR. LA global longitudinal strain was evaluated for the reservoir, conduit, and contraction (LASct) phases. Results: A total of 121 patients without clinical heart failure (HF) were prospectively included, between June 2015 and October 2018 (age 58.3 ± 12.5 years, male 98 (81%)). Baseline and follow‐up LV ejection fraction (LVEF) were 46.8% [41.0, 52.9] and 52.1% [45.8, 57.0] respectively (p <.001). Compared to other patients, those with LVR had significantly lower values of LASct at baseline (−7.4% [−10.1, −6.5] vs. −9.9% [−12.8, −8.1], p <.01), both on univariate and baseline LV volumes‐adjusted analyses. Baseline LA strain for reservoir and conduit phases were not associated with significant LVR at follow‐up. Intra‐ and interobserver analysis showed good reproducibility of LA strain. Conclusions: Baseline LASct may help identifying patients without HF after STEMI who are at higher risk of further early LVR and subsequent HF and who may benefit from more intensive management. [ABSTRACT FROM AUTHOR]

Background: Clinical practice guidelines recommend integrating palliative care (PC) into the care of patients with heart failure (HF) to address their many palliative needs. However, the incidence rates of PC use among HF subtypes are unknown. Methods: We conducted a retrospective cohort study of patients with the following HF subtypes in the Department of Veterans Affairs: reduced ejection fraction (HFrEF), mid-range ejection fraction (HFmEF), and preserved ejection fraction (HFpEF). Patients were included at the time of HF diagnosis from 2011 to 2015 and followed until a minimum of five years or death. Incidence rates of receipt of PC (primary outcome) were calculated using generalized estimating equations. We evaluated the time to incident PC by HF subtype with Kaplan–Meier analyses and with adjusted restricted mean survival time. Results: Of the 113,555 patients, 69% were ≥65 years, 98% were male, 73% White, and 18% Black; 58% had HFrEF, 7% HFmEF, and 34% HFpEF. Twenty percent received PC during follow-up, and 66% died. Adjusted PC incidence rates were higher among patients with HFrEF (47 per 1000 person-years, confidence interval [95% CI] 43–52) than for HFmEF and HFpEF (42 per 1000 person-years, CI 38–47 for both). Restricting follow-up to five years, patients with HFrEF received PC six weeks earlier than patients with HFpEF. There was no significant difference in time to PC between patients with HFmEF versus HFpEF. Conclusion: About 1 in 20 patients with HFrEF and 1 in 25 patients with HFmEF and HFpEF receive PC annually. Patients with HFrEF receive PC sooner than patients with HFmEF and HFpEF. [ABSTRACT FROM AUTHOR]

Summary: Background: Neighbourhood socio‐economic environment (SEE) is associated with obesity in older children and adults, but little is known about this relationship in younger children. Breastfeeding is an important preventative of adiposity in childhood, but its relationship with neighbourhood SEE is unknown. Aims: We assessed differences in adiposity and obesity in children before age two by neighbourhood SEE, controlling for family socio‐demographics and breastfeeding duration. Materials and Methods: Family socio‐demographics, child body mass index z scores (BMIz), and breastfeeding duration were collected at periodic study visits from participants in PREVAIL (n = 245), a birth cohort in Cincinnati, OH. Addresses were assigned a Deprivation Index score, a validated measure of SEE, and dichotomized into highest SEE (least deprived quartile of scores) and not highest SEE (remaining quartiles). Longitudinal and Poisson models assessed differences in BMIz by SEE over the second year of life and obesity risk at age two, respectively (highest SEE, reference), while attenuation of obesity risk by breastfeeding duration was tested in mediation models. Results: Residing outside of the highest SEE neighbourhoods was associated with an increased BMIz of 0.04 (95%CI 0.02, 0.06) per month of life and increased obesity risk at age two (aRR: 3.7, 95%CI 1.2, 16.2), controlling for family socio‐demographics. Breastfeeding duration attenuated >9% of the obesity risk attributable to SEE (mediated RR: 3.4, 95%CI 1.1, 14.8). Discussion: In the PREVAIL Cohort, residing outside of the highest SEE neighbourhoods predicted a significant increase in BMIz and obesity risk in children before age two, a relationship that was partially mediated by breastfeeding duration. Conclusion: Breastfeeding support may play an important role in reducing obesity rates in children in lower SEE neighbourhoods. [ABSTRACT FROM AUTHOR]

Background. Roxadustat is a newly listed oral hypoxia-inducible factor-proline enhancing enzyme inhibitor (HIF-PHI) in recent years. There have been some studies that have proved the efficacy of roxadustat on the treatment of renal anemia in patients with chronic kidney disease (CKD), but there are still different conclusions on its safety. Methods. PubMed, Embase, Cochrane, and ClinicalTrials were searched for randomized controlled trials (RCTs) that assess efficacy and safety of roxadustat treatment for anemia in CKD patients. The Cochrane Literature Quality Evaluation Scale was used to evaluate the quality of included literature. We choose fixed-effects model or random effects model for data processing based on heterogeneity. It was considered statistically significant when p value <0.05. Results. A total of 842 articles were retrieved, and 16 trials in the 15 articles were finally included. Roxadustat treatment significantly increased Hb levels. Iron (SMD 1.43, 95% CI 0.31 to 2.55), total iron-binding capacity (SMD 2.06, 95% CI 0.91 to 3.22), ferritin (WMD 21.33, 95% CI 3.04 to 39.62), transferrin saturation (SMD 4.17, 95% CI 3.90 to 4.45), and LDL-cholesterol (SMD -0.64, 95% CI -0.73 to -0.55) showed statistical significance in dialysis-dependent (DD) study. And hepcidin (SMD -1.56, 95% CI -2.63 to -0.50), transferrin (SMD 1.80, 95% CI 1.53 to 2.06), total iron-binding capacity (SMD 1.62, 95% CI 1.39 to 1.86), total cholesterol (SMD -0.88, 95% CI -1.68 to -0.09), ferritin (WMD -52.68, 95% CI -62.68 to -42.67), transferrin saturation (SMD -5.57, 95% CI -7.47 to -3.68), and LDL-cholesterol (SMD -0.85, 95% CI -1.37 to -0.34) showed statistical significance in not dialysis-dependent (NDD) study. In terms of safety, roxadustat treatment did not increase risk of total adverse events either in dialysis-dependent or not dialysis-dependent patients. Conclusion. Roxadustat can effectively improve anemia in patients with chronic kidney disease. There was no significant difference in total adverse events compared with the control group. [ABSTRACT FROM AUTHOR]

Simple Summary: In the past few decades, targeted therapy and immunotherapy have transformed tremendously the chances of survival. Checkpoint inhibitors that block programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathways hold the most promise. However, more than half of the patients treated with CTLA-4-PD1 inhibition suffered from grade 3 or 4 treatment-related adverse events (TRAEs). Recently, Tawbi et al. reported the initial results of the phase 2–3 RELATIVITY-047 trial which evaluated LAG3-PD1 inhibition of relatlimab plus nivolumab in patients with previously untreated advanced melanoma. Here, we performed an indirect cross-comparison of LAG3-PD1 and CTLA4-PD1 inhibition in patients with previously untreated advanced melanoma by deriving individual patient survival data and safety profiles. We found that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar. Compared with CTLA4-PD1-inhibition, LAG3-PD1 inhibition tended to exhibit earlier survival benefit and lesser TRAEs. Objective: To compare the inhibition of LAG3-PD1 versus the inhibition of CTLA-4-PD1 in patients with previously untreated advanced melanoma. Methods: The individual participant data (IPD) were extracted from the KM plots using a graphical reconstructive algorithm. Log-rank, Cox proportional hazard model, Bayesian hierarchical model with time-varying hazard ratio (HR) effect, and restricted mean survival time (RMST) were performed to estimate survival benefits. Results: The CheckMate-067 (n = 630) and RELATIVITY-047 (n = 714) trials were included for analysis. The graphical reconstructive algorithm showed that IPD had similar HRs and log-rank values as the original plots. The HR of nivolumab plus relatlimab (LAG3 inhibitor) versus nivolumab plus ipilimumab (CTLA4 inhibitor) was 1.19 (95% confidence interval [CI] 0.96 to1.48). The 24-months RMST of nivolumab plus relatlimab versus nivolumab was 2.35 (95% CI 0.77–3.94) months, compared with 1.87 (95% CI, 0.25–3.49) months for nivolumab plus ipilimumab versus nivolumab. The Bayesian hierarchical model showed that patients treated with nivolumab plus relatlimab had earlier PFS benefits than those with nivolumab plus ipilimumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients using nivolumab plus relatlimab and 55.0% of patients using nivolumab plus ipilimumab. Conclusions: These findings suggest that the PFS of LAG3-PD1 and CTLA4-PD1 inhibition were similar and LAG3-PD1 inhibition exhibited earlier survival benefit and lesser TRAEs. [ABSTRACT FROM AUTHOR]

What Is Known and Objective: Erythropoiesis‐stimulating agent (ESA) hyporesponsiveness is an important cause for the undertreatment of anaemia. A decrease in haemoglobin (Hb) levels was observed during the initial stage of the conversion from ESA to roxadustat. The study aims to investigate the effectiveness and safety of adding roxadustat to an ESA for the treatment of ESA‐hyporesponsive anaemia in patients on peritoneal dialysis (PD). Methods: Patients on PD with ESA‐hyporesponsive anaemia were enrolled from January 2020 to April 2020 with a 24‐week follow‐up period. Patients were treated with roxadustat at a starting dose of 50 or 100 mg thrice weekly without changing the ESA dose. Roxadustat and ESA dose adjustments were made as needed to maintain Hb levels within 11.0 to 13.0 g/dl. Efficacy outcomes and safety were assessed. Results and Discussion: Nine patients were recruited in the study. Both the cumulative responsive rate and maintenance rate of Hb > 11 g/dl were 100%. Six patients required ESA dose reduction from ≥15,000 UI/week to ≤7000 IU/week at week 24. No drug‐related severe adverse events were observed in this study. What Is New and Conclusion: The addition of roxadustat effectively and smoothly corrected anaemia in patients who were hyporesponsive to ESA, and permitted reduction of the ESA dose. [ABSTRACT FROM AUTHOR]

Background: Many clinical and financial decisions for older adults depend on the future risk of disability and mortality. Prognostic tools for long‐term disability risk in a general population are lacking. We aimed to create a comprehensive prognostic tool that predicts the risk of mortality, of activities of daily living (ADL) disability, and walking disability simultaneously using the same set of variables. Methods: We conducted a longitudinal analysis of the nationally‐representative Health and Retirement Study (HRS). We included community‐dwelling adults aged ≥70 years who completed a core interview in the 2000 wave of HRS, with follow‐up through 2018. We evaluated 40 predictors encompassing demographics, diseases, physical functioning, and instrumental ADLs. We applied novel methods to optimize three models simultaneously while prioritizing variables that take less time to ascertain during backward stepwise elimination. The death prediction model used Cox regression and both the models for walking disability and for ADL disability used Fine and Gray competing‐risk regression. We examined calibration plots and generated optimism‐corrected statistics of discrimination using bootstrapping. To simulate unavailable patient data, we also evaluated models excluding one or two variables from the final model. Results: In 6646 HRS participants, 2662 developed walking disability, 3570 developed ADL disability, and 5689 died during a median follow‐up of 9.5 years. The final prognostic tool had 16 variables. The optimism‐corrected integrated area under the curve (iAUC) was 0.799 for mortality, 0.685 for walking disability, and 0.703 for ADL disability. At each percentile of predicted mortality risk, there was a substantial spread in the predicted risks of walking disability and ADL disability. Discrimination and calibration remained good even when missing one or two predictors from the model. This model is now available on ePrognosis (https://eprognosis.ucsf.edu/alexlee.php) Conclusions: Given the variability in disability risk for people with similar mortality risks, using individualized risks of disabilities may inform clinical and financial decisions for older adults. [ABSTRACT FROM AUTHOR]

Summary: The widely recommended fracture prediction tool FRAX was developed based on and for the general population. Although several adjusted FRAX methods were suggested for type 2 diabetes (T2DM), they still need to be evaluated in T2DM cohort. Introduction: This study was undertaken to develop a prediction model for Chinese diabetes fracture risk (CDFR) and compare its performance with those of FRAX. Methods: In this retrospective cohort study, 1730 patients with T2DM were enrolled from 2009.08 to 2013.07. Major osteoporotic fractures (MOFs) during follow-up were collected from Electronic Health Records (EHRs) and telephone interviews. Multivariate Cox regression with backward stepwise selection was used to fit the model. The performances of the CDFR model, FRAX, and adjusted FRAX were compared in the aspects of discrimination and calibration. Results: 6.3% of participants experienced MOF during a median follow-up of 10 years. The final model (CDFR) included 8 predictors: age, gender, previous fracture, insulin use, diabetic peripheral neuropathy (DPN), total cholesterol, triglycerides, and apolipoprotein A. This model had a C statistic of 0.803 (95%CI 0.761–0.844) and calibration χ2 of 4.63 (p = 0.86). The unadjusted FRAX underestimated the MOF risk (calibration χ2 134.5, p < 0.001; observed/predicted ratio 2.62, 95%CI 2.17–3.08), and there was still significant underestimation after diabetes adjustments. Comparing FRAX, the CDFR had a higher AUC, lower calibration χ2, and better reclassification of MOF. Conclusion: The CDFR model has good performance in 10-year MOF risk prediction in T2DM, especially in patients with insulin use or DPN. Future work is needed to validate our model in external cohort(s). [ABSTRACT FROM AUTHOR]

Telemedicine use surged during COVID-19, and a significant amount of recent research has relied solely on online surveys to assess patient perceptions. However, these surveys may be biased since they require an internet connection and digital literacy skills. We compare local perceptions of telemedicine visits in rural areas across two methods of data collection: online-only vs. paper surveys. We collected 100 paper and 108 online surveys in two rural counties with a total population of 10,000. The results show that significant differences exist in the demographics of people completing each type of survey and in the perceptions of telemedicine, with paper-based respondents generally demonstrating a higher degree of confidence in telemedicine. Ordered logistic regressions controlling for potentially influential underlying demographic characteristics (income, hours worked, and presence of children) show that paper-based respondents tend to have higher opinions of telemedicine, but that overall levels of comfort are similar across survey types. [ABSTRACT FROM AUTHOR]

Aims Left atrial (LA) function is a marker of prognosis in patients with heart failure. The prognostic implications of an improvement in LA function in addition to an improvement in left ventricular (LV) function after cardiac resynchronization therapy (CRT) implantation are unknown. This study aimed to evaluate the prognostic value of a significant change in LA reservoir strain (RS) and/or LV global longitudinal strain (GLS) after initiation of CRT. Methods and results LARS and LVGLS were measured with speckle-tracking echocardiography. Significant improvement in LARS and LVGLS was defined as a percentage change of +5% and +20% at 6 months after CRT implantation, respectively. Patients were divided into three groups: no significant reverse remodelling (no improvement in LARS and LVGLS), incomplete reverse remodelling (improvement in LARS or LVGLS), and complete reverse remodelling (improvement in LARS and LVGLS). The primary endpoint was all-cause mortality. A total of 923 patients (mean age 65 ± 10 years, 77% male) were included, of which 221 (24%) had complete reverse remodelling, 414 (45%) incomplete reverse remodelling, and 288 (31%) no significant reverse remodelling. Five-years' mortality was 24%, 29%, and 36% for patients with complete, incomplete, and no significant reverse remodelling, respectively (P < 0.001). On multivariable analysis, complete reverse remodelling (hazard ratio 0.477; 95% confidence interval: 0.362–0.628; P < 0.001) was associated with the lowest risk of mortality. Conclusions Patients with complete reverse remodelling have a lower mortality risk than those showing incomplete or no significant reverse remodelling. The use of integrated LA and LV deformation imaging may improve risk-stratification of CRT recipients. [ABSTRACT FROM AUTHOR]

Objective: To evaluate and describe attitudes, quality of life (Qol), needs and preferences of patients with head and neck cancer after 3 years of follow‐up care. Methods: This is an exploratory prospective study of recurrence‐free patients. Survey results were compared between 1‐, 2‐ and 3‐year post‐treatment and by disease characteristics. Results A total of 116 patients were included with 46% oropharyngeal cancer, 66% early stage disease and 41% having had surgery. After 3 years, most patients reported good to excellent health (88%), however expressed uncertainty regarding recurrence (66%), multiple needs (information on prognosis 91%, long‐term sequalae 72%) and wanted to continue with follow‐up (96%). Few changes were observed over time, with exceptions. Patients with more advanced disease, oral cancer or who had surgery experienced declining Qol (p < 0.050). Women experienced improvements in Qol domains (pain p = 0.028, speech p = 0.009) over time. Attitudes towards communication with oncologists demonstrated improved patient comfort (p = 0.044) over the 3 years; however, patients' beliefs about their prognosis did not (71% vs. 73% vs. 77% did not believe they were cured, p = 0.581). Conclusion: Although patients' needs, preferences and attitudes towards follow‐up did not change drastically, important needs persist. This work supports identifying individual patient needs and the challenges in addressing prognostic expectations. [ABSTRACT FROM AUTHOR]

Simple Summary: 90% of breast cancer mortality is caused by distant metastasis, a process that involves both dissemination of cancer cells to distant sites as well as their proliferation after arrival. However, prognostic assays currently used in the clinic are based on proliferation and do not measure tumor cell dissemination potential. We previously reported that the density of Tumor Microenvironment of Metastasis (TMEM) doorways (portals for cancer cell intravasation and dissemination) is a prognostic biomarker for the development of distant metastasis in hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) patients. We have shown further that MenaCalc, a mechanistically linked (but independent) biomarker for distant metastasis, is prognostic in some cohorts of triple-negative patients. Here, we develop and compare several digital pathology-based machine vision algorithms to investigate if a combined TMEM-MenaCalc biomarker could provide improved prognostic information over and above that of either biomarker alone. Purpose: to develop several digital pathology-based machine vision algorithms for combining TMEM and MenaCalc scores and determine if a combination of these biomarkers improves the ability to predict development of distant metastasis over and above that of either biomarker alone. Methods: This retrospective study included a subset of 130 patients (65 patients with no recurrence and 65 patients with a recurrence at 5 years) from the Calgary Tamoxifen cohort of breast cancer patients. Patients had confirmed invasive breast cancer and received adjuvant tamoxifen therapy. Of the 130 patients, 86 cases were suitable for analysis in this study. Sequential sections of formalin-fixed paraffin-embedded patient samples were stained for TMEM doorways (immunohistochemistry triple staining) and MenaCalc (immunofluorescence staining). Stained sections were imaged, aligned, and then scored for TMEM doorways and MenaCalc. Different ways of combining TMEM doorway and MenaCalc scores were evaluated and compared to identify the best performing combined marker by using the restricted mean survival time (RMST) difference method. Results: the best performing combined marker gave an RMST difference of 5.27 years (95% CI: 1.71–8.37), compared to 3.56 years (95% CI: 0.95–6.1) for the associated standalone TMEM doorway analysis and 2.94 years (95% CI: 0.25–5.87) for the associated standalone MenaCalc analysis. Conclusions: combining TMEM doorway and MenaCalc scores as a new biomarker improves prognostication over that observed with TMEM doorway or MenaCalc Score alone in this cohort of 86 patients. [ABSTRACT FROM AUTHOR]

The Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram has been developed to estimate five-year overall survival (OS) after curative-intent surgery of colon cancer based on age, sex, T stage, differentiation grade, number of positive and examined regional lymph nodes. This is the first evaluation of the performance of the MSKCC model in a European population regarding prediction of OS. Population-based data from patients with stage I–III colon cancer diagnosed between 2010 and 2016 were obtained from the Netherlands Cancer Registry (NCR) for external validation of the MSKCC prediction model. Five-year survival probabilities were estimated for all patients in our dataset by using the MSKCC prediction equation. Histogram density plots were created to depict the distribution of the estimated probability and prognostic index. The performance of the model was evaluated in terms of its overall performance, discrimination, and calibration. A total of 39,805 patients were included. Five-year OS was 71.9% (95% CI 71.5; 72.3) (11,051 events) with a median follow up of 5.6 years (IQR 4.1; 7.7). The Brier score was 0.10 (95% CI 0.10; 0.10). The C-index was 0.75 (95% CI 0.75; 0.76). The calibration measures and plot indicated that the model slightly overestimated observed mortality (observed/expected ratio = 0.86 [95% CI 0.86; 0.87], calibration intercept = −0.14 [95% CI −0.16; −0.11], and slope 1.07 [95% CI 1.05; 1.09], ICI = 0.04, E50 = 0.04, and E90 = 0.05). The external validation of the MSKCC prediction nomogram in a large Dutch cohort supports the use of this practical tool in the European patient population. These personalised estimated survival probabilities may support clinicians when informing patients about prognosis. Adding potential relevant prognostic factors to the model, such as primary tumour location, might further improve the model. [ABSTRACT FROM AUTHOR]