Correction: Referral for Cardiac Amyloidosis in Patients Who Underwent Transcatheter Aortic Valve Replacement: Results of the Quality Outcome Project.

[This corrects the article DOI: 10.7759/cureus.45024.].

Referral for Cardiac Amyloidosis in Patients Who Underwent Transcatheter Aortic Valve Replacement: Results of the Quality Outcome Project.

Background Transthyretin cardiac amyloidosis (ATTR) is an important comorbidity present in severe aortic stenosis (AS). The purpose of this study was to raise awareness of ATTR in patients who underwent transcatheter aortic valve replacement (TAVR) for severe AS among healthcare providers and patients. Methodology We reviewed 197 consecutive TAVR cases performed from 2019 to 2020. Adapting predefined high-risk features for ATTR based on prior literature, we contacted the patients to discuss our clinical suspicion of ATTR and offered a referral to a cardiac amyloid specialist. Results We identified 125 (69.4%) patients who had high-risk features of ATTR. Of the 105 patients contacted, 44 patients agreed to referral, 46 patients were not able to be contacted after several attempts, and 15 patients declined referral. Of the 44 patients who agreed to the referral, 20 patients completed the evaluation for cardiac amyloidosis, all of whom were negative for transthyretin and light-chain cardiac amyloidosis. Conclusions Our attempt to detect ATTR in prior TAVR patients was unsuccessful two to three years post-TAVR. We believe that early detection of cardiac amyloidosis close to the timing of TAVR is important and the most effective means.

Saline at lower tonicity in cystic fibrosis (SALTI-CF) trial comparing 0.9% versus 3% versus 6% nebulised saline.

BACKGROUND: In people with cystic fibrosis (CF), regular nebulisation of 6% or 7% saline improves lung function; however, these concentrations are not always tolerable. Clinically, some CF patients report using lower concentrations of saline to improve tolerability, yet the effects of lower concentrations are unknown. This study therefore aimed to evaluate the relative effectiveness and tolerability of 0.9% versus 3% versus 6% saline nebulised twice daily with an eFlow rapid nebuliser. METHODS: This was a randomised, blinded, placebo-controlled, parallel-group, multicentre study where subjects inhaled 4 mL of 0.9%, 3% or 6% saline twice daily for 16 weeks. The primary outcome was forced expiratory volume in 1 s. The secondary outcomes were: forced vital capacity (FVC) and forced expiratory flow at 25-75% of FVC; quality of life; exercise capacity; acquisition or loss of bacterial organisms in expectorated sputum; tolerability of nebulised saline; pulmonary exacerbations; and adverse events. RESULTS: 140 participants were randomised to 0.9% (n=47), 3% (n=48) or 6% (n=45) saline. 134 participants (96%) contributed to the intention-to-treat analysis. 3% saline significantly improved lung function and increased the time to first pulmonary exacerbation compared with 0.9% saline but did not improve quality of life. 6% saline had similar benefits to 3% saline but also significantly improved quality of life compared with 3% saline. Only 6% saline delayed the time to intravenous antibiotics for pulmonary exacerbation. Tolerability and adherence were similar. CONCLUSIONS: Dilution of 6% saline to 3% maintains the benefits for lung function and exacerbation prevention; however, the positive impacts of 6% saline on quality of life and time to i.v. antibiotics for pulmonary exacerbations are lost.

Web-based physical activity promotion in young people with CF: a randomised controlled trial.

BACKGROUND: Physical activity levels are known to decline following hospitalisation for people with cystic fibrosis (pwCF). However, optimal physical activity promotion strategies are unclear. This study investigated the effect of a web-based application (ActivOnline) in promoting physical activity in young pwCF. METHODS: Multicentre randomised controlled trial with assessor blinding and qualitative evaluation. People with CF (12-35 years) admitted to hospital for a respiratory cause were eligible and randomised to the 12-week ActivOnline intervention (AO) or usual care (UC). The primary outcome was change in device-based time spent in moderate-to-vigorous physical activity (MVPA) from baseline to post-intervention. Follow-up was at 6 months from hospital discharge when qualitative evaluation was undertaken. RESULTS: 107 participants were randomised to AO (n=52) or UC (n=55). Sixty-three participants (59%) contributed to the intention-to-treat analysis. Mean (SD) age was 21 (6) years (n=46, <18 years). At baseline, physical activity levels were high in both groups (AO 102 (52) vs UC 127 (73) min/day). There was no statistically significant difference in MVPA between groups at either timepoint (post-intervention mean difference (95% CI) -14 mins (-45 to 16)). Uptake of the intervention was low with only 40% (n=21) of participants accessing the web application. CONCLUSION: A web-based application, including individualised goal setting, real-time feedback and motivation for behavioural change, was no better than usual care at promoting physical activity in young pwCF following hospital discharge. High levels of baseline physical activity levels in both groups, and limited engagement with the intervention, suggest alternative strategies may be necessary to identify and support young pwCF who would benefit from enhanced physical activity. TRIAL REGISTRATION NUMBER: ACTRN12617001009303, 13 July 13 2017.

Transition to adult care in cystic fibrosis: The challenges and the structure.

In developed countries, it is projected that there will be a 70% increase in the number of adults living with Cystic Fibrosis (CF) between 2010 and 2025. This shift in demographics highlights the importance of high-quality transition programmes with developmentally appropriate integrated health care services as the individual moves through adolescence to adulthood. Adolescents living with CF face additional and unique challenges that may have long-term impacts on their health, quality of life and life-expectancy. CF specific issues around socially challenging symptoms, body image, reproductive health and treatment burden differentiate people with CF from their peers and require clinicians to identify and address these issues during the transition process. This review provides an overview of the health, developmental and psychosocial challenges faced by individuals with CF, their guardians and health care teams considering the fundamental components and tools that are required to build a transition programme that can be tailored to suit individual CF clinics.

Intimate Partner and Sexual Violence Prevention Among Youth: A Community Guide Systematic Review.

INTRODUCTION: Intimate partner violence and sexual violence are widespread and often occur early in life. This systematic review examines the effectiveness of interventions for primary prevention of intimate partner violence and sexual violence among youth. METHODS: Studies were identified from 2 previous systematic reviews and an updated search (January 2012-June 2016). Included studies were implemented among youth, conducted in high-income countries, and aimed to prevent or reduce the perpetration of intimate partner violence or sexual violence. In 2016-2017, Guide to Community Preventive Services (Community Guide) methods were used to assess effectiveness as determined by perpetration, victimization, or bystander action. When heterogeneity of outcomes prevented usual Community Guide methods, the team systematically applied criteria for favorability (statistically significant at p<0.05 or approaching significance at p<0.10) and consistency (75% of results in the same direction). RESULTS: A total of 28 studies (32 arms) met inclusion and quality of execution criteria. Interventions used combinations of teaching healthy relationship skills, promoting social norms to protect against violence, or creating protective environments. Overall, 18 of 24 study arms reported favorable results on the basis of the direction of effect for decreasing perpetration; however, favorability for bystander action diminished with longer follow-up. Interventions did not demonstrate consistent results for decreasing victimization. A bridge search conducted during Fall 2020 confirmed these results. DISCUSSION: Interventions for the primary prevention of intimate partner violence and sexual violence are effective in reducing perpetration. Increasing bystander action may require additional follow-up as effectiveness diminishes over time. Findings may inform researchers, school personnel, public health, and other decision makers about effective strategies to prevent intimate partner violence and sexual violence among youth.

Improving patient flow during infectious disease outbreaks using machine learning for real-time prediction of patient readiness for discharge.

BACKGROUND: Delays in patient flow and a shortage of hospital beds are commonplace in hospitals during periods of increased infection incidence, such as seasonal influenza and the COVID-19 pandemic. The objective of this study was to develop and evaluate the efficacy of machine learning methods at identifying and ranking the real-time readiness of individual patients for discharge, with the goal of improving patient flow within hospitals during periods of crisis. METHODS AND PERFORMANCE: Electronic Health Record data from Oxford University Hospitals was used to train independent models to classify and rank patients' real-time readiness for discharge within 24 hours, for patient subsets according to the nature of their admission (planned or emergency) and the number of days elapsed since their admission. A strategy for the use of the models' inference is proposed, by which the model makes predictions for all patients in hospital and ranks them in order of likelihood of discharge within the following 24 hours. The 20% of patients with the highest ranking are considered as candidates for discharge and would therefore expect to have a further screening by a clinician to confirm whether they are ready for discharge or not. Performance was evaluated in terms of positive predictive value (PPV), i.e., the proportion of these patients who would have been correctly deemed as 'ready for discharge' after having the second screening by a clinician. Performance was high for patients on their first day of admission (PPV = 0.96/0.94 for planned/emergency patients respectively) but dropped for patients further into a longer admission (PPV = 0.66/0.71 for planned/emergency patients still in hospital after 7 days). CONCLUSION: We demonstrate the efficacy of machine learning methods at making operationally focused, next-day discharge readiness predictions for all individual patients in hospital at any given moment and propose a strategy for their use within a decision-support tool during crisis periods.

An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer.

Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes.

Sharing a household with children and risk of COVID-19: a study of over 300 000 adults living in healthcare worker households in Scotland.

OBJECTIVE: Children are relatively protected from COVID-19, due to a range of potential mechanisms. We investigated if contact with children also affords adults a degree of protection from COVID-19. DESIGN: Cohort study based on linked administrative data. SETTING: Scotland. STUDY POPULATION: All National Health Service Scotland healthcare workers and their household contacts as of March 2020. MAIN EXPOSURE: Number of young children (0-11 years) living in the participant's household. MAIN OUTCOMES: COVID-19 requiring hospitalisation, and any COVID-19 (any positive test for SARS-CoV-2) in adults aged ≥18 years between 1 March and 12 October 2020. RESULTS: 241 266, 41 198, 23 783 and 3850 adults shared a household with 0, 1, 2 and 3 or more young children, respectively. Over the study period, the risk of COVID-19 requiring hospitalisation was reduced progressively with increasing numbers of household children-fully adjusted HR (aHR) 0.93 per child (95% CI 0.79 to 1.10). The risk of any COVID-19 was similarly reduced, with the association being statistically significant (aHR per child 0.93; 95% CI 0.88 to 0.98). After schools reopened to all children in August 2020, no association was seen between exposure to young children and risk of any COVID-19 (aHR per child 1.03; 95% CI 0.92 to 1.14). CONCLUSION: Between March and October 2020, living with young children was associated with an attenuated risk of any COVID-19 and COVID-19 requiring hospitalisation among adults living in healthcare worker households. There was no evidence that living with young children increased adults' risk of COVID-19, including during the period after schools reopened.

Comorbidities Predict Inferior Survival in Patients Receiving Chimeric Antigen Receptor T Cell Therapy for Diffuse Large B Cell Lymphoma: A Multicenter Analysis.

Chimeric antigen receptor T cell (CAR-T) therapy is approved for treatment of relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL). Here we evaluate whether comorbidities, calculated using the Cumulative Illness Rating Scale (CIRS), predict survival for these patients. A retrospective chart review was performed at 4 academic institutions. All patients who underwent leukapheresis for commercial CAR-T therapy for R/R DLBCL were included. CIRS scores were calculated at the time of leukapheresis. High comorbidity was defined as either CIRS ≥7 or the presence of severe impairment (CIRS 3/4 in ≥1 system; CIRS-3+). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and differences in curves were detected by the log-rank test. A total of 130 patients were analyzed, 56.9% with CIRS ≥7 and 56.2% with CIRS-3+. After a median follow-up of 13 months, the median PFS was 6.7 months, and the median OS was not reached. On univariable analysis, Eastern Cooperative Oncology Group (ECOG) performance status (PS) was associated with inferior PFS (hazard ratio [HR], 1.45; 95% confidence interval [CI], 1.03-2.05; P = .03) and OS (HR, 1.76; 95% CI, 1.17-2.64; P = .007). Higher CIRS (CIRS ≥7 or CIRS-3+) was associated with inferior OS (HR, 2.12; 95%, CI, 1.06-4.22; P = .03) and a nonsignificant trend in worse PFS (HR, 1.45; 95% CI, .87-2.44; P = .16). In multivariable analyses, CIRS ≥7 or CIRS-3+ and ECOG PS maintained independent prognostic significance. Comorbidities as determined by CIRS and ECOG PS predict inferior survival in patients receiving CAR-T therapy for R/R DLBCL.

Risk of hospital admission with coronavirus disease 2019 in healthcare workers and their households: nationwide linkage cohort study.

OBJECTIVE: To assess the risk of hospital admission for coronavirus disease 2019 (covid-19) among patient facing and non-patient facing healthcare workers and their household members. DESIGN: Nationwide linkage cohort study. SETTING: Scotland, UK, 1 March to 6 June 2020. PARTICIPANTS: Healthcare workers aged 18-65 years, their households, and other members of the general population. MAIN OUTCOME MEASURE: Admission to hospital with covid-19. RESULTS: The cohort comprised 158 445 healthcare workers, most of them (90 733; 57.3%) being patient facing, and 229 905 household members. Of all hospital admissions for covid-19 in the working age population (18-65 year olds), 17.2% (360/2097) were in healthcare workers or their households. After adjustment for age, sex, ethnicity, socioeconomic deprivation, and comorbidity, the risk of admission due to covid-19 in non-patient facing healthcare workers and their households was similar to the risk in the general population (hazard ratio 0.81 (95% confidence interval 0.52 to 1.26) and 0.86 (0.49 to 1.51), respectively). In models adjusting for the same covariates, however, patient facing healthcare workers, compared with non-patient facing healthcare workers, were at higher risk (hazard ratio 3.30, 2.13 to 5.13), as were household members of patient facing healthcare workers (1.79, 1.10 to 2.91). After sub-division of patient facing healthcare workers into those who worked in "front door," intensive care, and non-intensive care aerosol generating settings and other, those in front door roles were at higher risk (hazard ratio 2.09, 1.49 to 2.94). For most patient facing healthcare workers and their households, the estimated absolute risk of hospital admission with covid-19 was less than 0.5%, but it was 1% and above in older men with comorbidity. CONCLUSIONS: Healthcare workers and their households contributed a sixth of covid-19 cases admitted to hospital. Although the absolute risk of admission was low overall, patient facing healthcare workers and their household members had threefold and twofold increased risks of admission with covid-19.

A web-based intervention to promote physical activity in adolescents and young adults with cystic fibrosis: protocol for a randomized controlled trial.

BACKGROUND: Regular participation in physical activity by people with cystic fibrosis (CF) promotes positive clinical and health outcomes including reduced rate of decline in lung function, fewer hospitalizations and greater wellbeing. However adherence to exercise and activity programs is low, in part due to the substantial daily therapy burden for young people with CF. Strict infection control requirements limit the role of group exercise programs that are commonly used in other clinical groups. Investigation of methods to promote physical activity in this group has been limited. The Active Online Physical Activity in Cystic fibrosis Trial (ActionPACT) is an assessor-blinded, multi-centre, randomized controlled trial designed to compare the efficacy of a novel web-based program (ActivOnline) compared to usual care in promoting physical activity participation in adolescents and young adults with CF. METHODS: Adolescents and young adults with CF will be recruited on discharge from hospital for a respiratory exacerbation. Participants randomized to the intervention group will have access to a web-based physical activity platform for the 12-week intervention period. ActivOnline allows users to track their physical activity, set goals, and self-monitor progress. All participants in both groups will be provided with standardised information regarding general physical activity recommendations for adolescents and young adults. Outcomes will be assessed by a blinded assessor at baseline, after completion of the intervention, and at 3-months followup. Healthcare utilization will be assessed at 12 months from intervention completion. The primary outcome is change in moderate-to-vigorous physical activity participation measured objectively by accelerometry. Secondary outcomes include aerobic fitness, health-related quality of life, anxiety and depression and sleep quality. DISCUSSION: This trial will establish whether a web-based application can improve physical activity participation more effectively than usual care in the period following hospitalization for a respiratory exacerbation. The web-based application under investigation can be made readily and widely available to all individuals with CF, to support physical activity and exercise participation at a time and location of the user's choosing, regardless of microbiological status. TRIAL REGISTRATION: Clinical trial registered on July 13, 2017 with the Australian and New Zealand Clinical Trials Register at (ACTRN12617001009303).

PEG10 is associated with treatment-induced neuroendocrine prostate cancer.

Neuroendocrine (NE) differentiation of advanced prostate adenocarcinoma following androgen receptor (AR) axis-directed therapy is becoming increasingly recognized. Several models of this transdifferentiation provide insight into its molecular pathogenesis and have highlighted the placental gene PEG10 for further study. Using our unique model of enzalutamide resistance (ENZR) and NE differentiation, we studied PEG10/AR interplay in enzalutamide treatment-resistant cell lines 42DENZR and 42FENZR compared to LNCaP and castration-resistant 16DCRPC cells. ENZR cell lines with positive terminal NE marker status also displayed higher baseline expression of PEG10 compared to LNCaP and 16DCRPC. Antagonism of AR activity increased PEG10 expression followed by an increase in terminal NE markers. Conversely, stimulating AR activity via androgen supplementation reversed PEG10 and NE marker expression in a time and dose-dependent manner. These results were supported by human data showing that PEG10 expression is highest in NEPC and that AR-dependent gene, PSA, is negatively correlated with PEG10 in adenocarcinoma. Further, ChIP assay confirmed binding of activated AR to the PEG10 enhancer, decreasing PEG10 expression. While PEG10 did not drive NEPC, its knockdown reduced NE markers in our cell lines. Moreover, PEG10 knockdown in vitro- and in vivo-attenuated tumor growth. Overall, these observations indicate that PEG10 is an AR-repressed gene which modulates NE markers in ENZR cells and targeting PEG10 in advanced prostate cancer with NE features is a rational and viable option.

Precision Measurements to Assess Baseline Status and Efficacy of Healthy Living Medicine.

Precision medicine recently has gained popularity, calling for more individualized approaches to prevent and/or reduce chronic-disease risk and to reduce non-communicable diseases such as cardiovascular disease (CVD). Encompassed under Precision medicine initiatives is the concept of healthy living medicine (HLM), which emphasizes the promotion of lifestyle and behavioral practices including physical activity and healthy dietary pattern. Precision measurements have the potential to improve the understanding of how risk factors influence disease trajectory, and further inform on how to precisely tailor clinical strategies to manage risk factors to prevent disease manifestation, and refine therapies according the patient's demographic, environment, and disease etiology. The purpose of this review is to summarize the application of established and emerging measurements that may be used in HLM to manage and optimize care in CVD prevention.

Galiellalactone inhibits the STAT3/AR signaling axis and suppresses Enzalutamide-resistant Prostate Cancer.

Most prostate cancer patients will progress to a castration-resistant state (CRPC) after androgen ablation therapy and despite the development of new potent anti-androgens, like enzalutamide (ENZ), which prolong survival in CRPC, ENZ-resistance (ENZR) rapidly occurs. Re-activation of the androgen receptor (AR) is a major mechanism of resistance. Interrogating our in vivo derived ENZR model, we discovered that transcription factor STAT3 not only displayed increased nuclear localization but also bound to and facilitated AR activity. We observed increased STAT3 S727 phosphorylation in ENZR cells, which has been previously reported to facilitate AR binding. Strikingly, ENZR cells were more sensitive to inhibition with STAT3 DNA-binding inhibitor galiellalactone (GPA500) compared to CRPC cells. Treatment with GPA500 suppressed AR activity and significantly reduced expression of Cyclin D1, thus reducing cell cycle progression into S phase and hindering cell proliferation. In vivo, GPA500 reduced tumor volume and serum PSA in ENZR xenografts. Lastly, the combination of ENZ and GPA500 was additive in the inhibition of AR activity and proliferation in LNCaP and CRPC cells, providing rationale for combination therapy. Overall, these results suggest that STAT3 inhibition is a rational therapeutic approach for ENZR prostate cancer, and could be valuable in CRPC in combination with ENZ.