The past, present, and the future of disc nucleus replacement. A systematic review of a large diversity of ideas and experiences.

Disc nucleus replacement (NR) is a challenging surgical technique used as a medical treatment for early-stage disc herniation to restore disc height and the biomechanical function of a motion segment, which may reduce low back pain. The surgical procedure involves the removal and replacement of the degenerated nucleus pulposus with a substitute by accessing the annulus fibrosos via a created hole. Over the decades, nucleus replacement has been an important issue, leading to the development of different substitute alternatives. The first ideas are dated to the 1950s and since then, more than a hundred nucleus replacement concepts can be identified. There were numerous attempts and several clinical trials; however, after more than 70 years of research, no gold standard for nucleus pulposus replacement has been identified. This review aims to collect the different nucleus replacements reported in the literature, thus understanding what failed, what could be improved and what are the opportunities for the future. A systematic review of the literature was performed using a keyword-based search on PubMed, Web of Science, and Scopus databases to detect all nucleus replacements presented in the past by clinicians and engineers. Several studies were extracted from which the main nucleus replacements over the years were investigated, including the ones that received CE mark, FDA approval, or IDE approval and, also those involved in clinical trials. A total of 116 studies were included in this review. The extracted data concern the nucleus replacements proposed over the years to create a historical background as complete as possible, including their mechanical and biomechanical characterization and the clinical trials conducted over the years. Nucleus disc arthroplasty has been explored for many years. Unfortunately, even today there is still nothing safe and definitive in this surgical practice. This review provides an overview of the nucleus replacement history. A breakthrough could be the improvements in technologies for the annulus fibrous closing or sealing and the tissue engineering and medical regenerative techniques which could certainly ensure a higher NR implantation success rate in the future of this clinical treatment. It is not yet clear what is the future of this clinical practice. Only scientific research can answer the question: is the nucleus replacement still a possible clinical solution?

Sex-related Differences among Patients Undergoing Surgical Aortic Valve Replacement - A Propensity Score Matched Study.

OBJECTIVES: We investigated the sex-related difference in characteristics and 2-year outcomes after surgical aortic valve replacement (SAVR) by propensity-score matching (PSM). METHODS: Data from two prospective registries, INDURE and IMPACT, were merged, resulting in a total of 933 patients: 735 males and 253 females undergoing first-time SAVR. PSM was performed to assess the impact of sex on the SAVR outcomes, yielding 433 males and 243 females with comparable baseline characteristics. RESULTS: Females had a lower body mass index (BMI; median 27.1 vs 28.0 kg/m2; p = 0.008), fewer bicuspid valves (52% vs 59%; p = 0.036), higher EuroSCORE II (mean 2.3 vs 1.8%; p < 0.001) and STS score (mean 1.6 vs 0.9%; p < 0.001), were more often in NYHA class III/IV (47% vs 30%; p < 0.001) and angina CCS III/IV (8.2% vs 4.4%; p < 0.001), but had a lower rate of myocardial infarction (1.9% vs 5.2%; p = 0.028) compared to males. These differences vanished after PSM, except for EuroSCORE II and STS scores, which were still significantly higher in females. Furthermore, females required smaller valves (median diameter 23.0 vs 25.0 mm, p < 0.001). There were no differences in the length of hospital stay (median 8 days) or ICU stay (median 24 vs 25 hours) between both sexes. At two years, post-SAVR outcomes were comparable between males and females, even after PSM. CONCLUSIONS: Despite females presenting with a significantly higher surgical risk profile, 2-year outcomes following SAVR were comparable between males and females.

Upregulation of Fatty Acid Synthesis Genes in the Livers of Adolescent Female Rats Caused by Inhalation Exposure to PCB52 (2,2',5,5'-Tetrachlorobiphenyl).

Elevated airborne PCB levels in older schools are concerning due to their health impacts, including cancer, metabolic dysfunction-associated steatotic liver disease (MASLD), cardiovascular issues, neurodevelopmental diseases, and diabetes. During a four-week inhalation exposure to PCB52, an air pollutant commonly found in school environments, adolescent rats exhibited notable presence of PCB52 and its hydroxylated forms in their livers, alongside changes in gene expression. Female rats exhibited more pronounced changes in gene expression compared to males, particularly in fatty acid synthesis genes regulated by the transcription factor SREBP1. In vitro studies with human liver cells showed that the hydroxylated metabolite of PCB52, 4-OH-PCB52, but not the parent compound, upregulated genes involved in fatty acid biosynthesis similar to in vivo exposure. These findings highlight the sex-specific effects of PCB52 exposure on livers, particularly in females, suggesting a potential pathway for increased MASLD susceptibility.

Clozapine levels and outcomes in Serbian patients with treatment-resistant psychotic disorders previously treated without measuring clozapine levels (CLOSER).

Clozapine remains the only pharmacological treatment option for treatment-resistant schizophrenia. Therapeutic drug monitoring (TDM) of clozapine is recommended, although evidence for the therapeutic range of 350-600 ng/ml is limited. In various countries including Serbia, TDM of clozapine is not routinely performed. This study evaluated the distribution of clozapine levels and their relationship with clinical outcomes in Serbian patients who had not undergone prior TDM. 140 Patients with treatment-resistant schizophrenia and schizo-affective disorder were enrolled. Clozapine levels were measured by dried blood spot (DBS) analysis. Side effects were evaluated by GASS-c, severity of symptoms and functional impairment with WHODAS, CGI-S and GAF. Of the patients, 51.2% had subtherapeutic levels, 24.8% were in the therapeutic window, and 24% had supratherapeutic levels. Clozapine levels showed no association with side effects and a weak positive association with symptom severity and functional impairment. No serious side effects were observed in patients with clozapine levels surpassing 1000 ng/ml (n = 8). Based on these findings, we propose that the upper limit of the therapeutic range should not be regarded as an absolute barrier, and guidelines should allow for a personalized approach when prescribing clozapine.

Assessing the efficacy and tolerability of PET-guided BrECADD versus eBEACOPP in advanced-stage, classical Hodgkin lymphoma (HD21): a randomised, multicentre, parallel, open-label, phase 3 trial.

BACKGROUND: Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. METHODS: This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1-3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1-7), and prednisone (40 mg/m2 orally on days 1-14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). FINDINGS: Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24-42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65-0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45-0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6-96·1) for BrECADD and 90·9% (88·7-93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7-99·5) and 98·2% (97·2-99·3), respectively. INTERPRETATION: BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. FUNDING: Takeda Oncology.

Cysteine Oxidation in Human Galectin-1 Occurs Sequentially via a Folded Intermediate to a Fully Oxidized Unfolded Form.

Galectins are multifunctional effectors in cellular homeostasis and dysregulation. Oxidation of human galectin-1 (Gal-1) with its six sulfhydryls produces a disulfide-bridged oxidized form that lacks normal lectin activity yet gains new glycan-independent functionality. Nevertheless, the mechanistic details as to how Gal-1 oxidation occurs remain unclear. Here, we used 15N and 13C HSQC NMR spectroscopy to gain structural insight into the CuSO4-mediated path of Gal-1 oxidation and identified a minimum two-stage conversion process. During the first phase, disulfide bridges form slowly between C16-C88 and/or C42-C66 to produce a partially oxidized, conformationally flexible intermediate that retains the ability to bind lactose. Site-directed mutagenesis of C16 to S16 impedes the onset of this overall slow process. During the second phase, increased motional dynamics of the intermediate enable the relatively distant C2 and C130 residues to form the third and final disulfide bond, leading to an unfolded state and consequent dimer dissociation. This fully oxidized end state loses the ability to bind lactose, as shown by the hemagglutination assay. Consistent with this model, we observed that the Gal-1 C2S mutant maintains intermediate-state structural features with a free sulfhydryl group at C130. Incubation with dithiothreitol reduces all disulfide bonds and allows the lectin to revert to its native state. Thus, the sequential, non-random formation of three disulfide bridges in Gal-1 in an oxidative environment acts as a molecular switch for fundamental changes to its functionality. These data inspire detailed bioactivity analysis of the structurally defined oxidized intermediate in, e.g., acute and chronic inflammation.

GAIN2 trial overall survival with intense versus tailored dose dense chemotherapy in early breast cancer.

GAIN-2 trial evaluated the optimal intense dose-dense (idd) strategy for high-risk early breast cancer. This study reports the secondary endpoints pathological complete response (pCR) and overall survival (OS). Patients (n = 2887) were randomized 1:1 between idd epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) versus leukocyte nadir-based tailored regimen of dose-dense EC and docetaxel (dtEC-dtD) as adjuvant therapy, with neoadjuvant therapy allowed after amendment. At median follow-up of 6.5 years (overall cohort) and 5.7 years (neoadjuvant cohort, N = 593), both regimens showed comparable 5-year OS rates (iddEnPC 90.8%, dtEC-dtD 90.0%, p = 0.320). In the neoadjuvant setting, iddEnPC yielded a higher pCR rate than dtEC-dtD (51.2% vs. 42.6%, p = 0.045). Patients achieving pCR had significantly improved 5-year iDFS (88.7% vs. 70.1%, HR 0.33, p < 0.001) and OS rates (93.9% vs. 83.1%, HR 0.32, p < 0.001), but OS outcomes were comparable regardless of pCR status. Thus, iddEnPC demonstrates superior pCR rates compared to dtEC-dtD, yet with comparable survival outcomes.

Isothermal Amplification Using Temperature-Controlled Frequency Mixing Magnetic Detection-Based Portable Field-Testing Platform.

Sensitive magnetic nucleic acid (NA) detection via frequency mixing magnetic detection (FMMD) requires amplified NA samples for which a reliable temperature control is necessary. The feasibility of recombinase polymerase amplification (RPA) was studied within a newly integrated temperature-controlled sensor unit of a mobile FMMD based setup. It has been demonstrated that the inherently generated heat of the low frequency (LF) excitation signal of FMMD can be utilized and controlled by means of pulse width modulation (PWM). To test control performance in a point of care (PoC) setting with changing ambient conditions, a steady state and dynamic response model for the thermal behavior at the sample position of the sensor were developed. We confirmed that in the sensor unit of the FMMD device, RPA performs similar as in a temperature-controlled water bath. For narrow steady state temperature regions, a linear extrapolation suffices for estimation of the sample position temperature, based on the temperature feedback sensor for PWM control. For any other ambient conditions, we identified and validated a lumped parameter model (LPM) performing with high estimation accuracy. We expect that the method can be used for NA amplification and magnetic detection using FMMD in resource-limited settings.

Prognostic impact of selection criteria of current adjuvant endocrine therapy trials NATALEE and monarchE in postmenopausal HRpos/HER2neg breast cancer patients treated with upfront letrozole.

BACKGROUND: The monarchE and NATALEE trials demonstrated the benefit of CDK4/6 inhibitor (CDK4/6i) therapy in adjuvant breast cancer (BC) treatment. Patient selection, based on clinical characteristics, delineated those at high (monarchE) and high/intermediate recurrence risk (NATALEE). This study employed a historical patient cohort to describe the proportion and prognosis of patients eligible for adjuvant CDK4/6i trials. METHODS: Between 2009 and 2011, 3529 patients were enrolled in the adjuvant PreFace clinical trial (NCT01908556). Eligibility criteria included postmenopausal patients with hormone receptor-positive (HRpos) BC for whom a five-year upfront therapy with letrozole was indicated. Patients were categorized into prognostic groups according to monarchE and NATALEE inclusion criteria, and their invasive disease-free survival (iDFS) and overall survival (OS) were assessed. RESULTS: Among 2891 HRpos patients, 384 (13.3 %) met the primary monarchE inclusion criteria. The majority (n = 261) qualified due to having ≥ 4 positive lymph nodes. For NATALEE, 915 out of 2886 patients (31.7 %) met the eligibility criteria, with 126 patients (13.7 %) being node-negative. Patients from monarchE with ≥ 4 positive lymph nodes and NATALEE with stage III BC exhibited the poorest prognosis (3-year iDFS rate 0.87). Patients ineligible for the trials demonstrated prognoses similar to the most favorable patient groups within the eligibility criteria. CONCLUSION: Patient populations eligible for monarchE and NATALEE trials differed. Nearly a third of the postmenopausal HRpos population, previously under upfront letrozole treatment, met the NATALEE prognostic eligibility criteria. As certain eligible groups had a prognosis similar to non-eligible patients, it might be interesting to explore additional patient groups for CDK4/6i therapy.

Aortic root remodeling in the tricuspid aortic valve.

BACKGROUND: Aortic root remodeling is one of the principal forms of valve-preserving root replacement. Its value has been questioned by some, while others have achieved excellent valve durability. The purpose of this review is to summarize the existing information to determine which factors may have contributed both to failures and to successes. METHODS: Publications with > 15 patients on root remodeling for aneurysm or dissection with tricuspid aortic valves were reviewed for specific details of pre- and intraoperative management. RESULTS: The series were very heterogeneous. Most operations were performed for root aneurysm, 10 publications included type A dissection. Connective tissue disease was present in 22% of patients. Mean patient age was 52 years, 5-year survival varied between 58 and 100%. Most series did not include an annuloplasty. Importantly, no details on quantitative assessment of valve configuration were specified in most series, especially those with suboptimal valve function and durability. The introduction of the effective height concept to control valve configuration was associated with improved results and more frequent correction of cusp prolapse. Late freedom from aortic regurgitation and freedom from reoperation are good in the larger series. CONCLUSIONS: Root remodeling can lead to excellent valve durability if quantitative intraoperative measurement of valve configuration is performed. The addition of an annuloplasty seems to improve aortic valve competence further, even though its effect on durability is not unequivocally proven. The long-term results of root remodeling are good, also in the second postoperative decade; it is a valid form of valve-preserving root replacement.

What helps, what hinders?-Focus group findings on barriers and facilitators for mobile service robot use in a psychosocial group therapy for people with dementia.

Introduction: Many countries are facing a shortage of healthcare workers. Furthermore, healthcare workers are experiencing many stressors, resulting in psychological issues, impaired health, and increased intentions to leave the workplace. In recent years, different technologies have been implemented to lighten workload on healthcare workers, such as electronic patient files. Robotic solutions are still rather uncommon. To help with acceptance and actual use of robots their functionalities should correspond to the users' needs. Method: In the pilot study Care4All-Initial, we developed and field-tested applications for a mobile service robot in a psychosocial, multimodal group therapy for people with dementia. To guide the process and assess possible facilitators and barriers, we conducted a reoccurring focus group including people with dementia, therapists, professional caregivers as well as researchers from different disciplines with a user-centered design approach. The focus group suggested and reviewed applications and discussed ethical implications. We recorded the focus group discussions in writing and used content analysis. Results: The focus group discussed 15 different topics regarding ethical concerns that we used as a framework for the research project: Ethical facilitators were respect for the autonomy of the people with dementia and their proxies regarding participating and data sharing. Furthermore, the robot had to be useful for the therapists and attendees. Ethical barriers were the deception and possible harm of the people with dementia or therapists. The focus group suggested 32 different applications. We implemented 13 applications that centered on the robot interacting with the people with dementia and lightening the workload off the therapists. The implemented applications were facilitated through utilizing existing hard- and software and building on applications. Barriers to implementation were due to hardware, software, or applications not fitting the scope of the project. Discussion: To prevent barriers of robot employment in a group therapy for people with dementia, the robot's applications have to be developed sufficiently for a flawless and safe use, the use of the robot should not cause irritation or agitation, but rather be meaningful and useful to its users. To facilitate the development sufficient time, money, expertise and planning is essential.

Predicting Benefit From FOLFOXIRI Plus Bevacizumab in Patients With Metastatic Colorectal Cancer.

PURPOSE: Patient outcomes may differ from randomized trial averages. We aimed to predict benefit from FOLFOXIRI versus infusional fluorouracil, leucovorin, and oxaliplatin/fluorouracil, leucovorin, and irinotecan (FOLFOX/FOLFIRI), both plus bevacizumab, in patients with metastatic colorectal cancer (mCRC). METHODS: A Cox model with prespecified clinical, molecular, and laboratory variables was developed in 639 patients from the TRIBE2 trial for predicting 2-year mortality. Data from the CHARTA (n = 232), TRIBE1 (n = 504), and CAIRO5 (liver-only mCRC, n = 287) trials were used for external validation and heterogeneity of treatment effects (HTE) analysis. This involves categorizing patients into risk groups and assessing treatment effects across these groups. Performance was assessed by the C-index and calibration plots. The C-for-benefit was calculated to assess evidence for HTE. The c-for-benefit is specifically designed for HTE analysis. Like the commonly known c-statistic, it summarizes the discrimination of a model. Values over 0.5 indicate evidence for HTE. RESULTS: In TRIBE2, the overoptimism-corrected C-index was 0.66 (95% CI, 0.63 to 0.69). At external validation, the C-index was 0.69 (95% CI, 0.64 to 0.75), 0.68 (95% CI, 0.64 to 0.72), and 0.65 (95% CI, 0.65 to 0.66), in CHARTA, TRIBE1, and CAIRO5, respectively. Calibration plots indicated slight underestimation of mortality. The c-for-benefit indicated evidence for HTE in CHARTA (0.56, 95% CI, 0.48 to 0.65), but not in TRIBE1 (0.49, 95% CI, 0.44 to 0.55) and CAIRO5 (0.40, 95% CI, 0.32 to 0.48). CONCLUSION: Although 2-year mortality could be reasonably estimated, the HTE analysis showed that clinically available variables did not reliably identify which patients with mCRC benefit from FOLFOXIRI versus FOLFOX/FOLFIRI, both plus bevacizumab, across the three studies.

Impact of Particle Size on the Nonlinear Magnetic Response of Iron Oxide Nanoparticles during Frequency Mixing Magnetic Detection.

Magnetic nanoparticles (MNPs), particularly iron oxide nanoparticles (IONPs), play a pivotal role in biomedical applications ranging from magnetic resonance imaging (MRI) enhancement and cancer hyperthermia treatments to biosensing. This study focuses on the synthesis, characterization, and application of IONPs with two different size distributions for frequency mixing magnetic detection (FMMD), a technique that leverages the nonlinear magnetization properties of MNPs for sensitive biosensing. IONPs are synthesized through thermal decomposition and subsequent growth steps. Our findings highlight the critical influence of IONP size on the FMMD signal, demonstrating that larger particles contribute dominantly to the FMMD signal. This research advances our understanding of IONP behavior, underscoring the importance of size in their application in advanced diagnostic tools.

BIM-enabled built-asset information management conceptual framework: A case of public university buildings in Addis Ababa, Ethiopia.

The integration of BIM with other digital advancements has demonstrably led to an increase of performance in the Architecture, Engineering, Construction and Operation (AECO) industry. This integration not only is showing promising results in boosting the industry's performance, but also the productivity and promotes data-driven decision-making. Despite these benefits, there are limited studies that address the integration of BIM and digital data for managing built-assets in general and in developing countries in particular. To fill this gap, a closer assessment of current built-asset information management practice is necessary. The assessment of the practice examines how digital processes and/or technology can be seamlessly integrated into existing practices. In this regard, this study aims to provide valuable insights into increasing the maturity of built-asset information management by integrating digital data with BIM. The study uses a case-based research design using built-assets (universities in Addis Ababa) as public building representative to capture the prevailing information management practices in Ethiopian public buildings. The findings reveal that traditional paper-based practices still dominate the management of built-assets. This leads to difficulties in terms of data loss, unavailability, inaccuracy, and unreliability, all of which are detrimental to the overall performance. Based on these findings, a conceptual framework is designed to improve the performance of built-assets and help owners, end-users, and managers in defining data and information requirements for BIM-enabled asset information management. The framework delineates processes for structured information requirements definition and validation of various asset data from varying sources. The framework utilizes a BIM-enabled platform as a single source of truth and offers a comprehensive solution to the identified challenges. The findings of this study holds significant promise for improving the existing practice of built-asset information management within the study context.

Astrocyte Mitochondria Are a Sensitive Target of PCB52 and its Human-Relevant Metabolites.

Polychlorinated biphenyls (PCBs) are industrial chemicals that are ubiquitously found in the environment. Exposure to these compounds has been associated with neurotoxic outcomes; however, the underlying mechanisms for such outcomes remain to be fully understood. Recent studies have shown that astrocytes, the most abundant glial cell type in the brain, are susceptible to PCB exposure as well as exposure to human-relevant metabolites of PCBs. Astrocytes are critical for maintaining healthy brain function due to their unique functional attributes and positioning within the neuronal networks in the brain. In this study, we assessed the toxicity of PCB52, one of the most abundantly found PCB congeners in outdoor and indoor air, and two of its human-relevant metabolites, on astrocyte mitochondria. We exposed C6 cells, an astrocyte cell line, to PCB52 or its human-relevant metabolites and found that all the compounds showed increased toxicity in galactose-containing media compared to that in the glucose-containing media, indicating the involvement of mitochondria in observed toxicity. Additionally, we also found increased oxidative stress upon exposure to PCB52 metabolites. All three compounds caused a loss of mitochondrial membrane potential, distinct changes in the mitochondrial structure, and impaired mitochondrial function. The hydroxylated metabolite 4-OH-PCB52 likely functions as an uncoupler of mitochondria. This is the first study to report the adverse effects of exposure to PCB52 and its human-relevant metabolites on the mitochondrial structure and function in astrocytes.

Role of Psychosocial Factors and Mental Well-Being for Baby WASH- and Nutrition-Related Behaviors in Lao PDR.

In Lao PDR, 30% of children under age 5 years are affected by stunting. Stunting in childhood is associated with poorer outcomes for both physical and cognitive development. Baby WASH is a focused approach to water supply, sanitation, and hygiene for infants and children that targets numerous contextual and psychosocial factors including child handwashing, food hygiene, clean play spaces, and management of animal feces in the household environment. Using the risks, attitudes, norms, abilities, and self-regulation approach to behavior change (BC), the objective of this study was to investigate psychosocial factors of Baby WASH and nutrition related-behaviors, considering caregivers mental well-being, to design evidence-based BC interventions. A cross-sectional survey of 616 caregivers of a child under 2 years was conducted in Lao PDR. Caregivers well-being was significantly associated with handwashing before feeding a baby, controlling "mouthing," and the intention to exclusively breastfeed for the first 6 months. All psychosocial factors of the three behaviors were correlated with mental well-being. Results suggest that attitudinal and ability factors underlying handwashing with soap before feeding a child should be the primary focus of BC interventions. For controlling mouthing factors, interventions should target attitude and norm factors. To increase the intention of exclusive breastfeeding for the first 6 months attitude, ability, and self-regulation factors should be targeted through BC interventions. The findings of this study can be used to support the inclusion of vulnerable caregivers with poor mental well-being with BC interventions designed to improve child health and prevent stunting.

Smooth muscle cell phenotypic switching occurs independent of aortic dilation in bicuspid aortic valve-associated ascending aortas.

BACKGROUND: Bicuspid aortic valves (BAV) are frequently associated with ascending aortic aneurysms. The etiology is incompletely understood, but genetic factors, in addition to flow perturbations, are likely involved. Since loss of contractility and elaboration of extracellular matrix in the vessel wall are features of BAV-associated aortopathy, phenotypic modulation of smooth muscle cells (SMCs) may play a role. METHODS: Ascending aortic tissue was collected intra-operatively from 25 individuals with normal (i.e., tricuspid) aortic valves (TAV) and from 25 individuals with BAVs. For both TAV and BAV, 10 patients had non-dilated (ND) and 15 patients had dilated (D) aortas. SMCs were isolated and cultured from a subset of patients from each group. Aortic tissue and SMCs were fluorescently immunolabeled for SMC phenotypic markers (i.e., alpha-smooth muscle actin (ASMA, contractile), vimentin (synthetic) and p16INK4a and p21Cip1 (senescence). SMCs were also analyzed for replicative senescence in culture. RESULTS: In normal-sized and dilated BAV aortas, SMCs switched from the contractile state to either synthetic or senescent phenotypes, as observed by loss of ASMA (ND: P = 0.001, D: P = 0.002) and associated increases in vimentin (ND: P = 0.03, D: P = 0.004) or p16/p21 (ND: P = 0.03, D: P<0.0001) compared to TAV. Dilatation of the aorta exacerbated SMC phenotypic switching in both BAV and TAV aortas (all P<0.05). In SMCs cultured from normal and dilated aortas, those isolated from BAV reached replicative senescence faster than those from TAV aortas (all P = 0.02). Furthermore, there was a stark inverse correlation between ASMA and cell passage number in BAV SMCs (ND: P = 0.0006, D: P = 0.01), but not in TAV SMCs (ND: P = 0.93, D: P = 0.20). CONCLUSIONS: The findings of this study provide direct evidence from cell culture studies implying that SMCs switch from the contractile state to either synthetic or senescent phenotypes in the non-dilated BAV aorta. In cultured SMCs from both non-dilated and dilated aortas, we found that this process may precede dilatation and accompany aneurysm development in BAV. Our findings suggest that therapeutically targeting SMC phenotypic modulation in BAV patients may be a viable option to prevent or delay ascending aortic aneurysm formation.

Aortic valve cusp size and shape in dilated trileaflet aortic roots.

OBJECTIVES: Objective of the study was to quantify the differences in cusp size and shape in patients with normal and dilated trileaflet aortic roots and in dilated roots with or without aortic regurgitation. METHODS: Retrospective analysis of computed tomography studies in patients with normal and dilated trileaflet aortic roots was performed measuring root and cusp dimensions. Normal root size was defined as sinuses of Valsalva diameter < 40 mm, dilated as ≥ 45 mm. Root measurements normalized to basal ring diameter and cusp measurements normalized to geometric height were analyzed to assess the shape. Additionally, comparison of dilated roots with or without aortic regurgitation was made. RESULTS: We analyzed 146 normal and 104 dilated aortic roots and 73 propensity-matched pairs. Dilated roots were larger in all dimensions and had increased ratio between commissural and basal ring diameter (1.58±0.23 vs. 1.11±0.10, p<0.001). Cusps in dilated roots were larger in all measured dimensions and were elongated with increased normalized cusp insertion length (3.64±0.39 vs. 3.26±0.20, p<0.001) and normalized free margin length (2.53±0.30 vs. 2.16±0.19, p<0.001). In patients with dilated root and no cusp prolapse (n = 83), those with moderate or severe aortic regurgitation had larger commissural diameter but similar cusp dimensions compared to those with no or mild aortic regurgitation. CONCLUSIONS: The cusps in dilated roots elongate transversely and to a lesser degree radially. Functional aortic regurgitation is caused by extensive commissural dilatation and not by inadequate cusp adaptation.