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Chordoma is a rare bone cancer with variable clinical outcomes. Here, we recruited 184 sporadic chordoma patients from the US and Canada and collected their clinical and treatment data. The average age at diagnosis was 45.5 years (Range 5-78) and the chordoma site distribution was 49.2% clivus, 26.2% spinal, and 24.0% sacral. Most patients (97.5%) received surgery as the primary treatment, among whom 85.3% also received additional treatment. Except for the most prevalent cancers like prostate, lung, breast, and skin cancer, there was no discernible enrichment for any specific cancer type among patients or their family members. Among a subset of patients (N = 70) with tumor materials, we conducted omics analyses and obtained targeted panel sequencing and SNP array genotyping data for 51 and 49 patients, respectively. The most recurrent somatic driver mutations included PIK3CA (12%), followed by chromatin remodeling genes PBRM1 and SETD2. Amplification of the 6q27 region, containing the chordoma susceptibility gene TBXT, was detected in eight patients (16.3%). Clival patients appeared to be less likely to carry driver gene mutations, chromosome arm level deletion events (e.g., 5p, 5p, and 9p), or 6q27 amplification compared to sacral patients. After adjusting for age, sex, tumor site, and additional treatment, patients with somatic deletions of 14q (OR = 13.73, 95% CI 1.96-96.02, P = 0.008) and 18p (OR = 13.68, 95% CI 1.77-105.89, P = 0.012) were more likely to have persistent chordoma. The study highlights genomic heterogeneity in chordoma, potentially linked to location and clinical progression.

MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q10, an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

Characterization of how the microenvironment, or niche, regulates stem cell activity is central to understanding stem cell biology and to developing strategies for the therapeutic manipulation of stem cells. Low oxygen tension (hypoxia) is commonly thought to be a shared niche characteristic in maintaining quiescence in multiple stem cell types. However, support for the existence of a hypoxic niche has largely come from indirect evidence such as proteomic analysis, expression of hypoxia inducible factor-1α (Hif-1α) and related genes, and staining with surrogate hypoxic markers (for example, pimonidazole). Here we perform direct in vivo measurements of local oxygen tension (pO2) in the bone marrow of live mice. Using two-photon phosphorescence lifetime microscopy, we determined the absolute pO2 of the bone marrow to be quite low (

Health professional competency building is one of nine national responsibilities (to achieve universal coverage and sustainability) described in the 2018 World Health Organization/UNICEF implementation guidance for the Baby‐Friendly Hospital Initiative (BFHI). Skilled breastfeeding support as a standard of newborn care is critical to the establishment of lactation and exclusive breastfeeding. This qualitative case study describes the Kyrgyz Republic's experience with health professional competency building related to breastfeeding counselling and support. We interviewed 38 key informants and reviewed national policies and international guidelines related to BFHI. The study found that although the country has a new policy reflecting BFHI global standards and guidance, the policy has not been disseminated nationally. Additionally, the policy lacks guidance on competency monitoring and verification and does not mention preservice training, even though preservice training on breastfeeding support exists. To achieve universal coverage for health professional competencies, the Kyrgyz Republic uses preservice, in‐service and refresher training. However, the main limitations to aligning with the new guidance are a lack of preservice BFHI‐ and breastfeeding‐specific curricula, experienced trainers and sufficient time and funding to dedicate to practical skill development. Conducted during the COVID‐19 pandemic, this study confirmed disruptions to BFHI training and service delivery but also documents the Kyrgyz Republic's resilient strides to mitigate impacts on breastfeeding support through facility‐level individual champions and adjustments to training such as going online. Opportunities exist for strengthening the competencies of service providers through strengthened preservice training, comprehensive and consistent in‐service training, solutions for overworked service providers and clear and sufficiently funded monitoring guidance. Key messages: The Kyrgyz Republic government has proactively enacted policies (Order 1078) reflecting the updated Baby‐Friendly Hospital Initiative (BFHI) guidance and has demonstrated a commitment to institutionalizing BFHI.Insufficient funding and the COVID‐19 pandemic derailed plans for implementing the new policy and guidance beyond the regional levels.There remain gaps in prioritizing, funding, and monitoring breastfeeding counselling and support competency building for both preservice and in‐service.Multi‐sectoral advocacy for BFHI is needed to secure national and local commitment and funding across and beyond the health system. [ABSTRACT FROM AUTHOR]

Compression therapy Compression therapies are used to treat leg swelling and to help the calf muscles return blood up the leg. For example, if one of the superficial veins in the lower leg is found to have venous reflux (leaky vein valves), the doctor may collapse the vein to re-route the blood through a healthy vein with functioning valves. Keywords: chronic venous disease; venous insufficiency; venous leg ulcer; venous reflux; wound care EN chronic venous disease venous insufficiency venous leg ulcer venous reflux wound care 89 92 4 02/14/23 20230201 NES 230201 What is a venous leg ulcer (VLU)? Other symptoms of chronic venous disease include swelling of the leg, leg muscle fatigue, leg cramping or throbbing, and discoloration of the skin. [Extracted from the article]

The 2018 implementation guidance for the Baby‐Friendly Hospital Initiative (BFHI) recommends institutionalising the ten Steps through nine national responsibilities for universal coverage and sustainability. As countries adapt BFHI programmes to this paradigm shift away from traditional designation programmes, documenting and sharing policy and programme experience are critical and currently sparse. This qualitative case study included desk reviews of published and grey literature on BFHI programming, national plans and policy documents specific to the selected national responsibilities for universal coverage and key informant (KI) interviews across a range of actors. In the Kyrgyz Republic, the case study explored responsibility 5, development and implementation of incentives and/or sanctions, and responsibility 6 in Malawi, providing technical assistance (TA). In both countries, the three sustainability responsibilities (national monitoring [7] communication and advocacy [8] and financing [9]) as they relate to the universal coverage of the targeted responsibilities were also explored. Thirty‐eight respondents in the Kyrgyz Republic described approaches that were used in the health system, including BFHI designation plaques, performance‐based financing and financial sanctions. However, currently, there are no formal incentives and sanctions. In Malawi, TA was utilised for national planning and to introduce quality improvement processes. Forty‐seven respondents mostly described provisions of TA in building and strengthening the capacity of providers. More programmatic evidence to demonstrate which types of incentives or sanctions can be effective and sustained and more documentation of how TA is provided across multiple aspects of implementation are needed as countries institutionalise BFHI. Key messages: 1.National policies and national and subnational plans need to be effectively communicated throughout the health system and systematic coordination are important to institutionalising Baby‐Friendly Hospital Initiative (BFHI).2.Technical assistance, commonly provided for professional competency building, could support hospital practices, procedures and management.3.Understanding the motivations of providers and health systems and monitoring key indicators are important for incentives and sanctions to be effective.4.Documenting and sharing programmatic experiences are critical as countries adopt the new BFHI guidance.5.Multisectoral advocacy for the ten Steps is needed to secure national and local commitment and funding across and beyond the health system. [ABSTRACT FROM AUTHOR]