Morphological characterisation of pediatric Turner syndrome aortae: Insights from a small cohort study.

Cardiovascular disease is widespread in girls and women living with Turner syndrome (TS). Despite this prevalence, cardiovascular risk evaluation using the current guidelines has seen life-threatening aortic events occurring at dimensions classified within the normal threshold. In this study, we characterized the three-dimensional aortic geometries of Turner syndrome children and their age-matched healthy counterparts to evaluate various morphological parameters. Turner syndrome girls had overall greater values in ten out of fifteen parameters examined (p > 0.05), when compared to healthy children: the aortic arch height and width; the ascending aorta, aortic arch (2 locations), and descending aorta diameters; the ratio of the ascending to descending aorta diameter; average curvature; average torsion; and average curvature-torsion score. Additionally, significant associations were found in the TS group: body surface area and both arch height (p = 0.03) and arch height to width ratio (p = 0.05), and aortic arch diameter and both body surface area (p = 0.04) and weight (p = 0.04). The new information resulting from this small cohort study contributes to an improved understanding of the morphological parameters affecting the hemodynamic environment in TS, and the clinical assessment of the increased cardiovascular risk in this population.

The economic impact of the COVID-19 pandemic on ethnic minorities in Manchester: lessons from the early stage of the pandemic.

This review summarizes the economic impacts of the pandemic on ethnic minorities, focusing on the city of Manchester. It utilizes multiple reporting sources to explore various dimensions of the economic shock in the UK, linking this to studies of pre-COVID-19 economic and ethnic composition in Manchester and in the combined authority area of Greater Manchester. We then make inferences about the pandemic's short-term impact specific to the city region. Greater Manchester has seen some of the highest rates of COVID-19 and as a result faced particularly stringent "lockdown" regulations. Manchester is the sixth most deprived Local Authority in England, according to 2019 English Indices of Multiple Deprivation. As a consequence, many neighborhoods in the city were always going to be less resilient to the economic shock caused by the pandemic compared with other, less-deprived, areas. Particular challenges for Manchester include the high rates of poor health, low-paid work, low qualifications, poor housing conditions and overcrowding. Ethnic minority groups also faced disparities long before the onset of the pandemic. Within the UK, ethnic minorities were found to be most disadvantaged in terms of employment and housing-particularly in large urban areas containing traditional settlement areas for ethnic minorities. Further, all Black, Asian, and Minority ethnic (BAME) groups in Greater Manchester were less likely to be employed pre-pandemic compared with White people. For example, people of Pakistani and Bangladeshi ethnic backgrounds, especially women, have the lowest levels of employment in Greater Manchester. Finally, unprecedented cuts to public spending as a result of austerity have also disproportionately affected women of an ethnic minority background alongside disabled people, the young and those with no or low-level qualifications. This environment has created and sustained a multiplicative disadvantage for Manchester's ethnic minority residents through the course of the COVID-19 pandemic.

Intratumoral CD16+ Macrophages Are Associated with Clinical Outcomes of Patients with Metastatic Melanoma Treated with Combination Anti-PD-1 and Anti-CTLA-4 Therapy.

PURPOSE: This study characterizes intratumoral macrophage populations within baseline melanoma biopsies from patients with advanced melanoma who received either anti-PD-1 monotherapy or a combination with anti-CTLA-4. Particularly, FcγRIIIa (CD16)-expressing macrophage densities were investigated for associations with response and progression-free survival. EXPERIMENTAL DESIGN: Patients with advanced melanoma who received either anti-PD-1 monotherapy or combination anti-PD-1 and anti-CTLA-4 were retrospectively identified. Macrophage populations were analyzed within baseline melanoma biopsies via multiplex IHC in relation to treatment outcomes. RESULTS: Patients who responded to combination immune checkpoint inhibitor contained higher CD16+ macrophage densities than those who did not respond (196 vs. 7 cells/mm2; P = 0.0041). There was no diffidence in CD16+ macrophage densities in the PD-1 monotherapy-treated patients based on response (118 vs. 89 cells/mm2; P = 0.29). A significantly longer 3-year progression-free survival was observed in combination-treated patients with high intratumoral densities of CD16+ macrophages compared with those with low densities (87% vs. 42%, P = 0.0056, n = 40). No association was observed in anti-PD-1 monotherapy-treated patients (50% vs. 47%, P = 0.4636, n = 50). Melanoma biopsies with high densities of CD16+ macrophages contained upregulated gene expression of critical T-cell recruiting chemokines (CXCL9, CXCL10, and CXCL11). CONCLUSIONS: Our data demonstrate that tumor microenvironments enriched with CD16+ macrophages are favorable for response to combination anti-PD-1 and anti-CTLA-4 therapy but not anti-PD-1 monotherapy. These data provides a potential biomarker of response for combination immunotherapies in patients with metastatic melanoma. See related commentary by Smithy and Luke, p. 2345.

Three-Component Stereoselective Enzymatic Synthesis of Amino-Diols and Amino-Polyols.

Amino-polyols represent attractive chemical building blocks but can be challenging to synthesize because of the high density of asymmetric functionalities and the need for extensive protecting-group strategies. Here we present a three-component strategy for the stereoselective enzymatic synthesis of amino-diols and amino-polyols using a diverse set of prochiral aldehydes, hydroxy ketones, and amines as starting materials. We were able to combine biocatalytic aldol reactions, using variants of d-fructose-6-phosphate aldolase (FSA), with reductive aminations catalyzed by IRED-259, identified from a metagenomic library. A two-step process, without the need for intermediate isolation, was developed to avoid cross-reactivity of the carbonyl components. Stereoselective formation of the 2R,3R,4R enantiomers of amino-polyols was observed and confirmed by X-ray crystallography.

Distinct pretreatment innate immune landscape and posttreatment T cell responses underlie immunotherapy-induced colitis.

Immune-related adverse events represent a major hurdle to the success of immunotherapy. The immunological mechanisms underlying their development and relation to antitumor responses are poorly understood. By examining both systemic and tissue-specific immune changes induced by combination anti-CTLA-4 and anti-PD-1 immunotherapy, we found distinct repertoire changes in patients who developed moderate-severe colitis, irrespective of their antitumor response to therapy. The proportion of circulating monocytes were significantly increased at baseline in patients who subsequently developed colitis compared with patients who did not develop colitis, and biopsies from patients with colitis showed monocytic infiltration of both endoscopically and histopathologically normal and inflamed regions of colon. The magnitude of systemic expansion of T cells following commencement of immunotherapy was also greater in patients who developed colitis. Importantly, we show expansion of specific T cell subsets within inflamed regions of the colon, including tissue-resident memory CD8+ T cells and Th1 CD4+ T cells in patients who developed colitis. Our data also suggest that CD8+ T cell expansion was locally induced, while Th1 cell expansion was systemic. Together, our data show that exaggerated innate and T cell responses to combination immunotherapy synergize to propel colitis in susceptible patients.

High-Dimensional and Spatial Analysis Reveals Immune Landscape-Dependent Progression in Cutaneous Squamous Cell Carcinoma.

PURPOSE: The tumor immune microenvironment impacts the biological behavior of the tumor, but its effect on clinical outcomes in head and neck cutaneous squamous cell carcinomas (HNcSCC) is largely unknown. EXPERIMENTAL DESIGN: We compared the immune milieu of high-risk HNcSCC that never progressed to metastasis with those that metastasized using multiparameter imaging mass cytometry. The cohort included both immunosuppressed patients (IS) and patients with an absence of clinical immune-suppression (ACIS). Spatial analyses were used to identify cellular interactions that were associated with tumor behavior. RESULTS: Nonprogressing primary HNcSCC were characterized by higher CD8+ and CD4+ T-cell responses, including numerically increased regulatory T cells. In contrast, primary lesions from HNcSCC patients who progressed were largely devoid of T cells with lower numbers of innate immune cells and increased expression of checkpoint receptors and in the metastatic lesions were characterized by an accumulation of B cells. Spatial analysis reveals multiple cellular interactions associated with nonprogressing primary tumors that were distinct in primary tumors of disease-progressing patients. Cellular regional analysis of the tumor microenvironment also shows squamous cell-enriched tumor regions associated with primary nonprogressing tumors. CONCLUSIONS: Effective responses from both CD8+ and CD4+ T cells in the tumor microenvironment are essential for immune control of primary HNcSCC. Our findings indicate that the early events that shape the immune responses in primary tumors dictate progression and disease outcomes in HNcSCC.

Trends in termination of pregnancy for neural tube defects in England and Wales from 2007 to 2017: Observational prospective study.

BACKGROUND/OBJECTIVE: Neural tube defects (NTDs) affect approximately 300,000 pregnancies worldwide each year. Many of these pregnancies are lost to miscarriage or termination of pregnancy. Here, we have analysed the trends of termination of pregnancy for NTDs from the national data for England and Wales. METHODS: Data for all terminations for residents in England and Wales for the period of 2007-2017 were obtained through Health and Social Act 4 (HSA4) submitted to the Department of Health. Using the ICD-10 codes, terminations for NTDs were selected for analysis. The statistical test Chi-squared was performed using SPSS-v25, where appropriate. RESULTS: In the 11-year period, there were 28,866 terminations under Ground E; of which 4425 (15.33%) had a diagnosis of NTD. The number of NTD cases increased over the time period from 308 in 2007 to 517 in 2017 (67.9%). Significant results were also seen when analysing the relationship between ethnicity, gestation and terminations where an NTD was diagnosed. CONCLUSION: With the availability of routine prenatal ultrasound, the termination for NTDs is on the rise in England and Wales, in spite of the health advice of periconceptional folic acid. This study demonstrates the need for implementation of further programmes to increase public health awareness of folic supplementation and government initiation of fortification to reduce NTDs.

Post-COVID symptoms reported at asynchronous virtual review and stratified follow-up after COVID-19 pneumonia.

BACKGROUND: The COVID-19 pandemic has strained healthcare systems and how best to address post-COVID health needs is uncertain. Here we describe the post-COVID symptoms of 675 patients followed up using a virtual review pathway, stratified by severity of acute COVID infection. METHODS: COVID-19 survivors completed an online/telephone questionnaire of symptoms after 12+ weeks and a chest X-ray. Dependent on findings at virtual review, patients were provided information leaflets, attended for investigations and/or were reviewed face-to-face. Outcomes were compared between patients following high-risk and low-risk admissions for COVID pneumonia, and community referrals. RESULTS: Patients reviewed after hospitalisation for COVID pneumonia had a median of two ongoing physical health symptoms post-COVID. The most common was fatigue (50.3% of high-risk patients). Symptom burden did not vary significantly by severity of hospitalised COVID pneumonia but was highest in community referrals. Symptoms suggestive of depression, anxiety and post-traumatic stress disorder were common (depression occurred in 24.9% of high-risk patients). Asynchronous virtual review facilitated triage of patients at highest need of face-to-face review. CONCLUSION: Many patients continue to have a significant burden of post-COVID symptoms irrespective of severity of initial pneumonia. How best to assess and manage long COVID will be of major importance over the next few years.

Hemodynamic Abnormalities in the Aorta of Turner Syndrome Girls.

Congenital abnormalities in girls and women with Turner syndrome (TS), alongside an underlying predisposition to obesity and hypertension, contribute to an increased risk of cardiovascular disease and ultimately reduced life expectancy. We observe that children with TS present a greater variance in aortic arch morphology than their healthy counterparts, and hypothesize that their hemodynamics is also different. In this study, computational fluid dynamic (CFD) simulations were performed for four TS girls, and three age-matched healthy girls, using patient-specific inlet boundary conditions, obtained from phase-contrast MRI data. The visualization of multidirectional blood flow revealed an increase in vortical flow in the arch, supra-aortic vessels, and descending aorta, and a correlation between the presence of aortic abnormalities and disturbed flow. Compared to the relatively homogeneous pattern of time-averaged wall shear stress (TAWSS) on the healthy aortae, a highly heterogeneous distribution with elevated TAWSS values was observed in the TS geometries. Visualization of further shear stress parameters, such as oscillatory shear index (OSI), normalized relative residence time (RRTn), and transverse WSS (transWSS), revealed dissimilar heterogeneity in the oscillatory and multidirectional nature of the aortic flow. Taking into account the young age of our TS cohort (average age 13 ± 2 years) and their obesity level (75% were obese or overweight), which is believed to accelerate the initiation and progression of endothelial dysfunction, these findings may be an indication of atherosclerotic disease manifesting earlier in life in TS patients. Age, obesity and aortic morphology may, therefore, play a key role in assessing cardiovascular risk in TS children.

Enzymatic C-H activation of aromatic compounds through CO2 fixation.

The direct C-H carboxylation of aromatic compounds is an attractive route to the corresponding carboxylic acids, but remains challenging under mild conditions. It has been proposed that the first step in anaerobic microbial degradation of recalcitrant aromatic compounds is a UbiD-mediated carboxylation. In this study, we use the UbiD enzyme ferulic acid decarboxylase (Fdc) in combination with a carboxylic acid reductase to create aromatic degradation-inspired cascade reactions, leading to efficient functionalization of styrene through CO2 fixation. We reveal that rational structure-guided laboratory evolution can expand the substrate scope of Fdc, resulting in activity on a range of mono- and bicyclic aromatic compounds through a single mutation. Selected variants demonstrated 150-fold improvement in the conversion of coumarillic acid to benzofuran + CO2 and unlocked reactivity towards naphthoic acid. Our data demonstrate that UbiD-mediated C-H activation is a versatile tool for the transformation of aryl/alkene compounds and CO2 into commodity chemicals.

Prevalence and Cellular Distribution of Novel Immune Checkpoint Targets Across Longitudinal Specimens in Treatment-naïve Melanoma Patients: Implications for Clinical Trials.

PURPOSE: Immunotherapies targeting costimulating and coinhibitory checkpoint receptors beyond PD-1 and CTLA-4 have entered clinical trials. Little is known about the relative abundance, coexpression, and immune cells enriched for each specific drug target, limiting understanding of the biological basis of potential treatment outcomes and development of predictive biomarkers for personalized immunotherapy. We sought to assess the abundance of checkpoint receptors during melanoma disease progression and identify immune cells enriched for them.Experimental Design: Multiplex immunofluorescence staining for immune checkpoint receptors (ICOS, GITR, OX40, PD-1, TIM-3, VISTA) was performed on 96 melanoma biopsies from 41 treatment-naïve patients, including patient-matched primary tumors, nodal metastases, and distant metastases. Mass cytometry was conducted on tumor dissociates from 18 treatment-naïve melanoma metastases to explore immune subsets enriched for checkpoint receptors. RESULTS: A small subset of tumor-infiltrating leukocytes expressed checkpoint receptors at any stage of melanoma disease. GITR and OX40 were the least abundant checkpoint receptors, with <1% of intratumoral T cells expressing either marker. ICOS, PD-1, TIM-3, and VISTA were most abundant, with TIM-3 and VISTA mostly expressed on non-T cells, and TIM-3 enriched on dendritic cells. Tumor-resident T cells (CD69+/CD103+/CD8+) were enriched for TIGIT (>70%) and other coinhibitory but not costimulatory receptors. The proportion of GITR+ T cells decreased from primary melanoma (>5%) to lymph node (<1%, P = 0.04) and distant metastases (<1%, P = 0.0005). CONCLUSIONS: This study provides the first comprehensive assessment of immune checkpoint receptor expression in any cancer and provides important data for rational selection of targets for trials and predictive biomarker development.

Terminal Alkenes from Acrylic Acid Derivatives via Non-Oxidative Enzymatic Decarboxylation by Ferulic Acid Decarboxylases.

Fungal ferulic acid decarboxylases (FDCs) belong to the UbiD-family of enzymes and catalyse the reversible (de)carboxylation of cinnamic acid derivatives through the use of a prenylated flavin cofactor. The latter is synthesised by the flavin prenyltransferase UbiX. Herein, we demonstrate the applicability of FDC/UbiX expressing cells for both isolated enzyme and whole-cell biocatalysis. FDCs exhibit high activity with total turnover numbers (TTN) of up to 55000 and turnover frequency (TOF) of up to 370 min-1. Co-solvent compatibility studies revealed FDC's tolerance to some organic solvents up 20 % v/v. Using the in-vitro (de)carboxylase activity of holo-FDC as well as whole-cell biocatalysts, we performed a substrate profiling study of three FDCs, providing insights into structural determinants of activity. FDCs display broad substrate tolerance towards a wide range of acrylic acid derivatives bearing (hetero)cyclic or olefinic substituents at C3 affording conversions of up to >99 %. The synthetic utility of FDCs was demonstrated by a preparative-scale decarboxylation.

Cognitive behavioural therapy stabilises glycaemic control in adolescents with type 1 diabetes-Outcomes from a randomised control trial.

BACKGROUND: To compare the impact of cognitive behavioural therapy (CBT) with non-directive supportive counselling (NDC) on glycaemic control and psychological well-being in adolescents with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Participants aged 11 to 16 years with T1DM (duration ≥1 year) from 4 UK-based paediatric diabetes centres were randomised to receive either 6 weekly sessions of 1-to-1 CBT (n = 43) or NDC (n = 42), with 2 further sessions at 6 and 12 months. Follow-up continued for 12 months postintervention. Outcome measures included glycated haemoglobin A1c (HbA1c) and psychological scores. RESULTS: The HbA1c levels were available in 33 patients in each group for analysis. Between group difference of the overall changes in HbA1c across the study period was statically significant (P = .018). Geometric mean (range) HbA1c in the NDC group deteriorated from 68 (46-113) to 78 (48-128) mmol/mol (ie, 8.4 [6.4-12.5]% to 9.3 [6.5-13.9]%; P = .001), but was maintained in the CBT group from 72 (46-129) to 73 (51-128) mmol/mol (P = .51) (ie, 8.7 [6.4-14]% to 8.9 [6.8-13.9]%). More patients who have undergone CBT showed an improved or maintained HbA1c levels at 24 months (62.5% vs 35.5%, P = .032). Patients offered CBT with depressive scores in the lowest tertile (least depressive symptoms) showed improvement in HbA1c over time from 70 (46-102) to 67 (57-87) mmol/mol (P = .041) (ie, 8.6 [6.4-11.5]% to 8.3 [7.4-10.1]%), but not in the NDC group. The CBT showed borderline improvements in Children's Health Locus of Control (internal) scores over time compared with NDC (P = .05). The self-efficacy score showed significant improvement in both CBT (P < .001) and NDC (P = .03) groups over time. CONCLUSIONS: CBT demonstrated better maintenance of glycaemic control compared with NDC.

Methodological considerations for researching the financial costs of family caregiving within a palliative care context.

BACKGROUND: The financial impact of family caregiving in a palliative care context has been identified as an issue which requires further research. However, little is known about how research should be conducted in this area. OBJECTIVE: The aim of this study was to explore the opinions of family caregivers in New Zealand regarding the need to conduct research relating to the financial costs of family caregiving and to explore their perspectives on acceptable and feasible methods of data collection. METHODS: A qualitative study design was adopted. Semistructured interviews were conducted with 30 family caregivers who were either currently caring for a person with palliative care needs or had done so in the past year. RESULTS: All participants felt that research relating to the costs of family caregiving within a palliative care context was important. There was little consensus regarding the most appropriate methods of data collection and administration. Online methods were preferred by many participants, although face-to-face methods were particularly favoured by Ma¯ori participants. Both questionnaires and cost diaries were felt to have strengths and weaknesses. CONCLUSIONS: Prospective longitudinal designs are likely to be most appropriate for future research, in order to capture variations in costs over time. The lack of consensus for a single preferred method makes it difficult to formulate specific recommendations regarding methods of data collection; providing participants with options for methods of completion may therefore be appropriate.

'No matter what the cost': A qualitative study of the financial costs faced by family and whanau caregivers within a palliative care context.

BACKGROUND: There has been significant attention paid in recent years to the economic costs of health service provision for people with palliative care needs. However, little is known about the costs incurred by family caregivers who typically provide the bulk of care for people at the end of life. AIM: To explore the nature and range of financial costs incurred by family caregiving within a palliative care context. DESIGN: In-depth qualitative interviews were conducted with 30 family/whanau caregivers who were currently caring for someone with a life-limiting illness or had done so within the preceding year. Narrative analysis was used to identify impacts and costs at the personal, interpersonal, sociocultural and structural levels. SETTING: Auckland, New Zealand. FINDINGS: Costs of caregiving were significant and, for participants, resulted in debt or even bankruptcy. A range of direct (transport, food and medication) and indirect costs (related to employment, cultural needs and own health) were reported. A multi-level qualitative analysis revealed how costs operated at a number of levels (personal, interpersonal, sociocultural and structural). The palliative care context increased costs, as meeting needs were prioritised over cost. In addition, support from statutory service providers to access sources of financial support was limited. CONCLUSION: Families incur significant financial costs when caring for someone at the end of life. Research is now needed to quantify the financial contribution of family and whanau caregiving within a palliative care context, particularly given attempts in many countries to shift more palliative care provision into community settings.

Receiving support when older: what makes it ok?

PURPOSE: Older people are seen as needing to receive support from other people as they age. But what are the experiences and expectations older people have of being "support receivers"? DESIGN AND METHODS: Community-dwelling childless elders (n = 38, aged 63-93) were interviewed about their experiences and expectations of support, as they comprise a group "at risk" of lack of support. Responses were analyzed within a narrative gerontology framework of positioning theory as to how receiving support was "positioned" and how it related to growing older. RESULTS: Participants defined support in widely diverse ways; it was not a straightforward concept. Receiving support could be warranted by particular circumstances such as illness, made acceptable by the qualities of the support giver, and/or by being part of reciprocal exchanges across time. Support receiving was resisted when associated with difficult interpersonal dynamics or assumptions of incapacity. It was also in tension with preferred positions of being "independent" or of needing "no support." Participants positioned "oldness" negatively and as both equivalent to the need for support and as a potential outcome of being a support receiver. IMPLICATIONS: This research shows that support can be hard to define and hard to receive. Needs assessors and researchers asking "Do you have enough support?" need to consider how support is positioned to better target appropriate help. Assumptions about at-risk groups can be misleading; many childless participants had a lifetime of self-support or an intentionally developed "web of contacts" at a size that suited them, even if they looked unsupported to others.

The utility of positioning theory to the study of ageing: Examples from research with childless older people.

Growing older is hard to make sense of. Opposing perspectives are presented on everything from individual to population ageing, and there is widespread ambivalence towards many aspects of ageing. Positioning theory is a research approach that can tolerate such ambiguity and provides a clear, useful framework to make sense of research data, while doing justice to its complexity. It is starting to be used in gerontology; the aim of this paper is to give gerontologists the tools and impetus to use it more. The positioning triad is outlined, comprising positions (how we position ourselves and others within a single conversation or across a lifetime), storylines (the individual and social narratives which furnish those positions), and the speech acts (and acts of research) through which storylines and positions are enacted. In addition, considering the rights and duties associated with different positions and storylines can usefully illuminate some of the tensions around competing positions on ageing. Worked examples from a qualitative study on childless older people (38 participants aged 63 to 93) in terms of their positioning of childlessness, views on residential care, and positioning of emotional support show how the complexity of such diverse topics can be usefully studied using a positioning theory framework.

The meaning of "aging in place" to older people.

PURPOSE: This study illuminates the concept of "aging in place" in terms of functional, symbolic, and emotional attachments and meanings of homes, neighbourhoods, and communities. It investigates how older people understand the meaning of "aging in place," a term widely used in aging policy and research but underexplored with older people themselves. DESIGN AND METHODS: Older people (n = 121), ranging in age from 56 to 92 years, participated in focus groups and interviews in 2 case study communities of similar size in Aotearoa New Zealand, both with high ratings on deprivation indices. The question, "What is the ideal place to grow older?" was explored, including reflections on aging in place. Thematic and narrative analyses on the meaning of aging in place are presented in this paper. RESULTS: Older people want choices about where and how they age in place. "Aging in place" was seen as an advantage in terms of a sense of attachment or connection and feelings of security and familiarity in relation to both homes and communities. Aging in place related to a sense of identity both through independence and autonomy and through caring relationships and roles in the places people live. IMPLICATIONS: Aging in place operates in multiple interacting ways, which need to be taken into account in both policy and research. The meanings of aging in place for older people have pragmatic implications beyond internal "feel good" aspects and operate interactively far beyond the "home" or housing.