AAV9:PKP2 improves heart function and survival in a Pkp2-deficient mouse model of arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease associated with ventricular arrhythmias and an increased risk of sudden cardiac death. Currently, there are no approved treatments that address the underlying genetic cause of this disease, representing a significant unmet need. Mutations in Plakophilin-2 (PKP2), encoding a desmosomal protein, account for approximately 40% of ARVC cases and result in reduced gene expression. METHODS: Our goal is to examine the feasibility and the efficacy of adeno-associated virus 9 (AAV9)-mediated restoration of PKP2 expression in a cardiac specific knock-out mouse model of Pkp2. RESULTS: We show that a single dose of AAV9:PKP2 gene delivery prevents disease development before the onset of cardiomyopathy and attenuates disease progression after overt cardiomyopathy. Restoration of PKP2 expression leads to a significant extension of lifespan by restoring cellular structures of desmosomes and gap junctions, preventing or halting decline in left ventricular ejection fraction, preventing or reversing dilation of the right ventricle, ameliorating ventricular arrhythmia event frequency and severity, and preventing adverse fibrotic remodeling. RNA sequencing analyses show that restoration of PKP2 expression leads to highly coordinated and durable correction of PKP2-associated transcriptional networks beyond desmosomes, revealing a broad spectrum of biological perturbances behind ARVC disease etiology. CONCLUSIONS: We identify fundamental mechanisms of PKP2-associated ARVC beyond disruption of desmosome function. The observed PKP2 dose-function relationship indicates that cardiac-selective AAV9:PKP2 gene therapy may be a promising therapeutic approach to treat ARVC patients with PKP2 mutations.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a heart disease that leads to abnormal heartbeats and a higher risk of sudden cardiac death. ARVC is often caused by changes in a gene called PKP2, that then makes less PKP2 protein. PKP2 protein is important for the normal structure and function of the heart. Human ARVC characteristics can be mimicked in a mouse model missing this gene. Given no therapeutic option, our goal was to test if adding a working copy of PKP2 gene in the heart of this mouse model, using a technique called gene therapy that can deliver genes to cells, could improve heart function. Here, we show that a single dose of PKP2 gene therapy can improve heart function and heartbeats as well as extend lifespan in mice. PKP2 gene therapy may be a promising approach to treat ARVC patients with PKP2 mutations.

Complement dysregulation is a prevalent and therapeutically amenable feature of long COVID.

BACKGROUND: Long COVID encompasses a heterogeneous set of ongoing symptoms that affect many individuals after recovery from infection with SARS-CoV-2. The underlying biological mechanisms nonetheless remain obscure, precluding accurate diagnosis and effective intervention. Complement dysregulation is a hallmark of acute COVID-19 but has not been investigated as a potential determinant of long COVID. METHODS: We quantified a series of complement proteins, including markers of activation and regulation, in plasma samples from healthy convalescent individuals with a confirmed history of infection with SARS-CoV-2 and age/ethnicity/sex/infection/vaccine-matched patients with long COVID. FINDINGS: Markers of classical (C1s-C1INH complex), alternative (Ba, iC3b), and terminal pathway (C5a, TCC) activation were significantly elevated in patients with long COVID. These markers in combination had a receiver operating characteristic predictive power of 0.794. Other complement proteins and regulators were also quantitatively different between healthy convalescent individuals and patients with long COVID. Generalized linear modeling further revealed that a clinically tractable combination of just four of these markers, namely the activation fragments iC3b, TCC, Ba, and C5a, had a predictive power of 0.785. CONCLUSIONS: These findings suggest that complement biomarkers could facilitate the diagnosis of long COVID and further suggest that currently available inhibitors of complement activation could be used to treat long COVID. FUNDING: This work was funded by the National Institute for Health Research (COV-LT2-0041), the PolyBio Research Foundation, and the UK Dementia Research Institute.

Improved Cardiac Function in Postischemic Rats Using an Optimized Cardiac Reprogramming Cocktail Delivered in a Single Novel Adeno-Associated Virus.

BACKGROUND: Cardiac reprogramming is a technique to directly convert nonmyocytes into myocardial cells using genes or small molecules. This intervention provides functional benefit to the rodent heart when delivered at the time of myocardial infarction or activated transgenically up to 4 weeks after myocardial infarction. Yet, several hurdles have prevented the advancement of cardiac reprogramming for clinical use. METHODS: Through a combination of screening and rational design, we identified a cardiac reprogramming cocktail that can be encoded in a single adeno-associated virus. We also created a novel adeno-associated virus capsid that can transduce cardiac fibroblasts more efficiently than available parental serotypes by mutating posttranslationally modified capsid residues. Because a constitutive promoter was needed to drive high expression of these cell fate-altering reprogramming factors, we included binding sites to a cardiomyocyte-restricted microRNA within the 3' untranslated region of the expression cassette that limits expression to nonmyocytes. After optimizing this expression cassette to reprogram human cardiac fibroblasts into induced cardiomyocyte-like cells in vitro, we also tested the ability of this capsid/cassette combination to confer functional benefit in acute mouse myocardial infarction and chronic rat myocardial infarction models. RESULTS: We demonstrated sustained, dose-dependent improvement in cardiac function when treating a rat model 2 weeks after myocardial infarction, showing that cardiac reprogramming, when delivered in a single, clinically relevant adeno-associated virus vector, can support functional improvement in the postremodeled heart. This benefit was not observed with GFP (green fluorescent protein) or a hepatocyte reprogramming cocktail and was achieved even in the presence of immunosuppression, supporting myocyte formation as the underlying mechanism. CONCLUSIONS: Collectively, these results advance the application of cardiac reprogramming gene therapy as a viable therapeutic approach to treat chronic heart failure resulting from ischemic injury.

Investigating the association between educational attainment and allostatic load with risk of cancer mortality among African American women.

BACKGROUND: African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. Studies suggest that AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined the joint effect of educational attainment and AL status with long-term risk of cancer mortality, and whether education moderated the association between AL and cancer mortality. METHODS: We performed a retrospective analysis among 4,677 AA women within the National Health and Nutrition Examination Survey (NHANES) from 1988 to 2010 with follow-up data through December 31, 2019. We fit weighted Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL (adjusted for age, income, and smoking status). RESULTS: AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk (unadjusted HR: 2.98; 95%C CI: 1.24-7.15) of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, this effect attenuated (age-adjusted HR: 1.11; 95% CI: 0.45-2.74). AA women with high AL had 2.3-fold increased risk of cancer death (fully adjusted HR: 2.26; 95% CI: 1.10-4.57) when compared to AA with low AL, specifically among women with high school diploma or equivalent and without history of cancer. CONCLUSIONS: Our findings suggest that high allostatic load is associated with a higher risk of cancer mortality among AA women with lower educational attainment, while no such association was observed among AA women with higher educational attainment. Thus, educational attainment plays a modifying role in the relationship between allostatic load and the risk of cancer death for AA women. Higher education can bring several benefits, including improved access to medical care and enhanced medical literacy, which in turn may help mitigate the adverse impact of AL and the heightened risk of cancer mortality among AA women.

The genome sequence of the Loggerhead sea turtle, Caretta caretta Linnaeus 1758.

We present a genome assembly of Caretta caretta (the Loggerhead sea turtle; Chordata, Testudines, Cheloniidae), generated from genomic data from two unrelated females. The genome sequence is 2.13 gigabases in size. The assembly has a busco completion score of 96.1% and N50 of 130.95 Mb. The majority of the assembly is scaffolded into 28 chromosomal representations with a remaining 2% of the assembly being excluded from these.

Gene and pathway based burden analyses in familial lymphoid cancer cases: Rare variants in immune pathway genes.

Genome-wide association studies have revealed common genetic variants with small effect sizes associated with diverse lymphoid cancers. Family studies have uncovered rare variants with high effect sizes. However, these variants explain only a portion of the heritability of these cancers. Some of the missing heritability may be attributable to rare variants with small effect sizes. We aim to identify rare germline variants associated with familial lymphoid cancers using exome sequencing. One case per family was selected from 39 lymphoid cancer families based on early onset of disease or rarity of subtype. Control data was from Non-Finnish Europeans in gnomAD exomes (N = 56,885) or ExAC (N = 33,370). Gene and pathway-based burden tests for rare variants were performed using TRAPD. Five putatively pathogenic germline variants were found in four genes: INTU, PEX7, EHHADH, and ASXL1. Pathway-based association tests identified the innate and adaptive immune systems, peroxisomal pathway and olfactory receptor pathway as associated with lymphoid cancers in familial cases. Our results suggest that rare inherited defects in the genes involved in immune system and peroxisomal pathway may predispose individuals to lymphoid cancers.

Multiscale deep learning framework captures systemic immune features in lymph nodes predictive of triple negative breast cancer outcome in large-scale studies.

The suggestion that the systemic immune response in lymph nodes (LNs) conveys prognostic value for triple-negative breast cancer (TNBC) patients has not previously been investigated in large cohorts. We used a deep learning (DL) framework to quantify morphological features in haematoxylin and eosin-stained LNs on digitised whole slide images. From 345 breast cancer patients, 5,228 axillary LNs, cancer-free and involved, were assessed. Generalisable multiscale DL frameworks were developed to capture and quantify germinal centres (GCs) and sinuses. Cox regression proportional hazard models tested the association between smuLymphNet-captured GC and sinus quantifications and distant metastasis-free survival (DMFS). smuLymphNet achieved a Dice coefficient of 0.86 and 0.74 for capturing GCs and sinuses, respectively, and was comparable to an interpathologist Dice coefficient of 0.66 (GC) and 0.60 (sinus). smuLymphNet-captured sinuses were increased in LNs harbouring GCs (p < 0.001). smuLymphNet-captured GCs retained clinical relevance in LN-positive TNBC patients whose cancer-free LNs had on average ≥2 GCs, had longer DMFS (hazard ratio [HR] = 0.28, p = 0.02) and extended GCs' prognostic value to LN-negative TNBC patients (HR = 0.14, p = 0.002). Enlarged smuLymphNet-captured sinuses in involved LNs were associated with superior DMFS in LN-positive TNBC patients in a cohort from Guy's Hospital (multivariate HR = 0.39, p = 0.039) and with distant recurrence-free survival in 95 LN-positive TNBC patients of the Dutch-N4plus trial (HR = 0.44, p = 0.024). Heuristic scoring of subcapsular sinuses in LNs of LN-positive Tianjin TNBC patients (n = 85) cross-validated the association of enlarged sinuses with shorter DMFS (involved LNs: HR = 0.33, p = 0.029 and cancer-free LNs: HR = 0.21 p = 0.01). Morphological LN features reflective of cancer-associated responses are robustly quantifiable by smuLymphNet. Our findings further strengthen the value of assessment of LN properties beyond the detection of metastatic deposits for prognostication of TNBC patients. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Association of Food Deserts and Food Swamps With Obesity-Related Cancer Mortality in the US.

Importance: Obesity-related cancers account for 40% of all cancers in the US. Healthy food consumption is a modifiable factor shown to reduce obesity-related cancer mortality, but residing in areas with less access to grocery stores (food deserts) or higher access to fast food (food swamps) reduces healthy food access and has been understudied. Objective: To analyze the association of food deserts and food swamps with obesity-related cancer mortality in the US. Design, Setting, and Participants: This cross-sectional ecologic study used US Department of Agriculture Food Environment Atlas data from 2012, 2014, 2015, 2017, and 2020 and Centers for Disease Control and Prevention mortality data from 2010 to 2020. A total of 3038 US counties or county equivalents with complete information on food environment scores and obesity-related cancer mortality data were included. An age-adjusted, generalized, mixed-effects regression model was performed for the association of food desert and food swamp scores with obesity-related cancer mortality rates. Data were analyzed from September 9, 2022, to September 30, 2022. Exposures: Food swamp score was calculated as the ratio of fast-food and convenience stores to grocery stores and farmers markets. Higher food swamp and food desert scores (20.0 to ≥58.0) indicated counties with fewer healthy food resources. Main Outcomes and Measures: Obesity-related cancer (based on the International Agency for Research on Cancer evidence between obesity and 13 types of cancer) mortality rates were categorized as high (≥71.8 per 100 000 population) vs low (<71.8 per 100 000 population) per county. Results: A total of 3038 counties or county equivalents with high obesity-related cancer mortality rates had a higher percentage of non-Hispanic Black residents (3.26% [IQR, 0.47%-26.35%] vs 1.77% [IQR, 0.43%-8.48%]), higher percentage of persons older than 65 years (15.71% [IQR, 13.73%-18.00%] vs 15.40% [IQR, 12.82%-18.09%]), higher poverty rates (19.00% [IQR, 14.20%-23.70%] vs 14.40% [IQR, 11.00%-18.50%]), higher adult obesity rates (33.00% [IQR, 32.00%-35.00%] vs 32.10% [IQR, 29.30%-33.20%]), and higher adult diabetes rates (12.50% [IQR, 11.00%-14.20%] vs 10.70% [IQR, 9.30%-12.40%]) compared with counties or county equivalents with low obesity-related cancer mortality. There was a 77% increased odds of having high obesity-related cancer mortality rates among US counties or county equivalents with high food swamp scores (adjusted odds ratio, 1.77; 95% CI, 1.43-2.19). A positive dose-response relationship among 3 levels of food desert and food swamp scores and obesity-related cancer mortality was also observed. Conclusions and Relevance: The findings of this cross-sectional ecologic study suggest that policy makers, funding agencies, and community stakeholders should implement sustainable approaches to combating obesity and cancer and establishing access to healthier food, such as creating more walkable neighborhoods and community gardens.

Investigating the Association between Educational Attainment and Allostatic Load with Risk of Cancer Mortality among African American Women.

Background African American (AA) women navigate the world with multiple intersecting marginalized identities. Accordingly, AA women have higher cumulative stress burden or allostatic load (AL) compared to other women. AL correlates with poorer health outcomes and increased risk of cancer death. However, research indicates AA women with a college degree or higher have lower AL than AA women with less than a high school diploma. We examined whether educational attainment differences and AL status in AA women are associated with long-term risk of cancer mortality. Methods We performed a retrospective analysis among 4,677 AA women respondents using National Health and Nutrition Examination Survey (NHANES) data from 1988 through 2010 with follow up data through December 31, 2019. We fit Cox proportional hazards models to estimate adjusted hazard ratios (aHRs) of cancer death between educational attainment/AL (adjusted for age, sociodemographic, and health factors). Results AA women with less than a high school diploma living with high AL had nearly a 3-fold increased risk (unadjusted HR: 2.98; 95%C CI: 1.24â€"7.15) of cancer death compared to AA college graduates living with low AL. However, after adjusting for age, the increased risk of cancer death in those with less than a high school diploma and high AL attenuated (age-adjusted HR: 1.11; 95% CI: .45-2.74). Conclusions Differences in educational attainment and AL in AA women were not associated with increased risk of cancer mortality when adjusted for age. Previous studies have shown that increased allostatic load is associated with increased risk of cancer death. However, for African American women, higher educational attainment does not modify the risk of cancer mortality. The benefits that may come along with higher education such as increased access to medical care and better medical literacy do not change the risk of cancer mortality in AA women.

Development and validation of the MAnchester Needs Tool for Injured Children (MANTIC).

OBJECTIVE: To develop a measure of the needs injured children and their families' needs throughout recovery; The MAnchester Needs Tool for Injured Children (MANTIC). DESIGN: Tool development, psychometric testing. SETTING: Five children's major trauma centres in England. PARTICIPANTS: Children aged 2 to 16 years with any type of moderate/severe injury(ies) treated in a major trauma centre within 12 months of injury, plus their parents. METHODS: Stage 1a (Item generation): Interviews with injured children and their parents to generate draft items. Stage 1b (Co-production): Feedback about item clarity, relevance and appropriate response options was provided by parents and the patient and public involvement group. Stage 2 (Psychometric development): Completion of the prototype MANTIC by injured children and their parents with restructuring (as necessary) to establish construct validity. Concurrent validity was assessed by correlation with quality of life (EQ-5D-Y). MANTICs were repeated 2 weeks later to assess test-retest reliability. RESULTS: Stages 1a,b: Interviews (13 injured children, 19 parents) generated 64 items with semantic differential four-point response scale (strongly disagree, disagree, agree, strongly agree). Stage 2: One hundred and forty-four participants completed MANTIC questionnaires (mean age 9.8 years, SD 3.8; 68.1% male). Item responses were strong requiring only minor changes to establish construct validity. Concurrent validity with quality of life was moderate (r = 0.55, P < 0.01) as was test-retest reliability (ICC = 0.46 and 0.59, P < 0.001). Uni-dimensionality was strong (Cronbach's α > 0.7). CONCLUSION: The MANTIC is a feasible, acceptable, valid self-report measure of the needs of injured children and their families, freely available for clinical or research purposes.

How Attributes of Place Threaten Community Trust in the American South: Opportunities for Improving Pandemic-Related Communication.

Trust and mistrust influence the utilization of health services, the quality of overall healthcare, and the prevalence of health disparities. Trust has significant bearing on how communities, and the individuals within them, perceive health information and recommendations. The People and Places Framework is utilized to answer what attributes of place threaten community trust in public health and medical recommendations.Augusta-Richmond County is ranked among the least healthy counties in Georgia despite being home to the best healthcare-to-residence ratios and a vast array of healthcare services. Semi-structured interviews were conducted with 31 neighborhood residents. Data were analyzed using the Sort & Sift, Think & Shift method. Threats to community trust were identified within four local-level attributes of place: availability of products and services, social structures, physical structures, and cultural and media messages. We found a broader web of services, policies, and institutions, beyond interactions with health care, that influence the trust placed in health officials and institutions. Participants spoke to both a potential lack of trust (e.g. needs not being met, as through lack of access to services) and mistrust (e.g. negative motives, such as profit seeking or experimentation). Across the four attributes of place, residents expressed opportunities to build trust. Our findings highlight the importance of examining trust at the community level, providing insight into an array of factors that impact trust at a local level, and extend the work on trust and its related constructs (e.g. mistrust). Implications for improving pandemic-related communication through community relationship building are presented.

Dynamic Biobanking for Advancing Breast Cancer Research.

Longitudinal patient biospecimens and data advance breast cancer research through enabling precision medicine approaches for identifying risk, early diagnosis, improved disease management and targeted therapy. Cancer biobanks must evolve to provide not only access to high-quality annotated biospecimens and rich associated data, but also the tools required to harness these data. We present the Breast Cancer Now Tissue Bank centre at the Barts Cancer Institute as an exemplar of a dynamic biobanking ecosystem that hosts and links longitudinal biospecimens and multimodal data including electronic health records, genomic and imaging data, offered alongside integrated data sharing and analytics tools. We demonstrate how such an ecosystem can inform precision medicine efforts in breast cancer research.

Exploring the intersectionality of race/ethnicity with rurality on breast cancer outcomes: SEER analysis, 2000-2016.

PURPOSE: Disparities in breast cancer survival have been observed within marginalized racial/ethnic groups and within the rural-urban continuum for decades. We examined whether there were differences among the intersectionality of race/ethnicity and rural residence on breast cancer outcomes. METHODS: We performed a retrospective analysis among 739,448 breast cancer patients using Surveillance Epidemiology and End Results (SEER) 18 registries years 2000 through 2016. We conducted multilevel logistic-regression and Cox proportional hazards models to estimate adjusted odds ratios (AORs) and hazard ratios (AHRs), respectively, for breast cancer outcomes including surgical treatment, radiation therapy, chemotherapy, late-stage disease, and risk of breast cancer death. Rural was defined as 2013 Rural-Urban Continuum Codes (RUCC) of 4 or greater. RESULTS: Compared with non-Hispanic white-urban (NH-white-U) women, NH-black-U, NH-black-rural (R), Hispanic-U, and Hispanic-R women, respectively, were at increased odds of no receipt of surgical treatment (NH-black-U, AOR = 1.98, 95% CI 1.91-2.05; NH-black-R, AOR = 1.72, 95% CI 1.52-1.94; Hispanic-U, AOR = 1.58, 95% CI 1.52-1.65; and Hispanic-R, AOR = 1.40, 95% CI 1.18-1.67), late-stage diagnosis (NH-black-U, AOR = 1.32, 95% CI 1.29-1.34; NH-black-R, AOR = 1.29, 95% CI 1.22-1.36; Hispanic-U, AOR = 1.25, 95% CI 1.23-1.27; and Hispanic-R, AOR = 1.17, 95% CI 1.08-1.27), and increased risks for breast cancer death (NH-black-U, AHR = 1.46, 95% CI 1.43-1.50; NH-black-R, AHR = 1.42, 95% CI 1.32-1.53; and Hispanic-U, AHR = 1.10, 95% CI 1.07-1.13). CONCLUSION: Regardless of rurality, NH-black and Hispanic women had significantly increased odds of late-stage diagnosis, no receipt of treatment, and risk of breast cancer death.

Home-based rehabilitation following anterior cruciate ligament reconstruction in the Kurdistan region of Iraq: epidemiology and outcomes.

PURPOSE: This study, set in in the Kurdistan region of Iraq, describes the epidemiology and outcomes of anterior cruciate ligament reconstruction (ACLR) followed by home-based rehabilitation alone. METHODS: A cohort observational study of patients aged ≥ 16 years with an ACL rupture who underwent an ACLR under a single surgeon. Followed by a home-based rehabilitation programme of appropriate simplicity for completion in the home setting; consisting of stretching, range of motion and strengthening exercises. Demographics, mechanism of injury, operative findings, and outcome data (Lysholm, Tegner Activity Scale (TAS), and revision rates) were collected from 2016 to 2021. Data were analysed using descriptive statistics. RESULTS: The cohort consisted of 545 patients (547 knees), 99.6% were male with a mean age of 27.8 years (SD 6.18 years). The mean time from diagnosis to surgery was 40.6 months (SD 40.3). Despite data attrition Lysholm scores improved over the 15-month follow-up period, matched data showed the most improvement occurred within the first 2 months post-operatively. Post-operative TAS results showed an improvement in level of function, but did not reach pre-injury levels by final follow-up. At final follow-up, six (1.1%) patients required an ACLR revision. CONCLUSION: Patients who completed a home-based rehabilitation programme in Kurdistan had low revision rates and improved Lysholm scores 15 months post-operatively. To optimise resources, further research should investigate the efficacy of home-based rehabilitation for trauma and elective surgery in low- to middle-income countries and the developed world.

Perceived discrimination and Latina college students' depressive symptoms: The roles of dyadic coping with sisters and familism values.

Latinx young adults' experiences of discrimination are associated with high levels of depressive symptoms and examining protective factors that buffer the negative consequences of discrimination is important. In a sample of 195 Latina college students, predominately of Mexican origin, we examined associations between perceived discrimination and depressive symptoms, and how sisters' dyadic coping behaviors and familism values moderated this association. We conducted hierarchical regression analyses to test our study hypotheses. We found that Latina college students who were older sisters reported more conflictual and antagonistic sibling relationships, or who perceived higher levels of discrimination also reported the most depressive symptoms, which supports prior research. Importantly, Latina college students who strongly endorsed supportive, obligatory, and referent familism values reported fewer depressive symptoms. Supportive familism values weakened the association between perceived discrimination and Latina college students' depressive symptoms but strengthened associations between sisters' negative dyadic coping behaviors and depressive symptoms. Furthermore, sisters' negative dyadic coping behaviors strengthened the positive association between perceived discrimination and depressive symptoms. Our findings highlight the importance of familism values for Latinx young adults' well-being, as well as the harmful effects of perceived discrimination, particularly in the context of sisters' negative dyadic coping behaviors.

CT coronary angiography first prior to rapid access chest pain clinic review: a retrospective feasibility study.

OBJECTIVES: Since rapid access chest pain clinics (RACPC) were established to streamline stable chest pain assessment, CT coronary angiography (CTCA) has become the recommended investigation for patients without known coronary artery disease (CAD), with well-defined indications. This single-centre retrospective study assessed the feasibility of General Practice (GP)-led CTCA prior to RACPC. METHODS: RACPC pathway patients without pre-existing CAD electronic records were reviewed (September-October 2019). Feasibility assessments included appropriateness for RACPC, referral clinical data vs RACPC assessment for CTCA indication and safety, and a comparison of actual vs hypothetical pathways, timelines and hospital encounters. RESULTS: 106/172 patients screened met inclusion criteria (mean age 61 ± 14, 51% female). 102 (96%) referrals were 'appropriate'. No safety concerns were identified to preclude a GP-led CTCA strategy. The hypothetical pathway increased CTCA requests vs RACPC (84 vs 71), whilst improving adherence to guidelines and off-loading other services. 22% (23/106) had no CAD, representing cases where one hospital encounter may be sufficient. The hypothetical pathway would have reduced referral-to-diagnosis by at least a median of 27 days (interquartile range 14-33). CONCLUSION: A hypothetical GP-led CTCA pathway would have been feasible and safe in a real-world RACPC patient cohort without pre-existing CAD. This novel strategy would have increased referrals for CTCA, whilst streamlining patient pathways and improved NICE guidance adherence. ADVANCES IN KNOWLEDGE: GP-led CTCA is a feasible and safe pathway for patients without pre-existing CAD referred to RACPC, reducing hospital encounters required and may accelerate time to diagnosis. This approach may have implications and opportunities for other healthcare pathways.

Intracerebroventricular dosing of N-sulfoglucosamine sulfohydrolase in mucopolysaccharidosis IIIA mice reduces markers of brain lysosomal dysfunction.

Mucopolysaccharidosis type IIIA (MPS IIIA) is a lysosomal storage disorder caused by N-sulfoglucosamine sulfohydrolase (SGSH) deficiency. SGSH removes the sulfate from N-sulfoglucosamine residues on the nonreducing end of heparan sulfate (HS-NRE) within lysosomes. Enzyme deficiency results in accumulation of partially degraded HS within lysosomes throughout the body, leading to a progressive severe neurological disease. Enzyme replacement therapy has been proposed, but further evaluation of the treatment strategy is needed. Here, we used Chinese hamster ovary cells to produce a highly soluble and fully active recombinant human sulfamidase (rhSGSH). We discovered that rhSGSH utilizes both the CI-MPR and LRP1 receptors for uptake into patient fibroblasts. A single intracerebroventricular (ICV) injection of rhSGSH in MPS IIIA mice resulted in a tissue half-life of 9 days and widespread distribution throughout the brain. Following a single ICV dose, both total HS and the MPS IIIA disease-specific HS-NRE were dramatically reduced, reaching a nadir 2 weeks post dose. The durability of effect for reduction of both substrate and protein markers of lysosomal dysfunction and a neuroimmune response lasted through the 56 days tested. Furthermore, seven weekly 148 µg doses ICV reduced those markers to near normal and produced a 99.5% reduction in HS-NRE levels. A pilot study utilizing every other week dosing in two animals supports further evaluation of less frequent dosing. Finally, our dose-response study also suggests lower doses may be efficacious. Our findings show that rhSGSH can normalize lysosomal HS storage and markers of a neuroimmune response when delivered ICV.

Exploring racial disparities on the association between allostatic load and cancer mortality: A retrospective cohort analysis of NHANES, 1988 through 2019.

Background: Several studies suggest that chronic stress may be associated with increased risk of cancer mortality. Our study sought to determine the association between allostatic load (AL), a measure of cumulative stress, and risk of cancer death; and whether these associations varied by race/ethnicity. Methods: We performed retrospective analysis using National Health and Nutrition Examination Survey (NHANES) years 1988 through 2010 linked with the National Death Index through December 31, 2019. We fit Fine & Gray Cox proportional hazards models to estimate sub-distribution hazard ratios (SHRs) of cancer death between high and low AL status (models adjusted for age, sociodemographics, and comorbidities). Results: In fully adjusted models, high AL was associated with a 14% increased risk of cancer death (adjusted (SHR): 1.14, 95% CI: 1.04-1.26) among all participants and a 18% increased risk of cancer death (SHR:1.18, 95% CI: 1.03-1.34) among Non-Hispanic White (NH-White) adults. When further stratified by age (participants aged <40 years), high AL was associated with a 80% increased risk (SHR: 1.80, 95% CI: 1.35-2.41) among all participants; a 95% increased risk (SHR: 1.95, 95% CI: 1.22-3.12) among NH-White adults; a 2-fold (SHR: 2.06, 95% CI: 1.27-3.34) increased risk among Non-Hispanic Black (NH-Black) adults; and a 36% increased risk among Hispanic adults (SHR: 1.36, 95% CI: 0.70-2.62). Conclusions: Overall, the risk of cancer death was associated with high AL; however, when stratified among NH-Black and Hispanic adults this association was slightly attenuated. Impact: High AL is associated with increased risk of overall cancer death, and future studies should delineate the association between AL and cancer-specific mortality to better understand the causal mechanisms between cumulative stress and cancer.