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Addressing Comorbidities in People with Parkinson's Disease: Considerations From An Expert Panel.
Carroll, C, Clarke, CE, Grosset, D, Rather, A, Mohamed, B, Parry, M, Reddy, P, Fackrell, R, Chaudhuri, KR
Journal of Parkinson's disease. 2024;(1):53-63
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Abstract
In the UK, guidance exists to aid clinicians and patients deciding when treatment for Parkinson's disease (PD) should be initiated and which therapies to consider. National Institute for Health and Care Excellence (NICE) guidance recommends that before starting PD treatment clinicians should discuss the following: the patient's individual clinical circumstances; lifestyle; preferences; needs and goals; as well as the potential benefits and harms of the different drug classes. Individualization of medicines and management in PD significantly improves patients' outcomes and quality of life. This article aims to provide simple and practical guidance to help clinicians address common, but often overlooked, co-morbidities. A multi-disciplinary group of PD experts discussed areas where clinical care can be improved by addressing commonly found co-morbidities in people with Parkinson's (PwP) based on clinical experience and existing literature, in a roundtable meeting organized and funded by Bial Pharma UK Ltd. The experts identified four core areas (bone health, cardiovascular risk, anticholinergic burden, and sleep quality) that, if further standardized may improve treatment outcomes for PwP patients. Focusing on anticholinergic burden, cardiac risk, sleep, and bone health could offer a significant contribution to personalizing regimes for PwP and improving overall patient outcomes. Within this opinion-based paper, the experts offer a list of guiding factors to help practitioners in the management of PwP.
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Drug-resilient Cancer Cell Phenotype Is Acquired via Polyploidization Associated with Early Stress Response Coupled to HIF2α Transcriptional Regulation.
Carroll, C, Manaprasertsak, A, Boffelli Castro, A, van den Bos, H, Spierings, DCJ, Wardenaar, R, Bukkuri, A, Engström, N, Baratchart, E, Yang, M, et al
Cancer research communications. 2024;(3):691-705
Abstract
UNLABELLED Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer. SIGNIFICANCE In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.
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Prognostic factors for liver, blood and kidney adverse events from glucocorticoid sparing immune-suppressing drugs in immune-mediated inflammatory diseases: a prognostic systematic review.
Leaviss, J, Carroll, C, Essat, M, van der Windt, D, Grainge, MJ, Card, T, Riley, R, Abhishek, A, ,
RMD open. 2024;(1)
Abstract
BACKGROUND Immune-suppressing drugs can cause liver, kidney or blood toxicity. Prognostic factors for these adverse-events are poorly understood. PURPOSE To ascertain prognostic factors associated with liver, blood or kidney adverse-events in people receiving immune-suppressing drugs. DATA SOURCES MEDLINE, Web of Science, EMBASE and the Cochrane library (01 January 1995 to 05 January 2023), and supplementary sources. DATA EXTRACTION AND SYNTHESIS Data were extracted by one reviewer using a modified CHARMS-PF checklist and validated by another. Two independent reviewers assessed risk of bias using Quality in Prognostic factor Studies tool and assessed the quality of evidence using a Grading of Recommendations Assessment, Development and Evaluation-informed framework. RESULTS Fifty-six studies from 58 papers were included. High-quality evidence of the following associations was identified: elevated liver enzymes (6 studies) and folate non-supplementation (3 studies) are prognostic factors for hepatotoxicity in those treated with methotrexate; that mercaptopurine (vs azathioprine) (3 studies) was a prognostic factor for hepatotoxicity in those treated with thiopurines; that mercaptopurine (vs azathioprine) (3 studies) and poor-metaboliser status (4 studies) were prognostic factors for cytopenia in those treated with thiopurines; and that baseline elevated liver enzymes (3 studies) are a prognostic factor for hepatotoxicity in those treated with anti-tumour necrosis factors. Moderate and low quality evidence for several other demographic, lifestyle, comorbidities, baseline bloods/serologic or treatment-related prognostic factors were also identified. LIMITATIONS Studies published before 1995, those with less than 200 participants and not published in English were excluded. Heterogeneity between studies included different cut-offs for prognostic factors, use of different outcome definitions and different adjustment factors. CONCLUSIONS Prognostic factors for target-organ damage were identified which may be further investigated for their potential role in targeted (risk-stratified) monitoring. PROSPERO REGISTRATION NUMBER CRD42020208049.
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Increased Lean Body Mass After Bodyweight-Based High Intensity Interval Training in Overweight and Obese Men.
Timmons, JF, Beatty, A, Stout, C, Ivory, A, Carroll, C, Egan, B
Research quarterly for exercise and sport. 2023;(2):418-426
Abstract
Purpose: The effects of 8 weeks of bodyweight exercise-based, high-intensity interval training (BWHIIT) on body composition and blood-based markers of metabolic health were investigated in overweight and obese, sedentary young men. Methods: In a parallel group, PRE-POST design, n = 30 men (age, 25.7 ± 4.3 y; body mass index, 27.7 ± 2.1 kg m-2; 26.1 ± 5.2% body fat) were randomized to BWHIIT (n = 20) or a control group (CON; n = 10). BWHIIT consisted of supervised, group-based training sessions (~30 minutes) performed 3 times weekly. Each session consisted of 6 high-intensity bodyweight-based exercises, with each exercise being performed for 4 minutes in the manner of 8 sets of 20 seconds of exercise, 10 seconds of rest. Prior to commencing training (PRE), and 36 h after the final training session (POST), an overnight fasted blood sample was drawn, and body composition was assessed by dual-energy X-ray absorptiometry. Eighteen participants completed the intervention (CON, n = 9; BWHIIT, n = 9). Results: Lean body mass (LBM) was increased at POST in BWHIIT compared to CON (P = .011, η2p = .359), with the mean (95% confidence limits) increase in LBM from PRE to POST within BWHIIT being 1.23 (0.55, 1.92) kg. Body mass and fat mass were unchanged in both groups from PRE to POST. BWHIIT had no effect on serum concentrations of total cholesterol, HDL-C, LDL-C, triglycerides, NEFA, hsCRP, or glucose. Conclusion: Eight weeks of bodyweight exercise-based high intensity interval training by overweight and obese sedentary young men increased LBM by ~2%, but fat mass and blood-based markers of metabolic health were unchanged.
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Unhealthy Food and Beverage Consumption during Childhood and Risk of Cardiometabolic Disease: A Systematic Review of Prospective Cohort Studies.
Markey, O, Pradeilles, R, Goudet, S, Griffiths, PL, Boxer, B, Carroll, C, Rousham, EK
The Journal of nutrition. 2023;(1):176-189
Abstract
BACKGROUND Global consumption of unhealthy foods, including ultra-processed foods (UPFs) and sugar-sweetened beverages (SSBs), has increased substantially among pediatric populations. Suboptimal diet during early life can track into adulthood, alongside risk factors for cardiometabolic disease. OBJECTIVE To inform the development of updated WHO guiding principles for complementary feeding of infants and young children, this systematic review sought to examine the association between unhealthy food consumption during childhood and cardiometabolic risk biomarkers. METHODS PubMed (Medline), EMBASE, and Cochrane CENTRAL were systematically searched, with no language restriction, up to 10 March 2022. Inclusion criteria were randomized controlled trials (RCTs), non-RCTs, and longitudinal cohort studies; children aged ≤10.9 y at exposure; studies reporting greater consumption of unhealthy foods and beverages (defined using nutrient- and food-based approaches) than no or low consumption; studies assessing critical nonanthropometric cardiometabolic disease risk outcomes (blood lipid profile, glycemic control, or blood pressure). RESULTS Of 30,021 identified citations, 11 articles from 8 longitudinal cohort studies were included. Six studies focused on exposure to unhealthy foods or UPF, and 4 focused on SSB only. Methodological heterogeneity was too high across studies to meta-analyze effect estimates. A narrative synthesis of quantitative data revealed that exposure to unhealthy foods and beverages, specifically NOVA-defined UPF, in children of preschool age may be associated with a worse blood lipid and blood pressure profile in later childhood (Grading of Recommendations Assessment, Development, and Evaluation [GRADE]: low and very low certainty, respectively). No associations were evident between SSB consumption and blood lipids, glycemic control, or blood pressure (GRADE all low certainty). CONCLUSIONS No definitive conclusion can be made because of quality of the data. More high-quality studies that purposefully assess the effects of unhealthy food and beverage exposure during childhood on cardiometabolic risk outcomes are needed. This protocol was registered at https://www.crd.york.ac.uk/PROSPERO/ as CRD42020218109.
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Unhealthy Food and Beverage Consumption in Children and Risk of Overweight and Obesity: A Systematic Review and Meta-analysis.
Rousham, EK, Goudet, S, Markey, O, Griffiths, P, Boxer, B, Carroll, C, Petherick, ES, Pradeilles, R
Advances in nutrition (Bethesda, Md.). 2022
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Plain language summary
Infants and children are consuming increasing amounts of foods with added sugars, high in salt, and high in saturated or trans fats. Commercially prepared foods are more likely to be high in energy, low in nutrients (energy dense, nutrient-poor), and ultra-processed. The aim of this study was to examine, in children aged ≤10.9 y, the risks of greater consumption of unhealthy foods and beverages compared with no or low consumption on overweight and obesity. This study is a systematic review and meta-analysis which included the summarized characterises of 71 articles from 60 included studies. Results indicate that in children aged ≤10.9 years, consumption of sugar-sweetened beverages and unhealthy foods may increase body mass index, percentage body fat, or the odds of overweight/obesity (low to very-low certainty). Furthermore, there was little or no difference to body mass index, percentage body fat, or overweight/obesity outcomes (low certainty) after consumption of artificially sweetened beverages and 100% fruit juices. Authors conclude that policy recommendations are needed to address the growing burden of overweight and obesity that children are experiencing worldwide.
Abstract
This WHO-commissioned review contributed to the update of complementary feeding recommendations, synthesizing evidence on effects of unhealthy food and beverage consumption in children on overweight and obesity. We searched PubMed (Medline), Cochrane CENTRAL and Embase for articles, irrespective of language or geography. Inclusion criteria were: 1) randomized controlled trials (RCTs); non-RCTs; cohort studies and pre/post studies with control; 2) participants ≤ 10.9 y at exposure; 3) studies reporting greater consumption of unhealthy foods/beverages vs. no or low consumption; 4) studies assessing anthropometric and/or body composition; and 5) publication date ≥ 1971. Unhealthy foods and beverages were defined using nutrient- and food-based approaches. Risk of bias was assessed using the ROBINS-I and RoB2 tools for non-randomized and randomized studies, respectively. Narrative synthesis was complemented by meta-analyses where appropriate. Certainty of evidence was assessed using GRADE. Of 26,542 identified citations, 60 studies from 71 articles were included. Most studies were observational (59/60), and no included studies were from low-income countries. The evidence base was low quality, as assessed by ROBINS-I and RoB2 tools. Evidence synthesis was limited by the different interventions and comparators across studies. Evidence indicated that consumption of sugar-sweetened beverages (SSB) and unhealthy foods in childhood may increase body mass index (BMI)/BMI z-score, % body fat or odds of overweight/obesity (low certainty of evidence). Artificially-sweetened beverages and 100% fruit juice consumption may make little/no difference to BMI, % body fat or overweight/obesity outcomes (low certainty of evidence). Meta-analyses of a subset of studies indicated a positive association between SSB intake and % body fat, but no association with change in BMI and BMI z-score. High-quality epidemiological studies that are designed to assess the effects of unhealthy food consumption during childhood on risk of overweight/obesity are needed to contribute to a more robust evidence base upon which to design policy recommendations. This protocol was registered at https://www.crd.york.ac.uk/PROSPERO as CRD42020218109.
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Stakeholder views of services for children and adolescents with obesity: Mega-ethnography of qualitative syntheses.
Carroll, C, Sworn, K, Booth, A, Pardo-Hernandez, H
Obesity (Silver Spring, Md.). 2022;(11):2167-2184
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Abstract
OBJECTIVE The efficacy of services for children and adolescents with obesity is well researched, but this review describes what actually matters to stakeholders (children, caregivers, and professionals) in relation to such services. METHODS A mega-ethnography, an innovative review-of-reviews approach that uses conceptual findings as primary data, was performed. Twelve bibliographic databases (2010-2020) were searched for reviews that considered the values and preferences of stakeholders concerning services or interventions (diet, exercise, lifestyle) that targeted children and adolescents with obesity. RESULTS From 485 citations, 17 relevant reviews were identified. The synthesis found that the perceived need to address obesity is determined by subjective norms of weight and interactions with health professionals. Children's and caregivers' participation in obesity management services is shaped by their response to content, acceptability, and perceived benefits and demands. Whether they continue with and complete an intervention are determined by its perceived success, beyond just weight loss, including behavior change, enhanced self-esteem, and the provision of timely and relevant support. CONCLUSIONS Obesity management services must be promoted in a sensitive manner and must be tailored, be varied, and make positive use of family and schools if children and caregivers are to seek and actively engage with them.
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Qualitative evidence syntheses of attitudes and preferences to inform guidelines on infant feeding in the context of Ebola Virus Disease (EVD) transmission risk.
Campbell, F, Booth, A, Carroll, C, Lee, A, Relton, C
PLoS neglected tropical diseases. 2022;(3):e0010080
Abstract
BACKGROUND Breast-feeding holds considerable potential to reduce infant mortality. Feeding choices, already complex, take on additional complexity against a backdrop of the risk of transmissible Ebola Virus. This review describes the factors that influence infant feeding and attitudes of pregnant women, mothers, family members and health practitioners, policy makers and providers (midwives) concerning infant feeding when there is a risk of Mother-to-Child (MTC) transmission of Ebola Virus Disease (EVD). METHODOLOGY A systematic review of qualitative studies identified through rigorous searches of thirteen online databases and additional citation searches of included studies was undertaken. Search terms included breast-feeding, breast-feeding, infant feeding; Ebola; and qualitative, interview(s) and findings. Independent extraction of data by two reviewers using predefined extraction forms. Studies were assessed using the CASP Qualitative checklist. PRINCIPAL FINDINGS 5219 references were screened. 38 references related specifically to Ebola, and five papers met the inclusion criteria with data gathered from two settings: Guinea and Sierra Leone. The EVD outbreak had a significant impact on beliefs, attitudes, and resources to support infant feeding practices negatively affecting the nutritional status of children. The evidence from these studies highlight the need for guidance and appropriate psychosocial support need to be available to mothers who display symptoms and become infected and to front-line staff who are giving advice. Communities need to be engaged because stigma and fear may hinder uptake of appropriate interventions. The EVD outbreak caused multi-level system disruption akin to that seen following a natural disaster, meaning that logistics and coordination are critical and need adequate resourcing. Food production and distribution, and malnutrition screening are also disrupted and thereby compounding compromised nutritional status. The limited number of relevant studies highlights the need for further primary research, particularly in translation of messages to local settings. CONCLUSIONS An EVD outbreak causes multi-level disruption that negatively impacts infant feeding and child care practices. Negative impacts have multiple causes and successful planning for Ebola outbreaks requires that nutrition of infants and young children is a priority. Lessons from the Ebola pandemic have wider applicability to other pandemic contexts including Covid-19.
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What are the implications of Zika Virus for infant feeding? A synthesis of qualitative evidence concerning Congenital Zika Syndrome (CZS) and comparable conditions.
Carroll, C, Booth, A, Campbell, F, Relton, C
PLoS neglected tropical diseases. 2020;(10):e0008731
Abstract
If a mother contracts the Zika Virus before or during pregnancy, then there is a risk of the child developing Congenital Zika Syndrome (CZS). An infant can then experience problems feeding due to the specific physical and developmental consequences of Congenital Zika Syndrome (CZS), such as microcephaly, dysphagia and an increased likelihood of choking. This qualitative evidence synthesis accesses direct and indirect evidence to inform WHO infant feeding guidelines. We conducted a qualitative evidence synthesis of the values and preferences of relevant stakeholders (e.g. pregnant women, mothers, family members and health practitioners) concerning infant (0-2 years) feeding in the presence of: 1) CZS (the'direct evidence'); 2) severe disability and nonprogressive, chronic encephalopathies ('indirect evidence'), which present with similar problems. Authors' findings were extracted, synthesised using thematic synthesis techniques, and confidence in the findings were assessed using GRADE-CERQual. Six CZS-specific studies (all from Brazil) were included in the direct evidence, with a further eight indirect studies reporting feeding difficulties in infants with severe disability and nonprogressive, chronic encephalopathies. Included studies highlighted: breast-feeding represented the preference for all mothers in the studies in both reviews, and the inability to do so affected bonding between parents and child, and generated fear and anxiety relating to feeding choices, especially around the risks of choking and swallowing; the perception that health professionals were often unable to offer appropriate advice; the potential value of training; and a strong desire to achieve individual maternal autonomy in infant feeding decisions. Confidence in most findings ranged from low to moderate. The evidence base has limitations, but consistently reported that parents of children with feeding difficulties due to Congenital Zika Syndrome, or similar, need information, advice and counselling, and substantial emotional support. Parents perceive that these needs are often neither recognised nor satisfied; optimal feeding and support strategies for this population have not yet been identified.
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Evaluation of point-of-care maternal glucose measurements for the diagnosis of gestational diabetes mellitus.
Daly, N, Carroll, C, Flynn, I, Harley, R, Maguire, PJ, Turner, MJ
BJOG : an international journal of obstetrics and gynaecology. 2017;(11):1746-1752
Abstract
OBJECTIVE Using updated laboratory standards as the reference, we aimed to compare point-of-care (POC) maternal capillary glucose testing with the diagnostic accuracy of reference and customary venous samples. DESIGN, SETTING, POPULATION Women screened selectively with a one-step 75-g oral glucose tolerance test (OGTT) at 24-28 weeks' gestation were conveniently recruited to this prospective observational study. METHODS Two venous samples and one capillary sample were taken at each OGTT time point. Venous sample one was a fluoride-EDTA (FE) tube placed on an ice-slurry until cell separation and analysis within 30 minutes (reference standard). Venous sample two was transported in a tube containing FE (without ice) (customary practice). A capillary sample was used for POC testing. Various cut-off points for the POC sample were examined to evaluate diagnostic accuracy. MAIN OUTCOME MEASURES The sensitivity, specificity, positive and negative predictive values and accuracy of POC capillary glucose for the diagnosis of GDM. RESULTS Of 108 women, GDM was detected in 47.2% (n = 51), 17.6% (n = 19) and 24.1% (n = 26) using the reference standard, customary practices and POC, respectively (P < 0.001). However, based on adjustment of the POC fasting diagnostic threshold from ≥5.1 to ≥4.8 mol/l (aPOC), sensitivity, specificity, PPV, NPV and accuracy improved to 92.5, 76.5, 69.8, 94.5 and 94.5%, respectively. CONCLUSIONS POC capillary maternal glucose tests were superior to customary laboratory practices for diagnosing GDM. This has considerable potential, particularly in healthcare settings where facilities for phlebotomy are distant from the laboratory or pre-analytical sample handling is substandard. TWEETABLE ABSTRACT Adjusted point-of-care glucose measurements have potential in the diagnosis of gestational diabetes mellitus.