Publications by authors named "Claire Smith"

218 Publications

Outcomes of Minnesota Detoxification Scale (MINDS) Assessment with High-Dose Front Loading Diazepam Treatment for Alcohol Withdrawal in Hospitalized Patients.

Am J Med Sci 2021 Oct 16. Epub 2021 Oct 16.

Care Delivery Research, Allina Health, Minneapolis, MN USA.

Background: Benzodiazepines are the gold standard for alcohol withdrawal treatment but choice and dosing vary widely. In 2015, our institution implemented a Minnesota detoxification scale (MINDS) and single standardized high-dose diazepam based protocol for treatment of alcohol withdrawal to replace multiple Clinical Institute Withdrawal Assessment for Alcohol (CIWA) based protocols using lower dose benzodiazepines.

Objective: We compared use of MINDS versus CIWA assessment protocols with high front loading diazepam treatment in care of patient experiencing alcohol withdrawal during hospitalization.

Methods: Retrospective cohort study of hospitalized patients experiencing alcohol withdrawal to statistically analyze difference in outcomes between CIWA based lower benzodiazepine dose protocols used in 2013-2015 versus the MINDS based high-dose front-loading diazepam protocol used in 2015-2017.

Results: Patients treated with MINDS based high dose diazepam protocol were less likely to have physical restraints used (AOR = 0.8, CI: 0.70 - 0.92), had a shorter hospital length of stay, and fewer days on benzodiazepines (p < 0.001). Patients were more likely to be readmitted to the hospital within 30 days (AOR = 1.13, CI: 1.03 - 1.26) in MINDS based diazepam treatment group. Total diazepam equivalent dosing was similar in both groups. Mortality rates and ICU use rates were similar between the groups.

Conclusions: Higher dose front loading long acting benzodiazepine can be safely used with beneficial outcomes in hospitalized alcohol withdrawal patients.
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http://dx.doi.org/10.1016/j.amjms.2021.10.003DOI Listing
October 2021

The "What", "Why" and "Whom" of Interrole Interference Among Home-Based Teleworkers.

Occup Health Sci 2021 Oct 9:1-22. Epub 2021 Oct 9.

Department of Psychology, Bowling Green State University, Bowling Green, OH USA.

Many employees are drawn to work-from-home arrangements based on expectations that such arrangements will help them manage both work and home life more effectively. Yet, mixed empirical findings suggest that telework arrangements do not uniformly result in less interrole interference (i.e., work-home and home-work interference). Applying and extending a border theory perspective, the present research offers insight into what factors may predict interrole interference, mediating mechanisms that may explain why such interference occurs, and a moderator that tests for whom interference is most damaging when employees work from home. Specifically, we test cross-role interruption behaviors as a predictor of interrole interference, with recovery experiences as a mediator of this relation and work-life border segmentation preference as a moderator. A sample of 504 home-based teleworkers recruited through Amazon's Mechanical Turk participated in a three-wave survey. Results from a structural equation modeling approach support our overall model. However, the extent valence of the impact of cross-role interruption behaviors had on teleworkers' interrole interference depended on the direction of the interruption, type of recovery experience, and personal work-life border preference. These findings provide theoretical and practical insights that may help explain the gap between expected and actual occurrence of interrole interference in home-based telework arrangements.
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http://dx.doi.org/10.1007/s41542-021-00084-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502093PMC
October 2021

Duodenal-Jejunal Bypass Liner for the management of Type 2 Diabetes Mellitus and Obesity: A Multicenter Randomized Controlled Trial.

Ann Surg 2021 Jun 14. Epub 2021 Jun 14.

Department of Surgery and Cancer, Imperial College, London, UK Department of Metabolism, Digestion and Reproduction, Imperial College, London, UK Division of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK PsychoNeuroEndocrinology Research Group, Neuropsychopharmacology Unit, Center for Psychiatry and Computational, Cognitive and Clinical Neuroimaging Laboratory, Department of Brain Sciences, Imperial College London, UK Imperial College London, Department of Public Health, Imperial Clinical Trials Unit, London, UK Psychiatry and Computational, Cognitive and Clinical Neuroimaging Laboratory, Department of Brain Sciences, Imperial College London, UK Diabetes Complications Research Center, University College Dublin, Ireland Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia Southampton Health Technology Assessment Center, University of Southampton, Southampton, UK Section of Nutritional research, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK Department of Endocrinology, King's College Hospital NHS Trust, London, UK University Hospital Southampton NHS Foundation Trust, Biomedical Research Center, Southampton, UK Primary Care, Population Sciences and Medical Education, University of Southampton Medical School, Southampton, UK.

Objective: The aim of this study was to examine the clinical efficacy and safety of the duodenal-jejunal bypass liner (DJBL) while in situ for 12 months and for 12 months after explantation.

Summary Background Data: This is the largest randomized controlled trial (RCT) of the DJBL, a medical device used for the treatment of people with type 2 diabetes mellitus (T2DM) and obesity. Endoscopic interventions have been developed as potential alternatives to those not eligible or fearful of the risks of metabolic surgery.

Methods: In this multicenter open-label RCT, 170 adults with inadequately controlled T2DM and obesity were randomized to intensive medical care with or without the DJBL. Primary outcome was the percentage of participants achieving a glycated hemoglobin reduction of ≥20% at 12 months. Secondary outcomes included weight loss and cardiometabolic risk factors at 12 and 24 months.

Results: There were no significant differences in the percentage of patients achieving the primary outcome between both groups at 12 months [DJBL 54.6% (n = 30) vs control 55.2% (n = 32); odds ratio (OR) 0.93, 95% confidence interval (CI): 0.44-2.0; P = 0.85]. Twenty-four percent (n = 16) patients achieved ≥15% weight loss in the DJBL group compared to 4% (n = 2) in the controls at 12 months (OR 8.3, 95% CI: 1.8-39; P = .007). The DJBL group experienced superior reductions in systolic blood pressure, serum cholesterol, and alanine transaminase at 12 months. There were more adverse events in the DJBL group.

Conclusions: The addition of the DJBL to intensive medical care was associated with superior weight loss, improvements in cardiometabolic risk factors, and fatty liver disease markers, but not glycemia, only while the device was in situ. The benefits of the devices need to be balanced against the higher rate of adverse events when making clinical decisions.

Trial Registration: ISRCTN30845205. isrctn.org; Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership reference 12/10/04.
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http://dx.doi.org/10.1097/SLA.0000000000004980DOI Listing
June 2021

Transorbital Debulking of Sphenoid Wing Meningioma.

J Craniofac Surg 2021 Sep 29. Epub 2021 Sep 29.

Stein Eye Institute, Department of Ophthalmology, UCLA Doheny Eye Institute, Department of Ophthalmology, UCLA, Los Angeles, CA.

Objective: To describe the clinical features and outcomes of patients who underwent transorbital debulking of sphenoid wing meningioma.

Methods: Patients with a diagnosis of sphenoid wing meningioma who underwent transorbital debulking were included in this series. Preoperative and postoperative symptoms and examination findings, including best corrected visual acuity (BCVA) and proptosis were extracted from patient charts. All imaging studies, records of additional surgical and medical management, and complications of surgery were collated.

Results: Eight patients were included. The most common symptoms at presentation were blurred vision (6/8) and proptosis (6/8). The most common clinical findings at presentation were decreased visual acuity and proptosis. Mean BCVA preoperatively was 0.93 in logMAR units and mean relative proptosis preoperatively was 4.88 mm. All patients underwent orbitotomy with or without bone flap with decompression of hyperostotic bone and subtotal resection of soft tissue mass. Mean follow-up time was 14 months. Five of eight patients experienced postoperative improvement in BCVA, for mean change of 0.32. All patients demonstrated reduction in proptosis postoperatively with a mean reduction of 3.63 mm.

Conclusions: Sphenoid wing meningioma can present with decreased visual acuity and/or proptosis. It is possible to address both of these problems in selected patients with transorbital debulking, an approach that avoids the aesthetic and functional consequences of craniotomy. The aim of this technique is not surgical cure, but rather improvement in vision and disfigurement.
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http://dx.doi.org/10.1097/SCS.0000000000008148DOI Listing
September 2021

Cultivating Doctors' Gut Feeling: Experience, Temporality and Politics of Gut Feelings in Family Medicine.

Cult Med Psychiatry 2021 Sep 26. Epub 2021 Sep 26.

Region Zealand, Primary Health Care, Alléen 15, 4180, Sorø, Denmark.

For the past decade, within family medicine there has been a focus on cultivating doctors gut feelings as 'a way of knowing' in cancer diagnostics. In this paper, building on interviews with family doctors in Oxford shire, UK we explore the embodied and temporal dimensions of clinical reasoning and how the cultivation of doctors' gut feelings is related to hierarchies of medical knowledge, professional training, and doctors' fears of litigation. Also, we suggest that the introduction of gut feeling in clinical practice is an attempt to develop a theory of clinical reasoning that fits the biopolitics of our contemporary. The turn towards predictive medicine and the values introduced by accelerated diagnostic regimes, we conclude, introduce a need for situated and embodied modes of reading bodies. We contribute theoretically by framing our analysis within a sensorial anthropology approach.
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http://dx.doi.org/10.1007/s11013-021-09736-3DOI Listing
September 2021

A retrospective, observational study on medication for opioid use disorder during pregnancy and risk for neonatal abstinence syndrome.

Fam Pract 2021 Sep 19. Epub 2021 Sep 19.

Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC, United States.

Objectives: The prevalence of opioid use disorder (OUD) among pregnant women is increasing. Research consistently demonstrates the efficacy of medications for OUD (MOUD); however, researchers have called for additional studies evaluating the safety of MOUD during pregnancy, particularly the relative safety of two commonly used MOUD medications-methadone and buprenorphine. This study aimed to evaluate the consequences of MOUD exposure during pregnancy on risk for neonatal abstinence syndrome (NAS).

Methods: In a clinical sample of infants born to women with OUD, we evaluated the risk of NAS among those exposed to (i) methadone and (ii) buprenorphine compared with those unexposed to MOUD, as well as the risk of NAS among those exposed to (i) methadone compared with those exposed to (ii) buprenorphine.

Results: Compared with buprenorphine-exposed infants (n = 37), methadone-exposed infants (n = 27) were at increased risk for NAS (odds ratio [OR] = 4.67, 95% confidence interval [CI]: 1.03, 21.17). Compared with unexposed infants (n = 43), buprenorphine-exposed infants were at decreased risk for NAS (OR = 0.45, 95% CI: 0.14, 1.39) and methadone-exposed infants were at increased risk for NAS (OR = 2.64, 95% CI: 0.79, 8.76), though these associations were not statistically significant.

Conclusions: Our study suggests that when methadone and buprenorphine are equally appropriate options for the treatment of OUD in pregnant women, buprenorphine may add the additional benefit of reduced risk of newborn NAS.
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http://dx.doi.org/10.1093/fampra/cmab121DOI Listing
September 2021

Projected resurgence of COVID-19 in the United States in July-December 2021 resulting from the increased transmissibility of the Delta variant and faltering vaccination.

medRxiv 2021 Sep 2. Epub 2021 Sep 2.

What Is Already Known About This Topic?: The highly transmissible SARS-CoV-2 Delta variant has begun to cause increases in cases, hospitalizations, and deaths in parts of the United States. With slowed vaccination uptake, this novel variant is expected to increase the risk of pandemic resurgence in the US in July-December 2021.

What Is Added By This Report?: Data from nine mechanistic models project substantial resurgences of COVID-19 across the US resulting from the more transmissible Delta variant. These resurgences, which have now been observed in most states, were projected to occur across most of the US, coinciding with school and business reopening. Reaching higher vaccine coverage in July-December 2021 reduces the size and duration of the projected resurgence substantially. The expected impact of the outbreak is largely concentrated in a subset of states with lower vaccination coverage.

What Are The Implications For Public Health Practice?: Renewed efforts to increase vaccination uptake are critical to limiting transmission and disease, particularly in states with lower current vaccination coverage. Reaching higher vaccination goals in the coming months can potentially avert 1.5 million cases and 21,000 deaths and improve the ability to safely resume social contacts, and educational and business activities. Continued or renewed non-pharmaceutical interventions, including masking, can also help limit transmission, particularly as schools and businesses reopen.
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http://dx.doi.org/10.1101/2021.08.28.21262748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8423228PMC
September 2021

The pathogenesis of mesothelioma is driven by a dysregulated translatome.

Nat Commun 2021 08 13;12(1):4920. Epub 2021 Aug 13.

MRC Toxicology Unit, Gleeson Building, University of Cambridge, Cambridge, UK.

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease.
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http://dx.doi.org/10.1038/s41467-021-25173-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363647PMC
August 2021

Outcomes in reported penicillin allergic mothers and neonates requiring Group B streptococcal prophylaxis: a retrospective observational cohort study.

BMC Pediatr 2021 07 27;21(1):327. Epub 2021 Jul 27.

Care Delivery Research, Allina Health, Minneapolis, MN, USA.

Background: Infectious morbidity and mortality in the first week of life is commonly caused by early-onset neonatal Group B streptococcus (GBS) disease. This infection is spread from GBS positive mothers to neonates by vertical transmission during delivery and results in serious illness for newborns. Intrapartum prophylactic antibiotics have decreased the incidence of early-onset neonatal GBS disease by 80%. Patients labeled with a penicillin allergy (PcnA) alternatively receive either vancomycin or clindamycin but effectiveness is controversial. We evaluated the influence of a reported PcnA label versus no PcnA label on inpatient maternal and neonatal outcomes.

Methods: Our goal was to examine the relationship between a PcnA label, maternal and neonatal outcomes, and hospital costs. We collected retrospective data with institutional IRB approval from 2016 - 2018 for hospitalized patients who were GBS positive, pregnant at time of admission, ≥ 18 years of age, received antibiotic prophylaxis for GBS, were labeled as PcnA or non-PcnA, and completed a vaginal delivery. Patient characteristics and maternal/neonatal outcomes were examined. Statistical tests included calculations of means, medians, proportions, Mann-Whitney, two-sample t-tests, Chi-squared or Fisher's Exact tests, and generalized linear and logistic regression models. Significance was set at p < 0.05.

Results: Most PcnA patients were white, older, had a higher median body mass index and mean heart rate, and a greater proportion used tobacco than non-PcnA patients. In regression analyses, PcnA hospitalized patients received a shorter duration of antibiotic treatment than non-PcnA patients [incidence rate ratio (IRR): 0.45, 95% CI: 0.38-0.53]. PcnA patients were also more likely to have their baby's hospital LOS be > 48 h [adjusted odds ratio (AOR): 1.35, 95% CI: 1.07-1.69] even though the PcnA mothers' LOS was not different from non-PcnA mothers. Cost of care, mortality, intensive care, median parity, mean gravidity, and miscarriage were similar between the groups.

Conclusions: In hospitalized obstetric patients, a PcnA label was associated with a shorter maternal course of antibiotic treatment and a longer neonatal LOS. Further prospective studies are needed to clarify the underlying reasons for these outcomes.
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http://dx.doi.org/10.1186/s12887-021-02797-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313667PMC
July 2021

Anatomy Education for Medical Students in the United Kingdom and Republic of Ireland in 2019: A twenty year follow up.

Anat Sci Educ 2021 Jul 27. Epub 2021 Jul 27.

Human Anatomy Unit, Department of Surgery and Cancer, Imperial College London, Charing Cross Campus, London, United Kingdom.

Anatomical education in the United Kingdom (UK) and Ireland has long been under scrutiny, especially since the reforms triggered in 1993 by the General Medical Council's "Tomorrow's Doctors". The aim of the current study was to investigate the state of medical student anatomy education in the UK and Ireland in 2019. Thirty-nine medical schools completed the survey (100% response rate) and trained 10,093 medical students per year cohort. The teachers comprised 760 individuals, of these 143 were employed on full-time teaching contracts and 103 were employed on education and research contracts. Since a previous survey in 1999, the number of part-time staff has increased by 300%, including a significant increase in the number of anatomy demonstrators. In 2019, anatomy was predominantly taught to medical students in either a system-based or hybrid curriculum. Thirty-four medical schools (87%) used human cadavers to teach anatomy, with a total of 1,363 donors being used per annum. Gross anatomy teaching was integrated with medical imaging in 95% of medical schools, embryology in 81%, living anatomy in 78%, neuroanatomy in 73% and histology in 68.3%. Throughout their five years of study, medical students are allocated on average 85 hours of taught time for gross anatomy, 24 hours for neuroanatomy, 24 hours for histology, 11 hours for living anatomy and 10 for embryology. In the past twenty years there has been an average loss of 39 hours dedicated to gross anatomy teaching and a reduction in time dedicated to all other anatomy subdisciplines.
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http://dx.doi.org/10.1002/ase.2126DOI Listing
July 2021

Human models for COVID-19 research.

J Physiol 2021 09 17;599(18):4255-4267. Epub 2021 Aug 17.

GOS Institute of Child Health, University College London, London, UK.

Currently, therapeutics for COVID-19 are limited. To overcome this, it is important that we use physiologically relevant models to reproduce the pathology of infection and evaluate the efficacy of antiviral drugs. Models of airway infection, including the use of a human infection challenge model or well-defined, disease relevant in vitro systems can help determine the key components that perpetuate the severity of the disease. Here, we briefly review the human models that are currently being used in COVID-19 research and drug development.
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http://dx.doi.org/10.1113/JP281499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447334PMC
September 2021

Identifying acute exacerbations of chronic obstructive pulmonary disease using patient-reported symptoms and cough feature analysis.

NPJ Digit Med 2021 Jul 2;4(1):107. Epub 2021 Jul 2.

ResApp Health, Brisbane, QLD, Australia.

Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are commonly encountered in the primary care setting, though the accurate and timely diagnosis is problematic. Using technology like that employed in speech recognition technology, we developed a smartphone-based algorithm for rapid and accurate diagnosis of AECOPD. The algorithm incorporates patient-reported features (age, fever, and new cough), audio data from five coughs and can be deployed by novice users. We compared the accuracy of the algorithm to expert clinical assessment. In patients with known COPD, the algorithm correctly identified the presence of AECOPD in 82.6% (95% CI: 72.9-89.9%) of subjects (n = 86). The absence of AECOPD was correctly identified in 91.0% (95% CI: 82.4-96.3%) of individuals (n = 78). The diagnostic agreement was maintained in milder cases of AECOPD (PPA: 79.2%, 95% CI: 68.0-87.8%), who typically comprise the cohort presenting to primary care. The algorithm may aid early identification of AECOPD and be incorporated in patient self-management plans.
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http://dx.doi.org/10.1038/s41746-021-00472-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253790PMC
July 2021

Assessment of New Molecular Entities Approved for Cancer Treatment in 2020.

JAMA Netw Open 2021 05 3;4(5):e2112558. Epub 2021 May 3.

Department of Medicine, University of California, San Francisco.

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http://dx.doi.org/10.1001/jamanetworkopen.2021.12558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164099PMC
May 2021

Do sleep interventions change sleep duration in children aged 0-5 years? A systematic review and meta-analysis of randomised controlled trials.

Sleep Med Rev 2021 Oct 30;59:101498. Epub 2021 Apr 30.

Department of Medicine, University of Otago, New Zealand. Electronic address:

This review investigated whether randomised controlled trials attempting to improve sleep or prevent sleep problems in 0-5 year olds influenced nocturnal sleep duration, day-time naps, or 24-h sleep. Medline (Ovid), EMBASE, and CINAHL were searched from inception until 9 July 2020 and supplemented with hand searching. Search results were screened, eligible data were extracted, and risk of bias was assessed by at least two reviewers. Of 8571 publications considered, 32 trials which used a variety of subjective and objective sleep measurements were included in generic inverse variance random effects meta-analysis of nocturnal (n = 24), day-time (n = 14), and 24-h (n = 13) sleep duration. Overall, sleep interventions increased nocturnal sleep duration by a mean of 9 min (95% CI 4.1 to 13.8, I28%) per night when compared with no sleep intervention. Increases were predominantly seen in sleep-only, rather than multi-component interventions. Total 24-h sleep duration tended to increase by a similar amount (8.6 min (95% CI -2.7 to 19.8, I = 59%)), but this was mainly only seen in studies that assessed sleep using diaries. There was no evidence that interventions changed day-time sleep duration. Future studies should involve sleep-only rather than multi-component interventions, and use objective sleep measures (reviewregistry857).
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http://dx.doi.org/10.1016/j.smrv.2021.101498DOI Listing
October 2021

Modeling of Future COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Rates and Nonpharmaceutical Intervention Scenarios - United States, April-September 2021.

MMWR Morb Mortal Wkly Rep 2021 May 14;70(19):719-724. Epub 2021 May 14.

After a period of rapidly declining U.S. COVID-19 incidence during January-March 2021, increases occurred in several jurisdictions (1,2) despite the rapid rollout of a large-scale vaccination program. This increase coincided with the spread of more transmissible variants of SARS-CoV-2, the virus that causes COVID-19, including B.1.1.7 (1,3) and relaxation of COVID-19 prevention strategies such as those for businesses, large-scale gatherings, and educational activities. To provide long-term projections of potential trends in COVID-19 cases, hospitalizations, and deaths, COVID-19 Scenario Modeling Hub teams used a multiple-model approach comprising six models to assess the potential course of COVID-19 in the United States across four scenarios with different vaccination coverage rates and effectiveness estimates and strength and implementation of nonpharmaceutical interventions (NPIs) (public health policies, such as physical distancing and masking) over a 6-month period (April-September 2021) using data available through March 27, 2021 (4). Among the four scenarios, an accelerated decline in NPI adherence (which encapsulates NPI mandates and population behavior) was shown to undermine vaccination-related gains over the subsequent 2-3 months and, in combination with increased transmissibility of new variants, could lead to surges in cases, hospitalizations, and deaths. A sharp decline in cases was projected by July 2021, with a faster decline in the high-vaccination scenarios. High vaccination rates and compliance with public health prevention measures are essential to control the COVID-19 pandemic and to prevent surges in hospitalizations and deaths in the coming months.
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http://dx.doi.org/10.15585/mmwr.mm7019e3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8118153PMC
May 2021

Current concepts in the rehabilitation of rotator cuff related disorders.

J Clin Orthop Trauma 2021 Jul 18;18:13-19. Epub 2021 Apr 18.

Upper Limb Department, Wrightington Hospital, Wigan, UK.

Rotator cuff related disorders (RCRD) are common. Exercise-based rehabilitation can improve outcomes, yet uncertainty exists regarding the characteristics of these exercises. This scoping review paper summarises the key characteristics of the exercise-based rehabilitation of rotator cuff related disorders (RCRD). An iterative search process was used to capture the breadth of current evidence and a narrative summary of the data was produced. 57 papers were included. Disagreement around terminology, diagnostic standards, and outcome measures limits the comparison of the data. Rehabilitation should utilise a biopsychosocial approach, be person-centred and foster self-efficacy. Biomedically framed beliefs can create barriers to rehabilitation. Pain drivers in RCRSD are unclear, as is the influence of pain during exercise on outcomes. Expectations and preferences around pain levels should be discussed to allow the co-creation of a programme that is tolerated and therefore engaged with. The optimal parameters of exercise-based rehabilitation remain unclear; however, programmes should be individualised and progressive, with a minimum duration of 12 weeks. Supervised or home-based exercises are equally effective. Following rotator cuff repair, rehabilitation should be milestone-driven and individualised; communication across the MDT is essential. For individuals with massive rotator cuff tears, the anterior deltoid programme is a useful starting point and should be supplemented by functional rehabilitation, exercises to optimise any remaining cuff and the rest of the kinetic chain. In conclusion, exercise-based rehabilitation improves outcomes for individuals with a range of RCRD. The optimal parameters of these exercises remain unclear. Variation exists across current physiotherapy practice and post-operative rehabilitation protocols, reflecting the wide-ranging spectrum of individuals presenting with RCRD. Clinicians should use their communication and rehabilitation expertise to plan an exercise-based program in conjunction with the individual with RCRSD, which is regularly reviewed and adjusted.
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http://dx.doi.org/10.1016/j.jcot.2021.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082254PMC
July 2021

Phase I Study of Ceralasertib (AZD6738), a Novel DNA Damage Repair Agent, in Combination with Weekly Paclitaxel in Refractory Cancer.

Clin Cancer Res 2021 Sep 11;27(17):4700-4709. Epub 2021 May 11.

Division of Hematology-Oncology, Department of Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein.

Patients And Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel.

Results: The RP2D was established as ceralasertib 240 mg BD days 1-14 plus paclitaxel 80 mg/m on D1, D8, D15 every 28 days. The most common toxicities were neutropenia ( = 39, 68%), anemia ( = 25, 44%), and thrombocytopenia ( = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5-35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0-51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0-5.8), the median duration of response was 9.9 months (95% CI, 3.7-23.2), and the mOS was 7.4 months (95% CI, 5.7-11.9).

Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment..
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0251DOI Listing
September 2021

Impact of high-risk glycemic control on habitual sleep patterns and sleep quality among youth (13-20 years) with type 1 diabetes mellitus compared to controls without diabetes.

Pediatr Diabetes 2021 08 28;22(5):823-831. Epub 2021 Apr 28.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand.

Background: In type 1 diabetes mellitus (T1D), glycemic control and sleep have a bidirectional relationship, with unhealthy glycemic control impacting sleep, and inadequate sleep impacting diabetes management. Youth are at risk for poor quality sleep; however, little is known about sleep among youth with high-risk glycemic control.

Objective: To assess differences in habitual sleep timing, duration, and quality among youth with T1D and controls.

Subjects: Two-hundred-thirty youth (13-20 years): 64 with T1D (mean age 16.6 ± 2.1 years, 48% female, diabetes duration 7.5 ± 3.8 years, HbA1c 96 ± 18.0 mmol/mol [10.9 ± 1.7%]), and 166 controls (mean age 15.3 ± 1.5, 58% female).

Methods: Comparison of data from two concurrent studies (from the same community) using subjective and objective methods to assess sleep in youth: Pittsburgh Sleep Quality Index evaluating sleep timing and quality; 7-day actigraphy measuring habitual sleep patterns. Regression analyses were used to compare groups.

Results: When adjusted for various confounding factors, youth with T1D reported later bedtimes (+36 min; p < 0.05) and shorter sleep duration (-53 min; p < 0.05) than controls, and were more likely to rate subjective sleep duration (OR 3.57; 95% CI 1.41-9.01), efficiency (OR 4.03; 95% CI 1.43-11.40), and quality (OR 2.59; 95% CI 1.16-5.76) as "poor" (p < 0.05). However, objectively measured sleep patterns were similar between the two groups.

Conclusions: Youth with high-risk T1D experience sleep difficulties, with later bedtimes contributing to sleep deficit. Despite a lack of objective differences, they perceive their sleep quality to be worse than peers without diabetes.
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http://dx.doi.org/10.1111/pedi.13215DOI Listing
August 2021

Single-cell multi-omics analysis of the immune response in COVID-19.

Nat Med 2021 05 20;27(5):904-916. Epub 2021 Apr 20.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Analysis of human blood immune cells provides insights into the coordinated response to viral infections such as severe acute respiratory syndrome coronavirus 2, which causes coronavirus disease 2019 (COVID-19). We performed single-cell transcriptome, surface proteome and T and B lymphocyte antigen receptor analyses of over 780,000 peripheral blood mononuclear cells from a cross-sectional cohort of 130 patients with varying severities of COVID-19. We identified expansion of nonclassical monocytes expressing complement transcripts (CD16C1QA/B/C) that sequester platelets and were predicted to replenish the alveolar macrophage pool in COVID-19. Early, uncommitted CD34 hematopoietic stem/progenitor cells were primed toward megakaryopoiesis, accompanied by expanded megakaryocyte-committed progenitors and increased platelet activation. Clonally expanded CD8 T cells and an increased ratio of CD8 effector T cells to effector memory T cells characterized severe disease, while circulating follicular helper T cells accompanied mild disease. We observed a relative loss of IgA2 in symptomatic disease despite an overall expansion of plasmablasts and plasma cells. Our study highlights the coordinated immune response that contributes to COVID-19 pathogenesis and reveals discrete cellular components that can be targeted for therapy.
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http://dx.doi.org/10.1038/s41591-021-01329-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121667PMC
May 2021

Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.

Eur Respir J 2021 Oct 14;58(4). Epub 2021 Oct 14.

UCL Great Ormond Street Institute of Child Health, London, UK

Background: Development of therapeutic approaches for rare respiratory diseases is hampered by the lack of systems that allow medium-to-high-throughput screening of fully differentiated respiratory epithelium from affected patients. This is a particular problem for primary ciliary dyskinesia (PCD), a rare genetic disease caused by mutations in genes that adversely affect ciliary movement and consequently mucociliary transport. Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air-liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by the limited number of basal cells that can be expanded from such biopsies.

Methods: We describe an immunofluorescence screening method, enabled by extensive expansion of basal cells from PCD patients and the directed differentiation of these cells into ciliated epithelium in miniaturised 96-well transwell format ALI cultures. As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the gene.

Results: Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures. The screening system in our proof-of-principal investigation allowed drugs that induce translational readthrough to be evaluated alone or in combination with nonsense-mediated decay inhibitors. We observed restoration of basal body formation but not the generation of cilia in the patient's nasal epithelial cells CONCLUSION: Our study provides a platform for higher throughput analyses of airway epithelia that is applicable in a range of settings and suggests novel avenues for drug evaluation and development in PCD caused by nonsense mutations.
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http://dx.doi.org/10.1183/13993003.00455-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514977PMC
October 2021

GPs' use of gut feelings when assessing cancer risk: a qualitative study in UK primary care.

Br J Gen Pract 2021 05 29;71(706):e356-e363. Epub 2021 Apr 29.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK.

Background: The use of gut feelings to guide clinical decision making in primary care has been frequently described but is not considered a legitimate reason for cancer referral.

Aim: To explore the role that gut feeling plays in clinical decision making in primary care.

Design And Setting: Qualitative interview study with 19 GPs in Oxfordshire, UK.

Method: GPs who had referred patients to a cancer pathway based on a gut feeling as a referral criterion were invited to participate. Interviews were conducted between November 2019 and January 2020, and transcripts were analysed using the one sheet of paper method.

Results: Gut feeling was seen as an essential part of decision making that facilitated appropriate and timely care. GPs distanced their gut feelings from descriptions that could be seen as unscientific, describing successful use as reliant on experience and clinical knowledge. This was especially true for patients who fell within a 'grey area' where clinical guidelines did not match the GP's assessment of cancer risk, either because the guidance inadequately represented or did not include the patient's presentation. GPs sought to legitimise their gut feelings by gathering objective clinical evidence, careful examination of referral procedures, and consultation with colleagues.

Conclusion: GPs described their gut feelings as important to decision making in primary care and a necessary addition to clinical guidance. The steps taken to legitimise their gut feelings matched that expected in good clinical practice.
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http://dx.doi.org/10.3399/bjgp21X714269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997673PMC
May 2021

Acetyl-leucine slows disease progression in lysosomal storage disorders.

Brain Commun 2021 20;3(1):fcaa148. Epub 2020 Dec 20.

Department of Pharmacology, University of Oxford, Oxford OX1 3QT, UK.

Acetyl-dl-leucine is a derivative of the branched chain amino acid leucine. In observational clinical studies, acetyl-dl-leucine improved symptoms of ataxia, in particular in patients with the lysosomal storage disorder, Niemann-Pick disease type C1. Here, we investigated acetyl-dl-leucine and its enantiomers acetyl-l-leucine and acetyl-d-leucine in symptomatic mice and observed improvement in ataxia with both individual enantiomers and acetyl-dl-leucine. When acetyl-dl-leucine and acetyl-l-leucine were administered pre-symptomatically to mice, both treatments delayed disease progression and extended life span, whereas acetyl-d-leucine did not. These data are consistent with acetyl-l-leucine being the neuroprotective enantiomer. Altered glucose and antioxidant metabolism were implicated as one of the potential mechanisms of action of the l-enantiomer in mice. When the standard of care drug miglustat and acetyl-dl-leucine were used in combination significant synergy resulted. In agreement with these pre-clinical data, when Niemann-Pick disease type C1 patients were evaluated after 12 months of acetyl-dl-leucine treatment, rates of disease progression were slowed, with stabilization or improvement in multiple neurological domains. A beneficial effect of acetyl-dl-leucine on gait was also observed in this study in a mouse model of GM2 gangliosidosis (Sandhoff disease) and in Tay-Sachs and Sandhoff disease patients in individual-cases of off-label-use. Taken together, we have identified an unanticipated neuroprotective effect of acetyl-l-leucine and underlying mechanisms of action in lysosomal storage diseases, supporting its further evaluation in clinical trials in lysosomal disorders.
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http://dx.doi.org/10.1093/braincomms/fcaa148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954382PMC
December 2020

Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with MMP20.

Hum Mutat 2021 May 6;42(5):567-576. Epub 2021 Mar 6.

Department of Oral Biology, School of Dentistry, St James's University Hospital, University of Leeds, Leeds, UK.

Amelogenesis imperfecta (AI) describes a heterogeneous group of developmental enamel defects that typically have Mendelian inheritance. Exome sequencing of 10 families with recessive hypomaturation AI revealed four novel and one known variants in the matrix metallopeptidase 20 (MMP20) gene that were predicted to be pathogenic. MMP20 encodes a protease that cleaves the developing extracellular enamel matrix and is necessary for normal enamel crystal growth during amelogenesis. New homozygous missense changes were shared between four families of Pakistani heritage (c.625G>C; p.(Glu209Gln)) and two of Omani origin (c.710C>A; p.(Ser237Tyr)). In two families of UK origin and one from Costa Rica, affected individuals were homozygous for the previously reported c.954-2A>T; p.(Ile319Phefs*19) variant. For each of these variants, microsatellite haplotypes appeared to exclude a recent founder effect, but elements of haplotype were conserved, suggesting more distant founding ancestors. New compound heterozygous changes were identified in one family of the European heritage: c.809_811+12delinsCCAG; p.(?) and c.1122A>C; p.(Gln374His). This report further elucidates the mutation spectrum of MMP20 and the probable impact on protein function, confirms a consistent hypomaturation phenotype and shows that mutations in MMP20 are a common cause of autosomal recessive AI in some communities.
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http://dx.doi.org/10.1002/humu.24187DOI Listing
May 2021

Diagnosing community-acquired pneumonia via a smartphone-based algorithm: a prospective cohort study in primary and acute-care consultations.

Br J Gen Pract 2021 Apr 26;71(705):e258-e265. Epub 2021 Mar 26.

Joondalup Health Campus, Joondalup; Genesis Care Sleep and Respiratory, Perth.

Background: Community-acquired pneumonia (CAP) is an essential consideration in patients presenting to primary care with respiratory symptoms; however, accurate diagnosis is difficult when clinical and radiological examinations are not possible, such as during telehealth consultations.

Aim: To develop and test a smartphone-based algorithm for diagnosing CAP without need for clinical examination or radiological inputs.

Design And Setting: A prospective cohort study using data from participants aged >12 years presenting with acute respiratory symptoms to a hospital in Western Australia.

Method: Five cough audio-segments were recorded and four patient-reported symptoms (fever, acute cough, productive cough, and age) were analysed by the smartphone-based algorithm to generate an immediate diagnostic output for CAP. Independent cohorts were recruited to train and test the accuracy of the algorithm. Diagnostic agreement was calculated against the confirmed discharge diagnosis of CAP by specialist physicians. Specialist radiologists reported medical imaging.

Results: The smartphone-based algorithm had high percentage agreement (PA) with the clinical diagnosis of CAP in the total cohort ( = 322, positive PA [PPA] = 86.2%, negative PA [NPA] = 86.5%, area under the receiver operating characteristic curve [AUC] = 0.95); in participants 22-<65 years ( = 192, PPA = 85.7%, NPA = 87.0%, AUC = 0.94), and in participants aged ≥65 years ( = 86, PPA = 85.7%, NPA = 87.5%, AUC = 0.94). Agreement was preserved across CAP severity: 85.1% ( = 80/94) of participants with CRB-65 scores 1 or 2, and 87.7% ( = 57/65) with a score of 0, were correctly diagnosed by the algorithm.

Conclusion: The algorithm provides rapid and accurate diagnosis of CAP. It offers improved accuracy over current protocols when clinical evaluation is difficult. It provides increased capabilities for primary and acute care, including telehealth services, required during the COVID-19 pandemic.
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http://dx.doi.org/10.3399/BJGP.2020.0750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007248PMC
April 2021

Seroconversion of severe acute respiratory syndrome coronavirus 2-infected patients on immunosuppression: A retrospective analysis.

J Am Acad Dermatol 2021 05 4;84(5):1409-1412. Epub 2021 Feb 4.

Department of Dermatology at Brigham and Women's Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts. Electronic address:

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http://dx.doi.org/10.1016/j.jaad.2021.01.100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860940PMC
May 2021

CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in women with breast cancer in real-world practice.

Eur J Haematol 2021 May 18;106(5):634-642. Epub 2021 Feb 18.

OHSU Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.

Purpose: Cyclin-dependent kinase (CDK) 4/6 inhibitors are integral treatment for advanced hormone receptor positive breast cancer; however, venous thromboembolic events (VTE) occurred in 1%-5% of clinical trial patients. Thrombosis rates in the real-world setting remain unclear. We aimed to define the rate of thromboembolic events, risk factors for thrombosis on CDK 4/6 inhibitors and evaluate the Khorana VTE risk score as a predictive tool for VTE in patients on CDK 4/6 therapy.

Methods: Multicenter retrospective analysis of adult breast cancer patients prescribed palbociclib, ribociclib, or abemaciclib. The primary endpoint was thrombosis during treatment or within 30 days of CDK inhibitor discontinuation. Cox regression was used to model time-to-thrombosis, starting from a patient's initiation of CDK 4/6 therapy. The extended Kaplan-Meier method and Cox modeling were used to assess the effect of time-varying thrombosis status on overall survival.

Results: Two hundred and sixty-six patients were included (89% on palbociclib, 14% on abemaciclib, 7% on ribociclib). Twenty-nine thrombotic events occurred in 26 (9.8%) women. Of these events, 72% were venous and 34% were arterial. The 1-year incidence of thrombosis was 10.4% overall, 10.9% on palbociclib, 8.3% on ribociclib, and 4.8% on abemaciclib. Hemoglobin less than 10 g/dL was a statistically significant predictor of thrombosis (HR 3.53, P: .014). Khorana score ranged from 0-3, with the majority between 0 and 1 and was not predictive of VTE. Thrombosis was associated with reduced overall survival (HR 1.28, P: .128, median 7.3 months) compared to not having a CDK-associated clot (median 35.7 months).

Discussion: VTE in our analysis is higher than reported in clinical trials and arterial thrombosis comprised over one-third of events. The highest incidence was with palbociclib, followed by ribociclib. Khorana score did not predict VTE risk. Larger, real-world studies are needed. The role for prophylactic anticoagulation is yet to be defined in this patient population.
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http://dx.doi.org/10.1111/ejh.13590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087188PMC
May 2021

Targeted Cancer Therapies.

Am Fam Physician 2021 02;103(3):155-163

University of California, San Francisco, CA, USA.

Targeted cancer therapies involve chemotherapeutic agents that attack, directly or indirectly, a specific genetic biomarker found in a given cancer. Targeted oncology includes monoclonal antibodies, small molecule inhibitors, antibody-drug conjugates, and immunotherapy. For example, the monoclonal antibodies trastuzumab and pertuzumab target human epidermal growth factor receptor 2 (HER2) and are used when treating HER2-positive breast cancer. Although targeted oncology has improved survival by years for some incurable cancers such as metastatic breast and lung cancer, as few as 8% of patients with advanced cancer qualify for targeted oncology medications, and even fewer benefit. Other limitations include serious adverse events, illustrated by a 20% to 30% rate of heart attack, stroke, or peripheral vascular events among patients taking ponatinib, which is used in treating chronic myelogenous leukemia. Immune checkpoint inhibitor therapy-related adverse effects such as hypothyroidism are common, and more severe adverse events such as colitis and pneumonitis can be fatal and require immediate intervention. Drug interactions with widely prescribed medications such as antacids and warfarin are common. Additionally, financial toxicities are a problem for patients with cancer who are using costly targeted therapies. Future directions for targeted oncology include tumor-agnostic drugs, which target a given mutation and could be used in treating cancers from multiple organ types. An overview of indications, mechanism of action, and toxicities of targeted cancer therapies is offered here.
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February 2021

Bidirectional associations between sleep quality or quantity, and dietary intakes or eating behaviors in children 6-12 years old: a systematic review with evidence mapping.

Nutr Rev 2021 09;79(10):1079-1099

Department of Medicine , University of Otago, Dunedin, New Zealand.

Context: Although dietary advice has long been a cornerstone of a healthy lifestyle, how sleep quality and quantity may interact with dietary intake or eating behaviors remains unclear.

Objective: To consider a bidirectional relationship between sleep and diet in children aged 6-12 years via a systematic review following PRISMA guidelines.

Data Sources: Relevant trials and observational studies were identified by searching the PubMed, Medline, Embase, and CENTRAL databases up to June 1, 2019, without language or date restrictions and supplemented with hand searching. Recognized procedures and reporting standards were applied.

Data Extraction: Data on participant characteristics, study parameters, diet measures, sleep measures, and findings of study quality assessment criteria were collected.

Data Analysis: Forty-five articles involving 308 332 participants on a diverse range of topics were included. Meta-analyses were planned but were impossible to perform due to high study heterogeneity. Most studies (82%) were cross-sectional, which prevented examining directionality of the observed associations. Risk of bias was assessed for trial, cohort studies, and cross-sectional studies, using the Cochrane Risk of Bias Tool or Newcastle Ottawa Scale.

Results: Of 16 studies in which the effect of sleep on dietary intake was investigated, 81% (n = 13) reported a significant association. All studies (n = 8) of sugar-sweetened or caffeinated beverages reported a negative association with sleep, and in 6 of 7 studies in which eating behaviors were investigated, associations with sleep were reported. The use of objective measures of sleep and diet were scarce, with most trials and studies relying on subjective measures of sleep (68%) or diet (93%).

Conclusion: Because most studies investigating the relationship between sleep and diet in this age group are cross-sectional, temporality could not be determined. Additional randomized controlled trials and long-term cohort studies in middle childhood, particularly those using objective rather than questionnaire measures of sleep, are required to better understand interactions between diet and sleep.

Systematic Review Registration: Prospectively registered with PROSPERO International Prospective Register of Systematic Reviews (CRD42018091647).
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http://dx.doi.org/10.1093/nutrit/nuaa125DOI Listing
September 2021
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