Publications by authors named "Sarah Martin"

296 Publications

Preoperative Administration of Hycet Elixir Reduces Hospital Length of Stay After Pediatric Outpatient Adeno/Tonsillectomy.

Ochsner J 2021 ;21(3):240-244

Department of Anesthesiology, Ochsner Clinic Foundation, New Orleans, LA.

Postoperative wound pain is commonly observed in the pediatric postanesthesia care unit (PACU) following tonsillectomy, adenoidectomy, and adenotonsillectomy (adeno/tonsillectomy), which contributes to increased medical care costs and delayed facility discharge. The purpose of this study was to review the benefits of preoperative administration of Hycet elixir (2.5 mg hydrocodone and 108 mg acetaminophen per 5 mL) in a pediatric population aged 1 to 9 years following adeno/tonsillectomy. Patient demographics, comorbidities, surgical and anesthetic times, need for postoperative rescue therapies, and PACU recovery and length of stay times were measured in pediatric patients who received preoperative administration of Hycet elixir (0.2 mg/kg hydrocodone) for adeno/tonsillectomy in an outpatient setting compared to a control group. The Hycet elixir group had significant reductions in PACU and hospital lengths of stay and significant reductions in the need for postoperative rescue analgesics. No significant differences were observed in emergence times or in the incidences of unplanned hospital admission between the control and Hycet elixir groups. These data show that the preoperative administration of Hycet elixir is well tolerated in the pediatric patient population undergoing adeno/tonsillectomy and appears to significantly reduce the need for postoperative rescue analgesics and postoperative care times. These data support the use of preoperative administration of Hycet elixir in this patient population.
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http://dx.doi.org/10.31486/toj.20.0101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442212PMC
January 2021

Sexual health service adaptations to the coronavirus disease 2019 (COVID-19) pandemic in Australia: a nationwide online survey.

Aust N Z J Public Health 2021 Sep 2. Epub 2021 Sep 2.

Central Clinical School, Monash University, Melbourne, Victoria.

Objective: Examine the changes in service delivery Australian public sexual health clinics made to remain open during lockdown.

Methods: A cross-sectional survey designed and delivered on Qualtrics was emailed to 21 directors of public sexual health clinics across Australia from July-August 2020 and asked about a variety of changes to service delivery. Descriptive statistics were calculated.

Results: Twenty clinics participated, all remained open and reported service changes, including suspension of walk-in services in eight clinics. Some clinics stopped offering asymptomatic screening for varying patient populations. Most clinics transitioned to a mix of telehealth and face-to-face consultations. Nineteen clinics reported delays in testing and 13 reported limitations in testing. Most clinics changed to phone consultations for HIV medication refills (n=15) and eleven clinics prescribed longer repeat prescriptions. Fourteen clinics had staff redeployed to assist the COVID-19 response.

Conclusion: Public sexual health clinics pivoted service delivery to reduce risk of COVID-19 transmission in clinical settings, managed staffing reductions and delays in molecular testing, and maintained a focus on urgent and symptomatic STI presentations and those at higher risk of HIV/STI acquisition. Implications for public health: Further research is warranted to understand what impact reduced asymptomatic screening may have had on community STI transmission.
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http://dx.doi.org/10.1111/1753-6405.13158DOI Listing
September 2021

Stress and Resilience Among Healthcare Workers During the COVID-19 Pandemic: Consideration of Case Studies.

Rehabil Nurs 2021 Aug 27. Epub 2021 Aug 27.

University of Massachusetts Amherst, Amherst, MA, USA Department of Nursing, Appalachian State University, Boone, NC, USA.

Abstract: The COVID-19 pandemic has caused a significant increase in stress for frontline healthcare workers, including rehabilitation workers. Contributing factors include disrupted workflows, heavier workloads, increased time restraints, and fear of contracting/passing the virus. Prolonged high stress levels can produce adverse health outcomes when unaddressed. Resilience can mitigate the negative effects of prolonged stress. Four healthcare workers relate their experiences from the frontlines of the pandemic, discussing their strategies to build resilience and maintain health. Highlighted strategies include mindfulness (the purposeful act of paying attention to the present moment without judgment), gratitude (the practice of being grateful for the positive things in life), self-care (the maintenance of a healthy lifestyle using physical, psychological, and emotional tools), and social support (the sense of belonging that comes from being cared for and valued). These strategies reduce negative outcomes produced by elevated stress levels and promote resilience in frontline healthcare workers.
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http://dx.doi.org/10.1097/RNJ.0000000000000344DOI Listing
August 2021

Stress and Resilience Among Healthcare Workers During the COVID-19 Pandemic: Consideration of Case Studies.

Rehabil Nurs 2021 Aug 27. Epub 2021 Aug 27.

University of Massachusetts Amherst, Amherst, MA, USA Department of Nursing, Appalachian State University, Boone, NC, USA.

Abstract: The COVID-19 pandemic has caused a significant increase in stress for frontline healthcare workers, including rehabilitation workers. Contributing factors include disrupted workflows, heavier workloads, increased time restraints, and fear of contracting/passing the virus. Prolonged high stress levels can produce adverse health outcomes when unaddressed. Resilience can mitigate the negative effects of prolonged stress. Four healthcare workers relate their experiences from the frontlines of the pandemic, discussing their strategies to build resilience and maintain health. Highlighted strategies include mindfulness (the purposeful act of paying attention to the present moment without judgment), gratitude (the practice of being grateful for the positive things in life), self-care (the maintenance of a healthy lifestyle using physical, psychological, and emotional tools), and social support (the sense of belonging that comes from being cared for and valued). These strategies reduce negative outcomes produced by elevated stress levels and promote resilience in frontline healthcare workers.
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http://dx.doi.org/10.1097/RNJ.0000000000000344DOI Listing
August 2021

Runs of homozygosity in killer whale genomes provide a global record of demographic histories.

Mol Ecol 2021 Aug 20. Epub 2021 Aug 20.

National Marine Mammal Laboratory, National Marine Fisheries Service, National Oceanic and Atmospheric Administration, Alaska Fisheries Science Center, Seattle, Washington, USA.

Runs of homozygosity (ROH) occur when offspring inherit haplotypes that are identical by descent from each parent. Length distributions of ROH are informative about population history; specifically, the probability of inbreeding mediated by mating system and/or population demography. Here, we investigated whether variation in killer whale (Orcinus orca) demographic history is reflected in genome-wide heterozygosity and ROH length distributions, using a global data set of 26 genomes representative of geographic and ecotypic variation in this species, and two F1 admixed individuals with Pacific-Atlantic parentage. We first reconstructed demographic history for each population as changes in effective population size through time using the pairwise sequential Markovian coalescent (PSMC) method. We found a subset of populations declined in effective population size during the Late Pleistocene, while others had more stable demography. Genomes inferred to have undergone ancestral declines in effective population size, were autozygous at hundreds of short ROH (<1 Mb), reflecting high background relatedness due to coalescence of haplotypes deep within the pedigree. In contrast, longer and therefore younger ROH (>1.5 Mb) were found in low latitude populations, and populations of known conservation concern. These include a Scottish killer whale, for which 37.8% of the autosomes were comprised of ROH >1.5 Mb in length. The fate of this population, in which only two adult males have been sighted in the past five years, and zero fecundity over the last two decades, may be inextricably linked to its demographic history and consequential inbreeding depression.
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http://dx.doi.org/10.1111/mec.16137DOI Listing
August 2021

Implementing PDSA Methodology for Pediatric Appendicitis Increases Care Value for a Tertiary Children's Hospital.

Pediatr Qual Saf 2021 Jul-Aug;6(4):e442. Epub 2021 Jul 28.

Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Ill.

Introduction: We used the plan-do-study-act (PDSA) framework to develop and implement an evidence-based clinical practice guideline (CPG) within an urban, tertiary children's referral center.

Methods: We developed an evidence-based CPG for appendicitis using iterative PDSA cycles. Similar CPGs from other centers were reviewed and modified for local implementation. Adjuncts included guideline-specific order sets and operative notes in the electronic medical record system. Outcomes included length of stay (LOS), 30-day readmissions, hospital costs, and patient and family experience (PFE) scores. Our team tracked outcome, process, and balancing measures using Statistical Process Charts. Outcome measures were compared over 2 fiscal quarters preimplementation and 3 fiscal quarters postimplementation, using interrupted time series, student test, and chi-square tests when appropriate.

Results: LOS for simple (uncomplicated) appendicitis decreased to 0.87 days (interquartile range [IQR] 0.87-0.94 days) from 1.1 days (IQR 0.97-1.42 days). LOS for complicated appendicitis decreased to 4.96 days (IQR 4.95-6.15) from 5.58 days (IQR 5.16-6.09). This reduction equated to an average cost-savings of $1,122/patient. Thirty-day readmission rates have remained unchanged. PFE scores increased across all categories and have remained higher than national benchmarks.

Conclusion: Development and Implementation of a CPG for pediatric appendicitis using the PDSA framework adds value to care provided within a large tertiary center.
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http://dx.doi.org/10.1097/pq9.0000000000000442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322485PMC
July 2021

Peptide amphiphile nanofiber hydrogel delivery of Sonic hedgehog protein to the penis and cavernous nerve suppresses intrinsic and extrinsic apoptotic signaling mechanisms, which are an underlying cause of erectile dysfunction.

Nanomedicine 2021 10 24;37:102444. Epub 2021 Jul 24.

Departments of Urology, Physiology, Bioengineering, and Biochemistry, University of Illinois at Chicago, Chicago, IL. Electronic address:

Erectile dysfunction (ED) is a common and debilitating condition with high impact on quality of life. An underlying cause of ED is apoptosis of penile smooth muscle, which occurs with cavernous nerve injury, in prostatectomy, diabetic and aging patients. We are developing peptide amphiphile (PA) nanofiber hydrogels as an in vivo delivery vehicle for Sonic hedgehog protein to the penis and cavernous nerve to prevent the apoptotic response. We examine two important aspects required for clinical application of the biomaterials: if SHH PA suppresses intrinsic (caspase 9) and extrinsic (caspase 8) apoptotic mechanisms, and if suppressing one apoptotic mechanism forces apoptosis to occur via a different mechanism. We show that SHH PA suppresses both caspase 9 and 8 apoptotic mechanisms, and suppressing caspase 9 did not shift signaling to caspase 8. SHH PA has significant clinical potential as a preventative ED therapy, by management of intrinsic and extrinsic apoptotic mechanisms.
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http://dx.doi.org/10.1016/j.nano.2021.102444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464506PMC
October 2021

Quantitative EEG and cholinergic basal forebrain atrophy in Parkinson's disease and mild cognitive impairment.

Neurobiol Aging 2021 10 5;106:37-44. Epub 2021 Jun 5.

Department of Psychology, Health, Psychology, and Communities Research Centre, Manchester Metropolitan University, Manchester, UK.

Cholinergic degeneration is a key feature of dementia in neurodegenerative conditions including Alzheimer's disease (AD) and Parkinson's disease (PD). Quantitative electro-encephalography (EEG) metrics are altered in both conditions from early stages, and recent research in people with Lewy body and AD dementia suggests these changes may be associated with atrophy in cholinergic basal forebrain nuclei (cBF). To determine if these relationships exist in predementia stages of neurodegenerative conditions, we studied resting-state EEG and in vivo cBF volumes in 31 people with PD (without dementia), 21 people with mild cognitive impairment (MCI), and 21 age-matched controls. People with PD showed increased power in slower frequencies and reduced alpha reactivity compared to controls. Volumes of cholinergic cell clusters corresponding to the medial septum and vertical and horizontal limb of the diagonal band, and the posterior nucleus basalis of Meynert, correlated positively with; alpha reactivity in people with PD (p< 0.01); and pre-alpha power in people with MCI (p< 0.05). These results suggest that alpha reactivity and pre-alpha power are related to changes in cBF volumes in MCI and PD without dementia.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.05.023DOI Listing
October 2021

Long-term protection from HIV infection with oral HIV pre-exposure prophylaxis in gay and bisexual men: findings from the expanded and extended EPIC-NSW prospective implementation study.

Lancet HIV 2021 08 1;8(8):e486-e494. Epub 2021 Jul 1.

Clinic 16, St Leonards, NSW, Australia.

Background: Daily pre-exposure prophylaxis (PrEP) is effective in preventing HIV, but few long-term data are available on effectiveness and adherence in real-world settings. Here, we report trends in HIV incidence over 3 years in individuals at high risk who were prescribed PrEP in New South Wales (NSW), as well as adherence before the transition to subsidised PrEP.

Methods: Expanded PrEP Implementation in Communities-New South Wales (EPIC-NSW) was a pragmatic, prospective, single-arm, implementation study of daily, oral PrEP in 31 sites (sexual health clinics, general practices, and a hospital) in NSW, Australia. Eligible participants were HIV-negative adults (aged ≥18 years) who were at high risk of HIV infection as defined in local PrEP guidelines. Participants were prescribed coformulated (once-daily, oral tablet) tenofovir disoproxil fumarate (300 mg) and emtricitabine (200 mg) as HIV PrEP and were followed up with HIV testing, sexually transmitted infection testing, and PrEP dispensing. Originally planned for 3700 participants followed for 1 year, the study was expanded so that all eligible participants in the state could obtain PrEP and extended until publicly subsidised PrEP became available in Australia. The primary outcome was new HIV infection among all participants who were dispensed PrEP at least once and had at least one follow-up HIV test result. Adherence was estimated by medication possession ratio (MPR), defined as the proportion of PrEP pills dispensed in 90 days, assuming daily dosing. This study is registered with ClinicalTrials.gov, NCT02870790.

Findings: Between March 1, 2016, and April 30, 2018, we enrolled 9709 participants. 9596 participants were dispensed PrEP, of whom 9448 (98·3%) were gay or bisexual men. Participants were followed up until March 31, 2019, with at least one follow-up HIV test available in 9520 (99·2%) participants. Mean MPR declined from 0·93 to 0·64 from the first to the ninth quarter. There were 30 HIV seroconversions over 18 628 person-years, an incidence of 1·61 per 1000 person-years (95% CI 1·13-2·30). Being younger, living in a postcode with fewer gay men, reporting more risk behaviours at baseline, and having an MPR of less than 0·6 were each univariately associated with increased HIV incidence. In the final year of follow-up, when PrEP was mostly purchased rather than provided free by the study, HIV incidence remained low at 2·24 per 1000 person-years (1·46-3·44).

Interpretation: HIV incidence remained low over up to 3 years of follow-up, including during a transition from study-provided to publicly subsidised PrEP. In a setting of affordable PrEP and associated health-care services, very low HIV incidence of 1 to 2 per 1000 person-years can be maintained in gay and bisexual men who were previously at high risk.

Funding: New South Wales Ministry of Health, Australian Capital Territory Health Directorate, Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(21)00074-6DOI Listing
August 2021

The mA landscape of polyadenylated nuclear (PAN) RNA and its related methylome in the context of KSHV replication.

RNA 2021 09 29;27(9):1102-1125. Epub 2021 Jun 29.

Department of Biological Sciences, Auburn University, Auburn, Alabama 36849, USA.

Polyadenylated nuclear (PAN) RNA is a long noncoding transcript involved in Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation and regulation of cellular and viral gene expression. We have previously shown that PAN RNA has dynamic secondary structure and protein binding profiles that can be influenced by epitranscriptomic modifications. -methyladenosine (mA) is one of the most abundant chemical signatures found in viral RNA genomes and virus-encoded RNAs. Here, we combined antibody-independent next-generation mapping with direct RNA sequencing to address the epitranscriptomic status of PAN RNA in KSHV infected cells. We showed that PAN mA status is dynamic, reaching the highest number of modifications at the late lytic stages of KSHV infection. Using a newly developed method, termed elenium-modified deoxythymidine triphosphate (SedTTP)-reverse transcription (RT) and igation ssisted CR analysis of mA (SLAP), we gained insight into the fraction of modification at identified sites. By applying comprehensive proteomic approaches, we identified writers and erasers that regulate the mA status of PAN, and readers that can convey PAN mA phenotypic effects. We verified the temporal and spatial subcellular availability of the methylome components for PAN modification by performing confocal microscopy analysis. Additionally, the RNA biochemical probing (SHAPE-MaP) outlined local and global structural alterations invoked by mA in the context of full-length PAN RNA. This work represents the first comprehensive overview of the dynamic interplay that takes place between the cellular epitranscriptomic machinery and a specific viral RNA in the context of KSHV infected cells.
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http://dx.doi.org/10.1261/rna.078777.121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8370742PMC
September 2021

Sex differences and shifts in body composition, physical activity, and total energy expenditure across a 3-month expedition.

Am J Hum Biol 2021 Jun 28:e23634. Epub 2021 Jun 28.

Department of Anthropology, University of Notre Dame, Notre Dame, Indiana, USA.

Objectives: An energetically demanding environment like a wilderness expedition can lead to potent stressors on human physiology and homeostatic balance causing shifts in energy expenditure and body composition. These shifts likely have consequences on overall health and performance and may potentially differ by sex. It is therefore critical to understand the potential differential body composition and energy expenditure changes in response to a novel and challenging environment in both males and female bodies.

Methods: Data were collected from 75 healthy individuals (female = 41; ages 18-53) throughout a 3-month long expedition in the American Rockies. Body mass, body fat, and lean muscle mass were measured before, during, and after the course. Physical activity intensity and energy expenditure were also measured in a subset of participants using the wGT3X-BT Actigraph wrist monitor and an accompanying Bluetooth heart rate monitor.

Results: Over the 3-month period, individuals initially experienced declines in body mass, body fat percentage, and lean muscle mass. Participants partially rebounded from these deficits to maintain overall body mass with a slight recomposition of body fat and lean muscle mass. Our data also demonstrated that sex moderated total energy expenditure, where females experienced a modest decline whereas males experienced an increase in energy expenditure from the beginning to the end of the course.

Conclusions: Understanding changes in energy storage in the body and variation in energy expenditure between sexes during a 3-month expedition has critical implications for maintaining health and performance in an energetically demanding environment where resources may be scarce.
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http://dx.doi.org/10.1002/ajhb.23634DOI Listing
June 2021

Predictors for COVID-19-related new-onset maladaptive behaviours in children presenting to a paediatric emergency department.

J Paediatr Child Health 2021 Oct 27;57(10):1634-1639. Epub 2021 May 27.

Children's Hospital of Orange County, Orange, California, USA.

Background And Objective: The goal of the present study was to determine the incidence of new onset maladaptive behaviours in paediatric emergency department (PED) patients during the COVID-19 pandemic and to examine whether child and parent anxiety and parental health status were predictors for the new-onset of maladaptive behaviours.

Methods: Participants included child-parent dyads seen in a PED following the state's issuance of mandatory stay-at-home orders on 19 March 2020. A total of 351 children age 0-25 years and 335 parents enrolled in the study. Parents provided baseline demographic data and completed standardised surveys that assessed aspects of parental and child anxiety and parental health, as well as child new-onset maladaptive behaviours. Children ≥8 years of age completed surveys that assessed child anxiety.

Findings: Parents reported the new onset of maladaptive behaviours in children during the pandemic with frequencies up to 43%. Bivariate analysis identified predictors such as child anxiety (t(96) = -2.04, P = 0.044) as well as parental variables such as state anxiety (t(190) = -4.91, P < 0.001) and parental sensitivity to anxiety (t(243) = -3.19, P = 0.002). A logistic regression model identified parent mental health and COVID-19 anxiety as predictors of new onset maladaptive behaviours in children (X (6) = 42.514, P < 0.001). Specifically, every unit change in parental anxiety of COVID-19 was associated with a unit increase in maladaptive behaviours in children.

Conclusions: We identified distinct parent and child-related factors that predicted new onset child maladaptive behaviours during the COVID-19 pandemic. The identification of such predictors may help clinicians to prevent maladaptive responses to the pandemic quarantine.
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http://dx.doi.org/10.1111/jpc.15579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242733PMC
October 2021

PrEP your team! Clinician initiation of HIV pre-exposure prophylaxis discussion at sexually transmissible infection testing and diagnosis in gay and bisexual men.

Int J STD AIDS 2021 May 12:9564624211014406. Epub 2021 May 12.

Canberra Sexual Health Centre, 34381Canberra Hospital, Canberra, Australia.

HIV pre-exposure prophylaxis (PrEP) is recommended for gay and bisexual men (GBM) with recent diagnosis of rectal chlamydia (CT), rectal gonorrhoea (NG) or infectious syphilis. A retrospective medical record audit was undertaken at Canberra Sexual Health Centre (CSHC) of all GBM who met this criterion in 2019 and were thus determined to be at higher risk of acquisition of human immunodeficiency virus (HIV). Pre-exposure prophylaxis was discussed and/or commenced in 85% of GBM at higher risk of HIV. Audit results and education were provided to the team with a post-interventional audit in 2020 showing significant improvement. This audit is easily replicated and may be applicable to other settings engaged in GBM care.
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http://dx.doi.org/10.1177/09564624211014406DOI Listing
May 2021

Knowledge, attitudes, and perceptions of Kenyan healthcare workers regarding pediatric discharge from hospital.

PLoS One 2021 23;16(4):e0249569. Epub 2021 Apr 23.

Department of Global Health, University of Washington School of Public Health, Seattle, Washington, United States of America.

Objective: To assess attitudes, perceptions, and practices of healthcare workers regarding hospital discharge and follow-up care for children under age five in Migori and Homa Bay, Kenya.

Methods: This mixed-methods study included surveys and semi-structured telephone interviews with healthcare workers delivering inpatient pediatric care at eight hospitals between November 2017 and December 2018.

Results: The survey was completed by 111 (85%) eligible HCWs. Ninety-seven of the surveyed HCWs were invited for interviews and 39 (40%) participated. Discharge tasks were reported to be "very important" to patient outcomes by over 80% of respondents, but only 37 (33%) perceived their hospital to deliver this care "very well" and 23 (21%) believed their facility provides sufficient resources for its provision. The vast majority (97%) of participants underestimated the risk of pediatric post-discharge mortality. Inadequate training, understaffing, stock-outs of take-home therapeutics, and user fees were commonly reported health systems barriers to adequate discharge care while poverty was seen as limiting caregiver adherence to discharge and follow-up care. Respondents endorsed the importance of follow-up care, but reported supportive mechanisms to be lacking. They requested enhanced guidelines on discharge and follow-up care.

Conclusion: Kenyan healthcare workers substantially underestimated the risk of pediatric post-discharge mortality. Pre- and in-service training should incorporate instruction on discharge and follow-up care. Improved post-discharge deaths tracking-e.g., through vital registry systems, child mortality surveillance studies, and community health worker feedback loops-is needed, alongside dissemination which could leverage platforms such as routine hospital-based mortality reports. Finally, further interventional trials are needed to assess the efficacy and cost-effectiveness of novel packages to improve discharge and follow-up care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249569PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064546PMC
September 2021

The emerging relationship between metabolism and DNA repair.

Cell Cycle 2021 May 20;20(10):943-959. Epub 2021 Apr 20.

Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.

The DNA damage response (DDR) consists of multiple specialized pathways that recognize different insults sustained by DNA and repairs them where possible to avoid the accumulation of mutations. While loss of activity of genes in the DDR has been extensively associated with cancer predisposition and progression, in recent years it has become evident that there is a relationship between the DDR and cellular metabolism. The activity of the metabolic pathways can influence the DDR by regulating the availability of substrates required for the repair process and the function of its players. Additionally, proteins of the DDR can regulate the metabolic flux through the major pathways such as glycolysis, tricarboxylic acid cycle (TCA) and pentose phosphate pathway (PPP) and the production of reactive oxygen species (ROS). This newly discovered connection bears great importance in the biology of cancer and represents a new therapeutic opportunity. Here we describe the nature of the relationship between DDR and metabolism and its potential application in the treatment of cancer. Keywords: DNA repair, metabolism, mitochondria.
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http://dx.doi.org/10.1080/15384101.2021.1912889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172156PMC
May 2021

Chloroxine overrides DNA damage tolerance to restore platinum sensitivity in high-grade serous ovarian cancer.

Cell Death Dis 2021 04 14;12(4):395. Epub 2021 Apr 14.

Centre for Cancer Cell and Molecular Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.

High-grade serous cancer (HGSC) accounts for ~67% of all ovarian cancer deaths. Although initially sensitive to platinum chemotherapy, resistance is inevitable and there is an unmet clinical need for novel therapies that can circumvent this event. We performed a drug screen with 1177 FDA-approved drugs and identified the hydroxyquinoline drug, chloroxine. In extensive validation experiments, chloroxine restored sensitivity to both cisplatin and carboplatin, demonstrating broad synergy in our range of experimental models of platinum-resistant HGSC. Synergy was independent of chloroxine's predicted ionophore activity and did not relate to platinum uptake as measured by atomic absorption spectroscopy. Further mechanistic investigation revealed that chloroxine overrides DNA damage tolerance in platinum-resistant HGSC. Co-treatment with carboplatin and chloroxine (but not either drug alone) caused an increase in γH2AX expression, followed by a reduction in platinum-induced RAD51 foci. Moreover, this unrepaired DNA damage was associated with p53 stabilisation, cell cycle re-entry and triggering of caspase 3/7-mediated cell death. Finally, in our platinum-resistant, intraperitoneal in vivo model, treatment with carboplatin alone resulted in a transient tumour response followed by tumour regrowth. In contrast, treatment with chloroxine and carboplatin combined, was able to maintain tumour volume at baseline for over 4 months. In conclusion, our novel results show that chloroxine facilitates platinum-induced DNA damage to restore platinum sensitivity in HGSC. Since chloroxine is already licensed, this exciting combination therapy could now be rapidly translated for patient benefit.
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http://dx.doi.org/10.1038/s41419-021-03665-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047034PMC
April 2021

The Role of Social Media in Providing Support from Friends for Adolescent and Young Adult (AYA) Patients and Survivors of Sarcoma: Perspectives of AYA, Parents, and Providers.

J Adolesc Young Adult Oncol 2021 Apr 12. Epub 2021 Apr 12.

Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.

The aims of the current study were to better understand, from the perspective of adolescents and young adults (AYAs) with sarcoma, parents, and providers, the friendship support needs of AYAs with bone and soft tissue sarcoma and the role of social media in facilitating social support for AYAs with sarcoma. Semistructured interviews were conducted with 21 participants. AYA ( = 10) ranged in age from 14 to 23 years (mean 19.3, standard deviation 3.4 years; 50% female). All AYAs reported a current or past diagnosis of sarcoma, except for one patient who had another cancer diagnosis but was receiving treatment through the sarcoma clinic. Five parents of the adolescent participants were interviewed, as well as six health care providers. Data analysis was conducted using theory-driven immersion/crystallization, incorporating the Resilience in Illness Model as a framework to guide interpretation of the data. Four main themes associated with social support from friends and social media were identified: (1) Social media provides a way to feel normal and connected to friends; (2) Social media accentuates the frustration of being left behind; (3) Social media facilitates the need to be understood by peers who have experienced sarcoma, and (4) Social media can lead to despair, and also provide hope for the future. Connecting with peers through social media can play an important role in providing support for AYAs with sarcoma, but it may also amplify feelings of frustration and anxiety. Future work is needed to determine intervention components that can maximize the benefits of social media for social support of AYAs with sarcoma. Clinical Trial Registration number: NCT03130751.
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http://dx.doi.org/10.1089/jayao.2020.0200DOI Listing
April 2021

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

J Med Chem 2021 04 30;64(8):5018-5036. Epub 2021 Mar 30.

CHDI Management/CHDI Foundation, 6080 Center Drive, Los Angeles, California 90045, United States.

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., ) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00114DOI Listing
April 2021

Napping on the night shift and its impact on blood pressure and heart rate variability among emergency medical services workers: study protocol for a randomized crossover trial.

Trials 2021 Mar 16;22(1):212. Epub 2021 Mar 16.

Department of Emergency Medicine, University of Pittsburgh, School of Medicine, 3600 Forbes Ave., Iroquois Building, Suite 400A, Pittsburgh, PA, 15261, USA.

Background: There is an emerging body of evidence that links exposure to shift work to cardiovascular disease (CVD). The risk of coronary events, such as myocardial infarction, is greater among night shift workers compared to day workers. There is reason to believe that repeated exposure to shift work, especially night shift work, creates alterations in normal circadian patterns of blood pressure (BP) and heart rate variability (HRV) and that these alterations contribute to increased risk of CVD. Recent data suggest that allowing shift workers to nap during night shifts may help to normalize BP and HRV patterns and, over time, reduce the risk of CVD. The risk of CVD related to shift work is elevated for emergency medical services (EMS) shift workers due in part to long-duration shifts, frequent use of night shifts, and a high prevalence of multiple jobs.

Methods: We will use a randomized crossover trial study design with three study conditions. The targeted population is comprised of EMS clinician shift workers, and our goal enrollment is 35 total participants with an estimated 10 of the 35 enrolled not completing the study protocol or classified as lost to attrition. All three conditions will involve continuous monitoring over 72 h and will begin with a 36-h at-home period, followed by 24 total hours in the lab (including a 12-h simulated night shift), ending with 12 h at home. The key difference between the three conditions is the intra-shift nap. Condition 1 will involve a simulated 12-h night shift with total sleep deprivation. Condition 2 will involve a simulated 12-h night shift and a 30-min nap opportunity. Condition 3 will involve a simulated 12-h night shift with a 2-h nap opportunity. Our primary outcomes of interest include blunted BP dipping and reduced HRV as measured by the standard deviation of the inter-beat intervals of normal sinus beats. Non-dipping status will be defined as sleep hours BP dip of less than 10%.

Discussion: Our study will address two indicators of cardiovascular health and determine if shorter or longer duration naps during night shifts have a clinically meaningful impact.

Trial Registration: ClinicalTrials.gov NCT04469803 . Registered on 9 July 2020.
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http://dx.doi.org/10.1186/s13063-021-05161-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962082PMC
March 2021

Colon Cancer Screening Could Save Your Life.

Authors:
Sarah A Martin

J Pediatr Health Care 2021 Mar-Apr;35(2):141-142

Pediatric Nurse Practitioner, Division of Pediatric Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL. Electronic address:

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http://dx.doi.org/10.1016/j.pedhc.2020.11.005DOI Listing
October 2021

Caspase Signaling in ED Patients and Animal Models.

J Sex Med 2021 04 9;18(4):711-722. Epub 2021 Mar 9.

Departments of Urology, Physiology, Bioengineering, and Biochemistry, University of Illinois at Chicago, Chicago, IL, USA. Electronic address:

Background: Current treatments for erectile dysfunction (ED) are ineffective in prostatectomy and diabetic patients due to cavernous nerve (CN) injury, which causes smooth muscle apoptosis, penile remodeling, and ED. Apoptosis can occur via the intrinsic (caspase 9) or extrinsic (caspase 8) pathway.

Aim: We examined the mechanism of how apoptosis occurs in ED patients and CN injury rat models to determine points of intervention for therapy development.

Methods And Outcomes: Immunohistochemical and western analyses for caspase 3-cleaved, caspase-8 and caspase-9 (pro and active forms) were performed in corpora cavernosal tissue from Peyronie's, prostatectomy and diabetic ED patients (n = 33), penis from adult Sprague Dawley rats that underwent CN crush (n = 24), BB/WOR diabetic and control rats (n = 8), and aged rats (n = 9).

Results: Caspase 3-cleaved was observed in corpora cavernosa from Peyronie's patients and at higher abundance in prostatectomy and diabetic tissues. Apoptosis takes place primarily through the extrinsic (caspase 8) pathway in penis tissue of ED patients. In the CN crushed rat, caspase 3-cleaved was abundant from 1-9 days after injury, and apoptosis takes place primarily via the intrinsic (caspase 9) pathway. Caspase 9 was first observed and most abundant in a layer under the tunica, and after several days was observed in the lining of and between the sinuses of the corpora cavernosa. Caspase 8 was initially observed at low abundance in the rat corpora cavernosa and was not observed at later time points after CN injury. Aged and diabetic rat penis primarily exhibited intrinsic mechanisms, with diabetic rats also exhibiting mild extrinsic activation.

Clinical Translation: Knowing how and when to intervene to prevent the apoptotic response most effectively is critical for the development of drugs to prevent ED, morphological remodeling of the corpora cavernosa, and thus, disease management.

Strengths And Limitations: Animal models may diverge from the signaling mechanisms observed in ED patients. While the rat utilizes primarily caspase 9, there is a significant flux through caspase 8 early on, making it a reasonable model, as long as the timing of apoptosis is considered after CN injury.

Conclusions: Apoptosis takes place primarily through the extrinsic caspase 8 dependent pathway in ED patients and via the intrinsic caspase 9 dependent pathway in commonly used CN crush ED models. This is an important consideration for study design and interpretation that must be taken into account for therapy development and testing of drugs, and our therapeutic targets should ideally inhibit both apoptotic mechanisms. Martin S, Harrington DA, Ohlander S, et al. Caspase Signaling in ED Patients and Animal Models. J Sex Med 2021;18:711-722.
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http://dx.doi.org/10.1016/j.jsxm.2021.01.175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068676PMC
April 2021

Drug-repositioning screening identified fludarabine and risedronic acid as potential therapeutic compounds for malignant pleural mesothelioma.

Invest New Drugs 2021 06 9;39(3):644-657. Epub 2020 Dec 9.

Department of Biology, Genetic Unit, University of Pisa, 56126, Pisa, Italy.

Objectives Malignant pleural mesothelioma (MPM) is an occupational disease mainly due to asbestos exposure. Effective therapies for MPM are lacking, making this tumour type a fatal disease. Materials and Methods In order to meet this need and in view of a future "drug repositioning" approach, here we screened five MPM (Mero-14, Mero-25, IST-Mes2, NCI-H28 and MSTO-211H) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model, with a library of 1170 FDA-approved drugs. Results Among several potential compounds, we found that fludarabine (F-araA) and, to a lesser extent, risedronic acid (RIS) were cytotoxic in MPM cells, in comparison to the non-malignant Met-5A cells. In particular, F-araA reduced the proliferation and the colony formation ability of the MPM malignant cells, in comparison to the non-malignant control cells, as demonstrated by proliferation and colony formation assays, in addition to measurement of the phospho-ERK/total-ERK ratio. We have shown that the response to F-araA was not dependent upon the expression of DCK and NT5E enzymes, nor upon their functional polymorphisms (rs11544786 and rs2295890, respectively). Conclusion This drug repositioning screening approach has identified that F-araA could be therapeutically active against MPM cells, in addition to other tumour types, by inhibiting STAT1 expression and nucleic acids synthesis. Further experiments are required to fully investigate this.
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http://dx.doi.org/10.1007/s10637-020-01040-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8068714PMC
June 2021

Building Nurses' Resilience to Trauma Through Contemplative Practices.

Creat Nurs 2020 Nov;26(4):e90-e96

Nurses can benefit from strategies that build resilience to counterbalance trauma exposures. Adverse childhood experiences (ACEs) and adverse community environments are common; nurses frequently encounter trauma victims and hear trauma narratives in most care settings. Having skills to manage the triggers present in health-care environments is essential. Contemplative practices can help to meet these needs. Breathing exercises can be used as needed throughout the work day; gratitude practices are simple but powerful; and visual journaling can help nurses process experiences. These practices are easy to implement and can profoundly affect health outcomes for nurses.
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http://dx.doi.org/10.1891/CRNR-D-20-00054DOI Listing
November 2020

Resilience Education for Health-Care Professionals.

Creat Nurs 2020 Nov;26(4):225-231

Background: Burnout among health-care professionals is a growing problem having a sizeable impact on patient safety and health care as a whole. High levels of resilience in health-care professionals have been associated with safer care environments, improved health outcomes, higher quality care, and improved caregiver well-being and mental health. Resilience education can improve personal and professional resilience.

Objective: The goal of this project was to evaluate a resilience education program to improve measures of burnout and resilience in health-care professionals.

Design: A quantitative cross-sectional pretest/posttest design was used.

Setting: The resilience education program was implemented in a large, not-for-profit health-care system in the southeastern United States.

Methods: Participants completed the Copenhagen Burnout Inventory (CBI) and The Connor-Davidson Resilience Scale-25 (CD-RISC-25) immediately before the workshop and 2 weeks afterward. Participants also completed an evaluation survey one day after the education.

Results: Scores on the CD-RISC-25 showed statistically significant increases in resilience qualities after the education. Although not statistically significant, burnout as measure by CBI scores decreased following the workshop.

Conclusion: A relatively short educational program can positively impact resilience and burnout levels in health-care professionals. Positive outcomes included successful learning outcomes and increased resilience qualities.
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http://dx.doi.org/10.1891/CRNR-D-19-00077DOI Listing
November 2020

Pre-exposure Prophylaxis for HIV-An Opportunity for the Global Control of Sexually Transmitted Infections.

J Acquir Immune Defic Syndr 2021 04;86(4):e116-e117

Monash University, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1097/QAI.0000000000002582DOI Listing
April 2021

Evaluation of the Bidirectional Relations of Perceived Physical Fatigability and Physical Activity on Slower Gait Speed.

J Gerontol A Biol Sci Med Sci 2021 Sep;76(10):e237-e244

Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania.

Background: Lower physical activity levels and greater fatigability contribute independently to slower gait speed in older adults. To fully understand the bidirectional relations between physical activity and fatigability, and to inform potential intervention strategies, we examined whether physical activity or fatigability explains more of the other factor's association on slower gait speed.

Methods: Two generations (probands and offspring) of older adults (N = 2079, mean age 73.0 ± 10.0 years, 54.2% women, 99.7% White) enrolled in the Long Life Family Study were assessed at Visit 2 (2014-2017). Self-reported physical activity was measured with the Framingham Physical Activity Index and perceived physical fatigability using the Pittsburgh Fatigability Scale. Statistical mediation analyses were conducted separately by generation with linear mixed-effect models accounting for family relatedness and adjusted for demographics, health conditions, and field center.

Results: Greater perceived physical fatigability explained the association of lower physical activity on slower gait speed via a 22.5% attenuation of the direct association (95% confidence interval [CI]: 15.0%-35.2%) for the probands and 39.5% (95% CI: 22.8%-62.6%) for the offspring. Whereas lower physical activity explained the association of greater perceived fatigability on slower gait speed via a 22.5% attenuation of the direct association (95% CI: 13.4%-32.8%) for the probands and 6.7% (95% CI: 3.8%-15.4%) for the offspring.

Conclusions: Our findings suggest that the impact of greater perceived physical fatigability on the association between lower physical activity and slower gait speed differs between younger-old and middle-to-oldest-old adults, indicating perceived physical fatigability as a potential mediator in the disablement pathway.
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http://dx.doi.org/10.1093/gerona/glaa281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436994PMC
September 2021

Characteristics and Impacts of Sexual Violence Against Men and Boys in Conflict and Displacement: A Multicountry Exploratory Study.

J Interpers Violence 2020 Oct 29:886260520967132. Epub 2020 Oct 29.

The University of New South Wales, Sydney, NSW, Australia.

Evidence of sexual violence against men and boys in many conflict-affected settings is increasingly recognized. Yet relatively little is currently known about the varied forms, sites, and impacts of this violence. Further, scant research on sexual violence against men and boys in displacement contexts has been undertaken to date. To begin to address these knowledge gaps, we undertook a multicountry, qualitative, exploratory study to gain insights into these issues. Study settings and populations were Rohingya refugees in Bangladesh; refugees and migrants who had traveled through Libya residing in Italy; and refugees from eastern Democratic Republic of the Congo (DRC), Somalia, and South Sudan residing in Nairobi and Mombasa, Kenya. Methods included 55 semi-structured focus group discussions with 310 refugees and semi-structured key informant interviews with 148 aid workers and human rights experts. Data were thematically analyzed using NVivo 12. Findings suggest that sexual violence against men and boys may not be rare in Myanmar (northern Rakhine state), Libya, eastern DRC, and South Sudan. Frequently reported forms of violence in these settings were genital violence, forced witnessing of sexual violence, and rape. Sites where violence was often reported included border crossings, along the roadside, and during imprisonment. In host countries, forms of sexual violence included sexual abuse of boys, sexual exploitation particularly of adolescents and persons with diverse sexual orientation and gender identity, and rape. Impacts on survivors involved short- and long-term physical, mental, economic, and familial dimensions. These findings aim to inform sexual violence-related prevention, mitigation, and response efforts in humanitarian settings. More research is warranted, including on sexual violence against men and boys in Somalia, sexual violence by family and community members in conflict and displacement settings, sexual exploitation of adolescent boys, and sexual violence including sexual exploitation of persons with diverse sexual orientation and gender identity.
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October 2020

Endocannabinoids Inhibit the Induction of Virulence in Enteric Pathogens.

Cell 2020 10 7;183(3):650-665.e15. Epub 2020 Oct 7.

Department of Microbiology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Endocannabinoids are host-derived lipid hormones that fundamentally impact gastrointestinal (GI) biology. The use of cannabis and other exocannabinoids as anecdotal treatments for various GI disorders inspired the search for mechanisms by which these compounds mediate their effects, which led to the discovery of the mammalian endocannabinoid system. Dysregulated endocannabinoid signaling was linked to inflammation and the gut microbiota. However, the effects of endocannabinoids on host susceptibility to infection has not been explored. Here, we show that mice with elevated levels of the endocannabinoid 2-arachidonoyl glycerol (2-AG) are protected from enteric infection by Enterobacteriaceae pathogens. 2-AG directly modulates pathogen function by inhibiting virulence programs essential for successful infection. Furthermore, 2-AG antagonizes the bacterial receptor QseC, a histidine kinase encoded within the core Enterobacteriaceae genome that promotes the activation of pathogen-associated type three secretion systems. Taken together, our findings establish that endocannabinoids are directly sensed by bacteria and can modulate bacterial function.
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http://dx.doi.org/10.1016/j.cell.2020.09.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606741PMC
October 2020

Peripheral nerve regeneration following injury is altered in mice lacking P2X7 receptor.

Eur J Neurosci 2021 09 22;54(5):5798-5814. Epub 2020 Oct 22.

Blond McIndoe Laboratories, Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.

Peripheral nerve injuries are debilitating, and current clinical management is limited to surgical intervention, which often leads to poor functional outcomes. Development of pharmacological interventions aimed at enhancing regeneration may improve this. One potential pharmacological target is the P2X purinergic receptor 7 (P2X7R) expressed in Schwann cells, which is known to play a role during the development of the peripheral nerves. Herein, we analysed differences in regeneration between genetically engineered P2X7 knockout mice and wild-type controls, using in vivo and ex vivo models of peripheral nerve regeneration. We have found that the speed of axonal regeneration is unaltered in P2X7 knockout mice, nevertheless regenerated P2X7 knockout nerves are morphologically different to wild-type nerves following transection and immediate repair. Indeed, the detailed morphometric analysis at 4 and 8 weeks after injury showed evidence of delayed remyelination in P2X7 knockout mice, compared to the wild-type controls. Furthermore, the Wallerian degeneration phase was unaltered between the two experimental groups. We also analysed gene expression changes in the dorsal root ganglia neurones as a result of the peripheral nerve injury, and found changes in pathways related to pain, inflammation and cell death. We conclude that P2X7 receptors in Schwann cells may be a putative pharmacological target to control cell fate following injury, thus enhancing nerve re-myelination.
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http://dx.doi.org/10.1111/ejn.14995DOI Listing
September 2021

Distilling the Key Elements of Pediatric Appendicitis Clinical Practice Guidelines.

J Surg Res 2021 02 30;258:105-112. Epub 2020 Sep 30.

Division of Pediatric Surgery, Department of Surgery, Northwestern University, Feinberg School of Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois.

Background: Use of clinical practice guidelines (CPGs) have been shown to reduce care delays, optimize resource utilization, and improve patient outcomes. We conducted a systematized review to identify key elements that should be included in an evidence-based CPG for pediatric appendicitis.

Methods: We characterized key decision points and content areas from CPGs developed from 2000 to 2019 that were identified using publicly available platforms and manual search/personal communications.

Results: Twenty-seven CPGs were reviewed with content saturation achieved after reviewing eight. We found 16 key elements spanning from triage to postoperative care. Elements with high accord among CPGs included use of laparoscopy and delay of postoperative imaging for abscess screening until postoperative day seven. For simple appendicitis, all CPGs endorsed antibiotic cessation, diet advancement, and early activity, and 11 CPGs included same-day discharge. Elements with heterogeneity in decision-making included antibiotic selection/duration for perforated appendicitis, criteria defining perforation, and utility of postoperative laboratory evaluations.

Conclusions: Development of an evidence-based CPGs for pediatric appendicitis requires attention to a finite number of key decision points and content areas. Existing literature demonstrates improved patient outcomes with CPG implementation.
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http://dx.doi.org/10.1016/j.jss.2020.08.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736270PMC
February 2021
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