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Follow‐up | acute respiratory illness, ARI | Following antiviral receipt, influenza‐positive participants were asked to return to the kiosk for symptom surveys and nasal swab collection 2–3 and 5–7 days after diagnosis (Figure (A) Study design overview including participant‐level study flow of the test‐and‐treat strategy from 11/15/19 to 4/30/21. (B) Total number of participants completing intervention study procedure steps based on eligibility screening. ARI, acute respiratory illness; RT‐PCT, reverse transcription polymerase chain reaction | PMC9835442 |
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Impact of the COVID‐19 pandemic on study protocol | ARI | VIRUS, RECRUITMENT, APPENDIX, INFLUENZA | In response to SARS‐CoV‐2 community transmission in WA, study Year 1's intervention was paused on 4/1/2020. Study Year 2 recommenced on 11/2/20 but was terminated early on 4/1/2021 due to operational futility based on minimal influenza activity in King County, WA. During the second year of the study, 5 of the 9 shelters relocated their residents to new facilities to enable improved adherence to SARS‐CoV‐2 transmission mitigation measures (Table Concurrent study recruitment of shelter residents that did not fit ARI criteria to improve SARS‐CoV‐2 surveillance sensitivity was initiated on 4/1/2020. For protocol details and data on non‐ARI influenza virus detection, see Appendix | PMC9835442 |
UW laboratory testing | INFLUENZA A, INFLUENZA | For samples that were sent to the laboratory, total nucleic acids were extracted using the Magna Pure 96 kit (Roche) and tested by TaqMan OpenArray RT‐PCR (Thermo) for multiple viral pathogens, including influenza A (H3 and H1 hemagglutinin subtypes) and influenza B. OpenArray relative threshold (CRT) values were used to determine the viral load of each sample; CRT values are inversely related to the viral load. Viral genome sequencing by hybrid capture was attempted on all influenza‐positive samples with viral loads > ~50,000 genomic copies/ml using a protocol described previously. | PMC9835442 |
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Outcomes and statistical analyses | INFLUENZA | All data in this analysis are presented by participant encounter, defined as each time an eligible individual provided a nasal swab and completed a survey with study staff. We used descriptive statistics to evaluate the sociodemographic and clinical characteristics at baseline in control and intervention periods for study Years 1 and 2; these characteristics were also described by lab‐confirmed influenza result. Descriptive and statistical analyses were performed using R Statistical Software (Version 4.0.3, Foundation for Statistical Computing, Vienna, Austria). | PMC9835442 |
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Primary objective: Effects on reducing secondary spread of influenza virus | cough, ILI, sore throat, fever | SORE THROAT, VIRUS, VIRUS INFECTION, INFLUENZA | The primary endpoint was monthly number of influenza‐positive samples in the control versus intervention periods among ARI‐participant encounters. The predictor of interest was test‐and‐treat at the shelter/cluster‐month level (i.e., intervention vs. control periods). Shelters were analyzed with an intent‐to‐treat (ITT) analysis to preserve the advantages of randomization. Relative risk of influenza virus infection during the intervention period compared with the control period was calculated using a generalized linear mixed model (GLMM) following a Poisson distribution with a log link. The model was adjusted for calendar time with an offset of shelter maximum capacity and random effect for shelter and time. Due to low influenza virus circulation in Year 2, the primary outcome analysis for this study was calculated based on data collected only from Year 1. Influenza‐like illness (ILI) was defined as fever and cough, or fever and sore throat. | PMC9835442 |
Secondary objective A: Assess feasibility of test‐and‐treat strategy for influenza in shelters | INFLUENZA | Feasibility of implementation of point‐of‐care influenza molecular testing was measured as the time between symptom onset until diagnosis through rapid test or laboratory test. Feasibility of implementation of antiviral treatment was measured as the time between symptom onset until initiation of antiviral treatment. Additional endpoints used to characterize feasibility were proportion of participants lost‐to‐follow‐up (LTFU) and proportion of participants non‐compliant with oseltamivir therapy (self‐reported measure collected during on‐site follow‐up visits with kiosk staff). | PMC9835442 |
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Secondary objective B: Characterize influenza transmission | INFLUENZA | To better understand the relationship among the influenza cases detected by this study and between these cases and cases with a viral genomic sequence publicly available in the GISAID database, we attempted sequencing on all influenza‐positive samples from Year 1 with viral loads > ~50,000 genomic copies/ml. We were able to generate influenza genome sequences for 23 of these samples (7 influenza A(H1N1)pdm09 and 16 influenza B/Victoria) (Table | PMC9835442 |
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RESULTS | PMC9835442 |
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Study population and demographics | respiratory illness, ARI | INFLUENZA | Overall, we observed 1283 ARI encounters (1159 from Year 1 and 124 from Year 2) from 668 unique participants who met eligibility criteria. Of these, 514 and 769 encounters occurred during the control and intervention periods, respectively. The median age of participants was 45 years (interquartile range [IQR]: 24), and 8.3% were children (Table Baseline sociodemographic and health characteristics of ARI‐participant encounters, overall and by study period, 2019–2020 and 2020–2021 influenza seasons
Abbreviations: ARI, acute respiratory illness; IQR, interquartile range.Not mutually exclusive. | PMC9835442 |
Clinical characteristics of ARI encounters | sore throat, Chronic obstructive pulmonary disorder, fever, rhinorrhea, respiratory illness, ARI, emphysema, cough, asthma, Fever | SORE THROAT, REACTIVE AIRWAY DISEASE, EMPHYSEMA, ASTHMA, INFLUENZA | The most common symptoms reported were rhinorrhea (76.9%) and cough (72.3%) (Table Baseline sociodemographic and clinical characteristics of ARI‐participant encounters, by laboratory multiplex assay‐confirmed influenza result and rapid influenza molecular test result, 2019–2020 and 2020–2021 influenza seasonsAbbreviations: ARI, acute respiratory illness; IQR, interquartile range; NA, not applicable.Chronic obstructive pulmonary disorder, emphysema, asthma, or reactive airway disease.Fever and cough or fever and sore throat.Only eligible trigger symptoms for participants < 18 years.Not applicable to participants who had a rapid test conducted as prior antiviral treatment was an exclusion criterion for receipt of the intervention. | PMC9835442 |
Influenza detection and intervention effect on reducing secondary spread of influenza virus | respiratory illness, infection, ARI, infections | VIRUS INFECTION, INFECTIONS, INFECTION, INFLUENZA A, INFLUENZA | Among all ARI‐participant encounters, 51 (4.0%) influenza virus infections (A = 15; B = 37) were identified through RT‐PCR. Of the influenza A subtypes, A(H1N1)pdm09 predominated (93.3%). Most infections were identified among participants 18–59 years (54.9%; Table Among the 269 ARI encounters that were eligible for the intervention, 21 (7.8%; Table Overall, more infections were identified during intervention periods (n = 32) compared with control periods (n = 19). Restricting analysis to Year 1 of the study, the relative risk of infection during the intervention periods compared with control periods, adjusted for calendar time, was 1.73 (95% confidence interval [CI] 0.50–6.00, p‐value = 0.386; Table Relative risk of infection during the intervention period compared with the control period using a generalized linear mixed model following a Poisson distribution with a log link and robust variance, adjusted for calendar time and an exposure time variable based on shelter capacity. This model includes ARI‐participant encounters from Year 1 of the study (11/15/2019–4/31/2020).
Abbreviations: ARI, acute respiratory illness; RT‐PCR, reverse transcription polymerase chain reaction.Persons at risk determined by static measure of maximum nightly shelter capacity. | PMC9835442 |
Feasibility of influenza test‐and‐treat strategy | infections | ADVERSE EVENTS, INFECTIONS | Of all ARI‐participant encounters, 37.4% reported symptom onset < 48 h (Table All 21 positives were treated with an antiviral, including 12 with oseltamivir and 9 with baloxavir; 38% of those treated were <5 years old. Of the 51 symptomatic infections identified through RT‐PCR, 64.7% had symptom onset < 48 h of specimen collection. Of the 32 symptomatic infections identified through RT‐PCR during intervention periods, 19 (59.4%) also were detected <48 h of symptom onset by the rapid molecular test and received immediate antiviral treatment. Of the 6 oseltamivir recipients with follow‐up data, 4 (66%) were fully treatment adherent with no missed doses. Of the 21 participants who received either antiviral, 14 (66.7%) returned for their first follow‐up study visit; only 1 (4.8%) returned for both study visits in the week following treatment. No severe adverse events were identified over the study period. | PMC9835442 |
Genomics | INFLUENZA A, INFLUENZA B, INFLUENZA | All seven full genome sequences generated for the influenza A‐positive samples from three different shelters were identified as A(H1N1)pdm09 viruses. We generated a maximum likelihood phylogenetic tree containing these seven samples along with all A(H1N1)pdm09 genomes deposited in GISAID that were collected in WA from 10/2019 to 3/2020 (N = 158) (Figure Maximum likelihood phylogenetic trees for (A) influenza A and (B) influenza B. Trees include all sequenced study samples and all genomes for samples collected in Washington (WA) during the study timeframe that have been deposited in GISAID.All 16 full genome sequences generated for the influenza B‐positive samples from five different shelters were identified as Victoria lineage viruses. A phylogenetic tree containing these samples along with all Victoria genomes deposited in WA GISAID collected from 10/2019 to 3/2020 (N = 189) was generated (Figure A total of 86% (6 of 7) of sequenced A(H1N1)pdm09 and 81% (13 of 16) of B/Victoria lineage viruses were most closely related to another sequence from the same shelter when analyzed with WA GISAID sequences. There were cases where inter‐shelter transmission was a possibility, most notably the close relationship between the influenza B shelter D sample and two shelter E samples (pairwise distance of two). The average pairwise distances between influenza A genomes and influenza B genomes from the same shelter were 2.0 and 7.0, respectively, versus average pairwise distances of 53.4 and 16.8 for genomes from different shelters.The NA and PA genic regions of the 23 shelter genomes were reviewed at the consensus level for known mutations associated with reduced susceptibility to oseltamivir or baloxavir, respectively, and no evidence of reduced antiviral susceptibility was identified. | PMC9835442 |
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DISCUSSION | illness, ARI, infections, infection, transiency | VIRUS, VIRUS INFECTION, SPECIFIC VIRAL INFECTIONS, INFECTIONS, INFECTION, SECONDARY, APPENDIX, INFLUENZA | This study assessed the feasibility and impact of an on‐site test‐and‐treat intervention for influenza among persons experiencing homelessness in a congregate setting. Although the study was limited by operational futility from a near absence of influenza virus circulation in WA in Year 2,Using on‐site surveillance, we observed a substantial proportion of overall ARI encounters (37.4%) within 48 h, a group that would be eligible to receive antiviral treatment if influenza‐positive. The COVID‐19 pandemic has also shown that rapid viral testing at shelters is feasible and effective when combined with mitigation measures; however, the impact of using antivirals for influenza treatment and chemoprophylaxis to reduce intra‐shelter transmission has not yet been explored.A majority of RT‐PCR influenza‐positive participants identified during intervention periods received antiviral treatment (59.4%), suggesting that immediate treatment is feasible. Use of single‐dose baloxavir treatment in this study was an advantage as it was compliance independent and has shown to be effective as both a prophylactic and means of reducing secondary influenza transmission in households.We found that less than half of symptomatic influenza virus infections met ILI criteria. This suggests that the ILI definition is less valuable as a diagnostic criterion than a means of surveilling community‐level influenza virus circulation and that viral diagnostic testing is needed to distinguish signs and symptoms caused by specific viral infections. Based on the World Health Organization (WHO) global influenza update from June 2022, countries are recommended to prepare for the co‐circulation of influenza and SARS‐CoV‐2 viruses and to enhance integrated surveillance to monitor influenza and SARS‐CoV‐2 simultaneously.In this study, rapid influenza molecular testing had high concordance with RT‐PCR results, supporting use in shelters (see Appendix We found that sequenced influenza viruses from the same shelter were frequently closely related, likely reflective of intra‐shelter transmission. However, there were two examples of genetic diversity among samples collected from a single shelter over a short time period, both from family shelters, raising the possibility of multiple influenza viral introductions.Individuals frequently sought clinical care for their ARI in this study, yet few were prescribed an antiviral prior to study enrollment. This may be due to lack of provider awareness regarding antiviral treatment, or delays in seeking clinical care outside of the shelter setting making outside the recommended 48‐h window for antiviral treatment since symptom onset.This study was subject to several limitations. First, the COVID‐19 pandemic and subsequent reduction of influenza virus circulation led to low study power and limited ability to assess the effect of the intervention. We therefore view these results as inconclusive rather than negative. Second, the use of shelter capacity to determine persons at risk in the GLMM calculation does not account for resident transiency and may have over‐estimated the population if shelters were not at maximum capacity during study Year 1. Third, selection biases may have occurred as the nature of the stepped‐wedge cluster‐randomized trial design does not allow for blinding of the intervention. Study participation may have been perceived as more desirable during intervention periods when immediate testing results and actionable intervention for illness episodes were made available. Fourth, our study design may have under‐estimated influenza virus transmission in shelters as we did not assess transmission from residents with asymptomatic infection or capture secondary asymptomatic infections. Finally, survey data were based on self‐report, which may be subjective particularly for variables such as symptoms experienced and illness duration. | PMC9835442 |
CONCLUSION | INFLUENZA EPIDEMIC, VIRUS INFECTION, INFLUENZA | Our findings establish the feasibility of an on‐site influenza test‐and‐treat strategy in shelters that has the potential to be applied during influenza epidemics and pandemics. Our genomic data suggest that intra‐shelter spread of influenza viruses is common and is responsible for a large proportion of symptomatic influenza virus infections in shelters. Possible distinct transmission dynamics within family and adult shelters suggests that interventions tailored to shelters serving children should be explored (e.g., on‐site antiviral treatment for symptomatic residents and chemoprophylaxis for exposed residents, baloxavir‐only treatment for children ≥ 5 years old, | PMC9835442 |
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CONFLICTS OF INTEREST | Dr. Chu reported consulting with Ellume, Pfizer, The Bill and Melinda Gates Foundation, GlaxoSmithKline, and Merck. She has received research funding from Sanofi Pasteur, and support and reagents from Ellume and Cepheid outside of the submitted work. Dr. Englund reported research support from Merck, AstraZeneca, Pfizer, and GlaxoSmithKline. She is a consultant for Meissa Vaccines, Sanofi Pasteur, and AstraZeneca. | PMC9835442 |
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AUTHOR CONTRIBUTIONS | PMC9835442 |
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ETHICS STATEMENT | The University of Washington Institutional Review Board approved this study. All participants provided informed consent and/or assent. | PMC9835442 |
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PEER REVIEW | The peer review history for this article is available at | PMC9835442 |
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Supporting information |
Click here for additional data file. | PMC9835442 |
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ACKNOWLEDGMENTS | FLU | We would like to acknowledge the homeless shelter staff, program managers, and all the participants who made this work possible. We would also like to acknowledge the Seattle Flu Study co‐investigators and the BAT‐Lab Pathogen Detection Lab Team for their contributions to this project. | PMC9835442 |
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DATA AVAILABILITY STATEMENT | Patient‐level data and statistical code are available upon request from the corresponding author at | PMC9835442 |
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REFERENCES | PMC9835442 |
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Objective | cranial suture, craniosynostosis | CRANIOSYNOSTOSIS | Analgesia is very important for children with craniosynostosis who are undergoing cranial suture reconstruction. This study investigated the effectiveness and safety of an analgesic technique based on scalp nerve block combined with general anesthesia versus general anesthesia alone. | PMC10391876 |
Methods | cranial suture, scalp nerve block, pain | This was a single-center, prospective, randomized, controlled study. A total of 60 children aged 6-24 months who underwent cranial suture reconstruction were randomly divided into two groups: Group A (general anesthesia combined with scalp nerve block) and Group N (general anesthesia). The hemodynamics were recorded preoperatively, at 5 min after incision and at 1, 6 and 12 h after surgery; the pain was scored at 1, 6 and 12 h after surgery, and blood glucose was detected at 1 h after surgery. | PMC10391876 |
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Results | The mean arterial pressure and heart rate at 5 min after incision and 1 h after surgery in Group N were higher than those in Group A; the blood glucose and FLACC score in Group N were higher than those in Group A; and the number of postoperative analgesic pump presses were also significantly increased in Group N. | PMC10391876 |
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Conclusion | cranial suture, postoperative pain, scalp nerve block | CRANIOSYNOSTOSIS | Preoperative scalp nerve block can reduce hemodynamic fluctuation and postoperative pain in children undergoing cranial suture reconstruction for craniosynostosis. Thus, it can be safely and effectively applied in the anesthesia of these children. | PMC10391876 |
Keywords | PMC10391876 |
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Background | cranial suture, Craniosynostosis | DISEASE, CRANIOSYNOSTOSIS | Craniosynostosis is a relatively uncommon disease in pediatric neurosurgery that affects skull and brain development due to premature closure of the cranial suture [ | PMC10391876 |
Methods | PMC10391876 |
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Patients | ST-T depression, scalp nerve block, cranial suture, infection, left atrial enlargement, hypersensitivity | CONGENITAL DISORDERS, INFECTION, LEFT VENTRICULAR HYPERTROPHY, BUNDLE BRANCH BLOCK, CRANIOSYNOSTOSIS, HYPERSENSITIVITY, NEUROLOGICAL DISORDERS | The study was performed between Oct 1, 2021, and Oct 1, 2022. Written informed consent was obtained from the parents or relatives of patients. A total of 60 children (ASA I or II, aged 6 months to 24 months) who were scheduled for elective cranial suture reconstruction in the Department of Neurosurgery in Shanghai Children's Hospital were enrolled in this study. Exclusion criteria were as follows: hypersensitivity to ropivacaine, neurological disorders (except for craniosynostosis), local infection at the predesigned puncture site, diagnosis with other congenital disorders, participation in other clinical studies within 4 weeks before surgery, and abnormal electrocardiograph (ECG; presence of 1 or more of following features: bundle branch block, conduction delay, signs of right or left ventricular hypertrophy or left atrial enlargement, prolonged QTC interval, or ST-T depression exceeding 0.5 mm and/or pathological Q waves). Patients were randomly allocated into two groups by using computer-generated random numbers: Group A (general anesthesia combined with scalp nerve block) and Group N (general anesthesia). This was a single-center study designed according to the CONSORT statement and approved by the Institution Review Board (Ethics Commission of Children’s Hospital of Shanghai, Ref. No. 2021R029-F02; registered at the China Clinical Trial Registry Center, registration number ChiCTR2200066131). | PMC10391876 |
Anesthesia, surgery | breast milk | After preoperative fasting (6 h for solid food and then 4 h for breast milk), anesthesia and monitoring were standardized for all children. ECG, pulse oximetry and end-tidal CO | PMC10391876 |
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Scalp nerve block | scalp nerve block, nerve block | In Group A, an ultrasound-guided bilateral scalp nerve block was performed with 0.3% ropivacaine before incision. The total dose of local anesthetic was 3.6 mg/kg in each patient. The procedures for nerve block were as follows: | PMC10391876 |
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Supratrochlear nerve block | CORTEX | The nerve block was guided with an S-NERVE ultrasound machine (Sono Site, USA), an ultrahigh frequency line array probe was placed parallel to the brow arch, the probe position was adjusted, and the supraorbital notch was found on the ultrasound image (an interruption of the bony surface echo). In-plane technology was used with an interior approach, 0.1 ml/kg local anesthetic was injected at the medial side of the supraorbital notch, and local anesthetic spread along the brow arch bone cortex (Fig. Supraorbital nerve and supratrochlear nerve block | PMC10391876 |
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Supraorbital nerve block | CORTEX, LOCAL ANESTHETICS | When the supratrochlear nerve block was completed, the puncture needle continued parallel to the supraorbital notch. Then, 0.1 ml/kg local anesthetic was injected. Local anesthetic could be seen spread along the bone cortex of the brow arch and wrapped around the supraorbital notch (Fig. | PMC10391876 |
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Auriculotemporal nerve block | Auriculotemporal nerve block | The ultrasound probe was placed parallel to and above the zygomatic arch, and the superficial temporal artery was found 1 cm above the root of the zygomatic arch in front of the tragus. An ultrasound-guided out-of-plane technique was employed, and 0.1 ml/kg local anesthetic was injected into the deep surface of the superficial temporal artery (Fig. Auriculotemporal nerve block | PMC10391876 |
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Lesser occipital nerve block | occipital nerve block | Due to the limitation of resolution of the ultrasound probe, the superficial cervical plexus was blocked to block the lesser occipital nerve. The child lay in a supine position with the head tilted to the opposite side. The superficial cervical plexus was positioned ipsilateral to the superficial cervical plexus and then punctured in-plane from the lateral side. The superficial cervical plexus (including the lesser occipital nerve) was located at the deep surface of the lateral border of the sternocleidomastoid muscle. Then, 0.1 ml/kg local anesthetic was injected, and the local anesthetic was observed to be spread in the interstitial space below the sternocleidomastoid muscle (Fig. Lesser occipital nerve block | PMC10391876 |
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Greater occipital nerve block | The child was placed in a lateral position, and the ultrasound probe was placed parallel to the superior collar line. The greater occipital artery was found lateral to the external occipital ridge, and 0.2 ml/kg local anesthetic was injected into the medial artery with the in-plane technique (Fig. Greater occipital nerve blockAll anesthesia procedures were performed by the same experienced anesthetist, and the operations were completed by the same team of neurosurgeons. During the operation, if the mean arterial pressure (MAP) or HR rose by more than 30% of the baseline level, 0.1 μg/kg sufentanil was administered intravenously. The total amount of sufentanil during the operation was calculated. | PMC10391876 |
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Postoperative pain relief | consolability, Pain, pain | After the operation, extubation was performed, and then the patients were transferred to the surgical intensive care unit (SICU). Patients in both groups received nurse-controlled analgesia (NCA) via an intravenous analgesia pump. The drug used for analgesia was 1 µg/kg sufentanil in saline (100 ml). The background dose was 0 ml, the NCA dose was 4 ml (sufentanil 0.04 μg/kg), and the lock time was 20 min. Pain was assessed by observing the face, legs, activity, cry, and consolability (FLACC). An FLACC score ≥ 4 indicated moderate pain, and the nurse pressed the analgesia pump to control the drug administration; an FLACC score ≥ 7 indicated severe pain, and oral paracetamol was administered for remedial analgesia. The consort diagram is shown in Fig. CONSORT flow diagram | PMC10391876 |
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Outcome measurements | venous blood glucose | SECONDARY | The primary outcome objective of the study was the MAP, and the secondary objectives were the HR, FLACC scores, and venous blood glucose. The MAP and HR were recorded in 2 groups preoperatively (T | PMC10391876 |
Statistical analysis | Statistical analysis was performed with SPSS version 20.0 (SPSS, Inc., Chicago, Illinois, USA), and a value of Sample size calculation was performed based on the assumption that a difference of 30% in MAP was clinically relevant. With an α of 0.05 and power of 80%, 26 patients in each group were needed. Therefore, we chose 30 patients per group in the study. | PMC10391876 |
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Results | PMC10391876 |
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Patient demographics and perioperative characteristics | Sixty children were included in this study. The results showed that there were no significant differences between the two groups in terms of sex, age, weight, height, duration of surgery and anesthesia, blood transfusion and loss (Table General characteristics of children in the 2 groups (x¯±s) | PMC10391876 |
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Blood glucose, postoperative pain scores and analgesic consumption | pain | The blood glucose in Group N was significantly higher than that in Group A; pain scores at TPostoperative blood glucose level and FLACC score in the 2 groups (x¯±s)There was no significant difference in intraoperative sufentanil consumption between the 2 groups (P>0.05). The number of analgesic pump presses in Group N was significantly higher than that in Group A (Intraoperative sufentanil consumption and number of times the analgesic pump was pressed in the 2 groups (x¯±s) | PMC10391876 |
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Pain control-related adverse events during the study period | toxicity, hematoma, pain | HEMATOMA, COMPLICATIONS, PUNCTURE SITE INFECTION | The hemodynamics, oxygen saturation and respiratory rate were stable in both groups in the postanesthetic care unit (PACU). There were no complications, such as puncture site infection, local anesthetic toxicity, or hematoma, in any of the patients, and no remedial analgesia was administered for severe pain. | PMC10391876 |
Discussion | toxicity, muscle breaks, pain, cranial suture, nerve block | PERIOSTEUM | In cranial suture reconstruction procedures, skin incision and peeling of the periosteum are the most painful processes and may increase the patient’s blood pressure and HR [Craniotomy-related pain is mainly caused by skin incisions and muscle breaks rather than the operation on the brain parenchyma. The scalp is mainly innervated by the trigeminal nerve and the second and third cervical nerve roots [The MAP and HR at THowever, there were still limitations in this study: the scalp sensory nerves are thin and difficult to distinguish on ultrasonography, and the identification of these nerves requires ultrasound-assisted localization of anatomical landmarks such as bone and blood vessels. However, the fact that there are variants of scalp nerves may affect the accuracy of nerve blocking. The amount of local anesthetic used may also affect the effectiveness of nerve block. In adult studies, the amount of local anesthetic used at each puncture site ranged from 2 to 5 ml. Few studies have been conducted to investigate the amount of local anesthetic in pediatrics, and the amount of local anesthetic is often reduced to avoid the risk of local anesthetic toxicity, which may also compromise the efficacy and duration of the nerve block. In the present study, the children undergoing cranial suture reconstruction were 6-24 months old, and their body weight was very low; thus, the dose of local anesthetic was calculated based on the body weight of each child. The scalp nerves were relatively superficial compared to other nerves, and less local anesthetic was needed. Therefore, the dose of local anesthetic was adjusted based on the body weight according to previously reported methods [ | PMC10391876 |
Authors’ contributions | Tianxiao Zou designed the experiment, performed the experiments, analyzed the data and drafted the manuscript. Shenghua Yu designed and performed the experiments. Guili Ding and Rong Wei designed the experiment and revised the manuscript. All the authors read and approved the final manuscript. | PMC10391876 |
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Funding | No funding was received for this study. | PMC10391876 |
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Availability of data and materials | The datasets are not publicly available but are available from the corresponding author upon reasonable request. | PMC10391876 |
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Declarations | PMC10391876 |
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Ethics approval and consent to participate | This study was approved by the Institution Review Board (Ethics Commission of Children’s Hospital of Shanghai, Ref. No. 2021R029-F02; registered at the China Clinical Trial Registry Center, registration number ChiCTR2200066131), in accordance with the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from the parents or relatives of patients. We confirm that all methods were performed in accordance with the relevant guidelines and regulations. | PMC10391876 |
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Consent for publication | Not applicable. | PMC10391876 |
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Competing interests | The authors declare no competing interests. | PMC10391876 |
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References | PMC10391876 |
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1. Introduction | Pregnancy nutrition is important for maternal and child health and may affect the development of the infant gut microbiome. Our objective was to assess the feasibility of implementing a food-based intervention designed to increase fiber intake among pregnant women in a rural setting. Participants were enrolled (Diet interventions designed to increase fiber intake have been shown to alter the gut microbiome in adults [The range of dietary intervention strategies that have been employed to promote healthy dietary intake during pregnancy has recently been reviewed [Rural regions have been characterized by limited access to quality healthcare, education, and transportation, contributing to inequities in healthcare outcomes compared with their urban counterparts [The overall goal of the Pregnancy EAting and POstpartum Diapers (PEAPOD) pilot study was to gather information to effectively refine an intervention so that it can be tested in a larger, longer study using a factorial design to assess the separate and combined effects of maternal diet during pregnancy and lactation on the establishment of the infant gut microbiome. The specific objectives were to test methods of randomization and outcome measurement and to assess the feasibility and acceptability of implementing the intervention and the study procedures, which included collecting survey data and multiple biospecimens (blood, urine, and stool) at multiple locations (prenatal clinic, telephone, and home), via multiple modes (interviewer-administered and self-collection). We present results indicating that this type of pragmatic food-based diet intervention is a feasible approach to use during pregnancy. | PMC9958944 |
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2. Materials and Methods | PMC9958944 |
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2.1. Recruitment | Pregnant participants were recruited from a single prenatal care clinic serving a rural population in the northwest region of Michigan’s Lower Peninsula. Inclusion criteria were maternal age of at least 18 years, pregnant with a gestational age of approximately 22 weeks at enrollment, and no self-reported contraindication to increasing dietary fiber. Inclusion criteria were broad in an attempt to enroll a sample generally representative of the area, but we did restrict enrollment to those women living within a three-county region because of the food delivery component. All participants met in-person with a research assistant to complete the informed consent process and receive oral and written directions about the next steps of the study. The PEAPOD study was approved by the Institutional Review Boards at Michigan State University (#16-1515) and Munson Medical Center (#1026493). | PMC9958944 |
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2.2. Intervention and Usual Care | A two-arm randomized controlled trial design was implemented with women enrolled in mid-pregnancy ( | PMC9958944 |
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2.3. Diet Assessment | Cancer | CANCER | Maternal diet was assessed before (i.e., 24-weeks gestation) and 4 weeks after the initiation of the intervention (i.e., 36-weeks gestation), and at 6 weeks postpartum. Participants were asked to complete self-administered 24-hour dietary recalls utilizing the 2016 version of the Automated Self-Administered 24-hr (ASA-24) Dietary Assessment Tool developed by the US National Cancer Institute [ | PMC9958944 |
2.4. Survey and Biospecimen Collection, Storage, and Analyses | BLOOD | Data collection included surveys (including sociodemographic and behavioral information as well as the ASA-24 described above), maternal blood, urine, and stool collection at three time points (24- and 36-weeks gestation [pre- and 4-weeks post-intervention initiation, respectively]; and at 6 weeks postpartum), and infant stool at age 6 weeks. Blood and urine specimens were obtained in the prenatal clinic and immediately aliquoted and stored at –80 °C. Fecal samples were self-collected at home and sent to the laboratory by mail. Fecal aliquots were stored at –80 °C upon reaching the lab. The average time between home sample collection and laboratory receipt was 3.8 ± 1.9 days (median = 3.5 days). We utilized the laboratory services provided by the National Institutes of Health Children’s Health Exposure Analysis Resource (CHEAR) Pilot and Feasibility (P&F) Program to measure plasma carotenoids and lipids, as well as urinary heavy metals and urinary metabolites. Trace elements reported in this manuscript were assessed from urine samples collected at 36-weeks gestation and were measured using an Agilent 8800 Triple Quadrupole ICP-MS (Santa Clara, CA, USA). These elements were analyzed in part to determine if metals serve as a marker for the presence of environmental contaminants, but they are reported here to show the feasibility of outcome assessment. Stool sample DNA extraction and amplification were performed in the laboratory of one of the study principal investigators (S Comstock). 16SrRNA gene sequencing was performed at the Michigan State University Research Technology Support Facility Genomics Core. All stool microbiome methods used this previously described protocol [ | PMC9958944 |
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3. Results | PMC9958944 |
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3.1. Participants | Our sample was considered entirely rural, and maternal characteristics reflected the local population ( | PMC9958944 |
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3.2. Feasibility and Acceptability of Implementing Study Procedures | Data collection adherence was high with few missing data points. Overall satisfaction was high, with 85% reporting satisfied or very satisfied, and important qualitative insights were gained from participants. Participants who completed the final study visit ( | PMC9958944 |
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3.3. Dietary Intake Data | Per protocol, participants were instructed to self-complete two 24-hour dietary recalls using the ASA-24 online system at three different time points (24- and 36-weeks gestation, and 6 weeks postpartum). | PMC9958944 |
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3.4. Urinary Trace Elements | Descriptive measures of trace element concentrations assessed from urine samples collected at 36-weeks gestation are reported in | PMC9958944 |
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3.5. Results Published To-Date | In this publication, we focus on the feasibility and acceptability of data, but there are both ongoing and previously published findings from the biospecimen analyses resulting from this pilot study. Data published elsewhere reported the positive association between dietary and plasma carotenoids with alpha diversity in the maternal fecal microbiota collected during the third trimester of pregnancy [We have also shown that fecal bacterial communities differ by lactation status in postpartum women and their infants [Finally, while it is well-known that diet affects the gut microbiota and the subsequent production of metabolites, many specific interactions and associations have yet to be characterized. This is especially the case during pregnancy, a time of great metabolic and physiological upheaval. We recently published data from the trial described herein showing associations between urinary metabolites, diet, and the gut microbiota in the third trimester of pregnancy [ | PMC9958944 |
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4. Discussion | CHRONIC DISEASE | The aim of this study was to test procedures, including methods of randomization and outcome measurement, to assess the feasibility and acceptability of implementing a pragmatic, scalable, and replicable food-based intervention that can be used for answering important research questions, especially pertaining to infant gut microbiome development. The purpose of reporting the results is to encourage other researchers to develop similar pragmatic food-based dietary interventions that may not have the same rigor as providing participants with 100% of their food intake—prepared, for example, in a metabolic kitchen—but would allow for lower cost testing of important diet-related research questions. As such, we report feasibility results for collecting a variety of survey data and biospecimens to indicate that this type of food-based diet intervention is a feasible approach to use for research during pregnancy in a rural population where access to health care is often a barrier to research participation.In our study population, this intervention was feasible and acceptable. Participation rates were high (93–100%) for all study components except the ASA-24 dietary recall. Self-administration of dietary recall via the ASA-24 was not well-liked by participants (n = 6 out of 25 participants who completed the final study visit noted this in a free text response on the satisfaction survey). However, for this study, we used the 2016 version of the ASA-24, which has now been updated three more times (2018, 2020, and 2022), in part to address some of the user-friendliness issues in previous versions (In terms of the composition of the food-based intervention, participants recommended providing choices in food selection to increase consumption (n = 6 out of 12 intervention participants who completed the final visit noted a version of this in a free text response). Usual care participants used their gift card incentives to buy healthy foods (n = 6 usual care group participants noted a version of this in a free text response) potentially leading to group contamination, which may be relevant for future research, depending on the study objectives. The main limitation of this work is the small sample size. We were able to test study procedures, but we are not able to make any inferences about the effect of the food-based diet intervention. However, by combining the usual care and intervention groups into a single study population, we have been able to ascertain important associations between diet, metabolites, and both adult and infant gut microbiota composition and diversity. In some small studies, nutrition education has been shown to have an impact on clinically important biomarkers. For example, in a study of 31 patients with chronic disease, an intensive nutrition education model with group and individual visits emphasizing whole, plant-based foods, significant improvements were shown in BMI, blood pressure, and cholesterol levels after 8 weeks [The scope of dietary Interventions designed specifically for pregnant women has recently been reviewed [ | PMC9958944 |
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5. Conclusions | This pilot trial produced valuable information. The intervention was tested with 27 pregnant women residing in rural Michigan. Retention was high at 93%, with 85% of participants reporting high satisfaction. Among the parameters compared across or within study arms, no significant differences were observed in dietary intake, plasma carotenoid levels, urinary metabolites, or gut microbiota composition. However, this test case can be used to effectively refine practical food-based interventions so they can be tested in larger, longer studies using, for example, a factorial design to test the effects of pregnancy diet and/or postpartum diet of breastfeeding moms on the establishment of the infant microbiome. | PMC9958944 |
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Author Contributions | J.M.K. and S.S.C. conceptualized the study, acquired funding, provided oversight for all study activities, and reviewed and edited the manuscript. J.C.G. assisted in conceptualizing the study and conducted the randomization schema. Y.K. assisted in the original draft preparation. J.M.G. provided oversight for study implementation and drafted sections of the methods. All authors have read and agreed to the published version of the manuscript. | PMC9958944 |
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Institutional Review Board Statement | MAY | This study was conducted in accordance with the Declaration of Helsinki, and approved on 19 May 2017 by the Institutional Review Board (or Ethics Committee) of Michigan State University and Munson Medical Center (IRB #16-1515 and 1026493). | PMC9958944 |
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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9958944 |
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Data Availability Statement | Data are available upon request from the corresponding author. | PMC9958944 |
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Conflicts of Interest | The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. | PMC9958944 |
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References | Study flyer with timeline and incentive structure.Maternal characteristics at study enrollment.Visit participation rates.Patient satisfaction (free-text responses).Dietary intake pre- and post-intervention by study arm (Trace elements (μg/L) from urine specimens collected at 36-weeks gestation ( | PMC9958944 |
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Background | drink-flavored bowel preparation, drink bowel preparation, colon cancer | COLON CANCER | Acceptability and tolerance of bowel preparation is critical to overcome patient hesitancy in undergoing colon cancer screening and surveillance colonoscopy. To improve patient experience, a new sports drink-flavored bowel preparation containing polyethylene glycol (PEG) and sulfate salts (FPSS) was developed to provide a similar experience to a commonly used but not United States Food and Drug Administration (FDA) approved PEG and sports drink bowel preparation (PEG-SD), while also achieving improved cleansing efficacy. | PMC10712137 |
Methods | This FPSS preparation, approved by the FDA in June 2023, was evaluated in a non-randomized Phase 2 study in which 40 patients requiring colonoscopy were prepared with FPSS and 20 with PEG-SD. | PMC10712137 |
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Results | Overall cleansing success was high with FPSS based on unblinded local endoscopist assessment (93%) and blinded central reading (97%), exceeding PEG-SD which achieved success rates of 84% (local read), 74% and 68% (blinded central reads). Similar differences favoring FPSS were seen for excellent preparations and cleansing success by colon segment as rated by local endoscopists. Both preparations were well-tolerated, with 93% of FPSS patients rating their preparation as Tolerable to Very Easy to consume, compared to 100% of PEG-SD. Patients who had previously taken a preparation for colonoscopy found FPSS and PEG-SD better than their prior preparation (73% and 70%, respectively) and nearly all would request their assigned study preparation again in the future. About two thirds of FPSS patients agreed that the preparation tasted similar to a sports drink. | PMC10712137 |
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Conclusion | The new sports drink-like flavored preparation compares favorably to PEG-SD for bowel cleansing efficacy while achieving similar patient satisfaction. The study was registered at | PMC10712137 |
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Keywords | PMC10712137 |
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Introduction | Despite improvements in prescription bowel preparation technology, a significant proportion of colonoscopy preparations offered to patients are not approved by the FDA, but rather are over-the-counter laxative combinations [Studies by Walker et al. [To provide healthcare practitioners and patients the positive attributes of PEG-SD (e.g., taste, low volume) in an electrolyte-balanced formulation, a new sports drink-like flavored PEG and sulfate solution (FPSS, SUFLAVE | PMC10712137 |
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Methods | colorectal cancer, the bowel preparation | ADVERSE EVENTS, COLORECTAL CANCER, COLON | This was an open-label, active-controlled, sequential-cohort study in adult patients undergoing colonoscopy for colorectal cancer screening and surveillance or for diagnostic purposes. This study was conducted at 4 U.S. endoscopy centers and approved by Aspire, Institutional Review Board and registered on A screening visit was performed for eligible patients within 30 days prior to their scheduled colonoscopy which included routine blood chemistry. In this adaptive design study conducted over a two-year period, twenty subjects were planned to take the PEG-SD control, with various experimental formulations concurrently and subsequently evaluated (not discussed here) with 40 subjects ultimately planned to take the FPSS to-be-marketed formulation. Preparation administration was not randomized.On the day prior to colonoscopy, subjects were allowed a low residue breakfast followed by clear liquids until the colonoscopy was completed the following day. Both preparations were administered using the American College of Gastroenterology recommended split-dose (PM/AM) regimen. Subjects assigned to FPSS reconstituted the one-liter dose with water on the evening prior to colonoscopy and consumed 8 oz of solution every 15 min until complete. A second one-liter dose was taken the morning of colonoscopy. FPSS subjects drank an additional 16oz of water following each preparation dose. Subjects assigned to PEG-SD received two 5 mg over-the-counter bisacodyl laxative tablets, two 32-ounce bottles of Lemon-Lime flavored sports drink (Gatorade; PepsiCo, Inc., Chicago, IL, USA), and two 119 g bottles of Polyethylene glycol 3350 (PEG 3350). Subjects were instructed to take the bisacodyl at approximately 3PM on the day prior to colonoscopy. Subjects then mixed one bottle of PEG 3350 with one bottle of Gatorade and consumed 8 oz every 15 min until complete, along with additional water. A second one-liter dose was taken the morning of colonoscopy.Subjects returned to the clinic the day of colonoscopy. Patients were queried for occurrence of adverse events, given a physical examination, and a blood sample was taken for routine chemistry. Colonoscopies were performed by unblinded endoscopists according to the site’s standard procedures. Colon cleanliness was assessed following completion of the exam using a 4-point scale (Table
Bowel Preparation Cleansing ScalePrior to their procedure, all patients were asked to complete a questionnaire which included questions related to preparation satisfaction, including: How easy or difficult was it to consume the study preparation (Very Difficult to Very Easy)?; Please describe your overall experience with the bowel preparation (Bad to Excellent); How did this bowel preparation experience compare to your prior experiences (Worse to Better)?; Would you ask your doctor for this preparation again if you need another colonoscopy in the future? (Yes or No); Would you refuse the same preparation again if it were to be prescribed to you in the future? (Yes or No). In addition, FPSS patients were asked the following: Please rate your feelings about the aftertaste of the preparation (Very Pleasant to Very Unpleasant), and; To what degree do you believe the product tastes similar to a sports drink? (Agree Extremely to Disagree Extremely). | PMC10712137 |
Author contributions | J.A. D., M.vB.C., and J.D.M. conceived and designed the project. G.W. and P.W. collected the data. M.vB.C., and J.D.M. analyzed and interpreted the data. J.A.D., M.vB.C., and J.D.M. drafted the manuscript. All authors read and approved the final manuscript. | PMC10712137 |
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Funding | This work was supported by Braintree Laboratories, Inc. | PMC10712137 |
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Data Availability | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10712137 |
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Declarations | PMC10712137 |
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Ethics approval and consent to participate | All methods were carried out in accordance with relevant guidelines and regulations. The study protocol was approved by WCG IRB (Payallup, WA) and informed consent was obtained from all subjects. | PMC10712137 |
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Consent for publication | Not Applicable. | PMC10712137 |
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Competing interests | Di | Dr. Di Palma is a consultant medical director for Braintree Laboratories. Dr. Cleveland is a scientific consultant. Mr. McGowan is a Braintree employee. The other authors have no competing interests. | PMC10712137 |
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References | PMC10712137 |
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Key Points | PMC10394570 |
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Question | CASTRATION-SENSITIVE PROSTATE CANCER | Do Black patients with metastatic castration-sensitive prostate cancer have worse outcomes than White patients when treated with systemic androgen deprivation therapy combined with a first- or a second-generation androgen receptor pathway inhibitor? | PMC10394570 |
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Findings | CASTRATION-SENSITIVE PROSTATE CANCER, SECONDARY | In this secondary analysis of a randomized phase 3 clinical trial with 1313 patients with metastatic castration-sensitive prostate cancer, there was no statistically significant difference in overall survival and progression-free survival between Black and White patients. | PMC10394570 |
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Meaning | CASTRATION-SENSITIVE PROSTATE CANCER, SECONDARY | These results suggest that providing fair and equal access to health care may reduce the disparities in treatment outcomes between Black and White patients with advanced prostate cancer.This secondary analysis of a randomized clinical trial evaluates the association of race with survival among patients with metastatic castration-sensitive prostate cancer. | PMC10394570 |
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Importance | aggressive disease | PROSTATE CANCER, PROSTATE | Black patients present with more aggressive disease and experience higher mortality than White patients with prostate cancer. Race and social determinants of health influence prostate cancer-specific mortality and overall survival (OS); however, in a previous trial, Black patients did not have inferior outcomes compared with White patients, possibly because of equitable access to care available in a clinical trial setting. | PMC10394570 |
Objective | CASTRATION-SENSITIVE PROSTATE CANCER | To compare differences in survival outcomes of patients with metastatic castration-sensitive prostate cancer (mCSPC) by race in a phase 3 trial with a large proportion of Black patients. | PMC10394570 |
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Design, Setting, and Participants | SECONDARY | This secondary analysis of patient-level data of a prospective phase 3 randomized clinical trial included patients with newly diagnosed mCSPC enrolled between March 1, 2013, and July 15, 2017. Analysis was conducted between December 2022 and February 2023. | PMC10394570 |
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Interventions | Patients receiving androgen deprivation therapy were randomized (1:1) to receive either orteronel 300 mg orally twice daily (experimental group) or bicalutamide 50 mg orally daily (control group). | PMC10394570 |
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Main Outcomes and Measures | SECONDARY | OS, with progression-free survival (PFS) as a secondary end point. | PMC10394570 |
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Results | Among 1313 participants, 135 (10%) identified as Black and 1077 (82%) as White, with an equal racial distribution between groups. Black patients were younger (median [IQR] age, 65.8 [60-70] vs 68.4 [62.5-74.1] years; | PMC10394570 |
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Conclusions and Relevance | SECONDARY | In this secondary analysis of a randomized clinical trial studying androgen deprivation therapy with first- or second-generation androgen receptor pathway inhibitors, both Black and White patients demonstrated similar OS and PFS. Equitable access to care may reduce historical differences in outcomes between Black and White patients with advanced prostate cancer. | PMC10394570 |
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