Abstract DNA damage can cause (and result from) oxidative stress and mitochondrial impairment, both of which are implicated in the pathogenesis of Parkinson's disease (PD). We therefore examined the ...role of mitochondrial DNA (mtDNA) damage in human postmortem brain tissue and in in vivo and in vitro models of PD, using a newly adapted histochemical assay for abasic sites and a quantitative polymerase chain reaction (QPCR)-based assay. We identified the molecular identity of mtDNA damage to be apurinic/apyrimidinic (abasic) sites in substantia nigra dopamine neurons, but not in cortical neurons from postmortem PD specimens. To model the systemic mitochondrial impairment of PD, rats were exposed to the pesticide rotenone. After rotenone treatment that does not cause neurodegeneration, abasic sites were visualized in nigral neurons, but not in cortex. Using a QPCR-based assay, a single rotenone dose induced mtDNA damage in midbrain neurons, but not in cortical neurons; similar results were obtained in vitro in cultured neurons. Importantly, these results indicate that mtDNA damage is detectable prior to any signs of degeneration — and is produced selectively in midbrain neurons under conditions of mitochondrial impairment. The selective vulnerability of midbrain neurons to mtDNA damage was not due to differential effects of rotenone on complex I since rotenone suppressed respiration equally in midbrain and cortical neurons. However, in response to complex I inhibition, midbrain neurons produced more mitochondrial H2 O2 than cortical neurons. We report selective mtDNA damage as a molecular marker of vulnerable nigral neurons in PD and suggest that this may result from intrinsic differences in how these neurons respond to complex I defects. Further, the persistence of abasic sites suggests an ineffective base excision repair response in PD.
This study was aimed to evaluate opioid use after cesarean delivery (CD) and to assess implementation of an enhanced recovery after CD (ERAS-CD) pathway and its association with inpatient and ...postdischarge pain control and opioid use.
We conducted a baseline survey of women who underwent CD from January to March 2017 at a single, urban academic hospital. Patients were called 5 to 8 days after discharge and asked about their pain and postdischarge opioid use. An ERAS-CD pathway was implemented as a quality improvement initiative, including use of nonopioid analgesia and standardization of opioid discharge prescriptions to ≤25 tablets of oxycodone of 5 mg. From November to January 2019, a postimplementation survey was conducted to assess the association between this initiative and patients' pain control and postoperative opioid use, both inpatient and postdischarge.
Data were obtained from 152 women preimplementation (PRE) and 137 women post-implementation (POST); complete survey data were obtained from 102 women PRE and 98 women POST. The median inpatient morphine milligram equivalents consumed per patient decreased significantly from 141 range: 90-195 PRE to 114 range: 45-168 POST (
= 0.002). On a 0- to 10-point scale, median patient-reported pain scores at discharge decreased significantly (PRE: 7 range: 5-8 vs. POST 5 range: 3-7,
< 0.001). The median number of pills consumed after discharge also decreased significantly (PRE: 25 range: 16-30 vs. POST 17.5 range: 4-25,
= 0.001). The number of pills consumed was significantly associated with number prescribed (
< 0.001). The median number of leftover pills and number of refills did not significantly differ between groups. Median patient-reported pain scores at the week after discharge were lower in the POST group (PRE: 4 range: 2-6 vs. POST 3range: 1-5,
= 0.03).
Implementing an ERAS-CD pathway was associated with a significant decrease in inpatient and postdischarge opioid consumption while improving pain control. Our data suggest that even fewer pills could be prescribed for some patients.
· An ERAS-CD pathway was associated with decreased opioid use.. · Outpatient opioid consumption after cesarean warrants further study.. · Physician prescribing drives patients' opioid consumption..
Rheumatoid arthritis (RA) is a chronic inflammatory disorder leading to bone and cartilage destruction. A substantial body of evidence suggests that prostaglandin E2 (PGE2) contributes to the ...pathogenesis of RA, and nonsteroidal anti-inflammatory drugs, inhibitors of the synthesis of PGE2 and other prostanoids, continue to be used in the treatment of this disease. To begin to understand the mechanism by which prostaglandins modulate the pathophysiology of this disease, we examined mice lacking each of the four known PGE2 (EP) receptors after generation of collagen antibody-induced arthritis, an animal model of RA. Homozygous deletion of the EP1, EP2, or EP3 receptors did not affect the development of arthritis, whereas EP4 receptor-deficient mice showed decreased incidence and severity of disease. These animals also showed reduced inflammation as assessed by circulating IL-6 and serum amyloid A levels. Joint histopathology of EP4(-/-) animals revealed reduced bone destruction, proteoglycan loss, and type II collagen breakdown in cartilage compared with EP4(+/+) mice. Furthermore, liver and macrophages isolated from EP4(-/-) animals produced significantly less IL-1 beta and IL-6 than control samples. Thus, PGE2 contributes to disease progression at least in part by binding to the EP4 receptor. Antagonists of this receptor might therefore provide novel agents for the treatment of RA.
To compare maternal and cord blood penicillin concentrations in women with and without obesity who are receiving intrapartum group B streptococcus (GBS) prophylaxis.
We performed a prospective cohort ...study of term women receiving intrapartum penicillin prophylaxis for GBS colonization (determined by antenatal rectovaginal culture). The following outcomes were compared between obese (body mass index BMI 35 or higher at delivery) and nonobese (BMI less than 30 at delivery) groups: penicillin concentration in maternal blood (after two penicillin doses) and umbilical cord blood, GBS rectovaginal colonization status on admission and after two completed doses, and neonatal GBS colonization (using a postnatal ear swab). Fifty-five women were needed to detect a 0.75 SD difference in cord blood penicillin concentrations.
Fifty-five women were enrolled and had all specimens collected; 49 had complete data for analysis (obese n=25, nonobese n=24). There was no difference in the median maternal penicillin concentration between groups (obese 4.2 micrograms/mL vs nonobese 4.0 micrograms/mL, P=.58). There was, however, a 60% lower median cord blood penicillin concentration in the obese compared with the nonobese group (2.7 micrograms/mL vs 6.7 micrograms/mL, respectively, P<.01), with no significant difference in time from last penicillin dose to delivery (obese 2.9 hours vs nonobese 1.7 hours, P=.07). The difference in cord blood concentrations remained significant after adjustment for nulliparity, hypertensive disorders, and time from last penicillin dose to delivery. Only 59.6% of women tested positive for GBS by rectovaginal culture on admission (obese 60.9% vs nonobese 58.3%, P=.86).
The median cord blood penicillin concentration was 60% lower in neonates born to women with obesity compared with those born to women without obesity. However, all concentrations exceeded the minimum inhibitory concentration. Maternal penicillin levels were not significantly different between groups. More than 40% of women who previously tested positive for GBS by antenatal culture tested negative for GBS on admission for delivery.
Botox is frequently used for sialorrhea in patients with compromised airways and those with etiologies causing difficulty with secretion management (i.e. strokes, neurologic disorders, etc.). There ...are no published studies regarding the use of botulinum toxin (BoNT) in the neonate population. We aim to discuss our experience and safety of BoNT use in the neonate population in regards to alleviating secretion management and airway protection.
Retrospective review of neonates admitted to the neonatal intensive care unit (NICU) ≤12 months of age who received BoNT injection to submandibular (SMG) and parotid (PG) glands for sialorrhea/dysphagia. BoNT was administered under ultrasound (u/s) guidance by interventional radiology.
6 children were examined. 2 (33 %) were male. Avg NICU stay was 87.5 ± 33.1 days. 2 underwent surgical airway intervention prior to injection. Mean age at initial BoNT was 1.5 ± 0.7 months. Avg weight at injection was 4 ± 1.1 kg. Each PG and SMG were injected in 5/6 cases. Bilateral SMG were unidentified on u/s in 1 case and thus not injected. Dose range injected per gland was 5-15u. 100 % required tube feeds, 50 % with tubes distal to stomach (NJT/NDT). 83 % were completely NPO prior to injection and there was no noted clinical improvement in oral skills post injection. All had noted desats/apneas prior to injection and 83 % had reported decreased events post injection. 50 % had reported decrease O2 requirements and frequent suctioning 2wks after injection, however 2 (33 %) required surgical airway intervention after injection (trach, SGP/MDO). 4/6 (67 %) trialed medical therapy, anticholinergics being the most common. 50 % underwent 2nd injection (age = 6.5 ± 0.3 months) avg. 4.7 ± 0.7mo after 1st injection, and the same 3pts underwent 3rd injection (age = 12.5 ± 2.4 months) avg. 6.1 ± 2.5mo after 2nd injection. 1 pt. had a total 6 injections. There were no injection related complications.
BoNT injection is a safe, non-invasive alterative for management of sialorrhea in neonates. Further extensive study needs to be performed to identify the optimal dose per gland in this population.
Measure the prevalence of and factors associated with financial toxicity (FT) and caregiver burden in families of tracheostomy-dependent children. FT is defined as the objective and subjective ...patient-level impact of the costs of medical care and has been associated with lower quality of life, decreased compliance with treatment, and increased mortality.
A medical record review was performed on all children with a tracheostomy tube placed from 2009 to 2018 at a tertiary children's hospital to identify and include children younger than 18 years old, not deceased, and not decannulated at the time of review. Eligible children's caregivers were contacted to fill out a 36-item questionnaire and three validated instruments: The Comprehensive Score for Financial Toxicity (COST) and the Financial Distress Questionnaire (FDQ), both addressed to the parent/primary caregiver, and the Burden Scale for Family Caregivers – short version (BSFC-s).
Of the 140 eligible tracheostomy patients identified, 45 caregivers (32.1%) returned the survey. The average COST score was 18 ± 1.7 with 73.3% of caregivers reporting high toxicity based on FDQ, and 75.6% having severe-to-very severe caregiver burden. Significant increase in FT was seen in households where an adult had to leave a paid position (p = 0.047) or work less (p = 0.002) because of their child's condition; or needed to omit some of the child's medical services or medications due to cost-prohibitive reasons (p<0.001). Financial toxicity was associated with caregiver burden (by BSFC-s) r = −596; beta coefficient = −0.95, t(43) = -4.87, p<0.001 and financial distress (by FDQ; p<0.001).
Caregivers of children with medically complex, tracheostomy-dependent conditions suffer from FT and caregiver burden. As a result, harmful financial coping mechanisms such as missing necessary care components or forgoing prescribed treatments, may be adopted for cost-prohibitive reasons.
To compare the mean pre-operative air-bone gaps (ABG), mean post-operative ABGs, and extrusion rates between pediatric recipients of partial ossicular reconstruction prostheses (PORPs) and pediatric ...recipients of total ossicular reconstruction prostheses (TORPs) via a systematic review and meta-analysis.
A quantitative systematic review last updated on September 29, 2021 of PubMed, Scopus, and Embase databases was conducted for studies reporting mean post-operative ABGs or numbers of children with post-operative ABG ≤ 20 dB following PORP and TORP procedures in at least five children aged 0–18 years. Studies were excluded if they were review articles, conference abstracts, or not in English. Studies that primarily reported data on congenital aural atresia, stapedectomy/stapedotomy, congenital stapes fixation, or juvenile otosclerosis were also excluded. NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies was used to assess for risk of bias. Review Manager (RevMan) version 5.4.1 was used to perform the meta-analysis and generate forest plots.
Out of 648 unique abstracts retrieved, 11 papers were included in this systematic review with meta-analysis. Data from 449 children (247 TORP recipients and 202 TORP recipients) are represented among the various analyses. Data from nine studies, representing 84.2 % of all children in the systematic review, demonstrated that PORP recipients presented with a pre-operative ABG 6.30 dB less than TORP recipients (mean difference: −6.30, 95 %CI: −7.4, −5.18, p < 0.01). Data from these same children demonstrated that PORP recipients had a 1.80 dB less post-operative ABG compared to TORP recipients (mean difference: −1.80 dB, 95 %CI: −2.84, −0.77, p < 0.001). Data from seven studies, representing 49.4 % of all children in the systematic review, demonstrated that PORP recipients were more likely to have a successful closure of the post-operative ABG to ≤20 dB (OR: 2.12, 95 %CI: 1.18, 3.79, p = 0.01). In these same children, 62.5 % of PORP recipients had a post-operative ABG ≤ 20 dB and 48.3 % of TORP recipients had a post-operative ABG ≤ 20 dB. There was no difference in extrusion rates between PORP recipients compared to TORP recipients (OR: 1.08, 95 %CI: 0.31, 3.78, p = 0.90) from five studies representing 45.9 % children in the systematic review.
Children who receive a PORP have better pre-operative hearing baselines and post-operative hearing outcomes compared to those who receive TORP with similar rates of extrusion. More pediatric studies should report their mean pre- and post-operative ABGs stratifying by various material types, surgical indications, and surgical details to facilitate future meta-analyses.
Puberty has been shown to accelerate growth of vascular malformations, including lymphatic (LM) and venous malformations (VM). This study aims to compare the number of procedures performed before and ...after puberty in patients with LM and VM to assess whether the onset of puberty results in higher treatment frequency.
A retrospective review of head and neck LM and VM patients who were evaluated between January 2009 and December 2019 was performed. Patient demographics, lesion characteristics, and procedural details were recorded. For the purposes of this study, 11 years or older in females and 12 years or older in males were the established cut-offs for the onset of puberty.
After initial screening of 357 patients, 83 patients were included in the study based on inclusion criteria. There were 34 patients with LM (41 %) and 49 with VM (59 %). The mean age at diagnosis was 6.1 ± 10.9 years (LM: 4.2 ± 7.0, VM: 7.4 ± 12.9, p = 0.489). 68 patients underwent treatments, which included sclerotherapy, surgical excision, and/or laser. For all patients, the average number of lifetime treatments when initiated before puberty was 3.78 ± 2.81 and when initiated after puberty was 2.17 ± 1.37 (p = 0.022). Patients diagnosed pre-puberty were more likely to undergo treatments vs. those diagnosed after puberty (OR 10.00, 95 % CI: 2.61–38.28, p < 0.001).
We found that the number of treatments was fewer in those who started treatment after puberty. This finding suggests that providers may elect to proceed with observation in asymptomatic patients, given that waiting until after the onset of puberty has not shown an increase in the procedural load on patients.
Subperiosteal orbital abscesses (SPOA) are the most common suppurative complications of acute bacterial sinusitis. Medial SPOAs arise from infection of the ipsilateral ethmoid sinus and favor initial ...conservative management reserving surgical drainage for patients who do not demonstrate clinical improvement. No standard algorithm defining medical versus surgical treatment of medial SPOAs exist in the pediatric population.
To identify a size cutoff for medial SPOAs to predict the likelihood for surgical drainage.
This is a retrospective review of patients with medial SPOAs at a tertiary care center from 2003 to 2017. Diagnosis of SPOA was based on radiographic findings. Variables included are patient demographics, antibiotic therapy, surgical intervention, and length of stay.
82 patients with a medial SPOA were included with an average age at presentation of 6.27 (range 0–15) years were included in this study. 62 patients were male (75.6 %), and 20 were female (24.4 %). The average abscess length was 16.1 mm, range 4.5–30.7 mm. The average abscess width was 4.17 mm, range 1.5–14.6 mm. The odds ratio for surgical treatment with every 1 mm increase in abscess width was 1.89 (95CI:1.33–2.69, p < 0.001). Abscesses over 3.6 mm width were 6.65 times more likely to undergo surgical drainage than those less than 3.6 mm (OR:6.65, 95CI:2.52–17.54, p < 0.001). The average(SD) length of stay was 5.4(3.0) days for patients who underwent surgery and 4.0(0.9) days for patients treated with conservative measures, p < 0.001.
Medial SPOAs greater than 3.6 mm were more likely to undergo surgical drainage; however there was no difference in the likelihood of drainage between anteriorly and posteriorly based medial abscesses. These findings help further characterize the landscape of pediatric subperiosteal abscesses that are managed with surgical drainage.
Subperiosteal orbital abscess (SPOA) is a serious suppurative complication of pediatric sinusitis. The objective of this study is to stratify patient selection into those best treated medically ...versus surgically based on clinical outcomes.
This is a retrospective review of patients diagnosed with SPOA complicating sinusitis treated at a tertiary care pediatric hospital from 2002 through 2016. SPOA was diagnosed by CT scan. Characteristics evaluated include demographics, abscess size, location, and measurements, length of hospital stay, medical and surgical interventions, presenting symptoms, and complications.
A total of 108 total SPOA secondary to sinusitis patients were included. A majority, 72.2%, were male with an average age at presentation of 6.8 years. The mean ± standard deviation abscess cubic volume was 0.98 ± 1.27 cm3 (median(range) = 0.44(0.01–7.34 cmcm3)). With an abscess volume of 0.510 cm3, there was a sensitivity of 71.2% and a specificity of 84.4% for needing surgical drainage. Those with large abscesses at our volume threshold were 13 times more likely to require surgery than those with small abscesses, OR: 13.41, 95%CI: 5.02–35.86, p < .001. Patients that required surgery had an abscess closer to the orbital apex with the majority, 25 (61.0%), being the most proximal to the apex, p = .004. The likelihood of surgery decreased with increased distance from the orbital apex in medial abscesses (OR:.92, 95%CI: 0.86-0.98, p = .009).
In the pediatric population, SPOA is a serious consequence of sinusitis. This study provides evidence supporting that larger abscess size is a significant risk factor for requiring surgery. The appeal of our study is that it provides evidence and support that employ clinical parameters already assessed as standard practice in evaluating these patients. In summarizing the clinical translational relevance of our study, when determining whether to treat a patient with surgery and antimicrobial/medical therapy vs. non-surgical medical therapy alone, the clinician should focus on size of 0.510 cm3 or larger for abscesses in any location as a relative indication for surgery.
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