Postoperative outcomes and stimulation responses for sectioned nerve roots during selective dorsal rhizotomy in cerebral palsy.

BACKGROUND: Cerebral palsy (CP) is the most cause of motor dysfunction in children. Selective dorsal rhizotomy (SDR) plays a major role in long term spasticity control. However, limited data exists on the effect of SDR on postoperative spasticity treatment requirements and supraspinal effects, and the stimulation responses of dorsal nerve roots in those with CP. METHODS: The current study included the outcome for 35 individuals undergoing SDR for motor functional outcome, spasticity, baclofen dose changes, botulinum toxin injection frequency, and spasticity related orthopedic procedures. We also report on the stimulation responses in 112 individuals who underwent SDR at our institution. RESULTS: There was a significant difference in gross motor function measures (GMFM)-66 scores at last follow up that remained present when considering only ambulatory children but not with non-ambulatory children. Ashworth scores were significantly decreased for both upper and lower extremities after SDR at all follow up points. There was a significant decrease in Baclofen dose and botulinum toxin injections requirements after SDR, but no significant difference in the need for orthopedic intervention. A total of 5502 dorsal nerve roots were tested showing a decrease in stimulation intensity and increase in grade on the right side and for descending lumbosacral levels. CONCLUSIONS: SDR improves gross motor scores during short term follow up but has additional benefits in decreasing baclofen dosing and botulinum toxin injections requirements after surgery. They stimulation responses of sectioned dorsal nerve roots adds to the limited available data and our understanding of the pathological changes that occur in CP.

Evaluating the Outcomes and Trainee Performance of a Canadian Medical Imaging Clinician Investigator Program.

Purpose: To measure the research productivity of trainees from the University of Toronto's Medical Imaging Clinician Investigator Program (MI-CIP) and comparing it with the research productivity of trainees from MI-non-CIP and General Surgery (GSx) Clinician Investigator Program. Methods: We identified residents who completed an MI-CIP, MI-non-CIP and GSx-CIP from 2006-2016. In each group of trainees, we assessed 3 research productivity outcomes with non-parametric tests before residency and at 7 years post-CIP completion/post-graduation. Research productivity outcomes include the number of total publications, the number of first-author publications, and the publication's average journal impact factor (IF). Results: We identified 11 MI-CIP trainees (male/female: 9 [82%]/2 [18%]), 74 MI-non-CIP trainees (46 [62%]/28 [38%]) and 41 GSx-CIP trainees (23 [56%]/18 [44%]). MI-CIP trainees had statistically significant higher research productivity than MI-non-CIP in all measured outcomes. The median (interquartile range, IQR) number of total publications of MI-CIP vs MI-non-CIP trainees was 5.0 (8.0) vs 1.0 (2.0) before residency and 6.0 (10.0) vs .0 (2.0) at 7 years post-CIP completion/post-graduation. The median (IQR) first-author publications of MI-CIP vs MI-non-CIP trainees was 2.0 (3.0) vs .0 (1.0) before residency and 2.0 (4.0) vs (.0) (1.0) at 7 years post-CIP completion/post-graduation. The median (IQR) average journal IF of MI-CIP vs MI-non-CIP trainees was 3.2 (2.0) vs .3 (2.4) before residency and 3.9 (3.2) vs .0 (2.6) at 7 years post-CIP completion/post-graduation. Between MI-CIP and GSx-CIP trainees, there were no significant differences in research productivity in all measured outcomes. Conclusion: MI-CIP trainees actively conducted research after graduation. These trainees demonstrated early research engagement before residency. The similar research productivity of MI-CIP vs GSx-CIP trainees shows initial success of MI-CIP trainees.

The impact of response to iron therapy on maternal and neonatal outcomes among pregnant women with anemia.

BACKGROUND: Anemia during pregnancy is associated with increased risks of preterm birth, preeclampsia, cesarean delivery, and maternal morbidity. The most prevalent modifiable cause of pregnancy-associated anemia is iron deficiency. However, it is still unclear whether iron therapy can reduce the risks of adverse outcomes in women with anemia. OBJECTIVE: This study aimed to determine whether response to iron therapy among women with anemia is associated with a change in odds of adverse maternal and neonatal outcomes. STUDY DESIGN: This was a population-based cohort study (2011-2019) using an institutional database composed of obstetrical patients from 2 delivery hospitals. Patients with adequate prenatal care were classified as being anemic or nonanemic (reference). Patients with anemia were further stratified by success or failure of treatment with oral iron therapy using the American College of Obstetricians and Gynecologists criteria for anemia at the time of admission for delivery: successfully treated (Hgb≥11 g/dL) or unsuccessfully treated ("refractory;" Hgb<11 g/dL). All categories of women with anemia categories were compared with the reference group of women without anemia using chi-square and logistic regression analyses. The primary outcomes were preterm birth and preeclampsia. RESULTS: Among the 20,690 women observed, 7416 (35.8%) were anemic. Among women with anemia, 1319 (17.8%) were refractory to iron therapy, 2695 (36.3%) had a successful response to therapy, and 3402 (45.9%) were untreated. Successfully treated patients with anemia had a significant reduction in the odds of preterm birth (5.1% vs 8.3%; adjusted odds ratio, 0.59; 95% confidence interval, 0.47-0.72) and preeclampsia (5.9% vs 8.3%; adjusted odds ratio, 0.75; 95% confidence interval, 0.61-0.91). Refractory and untreated patients had significantly increased odds of preterm birth (adjusted odds ratio, 1.44 [95% confidence interval, 1.16-1.76] and 1.45 [95% confidence interval, 1.26-1.67], respectively) and preeclampsia (adjusted odds ratio, 1.54 [95% confidence interval, 1.24-1.89] and 1.44 [95% confidence interval, 1.25-1.67], respectively). All groups of women with anemia had increased odds of postpartum hemorrhage and decreased odds of delivering a small for gestational age neonate. There was no difference in composite neonatal morbidity. CONCLUSION: Successful treatment of anemia with oral iron therapy was associated with a reduction in the odds of preterm birth and preeclampsia. Women with refractory anemia had similar outcomes to those who were untreated, emphasizing the importance of monitoring response to iron therapy during pregnancy.

Outcomes That Matter Most to Young Adults Diagnosed with Cancer: A Qualitative Study.

Purpose: The purpose of this study is to provide insight for improvement in care for young adults diagnosed with cancer (YADC), by identifying underemphasized outcomes that strongly matter to YADC and the gaps in care that may limit achieving these outcomes for this unique and vulnerable population. Methods: Twenty-seven YADC, ages 25-39, participated in unstructured discussions focusing on topics relating to diagnosis, daily experiences living with cancer outside of the clinical setting, goals, concerns, and clinical care experience. Most participants engaged in group discussions using Experience Group methodology. Discussions were designed to collect information on three dimensions of health: capability, comfort, and calm (CCC). Data were coded using thematic analysis with NVivo software. Results: Several themes were identified within the CCC framework: capability in terms of confronting mortality at a young age, losing youthful identity and control over major life course decisions, especially fertility, and debilitating side effects, comfort in terms of the lack of understanding from peers and family and the fear of cancer recurrence, and calm was discussed as the difficulty of making complex medical decisions, financial toxicity, and loss of clinical support in survivorship. Conclusion: This research highlighted four care additions that are important for YADC: (1) concise and understandable education about their condition and treatment; (2) same-age support groups; (3) fertility support; and (4) better care transitions for life after cancer. These findings emphasize the importance of creating a collaborative, multidisciplinary care team and a holistic approach with care innovations that support clinicians to meet the unique needs of YADC.

Evaluation of human immunodeficiency virus-adapted group prenatal care.

BACKGROUND: Efforts to further decrease perinatal transmission of HIV include efforts to improve engagement and retention in prenatal care. Group prenatal care has been reported to have benefits in certain other high-risk groups of pregnant women but has not been previously evaluated in pregnant women living with HIV. OBJECTIVE: This study aimed to evaluate changes in HIV knowledge, stigma, social support, depression, self-efficacy, and medication adherence after HIV-adapted group prenatal care. STUDY DESIGN: All women living with HIV who presented for prenatal care at ≤30 weeks' gestation in Harris Health System (Houston, TX) between September 2013 and December 2017 were offered either group or individual HIV-focused prenatal care. Patients were recruited for the study at their initial prenatal visit. HIV topics, such as HIV facts, disclosure, medication adherence, safe sex and conception, retention in care, and postdelivery baby testing, were added to the standard CenteringPregnancy curriculum (ten 2-hour sessions per pregnancy). Knowledge and attitudes toward factors associated with adherence to HIV treatment regimens (stigma, loneliness, perceived social support, and depressive symptoms) were compared on written pre- and postsurveys. Surveys included 58 items derived from validated scales, with Likert and dichotomous responses. McNemar's test, Wilcoxon signed-rank test, and paired t-tests compared pre- and postsurvey responses. RESULTS: A total of 190 women living with HIV received prenatal care in the clinic during the study period, 93 (49%) of whom participated in CenteringHIV. A total of 66 Centering participants enrolled in the study and 42 of those completed the pre- and postsurveys. Among women in the Centering program who completed pre- and postsurveys, significant differences were noted with improved perceived social support from family (P=.011) and friends (P=.005), decreased depression (Edinburg Postnatal Depression Scale, ≥10; 43% vs 18%; P<.001; Edinburg Postnatal Depression Scale score mean (standard deviation), 9.3 (5.8) pre vs 5.2 (4.9) post; P<.001), and decreased missed medication doses related to depressed mood (P=.014). No statistically significant differences were noted in HIV knowledge, HIV stigma, attitude, or self-efficacy. CONCLUSION: HIV-focused group prenatal care may positively affect perceived social support and depression scores, factors that are closely associated with antiretroviral adherence and retention in the care for pregnant women living with HIV.

Distinct mechanisms of mutagenic processing of alternative DNA structures by repair proteins.

Repetitive sequences can form a variety of alternative DNA structures (non-B DNA) that can modulate transcription, replication, and repair. However, non-B DNA-forming sequences can also stimulate mutagenesis, and are enriched at mutation hotspots in human cancer genomes. Interestingly, different types of non-B DNA stimulate mutagenesis via distinct repair processing mechanisms.

Neurophysiologic intraoperative monitoring (NIOM) in pediatric patients with polyneuropathy.

PURPOSE: Neurophysiologic intraoperative monitoring (NIOM) abnormalities during scoliosis surgery led to a diagnosis of Friedreich's ataxia in this illustrative case. This prompted the retrospective examination of NIOM for pediatric scoliosis surgery in polyneuropathy patients. METHODS: Among patients who underwent scoliosis surgery in 2010-2017, there were six polyneuropathy patients identified. Their clinical history and baseline NIOM data were reviewed. RESULTS: Scoliosis accompanied Charcot-Marie-Tooth disease, Friedreich's ataxia, and ataxia telangiectasia. Some patients with no recorded somatosensory evoked potentials (SEPs) exhibited motor evoked potentials (MEPs); no patients with absent MEPs had SEPs present. NIOM modifications included SEP stimulation rate; type of SEP electrodes used; train parameters for MEP acquisition; and sweep speed. CONCLUSIONS: This sample of NIOM data for previously monitored scoliosis cases in children with polyneuropathy allowed investigation of patterns of findings and troubleshooting attempts to optimize monitoring. Attentiveness to pertinent medical history prepared the NIOM team to change typical recording parameters based on underlying polyneuropathy. A multimodality approach provided useful information as several of these cases would have been unmonitorable with use of SEPs alone. As for the case described, the awareness of NIOM patterns in polyneuropathy may guide evaluations of patients with presumed idiopathic scoliosis who have unrecognized polyneuropathy.

Distinct DNA repair pathways cause genomic instability at alternative DNA structures.

Alternative DNA structure-forming sequences can stimulate mutagenesis and are enriched at mutation hotspots in human cancer genomes, implicating them in disease etiology. However, the mechanisms involved are not well characterized. Here, we discover that Z-DNA is mutagenic in yeast as well as human cells, and that the nucleotide excision repair complex, Rad10-Rad1(ERCC1-XPF), and the mismatch repair complex, Msh2-Msh3, are required for Z-DNA-induced genetic instability in yeast and human cells. Both ERCC1-XPF and MSH2-MSH3 bind to Z-DNA-forming sequences, though ERCC1-XPF recruitment to Z-DNA is dependent on MSH2-MSH3. Moreover, ERCC1-XPF-dependent DNA strand-breaks occur near the Z-DNA-forming region in human cell extracts, and we model these interactions at the sub-molecular level. We propose a relationship in which these complexes recognize and process Z-DNA in eukaryotes, representing a mechanism of Z-DNA-induced genomic instability.

Exposure to group B Streptococcal antibiotic prophylaxis and early childhood body mass index in a vaginal birth cohort.

Purpose: Perinatal antibiotic exposure may be associated with changes in both early infancy gut microbiota and later childhood obesity. Our objective was to evaluate if group B Streptococcus (GBS) antibiotic prophylaxis is associated with higher body mass index (BMI) in early childhood.Materials and methods: This is a retrospective cohort study of mother/child dyads in a single hospital system over a 6-year period. All women with term, singleton, vertex, vaginal deliveries who received no antibiotics or received antibiotics only for GBS prophylaxis and whose children had BMIs available at 2-5 years of age were included. Children were divided into three groups for comparison: children born to GBS positive mothers that received antibiotics solely for GBS prophylaxis, children born to GBS negative women that received no antibiotics (healthy controls), and children born to GBS positive mothers who received no antibiotics. The primary outcome was the earliest available child BMI Z-score at 2-5 years of age. Multivariable linear regression was used to estimate differences in child BMI Z-scores between groups, adjusted for maternal BMI, age, race, parity, tobacco use, and child birthweight.Results: Of 4825 women, 786 (16.3%) were GBS positive and received prophylactic antibiotics, 3916 (81.2%) were GBS negative and received no antibiotics, and 123 (2.5%) were GBS positive but received no antibiotics. Childhood BMI Z-scores were similar between children exposed to intrapartum GBS prophylaxis and healthy controls who were unexposed in both unadjusted (mean (SE), 0.04 (0.04) versus -0.3 (0.02), p = .11) and adjusted (0.01 (0.05) versus -0.04 (0.03), p = .3) models.Conclusions: Exposure to intrapartum antibiotic prophylaxis for GBS was not associated with higher early childhood BMI Z-scores compared to healthy controls.

Parental preferences on diagnostic imaging tests for paediatric appendicitis.

OBJECTIVES: To determine parental preferences for diagnostic imaging tests (DITs) for paediatric appendicitis, to rank the attributes impacting the DIT selection and to identify DIT attributes that would cause parents to switch their DIT. METHODS: Parents of children who had an abdominal ultrasound (US) for right lower quadrant pain were interviewed. Two DITs were compared at a time, parents were asked to indicate their preferred test and to rank its attributes according to the impact each attribute had on their selection. The strength of their preference for the chosen DIT was measured by systematically adjusting attributes of the chosen DIT until the parent changed their choice. RESULTS: Fifty parents were interviewed. For US versus CT, more parents preferred US (68%, P=0.02) with higher importance ranks for cancer risk (P<0.0001), test accuracy (P=0.04), pain during test (P=0.3), and scan length (P<0.0001); and lower ranks for sedation (P=0.02), intravenous (IV) (P<0.02), and oral contrast (P=0.06). For US versus MRI, parents preferred MRI (78%, P<0.0001) with higher importance ranks for accuracy (P=0.2), pain during test (P=0.06), and scan length (P=0.06); and lower for noise (P<0.0001), claustrophobia (P<0.0001), use of IV contrast (P=0.06), and sedation (P=0.2). CONCLUSION: US and MRI were the DIT preferred by parents for the investigation of acute paediatric appendicitis.

Characterization and effect of metal ions on the formation of the Thermus thermophilus Sco mixed disulfide intermediate.

The Sco protein from Thermus thermophilus has previously been shown to perform a disulfide bond reduction in the CuA protein from T. thermophilus, which is a soluble protein engineered from subunit II of cytochrome ba 3 oxidase that lacks the transmembrane helix. The native cysteines on TtSco and TtCuA were mutated to serine residues to probe the reactivities of the individual cysteines. Conjugation of TNB to the remaining cysteine in TtCuA and subsequent release upon incubation with the complementary TtSco protein demonstrated the formation of the mixed disulfide intermediate. The cysteine of TtSco that attacks the disulfide bond in the target TtCuA protein was determined to be TtSco Cysteine 49. This cysteine is likely more reactive than Cysteine 53 due to a higher degree of solvent exposure. Removal of the metal binding histidine, His 139, does not change MDI formation. However, altering the arginine adjacent to the reactive cysteine in Sco (Arginine 48) does alter the formation of the MDI. Binding of Cu2+ or Cu+ to TtSco prior to reaction with TtCuA was found to preclude formation of the mixed disulfide intermediate. These results shed light on a mechanism of disulfide bond reduction by the TtSco protein and may point to a possible role of metal binding in regulating the activity. IMPORTANCE: The function of Sco is at the center of many studies. The disulfide bond reduction in CuA by Sco is investigated herein and the effect of metal ions on the ability to reduce and form a mixed disulfide intermediate are also probed.

Distinct Mechanisms of Nuclease-Directed DNA-Structure-Induced Genetic Instability in Cancer Genomes.

Sequences with the capacity to adopt alternative DNA structures have been implicated in cancer etiology; however, the mechanisms are unclear. For example, H-DNA-forming sequences within oncogenes have been shown to stimulate genetic instability in mammals. Here, we report that H-DNA-forming sequences are enriched at translocation breakpoints in human cancer genomes, further implicating them in cancer etiology. H-DNA-induced mutations were suppressed in human cells deficient in the nucleotide excision repair nucleases, ERCC1-XPF and XPG, but were stimulated in cells deficient in FEN1, a replication-related endonuclease. Further, we found that these nucleases cleaved H-DNA conformations, and the interactions of modeled H-DNA with ERCC1-XPF, XPG, and FEN1 proteins were explored at the sub-molecular level. The results suggest mechanisms of genetic instability triggered by H-DNA through distinct structure-specific, cleavage-based replication-independent and replication-dependent pathways, providing critical evidence for a role of the DNA structure itself in the etiology of cancer and other human diseases.

Accuracy of magnetic resonance imaging for measuring maturing cartilage: A phantom study

OBJECTIVES: To evaluate the accuracy of magnetic resonance imaging measurements of cartilage tissue-mimicking phantoms and to determine a combination of magnetic resonance imaging parameters to optimize accuracy while minimizing scan time. METHOD: Edge dimensions from 4 rectangular agar phantoms ranging from 10.5 to 14.5 mm in length and 1.25 to 5.5 mm in width were independently measured by two readers using a steel ruler. Coronal T1 spin echo (T1 SE), fast spoiled gradient-recalled echo (FSPGR) and multiplanar gradient-recalled echo (GRE MPGR) sequences were used to obtain phantom images on a 1.5-T scanner. RESULTS: Inter- and intra-reader reliability were high for both direct measurements and for magnetic resonance imaging measurements of phantoms. Statistically significant differences were noted between the mean direct measurements and the mean magnetic resonance imaging measurements for phantom 1 when using a GRE MPGR sequence (512x512 pixels, 1.5-mm slice thickness, 5:49 min scan time), while borderline differences were noted for T1 SE sequences with the following parameters: 320x320 pixels, 1.5-mm slice thickness, 6:11 min scan time; 320x320 pixels, 4-mm slice thickness, 6:11 min scan time; and 512x512 pixels, 1.5-mm slice thickness, 9:48 min scan time. Borderline differences were also noted when using a FSPGR sequence with 512x512 pixels, a 1.5-mm slice thickness and a 3:36 min scan time. CONCLUSIONS: FSPGR sequences, regardless of the magnetic resonance imaging parameter combination used, provided accurate measurements. The GRE MPGR sequence using 512x512 pixels, a 1.5-mm slice thickness and a 5:49 min scan time and, to a lesser degree, all tested T1 SE sequences produced suboptimal accuracy when measuring the widest phantom.

A multistep genomic screen identifies new genes required for repair of DNA double-strand breaks in Saccharomyces cerevisiae.

BACKGROUND: Efficient mechanisms for rejoining of DNA double-strand breaks (DSBs) are vital because misrepair of such lesions leads to mutation, aneuploidy and loss of cell viability. DSB repair is mediated by proteins acting in two major pathways, called homologous recombination and nonhomologous end-joining. Repair efficiency is also modulated by other processes such as sister chromatid cohesion, nucleosome remodeling and DNA damage checkpoints. The total number of genes influencing DSB repair efficiency is unknown. RESULTS: To identify new yeast genes affecting DSB repair, genes linked to gamma radiation resistance in previous genome-wide surveys were tested for their impact on repair of site-specific DSBs generated by in vivo expression of EcoRI endonuclease. Eight members of the RAD52 group of DNA repair genes (RAD50, RAD51, RAD52, RAD54, RAD55, RAD57, MRE11 and XRS2) and 73 additional genes were found to be required for efficient repair of EcoRI-induced DSBs in screens utilizing both MATa and MATα deletion strain libraries. Most mutants were also sensitive to the clastogenic chemicals MMS and bleomycin. Several of the non-RAD52 group genes have previously been linked to DNA repair and over half of the genes affect nuclear processes. Many proteins encoded by the protective genes have previously been shown to associate physically with each other and with known DNA repair proteins in high-throughput proteomics studies. A majority of the proteins (64%) share sequence similarity with human proteins, suggesting that they serve similar functions. CONCLUSIONS: We have used a genetic screening approach to detect new genes required for efficient repair of DSBs in Saccharomyces cerevisiae. The findings have spotlighted new genes that are critical for maintenance of genome integrity and are therefore of greatest concern for their potential impact when the corresponding gene orthologs and homologs are inactivated or polymorphic in human cells.