Steroid myopathy and rehabilitation in patients with cancer.

Steroids are broadly used in oncology, despite known adverse events such as glucocorticosteroid-induced myopathy (SM). To date there are no accepted guidelines on the diagnosis and treatment of SM. The purpose of this review is to provide up-to-date information regarding SM with emphasis on neuro-oncology and hematopoietic stem cell transplant patients, given they are at high risk of experiencing SM following routine treatment with steroids. Our work is a combination of a comprehensive narrative review regarding etiology, pathogenesis, incidence, clinical presentation and treatment options for SM and a scoping review on the exercise therapy for SM. We have identified 24 in vivo studies of different exercise modalities in the settings of glucocorticosteroid treatment. Twenty of 24 studies demonstrated decreased muscle catabolism with exercise training. Both endurance and resistance exercises at mild to moderate intensity were beneficial. The value of high-intensity activities remains questionable as it may worsen muscle atrophy. Rehabilitation interventions, along with pharmacologic and dietary considerations, may be beneficial in preventing or reversing SM. Potential adverse events of some of these interventions and expected caveats in translating findings in preclinical models to human settings warrant caution and demand controlled clinical studies.

Ambulation after in-utero fetoscopic and open spina bifida repair: predictors for ambulation at 30 months.

OBJECTIVE: Ambulatory outcomes from children who underwent a new minimally invasive fetal spina bifida surgery approach are included in this study for the first time. Identifying cases with better chances of independent ambulation from fetal life can have an important impact on patient counseling. The objectives of this study were: (1) To compare the ambulatory status of a cohort of children who had a prenatal spina bifida repair using two different methods (fetoscopic and open) with a cohort who underwent postnatal repair; and (2) to identify the best predictors for ambulation. METHODS: Retrospective review of a cohort of children who had spina bifida repair from 2011-2023 using prenatal fetoscopic surgery (N=73), prenatal open-hysterotomy surgery (N=37) or postnatal repair (N=51) in a single tertiary hospital. Consecutive sample of cases who underwent a spina bifida repair in utero following MoMs trial criteria and cases who underwent postnatal repair, meeting same criteria, also followed up after birth at the same institution. Motor function (MF) assessment by ultrasound was recorded at initial evaluation (MF1), 6 postoperative weeks or equivalent (MF2) and prior to delivery (MF3). Clinical exams to assess MF at birth and at 12 months were recorded. First sacral myotome (S1) MF was classified as "intact MF". Ambulatory status data at each follow-up visit was collected. The proportion of cases who were able to walk independently were compared between fetoscopic and open prenatal surgeries and between prenatal (by fetoscopic or open surgery) and postnatal spina bifida repair. Logistic regression analyses were performed to identify predictors for independent ambulation. RESULTS: At 30 months, the proportion of independent ambulators was higher in prenatally vs. postnatally repaired cases (51.8% vs.15.7%; p<0.01). No differences in ambulatory outcomes were seen in the comparison between fetoscopic (52%) vs. open (51.3%; p=0.95) prenatal repair. In the prenatal repair group, having an "intact MF" at 12 months [Odds ratio 7.71 (95%CI: 2.77-21.47), p<0.01] and at birth [4.38 (1.53-12.56), p<0.01], predicted significantly being an independent ambulator by 30 months; the anatomical level of lesion below L2 was also predictive for this outcome [3.68(1.33-9.88), p=0.01]. CONCLUSION: Ambulatory status by 30 months can be predicted by observing S1 MF postnatally. Results from this study have implications for parental counseling and planning for supportive therapies. This article is protected by copyright. All rights reserved.

Perforation of cavum septi pellucidi in open spina bifida and need for hydrocephalus treatment by 1 year of age.

OBJECTIVE: In-utero repair of an open neural tube defect (ONTD) reduces the risk of developing severe hydrocephalus postnatally. Perforation of the cavum septi pellucidi (CSP) may reflect increased intraventricular pressure in the fetal brain. We sought to evaluate the association of perforated CSP visualized on fetal imaging before and/or after in-utero ONTD repair with the eventual need for hydrocephalus treatment by 1 year of age. METHODS: This was a retrospective cohort study of consecutive patients who underwent laparotomy-assisted fetoscopic ONTD repair between 2014 and 2021 at a single center. Eligibility criteria for surgery were based on those of the Management of Myelomeningocele Study (MOMS), although a maternal prepregnancy body mass index of up to 40 kg/m2 was allowed. Fetal brain imaging was performed with ultrasound and magnetic resonance imaging (MRI) at referral and 6 weeks postoperatively. Stored ultrasound and MRI scans were reviewed retrospectively to assess CSP integrity. Medical records were reviewed to determine whether hydrocephalus treatment was needed within 1 year of age. Parametric and non-parametric tests were used as appropriate to compare outcomes between cases with perforated CSP and those with intact CSP as determined on ultrasound at referral. Logistic regression analysis was performed to assess the predictive performance of various imaging markers for the need for hydrocephalus treatment. RESULTS: A total of 110 patients were included. Perforated CSP was identified in 20.6% and 22.6% of cases on preoperative ultrasound and MRI, respectively, and in 26.6% and 24.2% on postoperative ultrasound and MRI, respectively. Ventricular size increased between referral and after surgery (median, 11.00 (range, 5.89-21.45) mm vs 16.00 (range, 7.00-43.5) mm; P < 0.01), as did the proportion of cases with severe ventriculomegaly (ventricular width ≥ 15 mm) (12.7% vs 57.8%; P < 0.01). Complete CSP evaluation was achieved on preoperative ultrasound in 107 cases, of which 22 had a perforated CSP and 85 had an intact CSP. The perforated-CSP group presented with larger ventricles (mean, 14.32 ± 3.45 mm vs 10.37 ± 2.37 mm; P < 0.01) and a higher rate of severe ventriculomegaly (40.9% vs 5.9%; P < 0.01) compared to those with an intact CSP. The same trends were observed at 6 weeks postoperatively for mean ventricular size (median, 21.0 (range, 13.0-43.5) mm vs 14.3 (range, 7.0-29.0) mm; P < 0.01) and severe ventriculomegaly (95.0% vs 46.8%; P < 0.01). Cases with a perforated CSP at referral had a lower rate of hindbrain herniation (HBH) reversal postoperatively (65.0% vs 88.6%; P = 0.01) and were more likely to require treatment for hydrocephalus (89.5% vs 22.7%; P < 0.01). The strongest predictor of the need for hydrocephalus treatment within 1 year of age was lack of HBH reversal on MRI (odds ratio (OR), 36.20 (95% CI, 5.96-219.12); P < 0.01) followed by perforated CSP on ultrasound at referral (OR, 23.40 (95% CI, 5.42-100.98); P < 0.01) and by perforated CSP at 6-week postoperative ultrasound (OR, 19.48 (95% CI, 5.68-66.68); P < 0.01). CONCLUSIONS: The detection of a perforated CSP in fetuses with ONTD can reliably identify those cases at highest risk for needing hydrocephalus treatment by 1 year of age. Evaluation of this brain structure can improve counseling of families considering fetal surgery for ONTD, in order to set appropriate expectations about postnatal outcome. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

IL-6 selectively suppresses cDC1 specification via C/EBPß.

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPß in the common dendritic cell progenitor (CDP). C/EBPß and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPß expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPß binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPß induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity.

Mechanisms of CD40-dependent cDC1 licensing beyond costimulation.

CD40 signaling in classical type 1 dendritic cells (cDC1s) is required for CD8 T cell-mediated tumor rejection, but the underlying mechanisms are incompletely understood. Here, we identified CD40-induced genes in cDC1s, including Cd70, Tnfsf9, Ptgs2 and Bcl2l1, and examined their contributions to anti-tumor immunity. cDC1-specific inactivation of CD70 and COX-2, and global CD27 inactivation, only partially impaired tumor rejection or tumor-specific CD8 T cell expansion. Loss of 4-1BB, alone or in Cd27-/- mice, did not further impair anti-tumor immunity. However, cDC1-specific CD40 inactivation reduced cDC1 mitochondrial transmembrane potential and increased caspase activation in tumor-draining lymph nodes, reducing migratory cDC1 numbers in vivo. Similar impairments occurred during in vitro antigen presentation by Cd40-/- cDC1s to CD8+ T cells, which were reversed by re-expression of Bcl2l1. Thus, CD40 signaling in cDC1s not only induces costimulatory ligands for CD8+ T cells but also induces Bcl2l1 that sustains cDC1 survival during priming of anti-tumor responses.

cDC1 Vaccines Drive Tumor Rejection by Direct Presentation Independently of Host cDC1.

As a cell-based cancer vaccine, dendritic cells (DC), derived from peripheral blood monocytes or bone marrow (BM) treated with GM-CSF (GMDC), were initially thought to induce antitumor immunity by presenting tumor antigens directly to host T cells. Subsequent work revealed that GMDCs do not directly prime tumor-specific T cells, but must transfer their antigens to host DCs. This reduces their advantage over strictly antigen-based strategies proposed as cancer vaccines. Type 1 conventional DCs (cDC1) have been reported to be superior to GMDCs as a cancer vaccine, but whether they act by transferring antigens to host DCs is unknown. To test this, we compared antitumor responses induced by GMDCs and cDC1 in Irf8 +32-/- mice, which lack endogenous cDC1 and cannot reject immunogenic fibrosarcomas. Both GMDCs and cDC1 could cross-present cell-associated antigens to CD8+ T cells in vitro. However, injection of GMDCs into tumors in Irf8 +32-/- mice did not induce antitumor immunity, consistent with their reported dependence on host cDC1. In contrast, injection of cDC1s into tumors in Irf8 +32-/- mice resulted in their migration to tumor-draining lymph nodes, activation of tumor-specific CD8+ T cells, and rejection of the tumors. Tumor rejection did not require the in vitro loading of cDC1 with antigens, indicating that acquisition of antigens in vivo is sufficient to induce antitumor responses. Finally, cDC1 vaccination showed abscopal effects, with rejection of untreated tumors growing concurrently on the opposite flank. These results suggest that cDC1 may be a useful future avenue to explore for antitumor therapy. See related Spotlight by Hubert et al., p. 918.

Structural and functional analysis of the human cone-rod homeobox transcription factor.

The cone-rod homeobox (CRX) protein is a critical K50 homeodomain transcription factor responsible for the differentiation and maintenance of photoreceptor neurons in the vertebrate retina. Mutant alleles in the human gene encoding CRX result in a variety of distinct blinding retinopathies, including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis. Despite the success of using in vitro biochemistry, animal models, and genomics approaches to study this clinically relevant transcription factor over the past 25 years since its initial characterization, there are no high-resolution structures in the published literature for the CRX protein. In this study, we use bioinformatic approaches and small-angle X-ray scattering (SAXS) structural analysis to further understand the biochemical complexity of the human CRX homeodomain (CRX-HD). We find that the CRX-HD is a compact, globular monomer in solution that can specifically bind functional cis-regulatory elements encoded upstream of retina-specific genes. This study presents the first structural analysis of CRX, paving the way for a new approach to studying the biochemistry of this protein and its disease-causing mutant protein variants.

Mortality risk associated with greenness, air pollution, and physical activity in a representative U.S. cohort.

Several cohort studies suggest greenness is associated with decreased mortality risk. Potential confounding by or interactions between physical activity and air pollution remains unclear. This study evaluates associations of greenness, air pollution, and physical activity with mortality risk and investigates confounding and effect modification across these key risk factors. National Health Interview Survey (NHIS) data covering 1997-2014 were linked to the National Death Index to generate a cohort of 403,748 individuals with 39,528 deaths. Greenness, represented by census-tract Normalized Difference Vegetation Index (NDVI) for the seasonal period of May-October, was averaged over the years 2003-2016. Air pollution was estimated by census-tract level PM2.5 concentrations from 1999 to 2015. Cox Proportional Hazard Models were used to estimate hazard ratios (HR) for differences in greenness, air pollution, and physical activity. Alternative models that evaluated potential confounding and stratified models that evaluated effect modification were examined. Mortality risks were associated with PM2.5 (HR = 1.14, 95% CI: 1.09-1.19 per 10 µg/m3) and physical inactivity (1.49, 1.44-1.54 relative to sufficiently active), but not with greenness (1.01, 0.99-1.03 per IQR). The PM2.5-mortality association was mitigated at high levels of greenness (1.05, 0.91-1.22). There was no strong evidence of confounding between air pollution, physical activity, and greenness. However, stratified analysis suggested effect modification for PM2.5 and NDVI by physical activity. A significant protective greenness-mortality association was observed for only highly active individuals (0.91, 0.86-0.96). Also, relatively high PM2.5-mortality HRs were observed for more physically active individuals (1.25, 1.12-1.40). PM2.5 air pollution and physical inactivity are robustly associated with mortality risk. Greenness may be most beneficial and air pollution relatively harmful to highly active individuals. This analysis provides evidence that, in addition to not smoking, being physically active and living in a clean, green environment contributes to improved health and reduced risk of mortality.

HPV Vaccine Intent among Adult Women Receiving Care at Community Health Centers.

Human papillomavirus (HPV) is a disease that exacts substantial costs in human life and public health expenditures. Fortunately, a vaccine exists that can mitigate these costs. This study reports the development and evaluation of the intervention designed to overcome these barriers by using culturally grounded narratives to promote HPV vaccination. Women's Stories (WS) targets women over the age of 18 and was originally successfully validated for use among college students resulting in NCI recognition. WS was adapted for touch pad delivery in Planned Parenthood clinics where a randomized clinical trial was conducted in 8 clinics in 3 cities. Two hundred seventeen women were randomly assigned to treatment and control, completing pretest and posttest surveys. This study examined data from the immediate posttest. An intent to treat analysis was conducted using a generalized linear mixed modeling approach using a multinomial link and accounting for repeated measures by site. Results demonstrate significant short-term effects on vaccine intentions and vaccine self-efficacy. When compared to control group participants, women in the treatment condition more likely to intend to get the shot today/the day of interview (p < 0.01), as well as in 1 (p < 0.01) and 6 (p < 0.01) months and had greater self-efficacy to receive the HPV vaccination (B = 0.54; p = 0.0002). These results are promising for the potential impact of the intervention in clinical settings as well as providing a model for overcoming lack of awareness and vaccine resistance in other segments of the population.

Safety evaluation of odd-chain fatty acid algal oil.

In the food industry, most fatty acid-rich oils are primarily composed of saturated even-chain fatty acids. However, saturated odd-chain fatty acids are potentially a beneficial alternative to other saturated fatty acid-containing oils. In this communication, we examine the safety of odd-chain fatty acid (OCFA) algal oil, a microalgal-sourced oil composed primarily of the saturated odd-chain fatty acids pentadecanoic acid and heptadecanoic acid. OCFA algal oil was assessed for toxicity in a 14-day palatability study and comprehensive 13-week dietary study at inclusion levels of 5%, 10%, and 15% in the diet, utilizing a DHA-rich algal oil as a comparator control. No adverse effects attributed to the consumption of OCFA algal oil were observed in either study. Therefore, we report a No Observable Adverse Effect Level (NOAEL) of 150,000 ppm (15% in the diet), equivalent to an OCFA algal oil intake of 7553.9 and 8387.7 mg/kg bw/day for male and female rats, respectively. The genotoxic potential of OCFA algal oil was also examined in an in vitro bacterial reverse mutation assay and in vivo mammalian bone marrow chromosome aberration test. OCFA algal oil was non-mutagenic in Salmonella typhimurium and Escherichia coli test strains and did not exhibit clastogenicity in vivo.

Greenness, air pollution, and mortality risk: A U.S. cohort study of cancer patients and survivors.

BACKGROUND: Several studies suggest that living in areas of high surrounding greenness may be associated with a lower cardiopulmonary mortality risk. However, associations of greenness with specific causes of death in cancer patients and survivors has not been examined and it is unknown whether this relationship is affected by area levels of fine particulate matter air pollution (PM2.5). This study evaluated associations between greenness and PM2.5 on causes of death in a large, U.S.-based cohort of cancer patients and survivors. METHODS: Surveillance, Epidemiology and End Results (SEER) data were used to generate a cohort of 5,529,005 cancer patients and survivors from 2000 to 2016. Census-tract Normalized Difference Vegetation Index (NDVI) during May-October from 2003 to 2016 was population-weighted to act as a county-level greenness measure. County-level PM2.5 exposure was estimated from annual concentrations averaged from 1999 to 2015. Cox Proportional Hazards models were used to estimate the association between greenness, PM2.5, and cause-specific mortality while controlling for age, sex, race, and other individual and county level variables. FINDINGS: An IQR increase in greenness was associated with a decrease in cancer mortality for cancer patients (Hazard ratio of 0.94, 95% CI: 0.93-0.95), but not for cardiopulmonary mortality (0.98, 95% CI: 0.96-1.00). Inversely, an increase in 10 µg/m3 PM2.5 was associated with increased cardiopulmonary mortality (1.24, 95% CI: 1.19-1.29), but not cancer mortality (0.99, 95% CI: 0.97-1.00). Hazard ratios were robust to inclusion of PM2.5 in models with greenness and vice versa. Although exposure estimates were constant over most stratifications, greenness seemed to benefit individuals diagnosed with high survivability cancers (0.92, 95% CI: 0.90-0.95) more than those with low survivability cancers (0.98. 95% CI: 0.96-0.99). INTERPRETATION: Higher levels of greenness are associated with lower cancer mortality in cancer patients. The evidence suggests minimal confounding between greenness and PM2.5 exposures and risk of mortality.

Prenatal predictors of motor function in children with open spina bifida: a retrospective cohort study.

OBJECTIVE: To identify predictors for intact motor function (MF) at birth and at 12 months of life in babies with prenatally versus postnatally repaired open spina bifida (OSB). DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, 2011-2018. POPULATION: Patients who underwent either prenatal or postnatal OSB repair. METHODS: Prenatal MF of the lower extremities was evaluated by ultrasound following a metameric distribution at the time of diagnosis (US1), 6 weeks postoperatively (or 6 weeks after initial evaluation in postnatally repaired cases) (US2) and at the last ultrasound before delivery (US3). At birth and at 12 months, MF was assessed clinically. Intact MF (S1) was defined as the observation of plantar flexion of the ankle. Results from logistic regression analysis are expressed as odds ratios (95% confidence intervals, P values). RESULTS: A total of 127 patients were included: 93 with prenatal repair (51 fetoscopic; 42 open hysterotomy repair) and 34 with postnatal repair. In the prenatal repair group, predictors for intact MF at birth and at 12 months included: absence of clubfeet (OR 11.3, 95% CI 3.2-39.1, P < 0.01; OR 10.8 95% CI 2.4-47.6, P < 0.01); intact MF at US1 (OR 19.7, 95% CI 5.0-76.9, P < 0.01; OR 8.7, 95% CI 2.0-38.7, P < 0.01); intact MF at US2 (OR 22, 95% CI 6.5-74.2, P < 0.01; OR 13.5, 95% 3.0-61.4, P < 0.01); intact MF at US3 (OR 13.7, 95% CI 3.4-55.9, P < 0.01; OR 12.6, 95% CI 2.5-64.3, P < 0.01); and having a flat lesion (OR 11.2, 95% CI 2.4-51.1, P < 0.01; OR 4.1, 95% CI 1.1-16.5, P = 0.04). In the postnatal repair group, the only predictor of intact MF at 12 months was having intact MF at birth (OR 15.2, 95% CI 2.0-113.3, P = 0.03). CONCLUSIONS: The detection of intact MF in utero from mid-gestation to delivery predicts intact MF at birth and at 12 months in babies who undergo prenatal OSB repair. TWEETABLE ABSTRACT: Detection of intact motor function in utero predicts intact motor function at birth and at 1 year in fetuses who undergo prenatal OSB repair.

Impact of the size of the lesion in prenatal neural tube defect repair on imaging, neurosurgical and motor outcomes: a retrospective cohort study.

OBJECTIVES: (1) To compare brain findings between large and non-large neural tube defect (NTD); (2) to evaluate the impact of large lesion on the surgical parameters; (3) to study any associations between the size of the lesions and brain findings 6 weeks postoperatively and neurological short-term outcomes. DESIGN: Retrospective cohort study. SETTING: Texas Children's Hospital, between 2011 and 2018. POPULATION: Patients who underwent prenatal NTD repair. METHODS: Large lesion was defined when the lesion's surface was >75th centile of our cohorts' lesions. MAIN OUTCOME MEASURES: Time of referral: ventriculomegaly and anatomical level of the lesion; surgery: duration and need for relaxing incisions. 6 weeks postoperative: hindbrain herniation (HBH) and ventriculomegaly. After delivery: dehiscence, need for hydrocephalus treatment and motor function. RESULTS: A total of 99 patients were included, 25 of whom presented with large lesions. Type of lesion and ventriculomegaly were comparable between individuals with large and non-large lesions. Individuals with large lesions were associated with increased need for relaxing incisions by 5.4 times (95% CI 1.3-23.2, P = 0.02). Six weeks postoperatively, having a large lesion decreased by ten times the likelihood of having a postoperative reversal of HBH (odds ratio = 0.1, 95% CI 0.1-0.4, P < 0.01). At birth, larger lesions increased the risk for repair dehiscence by 6.1 times (95% CI 1.6-22.5, P < 0.01) and the risk of dehiscence or leakage of cerebrospinal fluid at birth by 5.5 times (95% CI 1.6-18.9, P < 0.01). CONCLUSION: Prenatal repair of patients with large NTD presents a lower proportion of HBH reversal 6 weeks after the surgery, a higher risk of dehiscence and a higher need for postnatal repair. TWEETABLE ABSTRACT: Evaluation of the size of fetal NTD can predict adverse neurological outcomes after prenatal NTD repair.

Longitudinal evaluation of motor function in patients who underwent prenatal or postnatal neural tube defect repair.

OBJECTIVE: To compare the evolution of motor function from mid-gestation to 12 months of age between prenatally and postnatally repaired cases of open neural tube defect (ONTD). METHODS: This was a retrospective cohort study of all fetuses that underwent prenatal (fetoscopic or open hysterotomy) or postnatal ONTD repair at a single institution between November 2011 and December 2018. The anatomical level of the lesion was defined as the upper bony spinal defect at initial magnetic resonance imaging assessment. Prenatal motor function of the lower extremities was evaluated by ultrasound according to the metameric level of the neurological lesion, based on the methodology of Carreras et al. Fetal motor function was assessed at referral, at 6 weeks after surgery in prenatally repaired cases or 6 weeks after referral in postnatally repaired cases (6-week follow-up) and at the last scan before delivery. In addition, motor function was assessed by a detailed neurological examination at birth and 12 months of age. First sacral (S1) neurological level of the lesion was considered as intact motor function. For statistical comparisons, we attributed numerical scores to each neurological level and motor function was expressed as median (range) neurological level. Motor function (as numerical score) and the proportion of cases with intact motor function and with motor function two or more levels better than expected based on the anatomical level of the lesion were compared between the prenatal- and postnatal-repair groups. Fetal motor function was compared to the anatomical level of the lesion at referral and a better motor function was defined when it was two or more levels better than the anatomical level of the lesion. To assess the evolution of motor function, we compared motor function at referral with that at each follow-up assessment using paired t-tests. RESULTS: We included 127 patients with ONTD, of whom 93 underwent prenatal (51 fetoscopic and 42 open hysterotomy) and 34 postnatal repair. At the time of referral, cases in the prenatal- and postnatal-repair groups presented with a similar anatomical level of lesion (L3 (T9-S1) vs L3 (T7-S1); P = 0.52), similar motor function (S1 (L1-S1) vs S1 (L1-S1); P = 0.52) and a similar proportion of cases with intact motor function (81% vs 79%; P = 0.88) and with motor function two or more levels better than expected based on the anatomical level of the lesion (62% vs 74%; P = 0.24). When compared with prenatally repaired cases, postnatally repaired cases showed worse motor function at birth (S1 (L1-S1) vs L4 (L1-S1); P < 0.01) and at 12 months of age (S1 (L1-S1) vs L4 (L1-S1); P < 0.01). In the prenatal-repair group, motor function remained stable from the time of referral to 12 months of age (P = 0.26). Furthermore, the proportion of patients with intact motor function at referral (81% (75/93)) was similar to that at the 6-week follow-up (74% (64/87)), at the last scan before birth (74% (42/57)), at birth (68% (63/93)) and at 12 months of age (67% (39/58)) in the prenatal-repair group. In the postnatal-repair group, worse motor function, starting from the third trimester to 12 months of age, was observed. The proportion of patients with intact motor function at referral (79% (27/34)) was similar to that at 6-week follow-up (80% (12/15); P = 0.92), but was lower at the last assessment before birth (25% (2/8); P < 0.01), at birth (24% (8/34); P < 0.01) and at 12 months of age (28% (7/25); P < 0.01). Similar findings were noted when assessing the evolution of the proportion of cases with motor function two or more levels better than expected based on the anatomical level of the lesion in each group. CONCLUSIONS: Infants with ONTD that underwent postnatal repair had worse motor function at birth and at 12 months of age than at mid-gestation and when compared with infants that underwent prenatal ONTD repair. Prenatal motor function assessment by ultrasound is an adequate tool to identify those infants who should have a good clinical motor function after delivery. Information obtained by fetal motor function assessment can have an important role for patient counseling and case selection for surgery. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Pilot Study of the Adaptation of an Alcohol, Tobacco, and Illicit Drug Use Intervention for Vulnerable Urban Young Adults.

Objectives: There is limited information about the applicability and effectiveness of tobacco and illicit drug use interventions in urban and racial/ethnic minority youth, a population with great need for prevention of alcohol and drug use. We pilot-tested the feasibility of a behavioral intervention to reduce alcohol, tobacco, and illicit drug use among urban young adults in New Orleans, Louisiana. Study Design: The 12-week intervention pilot project was developed to be implemented at a community-based social service organization that provides educational, juvenile justice-related case management, and mentoring services to youth with substance use and incarceration histories. Methods: One-hour intervention sessions included interactive discussions and lesson reviews guided by a health educator and peer facilitators. Recruitment was done by case managers. Thirty African American young adults aged 16-21 years participated between January 2016 and July 2017. Results: We were able to adapt the 14-session intervention to a 12-session, weekly curriculum that was well-received by the target population. Average rating for each session was 9.5 ± 0.3 (scale 0-10). Youth were willing to engage in the program, but retention was low. Rates of alcohol and drug use were significantly higher within our pilot population than national estimates. We found no significant decreases in self-reported alcohol, tobacco, or illicit drug use after participation in the intervention. Conclusion: Results emphasize the need to devote additional educational resources to intervention and retention factors for vulnerable youth. Individuals often experiment with drugs during adolescence; thus, this period represents a prime opportunity for education and intervention.

Matrix Metalloproteinase 13 from Satellite Cells is Required for Efficient Muscle Growth and Regeneration.

BACKGROUND/AIMS: Cell migration and extracellular matrix remodeling underlie normal mammalian development and growth as well as pathologic tumor invasion. Skeletal muscle is no exception, where satellite cell migration replenishes nuclear content in damaged tissue and extracellular matrix reforms during regeneration. A key set of enzymes that regulate these processes are matrix metalloproteinases (MMP)s. The collagenase MMP-13 is transiently upregulated during muscle regeneration, but its contribution to damage resolution is unknown. The purpose of this work was to examine the importance of MMP-13 in muscle regeneration and growth in vivo and to delineate a satellite cell specific role for this collagenase. METHODS: Mice with total and satellite cell specific Mmp13 deletion were utilized to determine the importance of MMP-13 for postnatal growth, regeneration after acute injury, and in chronic injury from a genetic cross with dystrophic (mdx) mice. We also evaluated insulin-like growth factor 1 (IGF-1) mediated hypertrophy in the presence and absence of MMP-13. We employed live-cell imaging and 3D migration measurements on primary myoblasts obtained from these animals. Outcome measures included muscle morphology and function. RESULTS: Under basal conditions, Mmp13-/- mice did not exhibit histological or functional deficits in muscle. However, following acute injury, regeneration was impaired at 11 and 14 days post injury. Muscle hypertrophy caused by increased IGF-1 was blunted with minimal satellite cell incorporation in the absence of MMP-13. Mmp13-/- primary myoblasts displayed reduced migratory capacity in 2D and 3D, while maintaining normal proliferation and differentiation. Satellite cell specific deletion of MMP-13 recapitulated the effects of global MMP-13 ablation on muscle regeneration, growth and myoblast movement. CONCLUSION: These results show that satellite cells provide an essential autocrine source of MMP-13, which not only regulates their migration, but also supports postnatal growth and resolution of acute damage.

Correction: AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

A Hand-Held Non-Robotic Surgical Tool With a Wrist and an Elbow.

OBJECTIVE: This paper describes a surgical device that provides both wrist and elbow dexterity without motors or electronics. The device provides dexterity advantages in minimally invasive surgery typically associated with robotic systems, but does so with many fewer components. Fully mechanical designs of this type promise to deliver "robot-like dexterity" at a lower financial cost than current surgical robotic systems. METHODS: Most non-robotic articulated surgical tools developed to date feature one or two degrees-of-freedom (DOF) close to the tool tip (i.e., a "wrist"). In this paper, we describe a new tool that not only features a two-DOF wrist, but also augments its dexterity with a two-DOF "elbow" consisting of a multi-backbone design seen previously only in robotic systems. Such an elbow offers high stiffness in a thin form factor. This elbow requires static balancing, which we accomplish with springs in the handle, so that the surgeon can benefit from the stiffness without feeling it while using the device. RESULTS: We report the overall tool design and experiments evaluating how well our static balance mechanism compensates for the multi-backbone elbow's intrinsic stiffness. CONCLUSION: We demonstrate the use of a multi-backbone elbow in a manual tool for the first time and show how to combine the elbow with a pin joint wrist in a fully mechanical (i.e., non-robotic) tool. SIGNIFICANCE: This paper is a step toward high dexterity, low-cost surgical instruments that bring some benefits of surgical robotic systems to patients and surgeons at a lower cost.

Gynaecological cancers and leptin: A focus on the endometrium and ovary.

Obesity has an influence on the risk and prognosis of different types of cancers of the female reproductive tract. In the uterus, a common site for neoplasms is the endometrium, the inner lining tissue. Generally, obesity has been documented to be involved in endometrioid carcinoma of the endometrium. Obesity may influence the cancer risk by various mechanisms such as chronic inflammation, dysregulation of sex hormones and abnormal secretion of hormone-like cytokines or adipokines from adipose tissue. One of the important pro-inflammatory adipokines is leptin, which acts via its transmembrane receptors (Ob-R). In normal conditions, leptin functions in the hypothalamic anorexigenic pathway to maintain the energy homeostasis. Conversely, in obesity, leptin participates in the pro-inflammatory processes. Several clinical studies have suggested that leptin and Ob-R play a role in the pathological processes of endometrial cancer. In different endometrial cancer cell lines, laboratory findings also have demonstrated leptin's link to various neoplastic phenomena such as cellular proliferation, angiogenesis, and oestrogenic activity. Furthermore, endometrial cancer risk could be increased in ovarian pathology like polycystic ovary syndrome, which is commonly associated with obesity. It is noteworthy that leptin participates in both physiological and pathological conditions of the ovary. Leptin has shown pro-tumorigenic effects in both in-vitro and in-vivo studies. Generally, reduced serum leptin levels have been observed in ovarian cancer patients. However, overexpression of leptin and Ob-R in ovarian cancer tissue has indicated aggressive disease. Understanding the role of leptin-related intracellular signalling pathways in tumour development could be helpful in early cancer detection.