Success rates of re-excision after positive margins for invasive lobular carcinoma of the breast.

Rates of positive margins after surgical resection of invasive lobular carcinoma (ILC) are high (ranging from 18 to 60%), yet the efficacy of re-excision lumpReceptor subtypeectomy for clearing positive margins is unknown. Concerns about the diffuse nature of ILC may drive increased rates of completion mastectomy to treat positive margins, thus lowering breast conservation rates. We therefore determined the success rate of re-excision lumpectomy in women with ILC and positive margins after surgical resection. We identified 314 cases of stage I-III ILC treated with breast conserving surgery (BCS) at the University of California, San Francisco. Surgical procedures, pathology reports, and outcomes were analyzed using univariate and multivariate statistics and Cox-proportional hazards models. We evaluated outcomes before and after the year 2014, when new margin management consensus guidelines were published. Positive initial margins occurred in 118 (37.6%) cases. Of these, 62 (52.5%) underwent re-excision lumpectomy, which cleared the margin in 74.2%. On multivariate analysis, node negativity was significantly associated with successful re-excision (odds ratio [OR] 3.99, 95% CI 1.15-13.81, p = 0.029). After 2014, we saw fewer initial positive margins (42.7% versus 25.5%, p = 0.009), second surgeries (54.6% versus 20.2%, p < 0.001), and completion mastectomies (27.7% versus 4.5%, p < 0.001). In this large cohort of women with ILC, re-excision lumpectomy was highly successful at clearing positive margins. Additionally, positive margins and completion mastectomy rates significantly decreased over time. These findings highlight improvements in management of ILC, and suggest that completion mastectomy may not be required for those with positive margins after initial BCS

Thermal Conductivity Measurements with Galvanic Metallization Lines on Porosified LTCC Applying the 3-Omega Technique

AbstractThe reduction of the thermal conductivity of low temperature co-fired ceramics (LTCC) caused by a porosification process originally developed for the local modification of the permittivity is determined by the 3ω measurement technique. Therefore, metallization lines of small width down to 20μm are applied by galvanic pulse plating onto the roughened LTCC surface. By this deposition technology it is possible, to cover the pores without any depth penetration. Compared to the ‘as fired’ state, a reduction in thermal conductivity of up to 70% is measured independent of the LTCC type

FGF-2-dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus-mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2-dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle

Subglacial Drainage Evolution Modulates Seasonal Ice Flow Variability of Three Tidewater Glaciers in Southwest Greenland

B.J.D was funded in the form of a PhD studentship provided by the Scottish Association for Geosciences, Environment and Society (SAGES) and the University of St Andrews, UK. J.M.L is supported by a UKRI Future Leaders Fellowship (Grant No. MR/S017232/1). D.F would like to acknowledge the support of this work through the EPSRC and ESRC Centre for Doctoral Training on Quantification and Management of Risk and Uncertainty in Complex Systems Environments Grant No. (EP/L015927/1).Surface‐derived meltwater can access the bed of the Greenland Ice Sheet, causing seasonal velocity variations. The magnitude, timing and net impact on annual average ice flow of these seasonal perturbations depends on the hydraulic efficiency of the subglacial drainage system. We examine the relationships between drainage system efficiency and ice velocity, at three contrasting tidewater glaciers in southwest Greenland during 2014‐2019, using high‐resolution remotely sensed ice velocities, modelled surface melting, subglacial discharge at the terminus and results from buoyant plume modelling. All glaciers underwent a seasonal speed‐up, which usually coincided with surface melt‐onset, and subsequent slow‐down, which usually followed inferred subglacial channelisation. The amplitude and timing of these speed variations differed between glaciers, with the speed‐up being larger and more prolonged at our fastest study glacier. At all glaciers, however, the seasonal variations in ice flow are consistent with inferred changes in hydraulic efficiency of the subglacial drainage system, and qualitatively indicative of a flow regime in which annually‐averaged ice velocity is relatively insensitive to inter‐annual variations in meltwater supply – so‐called ‘ice flow self‐regulation’. These findings suggest that subglacial channel formation may exert a strong control on seasonal ice flow variations, even at fast‐flowing tidewater glaciers.Publisher PDFPeer reviewe

Genome-wide DNA methylation profiling confirms a case of low-level mosaic Kabuki syndrome 1

Kabuki syndrome is a Mendelian disorder of the epigenetic machinery characterized by typical dysmorphic features, intellectual disability, and postnatal growth deficiency. Pathogenic variants in the genes encoding the chromatin modifiers KMT2D and KDM6A are responsible for Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), respectively. In addition, 11 cases of KS1 caused by mosaic variants in KMT2D have been reported in the literature. Some of these individuals display milder craniofacial and growth phenotypes, and most do not have congenital heart defects. We report the case of an infant with severe hypoplastic left heart syndrome with mitral atresia and aortic atresia (HLHS MA-AA), pulmonary vein stenosis, and atypical facies with a somatic mosaic de novo nonsense variant in KMT2D (c.8200C\u3eT, p.R2734*) identified on trio exome sequencing of peripheral blood and present in 11.2% of sequencing reads. KS was confirmed with EpiSign, a diagnostic genome-wide DNA methylation platform used to identify epigenetic signatures. This case suggests that use of this newly available clinical test can guide the interpretation of low-level mosaic variants identified through sequencing and suggests a new lower limit of mosaicism in whole blood required for a diagnosis of KS

Individuals with Wiedemann-Steiner syndrome show nonverbal reasoning and visuospatial defects with relative verbal skill sparing

OBJECTIVES: Wiedemann-Steiner syndrome (WSS) is a rare Mendelian disorder of the epigenetic machinery caused by heterozygous pathogenic variants in KMT2A. Currently, the specific neurocognitive profile of this syndrome remains unknown. This case series provides insight into the cognitive phenotype of WSS. METHODS: This study involves a retrospective medical chart review of 10 pediatric patients, each with a molecularly confirmed diagnosis of WSS who underwent clinical neuropsychological evaluation at an academic medical center. RESULTS: The majority of patients performed in the below average to very low ranges in Nonverbal Reasoning, Visual/Spatial Perception, Visuoconstruction, Visual Memory, Attention, Working Memory and Math Computation skills. In contrast, over half the sample performed within normal limits on Receptive Vocabulary, Verbal Memory, and Word Reading. Wilcoxon signed rank test showed weaker Nonverbal versus Verbal Reasoning skills (p = .005). Most caregivers reported deficits in executive functioning, most notably in emotion regulation. CONCLUSIONS: Nonverbal reasoning/memory, visuospatial/construction, attention, working memory, executive functioning, and math computation skills are areas of weakness among those with WSS. These findings overlap with research on Kabuki syndrome, which is caused by variants in KMT2D, and suggest disruption in the neurogenesis of the hippocampal formation may drive shared pathogenesis of the two syndromes.Peer reviewe

Unique profile of academic learning difficulties in Wiedemann–Steiner syndrome

Funding Information: R.N. and H.T.B. are supported by grants from the Wiedemann‐Steiner Syndrome Foundation. J.A.F. acknowledges support from The Hartwell Foundation (Individual Biomedical Research Award) and the National Institute of Child Health and Development (NICHD)(K08HD086250). J.H. acknowledges support from the NICHD (K23HD101646). R.N. also received research support from NICHD (P50HD103538). Publisher Copyright: © 2022 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.Background: Wiedemann–Steiner syndrome (WSS) is a rare genetic disorder caused by heterozygous variants in KMT2A. To date, the cognitive profile associated with WSS remains largely unknown, although emergent case series implicate increased risk of non-verbal reasoning and visual processing deficits. This study examines the academic and learning concerns associated with WSS based on a parent-report screening measure. Participants and Methods: A total of 25 parents of children/adults with a molecularly-confirmed diagnosis of WSS (mean age = 12.85 years, SD = 7.82) completed the Colorado Learning Difficulties Questionnaire (CLDQ), a parent-screening measure of learning and academic difficulties. Parent ratings were compared to those from a normative community sample to determine focal areas in Math, Reading and Spatial skills that may be weaker within this clinical population. Results: On average, parent ratings on the Math (mean Z = -3.08, SD = 0.87) and Spatial scales (mean Z = -2.52, SD = 0.85) were significantly more elevated than that of Reading (mean Z = -1.31, SD = 1.46) (Wilcoxon sign rank test Z < −3.83, P < 0.001), reflecting relatively more challenges observed in these areas. Distribution of parent ratings in Math items largely reflect a positively skewed distribution with most endorsing over three standard deviations below a community sample. In contrast, distributions of parent ratings in Reading and Spatial domains were more symmetric but flat. Ratings for Reading items yielded much larger variance than the other two domains, reflecting a wider range of performance variability. Conclusions: Parent ratings on the CLDQ suggest more difficulties with Math and Spatial skills among those with WSS within group and relative to a community sample. Study results are consistent with recent case reports on the neuropsychological profile associated with WSS and with Kabuki syndrome, which is caused by variants in the related gene KMT2D. Findings lend support for overlapping cognitive patterns across syndromes, implicating potential common disease pathogenesis.Peer reviewe

Sleep disturbances correlate with behavioral problems among individuals with Wiedemann-Steiner syndrome

Funding Information: RN would like to acknowledge support for open access publication from NIH (R25 NS117356). HB and RN are supported by grants from the WSS Foundation, JF has support from The Hartwell Foundation (Individual Biomedical Research Award) and the NIH (K08HD086250), and JH has support from the National Institute of Child Health and Development (K23HD101646). This study was also supported by Kennedy Krieger IDDRC NIH (P50HD103538). Publisher Copyright: Copyright © 2022 Ng, Bjornsson, Fahrner and Harris.Wiedemann-Steiner syndrome (WSS) is a rare genetic disorder caused by mutation in KMT2A and characterized by neurodevelopmental delay. This study is the first prospective investigation to examine the sleep and behavioral phenotypes among those with WSS through parent-informant screening inventories. A total of 24 parents of children/adults with WSS (11F, Mean age = 12.71 years, SD = 8.17) completed the Strengths and Difficulties Questionnaire (SDQ) and 22 of these caregivers also completed the Modified Simonds and Parraga Sleep Questionnaire (MSPSQ). On average, the majority of those with WSS (83%) were rated to show borderline to clinical level of behavioral difficulties on the SDQ. Approximately 83% were rated in these ranges for hyperactivity, 63% for emotional problems, and 50% for conduct problems. When applying prior published clinical cut-off for risk of sleep disturbance among those with neurodevelopmental disorders, over 80% of our sample exceeded this limit on the MSPSQ. Largely, caregivers’ ratings suggested restless sleep, rigid bedtime rituals, sleep reluctance and breathing through the mouth in sleep were most consistent problems observed. Partial correlations between sleep and behavioral domains showed elevated emotional problems were associated with parasomnia characteristics after controlling for age. Daytime drowsiness and activity were associated with more hyperactivity. Those with more night waking problems and delayed sleep onset were rated to show more severe conduct problems. Overall, these findings suggest dysfunctional sleep behaviors, hyperactivity, and affective problems are part of the neurobehavioral phenotype of WSS. Routine clinical care for those affected by WSS should include close monitoring of sleep and overactive behaviors.Peer reviewe

Paediatric thyroid surgery is safe - experiences at a tertiary surgical centre.

PRINCIPLES Thyroidectomy in children is rare and mostly performed because of thyroid neoplasms. The aim of this study based on prospective data acquisition was to evaluate whether thyroid surgery in children can be performed as safely as in adults when undertaken by a team of adult endocrine surgeons and paediatric surgeons. METHODS Between 2002 and 2012, 36 patients younger than 18 years underwent surgery for thyroid gland pathologies. All surgical procedures were performed by an experienced endocrine surgeon and a paediatric surgeon. Baseline demographic data, surgical procedure, duration of operation, length of hospital stay, and postoperative morbidity and mortality were analysed. RESULTS The median age of all patients was 13 years (range 2-17 years), with predominantly female gender (n = 30, 83%). The majority of operations were performed because of benign thyroid disease (n = 27, 75%) and only a minority because of malignancy or genetic abnormality with predisposition for malignant transformation (MEN) (n = 9, 25%). Total thyroidectomy was performed in the majority of the patients (n = 24, 67%). The median duration of the surgical procedure was 153 minutes (range 90-310 minutes). The median hospital stay was 5 days (3-1 days). One patient developed persistent hypoparathyroidism after neck dissection due to cancer. One persistent and two temporary recurrent nerve palsies occurred. CONCLUSION This study demonstrated that paediatric thyroidectomy is safe as performed by this team of endocrine and paediatric surgeons, with acceptable morbidity even when total thyroidectomy was performed in the case of benign disease