Burnout is not associated with trainee performance on the Vascular Surgery In-Training Exam.

OBJECTIVE: The Vascular Surgery In-Training Examination (VSITE) is a yearly exam evaluating vascular trainees' knowledge base. Although multiple studies have evaluated variables associated with exam outcomes, few have incorporated training program-specific metrics. The purpose of this study is to evaluate the impact of the learning environment and burnout on VSITE performance. METHODS: Data was collected from a confidential, voluntary survey administered after the 2020 to 2022 VSITE as part of the SECOND Trial. VSITE scores were calculated as percent correct then standardized per the American Board of Surgery. Generalized estimating equations with robust standard errors and an independent correlation structure were used to evaluate trainee and program factors associated with exam outcomes. Analyses were further stratified by integrated and independent training paradigms. RESULTS: A total of 1385 trainee responses with burnout data were collected over 3 years (408 in 2020, 459 in 2021, 498 in 2022). On average, 46% of responses reported at least weekly burnout symptoms. On unadjusted analysis, burnout symptoms correlated with a 14 point drop in VSITE score (95% confidence interval [CI], -24 to -4; P = .006). However, burnout was no longer significant after adjusted analysis. Instead, higher postgraduate year level, being in a relationship, identifying as male gender with or without kids, identifying as non-Hispanic white, larger programs, and having a sense of belonging within a program were associated with higher VSITE scores. CONCLUSIONS: Despite high rates of burnout, trainees generally demonstrate resilience in gaining the medical knowledge necessary to pass the VSITE. Performance on standardized exams is associated with trainee and program characteristics, including availability of support systems and program belongingness.

Multi-institutional quality improvement algorithm for home nasogastric tube care for neonates.

BACKGROUND: High-risk neonates continuing to need enteral nutrition, but otherwise medically ready for discharge home from the NICU, are often offered ongoing hospitalization for nasogastric tube (NGT) feeding, versus discharge after placement of gastrostomy tube. Our group developed an interdisciplinary algorithm to support a third option-discharge home with enteral nutrition via NGT. Our objective was to develop a cross-institutional and interdisciplinary pathway to optimize outcomes for neonates discharged with NGTs. METHODS: A program to support home NGT feeding use was created, "Passport Home Program," based upon feedback from parents, nurses, speech-language pathologists, otolaryngologists, and neonatal intensivists, amongst others, spanning four hospitals across our health system. RESULTS: Standardized educational materials for caregivers of neonates requiring ongoing NGT feeding on discharge were created and consist of an in-hospital curriculum with specific competency thresholds, including demonstrating NGT replacement and confirmation with pH test strips. A discharge kit, including a QR code for a video reviewing safe techniques for home NGT placement, is distributed, along with support staff contact information. Members of an emergency department were trained in neonatal NGT replacement in case of issues after business hours. Each patient is followed in a dedicated outpatient multi-disciplinary clinic. DISCUSSION: This is an interdisciplinary and multi-institutional effort to standardize a pathway for neonates discharged home from the NICU with NGTs. This has the potential to lead to earlier discharge, better outcomes for patients and families, as well as lower costs. This best practice algorithm serves as an example pathway applicable across fields of medicine.

Upper limb function changes over 12 months in untreated SMA II and III individuals: an item-level analysis using the Revised Upper Limb Module.

The Revised upper limb module (RULM) has been increasingly used in clinical trials and in clinical settings. The aim of this study was to use the 'shift analysis' to assess the patterns of lost or gained abilities for each item on the RULM in an untreated cohort, stratified by SMA type, age, SMN2 copy number, and motor functional status. The analysis was performed on 222 12-month paired assessments from 129 individuals (115 assessment from type II and 107 from type III) who had at least two assessments at yearly intervals. There was a loss of one or more activities in 54% in type II and in 29% type III. A gain of one or more activities was found in 42% type II and in 22% type III. There were concomitant gains and losses in 27% in SMA II and in 9% in SMA III. Our results, measuring the number of abilities that are lost or gained, provide an additional method of detecting changes that can be used for the interpretation of the longitudinal data collected in treated SMA individuals.

Identification and characterization of human GDF15 knockouts.

Growth differentiation factor 15 (GDF15) is a secreted protein that regulates food intake, body weight and stress responses in pre-clinical models1. The physiological function of GDF15 in humans remains unclear. Pharmacologically, GDF15 agonism in humans causes nausea without accompanying weight loss2, and GDF15 antagonism is being tested in clinical trials to treat cachexia and anorexia. Human genetics point to a role for GDF15 in hyperemesis gravidarum, but the safety or impact of complete GDF15 loss, particularly during pregnancy, is unknown3-7. Here we show the absence of an overt phenotype in human GDF15 loss-of-function carriers, including stop gains, frameshifts and the fully inactivating missense variant C211G3. These individuals were identified from 75,018 whole-exome/genome-sequenced participants in the Pakistan Genomic Resource8,9 and recall-by-genotype studies with family-based recruitment of variant carrier probands. We describe 8 homozygous ('knockouts') and 227 heterozygous carriers of loss-of-function alleles, including C211G. GDF15 knockouts range in age from 31 to 75 years, are fertile, have multiple children and show no consistent overt phenotypes, including metabolic dysfunction. Our data support the hypothesis that GDF15 is not required for fertility, healthy pregnancy, foetal development or survival into adulthood. These observations support the safety of therapeutics that block GDF15.

High energy density picoliter-scale zinc-air microbatteries for colloidal robotics.

The recent interest in microscopic autonomous systems, including microrobots, colloidal state machines, and smart dust, has created a need for microscale energy storage and harvesting. However, macroscopic materials for energy storage have noted incompatibilities with microfabrication techniques, creating substantial challenges to realizing microscale energy systems. Here, we photolithographically patterned a microscale zinc/platinum/SU-8 system to generate the highest energy density microbattery at the picoliter (10-12 liter) scale. The device scavenges ambient or solution-dissolved oxygen for a zinc oxidation reaction, achieving an energy density ranging from 760 to 1070 watt-hours per liter at scales below 100 micrometers lateral and 2 micrometers thickness in size. The parallel nature of photolithography processes allows 10,000 devices per wafer to be released into solution as colloids with energy stored on board. Within a volume of only 2 picoliters each, these primary microbatteries can deliver open circuit voltages of 1.05 ± 0.12 volts, with total energies ranging from 5.5 ± 0.3 to 7.7 ± 1.0 microjoules and a maximum power near 2.7 nanowatts. We demonstrated that such systems can reliably power a micrometer-sized memristor circuit, providing access to nonvolatile memory. We also cycled power to drive the reversible bending of microscale bimorph actuators at 0.05 hertz for mechanical functions of colloidal robots. Additional capabilities, such as powering two distinct nanosensor types and a clock circuit, were also demonstrated. The high energy density, low volume, and simple configuration promise the mass fabrication and adoption of such picoliter zinc-air batteries for micrometer-scale, colloidal robotics with autonomous functions.

Annelid methylomes reveal ancestral developmental and aging-associated epigenetic erosion across Bilateria.

BACKGROUND: DNA methylation in the form of 5-methylcytosine (5mC) is the most abundant base modification in animals. However, 5mC levels vary widely across taxa. While vertebrate genomes are hypermethylated, in most invertebrates, 5mC concentrates on constantly and highly transcribed genes (gene body methylation; GbM) and, in some species, on transposable elements (TEs), a pattern known as "mosaic". Yet, the role and developmental dynamics of 5mC and how these explain interspecies differences in DNA methylation patterns remain poorly understood, especially in Spiralia, a large clade of invertebrates comprising nearly half of the animal phyla. RESULTS: Here, we generate base-resolution methylomes for three species with distinct genomic features and phylogenetic positions in Annelida, a major spiralian phylum. All possible 5mC patterns occur in annelids, from typical invertebrate intermediate levels in a mosaic distribution to hypermethylation and methylation loss. GbM is common to annelids with 5mC, and methylation differences across species are explained by taxon-specific transcriptional dynamics or the presence of intronic TEs. Notably, the link between GbM and transcription decays during development, alongside a gradual and global, age-dependent demethylation in adult stages. Additionally, reducing 5mC levels with cytidine analogs during early development impairs normal embryogenesis and reactivates TEs in the annelid Owenia fusiformis. CONCLUSIONS: Our study indicates that global epigenetic erosion during development and aging is an ancestral feature of bilateral animals. However, the tight link between transcription and gene body methylation is likely more important in early embryonic stages, and 5mC-mediated TE silencing probably emerged convergently across animal lineages.

Eight hydroxyproline-O-galactosyltransferases play essential roles in female reproductive development.

In angiosperms, ovules give rise to seeds upon fertilization. Thus, seed formation is dependent on both successful ovule development and tightly controlled communication between female and male gametophytes. During establishment of these interactions, cell walls play a pivotal role, especially arabinogalactan-proteins (AGPs). AGPs are highly glycosylated proteins decorated by arabinogalactan side chains, representing 90 % of the AGP molecule. AGP glycosylation is initiated by a reaction catalysed by hydroxyproline-O-galactosyltransferases (Hyp-GALTs), specifically eight of them (GALT2-9), which add the first galactose to Hyp residues. Five Hyp-GALTs (GALT2, 5, 7, 8 and 9) were previously described as essential for AGP functions in pollen and ovule development, pollen-pistil interactions, and seed morphology. In the present work, a higher order Hyp-GALT mutant (23456789) was studied, with a high degree of under-glycosylated AGPs, to gain deeper insight into the crucial roles of these eight enzymes in female reproductive tissues. Notably, the 23456789 mutant demonstrated a high quantity of unfertilized ovules, displaying abnormal callose accumulation both at the micropylar region and, sometimes, throughout the entire embryo sac. Additionally, this mutant displayed ovules with abnormal embryo sacs, had a disrupted spatiotemporal distribution of AGPs in female reproductive tissues, and showed abnormal seed and embryo development, concomitant with a reduction in AGP-GlcA levels. This study revealed that at least three more enzymes exhibit Hyp-O-GALT activity in Arabidopsis (GALT3, 4 and 6), and reinforces the crucial importance of AGP carbohydrates in carrying out the biological functions of AGPs during plant reproduction.

A Rare Ovarian Mixed Sex Cord Stromal Tumor in a Patient with Ollier Disease: A Case Report.

This is a case report of a 10-year-old with Ollier disease and an ovarian mass. Ollier disease, a rare disorder characterized by multiple enchondromas resulting in bone deformities, has been occasionally associated with ovarian juvenile granulosa cell tumor. This patient developed signs of precocious puberty and was found to have an ovarian tumor; however, pathology revealed a mixed sex-cord stromal tumor with components of juvenile granulosa and Sertoli-Leydig cell tumor. Tumor genomic testing revealed an IDH1 mutation. Mixed sex-cord stromal tumors of this type, also called "gynandroblastomas," have been associated with DICER1 mutations and DICER1 tumor predisposition syndrome but never with Ollier disease. Our findings expand the known spectrum of syndromic associations with this tumor type, with implications for tumor screening.

Resolving Resident Colonic Muscularis Macrophage Diversity and Plasticity During Colitis.

BACKGROUND: Immune cell populations in the intestinal muscularis propria during colitis are poorly resolved. Maintaining homeostasis in this niche is critical, highlighted by the poorer prognosis of inflammatory bowel disease associated with muscularis propria inflammation. METHODS: This study utilizes single-cell RNA sequencing to survey the immune cell populations within the muscularis propria of normal colon and dextran sodium sulfate-induced colitis. Findings are validated by immunohistochemistry, flow cytometry and cell-lineage tracing in vivo, and in vitro assays with muscularis macrophages (MMφ). RESULTS: In naïve conditions, transcriptional duality is observed in MMφs with 2 major subpopulations: conventional resident Cx3cr1+ MMφs and Lyve1+ MMφs. The Lyve1+ population is phagocytic and expresses several known MMφ markers in mouse and human, confirming their identity as a bona fide MMφ subset. Single-cell transcriptomics indicate that resident MMφs are retained during colitis and exhibit plasticity toward an inflammatory profile. Lyve1+ MMφs, which express anti-inflammatory marker CD163, are absent during colitis, as confirmed by flow cytometry. In contrast, lineage tracing finds that resident Cx3cr1+ MMφs remain during colitis and are not completely replaced by the inflammatory infiltrating monocytes. In vitro studies provide biological evidence of the plasticity of resident Cx3cr1+ MMφs in response to lipopolysaccharide (LPS), mirroring transcriptional observations in vivo of their inflammatory plasticity. Potential markers for colitic MMφs, validated in animal models and in individuals with ulcerative colitis, are identified. CONCLUSIONS: Our findings contribute to the understanding of the immune system in the muscularis propria niche during colitis by resolving the heterogeneity and origins of colitic MMφs.

Involvement of the muscularis propria accompanies a poorer prognosis in IBD. This study characterizes muscularis macrophage subpopulations during colitis, highlighting the loss of anti-inflammatory LYVE-1+ macrophages and inflammatory plasticity in resident CX3CR1+ macrophages, providing insights into prognostic and therapeutic targets.

Mature enteric neurons have the capacity to reinnervate the intestine with glial cells as their guide.

Here, we establish that plasticity exists within the postnatal enteric nervous system by demonstrating the reinnervation potential of post-mitotic enteric neurons (ENs). Employing BAF53b-Cre mice for selective neuronal tracing, the reinnervation capabilities of mature postnatal ENs are shown across multiple model systems. Isolated ENs regenerate neurites in vitro, with neurite complexity and direction influenced by contact with enteric glial cells (EGCs). Nerve fibers from transplanted ENs exclusively interface and travel along EGCs within the muscularis propria. Resident EGCs persist after Cre-dependent ablation of ENs and govern the architecture of the myenteric plexus for reinnervating ENs, as shown by nerve fiber projection tracing. Transplantation and optogenetic experiments in vivo highlight the rapid reinnervation potential of post-mitotic neurons, leading to restored gut muscle contractile activity within 2 weeks. These studies illustrate the structural and functional reinnervation capacity of post-mitotic ENs and the critical role of EGCs in guiding and patterning their trajectories.

CT-derived body composition and differential association with age, TNM stage and systemic inflammation in patients with colon cancer.

Low skeletal muscle index/density (SMI/SMD) is prevalent in cancer, adversely prognostic and associated with tumour stage and the systemic inflammatory response (SIR). Age and SMI/SMD has not been widely studied. The present study analyses the association between age and SMI/SMD after adjustment for other clinicopathological factors. Patients undergoing resectional surgery for TNM Stage I-III disease within the West of Scotland between 2011 and 2014 were identified. A single CT slice was obtained from each patients staging CT scan. SMI and SMD were stratified normal/abnormal. The SIR was stratified using Systemic Inflammatory Grade (SIG). When stratified by age (< 50/50s/60s/70s/80+), 39%/38%/48%/62%/74% and 27%/48%/64%/82%/92% of patients had a low SMI and SMD respectively (both p < 0.001). Older age (OR 1.47, p < 0.001), female sex (OR 1.32, p = 0.032), lower socioeconomic deprivation (OR 1.15, p = 0.004), higher ASA (OR 1.30, p = 0.019), emergency presentation (OR 1.82, p = 0.003), lower BMI (OR 0.67, p < 0.002) and higher SIG (OR 1.23, p < 0.001) were independently associated with low SMI. Older age (OR 2.28, p < 0.001), female sex (OR 1.38, p = 0.038), higher ASA (OR 1.92, p < 0.001), emergency presentation (OR 1.71, p = 0.023), and higher SIG (OR 1.37, p < 0.001) were independently associated with lower SMD. Tumour factors were not independently associated with either SMI/SMD. Age was a major factor associated with low SMI/SMD in patients with colon cancer. Therefore, in these patients it is likely that this represents largely constitutional body composition as opposed to being a disease mediated effect. Adjustment for age is required when considering the cancer mediated effect on SMI/SMD in patients with colon cancer.

An Investigation into the In Vitro Targeted Killing of CD44-Expressing Triple-Negative Breast Cancer Cells Using Recombinant Photoimmunotherapeutics Compared to Auristatin-F-Based Antibody-Drug Conjugates.

Triple-negative breast cancer (TNBC) is the deadliest form of breast cancer with limited treatment options. The persistence of highly tumorigenic CD44-expressing subpopulation referred to as cancer stem cells (CSCs), endowed with the self-renewal capacity, has been associated with therapeutic resistance, hence clinical relapses. To mitigate these undesired events, targeted immunotherapies using antibody-photoconjugate (APC) or antibody-drug conjugate (ADC), were developed to specifically release cytotoxic payloads within targeted cells overexpressing cognate antigen receptors. Therefore, an αCD44(scFv)-SNAP-tag antibody fusion protein was engineered through genetic fusion of a single-chain antibody fragment (scFv) to a SNAPf-tag fusion protein, capable of self-conjugating with benzylguanine-modified light-sensitive near-infrared (NIR) phthalocyanine dye IRDye700DX (BG-IR700) or the small molecule toxin auristatin-F (BG-AURIF). Binding of the αCD44(scFv)-SNAPf-IR700 photoimmunoconjugate to antigen-positive cells was demonstrated by confocal microscopy and flow cytometry. By switching to NIR irradiation, CD44-expressing TNBC was selectively killed through induced phototoxic activities. Likewise, the αCD44(scFv)-SNAPf-AURIF immunoconjugate was able to selectively accumulate within targeted cells and significantly reduced cell viability through antimitotic activities at nano- to micromolar drug concentrations. This study provides an in vitro proof-of-concept for a future strategy to selectively destroy light-accessible superficial CD44-expressing TNBC tumors and their metastatic lesions which are inaccessible to therapeutic light.

Enteric neural stem cell transplant restores gut motility in mice with Hirschsprung disease.

The goal of this study was to determine if transplantation of enteric neural stem cells (ENSCs) can rescue the enteric nervous system, restore gut motility, reduce colonic inflammation, and improve survival in the Ednrb-KO mouse model of Hirschsprung disease (HSCR). ENSCs were isolated from mouse intestine, expanded to form neurospheres, and microinjected into the colons of recipient Ednrb-KO mice. Transplanted ENSCs were identified in recipient colons as cell clusters in "neo-ganglia." Immunohistochemical evaluation demonstrated extensive cell migration away from the sites of cell delivery and across the muscle layers. Electrical field stimulation and optogenetics showed significantly enhanced contractile activity of aganglionic colonic smooth muscle following ENSC transplantation and confirmed functional neuromuscular integration of the transplanted ENSC-derived neurons. ENSC injection also partially restored the colonic migrating motor complex. Histological examination revealed a significant reduction in inflammation in ENSC-transplanted aganglionic recipient colon compared with that of sham-operated mice. Interestingly, mice that received cell transplant also had prolonged survival compared with controls. This study demonstrates that ENSC transplantation can improve outcomes in HSCR by restoring gut motility and reducing the severity of Hirschsprung-associated enterocolitis, the leading cause of death in human HSCR.

Soft matter physics of the ground beneath our feet.

The soft part of the Earth's surface - the ground beneath our feet - constitutes the basis for life and natural resources, yet a general physical understanding of the ground is still lacking. In this critical time of climate change, cross-pollination of scientific approaches is urgently needed to better understand the behavior of our planet's surface. The major topics in current research in this area cross different disciplines, spanning geosciences, and various aspects of engineering, material sciences, physics, chemistry, and biology. Among these, soft matter physics has emerged as a fundamental nexus connecting and underpinning many research questions. This perspective article is a multi-voice effort to bring together different views and approaches, questions and insights, from researchers that work in this emerging area, the soft matter physics of the ground beneath our feet. In particular, we identify four major challenges concerned with the dynamics in and of the ground: (I) modeling from the grain scale, (II) near-criticality, (III) bridging scales, and (IV) life. For each challenge, we present a selection of topics by individual authors, providing specific context, recent advances, and open questions. Through this, we seek to provide an overview of the opportunities for the broad Soft Matter community to contribute to the fundamental understanding of the physics of the ground, strive towards a common language, and encourage new collaborations across the broad spectrum of scientists interested in the matter of the Earth's surface.

The Degradation of Botulinum Neurotoxin Light Chains Using PROTACs.

Botulinum neurotoxins are some of the most potent natural toxins known; they cause flaccid paralysis by inhibiting synaptic vesicle release. Some serotypes, notably serotype A and B, can cause persistent paralysis lasting for several months. Because of their potency and persistence, botulinum neurotoxins are now used to manage several clinical conditions, and there is interest in expanding their clinical applications using engineered toxins with novel substrate specificities. It will also be beneficial to engineer toxins with tunable persistence. We have investigated the potential use of small-molecule proteolysis-targeting chimeras (PROTACs) to vary the persistence of modified recombinant botulinum neurotoxins. We also describe a complementary approach that has potential relevance for botulism treatment. This second approach uses a camelid heavy chain antibody directed against botulinum neurotoxin that is modified to bind the PROTAC. These strategies provide proof of principle for the use of two different approaches to fine tune the persistence of botulinum neurotoxins by selectively targeting their catalytic light chains for proteasomal degradation.

Monitoring and integrated care coordination of patients with alpha-mannosidosis: A global Delphi consensus study.

INTRODUCTION: Current literature lacks consensus on initial assessments and routine follow-up care of patients with alpha-mannosidosis (AM). A Delphi panel was conducted to generate and validate recommendations on best practices for initial assessment, routine follow-up care, and integrated care coordination of patients with AM. METHODS: A modified Delphi method involving 3 rounds of online surveys was used. An independent administrator and 2 nonvoting physician co-chairs managed survey development, anonymous data collection, and analysis. A multidisciplinary panel comprising 20 physicians from 12 countries responded to 57 open-ended questions in the first survey. Round 2 consisted of 11 ranking questions and 44 voting statements. In round 3, panelists voted to validate 60 consensus statements. The panel response rate was ≥95% in all 3 rounds. Panelists used 5-point Likert scales to indicate importance (score of ≥3) or agreement (score of ≥4). Consensus was defined a priori as ≥75% agreement with ≥75% of panelists voting. RESULTS: Consensus was reached on 60 statements, encompassing 3 key areas: initial assessments, routine follow-up care, and treatment-related follow-up. The panel agreed on the type and frequency of assessments related to genetic testing, baseline evaluations, quality of life, biochemical measures, affected body systems, treatment received, and integrated care coordination in patients with AM. Forty-nine statements reached 90% to 100% consensus, 8 statements reached 80% to 85% consensus, and 1 statement reached 75% consensus. Two statements each reached consensus on 15 baseline assessments to be conducted at the initial follow-up visit after diagnosis in pediatric and adult patients. CONCLUSION: This is the first Delphi study providing internationally applicable, best-practice recommendations for monitoring patients with AM that may improve their care and well-being.

Impact of Food on the Oral Absorption of N-Acetyl-D-Mannosamine in Healthy Men and Women.

N-Acetyl-D-mannosamine (ManNAc) is an endogenous monosaccharide and precursor of N-acetylneuraminic acid (Neu5Ac), a critical sialic acid. ManNAc is currently under clinical development to treat GNE myopathy, a rare muscle-wasting disease. In this randomized, open-label, 2-sequence, crossover study, 16 healthy women and men were administered a single oral dose of ManNAc under fasting and fed conditions. Blood samples were collected for 48 hours after dosing for quantification of plasma ManNAc and Neu5Ac concentrations. Noncompartmental pharmacokinetic and deconvolution analyses were performed using baseline-corrected plasma concentration data. Administration of ManNAc in the fed state resulted in a 1.6-fold increase in ManNAc exposure, compared to fasting conditions. A concurrent increase in Neu5Ac exposure was observed in the presence of food. Deconvolution analysis indicated that the findings were attributed to prolonged absorption rather than an enhanced rate of absorption. The impact of food on ManNAc pharmacokinetics was greater in women than men (fed/fasted area under the concentration-time curve from time 0 to infinity mean ratio: 198% compared to 121%). It is hypothesized that the presence of food slows gastric emptying, allowing a gradual release of ManNAc into the small intestine, translating into improved ManNAc absorption. The results suggest that taking ManNAc with food may enhance its therapeutic activity and/or reduce the daily dosage requirement.

TGFß in Pancreas and Colorectal Cancer: Opportunities to Overcome Therapeutic Resistance.

TGFß is a pleiotropic signaling pathway that plays a pivotal role in regulating a multitude of cellular functions. TGFß has a dual role in cell regulation where it induces growth inhibition and cell death; however, it can switch to a growth-promoting state under cancerous conditions. TGFß is upregulated in colorectal cancer and pancreatic cancer, altering the tumor microenvironment and immune system and promoting a mesenchymal state. The upregulation of TGFß in certain cancers leads to resistance to immunotherapy, and attempts to inhibit TGFß expression have led to reduced therapeutic resistance when combined with chemotherapy and immunotherapy. Here, we review the current TGFß inhibitor drugs in clinical trials for pancreatic and colorectal cancer, with the goal of uncovering advances in improving clinical efficacy for TGFß combinational treatments in patients. Furthermore, we discuss the relevance of alterations in TGFß signaling and germline variants in the context of personalizing treatment for patients who show lack of response to current therapeutics.

Changes in abilities over the initial 12 months of nusinersen treatment for type II SMA.

Several studies have shown the efficacy of new disease-modifying therapies in slowing down type II SMA progression using the Hammersmith Functional Motor Scale Expanded (HFMSE). This research aims to enhance understanding of activity changes across age groups post-nusinersen treatment using shift analysis, compared with untreated individuals. Retrospective data from the, international SMA consortium (iSMAc) dataset were analyzed, assessing individual item changes over 12 months. Shift analysis was used to determine the gain or loss of abilities, defining "gain" as a positive change between scores from 0 to either 1 or 2 and "loss" as a negative change from either 2 or 1 to 0. The cohort included 130 SMA II patients who underwent 12-month assessments from their first nusinersen dose, with age range between 0.6 and 49.6 years. One-third of the entire cohort experienced at least a loss in one activity, while 60% experienced a gain, particularly notable in children aged 2.5 to 5 years and 5 to 13 years. Overall, the study demonstrates a positive impact of nusinersen treatment on SMA II patients, showing a trend of increased activity gains and decreased probability of ability loss across different age groups.

Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.