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.

Real-world safety data for MVA-BN: Increased frequency of syncope following intradermal administration for immunization against mpox disease.

BACKGROUND: MVA-BN vaccine (Jynneos, Imvamune, Imvanex) was used widely in the 2022 mpox outbreak. This experience provides real-world evidence about the vaccine's safety, particularly regarding intradermal use. METHODS: Bavarian Nordic's global safety database was searched for all adverse events following immunization (AEFIs) with MVA-BN. AEFI numbers were compared among administration routes. Selected events and administered doses were graphed over the mpox outbreak period. RESULTS: A total of 9585 AEFIs have been reported. The rate of myocarditis or pericarditis was <1 per 100,000 doses administered. Eighty-nine cases of syncope, fainting, or loss of consciousness were reported. This number rose after the August 2022 US emergency use authorization for intradermal administration, as did the proportion of all syncope AEFIs reported following intradermal administration (78,7 %). CONCLUSION: Real-world data from large-scale administration of MVA-BN has confirmed the vaccine's established safety profile when administered subcutaneously. Intradermal administration is likely associated with increased syncopal event frequency.

Pediatric chaplains iterative process to address religious & spiritual struggle: a qualitative study.

The growing body of literature on religious and spiritual (R/S) struggles consistently highlights its association with various health outcomes in Pediatrics. Chaplains or spiritual care providers, as members of interdisciplinary teams, frequently offer spiritual care to patients and families grappling with R/S struggles. However, there is a paucity of literature demonstrating how chaplains address R/S struggle in their practice. This study aimed to construct a theory describing the process by which pediatric chaplains conceptualize and address it. Employing a constructivist Grounded Theory study design, we sought to comprehend the approaches pediatric chaplains utilize in addressing R/S struggles. Following a semi-structured interview guide, we interviewed twelve Board Certified or Board Certification-eligible chaplains. Findings reveal that chaplains use an iterative three-phase process to address R/S struggles. Thirteen categories emerged, which were further organized into four major themes: Assessing, Processing, Intervening, and Navigating Limitations. A model depicting this iterative process was constructed.

Can long-read sequencing tackle the barriers, which the next-generation could not? A review.

The large-scale heterogeneity of genetic diseases necessitated the deeper examination of nucleotide sequence alterations enhancing the discovery of new targeted drug attack points. The appearance of new sequencing techniques was essential to get more interpretable genomic data. In contrast to the previous short-reads, longer lengths can provide a better insight into the potential health threatening genetic abnormalities. Long-reads offer more accurate variant identification and genome assembly methods, indicating advances in nucleotide deflect-related studies. In this review, we introduce the historical background of sequencing technologies and show their benefits and limits, as well. Furthermore, we highlight the differences between short- and long-read approaches, including their unique advances and difficulties in methodologies and evaluation. Additionally, we provide a detailed description of the corresponding bioinformatics and the current applications.

GTPase activity regulates FtsZ ring positioning in Caulobacter crescentus.

Bacterial cell division is crucial for replication and requires careful coordination via proteins collectively called the divisome. The tubulin-like GTPase FtsZ is the master regulator of this process and serves to recruit downstream divisome proteins and regulate their activities. Upon assembling at mid-cell, FtsZ exhibits treadmilling motion driven by GTP binding and hydrolysis. Treadmilling is proposed to play roles in Z-ring condensation and in distribution and regulation of peptidoglycan (PG) cell wall enzymes. FtsZ polymer superstructure and dynamics are central to its function, yet their regulation is incompletely understood. We addressed these gaps in knowledge by evaluating the contribution of GTPase activity to FtsZ's function in vitro and in Caulobacter crescentus cells. We observed that a lethal mutation that abrogates FtsZ GTP hydrolysis impacts FtsZ dynamics and Z-ring positioning, but not constriction. Aberrant Z-ring positioning was due to insensitivity to the FtsZ regulator MipZ when GTPase activity is reduced. Z-ring mislocalization resulted in DNA damage, likely due to constriction over the nucleoid. Collectively, our results indicate that GTP hydrolysis serves primarily to position the Z-ring at mid-cell in Caulobacter. Proper Z-ring localization is required for effective coordination with chromosome segregation to prevent DNA damage and ensure successful cell division.

BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience.

BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.

Pegvaliase for the treatment of phenylketonuria: Final results of a long-term phase 3 clinical trial program.

Phenylketonuria (PKU) is a genetic disorder caused by deficiency of the enzyme phenylalanine hydroxylase (PAH), which results in phenylalanine (Phe) accumulation in the blood and brain, and requires lifelong treatment to keep blood Phe in a safe range. Pegvaliase is an enzyme-substitution therapy approved for individuals with PKU and uncontrolled blood Phe concentrations (>600 µmol/L) despite prior management. Aggregated results from the PRISM clinical trials demonstrated substantial and sustained reductions in blood Phe with a manageable safety profile, but also noted individual variation in time to and dose needed for a first response. This analysis reports longer-term aggregate findings and characterizes individual participant responses to pegvaliase using final data from the randomized trials PRISM-1 (NCT01819727) and PRISM-2 (NCT01889862), and the open-label extension study 165-304 (NCT03694353). In 261 adult participants with a mean of 36.6 months of pegvaliase treatment, 71.3%, 65.1%, and 59.4% achieved clinically significant blood Phe levels of ≤600, ≤360, and ≤ 120 µmol/L, respectively. Some participants achieved blood Phe reductions with <20 mg/day pegvaliase, although most required higher doses. Based on Kaplan-Meier analysis, median (minimum, maximum) time to first achievement of a blood Phe threshold of ≤600, ≤360, or ≤ 120 µmol/L was 4.4 (0.0, 54.0), 8.0 (0.0, 57.0), and 11.6 (0.0, 66.0) months, respectively. Once achieved, blood Phe levels remained below clinical threshold in most participants. Sustained Phe response (SPR), a new method described within for measuring durability of blood Phe response, was achieved by 85.5%, 84.7%, and 78.1% of blood Phe responders at blood Phe thresholds of ≤600, ≤360, or ≤ 120 µmol/L, respectively. Longer-term safety data were consistent with previous reports, with the most common adverse events (AEs) being arthralgia, injection site reactions, headache, and injection site erythema. The incidence of most AEs, including hypersensitivity AEs, was higher during the early treatment phase (≤6 months) than later during treatment. In conclusion, using data from three key pegvaliase clinical trials, participants treated with pegvaliase were able to reach clinically significant blood Phe reductions to clinical thresholds of ≤600, ≤360, or ≤ 120 µmol/L during early treatment, with safety profiles improving from early to sustained treatment. This study also supports the use of participant-level data and new ways of looking at durable blood Phe responses to better characterize patients' individual PKU treatment journeys.

New light on an old syndrome: Role of Api g 7 in mugwort pollen-related celery allergy.

BACKGROUND: Celery root is known to cause severe allergic reactions in patients sensitized to mugwort pollen. OBJECTIVE: We studied clinically well-characterized patients with celery allergy by IgE testing with a comprehensive panel of celery allergens to disentangle the molecular basis of what is known as the celery-mugwort syndrome. METHODS: Patients with suspected food allergy to celery underwent a standardized interview. Main inclusion criteria were a positive food challenge with celery or an unambiguous case history of severe anaphylaxis. IgE to celery allergens (rApi g 1.01, rApi g 1.02, rApi g 2, rApi g 4, nApi g 5, rApi g 6, rApi g 7) and to mugwort allergens (rArt v 1, rArt v 3, rArt v 4) were determined. IgE levels ≥0.35 kUA/L were regarded positive. RESULTS: Seventy-nine patients with allergy to celery were included. Thirty patients had mild oral or rhinoconjunctival symptoms, and 49 had systemic reactions. Sixty-eight percent had IgE to celery extract, 80% to birch pollen, and 77% to mugwort pollen. A combination of Api g 1.01, 1.02, 4, 5, and 7 increased the diagnostic sensitivity for celery allergy to 92%. The lipid transfer proteins Api g 2 and Api g 6 were not relevant in our celery-allergic population. IgE to Api g 7, detected in 52% of patients, correlated closely (r = 0.86) to Art v 1 from mugwort pollen. Eleven of 12 patients with monosensitization to Api g 7 were IgE negative to celery extract. The odds ratio for developing a severe anaphylactic reaction rather than only mild oral symptoms was about 6 times greater (odds ratio, 5.87; 95% confidence interval, 1.08-32.0; P = .0410) for Api g 7-sensitized versus -nonsensitized subjects. CONCLUSION: There is an urgent need for routine diagnostic tests to assess sensitization to Api g 7, not only to increase test sensitivity but also to identify patients at risk of a severe allergic reaction to celery.

From Vessels to Neurons-The Role of Hypoxia Pathway Proteins in Embryonic Neurogenesis.

Embryonic neurogenesis can be defined as a period of prenatal development during which divisions of neural stem and progenitor cells give rise to neurons. In the central nervous system of most mammals, including humans, the majority of neocortical neurogenesis occurs before birth. It is a highly spatiotemporally organized process whose perturbations lead to cortical malformations and dysfunctions underlying neurological and psychiatric pathologies, and in which oxygen availability plays a critical role. In case of deprived oxygen conditions, known as hypoxia, the hypoxia-inducible factor (HIF) signaling pathway is activated, resulting in the selective expression of a group of genes that regulate homeostatic adaptations, including cell differentiation and survival, metabolism and angiogenesis. While a physiological degree of hypoxia is essential for proper brain development, imbalanced oxygen levels can adversely affect this process, as observed in common obstetrical pathologies such as prematurity. This review comprehensively explores and discusses the current body of knowledge regarding the role of hypoxia and the HIF pathway in embryonic neurogenesis of the mammalian cortex. Additionally, it highlights existing gaps in our understanding, presents unanswered questions, and provides avenues for future research.

Signatures of adaptation at key insecticide resistance loci in Anopheles gambiae in Southern Ghana revealed by reduced-coverage WGS.

Resistance to insecticides and adaptation to a diverse range of environments present challenges to Anopheles gambiae s.l. mosquito control efforts in sub-Saharan Africa. Whole-genome-sequencing is often employed for identifying the genomic basis underlying adaptation in Anopheles, but remains expensive for large-scale surveys. Reduced coverage whole-genome-sequencing can identify regions of the genome involved in adaptation at a lower cost, but is currently untested in Anopheles mosquitoes. Here, we use reduced coverage WGS to investigate population genetic structure and identify signatures of local adaptation in Anopheles mosquitoes across southern Ghana. In contrast to previous analyses, we find no structuring by ecoregion, with Anopheles coluzzii and Anopheles gambiae populations largely displaying the hallmarks of large, unstructured populations. However, we find signatures of selection at insecticide resistance loci that appear ubiquitous across ecoregions in An. coluzzii, and strongest in forest ecoregions in An. gambiae. Our study highlights resistance candidate genes in this region, and validates reduced coverage WGS, potentially to very low coverage levels, for population genomics and exploratory surveys for adaptation in Anopheles taxa.

Taking High-Fidelity Simulation to the Next Level: Nursing in Nontraditional Environments.

ABSTRACT: Nurse educators must prepare nursing students to be competent first responders and providers in nontraditional situations. We developed a course that provides in-depth experiential instruction in disaster nursing, remote/austere nursing, and global health. The Nursing in Nontraditional Environments course provides nursing students with the knowledge and skills to provide quality care to patients in environments outside traditional hospitals and clinics. The course merges survival skills with austere care using evidence-based practice derived from the US Military and the Wilderness Medical Society.

The Effect of Lens Shape, Zonular Insertion and Finite Element Model on Simulated Shape Change of the Eye Lens.

The process of lens shape change in the eye to alter focussing (accommodation) is still not fully understood. Modelling approaches have been used to complement experimental findings in order to determine how constituents in the accommodative process influence the shape change of the lens. An unexplored factor in modelling is the role of the modelling software on the results of simulated shape change. Finite element models were constructed in both Abaqus and Ansys software using biological parameters from measurements of shape and refractive index of two 35-year-old lenses. The effect of zonular insertion on simulated shape change was tested on both 35-year-old lens models and with both types of software. Comparative analysis of shape change, optical power, and stress distributions showed that lens shape and zonular insertion positions affect the results of simulated shape change and that Abaqus and Ansys show differences in their respective models. The effect of the software package used needs to be taken into account when constructing finite element models and deriving conclusions.

Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU-MOMs sub-registries.

Infants born to mothers with phenylketonuria (PKU) may develop congenital abnormalities because of elevated phenylalanine (Phe) levels in the mother during pregnancy. Maintenance of blood Phe levels between 120 and 360 µmol/L reduces risks of birth defects. Sapropterin dihydrochloride helps maintain blood Phe control, but there is limited evidence on its risk-benefit ratio when used during pregnancy. Data from the maternal sub-registries-KAMPER (NCT01016392) and PKUDOS (NCT00778206; PKU-MOMs sub-registry)-were collected to assess the long-term safety and efficacy of sapropterin in pregnant women in a real-life setting. Pregnancy and infant outcomes, and the safety of sapropterin were assessed. Final data from 79 pregnancies in 57 women with PKU are reported. Sapropterin dose was fairly constant before and during pregnancy, with blood Phe levels maintained in the recommended target range during the majority (82%) of pregnancies. Most pregnancies were carried to term, and the majority of liveborn infants were reported as 'normal' at birth. Few adverse and serious adverse events were considered related to sapropterin, with these occurring in participants with high blood Phe levels. This report represents the largest population of pregnant women with PKU exposed to sapropterin. Results demonstrate that exposure to sapropterin during pregnancy was well-tolerated and facilitated maintenance of blood Phe levels within the target range, resulting in normal delivery. This critical real-world data may facilitate physicians and patients to make informed treatment decisions about using sapropterin in pregnant women with PKU and in women of childbearing age with PKU who are responsive to sapropterin.

Model of zonular forces on the lens capsule during accommodation.

How the human eye focuses for near; i.e. accommodates, is still being evaluated after more than 165 years. The mechanism of accommodation is essential for understanding the etiology and potential treatments for myopia, glaucoma and presbyopia. Presbyopia affects 100% of the population in the fifth decade of life. The lens is encased in a semi-elastic capsule with attached ligaments called zonules that mediate ciliary muscle forces to alter lens shape. The zonules are attached at the lens capsule equator. The fundamental issue is whether during accommodation all the zonules relax causing the central and peripheral lens surfaces to steepen, or the equatorial zonules are under increased tension while the anterior and posterior zonules relax causing the lens surface to peripherally flatten and centrally steepen while maintaining lens stability. Here we show with a balloon capsule zonular force model that increased equatorial zonular tension with relaxation of the anterior and posterior zonules replicates the topographical changes observed during in vivo rhesus and human accommodation of the lens capsule without lens stroma. The zonular forces required to simulate lens capsule configuration during in vivo accommodation are inconsistent with the general belief that all the zonules relax during accommodation.

Optical development in the murine eye lens of accelerated senescence-prone SAMP8 and senescence-resistant SAMR1 strains.

The eye lens is responsible for focusing objects at various distances onto the retina and its refractive power is determined by its surface curvature as well as its internal gradient refractive index (GRIN). The lens continues to grow with age resulting in changes to the shape and to the GRIN profile. The present study aims to investigate how the ageing process may influence lens optical development. Murine lenses of accelerated senescence-prone strain (SAMP8) aged from 4 to 50 weeks; senescence-resistant strain (SAMR1) aged from 5 to 52 weeks as well as AKR strain (served as control) aged from 6 to 70 weeks were measured using the X-ray interferometer at the SPring-8 synchrotron Japan within three consecutive years from 2020 to 2022. Three dimensional distributions of the lens GRIN were reconstructed using the measured data and the lens shapes were determined using image segmentation in MatLab. Variations in the parameters describing the lens shape and the GRIN profile with age were compared amongst three mouse strains. With advancing age, both the lens anterior and posterior surface flattens and the lens sagittal thickness increase in all three mouse strains (Anterior radius of curvature increase at 0.008 mm/week, 0.007 mm/week and 0.002 mm/week while posterior radius of curvature increase at 0.002 mm/week, 0.007 mm/week and 0.003 mm/week respectively in AKR, SAMP8 and SAMR1 lenses). Compared with the AKR strain, the SAMP8 samples demonstrate a higher rate of increase in the posterior curvature radius (0.007 mm/week) and the thickness (0.015 mm/week), whilst the SAMR1 samples show slower increases in the anterior curvature radius (0.002 mm/week) and its thickness (0.013 mm/week). There are similar age-related trends in GRIN shape in the radial direction (in all three types of murine lenses nr2 and nr6 increase with age while nr4 decrease with age consistently) but not in the axial direction amongst three mouse strains (nz1 of AKR lens decrease while of SAMP8 and SAMR1 increase with age; nz2 of all three models increase with age; nz3 of AKR lens increase while of SAMP8 and SAMR1 decrease with age). The ageing process can influence the speed of lens shape change and affect the GRIN profile mainly in the axial direction, contributing to an accelerated decline rate of the optical power in the senescence-prone strain (3.5 D/week compared to 2.3 D/week in the AKR control model) but a retardatory decrease in the senescence-resistant strain (2.1 D/week compared to the 2.3D/week in the AKR control model).

Protocol for the development of a tool (INSPECT-SR) to identify problematic randomised controlled trials in systematic reviews of health interventions.

INTRODUCTION: Randomised controlled trials (RCTs) inform healthcare decisions. It is now apparent that some published RCTs contain false data and some appear to have been entirely fabricated. Systematic reviews are performed to identify and synthesise all RCTs that have been conducted on a given topic. While it is usual to assess methodological features of the RCTs in the process of undertaking a systematic review, it is not usual to consider whether the RCTs contain false data. Studies containing false data therefore go unnoticed and contribute to systematic review conclusions. The INveStigating ProblEmatic Clinical Trials in Systematic Reviews (INSPECT-SR) project will develop a tool to assess the trustworthiness of RCTs in systematic reviews of healthcare-related interventions. METHODS AND ANALYSIS: The INSPECT-SR tool will be developed using expert consensus in combination with empirical evidence, over five stages: (1) a survey of experts to assemble a comprehensive list of checks for detecting problematic RCTs, (2) an evaluation of the feasibility and impact of applying the checks to systematic reviews, (3) a Delphi survey to determine which of the checks are supported by expert consensus, culminating in, (4) a consensus meeting to select checks to be included in a draft tool and to determine its format and (5) prospective testing of the draft tool in the production of new health systematic reviews, to allow refinement based on user feedback. We anticipate that the INSPECT-SR tool will help researchers to identify problematic studies and will help patients by protecting them from the influence of false data on their healthcare. ETHICS AND DISSEMINATION: The University of Manchester ethics decision tool was used, and this returned the result that ethical approval was not required for this project (30 September 2022), which incorporates secondary research and surveys of professionals about subjects relating to their expertise. Informed consent will be obtained from all survey participants. All results will be published as open-access articles. The final tool will be made freely available.

Policy and Practice Changes Associated with a Tobacco-Free Initiative in Residential Substance Use Disorder Treatment.

A California-sponsored, 18-month, tobacco-free intervention in residential substance use disorder (SUD) programs was associated with increases in tobacco-free grounds and tobacco-related client services. The current study examined whether positive results would be replicated in 11 programs participating subsequently. Program directors (N = 11) completed surveys of tobacco-related policies pre- and post-intervention. Pre- (n = 163) and post-intervention (n = 128) cross-sectional staff surveys examined tobacco-related training, beliefs, practices, smoking policy, and smoking status. Directors reported increases in tobacco-free grounds (from 3 to 8 programs), tobacco-related staff training (1 to 10 programs), tobacco cessation staff services (1 to 9 programs) and nicotine replacement therapy (NRT) provision (6 to 10 programs). At post-intervention, staff were more likely to report smoke-free workplaces (p = 0.008), positive beliefs about treating tobacco use (p = 0.017) and less likely to report current smoking (p = 0.003). Clinical staff were more likely to report tobacco-related training receipt (p = 0.001), program-level NRT provision (p = 0.009) and conducting tobacco-related client services (p < 0.0001) post-intervention. Findings of increases in tobacco-free grounds and tobacco cessation client services corroborated prior results. These and the additional finding of decreases in staff smoking strengthen evidence that initiatives supporting tobacco-free policies can be successfully implemented in SUD treatment.

Evaluation of the safety and efficacy of fecal microbiota transplantations in bottlenose dolphins (Tursiops truncatus) using metagenomic sequencing.

AIMS: Gastrointestinal disease is a leading cause of morbidity in bottlenose dolphins (Tursiops truncatus) under managed care. Fecal microbiota transplantation (FMT) holds promise as a therapeutic tool to restore gut microbiota without antibiotic use. This prospective clinical study aimed to develop a screening protocol for FMT donors to ensure safety, determine an effective FMT administration protocol for managed dolphins, and evaluate the efficacy of FMTs in four recipient dolphins. METHODS AND RESULTS: Comprehensive health monitoring was performed on donor and recipient dolphins. Fecal samples were collected before, during, and after FMT therapy. Screening of donor and recipient fecal samples was accomplished by in-house and reference lab diagnostic tests. Shotgun metagenomics was used for sequencing. Following FMT treatment, all four recipient communities experienced engraftment of novel microbial species from donor communities. Engraftment coincided with resolution of clinical signs and a sustained increase in alpha diversity. CONCLUSION: The donor screening protocol proved to be safe in this study and no adverse effects were observed in four recipient dolphins. Treatment coincided with improvement in clinical signs.

Longitudinal changes of swallowing safety and efficiency in infants with spinal muscular atrophy who received disease modifying therapies.

BACKGROUND: Dysphagia is a common feature of the natural history of patients with spinal muscular atrophy (SMA). Literature regarding swallowing safety and efficiency is scarce in patients with SMA, particularly in the era of newborn screening programs and disease-modifying therapies. OBJECTIVE: To describe the longitudinal changes of swallowing safety and efficiency in children with SMA who received one or more disease modifying therapies METHODS: Case series of patients with SMA followed at the University of Florida from 1 May 2019 to 31 December 2022 who had two or more videofluoroscopy swallowing studies (VFSS), with the first being within 30 days of their first treatment. Data extracted from the electronic health record included: neuromotor outcomes, VFSS penetration aspiration scores (PAS), presence of abrnormal oral or pharyngeal residue, clinical history, and timing of disease-modifying therapies administration. RESULTS: Seven subjects were included (five male); three were diagnosed via newborn screen. Median age at diagnosis was 10 days (range: 4-250). Median age at initial VFSS was 29 days (range: 9-246), and age at the last VFSS was 26.1 months (range: 18.2-36.2). All subjects received onasemnogene-abeparvovec (OA); four received additional therapies. PAS at diagnosis was abnormal in four subjects. Six subjects required feeding modifications after VFSS results. Of these, three had silent aspiration (PAS 8) and three of them improved after treatment. CONCLUSIONS: Swallowing safety and efficiency can be impaired in patients with SMA despite early treatment. Larger, prospective studies are needed to define optimal timiing of longitudinal instrumental evaluations.

PCYT2 deficiency in Saarlooswolfdogs with progressive retinal, central, and peripheral neurodegeneration.

We investigated a syndromic disease comprising blindness and neurodegeneration in 11 Saarlooswolfdogs. Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. Histopathology in one affected dog demonstrated cataract, retinal degeneration, central and peripheral axonal degeneration, and severe astroglial hypertrophy and hyperplasia in the central nervous system. Pedigrees indicated autosomal recessive inheritance. We mapped the suspected genetic defect to a 15 Mb critical interval by combined linkage and autozygosity analysis. Whole genome sequencing revealed a private homozygous missense variant, PCYT2:c.4A>G, predicted to change the second amino acid of the encoded ethanolamine-phosphate cytidylyltransferase 2, XP_038402224.1:(p.Ile2Val). Genotyping of additional Saarlooswolfdogs confirmed the homozygous genotype in all eleven affected dogs and demonstrated an allele frequency of 9.9% in the population. This experiment also identified three additional homozygous mutant young dogs without overt clinical signs. Subsequent examination of one of these dogs revealed early-stage progressive retinal atrophy (PRA) and expansion of subarachnoid CSF spaces in MRI. Dogs homozygous for the pathogenic variant showed ether lipid accumulation, confirming a functional PCYT2 deficiency. The clinical and metabolic phenotype in affected dogs shows some parallels with human patients, in whom PCYT2 variants lead to a rare form of spastic paraplegia or axonal motor and sensory polyneuropathy. Our results demonstrate that PCYT2:c.4A>G in dogs cause PCYT2 deficiency. This canine model with histopathologically documented retinal, central, and peripheral neurodegeneration further deepens the knowledge of PCYT2 deficiency.