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Quality assurance remains a significant challenge for laser powder bed fusion and metal additive manufacturing. Despite system manufacturers offering process monitoring as a possible solution, datasets are large and cumbersome with practical use limited without direct comparative data. Model datasets would enable individual build validation, highlight deviations, and facilitate intelligent build planning whereby challenging features or build strategies could be pre-emptively assessed.Herein a pragmatic approach has been developed to model process monitoring data from a commercial system using a relatively simple algorithm. Using a heuristic method, the algorithm response has been fitted to an experimental dataset to derive governing constants and their relationship to key process parameters. Predictability of constants and model fit has been shown to improve with increasing line energy up to a maximum R2=0.8. Algorithm variable trends, supported by corresponding sensitivity analysis, identified two different behavioural regimes. Under low linear energy density (

Purpose Prior research has indicated that several theories might be incorporated to understand perpetration of post-relationship pursuit behaviors (PPBs). However, difficulties coping with relationship loss have not been directly assessed as potential predictors of PPB perpetration, despite their potential relevance. Thus, the present study tests an integrative model to assess whether acceptance or denial-based coping with relationship loss are associated with minor PPBs (e.g., following, excessive contact) and severe PPBs (e.g., aggression) when including prior theoretically relevant variables, such as prior relationship violence (part of coercive control theory) and break-up related distress and rumination (relational goal pursuit theory). Potential differences in predictors of in-person and cyber PPBs are explored, as are moderating effects of gender. Method N= 821 undergraduates (59.4% women) who experienced a break-up within the past two years completed measures related to in-person and severe PPBs, coping strategies, prior relationship violence, and relational goal pursuit constructs. Results Coping by acceptance was associated with reductions in minor PPBs among men (but not women), whereas coping by denial was associated with increases in minor and severe PPBs across genders, through direct and indirect paths. Supporting prior research, relational goal pursuit was related only to minor PPBs, whereas prior relationship violence was associated with all PPBs, particularly among men. There were few differences in predictors of in-person and cyber PPBs. Conclusion Denial over relationship loss may serve as a risk factor for PPB engagement, whereas coping by acceptance may serve a more limited protective role. Additional risk factors remain important to study in future research., Author(s): Christina M. Dardis [sup.1] Author Affiliations: (1) https://ror.org/044w7a341, grid.265122.0, 0000 0001 0719 7561, Department of Psychology, Towson University, , 8000 York Road, 21252, Towson, MD, USA Experiencing the break-up [...]

Abstract Niemann-Pick type C (NPC) disease is a lysosomal storage disease (LSD) characterized by the buildup of endo-lysosomal cholesterol and glycosphingolipids due to loss of function mutations in the NPC1 and NPC2 genes. NPC patients can present with a broad phenotypic spectrum, with differences at the age of onset, rate of progression, severity, organs involved, effects on the central nervous system, and even response to pharmacological treatments. This article reviews the phenotypic variation of NPC and discusses its possible causes, such as the remaining function of the defective protein, modifier genes, sex, environmental cues, and splicing factors, among others. We propose that these factors should be considered when designing or repurposing treatments for this disease. Despite its seeming complexity, this proposition is not far-fetched, considering the expanding interest in precision medicine and easier access to multi-omics technologies.

Digital marketing to children, teens, and adults contributes to substantial exposure to cues and persuasive messages that drive the overconsumption of energy dense foods and sugary beverages. Previous food marketing research has focused on traditional media, but less is known about how marketing techniques translate within digital platforms, such as social media, livestreaming, and gaming. Building upon previous theories and models, we propose a new model entitled food and beverage cues in digital marketing (FBCDM). The FBCDM model specifies key marking elements and marketing integration strategies that are common on digital platforms and are hypothesized to enhance the effects of advertising and incentive sensitization process. FBCDM also categorizes measurable outcomes into three domains that include brand, food, and social outcomes. Additionally, repeated marketing exposure and the resulting outcomes are hypothesized to have long term consequences related to consumer markets, consumption behavior, culture, and health. We include a discussion of what is currently known about digital marketing exposure within the outcome domains, and we highlight gaps in research including the long-term consequences of digital marketing exposure. The FBCDM model provides a conceptual framework to guide future research to examine the digital marketing of food and beverages to children and adolescents in order to inform government and industry policies that restrict the aggressive marketing of products associated with obesity and adverse diet related outcomes.

Neuropathic pain is one of the most invalidating symptoms in patients with Fabry disease (FD), affecting their quality of life, it is linked to small fiber neuropathy and it may not respond to available disease specific treatments. We report the case of a 32 years old man with classic FD and severe neuropathic pain who, after the failure of several standard pharmaceutical approaches, was treated with medical cannabis with relief of nocturnal pain and sleep improvement.

Abstract Background Acid Sphingomyelinase Deficiency (ASMD) is a rare autosomal recessive disorder caused by mutations in the SMPD1 gene. This rarity contributes to misdiagnosis, delayed diagnosis and barriers to good care. There are no published national or international consensus guidelines for the diagnosis and management of patients with ASMD. For these reasons, we have developed clinical guidelines that defines standard of care for ASMD patients. Methods The information contained in these guidelines was obtained through a systematic literature review and the experiences of the authors in their care of patients with ASMD. We adopted the Appraisal of Guidelines for Research and Evaluation (AGREE II) system as method of choice for the guideline development process. Results The clinical spectrum of ASMD, although a continuum, varies substantially with subtypes ranging from a fatal infantile neurovisceral disorder to an adult-onset chronic visceral disease. We produced 39 conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. In addition, these guidelines have identified knowledge gaps that must be filled by future research. Conclusion These guidelines can inform care providers, care funders, patients and their carers about best clinical practice and leads to a step change in the quality of care for patients with ASMD with or without enzyme replacement therapy (ERT).

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Objective: Examine uptake (e.g., initial session participation) and retention (e.g., booster session participation) in an intervention about responding to sexual assault and partner abuse disclosures. Participants: Participants were 836 students (primarily White; upper-middle class) at a medium-sized university. Method: Participants completed baseline surveys, were invited to a two-session intervention, and responded to a follow-up survey. Results: Initial session attendance was 36.2% (n = 303); of those, 83.1% (n = 252) attended the booster. Female, sexual minority students, and students with fewer prior negative reactions, and higher initial session satisfaction were more likely to attend than other students. Participants' reported reasons for not attending included scheduling problems and topic discomfort. Participants reported that remote attendance and higher cash incentives would have made attendance more likely. Conclusion: Findings indicate the draw of cash incentives, a need to reach high-risk students and integrate into existing organizations, and the potential for individualized prevention.

Abstract Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder due to the deficient activity of the acid beta-glucosidase (GCase) enzyme, resulting in the progressive lysosomal accumulation of glucosylceramide (GlcCer) and its deacylated derivate, glucosylsphingosine (GlcSph). GCase is encoded by the GBA1 gene, located on chromosome 1q21 16 kb upstream from a highly homologous pseudogene. To date, more than 400 GBA1 pathogenic variants have been reported, many of them derived from recombination events between the gene and the pseudogene. In the last years, the increased access to new technologies has led to an exponential growth in the number of diagnostic laboratories offering GD testing. However, both biochemical and genetic diagnosis of GD are challenging and to date no specific evidence-based guidelines for the laboratory diagnosis of GD have been published. The objective of the guidelines presented here is to provide evidence-based recommendations for the technical implementation and interpretation of biochemical and genetic testing for the diagnosis of GD to ensure a timely and accurate diagnosis for patients with GD worldwide. The guidelines have been developed by members of the Diagnostic Working group of the International Working Group of Gaucher Disease (IWGGD), a non-profit network established to promote clinical and basic research into GD for the ultimate purpose of improving the lives of patients with this disease. One of the goals of the IWGGD is to support equitable access to diagnosis of GD and to standardize procedures to ensure an accurate diagnosis. Therefore, a guideline development group consisting of biochemists and geneticists working in the field of GD diagnosis was established and a list of topics to be discussed was selected. In these guidelines, twenty recommendations are provided based on information gathered through a systematic review of the literature and two different diagnostic algorithms are presented, considering the geographical differences in the access to diagnostic services. Besides, several gaps in the current diagnostic workflow were identified and actions to fulfill them were taken within the IWGGD. We believe that the implementation of recommendations provided in these guidelines will promote an equitable, timely and accurate diagnosis for patients with GD worldwide.

Summary: The histone methyltransferase EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting paradoxical gene expression through interactions with transcription factors, including NF-κB in triple negative breast cancer (TNBC). We profile EZH2 and NF-κB factor co-localization and positive gene regulation genome-wide, and define a subset of NF-κB targets and genes associated with oncogenic functions in TNBC that is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified transactivation domain (TAD) which mediates EZH2 recruitment to, and activation of certain NF-κB-dependent genes, and supports downstream migration and stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-κB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-κB-dependent regulatory mechanisms.

Objective: Much is known about how alcohol increases the risk of sexual assault or intimate partner violence victimization during college. This research qualitatively explores perceptions about how alcohol influences disclosures about these events to informal supports. Participants: Participants included college students who received a disclosure wherein they or the survivor were drinking during the disclosure (n = 81). Methods: Responses were coded with regard to who was drinking and whether the effect of drinking during the disclosure was perceived as positive, negative, mixed, or neutral/none. Results: Participants perceived alcohol to have both positive (e.g., increasing the likelihood of discussing difficult topics) and negative (e.g., cognitive impairment increased negative emotions) effects on disclosures. Conclusion: Prevention and intervention efforts should identify targeted strategies (e.g., remembering one or two easy and helpful phrases; revisiting the topic again while sober) to help survivors and disclosure recipients have constructive conversations in the presence of alcohol. [ABSTRACT FROM AUTHOR]

The article discusses a case report of a 40-year-old White female with SCARB2-related Action Myoclonus Renal Failure (AMRF) syndrome, a rare genetic disorder. The patient experienced progressive myoclonus epilepsy and renal failure, leading to severe motor impairments. Off-label use of miglustat, a drug used in Gaucher's disease, showed promising results in improving GCase activity and reducing myoclonus symptoms. The study highlights the potential of miglustat as a disease-modifying therapy for AMRF, emphasizing the need for further research in this area. [Extracted from the article]

Abstract Background Niemann-Pick Disease Type C (NPC) is an autosomal recessive rare disease characterised by progressive neurovisceral manifestations. The collection of on-going large-scale NPC clinical data may generate better understandings of the natural history of the disease. Here we report NPC patient data from the International Niemann-Pick Disease Registry (INPDR). Method The INPDR is a web-based, patient-led independent registry for the collection of prospective and retrospective clinical data from Niemann-Pick Disease patients. Baseline data from NPC patients enrolled into the INPDR from September 2014 to December 2019 was extracted to analyse the demographic, genetic and clinical features of the disease. Results A total of 203 NPC patients from six European countries were included in this study. The mean age (SD) at diagnosis was 11.2 years (14.2). Among enrolled patients, 168 had known neurological manifestations: 43 (24.2%) had early-infantile onset, 47 (26.4%) had late-infantile onset, 41 (23.0%) had juvenile onset, and 37 (20.8%) had adult onset. 10 (5.6%) patients had the neonatal rapidly fatal systemic form. Among the 97 patients with identified NPC1 variants, the most common variant was the c. 3182T > C variant responsible for the p.lle1061Thr protein change, reported in 35.1% (N = 34) of patients. The frequencies of hepatomegaly and neonatal jaundice were greatest in patients with early-infantile and late-infantile neurological onset. Splenomegaly was the most commonly reported observation, including 80% of adult-onset patients. The most commonly reported neurological manifestations were cognitive impairment (78.5%), dysarthria (75.9%), ataxia (75.9%), vertical supranuclear gaze palsy (70.9%) and dysphagia (69.6%). A 6-domain composite disability scale was used to calculate the overall disability score for each neurological form. Across all with neurological onset, the majority of patients showed moderate to severe impairments in all domains, except for ‘swallowing’ and ‘seizure’. The age at diagnosis and death increased with increased age of neurological symptom onset. Miglustat use was recorded in 62.4% of patients and the most common symptomatic therapies used by patients were antiepileptics (32.9%), antidepressants (11.8%) and antacids (9.4%). Conclusion The proportion of participants at each age of neurological onset was relatively equal across the cohort. Neurological manifestations, such as ataxia, dysphagia, and dysarthria, were frequently observed across all age categories.

Summary: Background: Cauda equina syndrome (CES) results from nerve root compression in the lumbosacral spine, usually due to a prolapsed intervertebral disc. Evidence for management of CES is limited by its infrequent occurrence and lack of standardised clinical definitions and outcome measures. Methods: This is a prospective multi-centre observational cohort study of adults with CES in the UK. We assessed presentation, investigation, management, and all Core Outcome Set domains up to one year post-operatively using clinician and participant reporting. Univariable and multivariable associations with the Oswestry Disability Index (ODI) and urinary outcomes were investigated. Findings: In 621 participants with CES, catheterisation for urinary retention was required pre-operatively in 31% (191/615). At discharge, only 13% (78/616) required a catheter. Median time to surgery from symptom onset was 3 days (IQR:1–8) with 32% (175/545) undergoing surgery within 48 h. Earlier surgery was associated with catheterisation (OR:2.2, 95%CI:1.5–3.3) but not with admission ODI or radiological compression. In multivariable analyses catheter requirement at discharge was associated with pre-operative catheterisation (OR:10.6, 95%CI:5.8–20.4) and one-year ODI was associated with presentation ODI (r = 0.3, 95%CI:0.2–0.4), but neither outcome was associated with time to surgery or radiological compression. Additional healthcare services were required by 65% (320/490) during one year follow up. Interpretation: Post-operative functional improvement occurred even in those presenting with urinary retention. There was no association between outcomes and time to surgery in this observational study. Significant healthcare needs remained post-operatively. Funding: DCN Endowment Fund funded study administration. Castor EDC provided database use. No other study funding was received.

Este trabalho objetiva investigar a temporalidade no que tange ao adoecimento psíquico pós-moderno, através de um olhar fenomenológico. Para isso, buscou-se compreender, através de uma revisão bibliográfica narrativa, como estão construídos esses conceitos, a fim de visualizar como podem interligar-se. O percurso evidenciou que a pós-modernidade reúne características modificadoras da experiência de tempo, por meio de uma aceleração imparável que acentua um desassossego epocal descrito como adoecimento psíquico. A fenomenologia-existencial sugere que se coloque em suspensão esses rótulos para pensar os modos de ser enquanto denúncia e possibilidade, haja vista que, nessa perspectiva, o adoecimento diz respeito a uma parada no ritmo do cotidiano, propiciando uma abertura sustentada na ideia de que o problema não reside no adoecimento e sim no enrijecimento dele como única possibilidade de existir, tirando a liberdade do Ser. Ao cuidado terapêutico, caberia acolher a angústia livre de rótulos para não repetir a lógica do sofrimento.

Among college survivors of unwanted pursuit behaviors (UPBs; 40.1%, n = 189) or intimate partner stalking (IPS, i.e., UPBs causing emotional distress; 32.1%, n = 151), the present study examined effects of social reactions to disclosures on post-traumatic stress disorder (PTSD) symptomatology, academic outcomes, and personal empowerment. Compared to UPB survivors, IPS survivors were more likely to disclose and reported higher positive and negative reactions to disclosure as well as greater frequency of UPBs/IPS, IPV, and PTSD symptoms. Among both groups, only negative social reactions were positively associated with PTSD symptoms. However, among IPS (but not UPB) survivors, only positive social reactions were related to academic outcomes and empowerment when controlling for PTSD and IPS frequency. Implications for research and practice are discussed. [ABSTRACT FROM AUTHOR]

Objectives To compare the accuracy of trained level 1 diabetic retinopathy (DR) graders (nurses, endocrinologists and one general practitioner), level 2 graders (midlevel ophthalmologists) and level 3 graders (senior ophthalmologists) in Vietnam against a reference standard from the UK and assess the impact of supplementary targeted grader training.Design Diagnostic test accuracy study.Setting Secondary care hospitals in Southern Vietnam.Participants DR training was delivered to Vietnamese graders in February 2018 by National Health Service (NHS) UK graders. Two-field retinal images (412 patient images) were graded by 14 trained graders in Vietnam between August and October 2018 and then regraded retrospectively by an NHS-certified reference standard UK optometrist (phase I). Further DR training based on phase I results was delivered to graders in November 2019. After training, a randomised subset of images from January to October 2020 (115 patient images) was graded by six of the original cohort (phase II). The reference grader regraded all images from phase I and II retrospectively in masked fashion.Primary and secondary outcome measures Sensitivity was calculated at the two different time points, and χ2 was used to test significance.Results In phase I, the sensitivity for detecting any DR for all grader groups in Vietnam was low (41.8–42.2%) and improved in phase II after additional training was delivered (51.3–87.2%). The greatest improvement was seen among level 1 graders (p

Abstract Background Gliosarcoma (GS) refers to the presence of mesenchymal differentiation (as seen using light microscopy) in the setting of glioblastoma (GB, an astrocytoma, WHO Grade 4). Although the same approach to treatment is typically adopted for GS and GB, there remains some debate as to whether GS should be considered a discrete pathological entity. Differences between these tumors have not been clearly established at the molecular level. Methods Patients with GS (n=48) or GB (n=1229) underwent molecular profiling (MP) with a pan-cancer panel of tests as part of their clinical care. The methods employed included next-generation sequencing (NGS) of DNA and RNA, copy number variation (CNV) of DNA and immunohistochemistry (IHC). The MP comprised 1153 tests in total, although results for each test were not available for every tumor profiled. We analyzed this data retrospectively in order to determine if our results were in keeping with what is known about the pathogenesis of GS by contrast with GB. We also sought novel associations between the MP and GS vs. GB which might improve our understanding of pathogenesis of GS. Results Potentially meaningful associations (p

While prior research has studied associations between child abuse and nonsuicidal self-injury (NSSI), there is limited research assessing unwanted pursuit behavior (UPB) victimization and NSSI. In addition, few studies have assessed the self-reported functions of NSSI among survivors of violence. Among a sample of 18–25-year-old young adults (N = 333), both UPB victimization and child abuse were significantly associated with NSSI frequency. In regression models, UPB victimization was associated with increased use of affect regulation, antidissociation/feeling-generation, self-punishment, and antisuicide functions, while child abuse was associated only with antidissociation/feeling-generation and self-punishment. Affect regulation mediated the association between UPB victimization and NSSI frequency, but not the association between child victimization and NSSI frequency. Implications for research and clinical practice will be discussed. [ABSTRACT FROM AUTHOR]

Pompe disease (PD) is an autosomal recessive lysosomal storage disorder due to deficient activity of the acid alpha glucosidase enzyme (GAA). As a consequence of the enzymatic defect, undigested glycogen accumulates within lysosomes. Most patients affected by the late-onset (LO) phenotype carry in at least one allele the c.-32-13T>G variant, which leads to exon 2 exclusion from the pre-mRNA. These patients display a variable and suboptimal response to enzyme replacement therapy. To identify novel therapeutic approaches, we developed a fluorescent GAA exon 2 splicing assay and screened a library of US Food and Drug Administration (FDA)-approved compounds. This led to the identification of several drugs able to restore normal splicing. Among these, we further validated the effects of the iron chelator deferoxamine (Defe) in c.-32-13T>G fibroblasts. Defe treatment resulted in a 2-fold increase of GAA exon 2 inclusion and a 40% increase in enzymatic activity. Preliminary results suggest that this effect is mediated by the regulation of iron availability, at least partially. RNA-seq experiments also showed that Defe might shift the balance of splicing factor levels toward a profile promoting GAA exon 2 inclusion. This work provides the basis for drug repurposing and development of new chemically modified molecules aimed at improving the clinical outcome in LO-PD patients.

Introduction Globally, diabetic retinopathy (DR) is the leading cause of blindness in working-aged adults. Early detection and treatment of DR is essential for preventing sight loss. Services must be available, accessible and acceptable to patients if we are to ensure they seek such care.Objectives To understand patients’ knowledge and attitudes towards laser versus antivascular endothelial growth factor (VEGF) injections to treat DR in Vietnam, and to identify factors Vietnamese ophthalmologists consider when making treatment decisions.Methods This is a descriptive qualitative study based on semi-structured interviews with 18 patients (12 from Ho Chi Minh City and 6 from Hanoi) plus individual interviews with 24 ophthalmologists working in eye clinics in these cities. Thematic analysis was used to analyse the data.Results In total, 10/24 (41.7%) ophthalmologists were female, and their median age was 41 years (range 29–69 years). The median age of patients was 56.5 years (range 28–72 years), and 7/18 (38.9%) were female. Briefly, factors that influence DR treatment decisions for ophthalmologists are medical considerations (ie, severity of disease, benefits and risks), availability (ie, treatment and resources) and patient-related factors (ie, costs and adherence). Patient’s perceived barriers and facilitators to treatments were based on patient and family related factors (ie, treatment and transportation costs) and previous treatment experiences (ie, positive and negative). Recommendations by all participants included ensuring that both laser and anti-VEGF injections are widely available across the country and controlling costs for patients and the healthcare system.Conclusions Reducing DR treatment costs, optimising treatments options, and expanding the network of clinics offering treatment outside metropolitan areas were the main issues raised by participants. These findings can help inform policy changes in Vietnam and may be generalisable to other low-resource settings.

Here, we report the identification and functional characterization of a novel GLA variant, not detectable by routine molecular tests, in a family with FD suspicion. [ABSTRACT FROM AUTHOR]

Abstract Alpha mannosidosis is an ultrarare pathology with variable phenotypic manifestations, characterized by the deficiency of lysosomal alpha mannosidase which causes accumulation of neutral oligosaccharides. Until recently, the hematopoietic stem cell transplantation was the only clinical feasible therapeutic option. Only in 2018, the European Medicines Agency's committee approved the recombinant enzyme velmanase alfa for long‐term treatment of non‐neurological manifestations in mild and moderate forms of alpha‐mannosidosis. In this study, the very early biochemical effects of enzyme replacement therapy in in a 7‐month‐old patient with alpha‐mannosidosis were described. Velmanase alpha was administered as supporting therapy awaiting for hematopoietic stem cell transplantation, the treatment chosen for the patient because of the early onset form. The results showed that the enzyme replacement therapy was able to reduce the content of three different mannosyl‐oligosaccharides monitored by tandem mass spectrometry after 2 months of treatment. In particular, the mean relative changes from baseline values were −67% in urine and −53% in serum at the latest observation. The study also showed that the enzymatic activity detected in serum 1 week after the first infusion was four times higher than the normal values and constant in the following points of observation. These findings led us to assume that velmanase alfa might be biologically active in this young patient.

Abstract Background Late onset Pompe disease (LOPD) is a lysosomal neuromuscular disorder which can progressively impair the patients’ exercise tolerance, motor and respiratory functions, and quality of life. The available enzyme replacement therapy (ERT) does not completely counteract disease progression. We investigated the effect of exercise training alone, or associated with a high-protein diet, on the exercise tolerance, muscle and pulmonary functions, and quality of life of LOPD patients on long term ERT. Methods The patients were asked to participate to a crossover randomized study comprehending a control period (free diet, no exercise) followed by 2 intervention periods: exercise or exercise + diet, each lasting 26 weeks and separated by 13 weeks washout periods. Exercise training included moderate-intensity aerobic exercise on a cycle ergometer, stretching and balance exercises, strength training. The diet was composed by 25–30% protein, 30–35% carbohydrate and 35–40% fat. Before and after each period patients were assessed for: exercise tolerance test on a cycle-ergometer, serum muscle enzymes, pulmonary function tests and SF36 questionnaire for quality of life. Compliance was evaluated by training and dietary diaries. Patients were contacted weekly by researchers to optimize adherence to treatments. Results Thirteen LOPD patients, median age 49 ± 11 years, under chronic ERT (median 6.0 ± 4.0 years) were recruited. Peak aerobic power (peak pulmonary O2 uptake) decreased after control, whereas it increased after exercise, and more markedlyafter exercise + diet. Serum levels of lactate dehydrogenase (LDH) significantly decreased after exercise + diet; both creatine kinase (CK) and LDH levels were significantly reduced after exercise + diet compared to exercise. Pulmonary function showed no changes after control and exercise, whereas a significant improvement of forced expiratory volume in 1 sec (FEV1) was observed after exercise + diet. SF36 showed a slight improvement in the “mental component” scale after exercise, and a significant improvement in “general health” and “vitality” after exercise + diet. The compliance to prescriptions was higher than 70% for both diet and exercise. Conclusions Exercise tolerance (as evaluated by peak aerobic power) showed a tendency to decrease in LOPD patients on long term ERT. Exercise training, particularly if combined with high-protein diet, could reverse this decrease and result in an improvement, which was accompanied by improved quality of life. The association of the two lifestyle interventions resulted also in a reduction of muscle enzyme levels and improved pulmonary function.

Impaired glycosaminoglycans (GAGs) catabolism may lead to a cluster of rare metabolic and genetic disorders called mucopolysaccharidoses (MPSs). Each subtype is caused by the deficiency of one of the lysosomal hydrolases normally degrading GAGs. Affected tissues accumulate undegraded GAGs in cell lysosomes and in the extracellular matrix, thus leading to the MPS complex clinical phenotype. Although each MPS may present with recognizable signs and symptoms, these may often overlap between subtypes, rendering the diagnosis difficult and delayed. Here, we performed an exploratory analysis to develop a model that predicts MPS subtypes based on UHPLC-MS/MS measurement of a urine free GAG profile (or GAGome). We analyzed the GAGome of 78 subjects (38 MPS, 37 healthy and 3 with other MPS symptom-overlapping disorders) using a standardized kit in a central-blinded laboratory. We observed several MPS subtype-specific GAGome changes. We developed a multivariable penalized Lasso logistic regression model that attained 91.2% balanced accuracy to distinguish MPS type II vs. III vs. any other subtype vs. not MPS, with sensitivity and specificity ranging from 73.3% to 91.7% and from 98.4% to 100%, depending on the predicted subtype. In conclusion, the urine GAGome was revealed to be useful in accurately discriminating the different MPS subtypes with a single UHPLC-MS/MS run and could serve as a reliable diagnostic test for a more rapid MPS biochemical diagnosis.

Acid sphingomyelinase deficiency (ASMD) is a rare metabolic disorder due to biallelic mutation in the SMPD1 gene. The defect leads to the accumulation of sphingomyelin within the cells of the reticulo-endothelial system, particularly in the spleen, liver, lungs, and bone marrow causing hepato-splenomegaly, lung disease and hematological abnormalities. At present, data on abdominal imaging in ASMD are limited. Here we describe the characteristics of focal liver lesions observed in a 30 years old female. During the Magnetic Resonance follow up an increase in number and size of the lesions, showing T1 hypointensity and T2 hyperintensity with contrast enhancement, was observed. Contrast enhanced ultrasound evidenced rapid wash-in and steady isoecogenicity without appreciable wash-out at 80 seconds. The main lesion was biopsied to rule out the presence of a hepatocellular carcinoma, and showed to be a benign foamy macrophages aggregate. In this report, we discuss the possible pathogenesis of focal hepatic lesions in ASMD and their differential diagnosis.

ABSTRACT Microbial genomes are being extensively studied using next-generation sequencing technologies in order to understand the changes that occur under different selection regimes. In this work, the number and type of mutations that have occurred in three Bradyrhizobium diazoefficiens USDA 110T strains under laboratory conditions and during selection for a more motile phenotypic variant were analyzed. Most of the mutations found in both processes consisted of single nucleotide polymorphisms, single nucleotide deletions or insertions. In the case of adaptation to laboratory conditions, half of the changes occurred within intergenic regions, and around 80% were insertions. When the more motile phenotypic variant was evaluated, eight single nucleotide polymorphisms and an 11-bp deletion were found, although none of them was directly related to known motility or chemotaxis genes. Two mutants were constructed to evaluate the 11-bp deletion affecting the alpha subunit of 2-oxoacid:acceptor oxidoreductase (AAV28_RS30705-blr6743). The results showed that this single deletion was not responsible for the enhanced motility phenotype. IMPORTANCE The genetic and genomic changes that occur under laboratory conditions in Bradyrhizobium diazoefficiens genomes remain poorly studied. Only a few genome sequences of this important nitrogen-fixing species are available, and there are no genome-wide comparative analyses of related strains. In the present work, we sequenced and compared the genomes of strains derived from a parent strain, B. diazoefficiens USDA 110, that has undergone processes of repeated culture in the laboratory environment, or phenotypic selection toward antibiotic resistance and enhanced motility. Our results represent the first analysis in B. diazoefficiens that provides insights into the specific mutations that are acquired during these processes.