The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: data from individual patients and family studies.

Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n=11; 4 males), or on unbiased cascade screening of probands' close relatives (n=11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n=696) has been estimated as 0.001, therefore not qualifying for "rare" condition.

A process evaluation of a randomized-controlled trial of community gardening to improve health behaviors and reduce stress and anxiety.

As part of the Community Activation for Prevention (CAPS) randomized controlled trial (RCT) of community gardening, we conducted a process evaluation to assess the implementation of a community gardening intervention over nine months, as measured by reach, fidelity (delivery, receipt, enactment), and acceptability. Evaluation instruments included repeated semi-structured interviews with study participants, direct observation of community garden sites, and an exit survey of participants. Primary outcomes were diet, physical activity, and anthropometry; secondary outcomes were stress and anxiety. The CAPS trial included 291 participants (19% non-white; 34% Hispanic/Latino; 35% without a college degree; 58% with income < $50,000 per year). Intervention delivery and receipt were high for environmental supports. Garden social events were offered by 73% of gardens, although only 48% of intervention participants reported attending these events. Of the 145 participants assigned to the gardening intervention, 97 (67%) reported gardening the entire season and reported visiting the community garden a median of 90 min per week (range: 0-840). Of the participants who completed the exit survey (48%), 89% were highly satisfied with the overall garden experience. The CAPS trial was favorably received and implemented with high fidelity, supporting the validity of the trial outcomes. These findings suggest that community gardens are a viable health promotion strategy that can be successfully implemented among new gardeners from diverse backgrounds. Strategies that engage new gardeners in the social aspects of the garden environment and connect gardeners with garden "mentors" or "buddies" to ensure new gardeners achieve success in their first years of gardening are recommended.Trial registration: NCT03089177. Registered 24 March 2017, https://clinicaltrials.gov/study/NCT03089177 .

Effects of a community gardening intervention on diet, physical activity, and anthropometry outcomes in the USA (CAPS): an observer-blind, randomised controlled trial.

BACKGROUND: Unhealthy diet, physical inactivity, and social disconnection are important modifiable risk factors for non-communicable and other chronic diseases, which might be alleviated through nature-based community interventions. We tested whether a community gardening intervention could reduce these common health risks in an adult population that is diverse in terms of age, ethnicity, and socioeconomic status. METHODS: In this observer-blind, randomised, controlled trial, we recruited individuals who were on Denver Urban Garden waiting lists for community gardens in Denver and Aurora (CO, USA), aged 18 years or older, and had not gardened in the past 2 years. Participants were randomly assigned (1:1), using a randomised block design in block sizes of two, four, or six, to receive a community garden plot (intervention group) or remain on a waiting list and not garden (control group). Researchers were masked to group allocation. Primary outcomes were diet, physical activity, and anthropometry; secondary outcomes were perceived stress and anxiety. During spring (April to early June, before randomisation; timepoint 1 [T1]), autumn (late August to October; timepoint 2 [T2]), and winter (January to March, after the intervention; timepoint 3 [T3]), participants completed three diet recalls, 7-day accelerometry, surveys, and anthropometry. Analyses were done using the intention-to-treat principle (ie, including all participants randomly assigned to groups, and assessed as randomised). We used mixed models to test time-by-intervention hypotheses at an α level of 0·04, with T2 and T3 intervention effects at an α level of 0·005 (99·5% CI). Due to potential effects of the COVID-19 pandemic on outcomes, we excluded all participant data collected after Feb 1, 2020. This study is registered with ClinicalTrials.gov, NCT03089177, and data collection is now complete. FINDINGS: Between Jan 1, 2017, and June 15, 2019, 493 adults were screened and 291 completed baseline measures and were randomly assigned to the intervention (n=145) or control (n=146) groups. Mean age was 41·5 years (SD 13·5), 238 (82%) of 291 participants were female, 52 (18%) were male, 99 (34%) identified as Hispanic, and 191 (66%) identified as non-Hispanic. 237 (81%) completed measurements before the beginning of the COVID-19 pandemic. One (<1%) participant in the intervention group had an adverse allergic event in the garden. Significant time-by-intervention effects were observed for fibre intake (p=0·034), with mean between-group difference (intervention minus control) at T2 of 1·41 g per day (99·5% CI -2·09 to 4·92), and for moderate-to-vigorous physical activity (p=0·012), with mean between-group difference of 5·80 min per day (99·5% CI -4·44 to 16·05). We found no significant time-by-intervention interactions for combined fruit and vegetable intake, Healthy Eating Index (measured using Healthy Eating Index-2010), sedentary time, BMI, and waist circumference (all p>0·04). Difference score models showed greater reductions between T1 and T2 in perceived stress and anxiety among participants in the intervention group than among those in the control group. INTERPRETATION: Community gardening can provide a nature-based solution, accessible to a diverse population including new gardeners, to improve wellbeing and important behavioural risk factors for non-communicable and chronic diseases. FUNDING: American Cancer Society, University of Colorado Cancer Centre, University of Colorado Boulder, National Institutes of Health, US Department of Agriculture National Institute of Food and Agriculture, Michigan AgBioResearch Hatch projects.

Soft-Tissue Simulation for Computational Planning of Orthognathic Surgery.

Simulation technologies offer interesting opportunities for computer planning of orthognathic surgery. However, the methods used to date require tedious set up of simulation meshes based on patient imaging data, and they rely on complex simulation models that require long computations. In this work, we propose a modeling and simulation methodology that addresses model set up and runtime simulation in a holistic manner. We pay special attention to modeling the coupling of rigid-bone and soft-tissue components of the facial model, such that the resulting model is computationally simple yet accurate. The proposed simulation methodology has been evaluated on a cohort of 10 patients of orthognathic surgery, comparing quantitatively simulation results to post-operative scans. The results suggest that the proposed simulation methods admit the use of coarse simulation meshes, with planning computation times of less than 10 seconds in most cases, and with clinically viable accuracy.

Feasibility of collection and analysis of microbiome data in a longitudinal randomized trial of community gardening.

Aim: We explored the feasibility of collecting and analyzing human microbiome data in a longitudinal randomized controlled trial of community gardening. Methods & materials: Participants were randomly assigned to gardening (N = 8) or control (N = 8). Participants provided stool, mouth, hand and forehead microbiome samples at six timepoints. Analyses combined mixed models with Qiita output. Results: Participant satisfaction was high, with 75% of participants completing evaluations. While no microbial effects were statistically significant due to small sample size, the analysis pipeline utility was tested. Conclusion: Longitudinal collection and analysis of microbiome data in a community gardening randomized controlled trial is feasible. The analysis pipeline will be useful in larger studies for assessment of the pathway between microbiota, gardening and health outcomes.

Deferasirox-induced iron depletion promotes BclxL downregulation and death of proximal tubular cells.

Iron deficiency has been associated with kidney injury. Deferasirox is an oral iron chelator used to treat blood transfusion-related iron overload. Nephrotoxicity is the most serious and common adverse effect of deferasirox and may present as an acute or chronic kidney disease. However, scarce data are available on the molecular mechanisms of nephrotoxicity. We explored the therapeutic modulation of deferasirox-induced proximal tubular cell death in culture. Deferasirox induced dose-dependent tubular cell death and AnexxinV/7AAD staining showed features of apoptosis and necrosis. However, despite inhibiting caspase-3 activation, the pan-caspase inhibitor zVAD-fmk failed to prevent deferasirox-induced cell death. Moreover, zVAD increased deferasirox-induced cell death, a feature sometimes found in necroptosis. Electron microscopy identified mitochondrial injury and features of necrosis. However, neither necrostatin-1 nor RIP3 knockdown prevented deferasirox-induced cell death. Deferasirox caused BclxL depletion and BclxL overexpression was protective. Preventing iron depletion protected from BclxL downregulation and deferasirox cytotoxicity. In conclusion, deferasirox promoted iron depletion-dependent cell death characterized by BclxL downregulation. BclxL overexpression was protective, suggesting a role for BclxL downregulation in iron depletion-induced cell death. This information may be used to develop novel nephroprotective strategies. Furthermore, it supports the concept that monitoring kidney tissue iron depletion may decrease the risk of deferasirox nephrotoxicity.

Deferasirox nephrotoxicity-the knowns and unknowns.

In 2005, the oral iron chelator deferasirox was approved by the FDA for clinical use as a first-line therapy for blood-transfusion-related iron overload. Nephrotoxicity is the most serious and frequent adverse effect of deferasirox treatment. This nephrotoxicity can present as an acute or chronic decrease in glomerular filtration rate (GFR). Features of proximal tubular dysfunction might also be present. In clinical trials and observational studies, GFR is decreased in 30-100% of patients treated with deferasirox, depending on dose, method of assessment and population studied. Nephrotoxicity is usually nonprogressive and/or reversible and rapid iron depletion is one of several risk factors. Scarce data are available on the molecular mechanisms of nephrotoxicity and the reasons for the specific proximal tubular sensitivity to the drug. Although deferasirox promotes apoptosis of cultured proximal tubular cells, the trigger has not been well characterized. Observational studies are required to track current trends in deferasirox prescription, assess the epidemiology of deferasirox nephrotoxicity in routine clinical practice, explore the effect on outcomes of various monitoring and dose-adjustment protocols and elucidate the long-term consequences of the different features of nephrotoxicity. Deferasirox nephrotoxicity can be more common in the elderly; thus, specific efforts should be dedicated to investigate the effect of deferasirox use in this group of patients.

Use of radioactive iodine I-131 and monitoring of radioactivity in patients with chronic kidney disease on haemodialysis.

Thyroid carcinoma is a neoplasia with a higher incidence in patients with chronic kidney disease. In recent years advances have been made in diagnostic and therapeutic trials. Dialysis patients are a particular group, their cancer being detected indirectly in the study of secondary hyperparathyroidism and during the study prior to renal transplantation. Thyroidectomy is the definitive treatment, but in patients with risk of recurrence, ablative therapy is required using radioactive iodine I-131, which is predominantly eliminated by renal excretion, therefore its use in patients on dialysis poses a problem in terms of dosage. Two cases are presented of patients on haemodialysis undergoing radioablation with radioactive iodine I-131, which with multidisciplinary treatment had the expected results in the patients.

Manifestaciones paraneoplásicas cutáneas en pacientes con carcinoma pulmonar / Paraneoplastic cutaneous manifestations in patients with lung cancer

Un tumor maligno puede manifestarse externamente en piel y su reconocimiento puede conducir al diagnóstico de una neoplasia previamente no sospechada. Es difícil determinar la frecuenticia exacta de todos los síndromes paraneoplásicos debido a: distintas definiciones, etiologías desconocidas y la falta de estudios controlados sistemáticos. Se presenta un estudio clínico descriptivo sobre las manifestaciones cutáneas paraneoplásicas en pacientes con carcinoma pulmonar; para ello se evaluaron los pacientes que ingresaron con el diagnóstico de cáncer de pulmón o a quienes se les hizo este diagnóstico durante su hospitalización en el Hospital José Ignacio Baldó en el lapso noviembre/92-junio/94 y que presentaran alguna dermatosis. La muestra estuvo compuesta por 48 pacientes de los cuales 5 presentaron manifestaciones paraneoplásicas, a saber: tromboflebitis superficial (2 casos), ictiosis adquirida, esclerodermia y prurito generalizado con un caso cada uno. Estas condiciones son discutidas con amplitud