Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has ...proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients.
Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018.
Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome.
This study describes the natural history of classic galactosemia based on the hitherto largest data set.
Patterns of environmental spatial structure lie at the heart of the most fundamental and familiar patterns of diversity on Earth. Antarctica contains some of the strongest environmental gradients on ...the planet and therefore provides an ideal study ground to test hypotheses on the relevance of environmental variability for biodiversity. To answer the pivotal question, "How does spatial variation in physical and biological environmental properties across the Antarctic drive biodiversity?" we have synthesized current knowledge on environmental variability across terrestrial, freshwater, and marine Antarctic biomes and related this to the observed biotic patterns. The most important physical driver of Antarctic terrestrial communities is the availability of liquid water, itself driven by solar irradiance intensity. Patterns of biota distribution are further strongly influenced by the historical development of any given location or region, and by geographical barriers. In freshwater ecosystems, free water is also crucial, with further important influences from salinity, nutrient availability, oxygenation, and characteristics of ice cover and extent. In the marine biome there does not appear to be one major driving force, with the exception of the oceanographic boundary of the Polar Front. At smaller spatial scales, ice cover, ice scour, and salinity gradients are clearly important determinants of diversity at habitat and community level. Stochastic and extreme events remain an important driving force in all environments, particularly in the context of local extinction and colonization or recolonization, as well as that of temporal environmental variability. Our synthesis demonstrates that the Antarctic continent and surrounding oceans provide an ideal study ground to develop new biogeographical models, including life history and physiological traits, and to address questions regarding biological responses to environmental variability and change.
ObjectivesTo assess the relationship between changes in clinician attitude and changes in postoperative outcomes following a checklist-based surgical safety intervention.DesignPre- and post ...intervention survey.SettingEight hospitals participating in a trial of a WHO surgical safety checklist.ParticipantsClinicians actively working in the designated study operating rooms at the eight hospitals.Survey instrumentModified operating-room version Safety Attitudes Questionnaire (SAQ).Main outcome measuresChange in mean safety attitude score and correlation between change in safety attitude score and change in postoperative outcomes, plus clinician opinion of checklist efficacy and usability.ResultsClinicians in the preintervention phase (n=281) had a mean SAQ score of 3.91 (on a scale of 1 to 5, with 5 representing better safety attitude), while the postintervention group (n=257) had a mean of 4.01 (p=0.0127). The degree of improvement in mean SAQ score at each site correlated with a reduction in postoperative complication rate (r=0.7143, p=0.0381). The checklist was considered easy to use by 80.2% of respondents, while 19.8% felt that it took a long time to complete, and 78.6% felt that the programme prevented errors. Overall, 93.4% would want the checklist used if they were undergoing operation.ConclusionsImprovements in postoperative outcomes were associated with improved perception of teamwork and safety climate among respondents, suggesting that changes in these may be partially responsible for the effect of the checklist. Clinicians held the checklist in high regard and the overwhelming majority would want it used if they were undergoing surgery themselves.
During austral summer field seasons between 1999 and 2018, we sampled at 91 locations throughout southern Victoria Land and along the Transantarctic Mountains for six species of endemic ...microarthropods (Collembola), covering a latitudinal range from 76.0°S to 87.3°S. We assembled individual mitochondrial cytochrome c oxidase subunit 1 (COI) sequences (n = 866) and found high levels of sequence divergence at both small (<10 km) and large (>600 km) spatial scales for four of the six Collembola species. We applied molecular clock estimates and assessed genetic divergences relative to the timing of past glacial cycles, including collapses of the West Antarctic Ice Sheet (WAIS). We found that genetically distinct lineages within three species have likely been isolated for at least 5.54 My to 3.52 My, while the other three species diverged more recently (<2 My). We suggest that Collembola had greater dispersal opportunities under past warmer climates, via flotation along coastal margins. Similarly increased opportunities for dispersal may occur under contemporary climate warming scenarios, which could influence the genetic structure of extant populations. As Collembola are a living record of past landscape evolution within Antarctica, these findings provide biological evidence to support geological and glaciological estimates of historical WAIS dynamics over the last ca. 5 My.
Selective G‐quadruplex ligands offer great promise for the development of anti‐cancer therapies. A novel series of divalent cationic naphthalene diimide ligands that selectively bind to the hybrid ...form of the human telomeric G‐quadruplex in K+ buffer are described herein. We demonstrate that an imidazolium‐bearing mannoside‐conjugate is the most selective ligand to date for this quadruplex against several other quadruplex and duplex structures. We also show that a similarly selective methylpiperazine‐bearing ligand was more toxic to HeLa cancer cells than doxorubicin, whilst exhibiting three times less toxicity towards fetal lung fibroblasts WI‐38.
Get into the groove…: A series of divalent naphthalene diimide ligands selectively bind to the human telomeric G‐quadruplex in K+ buffer. An imidazolium‐bearing mannoside conjugate is the most selective ligand discovered to date for this quadruplex structure, and a similarly selective methylpiperazine‐bearing ligand was more toxic to HeLa cancer cells than doxorubicin, but with three times less toxicity towards fetal lung fibroblasts WI‐38.
In vitro primary hepatocyte systems typically elicit drug induction and toxicity responses at concentrations much higher than corresponding in vivo or clinical plasma C(max) levels, contributing to ...poor in vitro-in vivo correlations. This may be partly due to the absence of physiological parameters that maintain metabolic phenotype in vivo. We hypothesized that restoring hemodynamics and media transport would improve hepatocyte architecture and metabolic function in vitro compared with nonflow cultures. Rat hepatocytes were cultured for 2 wk either in nonflow collagen gel sandwiches with 48-h media changes or under controlled hemodynamics mimicking sinusoidal circulation within a perfused Transwell device. Phenotypic, functional, and metabolic parameters were assessed at multiple times. Hepatocytes in the devices exhibited polarized morphology, retention of differentiation markers E-cadherin and hepatocyte nuclear factor-4α (HNF-4α), the canalicular transporter multidrug-resistant protein-2 (Mrp-2), and significantly higher levels of liver function compared with nonflow cultures over 2 wk (albumin ~4-fold and urea ~5-fold). Gene expression of cytochrome P450 (CYP) enzymes was significantly higher (fold increase over nonflow: CYP1A1: 53.5 ± 10.3; CYP1A2: 64.0 ± 15.1; CYP2B1: 15.2 ± 2.9; CYP2B2: 2.7 ± 0.8; CYP3A2: 4.0 ± 1.4) and translated to significantly higher basal enzyme activity (device vs. nonflow: CYP1A: 6.26 ± 2.41 vs. 0.42 ± 0.015; CYP1B: 3.47 ± 1.66 vs. 0.4 ± 0.09; CYP3A: 11.65 ± 4.70 vs. 2.43 ± 0.56) while retaining inducibility by 3-methylcholanthrene and dexamethasone (fold increase over DMSO: CYP1A = 27.33 and CYP3A = 4.94). These responses were observed at concentrations closer to plasma levels documented in vivo in rats. The retention of in vivo-like hepatocyte phenotype and metabolic function coupled with drug response at more physiological concentrations emphasizes the importance of restoring in vivo physiological transport parameters in vitro.
Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder affecting CNS gamma-aminobutyric acid (GABA) degradation. SSADH, in conjunction with GABA transaminase, ...converts GABA to succinate. In the absence of SSADH, GABA is converted to 4-OH-butyrate. The presence of 4-OH-butyrate, a highly volatile compound, may be undetected on routine organic acid analysis. Urine organic acid testing was modified at the authors' institution in 1999 to screen for the excretion of 4-OH-butyrate by selective ion monitoring gas chromatography-mass spectrometry in addition to total ion chromatography. Since then, five patients with 4-hydroxybutyric aciduria have been identified. The authors add the clinical, neuroimaging, and EEG findings from a new cohort of patients to 51 patients reported in the literature with clinical details. Ages ranged from 1 to 21 years at diagnosis. Clinical findings include mild-moderate mental retardation, disproportionate language dysfunction, hypotonia, hyporeflexia, autistic behaviors, seizures, and hallucinations. Brain MRI performed in five patients at the authors' institution revealed symmetric increased T2 signal in the globus pallidi. SSADH deficiency is an under-recognized, potentially manageable neurometabolic disorder. Urine organic acid analysis should include a sensitive method for the detection of 4-hydroxybutyrate and should be obtained from patients with mental retardation or neuropsychiatric disturbance of unknown etiology.
Tennis is a multidirectional high-intensity intermittent sport for male and female individuals played across multiple surfaces. Although several studies have attempted to characterise the physical ...demands of tennis, a meta-analysis is still lacking.
We aimed to describe and synthesise the physical demands of tennis across the different court surfaces, performance levels and sexes.
PubMed, Embase, CINAHL and SPORTDiscus were searched from inception to 19 April, 2022. A backward citation search was conducted for included articles using Scopus. The PECOS framework was used to formulate eligibility criteria.
tennis players of regional, national or international playing levels (juniors and adults).
singles match play. Comparison: sex (male/female), court surface (hard, clay, grass).
duration of play, on-court movement and stroke performance.
cross-sectional, longitudinal. Pooled means or mean differences with 95% confidence intervals were calculated. A random-effects meta-analysis with robust variance estimation was performed. The measures of heterogeneity were Cochrane Q and 95% prediction intervals. Subgroup analysis was used for different court surfaces.
The literature search generated 7736 references; 64 articles were included for qualitative and 42 for quantitative review. Mean 95% confidence interval rally duration, strokes per rally and effective playing time on all surfaces were 5.5 s 4.9, 6.3, 4.1 3.4, 5.0 and 18.6% 15.8, 21.7 for international male players and 6.4 s 5.4, 7.6, 3.9 2.4, 6.2 and 20% 17.3, 23.3 for international female players. Mean running distances per point, set and match were 9.6 m 7.6, 12.2, 607 m 443, 832 and 2292 m 1767, 2973 (best-of-5) for international male players and 8.2 m 4.4, 15.2, 574 m 373, 883 and 1249 m 767, 2035 for international female players. Mean first- and second-serve speeds were 182 km·h
178, 187 and 149 km·h
135, 164 for international male players and 156 km·h
95% confidence interval 151, 161 and 134 km·h
107, 168 for international female players.
The findings from this study provide a comprehensive summary of the physical demands of tennis. These results may guide tennis-specific training programmes. We recommend more consistent measuring and reporting of data to enable future meta-analysts to pool meaningful data.
The protocol for this systematic review was registered a priori at the Open Science Framework (Registration DOI https://doi.org/10.17605/OSF.IO/MDWFY ).
Investigating a large and ethnically diverse cohort from the Pacific region, we aimed to replicate and extend the recently reported findings that a CREBRF genetic variant is strongly associated with ...body mass index in Samoans.
A birth cohort of more than six thousand children was utilised. In this study, genotyping of two markers (rs12513649 and rs373863828) was undertaken in Māori, Pacific, European and Asian individuals in the cohort.
We report that these CREBRF genetic variants are not confined to Samoans but are prevalent in all other Pacific populations sampled, including Māori. We found that the rs373863828 variant was significantly associated with growth at 4 years of age. On average, we observed allele-specific increases in weight (P=0·004, +455 g, s.e. 0.158), height (P=0·007, +0·70 cm, s.e. 0.26) and waist circumference (P=0·004, +0·70 cm, s.e. 0.24) at 4 years of age. The rs373863828 variant was not associated with birth weight (P=0·129).
We replicated the finding that a CREBRF variant is associated with increased body mass. We then built on the original findings by demonstrating the prevalence of the rs12513649 and rs373863828 variants in multiple Pacific population groups and by demonstrating that the rs373863828 variant is associated with growth in early childhood. Pacific population groups experience a disproportionately high burden of obesity, starting in early childhood. This new knowledge offers potential for evidence-based interventions aimed at establishing healthy growth trajectories from the earliest possible age.
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