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Background Dupuytren's disease is a progressive fibroproliferative disorder which can result in fixed flexion contractures of digits and impaired hand function. Standard treatment involves surgical release or excision followed by post-operative hand therapy and splinting, however the evidence supporting night splinting is of low quality and equivocal. Methods A multi-centre, pragmatic, open, randomised controlled trial was conducted to evaluate the effect of night splinting on self-reported function, finger extension and satisfaction in patients undergoing fasciectomy or dermofasciectomy. 154 patients from 5 regional hospitals were randomised after surgery to receive hand therapy only (n = 77) or hand therapy with night-splinting (n = 77). Primary outcome was self-reported function using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. Secondary outcomes were finger range of motion and patient satisfaction. Primary analysis was by intention to treat. Results 148 (96%) patients completed follow-up at 12 months. No statistically significant differences were observed on the DASH questionnaire (0-100 scale: adjusted mean diff. 0.66, 95%CI - 2.79 to 4.11, p = 0.703), total extension deficit of operated digits (degrees: adjusted mean diff 5.11, 95%CI -2.33 to 12.55, p = 0.172) or patient satisfaction (0-10 numerical rating scale: adjusted mean diff -0.35, 95%CI -1.04 to 0.34, p = 0.315) at 1 year post surgery. Similarly, in a secondary per protocol analysis no statistically significant differences were observed between the groups in any of the outcomes. Conclusions No differences were observed in self-reported upper limb disability or active range of motion between a group of patients who were all routinely splinted after surgery and a group of patients receiving hand therapy and only splinted if and when contractures occurred. Given the added expense of therapists' time, thermoplastic materials and the potential inconvenience to patients having to wear a device, the routine addition of night-time splinting for all patients after fasciectomy or dermofasciectomy is not recommended except where extension deficits reoccur. Trial registration The trial was registered as an International Standard Randomised Controlled Trial ISRCTN57079614

Trichothecenes are a family of terpenoid toxins produced by multiple genera of fungi, including plant and insect pathogens. Some trichothecenes produced by the fungus Fusarium are among the mycotoxins of greatest concern to food and feed safety because of their toxicity and frequent occurrence in cereal crops, and trichothecene production contributes to pathogenesis of some Fusarium species on plants. Collectively, fungi produce over 150 trichothecene analogs: i.e., molecules that share the same core structure but differ in patterns of substituents attached to the core structure. Here, we carried out genomic, phylogenetic, gene-function, and analytical chemistry studies of strains from nine fungal genera to identify genetic variation responsible for trichothecene structural diversity and to gain insight into evolutionary processes that have contributed to the variation. The results indicate that structural diversity has resulted from gain, loss, and functional changes of trichothecene biosynthetic (TRI) genes. The results also indicate that the presence of some substituents has arisen independently in different fungi by gain of different genes with the same function. Variation in TRI gene duplication and number of TRI loci was also observed among the fungi examined, but there was no evidence that such genetic differences have contributed to trichothecene structural variation. We also inferred ancestral states of the TRI cluster and trichothecene biosynthetic pathway, and proposed scenarios for changes in trichothecene structures during divergence of TRI cluster homologs. Together, our findings provide insight into evolutionary processes responsible for structural diversification of toxins produced by pathogenic fungi.

The Fusarium sambucinum species complex (FSAMSC) is one of the most taxonomically challenging groups of fusaria, comprising prominent mycotoxigenic plant pathogens and other species with various lifestyles. Among toxins produced by members of the FSAMSC, trichothecenes pose the most significant threat to public health. Herein a global collection of 171 strains, originating from diverse hosts or substrates, were selected to represent FSAMSC diversity. This strain collection was used to assess their species diversity, evaluate their potential to produce trichothecenes, and cause disease on wheat. Maximum likelihood and Bayesian analyses of a combined 3-gene dataset used to infer evolutionary relationships revealed that the 171 strains originally received as 48 species represent 74 genealogically exclusive phylogenetically distinct species distributed among six strongly supported clades: Brachygibbosum , Graminearum , Longipes , Novel , Sambucinum , and Sporotrichioides . Most of the strains produced trichothecenes in vitro but varied in type, indicating that the six clades correspond to type A, type B, or both types of trichothecene-producing lineages. Furthermore, five strains representing two putative novel species within the Sambucinum Clade produced two newly discovered type A trichothecenes, 15-keto NX-2 and 15-keto NX-3. Strains of the two putatively novel species together with members of the Graminearum Clade were aggressive toward wheat when tested for pathogenicity on heads of the susceptible cultivar Apogee. In planta , the Graminearum Clade strains produced nivalenol or deoxynivalenol and the aggressive Sambucinum Clade strains synthesized NX-3 and 15-keto NX-3. Other strains within the Brachygibbosum , Longipes , Novel , Sambucinum , and Sporotrichioides Clades were nonpathogenic or could infect the inoculated floret without spreading within the head. Moreover, most of these strains did not produce any toxin in the inoculated spikelets. These data highlight aggressiveness toward wheat appears to be influenced by the type of toxin produced and that it is not limited to members of the Graminearum Clade.

The locus coeruleus (LC), or ‘blue spot’, is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.Major compelling questions about the functional role of the locus coeruleus nucleus that had been difficult to answer, given its remote location and diminutive size, have now become accessible via new neuroscience tools. In this Perspective, 14 investigators provide a historical context for recent discoveries and outline new vistas for investigation.

Background Whilst observational studies establish that lower plasma 25-hydroxyvitamin D (25-OHD) levels are associated with higher risk of colorectal cancer (CRC), establishing causality has proven challenging. Since vitamin D is modifiable, these observations have substantial clinical and public health implications. Indeed, many health agencies already recommend supplemental vitamin D. Here, we explore causality in a large Mendelian randomisation (MR) study using an improved genetic instrument for circulating 25-OHD. Methods We developed a weighted genetic score for circulating 25-OHD using six genetic variants that we recently reported to be associated with circulating 25-OHD in a large genome-wide association study (GWAS) meta-analysis. Using this score as instrumental variable in MR analyses, we sought to determine whether circulating 25-OHD is causally linked with CRC risk. We conducted MR analysis using individual-level data from 10,725 CRC cases and 30,794 controls (Scotland, UK Biobank and Croatia). We then applied estimates from meta-analysis of 11 GWAS of CRC risk (18,967 cases; 48,168 controls) in a summary statistics MR approach. Results The new genetic score for 25-OHD was strongly associated with measured plasma 25-OHD levels in 2821 healthy Scottish controls ( P  = 1.47 × 10 − 11 ), improving upon previous genetic instruments (F-statistic 46.0 vs. 13.0). However, individual-level MR revealed no association between 25-OHD score and CRC risk (OR 1.03/unit log-transformed circulating 25-OHD, 95% CI 0.51–2.07, P  = 0.93). Similarly, we found no evidence for a causal relationship between 25-OHD and CRC risk using summary statistics MR analysis (OR 0.91, 95% CI 0.69–1.19, P  = 0.48). Conclusions Despite the scale of this study and employing an improved score capturing more of the genetic contribution to circulating 25-OHD, we found no evidence for a causal relationship between circulating 25-OHD and CRC risk. Although the magnitude of effect for vitamin D suggested by observational studies can confidently be excluded, smaller effects sizes and non-linear relationships remain plausible. Circulating vitamin D may be a CRC biomarker, but a causal effect on CRC risk remains unproven.

BackgroundMany individuals with diabetes live in low- or middle-income settings. Glycemic control is challenging, particularly in resource-limited areas that face numerous healthcare barriers.ObjectiveTo compare HbA1c outcomes for individuals randomized to TIME, a Telehealth-supported, Integrated care with CHWs (Community Health Workers), and MEdication-access program (intervention) versus usual care (wait-list control).DesignRandomized clinical trial.ParticipantsLow-income Latino(a) adults with type 2 diabetes.InterventionsTIME consisted of (1) CHW-participant telehealth communication via mobile health (mHealth) for 12 months, (2) CHW-led monthly group visits for 6 months, and (3) weekly CHW-physician diabetes training and support via telehealth (video conferencing).Main MeasuresInvestigators compared TIME versus control participant baseline to month 6 changes of HbA1c (primary outcome), blood pressure, body mass index (BMI), weight, and adherence to seven American Diabetes Association (ADA) standards of care. CHW assistance in identifying barriers to healthcare in the intervention group were measured at the end of mHealth communication (12 months).Key ResultsA total of 89 individuals participated. TIME individuals compared to control participants had significant HbA1c decreases (9.02 to 7.59% (− 1.43%) vs. 8.71 to 8.26% (− 0.45%), respectively, p = 0.002), blood pressure changes (systolic: − 6.89 mmHg vs. 0.03 mmHg, p = 0.023; diastolic: − 3.36 mmHg vs. 0.2 mmHg, respectively, p = 0.046), and ADA guideline adherence (p < 0.001) from baseline to month 6. At month 6, more TIME than control participants achieved > 0.50% HbA1c reductions (88.57% vs. 43.75%, p < 0.001). BMI and weight changes were not significant between groups. Many (54.6%) TIME participants experienced > 1 barrier to care, of whom 91.7% had medication issues. CHWs identified the majority (87.5%) of barriers.ConclusionsTIME participants resulted in improved outcomes including HbA1c. CHWs are uniquely positioned to identify barriers to care particularly related to medications that may have gone unrecognized otherwise. Larger trials are needed to determine the scalability and sustainability of the intervention.Clinical TrialNCT03394456, accessed at https://clinicaltrials.gov/ct2/show/NCT03394456

Background: The genetic regulation of flower color has been widely studied, notably as a character used by Mendel and his predecessors in the study of inheritance in pea. Methodology/Principal Findings: We used the genome sequence of model legumes, together with their known synteny to the pea genome to identify candidate genes for the A and A2 loci in pea. We then used a combination of genetic mapping, fast neutron mutant analysis, allelic diversity, transcript quantification and transient expression complementation studies to confirm the identity of the candidates. Conclusions/Significance: We have identified the pea genes A and A2. A is the factor determining anthocyanin pigmentation in pea that was used by Gregor Mendel 150 years ago in his study of inheritance. The A gene encodes a bHLH transcription factor. The white flowered mutant allele most likely used by Mendel is a simple G to A transition in a splice donor site that leads to a mis-spliced mRNA with a premature stop codon, and we have identified a second rare mutant allele. The A2 gene encodes a WD40 protein that is part of an evolutionarily conserved regulatory complex.

Species of the fungus Fusarium cause Fusarium head blight (FHB) of cereal crops and contaminate grain with sesquiterpenoid mycotoxins, including culmorin (CUL) and trichothecenes. While the phytotoxicity of trichothecenes, such as deoxynivalenol (DON), and their role in virulence are well characterized, less is known about the phytotoxicity of CUL and its role in the development of FHB. Herein, we evaluated the phytotoxic effects of purified CUL and CUL-trichothecene mixtures using Chlamydomonas reinhardtii growth and Triticum aestivum (wheat) root elongation assays. By itself, CUL did not affect growth in either system. However, mixtures of CUL with DON, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, or NX-3, but not with nivalenol, inhibited growth in a synergistic manner. Synergistic phytotoxic effects of CUL and DON were also observed on multiple plant varieties and species. The severity of wheat FHB caused by 15 isolates of Fusarium graminearum was negatively correlated with the CUL/DON ratio, but positively correlated with the sum of both CUL and DON. Additionally, during the first week of infection, CUL biosynthetic genes were more highly expressed than the TRI5 trichothecene biosynthetic gene. Furthermore, genomic analysis of Fusarium species revealed that CUL and trichothecene biosynthetic genes consistently co-occur among species closely related to F. graminearum.

Background Low circulating vitamin D levels are associated with poor colorectal cancer (CRC) survival. We assess whether vitamin D supplementation improves CRC survival outcomes. Methods PubMed and Web of Science were searched. Randomised controlled trial (RCTs) of vitamin D supplementation reporting CRC mortality were included. RCTs with high risk of bias were excluded from analysis. Random-effects meta-analysis models calculated estimates of survival benefit with supplementation. The review is registered on PROSPERO, registration number: CRD42020173397. Results Seven RCTs ( n  = 957 CRC cases) were identified: three trials included patients with CRC at outset, and four population trials reported survival in incident cases. Two RCTs were excluded from meta-analysis (high risk of bias; no hazard ratio (HR)). While trials varied in inclusion criteria, intervention dose and outcomes, meta-analysis found a 30% reduction in adverse CRC outcomes with supplementation ( n  = 815, HR = 0.70; 95% confidence interval (CI): 0.48–0.93). A beneficial effect was seen in trials of CRC patients (progression-free survival, HR = 0.65; 95% CI: 0.36–0.94), with suggestive effect in incident CRC cases from population trials (CRC-specific survival, HR = 0.76; 95% CI: 0.39–1.13). No heterogeneity or publication bias was noted. Conclusions Meta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on CRC survival outcomes. Further well-designed, adequately powered RCTs are needed to fully evaluate benefit of supplementation in augmenting ‘real-life’ follow-up and adjuvant chemotherapy regimens, as well as determining optimal dosing.

[This corrects the article DOI: 10.1371/journal.pone.0245037.].