Thermal stress accelerates Arabidopsis thaliana mutation rate.

Mutations are the source of both genetic diversity and mutational load. However, the effects of increasing environmental temperature on plant mutation rates and relative impact on specific mutational classes (e.g., insertion/deletion [indel] vs. single nucleotide variant [SNV]) are unknown. This topic is important because of the poorly defined effects of anthropogenic global temperature rise on biological systems. Here, we show the impact of temperature increase on Arabidopsis thaliana mutation, studying whole genome profiles of mutation accumulation (MA) lineages grown for 11 successive generations at 29°C. Whereas growth of A. thaliana at standard temperature (ST; 23°C) is associated with a mutation rate of 7 × 10-9 base substitutions per site per generation, growth at stressful high temperature (HT; 29°C) is highly mutagenic, increasing the mutation rate to 12 × 10-9 SNV frequency is approximately two- to threefold higher at HT than at ST, and HT-growth causes an ∼19- to 23-fold increase in indel frequency, resulting in a disproportionate increase in indels (vs. SNVs). Most HT-induced indels are 1-2 bp in size and particularly affect homopolymeric or dinucleotide A or T stretch regions of the genome. HT-induced indels occur disproportionately in nucleosome-free regions, suggesting that much HT-induced mutational damage occurs during cell-cycle phases when genomic DNA is packaged into nucleosomes. We conclude that stressful experimental temperature increases accelerate plant mutation rates and particularly accelerate the rate of indel mutation. Increasing environmental temperatures are thus likely to have significant mutagenic consequences for plants growing in the wild and may, in particular, add detrimentally to mutational load.

Probiotic capsules and xylitol chewing gum to manage symptoms of pharyngitis: a randomized controlled factorial trial.

BACKGROUND: Reducing the use of antibiotics for upper respiratory tract infections is needed to limit the global threat of antibiotic resistance. We estimated the effectiveness of probiotics and xylitol for the management of pharyngitis. METHODS: In this parallel-group factorial randomized controlled trial, participants in primary care (aged 3 years or older) with pharyngitis underwent randomization by nurses who provided sequential intervention packs. Pack contents for 3 kinds of material and advice were previously determined by computer-generated random numbers: no chewing gum, xylitol-based chewing gum (15% xylitol; 5 pieces daily) and sorbitol gum (5 pieces daily). Half of each group were also randomly assigned to receive either probiotic capsules (containing 24 × 109 colony-forming units of lactobacilli and bifidobacteria) or placebo. The primary outcome was mean self-reported severity of sore throat and difficulty swallowing (scale 0-6) in the first 3 days. We used multiple imputation to avoid the assumption that data were missing completely at random. RESULTS: A total of 1009 individuals consented, 934 completed the baseline assessment, and 689 provided complete data for the primary outcome. Probiotics were not effective in reducing the severity of symptoms: mean severity scores 2.75 with no probiotic and 2.78 with probiotic (adjusted difference -0.001, 95% confidence interval [CI] -0.24 to 0.24). Chewing gum was also ineffective: mean severity scores 2.73 without gum, 2.72 with sorbitol gum (adjusted difference 0.07, 95% CI -0.23 to 0.37) and 2.73 with xylitol gum (adjusted difference 0.01, 95% CI -0.29 to 0.30). None of the secondary outcomes differed significantly between groups, and no harms were reported. INTERPRETATION: Neither probiotics nor advice to chew xylitol-based chewing gum was effective for managing pharyngitis. Trial registration: ISRCTN, no. ISRCTN51472596.

Effectiveness of steam inhalation and nasal irrigation for chronic or recurrent sinus symptoms in primary care: a pragmatic randomized controlled trial.

BACKGROUND: Systematic reviews support nasal saline irrigation for chronic or recurrent sinus symptoms, but trials have been small and few in primary care settings. Steam inhalation has also been proposed, but supporting evidence is lacking. We investigated whether brief pragmatic interventions to encourage use of nasal irrigation or steam inhalation would be effective in relieving sinus symptoms. METHODS: We conducted a pragmatic randomized controlled trial involving adults (age 18-65 yr) from 72 primary care practices in the United Kingdom who had a history of chronic or recurrent sinusitis and reported a "moderate to severe" impact of sinus symptoms on their quality of life. Participants were recruited between Feb. 11, 2009, and June 30, 2014, and randomly assigned to 1 of 4 advice strategies: usual care, daily nasal saline irrigation supported by a demonstration video, daily steam inhalation, or combined treatment with both interventions. The primary outcome measure was the Rhinosinusitis Disability Index (RSDI). Patients were followed up at 3 and 6 months. We imputed missing data using multiple imputation methods. RESULTS: Of the 961 patients who consented, 871 returned baseline questionnaires (210 usual care, 219 nasal irrigation, 232 steam inhalation and 210 combined treatment). A total of 671 (77.0%) of the 871 participants reported RSDI scores at 3 months. Patients' RSDI scores improved more with nasal irrigation than without nasal irrigation by 3 months (crude change -7.42 v. -5.23; estimated adjusted mean difference between groups -2.51, 95% confidence interval -4.65 to -0.37). By 6 months, significantly more patients maintained a 10-point clinically important improvement in the RSDI score with nasal irrigation (44.1% v. 36.6%); fewer used over-the-counter medications (59.4% v. 68.0%) or intended to consult a doctor in future episodes. Steam inhalation reduced headache but had no significant effect on other outcomes. The proportion of participants who had adverse effects was the same in both intervention groups. INTERPRETATION: Advice to use steam inhalation for chronic or recurrent sinus symptoms in primary care was not effective. A similar strategy to use nasal irrigation was less effective than prior evidence suggested, but it provided some symptomatic benefit. TRIAL REGISTRATION: ISRCTN, no. 88204146.

Clozapine and Sweet's syndrome: case report.

A patient developed fever, raised inflammatory markers and a maculopapular rash following commencement of clozapine for treatment of his schizoaffective disorder. Skin biopsy confirmed Sweet's syndrome. Identification of the cause was challenging, with a number of possible considerations including infection, malignancy and various potential drug triggers.This case highlights the difficulties in the diagnosis of Sweet's syndrome, as well as in identifying the original trigger, which can have significant consequences for management. Withdrawal of potentially causative drugs must be balanced with their benefits, and decisions must be made in the best interests of the patient. Following two courses of prednisolone and withdrawal of clozapine, the patient's rash and systemic symptoms resolved. This confirmed the diagnosis of drug-induced Sweet's syndrome, with clozapine as the offending agent. His mental state stabilised on an alternative antipsychotic.

A Year at the Forefront of Engineering Photosynthesis.

Multiple proof-of-principle experiments and successful field trials have demonstrated that engineering photosynthesis is a viable strategy for improving crop yields. Advances to engineering technologies have accelerated efforts to improve photosynthesis, generating a large volume of published literature: this Review therefore aims to highlight the most promising results from the period February 2021 to January 2022. Recent research has demonstrated the importance of understanding the impact of changing climates on photosynthesis to ensure that proposed engineering strategies are resilient to climate change. Encouragingly, there have been several reports of strategies that have benefits at temperatures higher than current ambient conditions. There has also been success in engineering synthetic bypass pathways, providing support for the feasibility of a synthetic biology approach. Continued developments in all areas of engineering photosynthesis will be necessary for sustainably securing sufficient crop yields for the future. This article has an associated First Person interview with the first author of the paper.

Reflections on my remote internship with Biology Open.

Sophie Johnson recounts her experience completing a remote internship at Biology Open, hosted by Editor-in-Chief Steve Kelly. Sophie is a third year BBSRC Doctoral Training Partnership (DTP) PhD student studying plant vein development at the University of Oxford. She was keen to get some experience in academic publishing and so carried out a PIPS (Professional Internships for PhD Students) placement working with Biology Open.

Experiences of Using the Digital Support Tool MeeToo: Mixed Methods Study.

BACKGROUND: Digital peer support is an increasingly used form of mental health support for young people. However, there is a need for more research on the impact of digital peer support and why it has an impact. OBJECTIVE: The aim of this research is to examine young people's experiences of using a digital peer support tool: MeeToo. After the time of writing, MeeToo has changed their name to Tellmi. MeeToo is an anonymous, fully moderated peer support tool for young people aged 11-25 years. There were two research questions: (1) What impacts did using MeeToo have on young people? (2) Why did using MeeToo have these impacts on young people? METHODS: A mixed methods study was conducted. It involved secondary analysis of routinely collected feedback questionnaires, which were completed at two time points (T1 and T2) 2-3 months apart. Questionnaires asked about young people's (N=876) experience of using MeeToo, mental health empowerment, and well-being. Primary data were collected from semistructured interviews with 10 young people. RESULTS: Overall, 398 (45.4%) of 876 young people completed the T1 questionnaire, 559 (63.8%) completed the T2 questionnaire, and 81 (9.2%) completed both. Descriptive statistics from the cross-sectional analysis of the questionnaires identified a range of positive impacts of using MeeToo, which included making it easier to talk about difficult things, being part of a supportive community, providing new ways to help oneself, feeling better, and feeling less alone. Subgroup analysis (paired-sample t test) of 58 young females who had completed both T1 and T2 questionnaires showed a small but statistically significant increase in levels of patient activation, one of the subscales of the mental health empowerment scale: time 1 mean=1.83 (95% CI 1.72-1.95), time 2 mean=2.00 (95% CI 1.89-2.11), t59=2.15, and P=.04. Anonymity and the MeeToo sense of community were identified from interviews as possible reasons for why using MeeToo had these impacts. Anonymity helped to create a safe space in which users could express their feelings, thoughts, and experiences freely without the fear of being judged by others. The MeeToo sense of community was described as a valuable form of social connectedness, which in turn had a positive impact on young people's mental health and made them feel less isolated and alone. CONCLUSIONS: The findings of this research showed a range of positive impacts and possible processes for young people using MeeToo. Future research is needed to examine how these impacts and processes can be sustained.

Oral iron exacerbates colitis and influences the intestinal microbiome.

Inflammatory bowel disease (IBD) is associated with anaemia and oral iron replacement to correct this can be problematic, intensifying inflammation and tissue damage. The intestinal microbiota also plays a key role in the pathogenesis of IBD, and iron supplementation likely influences gut bacterial diversity in patients with IBD. Here, we assessed the impact of dietary iron, using chow diets containing either 100, 200 or 400 ppm, fed ad libitum to adult female C57BL/6 mice in the presence or absence of colitis induced using dextran sulfate sodium (DSS), on (i) clinical and histological severity of acute DSS-induced colitis, and (ii) faecal microbial diversity, as assessed by sequencing the V4 region of 16S rRNA. Increasing or decreasing dietary iron concentration from the standard 200 ppm exacerbated both clinical and histological severity of DSS-induced colitis. DSS-treated mice provided only half the standard levels of iron ad libitum (i.e. chow containing 100 ppm iron) lost more body weight than those receiving double the amount of standard iron (i.e. 400 ppm); p<0.01. Faecal calprotectin levels were significantly increased in the presence of colitis in those consuming 100 ppm iron at day 8 (5.94-fold) versus day-10 group (4.14-fold) (p<0.05), and for the 400 ppm day-8 group (8.17-fold) versus day-10 group (4.44-fold) (p<0.001). In the presence of colitis, dietary iron at 400 ppm resulted in a significant reduction in faecal abundance of Firmicutes and Bacteroidetes, and increase of Proteobacteria, changes which were not observed with lower dietary intake of iron at 100 ppm. Overall, altering dietary iron intake exacerbated DSS-induced colitis; increasing the iron content of the diet also led to changes in intestinal bacteria diversity and composition after colitis was induced with DSS.

Road traffic accidents: more than just whiplash?

Following a minor road traffic accident (RTA) a 55-year-old woman developed a new onset of whole body tremor and abnormal gait. This was in the context of significant previous depressive episodes and a traumatic background relating to RTAs. After extensive investigation, no organic causes were identified. The patient was subsequently referred to psychiatry and diagnosed with conversion disorder. Subsequently, various treatments including mirtazepine, venlafaxine, clonazepam, diazepam and lithium have been tried. Currently, the patient remains on mirtazepine 15 mg nocte, diazepam 2 mg twice daily, venlafaxine 225 mg and recently has been started on lithium 400 mg nocte. The patient has also been seen regularly by a psychologist for mindfulness therapy. There has been a significant improvement after seven sessions of mindfulness therapy and the patient has long periods without a tremor and is now able to walk normally. In addition, this case highlights the importance of communication skills with our patients in diagnostic uncertainty.

Sacro-iliac osteomyelitis in a 13 year old boy following perforated appendicitis.

Appendicitis is a common cause of acute abdominal pain in children and is treated by an open or laparoscopic appendicectomy. Well documented post-operative complications include wound infection, intra-abdominal collection, and adhesional bowel obstruction. We present the rare case of right sacro-iliitis and iliac bone osteomyelitis in a 13 year old boy following an open appendicectomy for a perforated appendicitis.

A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia.

Previous linkage analyses of families with multiple cases of schizophrenia by us and others have confirmed the involvement of the chromosome 11q22-24 region in the etiology of schizophrenia, with LOD scores of 3.4 and 3.1. We now report fine mapping of a susceptibility gene in the 11q22-24 region, determined on the basis of a University College London (UCL) sample of 496 cases and 488 supernormal controls. Confirmation was then performed by the study of an Aberdeen sample consisting of 858 cases and 591 controls (for a total of 2,433 individuals: 1,354 with schizophrenia and 1,079 controls). Seven microsatellite or single-nucleotide polymorphism (SNP) markers localized within or near the FXYD6 gene showed empirically significant allelic associations with schizophrenia in the UCL sample (for D11S1998, P=.021; for rs3168238, P=.009; for TTTC20.2, P=.048; for rs1815774, P=.049; for rs4938445, P=.010; for rs4938446, P=.025; for rs497768, P=.023). Several haplotypes were also found to be associated with schizophrenia; for example, haplotype Hap-F21 comprising markers rs10790212-rs4938445-rs497768 was found to be associated with schizophrenia, by a global permutation test (P=.002). Positive markers in the UCL sample were then genotyped in the Aberdeen sample. Two of these SNPs were found to be associated with schizophrenia in the Scottish sample (for rs4938445, P=.044; for rs497768, P=.037). The Hap-F21 haplotype also showed significant association with schizophrenia in the Aberdeen sample, with the same alleles being associated (P=.013). The FXYD6 gene encodes a protein called "phosphohippolin" that is highly expressed in regions of the brain thought to be involved in schizophrenia. The protein functions by modulating the kinetic properties of Na,K-ATPase to the specific physiological requirements of the tissue. Etiological base-pair changes in FXYD6 or in associated promoter/control regions are likely to cause abnormal function or expression of phosphohippolin and to increase genetic susceptibility to schizophrenia.