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VMXm joins the suite of operational macromolecular crystallography beamlines at Diamond Light Source. It has been designed to optimize rotation data collections from protein crystals less than 10 µm and down to below 1 µm in size. The beamline has a fully focused beam of 0.3 × 2.3 µm (vertical × horizontal) with a tuneable energy range (6–28 keV) and high flux (1.6 × 1012 photons s−1 at 12.5 keV). The crystals are housed within a vacuum chamber to minimize background scatter from air. Crystals are plunge-cooled on cryo-electron microscopy grids, allowing much of the liquid surrounding the crystals to be removed. These factors improve the signal-to-noise during data collection and the lifetime of the microcrystals can be prolonged by exploiting photoelectron escape. A novel in vacuo sample environment has been designed which also houses a scanning electron microscope to aid with sample visualization. This combination of features at VMXm allows measurements at the physical limits of X-ray crystallography on biomacromolecules to be explored and exploited.

Abstract Background and Objective Sepiapterin, also known as PTC923 and CNSA-001, is a synthetic form of endogenous sepiapterin being developed as a novel oral treatment for phenylketonuria. Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4) and, when orally administered, is converted to BH4 via the pterin salvage pathway. In vitro studies have demonstrated that both sepiapterin and BH4 are both substrates and inhibitors of the breast cancer resistance protein (BCRP) transporter. This phase I study investigated BCRP-mediated drug–drug interactions of sepiapterin as a victim and as a perpetrator. Methods An open-label, fixed-sequence, four-period, crossover, single-dose study was conducted in adult male and female healthy volunteers (18–55 years of age). In a given treatment period, subjects received a single oral dose of sepiapterin (20 mg/kg), sepiapterin (20 mg/kg) plus curcumin (2 g), rosuvastatin (10 mg), or rosuvastatin (10 mg) plus sepiapterin (60 mg/kg). The pharmacokinetics of sepiapterin, its metabolite BH4, and rosuvastatin were studied, and geometric mean ratios of exposures in the presence and absence of the BCRP inhibitor curcumin or sepiapterin were estimated. The presence of the BCRP c.421C>A polymorphism was evaluated in all subjects. Results A total of 29 subjects were enrolled and included in the safety analysis. Among them, 26 subjects were included in the pharmacokinetic and drug–drug interaction analyses. Following oral administration 20 mg/kg sepiapterin, sepiapterin was rapidly and extensively converted to BH4, and BH4 maximum observed concentration (415.0 ng/mL) was observed 4.95 h (time to maximum observed concentration) post-dose. Sepiapterin maximum observed concentration and area under the concentration–time curve from time 0 to time of the last quantifiable measurement or the last sample collection time (AUClast) were

Immersive events are becoming increasingly popular, allowing multiple people to experience a range of VR content simultaneously. Onboarders help people do VR experiences in these situations. Controlling VR headsets for others without physically having to put them on first is an important requirement here, as it streamlines the onboarding process and maximizes the number of viewers. Current off-the-shelf solutions require headsets to be connected to a cloud-based app via an active internet connection, which can be problematic in some locations. To address this challenge, we present Story Starter, a solution that enables the control of VR headsets without an active internet connection. Story Starter can start, stop, and install VR experiences, adjust device volume, and display information such as remaining battery life. We developed Story Starter in response to the UK-wide StoryTrails tour in the summer of 2022, which was held across 15 locations and attracted thousands of attendees who experienced a range of immersive content, including six VR experiences. Story Starter helped streamline the onboarding process by allowing onboarders to avoid putting the headset on themselves to complete routine tasks such as selecting and starting experiences, thereby minimizing COVID risks. Another benefit of not needing an active internet connection was that our headsets did not automatically update at inconvenient times, which we have found sometimes to break experiences. Converging evidence suggests that Story Starter was well-received and reliable. However, we also acknowledge some limitations of the solution and discuss several next steps we are considering.

Background: Colorectal cancer is the second leading cause of cancer-related mortality in the UK and a significant contributor to morbidity and mortality worldwide. Early diagnosis provides opportunities for intervention and improved survival. Significant event analysis (SEA) is a well-established quality improvement method for learning from new cancer diagnoses. Aim: To provide additional insights into diagnostic processes for colorectal cancer and to identify areas for improvement in patient care pathways. Design & setting: Fifty-three general practices across Pennine Lancashire, England, submitted one or more SEA reports as part of an incentivised scheme. Method: A standardised data collection form was used to collate learning points and recommendations for improvements. In total, 161 reports were analysed using an inductive framework analysis approach. Results: There was an overarching theme of building vigilance and collaboration between and within general practices and secondary care. The following four main sub-themes were also identified: education; individualised and flexible care; ownership and continuity; and communication. Conclusion: These findings provide additional insights into colorectal cancer pathways from a primary care perspective. Practices should be supported in developing protocols for assessment and follow-up of patients with varying presentations. Screening and access to investigations are paramount for improving early diagnosis; however, a flexible diagnostic approach is required according to the individual circumstances of each patient.

Background: Sepiapterin is a natural precursor of tetrahydrobiopterin (BH4), a key cofactor for phenylalanine hydroxylase. It is being developed for the treatment of patients with phenylketonuria. In this study, the ethnic differences in pharmacokinetics and safety of sepiapterin in Japanese and non-Japanese participants and food effects were evaluated. Methods: Healthy participants (n = 60) received a single oral dose of sepiapterin at either 20, 40, or 60 mg/kg with a low-fat diet. The Japanese participants received two doses at 40 mg/kg, either under fasted conditions or with a low-fat diet with a 3-day washout period in between. Results: Sepiapterin was well tolerated in all participants, with no serious adverse events. Sepiapterin was quickly absorbed (Tmax 1.4–4.5 h) and rapidly and extensively converted to BH4 (Tmax ~4 h). Exposures to sepiapterin were 4. BH4 exposures were essentially dose-independent between 20 and 60 mg/kg. A low-fat diet increased BH4 exposures in Japanese participants by 1.7-fold compared with fasted conditions. Conclusions: BH4 exposures (Cmax and AUC0–last) in Japanese participants were 10–30% higher than in non-Japanese participants, which is deemed not clinically relevant; no dose adjustment is warranted. The slightly higher BH4 exposures in Japanese participants are likely due to the higher frequency of ABCG2 c.421C>A mutation in the Japanese population.

Objective: To determine if the Clinical Frailty Scale (CFS) predicts out-of-hospital cardiac arrest (OHCA) outcomes better than age?Design: The analysed data was collected as part of a larger study run by NCEPOD on hospital admissions for OHCA in 2018. Study selection was OHCA in over 16-year-olds with restoration of spontaneous circulation (ROSC) for >20 mins and who were admitted to hospital, or who died in the emergency department. Patients from hospitals in England, Wales and Northern Ireland were identified using standard coding for cardiac arrest. CFS, age and gender were examined against two binary outcomes (non-shockable rhythm and survival) Results: 304 patients with a known CFS, known original rhythm, and known outcome were included. Younger patients had lower CFSs, as a continuous variable (Pearson correlation coefficient 0.44, p-value

Abstract Background Rare disease research is hampered in part by the fact that patients are geographically dispersed. Rare disease patient communities are recognized for their use of the internet to learn about their condition and find peer-to-peer support. As such, web-based technologies offer promise for overcoming geographic barriers in rare disease research for many. Qualitative focus groups (FGs) are a widely used methodology used to understand patients and parents/families ‘lived experience’ and unmet needs is important to improve care for rare diseases. It is unclear if web-enabled (virtual) FGs are comparable to traditional in-person approaches. We conducted in-person (n = 3) and virtual (n = 3) FGs with rare disease patients to determine if virtual FGs produce similar results in-person FGs. Results Three in-person (n = 33 participants) and three virtual (n = 25 participants) FGs were conducted examining attitudes and beliefs regarding genetic testing and family communication of risk. Participants included 30 males, 18 females, and 10 parents/guardians. Two independent investigators identified excerpts (meaningful sections of text) and coded themes/sub-themes using a codebook. Inter-coder agreement across identified excerpts (n = 530) in both FG formats was 844/875 (96.5%). Two additional investigators reviewed coded excerpts and did not identify additional themes/sub-themes—supporting data saturation across FG formats. Virtual FGs accounted for 303/530 (57.2%) of total excerpts and 957/1721 (55.7%) of all identified themes/sub-themes. Formats were similar in terms of overall number of excerpts (101 ± 7.8 vs. 75.7 ± 18.8, p = 0.26) and themes/sub-themes (319 ± 6.1 vs. 254.7 ± 103.6, p = 0.34) between virtual and in-person FGs. However, virtual FGs had significantly more coded excerpts specifically relating to sensitive/intimate topics including ‘attitudes and beliefs’ (n = 320 vs. n = 235, p

BackgroundDelayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with “red flag” features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa).Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH.Materials and methodsRetrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adult men who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured.Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB.Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54.ResultsMedian INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p

Objectives Hospital-acquired pressure injuries (PIs) are a source of morbidity and mortality, and many are potentially preventable.Design This study prospectively evaluated the prevalence and the associated factors of PIs in adult critical care patients admitted to intensive care units (ICU) in the UK.Setting This service evaluation was part of a larger, international, single-day point prevalence study of PIs in adult ICU patients. Training was provided to healthcare givers using an electronic platform to ensure standardised recognition and staging of PIs across all sites.Participants The characteristics of the ICUs were recorded before the survey; deidentified patient data were collected using a case report form and uploaded onto a secure online platform.Primary and secondary outcome measures Factors associated with ICU-acquired PIs in the UK were analysed descriptively and using mixed multiple logistic regression analysis.Results Data from 1312 adult patients admitted to 94 UK ICUs were collected. The proportion of individuals with at least one PI was 16% (211 out of 1312 patients), of whom 8.8% (n=115/1312) acquired one or more PIs in the ICU and 7.3% (n=96/1312) prior to ICU admission. The total number of PIs was 311, of which 148 (47.6%) were acquired in the ICU. The location of majority of these PIs was the sacral area, followed by the heels. Braden score and prior length of ICU stay were associated with PI development.Conclusions The prevalence and the stage of severity of PIs were generally low in adult critically ill patients admitted to participating UK ICUs during the study period. However, PIs are a problem in an important minority of patients. Lower Braden score and longer length of ICU stay were associated with the development of injuries; most ICUs assess risk using tools which do not account for this.Trial registration number NCT03270345.

Objectives We sought to investigate if duplicate faecal immunochemical testing (FIT) sampling improves the negative and positive predictive value of patients thought to be at risk of colorectal cancer (CRC). Specifically, we aimed to investigate whether the proportion of FIT-negative CRC missed by a single FIT test in symptomatic patients could be reduced by duplicate FIT testing.Design A retrospective service evaluation cohort study of the diagnostic accuracy of duplicate FIT testing.Setting Patients referred from primary care with suspected CRC to four secondary care trusts in North-West England.Participants 28 622 patients over 18-years-old with lower gastrointestinal symptoms suggestive of CRC who completed two FIT samples.Primary and secondary outcome measures The performance of duplicate FIT for detecting CRC at a threshold of 10 µgHb/g.Results The sensitivity if either test was >10 µgHb/g was 0.978 (0.955–0.989), specificity was 0.662 (0.657–0.668), positive predictive value 0.031 (0.028–0.035) and negative predictive value 1.00 (0.999–1.00). Despite two-thirds of patients (18952) being negative following two tests, at this threshold only seven CRC were missed over a 26-month period. All seven patients had other high-risk features which should have prompted investigation.Conclusions This study suggests that in routine NHS practice, a duplicate FIT sample strategy together with clinical evaluation for evidence of anaemia and weight loss is superior to a single FIT sample alone and would allow symptomatic patients to be managed in primary care without the need for urgent referral to secondary care for urgent colonic imaging.

A 56-year-old female presented with popliteal venous thrombosis, splenomegaly, and sclerotic bone lesions. Bone marrow biopsy showed fibrosis, proliferation of abnormal blood vessels and lymphatics, bone remodelling, and no significant changes in haematopoietic elements. Following a relatively indolent initial clinical course, one year later she rapidly deteriorated and died of respiratory failure associated with widespread disease. Ingrowth of podoplanin+ lymphatics mixed with CD34+/podoplanin– blood vessels into the bone marrow is a new finding and may be a unique feature of this disease.

Tetrahydrobiopterin (BH4) is a cofactor for the enzymes tyrosine hydroxylase and tryptophan hydroxylase, the rate-limiting enzymes in the production of the neurotransmitters, dopamine and serotonin, respectively, in the central nervous system (CNS). Administration of BH4 is used clinically within the management of persons with genetic BH4 deficiencies, but the BH4 molecule does not cross the blood-brain barrier sufficiently. CNSA-001 is a pharmaceutical preparation of sepiapterin, a natural precursor of BH4 that induced larger increases in plasma BH4 compared with administration of the same doses of BH4 itself in healthy volunteers in a randomized trial. Here, we report the effects of 7 days of once-daily treatment with CNSA-001 60 mg/kg (n = 6) or placebo (n = 2) on metabolites of the BH4 synthetic pathway and on biomarkers of the serotonin (5-hydroxyindoleacetic acid [5-HIAA]) and dopamine (homovanillic acid [HVA]) pathways in cerebrospinal fluid (CSF) in subjects from this trial. There were no notable changes in any metabolite in placebo-treated subjects. Administration of CNSA-001 increased mean BH4 from 18.1 (SD 3.0) to 35.1 (10.0) nmol/L, and of dihydrobiopterin (BH2) from 2.1 (0.3) to 7.9 (1.5) nmol/L. Overall, administration of CNSA-001 had little effect on mean levels (pre- vs. post-treatment) of 5-HIAA (76.1 [SD 29.8] vs. 70.1 [23.1] nmol/L) or HVA (177.2 [66.5] vs. 184.8 [35.3]) nmol/L. One subject with low 5-HIAA and HVA at baseline responded with approximately three-fold increases in CNS levels of these metabolites after CNSA-001 treatment, with post-treatment levels within the range of those seen in other subjects. Administration of CNSA-001 60 mg/kg markedly increased levels of BH4 in the CNS of healthy volunteers, with apparently little overall effect in CNS levels of already normal key neurotransmitter metabolites. Keywords: Sepiapterin, Tetrahydrobiopterin, Phenylketonuria, Tetrahydrobiopterin deficiencies, Biogenic amines

Gentrifizierung wird vorrangig unter Verweis auf Konsumentensouveränität erklärt, aber Daten zur Zahl der Vorstädter, die in die Stadt zurückziehen, werfen Zweifel an dieser Hypothese auf. Tatsächlich ist Gentrifizierung ein erwartbares Ergebnis der weitgehend ungehinderten Funktionsweise des Grundstücks- und Wohnungsmarktes. Die wirtschaftliche Entwertung des in innerstädtische Quartiere aus dem 19. Jahrhundert investierten Kapitals bei gleichzeitigem Anstieg der potentiellen Höhe der Grundrente eröffnet die Möglichkeit profitabler Stadterneuerung. Auch wenn die deutlich sichtbaren sozialen Merkmale heruntergekommener Quartiere abschreckend wirken mögen, können die hintergründigen ökonomischen Merkmale durchaus für eine Sanierung sprechen. Ob Gentrifizierung eine fundamentale Neuordnung des urbanen Raums bedeutet, hängt nicht davon ab, wo die neuen Bewohner herkommen, sondern davon, wie viel Produktivkapital aus dem suburbanen Raum in die Stadt zurückkehrt.

Congenital hypogonadotropic hypogonadism/Kallmann syndrome (CHH/KS) is a rare, treatable form of infertility. Like other rare disease patients, individuals with CHH/KS frequently experience feelings of isolation, shame, and alienation. Unlike many rare diseases, CHH/KS is not life threatening and effective treatments are available. Nevertheless, it remains a profoundly life-altering condition with psychosocial distress on a par with untreatable or life-limiting disease. Patients with CHH/KS frequently express lasting adverse psychological, emotional, social, and psychosexual effects resulting from disrupted puberty. They also frequently experience a “diagnostic odyssey,” characterized by distressing and convoluted medical referral pathways, lack-of-information, misinformation, and sometimes-incorrect diagnoses. Unnecessary delays in diagnosis and treatment-initiation can significantly contribute to poor body image and self-esteem. Such experiences can erode confidence and trust in medical professionals as well as undermine long-term adherence to treatment–with negative sequelae on health and wellbeing. This review provides a summary of the psychological aspects of CHH/KS and outlines an approach to comprehensive care that spans medical management as well as appropriate attention, care and referrals to peer-to-peer support and mental health services to ameliorate the psychological aspects of CHH/KS.

Background: There is limited evidence for public health policy-makers on the health impacts of urban regeneration programmes. Objectives: To assess whether or not the London 2012 Olympic and Paralympic Games, and related urban regeneration, were associated with an increase in physical activity and mental health and well-being; to assess whether or not any benefits were sustained over time; and to capture the experiences of residents of the Olympic host boroughs. Design: Quasi-experimental prospective cohort study of adolescents and their parents/carers, with a nested qualitative longitudinal study of families. Setting: London boroughs of Newham, Barking and Dagenham, Tower Hamlets and Hackney. Participants: A cohort of 2254 adolescents in 25 schools; a repeat cross-sectional study of parents/carers and a sample of 20 families for the qualitative study. Intervention: The London 2012 Olympic and Paralympic Games, and urban regeneration primarily associated with the redevelopment of the Olympic Park for legacy use. Primary outcome measures: Change in the proportion of respondents meeting physical activity recommendations (using self-reported physical activity); change in the proportion of respondents reporting depression and anxiety and change in well-being score. Main results: At 6 months, adolescents who became inactive were less likely to come from the intervention borough (Newham) than from comparison boroughs [risk ratio (RR) = 0.69, 95% confidence interval (CI) 0.51 to 0.93]. At 18 months, there were no statistically significant differences between intervention and comparison boroughs for all adolescent physical activity and screen-time transitions. Those who visited the Olympic Park more than once a month were the least likely to remain inactive (RR 0.11, 95% CI 0.02 to 0.48) and the least likely to become inactive (RR 0.38, 95% CI 0.24 to 0.60) compared with those who were active at baseline and at the 18-month follow-up. No impacts on parental/carer physical activity were observed. Adolescents who were ‘no longer depressed’ (RR 1.53, 95% CI 1.07 to 2.20) or ‘remained depressed’ (RR 1.78, 95% CI 1.12 to 2.83) at 6 months were more likely to be from the intervention borough. For well-being, there was no association between boroughs and change in well-being between baseline and the 6-month follow-up. At 18 months’ follow-up, adolescents who ‘remained depressed’ (RR 1.93, 95% CI 1.01 to 3.70) were more likely to be from the intervention borough than from comparison boroughs. No associations were observed for well-being at 18 months. There was limited evidence of change for parental mental health and well-being. The qualitative study found that residents generally welcomed the unexpected chance to live in a cleaner, safer and more unified environment. The findings suggested that the Games temporarily alleviated certain stressors in the social and physical environment. Overall, the Games lessened participants’ sense of social exclusion and appeared to generate a sense of inclusion and respite, even if this was only temporary. Study limitations include the potential for adolescents to not be assigned the correct level of exposure to urban regeneration and the effect of reductions in central and local public budgets owing to the UK Government’s deficit reduction programme. Conclusions: This study provided the highest quality data to date on the short- and medium-term social and health impacts of sporting mega-events. We found limited evidence that the London 2012 Olympic and Paralympic Games had a positive effect on adolescent or parental physical activity, mental health or well-being. Funding: The National Institute for Health Research Public Health Research programme.

Purpose: Computed tomography (CT) is the gold standard imaging modality for the diagnosis and follow-up of urolithiasis. Before the use of CT, intravenous urography (IVU) was the imaging modality of choice. CT remains contentious because of the cancer risk related to radiation exposure above a threshold level. We aimed to compare the radiation exposure dose to the average patient with urolithiasis in the era of CT with that of IVU. Materials and Methods: Our hospital medical records database was searched for patients who presented to the Emergency Department over a 1-month period in 1990 with a diagnosis of renal colic. Patients with the same presentation, from the same month, in 2013 were also identified. A total of 14 patients from each year fulfilled the inclusion criteria. The estimated effective radiation exposure dose for each patient was calculated by using data from population-based studies. Results: The median effective radiation dose per patient in the 1990 group, for initial diagnosis and subsequent follow-up, was 4.05 mSv (interquartile range [IQR], 3.7–4.4 mSv). The corresponding median dose in the 2013 group was 4.2 mSv (IQR, 4.2–4.9 mSv), and there was no evidence of a statistical difference between the groups (p=0.8). Conclusions: Despite the contentiousness related to the use of serial CT scanning, our study demonstrated that for radiological investigation and follow-up of urolithiasis, the estimated effective radiation exposure dose to each patient is only marginally higher than in the era of IVU, with improvements in length of hospital stay and time to definitive diagnosis.