Cell division angle predicts the level of tissue mechanics that tune the amount of cerebellar folding.

Modeling has led to proposals that the amount of neural tissue folding is set by the level of differential expansion between tissue layers and that the wavelength is set by the thickness of the outer layer. Here, we used inbred mouse strains with distinct amounts of cerebellar folding to investigate these predictions. We identified a distinct critical period during which the folding amount diverges between the two strains. In this period, regional changes in the level of differential expansion between the external granule layer (EGL) and underlying core correlate with the folding amount in each strain. Additionally, the thickness of the EGL varies regionally during the critical period alongside corresponding changes in wavelength. The number of SHH-expressing Purkinje cells predicts the folding amount, but the proliferation rate in the EGL is the same between the strains. However, regional changes in the cell division angle within the EGL predicts both the tangential expansion and the thickness of the EGL. Cell division angle is likely a tunable mechanism whereby both the level of differential expansion along the perimeter and the thickness of the EGL are regionally tuned to set the amount and wavelength of folding.

SirA inhibits the essential DnaA:DnaD interaction to block helicase recruitment during Bacillus subtilis sporulation.

Bidirectional DNA replication from a chromosome origin requires the asymmetric loading of two helicases, one for each replisome. Our understanding of the molecular mechanisms underpinning helicase loading at bacterial chromosome origins is incomplete. Here we report both positive and negative mechanisms for directing helicase recruitment in the model organism Bacillus subtilis. Systematic characterization of the essential initiation protein DnaD revealed distinct protein interfaces required for homo-oligomerization, interaction with the master initiator protein DnaA, and interaction with the helicase co-loader protein DnaB. Informed by these properties of DnaD, we went on to find that the developmentally expressed repressor of DNA replication initiation, SirA, blocks the interaction between DnaD and DnaA, thereby restricting helicase recruitment from the origin during sporulation to inhibit further initiation events. These results advance our understanding of the mechanisms underpinning DNA replication initiation in B. subtilis, as well as guiding the search for essential cellular activities to target for antimicrobial drug design.

The DNA replication initiation protein DnaD recognises a specific strand of the Bacillus subtilis chromosome origin.

Genome replication is a fundamental biological activity shared by all organisms. Chromosomal replication proceeds bidirectionally from origins, requiring the loading of two helicases, one for each replisome. However, the molecular mechanisms underpinning helicase loading at bacterial chromosome origins (oriC) are unclear. Here we investigated the essential DNA replication initiation protein DnaD in the model organism Bacillus subtilis. A set of DnaD residues required for ssDNA binding was identified, and photo-crosslinking revealed that this ssDNA binding region interacts preferentially with one strand of oriC. Biochemical and genetic data support the model that DnaD recognizes a new single-stranded DNA (ssDNA) motif located in oriC, the DnaD Recognition Element (DRE). Considered with single particle cryo-electron microscopy (cryo-EM) imaging of DnaD, we propose that the location of the DRE within oriC orchestrates strand-specific recruitment of helicase during DNA replication initiation. These findings significantly advance our mechanistic understanding of bidirectional replication from a bacterial chromosome origin.

Positive airway pressure therapy adherence and outcomes in obstructive sleep apnea: An exploratory longitudinal retrospective randomized chart review.

Background: Positive airway pressure (PAP) therapy is prescribed to patients with obstructive sleep apnea (OSA). A commonly used definition for PAP therapy adherence is based upon the minimum requirements to receive Medicare coverage in the US, defined as PAP usage of four or more hours per night on 70 percent of nights for at least 30 consecutive days. However, little evidence exists to support this definition for PAP therapy adherence. Therefore, the present study sought to determine the efficacy of the present definition of PAP therapy adherence on longitudinal outcomes in patients with OSA, using objectively measured PAP device usage time. Methods: An exploratory longitudinal, retrospective, randomized chart review was done to assess clinical outcomes between patients with OSA who were defined as PAP therapy adherent (n=50) and non-adherent (n=50) during an eight-year observation period. Results: No significant differences were shown between groups for mortality, hospitalizations, or development of co-morbidities during the observation period. However, logistic regression showed significantly higher odds of adherence in male patients compared to female patients (OR=8.519; 95%CI=1.301-55.756; p=0.025) and significantly lower odds of adherence in patients with higher normal (OR=0.039; 95%CI=0.005-0.392; p=0.003), mild excessive (OR=0.039; 95%CI=0.003-0.517; p=0.014), and severe excessive (OR=0.088; 95%CI=0.012-0.635; p=0.016) daytime sleepiness compared to patients with lower normal daytime sleepiness. An increasing number of hospitalizations also corresponded with a significant decrease in odds of being adherent (OR=0.741; 95%CI=0.551-0.995; p=0.046). Conclusion: The present study supports a steadily growing body of literature calling for more consideration and evidence to support a definition of PAP therapy adherence that is clinically meaningful.

Identification of a basal system for unwinding a bacterial chromosome origin.

Genome duplication is essential for cell proliferation, and DNA synthesis is generally initiated by dedicated replication proteins at specific loci termed origins. In bacteria, the master initiator DnaA binds the chromosome origin (oriC) and unwinds the DNA duplex to permit helicase loading. However, despite decades of research it remained unclear how the information encoded within oriC guides DnaA-dependent strand separation. To address this fundamental question, we took a systematic genetic approach in vivo and identified the core set of essential sequence elements within the Bacillus subtilis chromosome origin unwinding region. Using this information, we then show in vitro that the minimal replication origin sequence elements are necessary and sufficient to promote the mechanical functions of DNA duplex unwinding by DnaA. Because the basal DNA unwinding system characterized here appears to be conserved throughout the bacterial domain, this discovery provides a framework for understanding oriC architecture, activity, regulation and diversity.

A giant planet undergoing extreme-ultraviolet irradiation by its hot massive-star host.

The amount of ultraviolet irradiation and ablation experienced by a planet depends strongly on the temperature of its host star. Of the thousands of extrasolar planets now known, only six have been found that transit hot, A-type stars (with temperatures of 7,300-10,000 kelvin), and no planets are known to transit the even hotter B-type stars. For example, WASP-33 is an A-type star with a temperature of about 7,430 kelvin, which hosts the hottest known transiting planet, WASP-33b (ref. 1); the planet is itself as hot as a red dwarf star of type M (ref. 2). WASP-33b displays a large heat differential between its dayside and nightside, and is highly inflated-traits that have been linked to high insolation. However, even at the temperature of its dayside, its atmosphere probably resembles the molecule-dominated atmospheres of other planets and, given the level of ultraviolet irradiation it experiences, its atmosphere is unlikely to be substantially ablated over the lifetime of its star. Here we report observations of the bright star HD 195689 (also known as KELT-9), which reveal a close-in (orbital period of about 1.48 days) transiting giant planet, KELT-9b. At approximately 10,170 kelvin, the host star is at the dividing line between stars of type A and B, and we measure the dayside temperature of KELT-9b to be about 4,600 kelvin. This is as hot as stars of stellar type K4 (ref. 5). The molecules in K stars are entirely dissociated, and so the primary sources of opacity in the dayside atmosphere of KELT-9b are probably atomic metals. Furthermore, KELT-9b receives 700 times more extreme-ultraviolet radiation (that is, with wavelengths shorter than 91.2 nanometres) than WASP-33b, leading to a predicted range of mass-loss rates that could leave the planet largely stripped of its envelope during the main-sequence lifetime of the host star.

Impact of an outdoor loose parts play intervention on Nova Scotian preschoolers' physical literacy: a mixed-methods randomized controlled trial.

BACKGROUND: Physical activity participation among preschoolers in childcare settings are low, and interventions to increase physical activity levels have produced mixed results. The Physical Literacy in the Early Years (PLEY) project implemented a six-month childcare-based outdoor loose parts play intervention in childcare centres in Nova Scotia, Canada. The purpose of this study was to examine the impact of the PLEY project on the development of domains of physical literacy (physical activity, physical competence, confidence and motivation, knowledge and understanding) in preschoolers attending childcare centres using mixed-methods. METHODS: Preschoolers (3-5 years) were recruited from 19 childcare centres in Nova Scotia and centres were randomized (parallel design) to the outdoor loose parts play intervention group (n = 11) or control (n = 8) group for 6 months. Participants, early childhood educators, and assessors were not blinded to group assignment. Quantitative and qualitative measures were used to comprehensively assess the impact of the PLEY project on all domains of physical literacy. At 3- and 6-months, early childhood educators participated in focus groups to assess how the intervention supported the development of 4 physical literacy domains: physical activity, physical competence, confidence and motivation, and knowledge and understanding. Physical activity and physical competence were also assessed with accelerometry and the Test of Gross Motor Development-3, respectively. RESULTS: Two hundred and nine preschoolers participated in the study (intervention group: n = 115; control group: n = 94). Accelerometer data showed that while baseline physical activity was similar between groups, children in the intervention group had higher physical activity at 3- (F(1,187) = 8.30, p = 0.004) and 6-months (F(1,187) = 9.90, p = 0.002) post-intervention. There was no intervention effect on physical competence scores. Thematic analysis of focus group data revealed that outdoor loose parts play contributed to development in all 4 physical literacy domains, including increased movement repertoires, social development, and enjoyment of physical activity. No adverse events or side effects of the intervention were reported. CONCLUSIONS: Participation in the PLEY project was associated with increased development of various domains of physical literacy and perceived physical literacy among preschoolers, and outdoor loose parts play may be encouraged as an effective strategy to increase physical literacy in early learning settings. TRIAL REGISTRATION: Biomed Central (ISRCTN14058106), 20/10/2017.

Parent Risk Perceptions, Physical Literacy, and Fundamental Movement Skills in Children With Juvenile Idiopathic Arthritis.

PURPOSE: This pilot study sought to examine the fundamental movement skills (FMS) and physical literacy (PL) of children with juvenile idiopathic arthritis (JIA) and to explore their relationship with physical activity (PA) and parent perceptions of PA-related risks. METHODS: Twenty-five children with JIA and their parents completed questionnaires. Fundamental movement skills were assessed in the laboratory and PA through accelerometry data. RESULTS: Children spent a median of 39.4%, 40.9%, and 18.2% of their day sedentary, in light, and in moderate to vigorous PA, respectively. Fundamental movement skills and PL scores were within the average range, although were related to which joints (upper/lower body) were affected by JIA. Parents who viewed activities such as biking and climbing as risky tended to have children with weaker locomotor skills and lower PL. CONCLUSION: Children with JIA had age-appropriate PA, FMS, and PL; however, parent perceptions of PA-related risks are related to their child's FMS and PL.

Is Persistent Motor or Vocal Tic Disorder a Milder Form of Tourette Syndrome?

BACKGROUND: Persistent motor or vocal tic disorder (PMVT) has been hypothesized to be a forme fruste of Tourette syndrome (TS). Although the primary diagnostic criterion for PMVT (presence of motor or vocal tics, but not both) is clear, less is known about its clinical presentation. OBJECTIVE: The goals of this study were to compare the prevalence and number of comorbid psychiatric disorders, tic severity, age at tic onset, and family history for TS and PMVT. METHODS: We analyzed data from two independent cohorts using generalized linear equations and confirmed our findings using meta-analyses, incorporating data from previously published literature. RESULTS: Rates of obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD) were lower in PMVT than in TS in all analyses. Other psychiatric comorbidities occurred with similar frequencies in PMVT and TS in both cohorts, although meta-analyses suggested lower rates of most psychiatric disorders in PMVT compared with TS. ADHD and OCD increased the odds of comorbid mood, anxiety, substance use, and disruptive behaviors, and accounted for observed differences between PMVT and TS. Age of tic onset was approximately 2 years later, and tic severity was lower in PMVT than in TS. First-degree relatives had elevated rates of TS, PMVT, OCD, and ADHD compared with population prevalences, with rates of TS equal to or greater than PMVT rates. CONCLUSIONS: Our findings support the hypothesis that PMVT and TS occur along a clinical spectrum in which TS is a more severe and PMVT a less severe manifestation of a continuous neurodevelopmental tic spectrum disorder. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

DNA replication initiation in Bacillus subtilis: structural and functional characterization of the essential DnaA-DnaD interaction.

The homotetrameric DnaD protein is essential in low G+C content gram positive bacteria and is involved in replication initiation at oriC and re-start of collapsed replication forks. It interacts with the ubiquitously conserved bacterial master replication initiation protein DnaA at the oriC but structural and functional details of this interaction are lacking, thus contributing to our incomplete understanding of the molecular details that underpin replication initiation in bacteria. DnaD comprises N-terminal (DDBH1) and C-terminal (DDBH2) domains, with contradicting bacterial two-hybrid and yeast two-hybrid studies suggesting that either the former or the latter interact with DnaA, respectively. Using Nuclear Magnetic Resonance (NMR) we showed that both DDBH1 and DDBH2 interact with the N-terminal domain I of DnaA and studied the DDBH2 interaction in structural detail. We revealed two families of conformations for the DDBH2-DnaA domain I complex and showed that the DnaA-interaction patch of DnaD is distinct from the DNA-interaction patch, suggesting that DnaD can bind simultaneously DNA and DnaA. Using sensitive single-molecule FRET techniques we revealed that DnaD remodels DnaA-DNA filaments consistent with stretching and/or untwisting. Furthermore, the DNA binding activity of DnaD is redundant for this filament remodelling. This in turn suggests that DnaA and DnaD are working collaboratively in the oriC to locally melt the DNA duplex during replication initiation.

Review of metastatic colorectal cancer treatment pathways and early clinical experience of trifluridine/tipiracil in the UK named patient programme.

BACKGROUND: The standard first- and second- line chemotherapy backbone regimens for metastatic colorectal cancer (mCRC) are 5-fluorouracil (5-FU)/capecitabine-based with addition of irinotecan or oxaliplatin. Until recently, evidence for optimal sequencing post second-line was sparse. Trifluridine/tipiracil (indicated for mCRC and gastric cancer after standard chemotherapies) was made available to UK patients via a named patient programme (NPP) before receiving marketing authorisation in Europe in 2016, allowing characterisation of UK treatment pathways, and evaluation of trifluridine/tipiracil in a UK non-trial population. METHODS: Data collected routinely for the NPP were analysed to describe the patient demographics, clinical characteristics and treatment pathways. Patients eligible for the programme were adults (≥18 years) with histologically or cytologically confirmed mCRC who had previously received chemotherapy treatment(s). RESULTS: Of the 250 eligible patients enrolled in the NPP, 194 patients received ≥1 dose of trifluridine/tipiracil and 56 patients did not receive trifluridine/tipiracil. The following results are reported first for patients who received trifluridine/tipiracil and second for those who did not receive trifluridine/tipiracil: median (IQR) age was 63.0 (54.0-69.0) and 62.0 (54.8-69.0) years; Eastern Cooperative Oncology Group performance status score was 0 for 28 and 14%, 1 for 65 and 70%, 2 for 7 and 16%. In terms of previous systemic treatments 47 and 43% had 2 prior lines of therapy. FOLFOX-, FOLFIRI- and CAPOX-based therapies were the most common first-line regimens in patients receiving trifluridine/tipiracil (37, 35 and 21%, respectively), and in patients not receiving trifluridine/tipiracil (41, 30 and 20%, respectively). Second-line treatment regimens in patients receiving and not receiving trifluridine/tipiracil were most commonly FOLFIRI-based (48 and 41%, respectively) and FOLFOX-based (19 and 21%, respectively). Patients received a median of 2 cycles of trifluridine/tipiracil with a median treatment duration of 1.8 (95% CI: 1.8-2.4) months. In patients who discontinued treatment due to disease progression, the median progression-free duration was 2.8 (95% CI: 2.4-2.9) months. CONCLUSIONS: The results highlight the number of treatment pathways used to treat mCRC in routine UK clinical practice prior to the marketing authorisation and National Institute for Health and Care Excellence approval of trifluridine/tipiracil and highlight the lack of clinical guidelines for mCRC.

Chronopharmacokinetics and Food Effects of Single-Dose LCP-Tacrolimus in Healthy Volunteers.

BACKGROUND: A modified-release version of tacrolimus, LCP-tacrolimus (LCPT; Envarsus XR, Veloxis Pharmaceuticals, Cary, NC), has been licensed in the United States for prophylaxis of organ rejection in de novo kidney transplant patients. As tacrolimus has a narrow therapeutic window, the impact of circadian patterns on LCPT drug exposure, including food and chronopharmacokinetic effects, needs to be elucidated to optimize dosing. METHODS: Two randomized, crossover, phase 1 studies were conducted in healthy volunteers. The first assessed the effect of morning versus evening dosing on the pharmacokinetic profile of LCPT 2 mg; the second assessed the effect of food on the pharmacokinetic profile of LCPT 5 mg. In both, blood samples were drawn from participants for up to 144 hours after administration of a single LCPT dose. RESULTS: No significant differences were observed between evening and morning dosing in peak blood concentration (4.4 versus 4.0 ng/mL; P = 0.27), area under the time-concentration curve (AUC) from time 0 to time of the last concentration (89.1 versus 102.6 ng/mL; P = 0.20), AUC from time 0 to infinity (99.7 versus 114.3 ng·h/mL; P = 0.18), AUC from 0 to 24 hours post-dose (AUC0-24; 49.4 versus 51.6 ng·h/mL; P = 0.56), time to reach maximum blood concentration (median, 6.0 versus 6.0 hours; P = 0.91), total clearance (arithmetic mean = 21.5 versus 19.5 L/h; P = 0.50), or terminal half-life (arithmetic mean = 26.8 versus 28.1 hours; P = 0.26). After a high-calorie meal in the morning, the AUC0-24 reduced by 54% (ratio of geometric means = 45.6%; P < 0.0001) and peak blood concentration reduced by 22% (ratio of geometric means = 78.4%; P = 0.0006). However, the terminal half-life did not differ between fasted and fed states (33.3 versus 34.8 hours; P = 0.16), implying that these differences occurred because of altered bioavailability rather than modified clearance. CONCLUSIONS: For LCPT, no chronopharmacokinetic effects were observed, whereas food significantly reduced the 24-h exposure and the peak blood concentration.

Contact electrification between identical polymers as the basis for triboelectric/flexoelectric materials.

Polymer contact electrification offers the possibility to harvest mechanical energy using lightweight, flexible and low-cost materials, but the mechanism itself is still unresolved. Several recent studies confirm heterolytic covalent bond breaking as the mechanism for surface charge formation. Here it is shown that the reason for the formation of surface charge by contacting two identical polymers results from the fluctuation in the surface irregularities, and that contacted materials with a greater porosity or surface roughness differential result in a greater generation of surface charge. Porosity and surface roughness create uneven surface length percentage changes in the lateral direction during deformation, which changes the charge density across the surface during relaxation. Multilayered membranes exhibit flexoelectric properties upon pressing and releasing by generating charge without separating individual membrane layers. This new insight deepens the understanding of polymer contact electrification and highlights better ways to prepare triboelectric or flexoelectric nanogenerator devices.

Domain-specific cognitive impairment in non-demented Parkinson's disease psychosis.

INTRODUCTION: In Parkinson's disease (PD), psychosis is associated with cognitive impairment that may be more profound in particular cognitive domains. Our goal was to determine whether psychosis in non-demented PD participants is associated with domain-specific cognitive impairment on the Mini-Mental State Exam (MMSE). METHODS: The Morris K. Udall Parkinson's Disease Research Center of Excellence Longitudinal Study at Johns Hopkins is a prospective study that was initiated in 1998. Clinical assessments are conducted at two-year intervals at the Johns Hopkins Hospital. We analyzed data from 137 enrolled participants with idiopathic PD. Psychosis diagnoses were established by psychiatrist interview per DSM-IV criteria. An incident dementia diagnosis resulted in exclusion from analysis for that evaluation and any future evaluations in that participant. We used logistic regression with generalized estimated equations (GEE) to model the time-varying relationship between MMSE subscale scores and psychosis, adjusting for potential confounding variables identified through univariable analysis. RESULTS: Thirty-one unique psychosis cases were recorded among non-demented participants. Fifty total evaluations with psychosis present were analyzed. In multivariable regressions, psychosis was associated with lower scores on the orientation (relative odds ratio, rOR: 0.73; 95% CI: 0.58-0.93; p = 0.011), language (rOR: 0.64; 95% CI: 0.48-0.86; p = 0.003), and intersecting pentagon (rOR: 0.43; 95% CI: 0.20-0.92 p = 0.030) subscales of the MMSE. CONCLUSIONS: In PD, executive dysfunction, disorientation, and impaired language comprehension may be associated with psychosis. Our findings suggest that the corresponding MMSE subscales may be useful in identifying participants with a higher likelihood of developing psychosis. Copyright © 2017 John Wiley & Sons, Ltd.

Analysis of oxygen uptake efficiency parameters in young people with cystic fibrosis.

PURPOSE: This study characterised oxygen uptake efficiency (OUE) in children with mild-to-moderate cystic fibrosis (CF). Specifically, it investigated (1) the utility of OUE parameters as potential submaximal surrogates of peak oxygen uptake ([Formula: see text]), and (2) the relationship between OUE and disease severity. METHODS: Cardiopulmonary exercise test (CPET) data were collated from 72 children [36 CF, 36 age- and sex-matched controls (CON)], with OUE assessed as its highest 90-s average (plateau; OUEP), the gas exchange threshold (OUEGET) and respiratory compensation point (OUERCP). Pearson's correlation coefficients, independent t tests and factorial ANOVAs assessed differences between groups and the use of OUE measures as surrogates for [Formula: see text]. RESULTS: A significant (p < 0.05) reduction in allometrically scaled [Formula: see text] and all OUE parameters was found in CF. Significant (p < 0.05) correlations between measurements of OUE and allometrically scaled [Formula: see text], were observed in CF (r = 0.49-0.52) and CON (r = 0.46-0.52). Furthermore, measures of OUE were significantly (p < 0.05) correlated with pulmonary function (FEV1%predicted) in CF (r = 0.38-0.46), but not CON (r = -0.20-0.14). OUEP was able to differentiate between different aerobic fitness tertiles in CON but not CF. CONCLUSIONS: OUE parameters were reduced in CF, but were not a suitable surrogate for [Formula: see text]. Clinical teams should, where possible, continue to utilise maximal CPET parameters to measure aerobic fitness in children and adolescents with CF. Future research should assess the prognostic utility of OUEP as it does appear sensitive to disease status and severity.

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration.

Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death.

Poly(ADP-ribose) polymerase-dependent energy depletion occurs through inhibition of glycolysis.

Excessive poly(ADP-ribose) (PAR) polymerase-1 (PARP-1) activation kills cells via a cell-death process designated "parthanatos" in which PAR induces the mitochondrial release and nuclear translocation of apoptosis-inducing factor to initiate chromatinolysis and cell death. Accompanying the formation of PAR are the reduction of cellular NAD(+) and energetic collapse, which have been thought to be caused by the consumption of cellular NAD(+) by PARP-1. Here we show that the bioenergetic collapse following PARP-1 activation is not dependent on NAD(+) depletion. Instead PARP-1 activation initiates glycolytic defects via PAR-dependent inhibition of hexokinase, which precedes the NAD(+) depletion in N-methyl-N-nitroso-N-nitroguanidine (MNNG)-treated cortical neurons. Mitochondrial defects are observed shortly after PARP-1 activation and are mediated largely through defective glycolysis, because supplementation of the mitochondrial substrates pyruvate and glutamine reverse the PARP-1-mediated mitochondrial dysfunction. Depleting neurons of NAD(+) with FK866, a highly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, does not alter glycolysis or mitochondrial function. Hexokinase, the first regulatory enzyme to initiate glycolysis by converting glucose to glucose-6-phosphate, contains a strong PAR-binding motif. PAR binds to hexokinase and inhibits hexokinase activity in MNNG-treated cortical neurons. Preventing PAR formation with PAR glycohydrolase prevents the PAR-dependent inhibition of hexokinase. These results indicate that bioenergetic collapse induced by overactivation of PARP-1 is caused by PAR-dependent inhibition of glycolysis through inhibition of hexokinase.

Oligometastatic Prostate Cancer.

OPINION STATEMENT: The mainstay of treatment for men with three or fewer non-castrate metastatic lesions outside of the prostate remains morbid palliative androgen deprivation therapy. We believe there is now a significant body of retrospective literature to suggest a survival benefit if these men have radical treatment to their primary tumour alongside 'metastasis-directed therapy' to the metastatic deposits. However, this regimen should be reserved to high-volume centres with quality assurance programmes and excellent outcomes. Patients should be made clear as to the uncertainty of benefit for this multi-site treatment strategy, and we await the publication of randomised controlled trials reporting in the next 5 years.

A Systematic Review of Patient-reported Outcomes in Randomized Controlled Trials of Unplanned General Surgery.

Unplanned general surgery represents a major workload and requires comprehensive evaluation with appropriate outcomes. This study aimed to summarize current reporting of patient-reported outcomes (PROs) in randomized clinical trials (RCTs) in unplanned general surgery. A systematic review identified RCTs reporting PROs in the commonest six areas of unplanned general surgery. Details of the PRO measures were examined using the CONSORT extension for PRO reporting in RCTs. Extracted information about each PRO domain included the reporting of baseline PROs, rationale for PRO selection and whether PRO findings were used in conjunction with clinical outcomes to inform treatment recommendations. The internal validity of included studies was assessed using the Cochrane risk of bias tool. 12,519 abstracts were screened and 20 RCTs containing data from 2037 patients included. Included studies used 14 separate PRO measures covering 35 different health domains. A visual analogue assessment of pain was most frequently reported (n = 13). Reporting of baseline PRO data was uncommon (11/35 PRO domains). The rationale for PRO data collection and a PRO-specific hypothesis were provided for 9 (25.7 %) and 5 (14.3 %) domains, respectively. Seventeen RCTs (85.0 %) used the PRO data alongside clinical outcomes to inform treatment recommendations. Of the 116 risk of bias assessments, 77 (66.0 %) were judged as high or unclear. There is a lack of well designed, and conducted RCTs in unplanned general surgery that include PROs. Future work to define relevant PROs and methods for optimal assessment are needed to inform health care decision-making.

The Utility of Molecular Imaging in Prostate Cancer.

Prostate cancer is the commonest solid-organ cancer diagnosed in males and represents an important source of morbidity and mortality worldwide. Imaging plays a crucial role in diagnosing prostate cancer and informs the ongoing management of the disease at all stages. Several novel molecular imaging technologies have been developed recently that have the potential to revolutionise disease diagnosis and the surveillance of patients living with prostate cancer. These innovations include hyperpolarised MRI, choline PET/CT and PSMA PET/CT. The major utility of choline and PSMA PET/CT currently lies in their sensitivity for detecting early recurrence after radical treatment for prostate cancer and identifying discrete lesions that may be amenable to salvage therapy. Molecular imaging is likely to play a future role in characterising genetic and biochemical signatures in individual tumours, which may be of particular significance as cancer therapies move into an era of precision medicine.