Cellular production of a de novo membrane cytochrome.

Heme-containing integral membrane proteins are at the heart of many bioenergetic complexes and electron transport chains. The importance of these electron relay hubs across biology has inspired the design of de novo proteins that recreate their core features within robust, versatile, and tractable protein folds. To this end, we report here the computational design and in-cell production of a minimal diheme membrane cytochrome which successfully integrates into the cellular membrane of live bacteria. This synthetic construct emulates a four-helix bundle found in modern respiratory complexes but has no sequence homology to any polypeptide sequence found in nature. The two b-type hemes, which appear to be recruited from the endogenous heme pool, have distinct split redox potentials with values close to those of natural membrane-spanning cytochromes. The purified protein can engage in rapid biomimetic electron transport with small molecules, with other redox proteins, and with biologically relevant diffusive electron carriers. We thus report an artificial membrane metalloprotein with the potential to serve as a functional electron transfer module in both synthetic protocells and living systems.

An expandable, modular de novo protein platform for precision redox engineering.

The electron-conducting circuitry of life represents an as-yet untapped resource of exquisite, nanoscale biomolecular engineering. Here, we report the characterization and structure of a de novo diheme "maquette" protein, 4D2, which we subsequently use to create an expanded, modular platform for heme protein design. A well-folded monoheme variant was created by computational redesign, which was then utilized for the experimental validation of continuum electrostatic redox potential calculations. This demonstrates how fundamental biophysical properties can be predicted and fine-tuned. 4D2 was then extended into a tetraheme helical bundle, representing a 7 nm molecular wire. Despite a molecular weight of only 24 kDa, electron cryomicroscopy illustrated a remarkable level of detail, indicating the positioning of the secondary structure and the heme cofactors. This robust, expressible, highly thermostable and readily designable modular platform presents a valuable resource for redox protein design and the future construction of artificial electron-conducting circuitry.

Needle-like structures discovered on positively charged lightning branches.

Lightning is a dangerous yet poorly understood natural phenomenon. Lightning forms a network of plasma channels propagating away from the initiation point with both positively and negatively charged ends-called positive and negative leaders1. Negative leaders propagate in discrete steps, emitting copious radio pulses in the 30-300-megahertz frequency band2-8 that can be remotely sensed and imaged with high spatial and temporal resolution9-11. Positive leaders propagate more continuously and thus emit very little high-frequency radiation12. Radio emission from positive leaders has nevertheless been mapped13-15, and exhibits a pattern that is different from that of negative leaders11-13,16,17. Furthermore, it has been inferred that positive leaders can become transiently disconnected from negative leaders9,12,16,18-20, which may lead to current pulses that both reconnect positive leaders to negative leaders11,16,17,20-22 and cause multiple cloud-to-ground lightning events1. The disconnection process is thought to be due to negative differential resistance18, but this does not explain why the disconnections form primarily on positive leaders22, or why the current in cloud-to-ground lightning never goes to zero23. Indeed, it is still not understood how positive leaders emit radio-frequency radiation or why they behave differently from negative leaders. Here we report three-dimensional radio interferometric observations of lightning over the Netherlands with unprecedented spatiotemporal resolution. We find small plasma structures-which we call 'needles'-that are the dominant source of radio emission from the positive leaders. These structures appear to drain charge from the leader, and are probably the reason why positive leaders disconnect from negative ones, and why cloud-to-ground lightning connects to the ground multiple times.

iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells.

Dysregulation of the ERBB/EGFR signalling pathway causes multiple types of cancer. Accordingly, ADAM17, the primary shedding enzyme that releases and activates ERBB ligands, is tightly regulated. It has recently become clear that iRhom proteins, inactive members of the rhomboid-like superfamily, are regulatory cofactors for ADAM17. Here, we show that oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 (also known as RHBDF2) to induce ADAM17-dependent shedding and the release of ERBB ligands. Activation of ERK1/2 by oncogenic KRAS induces the phosphorylation of iRhom2, recruitment of the phospho-binding 14-3-3 proteins, and consequent ADAM17-dependent shedding of ERBB ligands. In addition, cancer-associated mutations in iRhom2 act as sensitisers in this pathway by further increasing KRAS-induced shedding of ERBB ligands. This mechanism is conserved in lung cancer cells, where iRhom activity is required for tumour xenograft growth. In this context, the activity of oncogenic KRAS is modulated by the iRhom2-dependent release of ERBB ligands, thus placing the cytoplasmic domain of iRhom2 as a central component of a positive feedback loop in lung cancer cells. This article has an associated First Person interview with the first authors of the paper.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Measurement of Jupiter's asymmetric gravity field.

The gravity harmonics of a fluid, rotating planet can be decomposed into static components arising from solid-body rotation and dynamic components arising from flows. In the absence of internal dynamics, the gravity field is axially and hemispherically symmetric and is dominated by even zonal gravity harmonics J2n that are approximately proportional to qn, where q is the ratio between centrifugal acceleration and gravity at the planet's equator. Any asymmetry in the gravity field is attributed to differential rotation and deep atmospheric flows. The odd harmonics, J3, J5, J7, J9 and higher, are a measure of the depth of the winds in the different zones of the atmosphere. Here we report measurements of Jupiter's gravity harmonics (both even and odd) through precise Doppler tracking of the Juno spacecraft in its polar orbit around Jupiter. We find a north-south asymmetry, which is a signature of atmospheric and interior flows. Analysis of the harmonics, described in two accompanying papers, provides the vertical profile of the winds and precise constraints for the depth of Jupiter's dynamical atmosphere.

The evaluation of skin sensitization potential of the UVCB substance diisopentyl phthalate by in silico and in vitro methods.

Diisopentyl phthalate (DiPeP) is primarily used as a plasticizer or additive within the production of polyvinyl chloride (PVC), and has many additional industrial applications. Its metabolites were recently found in urinary samples of pregnant women; thus, this substance is of concern as relates to human exposure. Depending upon the nature of the alcohol used in its synthesis, DiPeP may exist either as a mixture consisting of several branched positional isomers, or as a single defined structure. This article investigates the skin sensitization potential and immunomodulatory effects of DiPeP CAS No. 84777-06-0, which is currently marketed and classified as a UVCB substance, by in silico and in vitro methods. Our findings showed an immunomodulatory effect for DiPeP in LPS-induced THP-1 activation assay (increased CD54 expression). In silico predictions using QSAR TOOLBOX 4.5, ToxTree, and VEGA did not identify DiPeP, in the form of a discrete compound, as a skin sensitizer. The keratinocyte activation (Key Event 2 (KE2) of the adverse outcome pathway (AOP) for skin sensitization) was evaluated by two different test methods (HaCaT assay and RHE assay), and results were discordant. While the HaCaT assay showed that DiPeP can activate keratinocytes (increased levels of IL-6, IL-8, IL-1α, and ILA gene expression), in the RHE assay, DiPeP slightly increased IL-6 release. Although inconclusive for KE2, the role of DiPeP in KE3 (dendritic cell activation) was demonstrated by the increased levels of CD54 and IL-8 and TNF-α in THP-1 cells (THP-1 activation assay). Altogether, findings were inconclusive regarding the skin sensitization potential of the UVCB DiPeP-disagreeing with the results of DiPeP in the form of discrete compound (skin sensitizer by the LLNA assay). Additional studies are needed to elucidate the differences between DiPeP isomer forms, and to better understand the applicability domains of non-animal methods in identifying skin sensitization hazards of UVCB substances.

Compliance with yellow fever and measles vaccines in the revaccination program post-hematopoietic cell transplantation.

INTRODUCTION: Measles, mumps, rubella, and even poliomyelitis outbreaks have recently perplexed infectious disease clinicians and epidemiologists globally due to the decline in vaccination coverage rates in children and adults. Measles and yellow fever (YF) have represented an increasing burden on the Brazilian public health system in recent decades. Both diseases are preventable by live-attenuated viral vaccines (LAVV), which have restricted use in hematopoietic cell transplant (HCT) recipients. METHODS: Autologous and allogeneic HCT recipients returning for regular appointments at the outpatient clinic were invited to participate in the study. Patients transplanted for at least 2 years and with a printed copy of the vaccination record were included. RESULTS: We assessed the vaccination records of 273 HCT recipients after the second year of HCT (193 allogeneic and 80 autologous) and observed lower compliance with the YF vaccine (58 patients, 21.2%) than with the measles vaccine (138 patients, 50.5%, p ≤ .0001). This is the largest published series of YF vaccination in HCT recipients so far. No severe adverse events occurred. Although expected, chronic graft-versus-host disease (GVHD) did not affect the compliance with measles (p = .08) or YF vaccination (p = .7). Indeed, more allogeneic recipients received measles vaccine in comparison with autologous patients (p < .0001), suggesting that chronic GVHD was not the main reason for not being vaccinated. Children and allogeneic HCT were more likely to receive measles vaccine. Time elapsed from HCT >5 years favored both measles and YF vaccination. CONCLUSION: A better understanding of the reasons for low compliance with LAVV is necessary to overcome this problem.

Second-trimester growth velocities in twin and singleton pregnancies.

OBJECTIVE: Previous small studies used individualized growth assessment (IGA) to characterize prenatal growth velocities of singletons and twins. We aimed to compare second-trimester growth velocities of individual anatomical parameters between monochorionic diamniotic (MCDA) twins, dichorionic diamniotic (DCDA) twins and singleton fetuses in a larger study. METHODS: This was a study of a novel cohort of 222 MCDA twins and previously published cohorts of 40 DCDA twins and 118 singletons with serial ultrasound data. Fetal biometric measurements of biparietal diameter, head circumference, abdominal circumference and femur diaphysis length from prenatal ultrasound examinations were used to calculate second-trimester growth velocities using direct calculation or linear regression analysis. Linear fit was assessed based on the coefficient of determination (R2 ). Mean growth velocities and variances were compared among the three groups. RESULTS: The majority of cases underwent three second-trimester ultrasound examinations with fetal biometry available. All fetuses had linear growth, with R2 > 99% for all parameters. Only 1-2% of all MCDA and DCDA anatomical parameters had abnormal growth velocity scores outside the 95% reference range for singletons. There were no significant differences in mean growth velocity for any parameter between MCDA twins and singletons. Femur diaphysis length growth velocity was significantly lower in DCDA twins than in both MCDA twins and singletons. There were no other significant differences among the groups. CONCLUSIONS: Expanding on prior work using IGA, we found that second-trimester growth velocity of the four major anatomical parameters overall was similar between twins and singletons and between MCDA and DCDA twins, supporting the use of singleton-derived growth standards for IGA in twins. Twin growth potential appears to be similar to that of singletons in the second trimester, suggesting that subsequent growth divergence may be due to third-trimester physiological or pathological changes in twin pregnancies. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

A kilonova as the electromagnetic counterpart to a gravitational-wave source.

Gravitational waves were discovered with the detection of binary black-hole mergers and they should also be detectable from lower-mass neutron-star mergers. These are predicted to eject material rich in heavy radioactive isotopes that can power an electromagnetic signal. This signal is luminous at optical and infrared wavelengths and is called a kilonova. The gravitational-wave source GW170817 arose from a binary neutron-star merger in the nearby Universe with a relatively well confined sky position and distance estimate. Here we report observations and physical modelling of a rapidly fading electromagnetic transient in the galaxy NGC 4993, which is spatially coincident with GW170817 and with a weak, short γ-ray burst. The transient has physical parameters that broadly match the theoretical predictions of blue kilonovae from neutron-star mergers. The emitted electromagnetic radiation can be explained with an ejected mass of 0.04 ± 0.01 solar masses, with an opacity of less than 0.5 square centimetres per gram, at a velocity of 0.2 ± 0.1 times light speed. The power source is constrained to have a power-law slope of -1.2 ± 0.3, consistent with radioactive powering from r-process nuclides. (The r-process is a series of neutron capture reactions that synthesise many of the elements heavier than iron.) We identify line features in the spectra that are consistent with light r-process elements (atomic masses of 90-140). As it fades, the transient rapidly becomes red, and a higher-opacity, lanthanide-rich ejecta component may contribute to the emission. This indicates that neutron-star mergers produce gravitational waves and radioactively powered kilonovae, and are a nucleosynthetic source of the r-process elements.

Heterogeneity of quality of life in the later stages of first-episode psychosis recovery.

PURPOSE: First-episode psychosis (FEP) is characterised by wide heterogeneity in terms of symptom presentation and illness course. However, the heterogeneity of quality of life (QoL) in FEP is not well understood. We investigated whether subgroups can be identified using participants' responses on four QoL domains (physical health, psychological, social relationships, and environmental) 18-months into the recovery phase of FEP. We then examined the discriminant validity of these subgroups with respect to clinical, cognitive, and functioning features of FEP. METHOD: Demographic and clinical characteristics, QoL, cognition, and functioning were assessed in 100 people with FEP at the 18-month follow-up of a randomised controlled trial of Individual Placement Support, which aims to facilitate vocational recovery. QoL was measured using the World Health Organisation's QoL-BRIEF. A two-stage clustering approach using Ward's method and Squared Euclidean Distance with a k-means confirmation was conducted. Multinomial logistic regressions were used to establish external validity. RESULTS: Three QoL subgroups emerged: a 'good' subgroup with relatively high QoL across all domains (31%), an 'intermediate' subgroup with relatively low psychological QoL (48%) and a 'poor' subgroup with markedly low social relationship QoL (21%). Negative symptoms, depressive symptoms, social/occupational functioning, and social inclusion at follow-up predicted subgroup membership. Sensitivity analysis found similar results. CONCLUSION: Although some individuals with FEP have QoL comparable to individuals without mental ill health, QoL can remain concerningly low despite treatment efforts. Future research on interventions that target factors associated with poor QoL, such as low social inclusion, is required to counteract prolonged poor QoL in FEP.

A de novo peroxidase is also a promiscuous yet stereoselective carbene transferase.

By constructing an in vivo-assembled, catalytically proficient peroxidase, C45, we have recently demonstrated the catalytic potential of simple, de novo-designed heme proteins. Here, we show that C45's enzymatic activity extends to the efficient and stereoselective intermolecular transfer of carbenes to olefins, heterocycles, aldehydes, and amines. Not only is this a report of carbene transferase activity in a completely de novo protein, but also of enzyme-catalyzed ring expansion of aromatic heterocycles via carbene transfer by any enzyme.

Trypanosoma sp. infection in Boa constrictor snakes: morphological, hematological, clinical biochemistry, molecular, and phylogenetic characteristics.

There are few reports of Trypanosoma in snakes, as well as little information about its pathogenicity in these animals. Thus, the present study aimed to characterize Trypanosoma found in Boa constrictor snakes, to verify the influence of the parasitism on hematological and clinical biochemistry parameters, and to perform a phylogenetic study of the isolates. Blood samples from sixty-one boas were analyzed for the presence of trypanosomatids and by hematological and clinical biochemistry assays. The flagellates that were found in this analysis were used for cell culture, morphometry, and molecular analysis. Later, molecular typing phylogenetic studies were performed. Nine positive animals (14.75%) were identified by microscopy analysis. The hematological results showed that parasitized animals presented significantly lower levels of packed cell volume, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. In the leukogram, eosinophils and heterophils counts were higher in parasitized animals. Considering the molecular analyses, the isolates presented a higher identity of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the 18S small subunit ribosomal RNA (SSU rRNA) gene fragments with Trypanosoma serpentis. The phylogenetic tree, using the GAPDH, clustered all isolates with T. serpentis and Trypanosoma cascavelli. This is the first description of T. serpentis parasitizing boas and of the clinical changes caused by trypanosomatid infection in snakes.

The top sports medicine influencers on X (formerly Twitter).

BACKGROUND: With increasing sports medicine content on social media, we sought to identify the top sports medicine influencers on X (formerly Twitter) and analyse their common characteristics. METHODS: X influence scores for "Sports Medicine" were collected in November 2021 from Right Relevance. Accounts were then screened in a blind, duplicate manner for personal and X profile characteristics. RESULTS: Physical therapists/physiotherapists made up 48% of the top sports science and medicine influencers. Locations in the U.S. and U.K. were listed for half of the influencers. The mean h-index was 30.2 (95% CI = [24.8-35.6]) with a median of 22.0 (range = 1-101). Most individuals reported multiple practice settings (63%), with 60% associated with an academic setting. Professional (62%) and Olympic (49%) level athletics were most frequently mentioned, with soccer (48%) and rugby (30%) as the most common sports. Among 76 profiles with URLs, most were linked to personal websites (57.9%). CONCLUSION: The top influencers on X consisted of accredited sports science and medicine professionals across various locations and occupations, providing ample networking and collaboration opportunities. The relatively high h-index in this study suggests sports science and medicine influencers on X are notable contributors to academic literature.

Structure and Dynamics of Three Escherichia coli NfsB Nitro-Reductase Mutants Selected for Enhanced Activity with the Cancer Prodrug CB1954.

Escherichia coli NfsB has been studied extensively for its potential for cancer gene therapy by reducing the prodrug CB1954 to a cytotoxic derivative. We have previously made several mutants with enhanced activity for the prodrug and characterised their activity in vitro and in vivo. Here, we determine the X-ray structure of our most active triple and double mutants to date, T41Q/N71S/F124T and T41L/N71S. The two mutant proteins have lower redox potentials than wild-type NfsB, and the mutations have lowered activity with NADH so that, in contrast to the wild-type enzyme, the reduction of the enzyme by NADH, rather than the reaction with CB1954, has a slower maximum rate. The structure of the triple mutant shows the interaction between Q41 and T124, explaining the synergy between these two mutations. Based on these structures, we selected mutants with even higher activity. The most active one contains T41Q/N71S/F124T/M127V, in which the additional M127V mutation enlarges a small channel to the active site. Molecular dynamics simulations show that the mutations or reduction of the FMN cofactors of the protein has little effect on its dynamics and that the largest backbone fluctuations occur at residues that flank the active site, contributing towards its broad substrate range.

An Evaluation of Evidence Underpinning Management Recommendations in Tobacco Use Disorder Clinical Practice Guidelines.

INTRODUCTION: Clinical practice guidelines(CPGs) are important tools for medical decision-making. Given the high prevalence and financial burden associated with tobacco use disorder(TUD), it is critical that recommendations within CPGs are based on robust evidence. Systematic reviews(SRs) are considered the highest level of evidence, thus, we evaluated the quality of SRs underpinning CPG recommendations for TUD. METHODS: We used PubMed to search for CPGs relating to TUD published between January 1, 2010 and May 21, 2021. SRs were extracted from CPG references and evaluated using Preferred Reporting Items for Systematic Reviews and Meta-Analyses(PRISMA) and A MeaSurement Tool to Assess Systematic Reviews(AMSTAR-2) tools. We then compared SRs conducted by the Cochrane Collaboration with non-Cochrane SRs using a Mann-Whitney U test and determined associations between PRISMA and AMSTAR-2 extracted characteristics using multiple regression. RESULTS: Our search generated 10 CPGs with 98 SRs extracted. Mean PRISMA completion was 74.7%(SD = 16.7) and mean AMSTAR-2 completion was 53.8%(SD = 22.0) across all guidelines. Cochrane SRs were more complete than non-Cochrane studies in the PRISMA and AMSTAR-2 assessments. The regression model showed a statistically significant association between PRISMA completion and AMSTAR-2 rating, with those classified as "low" or "moderate" quality having higher PRISMA completion than those with "critically low" ratings. CONCLUSION: We found substandard adherence to PRISMA and AMSTAR-2 checklists across SRs cited in TUD CPGs. A lack of recent SRs in CPGs could lead to outdated recommendations. Therefore, frequent guideline updates with recently published evidence may ensure more accurate clinical recommendations and improve patient care. IMPLICATIONS: Systematic reviews used to underpin clinical practice guideline recommendations influence treatment decisions and, ultimately, patient outcomes. We found that many systematic reviews underpinning tobacco use disorder guideline recommendations were out of date and unsatisfactory in reporting and quality. Thus, including newer systematic reviews containing more recently conducted trials and better reporting could alter recommendations and improve the rate of successful tobacco cessation attempts.

A large light-mass component of cosmic rays at 10(17)-10(17.5) electronvolts from radio observations.

Cosmic rays are the highest-energy particles found in nature. Measurements of the mass composition of cosmic rays with energies of 10(17)-10(18) electronvolts are essential to understanding whether they have galactic or extragalactic sources. It has also been proposed that the astrophysical neutrino signal comes from accelerators capable of producing cosmic rays of these energies. Cosmic rays initiate air showers--cascades of secondary particles in the atmosphere-and their masses can be inferred from measurements of the atmospheric depth of the shower maximum (Xmax; the depth of the air shower when it contains the most particles) or of the composition of shower particles reaching the ground. Current measurements have either high uncertainty, or a low duty cycle and a high energy threshold. Radio detection of cosmic rays is a rapidly developing technique for determining Xmax (refs 10, 11) with a duty cycle of, in principle, nearly 100 per cent. The radiation is generated by the separation of relativistic electrons and positrons in the geomagnetic field and a negative charge excess in the shower front. Here we report radio measurements of Xmax with a mean uncertainty of 16 grams per square centimetre for air showers initiated by cosmic rays with energies of 10(17)-10(17.5) electronvolts. This high resolution in Xmax enables us to determine the mass spectrum of the cosmic rays: we find a mixed composition, with a light-mass fraction (protons and helium nuclei) of about 80 per cent. Unless, contrary to current expectations, the extragalactic component of cosmic rays contributes substantially to the total flux below 10(17.5) electronvolts, our measurements indicate the existence of an additional galactic component, to account for the light composition that we measured in the 10(17)-10(17.5) electronvolt range.

Quality of life in first episode psychosis: a cluster analytic approach.

PURPOSE: Quality of life is increasingly recognised as an important outcome for young people with first episode psychosis (FEP). The first aim was to determine whether distinct homogenous subgroups of young people with FEP could be delineated based on profiles on quality of life domains (Physical Health, Psychological, Social relationships and Environmental). The second aim was to examine the discriminant validity of these subgroups with respect to demographic, functioning and clinical features of FEP. METHOD: Quality of life, demographic characteristics, clinical characteristics, cognition and functioning were assessed in 145 people with FEP. Cluster analysis using Ward's methods and Squared Euclidean Distance with a k-means verification were employed to identify subgroups with homogenous quality of life profiles. The clusters were externally validated using multinomial logistic regressions. RESULTS: Three distinct quality of life profiles were identified: one with good quality of life across all domains (30%), one with poor quality of life particularly in Psychological and Social relationships domains (28%), and one 'intermediate' group with comparatively low Psychological quality of life (42%). Depression, semantic verbal fluency, social inclusion and social/occupational functioning showed associations with group membership. CONCLUSION: Our results suggest the potential of maintaining relatively good quality of life despite the experience of FEP. Future research on interventions to improve quality of life may consider the potential of addressing depression, social inclusion and social/occupational functioning.

Conflicts of Interest Among Authors of Systematic Reviews Regarding the Management of Chronic Non-Cancer Pain with Opioids Analgesics.

OBJECTIVE: We sought to determine whether author conflict of interest (disclosed or undisclosed) or industry sponsorship influenced the favorability of reporting of systematic reviews and meta-analyses investigating the use of opioid analgesics for the management of chronic non-cancer pain. METHODS: Our search included the MEDLINE (Ovid) and Embase (Ovid) databases. Study sponsorship was determined using the funding statement provided in each systematic review. Author COI information was extracted from the COI disclosure statement. This information was cross-referenced with information available on the CMS Open Payments Database, Dollars for Profs, Google Patents, the United States Patent and Trademark Office (USPTO), and previously published COI disclosures. RESULTS: Eight systematic reviews authored by 83 authors were included. Of these authors, 19 (23.0%) were found to have a COI, of which the majority (17/19; 89.5%) had at least one undisclosed COI. Despite nearly one-quarter of authors having a COI, we found no association between the presence of a COI and the favorability of results (P = 0.64) or conclusions (P = 0.07). CONCLUSIONS: COI are common and frequently undisclosed among systematic review authors investigating opioid analgesics for the management of chronic non-cancer pain. Despite a high prevalence of COI, we did not find that these author-industry relationships had a significant influence on the favorability of results and conclusions; however, our findings should be considered a lower bound estimate of the true influence author COI have on outcomes of pain medicine systematic reviews secondary to the low sample size included in the present study.

Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus.

Cancer gene therapies are usually designed either to express wild-type copies of tumor suppressor genes or to exploit tumor-associated phenotypic changes to endow selective cytotoxicity. However, these approaches become less relevant to cancers that contain many independent mutations, and the situation is made more complex by our increased understanding of clonal evolution of tumors, meaning that different metastases and even regions of the same tumor mass have distinct mutational and phenotypic profiles. In contrast, the relatively genetically stable tumor microenvironment (TME) therefore provides an appealing therapeutic target, particularly since it plays an essential role in promoting cancer growth, immune tolerance, and acquired resistance to many therapies. Recently, a variety of different TME-targeted gene therapy and armed oncolytic strategies have been explored, with particular success observed in strategies targeting the cancer stroma, reducing tumor vasculature, and repolarizing the immunosuppressive microenvironment. Herein, we review the progress of these TME-targeting approaches and try to highlight those showing the greatest promise.