Brief Report: Determinants of Potential Sexual Activity Reduction in the Face of the Mpox Epidemic.

BACKGROUND: The current mpox epidemic is most prevalent among men-who-have-sex-with-men (MSM). Vaccination programs are being rolled-out to curb the epidemic. Behavioural measures have been called for as well, for example, by the WHO and national public health authorities to reduce the number of sexual partners and sexual activity. We investigated intentions and determinants among Dutch MSM to follow such behavioural measures. METHODS: Early in July 2022, in the context of a dynamic ongoing epidemic, 394 MSM answered an online questionnaire investigating concepts such as perceived mpox risk, vaccination and behavioural change intentions and collecting socio-demographic and sexual behaviour information. RESULTS: The overall intentions to reduce number of partners and sexual activity were high, but only a minority had developed definite intentions. Determinant analysis revealed that dating/open relationship status was a positive predictor; vaccination intentions did not predict sexual behaviour change; those not on PrEP were more likely to change their sexual behaviour. Mpox infection concern was the main predictor for behaviour change intentions. CONCLUSIONS: Our results show that behavioural measures to avoid an mpox infection are present in majority of participants in our survey, but high intentions are held by a minority. Taking the historic complexity of behavioural change pleas among MSM into account sensitive, additional public health measures are necessary to reach and to inform MSM about potential benefits of sexual behaviour change.

Healthcare use attributable to COVID-19: a propensity-matched national electronic health records cohort study of 249,390 people in Wales, UK.

BACKGROUND: To determine the extent and nature of changes associated with COVID-19 infection in terms of healthcare utilisation, this study observed healthcare contact 1 to 4 and 5 to 24 weeks following a COVID-19 diagnosis compared to propensity-matched controls. METHODS: Two hundred forty nine thousand three hundred ninety Welsh individuals with a positive reverse transcription-polymerase chain reaction (RT-PCR) test were identified from data from national PCR test results. After elimination criteria, 98,600 positive individuals were matched to test negative and never tested controls using propensity matching. Cohorts were split on test location. Tests could be taken in either the hospital or community. Controls were those who had tested negative in their respective environments. Survival analysis was utilised for first clinical outcomes which are grouped into primary and secondary. Primary outcomes include post-viral-illness and fatigue as an indication of long-COVID. Secondary outcomes include clinical terminology concepts for embolism, respiratory conditions, mental health conditions, fit notes, or hospital attendance. Increased instantaneous risk for positive individuals was quantified using hazard ratios (HR) from Cox regression, while absolute risk (AR) and relative risk were quantified using life table analysis. RESULTS: Analysis was conducted using all individuals and stratified by test location. Cases are compared to controls from the same test location. Fatigue (HR: 1.77, 95% CI: 1.34-2.25, p = < 0.001) and embolism (HR: 1.50, 95% CI: 1.15-1.97, p = 0.003) were more likely to occur in all positive individuals in the first 4 weeks; however, anxiety and depression (HR: 0.83, 95% CI: 0.73-0.95, p = 0.007) were less likely. Positive individuals continued to be more at risk of fatigue (HR: 1.47, 95% CI: 1.24-1.75, p = < 0.001) and embolism (HR: 1.51, 95% CI: 1.13-2.02, p = 0.005) after 4 weeks. All positive individuals are also at greater risk of post-viral illness (HR: 4.57, 95% CI: 1.77-11.80, p = 0.002). Despite statistical association between testing positive and several conditions, life table analysis shows that only a small minority of the study population were affected. CONCLUSIONS: Community COVID-19 disease is associated with increased risks of post-viral-illness, fatigue, embolism, and respiratory conditions. Despite elevated risks, the absolute healthcare burden is low. Subsequently, either very small proportions of people experience adverse outcomes following COVID-19 or they are not presenting to healthcare.

Close proximity to blast: No long-term or lasting effect on cognitive performance in service members with and without TBI during blast exposure.

OBJECTIVE: Blast related characteristics may contribute to the diversity of findings on whether mild traumatic brain injury sustained during war zone deployment has lasting cognitive effects. This study aims to evaluate whether a history of blast exposure at close proximity, defined as exposure within 30 feet, has long-term or lasting influences on cognitive outcomes among current and former military personnel. METHOD: One hundred participants were assigned to one of three groups based on a self-report history of blast exposure during combat deployments: 47 close blast, 14 non-close blast, and 39 comparison participants without blast exposure. Working memory, processing speed, verbal learning/memory, and cognitive flexibility were evaluated using standard neuropsychological tests. In addition, assessment of combat exposure and current post-concussive, posttraumatic stress, and depressive symptoms, and headache was performed via self-report measures. Variables that differed between groups were controlled as covariates. RESULTS: No group differences survived Bonferroni correction for family-wise error rate; the close blast group did not differ from non-close blast and comparison groups on measures of working memory, processing speed, verbal learning/memory, or cognitive flexibility. Controlling for covariates did not alter these results. CONCLUSION: No evidence emerged to suggest that a history of close blast exposure was associated with decreased cognitive performance when comparisons were made with the other groups. Limited characterization of blast contexts experienced, self-report of blast distance, and heterogeneity of injury severity within the groups are the main limitations of this study.

Generating and testing the efficacy of transgenic Cas9 in Tribolium castaneum.

CRISPR/Cas9 genome editing has now expanded to many insect species, including Tribolium castaneum. However, compared to Drosophila melanogaster, the CRISPR toolkit of T. castaneum is limited. A particularly apparent gap is the lack of Cas9 transgenic animals, which generally offer higher editing efficiency. We address this by creating and testing transgenic beetles expressing Cas9. We generated two different constructs bearing basal heat shock promoter-driven Cas9, two distinct 3' UTRs, and one containing Cas9 fused to EGFP by a T2A peptide. Analyses of Cas9 activity in each transgenic line demonstrated that both designs are capable of inducing CRISPR- mediated changes in the genome in the absence of heat induction. Overall, these resources enhance the accessibility of CRISPR/Cas9 genome editing for the Tribolium research community and provide a benchmark against which to compare future transgenic Cas9 lines.

Effect of Ag doped MnO2 nanostructures suitable for wastewater treatment and other environmental pollutant applications.

A modest sol-gel method has been employed to prepare the pure and Ag doped MnO2 nanoparticles and methodologically studied their physical, morphological, and photosensitive properties through XRD, TEM, EDAX, Raman, UV, PL and N2 adsorption - desorption study. Tetragonal crystalline arrangement with spherical nanoparticles was found out through XRD and TEM studies. The EDAX studies further supported that formation Ag in the MnO2 crystal matrix. The bandgap energy of Ag doped MnO2 was absorbed through UV spectra. Photo -generated recombination process and surface related defects were further recognized by PL spectra. Through visible light irradiation, the photo - degradation of methyl orange (MO) and phenol dye solutions were observed. The optimum condition of (10 wt% of Ag) Ag doped MnO2 catalyst showed tremendous photocatalytic efficiency towards MO than phenol under same experimental study.

Monkeypox self-diagnosis abilities, determinants of vaccination and self-isolation intention after diagnosis among MSM, the Netherlands, July 2022.

Monkeypox is a zoonotic disease and leads to a smallpox-like disease in humans. The current epidemic in European countries requires informed responses. We investigated the ability to self-diagnose a potential infection, and determinants of vaccination and self-isolation intention after diagnosis among 394 MSM in the Netherlands. We found that about half were able to self-diagnose monkeypox, that 70% had a high intention to get vaccinated and 44% to self-isolate after monkeypox diagnosis. Determinants went beyond mere risk behaviour criteria.

Noncanonical CTD kinases regulate RNA polymerase II in a gene-class-specific manner.

Phosphorylation of the carboxyl-terminal domain (CTD) of the largest subunit of RNA polymerase II (Pol II) governs stage-specific interactions with different cellular machines. The CTD consists of Y1S2P3T4S5P6S7 heptad repeats and sequential phosphorylations of Ser7, Ser5 and Ser2 occur universally at Pol II-transcribed genes. Phosphorylation of Thr4, however, appears to selectively modulate transcription of specific classes of genes. Here, we identify ten new Thr4 kinases from different kinase structural groups. Irreversible chemical inhibition of the most active Thr4 kinase, Hrr25, reveals a novel role for this kinase in transcription termination of specific class of noncoding snoRNA genes. Genome-wide profiles of Hrr25 reveal a selective enrichment at 3' regions of noncoding genes that display termination defects. Importantly, phospho-Thr4 marks placed by Hrr25 are recognized by Rtt103, a key component of the termination machinery. Our results suggest that these uncommon CTD kinases place phospho-Thr4 marks to regulate expression of targeted genes.

Sublethal and transgenerational effects of spinetoram on the biological traits of Plutella xylostella (L.) (Lepidoptera: Plutellidae).

Spinetoram, a spinosyn insecticide is used to manage lepidopteran pests, including diamondback moth, Plutella xylostella. In addition to determining the lethal effects, identifying low and/or sublethal effects of an insecticide is crucial to understanding the total impact of an insecticide. We assessed the low lethal and sublethal effects of spinetoram on two successive generations of P. xylostella. The initial bioassay results showed that spinetoram exhibited high toxicity against P. xylostella with an LC50 of 0.114 mg L-1 after 48 h exposure. The low lethal (LC25) and sublethal (LC10) concentrations of spinetoram showed significant reduction in pupation rate, pupal weight and adult emergence. The fecundity of F1 generation was significantly lower in LC25 (117.85 eggs/female) and LC10 (121.34 eggs/female) treated group than untreated control (145.32 eggs/female). The intrinsic rates of increase (r) was significantly lower (r = 0.1984 day-1) in spinetoram treated P. xylostella F1 progeny compared to untreated control (r = 0.2394 day-1). Our results suggest that LC10 and LC25 concentration of spinetoram might affect P. xylostella population growth by reducing its survival, development, and reproduction.

Synthesis of phenanthridines via a novel photochemically-mediated cyclization and application to the synthesis of triphaeridine.

Readily synthesized biphenyl-2-carbaldehyde O-acetyl oximes were exposed to UV radiation affording phenanthridines. The scope and limitations of this novel reaction were explored. For example, exposure of 2',3'-dimethoxy-[1,1'-biphenyl]-2-carbaldehyde O-acetyl oxime to UV radiation afforded 4-methoxyphenanthridine in 54% yield. This methodology was applied to the synthesis of trisphaeridine to afford the product in four linear steps in an overall yield of 6.5% from 1-bromo-2,4,5-trimethoxybenzene.

Lifetime revision risk for medial unicompartmental knee replacement is lower than expected.

PURPOSE: Unicompartmental knee replacement (UKR) is widely considered to be a pre-total knee replacement (TKR) particularly in the young. The implication of this is that it is sensible to do a UKR, even though it will be revised at some stage, as it will delay the need for a TKR. The chance of a UKR being revised during a patient's life time has not previously been calculated. The aim of this study was to estimate this lifetime revision risks for patients of different ages undergoing UKR. METHODS: Calculations were based on data from a designer series of 1000 medial Oxford UKR with mean 10-year follow up. These UKR were implanted for the recommended indications using the recommended surgical technique. Parametric survival models were developed for patients of different ages based on observed data, and were extrapolated using a Markov model to estimate lifetime revision risk. RESULTS: The estimated lifetime revision risk reduced with increasing age at surgery. Lifetime revision risk at age 55 was 15% (95% CI 12-19), at 65 it was 11% (8-13), at 75 it was 7% (5-9), and at 85 it was 4% (3-5). CONCLUSION: Provided UKR is used appropriately, the lifetime revision risk is markedly lower than expected. UKR should be considered to be a definitive knee replacement rather than a Pre-TKR even in the young. These lifetime estimates, alongside established benefits for UKR in speed of recovery, morbidity, mortality and function, can be discussed with appropriate patients when considering whether to implant a UKR or TKR. LEVEL OF EVIDENCE: III.

Bupivacaine Extended-Release Liposomal Injection Versus Bupivacaine HCl for Early Postoperative Pain Control Following Wrist Operations: A Prospective, Randomized Control Trial.

PURPOSE: This study evaluated pain control after wrist operations using a long-acting local anesthetic, liposomal bupivacaine, compared with the standard local anesthetic, bupivacaine HCl. METHODS: Patients undergoing elective carpometacarpal joint arthroplasty and proximal row carpectomy were eligible. Those meeting inclusion criteria were enrolled before surgery and were randomized to receive an intraoperative injection of liposomal bupivacaine or bupivacaine HCl. Primary outcomes included intraoperative and postoperative opioid requirements and pain levels. On the first 4 postoperative days, phone contact assessed pain level by numeric rating scale, number of opioids taken in each 24-hour period, and efficacy of anesthesia and opioid side effects with overall benefit of analgesia score. RESULTS: Postoperative pain scores for 52 patients measured by numeric rating scale demonstrated that liposomal bupivacaine and bupivacaine HCl were similar for pain control. Pain scores and opioid use were similar during the first 4 postoperative days. Opioid use on day 1 was slightly lower with liposomal bupivacaine. There were no statistically significant differences in any postoperative outcome between groups. CONCLUSIONS: Liposomal bupivacaine and bupivacaine HCl have similar effects in the treatment of early postoperative pain after trapeziometacarpal suspension arthroplasty and proximal row carpectomy. Neither drug demonstrated a clear advantage in this study. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic II.

ICA-based denoising for ASL perfusion imaging.

Arterial Spin Labelling (ASL) imaging derives a perfusion image by tracing the accumulation of magnetically labeled blood water in the brain. As the image generated has an intrinsically low signal to noise ratio (SNR), multiple measurements are routinely acquired and averaged, at a penalty of increased scan duration and opportunity for motion artefact. However, this strategy alone might be ineffective in clinical settings where the time available for acquisition is limited and patient motion are increased. This study investigates the use of an Independent Component Analysis (ICA) approach for denoising ASL data, and its potential for automation. 72 ASL datasets (pseudo-continuous ASL; 5 different post-labeling delays: 400, 800, 1200, 1600, 2000 m s; total volumes = 60) were collected from thirty consecutive acute stroke patients. The effects of ICA-based denoising (manual and automated) where compared to two different denoising approaches, aCompCor, a Principal Component-based method, and Enhancement of Automated Blood Flow Estimates (ENABLE), an algorithm based on the removal of corrupted volumes. Multiple metrics were used to assess the changes in the quality of the data following denoising, including changes in cerebral blood flow (CBF) and arterial transit time (ATT), SNR, and repeatability. Additionally, the relationship between SNR and number of repetitions acquired was estimated before and after denoising the data. The use of an ICA-based denoising approach resulted in significantly higher mean CBF and ATT values (p < 0.001), lower CBF and ATT variance (p < 0.001), increased SNR (p < 0.001), and improved repeatability (p < 0.05) when compared to the raw data. The performance of manual and automated ICA-based denoising was comparable. These results went beyond the effects of aCompCor or ENABLE. Following ICA-based denoising, the SNR was higher using only 50% of the ASL-dataset collected than when using the whole raw data. The results show that ICA can be used to separate signal from noise in ASL data, improving the quality of the data collected. In fact, this study suggests that the acquisition time could be reduced by 50% without penalty to data quality, something that merits further study. Independent component classification and regression can be carried out either manually, following simple criteria, or automatically.

Theta-gamma cascades and running speed.

Oscillations in the hippocampal local field potential at theta and gamma frequencies are prominent during awake behavior and have demonstrated several behavioral correlates. Both oscillations have been observed to increase in amplitude and frequency as a function of running speed. Previous investigations, however, have examined the relationship between speed and each of these oscillation bands separately. Based on energy cascade models where "…perturbations of slow frequencies cause a cascade of energy dissipation at all frequency scales" (Buzsaki G. Rhythms of the Brain, 2006), we hypothesized that cross-frequency interactions between theta and gamma should increase as a function of speed. We examined these relationships across multiple layers of the CA1 subregion, which correspond to synaptic zones receiving different afferents. Across layers, we found a reliable correlation between the power of theta and the power of gamma, indicative of an amplitude-amplitude relationship. Moreover, there was an increase in the coherence between the power of gamma and the phase of theta, demonstrating increased phase-amplitude coupling with speed. Finally, at higher velocities, phase entrainment between theta and gamma increases. These results have important implications and provide new insights regarding how theta and gamma are integrated for neuronal circuit dynamics, with coupling strength determined by the excitatory drive within the hippocampus. Specifically, rather than arguing that different frequencies can be attributed to different psychological processes, we contend that cognitive processes occur across multiple frequency bands simultaneously with organization occurring as a function of the amount of energy iteratively propagated through the brain. NEW & NOTEWORTHY Often, the theta and gamma oscillations in the hippocampus have been believed to be a consequence of two marginally overlapping phenomena. This perspective, however, runs counter to an alternative hypothesis in which a slow-frequency, high-amplitude oscillation provides energy that cascades into higher frequency, lower amplitude oscillations. We found that as running speed increases, all measures of cross-frequency theta-gamma coupling intensify, providing evidence in favor of the energy cascade hypothesis.

Partial volume correction for quantitative CEST imaging of acute ischemic stroke.

PURPOSE: Contributions of cerebrospinal fluid (CSF) have not been previously taken into account in the quantification of APT CEST effects, and correction for the dilution of CEST effects by CSF may allow for more robust measurement of CEST signals. The objective of this study was to compare the robustness of a partial volume (PV) correction model against a standard (4-pool) multi-pool model as far as their ability to quantify CEST effects in healthy, normal, and pathological tissue. METHODS: MRI data from 12 patients presenting with ischemic stroke, and 6 healthy subjects, were retrospectively analyzed. CEST signals derived from a 4-pool model and a PV correction model were compared for repeatability and pathological tissue contrast. The effect of PV correction (PVC) was assessed within 3 ranges of tissue PV estimate (PVE): high PVE voxels, low PVE voxels, and the whole slice. RESULTS: In voxels with a high tissue PVE, PV correction did not make a significant difference to absolute APTR* . In low PVE voxels, the PVC model exhibited a significantly decreased ischemic core signal. The PVC measures exhibited higher repeatability between healthy subjects (4 pools: 3.4%, PVC: 2.4%) while maintaining a similar ischemic core CNR (0.7) to the 4-pool model. In whole slice analysis it was found that both models exhibited similar results. CONCLUSIONS: PV correction yielded a measure of APT effects that was more repeatable than standard 4-pool analysis while achieving a similar CNR in pathological tissue, suggesting that PV-corrected analysis was more robust at low values of tissue PVE.

Validity of the CES-D for depression screening in military service members with a history of mild traumatic brain injury.

Primary Objective: To advance knowledge about the value of the Center for Epidemiologic Studies - Depression scale (CES-D) for depression screening in military service members with a history of mild traumatic brain injury (mTBI). Research Design: Retrospective data from 336 military service members with a history of mTBI were extracted from a TBI Repository at a large military medical center. Participants included in this study screened positive for mTBI in a primary care clinic or soldier readiness processing center and were enrolled in the TBI repository from November 6, 2014 to May 31, 2017. At the time of enrollment, participants completed the CES-D and their electronic medical records (EMR) were searched for diagnoses of depressive disorders. Methods and Procedures: Receiver-operating characteristic (ROC) analysis of the CES-D was used to discriminate cases with and without depression diagnoses. Main Outcomes and Results: Area under the ROC curve (AUC) was .897. Sensitivity (.824) and specificity (.826) were maximized at a cut score of 18 or greater, slightly higher than the standard cut of 16 established for civilian samples. Conclusions: Results suggest that the CES-D is a valid screening instrument for depressive disorders in military samples with a history of mTBI.

Genome-wide association studies of placebo and duloxetine response in major depressive disorder.

We investigated variants associated with treatment response in depressed patients treated with either the antidepressant duloxetine or placebo using a genome-wide approach. Our sample (N=391) included individuals aged 18-75 years, diagnosed with major depressive disorder and treated with either duloxetine or placebo for up to 8 weeks. We conducted genome-wide associations for treatment response as operationalized by percentage change in Montgomery-Åsberg Depression Rating Scale score from baseline, as well as mixed models analyses across five time points. In the placebo-treated subsample (N=205), we observed a genome-wide association with rs76767803 (ß=0.69, P=1.25 × 10-8) upstream of STAC1. STAC1 rs76767803 was also associated with response using mixed model analysis (χ2=3.95; P=0.001). In the duloxetine-treated subsample (N=186), we observed suggestive associations with ZNF385D (rs4261893; ß=-0.46, P=1.55 × 10-5), NCAM1 (rs2303377; ß=0.45, P=1.76 × 10-5) and MLL5 (rs117986340; ß=0.91, P=3.04 × 10-5). Our findings suggest that a variant upstream of STAC1 is associated with placebo response, which might have implications for treatment optimization, clinical trial design and drug development.

Phosphatidylinositol-3,4-Bisphosphate and Its Binding Protein Lamellipodin Regulate Chemotaxis of Malignant B Lymphocytes.

Cell migration is controlled by PI3Ks, which generate lipid messengers phosphatidylinositol-3,4,5-trisphosphate and phosphatidylinositol-3,4-bisphosphate [PI(3,4)P2] and consequently recruit pleckstrin homology (PH) domain-containing signaling proteins. PI3K inhibition impairs migration of normal and transformed B cells, an effect thought to partly underlie the therapeutic efficacy of PI3K inhibitors in treatment of B cell malignancies such as chronic lymphocytic leukemia. Although a number of studies have implicated phosphatidylinositol-3,4,5-trisphosphate in cell migration, it remains unknown whether PI(3,4)P2 plays a distinct role. Using the PI(3,4)P2-specific phosphatase inositol polyphosphate 4-phosphatase, we investigate the impact of depleting PI(3,4)P2 on migration behavior of malignant B cells. We find that cells expressing wild-type, but not phosphatase dead, inositol polyphosphate 4-phosphatase show impaired SDF-induced PI(3,4)P2 responses and reduced migration in Transwell chamber assays. Moreover, PI(3,4)P2 depletion in primary chronic lymphocytic leukemia cells significantly impaired their migration capacity. PI(3,4)P2 depletion reduced both overall motility and migration directionality in the presence of a stable chemokine gradient. Within chemotaxing B cells, the PI(3,4)P2-binding cytoskeletal regulator lamellipodin (Lpd) was found to colocalize with PI(3,4)P2 on the plasma membrane via its PH domain. Overexpression and knockdown studies indicated that Lpd levels significantly impact migration capacity. Moreover, the ability of Lpd to promote directional migration of B cells in an SDF-1 gradient was dependent on its PI(3,4)P2-binding PH domain. These results demonstrate that PI(3,4)P2 plays a significant role in cell migration via binding to specific cytoskeletal regulators such as Lpd, and they suggest that impairment of PI(3,4)P2-dependent processes may contribute to the therapeutic efficacy of PI3K inhibitors in B cell malignancies.

A scoping review to explore how universal design for learning is described and implemented by rehabilitation health professionals in school settings.

BACKGROUND: Universal design for learning (UDL) is a framework that provides guidelines to support children with diverse needs in the classroom and promotes inclusion of all children. Although UDL is recognized as a promising approach for school-based rehabilitation health professionals (RHPs), there are no studies that synthesize evidence on the use of UDL by RHPs in the school setting. Therefore, the research question for this study is: How is UDL described and implemented in school settings by RHPs? This study specifically examined literature from occupational therapy, physiotherapy, and speech-language pathology. METHODS: A scoping review was completed to (a) summarize how UDL is described in the rehabilitation literature, (b) summarize the recommended and reported role of RHPs in the delivery of UDL, and (c) identify gaps in the evidence base. CINAHL, Embase, MEDLINE, PsychINFO, Sociological Abstracts, Web of Science, and ERIC electronic databases were searched. Numerical summaries and theoretical thematic analysis were used to describe the data both quantitatively and qualitatively. RESULTS: Inclusion criteria were achieved for 45 of the 3,998 screened documents. Most of the included documents lacked a definition of UDL. Analysis suggested that speech-language pathologists and occupational therapists implement UDL in a variety of ways within the school setting. No physiotherapy literature was found, and limited high-level empirical research has been conducted within rehabilitation. CONCLUSION: This scoping review provides a broad understanding of how RHPs describe and implement UDL-aligned services in school settings. UDL is a promising framework that provides RHPs with guidance on how to support children with diverse needs in the classroom, with the overall aim to promote inclusion of all children. There is a need for further research to determine the effectiveness of UDL as implemented by RHPs and to examine the role of physiotherapists in using UDL-type services.

Obesity paradox in group 1 pulmonary hypertension: analysis of the NIH-Pulmonary Hypertension registry.

BACKGROUND: The 'obesity paradox' refers to the fact that obese patients have better outcomes than normal weight patients. This has been observed in multiple cardiovascular conditions, but evidence for obesity paradox in pulmonary hypertension (PH) remains sparse. METHODS: We categorized 267 patients from the National Institute of Health-PH registry into five groups based on body mass index (BMI): underweight, normal weight, overweight, obese and morbidly obese. Mortality was compared in BMI groups using the χ2 statistic. Five-year probability of death using the PH connection (PHC) risk equation was calculated, and the model was compared with BMI groups using Cox proportional hazards regression and Kaplan-Meier (KM) survival curves. RESULTS: Patients had a median age of 39 years (interquartile range 30-50 years), a median BMI of 23.4 kg m-2 (21.0-26.8 kg m-2) and an overall mortality at 5 years of 50.2%. We found a U-shaped relationship between survival and 1-year mortality with the best 1-year survival in overweight patients. KM curves showed the best survival in the overweight, followed by obese and morbidly obese patients, and the worst survival in normal weight and underweight patients (log-rank P=0.0008). In a Cox proportional hazards analysis, increasing BMI was a highly significant predictor of improved survival even after adjustment for the PHC risk equation with a hazard ratio for death of 0.921 per kg m-2 (95% confidence interval: 0.886-0.954) (P<0.0001). CONCLUSION: We observed that the best survival was in the overweight patients, making this more of an 'overweight paradox' than an 'obesity paradox'. This has implications for risk stratification and prognosis in group 1 PH patients.

Approach for targeting Ras with small molecules that activate SOS-mediated nucleotide exchange.

Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure-activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.