Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial.

Background and objective: The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. Methods: Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitations: Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implications: UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summary: We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.

Year-round activity levels reveal diurnal foraging constraints in the annual cycle of migratory and non-migratory barnacle geese.

Performing migratory journeys comes with energetic costs, which have to be compensated within the annual cycle. An assessment of how and when such compensation occurs is ideally done by comparing full annual cycles of migratory and non-migratory individuals of the same species, which is rarely achieved. We studied free-living migratory and resident barnacle geese belonging to the same flyway (metapopulation), and investigated when differences in foraging activity occur, and when foraging extends beyond available daylight, indicating a diurnal foraging constraint in these usually diurnal animals. We compared foraging activity of migratory (N = 94) and resident (N = 30) geese throughout the annual cycle using GPS-transmitters and 3D-accelerometers, and corroborated this with data on seasonal variation in body condition. Migratory geese were more active than residents during most of the year, amounting to a difference of over 370 h over an entire annual cycle. Activity differences were largest during the periods that comprised preparation for spring and autumn migration. Lengthening days during spring facilitated increased activity, which coincided with an increase in body condition. Both migratory and resident geese were active at night during winter, but migratory geese were also active at night before autumn migration, resulting in a period of night-time activity that was 6 weeks longer than in resident geese. Our results indicate that, at least in geese, seasonal migration requires longer daily activity not only during migration but throughout most of the annual cycle, with migrants being more frequently forced to extend foraging activity into the night.

Resistance Exercise Training Increases Muscle Mass and Strength in Prostate Cancer Patients on Androgen Deprivation Therapy.

PURPOSE: This study aimed to assess the effects of 20 wk resistance exercise training with or without protein supplementation on body composition, muscle mass, muscle strength, physical performance, and aerobic capacity in prostate cancer patients receiving androgen deprivation therapy (ADT). METHODS: Sixty prostate cancer patients receiving ADT were randomly assigned to perform 20 wk of resistance exercise training with supplementation of 31 g whey protein (EX + PRO, n = 30) or placebo (EX + PLA, n = 30), consumed immediately after exercise and every night before sleep. A separate control group (CON, n = 36) only received usual care. At baseline and after 20 wk, body composition (dual-energy x-ray absorptiometry), muscle mass (computed tomography scan), muscle strength (1-repetition maximum strength tests), physical performance (Timed Up and Go Test, 30-Second Chair Stand Test, and Stair Climb Test), aerobic capacity (cardiopulmonary exercise test), and habitual dietary intake (food diary) were assessed. Data were analyzed using a two-factor repeated-measures ANOVA. RESULTS: Over time, muscle mass and strength increased in EX + PRO and EX + PLA and decreased in CON. Total fat mass and fat percentage increased in EX + PRO and CON, but not in EX + PLA. Physical performance did not significantly change over time in either group. Aerobic capacity was maintained in EX + PLA, but it decreased in EX + PRO and CON. Habitual protein intake (without supplements) averaged >1.0 g·kg body weight -1 ·d -1 , with no differences over time or between groups. CONCLUSIONS: In prostate cancer patients, resistance exercise training counteracts the adverse effects of ADT on body composition, muscle mass, muscle strength, and aerobic capacity, with no additional benefits of protein supplementation.

Uncertainty in individual risk judgments associates with vulnerability and curtailed climate adaptation.

Risk assessments are key for the effective management of potential environmental threats. Across probabilistic phenomena, climate change is an exemplar of paramount uncertainties. These uncertainties have been embraced in supporting governments' decisions; yet receive scarce attention when studying individual behavior. Analyzing a survey conducted in the USA, China, Indonesia, and the Netherlands (N=6242), we explore socio-economic, psychological, and behavioral differences between individuals who can subjectively assess risks, and those who are risk-uncertain. We find that risk-uncertain individuals are more likely to belong to societal subgroups classically considered as vulnerable, and have reduced capacities and intentions to adapt to hazards-specifically floods. The distinctions between risk-aware and risk-uncertain individuals indicate that ignoring differences in individuals' capacity to assess risks could amount to persistent vulnerability and undermine climate-resilience efforts. While we use floods emblematically, these finding have consequences for the standard practice of dropping or bootstrapping uncertain responses, irrespective of the hazard, with implications for environmental management.

Optimization of Preoperative Lymph Node Staging in Patients with Muscle-Invasive Bladder Cancer Using Radiomics on Computed Tomography.

Approximately 25% of the patients with muscle-invasive bladder cancer (MIBC) who are clinically node negative have occult lymph node metastases at radical cystectomy (RC) and pelvic lymph node dissection. The aim of this study was to evaluate preoperative CT-based radiomics to differentiate between pN+ and pN0 disease in patients with clinical stage cT2-T4aN0-N1M0 MIBC. Patients with cT2-T4aN0-N1M0 MIBC, of whom preoperative CT scans and pathology reports were available, were included from the prospective, multicenter CirGuidance trial. After manual segmentation of the lymph nodes, 564 radiomics features were extracted. A combination of different machine-learning methods was used to develop various decision models to differentiate between patients with pN+ and pN0 disease. A total of 209 patients (159 pN0; 50 pN+) were included, with a total of 3153 segmented lymph nodes. None of the individual radiomics features showed significant differences between pN+ and pN0 disease, and none of the radiomics models performed substantially better than random guessing. Hence, CT-based radiomics does not contribute to differentiation between pN+ and pN0 disease in patients with cT2-T4aN0-N1M0 MIBC.

Cross-reactive antibodies after SARS-CoV-2 infection and vaccination.

Current SARS-CoV-2 vaccines are losing efficacy against emerging variants and may not protect against future novel coronavirus outbreaks, emphasizing the need for more broadly protective vaccines. To inform the development of a pan-coronavirus vaccine, we investigated the presence and specificity of cross-reactive antibodies against the spike (S) proteins of human coronaviruses (hCoV) after SARS-CoV-2 infection and vaccination. We found an 11- to 123-fold increase in antibodies binding to SARS-CoV and MERS-CoV as well as a 2- to 4-fold difference in antibodies binding to seasonal hCoVs in COVID-19 convalescent sera compared to pre-pandemic healthy donors, with the S2 subdomain of the S protein being the main target for cross-reactivity. In addition, we detected cross-reactive antibodies to all hCoV S proteins after SARS-CoV-2 vaccination in macaques and humans, with higher responses for hCoV more closely related to SARS-CoV-2. These findings support the feasibility of and provide guidance for development of a pan-coronavirus vaccine.

"Psyosphere": A GPS Data-Analysing Tool for the Behavioural Sciences.

Positioning technologies, such as GPS are widespread in society but are used only sparingly in behavioural science research, e.g., because processing positioning technology data can be cumbersome. The current work attempts to unlock positioning technology potential for behavioural science studies by developing and testing a research tool to analyse GPS tracks. This tool-psyosphere-is published as open-source software, and aims to extract behaviours from GPSs data that are more germane to behavioural research. Two field experiments were conducted to test application of the research tool. During these experiments, participants played a smuggling game, thereby either smuggling tokens representing illicit material past border guards or not. Results suggested that participants varied widely in variables, such as course and speed variability and distance from team members in response to the presence of border guards. Subsequent analyses showed that some of these GPS-derived behavioural variables could be linked to self-reported mental states, such as fear. Although more work needs to be done, the current study demonstrates that psyosphere may enable researchers to conduct behavioural experiments with positioning technology, outside of a laboratory setting.

Long-term Follow-up of Intravesical Onabotulinum Toxin-A Injections in Male Patients with Idiopathic Overactive Bladder: Comparing Surgery-naïve Patients and Patients After Prostate Surgery.

BACKGROUND: Evidence regarding long-term results in male idiopathic overactive bladder (iOAB) patients is limited and rarely focuses on the effects of prior prostatic surgery. OBJECTIVE: This study aims to identify the long-term treatment persistency and occurrence of adverse events of intravesical onabotulinum toxin-A (BoNT-A) injections in male iOAB patients after prostatic surgery (ie, transurethral resection of the prostate [TURP] or radical prostatectomy [RP]) compared with surgery-naïve patients. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective, single-centre study, data from 477 patients treated with intravesical BoNT-A injections were collected. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcome data of 120 male patients with iOAB, with collectively 207 BoNT-A injections, were analysed and presented in this study. RESULTS AND LIMITATIONS: At the last point of follow-up, 35 patients (29.2%) were still on active treatment. Twenty patients (16.7%) required de novo clean intermittent self-catheterisation (CISC). Three groups were identified: 56 patients without prostate surgery, 40 patients with TURP, and 24 patients with RP prior to treatment. Discontinuation rates and patient-reported outcomes of BoNT-A treatment (none, insufficient, or satisfactory) were similar, but a significant difference was seen in de novo CISC (p=0.004): 28.6% in the group without prior surgery, 7.5% in the TURP subgroup, and 4.2% in the RP subgroup. Odds of de novo CISC was significantly higher for the group without prior surgery than for both the TURP subgroup (odds ratio [OR] 4.9; 95% confidence interval [CI]: 1.33-18.31; p=0.017) and the RP subgroup (OR 9.2; 95% CI: 1.14-73.96; p= 0.037). CONCLUSIONS: The data of this retrospective, single-centre cohort suggest that BoNT-A treatment leads to lower CISC rates in male patients after prior desobstructive surgery than in surgery-naïve patients. PATIENT SUMMARY: This study describes the results of onabotulinum toxin-A (BoNT-A) injections in the bladder of male patients with idiopathic overactive bladder after initial prostate surgery compared with surgery-naïve patients. The results showed that BoNT-A treatment leads to lower catheterisation rates in patients after prior prostate surgery than in men without prior prostate surgery.

Patient-reported Quality of Life in Patients with Primary Metastatic Prostate Cancer Treated with Androgen Deprivation Therapy with and Without Concurrent Radiation Therapy to the Prostate in a Prospective Randomised Clinical Trial; Data from the HORRAD Trial.

BACKGROUND: A survival benefit was demonstrated for patients with low-volume metastatic prostate cancer (mPCa) when local radiotherapy was added to androgen deprivation therapy (ADT). OBJECTIVE: To determine the effect of ADT combined with external beam radiotherapy (EBRT) to the prostate on health-related quality of life (HRQoL) of patients with primary bone mPCa. DESIGN, SETTING, AND PARTICIPANTS: The HORRAD trial is a multicentre randomised controlled trial recruiting 432patients with primary bone mPCa between 2004 and 2014. INTERVENTION: Patients were randomised to ADT with EBRT or to ADT alone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients completed two validated HRQoL questionnaires (European Organization for Research and Treatment of Cancer [EORTC] Quality of Life Questionnaire Core Module (QLQ-C30) and EORTC Quality of Life Questionnaire Prostate Module [QLQ-PR25]) at baseline and at 3, 6, 12, and24 mo after the initiation of treatment. The effect of both treatments was evaluated based on mixed-effect models. RESULTS AND LIMITATIONS: Patient characteristics and HRQoL scores at baseline were similar in both arms. At baseline, 98% of patients completed the questionnaires, compared with 58% at 24 mo. Patients reported significantly more diarrhoea (difference between the groups 10.8; 95% confidence interval [CI] 7.3-14.2), bowel symptoms (4.5; 95% CI 2.1-6.8), and urinary symptoms (11.9; 95% CI 8.9-14.8) after EBRT and ADT compared with ADT alone (all between-arm difference p < 0.001). Urinary complaints levelled at 6 mo. At 2 yr, only bowel symptom scores were significantly different (8.0; 95% CI 4.8-11.1, p ≤ 0.001), but 68% of patients in the radiotherapy group did not report clinically relevant worsening of their bowel symptom scores. CONCLUSIONS: Patients with bone mPCa reported temporary modest urinary and bowel symptoms after combined treatment with EBRT of the prostate and ADT compared with ADT alone. For some patients (22%), deterioration of bowel functions remains at 2 yr, whereas general HRQoL does not deteriorate.. PATIENT SUMMARY: This study investigated the effect of radiotherapy to the prostate added to hormonal therapy on patient-reported health-related quality of life (HRQoL) in patients with primary bone metastatic prostate cancer. Most patients reported only temporary urinary and bowel symptoms. In 22% of patients, bowel symptoms remained at 2 yr, whereas general HRQoL did not deteriorate.

Autochthonous dengue in two Dutch tourists visiting Département Var, southern France, July 2020.

We report dengue virus (DENV) infection in two Dutch tourists who visited Département Var, southern France, in July and August 2020. As some autochthonous dengue cases have occurred in Europe in recent years, awareness among physicians and public health experts about possible intermittent presence of DENV in southern Europe is important to minimise delay in diagnosis and treatment. Quick diagnosis can lead to timely action to contain the spread of vector-borne diseases and minimise transmission.

Associations of Affect, Action Readiness, and Sexual Functioning.

INTRODUCTION: Emotions are theorized to contain the components of affect and action readiness. Affect guides behavior by causing an approach or withdrawal orientation. Action readiness is the individual's degree of willingness to interact with the environment. Emotions contribute to changes in behavior and physiological responses. AIM: The present study applied these notions to sexuality and examined the associations between affect, action readiness, and sexual functioning. METHODS: Participants were male patients with urologic condition (N = 70) with and without sexual problems. MAIN OUTCOME MEASURE: Affect and action readiness were jointly assessed using the latent factor of affective polarity of the Positive and Negative Affect Schedule. Trait affective polarity was assessed questioning generally experienced feelings. State affective polarity was assessed after exposure to an erotic stimulus and questioning momentaneously experienced feelings. Sexual functioning was assessed using the International Index of Erectile Functioning questionnaire. RESULTS: A significant increase of approach-oriented action readiness was found after erotic stimulation, relative to trait levels. In addition, significant associations were found between state approach-oriented action readiness and various aspects of sexual functioning. Interventions based on principles of positive psychology might be developed to reinforce action readiness in men with erectile dysfunction. The strength of the current research concerns the introduction of action readiness as a potential psychological factor implied in sexual functioning. Limitations pertain to the use of the algorithm used to calculate state approach-oriented action readiness and the use of the current sample of patients with urological conditions, limiting generalizability of findings. CONCLUSION: Action readiness was found to correlate positively with all aspects of sexual functioning. Further research into the role of action readiness in sexuality is recommended. Henckens MJMJ, de Vries P, Janssen E, et al. Associations of Affect, Action Readiness, and Sexual Functioning. Sex Med 2020;8:691-698.

[Chloroquine as a possible treatment for COVID-19]. / Chloroquine als mogelijke behandeling van COVID-19.

Since the outbreak of COVID-19, chloroquine has been mentioned as a possible treatment. In vitro studies have shown anti-viral activity of chloroquine against SARS-CoV-2. Recently, the Dutch National Institute for Public Health and the Environment published treatment options for antiviral treatment for COVID-19 where chloroquine was suggested as first choice for off-label treatment, beside remdesivir en lopinavir/ritonavir. In this commentary, we provide a background and history of chloroquine, the evidence for antiviral efficacy of chloroquine and the arguments for off-label use of chloroquine in COVID-19.

Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models.

HER2 is a transmembrane tyrosine kinase receptor that mediates cell growth, differentiation, and survival. HER2 is overexpressed in approximately 20% of breast cancers and in subsets of gastric, colorectal, and esophageal cancers. Both antibody and small-molecule drugs that target HER2 and block its tyrosine kinase activity are effective in treating HER2-driven cancers. In this article, we describe the preclinical properties of tucatinib, an orally available, reversible HER2-targeted small-molecule tyrosine kinase inhibitor. In both biochemical and cell signaling experiments, tucatinib inhibits HER2 kinase activity with single-digit nanomolar potency and provides exceptional selectivity for HER2 compared with the related receptor tyrosine kinase EGFR, with a >1,000-fold enhancement in potency for HER2 in cell signaling assays. Tucatinib potently inhibits signal transduction downstream of HER2 and HER3 through the MAPK and PI3K/AKT pathways and is selectively cytotoxic in HER2-amplified breast cancer cell lines in vitro. In vivo, tucatinib is active in multiple HER2+ tumor models as a single agent and shows enhanced antitumor activity in combination with trastuzumab or docetaxel, resulting in improved rates of partial and complete tumor regression. These preclinical data, taken together with the phase-I tucatinib clinical trial results demonstrating preliminary safety and activity, establish the unique pharmacologic properties of tucatinib and underscore the rationale for investigating its utility in HER2+ cancers. GRAPHICAL ABSTRACT: http://mct.aacrjournals.org/content/molcanther/19/4/976/F1.large.jpg.

The haematological consequences of Plasmodium vivax malaria after chloroquine treatment with and without primaquine: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis.

BACKGROUND: Malaria causes a reduction in haemoglobin that is compounded by primaquine, particularly in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. The aim of this study was to determine the relative contributions to red cell loss of malaria and primaquine in patients with uncomplicated Plasmodium vivax. METHODS: A systematic review identified P. vivax efficacy studies of chloroquine with or without primaquine published between January 2000 and March 2017. Individual patient data were pooled using standardised methodology, and the haematological response versus time was quantified using a multivariable linear mixed effects model with non-linear terms for time. Mean differences in haemoglobin between treatment groups at day of nadir and day 42 were estimated from this model. RESULTS: In total, 3421 patients from 29 studies were included: 1692 (49.5%) with normal G6PD status, 1701 (49.7%) with unknown status and 28 (0.8%) deficient or borderline individuals. Of 1975 patients treated with chloroquine alone, the mean haemoglobin fell from 12.22 g/dL [95% CI 11.93, 12.50] on day 0 to a nadir of 11.64 g/dL [11.36, 11.93] on day 2, before rising to 12.88 g/dL [12.60, 13.17] on day 42. In comparison to chloroquine alone, the mean haemoglobin in 1446 patients treated with chloroquine plus primaquine was - 0.13 g/dL [- 0.27, 0.01] lower at day of nadir (p = 0.072), but 0.49 g/dL [0.28, 0.69] higher by day 42 (p < 0.001). On day 42, patients with recurrent parasitaemia had a mean haemoglobin concentration - 0.72 g/dL [- 0.90, - 0.54] lower than patients without recurrence (p < 0.001). Seven days after starting primaquine, G6PD normal patients had a 0.3% (1/389) risk of clinically significant haemolysis (fall in haemoglobin > 25% to < 7 g/dL) and a 1% (4/389) risk of a fall in haemoglobin > 5 g/dL. CONCLUSIONS: Primaquine has the potential to reduce malaria-related anaemia at day 42 and beyond by preventing recurrent parasitaemia. Its widespread implementation will require accurate diagnosis of G6PD deficiency to reduce the risk of drug-induced haemolysis in vulnerable individuals. TRIAL REGISTRATION: This trial was registered with PROSPERO: CRD42016053312. The date of the first registration was 23 December 2016.

Population Pharmacokinetics of Artemether, Dihydroartemisinin, and Lumefantrine in Rwandese Pregnant Women Treated for Uncomplicated Plasmodium falciparum Malaria.

The artemisinin-based combination therapy artemether-lumefantrine is commonly used in pregnant malaria patients. However, the effect of pregnancy-related changes on exposure is unclear, and pregnancy has been associated with decreased efficacy in previous studies. This study aimed to characterize the population pharmacokinetics of artemether, its active metabolite dihydroartemisinin, and lumefantrine in 22 Rwandese pregnant women in their second (n = 11) or third (n = 11) trimester with uncomplicated Plasmodium falciparum malaria. These patients were enrolled from Rwamagana district hospital and received the standard fixed oral dose combination of 80 mg of artemether and 480 mg of lumefantrine twice daily for 3 days. Venous plasma concentrations were quantified for all three analytes using liquid chromatography coupled with tandem mass spectroscopy, and data were analyzed using nonlinear mixed-effects modeling. Lumefantrine pharmacokinetics was described by a flexible but highly variable absorption, with a mean absorption time of 4.04 h, followed by a biphasic disposition model. The median area under the concentration-time curve from 0 h to infinity (AUC0-∞) for lumefantrine was 641 h · mg/liter. Model-based simulations indicated that 11.7% of the study population did not attain the target day 7 plasma concentration (280 ng/ml), a threshold associated with increased risk of recrudescence. The pharmacokinetics of artemether was time dependent, and the autoinduction of its clearance was described using an enzyme turnover model. The turnover half-life was predicted to be 30.4 h. The typical oral clearance, which started at 467 liters/h, increased 1.43-fold at the end of treatment. Simulations suggested that lumefantrine pharmacokinetic target attainment appeared to be reassuring in Rwandese pregnant women, particularly compared to target attainment in Southeast Asia. Larger cohorts will be required to confirm this finding.

Citizen participation in the police domain: The role of citizens' attitude and morality.

Although there is a large potential of citizen capital in fighting crime and creating safer neighborhoods, in reality, only a small fraction of citizens is actively participating. This study examines the relationship between different types of actual participation behavior in the police domain from a citizen's stance and 3 different but interconnected psychological drivers: the attitude toward citizen participation, moral values, and moral emotions. A total of 217 Dutch citizens filled out an online questionnaire, assessing these drivers and the actual participatory actions they engaged in over the past year. The results show that 4 broad categories of participation behavior can be distinguished: social control (e.g., correcting others regarding their behavior); responsive participation (e.g., calling the police); collaborative participation (e.g., meeting with a police officer); and detection (e.g., joining a neighborhood watch). As expected, moral values had an indirect influence on participation via attitude and moral emotions. The attitude toward citizen participation was positively related to all four types of reported behavior, while the influence of moral emotions only related to social control and responsive behavior. These results can be used in the design and testing of interventions to stimulate citizen participation.

The effect of chloroquine dose and primaquine on Plasmodium vivax recurrence: a WorldWide Antimalarial Resistance Network systematic review and individual patient pooled meta-analysis.

BACKGROUND: Chloroquine remains the mainstay of treatment for Plasmodium vivax malaria despite increasing reports of treatment failure. We did a systematic review and meta-analysis to investigate the effect of chloroquine dose and the addition of primaquine on the risk of recurrent vivax malaria across different settings. METHODS: A systematic review done in MEDLINE, Web of Science, Embase, and Cochrane Database of Systematic Reviews identified P vivax clinical trials published between Jan 1, 2000, and March 22, 2017. Principal investigators were invited to share individual patient data, which were pooled using standardised methods. Cox regression analyses with random effects for study site were used to investigate the roles of chloroquine dose and primaquine use on rate of recurrence between day 7 and day 42 (primary outcome). The review protocol is registered in PROSPERO, number CRD42016053310. FINDINGS: Of 134 identified chloroquine studies, 37 studies (from 17 countries) and 5240 patients were included. 2990 patients were treated with chloroquine alone, of whom 1041 (34·8%) received a dose below the target 25 mg/kg. The risk of recurrence was 32·4% (95% CI 29·8-35·1) by day 42. After controlling for confounders, a 5 mg/kg higher chloroquine dose reduced the rate of recurrence overall (adjusted hazard ratio [AHR] 0·82, 95% CI 0·69-0·97; p=0·021) and in children younger than 5 years (0·59, 0·41-0·86; p=0·0058). Adding primaquine reduced the risk of recurrence to 4·9% (95% CI 3·1-7·7) by day 42, which is lower than with chloroquine alone (AHR 0·10, 0·05-0·17; p<0·0001). INTERPRETATION: Chloroquine is commonly under-dosed in the treatment of vivax malaria. Increasing the recommended dose to 30 mg/kg in children younger than 5 years could reduce substantially the risk of early recurrence when primaquine is not given. Radical cure with primaquine was highly effective in preventing early recurrence and may also improve blood schizontocidal efficacy against chloroquine-resistant P vivax. FUNDING: Wellcome Trust, Australian National Health and Medical Research Council, and Bill & Melinda Gates Foundation.

Author Correction: Discovery of a selective catalytic p300/CBP inhibitor that targets lineage-specific tumours.

In the originally published version of this Letter, the authors Arthur F. Kluge, Michael A. Patane and Ce Wang were inadvertently omitted from the author list. Their affiliations are: I-to-D, Inc., PO Box 6177, Lincoln, Massachusetts 01773, USA (A.F.K.); Mitobridge, Inc. 1030 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA (M.A.P.); and China Novartis Institutes for BioMedical Research, No. 4218 Jinke Road, Zhangjiang Hi-Tech Park, Pudong District, Shanghai 201203, China (C.W.). These authors contributed to the interpretation of results and design of compounds. In addition, author 'Edward A. Kesicki' was misspelled as 'Ed Kesicki'. These errors have been corrected online.

Discovery of Spiro Oxazolidinediones as Selective, Orally Bioavailable Inhibitors of p300/CBP Histone Acetyltransferases.

p300 and its paralog CBP can acetylate histones and other proteins and have been implicated in a number of diseases characterized by aberrant gene activation, such as cancer. A novel, highly selective, orally bioavailable histone acetyltransferase (HAT) domain inhibitor has been identified through virtual ligand screening and subsequent optimization of a unique hydantoin screening hit. Conformational restraint in the form of a spirocyclization followed by substitution with a urea led to a significant improvement in potency. Replacement of the hydantoin moiety with an oxazolidinedione followed by fluoro substitution led to A-485, which exhibits potent cell activity, low clearance, and high oral bioavailability.

Automatic Sex-Liking and Sex-Failure Associations in Men With Sexual Dysfunction.

Current models of sexual functioning imply an important role for both automatic and controlled appraisals. Accordingly, it can be hypothesized that erectile dysfunction may be due to the automatic activation of negative appraisals at the prospect of sexual intercourse. However, previous research showed that men with sexual dysfunction exhibited relatively strong automatic sex-positive instead of sex-negative associations. This study tested the robustness of this unexpected finding and, additionally, examined the hypothesis that perhaps more specific sex-failure versus sex-success associations are relevant in explaining sexual dysfunction and distress. Male urological patients (N = 70), varying in level of sexual functioning and distress, performed two Single-Target Implicit Association Tests (ST-IATs) to assess automatic associations of visual erotic stimuli with attributes representing affective valence ("liking"; positive versus negative) and sexual success versus sexual failure. Consistent with the earlier findings, the lower the scores on sexual functioning, the stronger the automatic sex-positive associations. This association was independent of explicit associations and most prominent in the younger age group. Automatic sex-positive and sex-failure associations showed independent relationships with sexual distress. The relationship between sexual distress and sex-failure associations is consistent with the view that automatic associations with failure may contribute to sexual distress.