Hydrocortisone in Severe Community-Acquired Pneumonia.

BACKGROUND: Whether the antiinflammatory and immunomodulatory effects of glucocorticoids may decrease mortality among patients with severe community-acquired pneumonia is unclear. METHODS: In this phase 3, multicenter, double-blind, randomized, controlled trial, we assigned adults who had been admitted to the intensive care unit (ICU) for severe community-acquired pneumonia to receive intravenous hydrocortisone (200 mg daily for either 4 or 7 days as determined by clinical improvement, followed by tapering for a total of 8 or 14 days) or to receive placebo. All the patients received standard therapy, including antibiotics and supportive care. The primary outcome was death at 28 days. RESULTS: A total of 800 patients had undergone randomization when the trial was stopped after the second planned interim analysis. Data from 795 patients were analyzed. By day 28, death had occurred in 25 of 400 patients (6.2%; 95% confidence interval [CI], 3.9 to 8.6) in the hydrocortisone group and in 47 of 395 patients (11.9%; 95% CI, 8.7 to 15.1) in the placebo group (absolute difference, -5.6 percentage points; 95% CI, -9.6 to -1.7; P = 0.006). Among the patients who were not undergoing mechanical ventilation at baseline, endotracheal intubation was performed in 40 of 222 (18.0%) in the hydrocortisone group and in 65 of 220 (29.5%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.40 to 0.86). Among the patients who were not receiving vasopressors at baseline, such therapy was initiated by day 28 in 55 of 359 (15.3%) of the hydrocortisone group and in 86 of 344 (25.0%) in the placebo group (hazard ratio, 0.59; 95% CI, 0.43 to 0.82). The frequencies of hospital-acquired infections and gastrointestinal bleeding were similar in the two groups; patients in the hydrocortisone group received higher daily doses of insulin during the first week of treatment. CONCLUSIONS: Among patients with severe community-acquired pneumonia being treated in the ICU, those who received hydrocortisone had a lower risk of death by day 28 than those who received placebo. (Funded by the French Ministry of Health; CAPE COD ClinicalTrials.gov number, NCT02517489.).

Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia.

BACKGROUND: Whether preventive inhaled antibiotics may reduce the incidence of ventilator-associated pneumonia is unclear. METHODS: In this investigator-initiated, multicenter, double-blind, randomized, controlled, superiority trial, we assigned critically ill adults who had been undergoing invasive mechanical ventilation for at least 72 hours to receive inhaled amikacin at a dose of 20 mg per kilogram of ideal body weight once daily or to receive placebo for 3 days. The primary outcome was a first episode of ventilator-associated pneumonia during 28 days of follow-up. Safety was assessed. RESULTS: A total of 850 patients underwent randomization, and 847 were included in the analyses (417 assigned to the amikacin group and 430 to the placebo group). All three daily nebulizations were received by 337 patients (81%) in the amikacin group and 355 patients (83%) in the placebo group. At 28 days, ventilator-associated pneumonia had developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group (difference in restricted mean survival time to ventilator-associated pneumonia, 1.5 days; 95% confidence interval [CI], 0.6 to 2.5; P = 0.004). An infection-related ventilator-associated complication occurred in 74 patients (18%) in the amikacin group and in 111 patients (26%) in the placebo group (hazard ratio, 0.66; 95% CI, 0.50 to 0.89). Trial-related serious adverse effects were seen in 7 patients (1.7%) in the amikacin group and in 4 patients (0.9%) in the placebo group. CONCLUSIONS: Among patients who had undergone mechanical ventilation for at least 3 days, a subsequent 3-day course of inhaled amikacin reduced the burden of ventilator-associated pneumonia during 28 days of follow-up. (Funded by the French Ministry of Health; AMIKINHAL ClinicalTrials.gov number, NCT03149640; EUDRA Clinical Trials number, 2016-001054-17.).

A cytosolic bifunctional geranyl/farnesyl diphosphate synthase provides MVA-derived GPP for geraniol biosynthesis in rose flowers.

Geraniol derived from essential oils of various plant species is widely used in the cosmetic and perfume industries. It is also an essential trait of the pleasant smell of rose flowers. In contrast to other monoterpenes which are produced in plastids via the methyl erythritol phosphate pathway, geraniol biosynthesis in roses relies on cytosolic NUDX1 hydrolase which dephosphorylates geranyl diphosphate (GPP). However, the metabolic origin of cytosolic GPP remains unknown. By feeding Rosa chinensis "Old Blush" flowers with pathway-specific precursors and inhibitors, combined with metabolic profiling and functional characterization of enzymes in vitro and in planta, we show that geraniol is synthesized through the cytosolic mevalonate (MVA) pathway by a bifunctional geranyl/farnesyl diphosphate synthase, RcG/FPPS1, producing both GPP and farnesyl diphosphate (FPP). The downregulation and overexpression of RcG/FPPS1 in rose petals affected not only geraniol and germacrene D emissions but also dihydro-ß-ionol, the latter due to metabolic cross talk of RcG/FPPS1-dependent isoprenoid intermediates trafficking from the cytosol to plastids. Phylogenetic analysis together with functional characterization of G/FPPS orthologs revealed that the G/FPPS activity is conserved among Rosaceae species. Site-directed mutagenesis and molecular dynamic simulations enabled to identify two conserved amino acids that evolved from ancestral FPPSs and contribute to GPP/FPP product specificity. Overall, this study elucidates the origin of the cytosolic GPP for NUDX1-dependent geraniol production, provides insights into the emergence of the RcG/FPPS1 GPPS activity from the ancestral FPPSs, and shows that RcG/FPPS1 plays a key role in the biosynthesis of volatile terpenoid compounds in rose flowers.

Cost-effectiveness of maribavir versus conventional antiviral therapies for post-transplant refractory cytomegalovirus infection with or without genotypic resistance: A US perspective.

This study evaluated the cost-effectiveness of maribavir versus investigator-assigned therapy (IAT; valganciclovir/ganciclovir, foscarnet, or cidofovir) for post-transplant refractory cytomegalovirus (CMV) infection with or without resistance. A two-stage Markov model was designed using data from the SOLSTICE trial (NCT02931539), real-world multinational observational studies, and published literature. Stage 1 (0-78 weeks) comprised clinically significant CMV (csCMV), non-clinically significant CMV (n-csCMV), and dead states; stage 2 (78 weeks-lifetime) comprised alive and dead states. Total costs (2022 USD) and quality-adjusted life years (QALYs) were estimated for the maribavir and IAT cohorts. An incremental cost-effectiveness ratio was calculated to determine cost-effectiveness against a willingness-to-pay threshold of $100 000/QALY. Compared with IAT, maribavir had lower costs ($139 751 vs $147 949) and greater QALYs (6.04 vs 5.83), making it cost-saving and more cost-effective. Maribavir had higher acquisition costs compared with IAT ($80 531 vs $65 285), but lower costs associated with administration/monitoring ($16 493 vs $27 563), adverse events (AEs) ($11 055 vs $16 114), hospitalization ($27 157 vs $33 905), and graft loss ($4516 vs $5081), thus making treatment with maribavir cost-saving. Maribavir-treated patients spent more time without CMV compared with IAT-treated patients (0.85 years vs 0.68 years), leading to lower retreatment costs for maribavir (cost savings: -$42 970.80). Compared with IAT, maribavir was more cost-effective for transplant recipients with refractory CMV, owing to better clinical efficacy and avoidance of high costs associated with administration, monitoring, AEs, and hospitalizations. These results can inform healthcare decision-makers on the most effective use of their resources for post-transplant refractory CMV treatment.

Daidzein Hydroxylation by CYP81E63 Is Involved in the Biosynthesis of Miroestrol in Pueraria mirifica.

White Kwao Krua (Pueraria candollei var. mirifica), a Thai medicinal plant, is a rich source of phytoestrogens, especially isoflavonoids and chromenes. These phytoestrogens are well known; however, their biosynthetic genes remain largely uncharacterized. Cytochrome P450 (P450) is a large protein family that plays a crucial role in the biosynthesis of various compounds in plants, including phytoestrogens. Thus, we focused on P450s involved in the isoflavone hydroxylation that potentially participates in the biosynthesis of miroestrol. Three candidate P450s were isolated from the transcriptome libraries by considering the phylogenetic and expression data of each tissue of P. mirifica. The candidate P450s were functionally characterized both in vitro and in planta. Accordingly, the yeast microsome harboring PmCYP81E63 regiospecifically exhibited either 2' or 3' daidzein hydroxylation and genistein hydroxylation. Based on in silico calculation, PmCYP81E63 had higher binding energy with daidzein than with genistein, which supported the in vitro result of the isoflavone specificity. To confirm in planta function, the candidate P450s were then transiently co-expressed with isoflavone-related genes in Nicotiana benthamiana. Despite no daidzein in the infiltrated N. benthamiana leaves, genistein and hydroxygenistein biosynthesis were detectable by liquid Chromatography with tandem mass spectrometry (LC-MS/MS). Additionally, we demonstrated that PmCYP81E63 interacted with several enzymes related to isoflavone biosynthesis using bimolecular fluorescence complementation studies and a yeast two-hybrid analysis, suggesting a scheme of metabolon formation in the pathway. Our findings provide compelling evidence regarding the involvement of PmCYP81E63 in the early step of the proposed miroestrol biosynthesis in P. mirifica.

An Independent Evolutionary Origin for Insect Deterrent Cucurbitacins in Iberis amara.

Pieris rapae and Phyllotreta nemorum are Brassicaceae specialists, but do not feed on Iberis amara spp. that contain cucurbitacins. The cucurbitacins are highly oxygenated triterpenoid, occurring widespread in cucurbitaceous species and in a few other plant families. Using de novo assembled transcriptomics from I. amara, gene co-expression analysis and comparative genomics, we unraveled the evolutionary origin of the insect deterrent cucurbitacins in I. amara. Phylogenetic analysis of five oxidosqualene cyclases and heterologous expression allowed us to identify the first committed enzyme in cucurbitacin biosynthesis in I. amara, cucurbitadienol synthase (IaCPQ). In addition, two species-specific cytochrome P450s (CYP708A16 and CYP708A15) were identified that catalyze the unique C16 and C22 hydroxylation of the cucurbitadienol backbone, enzymatic steps that have not been reported before. Furthermore, the draft genome assembly of I. amara showed that the IaCPQ was localized to the same scaffold together with CYP708A15 but spanning over 100 kb, this contrasts with the highly organized cucurbitacin gene cluster in the cucurbits. These results reveal that cucurbitacin biosynthesis has evolved convergently via different biosynthetic routes in different families rather than through divergence from an ancestral pathway. This study thus provides new insight into the mechanism of recurrent evolution and diversification of a plant defensive chemical.

Pretransplant Intensive Care Unit Management and Selection of Grade 3 Acute-on-Chronic Liver Failure Transplant Candidates.

The aim of this study is to report on the liver transplantation (LT) activity and posttransplant outcome, over time, of patients with grade 3 acute-on-chronic liver failure (ACLF-3) in a single transplant center performing a large number of LTs for patients with ACLF-3. It aims at showing how pre-LT intensive care unit (ICU) management impacts post-LT outcomes, in particular through monitoring the transplantation for ACLF-3 model (TAM) score. A total of 100 patients who had ACLF-3 at the time of LT between 2007 and 2019 were included retrospectively. The cohort was divided in 2 periods, with 50 patients in each period. There was an increase in the number of patients with ACLF-3 who received an LT during the course of the study period and significantly higher 1-year post-LT survival rates in the second period compared with the first period (86% versus 66%, respectively; P = 0.02). Interestingly, patients during both periods had similar severity profiles and scores apart from a significantly lower number of patients with TAM scores >2 at the time of LT in the second period compared with the first period (1 [2%] versus 11 [22%], respectively; P ≤ 0.01). In addition, patients whose clinical condition improved in the ICU (with a TAM score downstaged between admission and LT) had significantly higher post-LT survival rates than those whose TAM score stayed the same or increased: 88% versus 70%, respectively (P = 0.04). This study shows a learning curve in LT for patients with ACLF-3, with optimized ICU management and patient selection leading to increased numbers of LTs for patients with ACLF-3 and improved post-LT outcomes. It also delineates how the TAM score can be used to identify the optimal transplantability window for patients with ACLF-3.

A Promiscuous CYP706A3 Reduces Terpene Volatile Emission from Arabidopsis Flowers, Affecting Florivores and the Floral Microbiome.

Flowers are essential but vulnerable plant organs, exposed to pollinators and florivores; however, flower chemical defenses are rarely investigated. We show here that two clustered terpene synthase and cytochrome P450 encoding genes (TPS11 and CYP706A3) on chromosome 5 of Arabidopsis (Arabidopsis thaliana) are tightly coexpressed in floral tissues, upon anthesis and during floral bud development. TPS11 was previously reported to generate a blend of sesquiterpenes. By heterologous coexpression of TPS11 and CYP706A3 in yeast (Saccharomyces cerevisiae) and Nicotiana benthamiana, we demonstrate that CYP706A3 is active on TPS11 products and also further oxidizes its own primary oxidation products. Analysis of headspace and soluble metabolites in cyp706a3 and 35S:CYP706A3 mutants indicate that CYP706A3-mediated metabolism largely suppresses sesquiterpene and most monoterpene emissions from opening flowers, and generates terpene oxides that are retained in floral tissues. In flower buds, the combined expression of TPS11 and CYP706A3 also suppresses volatile emissions and generates soluble sesquiterpene oxides. Florivory assays with the Brassicaceae specialist Plutella xylostella demonstrate that insect larvae avoid feeding on buds expressing CYP706A3 and accumulating terpene oxides. Composition of the floral microbiome appears also to be modulated by CYP706A3 expression. TPS11 and CYP706A3 simultaneously evolved within Brassicaceae and form the most versatile functional gene cluster described in higher plants so far.plantcell;31/12/2947/FX1F1fx1.

Predictors of Curvature Improvement in Men With Peyronie's Disease Treated With Intralesional Collagenase Clostridium Histolyticum.

INTRODUCTION: Penile curvature is the most common abnormality that is observed by men with Peyronie's disease (PD). Collagenase Clostridium histolyticum (CCH) has become a standard treatment for PD patients. AIM: To identify predictor factors associated with improvements of penile curvature outcomes in men with PD treated with CCH. METHODS: We retrospectively collected the data of patients with PD treated with CCH up to 8 injections divided into 4 cycles between January 2014 and July 2020. Per protocol, penile curvature was assessed at baseline, and after the second and ford CCH cycle. If after cycle 2, curvature demonstrated no improvement, or penile curvature was significantly improved and the patient was happy, no further treatment was recommended. However, if penile curvature was significantly improved and the patient remained dissatisfied, 4 cycles were completed. Three categories of response were evaluated: improvement (≥10 degrees or ≥20%, either 1 happens), unchanged (±10 degrees or ±20%) or worsened (≥10 degrees or ≥20%, either 1 happens). Logistic regression analyses were performed to evaluate predictive factors associated with penile curvature improvements. OUTCOMES: Degrees of the curvature changes between the baseline and after the cycles of CCH. RESULTS: A total of 114 patients underwent CCH treatment. Median age was 57 years. Median PD duration was 11 months. At baseline, mean curvature was 47 degrees, 65% had dorsal curvature, 53% mid-shaft location, and 15% calcification. After CCH treatment, the mean final curvature was 40 degrees. A total of 44% improved the curvature, 39% had no change while 17% worsened after CCH treatment. Of men who had penile curvature improvement with CCH treatment, the mean curvature decreasing in degrees and percentage were 22 degrees and 41%, respectively. Men with baseline curvature ≤ 30, 31-59, and ≥ 60 degrees, the percentage curvature improvement were 29%, 43%, and 60%, respectively. Baseline curvature was the only significant predictor of penile curvature improvement after CCH (OR 1.33, 95% CI = 1.1, 1.7). CLINICAL IMPLICATIONS: We confirmed baseline penile curvature is the most important predictive factor, and this is the first report describing proportions of penile curvature improvement with CCH treatment. STRENGTHS AND LIMITATIONS: This study has several strengths, including the use of validated instruments. Nonetheless, there are limitations: the retrospective nature of the study, a single institution; and modelling device was not controlled. CONCLUSION: Penile curvature improvement was significantly more common in patients with greater baseline curvature, reaching up to 60% for patients with ≥ 60 degrees. Flores JM, Nascimento B, Punjani N, et al. Predictors of Curvature Improvement in Men With Peyronie's Disease Treated With Intralesional Collagenase Clostridium Histolyticum. J Sex Med 2022;19:1680-1686.

Immunosuppression in patients with grade 3 acute-on-chronic liver failure at transplantation: A practice analysis study.

Transplantation for patients with acute-on-chronic liver failure grade 3 (ACLF3) has encouraging results with 1-year-survival of 80-90%. These patients with multiple organ failure meet the conditions for serious alterations of drug metabolism and increased toxicity. The goal of this study was to identify immunosuppression-dependent factors that affect survival. This retrospective monocentric study was conducted in patients with ACLF3 consecutively transplanted between 2007 and 2019. The primary endpoint was 1-year survival. Secondary endpoints were overall survival, treated rejection, and surgical complications. Immunosuppression was evaluated as to type of immunosuppression, post-transplant introduction timing, trough levels, and trough level intra-patient variability (IPV). One hundred patients were included. Tacrolimus IPV < 40% (P = .019), absence of early tacrolimus overdose (P = .033), use of anti-IL2-receptor antibodies (P = .034), and early mycophenolic acid introduction (P = .038) predicted 1-year survival. Treated rejection was an independent predictor of survival (P = .001; HR 4.2 (CI 95%: 1.13-15.6)). Early everolimus introduction was neither associated with higher rejection rates nor with more surgical complications. Management of immunosuppression in ACLF3 critically ill patients undergoing liver transplantation is challenging. Occurrence and treatment of rejection impacts on survival. Early introduction of mTOR inhibitor seems safe and efficient in this situation.

Brain Infarction MRI Pattern in Stroke Patients with Intracardiac Thrombus.

BACKGROUND: Acute infarction patterns have been described in cardioembolic stroke, mainly with atrial fibrillation (AF) or patent foramen ovale. We aimed to analyse acute infarction magnetic resonance imaging (MRI) characteristics in stroke patients with intracardiac thrombus (ICT) compared with stroke patients with AF. METHODS: We performed a retrospective study analysing brain MRI scans of consecutive acute symptomatic cardioembolic infarction patients associated with ICT or AF who were recruited and registered in the stroke database between June 2018 and November 2019. Diffusion-weighted imaging performed within 1 week after symptom onset, intra-/extracranial vessel imaging, echocardiography, and ≥24-h ECG monitoring were required for inclusion. Baseline, biological, and echocardiography characteristics were assessed. Analysed MRI characteristics were infarction location (anterior/middle/posterior cerebral artery territory; anterior/posterior/mixed anterior-posterior circulation; multiterritorial infarction; brainstem; cerebellum; small cortical cerebellar infarctions [SCCIs] or non-SCCI; cortical/subcortical/cortico-subcortical), lesion number, subcortical lesion size (> or <15 mm), and total infarction volume. RESULTS: We included 28 ICT and 94 AF patients presenting with acute stroke. ICT patients were younger (median age 66 vs. 81 years, p < 0.001), more frequently male (79 vs. 47%, p = 0.003), and smokers (39 vs. 17%, p = 0.013), had more frequent history of diabetes (36 vs. 18%, p = 0.049) and ischaemic heart disease (57 vs. 21%, p < 0.001), and had lower HDL cholesterol levels (0.39 vs. 0.53 g/L, p < 0.001). On MRI, SCCI was more frequent in the ICT group (25 vs. 5%, p = 0.006) in the absence of other differences in infarction localisation, number, size, or volume on MRI. On multivariate analysis, younger age (p < 0.001), history of ischaemic heart disease (p < 0.001), and low HDL cholesterol levels (p = 0.01) were significantly associated with ICT. Results approaching statistical significance were observed for SCCI (more frequent in the ICT group, p = 0.053) and non-SCCI (more frequent in the AF group, p = 0.053) on MRI. CONCLUSIONS: ICT-related stroke is associated with acute SCCI presence on MRI. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT04456309.

Effects of Low Intraperitoneal Pressure on Quality of Postoperative Recovery after Laparoscopic Surgery for Genital Prolapse in Elderly Patients Aged 75 Years or Older.

STUDY OBJECTIVE: Previous clinical trials for laparoscopic surgery have included few elderly patients aged ≥75 years. We aimed to evaluate the quality of postoperative recovery after laparoscopic surgery using low intraperitoneal pressure (IPP) (6 mm Hg) and warmed, humidified carbon dioxide gas for genital prolapse in elderly patients aged ≥75 years. DESIGN: Prospective consecutive case series. SETTING: University hospital. PATIENTS: Consecutive patients (n = 30) aged ≥75 years planning to undergo laparoscopic surgery for genital prolapse by the same surgeon were recruited from October 2016 through December 2019. INTERVENTIONS: Laparoscopic promontofixation for the treatment of genital prolapse was performed using low IPP and warmed, humidified carbon dioxide gas. When a promontory could not be easily identified, laparoscopic pectopexy was alternatively performed. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the Quality of Recovery-40 (QoR-40) score at 24 hours postoperatively. The secondary outcomes were postoperative pain using a 100-mm visual analog scale and the length of hospital stay after surgery (LHSS). For the global QoR-40 score and for 4 dimensions of the QoR-40, "emotional state," "physical comfort," "psychologic support," and "pain," no differences were observed between the baseline score and the score at 24 hours. The score for the "physical independence" dimension at 24 hours was significantly lower than the baseline score (p <.001). No patient had visual analog scale pain scores >30 out of 100 at 12 hours or later. LHSS was <48 hours in 22 patients (73.3%) and <72 hours in 8 patients (26.7%). Multivariable analysis showed that the odds of an LHSS >48 hours were more than 8 times higher in patients who were discharged from the operating room in the afternoon compared with those with a morning discharge. CONCLUSION: The use of a low IPP is feasible, safe, and has clinical benefits for elderly patients aged ≥75 years who undergo laparoscopic surgery for genital prolapse.

Evolution of coumaroyl conjugate 3-hydroxylases in land plants: lignin biosynthesis and defense.

Multiple adaptations were necessary when plants conquered the land. Among them were soluble phenylpropanoids related to plant protection and lignin necessary for upright growth and long-distance water transport. Cytochrome P450 monooxygenase 98 (CYP98) catalyzes a rate-limiting step in phenylpropanoid biosynthesis. Phylogenetic reconstructions suggest that a single copy of CYP98 founded each major land plant lineage (bryophytes, lycophytes, monilophytes, gymnosperms and angiosperms), and was maintained as a single copy in all lineages but the angiosperms. In angiosperms, a series of independent gene duplications and losses occurred. Biochemical assays in four angiosperm species tested showed that 4-coumaroyl-shikimate, a known intermediate in lignin biosynthesis, was the preferred substrate of one member in each species, while independent duplicates in Populus trichocarpa and Amborella trichopoda each showed broad substrate ranges, accepting numerous 4-coumaroyl-esters and -amines, and were thus capable of producing a wide range of hydroxycinnamoyl conjugates. The gymnosperm CYP98 from Pinus taeda showed a broad substrate range, but preferred 4-coumaroyl-shikimate as its best substrate. In contrast, CYP98s from the lycophyte Selaginella moellendorffii and the fern Pteris vittata converted 4-coumaroyl-shikimate poorly in vitro, but were able to use alternative substrates, in particular 4-coumaroyl-anthranilate. Thus, caffeoyl-shikimate appears unlikely to be an intermediate in monolignol biosynthesis in non-seed vascular plants, including ferns. The best substrate for CYP98A34 from the moss Physcomitrella patens was also 4-coumaroyl-anthranilate, while 4-coumaroyl-shikimate was converted to lower extents. Despite having in vitro activity with 4-coumaroyl-shikimate, CYP98A34 was unable to complement the Arabidopsis thaliana cyp98a3 loss-of-function phenotype, suggesting distinct properties also in vivo.

A Critical Analysis of Methodology Pitfalls in Duplex Doppler Ultrasound in the Evaluation of Patients With Erectile Dysfunction: Technical and Interpretation Deficiencies.

BACKGROUND: Penile duplex Doppler ultrasound (PDDU) is a minimally invasive tool to evaluate erectile hemodynamics in patients with erectile dysfunction (ED). Despite decades of use, there is still a large variability in PDDU protocols, and a high rate of false diagnosis is reported. AIM: Review of PDDU methodology in the published literature addressing protocol heterogeneity, technical and interpretation challenges. METHODS: A PubMed literature search was performed using the search terms "penile doppler ultrasound", "penile duplex ultrasound" or "penile ultrasound", and "Erectile dysfunction". Studies were analyzed for the presence of the following elements in reporting of the PDDU protocol: (i) intracavernosal vasoactive agents used, (ii) use of a redosing protocol, (iii) means of rigidity assessment, (iv) report of at-home best-quality erection, (v) normative criteria for peak systolic velocity (PSV) and end-diastolic velocity (EDV), and (vi) use of time-based hemodynamics assessment. Inclusion criteria were studies available in English, from 2005 onwards, and with full text. Exclusion criteria were review, descriptive or short communication articles, animal studies, and studies in populations other than those with ED. OUTCOMES: A critical review of the heterogeneity in published literature was performed to guide a structured discussion of methodological challenges and to create a list of recommendations. RESULTS: Significant heterogeneity was seen in key methodological aspects. Fifty percent of studies reported the use of prostaglandin E1 only, and 12% of studies did not mention the agent used. Redosing as part of the PDDU protocol was mentioned in only 26% of studies. The majority (56%) did not mention any form of rigidity assessment. The most frequently used grading system was the Erection Hardness Score (14%). Overall, most studies (59%) used a timed-base protocol for hemodynamic assessment. No clear consensus was defined for normative criteria for PSV and EDV, 39% defining a normal PSV as ≥30 cm/s, and 57% using EDV values ≤5 cm/sec as normal. CLINICAL IMPLICATIONS: The absence of standardization has led to inadequate reporting of key factors which has rendered data interpretation and comparison between studies challenging. STRENGTHS AND LIMITATIONS: Our strengths include an extensive review of literature, with a structured analysis of the impact of each methodological pitfall. Our main limitation is the fact that protocol reporting, and not its application, was assessed. CONCLUSION: Despite its widespread use, analysis of the literature on PDDU use in the ED population shows marked protocol heterogeneity, rendering data interpretation a problem. Nascimento B, Miranda EP, Terrier JE, et al. A Critical Analysis of Methodology Pitfalls in Duplex Doppler Ultrasound in the Evaluation of Patients With Erectile Dysfunction: Technical and Interpretation Deficiencies. J Sex Med 2020;17:1416-1422.

Evaluating the Impact of Penile Girth Discrepancy on Patient Bother in Men With Peyronie's Disease: An Observational Study.

BACKGROUND: Men with Peyronie's disease (PD) may experience penile narrowing. Little data on penile girth changes and their psychosocial impact exist. AIM: To assess girth discrepancy in men with PD and its association with patient bother. METHODS: This was a retrospective observational study. All patients with PD at our institution who were seen in the sexual medicine clinic and who completed 3 validated instruments the PD questionnaire (PDQ), Self-Esteem and Relationship (SEAR) questionnaire, and a depression questionnaire, the Center for Epidemiologic Studies Depression Scale (CES-D), and a curvature assessment were included. Patient and PD characteristics are described. Associations of instability and bother to girth differences are assessed. 2 outcomes for girth differences are classified as (i) girth difference of ≥ 1 cm vs less and (ii) girth differences of ≥10% vs less. Unadjusted and adjusted effects of PD and patient characteristics are assessed on the outcome of high bother using logistic regression models. OUTCOMES: The main outcomes of this study were penile girth changes, instability, and questionnaire scores. High bother was defined as a PDQ bother score of ≥9. RESULTS: A total of131 men had midshaft curvature and were the focus of the study. Their mean age was 59 ± 9 (range 31-78) years. PD duration was 16 ± 25 (range 1-180) months, with a mean degree of primary curvature of 37 ± 20o. Mean girth difference between base and point of maximum curvature was 0.78 ± 0.53 cm equating to a mean girth difference at point of maximum curvature of 6 ± 4%. Instability was present in 53% of men. There were 54 men with a girth difference of ≥ 1 cm and 23 men with a ≥10% change in girth. There was no difference in CES-D, SEAR, or PDQ domain scores or high bother in men with significant girth changes. Univariable analysis of predictors of high bother included the degree of curvature (odds ratio [OR]: 1.06; P < .001), instability (OR 6.62; P < .001), CES-D sum (OR 1.09; P = .002), and SEAR score (OR 0.96; P = .001). On multivariate analysis, only the degree of primary curvature was predictive of high bother (OR 1.06; P < .001). CLINICAL IMPLICATIONS: Penile girth changes have little impact on overall psychosocial well-being. The degree of penile curvature is the primary predictor of patient bother. STRENGTHS AND LIMITATIONS: Strengths include a large patient population and use of validated questionnaires. Limitations include single-center, retrospective study and subjective instability grading. CONCLUSIONS: Penile girth discrepancy in men with PD has limited psychosocial impact. Clinically significant bother was associated with the degree of primary curvature. Salter CA, Nascimento B, Terrier, JE, et al. Evaluating the Impact of Penile Girth Discrepancy on Patient Bother in Men With Peyronie's Disease: An Observational Study. J Sex Med 2020;17:1560-1565.

Adrenal gland-released vasostatin-I is a myocardial depressant factor.

Pheochromocytoma crisis is an exceptional consequence of the release of storage vesicles of the adrenal medulla. It is complicated by fulminant adrenergic myocarditis. It offers a unique opportunity to detect inotropic negative factors from neuroendocrine origin. Our objectives were (a) to describe a pheochromocytoma crisis, (b) to investigate in vivo myocardial depressant activities for the N-terminal 1-76 Chromogranin A-derived peptide, vasostatin-I (VS-I). A patient with a pheochromocytoma crisis was treated, including extracorporeal membrane oxygenation, until mass resection. Plasma concentrations of VS-I were time-dependently assessed with a specific immunoassay; correlations with invasive cardiovascular parameters were investigated. Increased VS-I concentrations were observed over 7 days until tumour resection. VS-I concentrations correlated positively with Chromogranin A levels, negatively with cardiac output and left ventricular stroke work index, but not with heart rate. This case illustrates the pharmacokinetics of VS-I in a pheochromocytoma crisis. It highlights myocardial depressant activity for this peptide at high concentrations.

Chronic Small Cortical Cerebellar Infarctions on MRI are Associated with Patent Foramen Ovale in Young Cryptogenic Stroke.

BACKGROUND: In acute infarction patients, small cortical cerebellar infarctions (SCCI) on MRI (assessed on diffusion-weighted imaging, with SCCI often chronic and asymptomatic) are associated with acute cardioembolic infarction. In young cryptogenic stroke patients, patent foramen ovale (PFO) is thought to be a potential source of cardioembolic infarction. We hypothesize that SCCI on MRI would be associated with PFO in young cryptogenic stroke patients. METHODS: A total of 321 consecutive young (≤50 years) stroke patients admitted between January 2015 and July 2019 were screened. Of these patients, 287 patients had diagnostic work-up including early-phase MRI, intra- and extracranial vessel imaging, contrast transoesophageal or contrast transthoracic echocardiography, and ≥24 h ECG-monitoring. We retrospectively analyzed MRI scans of the 112 patients with cryptogenic stroke, including 63 with and 49 without PFO. Between both groups, we compared baseline characteristics (including cardiovascular risk factors and history of stroke), MRI characteristics of acute symptomatic infarction (cortical/subcortical localization, arterial territory, lesion number, and lesion size in case of subcortical infarction), atrial septum aneurysm (ASA) presence, and acute and chronic SCCI and non-SCCI lesions assessed on diffusion-weighted imaging. RESULTS: Groups with and without PFO were comparable in regard to performed vessel imaging and echocardiography modalities, baseline characteristics, and acute infarction characteristics, except for more frequent current smoking (67 vs. 44%, p = 0.022) and multiterritorial infarction (14 vs. 0%, p = 0.0024) and less frequent ASA (10 vs. 48%, p < 0.001) in the group without PFO. Risk of Paradoxal Embolism score was >6 in 76% of patients with PFO. SCCI was more frequent in patients with than without PFO (33 vs. 10%, p = 0.0061; OR 4.4, 95% CI 1.5-12.7), with chronic and asymptomatic SCCI in the vast majority of cases. No difference was observed for non-SCCI lesions. CONCLUSIONS: Chronic SCCI are strongly associated with PFO in young cryptogenic stroke patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT04043559.

Antichagasic effect of hemocyanin derived from antimicrobial peptides of penaeus monodon shrimp.

Trypanosoma cruzi, the etiological agent of Chagas disease, is responsible for the infection of millions of people worldwide and it is a public health problem, without an effective cure. Four fragments with antimicrobial potential from the hemocyanin of Penaeus monodon shrimp were identified using a computer software AMPA. The present study aimed to evaluate the antichagasic effect of these four peptides (Hmc364-382, Hmc666-678, Hmc185-197 and Hmc476-498). The peptides were tested against the epimastigote, trypomastigote and amastigote forms of Trypanosoma cruzi Y strain (benznidazole-resistant strain) and cytotoxicity in mammalian cells was evaluated against LLC-MK2 lineage cells. Two fragments (Hmc364-382, Hmc666-678) showed activity against the epimastigote and trypomastigote forms and their selectivity index (SI) was calculated. The Hmc364-382 peptide was considered the most promising (SI > 50) one and it was used for further studies, using flow cytometry analyses with specific molecular probes and scanning electron microscopy (SEM). Hmc364-382 was able to induce cell death in T. cruzi through necrosis, observed by loss of membrane integrity in flow cytometry analyses and pore formation in SEM. Overall, Hmc364-382 open perspectives to the development of new antichagasic agents.

Transcultural validation of a French version of the Iowa Satisfaction with Anesthesia Scale (ISAS-F).

PURPOSE: We sought to validate a French translation of the Iowa Satisfaction with Anesthesia Scale (ISAS), a tool to assess the patient's satisfaction with monitored anesthesia care for surgery. The ISAS tool is particularly pertinent as surgery with monitored anesthesia care is increasingly used in ambulatory surgery settings. METHODS: We studied content validity, internal consistency, convergent validity (vs physician-estimated satisfaction), and test-retest reliability of the French version of the ISAS (ISAS-F) in 122 adult patients undergoing a brief outpatient invasive procedure under conscious sedation. The ISAS-F was answered twice by the patient, once in the postanesthesia care unit and once before discharge from the ambulatory care unit. RESULTS: The median [interquartile range (IQR)] time of completion at the first assessment was 2 [2-4] min. The total median [IQR] ISAS-F score was 2.3 [1.8-2.7]. Internal consistency of the ISAS-F was found to be good (Cronbach's α = 0.68). Test-retest reliability was significant, with an intra-class correlation coefficient at 0.74 (95% confidence interval [CI], 0.63 to 0.85). The ISAS-F score correlated with the physician-estimated satisfaction score, with an intra-class correlation coefficient of 0.28 (95% CI, 0.12 to 0.44; P = 0.01). DISCUSSION: This validated version of the ISAS can now be used by French-speaking researchers and physicians to assess patient satisfaction with the anesthesia technique.

RéSUMé: OBJECTIF: Nous avons voulu valider une traduction française de l'échelle de satisfaction par rapport à l'anesthésie de l'Iowa (ISAS), un outil d'évaluation de la satisfaction du patient par rapport aux soins sous surveillance anesthésique lors de chirurgies. L'outil ISAS est particulièrement pertinent étant donné que les chirurgies réalisées sous surveillance anesthésique sont de plus en plus fréquemment utilisées dans le contexte de chirurgie ambulatoire. MéTHODE: Nous avons étudié la validité de contenu, la cohérence interne, la validité convergente (vs la satisfaction estimée par le médecin) et la fiabilité de test-retest de la version française de l'ISAS (ISAS-F) auprès de 122 patients adultes subissant une courte intervention ambulatoire sous sédation légère. Les patients ont répondu deux fois au ISAS-F, soit une fois en salle de réveil et une seconde fois avant de recevoir leur congé de l'unité de soins ambulatoires. RéSULTATS: Le temps médian [écart interquartile (ÉIQ)] pour compléter le test lors de la première évaluation était de 2 [2­4] min. Le score total médian [ÉIQ] sur l'ISAS-F était de 2,3 [1,8­2,7]. La cohérence interne de l'ISAS-F était bonne (α de Cronbach = 0,68). La fiabilité de test-retest était appréciable, avec un coefficient de corrélation intraclasse de 0,74 (intervalle de confiance [IC] 95 %, 0,63 à 0,85). Le score sur l'ISAS-F était corrélé au score de satisfaction tel qu'estimé par le médecin, avec un coefficient de corrélation intraclasse de 0,28 (IC 95 %, 0,12 à 0,44; P = 0,01). DISCUSSION: Cette version validée de l'ISAS peut désormais être utilisée par les chercheurs et médecins francophones afin d'évaluer la satisfaction des patients avec la technique anesthésique employée.

Effect of Hydroxyethyl Starch vs Saline for Volume Replacement Therapy on Death or Postoperative Complications Among High-Risk Patients Undergoing Major Abdominal Surgery: The FLASH Randomized Clinical Trial.

Importance: It is not known if use of colloid solutions containing hydroxyethyl starch (HES) to correct for intravascular deficits in high-risk surgical patients is either effective or safe. Objective: To evaluate the effect of HES 130/0.4 compared with 0.9% saline for intravascular volume expansion on mortality and postoperative complications after major abdominal surgery. Design, Setting, and Participants: Multicenter, double-blind, parallel-group, randomized clinical trial of 775 adult patients at increased risk of postoperative kidney injury undergoing major abdominal surgery at 20 university hospitals in France from February 2016 to July 2018; final follow-up was in October 2018. Interventions: Patients were randomized to receive fluid containing either 6% HES 130/0.4 diluted in 0.9% saline (n = 389) or 0.9% saline alone (n = 386) in 250-mL boluses using an individualized hemodynamic algorithm during surgery and for up to 24 hours on the first postoperative day, defined as ending at 7:59 am the following day. Main Outcomes and Measures: The primary outcome was a composite of death or major postoperative complications at 14 days after surgery. Secondary outcomes included predefined postoperative complications within 14 days after surgery, durations of intensive care unit and hospital stays, and all-cause mortality at postoperative days 28 and 90. Results: Among 826 patients enrolled (mean age, 68 [SD, 7] years; 91 women [12%]), 775 (94%) completed the trial. The primary outcome occurred in 139 of 389 patients (36%) in the HES group and 125 of 386 patients (32%) in the saline group (difference, 3.3% [95% CI, -3.3% to 10.0%]; relative risk, 1.10 [95% CI, 0.91-1.34]; P = .33). Among 12 prespecified secondary outcomes reported, 11 showed no significant difference, but a statistically significant difference was found in median volume of study fluid administered on day 1: 1250 mL (interquartile range, 750-2000 mL) in the HES group and 1500 mL (interquartile range, 750-2150 mL) in the saline group (median difference, 250 mL [95% CI, 83-417 mL]; P = .006). At 28 days after surgery, 4.1% and 2.3% of patients had died in the HES and saline groups, respectively (difference, 1.8% [95% CI, -0.7% to 4.3%]; relative risk, 1.76 [95% CI, 0.79-3.94]; P = .17). Conclusions and Relevance: Among patients at risk of postoperative kidney injury undergoing major abdominal surgery, use of HES for volume replacement therapy compared with 0.9% saline resulted in no significant difference in a composite outcome of death or major postoperative complications within 14 days after surgery. These findings do not support the use of HES for volume replacement therapy in such patients. Trial Registration: ClinicalTrials.gov Identifier: NCT02502773.