Efficacy and safety of oral ibrexafungerp for the treatment of acute vulvovaginal candidiasis: a global phase 3, randomised, placebo-controlled superiority study (VANISH 306).

OBJECTIVE: To evaluate the efficacy and safety of ibrexafungerp versus placebo for acute vulvovaginal candidiasis (VVC) treatment. DESIGN: Global phase 3, randomised, placebo-controlled superiority study. SETTING: Study sites in the USA (n = 19) and Bulgaria (n = 18). POPULATION: Female patients aged ≥12 years with acute VVC and a vulvovaginal signs and symptoms (VSS) score ≥4 at baseline. METHODS: Patients were randomly assigned 2:1 to ibrexafungerp (300 mg twice for 1 day) or placebo. MAIN OUTCOME MEASURES: The primary endpoint was the percentage of patients with a clinical cure (VSS = 0) at the test-of-cure visit (day 11 ± 3). Secondary endpoints included percentages of patients with mycological eradication, clinical cure and mycological eradication (overall success), clinical improvement (VSS ≤1) at test-of-cure visit, and complete resolution of symptoms at follow-up visit (day 25 ± 4). RESULTS: At the test-of-cure visit, patients receiving ibrexafungerp had significantly higher rates of clinical cure (63.3% [119/188] versus 44.0% [37/84]; P = 0.007), mycological eradication (58.5% [110/188] versus 29.8% [25/84]; P < 0.001), overall success (46.1% [82/188] versus 28.4% [23/84]; P = 0.022) and clinical improvement (72.3% [136/188] versus 54.8% [46/84]; P = 0.01) versus those receiving placebo. Symptom resolution was sustained and further increased with ibrexafungerp (73.9%) versus placebo (52.4%) at follow-up (P = 0.001). Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mild to moderate in severity. CONCLUSIONS: Ibrexafungerp demonstrated statistical superiority over placebo for the primary and secondary endpoints. Ibrexafungerp is a promising novel, well-tolerated and effective oral 1-day treatment for acute VVC. TWEETABLE ABSTRACT: Ibrexafungerp is statistically superior to placebo for the treatment of vulvovaginal candidiasis.

The potential of using climate indices as powerful tools to explain mortality anomalies: An application to mainland Spain.

Changes in the frequency and magnitude of extreme weather events represent one of the key indicators of climate change and variability. These events can have an important impact on mortality rates, especially in the ageing population. This study assessed the spatial and seasonal distributions of mortality rates in mainland Spain and their association with climatic conditions over the period 1979-2016. The analysis was done on a seasonal and annual basis using 79 climatic indices and regional natural deaths data. Results indicate large spatial variability of natural deaths, which is mostly related to how the share of the elderly in the population varied across the studied regions. Spatially, both the highest mortality rates and the largest percentage of elders were found in the northwest areas of the study domain, where an extreme climate prevails, with very cold winters and hot summers. A strong seasonality effect was observed, winter shows more than 10% of natural deaths compared to the rest of the seasons. Also, results suggest a strong relation between climatic indices and natural deaths, albeit with a high spatial and seasonal variability. Climatic indices and natural deaths show a stronger correlation in winter and summer than in spring and autumn.

Efficacy of Ibrexafungerp (SCY-078) against Candida auris in an In Vivo Guinea Pig Cutaneous Infection Model.

Candida auris has been shown to have a high risk of skin colonization in hospitalized patients, possibly contributing to nosocomial spread. In a guinea pig skin model, animals were evaluated for clinical appearance, tissue fungal burden, histology, and pharmacokinetics. Oral dosing with 10 mg/kg ibrexafungerp (IBX) reduced the severity of lesions and significantly reduced the C. auris fungal burden in infected animals compared with untreated controls. This indicates promise for use of IBX in controlling skin infection and colonization of hospitalized patients.

A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis.

Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. Studies were 3-fold, as follows: (i) pharmacokinetic study following oral administration in a murine model; (ii) susceptibility testing of isolates from a phase 2 VVC clinical trial by CLSI M27-A4 methodology; and (iii) susceptibility testing of Candida albicans and Candida glabrata isolates obtained from this trial group in RPMI 1640 adjusted to 3 different pH values, 7.0, 5.72, and 4.5, compared to susceptibility testing for micafungin and fluconazole. IBX readily accumulated in vaginal tissues and secretions following oral administration. Potent in vitro activity was demonstrated against Candida strains obtained at baseline and end of study visits. Moreover, the geometric mean (GM) values for IBX at pH 4.5 were dramatically lower than those at pH 7.0 and 5.72. The MIC90 values of micafungin remained the same regardless of pH value, while those of fluconazole tended to increase with lower pH values. IBX is able to reach target tissues following oral administration at pharmacologically meaningful levels. IBX demonstrated potent in vitro activity, with no development of resistance, following repeated exposure over the course of the clinical trial. Importantly, activity of IBX in an acidic medium suggests a therapeutic advantage of this novel antifungal in the treatment of vaginal Candida infections.

Activity of a novel 1,3-beta-D-glucan Synthase Inhibitor, Ibrexafungerp (formerly SCY-078), Against Candida glabrata.

Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata Susceptibility of clinical strains to Ibrexafungerp was determined by microdilution and time kill assays. The MIC range against wild type strains was 1-2 µg/mL. IBX was also active against the majority of echinocandin-resistant strains. Time kill studies showed a 4 to 6-log reduction in growth at concentrations of 0.25 to 4 µg/ml at 24 and 48 hr.

Evaluation of the Antifungal Activity of the Novel Oral Glucan Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of Invasive Aspergillosis.

Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non-fumigatus Aspergillus strains showed that SCY-078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 µg/ml) compared with the activities of amphotericin B (MIC90 = 8 µg/ml) and voriconazole (MIC90 = 2 µg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis.

Plant size, latitude, and phylogeny explain within-population variability in herbivory.

Interactions between plants and herbivores are central in most ecosystems, but their strength is highly variable. The amount of variability within a system is thought to influence most aspects of plant-herbivore biology, from ecological stability to plant defense evolution. Our understanding of what influences variability, however, is limited by sparse data. We collected standardized surveys of herbivory for 503 plant species at 790 sites across 116° of latitude. With these data, we show that within-population variability in herbivory increases with latitude, decreases with plant size, and is phylogenetically structured. Differences in the magnitude of variability are thus central to how plant-herbivore biology varies across macroscale gradients. We argue that increased focus on interaction variability will advance understanding of patterns of life on Earth.

Hemorrhagic cholecystitis and hemobilia: two infrequent complications of systemic lupus erythematosus.

INTRODUCTION: the patients affected by systemic lupus erythematosus (SLE) often suffer gastrointestinal symptoms. The differential diagnosis should contemplate pathology of the gall bladder. We present the case of a patient with hemorrhagic lithiasic cholecystitis and hemobilia. CASE REPORT: 24 year old female diagnosed with SLE under treatment with Sintrom®, Dacortin® and Dolquine® that presented acute lithiasic cholecystitis and hemobilia with a distal calculus. Cholecystectomy and aperture of the ductus choledochus were performed allowing to confirm the hemobilia and to extract the calculus. DISCUSSION: The treatment of cholecystitis in the patients with SLE is controversial due to the fact that most reviewed cases have been solved with cholecystectomy, or in other cases with conservative treatment with corticosteroids. We believe that the presence of cholelithiasis in a patient with SLE with pain on the right hypochondrium and ultrasound confirming the suspicion of cholecystitis demands a surgical treatment since the cause may be vascular, lithiasic or combined. Besides, the possible complications will not respond to pharmaceutical treatment.

20-Years of hindsight into hydrological dynamics of a mountain forest catchment in the Central Spanish Pyrenees.

Mediterranean mountain forests play a significant role in hydrological regulation. In this study, hydrological dynamics was examined at different temporal scales in a small mountain forest catchment in the Central Spanish Pyrenees (San Salvador), based on a 20-year dataset (1999-2019). Mean annual runoff coefficient is 0.21, and ranged from 0.02 to 0.58. The catchment has a bi-modal hydrological behavior with two hydrological periods: a dry-period between July and December, and a wet-period between January and June. During the study period, only 108 floods were recorded, suggesting a low responsiveness of the catchment, with a high variable response. Spearman correlation analysis and stepwise multivariate regression suggest that the hydrological response in the San Salvador catchment is mainly depending on water table, with antecedent moisture conditions and rainfall depth as secondary factors. Seasonal differences were also observed: during dry season, the response was mainly related to rainfall depth and rainfall intensity; in contrast in wet season, the response was mainly related to antecedent conditions (previous rainfall and base flow). Thus, the already challenging water resources management in the Mediterranean basin is magnified by the key function of forests as natural modulators of water cycle. Consequently, the study of natural forested catchments is needed and long-datasets have to be analysed to understand the role of natural Mediterranean forest in the hydrological dynamics and its evolution and adaptation in a context of Global Change.

The complex multi-sectoral impacts of drought: Evidence from a mountainous basin in the Central Spanish Pyrenees.

We analyzed the impacts of drought severity on a variety of sectors in a topographically complex basin (the upper Aragón basin 2181 km2) in the Central Spanish Pyrenees. Using diverse data sources including meteorological and hydrological observations, remote sensing and tree rings, we analyze the possible hydrological implications of drought occurrence and severity on water availability in various sectors, including downstream impacts on irrigation water supply for crop production. Results suggest varying responses in forest activity, secondary growth, plant phenology, and crop yield to drought impacts. Specifically, meteorological droughts have distinct impacts downstream, mainly due to water partitioning between streamflow and irrigation channels that transport water to crop producing areas. This implies that drought severity can extend beyond the physical boundaries of the basin, with impacts on crop productivity. This complex response to drought impacts makes it difficult to develop objective basin-scale operational definitions for monitoring drought severity. Moreover, given the high spatial variability in responses to drought across sectors, it is difficult to establish reliable drought thresholds from indices that are relevant across all socio-economic sectors. The anthropogenic impacts (e.g. water regulation projects, ecosystem services, land cover and land use changes) pose further challenges to assessing the response of different systems to drought severity. This study stresses the need to consider the seasonality of drought impacts and appropriate drought time scales to adequately assess and understand their complexity.

Effectiveness of a written clinical pathway for enhanced recovery after transthoracic (Ivor Lewis) oesophagectomy.

BACKGROUND: This study assessed the feasibility of a protocol-driven written clinical pathway for multidisciplinary postoperative management after oesophagectomy for oesophageal neoplasia, and examined whether the application of such a protocol could shorten hospital stay and reduce postoperative morbidity and mortality. METHODS: Consecutive patients undergoing transthoracic oesophagectomy for oesophageal neoplasia were divided into those treated between 2003 and 2008 to whom a clinical pathway was applied for postoperative management (group 1), and a control group treated between 1998 and 2002 when no clinical pathway was applied (group 2). RESULTS: There were 74 patients in each group. Morbidity rates were similar in the two groups: 31 per cent in group 1 and 38 per cent in group 2. There were more pulmonary complications in group 2 (23 versus 14 per cent; P = 0.025). One patient (1 per cent) in group 1 and four (5 per cent) in group 2 died after surgery (P = 0.010). The median (range) length of hospital stay was 9 (5-98) days for group 1 and 13 (8-106) days in group 2 (P = 0.012). CONCLUSION: Use of a written clinical pathway in patients undergoing oesophageal resection significantly reduced pulmonary complications, postoperative mortality and hospital stay.

Zenker's and epiphrenic diverticula in a patient with cutis laxa: should the surgical technique be modified?

Currently, most of esophageal diverticula arise as the result of a pulsion effect. Some esophageal motor disorders increase the intraluminal pressure and after some time, the diverticula grow through a weak point of esophageal wall. In these cases, the surgical treatment of choice is the myotomy associated with diverticulopexy or diverticulectomy. Adding a fundoplication is accepted to avoid the consequences of gastroesophageal reflux after myotomy in the epiphrenic diverticula surgery. There are other causes of esophageal diverticula that change the resistance of esophageal wall. Cutis laxa, a congenital or acquired connective disease, is a strange one. In our patient, a good result was reached modifying the standard technique accord to its ethiopathogenic mechanism.

Management of 3 Proliferating Pilar Tumors: Definition, Differential Diagnosis, and Treatment Options. / Experiencia en el manejo de 3 tumores pilares proliferantes: definición, diagnósticos diferenciales y alternativas terapéuticas.

A proliferating pilar tumor is a rare skin neoplasm that arises from the outer root sheath of a hair follicle. Presentation varies widely, as the tumor can be benign or malignant and has a high probability of recurring after excision. We report our experience managing 3 proliferating pilar tumors with different clinical presentations and pathology findings at Hospital de San José, Bogota, Colombia.

Effects of amount and recurrence of leaf herbivory on the induction of direct and indirect defences in wild cotton.

The induction of defences in response to herbivory is a key mechanism of plant resistance. While a number of studies have investigated the time course and magnitude of plant induction in response to a single event of herbivory, few have looked at the effects of recurrent herbivory. Furthermore, studies measuring the effects of the total amount and recurrence of herbivory on both direct and indirect plant defences are lacking. To address this gap, here we asked whether insect leaf herbivory induced changes in the amount and concentration of extrafloral nectar (an indirect defence) and concentration of leaf phenolic compounds (a direct defence) in wild cotton (Gossypium hirsutum). We conducted a greenhouse experiment where we tested single event or recurrent herbivory effects on defence induction by applying mechanical leaf damage and caterpillar (Spodoptera frugiperda) regurgitant. Single events of 25% and 50% leaf damage did not significantly influence extrafloral nectar production or concentration. Extrafloral nectar traits did, however, increase significantly relative to controls when plants were exposed to recurrent herbivory (two episodes of 25% damage). In contrast, phenolic compounds increased significantly in response to single events of  leaf damage but not to recurrent damage. In addition, we found. that local induction of extrafloral nectar production was stronger than systemic induction, whereas the reverse pattern was observed for phenolics. Together, these results reveal seemingly inverse patterns of induction of direct and indirect defences in response to herbivory in wild cotton.

Prevalence of eosinophilic esophagitis: A multicenter study on a pediatric population evaluated at thirty-six Latin American gastroenterology centers. / Prevalencia de esofagitis eosinofílica: estudio multicéntrico en población pediátrica evaluada en 36 centros de gastroenterología de América Latina.

INTRODUCTION AND OBJECTIVE: Eosinophilic esophagitis is a chronic, immune-mediated disease described in case series and publications worldwide. Over the past twenty years, the authors of different studies have attempted to evaluate its incidence and prevalence. The objetive of the present study was to estimate the prevalence of eosinophilic esophagitis in a group of children seen at 36 pediatric gastroenterology centers in ten Latin American countries. MATERIALS AND METHODS: A multicenter, observational, and cross-sectional study was conducted that estimated the period prevalence of eosinophilic esophagitis in children seen at outpatient consultation and that underwent diagnostic upper gastrointestinal endoscopy for any indication at 36 centers in 10 Latin American countries, within a 3-month time frame. RESULTS: Between April and June 2016, 108 cases of eosinophilic esophagitis were evaluated. Likewise, an average of 29,253 outpatient consultations and 4,152 diagnostic upper gastrointestinal endoscopies were carried out at the 36 participating centers. The period prevalence of eosinophilic esophagitis in the population studied (n=29,253) was 3.69 cases×1,000 (95% CI: 3.04 to 4.44), and among the children that underwent routine upper gastrointestinal endoscopy (n=4,152), it was 26x1,000 (95% CI: 22.6 to 29.4). CONCLUSIONS: The general period prevalence of eosinophilic esophagitis in a group of children evaluated at 36 Latin American pediatric gastroenterology centers was 3.69×1,000, and in the children that underwent endoscopy, it was 26×1,000. There was important prevalence variability between the participating countries and centers. The present analysis is the first study conducted on the prevalence of pediatric eosinophilic esophagitis in Latin America.

Post-keratoplasty Endophthalmitis by Multidrug-resistant Pseudomonas Aeruginosa With Positive Culture of the Contralateral Donor Cornea: A Case Report.

PURPOSE: The aim of this paper is to present the case report of a patient developing endophthalmitis after penetrating keratoplasty caused by a multidrug-resistant Pseudomonas aeruginosa, detected only in the contralateral donor tissue. CASE REPORT: A 77-year-old man underwent an uneventful penetrating keratoplasty with a preoperative culture-negative donor cornea; however, the fellow cornea grew multidrug-resistant Pseudomonas aeruginosa. The patient developed and was treated for endophthalmitis after penetrating keratoplasty, and aqueous and vitreous taps grew P. aeruginosa with antibiotic resistance identical to the isolate from the mate cornea. Sequence analysis of the 16S ribosomal gene from the two isolates and confirmation analyzing the sequence of P. aeruginosa heat shock protein gene (groES) were performed showing the same strain for both organisms. CONCLUSION: This case report documents the presence of the same multidrug-resistant P. aeruginosa causing endophthalmitis after penetrating keratoplasty and in the contralateral donor tissue, suggesting that we must be cautious in deciding to transplant tissues with positive culture in the contralateral donor cornea.

Description of a new auxiliary heterotopic partial liver transplantation technique with portal vein arteriolization of applicability in heterotopic liver xenotransplantation.

OBJECTIVE: The aim of this study was to describe a new model of auxiliary heterotopic partial liver transplantation with portal vein arterialization. MATERIALS AND METHODS: Three standard hepatectomies were performed in pigs. The left lateral lobe was surgically resected and portal vein arteriolization constructed by an end-to-side "Y" anastomoses between the distal to the celiac axis aorta and the portal vein. RESULTS: The graft was placed in the left iliaca fossa using anastomoses of the donor infrahepatic inferior cava vein end-to-side to the host infrarenal inferior vein and the donor aortic stump with portal vein arteriolization end-to-side to the left iliac artery. After graft reperfusion, the 3 recipients showed intraoperative hypotension, which was treated with fluid administration and vasoactive drugs. At the end of the operation, the graft displayed normal arterial blood flow and good venous drainage. The donor liver graft appeared more red than the host liver, which was due to the increased arterial blood flow. One pig of 3 died at 24 hours after surgery, probably due to hypothermia. However, the other 2 pigs survived the procedure and remained stable. Echographic monitoring showed intrahepatic arterial expansion, which may be the result of high blood pressure due to the arteriolization procedure. CONCLUSIONS: We have developed a novel and easy to perform technique that diminishes the number of anastomoses and does not involve vessels from other organs.

Use of Postoperative TENS and Continuous Passive Motion Following Total Knee Replacement.

This randomized study analyzed the effectiveness of postoperative transcutaneous electrical nerve stimulation (TENS) used continuously for the first three postoperative days following total knee replacement (TKR) for 1) pain relief, 2) knee flexion arc, 3) narcotic dosage, and 4) hospital stay. Group 1 (N = 18) received sensory threshold TENS and group 2 (N = 18) received subthreshold TENS. Both groups also used continuous passive motion during their hospitalization as did patients from group 3 (control, N = 12) that did not receive TENS. Pain decrease from postoperative day 1-3 was 50% for group 1 patients and 38% for group 2 patients, as measured by the visual analog scale. Wilcoxon Rank Sum did not show a significant difference (p > 0.05) for pain relief or hospital stay for these two groups. Analysis of variance failed to show significant differences (p > 0.05) for knee flexion arc or narcotic dosage for the three groups. Although not statistically significant, an observed decrease in pain may be the only indication for postoperative TENS after TKR. J Orthop Sports Phys Ther 1990;11(12):599-604.

[Multiple angiodysplasia of the small intestine. A diagnostic and therapeutic challenge]. / Angiodisplasia múltiple de intestino delgado. Un reto diagnóstico y terapéutico.

Small bowel bleeding is infrequent and presents a challenge to the clinician. Approximately 30-40% of gastrointestinal bleeding localized in the small bowel is due to angiodysplasia, a vascular malformation. We present the case of a patient with multiple angiodysplasia of the small bowel who required push enteroscopy and capsule endoscopy to establish the diagnosis. Treatment with subcutaneous octreotide was successful. In conclusion, in doubtful cases or in patients with persistent hemorrhage, capsule endoscopy can improve the diagnostic yield of enteroscopy in bleeding gastrointestinal vascular lesions such as angiodysplasia. Endoscopic treatment (laser coagulation) and drug therapy (somatostatin or analogs) are valid alternatives in inoperable or non-resectable cases.