An optimisation approach for planning preventive drought management measures.

While drought impacts are widespread across the globe, climate change projections indicate more frequent and severe droughts. This underscores the pressing need to increase resistance and resilience to drought. The strategic application of Preventive Drought Management Measures (PDMMs) is a suitable avenue to reduce the likelihood of drought and ameliorate associated damages. In this study, we use an optimisation approach with a multicriteria decision-making method to allocate PDMMs for reducing the severity of agricultural and hydrological droughts. The results indicate that implementing PDMMs can reduce the severity of agricultural and hydrological droughts, and the obtained management scenarios (solutions) highlight the utility of multi-objective optimisation for PDMMs planning. However, examined management scenarios also illustrate the trade-off between managing agricultural and hydrological droughts. PDMMs can alleviate the severity of agricultural droughts while producing opposite effects for hydrological droughts (or vice versa). Furthermore, the impact of PDMMs displays temporal and spatial variabilities. For instance, PDMMs implementation within a specific subbasin may mitigate the severity of one type of drought in a given month yet exacerbate drought conditions in preceding or subsequent months. In the case of hydrological droughts, the PDMMs may intensify streamflow deficits in the intervened subbasins while alleviating the hydrological drought severity downstream (or vice versa). These complexities emphasise a customised implementation of PDMMs, considering the basin characteristics (e.g., rainfall distribution over the year, soil properties, land use, and topography) and the quantification of PDMMs' effect on the severity of each type of drought.

A high content imaging assay for identification of specific inhibitors of native Plasmodium liver stage protein synthesis.

Plasmodium parasite resistance to antimalarial drugs is a serious threat to public health in malaria-endemic areas. Compounds that target core cellular processes like translation are highly desirable, as they should be multistage actives, capable of killing parasites in the liver and blood, regardless of molecular target or mechanism. Assays that can identify these compounds are thus needed. Recently, specific quantification of native Plasmodium berghei liver stage protein synthesis as well as that of the hepatoma cells supporting parasite growth, was achieved via automated confocal feedback microscopy of the o-propargyl puromycin (OPP)-labeled nascent proteome, but this imaging modality is limited in throughput. Here, we developed and validated a miniaturized high content imaging (HCI) version of the OPP assay that increases throughput, before deploying this approach to screen the Pathogen Box. We identified only two hits, both of which are parasite-specific quinoline-4-carboxamides, and analogues of the clinical candidate and known inhibitor of blood and liver stage protein synthesis, DDD107498/cabamiquine. We further show that these compounds have strikingly distinct relationships between their antiplasmodial and translation inhibition efficacies. These results demonstrate the utility and reliability of the P. berghei liver stage OPP HCI assay for specific, single-well quantification of Plasmodium and human protein synthesis in the native cellular context, allowing identification of selective Plasmodium translation inhibitors with the highest potential for multistage activity.

Does time of intraoperative exposure to the aerobiome increase microbial growth on inflatable penile prostheses?

Inflatable penile prosthesis (IPP) implantation is a surgical approach for the management of erectile dysfunction (ED). A feared complication is IPP infection, and increased operative time is a risk factor for infection. Exposure of an IPP implant to ambient air in the operating room (OR aerobiome) is thought to contribute to risk of infection from increased operative time, but this is not well-supported. The objective of this study was to evaluate if exposure to the OR aerobiome increased microbial colonization of IPPs. This was an ex vivo study using an uncoated IPP, observing standard surgical sterility and OR conditions. A sterile swab was collected every 30 min for 3 h from each IPP component. Positive controls consisted of swabs exposed to unprepped scrotal skin during in-office vasectomies. All swabs underwent quantitative polymerase chain reaction (qPCR) and next generation sequencing (NGS). Bioinformatic processing was carried out and taxonomic assignment was performed. No microbial growth was detected on any component of the IPPs at any time point, while positive control swabs all detected various skin flora, including bacterial and fungal growth. These findings suggest that exposure to the OR aerobiome does not increase the risk of IPP microbial colonization, at least within a 3-hour period. Further in vivo studies are needed.

Dynamics of Single-Chain Nanoparticles under Crowding: A Neutron Spin Echo Study.

We present a neutron spin echo (NSE) investigation to examine the impact of macromolecular crowding on the dynamics of single-chain nanoparticles (SCNPs), serving as synthetic models for biomacromolecules with flexibility and internal degrees of freedom, such as intrinsically disordered proteins (IDPs). In particular, we studied the dynamics of a medium-size poly(methyl methacrylate) (PMMA)-based SCNP (33 kDa) in solutions with low- (10 kDa) and high- (100 kDa) molecular weight analogous deuterated PMMA linear crowders. The dynamic structure factors of the SCNPs in dilute solution show certain degrees of freedom, yet the analysis in terms of the Zimm model reveals high internal friction that effectively stiffens the chain-a phenomenon also observed for IDPs. Under crowding conditions, the internal dynamics remains essentially unchanged, but the center-of-mass diffusion slows down. The effective viscosity felt by the SCNPs at the timescales probed by NSE is lower than the macroscopic viscosity of the crowder solution, and it does not depend significantly on the molecular weight.

Safe administration of noradrenaline by the peripheral route: A systematic review. / Administración segura de noradrenalina por vía periférica: una revisión sistemática.

PURPOSE: To review and analyze the available literature on peripheral administration of noradrenaline (NA) with the aim of providing recommendations to ensure correct use and patient safety. METHODS: Systematic review on the databases PubMed, ISI Web of Science, SCOPUS and Science Direct, using the following search terms: ("Noradrenaline" [Mesh]) AND ("Norepinephrine" [Mesh]) AND ("Vasopressors" [Mesh]) AND ("Peripheral infusions" [Mesh]) OR ("Extravasations" [Mesh]). A total of 1,040 articles were identified. Animal studies and studies written in languages other than English were excluded. Finally, 83 articles were included. RESULTS: NA can be administered peripherally. The risk of extravasation should be taken into account, with phentolamine being the first pharmacological line of treatment. It has also been related to the appearance of thrombophlebitis, cellulitis, tissue necrosis, limb ischemia and gangrene, although its incidence seems to be low. The use of peripheral NA in children seems to be carried out without obvious complications. The use of standard concentrations is suggested to reduce the risk of errors. It is recommended to use 0.9% saline as the default diluent for peripheral NA. CONCLUSIONS: Peripheral infusions of NA could be a safe and beneficial option in early resuscitation provided that a number of guidelines are followed that reduce the likelihood of complications associated with this route.

Indirect assessment of low-intensity shockwave therapy's energy density and pulse frequency for erectile dysfunction: a systematic review, bayesian network meta-analysis and meta-regression.

Shockwaves are thought to activate regenerative and angiogenic pathways, providing a possible therapeutic benefit for patients with erectile dysfunction. This study aimed to analyze the effectiveness of low-intensity extracorporeal shockwave therapy energy density and pulse frequency. In May 2022, a systematic search of online databases was performed to identify randomized clinical trials related to low-intensity extracorporeal shockwave therapy in erectile dysfunction. Eligible articles compared low-intensity extracorporeal shockwave therapy to controls or sham procedures. A Bayesian framework with 200,000 Markov chains was performed. We included a total of 1272 patients from 18 studies. The energy flux density measured in joules included 0.09 mJ/mm2 (mean difference 3.2 IIEF [95% CrI 2.8, 3.6]), 0.15 mJ/mm2 (mean difference 4.9 IIEF [95% CrI 2.8, 7.2]) and 0.20 mJ/mm2 (mean difference 1.2 IIEF [95% CrI 0.11, 2.3]). Of these, 0.15 mJ/mm2 had the greatest ranking (SUCRA = 0.983) compared with placebo. When analyzed by pulse frequency, significant increases were found in 500 pulses/session (mean difference 2.5 IIEF [CrI 1.9, 3.2]), 1500 pulses/session (mean difference 4.6 IIEF [95% CrI 3.9, 5.4]) and > 3000 pulses/session (mean difference 3.1 IIEF [95% CrI 2.1, 4.2]). Of these, 1500 pulses/session had the highest SUCRA, at 0.996. Our network meta-analysis suggests that low-intensity extracorporeal shockwave therapy is an effective intervention for erectile dysfunction, as measured by increases in the IIEF-EF. Sessions featuring 1500 pulses and an energy flux density of 0.15 mJ/mm2 appear to be the most effective.

KSHV promotes oncogenic FOS to inhibit nuclease AEN and transactivate RGS2 for AKT phosphorylation.

Kaposi's sarcoma-associated herpesvirus (KSHV) ORF57 is a lytic RNA-binding protein. We applied BCBL-1 cells in lytic KSHV infection and performed UV cross-linking immunoprecipitation (CLIP) followed by RNA-seq of the CLIPed RNA fragments (CLIP-seq). We identified ORF57-bound transcripts from 544 host protein-coding genes. By comparing with the RNA-seq profiles from BCBL-1 cells with latent and lytic KSHV infection and from HEK293T cells with and without ORF57 expression, we identified FOS and CITED2 RNAs being two common ORF57-specific RNA targets. FOS dimerizes with JUN as a transcription factor AP-1 involved in cell proliferation, differentiation, and transformation. Knockout of the ORF57 gene from the KSHV genome led BAC16-iSLK cells incapable of FOS expression in KSHV lytic infection. The dysfunctional KSHV genome in FOS expression could be rescued by Lenti-ORF57 virus infection. ORF57 protein does not regulate FOS translation but binds to the 13-nt RNA motif near the FOS RNA 5' end and prolongs FOS mRNA half-life 7.7 times longer than it is in the absence of ORF57. This binding of ORF57 to FOS RNA is competitive to the binding of a host nuclease AEN (also referred to as ISG20L1). KSHV infection inhibits the expression of AEN, but not exosomal RNA helicase MTR4. FOS expression mediated by ORF57 inhibits AEN transcription, but transactivates RGS2, a regulator of G-protein coupled receptors. FOS binds a conserved AP-1 site in the RGS2 promoter and enhances RGS2 expression to phosphorylate AKT. Altogether, we have discovered that KSHV ORF57 specifically binds and stabilizes FOS RNA to increase FOS expression, thereby disturbing host gene expression and inducing pathogenesis during KSHV lytic infection.

Tratamiento crónico ambulatorio con sevoflurano tópico en pacientes con úlceras vasculares / Chronic outpatient treatment with topical sevoflurane in patients with vascular ulcers

Objetivo mostrar la efectividad y seguridad del sevoflurano tópico tras la administración ambulatoria y prolongada en los pacientes con úlceras vasculares refractarias. Métodos estudio observacional retrospectivo de pacientes con úlceras vasculares dolorosas refractarias a terapias habituales y que fueron tratados con sevoflurano tópico durante al menos 36 meses. Se recogieron las variables: edad, sexo, antecedentes médicos, comorbilidad asociada, etiología de úlcera y tratamiento médico. Se analizó la mejoría clínica y la variación de la superficie de las úlceras vasculares. Para cuantificar la intensidad del dolor basal e irruptivo antes y después del tratamiento se utilizó la escala visual analógica. Resultados del total de pacientes tratados, 9 cumplían los criterios de inclusión. La edad media fue de 74,8 ± 7,5 años. Los casos 2 y 9 fallecieron durante el seguimiento. La acción analgésica del sevoflurano tópico fue rápida (3,1 ± 2,1 min), intensa (escala visual analógica: 7 ± 1,1 a 1,4 ± 1,1 puntos) y duradera (de 6 a 24 h). Salvo el caso 4, todos experimentaron una reducción de la superficie (15,1 ± 5,0 a 2,7 ± 4,2) de las úlceras vasculares y no se observó tolerancia a lo largo del tiempo. Conclusión la aplicación de sevoflurano tópico es una estrategia analgésica y reepitelizante para las úlceras vasculares que presenta un perfil correcto de seguridad (AU)

Objective To show the effectiveness and safety of topical sevoflurane after ambulatory and prolonged administration in patients with refractory vascular ulcers. Methods Retrospective observational study analyzing clinical improvement and vascular ulcers surface area variation after topical application of sevoflurane. Inclusion criteria were patients with painful vascular ulcers refractory to usual therapies and who were treated with topical sevoflurane for at least 36 months. The following variables were collected: age, sex, medical history, associated comorbidity, ulcer etiology and medical treatment. The visual analog scale was used to measure baseline and break through pain intensity before and after treatment. Results Nine patients met the inclusion criteria of the total number of patients treated whose median age was 74.8 ± 7.5 years. Cases 2 and 9 died during follow-up. In all cases, the analgesic action of topical sevoflurane was rapid (3.1 ± 2.1 minutes), intense (visual analog scale: 7 ± 1.1 to 1.4 ± 1.1 points) and long-lasting (6 to 24 h). With the exception of case 4, all patients experienced a large reduction in vascular ulcers surface area (15.1 ± 5.0 a 2.7 ± 4.2) and tolerance was not observed over time. Conclusion Topical application of sevoflurane is an analgesic and re-epithelializing strategy for vascular ulcers with a successful safety profile (AU)

Síndrome de VEXAS: manifestaciones clínicas, diagnóstico y tratamiento / VEXAS syndrome: Clinical manifestations, diagnosis, and treatment

El síndrome de VEXAS (Vacuolas, enzima E1, ligado al X, Autoinflamatorio, Somático) es un síndrome autoinflamatorio de inicio en la edad adulta que se caracteriza por mutaciones somáticas en el gen UBA1 y se considera el prototipo de enfermedad hematoinflamatoria. Los pacientes con síndrome de VEXAS exhiben manifestaciones inflamatorias y hematológicas que pueden conducir a diagnósticos clínicos como policondritis recidivante, poliarteritis nodosa, síndrome de Sweet y síndrome mielodisplásico. El diagnóstico requiere la evaluación de la médula ósea en búsqueda de vacuolas citoplásmicas en precursores mieloides y eritroides. Sin embargo, la confirmación genética de las mutaciones en UBA1 es necesaria. El tratamiento es un desafío y a menudo incluye glucocorticoides e inmunosupresores, con respuestas variables. Las terapias hipometilantes y el trasplante alogénico de células progenitoras hematopoyéticas se consideran terapias prometedoras. El pronóstico es influido por factores genéticos y clínicos. El objetivo de esta revisión es proporcionar una visión general sobre la patogénesis, la presentación clínica, el tratamiento y el pronóstico del síndrome de VEXAS para la comunidad médica latinoamericana.(AU)

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.(AU)

Chronic outpatient treatment with topical sevoflurane in patients with vascular ulcers. / Tratamiento crónico ambulatorio con sevoflurano tópico en pacientes con úlceras vasculares.

OBJECTIVE: To show the effectiveness and safety of topical sevoflurane after ambulatory and prolonged administration in patients with refractory vascular ulcers. METHODS: Retrospective observational study analyzing clinical improvement and vascular ulcers surface area variation after topical application of sevoflurane. Inclusion criteria were patients with painful vascular ulcers refractory to usual therapies and who were treated with topical sevoflurane for at least 36 months. The following variables were collected: age, sex, medical history, associated comorbidity, ulcer etiology and medical treatment. The visual analog scale was used to measure baseline and break through pain intensity before and after treatment. RESULTS: Nine patients met the inclusion criteria of the total number of patients treated whose median age was 74.8 ± 7.5 years. Cases 2 and 9 died during follow-up. In all cases, the analgesic action of topical sevoflurane was rapid (3.1 ± 2.1 minutes), intense (visual analog scale: 7 ± 1.1 to 1.4 ± 1.1 points) and long-lasting (6 to 24 h). With the exception of case 4, all patients experienced a large reduction in vascular ulcers surface area (15.1 ± 5.0 a 2.7 ± 4.2) and tolerance was not observed over time. CONCLUSION: Topical application of sevoflurane is an analgesic and re-epithelializing strategy for vascular ulcers with a successful safety profile.

Antiplasmodial peptaibols act through membrane directed mechanisms.

Our previous study identified 52 antiplasmodial peptaibols isolated from fungi. To understand their antiplasmodial mechanism of action, we conducted phenotypic assays, assessed the in vitro evolution of resistance, and performed a transcriptome analysis of the most potent peptaibol, HZ NPDG-I. HZ NPDG-I and 2 additional peptaibols were compared for their killing action and stage dependency, each showing a loss of digestive vacuole (DV) content via ultrastructural analysis. HZ NPDG-I demonstrated a stepwise increase in DV pH, impaired DV membrane permeability, and the ability to form ion channels upon reconstitution in planar membranes. This compound showed no signs of cross resistance to targets of current clinical candidates, and 3 independent lines evolved to resist HZ NPDG-I acquired nonsynonymous changes in the P. falciparum multidrug resistance transporter, pfmdr1. Conditional knockdown of PfMDR1 showed varying effects to other peptaibol analogs, suggesting differing sensitivity.

Comparison of Urinary Diversion in Patients With Prostatic Fistula to Those with Localized Radiation Injury After Radiotherapy for the Treatment of Prostate Cancer.

OBJECTIVE: To compare characteristics and outcomes in patients who had radiotherapy (RT) for prostate cancer (PCa) and underwent urinary diversion (UD) due to prostatic fistula (Fistula) vs localized radiation injury (Localized). METHODS: This study was a retrospective single-institution study. Exclusion criteria included follow-up <3 months, large pelvic tumor, and surgery for cancer control. The Fistula group included fistulization outside of the urinary tract (rectal, soft tissue, thigh, pubic symphysis, and extensive necrosis surrounding the prostate). The group Localized had a multitude of problems; however, all were confined to the urinary tract. Patient characteristics, perioperative variables, and outcomes were compared between groups. RESULTS: Sixty-nine patients were included and had UD from 2009-2022. Median age and time from RT to UD were 73 (interquartile range (IQR) 67.9, 78.1) and 7.3 (IQR 3.2, 12.5) years. There were 29 (42%) and 40 (58%) patients in the Fistula and Localized groups. The Fistula group had a higher rate of abdominal/perineal approach (62.1% vs 12.5%, P <.001), a lower rate of right colon pouch (17.2% vs 40%, P = .043), and a longer operative time (515.7 vs 414.2 minutes, P = .017). Clavien-Dindo complications ≥3 were higher in the Fistula group (44.8% vs 20%, P = .027), including a higher rate of re-operation for recurrent pelvic abscess (37.9% vs 5%, P <.001). Survival for the cohort was 85.5% and did not differ between groups. CONCLUSION: Patients with prostate fistula after RT for PCa undergoing UD had longer, more complex operations, and higher rates of complications, notably post-operative pelvic abscesses, compared to men with localized RT injury. Long-term survival was comparable in both groups.

VEXAS syndrome: Clinical manifestations, diagnosis, and treatment.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is an adult-onset autoinflammatory syndrome characterized by somatic mutations in the UBA1 gene and is considered the prototype of hematoinflammatory diseases. Patients with VEXAS syndrome exhibit inflammatory and hematological manifestations that can lead to clinical diagnoses such as relapsing polychondritis, polyarteritis nodosa, Sweet syndrome, and myelodysplastic syndrome. Diagnosis requires bone marrow evaluation to identify cytoplasmic vacuoles in myeloid and erythroid precursors. However, genetic confirmation of mutations in UBA1 is necessary. Treatment is challenging and often involves glucocorticoids and immunosuppressants with variable responses. Hypomethylating agents and allogenic haemopoietic stem cell transplant are considered promising therapies. Prognosis is influenced by genetic and clinical factors. The aim of this review is to provide an overview of the pathogenesis, clinical presentation, treatment, and prognosis of VEXAS syndrome for the Latin American medical community.

Vision for a sustainable energy transition and decarbonization: A case study of students surveyed at a Chilean University.

This study analyzes public perception towards the energy transition and decarbonization in Chile, and how these preferences change with political ideology, as well as distance between power plant installations and people's homes. Due to a lack of scientific research on civil society preferences for energy production in Chile, we used a convenience sample and conducted a survey among future decision makers (current university students) to identify which factors impact their acceptance or rejection of energy sources. In addition, we asked them about their vision for the future energy mix. In total, 164 valid questionnaires were collected. Results show that the level of acceptance and preference changes with political ideology, with social liberals being more willing to change their lifestyle and increase their willingness to pay for a faster inclusion of clean technologies in the energy mix. Higher levels of education increase this willingness to pay. The level of acceptance decreases up to 56% for solar and wind when the installation is located within a radius less than 5 km from the population's homes. The level of rejection is 97% for hydroelectricity and 99% for non-renewable power plants if they are located at distances lower than 5 km. The decentralization of energy policy decisions and the consideration of local society would be relevant for an energy transition towards renewable sources.

Impact of the Identification of Nonhuman Genetic Signatures in the Diagnosis and Management of Carcinoma of Unknown Primary.

This report presents the case of a 62-year-old woman who was diagnosed in 1999 with stage I cervical carcinoma treated by surgical resection. In 2021, she presented to the emergency department with a complaint of predominantly right-sided lower back pain. A CT scan of the lumbosacral region revealed a bone lesion in the L5 vertebra and retroperitoneal lymphadenopathies suggestive of malignancy. Histology of the L5 vertebra biopsy showed a poorly differentiated carcinoma with an inconclusive immunophenotypic profile. Treatment for carcinoma of unknown primary was started with a combination of carboplatin and paclitaxel every 21 days. A genomic study of the biopsy specimen performed on the FoundationOne CDx platform identified a nonhuman genetic signature compatible with HPV. The presence of HPV 18 DNA in the specimen was confirmed by PCR-reverse dot blot, and the immunophenotypic profile was expanded, revealing strong and diffuse p16 expression, thus corroborating the molecular findings. In view of these findings, the case was reclassified as a recurrence of the cervical adenocarcinoma that had been diagnosed and treated 23 years earlier. Based on the new results, and according to first-line cervical carcinoma protocols, bevacizumab at 15 mg/kg every 21 days was added to her chemotherapy regimen. The identification of HPV DNA sequences by next-generation sequencing facilitated the correct diagnosis and led to a modification of the first-line therapeutic approach.

Structure of Single-Chain Nanoparticles under Crowding Conditions: A Random Phase Approximation Approach.

The conformation of poly(methyl methacrylate) (PMMA)-based single-chain nanoparticles (SCNPs) and their corresponding linear precursors in the presence of deuterated linear PMMA in deuterated dimethylformamide (DMF) solutions has been studied by small-angle neutron scattering (SANS). The SANS profiles were analyzed in terms of a three-component random phase approximation (RPA) model. The RPA approach described well the scattering profiles in dilute and crowded solutions. Considering all the contributions of the RPA leads to an accurate estimation of the single chain form factor parameters and the Flory-Huggins interaction parameter between PMMA and DMF. The value of the latter in the dilute regime indicates that the precursors and the SCNPs are in good solvent conditions, while in crowding conditions, the polymer becomes less soluble.