Evaluating the potency of zoliflodacin against Helicobacter pylori: In vitro activity and conserved GyrB target.

BACKGROUND: The current standard treatment for Helicobacter pylori infection, which involves a combination of two broad-spectrum antibiotics, faces significant challenges due to its detrimental impact on the gut microbiota and the emergence of drug-resistant strains. This underscores the urgent requirement for the development of novel anti-H. pylori drugs. Zoliflodacin, a novel bacterial gyrase inhibitor, is currently undergoing global phase III clinical trials for treating uncomplicated Neisseria gonorrhoeae. However, there is no available data regarding its activity against H. pylori. MATERIALS AND METHODS: We evaluated the in vitro activity of zoliflodacin against H. pylori clinical isolates (n = 123) with diverse multidrug resistance. We performed DNA gyrase supercoiling and microscale thermophoresis assays to identify the target of zoliflodacin in H. pylori. We analyzed 2262 H. pylori whole genome sequences to identify Asp424Asn and Lys445Asn mutations in DNA gyrase subunit B (GyrB) that are associated with zoliflodacin resistance. RESULTS: Zoliflodacin exhibits potent activity against all tested isolates, with minimal inhibitory concentration (MIC) values ranging from 0.008 to 1 µg/mL (MIC50: 0.125 µg/mL; MIC90: 0.25 µg/mL). Importantly, there was no evidence of cross-resistance to any of the four first-line antibiotics commonly used against H. pylori. We identified GyrB as the primary target of zoliflodacin, with Asp424Asn or Lys445Asn substitutions conferring resistance. Screening of 2262 available H. pylori genomes for the two mutations revealed only one clinical isolate carrying Asp424Asn substitution. CONCLUSION: These findings support the potential of zoliflodacin as a promising candidate for H. pylori treatment, warranting further development and evaluation.

Gonococcal resistance to zoliflodacin could emerge via transformation from commensal Neisseria species. An in-vitro transformation study.

One of the most promising new treatments for gonorrhoea currently in phase 3 clinical trials is zoliflodacin. Studies have found very little resistance to zoliflodacin in currently circulating N. gonorrhoeae strains, and in-vitro experiments demonstrated that it is difficult to induce resistance. However, zoliflodacin resistance may emerge in commensal Neisseria spp., which could then be transferred to N. gonorrhoeae via transformation. In this study, we investigated this commensal-resistance-pathway hypothesis for zoliflodacin. To induce zoliflodacin resistance, ten wild-type susceptible isolates belonging to 5 Neisseria species were serially passaged for up to 48 h on gonococcal agar plates containing increasing zoliflodacin concentrations. Within 7 to 10 days, all strains except N. lactamica, exhibited MICs of ≥ 4 µg/mL, resulting in MIC increase ranging from 8- to 64-fold. The last passaged strains and their baseline were sequenced. We detected mutations previously reported to cause zoliflodacin resistance in GyrB (D429N and S467N), novel mutations in the quinolone resistance determining region (QRDR) (M464R and T472P) and mutations outside the QRDR at amino acid positions 28 and 29 associated with low level resistance (MIC 2 µg/mL). Genomic DNA from the laboratory evolved zoliflodacin-resistant strains was transformed into the respective baseline wild-type strain, resulting in MICs of ≥ 8 µg/mL in most cases. WGS of transformants with decreased zoliflodacin susceptibility revealed presence of the same zoliflodacin resistance determinants as observed in the donor strains. Two inter-species transformation experiments were conducted to investigate whether zoliflodacin resistance determinants of commensal Neisseria spp. could be acquired by N. gonorrhoeae. N. gonorrhoeae strain WHO P was exposed to (i) pooled genomic DNA from the two resistant N. mucosa strains and (ii) a gyrB amplicon of the resistant N. subflava strain 45/1_8. Transformants of both experiments exhibited an MIC of 2 µg/mL and whole genome analysis revealed uptake of the mutations detected in the donor strains. This is the first in-vitro study to report that zoliflodacin resistance can be induced in commensal Neisseria spp. and subsequently transformed into N. gonorrhoeae.

Evaluating the efficacy of different antibiotics against Neisseria gonorrhoeae: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

BACKGROUND: With the widespread use of antibiotics, antimicrobial resistance in Neisseria gonorrhoeae is worsening. The objective of this study was to evaluate the efficacy changes of seven antibiotics in the treatment of N. gonorrhoeae by using Monte Carlo simulation combined with pharmacokinetics/pharmacodynamics/ (PK/PD). METHODS: The minimum inhibitory concentration (MIC) of antibiotics against clinical isolates from 2013 to 2020 in Nanjing, China, was determined by agar dilution method. The probability of target attainment (PTA) was estimated at each MIC value and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. RESULTS: All dosage regimens of seven antibiotics achieved PTAs ≥ 90% for MIC ≤ 0.06 µg/ml. But when the MIC was increased to 1 µg/ml, PTAs at each MIC value exceeded 90% only for ceftriaxone 1,000 mg and 2,000 mg, zoliflodacin 2,000 mg and 3,000 mg. Among them, the CFR values of each dosing regimen against N. gonorrhoeae only for ceftriaxone, cefixime and zoliflodacin were ≥ 90% in Nanjing from 2013 to 2020. CONCLUSIONS: Cephalosporins are still the first-line drugs in the treatment of gonorrhea. However, the elevated MIC values of cephalosporins can lead to decline in clinical efficacy of the conventional dose regimens, and increasing the dose of ceftriaxone to 1,000 mg-2,000 mg may improve the efficacy. In addition, zoliflodacin is possible to be a potential therapeutic agent in the future.

Immunoassay testing for barbiturates using alternative matrices in postmortem tissues from cats and dogs.

The barbiturate drug pentobarbital is commonly used by veterinarians for the euthanasia of domestic animals. During the veterinary forensic autopsy, it is sometimes necessary to determine whether the animal was chemically euthanized with pentobarbital. The use of a human immunochromatographic test for barbiturate screening utilizing dog or cat urine has been previously validated; however, the use of alternative matrices for this purpose is yet to be explored when urine is not available. Postmortem heart, liver, spleen, skeletal muscle, blood and/or urine samples from 20 dogs and 26 cats with a reported chemical euthanasia status were processed using two different methods, bead homogenization and sonication, and screened for barbiturates using a human immunochromatographic test. There was 100% agreement of the immunochromatographic test results using the sonication method with the reported euthanasia status of both dogs and cats. Using the bead homogenization method, agreement with the reported euthanasia status was 93.3% and 96.7% for dogs and cats, respectively, due to invalid test results from four dog and two cat samples. A subset of liver samples (10 canine and 10 feline) was analyzed via gas chromatography-mass spectrometry, and there was 100% agreement between the immunochromatographic test results and gas chromatography-mass spectrometry results for both cats and dogs. Overall, our results support the use of a variety of alternative matrices for barbiturate screening in cats and dogs.

An Erythrocyte Membrane-Derived Nanosystem for Efficient Reversal of Endothelial Injury in Sepsis.

Sepsis is caused by a disordered host immune in response to infection and endothelial cells perform a crucial role in boosting immunity reaction in the pathophysiology of sepsis and septic organ failure. The aim of this study is to construct a novel erythrocyte membrane-derived nanosystems to reverse endothelial damage in sepsis. Herein, an innovative nanometer calcium metal-organic framework (Ca-MOF) is generated for the first time by using chelidonic acid as a ligand and calcium chloride as an ion donor for anti-inflammation. Then, zoliflodacin is loaded into Ca-MOF (CMZ) to sterilize and nanoscale erythrocyte membrane vesicles are prepared by modification with a γ3 peptide on the surface (γ3-RM) for precise targeting. Finally, γ3-RM camouflages the nanocore CMZ, to form novel erythrocyte membrane-camouflaged nanoparticle γ3-RCMZ. The superior performance of novel nanosystem results from its suitable biocompatibility, nontoxicity, specific targeting, and anti-inflammatory and bactericidal effects. Its anti-inflammatory mechanism mainly involves inhibiting the Caspase1-nuclear factor kappa-B (Caspase1-NF-κB) pathway and oxidative stress reduction to alleviate endothelial damage. Moreover, the findings have revealed for the first time that the bactericidal drug zoliflodacin also has anti-inflammatory effects in vivo and in vitro. Therefore, the novel nanosystem (γ3-RCMZ) provides a new nanotherapy strategy for sepsis treatment.

Phencyclidine Positivity on Urine Drug Screening in Patients Treated for Alcohol Withdrawal on a Dual-diagnosis Medically Assisted Withdrawal Unit.

OBJECTIVES: Little contemporary research has explored phencyclidine (PCP) use in people with alcohol use disorder. Therefore, we sought to determine the prevalence of PCP positivity on urine toxicology screening among patients admitted for alcohol withdrawal, identify correlates of PCP positivity, and investigate PCP positivity's relationship to length of stay (LOS) and risk of facility readmission. METHODS: This was a retrospective study of patients admitted to a dual-diagnosis medically assisted withdrawal unit for alcohol withdrawal from 2014 to 2019. Univariate tests and logistic regression were used to investigate potential correlates of PCP positivity on admission toxicology screening (primary outcome). Multivariable linear regression models and survival analyses analyzing LOS and risk of readmission (secondary outcomes) were also developed. RESULTS: Ninety of 3731 patients (2.4%) screened positive for PCP. There were significant associations on univariate testing between PCP positivity and age, race, homeless status, and urine toxicology positivity for amphetamines, benzodiazepines, barbiturates, cocaine, tetrahydrocannabinol, and oxycodone. On multivariate logistic regression, only tetrahydrocannabinol, barbiturates, and cocaine positivity were associated with PCP positivity. Multivariate logistic regression and survival analysis found no statistically significant associations between PCP positivity and LOS or risk of readmission. CONCLUSIONS: This study provides rare analysis of contemporary data on PCP use among patients undergoing medically assisted alcohol withdrawal. Phencyclidine positivity was uncommon, but use appears considerably higher among this patient population than the general population. There was no significant association between PCP positivity and LOS or readmission risk.

Investigation of the human metabolism and disposition of the prolyl hydrolase inhibitor daprodustat using IV microtracer with Entero-Test bile string.

Daprodustat is an oral small molecule hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor (PHI) approved in Japan and the United States for the treatment of anemia associated with chronic kidney disease. This phase 1, nonrandomized, 2-period, crossover study in 6 healthy men characterized and quantified the metabolites generated after a microtracer IV infusion of 50 µg (125 nCi) [14 C]-daprodustat administered concomitantly with a nonradiolabeled therapeutic dose of a 6-mg daprodustat tablet, followed by a single oral solution dose of 25 mg (62.5 µCi) [14 C]-daprodustat. High-performance liquid chromatography (HPLC) coupled with radioactivity detection (TopCount or AMS) and HPLC-tandem mass spectrometry (HPLC-MSn ) were used for quantitative measurement and structural identification of radioactive metabolites in plasma, urine, feces, and bile. Following oral administration of [14 C]-daprodustat, unchanged daprodustat was the principal circulating drug-related component, accounting for 40% of plasma radioactivity. Predominant oxidative metabolites M2, M3, M4, and M13 individually represented 6-8% of the plasma radioactivity and together accounted for the majority of radioactivity in urine and feces (53% in both matrices; 12% and 41% of dose, respectively). Unchanged daprodustat was not detected in urine and was only 0.7% of total radioactivity in feces (<0.5% of dose), with the remainder of the dose accounted for by oxidative metabolites. The radio-metabolic profile of duodenal bile following IV infusion of [14 C]-daprodustat was similar to that observed in feces after oral administration. The data suggested that oral daprodustat was extensively absorbed, cleared exclusively by oxidative metabolism, and eliminated via hepatobiliary (primary) and urinary (secondary) excretion.

Crystal structures of non-uracil ring fragments in complex with Mycobacterium tuberculosis uracil DNA glycosylase (MtUng) as a starting point for novel inhibitor design: A case study with the barbituric acid fragment.

Uracil DNA glycosylase (UDG or Ung) is a key enzyme involved in uracil excision from the DNA as a repair mechanism. Designing Ung inhibitors is thus a promising strategy to treat different cancers and infectious diseases. The uracil ring and its derivatives have been shown to inhibit Mycobacterium tuberculosis Ung (MtUng), resulting from specific and strong binding with the uracil-binding pocket (UBP). To design novel MtUng inhibitors, we screened several non-uracil ring fragments hypothesised to occupy MtUng UBP due to their high similarity to the uracil structural motif. These efforts have resulted in the discovery of novel MtUng ring inhibitors. Here we report the co-crystallised poses of these fragments, confirming their binding within the UBP, thus providing a robust structural framework for the design of novel lead compounds. We selected the barbituric acid (BA) ring as a case study for further derivatisation and SAR analysis. The modelling studies predicted the BA ring of the designed analogues to interact with the MtUng UBP much like the uracil ring. The synthesised compounds were screened in vitro using radioactivity and a fluorescence-based assay. These studies led to a novel BA-based MtUng inhibitor 18a (IC50 = 300 µM) displaying ∼24-fold potency over the uracil ring.

First evidence of the incorporation of daprodustat and other hypoxia-inducible factor stabilizers into equine hair by passive transfer based on segmental quantitative analysis.

Daprodustat is a hypoxia-inducible factor prolyl hydroxylase domain (HIF-PHD) inhibitor and is used as an erythropoiesis stimulant for the treatment of anemia in humans. In general, administering daprodustat to horses will result in a lifetime ban from both equestrian sports and horseracing by the International Federation of Horseracing Authorities and the Fédération Équestre Internationale, respectively. To control the misuse/abuse of daprodustat, we conducted nasoesophageal administration of daprodustat (100 mg/day for 3 days) to three thoroughbred mares and the post-administration hair samples collected from the three horses over 6 months were analyzed to demonstrate the potential longer-term detection of daprodustat and its metabolites in hair compared with the detection times of daprodustat of 1 and 2 weeks in plasma and urine respectively. The results of the quantitative 2-cm segmental analysis showed that daprodustat was primarily localized in the proximal region (0-2 cm) at 0.375-0.463 pg/mg at 1 month post-administration. These drug bands were gradually spread out along the hair shaft at a rate consistent with the reported growth rate of horse mane hair (approximately 2.5 cm/month) over the following 6 months. In addition, to attain deeper insight into the mechanism of drug incorporation into hair, a total of 11 relevant parameters, including the actual PK parameters and simulated physicochemical and biopharmaceutical parameters for three HIF stabilizers (i.e., daprodustat, vadadustat, and IOX4), were investigated after normalization of the z-scores of all these parameters. Multiple regression analysis indicated that the major factors contributing to the incorporation of the three drugs into hair were their maximum plasma concentrations and lipophilicities, strongly suggesting that the three HIF stabilizers permeated from the bloodstream into the hair bulb via passive transfer with concentration gradients. This work is the first reported evidence showing the incorporation of HIF stabilizers into hair via passive transfer. In addition, cross-species comparison of drug incorporations into hair between daprodustat in horse and roxadustat in human was made in order to have a better understanding of the interactive interpretations about the analysis results obtained from different species. The above findings are not only useful and beneficial for the purpose of doping control but also provide a better understanding of the mechanism of drug incorporation into horse hair.

Estado actual y perspectivas futuras en el manejo de la hipertensión intracraneal posterior a traumatismo craneoencefálico: craniectomía descompresiva, hipotermia terapéutica y barbitúricos / Current status and outlook for the management of intracranial hypertension after traumatic brain injury: decompressive craniectomy, therapeutic hypothermia, and barbiturates

Introducción: El aumento de la presión intracraneal se ha asociado a un pronóstico neurológicodesfavorable y a un incremento en la mortalidad en pacientes con traumatismo craneoencefálico grave. Tradicionalmente, las terapias para disminuir la presión intracraneal se administranutilizando un enfoque progresivo, reservando el uso de opciones más agresivas para los casossin respuesta a intervenciones de primer nivel, o de hipertensión intracraneal refractaria. Desarrollo: El valor terapéutico de las intervenciones de rescate para la hipertensión intracraneal, así como el momento adecuado para su uso ha sido debatido constantemente en laliteratura. En esta revisión, discutiremos las principales opciones de tratamiento para la hipertensión intracraneal refractaria posterior a un traumatismo craneoencefálico grave en adultos.Tenemos la intención de llevar a cabo una revisión en profundidad de los ensayos controladosaleatorios más representativos sobre las diferentes intervenciones terapéuticas de rescate,incluyendo la craniectomía descompresiva, hipotermia terapéutica y barbitúricos. Además,discutiremos las perspectivas futuras de estas opciones de tratamiento. Conclusiones: La evidencia parece mostrar que se puede reducir la mortalidad al utilizar estasintervenciones de rescate como terapia de último nivel, sin embargo, este beneficio vieneacompanado de una discapacidad severa. La decisión de realizar o no estas intervencionesdebe ser individualizada y centrada en el paciente. El desarrollo e integración de diferentesvariables fisiológicas a través de monitorización multimodal es de suma importancia para poderproporcionar información pronóstica más sólida a los pacientes que enfrentan este tipo dedecisiones.(AU)

Introduction: Increased intracranial pressure has been associated with poor neurological out-comes and increased mortality in patients with severe traumatic brain injury. Traditionally,intracranial pressure-lowering therapies are administered using an escalating approach, withmore aggressive options reserved for patients showing no response to first-tier interventions,or with refractory intracranial hypertension. Development: The therapeutic value and the appropriate timing for the use of rescue treat-ments for intracranial hypertension have been a subject of constant debate in literature. Inthis review, we discuss the main management options for refractory intracranial hypertensionafter severe traumatic brain injury in adults. We intend to conduct an in-depth revision of themost representative randomised controlled trials on the different rescue treatments, includingdecompressive craniectomy, therapeutic hypothermia, and barbiturates. We also discuss futureperspectives for these management options. Conclusions: The available evidence appears to show that mortality can be reduced whenrescue interventions are used as last-tier therapy; however, this benefit comes at the cost ofsevere disability. The decision of whether to perform these interventions should always bepatient-centred and made on an individual basis. The development and integration of differentphysiological variables through multimodality monitoring is of the utmost importance to providemore robust prognostic information to patients facing these challenging decisions.(AU)

Current status and outlook for the management of intracranial hypertension after traumatic brain injury: decompressive craniectomy, therapeutic hypothermia, and barbiturates.

INTRODUCTION: Increased intracranial pressure (ICP) has been associated with poor neurological outcomes and increased mortality in patients with severe traumatic brain injury (TBI). Traditionally, ICP-lowering therapies are administered using an escalating approach, with more aggressive options reserved for patients showing no response to first-tier interventions, or with refractory intracranial hypertension. DEVELOPMENT: The therapeutic value and the appropriate timing for the use of rescue treatments for intracranial hypertension have been a subject of constant debate in literature. In this review, we discuss the main management options for refractory intracranial hypertension after severe TBI in adults. We intend to conduct an in-depth revision of the most representative randomised controlled trials on the different rescue treatments, including decompressive craniectomy, therapeutic hypothermia, and barbiturates. We also discuss future perspectives for these management options. CONCLUSIONS: The available evidence appears to show that mortality can be reduced when rescue interventions are used as last-tier therapy; however, this benefit comes at the cost of severe disability. The decision of whether to perform these interventions should always be patient-centred and made on an individual basis. The development and integration of different physiological variables through multimodality monitoring is of the utmost importance to provide more robust prognostic information to patients facing these challenging decisions.

Comparison of Low and High Doses of Pentobarbital or Thiopental for Euthanasia of Isoflurane-anesthetized Pigs.

Barbiturate overdose is a common method for euthanizing pigs. However, barbiturates can cause tissue damage and may affect experimental results, so the minimal dose should be used. The minimal dose of barbiturate for euthanasia in pigs under isoflurane anesthesia has not yet been determined. In this study, we compared the effect of low and high doses of 2 barbiturates (pentobarbital, 30 or 60 mg/kg; thiopental, 20 and 40 mg/kg) on hemodynamic parameters and time to cardiac arrest in female pigs maintained on isoflurane. Acute decreases in blood pressure and end-tidal CO2 occurred in all pigs shortly after administration of the barbiturate. However, these changes were not different between either of the high- and low dose groups. Cardiac arrest occurred significantly faster for high dose as compared with low dose thiopental groups, but this parameter was different between the 2 pentobarbital groups. The bispectral index fell immediately after dosing, in all pigs, but no significant differences were observed in the time needed to achieve 0 for the high or low-doses of either drug. In pigs maintained on isoflurane, a low dose of barbiturates is adequate for euthanasia and may result in less tissue damage.

Novel benzimidazole-linked (thio)barbiturates as non-hydroxamate HDAC6 inhibitors targeting leukemia: Design, synthesis, and structure-activity relationship.

Based on the well-established pharmacophoric features required for histone deacetylase (HDAC) inhibition, novel easy-to-prepare benzimidazole-linked (thio)barbiturate derivatives were designed and synthesized as HDAC6 inhibitors. The proposed structures of the title compounds were confirmed based on their spectral data and elemental analyses. The newly synthesized compounds were screened in vitro against HDAC6. All tested compounds showed potent HDAC6 inhibition at the nanomolar level. Several compounds displayed a remarkable HDAC6 inhibitory activity (IC50 = 48.85-75.62 nM), superior to that of the reference drug suberoylanilide hydroxamic acid (SAHA; IC50 = 91.73 nM). The most potent derivatives were further assessed for their in vitro anticancer activity against two human leukemia cell lines. Thiobarbiturate 3e was two times more potent than SAHA against the tested cells. The detailed structure-activity relationship was also described. Furthermore, molecular docking simulation revealed the ability of the title compounds to chelate the catalytic Zn+2 ion located within the binding pocket of HDAC6. In silico evaluation of physicochemical properties indicated that the target compounds are promising candidates in terms of pharmacokinetic aspects.

New approach for barbiturates, phenytoin, methyprylon and glutethimide determination and fragmentation (UHPLC-MS/MS).

Barbiturates which are old pharmaceutical drugs are still widely used in medical treatment of epilepsy and for general anesthesia. To date, more than 2500 different barbituric acid analogs have been synthesized, and 50 of them were introduced into medical use over the last century. Due to their highly addictive properties, pharmaceuticals containing barbiturates are under strict control in many countries. However, by considering the worldwide problem with new psychoactive substances (NPS) the introduction of new designer barbiturate analogs into the dark market might serve a serious public health problem in the near future. For this reason there is an increasing need for application methods for barbiturates monitoring in biological samples. The UHPLC-QqQ-MS/MS method for determination of 15 barbiturates, phenytoin, methyprylon and glutethimide was developed and fully validated. The biological sample volume was reduced to only 50 µL. A simple LLE (pH 3 with ethyl acetate) was successfully applied. The lower LOQ was 10 ng/mL. The method enables differentiation of structural isomers: hexobarbital and cyclobarbital; as well as amobarbital and pentobarbital. Chromatographic separation was achieved with the use of the alkaline mobile phase (pH 9) and Acquity UPLC BEH C18 column. Furthermore, the novel fragmentation mechanism of barbiturates was proposed, which may have a great impact in identification of novel barbiturates analogs introduced to illegal marketplaces. The presented technique has a great potential to be applied in forensic, clinical and veterinary toxicological laboratories, as was evidenced by the positive results of international proficiency tests.

The ASCEND-NHQ randomized trial found positive effects of daprodustat on hemoglobin and quality of life in patients with non-dialysis chronic kidney disease.

The ASCEND-NHQ trial evaluated the effects of daprodustat on hemoglobin and the Medical Outcomes Study 36-item Short Form Survey (SF-36) Vitality score (fatigue) in a multicenter, randomized, double-blind, placebo-controlled trial. Adults with chronic kidney disease (CKD) stages 3-5, hemoglobin 8.5-10.0 g/dl, transferrin saturation 15% or more, and ferritin 50 ng/ml or more without recent erythropoiesis-stimulating agent use were randomized (1:1) to oral daprodustat or placebo to achieve and maintain target hemoglobin of 11-12 g/dl over 28 weeks. The primary endpoint was the mean change in hemoglobin between baseline and the evaluation period (Weeks 24-28). Principal secondary endpoints were proportion of participants with a 1 g/dl or more increase in hemoglobin and mean change in the Vitality score between baseline and Week 28. Outcome superiority was tested (1-sided alpha level of 0.025). Overall, 614 participants with non-dialysis-dependent CKD were randomized. The adjusted mean change in hemoglobin from baseline to the evaluation period was greater with daprodustat (1.58 vs 0.19 g/dl). The adjusted mean treatment difference (AMD) was significant at 1.40 g/dl (95% confidence interval 1.23, 1.56). A significantly greater proportion of participants receiving daprodustat showed a 1 g/dl or greater increase in hemoglobin from baseline (77% vs 18%). The mean SF-36 Vitality score increased by 7.3 and 1.9 points with daprodustat and placebo, respectively; a clinically and statistically significant 5.4 point Week 28 AMD increase. Adverse event rates were similar (69% vs 71%); relative risk 0.98, (95% confidence interval 0.88, 1.09). Thus, in participants with CKD stages 3-5, daprodustat resulted in a significant increase in hemoglobin and improvement in fatigue without an increase in the overall frequency of adverse events.

External ventricular drainage for intracranial hypertension after traumatic brain injury: is it really useful?

PURPOSES: External ventricular drainage (EVD) is frequently used to control raised intracranial pressure after traumatic brain injury. However, the available evidence about its effectiveness in this context is limited. The aim of this study is to evaluate the effectiveness of EVD to control intracranial pressure and to identify the clinical and radiological factors associated with its success. METHODS: For this retrospective cohort study conducted in a Level 1 traumacenter in Paris area between May 2011 and March 2019, all patients with intracranial hypertension and treated with EVD were included. EVD success was defined as an efficient and continuous control of intracranial hypertension avoiding the use of third tier therapies (therapeutic hypothermia, decompressive craniectomy, and barbiturate coma) or avoiding a decision to withdraw life sustaining treatment due to both refractory intracranial hypertension and severity of brain injury lesions. RESULTS: 83 patients with EVD were included. EVD was successful in 33 patients (40%). Thirty-two patients (39%) required a decompressive craniectomy, eight patients (9%) received barbiturate coma. In ten cases (12%) refractory intracranial hypertension prompted a protocolized withdrawal of care. Complications occurred in nine patients (11%) (three cases of ventriculitis, six cases of catheter occlusion). Multivariate analysis identified no independent factors associated with EVD success. CONCLUSION: In a protocol-based management for traumatic brain injury, EVD allowed intracranial pressure control and avoided third tier therapeutic measures in 40% of cases with a favorable risk-benefit ratio.