Management of Paraneoplastic Syndromes in the Era of Immune Checkpoint Inhibitors.

OPINION STATEMENT: Our understanding of paraneoplastic neurologic syndromes (PNS) has blossomed over the past few decades. Clinicians have access to more robust diagnostic criteria and have a heightened index of suspicion for these disorders. Nonetheless, treatment, which typically includes immunosuppression, and response to treatment, varies. Due to persistent difficulty in making a definitive diagnosis, we favor empiric treatment when a possible diagnosis of PNS is suspected, and other alternative causes have substantially been excluded (e.g., infections, toxic-metabolic derangements, metastasis, or leptomeningeal disease). Treatment of the underlying cancer, if identified, is the first therapeutic step and can prevent disease worsening and in rare cases, can reverse neurologic symptoms. In addition to anti-cancer treatment, first line immunotherapies, which include corticosteroids, intravenous immunoglobulins (IVIG), or plasma exchange (PLEX) are typically used. If partial or no benefit is seen, second line immunotherapeutic agents such as rituximab are considered. Additionally, the severity of the initial presentation and possible risk for relapse influences the use of the latter agents. Symptomatic management is also an important component in our practice and will depend on the syndrome being treated. One of the more novel entities we are facing currently is the management of immune checkpoint (ICI)-induced PNS. In those cases, current American Society of Clinical Oncology (ASCO) guidelines are followed.

Reclassifying guesses to increase signal-to-noise ratio in psychological experiments.

This paper introduces a novel procedure that can increase the signal-to-noise ratio in psychological experiments that use accuracy as a selection variable for another dependent variable. This procedure relies on the fact that some correct responses result from guesses and reclassifies them as incorrect responses using a trial-by-trial reclassification evidence such as response time. It selects the optimal reclassification evidence criterion beyond which correct responses should be reclassified as incorrect responses. We show that the more difficult the task and the fewer the response alternatives, the more to be gained from this reclassification procedure. We illustrate the procedure on behavioral and ERP data from two different datasets (Caplette et al. NeuroImage 218, 116994, 2020; Faghel-Soubeyrand et al. Journal of Experimental Psychology: General 148, 1834-1841, 2019) using response time as reclassification evidence. In both cases, the reclassification procedure increased signal-to-noise ratio by more than 13%. Matlab and Python implementations of the reclassification procedure are openly available ( https://github.com/GroupeLaboGosselin/Reclassification ).

2023 French recommendations for diagnosing and managing prepatellar and olecranon septic bursitis.

Septic bursitis (SB) is a common condition accounting for one third of all cases of inflammatory bursitis. It is often related to professional activities. Management is heterogeneous and either ambulatory or hospital-based, with no recommendations available. This article presents recommendations for managing patients with septic bursitis gathered by 18 rheumatologists from the French Society for Rheumatology work group on bone and joint infections, 1 infectious diseases specialist, 2 orthopedic surgeons, 1 general practitioner and 1 emergency physician. This group used a literature review and expert opinions to establish 3 general principles and 11 recommendations for managing olecranon and prepatellar SB. The French Health authority (Haute Autorité de santé [HAS]) methodology was used for these recommendations. Designed for rheumatologists, general practitioners, emergency physicians and orthopedic surgeons, they focus on the use of biological tests and imaging in both outpatient and inpatient management. Antibiotic treatment options (drugs and duration) are proposed for both treatment modalities. Finally, surgical indications, non-drug treatments and prevention are covered by specific recommendations.

In inflammatory myopathies, dropped head/bent spine syndrome is associated with scleromyositis: an international case-control study.

BACKGROUND: Some myopathies can lead to dropped head or bent spine syndrome (DH/BS). The significance of this symptom has not been studied in inflammatory myopathies (IM). OBJECTIVES: To assess the significance of DH/BS in patients with IM. METHODS: Practitioners from five IM networks were invited to report patients with IM suffering from DH/BS (without other known cause than IM). IM patients without DH/BS, randomly selected in each participating centre, were included as controls at a ratio of 2 to 1. RESULTS: 49 DH/BS-IM patients (DH: 57.1%, BS: 42.9%) were compared with 98 control-IM patients. DH/BS-IM patients were older (65 years vs 53 years, p<0.0001) and the diagnosis of IM was delayed (6 months vs 3 months, p=0.009). Weakness prevailing in the upper limbs (42.9% vs 15.3%), dysphagia (57.1% vs 25.5%), muscle atrophy (65.3% vs 34.7%), weight loss (61.2% vs 23.5%) and loss of the ability to walk (24.5% vs 5.1%) were hallmarks of DH/BS-IM (p≤0.0005), for which the patients more frequently received intravenous immunoglobulins (65.3% vs 34.7%, p=0.0004). Moreover, DH/BS-IM patients frequently featured signs and/or complications of systemic sclerosis (SSc), fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology criteria for this disease in 40.8% of the cases (vs 5.1%, p<0.0001). Distribution of the myopathy, its severity and its association with SSc were independently associated with DH/BS (p<0.05). Mortality was higher in the DH/BS-IM patients and loss of walking ability was independently associated with survival (p<0.05). CONCLUSION: In IM patients, DH/BS is a marker of severity and is associated with SSc (scleromyositis).

Suspected medullary washout leading to severe polyuria following delayed cerebral ischemia: a case report.

BACKGROUND: Delayed cerebral ischemia is a clinical entity commonly encountered in patients presenting with acute neurological injury and is often complicated by dysnatremias, such as the cerebral salt wasting syndrome. In this case report, we described an exceptional case of polyuria attributed to an initial cerebral salt wasting phenomenon and iatrogenic-induced medullary washout. CASE PRESENTATION: A 53-year-old woman was admitted to our hospital for the management of a Modified Fisher scale grade 4 subarachnoid hemorrhage due to a ruptured posterior communicating aneurysm. She was initially managed with coil embolization and external ventricular drain due to secondary hydrocephalus. Throughout the course of her hospitalization, she developed severe polyuria reaching up to 40L per day. To keep up with the excessive urinary losses and maintain appropriate cerebral perfusion, fluid replacement therapy was adjusted every hour, reaching up to 1.3 L of crystalloid per hour in addition to aminergic support. An initial diagnosis of partial diabetes insipidus, followed by a cerebral salt wasting syndrome was suspected. While the urine output continued to increase, her serum urea concentration progressively decreased to a point of almost being undetectable on day 9. At that time, the presence of an interstitial medulla washout was hypothesized. Various pharmacological and non-pharmacological interventions were progressively introduced to regain normal renal homeostasis, including non-steroidal anti-inflammatory drugs, fludrocortisone, oral urea and high-protein intake. Medications were progressively weaned, and the patient was successfully discharged from the ICU. CONCLUSIONS: Cerebral salt wasting should be considered in the initial differential diagnosis of a patient presenting with polyuria in the context of acute neurological injury. Early recognition of this entity is critical to quickly implement proper management. However, as shown in this case report, the concomitance of delayed cerebral ischemia may complexify that management.

Comparison of Electrostatic Spray Drying, Spray Drying, and Freeze Drying for Lacticaseibacillus rhamnosus GG Dehydration.

Spray drying (SD) is extensively used to encapsulate lactic acid bacteria in large-scale industrial applications; however, bacteria combat several harms that reduce their viability. In this study, a novel technique called electrostatic spray drying (ESD) was used to explore the benefits and disadvantages of using electrostatic charge and lower temperatures in the system. Freeze drying (FD) was used as a reference. The effect of different encapsulation agents, like maltodextrin, arabic gum, and skim milk, on the viability of Lacticaseibacillus rhamnosus GG (LGG) was investigated. The initial cell concentration, particle size distribution, aspect ratio, sphericity, scanning-electron-microscopy images, moisture content, water activity, glass transition, rehydration abilities, and survival during storage were compared. Skim milk was proven to be the best protectant for LGG, regardless of the drying process or storage time. A huge reduction in cell numbers (4.49 ± 0.06 log CFU/g) was observed with maltodextrin using SD; meanwhile, it was protected with minimum loss (8.64 ± 0.62 log CFU/g) with ESD. In general, ESD preserved more LGG cells during processing compared to SD, and provided better stability than FD and SD during storage, regardless of the applied voltage. The ESD product analysis demonstrated an efficient LGG preservation, close to FD; therefore, ESD presented to be a promising and scalable substitute for SD and FD.

Fluid Management for Critically Ill Patients with Acute Kidney Injury Receiving Kidney Replacement Therapy: An International Survey.

BACKGROUND: In critically ill patients receiving KRT, high ultrafiltration rates and persistent fluid accumulation are associated with adverse outcomes. The purpose of this international survey was to evaluate current practices and evidence gaps related to fluid removal with KRT in critically ill patients. METHODS: This was a multinational, web-based survey distributed by seven networks comprising nephrologists and intensivists. Physicians involved in the care of critically ill patients were invited to complete a 39-question survey about fluid management practices on KRT. The survey was distributed from September 2021 to December 2021. RESULTS: There were 757 respondents from 96 countries (response rate of 65%). Most respondents practiced adult medicine (89%) and worked in an academic center (69%). The majority (91%) reported aiming for a 0.5- to 2-L negative fluid balance per day when fluid removal is indicated, although there was important variability in what respondents considered a safe maximal target. Intensivists were more likely than nephrologists to use adjunct volume status assessment methods ( i.e. , ultrasound, hemodynamic markers, and intra-abdominal pressure), while nephrologists were more likely to deploy cointerventions aimed at improving tolerance to fluid removal ( i.e. , osmotic agents and low-temperature dialysate). There was a broad consensus that rapid decongestion should be prioritized when fluid accumulation is present, but the prevention of hypotension was also reported as a competing priority. A majority (77%) agreed that performing trials that compare fluid management strategies would be ethical and clinically relevant. CONCLUSIONS: We have identified multiple areas of variability in current practice of fluid management for patients receiving KRT. Most nephrologists and intensivists agreed that several knowledge gaps related to fluid removal strategies should be investigated in future randomized controlled trials.

Online Hemodiafiltration Compared to Conventional Hemodialysis in Critically Ill Patients.

Introduction: Online hemodiafiltration (HDF) has been increasingly used for improved clearance of middle molecular weight toxins. The impact of this mode of clearance is unknown in critically ill patients. We aimed to determine whether the use of HDF in acute kidney injury (AKI) is associated with lower mortality and improved kidney recovery up to 90 days after initiation of therapy. Methods: Single-center retrospective cohort study using data from 2017 to 2020 of adults with AKI who initiated intermittent renal replacement therapy (IRRT) in the intensive care unit (ICU), using either hemodialysis (HD) or HDF depending on the maintenance status of the water system without regards for patient characteristics. We assessed association with patient-events and session-events using time-dependent Cox models and general estimating equations models, respectively. Results: We included 182 adults with AKI for whom 848 IRRT sessions were performed in the ICU. The 90-day mortality rate was 43 of 182 (24.6%). There was no significant association with the use of HDF and mortality (adjusted hazard ratio [aHR]: 0.85 (0.43; 1.67) P = 0.64), kidney recovery (aHR: 1.18 (0.76; 1.84) P = 0.47), or intradialytic hypotension (adjusted odds ratio [aOR]: 0.91 confidence interval [CI]: 0.64-1.28 P = 0.58). HDF treatment was associated with a lower rate of subsequent vasopressor use (aOR: 0.60 CI: 0.36-0.99 P = 0.047) and a greater reduction of the neutrophil-to-lymphocyte ratio (NLR) following the first session (-15.0% vs. +5.1%, P = 0.047) but was also associated with increased risk of filter thrombosis during treatment (aOR: 2.42 CI: 1.67-3.50 P < 0.001). Conclusion: The use of HDF in the setting of AKI was not associated with a differential risk of mortality or kidney recovery.

Diuretic combinations in critically ill patients with respiratory failure: A systematic review and meta-analysis.

BACKGROUND: In patients with respiratory failure, loop diuretics remain the cornerstone of the treatment to maintain fluid balance, but resistance is common. AIM: To determine the efficacy and safety of common diuretic combinations in critically ill patients with respiratory failure. METHODS: We searched MEDLINE, Embase, Cochrane Library and PROSPERO for studies reporting the effects of a combination of a loop diuretic with another class of diuretic. A meta-analysis using mean differences (MD) with 95% confidence interval (CI) was performed for the 24-h fluid balance (primary outcome) and the 24-h urine output, while descriptive statistics were used for safety events. RESULTS: Nine studies totalling 440 patients from a total of 6510 citations were included. When compared to loop diuretics alone, the addition of a second diuretic is associated with an improved negative fluid balance at 24 h [MD: -1.06 L (95%CI: -1.46; -0.65)], driven by the combination of a thiazide plus furosemide [MD: -1.25 L (95%CI: -1.68; -0.82)], while no difference was observed with the combination of a loop-diuretic plus acetazolamide [MD: -0.40 L (95%CI: -0.96; 0.16)] or spironolactone [MD: -0.65 L (95%CI: -1.66; 0.36)]. Heterogeneity was high and the report of clinical and safety endpoints varied across studies. CONCLUSION: Based on limited evidence, the addition of a second diuretic to a loop diuretic may promote diuresis and negative fluid balance in patients with respiratory failure, but only when using a thiazide. Further larger trials to evaluate the safety and efficacy of such interventions in patients with respiratory failure are required.

GFAP astrocytopathy presenting with profound intracranial hypertension and vision loss.

BACKGROUND: Glial fibrillary acidic protein (GFAP) astrocytopathy is a steroid-responsive autoimmune meningoencephalomyelitis commonly preceded by a viral illness. It is clinically characterized by encephalopathy, myelopathy and papillitis without significant effect on visual acuity. It can be associated with an underlying malignancy or autoimmune condition. OBJECTIVE: To report a novel case of GFAP astrocytopathy presenting with profound intracranial hypertension and bilateral vision loss. METHODS: Case report. RESULTS AND CONCLUSION: GFAP astrocytopathy should be considered when evaluating patients with intracranial hypertension or bilateral vision loss, particularly when other features of autoimmune encephalitis are present.

Epidemiological profile of COVID-19 in the French overseas department Mayotte, 2020 to 2021.

BackgroundDuring the COVID-19 pandemic, national and local measures were implemented on the island of Mayotte, a French overseas department in the Indian Ocean with critical socioeconomic and health indicators.AimWe aimed to describe the COVID-19 outbreak in Mayotte from March 2020 to March 2021, with two waves from 9 March to 31 December 2020 and from 1 January to 14 March 2021, linked to Beta (20H/501Y.V2) variant.MethodsTo understand and assess the dynamic and the severity of the COVID-19 outbreak in Mayotte, surveillance and investigation/contact tracing systems were set up including virological, epidemiological, hospitalisation and mortality indicators.ResultsIn total, 18,131 cases were laboratory confirmed, with PCR or RAT. During the first wave, incidence rate (IR) peaked in week 19 2020 (133/100,000). New hospitalisations peaked in week 20 (54 patients, including seven to ICU). Testing rate increased tenfold during the second wave. Between mid-December 2020 and mid-January 2021, IR doubled (851/100,000 in week 5 2021) and positivity rate tripled (28% in week 6 2021). SARS-CoV-2 Beta variant (Pangolin B.1.351) was detected in more than 80% of positive samples. Hospital admissions peaked in week 6 2021 with 225 patients, including 30 to ICU.ConclusionThis massive second wave could be linked to the high transmissibility of the Beta variant. The increase in the number of cases has naturally led to a higher number of severe cases and an overburdening of the hospital. This study shows the value of a real-time epidemiological surveillance for better understanding crisis situations.

Hepatitis B, C, and delta in the general population in Mayotte: hepatitis B as a major public health concern.

BACKGROUND: Located in southwestern Indian Ocean, Mayotte is a French territory, with a very specific demographic, social and health context. To date, epidemiological data on infections by hepatitis B (HBV), C (HCV), and delta (HDV) viruses in Mayotte have been sparse. We aimed to estimate, in the 15-69-year-old general population living in Mayotte, the prevalence of infections by hepatitis B (HBV), C (HCV), and delta (HDV) viruses and the distribution of HBV status: current infection with positive HBs antigen (Ag); resolved infection with positive HBc antibodies and negative HBsAg; immunisation by vaccination with only positive HBs antibodies; and no infection/no immunisation with negative markers. We also described the characteristics of infected people and assessed the determinants of lifetime HBV infection. METHODS: The Unono Wa Maore survey, implemented in a random sample of the general population in 2018-2019, consisted of an at-home collection of epidemiological data and venous blood samples. Detection of hepatitis B, C, and delta serological and molecular markers was performed. RESULTS: Among 5207 eligible people, 4643 responded to the questionnaire (89.2%), with 2917 being tested for HBV and HCV (62.8%). Estimated HBV status was as follows: current infection 3.0% (95% confidence interval [CI]: 2.3-3.9%) (n = 76); resolved infection 27.8% (95% CI: 25.8-29.9); immunisation by vaccination 27.7% (95% CI: 25.9-29.7); and no infection/no immunisation 41.5% (95% CI: 39.3-43.7). One participant was positive for HDV antibodies (Ab) (0.65%) with a negative HDV-RNA viral load. The risk of lifetime HBV infection was higher in men (adjusted prevalence ratio (aPR): 1.55, 95% CI: 1.29-1.89); in people aged 30-49 years (aPR: 3.83, 95% CI: 1.49-9.81) or 50-69 years (aPR: 4.52, 95% CI: 1.77-11.53) compared to those under 20; in individuals who reported no condom use during their first sexual intercourse (aPR: 1.46, 95% CI: 1.01-2.14); and in those living in Dembeni-Mamoudzou (aPR: 1.40, 95% CI: 1.09-1.80) compared to the West-Centre of Mayotte. Finally, six individuals were positive for HCV antibodies (0.21%), including three positive for HCV RNA. CONCLUSIONS: Mayotte is an area of intermediate endemicity for HBV and low endemicity for HCV and HDV. With a prevalence of HBsAg 10 times higher than in mainland France, a high proportion of people susceptible to HBV infection, and a demographic, health, and social context that may favour its transmission, hepatitis B is a major public health concern in Mayotte.

Clinical Implementation of NGAL Testing to Improve Diagnostic Assessment of AKI Episodes in a Canadian Center.

Background: The differential diagnosis of acute kidney injury (AKI) episodes is often challenging. Novel AKI biomarkers have shown their utility to improve prognostic prediction and diagnostic assessment in various research populations but their implementation in standard clinical practice is still rarely reported. Objective: To report the differential diagnostic ability and associated clinical utility of the neutrophil gelatinase-associated lipocalin (NGAL) testing in a real-life setting of a heterogeneous AKI population. Design: This is a retrospective cohort study combined with a clinical audit using questionnaires distributed to consultant nephrologists following NGAL results. Setting: The first 250 consecutive patients with a confirmed AKI where an NGAL test (plasma NGAL [pNGAL] or urine NGAL [uNGAL]) was ordered from a large academic center in Montreal, Canada from January 2021 to August 2021. Patients: Patients were classified into 3 groups based on the final AKI etiology category (functional, intrarenal, and postrenal) following definitive adjudication by 2 independent nephrologists. Methods: The ability of plasma NGAL (pNGAL), urine NGAL (uNGAL), and uNGAL-to-creatinine ratio (uNGAL/Cr) to discriminate intrarenal from functional AKI etiologies was compared to standard urine chemistry (FENa) and proteinuria. A logistic regression was used to evaluate the association between intrarenal AKI and increased biomarker levels. The overall clinical utility and appreciation of the NGAL test was evaluated using a questionnaire completed prospectively by the consultant nephrologist at the time of receiving the NGAL result. The NGAL results were prospectively available to clinicians with a median time of 2.9 (1.3-7.4) hours from the initial order. Results: A total of 214 uNGAL and 44 pNGAL were ordered from 100 functional, 139 intrarenal and 11 postrenal AKI episodes after final adjudication. The discriminative ability of FENa (AUC 0.68 [95% CI: 0.61-0.75]) was lower than uNGAL (AUC 0.80 [95% CI: 0.73-0.86]) and uNGAL/Cr (AUC 0.83 [95% CI: 0.77-0.88]) but better than pNGAL (AUC 0.66 [95% CI: 0.48-0.85]). According to consultant nephrologists, the NGAL testing has led to a change in clinical management in 42% of cases. Limitations: Data reported came from a single center and NGAL was reserved for more complex cases, which limits generalizability. No biopsy has been performed for most AKI cases as the final adjudication was based on a retrospective review of the hospitalization episode. Conclusions: Neutrophil gelatinase-associated lipocalin testing can be successfully integrated as part of the diagnostic workup for AKI in clinical practice. The integration of tubular damage biomarkers to functional biomarkers can further improve the differential diagnostic assessment. However, the impact of such biomarkers on AKI management and associated outcomes still needs further validation.

Contexte: Le diagnostic différentiel des épisodes d'insuffisance rénale aiguë (IRA) pose souvent un problème. De nouveaux biomarqueurs d'IRA ont montré leur utilité pour améliorer la prédiction pronostique et l'évaluation diagnostique dans diverses populations de recherche, mais leur application dans la pratique clinique est encore peu rapportée. Objectif: Rendre compte de la capacité de diagnostic différentiel et de l'utilité clinique du test NGAL (neutrophil gelatinase-associated lipocalin) dans le contexte réel d'une population hétérogène de patients atteints d'IRA. Devis: Étude de cohorte rétrospective combinée à un audit clinique mené par l'entremise de questionnaires distribués aux néphrologues consultants à la suite du résultat NGAL. Cadre: Les 250 premiers patients consécutifs avec une IRA confirmée, pour qui un test NGAL (plasmatique [pNGAL] ou urinaire [uNGAL]) avait été demandé entre janvier et août 2021 dans un grand centre universitaire de Montréal (Canada). Sujets: Les patients ont été classés en 3 groupes selon la catégorie étiologique finale de l'IRA (fonctionnelle, intrarénale, post-rénale) après révision par deux néphrologues indépendants. Méthodologie: La capacité du pNGAL, du uNGAL et du rapport uNGAL et du rapport uNGAL sur créatinine (uNGAL/Cr) à discriminer les étiologies fonctionnelles des étiologies intrarénales a été comparée à celle des indices urinaires standard de l'urine (FENa) et de la protéinurie. Une régression logistique a servi à évaluer l'association entre l'IRA intrarénale et la hausse des taux des biomarqueurs. L'appréciation du test NGAL et son utilité clinique globale ont été évaluées à l'aide d'un questionnaire rempli prospectivement par le néphrologue consultant lors de la réception du résultat NGAL. Les résultats NGAL ont été mis à la disposition des cliniciens de manière prospective, dans un délai médian de 2,9 [1,3-7,4] heures suivant la prescription initiale. Résultats: En tout, après la révision finale, 214 tests uNGAL et 44 tests pNGAL ont été demandés à partir de 100 épisodes d'IRA fonctionnelle, 139 épisodes d'IRA intrarénale et 11 épisodes d'IRA post-rénale. La capacité discriminante du FENa (SSC: 0,68 [IC 95 %: 0,61-0,75]) était inférieure à celles du uNGAL (SSC: 0,80 [IC 95 %: 0,73-0,86]) et du rapport uNGAL/ Cr (SSC: 0,83 [IC 95 %: 0,77-0,88]), mais supérieure à celle du pNGAL (SSC: 0,66 [IC 95 %: 0,48-0,85]). Les néphrologues ont indiqué que les tests NGAL avaient entraîné un changement dans la prise en charge clinique dans 42 % des cas. Limites: Les données provenaient d'un seul centre et le test NGAL était réservé aux cas plus complexes, ce qui limite la généralisabilité. Dans la plupart des cas, aucune biopsie n'a été effectuée et le diagnostic final était basé sur un examen rétrospectif de l'hospitalisation. Conclusions: En pratique clinique, les tests NGAL peuvent être intégrés avec succès au diagnostic de l'IRA. L'intégration des biomarqueurs de lésions tubulaires aux biomarqueurs fonctionnels peut améliorer davantage l'évaluation du diagnostic différentiel. Cependant, l'impact de ces biomarqueurs sur la prise en charge de l'IRA et les résultats connexes doit encore être validé.

Polyamine biosynthesis and eIF5A hypusination are modulated by the DNA tumor virus KSHV and promote KSHV viral infection.

Polyamines are critical metabolites involved in various cellular processes and often dysregulated in cancers. Kaposi's sarcoma-associated Herpesvirus (KSHV), a defined human oncogenic virus, leads to profound alterations of host metabolic landscape to favor development of KSHV-associated malignancies. In our studies, we identified that polyamine biosynthesis and eIF5A hypusination are dynamically regulated by KSHV infection through modulation of key enzymes (ODC1 and DHPS) of these pathways. During KSHV latency, ODC1 and DHPS are upregulated along with increase of hypusinated eIF5A (hyp-eIF5A), while hyp-eIF5A is further induced along with reduction of ODC1 and intracellular polyamines during KSHV lytic reactivation. In return these metabolic pathways are required for both KSHV lytic reactivation and de novo infection. Further analysis unraveled that synthesis of critical KSHV latent and lytic proteins (LANA, RTA) depends on hypusinated-eIF5A. We also demonstrated that KSHV infection can be efficiently and specifically suppressed by inhibitors targeting these pathways. Collectively, our results illustrated that the dynamic and profound interaction of a DNA tumor virus (KSHV) with host polyamine biosynthesis and eIF5A hypusination pathways promote viral propagation, thus defining new therapeutic targets to treat KSHV-associated malignancies.

Risk of acute kidney injury associated with anti-pseudomonal and anti-MRSA antibiotic strategies in critically ill patients.

BACKGROUND: An increased risk of acute kidney injury (AKI) with the widely prescribed piperacillin-tazobactam(PTZ)-vancomycin combination in hospitalized patients has recently been reported, but evidence in ICU patients remain uncertain. This study evaluates the association between the exposure of various broad-spectrum antibiotic regimens with Pseudomonas and/or methicillin-resistance Staphylococcus aureus (MRSA) coverage and the risk of AKI in critically ill patients. METHODS AND FINDINGS: A retrospective cohort study based on the publicly available MIMIC-III database reporting hospitalization data from ICU patients from a large academic medical center between 2001 and 2012. Adult patients receiving an anti-pseudomonal or an anti-MRSA agent in the ICU for more than 24-hours were included. Non-PTZ anti-pseudomonal agents were compared to PTZ; non-vancomycin agents covering MRSA were compared to vancomycin; and their combinations were compared to the PTZ-vancomycin combination. The primary outcome was defined as new or worsening AKI within 7 days of the antibiotic exposure using an adjusted binomial generalized estimating equation. Overall, 18 510 admissions from 15 673 individual patients, cumulating 169 966 days of antibiotherapy were included. When compared to PTZ, exposure to another anti-pseudomonal agent was associated with lower AKI risk (OR, 0.85; 95% CI, 0.80-0.91; p < .001). When compared to vancomycin, exposure to another anti-MRSA was also associated with lower AKI risk (OR, 0.71; 95% CI, 0.64-0.80; p < .001). Finally, when compared to the PTZ-vancomycin combination, exposure to another regimen with a similar coverage was associated with an even lower risk (OR, 0.63; 95% CI; 0.54-0.73; p < .001). A sensitivity analysis of patients with high illness severity showed similar results. CONCLUSIONS: These results suggest that the risk of AKI in ICU patients requiring antibiotherapy may be partially mitigated by the choice of antibiotics administered. Further clinical trials are required to confirm these findings.

Intermittent Convective Therapies in Patients with Acute Kidney Injury: A Systematic Review with Meta-Analysis.

INTRODUCTION: In critically ill patients requiring intermittent renal replacement therapy (RRT), the benefits of convective versus diffusive clearance remain uncertain. We conducted a systematic review and meta-analysis to determine the safety, clinical efficacy, and clearance efficiency of hemofiltration (HF) and hemodiafiltration (HDF) compared to hemodialysis (HD) in patients with acute kidney injury (AKI) receiving intermittent RRT. METHOD: We searched Medline, Embase, Cochrane Library, and PROSPERO. We included clinical trials and observational studies that reported the use of intermittent HF or HDF in adult patients with AKI. The following outcomes were included: mortality, renal recovery, clearance efficacy, intradialytic hemodynamic stability, circuit loss, and inflammation modulation. RESULTS: A total of 3,169 studies were retrieved and screened. Four randomized controlled trials and 4 observational studies were included (n: 615 patients). Compared with conventional HD, intermittent convective therapies had no effect on in-hospital mortality (relative risk, 1.23; 95% confidence interval (CI), 0.76-1.99), renal recovery at 30 days (RR, 0.98; 95% CI, 0.82-1.16), time-to-renal recovery (mean difference [MD], 0.77; 95% CI, -6.56 to 8.10), and number of dialysis sessions until renal recovery (MD, -1.34; 95% CI, -3.39 to 0.72). The overall quality of included studies was low, and dialysis parameters were suboptimal for all included studies. CONCLUSION: This meta-analysis suggests that there is no significant difference in short-term mortality and renal recovery in patients with severe AKI when treated with intermittent HF or HDF compared to conventional HD. This systematic review emphasizes the need for further trials evaluating optimal convective parameters in AKI patients treated with intermittent dialysis.