Insuffisance rénale aïgue à COVID-19: à propos de 02 cas au Mali / Acute renal failure due to covid-19: about the two cases in Mali

Le rein est une des cibles de Covid-19.L'atteinte peut se présenter sous forme d'une insuffisance rénale aigue (5-35% des patients), d'une hématurie (30-40%) et/ou d'une protéinurie (40-65%). Nous rapportons deux cas d'insuffisance rénale aigue due au Covid-19 au Mali. Il s'agit d'une femme de 63 ans et d'un homme de 60 ans, de race noire et tous deux diabétiques. Les circonstances de découverte de l'insuffisance rénale ont été l'oligurie dans les deux cas et l'hématurie macroscopique totale dans le deuxième cas. Conclusion : Les atteintes rénales deviennent de plus de plus fréquentes au cours de l'infection à Covid-19. Nous suggérons de les rechercher systématiquement dès que le diagnostic de cette infection est posé.

[Prevalence of the kidney disease at the emergency department of hospital Fousseyni Daou of Kayes]. / Prevalence de la maladie renale au service des urgences de l'hopital Fousseyni Daou de Kayes.

INTRODUCTION: Kidney disease (KD) is defined as a set of functional, morphological and histological kidney abnormalities. It is a truly global public health problem. Its prevalence is estimated to be 50 times that of end-stage renal disease (ESRD). In Kayes, there is no data on the prevalence of kidney disease, hence the interest of this study. OBJECTIVES: to determine the prevalence of renal disease, its main causes and the main factors of aggravation of this pathology in the emergency department at hospital Fousseyni DAOU of Kayes. METHODOLOGY: Retrospective cross-sectional study carried out from January 1, 2014 to February 1, 2015. We included all hospitalized patients in whom a renal damage marker (elevation of plasma creatinine, urinary sediment abnormality, ultrasound, histology and significant proteinuria) has been found. RESULTS: the prevalence of kidney disease was 9.9% (109/1099). Eighty-nine met the inclusion criteria. The study population was composed of 47 women (52.8%) and 42 men (47.2%), with a sex ratio of 0.89 in favor of women. The average age was 40.09 years with a predominance of patients in the age group [40-59]. The main reasons for consultation were hypercreatininaemia (48.3%), edematous syndrome (16.9%), low back pain (10.1%). High blood pressure (55.1%) and lower extremity edema (46.1%) were the medical history frequently found in our study. The kidney disease found was in order of growth: chronic renal failure (51%); acute renal failure (28%); proteinuria (16%), hematuria (3%), morphological abnormality of the kidneys (2%). Tubulointerstitial nephropathy represented 64% of acute renal failure with P = 0.000306. Vascular nephropathy constituted 46.7% of chronic renal failure with P = 0.000251. No cases of glomerular nephropathy were found in patients over 60 years of age.The most common causes were represented by nephrotoxic drugs injuries; infectious; high blood pressure and diabetes. The most observed aggravating factors are herbal medicine, urinary tract infections, renal hypoperfusion and unbalanced hypertension. CONCLUSION: kidney disease is not uncommon in the emergency room at Hospital Fousseyni Daou of Kayes. The most common causes are nephrotoxic drugs, hypertension and diabetes.

INTRODUCTION: La maladie rénale (MR) définie comme l'ensemble des anomalies rénales fonctionnelle, morphologique et histologique. Elle est un véritable problème mondial de santé publique. Sa prévalence serait 50 fois celle de l'insuffisance rénale terminale (IRT). A Kayes, il n'existe pas de donnée sur la prévalence de la maladie rénale, d'où l'intérêt de cette étude. OBJECTIFS: déterminer la prévalence de la maladie rénale, ses principales causes et les principaux facteurs d'aggravation de cette pathologie dans le service des urgences de l'hôpital Fousseyni DAOU de Kayes. MÉTHODOLOGIE: Etude transversale rétrospective réalisée du 1er janvier 2014 au 1er février 2015. Etaient inclus, tous les patients hospitalisés chez qui au moins un marqueur d'atteinte rénale (élévation de la créatinine plasmatique, anomalie du sédiment urinaire, anomalie échographique ou histologique et une protéinurie significative) a été retrouvé. Les paramètres analysés étaient socio-épidémiologiques, cliniques et para-cliniques. Nous avons exclu tous les patients dont les dossiers médicaux étaient inexploitables. RÉSULTATS: la prévalence de la maladie rénale était de 9,9% (109/1099). Quatre-vingtneuf répondaient aux critères d'inclusion. La population d'étude était composée de 47 femmes (52,8%) et de 42 hommes (47,2%), avec un sex-ratio de 0,89 en faveur des femmes. La moyenne d'âge était de 40,09 ans avec une prédominance des patients de la tranche d'âge [40-59]. Les principaux motifs de consultation étaient hypercréatininémie (48,3%), syndrome œdémateux (16,9%), douleur lombaire (10,1%). L'hypertension artérielle (55,1%) et œdème des membres inférieurs (46,1%) étaient les antécédents pathologiques fréquemment retrouvées dans notre étude. La maladie rénale retrouvée était par ordre de croissance : insuffisance rénale chronique (51%) ; insuffisance rénale aigue (28%) ; protéinurie (16%), hématurie (3%), anomalie morphologique des reins (2%). La néphropathie tubulo-interstitielle représentait 64% des insuffisances rénales aiguës avec P= 0,000306. La néphropathie vasculaire constituait 46,7% des insuffisances rénales chroniques avec P= 0,000251. Aucun cas de néphropathie glomérulaire n'a été retrouvé chez les patients de plus de 60 ans.Les causes les plus fréquentes étaient représentées par les causes toxiques (médicaments néphrotoxiques) ; infectieuses ; l'hypertension artérielle et le diabète. Les facteurs d'aggravations les plus observés sont la phytothérapie, l'infection urinaire, l'hypoperfusion rénale et l'HTA non équilibrée. CONCLUSION: la maladie rénale n'est pas rare aux urgences de l'hôpital Fousseyni Daou de Kayes. Les causes les plus fréquemment rencontrées sont les médicaments néphrotoxiques, l'HTA et le diabète.

[Epidemiological and prognostic aspects of obstructive renal deficiency in the nephrology department of the Point "G" hospital, Bamako, Mali]. / Aspects epidemiologiques et pronostiques de l'insuffisance renale obstructive dans le service de nephrologie du CHU du Point G, Bamako, Mali.

INTRODUCTION: Obstructive renal failure or obstructive uropathy is an entity defined by the simultaneous presence of impaired renal function and dilated urinary excretory pathways in medical imaging. It accounts for 2 to 10% of the causes of acute renal failure (ARF). The purpose of this work was to evaluate the prevalence of this condition in our department. METHOD: This was a retrospective study conducted from January 1, 2017 to June 30, 2018 in the said department. The parameters studied were age, sex, etiology, type of renal failure, actions performed, surgical results of the procedure, creatinine level before and after management, and death rate. RESULTS: obstructive renal failure accounted for 7.32% of all hospitalizations during the study period. The sex ratio was 1.86 in favor of men. The average age was 48.99 ± 6.81 years with extremes of 7 and 102 years. The etiologies were dominated by lithiasis (43.4%). Renal failure was acute and chronic in 20.5% and 54.2% of cases, respectively. It was indeterminate in 25.3% of cases. The obstructive character of renal failure has been confirmed in medical imaging. Lithiases accounted for 43.4% of cases. For therapeutic management, our patients received urinary catheterization (38.6%), nephrostomy (34.9%), urological surgery (22.9%) and hemodialysis (22%). The evolution was favorable in 59% of the cases. CONCLUSION: Obstructions of the upper urinary tract are becoming more frequent in our medical practice. They occur mainly in patients with lithiasis. There is a large proportion of kidney failure requiring hemodialysis.

INTRODUCTION: L'insuffisance rénale obstructive ou encore uropathie obstructive est une entité définie par la présencesimultanée d'une altération de la fonction rénale et d'une dilatation des voies excrétrices urinaires à l'imageriemédicale. Elle représente 2 à 10% des causes d'insuffisance rénale aiguë (IRA). L'objectif de ce travail était de déterminer la prévalence de cette affection dans notre service. MÉTHODE: Il s'agissait d'une étude rétrospective réalisée du 1er janvier 2017 au 30 juin 2018 dans le service de néphrologie du CHU du Point G.Ont été inclus, tous les patients hospitalisés dans le service durant la période d'étude et ayant un dossier médical exploitable. Les paramètres étudiés étaient l'âge, le sexe, l'étiologie, le type d'insuffisance rénale, les gestes réalisés, les résultats chirurgicaux de la procédure, le taux de créatinine avant et après la prise en charge et le taux de décès. RÉSULTAT: Durant la période d'étude, 83 patients répondaient aux critères d'inclusion sur les 1133 patients hospitalisés, soit 7, 32%.Le sex-ratio était de 1,86 en faveur des hommes. L'âge moyen était de 48,99±6,81 ans avec des extrêmes de 7 et 102 ans. A l'admission 97,6% des patients avaient une créatininémie augmentée. La créatininémie moyenne était de 1284,087 µmol/l avec des extrêmes de 506 et 2063 µmol/l. La créatininémie moyenne après traitement était de 579,605 µmol/l. L'échographie de l'arbre urinaire réalisée chez tous nos patients a montré une hydronéphrose et une urétérohydronéphrose dans respectivement 61,5% et 38,5% des cas. La tomodensitométrie abdomino-pelvienne réalisée chez 42 patients, montrait une urétérohydronéphrose bilatérale dans 50% des cas. La lithiase urétérale et les séquelles bilharziennes étaient les plus fréquemment retrouvées à la TDM avec 23,53% chacune. L'infection urinaire était présente dans 59,7% des cas et le germe isolé était Escherichia coli dans 32,8% des cas. Les étiologiesétaient dominées par les lithiases (43,4%). L'insuffisance rénale était aiguë et chronique dans respectivement 20,5% et 54,2% des cas. Elle était indéterminée dans 25,3% des cas. La prise en charge thérapeutique comportait le sondage urinaire (38,6%), la néphrostomie percutanée (34,9%), la chirurgie urologique (22,9%) et l'hémodialyse (22%).L'évolution a été favorable dans 59,04% des cas dont 20,48% des cas de guérison complète, 14, 46% des cas d'amélioration et 24,10% des cas ont été transférés. Le taux de mortalité était élevé soit 36,14%. CONCLUSION: les obstructions du haut appareil urinaire sont de plus en plus fréquentes dans notre pratique médicale. Elles sont essentiellement d'origine lithiasique. On compte une importante proportion d'insuffisance rénale nécessitant une prise en charge en hémodialyse.

[Acute renal failure due to covid-19: about the two cases in Mali]. / Insuffisance renale aigue a covid-19 : a propos de 02 cas au Mali.

The kidney is one of the target of Covid-19. Damage may present itself as acute renal failure (5-35% of patients), hematuria (30-40%) and/or proteinuria (40-65%). We report the first couple cases of acute renal failure due to Covid-19 in Mali : a 63years old woman and a 60years old man, both black and diabetics. The circumstances of discovery of renal failure were oliguria in both cases and total macroscopic hematuria for the man. CONCLUSION: The kidney damages become more and more frequent during Covid-19 infection. We suggest that they should be systematically investigated as soon as the diagnosis of this infection is made.

Le rein est une des cibles de Covid-19.L'atteinte peut se présenter sous forme d'une insuffisance rénale aigue (5-35% des patients), d'une hématurie (30-40%) et/ou d'une protéinurie (40-65%). Nous rapportons deux cas d'insuffisance rénale aigue due au Covid-19 au Mali. Il s'agit d'une femme de 63 ans et d'un homme de 60 ans, de race noire et tous deux diabétiques. Les circonstances de découverte de l'insuffisance rénale ont été l'oligurie dans les deux cas et l'hématurie macroscopique totale dans le deuxième cas. CONCLUSION: Les atteintes rénales deviennent de plus de plus fréquentes au cours de l'infection à Covid-19. Nous suggérons de les rechercher systématiquement dès que le diagnostic de cette infection est posé.

Bladder cancer-derived interleukin-1 converts the vascular endothelium into a pro-inflammatory and pro-coagulatory surface.

BACKGROUND: Bladder cancer cells orchestrate tumour progression by pro-inflammatory cytokines. Cytokines modulate the local tumour microenvironment and increase the susceptibility of tumour distant tissues for metastasis. Here, we investigated the impact of human bladder cancer cell derived factors on the ability to modulate and activate human vascular endothelial cells. METHODS: The pro-inflammatory and pro-coagulatory potential of four different bladder cancer cell lines was accessed by qRT-PCR arrays and ELISA. Modulation and activation of endothelial cells was studied in microfluidic devices. Clinical relevance of our findings was confirmed by immune histology in tissue samples of bladder cancer patients and public transcriptome data. RESULTS: The unbalanced ratio between interleukin (IL)-1 and IL-1 receptor antagonist (IL-1ra) in the secretome of bladder cancer cells converted the quiescent vascular endothelium into a pro-adhesive, pro-inflammatory, and pro-coagulatory surface. Microfluidic experiments showed that tumour cell induced endothelial cell activation promoted leukocyte recruitment and platelet adhesion. Human bladder cancer tissue analysis confirmed that loss of IL-1ra and elevated IL-1 expression was associated with enhanced cancer progression. CONCLUSIONS: Our data indicate that IL-1 and IL-1ra were dysregulated in bladder cancer and could facilitate tumour dissemination through endothelial cell activation. Targeting the IL-1/IL-1ra axis might attenuate tumour-mediated inflammation and metastasis formation.

[Mortality in the hemodialysis unit of the Gavardo hospital in sebenikoro]. / Mortalite dans l'unite d'hemodialyse de l'hopital mali Gavardo de sebenikoro (Bamako, Mali).

INTRODUCTION: Chronic kidney disease (CKD)is a serious public health problem in Africa with regard to mortality associated with it. According to global hospital data, CKD is involved in 4-22% of deaths in tropical Africa. In Mali, epidemiological studies are infrequent.Thus, this work is under taken with the objective of studying the epidemiological aspects and the factors associated with the mortality of hemodialysis patients in the hemodialysis unit of the Mali Gavardo Hospital (HMG) in Sébenikoro. METHOD: We conducted a descriptive retrospective cross-sectionalstudy of the hemodialysis unit of the HMG in Sébenikoro. Data were collected over a 12-month period from January to December 2017. Included were records of all hemodialysis patients for chronic renal failure who died, of either sex and anyage. RESULTS: A total of 52 patients were dialysed during the study period among whom 12 died or a mortality rate of 23%. The average age of the patients was 59.16 years with extremes of 39 and 71 years. Patients aged 60 and over accounted for 58.3% of cases. There was a male predominance with a sex ratio M / F: 2. In terms of chronic diseases, 83.3% of patients were hypertensive, 50% diabetic, and 16.66% hadhepatitis C. Compared to the initial nephropathies : glomerular nephropathy: 58.3%, vascular nephropathy: 25.0%, undetermined nephropathy: 16.7%. For the management of anemia, 100% ofour patients received EPO and iron injection. Regarding the management of hemodialysis, 83.3% had an AVF as a vascular approach and 16.7% had a central venous catheter as a vascular approach. The patients were all regular at their hemodialysis session with a rhythm of two sessions of 04H of time per session and per week. The causes of death were dominated by cardiovascular pathologies: 5 cases, 41.7%, infectious diseases: 4 cases, 33.3%, indeterminate pathologies: 3 cases or 25%. Deaths occurred in 58.3% of cases before one year of dialysis and 41.7% after one year of hemodialysis treatment. CONCLUSION: The mortality rate of hemodialysis patients is high in Mali, especially in the HMG of Sébénikoro. Cardiovascular causes have an important role in the mortality of hemodialysis patients, but other causes such as infections are not to be over looked.

INTRODUCTION: En Afrique, l'insuffisance rénale chronique (IRC) est un problème de santé publique au regard de la mortalité qui lui est associée. L'IRC est impliquée dans 4 à 22% de décès en Afrique tropicale . Au Mali les études épidémiologiques sont rares . Ce travail est entrepris pour étudier les aspects épidémiologiques et les facteurs associés à la mortalité chez les hémodialysés chroniques. MÉTHODE: il s'agissait d'une étude transversale rétrospective et descriptive ayant pour cadre l'unité d'hémodialyse de l'HMG. Les données ont été collectées sur une période de 12 mois. Ont été inclus, les dossiers de tous les patients hémodialysés chroniques décédés. RÉSULTATS: Au total 52 patients dialysés pendant la période d'étude parmi lesquels 12 sont décédés soit un taux de mortalité de 23%. L'âge moyen des patients était de 59,16 ans avec des extrêmes de 39 et 71 ans. Les patients âgés de 60 ans et plus constituaient 58,3% des cas. On notait une prédominance masculine avec un sexe ratio H/F : 2. Les néphropathies initiales étaient glomérulaire (58,3%), vasculaire (25,0%) et indéterminée (16,7%). Pour la prise en charge en hémodialyse, 83,3% avait une FAV et 16,7% avait bénéficié d'un cathéter veineux central. Les causes de mortalité étaient : les pathologies cardiovasculaires (41,7%,), les pathologies infectieuses (33,3), les pathologies indéterminées (25%). CONCLUSION: Le taux de mortalité des hémodialysés est élevé à l'HMG. Les causes cardiovasculaires ont une place importante dans la mortalité des hémodialysés.

[Spontaneous acute subdural hematoma of the chronic hemodialysis patient, a case study and review of the literature]. / Hematome sous-dural aigu spontane du patient en hemodialyse chronique : a propos de un cas et revue de la litterature.

INTRODUCTION: The appearance of spontaneous subdural hematoma (SSDH) is a rare phenomenon in chronic hemodialysis and is burdened with significant morbidity and mortality. It's prevalence remains low in Sub-Saharan Africa, is 0.43%. We report a case of SSDH in a young hemodialysis patient with favorable outcome after medico-surgical management. CLINICAL OBSERVATION: This is a 35-year-old patient who has been hemodialysed since June 2016 for chronic renal insufficiency of hypertensive origin. He was admitted on 18 July 2018 in the nephrology department of CHU Point G for intense headaches in a context of dysarthria. They associate themselves with speech disorders, photo-phonophobia, uncontrollable nausea and vomiting. It does not report any notion of head trauma. The physical examination noted dysarthria, a right pyramidal syndrome made of right Babinsky sign, right arm deficit at 4/5, and right hemicorporeal hyperkinesia. He weighed 62 kg for 165 cm, the blood pressure was 187 / 110 mmHg. The patient had clinical signs of extracellular dehydration. Non-injected cerebral CT showed an acute left sub-dural hematoma with peri-lesional cerebral hypodensity. Surgical evacuation of the hematoma through a trephine hole is performed under local anesthesia. The postoperative course was simple. His hemodialysis sessions were done without heparin from diagnosis until 23 days post operatively. CONCLUSION: Spontaneous subdural hematoma is multifactorial and rare in the dialysis patient. Despite high morbidity and mortality, hemodialysis should not refute surgical management of subdural hematoma.

INTRODUCTION: L'apparition d'un hématome sous-dural (HSD) spontané est un phénomène rare en hémodialyse chronique et est grevé d'une morbi-mortalité importante. Sa prévalence reste faible en Afrique Sub-Saharienne soit 0,43%. Nous rapportons un cas d'HSD spontané chez un patient jeune hémodialysé avec issue favorable après une prise en charge médico-chirurgicale. OBSERVATION CLINIQUE: Il s'agit d'un patient de 35 ans, hémodialysé depuis juin 2016 pour une insuffisance rénale chronique d'origine hypertensive. Il a été admis le 18 juillet 2018 dans le service de néphrologie du CHU Point G pour des céphalées intenses dans un contexte de dysarthrie. Ils s'y associent des troubles de langage, d'une photo-phonophobie, des nausées et des vomissements incoercibles. Il ne rapporte aucune notion de traumatisme crânien. L'examen physique notait une dysarthrie, un syndrome pyramidal droit fait de signe de Babinsky droit, un déficit du bras droit à 4/5, et une hyperkinésie hémicorporelle droite. Il pesait 62 kg pour 165 cm, la pression artérielle était à 187/110 mmHg. Le patient présentait des signes cliniques de déshydratation extracellulaire. La tomodensitométrie cérébrale sans injection montrait un hématome sous-dural aigu gauche avec hypodensité cérébrale péri-lésionnelle. L'évacuation chirurgicale de l'hématome à travers un trou Trépan est réalisée sous anesthésie locale. Les suites opératoires ont été simples. Ses séances d'hémodialyse étaient faites sans héparine depuis le diagnostic jusqu'à j 23 en post opératoire. CONCLUSION: L'hématome sous-dural spontané est multifactoriel et rare chez le patient dialysé. Malgré une forte morbi-mortalité, l'hémodialyse ne doit pas réfuter une prise en charge chirurgicale de l'hématome sous-dural.

Hematome sous-dural aigu spontane du patient en hemodialyse chronique: a propos de un cas et revue de la litterature

Introduction:L'apparition d'un hématome sous-dural (HSD) spontané est un phénomène rare en hémodialyse chronique et est grevé d'une morbi-mortalité importante. Sa prévalence reste faible en Afrique Sub-Saharienne soit 0,43%. Nous rapportons un cas d'HSD spontané chez un patient jeune hémodialysé avec issue favorable après une prise en charge médico-chirurgicale.Observation clinique:Il s'agit d'un patient de 35 ans,hémodialysé depuis juin 2016 pour une insuffisance rénale chronique d'origine hypertensive.Il a été admis le 18 juillet 2018 dans le service de néphrologie du CHU Point G pour des céphalées intenses dans un contexte de dysarthrie. Ils s'y associent des troubles de langage, d'une photo-phonophobie, des nausées et des vomissements incoercibles. Il ne rapporte aucune notion de traumatisme crânien.L'examen physique notait une dysarthrie, un syndrome pyramidal droit fait de signe de Babinsky droit, un déficitdu bras droit à 4/5, et une hyperkinésie hémicorporelle droite. Il pesait 62 kg pour 165 cm, la pression artérielle était à 187/110 mmHg. Le patient présentait des signes cliniques de déshydratation extracellulaire. La tomodensitométrie cérébrale sans injection montrait un hématome sous-dural aigu gauche avec hypodensité cérébrale péri-lésionnelle. L'évacuation chirurgicale de l'hématome à travers un trouTrépan est réalisée sous anesthésie locale. Les suites opératoires ont été simples. Ses séances d'hémodialyse étaient faites sans héparine depuis le diagnostic jusqu'à j 23 en post operatoire. Conclusion:L'hématome sous-dural spontané est multifactoriel et rare chez le patient dialysé. Malgré une forte morbi-mortalité, l'hémodialyse ne doit pas réfuter une prise en charge chirurgicale de l'hématome sous-dural

[Pregnancy In Chronic Hemodialysis, Case Study]. / Grossesse Au Cours De L'Hemodialyse Chronique : A Propos D'Un Cas.

For a long time, pregnancy in chronic hemodialysis was considered medically contraindicated, because of the many maternal complications that it could cause. Its management is as heavy for the medical teams (nephrologist, obstetrician and neonatologist) as for the patient herself. We report here a case of pregnancy in a dialysis patient observed at the Madeleine clinic in Dakar, Senegal. This pregnancy is the first described with a birth of a living child having a normal birth weight without abnormal malformative thanks to the multidisciplinary follow-up nephrologist, obstetrician and neonatologist), the intensification of dialysis care, the correction of anemia, control of blood pressure and improvement of the mother status nutritional.

Pendant très longtemps la grossesse chez l'hémodialysée chronique était considérée comme médicalement contre indiquée, à cause des nombreuses complications materno fœtales qu'elles pouvaient engendrer. Sa prise en charge est aussi lourde pour les équipes médicales (néphrologue, obstétricien et neonatologiste) que pour la patiente elle-même. Nous rapportons ici un cas de grossesse chez une dialysée observé à la clinique madeleine de Dakar au Sénégal. Cette grossesse est la première décrite avec une naissance d'un enfant vivant ayant un poids de naissance normal sans anomalie malformative grâce au suivi pluridisciplinaire (néphrologue, obstétricien et néonatologiste), l'intensification des soins de dialyse, la correction de l'anémie, la maitrise de la pression artérielle et l'amélioration de l'état nutritionnel de la mère.

A model-based analysis of pharmacokinetic-pharmacodynamic (PK/PD) indices of avibactam against Pseudomonas aeruginosa.

OBJECTIVE: The aim of the present work was to use a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) model developed from in vitro time-kill measurements with P. aeruginosa to compare different pharmacodynamic indices derived from simulated human avibactam exposures, with respect to their degree of correlation with the modelled bacterial responses. METHODS: A mathematical model of the effect of ceftazidime-avibactam on the growth dynamics of P. aeruginosa was used to simulate bacterial responses to modelled human exposures from fractionated avibactam dosing regimens with a fixed ceftazidime dosing regimen (2 or 8 g q8h as a 2-h infusion). The relatedness of the 24-h change in bacterial density and avibactam exposure parameters was evaluated to determine exposure parameter that closely correlated with bacterial growth/killing responses. RESULTS: Frequent dosing was associated with higher efficacy, resulting in a reduction of avibactam daily dose. The best-fit PD index of avibactam determined from the simulation was fT > CT of 1 mg/L avibactam and q8h was the longest dosing interval able to achieve 2-log kill: 41-87% (3.3 h to 7.0 h out of 8-h interval, respectively). The avibactam exposure magnitude required to achieve a 2-log kill in the simulations was dependent on the susceptibility of the bacterial isolate to ceftazidime. CONCLUSIONS: Avibactam activity in combination with ceftazidime against multidrug resistant P. aeruginosa correlated with fT > CT. Setting a threshold avibactam concentration to 1 mg/L, superimposed over a simulated human-like exposure of ceftazidime, achieved at least 2-log kill for the clinical dose of 500 mg q8h avibactam as a 2-h infusion, depending on the minimum inhibitory concentration of ceftazidime alone.

Grossesse au cours de l'hémodialyse chronique : à propos d'un cas

Pendant très longtemps la grossesse chez l'hémodialysée chronique était considérée comme médicalement contre indiquée, à cause des nombreuses complications materno fœtales qu'elles pouvaient engendrer. Sa prise en charge est aussi lourde pour les équipes médicales (néphrologue, obstétricien et néonatologie) que pour la patiente elle-même. Nous rapportons ici un cas de grossesse chez une dialysée observe à la clinique madeleine de Dakar au Sénégal. Cette grossesse est la première décrite avec une naissance d'un enfant vivant ayant un poids de naissance normal sans anomalie malformative grâce au suivi pluridisciplinaire (néphrologue, obstétricien et néonatologie), l'intensification des soins de dialyse, la correction de l'anémie, la maitrise de la pression artérielles et l'amélioration de l'état nutritionnel de la mer

Experimental design and modelling approach to evaluate efficacy of ß-lactam/ß-lactamase inhibitor combinations.

BACKGROUND: A ß-lactamase inhibitor (BLI) confers susceptibility of ß-lactamase-expressing multidrug resistant (MDR) organisms to the partnering ß-lactam (BL). AIMS: To discuss the experimental design and modelling strategies for two-drug combinations, using ceftazidime- and aztreonam-avibactam combinations, as examples. SOURCES: The information came from several publications on avibactam in vitro time-kill studies and corresponding pharmacodynamic models. CONTENT: The experimental design to optimally gather crucial information from constant-concentration time-kill studies is to use an agile matrix of two-drug concentration combinations that cover 0.25- to 4-fold BL minimum inhibitory concentration (MIC) relative to the BLI concentrations to be tested against the particular isolate. This shifting agile design can save substantial costs and resources, without sacrificing crucial information needed for model development. The complex synergistic BL/BLI interaction is quantitatively explored using a semi-mechanistic pharmacokinetic-pharmacodynamic (PK/PD) mathematical model that accounts for antimicrobial activities in the combination, bacteria-mediated BL degradation and inhibition of BL degradation by BLI. A predictive mathematical formulation for the two-drug killing effects preserves the correlation between the model-derived EC50 of BL and the BL MIC. The predictive value of PK/PD model is evaluated against external data that were not used for model development, including but not limited to in vitro hollow fibre and in vivo murine infection models. IMPLICATIONS: As a framework for translational predictions, the goal of this modelling strategy is to significantly decrease the decision-making time by running clinical trial simulations with MIC-substituted EC50 function for isolates of comparable susceptibility through established correlation between BL MIC and EC50 values.

Etirinotecan pegol administration is associated with lower incidences of neutropenia compared to irinotecan administration.

PURPOSE: The relationship between incidences of neutropenia and 10-hydroxy-7-ethyl camptothecin (SN38) exposure was explored using SN38 pharmacokinetic and neutrophil count data from toxicology studies of etirinotecan pegol (EP) and irinotecan in beagle dogs. METHODS: Dogs received four weekly intravenous infusions of either vehicle control (n = 22), EP (6, 15, 20, 25, 40/25 mg/kg; n = 3-9 dogs/dose group/sex; n = 48), or irinotecan (20 or 25 mg/kg n = 3-4 dogs/dose group/sex; n = 14). Blood samples were collected up to 50 days post-dose for characterization of SN38 pharmacokinetics. Two separate models were created describing SN38 concentration time profiles after either irinotecan or EP administrations to project the AUC0-168h after Day 1 and Day 22 doses. The relationship between incidence of neutropenia and SN38 exposure was explored using logistic regression. RESULTS: The incidence of neutropenia in dogs receiving weekly doses of irinotecan or EP was strongly correlated with maximum plasma SN38 concentration (C max), but not SN38 area under the concentration-time curve (AUC). Neutropenia occurred in approximately 80% of dogs receiving irinotecan (mean SN38 C max of 13.5 and 26.3 ng/mL for 20 and 25 mg/kg, respectively). No neutropenia occurred in dogs receiving EP at doses up to and including 25 mg/kg (mean SN38 C max of 3.4 and 4.9 ng/mL for 20 and 25 mg/kg, respectively), despite 2.5-3.6 times greater SN38 AUC after EP compared to irinotecan at equivalent doses. CONCLUSIONS: EP administration avoids both high SN38 C max values and development of dose-limiting neutropenia observed after irinotecan, while maintaining greater and sustained SN38 exposure between doses.

The value of male human papillomavirus vaccination in preventing cervical cancer and genital warts in a low-resource setting.

OBJECTIVE: To estimate health benefits and incremental cost-effectiveness of human papillomavirus (HPV) vaccination of pre-adolescent boys and girls compared with girls alone for preventing cervical cancer and genital warts. DESIGN: Model-based economic evaluation. SETTING: Southern Vietnam. POPULATION: Males and females aged ≥9 years. METHODS: We simulated dynamic HPV transmission to estimate cervical cancer and genital warts cases. Models were calibrated to epidemiological data from south Vietnam. MAIN OUTCOME MEASURES: Incremental cost-effectiveness ratios (ICERs): cost per quality-adjusted life-year (QALY). RESULTS: Vaccinating girls alone was associated with reductions in lifetime cervical cancer risk ranging from 20 to 56.9% as coverage varied from 25 to 90%. Adding boys to the vaccination programme yielded marginal incremental benefits (≤3.6% higher absolute cervical cancer risk reduction), compared with vaccinating girls alone at all coverages. At ≤25 international dollars (I$) per vaccinated adolescent (I$5 per dose), HPV vaccination of boys was below the threshold of Vietnam's per-capita GDP (I$2800), with ICERs ranging from I$734 per QALY at 25% coverage to I$2064 per QALY for 90% coverage. Including health benefits from averting genital warts yielded more favourable ICERs, and vaccination of boys at I$10/dose became cost-effective at or below 75% coverage. Using a lower cost-effectiveness threshold of 50% of Vietnam's GDP (I$1400), vaccinating boys was no longer attractive at costs above I$5 per dose regardless of coverage. CONCLUSION: Vaccination of boys may be cost-effective at low vaccine costs, but provides little benefit over vaccinating girls only. Focusing on achieving high vaccine coverage of girls may be more efficient for southern Vietnam and similar low-resource settings. TWEETABLE ABSTRACT: Limited cervical cancer reduction from including boys in HPV vaccination of girls in low-resource settings.

Cost-effectiveness of cervical cancer screening with primary human papillomavirus testing in Norway.

BACKGROUND: New screening technologies and vaccination against human papillomavirus (HPV), the necessary cause of cervical cancer, may impact optimal approaches to prevent cervical cancer. We evaluated the cost-effectiveness of alternative screening strategies to inform cervical cancer prevention guidelines in Norway. METHODS: We leveraged the primary epidemiologic and economic data from Norway to contextualise a simulation model of HPV-induced cervical cancer. The current cytology-only screening was compared with strategies involving cytology at younger ages and primary HPV-based screening at older ages (31/34+ years), an option being actively deliberated by the Norwegian government. We varied the switch-age, screening interval, and triage strategies for women with HPV-positive results. Uncertainty was evaluated in sensitivity analysis. RESULTS: Current cytology-only screening was less effective and more costly than strategies that involve switching to primary HPV testing in older ages. For unvaccinated women, switching at age 34 years to primary HPV testing every 4 years was optimal given the Norwegian cost-effectiveness threshold ($83,000 per year of life saved). For vaccinated women, a 6-year screening interval was cost-effective. When we considered a wider range of strategies, we found that an earlier switch to HPV testing (at age 31 years) may be preferred. CONCLUSIONS: Strategies involving a switch to HPV testing for primary screening in older women is expected to be cost-effective compared with current recommendations in Norway.

Cost-effectiveness of human papillomavirus vaccination and cervical cancer screening in Thailand.

OBJECTIVE: To assess the health and economic outcomes of various screening and vaccination strategies for cervical cancer prevention. DESIGN: Cost-effectiveness analysis from a societal perspective. SETTING: Thailand. POPULATION: Females aged 9 years and older. METHODS: Using a mathematical model of human papillomavirus (HPV) infection and cervical cancer, calibrated to epidemiological data from Thailand, we estimated the cost-effectiveness of pre-adolescent HPV vaccination, screening [visual inspection with acetic acid (VIA), HPV DNA testing, and cytology] between one and five times per lifetime in adulthood, and combined pre-adolescent vaccination and screening. Vaccine efficacy, coverage, cost, and screening frequency were varied in sensitivity analyses. MAIN OUTCOME MEASURES: Incremental cost-effectiveness ratios, expressed as cost per year of life saved (YLS). RESULTS: Assuming lifelong efficacy and 80% coverage, pre-adolescent HPV vaccination alone was projected to reduce the lifetime risk of cervical cancer by 55%, which was greater than any strategy of screening alone. When cost per vaccinated girl was I$10 (approximately $2 per dose) or less, HPV vaccination alone was cost saving. Pre-adolescent vaccination and HPV DNA testing five times per lifetime, starting at age 35 years, reduced the lifetime cervical cancer risk by 70%, and had a cost-effectiveness ratio less than Thailand's GDP per capita (I$8100), provided the cost per vaccinated girl was I$200 or less. CONCLUSIONS: Low cost pre-adolescent HPV vaccination followed by HPV screening five times per lifetime is an efficient strategy for Thailand. Costs may need to be lower, however, for this strategy to be affordable. If vaccination is not feasible, HPV DNA testing five times per lifetime is efficient.

Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung.

Squamous cell carcinoma (SqC) and adenocarcinoma (AdC) are the two most common subtypes of non-small cell lung cancer (NSCLC). Cumulative information suggests that the SqC and AdC subtypes progress through different carcinogenic pathways, but the genetic aberrations promoting such differences remain unclear. Here we have assessed the overall genomic imbalances and structural abnormalities in SqC and AdC. By parallel analyses with comparative genomic hybridisation (CGH) on tumorous lung tissues and spectral karyotyping (SKY) on short-term cultured primary tumours, genome-wide characterisation was carried out on 69 NSCLC (35 SqC, 34 AdC). Molecular cytogenetic characterisation indicated common and distinct genetic changes in SqC and AdC. Common events of +1q21-q24, +5p15-p14, and +8q22-q24.1, and -17p13-p12 were found in both groups, although hierarchical clustering simulation on CGH findings depicted +2p13-p11.2, +3q25-q29, +9q13-q34, +12p, +12q12-q15 and +17q21, and -8p in preferential association with SqC pathogenesis (P<0.05). Corresponding SKY analysis suggested that these changes occur in simple and complex rearrangements, and further indicated the clonal presence of translocation partners leading to chromosomal over-representations. These recurring rearrangements involved chromosome pairs of t(1;13), t(1;15), t(7;8), t(8;15), t(8;9), t(2;17) and t(15;20). Of particular interest was the finding that the t(8;12) translocation partner was exclusive to AdC. The combined application of SKY and CGH has thus uncovered the genome-wide chromosomal aberrations in NSCLC. Specific chromosomal imbalances and translocation partners found in SqC and AdC have highlighted regions for further molecular investigation into gene(s) that may hold importance in the carcinogenesis of NSCLC.

Simultaneous quantification of seven active metabolites of roxifiban in human plasma by LC/MS/MS in the presence of an interfering displacer at millimolar concentrations.

Roxifiban (DMP 754) is a glycoprotein (GP) IIb/IIIa antagonist. Following oral administration to humans, roxifiban is metabolized to its primary active zwitterionic form, XV459, and several minor, active, hydrolyzed and hydroxylated metabolites, namely, M1a (DPC-AD3508), M1b (DPC-AD6128), M2 (SW156), M3 (DPC-AG2185), M8a (DPC-AF5814), and M8b (DPC-AF5818). Quantification of these metabolites in humans was not workable with a previous analytical method due to ion suppression of at least four of the analytes by a competitive displacer, DMP 728. This compound, which is another GP IIb/IIIa antagonist with very high affinity for the platelet receptor, was added to harvested blood samples in millimolar quantity to liberate XV459 from the GP IIb/IIIa receptor. An automated ion exchange solid phase extraction (IX-SPE) procedure was developed to selectively extract the seven metabolites of roxifiban and its deuterated internal standard while specifically excluding DMP 728. Among the six hydroxylation metabolites, there were two pairs of epimeric diastereomers (M1a/M1b and M8a/M8b) and one pair of geometric isomers (M2/M3), corresponding to three critical chromatographic pairs that needed to be base-line resolved because of the lack of specificity of MS/MS detection for these isomers. A new LC/MS/MS assay was developed to simultaneously quantify the seven metabolites in human plasma. The assay method was validated under GLP conditions over the concentration range of 0.5 to 80 nM for each of the analytes and successfully applied to assaying approximately 500 plasma samples from clinical trials.