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Objective: The use of topical polymyxin and tobramycin to prevent intensive care infections is controversial. Moreover, these antibiotics are ineffective against methicillin-resistant Staphylococcus aureus. A decontamination regimen using mupirocin and chlorhexidine could prevent acquired infections, including those involving S. aureus. Because these two regimens could have a complementary role, we evaluated their effects when given both alone and combined.Design: The authors conducted a multiple-center, placebo-controlled, randomized, double-blind study performed according to a 2 x 2 factorial design.Setting: The study was conducted at three polyvalent medical intensive care units at university-affiliated hospitals in France.Patients: Adult patients (age, > or =18 yrs) intubated for <48 hrs who were likely to be ventilated for >48 hrs.Intervention: Two regimens were used: topical administration of polymyxin/tobramycin (or placebo) and nasal mupirocin with chlorhexidine body washing (or nasal placebo with liquid soap). The patients (n = 515) received polymyxin/tobramycin alone (n = 130), mupirocin/chlorhexidine alone (n = 130), both regimens (n = 129), or all placebos (n = 126) for the period of mechanical ventilation plus 24 hrs.Measurements and Main Results: The incidence of total infections acquired from the date of randomization until the termination date of study treatments plus 48 hrs was assessed. There were fewer acquired infections with both regimens than with polymyxin/tobramycin alone (odds ratio, 0.44; 95% confidence interval, 0.26-0.75; p = .003), mupirocin/chlorhexidine alone (0.43; 0.25-0.73; p = .002), or all placebos (0.42; 0.25-0.72; p = .001). There were no differences between polymyxin/tobramycin alone (0.95; 0.59-1.54; p = .84) and mupirocin/chlorhexidine alone (0.98; 0.60-1.58; p = .92) vs. all placebos. The probability of freedom from infection was higher with both regimens than with polymyxin/tobramycin alone (p = .002), mupirocin/chlorhexidine alone (p < .001), or all placebos (p < .001). Infection rates were also significantly lower with both regimens than with polymyxin/tobramycin alone (p = .017), mupirocin/chlorhexidine alone (p < .001), or all placebos (p < .001).Conclusion: Acquired infections were substantially reduced by mupirocin/chlorhexidine plus polymyxin/tobramycin, whereas each regimen given alone was ineffective. Whether both regimens could increase Candida infections deserves further investigation. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the short- and long-term outcomes of RPA in a large multicentric series., Summary Background: The current knowledge on RPA for portal reconstruction during LT in patients with diffuse PVT and a large splenorenal shunt is poor and limited to case reports and small case series., Methods: All consecutive LTs with RPA performed in 5 centers between 1998 and 2020 were included. RPA was physiological provided it drained the splanchnic venous return through a large splenorenal shunt (≥ 1 cm diameter). Complications of PHT, long-term RPA patency, and patient and graft survival were assessed. RPA success was achieved provided the 3 following criteria were all fulfilled: patients were alive with patent RPA and without clinical PHT., Results: RPA was attempted and feasible in 57 consecutive patients and was physiological in 51 patients (89.5%). Ninety-day mortality occurred in 5 (8.5%) patients, and PHT-related complications occurred in 42.9% of patients. With a median follow-up of 63 months, the 1-, 3- and 5-year patient and graft survival rates were 87%, 83%, and 76% and 82%, 80%, and 73%, respectively. The primary and primary-assisted patency rates at 5 years were 84.5% and 94.3%, respectively. Success was achieved in 90% (27/30) of patients with a follow-up ≥5 years., Conclusions: Despite a high rate of PHT-related complications, excellent long-term patient and graft survival could be achieved. RPA could be considered successful in the vast majority of patients. The expanded use of RPA is warranted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Currently, the recommended tacrolimus (TAC) trough level (Cmin) after liver transplantation (LT) is 6-10 ng/mL (when associated in triple immunosuppressive therapy). However, few studies have achieved the lower limit of this range, especially below 7 ng/mL. This study evaluated the efficacy of a target TAC Cmin of 4-7 ng/mL after LT., Methods: Of 1677 LTs performed between 2002 and 2017, 904 LT cases were analyzed. The cases were categorized into the following 3 groups and compared: low- (n = 247, 27.3%), intermediate- (n = 344, 37.9%), and high-exposure groups (n = 313, 34.5%) with TAC Cmin of 4-7 ng/mL, 7-10 ng/mL, and >10 ng/mL, respectively. In addition, propensity score matching was performed to reduce heterogeneity and population bias., Results: At months 1 and 3, when compared with the 2 other groups, the low-exposure group had similar grafts (P = 0.75) and patient (P = 0.77) survival, but lower alanine aminotransferase (P < 0.001), bilirubin (P < 0.001), international normalized ratio (P = 0.046), and creatinine (P < 0.001) levels. After propensity score matching, the bilirubin (P < 0.001) and creatinine (P = 0.001) levels in the low-exposure group still improved at months 3, but the graft (P = 0.86) and patient (P = 0.99) survival were still similar., Conclusions: A TAC Cmin of 4-7 ng/mL seems safe and capable of improving graft and kidney function. This finding should be confirmed in a prospective randomized trial.

Background: Tacrolimus (TAC) is the cornerstone of immunosuppressive regimen in liver transplantation (LT). Its pharmacokinetics is characterized by a high interpatient and intrapatient variability (IPV) leading to an unpredictable dose-response relationship. The aim of our study was to evaluate the impact of TAC IPV (IPV) on graft and patient outcomes after LT., Methods: We retrospectively analyzed 812 LT recipients treated with TAC. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of whole blood trough concentrations. Patients were categorized in 2 groups: low IPV (CV < 40%) and high IPV (CV ≥ 40%)., Results: There were significantly more neurologic complications (31.2% vs 16.6%, P < 0.001), cardiovascular complications (19.7% vs 9.7%, P < 0.001), and acute renal failure requiring dialysis (8.5% vs 2.2%, P < 0.001) in the high CV group than in the low CV group. Moreover, graft survival was significantly poorer in the high CV group (hazard ratio, 1.42; 95% confidence interval, 1.04-1.95; P = 0.03). A pretransplantation elevated Model for End-Stage Liver Disease score (P < 0.001) and Child-Pugh grade (P < 0.001) were identified as risk factors for presenting a high CV., Conclusions: A high CV of TAC concentrations was found to be predictive of TAC-related toxicity and poorer survival.

Objectives: Semen composition is influenced by HIV-1 infection, yet the impact of semen components on HIV infection of primary target cells has only been studied in samples from HIV-uninfected donors., Design: We compared the effect of seminal plasma (SP) from chronically HIV-infected (SP+) versus uninfected donors (SP-) on HIV-1 infection of peripheral blood mononuclear cells (PBMCs) and CD4 T cells., Methods: Primary cells were infected with HIV-1 in the presence of SP+ or SP- and analyzed for infection level, metabolic activity, HIV receptor expression, proliferation and activation. SP+ and SP- were compared for infection-enhancing peptides, cytokines and prostaglandin E2 levels., Results: SP- efficiently enhanced HIV-1 R5 infection of CD4 T cells, whereas SP+ enhancing activity was significantly reduced. RANTES (CCL5) concentrations were elevated in SP+ relative to SP-, whereas the concentrations of infectivity-enhancing peptides [semen-derived enhancer of viral infection (SEVI), SEM1, SEM2] were similar. CCR5 membrane expression levels were reduced on CD4 T cells shortly postexposure to SP+ compared with SP- and correlated to R5-tropic HIV-1 infection levels, and CCR5 ligands' concentrations in semen. SP+ and SP- displayed similar enhancing activity on PBMC infection by X4-tropic HIV-1. Addition/depletion of RANTES (regulated on activation, normal T-cell expressed and secreted) from SPs modulated their effect on PBMC infection by R5-tropic HIV-1., Conclusion: Semen from HIV-infected donors exhibits a significantly reduced enhancing potential on CD4 T-cell infection by R5-tropic HIV-1 when compared with semen from uninfected donors. Our data indicate that elevated seminal concentrations of RANTES in HIV-infected men can influence the ability of semen to enhance infection.

Objective: Drug-resistance mutations are routinely detected using standard Sanger sequencing, which does not detect minor variants with a frequency below 20%. The impact of detecting minor variants generated by ultra-deep sequencing (UDS) on HIV drug-resistance interpretations has not yet been studied., Design: Fifty HIV-1 patients who experienced virological failure were included in this retrospective study., Methods: The HIV-1 UDS protocol allowed the detection and quantification of HIV-1 protease and reverse transcriptase variants related to genotypes A, B, C, F and G. DeepChek-HIV simplified drug-resistance interpretation software was used to compare Sanger sequencing and UDS., Results: The total time required for the UDS protocol was found to be approximately three times longer than Sanger sequencing with equivalent reagent costs. UDS detected all of the mutations found by population sequencing and identified additional resistance variants in all patients. An analysis of drug resistance revealed a total of 643 and 224 clinically relevant mutations by UDS and Sanger sequencing, respectively. Three resistance mutations with more than 20% prevalence were detected solely by UDS: A98S (23%), E138A (21%) and V179I (25%). A significant difference in the drug-resistance interpretations for 19 antiretroviral drugs was observed between the UDS and Sanger sequencing methods. Y181C and T215Y were the most frequent mutations associated with interpretation differences., Conclusion: A combination of UDS and DeepChek software for the interpretation of drug resistance results would help clinicians provide suitable treatments. A cut-off of 1% allowed a better characterization of the viral population by identifying additional resistance mutations and improving the drug-resistance interpretation.

Objectives: In a multicenter, placebo-controlled, randomized, double-blind trial, we showed that acquired infections in intubated patients were reduced by the combination of topical polymyxin plus tobramycin and nasal mupirocin plus chlorhexidine body wash. Because intubated patients are particularly at risk for acquired infections, we reassessed the impact of this protocol as a routine procedure to control acquired infections in the ICU., Design: Nonrandomized study comparing acquired infections in ICU patients during two 1-year periods: the last year before (group A, n = 925) and the first year after the implementation of the protocol (group B, n = 1,022). Acquired infections were prospectively recorded., Setting: Polyvalent medical ICU at a university-affiliated hospital., Patients: All patients admitted to the ICU., Interventions: Administration of polymyxin/tobramycin/amphotericin B in the oropharynx and the gastric tube plus a mupirocin/chlorhexidine regimen in intubated patients and standard care in the other patients., Measurements and Main Results: The comparison of acquired infection rates between groups was adjusted for differences at baseline. Infection rates were lower in group B compared with group A (5.3% vs 11.0%; p < 0.001), as were the incidence rates of total acquired infections (9.4 vs 23.6 per 1,000 patient-days; p < 0.001), intubation-related pneumonia (5.1 vs 17.1 per 1,000 ventilator-days; p < 0.001), and catheter-related bloodstream infections (1.0 vs 3.5 per 1,000 catheter-days; p = 0.03). There were fewer acquired infections caused by ceftazidime-resistant Enterobacteriaceae (0.8‰ vs 3.6‰; p < 0.001), ciprofloxacin-resistant Enterobacteriaceae (0.8‰ vs 2.5‰; p = 0.02), ciprofloxacin-resistant Pseudomonas aeruginosa (0.5‰ vs 1.6‰; p = 0.05), and colistin-resistant Gram-negative bacilli (0.7‰ vs 1.9‰; p = 0.04). Fewer patients got acquired infections due to multidrug-resistant aerobic Gram-negative bacilli (p = 0.008)., Conclusions: In intubated patients, the use of topical polymyxin/tobramycin/amphotericin B plus mupirocin/chlorhexidine was associated with the reduction of all-cause ICU-acquired infections. Long-term emergence of multidrug-resistant organisms deserves further investigation.

Background: The early repolarization (ER) pattern on ECG is associated with an increased risk of idiopathic ventricular fibrillation (ID-VF). Hypothermia is known to result in similar electrocardiographic changes. In this retrospective cohort study, we examine the impact of therapeutic hypothermia on ER in survivors of cardiac arrest attributed to ID-VF and draw comparisons with a control group who experienced coronary artery disease-related VF (CAD-VF)., Methods and Results: All patients who had cardiac arrest and were treated with therapeutic hypothermia over a 7-year period were considered for inclusion in the study. Forty-three patients were identified with ID-VF or CAD-VF arrest. ECGs were obtained during cooling and again after rewarming. ECGs were digitized and assessed for the presence of ER by 2 independent observers. Cooling significantly increased the prevalence (74% during cooling versus 51% at baseline temperature; P=0.044) and mean amplitude (0.78±0.10 mV during cooling versus 0.56±0.09 mV at baseline temperature; P=0.038) of ER in the overall cohort. During cooling, ER was more common among survivors of ID-VF than of CAD-VF (100% versus 67%; P=0.043). ER magnitude was significantly greater among ID-VF survivors than CAD-VF survivors both during cooling (1.16±0.18 versus 0.70±0.11 mV; P=0.044) and at baseline temperature (1.02±0.21 versus 0.42±0.09 mV; P=0.005)., Conclusions: Hypothermia increases both the prevalence and magnitude of ER in cardiac arrest survivors. Despite the association of ER with ID-VF, therapeutic hypothermia only increases ER amplitude in CAD-VF survivors.

We conducted an epidemiologic survey in France on the use of bicaval dual-lumen cannulas for extracorporeal membrane oxygenation (ECMO). Every service that used the Avalon cannula was contacted. Practitioners answered questions concerning its practical usage and complications that were attributable to its usage. We report data for 52 instances of cannula usage. The primary indication was acute respiratory distress syndrome (ARDS) in 77% of cases. Of all of the patients who required cannulas, 46% died. The maximum flow was 2,175 ± 556 ml/minute for 20-Fr.-diameter cannulas, 3,207 ± 653 ml/minute for 23 Fr., 3,963 ± 729 ml/minute for 27 Fr., and 5,490 ± 984 ml/minute for 31 Fr. Surgeons placed the cannulas in 52% of cases, intensivists placed the cannulas in 23% of cases, and multidisciplinary teams placed the cannulas in 25% of cases. The mean insertion time was 26 ± 13 minutes, and insertion was performed under transesophageal electrocardiography (TEE) (67%), transthoracic echocardiography (TTE) (25%), fluoroscopy (4%), or no guidance (4%). The main complication was migration into the right ventricle. Problems with hemolysis were described in 21% of cases. No case of cannula thrombosis was found. No case of infection was reported. Bleeding was noted in 17% of cases. The mean time of use was 8 ± 7 days. Modifications to the supportive care system were required in 15% of cases. Monitoring was performed by chest x-rays (90%), TTE (42%), and TEE (46%). Five extubations occurred during the support period. Nine patients were mobilized. The use of this cannula yielded satisfactory results. We suggest placing these cannulas using TTE or TEE and recommend the use of large-caliber cannulas in hypoxemic patients.

Objectives: To characterize the factors associated with delayed defecation in long-term ventilated patients and to examine the relationship between delayed defecation and logistic organ dysfunction scores, acquired bacterial infections, and mortality in the intensive care unit., Design: Prospective observational cohort study., Setting: A 21-bed polyvalent intensive care unit in a university hospital., Patients: A total of 609 adult patients admitted over a 41-month period who underwent mechanical ventilation for ≥ 6 days., Interventions: None., Measurements and Main Results: Three hundred fifty-three patients (58%) passed stools ≥ 6 days after they were admitted to the intensive care unit ("late" defecation). Patients with early and late defecation had similar general characteristics when admitted to the intensive care unit and had similar logistic organ dysfunction scores on the first day of mechanical ventilation. Several variables were independently associated with a delay in defecation: a Pao2/Fio2 ratio of less than 150 mm Hg (adjusted hazard ratio 1.40; 95% confidence interval: 1.06-1.60; p = .0073), a systolic blood pressure between 70 and 89 mm Hg (adjusted hazard ratio 1.48; 95% confidence interval: 1.17-1.79; p = .002), and systolic blood pressure < 68 mm Hg (adjusted hazard ratio 1.29; 95% confidence interval: 1.01-1.60; p = .03). Logistic organ dysfunction scores were significantly higher on the fourth and ninth days of mechanical ventilation in patients with late defecation than in those with early defecation. The crude intensive care unit mortality rate was 18% in patients with early defecation and 30% in patients with late defecation (p < .001). Acquired bacterial infections at any site occurred in 34% of patients with early defecation and 66% of patients with late defecation (p < .001)., Conclusion: A Pao2/Fio2 ratio of < 150 mm Hg and systolic blood pressure of < 90 mm Hg during the first 5 days of mechanical ventilation were independently associated with a delay in defecation. Our results suggest that constipation is associated with adverse outcomes in long-term ventilated patients.

Background: Most studies designed to determine the factors associated with the acquisition of late-onset ventilator-associated pneumonia (VAP) were performed in critically ill trauma patients. The impact of enteral nutrition (EN) on the risk of acquiring VAP has been discussed. In this study, we assessed factors associated with late-onset VAP in nontrauma patients and determined whether nutrition provided early was associated with development of late-onset VAP in this population., Methods: We performed a prospective observational cohort study in a 21-bed polyvalent intensive care unit in a university hospital., Results: Three hundred sixty-one intubated adult patients with a duration of mechanical ventilation (MV) of 6 days or more were admitted over a 28-mo period. Late-onset VAP was confirmed in 76 patients (21%) by the presence of at least one microorganism at a concentration >or=10(4) colony-forming units/mL on the bronchoalveolar lavage. Gram-negative bacilli represented 75% and Staphylococcus aureus 21% of recovered organisms. Factors independently associated with late-onset VAP by multivariate analysis included a high simplified acute physiology score II score (odds ratio: 1.021; 95% confidence interval [CI]: 1.005-1.038; P = 0.01), development of acute respiratory distress syndrome during the first 5 days of MV (odds ratio: 1.98; 95% CI: 1.05-3.67; P = 0.04), and size of the endotracheal tube >or=7.5 (odds ratio: 2.06; 95% CI: 1.88-3.90; P = 0.03). EN started within 48 h of MV onset was not associated with a higher risk for late-onset VAP., Conclusion: In our nontrauma patient population, early EN was not associated with development of late-onset VAP. In this population, severity of the disease during the first 5 days of MV seemed to be associated with late-onset VAP. In addition, our results suggest that the risk of late-onset VAP is higher in patients with a tube size >or=7.5 than in patients with a tube size <7.5.

Background: Progress in liver imaging has made pretransplantation tumor biopsy no longer systematic in patients with hepatocellular carcinoma (HCC)., Objectives: Our aim was to evaluate the accuracy of a preoperative diagnosis of HCC based on clinical and radiological findings in 102 cirrhotics qualified for liver transplantation (LT) between January 1995 and August 2003 at our institution., Methods: The diagnostic accuracy of our policy was assessed by comparing pretransplant diagnosis with the pathologic report of explanted livers., Results: Sensitivity, specificity, positive, and negative predictive values for the preoperative clinical and radiological diagnosis of HCC were 89%, 94.3%, 77%, and 93.3%, respectively. A false-positive preoperative diagnosis was made in 20 of 102 patients (19.6%) (dysplastic nodules [n=9], regenerative nodules [n=5] cholangiocellular carcinoma [n=1], hemangioma [n=1], and no lesion [n=4]). All tumors larger than 3 cm were correctly diagnosed, irrespective of serum alpha-fetoprotein (sAFP) levels. The risk of overestimating the diagnosis of HCC in the subgroup of patients with tumors less than 3 cm was conversely correlated with preliver transplantation sAFP (sAFP100: 11%; sAFP>200: 0%)., Conclusion: In cirrhotics with nodules larger than 3 cm irrespective of sAFP or nodules less than 3 cm with sAFP greater than 200 ng/L, the pretransplant diagnosis of HCC can be made without performing biopsy. In other cases (i.e., nodules less than 3 cm and sAFP lower than 200 ng/L), histologic confirmation of HCC or a close follow-up imaging should be considered.

Objective: To assess the impact of HIV-1 protease and reverse transcriptase (RT) mutations, and pharmacokinetic parameters on virological responses to nelfinavir (NFV)-containing highly active antiretroviral therapy., Design: Naive or antiretroviral-experienced HIV-1-infected subjects were included in a non-randomized, observational cohort study and received two nucleoside RT inhibitors + NFV (750 mg three times per day or 1250 mg twice per day). Virologic success was defined as a virus load < 50 copies/ml for > 6 months., Methods: RT and protease genes were sequenced at baseline and at the time of virological failure. Plasma NFV trough concentration (Cmin), maximum concentration (Cmax), and AUC0-tau at steady-state were subjected to population pharmacokinetic analysis., Results: Patients (n = 154) enrolled between November 1998 and February 2000 started a twice per day (n = 84) or three times per day (n = 70) NFV-based regimen as first- (n = 48) or second-line therapy when protease inhibitor-naive (n = 64) or -experienced (n = 42). Median follow-up duration was 16 months. Virologic failure occurred in 88 patients. No significant differences were observed between twice per day and three times per day regimens. According to multivariate analysis, NFV Cmin and Cmax, CD4 cell count, number of baseline RT + protease gene mutations, D67N, M184V, T215F/Y in RT, and M36I in protease, were independent factors that were significantly predictive of failure. At failure, L10I, D30N, M36I, V77I, N88S/D or L90M protease mutations had emerged since baseline. Pharmacokinetic parameters were similar in patients with or without emergence of these neo-mutations. The more discriminating NFV Cmin efficacy-threshold was estimated to be 1 mg/l., Conclusions: Our data confirm the association among individual pharmacokinetic parameters, genotype pattern and virological response to NFV-containing regimens.