Exposure and virologic outcomes of dolutegravir combined with ritonavir boosted darunavir in treatment-naïve individuals enrolled in the Netherlands Cohort Study on Acute HIV infection (NOVA).

To the authors' knowledge, there is currently no literature or guidance recommendation regarding whether the dose of dolutegravir (DTG) should be increased when co-administered with darunavir/ritonavir (DRV/r) in patients with acute human immunodeficiency virus infection (AHI). This study assessed the pharmacokinetics (PK) of twice-daily (BID) DTG and once-daily (QD) DRV/r, and compared this with DTG QD without DRV/r in patients with AHI. Forty-six participants initiated antiretroviral therapy within <24 h of enrolment: DTG 50 mg BID, DRV/r 800/100 mg QD, and two nucleoside reverse transcriptase inhibitors (NRTIs) for 4 weeks (Phase I); and DTG 50 mg QD with two NRTIs thereafter (Phase II: reference). Total DTG trough concentration (Ctrough) and area under the concentration-time profile of 0-24 h (AUC0-24h) were predicted using a population PK model. DTG glucuronidation metabolic ratio (MR) and DTG free fraction were determined and compared per treatment phase using geometric mean ratio (GMR) and 90% confidence interval (CI). Participants had a predicted geometric mean steady-state DTG Ctrough of 2.83 [coefficient of variation (CV%) 30.3%] mg/L (Phase I) and 1.28 (CV% 52.4%) mg/L (Phase II), with GMR of 2.20 (90% CI 1.90-2.55). Total exposure during DTG BID increased but did not double [AUC0-24h GMR 1.65 (90% CI 1.50-1.81) h.mg/L]. DTG glucuronidation MR increased by approximately 29% during Phase I. DTG Ctrough was above in-vivo EC90 (0.32 mg/L) during both phases, except in one participant during Phase I. At Week 8, 84% of participants had viral loads ≤40 copies/mL. The drug-drug interaction between DTG (BID) and DRV/r (QD) was due to induced glucuronidation, and is not clinically relevant in patients with AHI.

Launching a multidisciplinary European collaboration towards a cure for HIV: The EU2Cure Consortium.

We felt the urgency to launch the EU2Cure Consortium to support research and find a cure for the human immunodeficiency virus (HIV) infection through intensified collaboration within Europe. This consortium is open to stakeholders on cure in Europe from academia and the community to connect. The aim of this consortium is to intensify the research collaboration amongst European HIV cure groups and the community and facilitate interactions with other academic and community cure consortia, private parties, and policy makers. Our main aim is to create a European research agenda, data sharing, and development of best practice for clinical and translational science to achieve breakthroughs with clinically feasible HIV cure strategies. This consortium should also enable setting up collaborative studies accessible to a broader group of people living with HIV. Besides reservoir studies, we have identified three overlapping scientific interests in the consortium that provide a starting point for further research within a European network: developing "shock and kill" cure strategies, defining HIV cure biomarkers, and connecting cure cohorts. This strategy should aid stakeholders to sustain progress in HIV cure research regardless of coincidental global health or political crises.

The dolutegravir/valproic acid drug-drug interaction is primarily based on protein displacement.

OBJECTIVES: The dolutegravir/valproic acid drug-drug interaction (DDI) is suggested to be caused by protein displacement. Here, we assess the underlying mechanism. METHODS: Participants in a randomized controlled trial investigating valproic acid as an HIV latency reversing agent were recruited in a predefined pharmacokinetic substudy if they were on once-daily 50 mg dolutegravir-containing combination ART (cART) for >12 months with a plasma HIV-RNA <50 copies/mL (trial registration: ClinicalTrials.gov NCT03525730). Participants were randomized to receive 30 mg/kg/day valproic acid orally (divided into two equal doses) for 14 days or not. Total and unbound dolutegravir concentrations were measured on day 0 (before intake of valproic acid and 6 h after intake of valproic acid) and on days 1, 7, 14 and 42. Intra- and inter-subject dolutegravir concentrations and geometric means (GMs) were evaluated. RESULTS: Six of 10 participants on dolutegravir were randomized to receive valproic acid. During 14 days of valproic acid treatment, the GM total dolutegravir concentration decreased sharply from 1.36 mg/L on day 0 to 0.85, 0.31 and 0.20 mg/L on days 0, 1, 7 and 14, respectively, while total dolutegravir concentrations in the controls remained comparable during the same period: 1.27-1.49 mg/L. We observed a parallel increase in unbound dolutegravir fractions ranging from 0.39% to 0.58% during valproic acid administration, compared with 0.25% to 0.28% without valproic acid. Unbound dolutegravir concentrations were above the established in vitro EC90 value for unbound dolutegravir in 85% of the tested samples. CONCLUSIONS: This study confirms protein displacement as the main mechanism for this DDI, although additional mechanisms might be involved too. If dolutegravir is taken with food, this DDI is probably not clinically relevant.

Data verification of nationwide clinical quality registries.

Background: Clinical auditing is an emerging instrument for quality assessment and improvement. Moreover, clinical registries facilitate medical research as they provide 'real world' data. It is important that entered data are robust and reliable. The aim of this study was to describe the evolving procedure and results of data verification within the Dutch Institute for Clinical Auditing (DICA). Methods: Data verification performed on several (disease-specific) clinical registries between 2013 and 2015 was evaluated. Sign-up, sample size and process of verification were described. For each procedure, hospitals were visited by external data managers to verify registered data. Outcomes of data verification were completeness and accuracy. An assessment of the quality of data was given per registry, for each participating hospital. Using descriptive statistics, analyses were performed for different sections within the individual registries. Results: Seven of the 21 registries were verified, involving 174 visits to hospital departments. A step-by-step description of the data verification process was provided. Completeness of data in the registries varied from 97·2 to 99·4 per cent. Accuracy of data ranged from 88·2 to 100 per cent. Most discrepancies were observed for postoperative complications (0·7-7·5 per cent) and ASA classification (8·5-11·4 per cent). Data quality was assessed as 'sufficient' for 145 of the 174 hospital departments (83·3 per cent). Conclusion: Data verification revealed that the data entered in the observed DICA registries were complete and accurate.

Antecedentes: La auditoría clínica es un instrumento emergente para la evaluación y mejora de la calidad. Además, los registros clínicos facilitan la investigación médica ya que proporcionan datos de la "vida real". Es importante que los datos introducidos sean completos y fiables. El objetivo de este estudio fue describir la evolución y los resultados del procedimiento de verificación de datos en el seno del Instituto Holandés de Auditorias Clínicas (Dutch Institute for Clinical Auditing, DICA). Métodos: Se evaluó la verificación de datos realizada en varios registros clínicos (específicos de enfermedad) entre 2013­2015. Se describió el sistema de registro, tamaño de la muestra y el proceso de verificación. Para cada procedimiento, los hospitales fueron visitados por administradores de datos externos para verificar los datos registrados. Los resultados de la verificación de datos fueron la integridad y la exactitud. Se proporcionó una evaluación de la calidad de los datos para cada registro en cada uno de los hospitales que participaron. Mediante la utilización de estadística descriptiva, se realizaron análisis de diferentes secciones para cada uno de los registros. Resultados: Siete de los 21 registros fueron verificados, lo que implicó un total 174 visitas a los departamentos de los hospitales. Se proporcionó una descripción paso a paso del proceso de verificación de los datos. La integridad de los datos en los registros varió entre 97,3­99,4%. La exactitud de los datos varió entre 86,6­97,0%. La mayoría de las discrepancias se observaron en las complicaciones postoperatorias (0,7­7,5%) y clasificación ASA (7,5­11%). La calidad de los datos se consideró "suficiente" en 145 de 174 (83%) departamentos hospitalarios. Conclusión: La verificación de los datos reveló que la introducción de datos en los registros DICA analizados era bastante completa y exacta.

Ending the epidemic: Critical role of primary HIV infection.

Early identification and immediate treatment of individuals newly infected with HIV is important for two reasons: it benefits the long-term health of the infected patient, and it reduces onward HIV transmission. Primary HIV infection (PHI) reflects the period following HIV acquisition during which viraemia bursts until the establishment of a stable plasma HIV-RNA level approximately six months post infection. During this period, patients are particularly contagious and are often unaware of the infection. As a consequence, PHI disproportionally affects onward transmission. During PHI the immune system is irreparably damaged and persistent viral reservoirs are formed. Initiating antiretroviral therapy (ART) during PHI could potentially lead to a functional cure through early and prolonged viral suppression. Unfortunately, symptoms of PHI are nonspecific and the diagnosis is frequently missed. This impedes timely diagnosis and prompt initiation of ART. To increase awareness and underscore the importance of immediate ART initiation, we describe here the pathogenesis, clinical presentation, and impact of treating PHI.

Single-port laparoscopic appendectomy in children: single center experience in 50 patients.

BACKGROUND: Recent years evolution of minimal invasive laparoscopic procedures led to new techniques, like single-port laparoscopy (SPL), resulting in nearly-scarless procedures. The purpose of this study is to evaluate that SPL appendectomy is a safe and feasible procedure using a commercially available trocar (LESS: Laparo Endoscopic Single Site trocar; Olympus TriPort+) in pediatric patients. METHODS: From July 2011 to March 2014 all patients undergoing SPL appendectomy under 18 years were included in this retrospective study. Per- en postoperative data were collected in a prospective database. RESULTS: A total of 50 children (mean age 12 years) diagnosed as acute appendicitis underwent SPL appendectomy. SPL appendectomy was feasible and safe in all cases, both in non-perforated and perforated appendicitis. In one procedure (2%) an extra trocar was placed. Seven patients (14%) were readmitted to the hospital after initial uncomplicated postoperative course. One patient (2%) needed reoperation due to a wound abscess. Three patients (6%) were readmitted due to intra-abdominal abscesses for which antibiotics were given. CONCLUSIONS: SPL appendectomy is a safe and feasible procedure in children with acute appendicitis.

Antioxidants as a treatment for acute pancreatitis: A meta-analysis.

OBJECTIVE: To assess the efficacy of antioxidants in acute (AP) pancreatitis. METHODS: We searched PubMed, Embase and the Cochrane library for all randomized controlled trials (RCT) involving administration of antioxidants in the therapy of AP until February 2012. AP studies were pooled to analyze the effect of antioxidants on hospital stay, mortality, and complications. Subgroup analyses were performed on the use of the antioxidant glutamine. RESULTS: In total, eleven RCTs were included. Among patients with AP, antioxidant therapy resulted in a borderline significant reduction in hospital stay (mean difference -1.74; 95%CI -3.56 to 0.08), a significant decrease in complications (RR 0.66; 95%CI 0.46-0.95) and a non-significant decrease in mortality rate (RR 0.66; 95%CI 0.30-1.46). Subgroup analyses showed that glutamine significantly reduced complications (RR 0.51; 95%CI 0.34-0.78) and mortality rate (RR 0.33; 95%CI 0.13-0.85). CONCLUSION: The present meta-analysis shows a possible benefit of glutamine supplementation in patients with acute pancreatitis. However, large randomized trials are needed to confirm these observations.

Results of construction of protective loop ileostomies and reversal surgery for colorectal surgery.

BACKGROUND: Protective loop ileostomies in colorectal surgery are constructed to reduce morbidity and reinterventions related to the primary operation. However, ileostomies are associated with stoma-related morbidity and postoperative complications following reversal surgery. Dutch national data show increased use of loop ileostomies in colorectal surgery for cancer justifying an adequate assessment of its morbidity. This study was undertaken to investigate morbidity associated with protective loop ileostomies in colorectal surgery. METHODS: Retrospectively, 118 consecutive patients undergoing left-sided colonic or rectal resection with protective loop ileostomy were included. Primary outcome was 30-day mortality. Secondary endpoints included total complication rate (including stoma-related morbidity), total reintervention risk, anastomotic leakage risk and total length of stay. RESULTS: No mortality was observed. Overall major complication, reintervention and anastomotic leakage risk for colorectal surgery were 20, 20 and 3.9%, respectively. Combined length of stay for stoma-related morbidity and reversal surgery was 12.7 days. The risk for stoma-related morbidity was 35%, and the risk for nonelective reversal was 12%. Closure rate (mean follow-up of 15 months) was 87% with a mean interval of 125 days. Reversal surgery was not correlated with mortality but with major complications (11%) and reintervention risk, anastomotic leakage risk (3.8%) and a mean length of stay of 9 days. CONCLUSION: Construction of loop ileostomies in left-sided colonic or rectal resection is associated with a low risk for anastomotic leakage at the expense of substantial stoma-related morbidity and morbidity related to reversal surgery. More accurate identification of colorectal cancer patients benefitting from protective loop ileostomy seems to be warranted.

Postconditioning hormesis put in perspective: an overview of experimental and clinical studies.

A beneficial effect of applying mild stress to cells or organisms, that were initially exposed to a high dose of stress, has been referred to as 'postconditioning hormesis'. The initial high dose of stress activates intrinsic self-recovery mechanisms. Modulation of these endogenous adaptation strategies by administration of a subsequent low dose of stress can confer effects that are beneficial to the biological system. Owing to its potentially therapeutic applications, postconditioning hormesis is subject to research in various scientific disciplines. This paper presents an overview of the dynamics of postconditioning hormesis and illustrates this phenomenon with a number of examples in experimental and clinical research.

Outcome of colonic surgery in elderly patients with colon cancer.

Introduction. Colonic cancer is one of the most commonly diagnosed malignancies and most often occurs in patients aged 65 years or older. Aim. To evaluate the outcome of colonic surgery in the elderly in our hospital and to compare five-year survival rates between the younger and elderly patients. Methods. 207 consecutive patients underwent surgery for colon cancer. Patients were separated in patients younger than 75 and older than 75 years. Results. Elderly patients presented significantly more (P < .05) as a surgical emergency, had a longer duration of admission and were more often admitted to the ICU (P < .01). Also, elderly patients had significant more co-morbidities, especially cardiovascular pathology (P < .01). Post-operative complications were seen more often in the elderly, although no significant difference was seen in anastomotic leakage. The five-year survival rate in the younger group was 62% compared with 36% in the elderly (P < .05). DFS was 61% in the younger patients compared with 32% in the elderly (P < .05). Conclusion. Curative resection of colonic carcinoma in the elderly is well tolerated and age alone should not be an indication for less aggressive therapy. However, the type and number of co-morbidities influence post-operative mortality and morbidity.

COLOR II. A randomized clinical trial comparing laparoscopic and open surgery for rectal cancer.

INTRODUCTION: Laparoscopic resection of rectal cancer has been proven efficacious but morbidity and oncological outcome need to be investigated in a randomized clinical trial. TRIAL DESIGN: Non-inferiority randomized clinical trial. METHODS: The COLOR II trial is an ongoing international randomized clinical trial. Currently 27 hospitals from Europe, South Korea and Canada are including patients. The primary endpoint is loco-regional recurrence rate three years post-operatively. Secondary endpoints cover quality of life, overall and disease free survival, post-operative morbidity and health economy analysis. RESULTS: By July 2008, 27 hospitals from the Netherlands, Belgium, Germany, Sweden, Spain, Denmark, South Korea and Canada had included 739 patients. The intra-operative conversion rate in the laparoscopic group was 17%. Distribution of age, location of the tumor and radiotherapy were equal in both treatment groups. Most tumors are located in the mid-rectum (41%). CONCLUSION: Laparoscopic surgery in the treatment of rectal cancer is feasible. The results and safety of laparoscopic surgery in the treatment of rectal cancer remain unknown, but are subject of interim analysis within the COLOR II trial. Completion of inclusion is expected by the end of 2009. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT00297791 (www.clinicaltrials.gov).

The effect of oral administration of L-arginine on anal resting pressure and anodermal blood flow in healthy volunteers.

BACKGROUND: Topical application of L-arginine, the precursor of nitric oxide, reduces anal resting pressure without significant side effects and may therefore be of benefit in the treatment of anal fissure. This in vivo study investigated the effect of orally administered L-arginine on anal resting pressure and anodermal blood flow in healthy volunteers. METHODS: Eight healthy volunteers took 3 sachets of Arginaid (Novartis Consumer Health, Breda, The Netherlands) containing 15 g L-arginine on a daily basis, for 7 days. At the start of the experiment (day 0) and on days 3 and 7, plasma levels of L-arginine, anal resting pressures and anodermal blood flow were determined. RESULTS: Arginine plasma levels increased from 107.0+/-8.6 micromol/l (day 0) to 283.7+/-44.0 micromol/l on day 3 (p< 0.01) and remained elevated at day 7 (157.3+/-19.6 micromol/l, p<0.05). Anodermal blood flow and anal resting pressures were similar on days 0, 3 and 7. CONCLUSIONS: Oral administration of 15 g arginine in healthy volunteers on a daily basis increased arginine plasma levels but had no influence on anodermal blood flow and anal resting pressure.

High plasma arginine concentrations in critically ill patients suffering from hepatic failure.

OBJECTIVE: In physiological conditions, the liver plays an important role in the regulation of plasma arginine concentrations by taking up large amounts of arginine from the hepatic circulation. When hepatic failure is present, arginine metabolism may be disturbed. Therefore, we hypothesized high arginine plasma concentrations in critically ill patients suffering from hepatic failure. DESIGN: We prospectively collected blood samples from a cross-section of intensive care unit patients. SETTING: Surgical intensive care unit of a Dutch university medical center. SUBJECTS: A total of 52 critically ill patients with clinical evidence of dysfunction of more than two organs were recruited. MEASUREMENTS: Plasma arginine concentrations were determined by HPLC. We identified correlations of arginine concentrations with organ failure scores and laboratory variables by univariate and multiple regression analyses. RESULTS: High plasma arginine concentrations were found in critically ill patients developing organ failure. Patients who were in the highest quartile of plasma arginine concentrations had significantly lower fibrinogen concentrations, higher lactic acid concentrations, and longer prothrombin time. Stepwise multiple regression analysis showed that concentrations of arginine were independently associated with the presence of hepatic failure (P=0.03) and renal failure (P=0.048). In addition, lactic acid proved to be an independent determinant of plasma arginine concentration (P=0.014). CONCLUSIONS: Critically ill patients who suffer from hepatic failure have elevated plasma arginine concentrations. Additional arginine in the treatment of these patients can be harmful, and therefore should not be used as a standard nutritional regimen until further evaluation.

Low arginine plasma levels do not aggravate renal blood flow after experimental renal ischaemia/reperfusion.

BACKGROUND: Ischaemic renal dysfunction is present in many clinical settings, including cardiovascular surgery. Renal hypoperfusion seems to be the most important pathophysiologic mechanism. Arginine plasma levels are rate limiting for NO synthesis, and low arginine plasma levels are seen after major vascular surgery. OBJECTIVE: to establish the effects of low arginine plasma levels on renal blood flow after renal ischaemia/reperfusion. DESIGN: Wistar rats were used in this unilateral renal ischaemia/reperfusion model. After 70 min of ischaemia, the kidney was reperfused for 150 min. Arginase infusion was used to lower arginine plasma levels. Blood flow measurement was performed at the end of the experiment using radiolabelled microspheres. Additional experiments were performed for histopathology. RESULTS: Arginase efficiently decreased arginine plasma levels to about 50% of normal. There was a lower blood flow in the ischaemic kidney than the contralateral (non-ischaemic) kidney. Lowering arginine plasma levels did not reduce renal blood flow in the ischaemic kidney. Renal histopathology was not influenced by lowered arginine plasma levels. CONCLUSIONS: Lowering arginine plasma levels did not affect blood flow or histology following renal ischaemia and reperfusion.

Arginase release from red blood cells: possible link in transfusion induced immune suppression?

Arginine stimulates lymphocyte function and is degraded by arginase, an enzyme that is abundantly present in red blood cells. Arginase impairs lymphocyte function and responses in vitro. Leakage of arginase from stored red blood cells may be involved in the lymphocyte dysfunction associated in allogenic blood transfusion. In the present study, arginase activity was determined in bags of red cells stored for transfusion. Buffy coat depleted red blood cells were obtained routinely from four healthy donors and stored in bags for a maximum period of five weeks at 4 degrees C. The bags were sampled for determination of arginase, lactate dehydrogenase, and potassium. In addition, a random sample of 36 bags of red blood cells about to be transfused to patients were studied. Levels of arginase, lactate dehydrogenase, and potassium showed a time dependent increase in the bags of the four donors. This time dependent increase in arginase activity could be confirmed in the additional bags sampled (P < 0.0001, r = 0.78). The results for the first time show that arginase is released from red blood cells during storage for transfusion. Arginase infusion may play an important role in the immune suppression observed after blood transfusion.

Major liver resection results in a changed plasma amino acid pattern as reflected by a decreased Fischer ratio which improves by bactericidal/permeability increasing protein.

BACKGROUND/AIMS: Major liver resection results in a high morbidity and mortality, and endotoxin plays a role in post-resection hepatic failure. Severe hepatic failure as seen in hepatitis and cirrhosis may be accompanied by hepatic encephalopathy and is characterized by a typical plasma amino acid pattern reflected by a decreased Fischer ratio. This study was performed to evaluate the plasma amino acid pattern in patients undergoing major liver surgery receiving placebo or the endotoxin-neutralizing agent bactericidal/permeability-increasing protein (rBPI21). PATIENTS AND METHODS: Forty-eight patients were randomized in this phase II, dose escalation, multicenter trial. Plasma amino acid profiles were determined preoperatively, and on the first (day 1) and third (day 3) postoperative day. RESULTS: In the placebo group the Fischer ratio decreased significantly on both postoperative days. Administration of rBPI21 also resulted in a decreased Fischer ratio on day 1, but not on day 3. Highly elevated alanine plasma levels were observed on day 1 in placebo-treated patients, whereas rBPI21 prevented this elevation. Plasma alanine levels on day 1 correlated with the duration of post-resection hepatic failure. CONCLUSIONS: Major liver resection results in a decreased Fischer ratio and a rise in plasma alanine levels. Plasma levels of alanine on the first postoperative day correlated with the duration of the post-resection hepatic failure. rBPI21 improved the Fischer ratio and prevented the rise of plasma alanine levels.

Low arginine plasma levels in patients after thoracoabdominal aortic surgery.

OBJECTIVE: Thoracoabdominal aortic surgery is a high-risk procedure and associated with a significant morbidity and mortality. Ischemia reperfusion of visceral organs and lower extremities is one of the most important determinants of this morbidity. Arginine is the precursor of nitric oxide and arginine plasma levels are important in maintaining organ blood flow. Furthermore, arginine is important in wound healing and the immune system. Because of increased utilization of arginine, low arginine plasma levels could be expected after thoracoabdominal aortic surgery. We therefore measured arginine plasma levels in these patients. DESIGN: Six patients with thoracoabdominal aortic aneurysm were included in this study. SETTING: University Hospital Vrije Universiteit, Department of Surgery, Amsterdam, The Netherlands. SUBJECTS: Six patients undergoing thoracoabdominal aortic surgery. INTERVENTION: Plasma levels of arginine were measured by high-performance liquid chromatography. RESULTS: Very low arginine plasma levels were seen on the first postoperative day. From day 1 arginine slowly increased, but did not reach normal plasma levels on day 6. CONCLUSIONS: A significant decrease of arginine plasma levels was found and because of the fact that arginine has multiple functions, it may be important to keep these arginine plasma levels at normal or even higher levels in patients undergoing major vascular surgery. European Journal of Clinical Nutrition (2000) 54, 615-617.