Effect of High-Dose Selenium on Postoperative Organ Dysfunction and Mortality in Cardiac Surgery Patients: The SUSTAIN CSX Randomized Clinical Trial.

Importance: Selenium contributes to antioxidative, anti-inflammatory, and immunomodulatory pathways, which may improve outcomes in patients at high risk of organ dysfunctions after cardiac surgery. Objective: To assess the ability of high-dose intravenous sodium selenite treatment to reduce postoperative organ dysfunction and mortality in cardiac surgery patients. Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled trial took place at 23 sites in Germany and Canada from January 2015 to January 2021. Adult cardiac surgery patients with a European System for Cardiac Operative Risk Evaluation II score-predicted mortality of 5% or more or planned combined surgical procedures were randomized. Interventions: Patients were randomly assigned (1:1) by a web-based system to receive either perioperative intravenous high-dose selenium supplementation of 2000 µg/L of sodium selenite prior to cardiopulmonary bypass, 2000 µg/L immediately postoperatively, and 1000 µg/L each day in intensive care for a maximum of 10 days or placebo. Main Outcomes and Measures: The primary end point was a composite of the numbers of days alive and free from organ dysfunction during the first 30 days following cardiac surgery. Results: A total of 1416 adult cardiac surgery patients were analyzed (mean [SD] age, 68.2 [10.4] years; 1043 [74.8%] male). The median (IQR) predicted 30-day mortality by European System for Cardiac Operative Risk Evaluation II score was 8.7% (5.6%-14.9%), and most patients had combined coronary revascularization and valvular procedures. Selenium did not increase the number of persistent organ dysfunction-free and alive days over the first 30 postoperative days (median [IQR], 29 [28-30] vs 29 [28-30]; P = .45). The 30-day mortality rates were 4.2% in the selenium and 5.0% in the placebo group (odds ratio, 0.82; 95% CI, 0.50-1.36; P = .44). Safety outcomes did not differ between the groups. Conclusions and Relevance: In high-risk cardiac surgery patients, perioperative administration of high-dose intravenous sodium selenite did not reduce morbidity or mortality. The present data do not support the routine perioperative use of selenium for patients undergoing cardiac surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02002247.

Challenges in the cultural adaptation of the German Myeloma Patient Outcome Scale (MyPOS): an outcome measure to support routine symptom assessment in myeloma care.

BACKGROUND: Patients with multiple myeloma report more problems with quality of life (QoL) than other haematological malignancies over the course of their incurable illness. The patient-centred Myeloma Patient Outcome Scale (MyPOS) was developed to assess and monitor symptoms and supportive care factors in routine care. Our aim was to translate and culturally adapt the outcome measure to the German context, and to explore its face and content validity. METHODS: Translation and cultural adaptation following established guidelines used an exploratory, sequential mixed method study design. Steps included: (1) forward translation to German; (2) backward translation to English; (3) expert review; (4) focus groups with the target population (patients, family members, healthcare professionals) to achieve conceptual equivalence; (5) cognitive interviews using Tourangeau's model with think-aloud technique to evaluate comprehension and acceptability; (6) final review. Results were analysed using thematic analysis. RESULTS: Cultural and linguistic differences were noted between the German and English original version. The focus groups (n = 11) and cognitive interviews (n = 9) both highlighted the need for adapting individual items and their answer options to the German healthcare context. Greater individuality regarding need for information with the right to not be informed was elaborated by patients. While the comprehensive nature of the tool was appreciated, item wording regarding satisfaction with healthcare was deemed not appropriate in the German context. Before implementation into routine care, patients' concerns about keeping their MyPOS data confidential need to be addressed as a barrier, whereas the MyPOS itself was perceived as a facilitator/prompt for a patient-centred discussion of QoL issues. CONCLUSION: With adaptations to answer options and certain items, the German version of the MyPOS can help monitor symptoms and problems afflicting myeloma patients over the course of the disease trajectory. It can help promote a model of comprehensive supportive and patient-centred care for these patients.

[Palliative Care in Intensive Care Units]. / Palliativmedizin meets Intensivmedizin.

Palliative care is becoming increasingly important in intensive care units. The main goal of palliative treatment is to improve quality of life in patients with critical and life-threatening conditions when curative therapies can no longer be achieved. Treatment is not limited to end-of-life care, but also includes relief of distressing symptoms such as pain, nausea, vomiting, dyspnea, delirium or anxiety, as well as communication with patients and their families. Defining patient-centred goals of care together with patients, relatives and intensive care staff supports shared decision-making. Aspects of palliative care can be integrated in the ICU in different ways. The "integrative model" presumes that all patients with critical illness may benefit from palliative care principles and interventions practiced by the ICU team. The "consultative model" involves palliative care consultants in the care of ICU patients with palliative care need that may be identified using trigger criteria. This article gives an overview on different aspects of palliative care in intensive care units and provides practical advice for the implementation of palliative care in the ICU.

Is 'anxiety sensitivity' predictive of postoperative nausea and vomiting?: A prospective observational study.

BACKGROUND: Postoperative nausea and vomiting (PONV) is an extremely distressing side effect for patients. Despite PONV prophylaxis guided by well established scoring systems, the incidence of PONV is still high. OBJECTIVE: The aim of the current study was to investigate the predictive value of anxiety sensitivity as an additional independent risk factor for PONV in patients with an increased risk of PONV. DESIGN: A noninterventional, observational study. SETTING: A tertiary care university hospital. PATIENTS: Patients with an increased risk of PONV (i.e. female, nonsmoking) undergoing elective surgery (general, gynaecological, urological, musculoskeletal or neurosurgical) under general anaesthesia. MAIN OUTCOME MEASURES: The number of patients with anxiety sensitivity assessed pre-operatively with the Anxiety Sensitivity Index-3 questionnaire, the number of patients experiencing PONV, predictive value of anxiety sensitivity compared with other established risk factors for PONV. RESULTS: Some 41.5% of the patients experienced PONV within the first 24 h after surgery. In these patients increased anxiety sensitivity (Anxiety Sensitivity Index-3 score higher than seven points) was associated with a five-fold increase in the odds ratio (OR) for PONV. From the regression model, the risk of PONV was increased by lack of PONV prophylaxis (OR, 3.68), the postoperative administration of opioids (OR, 3.60) and patient age (OR, 1.03), but laparoscopic surgery did not increase the risk. CONCLUSION: In addition to the well established risk factors, anxiety sensitivity can help to predict the risk of PONV. It seems justifiable to add psychological factors such as anxiety sensitivity to PONV risk-scores. PONV prophylaxis should be considered when anxiety sensitivity is high. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01875120.

Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

BACKGROUND: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy. METHODS: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9-10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5-9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect. DISCUSSION: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT03369210 ).

Genome-wide association study of myocardial infarction, atrial fibrillation, acute stroke, acute kidney injury and delirium after cardiac surgery - a sub-analysis of the RIPHeart-Study.

BACKGROUND: The aim of our study was the identification of genetic variants associated with postoperative complications after cardiac surgery. METHODS: We conducted a prospective, double-blind, multicenter, randomized trial (RIPHeart). We performed a genome-wide association study (GWAS) in 1170 patients of both genders (871 males, 299 females) from the RIPHeart-Study cohort. Patients undergoing non-emergent cardiac surgery were included. Primary endpoint comprises a binary composite complication rate covering atrial fibrillation, delirium, non-fatal myocardial infarction, acute renal failure and/or any new stroke until hospital discharge with a maximum of fourteen days after surgery. RESULTS: A total of 547,644 genotyped markers were available for analysis. Following quality control and adjustment for clinical covariate, one SNP reached genome-wide significance (PHLPP2, rs78064607, p = 3.77 × 10- 8) and 139 (adjusted for all other outcomes) SNPs showed promising association with p < 1 × 10- 5 from the GWAS. CONCLUSIONS: We identified several potential loci, in particular PHLPP2, BBS9, RyR2, DUSP4 and HSPA8, associated with new-onset of atrial fibrillation, delirium, myocardial infarction, acute kidney injury and stroke after cardiac surgery. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov NCT01067703, prospectively registered on 11 Feb 2010.

Association between pre-operative biological phenotypes and postoperative pulmonary complications: An unbiased cluster analysis.

BACKGROUND: Biological phenotypes have been identified within several heterogeneous pulmonary diseases, with potential therapeutic consequences. OBJECTIVE: To assess whether distinct biological phenotypes exist within surgical patients, and whether development of postoperative pulmonary complications (PPCs) and subsequent dependence of intra-operative positive end-expiratory pressure (PEEP) differ between such phenotypes. SETTING: Operating rooms of six hospitals in Europe and USA. DESIGN: Secondary analysis of the 'PROtective Ventilation with HIgh or LOw PEEP' trial. PATIENTS: Adult patients scheduled for abdominal surgery who are at risk of PPCs. INTERVENTIONS: Measurement of pre-operative concentrations of seven plasma biomarkers associated with inflammation and lung injury. MAIN OUTCOME MEASURES: We applied unbiased cluster analysis to identify biological phenotypes. We then compared the proportion of patients developing PPCs within each phenotype, and associations between intra-operative PEEP levels and development of PPCs among phenotypes. RESULTS: In total, 242 patients were included. Unbiased cluster analysis clustered the patients within two biological phenotypes. Patients with phenotype 1 had lower plasma concentrations of TNF-α (3.8 [2.4 to 5.9] vs. 10.2 [8.0 to 12.1] pg ml; P < 0.001), IL-6 (2.3 [1.5 to 4.0] vs. 4.0 [2.9 to 6.5] pg ml; P < 0.001) and IL-8 (4.7 [3.1 to 8.1] vs. 8.1 [6.0 to 13.9] pg ml; P < 0.001). Phenotype 2 patients had the highest incidence of PPC (69.8 vs. 34.2% in type 1; P < 0.001). There was no interaction between phenotype and PEEP level for the development of PPCs (43.2% in high PEEP vs. 25.6% in low PEEP in phenotype 1, and 73.6% in high PEEP and 65.7% in low PEEP in phenotype 2; P for interaction = 0.503). CONCLUSION: Patients at risk of PPCs and undergoing open abdominal surgery can be clustered based on pre-operative plasma biomarker concentrations. The two identified phenotypes have different incidences of PPCs. Biologic phenotyping could be useful in future randomised controlled trials of intra-operative ventilation. TRIAL REGISTRATION: The PROtective Ventilation with HIgh or LOw PEEP trial, including the substudy from which data were used for the present analysis, was registered at ClinicalTrials.gov (NCT01441791).

RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study: Myocardial Dysfunction, Postoperative Neurocognitive Dysfunction, and 1 Year Follow-Up.

BACKGROUND: Remote ischemic preconditioning (RIPC) has been suggested to protect against certain forms of organ injury after cardiac surgery. Previously, we reported the main results of RIPHeart (Remote Ischemic Preconditioning for Heart Surgery) Study, a multicenter trial randomizing 1403 cardiac surgery patients receiving either RIPC or sham-RIPC. METHODS AND RESULTS: In this follow-up paper, we present 1-year follow-up of the composite primary end point and its individual components (all-cause mortality, myocardial infarction, stroke and acute renal failure), in a sub-group of patients, intraoperative myocardial dysfunction assessed by transesophageal echocardiography and the incidence of postoperative neurocognitive dysfunction 5 to 7 days and 3 months after surgery. RIPC neither showed any beneficial effect on the 1-year composite primary end point (RIPC versus sham-RIPC 16.4% versus 16.9%) and its individual components (all-cause mortality [3.4% versus 2.5%], myocardial infarction [7.0% versus 9.4%], stroke [2.2% versus 3.1%], acute renal failure [7.0% versus 5.7%]) nor improved intraoperative myocardial dysfunction or incidence of postoperative neurocognitive dysfunction 5 to 7 days (67 [47.5%] versus 71 [53.8%] patients) and 3 months after surgery (17 [27.9%] versus 18 [27.7%] patients), respectively. CONCLUSIONS: Similar to our main study, RIPC had no effect on intraoperative myocardial dysfunction, neurocognitive function and long-term outcome in cardiac surgery patients undergoing propofol anesthesia. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01067703.

Anxiety and its predictive value for pain and regular analgesic intake after lumbar disc surgery - a prospective observational longitudinal study.

BACKGROUND: Ongoing pain after surgery is a major problem and influences recovery and the quality of life of the patient. Associations between anxiety and their impact on postoperative pain after herniated disc surgery have been reported, but the results are inconsistent. The aim of the present longitudinal study was to evaluate the predictive value of preoperative anxiety for postoperative ongoing pain and prolonged analgesic intake after herniated disc surgery. METHODS: 106 patients with lumbar disc herniation were evaluated in the study. Anxiety was measured with the Generalized Anxiety Disorder 7-Item Scale (GAD-7) before surgery. Pain intensity was assessed on a numeric rating scale (NRS) at baseline, 6-weeks and 6-months after surgery. Regression analysis was performed to identify independent predictors of pain and regular utilization of analgesics up to 6 months after surgery while controlling for confounding variables. RESULTS: 42.5% of the patients were rated as anxiety cases (sum scores GAD-7 > 5), mean scores of anxiety showed mild to moderate symptom severity, and 43% suffered from chronic pain before surgery. Six months after surgery, 55.6% of the patients indicated pain levels of 4/10 (NRS) or higher and about 40% still took pain medication on a regular basis, regardless of their preoperative classification as anxiety-case (37.7% and 41.5%). The preoperative pain level was statistically significant for ongoing postsurgical pain in all four analyses (p < 0.001). With binary logistic regression analyses, preoperative pain intensity, but neither demographic factors nor preoperative anxiety, was identified as predictor for postoperative pain and need for analgesic medication up to 6 months after lumbar disc surgery. CONCLUSION: We found no evidence for the presence of anxiety before disc surgery being a prognostic factor for ongoing pain and regular postoperative intake of analgesics. Only preoperative pain intensity was predictive for increased pain and continued need for analgesic medication up to 6 months after lumbar disc surgery. TRIAL REGISTRATION: Clinicaltrials.gov NCT01488617 . Registered 6 December 2011.

Kinetics of plasma biomarkers of inflammation and lung injury in surgical patients with or without postoperative pulmonary complications.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common after major abdominal surgery. The kinetics of plasma biomarkers could improve identification of patients developing PPCs, but the kinetics may depend on intraoperative ventilator settings. OBJECTIVE: To test whether the kinetics of plasma biomarkers are capable of identifying patients who will develop PPCs, and whether the kinetics depend on the intraoperative level of positive end-expiratory pressure (PEEP). DESIGN: A preplanned substudy of a randomised controlled trial. SETTING: Operation room of five centres. PATIENTS: Two hundred and forty-two adult patients scheduled for abdominal surgery at risk of developing PPCs. INTERVENTIONS: High (12 cmH2O) versus low (≤2 cmH2O) levels of PEEP. MAIN OUTCOME MEASURES: Individual PPCs were combined as a composite endpoint. Plasma samples were collected before surgery, directly after surgery and on the fifth postoperative day. The levels of the following were measured: tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, the soluble form of the Receptor for Advanced Glycation End-products (sRAGE), Surfactant Protein (SP)-D, Clara Cell protein (CC)-16 and Krebs von den Lungen 6 (KL6). RESULTS: Blood sampling was complete in 242 patients: 120 patients in the high PEEP group and 122 patients in the low PEEP group. Increases in plasma levels of TNF- IL-6, IL-8 and CC-16, and a decrease in plasma levels of SP-D were greater in patients who developed PPCs; however, the area under the receiver operating characteristic curve was low for all biomarkers. CC-16 was the only biomarker whose level increased more in patients who had received high levels of PEEP. CONCLUSION: In patients undergoing abdominal surgery and at risk of developing PPCs, plasma levels of biomarkers for inflammation or lung injury showed distinct kinetics with development of PPCs, but none of the biomarkers showed sufficient prognostic value. The use of high levels of PEEP was associated with increased levels of CC-16, suggesting lung overdistension. TRIAL REGISTRATION: The PROVHILO trial, including this substudy, was registered at clinicaltrials.gov (NCT01441791).

Prevalence of pain 6 months after surgery: a prospective observational study.

BACKGROUND: Pain after surgery is a major issue for patient discomfort and often associated with delayed recovery. The aim of the present study was to evaluate the prevalence of pain and requirement for analgesics up to 6 months after elective surgery, independent if new pain symptoms occurred after surgery or if preoperative pain persisted in the postoperative period. METHODS: A prospective observational single center cohort study was conducted between January 2012 and August 2013. Eligible patients were scheduled to undergo elective surgical interventions including joint (hip, knee arthroplasty), back (nucleotomy, spondylodesis), or urological surgery (cystectomy, prostatectomy, nephrectomy). Pain was assessed on an 11-point numerical rating scale (NRS) before, on postoperative day 2 and 6 months after surgery. Clinical information was collected with structured questionnaires and by telephone interview. RESULTS: Six hundred and forty-four patients gave informed consent, including 54.4 % men (mean age 62.2, SD 14.3). Higher preoperative pain scores were found in patients undergoing joint (mean 7.6; 95 % confidence interval [CI]: 7.2-8.0) and back surgery (mean 7.1, CI: 6.8-7.5) than in patients prior to urological surgery (mean 2.3; CI: 1.8-2.8). After 6 months, about 50 % of patients after joint or back surgery indicated pain levels ≥3/10, compared to 15.9 % of patients after urological surgery (p < .001). 35.3 % of the patients after joint surgery and 41.3 % after back surgery still use pain medication 6 months postoperatively, in contrast to 7.3 % of patients after urological surgery. 13.6 % of patients who underwent back surgery indicated the regular intake of opioids. CONCLUSIONS: Our results reveal that a significant percentage of patients undergoing procedures in joint or back surgery still need pain medication up to 6 months postoperatively due to ongoing pain symptoms. Improved monitoring of pain management is warranted, especially after discharge from hospital, to improve long-term results. TRIAL REGISTRATION: Clinicaltrials.gov (Identifier: NCT01488617 ); date of registration December 6th 2011.

Rationale and design of the RE-LATED AF--AFNET 7 trial: REsolution of Left atrial-Appendage Thrombus--Effects of Dabigatran in patients with Atrial Fibrillation.

BACKGROUND: Dabigatran etexilate, a direct thrombin inhibitor and non-vitamin K antagonist oral anticoagulant (NOAC), has been shown to effectively prevent thromboembolic events in patients with non-valvular atrial fibrillation (AF). However, there is a paucity of data on the antithrombotic efficacy and safety of dabigatran in the resolution of left atrial appendage (LAA) thrombi in AF patients. OBJECTIVE: The primary objective of the RE-LATED AF trial is to assess whether dabigatran results in a faster complete LAA thrombus resolution as compared to vitamin K antagonist phenprocoumon. Secondary objectives are to assess the impact of dabigatran on complete LAA thrombus resolution rate within 6 weeks of treatment and change in LAA thrombus volume under treatment. Furthermore, this study aims to assess and compare safety and tolerability of dabigatran vs. phenprocoumon. METHODS: The study is designed as a prospective, randomized, open-label, controlled, explorative, blinded endpoint (PROBE) trial. Patients with AF and left atrial appendage thrombus confirmed by transoesophageal echocardiography (TEE) will be randomized to receive either dabigatran (150 mg bid) or phenprocoumon (INR 2-3) for the resolution of LAA thrombus formation for at least 21 days. Thrombus resolution will be determined by TEE 3 weeks after treatment initiation and subsequently at weeks 4 and 6, if the LAA thrombus has not been resolved before. A total of 110 patients are planned to be randomized. CONCLUSION: This is the first prospective, multicentre, randomized controlled clinical trial investigating safety and efficacy of a NOAC for the resolution of LAA thrombi in patients with non-valvular AF.

A Multicenter Trial of Remote Ischemic Preconditioning for Heart Surgery.

BACKGROUND: Remote ischemic preconditioning (RIPC) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery, but uncertainty about clinical outcomes remains. METHODS: We conducted a prospective, double-blind, multicenter, randomized, controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol. The trial compared upper-limb RIPC with a sham intervention. The primary end point was a composite of death, myocardial infarction, stroke, or acute renal failure up to the time of hospital discharge. Secondary end points included the occurrence of any individual component of the primary end point by day 90. RESULTS: A total of 1403 patients underwent randomization. The full analysis set comprised 1385 patients (692 in the RIPC group and 693 in the sham-RIPC group). There was no significant between-group difference in the rate of the composite primary end point (99 patients [14.3%] in the RIPC group and 101 [14.6%] in the sham-RIPC group, P=0.89) or of any of the individual components: death (9 patients [1.3%] and 4 [0.6%], respectively; P=0.21), myocardial infarction (47 [6.8%] and 63 [9.1%], P=0.12), stroke (14 [2.0%] and 15 [2.2%], P=0.79), and acute renal failure (42 [6.1%] and 35 [5.1%], P=0.45). The results were similar in the per-protocol analysis. No treatment effect was found in any subgroup analysis. No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release, the duration of mechanical ventilation, the length of stay in the intensive care unit or the hospital, new onset of atrial fibrillation, and the incidence of postoperative delirium. No RIPC-related adverse events were observed. CONCLUSIONS: Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery. (Funded by the German Research Foundation; RIPHeart ClinicalTrials.gov number, NCT01067703.).

Hydroxychloroquine in children with interstitial (diffuse parenchymal) lung diseases.

Hydroxychloroquine (HCQ) is one of the drugs frequently used for the treatment of interstitial lung disease (ILD) in children (chILD). This use is off-label and studies to analyze the effect and safety of HCQ in chILD are lacking. Therefore, a literature research on the usage of chloroquine (CQ) and HCQ in these conditions was done. Eighty-five case reports and small series in the period from 1984 to 2013 were identified in which children with different diagnoses of ILD were treated with CQ or HCQ, sometimes in combination with other medication including steroids. A favorable response to HCQ or CQ was reported in 35 cases, whereas in the other cases the effect was negative or not clear. The dose of HCQ used was between 5 and 10 mg/kg body weight/day (bw/d). No pharmacokinetic studies have been done. The side effect profile in children seemed to be similar to that in adults. Most often gastrointestinal symptoms were reported. Three patients were found developing retinal changes during the treatment with CQ, whereas in none of the patients treated with HCQ retinal changes were reported. Based on retrospective case reports and small series likely to be reported with bias, the use of HCQ in chILD might be classified as safe. As no prospective data on efficacy and safety of HCQ in chILD are available, systematic collection is necessary. This may be achieved by web-based registers like the European Management Platform for Childhood Interstitial Lung Diseases. Prospective and controlled investigations of HCQ in patients with chILD are mandatory.

The CoxD protein of Oligotropha carboxidovorans is a predicted AAA+ ATPase chaperone involved in the biogenesis of the CO dehydrogenase [CuSMoO2] cluster.

CO dehydrogenase from the Gram-negative chemolithoautotrophic eubacterium Oligotropha carboxidovorans OM5 is a structurally characterized molybdenum-containing iron-sulfur flavoenzyme, which catalyzes the oxidation of CO (CO + H(2)O --> CO(2) + 2e(-) + 2H(+)). It accommodates in its active site a unique bimetallic [CuSMoO(2)] cluster, which is subject to post-translational maturation. Insertional mutagenesis of coxD has established its requirement for the assembly of the [CuSMoO(2)] cluster. Disruption of coxD led to a phenotype of the corresponding mutant OM5 D::km with the following characteristics: (i) It was impaired in the utilization of CO, whereas the utilization of H(2) plus CO(2) was not affected; (ii) Under appropriate induction conditions bacteria synthesized a fully assembled apo-CO dehydrogenase, which could not oxidize CO; (iii) Apo-CO dehydrogenase contained a [MoO(3)] site in place of the [CuSMoO(2)] cluster; and (iv) Employing sodium sulfide first and then the Cu(I)-(thiourea)(3) complex, the non-catalytic [MoO(3)] site could be reconstituted in vitro to a [CuSMoO(2)] cluster capable of oxidizing CO. Sequence information suggests that CoxD is a MoxR-like AAA+ ATPase chaperone related to the hexameric, ring-shaped BchI component of Mg(2+)-chelatases. Recombinant CoxD, which appeared in Escherichia coli in inclusion bodies, occurs exclusively in cytoplasmic membranes of O. carboxidovorans grown in the presence of CO, and its occurrence coincided with GTPase activity upon sucrose density gradient centrifugation of cell extracts. The presumed function of CoxD is the partial unfolding of apo-CO dehydrogenase to assist in the stepwise introduction of sulfur and copper in the [MoO(3)] center of the enzyme.

Complete nucleotide sequence of the circular megaplasmid pHCG3 of Oligotropha carboxidovorans: function in the chemolithoautotrophic utilization of CO, H(2) and CO(2).

Oligotropha carboxidovorans harbors the low-copy-number, circular, 133,058-bp DNA megaplasmid pHCG3, which is essential in the chemolithoautotrophic utilization of CO (carboxidotrophy), H(2) (hydrogenotrophy) and CO(2) under aerobic conditions. The complete nucleotide sequence of pHCG3 revealed 125 open reading frames. Of these, 95 were identified as putative structural genes. The plasmid carries the four gene clusters cox (14.54 kb, 12 genes), cbb (13.33 kb, 13 genes), hox (23.35 kb, 19 genes plus one ORF) and tra/trb (25.01 kb, 22 genes plus 2 ORFs), which assemble the functions required for the utilization of CO, CO(2) or H(2), and the conjugal transfer of the plasmid, respectively. The gene clusters cox, cbb and hox form a 51.2-kb chemolithoautotrophy module. The tra/trb cluster on the plasmid pHCG3 of O. carboxidovorans has a similar architecture as the Ti-plasmid of Agrobacterium tumefaciens. The tra/trb cluster is separated from the chemolithoautotrophy module by two regions (25.2 and 29.6 kb) with miscellaneous or mostly unknown functions. These regions carry a number of single genes coding for replication and stabilization of pHCG3 as well as the components of a putative system of global regulation of plasmid replication in O. carboxidovorans. An oriV encodes the replication proteins RepABC. Sequence comparisons of pHCG3-encoded genes suggest that major genetic exchange between O. carboxidovorans and the proteobacteria has occurred.