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Neonatal pulmonary hypertension (PH) is associated with many severe congenital abnormalities (congenital diaphragmatic hernia) or acquired cardiorespiratory diseases such as pneumonia, meconium aspiration and bronchopulmonary dysplasia (BPD). If no cause is found it may be labelled idiopathic persistent pulmonary hypertension of the newborn. Although PH may result in life threatening hypoxia and circulatory failure, in the majority of cases, it resolves in the neonatal period following treatment of the underlying cause. However, in some cases, neonatal PH progresses into infancy and childhood where symptoms include failure to thrive and eventually right heart failure or death if left untreated. This chronic condition is termed pulmonary vascular hypertensive disease (PHVD). Although classification and diagnostic criteria have only recently been proposed for pediatric PHVD, little is known about the pathophysiology of chronic neonatal PH, or why pulmonary vascular resistance may remain elevated well beyond infancy. This review explores the many factors involved in chronic PH and what implications this may have on long term outcome when the disease progresses beyond the neonatal period.

Sepsis is a major worldwide healthcare issue with unmet clinical need. Despite extensive animal research in this area, successful clinical translation has been largely unsuccessful. We propose one reason for this is that, sometimes, the experimental question is misdirected or unrealistic expectations are being made of the animal model. As sepsis models can lead to a rapid and substantial suffering – it is essential that we continually review experimental approaches and undertake a full harm:benefit impact assessment for each study. In some instances, this may require refinement of existing sepsis models. In other cases, it may be replacement to a different experimental system altogether, answering a mechanistic question whilst aligning with the principles of reduction, refinement and replacement (3Rs). We discuss making better use of patient data to identify potentially useful therapeutic targets which can subsequently be validated in preclinical systems. This may be achieved through greater use of construct validity models, from which mechanistic conclusions are drawn. We argue that such models could provide equally useful scientific data as face validity models, but with an improved 3Rs impact. Indeed, construct validity models may not require sepsis to be modelled, per se. We propose that approaches that could support and refine clinical translation of research findings, whilst reducing the overall welfare burden on research animals.

There is ample evidence to show that Marine Protected Areas (MPAs) are an effective and preferred tool for safeguarding biodiversity and ecosystem services (Babcock et al., 2010; Sala and Giakoumi, 2017; Sandin et al., 2008; Shears and Babcock, 2003). Current efforts to demonstrate Protected Area Management Effectiveness (PAME) rely heavily on assessments of the state of biological resources within the Protected Area (PA) (Leverington et al., 2010; Cook et al., 2014). Where they do address MPAs effectiveness as a ‘governance tool’ the outputs are largely narrative (Pomeroy et al., 2004) or rely heavily on subjective assessments of MPA performance (Staub and Hatziolos, 2004).

OBJECTIVES The interstage mortality rate after a Norwood stage 1 operation remains 12–20% in current series. In-hospital interstage facilitates escalation of care, possibly improving outcome. METHODS A retrospective study was designed for hypoplastic left heart syndrome (HLHS) and HLHS variants, offering an in-hospital stay after the Norwood operation until the completion of stage 2. Daily and weekly examinations were conducted systematically, including two-dimensional and speckle-tracking echocardiography. Primary end points included aggregate survival until the completion of stage 2 and interstage freedom from escalation of care. Moreover, we calculated the sensitivity and specificity of speckle-tracking echocardiographic myocardial deformation in predicting death/transplant after the Norwood procedure. RESULTS Between 2015 and 2019, 33 neonates with HLHS (24) or HLHS variants (9) underwent Norwood stage 1 (31) or hybrid palliation followed by a comprehensive stage 2 operation (2). Stage 1 Norwood–Sano was preferred in 18 (54.5%) neonates; the classic Norwood with Blalock–Taussig shunt was performed in 13 (39.4%) neonates. The Norwood stage 1 30-day mortality rate was 6.2%. The in-hospital interstage strategy was implemented after Norwood stage 1 with a 3.4% interstage mortality rate. The aggregate Norwood stage 1 and interstage Kaplan–Meier survival rate was 90.6 ± 5.2%. Escalation of care was necessary for 5 (17.2%) patients at 2.5 ± 1.2 months during the interstage for compromising atrial arrhythmias (2), Sano-shunt stenosis (1) and pneumonia requiring a high-frequency oscillator (2); there were no deaths. A bidirectional Glenn (25) or a comprehensive-Norwood stage 2 (2) was completed in 27 patients at 4.7 ± 1.2 months with a 92.6% survival rate. The overall Kaplan–Meier survival rate is 80.9 ± 7.0% at 4.3 years (mean 25.3 ± 15.7 months). An 8.7% Δ longitudinal strain 30 days after Norwood stage 1 had 100% sensitivity and 81% specificity for death/transplant. CONCLUSIONS In-hospital interstage facilitates escalation of care, which seems efficacious in reducing interstage Norwood deaths. A significant reduction of longitudinal strain after Norwood stage 1 is a strong predictor of poor outcome.

The objectives of this review are to discuss the pathophysiology, clinical impact and treatment of hyperglycemia, and disturbances in thyroid and adrenal function prior to and following cardiac surgery in children. MEDLINE and PubMed. Disturbances in glucose metabolism and thyroid and adrenal function are common in critically ill children with cardiac disease and in particular in children undergoing cardiac surgery for complex congenital heart disease. An understanding of the pathophysiology, clinical impact and treatment of these disturbances is essential for the management of these at risk patients.

Summary Background Paediatric acute respiratory distress syndrome (PARDS) is associated with high mortality in children, but until recently no paediatric-specific diagnostic criteria existed. The Pediatric Acute Lung Injury Consensus Conference (PALICC) definition was developed to overcome limitations of the Berlin definition, which was designed and validated for adults. We aimed to determine the incidence and outcomes of children who meet the PALICC definition of PARDS. Methods In this international, prospective, cross-sectional, observational study, 145 paediatric intensive care units (PICUs) from 27 countries were recruited, and over a continuous 5 day period across 10 weeks all patients were screened for enrolment. Patients were included if they had a new diagnosis of PARDS that met PALICC criteria during the study week. Exclusion criteria included meeting PARDS criteria more than 24 h before screening, cyanotic heart disease, active perinatal lung disease, and preparation or recovery from a cardiac intervention. Data were collected on the PICU characteristics, patient demographics, and elements of PARDS (ie, PARDS risk factors, hypoxaemia severity metrics, type of ventilation), comorbidities, chest imaging, arterial blood gas measurements, and pulse oximetry. The primary outcome was PICU mortality. Secondary outcomes included 90 day mortality, duration of invasive mechanical and non-invasive ventilation, and cause of death. Findings Between May 9, 2016, and June 16, 2017, during the 10 study weeks, 23 280 patients were admitted to participating PICUs, of whom 744 (3·2%) were identified as having PARDS. 95% (708 of 744) of patients had complete data for analysis, with 17% (121 of 708; 95% CI 14–20) mortality, whereas only 32% (230 of 708) of patients met Berlin criteria with 27% (61 of 230) mortality. Based on hypoxaemia severity at PARDS diagnosis, mortality was similar among those who were non-invasively ventilated and with mild or moderate PARDS (10–15%), but higher for those with severe PARDS (33% [54 of 165; 95% CI 26–41]). 50% (80 of 160) of non-invasively ventilated patients with PARDS were subsequently intubated, with 25% (20 of 80; 95% CI 16–36) mortality. By use of PALICC PARDS definition, severity of PARDS at 6 h after initial diagnosis (area under the curve [AUC] 0·69, 95% CI 0·62–0·76) discriminates PICU mortality better than severity at PARDS diagnosis (AUC 0·64, 0·58–0·71), and outperforms Berlin severity groups at 6 h (0·64, 0·58–0·70; p=0·01). Interpretation The PALICC definition identified more children as having PARDS than the Berlin definition, and PALICC PARDS severity groupings improved the stratification of mortality risk, particularly when applied 6 h after PARDS diagnosis. The PALICC PARDS framework should be considered for use in future epidemiological and therapeutic research among children with PARDS. Funding University of Southern California Clinical Translational Science Institute, Sainte Justine Children's Hospital, University of Montreal, Canada, Reseau en Sante Respiratoire du Fonds de Recherche Quebec-Sante, and Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care Medicine.

Cardiac arrest occurs at a higher rate in children with heart disease than in healthy children. Pediatric basic life support and advanced life support guidelines focus on delivering high-quality resuscitation in children with normal hearts. The complexity and variability in pediatric heart disease pose unique challenges during resuscitation. A writing group appointed by the American Heart Association reviewed the literature addressing resuscitation in children with heart disease. MEDLINE and Google Scholar databases were searched from 1966 to 2015, cross-referencing pediatric heart disease with pertinent resuscitation search terms. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. The recommendations in this statement concur with the critical components of the 2015 American Heart Association pediatric basic life support and pediatric advanced life support guidelines and are meant to serve as a resuscitation supplement. This statement is meant for caregivers of children with heart disease in the prehospital and in-hospital settings. Understanding the anatomy and physiology of the high-risk pediatric cardiac population will promote early recognition and treatment of decompensation to prevent cardiac arrest, increase survival from cardiac arrest by providing high-quality resuscitations, and improve outcomes with postresuscitation care.

The authors of the article entitled "Paediatric Intensive Care admission blood pressure and risk of death in 30,334 children" inform that due to an error in their database extraction, the following corrections to the data published should be notified.

OBJECTIVE: Extracorporeal life support has undergone a revolution in the past several years with the advent of new, miniaturized equipment and success in supporting patients with a variety of illnesses. Most experience has come with the use of extracorporeal membrane oxygenation, a modified form of cardiopulmonary bypass that can support the heart, lungs, and circulation for days to months at a time. To describe the recommendations for the use of extracorporeal membrane oxygenation in children with pediatric acute respiratory distress syndrome based on a review of the literature and expert opinion.DESIGN: Consensus conference of experts in pediatric acute lung injury.METHODS: A panel of 27 experts met over the course of 2 years to develop a taxonomy to define pediatric acute respiratory distress syndrome and to make recommendations regarding treatment and research priorities. The extracorporeal support subgroup comprised two international experts. When published data were lacking, a modified Delphi approach emphasizing strong professional agreement was used.RESULTS: The Pediatric Acute Lung Injury Consensus Conference experts developed and voted on a total of 151 recommendations addressing the topics related to pediatric acute respiratory distress syndrome, 11 of which related to extracorporeal support. All recommendations had agreement, with 10 recommendations (91%) achieving strong agreement. These recommendations included the utilization of extracorporeal support for reversible causes of pediatric acute respiratory distress syndrome, consideration of quality of life when making the decision to use extracorporeal support, and the use of the Extracorporeal Life Support Organization registry to report all extracorporeal support activity, among others.CONCLUSIONS: Pediatric extracorporeal membrane oxygenation for pediatric acute respiratory distress syndrome could benefit from more specific data collection and collaboration of focused investigators to establish validated criteria for optimal application of extracorporeal membrane oxygenation and patient management protocols. Until that time, consensus opinion offers some insight into guidelines.

Background Neonatal mortality accounts for nearly three quarters of all infant deaths in Vietnam. The nursing team are the largest professional group working with newborns, however do not routinely receive neonatal training and there is a lack of research into the impact of educational provision. This study explored changes in nursing perceptions towards their role following a neonatal educational intervention. Parents perceptions of nursing care were explored to determine any changes as nurses gained more experience. Method Semi-Structured qualitative interviews were conducted every 6 months over an 18 month period with 16 nurses. At each time point, parents whose infant was resident on the neonatal unit were invited to participate in an interview to explore their experiences of nursing care. A total of 67 parents participated over 18 months. Interviews were conducted and transcribed in Vietnamese before translation into English for manifest content analysis facilitated by NVivo V14. Results Analysis of nursing transcripts identified 14 basic categories which could be grouped (23) into 3 themes: (1) perceptions of the role of the neonatal nurse, (2) perception of the parental role and (3) professional recollections. Analysis of parent transcripts identified 14 basic categories which could be grouped into 3 themes: (1) information sharing, (2) participation in care, and (3) personal experience. Conclusions Qualitative interviews highlighted the short term effect that the introduction of an educational intervention can have on both nursing attitudes towards and parental experience of care in one neonatal unit in central Vietnam. Nurses shared a growing awareness of their role along with its ethical issues and challenges, whilst parents discussed their overall desire for more participation in their infants care. Further research is required to determine the long term impact of the intervention, the ability of nurses to translate knowledge into clinical practice through assessment of nursing knowledge and competence, and the impact and needs of parents. A greater understanding will allow us to continue to improve the experiences of nurses and parents, and highlight how these areas may contribute towards the reduction of infant mortality and morbidity in Vietnam. Electronic supplementary material The online version of this article (doi:10.1186/s12887-017-0909-6) contains supplementary material, which is available to authorized users.

Objective To assess the impact of service improvements implemented because of latent threats (LTs) detected during in situ simulation. Design Retrospective review from April 2008 to April 2015. Setting Paediatric Intensive Care Unit in a specialist tertiary hospital. Intervention Service improvements from LTs detection during in situ simulation. Action plans from patient safety incidents (PSIs). Main outcome measures The quantity, category, and subsequent service improvements for LTs. The quantity, category, and subsequent action plans for PSIs. Similarities between PSIs and LTs before and after service improvements. Results 201 Simulated inter-professional team training courses with 1,144 inter-professional participants. 44 LTs were identified (1 LT per 4.6 courses). Incident severity varied: 18 (41%) with the potential to cause harm, 20 (46%) that would have caused minimal harm, and 6 (13%) that would have caused significant temporary harm. Category analysis revealed the majority of LTs were resources (36%) and education and training (27%). The remainder consisted of equipment (11%), organizational and strategic (7%), work and environment (7%), medication (7%), and systems and protocols (5%). 43 service improvements were developed: 24 (55%) resources/equipment; 9 (21%) educational; 6 (14%) organizational changes; 2 (5%) staff communications; and 2 (5%) guidelines. Four (9%) service improvements were adopted trust wide. 32 (73%) LTs did not recur after service improvements. 24 (1%) of 1,946 PSIs were similar to LTs: 7 resource incidents, 7 catastrophic blood loss, 4 hyperkalaemia arrests, 3 emergency buzzer failures, and 3 difficulties contacting staff. 34 LTs (77%) were never recorded as PSIs. Conclusion An in situ simulation program can identify important LTs which traditional reporting systems miss. Subsequent improvements in workplace systems and resources can improve efficiency and remove error traps.

BACKGROUND Whether an insulin infusion should be used for tight control of hyperglycemia in critically ill children remains unclear. METHODS We randomly assigned children (≤16 years of age) who were admitted to the pedi atric intensive care unit (ICU) and were expected to require mechanical ventilation and vasoactive drugs for at least 12 hours to either tight glycemic control, with a target blood glucose range of 72 to 126 mg per deciliter (4.0 to 7.0 mmol per liter), or conventional glycemic control, with a target level below 216 mg per deciliter (12.0 mmol per liter). The primary outcome was the number of days alive and free from mechanical ventilation at 30 days after randomization. The main prespecified subgroup analysis compared children who had undergone cardiac surgery with those who had not. We also assessed costs of hospital and community health services. RESULTS A total of 1369 patients at 13 centers in England underwent randomization: 694 to tight glycemic control and 675 to conventional glycemic control; 60% had undergone cardiac surgery. The mean between-group difference in the number of days alive and free from mechanical ventilation at 30 days was 0.36 days (95% confidence interval [CI], −0.42 to 1.14); the effects did not differ according to subgroup. Severe hypogly cemia (blood glucose

Optimal strategies for reducing catheter-related blood stream infection (CR-BSI) differ for adults and children. National guidelines do not make child-specific recommendations. We determined whether evidence explained the inconsistencies between guidelines and reported practice in paediatric intensive care units (PICUs). We conducted a survey of eight interventions for reducing CR-BSI in all 25 British PICUs in 2009. Interventions were categorised as requiring child-specific evidence, generalisable to adults and children, or organisational recommendations. Twenty-four of the 25 PICUs responded. For child-specific interventions, practice diverged from guidelines for “Insert into subclavian/jugular veins” (18 PICUs frequently used femoral veins, supported by observational evidence for increased safety in children). Practice reflected guidelines for “Use standard but consider antimicrobial-impregnated central venous catheters (CVCs) for high-risk patients” (14 used standard only, 3 used standard and antimicrobial-impregnated despite no randomised controlled trial (RCT) evidence for antimicrobial-impregnated CVCs in children, 7 used heparin-bonded for some or all children); “Use 2% chlorhexidine for skin preparation” (20 PICUs); “Avoid routine CVC replacement” (20 PICUs). For generalisable interventions, practice was consistent with guidelines for “Administration set replacement” (21 PICUs) but deviated for “Maintenance of CVC asepsis” (11 PICUs used alcohol due to inconclusive evidence for chlorhexidine). Practice diverged from guidelines for organisational interventions: “Train healthcare workers in CVC care” (9 PICUs); “Monitor blood stream infection (BSI) rates” (8 PICUs). Guidelines should explicitly address paediatric practice and report the quality of evidence and strength of recommendations. Organisations should ensure doctors are trained in CVC insertion and invest in BSI monitoring, especially in PICUs. The type of CVC and insertion site are important gaps in evidence for children.

Melanotic neuroectodermal tumour of infancy is an extremely rare neoplasm arising in newborns and young children, typically involving the face or cranium. A case arising from the maxilla, requiring extensive resection with a near-total maxillectomy, is presented. A thorough review of the literature on this unusual tumour is provided, with emphasis on prognostic factors and appropriate treatment.

Year in review in Intensive Care Medicine, 2007. II. Haemodynamics, pneumonia, infections and sepsis, invasive and non-invasive mechanical ventilation, acute respiratory distress syndrome

Numerous bodies from many countries, including governments, government regulatory departments, research organizations, medical professional bodies, and health care providers, have issued guidance or legislation on the ethical conduct of clinical trials. It is possible to trace the development of current guidelines back to the post-World War II Nuremburg war crimes trials, more specifically the "Doctors' Trial." From that trial emerged the Nuremburg Code, which set out basic principles to be observed when conducting research involving human subjects and which subsequently formed the basis for comprehensive international guidelines on medical research, such as the Declaration of Helsinki. Most recently, the Council for International Organizations and Medical Sciences (CIOMS) produced detailed guidelines (originally published in 1993 and updated in 2002) on the implementation of the principles outlined in the Declaration of Helsinki. The CIOMS guidelines set in an appropriate context the challenges of present-day clinical research, by addressing complex issues including HIV/AIDS research, availability of study treatments after a study ends, women as research subjects, safeguarding confidentiality, compensation for adverse events, as well guidelines on consent.

When you hear people say “Senator Claghorn wields a lot of power in the government,” just what is meant by this assertion? Can power be quantitatively defined and measured? The concept of power, explored by Robert Dahl in this journal in 1957, is here reviewed with emphasis on the difficulties of defining power operationally.

Objective: To provide an overview of the current literature on pulmonary-specific therapeutic approaches to pediatric acute respiratory distress syndrome to determine recommendations for clinical practice and/or future research.Data Sources: PubMed, EMBASE, CINAHL, SCOPUS, and the Cochrane Library were searched from inception until January 2013 using the following keywords in various combinations: ARDS, treatment, nitric oxide, heliox, steroids, surfactant, etanercept, prostaglandin therapy, inhaled beta adrenergic receptor agonists, N-acetylcysteine, ipratroprium bromide, dornase, plasminogen activators, fibrinolytics or other anticoagulants, and children. No language restrictions were applied. References from identified articles were searched for additional publications.Study Selection: All clinical studies pertaining to pulmonary-specific therapeutic approaches to pediatric acute respiratory distress syndrome were reviewed. If clinical pediatric data were sparse or unavailable, the findings from studies of adult acute respiratory distress syndrome and animal models that might be relevant to pediatric acute respiratory distress syndrome were examined.Data Extraction: All relevant studies were reviewed and pertinent data abstracted.Data Synthesis: Over the course of three international meetings, the pertinent findings of the literature review were discussed by a panel of 24 experts in the field representing 21 academic institutions and 8 countries. Recommendations developed and the supporting literature were distributed to all panel members without a conflict of interest and were scored by using the Research ANd Development/University of California, Los Angeles Appropriateness method. The modified Delphi approach was used as the methodology to achieve consensus among the panel.Conclusions: Overall, the routine use of surfactant, inhaled nitric oxide, glucocorticoids, prone positioning, endotracheal suctioning, and chest physiotherapy cannot be recommended. Inhaled nitric oxide should only be used for patients with documented pulmonary hypertension and/or right ventricular failure. Prone positioning may be considered in patients with severe pediatric acute respiratory distress syndrome. Future studies are definitely warranted to establish the role, if any, of these ancillary treatment modalities in pediatric acute respiratory distress syndrome.

Inhaled nitric oxide (iNO) has been used for treatment of acute respiratory failure and pulmonary hypertension since 1991 in adult patients in the perioperative setting and in critical care. This contribution assesses evidence for the use of iNO in this population as presented to a expert group jointly organised by the European Society of Intensive Care Medicine and the European Association of Cardiothoracic Anaesthesiologists. Expert recommendations on the use of iNO in adults were agreed on following presentation of the evidence at the expert meeting held in June 2004.

Cyanosis may present in neonates for a number of reasons including pulmonary and cardiac. Cardiac cases of cyanosis are often due to inadequate flow of blood to the lungs, however in some cases, there may be unrestricted and/or increased pulmonary blood flow in the presence of cyanosis. Lesions where pulmonary flow is increased in the presence of cyanosis include Transposition of the great arteries, Truncus arteriosus, Total Anomalous Pulmonary Venous Connections, and single ventricle lesions without obstruction to pulmonary vascular flow. In such cases, early recognition and management are of great importance to prevent long term damage to the pulmonary vasculature. This review describes the anatomy, pathophysiology and clinical management of such cases.

The field of public policy analysis; centered about practical choices, is being extended by this journal to include useful comparisons among nations or other political units, as well as borrowing or lesson‐drawing. This extension should remain close to the practical orientation of the field, rather than seeking to contribute to those disciplinary theories that lack practical usefulness in the short term (several decades). Implications of this admonition are spelled out in the form of a list of suggested topics for articles in this journal.

From the time of Hippocrates, the practice of medicine has been largely authoritarian. Doctors relied on the notion of beneficence or ‘doing good' to justify a paternalistic view that it was often unnecessary to obtain what, in the current era, we would term ‘valid consent'. It is now clear that seeking consent before any healthcare intervention is both a matter of common courtesy and a legal and ethical imperative. Consent for healthcare interventions in children (aged

Any pulsatile neck mass after extracorporeal membrane oxygenation (ECMO) must be viewed as a pseudoaneurysm of the carotid artery, until proven otherwise. Prompt diagnosis is necessary utilizing ultrasound. Angiography may not be necessary. Carotid artery pseudoaneurysm requires urgent surgical intervention to prevent catastrophic hemorrhage. The utilization of cardiopulmonary bypass may facilitate safe repair.

To examine whether the early response to inhaled nitric oxide (iNO) is a measure of reversibility of lung injury and patient outcome in children with acute hypoxemic respiratory failure (AHRF).Retrospective review study.Pediatric ICUs.Thirty infants and children, aged 1 month to 13 years (median, 7 months) with severe AHRF (mean alveolar arterial oxygen gradient of 568+/-9.3 mm Hg, PaO2/fraction of inspired oxygen of 56+/-2.3, oxygenation index [OI] of 41+/-3.8, and acute lung injury score of 2.8+/-0.1). Eighteen patients had ARDS.The magnitude of the early response to iNO was quantified as the percentage change in OI occurring within 60 min of initiating 20 ppm iNO therapy. This response was compared to patient outcome data.There was a significant association between early response to iNO and patient outcome (Kendall tau B r=0.43, p0.02). All six patients who showed15% improvement in OI died; 4 of the 11 patients (36%) who had a 15 to 30% improvement in OI survived, while 8 of 13 (61%) who had a30% improvement in OI survived. Overall, 12 patients (40%) survived, 9 with ongoing conventional treatment including iNO, and 3 with extracorporeal support.In AHRF in children, greater early response to iNO appears to be associated with improved outcome. This may reflect reversibility of pulmonary pathophysiologic condition and serve as a bedside marker of disease stage.

The optimum time to begin antiretroviral therapy (ART) in HIV infected individuals is controversial. Using a Markov chain approach, the authors have re-analyzed several apparently inconsistent studies designed to measure the effect of early AZT on the progression of HIV disease. We find that, for at least up to three years, early AZT therapy is consistent with increasing the time to AIDS by a multiplicative factor (rate change) rather than a fixed delay. The negative judgments of early AZT, based on results reported by Hamilton et al. for survival and the Concorde study group in regard to both AIDS and death, may be owing to comparison with the null hypothesis that treatment has no effect rather than with the rate-change hypothesis. These results can lead to important policy decisions as early treatment might enhance treatment efficacy by decreasing the progression hazard by a factor of up to 1.7, especially if multi-drug ART is used. Multi-drug ART is needed for long-term therapy (greater than three years) because of the development of resistant viruses.