Fundación Santa Fe de Bogotá

Hemophilia is a rare disorder that is complex to diagnose and to manage. These evidence-based guidelines offer practical recommendations on the diagnosis and general management of hemophilia, as well as the management of complications including musculoskeletal issues, inhibitors, and transfusion-transmitted infections. By compiling these guidelines, the World Federation of Hemophilia aims to assist healthcare providers seeking to initiate and/or maintain hemophilia care programs, encourage practice harmonization around the world and, where recommendations lack adequate evidence, stimulate appropriate studies.

Peer Reviewed

CONTEXT: Both short and long interpregnancy intervals have been associated with an increased risk of adverse perinatal outcomes. However, whether this possible association is confounded by maternal characteristics or socioeconomic status is uncertain. OBJECTIVE: To examine the association between birth spacing and relative risk of adverse perinatal outcomes. DATA SOURCES: Studies published in any language were retrieved by searching MEDLINE (1966 through January 2006), EMBASE, ECLA, POPLINE, CINAHL, and LILACS, proceedings of meetings on birth spacing, and bibliographies of retrieved articles, and by contact with relevant researchers in the field. STUDY SELECTION: Included studies were cohort, cross-sectional, and case-control studies with results adjusted for at least maternal age and socioeconomic status, reporting risk estimates and 95% confidence intervals (or data to calculate them) of birth spacing and perinatal outcomes. Of 130 articles identified in the search, 67 (52%) were included. DATA EXTRACTION: Information on study design, participant characteristics, measure of birth spacing used, measures of outcome, control for potential confounding factors, and risk estimates was abstracted independently by 2 investigators using a standardized protocol. DATA SYNTHESIS: A random-effects model and meta-regression analyses were used to pool data from individual studies. Compared with interpregnancy intervals of 18 to 23 months, interpregnancy intervals shorter than 6 months were associated with increased risks of preterm birth, low birth weight, and small for gestational age (pooled adjusted odds ratios [95% confidence intervals]: 1.40 [1.24-1.58], 1.61 [1.39-1.86], and 1.26 [1.18-1.33], respectively). Intervals of 6 to 17 months and longer than 59 months were also associated with a significantly greater risk for the 3 adverse perinatal outcomes. CONCLUSIONS: Interpregnancy intervals shorter than 18 months and longer than 59 months are significantly associated with increased risk of adverse perinatal outcomes. These data suggest that spacing pregnancies appropriately could help prevent such adverse perinatal outcomes.

BACKGROUND: In light of the increasing rate of dengue infections throughout the world despite vector-control measures, several dengue vaccine candidates are in development. METHODS: In a phase 3 efficacy trial of a tetravalent dengue vaccine in five Latin American countries where dengue is endemic, we randomly assigned healthy children between the ages of 9 and 16 years in a 2:1 ratio to receive three injections of recombinant, live, attenuated, tetravalent dengue vaccine (CYD-TDV) or placebo at months 0, 6, and 12 under blinded conditions. The children were then followed for 25 months. The primary outcome was vaccine efficacy against symptomatic, virologically confirmed dengue (VCD), regardless of disease severity or serotype, occurring more than 28 days after the third injection. RESULTS: A total of 20,869 healthy children received either vaccine or placebo. At baseline, 79.4% of an immunogenicity subgroup of 1944 children had seropositive status for one or more dengue serotypes. In the per-protocol population, there were 176 VCD cases (with 11,793 person-years at risk) in the vaccine group and 221 VCD cases (with 5809 person-years at risk) in the control group, for a vaccine efficacy of 60.8% (95% confidence interval [CI], 52.0 to 68.0). In the intention-to-treat population (those who received at least one injection), vaccine efficacy was 64.7% (95% CI, 58.7 to 69.8). Serotype-specific vaccine efficacy was 50.3% for serotype 1, 42.3% for serotype 2, 74.0% for serotype 3, and 77.7% for serotype 4. Among the severe VCD cases, 1 of 12 was in the vaccine group, for an intention-to-treat vaccine efficacy of 95.5%. Vaccine efficacy against hospitalization for dengue was 80.3%. The safety profile for the CYD-TDV vaccine was similar to that for placebo, with no marked difference in rates of adverse events. CONCLUSIONS: The CYD-TDV dengue vaccine was efficacious against VCD and severe VCD and led to fewer hospitalizations for VCD in five Latin American countries where dengue is endemic. (Funded by Sanofi Pasteur; ClinicalTrials.gov number, NCT01374516.).

The evolutionary origins of the bacterial lineages that populate the human gut are unknown. Here we show that multiple lineages of the predominant bacterial taxa in the gut arose via cospeciation with humans, chimpanzees, bonobos, and gorillas over the past 15 million years. Analyses of strain-level bacterial diversity within hominid gut microbiomes revealed that clades of Bacteroidaceae and Bifidobacteriaceae have been maintained exclusively within host lineages across hundreds of thousands of host generations. Divergence times of these cospeciating gut bacteria are congruent with those of hominids, indicating that nuclear, mitochondrial, and gut bacterial genomes diversified in concert during hominid evolution. This study identifies human gut bacteria descended from ancient symbionts that speciated simultaneously with humans and the African apes.

Doctors are well positioned to provide physical activity (PA) counselling to patients. They are a respected source of health-related information and can provide continuing preventive counselling feedback and follow-up; they may have ethical obligations to prescribe PA. Several barriers to PA counselling exist, including insufficient training and motivation of doctors and improvable, personal PA habits. Rates of exercise counselling by doctors remain low; only 34% of US adults report exercise counselling at their last medical visit. In view of this gap, one of the US health objectives for 2010 is increasing the proportion of patients appropriately counselled about health behaviours, including exercise/PA. Research shows that clinical providers who themselves act on the advice they give provide better counselling and motivation of their patients to adopt such health advice. In summary, there is compelling evidence that the health of doctors matters and that doctors' own PA practices influence their clinical attitudes towards PA. Medical schools need to increase the proportion of students adopting and maintaining regular PA habits to increase the rates and quality of future PA counselling delivered by doctors.

Fat accumulation is one of the most common abnormalities of the liver depicted on cross-sectional images. Common patterns include diffuse fat accumulation, diffuse fat accumulation with focal sparing, and focal fat accumulation in an otherwise normal liver. Unusual patterns that may cause diagnostic confusion by mimicking neoplastic, inflammatory, or vascular conditions include multinodular and perivascular accumulation. All of these patterns involve the heterogeneous or nonuniform distribution of fat. To help prevent diagnostic errors and guide appropriate work-up and management, radiologists should be aware of the different patterns of fat accumulation in the liver, especially as they are depicted at ultrasonography, computed tomography, and magnetic resonance imaging. In addition, knowledge of the risk factors and the pathophysiologic, histologic, and epidemiologic features of fat accumulation may be useful for avoiding diagnostic pitfalls and planning an appropriate work-up in difficult cases.

BACKGROUND: Raltegravir is an HIV-1 integrase strand-transfer inhibitor with potent in vitro activity. This study explored the antiretroviral activity and safety of raltegravir in treatment-naive patients with plasma HIV-1 RNA levels > or = 5000 copies/mL and CD4 T-cell counts > or = 100 cells/mm. METHODS: Multicenter, double-blind, randomized, controlled study of raltegravir at doses of 100, 200, 400, and 600 mg twice daily versus efavirenz at a dose of 600 mg/d, all in combination with tenofovir at a dose of 300 mg/d and lamivudine at a dose of 300 mg/d (clinicaltrials.gov identifier: NCT00100048). RESULTS: In the 198 patients treated (160 on raltegravir and 38 on efavirenz), the mean HIV-1 RNA level ranged from 4.6 to 4.8 log10 copies/mL at baseline. At weeks 2, 4, and 8, the proportion of patients achieving an HIV-1 RNA level <50 copies/mL was greater in each of the raltegravir treatment groups than in the efavirenz group. By week 24, all treatment groups appeared similar, with plasma HIV-1 RNA levels <400 copies/mL in 85% to 98% of patients and <50 copies/mL in 85% to 95% of patients. These reductions were maintained through week 48 in 85% to 98% of patients and in 83% to 88% of patients, respectively. Five (3%) patients on raltegravir and 1 (3%) on efavirenz experienced virologic failure before week 48. Drug-related clinical adverse events were less common with raltegravir than with efavirenz. After 24 and 48 weeks of treatment, raltegravir did not result in increased serum levels of total cholesterol, low-density lipoprotein cholesterol, or triglycerides. CONCLUSIONS: Raltegravir at all doses studied was generally well tolerated in combination with tenofovir and lamivudine. Raltegravir exhibited potent and durable antiretroviral activity similar to that of efavirenz at 24 and 48 weeks but achieved HIV-1 RNA levels below detection at a more rapid rate.

Abstract Aim Predictive models of species’ distributions use occurrence records and environmental data to produce a model of the species’ requirements and a map of its potential distribution. To determine regions of suitable environmental conditions and assess biogeographical questions regarding their ranges, we modelled the potential geographical distributions of two spiny pocket mice (Rodentia: Heteromyidae) in north‐western South America. Location North‐western South America. Methods We used the Genetic Algorithm for Rule‐Set Prediction (GARP), environmental data from GIS maps and georeferenced collection localities from a recent systematic review of Heteromys australis and H. anomalus to produce the models. Results GARP models indicate the potential presence of H. australis throughout mesic montane regions of north‐western South America, as well as in some lowland regions of moderately high precipitation. In contrast, H. anomalus is predicted to occur primarily in drier areas of the Caribbean coast and rain‐shadowed valleys of the Andes. Conclusions The models support the disjunct status of the population of H. australis in the Cordillera de Mérida, but predict a continuous distribution between known populations of H. anomalus in the upper Magdalena Valley and the Caribbean coast. Regions of suitable environmental conditions exist disjunct from known distributional areas for both species, suggesting possible historical restrictions to their ranges. This technique holds wide application to other study systems.

Abdominal wall hernias are a common imaging finding in the abdomen and may be complicated by strangulation, incarceration, or trauma. Because of the risk of developing complications, most abdominal wall hernias are surgically repaired, even if asymptomatic. However, post-surgical complications are also common and include hernia recurrence, infected and noninfected fluid collections, and complications related to prosthetic material. Multi-detector row computed tomography (CT) with its multiplanar capabilities is particularly useful for the evaluation of unrepaired and surgically repaired abdominal wall hernias. Multi-detector row CT provides exquisite anatomic detail of the abdominal wall, thereby allowing accurate identification of wall hernias and their contents, differentiation of hernias from other abdominal masses (tumors, hematomas, abscesses), and detection of pre- or postoperative complications. These findings improve the communication of imaging results to clinicians and help optimize treatment planning. Knowledge of multi-detector row CT findings in unrepaired and surgically repaired abdominal wall hernias and their complications is essential for making the correct diagnosis and may help guide clinical management.

BACKGROUND: Iron deficiency, the most common cause of anaemia in pregnancy worldwide, can be mild, moderate or severe. Severe anaemia can have very serious consequences for mothers and babies, but there is controversy about whether treating mild or moderate anaemia provides more benefit than harm. OBJECTIVES: To assess the effects of different treatments for anaemia in pregnancy attributed to iron deficiency (defined as haemoglobin less than 11 g/dL or other equivalent parameters) on maternal and neonatal morbidity and mortality. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (7 June 2011), CENTRAL (2011, Issue 5), PubMed (1966 to June 2011), the International Clinical Trials Registry Platform (ICTRP) (2 May 2011), Health Technology Assessment Program (HTA) (2 May 2011) and LATINREC (Colombia) (2 May 2011). SELECTION CRITERIA: Randomised controlled trials comparing treatments for anaemia in pregnancy attributed to iron deficiency. DATA COLLECTION AND ANALYSIS: We identified 23 trials, involving 3.198 women. We assessed their risk of bias. Three further studies identified are awaiting classification. MAIN RESULTS: Many of the trials were from low-income countries; they were generally small and frequently methodologically poor. They covered a very wide range of differing drugs, doses and routes of administration, making it difficult to pool data. Oral iron in pregnancy showed a reduction in the incidence of anaemia (risk ratio 0.38, 95% confidence interval 0.26 to 0.55, one trial, 125 women) and better haematological indices than placebo (two trials). It was not possible to assess the effects of treatment by severity of anaemia. A trend was found between dose and reported adverse effects. Most trials reported no clinically relevant outcomes nor adverse effects. Although the intramuscular and intravenous routes produced better haematological indices in women than the oral route, no clinical outcomes were assessed and there were insufficient data on adverse effects, for example, on venous thrombosis and severe allergic reactions. Daily low-dose iron supplements may be effective at treating anaemia in pregnancy with less gastrointestinal side effects compared with higher doses. AUTHORS' CONCLUSIONS: Despite the high incidence and burden of disease associated with this condition, there is a paucity of good quality trials assessing clinical maternal and neonatal effects of iron administration in women with anaemia. Daily oral iron treatment improves haematological indices but causes frequent gastrointestinal adverse effects. Parenteral (intramuscular and intravenous) iron enhances haematological response, compared with oral iron, but there are concerns about possible important adverse effects (for intravenous treatment venous thrombosis and allergic reactions and for intramuscular treatment important pain, discolouration and allergic reactions). Large, good quality trials, assessing clinical outcomes (including adverse effects) as well as the effects of treatment by severity of anaemia are required.

BACKGROUND: While it is suggested that the prevalence of asthma in developed countries may have stabilized, this is not clear in currently developing countries. Current available information for both adults and children simultaneously on the burden and impact of allergic conditions in Colombia and in many Latin American countries is limited. The objectives of this study were to estimate the prevalence for asthma, allergic rhinitis (AR), atopic eczema (AE), and atopy in six colombian cities; to quantify costs to the patient and her/his family; and to determine levels of Immunoglobulin E (IgE) in asthmatic and healthy subjects. METHODS: We conducted a cross-sectional, population-based study in six cities during the academic year 2009-2010. We used a school-based design for subjects between 5-17 years old. We carried out a community-based strategy for subjects between 1-4 years old and adults between 18-59 years old. Serum samples for total and antigen-specific (IgE) levels were collected using a population-based, nested, case-control design. RESULTS: We obtained information on 5978 subjects. The largest sample of subjects was collected in Bogotá (2392). The current prevalence of asthma symptoms was 12% (95% CI, 10.5-13.7), with 43% (95% CI, 36.3-49.2) reporting having required an emergency department visit or hospitalization in the past 12 months. Physician diagnosed asthma was 7% (95% CI, 6.1-8.0). The current prevalence of AR symptoms was 32% (95% CI, 29.5-33.9), and of AE symptoms was 14% (95% CI, 12.5-15.3). We collected blood samples from 855 subjects; 60.2% of asthmatics and 40.6% of controls could be classified as atopic. CONCLUSIONS: In Colombia, symptom prevalence for asthma, AR and AE, as well as levels of atopy, are substantial. Specifically for asthma, symptom severity and absence from work or study due to symptoms are important. These primary care sensitive conditions remain an unmet public health burden in developing countries such as Colombia.

INTRODUCTION: The terminology for female and male pelvic floor muscle (PFM) assessment has expanded considerably since the first PFM function and dysfunction standardization of terminology document in 2005. New terms have entered assessment reports, and new investigations to measure PFM function and dysfunction have been developed. An update of this terminology was required to comprehensively document the terms and their definitions, and to describe the assessment method and interpretation of the finding, to standardize assessment procedures and aid diagnostic decision making. METHODS: This report combines the input of members of the Standardisation Committee of the International Continence Society (ICS) Working Group 16, with contributions from recognized experts in the field and external referees. A logical, sequential, clinically directed assessment framework was created against which the assessment process was mapped. Within categories and subclassifications, each term was assigned a numeric coding. A transparent process of 12 rounds of full working group and external review was undertaken to exhaustively examine each definition, plus additional extensive internal development, with decision making by collective opinion (consensus). RESULTS: A Terminology Report for the symptoms, signs, investigations, and diagnoses associated with PFM function and dysfunction, encompassing 185 separate definitions/descriptors, has been developed. It is clinically based with the most common assessment processes defined. Clarity and user-friendliness have been key aims to make it interpretable by clinicians and researchers of different disciplines. CONCLUSION: A consensus-based Terminology Report for assessment of PFM function and dysfunction has been produced to aid clinical practice and be a stimulus for research.

BACKGROUND: Sepsis is a common and frequently fatal condition. Human recombinant activated protein C (APC) has been used to reduce the high rate of death by severe sepsis or septic shock. This is an update of a Cochrane review (originally published in 2007 and updated in 2008). OBJECTIVES: We assessed the clinical effectiveness and safety of APC for the treatment of patients with severe sepsis or septic shock. SEARCH METHODS: For this updated review we searched CENTRAL (The Cochrane Library 2010, Issue 6); MEDLINE (1966 to June 2010); EMBASE (1980 to July 1, 2010); BIOSIS (1965 to July 1, 2010); CINAHL (1982 to 16 June 2010) and LILACS (1982 to 16 June 2010). There was no language restriction. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the effects of APC for severe sepsis in adults and children. We excluded studies on neonates. We considered all-cause mortality at day 28, at the end of study follow up, and hospital mortality as the primary outcomes. DATA COLLECTION AND ANALYSIS: We independently performed study selection, risk of bias assessment and data extraction. We estimated relative risks (RR) for dichotomous outcomes. We measured statistical heterogeneity using the I(2) statistic. We used a random-effects model. MAIN RESULTS: We identified one new RCT in this update. We included a total of five RCTs involving 5101 participants. For 28-day mortality, APC did not reduce the risk of death in adult participants with severe sepsis (pooled RR 0.97, 95% confidence interval (CI) 0.78 to 1.22; P = 0.82, I(2) = 68%). APC use was associated with an increased risk of bleeding (RR 1.47, 95% CI 1.09 to 2.00; P = 0.01, I(2) = 0%). In paediatric patients, APC did not reduce the risk of death (RR 0.98, 95% CI 0.66 to 1.46; P = 0.93). Although the included trials had no major limitations most of them modified their original completion or recruitment protocols. AUTHORS' CONCLUSIONS: This updated review found no evidence suggesting that APC should be used for treating patients with severe sepsis or septic shock. Additionally, APC is associated with a higher risk of bleeding. Unless additional RCTs provide evidence of a treatment effect, policy-makers, clinicians and academics should not promote the use of APC.Warning: On October 25th 2011, the European Medicines Agency issued a press release on the worldwide withdrawal of Xigris (activated protein C / drotrecogin alfa) from the market by Eli Lilly due to lack of beneficial effect on 28-day mortality in the PROWESS-SHOCK study. Furthermore, Eli Lily has announced the discontinuation of all other ongoing clinical trials. The final results of the PROWESS-SHOCK study are expected to be published in 2012. This systematic review will be updated when results of the PROWESS-SHOCK or other trials are published.

AIMS: To evaluate the effect of iron deficiency (ID) and/or anaemia on health-related quality of life (HRQoL) in patients with chronic heart failure (CHF). METHODS AND RESULTS: We undertook a post-hoc analysis of a cohort of CHF patients in a single-centre study evaluating cognitive function. At recruitment, patients provided baseline information and completed the Minnesota Living with Heart Failure questionnaire (MLHFQ) for HRQoL (higher scores reflect worse HRQoL). At the same time, blood samples were taken for serological evaluation. ID was defined as serum ferritin levels <100 ng/mL or serum ferritin <800 ng/mL with transferrin saturation <20%. Anaemia was defined as haemoglobin ≤12 g/dL. A total of 552 CHF patients were eligible for inclusion, with an average age of 72 years and 40% in NYHA class III or IV. The MLHFQ overall summary scores were 41.0 ± 24.7 among those with ID, vs. 34.4 ± 26.4 for non-ID patients (P = 0.003), indicating worse HRQoL. When adjusted for other factors associated with HRQoL, ID was significantly associated with worse MLHFQ overall summary (P = 0.008) and physical dimension scores (P = 0.002), whereas anaemia was not (both P > 0.05). Increased levels of soluble transferrin receptor were also associated with impaired HRQoL (P ≤ 0.001). Adjusting for haemoglobin and C-reactive protein, ID was more pronounced in patients with anaemia compared with those without (P < 0.001). CONCLUSION: In patients with CHF, ID but not anaemia was associated with reduced HRQoL, mostly due to physical factors.

PURPOSE: To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. PATIENTS AND METHODS: Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. RESULTS: A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. CONCLUSION: Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.

INTRODUCTION: The novel Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2, may need intensive care unit (ICU) admission in up to 12% of all positive cases for massive interstitial pneumonia, with possible long-term endotracheal intubation for mechanical ventilation and subsequent tracheostomy. The most common airway-related complications of such ICU maneuvers are laryngotracheal granulomas, webs, stenosis, malacia and, less commonly, tracheal necrosis with tracheo-esophageal or tracheo-arterial fistulae. MATERIALS AND METHODS: This paper gathers the opinions of experts of the Laryngotracheal Stenosis Committee of the European Laryngological Society, with the aim of alerting the medical community about the possible rise in number of COVID-19-related laryngotracheal stenosis (LTS), and the aspiration of paving the way to a more rationale concentration of these cases within referral specialist airway centers. RESULTS: A range of prevention strategies, diagnostic work-up, and therapeutic approaches are reported and framed within the COVID-19 pandemic context. CONCLUSIONS: One of the most important roles of otolaryngologists when encountering airway-related signs and symptoms in patients with previous ICU hospitalization for COVID-19 is to maintain a high level of suspicion for LTS development, and share it with colleagues and other health care professionals. Such a condition requires specific expertise and should be comprehensively managed in tertiary referral centers.

Abstract Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown 1 to be highly efficient for discovery of genetic associations 2 . Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group 3 . Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling ( JAK1 ), monocyte–macrophage activation and endothelial permeability ( PDE4A ), immunometabolism ( SLC2A5 and AK5 ), and host factors required for viral entry and replication ( TMPRSS2 and RAB2A ).

PURPOSE: TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group. EXPERIMENTAL DESIGN: We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function. RESULTS: In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P=0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P=0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P=0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS. CONCLUSIONS: Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.

OBJECTIVE: To evaluate claims that elevated soluble fms-like tyrosine kinase-1 receptor (sFlt-1) and decreased placental growth factor predict preeclampsia. DATA SOURCES: MEDLINE (1966-March 2006), EMBASE (1980-June 2006), POPLINE (1980-June 2006), CINAHL (1982-June 2006), and LILACS (1982-June 2006) were searched, and experts contacted. METHODS OF STUDY SELECTION: Studies identified and included were those reporting blood and urine levels of sFlt-1 or placental growth factor obtained before gestational week 30 or overt preeclampsia. TABULATION, INTEGRATION, AND RESULTS: Ten of 184 available studies analyzing sFlt-1 and 14 of 319 studies analyzing placental growth factor were included in this review. There was considerable interreport heterogeneity in methodology and results for sFlt-1 measured before gestational week 25. After week 25 placental growth factor and sFlt-1 levels varied consistently between the normal pregnancy group and women destined to develop preeclampsia, achieving significance in women who developed severe preeclampsia. CONCLUSION: Third-trimester increases in sFlt-1 and decreases in placental growth factor levels are associated with preeclampsia, specifically severe disease, based on retrospective data. The evidence is insufficient to recommend these markers to be used for screening, and prospective studies employing rigorous laboratory and study design criteria are needed to determine the clinical usefulness of these tests.