Advocate Illinois Masonic Medical Center

BACKGROUND: Questions persist concerning the comparative effectiveness of percutaneous coronary intervention (PCI) and coronary-artery bypass grafting (CABG). The American College of Cardiology Foundation (ACCF) and the Society of Thoracic Surgeons (STS) collaborated to compare the rates of long-term survival after PCI and CABG. METHODS: We linked the ACCF National Cardiovascular Data Registry and the STS Adult Cardiac Surgery Database to claims data from the Centers for Medicare and Medicaid Services for the years 2004 through 2008. Outcomes were compared with the use of propensity scores and inverse-probability-weighting adjustment to reduce treatment-selection bias. RESULTS: Among patients 65 years of age or older who had two-vessel or three-vessel coronary artery disease without acute myocardial infarction, 86,244 underwent CABG and 103,549 underwent PCI. The median follow-up period was 2.67 years. At 1 year, there was no significant difference in adjusted mortality between the groups (6.24% in the CABG group as compared with 6.55% in the PCI group; risk ratio, 0.95; 95% confidence interval [CI], 0.90 to 1.00). At 4 years, there was lower mortality with CABG than with PCI (16.4% vs. 20.8%; risk ratio, 0.79; 95% CI, 0.76 to 0.82). Similar results were noted in multiple subgroups and with the use of several different analytic methods. Residual confounding was assessed by means of a sensitivity analysis. CONCLUSIONS: In this observational study, we found that, among older patients with multivessel coronary disease that did not require emergency treatment, there was a long-term survival advantage among patients who underwent CABG as compared with patients who underwent PCI. (Funded by the National Heart, Lung, and Blood Institute.)

OBJECTIVE: The purpose of this study was to identify prognostic indicators that would lead to stratification of patients likely to have successful surgery for sleep-disordered breathing (SDB) versus those destined to fail. STUDY DESIGN: We retrospectively reviewed 134 patients to correlate palate position and tonsil size to the success of the UPPP as based on postoperative polysomnography results. Similar to our previously published data on the Friedman Score as a predictor of the presence and severity of SDB, the palate position was determined on physical examination of the oral cavity and was graded for each patient. This grade combined with tonsil size was used to stage the patients. Stage I was defined as having palate position 1 or 2 combined with tonsil size 3 or 4. Stage II was defined as having palate position 3 or 4 and tonsil size 3 or 4. Stage III patients had palate position 3 or 4 and tonsil size 0, 1, or 2. Any patient with body mass index of greater than 40 was placed in the stage III group. The results of uvulopalatopharyngoplasty (UPPP) were then graded as success or failure and success rates were compared by stage. SETTING: Academically affiliated tertiary care referral center. RESULTS: Stage I patients who underwent UPPP had a success rate of 80.6%, stage II patients had a success rate of 37.9%, and stage III patients had a success rate of 8.1%. CONCLUSION: A clinical staging system for SDB based on palate position, tonsil size, and body mass index is presented. It appears to be a valuable predictor of the success of UPPP. Additional studies and wider use of the staging system will ultimately define its role in the treatment of SDB.

OBJECTIVE: Perform an updated systematic review and meta-analysis to determine the cure rate of tonsillectomy and adenoidectomy (T&A) for pediatric obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: A systematic review was performed to identify English-language studies that evaluate the treatment of pediatric (age < 20 years) OSAHS patients with T&A using polysomnography as a metric of cure. Twenty-three studies fit the inclusion criteria and a meta-analysis was performed to determine the overall success. Meta-analysis was also performed to determine the success in obese and comorbid populations vs cohorts of healthy children. RESULTS: The meta-analysis included 1079 subjects (mean sample size of 42 patients) with a mean age of 6.5 years. The effect measure was the percentage of pediatric patients with OSAHS who were successfully treated (k = 22 studies) with T&A based on preoperative and postoperative PSG data. Random-effects model estimated the treatment success of T&A was 66.3 percent, when cure was defined per each individual study. When "cure" was defined as an apnea-hypopnea index (AHI) of <1 (k = 9 studies), random-effects model estimate for OSAHS treatment success with T&A was 59.8 percent. Postoperative mean AHI was significantly decreased from preoperative levels. CONCLUSIONS: Contrary to popular belief, meta-analysis of current literature demonstrates that pediatric sleep apnea is often not cured by T&A. Although complete resolution is not achieved in most cases, T&A still offers significant improvements in AHI, making it a valuable first-line treatment for pediatric OSAHS.

Cortisol, a critical glucocorticoid hormone produced by the adrenal glands, plays a pivotal role in various physiological processes. Its release is finely orchestrated by the suprachiasmatic nucleus, governing the circadian rhythm and activating the intricate hypothalamic-pituitary-adrenal (HPA) axis, a vital neuroendocrine system responsible for stress response and maintaining homeostasis. Disruptions in cortisol regulation due to chronic stress, disease, and aging have profound implications for multiple bodily systems. Animal models have been instrumental in elucidating these complex cortisol dynamics during stress, shedding light on the interplay between physiological, neuroendocrine, and immune factors in the stress response. These models have also revealed the impact of various stressors, including social hierarchies, highlighting the role of social factors in cortisol regulation. Moreover, chronic stress is closely linked to the progression of neurodegenerative diseases, like Alzheimer's and Parkinson's, driven by excessive cortisol production and HPA axis dysregulation, along with neuroinflammation in the central nervous system. The relationship between cortisol dysregulation and major depressive disorder is complex, characterized by HPA axis hyperactivity and chronic inflammation. Lastly, chronic pain is associated with abnormal cortisol patterns that heighten pain sensitivity and susceptibility. Understanding these multifaceted mechanisms and their effects is essential, as they offer insights into potential interventions to mitigate the detrimental consequences of chronic stress and cortisol dysregulation in these conditions.

Abstract Cytogenetic data are presented for 11 473 chorionic villus sampling (CVS) procedures from nine centres in the U.S. NICHD collaborative study. A successful cytogenetic diagnosis was obtained in 99.7 per cent of cases, with data obtained from the direct method only (26 per cent), culture method only (42 per cent), or a combination of both (32 per cent). A total of 1.1 per cent of patients had a second CVS or amniocentesis procedure for reasons related to the cytogenetic diagnostic procedure, including laboratory failures (27 cases), maternal cell contamination (4 cases), or mosaic or ambiguous cytogenetic results (98 cases). There were no diagnostic errors involving trisomies for chromosomes 21, 18, and 13. For sex chromosome aneuploidies, one patient terminated her pregnancy on the basis of non‐mosaic 47,XXX in the direct method prior to the availability of results from cultured cells. Subsequent analysis of the CVS cultures and fetal tissues showed only normal female cells. Other false‐positive predictions involving non‐mosaic aneuploidies ( n = 13) were observed in the direct or culture method, but these cases involved rare aneuploidies: four cases of tetraploidy, two cases of trisomy 7, and one case each of trisomies 3, 8, 11, 15, 16,20, and 22. This indicates that rare aneuploidies observed in the direct or culture method should be subjected to follow‐up by amniocentesis. Two cases of unbalanced structural abnormalities detected in the direct method were not confirmed in cultured CVS or amniotic fluid. In addition, one structural rearrangement was misinterpreted as unbalanced from the direct method, leading to pregnancy termination prior to results from cultured cells showing a balanced, inherited translocation. False‐negative results ( n = 8) were observed only in the direct method, including one non‐mosaic fetal abnormality (trisomy 18) detected by the culture method and seven cases of fetal mosaicism (all detected by the culture method). Mosaicism was observed in 0.8 per cent of all cases, while pseudomosaicism (including single trisomic cells) was observed in 1.6 per cent of cases. Mosaicism was observed with equal frequency in the direct and culture methods, but was confirmed as fetal mosaicism more often in cases from the culture method (24 per cent) than in cases from the direct method (10 per cent). The overall rate of maternal cell contamination was 1.8 per cent for the culture method, but there was only one case of incorrect sex prediction due to complete maternal cell contamination which resulted in the birth of a normal male. The rate of maternal cell contamination was significantly higher in samples obtained by the transcervical sampling method (2. 16 per cent) than in samples obtained by the transabdominal method (0.79 per cent). From these data, it is clear that the culture method has a higher degree of diagnostic accuracy than the direct method, which should not be used as the sole diagnostic technique. The direct method can be a useful adjunct to the culture method, in which maternal cell contamination can lead to incorrect sex prediction and potentially to false‐negative diagnostic results.

Abstract Objective Early studies by Friedman et al. have demonstrated the value of staging obstructive sleep apnea/hypopnea syndrome (OSAHS) patients for the prediction of success for uvulopalatopharyngoplasty (UPPP) on the basis of short‐term follow up. The goal of this study is to test the value of this staging system in a prospective study. Study Design This is a prospective study of two cohorts of patients: one was treated with the benefit of a clinical staging system and the other without. Methods Patients with symptoms of OSAHS were assessed by polysomnography and were staged according to a previously described staging system. The staging system is based on palate position, tonsil size, and body mass index (BMI). The control group was treated without the benefit of staging. All patients in the control group were treated with UPPP only. Patients in the experimental group were treated based on their clinical stage. Patients with stage I disease, regardless of the severity of disease, were treated with UPPP only. Selected patients with stage II and stage III disease were treated with UPPP in addition to a staged tongue‐base reduction using a radiofrequency technique (TBRF). Results Follow‐up at 6 months showed significant improvement compared with a group of patients treated without the benefit of a staging system. Successful treatment of patients with stage II disease improved from 37.9% to 74.0%. The overall success rate improved from 40% to 59.1%. Conclusion Clearly, patients with stage I disease had the best success rate, but a selective protocol based on clinical staging improves the overall success rate. In addition, it can eliminate as surgical candidates those patients with whom the procedure is likely to fail.

Preoxygenation before anesthetic induction and tracheal intubation is a widely accepted maneuver, designed to increase the body oxygen stores and thereby delay the onset of arterial hemoglobin desaturation during apnea. Because difficulties with ventilation and intubation are unpredictable, the need for preoxygenation is desirable in all patients. During emergence from anesthesia, residual effects of anesthetics and inadequate reversal of neuromuscular blockade can lead to hypoventilation, hypoxemia, and loss of airway patency. In accordance, routine preoxygenation before the tracheal extubation has also been recommended. The objective of this article is to discuss the physiologic basis, clinical benefits, and potential concerns about the use of preoxygenation. The effectiveness of preoxygenation is assessed by its efficacy and efficiency. Indices of efficacy include increases in the fraction of alveolar oxygen, increases in arterial oxygen tension, and decreases in the fraction of alveolar nitrogen. End points of maximal preoxygenation (efficacy) are an end-tidal oxygen concentration of 90% or an end-tidal nitrogen concentration of 5%. Efficiency of preoxygenation is reflected in the rate of decline in oxyhemoglobin desaturation during apnea. All investigations have demonstrated that maximal preoxygenation markedly delays arterial hemoglobin desaturation during apnea. This advantage may be blunted in high-risk patients. Various maneuvers have been introduced to extend the effect of preoxygenation. These include elevation of the head, apneic diffusion oxygenation, continuous positive airway pressure (CPAP) and/or positive end-expiratory pressure (PEEP), bilevel positive airway pressure, and transnasal humidified rapid insufflation ventilatory exchange. The benefit of apneic diffusion oxygenation is dependent on achieving maximal preoxygenation, maintaining airway patency, and the existence of a high functional residual capacity to body weight ratio. Potential risks of preoxygenation include delayed detection of esophageal intubation, absorption atelectasis, production of reactive oxygen species, and undesirable hemodynamic effects. Because the duration of preoxygenation is short, the hemodynamic effects and the accumulation of reactive oxygen species are insufficient to negate its benefits. Absorption atelectasis is a consequence of preoxygenation. Two approaches have been proposed to reduce the absorption atelectasis during preoxygenation: a modest decrease in the fraction of inspired oxygen to 0.8, and the use of recruitment maneuvers, such as CPAP, PEEP, and/or a vital capacity maneuver (all of which are commonly performed during the administration of anesthesia). Although a slight decrease in the fraction of inspired oxygen reduces atelectasis, it does so at the expense of a reduction in the protection afforded during apnea.

In women who are heterozygous for a genetic disease, genetic analysis of the first polar body allows the identification of oocytes that contain the maternal unaffected gene. These oocytes can be fertilized and transferred to the mother without risk of establishing a pregnancy with a genetically abnormal embryo. We have demonstrated that removal of the first polar body has no effect on subsequent fertilization rates or embryonic growth to the blastocyst stage. We have developed a PCR technique to successfully analyze the PI type Z and PI type M genotypes of alpha-1-antitrypsin deficiency and applied this technique for a couple at risk for PI type ZZ alpha-1-antitrypsin deficiency. After standard IVF treatment to stimulate multiple follicle development, eight oocytes were aspirated transvaginally. Polar bodies were removed by micromanipulation from seven oocytes and fertilization occurred in six cases. PCR analysis was successful in five oocytes. One was PI type M, two were PI type Z and two were heterozygous MZ due to crossing over. Embryos from the two oocytes containing the unaffected gene (polar body PI type Z) were transferred in the same cycle 48 h after insemination. No pregnancy was established. The accuracy of the polar body diagnosis was confirmed by polymerase chain reaction (PCR) analysis of an oocyte that failed to fertilize.

PURPOSE: To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others. METHODS: ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS: The literature search identified 124 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS: Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.

OBJECTIVE: Many patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) are incapable of using continuous positive airway pressure. These patients therefore turn to surgical options as a salvage treatment. Early studies and reviews focused on the efficacy of uvulopalatopharyngoplasty, a single-level procedure for the treatment of OSAHS. Since OSAHS is usually caused by multilevel obstructions, the true focus on efficacy should be on multilevel surgical intervention. The purpose of this paper is to provide an overview of the literature on multilevel surgery for OSAHS patients. STUDY DESIGN: Systematic review of the literature and meta-analysis focusing on subjective and objective outcomes of patients with OSAHS treated with multilevel surgery of the upper airway. METHODS: We searched PubMed, the Cochrane database, and MEDLINE bibliographic databases up to March 31, 2007, for studies dealing with multilevel surgical modification of the upper airway for the treatment of OSAHS. Additional studies were identified from their reference lists. Articles were included only if the surgical intervention involved at least two of the frequently involved anatomic sites: nose, oropharynx, and hypopharynx. RESULTS: After applying specific inclusion criteria, 49 multilevel surgery articles (58 groups) were identified. There were 1,978 patients included in the study. The mean minimal follow-up time was 7.3 months (range, 1 to 100 months). A meta-analysis was performed to redefine the success rate to be consistent with the commonly agreed upon criteria, namely "a reduction in the apnea/ hypopnea index (AHI) of 50% or more and an AHI of less than 20." "Success" implies an improved condition and is not meant to imply cure. The recalculated success rate was 66.4%. The overall complication rate was 14.6%. The evidence-base medicine (EBM) level of these 49 studies revealed that only one study was EBM level 1, two papers were EBM level 3, and the other 46 papers were ranked as level 4 evidence. CONCLUSIONS: Multilevel surgery for OSAHS is obviously associated with improved outcomes, although this benefit is supported largely by level 4 evidence. Future research should focus on prospective and controlled studies.

OBJECTIVE: To determine whether there is an increased incidence of persistent pulmonary hypertension in neonates delivered by cesarean, with or without labor, compared with those delivered vaginally. METHODS: We did a computerized retrospective review of 29,669 consecutive deliveries over 7 years (1992-1999). The incidences of persistent pulmonary hypertension of the newborn, transient tachypnea of the newborn, and respiratory distress syndrome (RDS) were tabulated for each delivery mode. Cases of persistent pulmonary hypertension were reviewed individually to determine delivery method and whether labor had occurred. The three groups defined were all cesarean deliveries, all elective cesareans, and all vaginal deliveries. RESULTS: Among 4301 cesareans done, 17 neonates had persistent pulmonary hypertension (four per 1000 live births). Among 1889 elective cesarean deliveries, seven neonates had persistent pulmonary hypertension (3.7 per 1000 live births). Among 21,017 vaginal deliveries, 17 neonates had persistent pulmonary hypertension (0.8 per 1000 live births). chi2 analysis showed an odds ratio 4.6 and P <.001 for comparison of elective cesarean and vaginal delivery for that outcome. CONCLUSION: The incidence of persistent pulmonary hypertension of the newborn was approximately 0.37% among neonates delivered by elective cesarean, almost fivefold higher than those delivered vaginally. The findings have implications for informed consent before cesarean and increased surveillance of neonates after cesarean.

BACKGROUND: Pelvic fractures from blunt force trauma place the bladder and urethra at risk for injury, often resulting in significant complications. We sought to compare morbidity, mortality, and health care resource utilization in patients with and without genitourinary injuries (GUI) associated with pelvic fractures. METHODS: In this retrospective study of patients with blunt force pelvic fractures, the incidence of GUI, initial emergency department data, mechanism of injury, morbidity, health care resource utilization, associated injuries, discharge disposition, and mortality were investigated using chi tests for categorical variables and Student's t test for continuous variables comparing pelvic fractures with and without GUI. Multiple logistic regression analysis was used to detect significant predictors of mortality. RESULTS: Of the 31,380 patients with pelvic fractures, 1,444 had GUI. Men more commonly sustained pelvic fractures with GUI than women (66.14% vs. 33.86%). The incidence of urogenital, bladder, and urethral injuries for men and women was 5.34%, 3.41%, 1.54%, and 3.62%, 3.37%, 0.15%, respectively. Patients with GUI remained hospitalized longer (median 10 vs. 6 d, p < 0.001), had more intensive care unit stay days (median 3 vs. 1 d, p < 0.001), were less often discharged home (31.02% vs. 42.82%), and had an increased mortality rate (13.99% vs. 8.08%, p < 0.001) when compared with patients without GUI. Motor vehicle collisions were the most common mechanism of injury for all pelvic fractures. Spleen and liver were the most commonly injured abdominal organs associated with pelvic fractures as a whole. Pelvic fractures with GUI were more likely to result in associated injuries of the bowel, and reproductive organs. Although GUI was not found to be an independent predictor of mortality, age >or=65 years, initial systolic blood pressure in the emergency department 0 mm Hg to 90 mm Hg, Injury Severity Score >or=25, Glasgow coma score of <or=8, and female gender were independent predictors of mortality. CONCLUSION: Patients sustaining a pelvic fracture with GUI have an increase in morbidity. Although GUI was not an independent predictor of mortality, patients who sustained a pelvic fracture with GUI had a greater number of concomitant injuries resulting in an increase in overall mortality compared with those without an associated GUI.

IMPORTANCE: Efficient diagnosis and early treatment of obstructive sleep apnea may help prevent the development of related morbidity and mortality. Compared with polysomnography (PSG), ambulatory sleep study devices offer the possibility of an accurate diagnosis with convenience and low cost. OBJECTIVE: To assess the correlation between sleep indexes measured by a portable sleep-testing device (peripheral arterial tonometry [PAT]) and those measured by PSG. DATA SOURCES: We searched PubMed, MEDLINE, the Cochrane Trial Registry (through May 2013), and relevant article bibliographies. STUDY SELECTION: Systematic review and meta-analysis of studies assessing correlation of sleep indexes between PAT devices and PSG in adults (aged >18 years). Included studies provided a bivariate correlation coefficient for sleep indexes, specifically the respiratory disturbance index (RDI), apnea-hypopnea index (AHI), and oxygen desaturation index (ODI). DATA EXTRACTION AND SYNTHESIS: Included studies were reviewed by 2 independent reviewers. Reported correlation values for the RDI, AHI, and ODI between a commercially available PAT device (WatchPAT) and PSG were systematically reviewed. A comprehensive meta-analysis software package was used for statistical analysis. MAIN OUTCOMES AND MEASURES: Assessment of the correlation between PAT and PSG as measured by AHI, RDI, and ODI. RESULTS: Fourteen studies met inclusion criteria and had data suitable for pooling (909 patients). Of these, 13 studies had blinded study designs, with PAT and PSG conducted simultaneously in the home or the laboratory setting. One study contained 2 trial phases for the same patient group (n = 29), one laboratory based and the other home based, which were analyzed separately. One study contained 2 different study groups based on age. Overall, correlation of the RDI and AHI was high (r = 0.889 [95% CI, 0.862-0.911]; P < .001). Studies comparing the RDI between PAT and PSG had a combined correlation of 0.879 (95% CI, 0.849-0.904; P < .001); those comparing the AHI, 0.893 (0.857-0.920; P < .001); and those comparing the ODI, 0.942 (0.894-0.969; P < .001). Analysis of publication bias revealed a nonsignificant Egger regression intercept. CONCLUSIONS AND RELEVANCE: Respiratory indexes calculated using PAT-based portable devices positively correlated with those calculated from the scoring of PSG. Strengthened by the blinded design of most of the included studies, this technology represents a viable alternative to PSG for confirmation of clinically suspected sleep apnea.

Neph1-deficient mice develop nephrotic syndrome at birth, indicating the importance of this protein in the development of a normal glomerular filtration barrier. While the precise subcellular localization of Neph1 remains unknown, its relationship with other components of the glomerular filtration barrier is of great interest in this field. In this paper, we localize the expression of Neph1 to the glomerular slit diaphragm by immunogold electron microscopy in rodents and describe its direct interaction with two other components of the slit diaphragm, nephrin and ZO-1. Both native and recombinant Neph1 associate with each other as dimers and multimers and interact with nephrin via their extracellular segments. Disruption of the Neph1-nephrin interaction in vivo by injecting combinations of individual subnephritogenic doses of anti-Neph1 and anti-nephrin results in complement- and leukocyte-independent proteinuria with preserved foot processes. This disruption modestly reduces Neph1 and nephrin protein expression in podocytes and dramatically reduces ZO-1 protein expression via the interaction of ZO-1 PDZ domains with the cytoplasmic tail of Neph1, independent of changes in mRNA expression of all three genes. The interaction between nephrin and Neph1 is specific and not shared by either protein with P-cadherin, another integral slit diaphragm protein. The interaction between nephrin and Neph1 therefore appears to be an important determinant of glomerular permeability.

Biological science does not try to distinguish between health and disease. Biology is concerned with the interaction between living organisms and their environment. What we call health or disease is quite irrelevant. These reactions between the individual and his environment are complex. The individual and his surroundings form an integrated system which we can arbitrarily divide into two parts. There is an “external” component, by which we mean such factors as light, heat, percentage of oxygen in the air, quantity of minerals or vitamins in food, micro-organisms in food or air, and so on. These can induce changes in what we arbitrarily call the “internal” component. Here we include such crude factors as anatomical structures, or finer details like composition of intercellular fluid, or secretions of glands, or changes of electrical potential in nerve or muscle.

Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate-one virally inactivated with solvent detergent, the other with an additional heat-treatment step--were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.

In Brief The sniffing position (SP) has traditionally been considered the optimal head position for direct laryngoscopy (DL). Its superiority over other head positions, however, has been questioned during the last decade. We reviewed the scarce literature on the subject to examine the evidence either in favor or against the routine use of the SP. A standard definition for the position should be used (e.g., 35° neck flexion and 15° head extension) to avoid confusion about what constitutes a proper SP and to compare the results from different studies. Although several theories were proposed to explain the superiority of the SP, the three axes alignment theory is still considered a valid anatomical explanation. Although head elevation is needed to achieve the desired neck flexion, the elevation height may vary from one patient to another depending on head and neck anatomy and size of the chest. In infants and small children, for example, no head elevation is needed because the size and shape of the head allow axes approximation in the head-flat position. Horizontal alignment of the external auditory meatus with the sternum, in both obese and non-obese patients, indicates, and can be used as a marker for, proper positioning. Analysis of the available literature supports the use of the SP for DL. To achieve a proper SP in obese patients, the “ramped” (or the back-up) position should be used. The SP does not guarantee adequate exposure in all patients, because many other anatomical factors control the final degree of visualization. However, it should be the starting head position for DL because it provides the best chance at adequate exposure. Attention to details during positioning and avoidance of minor technical errors are essential to achieve the proper position. DL should be a dynamic procedure and position adjustment should be instituted in case poor visualization is encountered in the SP. Published ahead of print May 19, 2011

Magnesium is the fourth most abundant cation in the body and the second most abundant intracellular cation. It plays an important role in different organ systems at the cellular and enzymatic levels. Despite its importance, it still has not received the needed attention either in the medical literature or in clinical practice in comparison to other electrolytes like sodium, potassium, and calcium. Hypomagnesemia can lead to many clinical manifestations with some being life-threatening. The reported incidence is less likely than expected in the general population. We present a comprehensive review of different aspects of magnesium physiology and hypomagnesemia which can help clinicians in understanding, identifying, and treating this disorder.

The rationale for use of intracoronary physiology assessment and imaging arises from the limitations of coronary angiography, the traditional method for determining the severity of coronary stenoses. The visual assessment of percent diameter reduction has significant interobserver variability 1-3, even among experienced angiographers 4. Computer-assisted quantitative coronary angiography only marginally improves diagnostic accuracy and its estimate of functional significance 5. Fractional flow reserve (FFR) is used to determine the functional significance of a coronary stenosis 6. Intravascular ultrasound (IVUS) offers excellent visualization of intraluminal and transmural coronary anatomy. Optical coherence tomography (OCT) further improves vascular visualization. There is now persuasive evidence regarding intracoronary diagnostic lesion assessments using physiology and anatomy. These adjunctive diagnostic procedures may influence the decision for coronary revascularization, guide the performance of percutaneous coronary interventions (PCI), and optimize procedural outcomes. There are substantial long-term outcome data showing benefit associated with FFR-guided decision-making. However, these techniques are underutilized in contemporary practice: the rates of use of IVUS and FFR during PCI for intermediate coronary stenoses (40–70% diameter stenosis) are 20.3% and 6.1% respectively 7. In 2011, the ACCF/AHA/SCAI PCI guidelines 8 assigned levels of evidence for the use of these modalities in various clinical situations (Table 1). The purpose of this consensus statement is to review recent studies, to develop a consensus of how these procedures are best utilized in practice, and to support their incorporation into guideline and appropriate use documents. A trans-lesional functional assessment is an important adjunct to coronary angiography for providing an objective evaluation of stenosis severity. FFR is the ratio of mean distal coronary pressure (Pd) to mean aortic pressure (Pa) during maximum hyperemia, usually induced by adenosine i.c. bolus or i.v. infusion, and represents the percentage of normal flow across a coronary stenosis. If the patient has active obstructive airways disease, i.c. adenosine can be used safely instead of IV adenosine. Alternative pharmacologic agents include nitroprusside, dobutamine, and regadenoson. Physiologic stenosis assessment by FFR is a lesion-specific index of epicardial conductance, which is independent of the microvasculature and hemodynamic changes induced by variations in heart rate, blood pressure or myocardial contractility. The FFR threshold for detecting ischemia has been corroborated by multiple tests for myocardial ischemia and reflects the functional significance (i.e. ischemic potential) of an epicardial stenosis. To establish an ischemic threshold, FFR was validated in patients with single vessel intermediate lesions and compared with the combination of three different noninvasive stress tests 9. FFR was first validated using a cutoff value of 0.75. With further experience with the technique, investigators appreciated that by extending the cutoff value to 0.80, the sensitivity of FFR could be improved without greatly compromising the specificity. For this reason, a cutoff value of ≤0.80 was used in FAME 1 and FAME 2 and shown to be clinically valid. This is now the recommended ischemic reference standard for the invasive assessment of myocardial ischemia 10 (Fig. 1). Three prospective randomized trials have demonstrated the clinical utility of FFR. To determine the safety of deferring PCI based on nonsignificant FFR, the Percutaneous Coronary Intervention of Functionally Non-significant Stenosis (DEFER) Study 12 randomized 181 patients with stable ischemic heart disease (SIHD) with FFR ≥0.75 across an intermediate stenosis to PCI or to deferral of PCI with medical treatment. At 5-year follow-up, the deferred group had a rate of death or myocardial infarction (MI) that was less than half the rate in the PCI group. To evaluate the utility of FFR for guiding the performance of PCI, the Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) trial 12 randomized 1005 patients with multivessel disease (including SIHD, unstable angina, and NSTEMI) to either FFR-guided PCI or to angiography-guided PCI. The primary outcome, the composite rate of death, MI, or repeat revascularization at 1 year, was significantly lower (13.2% vs. 18.3%, P = 0.02) in patients who received FFR-guided PCI (Fig. 2). This was due to non-significant reductions in each component of the primary endpoint and a significant reduction in the combined rate of death or MI (7.3% vs. 11.1%, P = 0.04) in the FFR-guided group. At 2-year follow-up, the combined rate of death and MI remained significantly lower. An economic evaluation verified that FFR-guided PCI is a cost-saving strategy 13, with significantly fewer stents deployed and significantly less contrast media used. Additionally, patients treated with the FFR-guided strategy had similar rates of freedom from angina compared with the angiography-guided strategy. To compare outcomes in ischemia-guided PCI with medical therapy, the Fractional Flow Reserve versus Angiography for Multivessel Evaluation 2 (FAME 2) trial 14 randomized 888 patients with single or multivessel SIHD to FFR-guided PCI with optimal medical therapy or optimal medical therapy alone. The key difference between FAME 2 and other studies evaluating PCI for SIHD, such as COURAGE 15, is that to be included in the randomized portion of FAME 2, patients had to have at least one lesion with FFR ≤0.80. Enrollment in FAME 2 was stopped early because there was a highly significant difference in the primary endpoint of death, MI and urgent revascularization favoring the FFR-guided PCI arm. This was due to a significantly greater rate of urgent revascularization in the medical therapy arm (11.1% vs. 1.6%, P < 0.001); there was no difference in death or MI. A landmark analysis suggested a higher rate of spontaneous MI in the medical therapy arm starting 1 week after randomization. Patients with angiographic disease that was not hemodynamically significant (based on FFR), and therefore not enrolled in the randomized trial but followed in a registry, had a very low event rate, which supports the role of medical therapy in this group. Thus, clinical outcome studies indicate that measuring FFR optimizes the benefit of PCI and distinguishes stenoses responsible for ischemia from functionally insignificant ones. FFR improves clinical outcomes and saves resources compared with angiography-guided PCI. For optimal outcomes, FFR should be employed when decisions regarding the need for PCI are ambiguous based on the coronary angiogram and available noninvasive data. FFR is especially useful when noninvasive testing is absent, equivocal, or does not provide objective evidence of ischemia in the myocardial segment subtended by the targeted lesion. FFR can justify a procedure if the clinical context suggests a potential benefit. Judgment should always be used when assessing the risk:benefit ratio in clinical decision-making, however, and thus an abnormal FFR does not compel a revascularization procedure. In the presence of intermediate stenoses, or when there is an apparent discordance between lesion severity, location of ischemia by noninvasive testing and clinical symptoms, FFR provides valuable data for clinical decision-making. The limitations of angiography in characterizing intermediate severity stenoses are another important lesson from FAME 12. In lesions with 50 to 70% diameter narrowing, only 35% were hemodynamically significant based on FFR. In lesions with 71 to 90% diameter stenosis, for which many operators would perform PCI, 20% were not hemodynamically significant based on FFR and did not require PCI. Therefore, FFR can be useful in guiding revascularization decisions even in more severe angiographic stenoses when noninvasive data is not available or discordant with coronary angiography. These findings have implications for determining the optimal treatment strategy in patients with multivessel CAD. By measuring FFR and discounting non-ischemic lesions, the Functional SYNTAX Score can be calculated and angiographic three-vessel CAD can be reclassified as one- or two-vessel CAD, which could benefit from PCI and not require CABG 16. Table 2 17-23 summarizes the studies that assess revascularization in left main coronary stenosis (LMCA) based on FFR. FFR <0.75 is a clinically effective tool when used as a cutoff for guiding revascularization decisions and is the preferred technique for evaluating intermediate LMCA lesions. FFR can be used to evaluate the significance of serial stenoses to guide the strategy for determining which lesion(s) should be revascularized and which should be managed medically 24. Observational studies have reported favorable outcomes using FFR in specific anatomic subsets, including diffuse disease 25, bifurcations 26, stent-jailed side branches 27, and nonculprit lesions in ST-segment elevation myocardial infarction 28, but none of these subsets have been the subject of randomized trials. FFR is valid in all nonculprit vessels in non-ST-elevation ACS and valid in most nonculprit vessels in STEMI, with the caveat that STEMI with markedly elevated LVEDP and impaired global microcirculatory function may result in transiently and falsely elevated FFR. The reason is that microvascular impairment reduces the flow across the stenosis, elevating FFR. Therefore, in this setting, a low FFR indicates hemodynamic significance of the non-culprit lesion but a normal FFR is not definitive. The application of FFR in these clinical situations remains to be fully elucidated. The potential role of "functional angioplasty" (i.e., performing PCI on lesions responsible for ischemia and treating medically those that are not), as opposed to complete anatomic revascularization (performing PCI on all lesions that appear angiographically significant) as tested in the FAME trials, would constitute a substantial change from traditional practice. It is quite likely that in the future, functional PCI using FFR or an equivalent physiologic guide will be the measure of PCI appropriateness 10. Instead of relying solely on angiographic criteria of severity when there is no stress test present, or the stress test/anatomy results are discordant, FFR would be the final arbiter, irrespective of lesion severity 29. IVUS is a catheter-based imaging modality that provides high-resolution cross-sectional images of the coronary artery, enabling measurements of luminal and vessel areas 30. Plaque morphology and constituents are identified by the amplitude and frequency of reflected ultrasound signals that correspond to normal tissue, fibrosis, calcium, and necrotic core. The axial resolution is 100 to 200 µm and lateral resolution is 250 µm with frequencies of 20 to 40 MHz 31. IVUS quantification of a stenosis has fewer anatomic limitations than angiography. IVUS algorithms accurately measure minimum luminal area (MLA), a more accurate dimension than luminal diameter. The main limitation is ensuring imaging in a coaxial position. IVUS is an excellent method for determining plaque volume; however, despite numerous investigative applications, its precise role in clinical decision-making has not been defined. IVUS can be especially useful in situations in which angiographic imaging is considered unreliable, such as the presence of ostial lesions or segments with multiple overlapping vessels. Bifurcation lesions are particularly difficult to assess by angiography because overlapping side branches often obscure the lesion. IVUS may provide an optimal assessment in these subsets. Perhaps the most important use of IVUS is as an adjunct before and during PCI. It is especially useful in planning PCI strategy in high-risk subsets, such as left main stenosis, calcified lesions, and bifurcations 32. It is also helpful during stent placement to assess stent sizing, expansion, and apposition. Although IVUS has not been definitively shown to impact procedural mortality or MI when routinely used during PCI, there are data suggesting that IVUS-guided stent placement reduces stent thrombosis, restenosis, and repeat revascularization 33. A meta-analysis by Zhang et al. 34 (Table 3) showed improved clinical outcomes using IVUS to direct PCI. While there was no significant reduction in MI rate, stent thrombosis, and mortality were significantly reduced in the IVUS guided group 32, 35-43. Recently, the ADAPT-DES study evaluated 1-year clinical outcomes in patients undergoing PCI with DES 44. IVUS-guided PCI changed the interventional strategy in 74% of cases; at 1 year, there was a significant reduction in definite/probable stent thrombosis (0.52% vs. 1.04%, P = 0.01) and MI (2.5% vs. 3.7%, P = 0.002) but no reduction in mortality (1.0% vs. 1.4%, P = 0.14). For LMCA stenosis, IVUS is an important procedural adjunct, both pre- and postintervention, if stenting is being considered 45. OCT uses the scattering and absorption of near-infrared light. The OCT light source operates on a wavelength range of 1,250 to 1,350 nm, providing tissue penetration of 1 to 3 mm, and a spatial resolution at the cellular level 46. It has very high axial and lateral resolution, which provides accurate characterization of plaque morphology and composition in real-time, including thin fibrous caps, lipid pools, and fibrocalcific plaques 47. OCT has better resolution than IVUS, but less power of penetration. OCT is better at looking at fine detail in the near field, around the lumen and stent edges, but is less valuable for imaging plaque size or determining tissue characteristics. The improved spatial resolution compared to IVUS has raised the possibility that OCT could ultimately replace IVUS. However, its limited depth of penetration mitigates its ability to visualize the external elastic lamina, especially in large or proximal vessels. There are no prospective randomized trials of OCT for guiding PCI, but there are several single center trials that suggest the potential for improving poststent clinical decision-making 48-51. OCT can demonstrate thrombus, unrecognized plaque rupture, stent underexpansion, significant edge dissections, and excessive plaque at the stent edges treatable with further stent expansion or the placement of additional stents. IVUS can also detect these conditions, but OCT provides improved resolution. In the multicenter CLI-OPCI trial 52, OCT identified adverse features requiring further intervention in 35% of cases. The OCT arm had a significantly lower risk of death and MI at 1 year. OCT has potential benefit as an adjunct means of evaluating the anatomy and composition of stenoses of uncertain severity or morphology, but this application needs further evaluation. Of particular interest is its capability to determine fibrous cap thickness, potentially identifying vulnerable plaque, and perhaps predict impending rupture 53-55. The identification of thrombus is more accurate with OCT than with IVUS. A recent study 52 identified patients with ST-elevation-MI who could be treated with thrombus aspiration alone based on an OCT finding of plaque erosion rather than fibrous cap rupture, suggesting unique medical and cost saving possibilities. To assess the correlation between OCT luminal dimensions and FFR, Shiono et al. 56 evaluated 62 intermediate coronary lesions in 59 patients. An OCT-derived MLA = 1.91 mm2 (sensitivity = 93.5%, specificity = 77.4%), MLD = 1.35 mm (sensitivity = 90.3%, specificity = 80.6%), and percent lumen area stenosis >70% (sensitivity = 96.8%, specificity = 83.9%) had the best cutoff values for a FFR <0.75. Gonzalo et al. 57 compared OCT and IVUS with FFR to determine the accuracy of OCT in identifying hemodynamically severe coronary stenoses in 61 stenoses studied in 56 patients. Although OCT and IVUS demonstrated a similar diagnostic accuracy in detecting lesions with FFR <0.80, OCT was superior in the subgroup of vessels <3 mm diameter. To date, no prospective randomized studies have been performed to demonstrate improvement in clinical outcomes from this technology. There is no proven impact on mortality, MI, stent thrombosis, or restenosis rates. There are also no prospective randomized trials assessing the role of OCT-guided PCI. Since OCT, like IVUS, evaluates anatomic dimensions rather than functional significance, its use in assessing lesion physiology will probably be limited. As a result, this imaging modality remains investigational in terms of improving clinical outcomes associated with the performance of PCI. Accurate quantification of the severity of LMCA stenoses can be a valuable adjunct to diagnosis when coronary angiography gives equivocal or ambiguous images. When using IVUS to determine LMCA severity, the most widely used parameter is MLA. IVUS assessment has a relatively strong correlation with FFR in evaluating intermediate LMCA stenoses. A normal FFR can be predicted reasonably well with IVUS dimensions 58, 59. Limited variability in LMCA length, diameter, and amount of supplied myocardium explains the better correlation in LMCA than non-LMCA stenoses. However, both techniques have theoretical and practical limitations. Proximal LAD and/or LCX disease can impact FFR of LMCA stenoses. With IVUS, distal LMCA lesions can be difficult to accurately image, and often requires pullback from both the LCX and LAD. Table 4 58, 60 summarizes the studies that correlated IVUS MLA in LMCA stenoses with FFR. Jasti et al. 58 showed good correlation between FFR and IVUS, with sensitivities and specificities >0.90. In a study of 55 intermediate LMCA lesions, an MLA <5.9 mm2 and an MLD <2.8 mm correlated well with FFR<0.75 61. In 354 intermediate left main stenoses, an MLA >6.0 mm2 identified patients at low risk for adverse events with deferred revascularization 32. A prospective application of these criteria was tested in the LITRO study 62. LMCA revascularization was performed in 90.5% (152 of 168) of patients with an MLA <6 mm2 and was deferred in 96% (179 of 186) of patients with an MLA >6 mm2. In a 2-year follow-up period, cardiac death-free survival was 97.7% in the deferred group versus 94.5% in the revascularized group (P = ns), and event-free survival was 87.3% versus 80.6%, respectively (P = ns). At 2-year follow-up, only eight (4.4%) patients in the deferred group required subsequent LMCA revascularization, none of who had an MI. Thus, it is safe to defer LMCA revascularization with MLA >6 mm2. Additionally, the data confirms that MLA<6.0 mm2 is clinically significant, correlates with FFR <0.75, and may warrant intervention to improve 1-year mortality 60. In Asian populations, with smaller normal coronary diameters, an MLA cutoff <4.8 mm2 correlates better with reduced FFR <0.8 and <4.1 mm2 with FFR <0.75 36, 60. The primary limitation of IVUS MLA in predicting hemodynamic significance in non-LMCA lesions is that the functional effects of a lesion are dependent on additional factors besides dimension. These include lesion location in the coronary tree, lesion length, eccentricity, entrance and exit angles, shear forces, reference vessel dimensions, and the amount of viable myocardium subtended by the lesion 25. Therefore, in non-LMCA lesions there is only moderate correlation between anatomic dimensions by IVUS and ischemia by physiological assessment. The IVUS and FFR correlation is best in demonstrating nonsignificant lesions 59; their correlation in demonstrating significant stenoses is weaker. Part of the reason for this deficiency is that attempting to determine a critical MLA without considering the reference vessel MLA leads to inaccuracy. An MLA = 3.0 mm2 in a proximal versus distal arterial segment has entirely different effects on flow and subsequent clinical implications. In non-LMCA stenosis, IVUS MLA <4.0 mm2 correlates with ischemia on single-photon emission computed tomography and also correlates moderately well with an FFR <0.75 (sensitivity and specificity 92% and 56%, respectively). Importantly, low event rates are observed in intermediate lesions when intervention is deferred with an IVUS MLA ≥4 mm2 63-65. In the largest study to date, IVUS was compared with FFR in 544 lesions 66. The optimal cut-off value for predicting an FFR ≤0.80 was an MLA = 2.9mm2 by IVUS, but the overall accuracy was only 66%. Moreover, of the 240 lesions that had an MLA <2.9 mm2, only 47% were hemodynamically significant by FFR. Similarly concerning, 19% of lesions with an MLA >2.9 mm2 had an FFR <0.80, limiting the utility of IVUS for lesion assessment. Kang et al. 60 evaluated 236 angiographically intermediate coronary lesions in which both IVUS and FFR measurements were performed. An IVUS MLA ≤2.4 mm2 had the maximum accuracy for predicting FFR <0.80. However, the overall diagnostic accuracy was 68% with a confidence interval ranging from 1.8 to 2.6 mm2. FIRST was a multicenter prospective registry of patients who underwent elective coronary angiography and had intermediate coronary stenoses (40–80%) 67. An IVUS-measured MLA <3.07 mm2 had the best sensitivity and specificity (64% and 64.9%, respectively) for correlating with FFR <0.80. Thus, FFR is better validated than IVUS as a physiologic assessment and should be considered the standard for assessing the hemodynamic significance of intermediate non-LMCA lesions. An MLA ≥4.0 mm2 has reasonable accuracy in identifying non-significant lesions for which PCI can be safely deferred. However, an MLA <4.0 mm2 does not accurately predict a hemodynamically significant lesion and should not be used in the absence of supporting functional data to recommend revascularization 25. An MLA <3.0 mm2 is most likely a significant stenosis, but due to its only modest sensitivity and specificity, physiologic testing is desirable before proceeding with revascularization. The writing group recommends that the following conclusions be adopted in clinical practice and in future guidelines and appropriateness documents. In SIHD, when noninvasive stress imaging is contraindicated, discordant, nondiagnostic, or unavailable, FFR should be used to assess the functional significance of intermediate coronary stenoses (50–70%) and more severe stenoses (<90%). In patients with multivessel coronary disease, PCI guided by FFR measurement improves outcomes and saves resources when compared to PCI guided by angiography alone. In patients with three-vessel coronary disease, measuring FFR could allow reclassification of number of vessels diseased and/or SYNTAX score, thereby guiding decisions regarding revascularization by CABG or PCI. In SIHD, PCI of lesions with FFR <0.80 improves symptom control and decreases the need for hospitalization requiring urgent revascularization when compared with medical therapy alone. In SIHD, medical therapy is indicated for an angiographically intermediate stenosis (LMCA or non-LMCA) of unclear clinical significance when FFR >0.80. FFR measurement of the culprit vessel in a patient with an acute ST segment elevation myocardial infarction or any unstable acute coronary syndrome presentation should not be performed. IVUS is an accurate method for determining optimal stent deployment (complete stent expansion and apposition and lack of edge dissection or other complications after implantation), and the size of the vessel undergoing stent implantation. IVUS can be used to appraise the significance of LMCA stenosis and, employing a cutoff MLA = 6 mm2, assess whether revascularization is warranted. IVUS can be useful for the assessment of plaque morphology. IVUS measurements for determination of non-LMCA lesion severity should not be relied upon, in the absence of additional functional evidence, for recommending revascularization. of optimal stent deployment and lack of edge with improved resolution compared with IVUS. OCT can be useful for the assessment of plaque morphology. OCT should not be performed to determine stenosis functional The writing group with guidelines that these modalities are not indicated when imaging and angiographic data are or when the result of the additional procedure will not the treatment strategy or of stent implantation.

BACKGROUND: Although trimethoprim-sulfamethoxazole is the drug of choice for the prevention of Pneumocystis carinii pneumonia, many patients cannot tolerate it and must switch to an alternative agent. METHODS: We conducted a multicenter, open-label, randomized trial comparing daily atovaquone (1500-mg suspension) with daily dapsone (100 mg) for the prevention of P. carinii pneumonia among patients infected with the human immunodeficiency virus who could not tolerate trimethoprim-sulfamethoxazole. The median follow-up period was 27 months. RESULTS: Of 1057 patients enrolled, 298 had a history of P. carinii pneumonia. P. carinii pneumonia developed in 122 of 536 patients assigned to atovaquone (15.7 cases per 100 person-years), as compared with 135 of 521 in the dapsone group (18.4 cases per 100 person-years; relative risk for atovaquone vs. dapsone, 0.85; 95 percent confidence interval, 0.67 to 1.09; P=0.20). The relative risk of death was 1.07 (95 percent confidence interval, 0.89 to 1.30; P=0.45), and the relative risk of discontinuation of the assigned medication because of adverse events was 0.94 (95 percent confidence interval, 0.74 to 1.19; P=0.59). Among the 546 patients who were receiving dapsone at base line, the relative risk of discontinuation because of adverse events was 3.78 for atovaquone as compared with dapsone (95 percent confidence interval, 2.37 to 6.01; P<0.001); among those not receiving dapsone at base line, it was 0.42 (95 percent confidence interval, 0.30 to 0.58; P<0.001). CONCLUSIONS: Among patients who cannot tolerate trimethoprim-sulfamethoxazole, atovaquone and dapsone are similarly effective for the prevention of P. carinii pneumonia. Our results support the continuation of dapsone prophylaxis among patients who are already receiving it. However, among those not receiving dapsone, atovaquone is better tolerated and may be the preferred choice for prophylaxis against P. carinii pneumonia.