Jon-Erik C Holty

Maxillomandibular advancement for the treatment of obstructive sleep apnea: A systematic review and meta-analysis

The reported efficacy of maxillomandibular advancement (MMA) for the treatment of obstructive sleep apnea (OSA) is uncertain. We performed a meta-analysis and systematic review to estimate the clinical efficacy and safety of MMA in treating OSA. We searched Medline and bibliographies of retrieved articles, with no language restriction. We used meta-analytic methods to pool surgical outcomes. Fifty-three reports describing 22 unique patient populations (627 adults with OSA) met inclusion criteria. Additionally, 27 reports provided individual data on 320 OSA subjects. The mean apnea-hypopnea index (AHI) decreased from 63.9/h to 9.5/h (p<0.001) following surgery. Using a random-effects model, the pooled surgical success and cure (AHI <5) rates were 86.0% and 43.2%, respectively. Younger age, lower preoperative weight and AHI, and greater degree of maxillary advancement were predictive of increased surgical success. The major and minor complication rates were 1.0% and 3.1%, respectively. No postoperative deaths were reported. Most subjects reported satisfaction after MMA with improvements in quality of life measures and most OSA symptomatology. We conclude that MMA is a safe and highly effective treatment for OSA.

Accuracy of transbronchial needle aspiration for mediastinal staging of non-small cell lung cancer: a meta-analysis

Background: The reported accuracy of transbronchial needle aspiration (TBNA) for mediastinal staging in non-small cell lung cancer (NSCLC) varies widely. We performed a meta-analysis to estimate the accuracy of TBNA for mediastinal staging in NSCLC. Methods: Medline, Embase, and the bibliographies of retrieved articles were searched for studies evaluating TBNA accuracy with no language restriction. Meta-analytical methods were used to construct summary receiver-operating characteristic curves and to pool sensitivity and specificity. Results: Thirteen studies met inclusion criteria, including six studies that surgically confirmed all TBNA results and enrolled at least 10 patients with and without mediastinal metastasis (tier 1). Methodological quality varied but did not affect diagnostic accuracy. In tier 1 studies the median prevalence of mediastinal metastasis was 34%. Using a random effects model, the pooled sensitivity and specificity were 39% (95% CI 17 to 61) and 99% (95% CI 96 to 100), respectively. Compared with tier 1 studies, the median prevalence of mediastinal metastasis (81%; p = 0.002) and pooled sensitivity (78%; 95% CI 71 to 84; p = 0.009) were higher in non-tier 1 studies. Sensitivity analysis confirmed that the sensitivity of TBNA depends critically on the prevalence of mediastinal metastasis. The pooled major complication rate was 0.3% (95% CI 0.01 to 4). Conclusions: When properly performed, TBNA is highly specific for identifying mediastinal metastasis in patients with NSCLC, but sensitivity depends critically on the study methods and patient population. In populations with a lower prevalence of mediastinal metastasis, the sensitivity of TBNA is much lower than reported in recent lung cancer guidelines.

Diagnosis of Obstructive Sleep Apnea in Adults: A Clinical Practice Guideline From the American College of Physicians

DESCRIPTION The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the diagnosis of obstructive sleep apnea in adults. METHODS This guideline is based on published literature on this topic that was identified by using MEDLINE (1966 through May 2013), the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews. Searches were limited to English-language publications. The clinical outcomes evaluated for this guideline included all-cause mortality, cardiovascular mortality, nonfatal cardiovascular disease, stroke, hypertension, type 2 diabetes, postsurgical outcomes, and quality of life. Sensitivities, specificities, and likelihood ratios were also assessed as outcomes of diagnostic tests. This guideline grades the evidence and recommendations by using ACPs clinical practice guidelines grading system. RECOMMENDATION 1 ACP recommends a sleep study for patients with unexplained daytime sleepiness. (Grade: weak recommendation, low-quality evidence). RECOMMENDATION 2 ACP recommends polysomnography for diagnostic testing in patients suspected of obstructive sleep apnea. ACP recommends portable sleep monitors in patients without serious comorbidities as an alternative to polysomnography when polysomnography is not available for diagnostic testing. (Grade: weak recommendation, moderate-quality evidence).

Systematic Review: A Century of Inhalational Anthrax Cases from 1900 to 2005

Key Summary Points Initiation of antibiotic or anthrax antiserum therapy during the prodromal phase of inhalational anthrax is associated with an improved short-term survival. Multidrug antibiotic regimens are associated with decreased mortality, especially when they are administered during the prodromal phase. Most surviving patients will probably require drainage of reaccumulating pleural effusions. Despite modern intensive care, fulminant-phase anthrax is rarely survivable. The 2001 anthrax attack demonstrated the vulnerability of the United States to anthrax bioterrorism. The mortality rate observed during the 2001 U.S. attack (45%) was considerably lower than that historically reported for inhalational anthrax (89% to 96%) (1, 2). This reduction generally is attributed to the rapid provision of antibiotics and supportive care in modern intensive care units (3). However, no comprehensive reviews of reports of inhalational anthrax cases (including those from 2001) that evaluate how patient factors and therapeutic interventions affect disease progression and mortality have been published. Before the introduction of antibiotics, anthrax infection was primarily treated with antiserum (4). Anthrax antiserum reportedly decreased mortality by 75% compared with no treatment (5-8), and its efficacy is supported by recent animal data (9). Later, effective antibiotics, such as penicillin and chloramphenicol, were added to anthrax treatment strategies (10, 11). Currently, combination antibiotic therapy with ciprofloxacin (or doxycycline), rifampin, and clindamycin is recommended on the basis of anecdotal evidence from the U.S. 2001 experience (1, 12, 13). Historically, the clinical course of untreated inhalational anthrax has been described as biphasic, with an initial benign prodromal latent phase, characterized by a nonspecific flu-like syndrome, followed by a severe fulminant acute phase, characterized by respiratory distress and shock that usually culminates in death (2, 14). The duration of the prodromal phase has been reported to range from 1 to 6 days (14, 15), whereas that of the fulminant phase has been described as less than 24 hours (14, 16). A 1957 study confirmed these estimates of disease progression but was based on only 6 patients (17). Because a report synthesizing the data from all reported cases of inhalational anthrax (including those from 2001) has not been published, we do not have accurate estimates of the time course associated with disease progression or a clear understanding of the extent to which patient characteristics and treatment factors affect disease progression and mortality. This information is important for developing appropriate treatment and prophylaxis protocols and for accurately simulating anthrax-related illness to inform planning efforts for bioterrorism preparedness. We systematically reviewed published cases of inhalational anthrax between 1900 and 2005 to evaluate the effects of patient factors (for example, age and sex) and therapeutic factors (for example, time to onset of treatment) on disease progression and mortality. Methods Literature Sources and Search Terms We searched MEDLINE to identify case reports of inhalational anthrax (January 1966 to June 2005) by using the Medical Subject Heading (MeSH) terms anthrax and case reports. Because many reports were published before 1966 (the earliest publication date referenced in MEDLINE), we performed additional comprehensive searches of retrieved bibliographies and the indexes of 14 selected journals from 1900 to 1966 (for example, New England Journal of Medicine, The Lancet, La Presse Mdicale, Deutsche Medizinische Wochenschrift, and La Semana Mdica) to obtain additional citations. We considered all case reports of inhalational anthrax to be potentially eligible for inclusion, regardless of language. Study Selection We considered a case report to be eligible for inclusion if its authors established a definitive diagnosis of inhalational anthrax. Appendix Table 1 presents the details of our inclusion criteria. We excluded articles that described cases presenting before 1900 because Bacillus anthracis was not identified as the causative agent of clinical inhalational anthrax until 1877 (18) and because the use of reliable microscopic (19) and culture examination techniques (20) to confirm the diagnosis were not developed until the late 19th century. Appendix Table 1. Inclusion Criteria Data Abstraction One author screened potentially relevant articles to determine whether they met inclusion criteria. Two authors independently abstracted data from each included English-language article and reviewed bibliographies for additional potentially relevant studies. One author abstracted data from nonEnglish-language articles. We resolved abstraction discrepancies by repeated review and discussion. If 2 or more studies presented the same data from 1 patient, we included these data only once in our analyses. We abstracted 4 types of data from each included article: year of disease onset, patient information (that is, age, sex, and nationality), symptom and disease progression information (for example, time of onset of symptoms, fulminant phase, and recovery or death and whether the patient developed meningitis), and treatment information (for example, time and disease stage of the initiation of appropriate treatment and hospitalization). We based our criteria for determining whether a patient had progressed from the prodromal phase to the fulminant phase on distinguishing clinical features of five 2001 (3, 21, 22) and five 1957 (17) cases of fulminant inhalational anthrax. The fulminant phase is described historically as a severe symptomatic disease characterized by abrupt respiratory distress (for example, dyspnea, stridor, and cyanosis) and shock. Meningoencephalitis has been reported to occur in up to 50% of cases of fulminant inhalational anthrax (23). We considered any patient who had marked cyanosis with respiratory failure, who needed mechanical ventilation, who had meningoencephalitis, or who died as having been in the fulminant phase of disease. We used the reported time of an acute change in symptoms or deteriorating clinical picture to estimate when a confirmed fulminant case had progressed from the prodromal phase. We considered therapy for inhalational anthrax to be appropriate if either an antibiotic to which anthrax is susceptible was given (by oral, intramuscular, or intravenous routes) (24-27) or anthrax antiserum therapy was initiated. We classified patients who received antibiotics that are resistant to strains of B. anthracis (<70% susceptibility) as having received no antibiotics. If treatment with antibiotics or antiserum was given, we assumed that the treatment was appropriately dosed and administered. Statistical Analyses We used univariate analyses with SAS software, version 9.1 (SAS Institute Inc., Cary, North Carolina), to summarize the key patient and treatment characteristics. We compared categorical variables with the Fisher exact test and continuous variables with a 2-tailed WilcoxonMannWhitney test. For single comparisons, we considered a P value less than 0.05 to be statistically significant. When comparing U.S. 2001 with pre-2001 cases (or comparing patients who lived with those who died), we applied a Bonferroni correction to account for multiple comparisons (we considered P< 0.025 to be statistically significant: 0.05/2 = 0.025). We computed correlations for pairs of predictors available for each case at the beginning of the course of disease. Adjustments for Censored Data Infectious disease data are subject to incomplete observations of event times (that is, to censoring), particularly in the presence of therapeutic interventions. This can lead to invalid estimation of relevant event time distributions. For example, patients with longer prodromal stage durations are more likely to receive antibiotics than patients with shorter prodromal stage durations, and they may be, therefore, less likely to progress to fulminant stage or death. To account for censoring of our time data, we used maximum likelihood estimates by using both Weibull and log-normal distributions (28). The Appendix provides a detailed description of these analyses. Evaluating Predictors of Disease Progression and Mortality We used a multivariate Cox proportional hazards model to evaluate the prognostic effects of the following features on survival: providing antibiotics or antiserum (a time-dependent covariate in 3 categories: none, single-drug regimen, or multidrug regimen); the stage during which treatment with antibiotics or antiserum was initiated (prodromal stage vs. fulminant stage or no therapy); age (continuous variable); sex; if therapy was given, whether patients received a multidrug regimen (for example, 2 appropriate antibiotics or combination antibioticanthrax antiserum therapy); the use of pleural fluid drainage (a time-dependent covariate); development of anthrax meningoencephalitis (a time-dependent covariate); and whether the case was from the 2001 U.S. attack. We assessed each variable by stepwise backward regression using a P value cutoff of 0.100 or less. We excluded 8 adult patients for whom age was not reported. Although we did not perform extensive goodness-of-fit tests of our models, we did at least fit models in which we entered time not only linearly but also quadratically. Improvement in fit, as judged by conventional Wald and other tests, did not result, nor did including quadratic time variables further explain the data. To estimate mortality as a function of duration from symptom onset to antibiotic initiation, we first calculated a disease progression curve describing the time from symptom onset to fulminant phase among untreated patients by using the Weibull maximum likelihood estimates from the 71 cases for which time estimates were known. We then assigned a mortality rate to patients who had treatmen

Tuberculosis in Liver Transplant Recipients: A Systematic Review and Meta-Analysis of Individual Patient Data

Mycobacterium tuberculosis (MTB) causes substantial morbidity and mortality in liver transplant recipients. We examined the efficacy of isoniazid latent Mycobacterium tuberculosis infection (LTBI) treatment in liver transplant recipients and reviewed systematically all cases of active MTB infection in this population. We found 7 studies that evaluated LTBI treatment and 139 cases of active MTB infection in liver transplant recipients. Isoniazid LTBI treatment was associated with reduced MTB reactivation in transplant patients with latent MTB risk factors (0.0% versus 8.2%, P = 0.02), and isoniazid‐related hepatotoxicity occurred in 6% of treated patients, with no reported deaths. The prevalence of active MTB infection in transplant recipients was 1.3%. Nearly half of all recipients with active MTB infection had an identifiable pretransplant MTB risk factor. Among recipients who developed active MTB infection, extrapulmonary involvement was common (67%), including multiorgan disease (27%). The short‐term mortality rate was 31%. Surviving patients were more likely to have received 3 or more drugs for MTB induction therapy (P = 0.003) and to have been diagnosed within 1 month of symptom onset (P = 0.01) and were less likely to have multiorgan disease (P = 0.01) or to have experienced episodes of acute transplant rejection (P = 0.02). Compared with the general population, liver transplant recipients have an 18‐fold increase in the prevalence of active MTB infection and a 4‐fold increase in the case‐fatality rate. For high‐risk transplant candidates, isoniazid appears safe and is probably effective at reducing MTB reactivation. All liver transplant candidates should receive a tuberculin skin test, and isoniazid LTBI treatment should be given to patients with a positive skin test result or MTB pretransplant risk factors, barring a specific contraindication. Liver Transpl 15:894–906, 2009.

Centers for disease control and prevention expert panel meetings on prevention and treatment of anthrax in adults.

The Centers for Disease Control and Prevention convened panels of anthrax experts to review and update guidelines for anthrax postexposure prophylaxis and treatment. The panels included civilian and military anthrax experts and clinicians with experience treating anthrax patients. Specialties represented included internal medicine, pediatrics, obstetrics, infectious disease, emergency medicine, critical care, pulmonology, hematology, and nephrology. Panelists discussed recent patients with systemic anthrax; reviews of published, unpublished, and proprietary data regarding antimicrobial drugs and anthrax antitoxins; and critical care measures of potential benefit to patients with anthrax. This article updates antimicrobial postexposure prophylaxis and antimicrobial and antitoxin treatment options and describes potentially beneficial critical care measures for persons with anthrax, including clinical procedures for infected nonpregnant adults. Changes from previous guidelines include an expanded discussion of critical care and clinical procedures and additional antimicrobial choices, including preferred antimicrobial drug treatment for possible anthrax meningitis.

Quality Improvement Strategies for Children With Asthma: A Systematic Review

OBJECTIVE To evaluate the evidence that quality improvement (QI) strategies can improve the processes and outcomes of outpatient pediatric asthma care. DATA SOURCES Cochrane Effective Practice and Organisation of Care Group database (January 1966 to April 2006), MEDLINE (January 1966 to April 2006), Cochrane Consumers and Communication Group database (January 1966 to May 2006), and bibliographies of retrieved articles. STUDY SELECTION Randomized controlled trials, controlled before-after trials, or interrupted time series trials of English-language QI evaluations. INTERVENTIONS Must have included 1 or more QI strategies for the outpatient management of children with asthma. MAIN OUTCOME MEASURES Clinical status (eg, spirometric measures); functional status (eg, days lost from school); and health services use (eg, hospital admissions). RESULTS Seventy-nine studies met inclusion criteria: 69 included at least some component of patient education, self-monitoring, or self-management; 13 included some component of organizational change; and 7 included provider education. Self-management interventions increased symptom-free days by approximately 10 days/y (P = .02) and reduced school absenteeism by about 0.1 day/mo (P = .03). Interventions of provider education and those that incorporated organizational changes were likely to report improvements in medication use. Quality improvement interventions that provided multiple educational sessions, had longer durations, and used combinations of instructional modalities were more likely to result in improvements for patients than interventions lacking these characteristics. CONCLUSIONS A variety of QI interventions improve the outcomes and processes of care for children with asthma. Use of similar outcome measures and thorough descriptions of interventions would advance the study of QI for pediatric asthma care.

Surgical Options for the Treatment of Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a prevalent condition characterized by repetitive airway obstruction during sleep with associated increased morbidity and mortality. Although CPAP is the preferred treatment, poor compliance is common. Patients intolerant of conventional OSA medical treatment may benefit from surgical therapy to alleviate pharyngeal obstruction. Case series suggest that maxillomandibular advancement has the highest surgical efficacy (86%) and cure rate (43%). Soft palate surgical techniques are less successful, with uvulopalatopharyngoplasty having an OSA surgical success rate of 50% and cure rate of 16%. Further research is needed to more thoroughly assess clinical outcomes (eg, quality of life, morbidity), better identify key preoperative patient and clinical characteristics that predict success, and confirm long-term effectiveness of surgical modalities to treat OSA.

Maxillomandibular Advancement for Treatment of Obstructive Sleep Apnea: A Meta-analysis.

IMPORTANCE Maxillomandibular advancement (MMA) is an invasive yet effective surgical option for obstructive sleep apnea (OSA) that achieves enlargement of the upper airway by physically expanding the facial skeletal framework. OBJECTIVE To identify criteria associated with surgical outcomes of MMA using aggregated individual patient data from multiple studies. DATA SOURCES The Cochrane Library, Scopus, Web of Science, and MEDLINE from June 1, 2014, to March 16, 2015, using the Medical Subject Heading keywords maxillomandibular advancement, orthognathic surgery, maxillary osteotomy, mandibular advancement, sleep apnea, surgical, surgery, sleep apnea syndrome, and obstructive sleep apnea. STUDY SELECTION Inclusion criteria consisted of studies in all languages of (1) adult patients who underwent MMA as treatment for OSA; (2) report of preoperative and postoperative quantitative outcomes for the apnea-hypopnea index (AHI) and/or respiratory disturbance index (RDI); and (3) report of individual patient data. Studies of patients who underwent adjunctive procedures at the time of MMA (including tonsillectomy, uvulopalatopharyngoplasty, and partial glossectomy) were excluded. DATA EXTRACTION Three coauthors systematically reviewed the articles and updated the review through March 16, 2015. The PRISMA statement was followed. Data were pooled using a random-effects model and analyzed from July 1, 2014, to September 23, 2015. MAIN OUTCOMES AND MEASURES The primary outcomes were changes in the AHI and RDI after MMA for each patient. Secondary outcomes included surgical success, defined as the percentage of patients with more than 50% reduction of the AHI to fewer than 20 events/h, and OSA cure, defined as a post-MMA AHI of fewer than 5 events/h. RESULTS Forty-five studies with individual data from 518 unique patients/interventions were included. Among patients for whom data were available, 197 of 268 (73.5%) had undergone prior surgery for OSA. Mean (SD) postoperative changes in the AHI and RDI after MMA were -47.8 (25.0) and -44.4 (33.0), respectively; mean (SE) reductions of AHI and RDI outcomes were 80.1% (1.8%) and 64.6% (4.0%), respectively; and 512 of 518 patients (98.8%) showed improvement. Significant improvements were also seen in the mean (SD) postoperative oxygen saturation nadir (70.1% [15.6%] to 87.0% [5.2%]; P < .001) and Epworth Sleepiness Scale score (13.5 [5.2] to 3.2 [3.2]; P < .001). Rates of surgical success and cure were 389 (85.5%) and 175 (38.5%), respectively, among 455 patients with AHI data and 44 (64.7%) and 13 (19.1%), respectively, among 68 patients with RDI data. Preoperative AHI of fewer than 60 events/h was the factor most strongly associated with the highest incidence of surgical cure. Nevertheless, patients with a preoperative AHI of more than 60 events/h experienced large and substantial net improvements despite modest surgical cure rates. CONCLUSIONS AND RELEVANCE Maxillomandibular advancement is an effective treatment for OSA. Most patients with high residual AHI and RDI after other unsuccessful surgical procedures for OSA are likely to benefit from MMA.

Modeling the Logistics of Response to Anthrax Bioterrorism

Background. A bioterrorism attack with an agent such as anthrax will require rapid deployment of medical and pharmaceutical supplies to exposed individuals. How should such a logistical system be organized? How much capacity should be built into each element of the bioterrorism response supply chain? Methods. The authors developed a compartmental model to evaluate the costs and benefits of various strategies for preattack stockpiling and postattack distribution and dispensing of medical and pharmaceutical supplies, as well as the benefits of rapid attack detection. Results. The authors show how the model can be used to address a broad range of logistical questions as well as related, nonlogistical questions (e.g., the cost-effectiveness of strategies to improve patient adherence to antibiotic regimens). They generate several key insights about appropriate strategies for local communities. First, stockpiling large local inventories of medical and pharmaceutical supplies is unlikely to be the most effective means of reducing mortality from an attack, given the availability of national and regional supplies. Instead, communities should create sufficient capacity for dispensing prophylactic antibiotics in the event of a large-scale bioterror attack. Second, improved surveillance systems can significantly reduce deaths from such an attack but only if the local community has sufficient antibiotic-dispensing capacity. Third, mortality from such an attack is significantly affected by the number of unexposed individuals seeking prophylaxis and treatment. Fourth, full adherence to treatment regimens is critical for reducing expected mortality. Conclusions. Effective preparation for response to potential bioterror attacks can avert deaths in the event of an attack. Models such as this one can help communities more effectively prepare for response to potential bioterror attacks.