Identification of Suppressors of top-2 Embryonic Lethality in Caenorhabditis elegans.

Topoisomerase II is an enzyme with important roles in chromosome biology. This enzyme relieves supercoiling and DNA and RNA entanglements generated during mitosis. Recent studies have demonstrated that Topoisomerase II is also involved in the segregation of homologous chromosomes during the first meiotic division. However, the function and regulation of Topoisomerase II in meiosis has not been fully elucidated. Here, we conducted a genetic suppressor screen in Caenorhabditis elegans to identify putative genes that interact with topoisomerase II during meiosis. Using a temperature-sensitive allele of topoisomerase II, top-2(it7ts), we identified eleven suppressors of top-2-induced embryonic lethality. We used whole-genome sequencing and a combination of RNAi and CRISPR/Cas9 genome editing to identify and validate the responsible suppressor mutations. We found both recessive and dominant suppressing mutations that include one intragenic and 10 extragenic loci. The extragenic suppressors consist of a known Topoisomerase II-interacting protein and two novel interactors. We anticipate that further analysis of these suppressing mutations will provide new insights into the function of Topoisomerase II during meiosis.

A Sleep Medicine Curriculum for Pulmonary and Pulmonary/Critical Care Fellowship Programs: A Multisociety Expert Panel Report.

BACKGROUND: Pulmonary medicine specialists find themselves responsible for the diagnosis and management of patients with sleep disorders. Despite the increasing prevalence of many of these conditions, many sleep medicine fellowship training slots go unfilled, leading to a growing gap between the volume of patients seeking care for sleep abnormalities and the number of physicians formally trained to manage them. To address this need, we convened a multisociety panel to develop a list of curricular recommendations related to sleep medicine for pulmonary fellowship training programs. METHODS: Surveys of pulmonary and pulmonary/critical care fellowship program directors and recent graduates of these programs were performed to assess the current state of sleep medicine education in pulmonary training, as well as the current scope of practice of pulmonary specialists. These data were used to inform a modified Delphi process focused on developing curricular recommendations relevant to sleep medicine. RESULTS: Surveys confirmed that pulmonary medicine specialists are often responsible for the diagnosis and treatment of a number of sleep conditions, including several that are not traditionally considered related to respiratory medicine. Through five rounds of voting, the panel crafted a list of 52 curricular competencies relevant to sleep medicine for recommended inclusion in pulmonary training programs. CONCLUSIONS: Practicing pulmonary specialists require a broad knowledge of sleep medicine to provide appropriate care to patients they will be expected to manage. Training program directors may use the list of competencies as a framework to ensure adequate mastery of important content by graduating fellows.

Inter-rater agreement for visual discrimination of phasic and tonic electromyographic activity in sleep.

Study Objectives: The objective of this study was to determine the confidence of expert raters in discriminating phasic and tonic electromyographic (EMG) activity. We undertook this study because we suspected that even expert scorers may disagree on whether a given EMG segment contained phasic activity, tonic activity, or both. Methods: Six individuals holding either Fellowship status in the American Academy of Sleep Medicine or Board Certification in Sleep Medicine with at least 5 years experience in interpreting polysomnography visually examined 60 segments containing EMG activity. Raters determined their relative confidence that each segment contained phasic and tonic activity by noting whether they were highly certain or somewhat certain that the segment contained such activity or somewhat certain or highly certain that each segment did not contain such activity. Every segment was rated by every rater twice, once for phasic and once for tonic activity. Results: Substantial differences among raters existed in certainty regarding presence/absence of both phasic and tonic activity, although raters agreed on segments far above chance. Consensus was higher on certainty regarding presence of phasic, relative to tonic, activity. Conclusions: These findings indicate the limitations of visual analyses for discriminating abnormal muscle activity during sleep. Conversely, when expert judgments are combined with digitized measurements of EMG activity in sleep (e.g. REM atonia index), some allowance must be made for the unique contribution of visual analyses to such judgments, most notably for short duration EMG signals. These results may have relevance for polysomnographic interpretation in suspected synucleinopathies.

Teaching a Hypothesis-driven Physical Diagnosis Curriculum to Pulmonary Fellows Improves Performance of First-Year Medical Students.

RATIONALE: Hypothesis-driven physical examination emphasizes the role of bedside examination in the refinement of differential diagnoses and improves diagnostic acumen. This approach has not yet been investigated as a tool to improve the ability of higher-level trainees to teach medical students. OBJECTIVES: To assess the effect of teaching hypothesis-driven physical diagnosis to pulmonary fellows on their ability to improve the pulmonary examination skills of first-year medical students. METHODS: Fellows and students were assessed on teaching and diagnostic skills by self-rating on a Likert scale. One group of fellows received the hypothesis-driven teaching curriculum (the "intervention" group) and another received instruction on head-to-toe examination. Both groups subsequently taught physical diagnosis to a group of first-year medical students. An oral examination was administered to all students after completion of the course. MEASUREMENTS AND MAIN RESULTS: Fellows were comfortable teaching physical diagnosis to students. Students in both groups reported a lack of comfort with the pulmonary examination at the beginning of the course and improvement in their comfort by the end. Students trained by intervention group fellows outperformed students trained by control group fellows in the interpretation of physical findings (P < 0.05). CONCLUSIONS: Teaching hypothesis-driven physical examination to higher-level trainees who teach medical students improves the ability of students to interpret physical findings. This benefit should be confirmed using validated testing tools.

Evaluating Simulation-Based ACLS Education on Patient Outcomes: A Randomized, Controlled Pilot Study.

BACKGROUND: Simulation training is widely accepted as an effective teaching tool, especially for dealing with high-risk situations. OBJECTIVE: We assessed whether standardized, simulation-based advanced cardiac life support (ACLS) training improved performance in managing simulated and actual cardiac arrests. METHODS: A total of 103 second- and third-year internal medicine residents were randomized to 2 groups. The first group underwent conventional ACLS training. The second group underwent two 2 1/2-hour sessions of standardized simulation ACLS teaching. The groups were assessed by evaluators blinded to their assignment during in-hospital monthly mock codes and actual inpatient code sheets at 3 large academic hospitals. Primary outcomes were time to initiation of cardiopulmonary resuscitation, time to administration of first epinephrine/vasopressin, time to delivery of first defibrillation, and adherence to American Heart Association guidelines. RESULTS: There were no differences in primary outcomes among the study arms and hospital sites. During 21 mock codes, the most common error was misidentification of the initial rhythm (67% [6 of 9] and 58% [7 of 12] control and simulation arms, respectively, P  =  .70). There were no differences in primary outcome among groups in 147 actual inpatient codes. CONCLUSIONS: This blinded, randomized study found no effect on primary outcomes. A notable finding was the percentage of internal medicine residents who misidentified cardiac arrest rhythms.

The appearance of central sleep apnea after treatment of obstructive sleep apnea.

Patients with a primary diagnosis of obstructive sleep apnea frequently demonstrate central sleep apnea that emerges during treatment with CPAP. Although a number of mechanisms for this finding have been hypothesized, the pathophysiology is not definitively known. Controversy exists as to whether the concomitant appearance of the two phenomena represents a distinct meaningful entity. Regardless, the coincidence of these diseases may have important clinical implications. Herein, we review the proposed mechanisms for obstructive sleep apnea complicated by central sleep apnea. Future research is needed to elucidate the relative importance and susceptibility to intervention of the various pathophysiologic mechanisms responsible for this phenomenon, and whether a treatment approach distinct from that of pure obstructive apnea is justified.

Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial.

RATIONALE: Twenty-eight percent of people with mild to moderate obstructive sleep apnea experience daytime sleepiness, which interferes with daily functioning. It remains unclear whether treatment with continuous positive airway pressure improves daytime function in these patients. OBJECTIVES: To evaluate the efficacy of continuous positive airway pressure treatment to improve functional status in sleepy patients with mild and moderate obstructive sleep apnea. METHODS: Patients with self-reported daytime sleepiness (Epworth Sleepiness Scale score >10) and an apnea-hypopnea index with 3% desaturation and from 5 to 30 events per hour were randomized to 8 weeks of active or sham continuous positive airway pressure treatment. After the 8-week intervention, participants in the sham arm received 8 weeks of active continuous positive airway pressure treatment. MEASUREMENTS AND MAIN RESULTS: The Total score on the Functional Outcomes of Sleep Questionnaire was the primary outcome measure. The adjusted mean change in the Total score after the first 8-week intervention was 0.89 for the active group (n = 113) and -0.06 for the placebo group (n = 110) (P = 0.006). The group difference in mean change corresponded to an effect size of 0.41 (95% confidence interval, 0.14-0.67). The mean (SD) improvement in Functional Outcomes of Sleep Questionnaire Total score from the beginning to the end of the crossover phase (n = 91) was 1.73 ± 2.50 (t[90] = 6.59; P < 0.00001) with an effect size of 0.69. CONCLUSIONS: Continuous positive airway pressure treatment improves the functional outcome of sleepy patients with mild and moderate obstructive sleep apnea.

Obstructive sleep apnea and cardiovascular disease.

OPINION STATEMENT: Obstructive sleep apnea is a highly prevalent disease that often goes undetected for many years before diagnosis. Although most patients seek treatment to improve symptoms of daytime sleepiness, a growing body of literature suggests that treatment may also modulate cardiovascular risk. This article summarizes the current literature regarding the associations between sleep-disordered breathing and adverse cardiovascular outcomes and reviews the lesser body of data demonstrating the cardiovascular benefits of therapy.

Evaluation of sham-CPAP as a placebo in CPAP intervention studies.

STUDY OBJECTIVES: To evaluate the use of sham-continuous positive airway pressure (CPAP) treatment as a placebo intervention. DESIGN AND SETTING: Analysis of polysomnograms performed in fixed order without sham-CPAP and on the first night of the sham-CPAP intervention in participants in the CPAP Apnea Trial North American Program (CATNAP), a randomized, placebo controlled trial evaluating the effects of CPAP treatment on daytime function in adults with newly diagnosed mild to moderate obstructive sleep apnea (apnea hypopnea index (AHI) 5-30). PARTICIPANTS: The first 104 CATNAP participants randomized to the sham-CPAP intervention arm. MEASUREMENTS AND RESULTS: Compared to the polysomnographic measures without sham-CPAP, the study on the first night with sham-CPAP had statistically significant differences that suggested a decrease in sleep quality: decreased sleep efficiency, increased arousal index, increased time in stage 1 NREM sleep, and prolonged latency to REM sleep. However, all of these differences had a relatively small effect size. Compared to the polysomnogram without sham-CPAP, the number of hypopneas on the sham-CPAP polysomnogram was significantly increased and the number of apneas significantly decreased. Relatively minor differences in AHI with and without sham-CPAP were present and were dependent on the criteria used to score hypopneas. CONCLUSION: Comparison of polysomnograms with and without sham-CPAP revealed differences that, although statistically significant, were small in magnitude and had relatively low effect sizes suggesting minimal clinical significance. The results support the use of sham-CPAP as a placebo intervention in trials evaluating the effects of CPAP treatment in patients with obstructive sleep apnea. CLINICAL TRIAL INFORMATION: This paper was a secondary analysis of clinical trial data. CATNAP: CPAP Apnea Trial North American Program, the trial from which the data were obtained, is registered with clinicaltrial.gov. Registration #NCT00089752.

Effect of supine knee position on obstructive sleep apnea.

We previously reported a case of a middle-aged man whose obstructive sleep apnea (OSA) was virtually eliminated when he slept in the supine "knees up" position. In this study, we attempt to replicate this phenomenon in a group of volunteers with previously diagnosed OSA. Results indicated no significant improvement in OSA when sleeping supine knees up. Examination of distribution of within subjects' change [calculated as Respiratory Disturbance Index (RDI) in the "knees down" position vs RDI in the knees up position] indicated a trend for improvement in the latter (p=0.12, two-tailed probability). These results suggest that knee position is unlikely to be a robust intervention for OSA though they allow for the possibility that some patients may have a moderation of their condition by such a manipulation.

The CDC's routine HIV testing recommendation: legally, not so routine.

In this feature article, Ann Hilton Fisher, Catherine Hanssens and David I. Schulman (from the ABA) analyze the new guidelines on HIV testing from the U.S. Centers for Disease Control and Prevention (CDC) and find them wanting. The authors argue that the CDC's recommendation to do away with specific written informed consent for HIV tests is primarily based on a false assumption that the process of securing informed consent constitutes a barrier to HIV testing; and that, on the contrary, streamlined HIV testing, with rapid testing and counselling tailored to each individual's needs, has proven effective while retaining informed consent.