Aspirin as a Treatment for ARDS: A Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: There is no pharmacologic treatment for ARDS. Platelets play an important role in the pathophysiology of ARDS. Preclinical, observational, and clinically relevant models of ARDS indicate aspirin as a potential therapeutic option. RESEARCH QUESTION: Is enteral aspirin (75 mg, once daily) safe and effective in improving surrogate outcomes in adult patients with ARDS? STUDY DESIGN AND METHODS: This randomized, double-blind (patient and investigator), allocation-concealed, placebo-controlled phase 2 trial was conducted in five UK ICUs. Patients fulfilling the Berlin definition of ARDS were randomly assigned at a 1:1 ratio to receive enteral aspirin (75 mg) or placebo, for a maximum of 14 days, using a computer-generated randomization schedule, with variable block size, stratified by vasopressor requirement. The primary end point was oxygenation index (OI) on day 7. Secondary outcomes included safety parameters and other respiratory physiological markers. Analyses were by intention to treat. RESULTS: The trial was stopped early, due to slow recruitment, after 49 of a planned 60 patients were recruited. Twenty-four patients were allocated to aspirin and 25 to placebo. There was no significant difference in day 7 OI [aspirin group: unadjusted mean, 54.4 (SD 26.8); placebo group: 42.4 (SD 25); mean difference, 12.0; 95% CI, -6.1 to 30.1; P = .19]. Aspirin did not significantly impact the secondary outcomes. There was no difference in the number of adverse events between the groups (13 in each; OR, 1.04; 95% CI, 0.56-1.94; P = .56). INTERPRETATION: Aspirin was well tolerated but did not improve OI or other physiological outcomes; a larger trial is not feasible in its current design. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT02326350; URL: www. CLINICALTRIALS: gov.

Over-the-counter bite splints: A randomized controlled trial of compliance and efficacy.

BACKGROUND: Occlusal splints are often used to curb the impacts of sleep bruxism (SB) on the dentition, and over-the-counter (OCT) options are becoming increasingly popular. OTC splints are usually fabricated at home by patients, but not routinely evaluated by dental professionals. It is unclear how OCT splints compare with more traditional splints that receive dental oversight. OBJECTIVES: The present randomized controlled study tested how an OTC splint compared with a gold standard bite splint in terms of patient compliance (primary outcome) and efficacy (secondary outcomes). METHODS: Sixty-seven subjects were randomly assigned to receive either the OTC (SOVA, N = 35) splint or the gold standard "Michigan" bite splint (MI, N = 32), with 61 completing the study (SOVA, N = 30; MI, N = 31). OTC-splint subjects were required to fabricate their splints to clinically acceptable standards. Both groups wore the splints nightly for four months. Compliance was measured via daily diary. Efficacy outcomes evaluated stability, retention, periodontal health, night-time rhythmic masticatory muscle activity (RMMA), and material wear. RESULTS: OTC-splint subjects had difficulty fabricating splints to clinically acceptable standards. The number of night-time RMMA bursts was significantly greater for the OTC splint group. Compliance and all other efficacy measurements were not significantly different between-groups. CONCLUSIONS: The results support the potential use of OTC splints for curbing the impacts of SB. However, the results strongly suggest that dentists should be actively engaged in overseeing patients' use of self-fabricated appliances. This clinical trial is registered at ClinicalTrials.gov, Identifier number NCT02340663.

Individuality of masticatory performance and of masticatory muscle temporal parameters.

OBJECTIVE: Mammalian mastication serves to improve intra-oral food reduction. Insufficient food reduction creates potential swallowing problems, whereas over-reduction may accelerate tooth wear and increase feeding time. Either extreme has consequences. The study's objectives were: (1) to study the relationship between food reduction, number of chews in a sequence, and chewing rate, (2) to study how controlling the number of chews and chewing rate variability affects food reduction, and (3) to assess how dentoskeletal morphological and electromyographical (EMG) characteristics impact food reduction. DESIGN: Twenty-three healthy, fully-dentate adults chewed a standardized test food under three conditions: (1) no control, (2) number of chews controlled, and (3) number of chews and chewing rate controlled. EMG activity was sampled from masseter and temporalis muscles bilaterally. Demographic, occlusal contact area in maximum intercuspation, and cephalometric data were obtained. RESULTS: In uncontrolled conditions, food reduction and bout duration varied more than expected across subjects. Subjects with poor reduction under controlled conditions were those with poor reduction under uncontrolled conditions. Only occlusal contact area correlated with chewing performance under uncontrolled conditions. Chewing cycle duration, EMG burst duration, and EMG peak onset latency increased when the number of chews was restricted. EMG amplitude, a surrogate for bite force, increased in tasks controlling the number of chews and chewing rate. Chewing rate variability was difficult to diminish below individual-specific levels. CONCLUSIONS: Results: provided evidence that bite force, chewing rate, chewing performance and chewing bout duration reflected individual preferences. Future work will determine whether similar findings occur among other mammals.

Sex-Specific Outcomes After Transcatheter Aortic Valve Replacement: A Review of the Literature.

Transcatheter aortic valve replacement (TAVR) is a safe and effective therapy for aortic valve replacement in patients ineligible for or at high risk for surgery. However, outcomes after TAVR based on an individual's sex remain to be fully elucidated. We searched PUBMED and EMBASE using the keywords: "transcatheter aortic valve replacement," "transcatheter aortic valve implantation," "sex differences," "gender," "sex characteristics" and collected information on baseline features, procedural characteristics, and postprocedural outcomes in women. Inclusion/exclusion resulted in 23 publications. Women had less preexisting comorbidities than men. Most studies reported better survival in women (range of hazard ratio [95% CI] = 0.27 [0.09-0.84] to 0.91 [0.75-1.10]). At 30 days, women also had more vascular complications (6-20% vs 2-14%) and higher bleeding rates (10-44% vs 8-25%). Stroke rates were similar at 30 days (women, 1-7%; men, 1-5%). This literature review showed better survival in women than men after TAVR. However, women had more vascular complications and bleeding; stroke rates were similar. These findings may partly be explained by fewer baseline comorbidities in women. These results should be interpreted with caution as most measures only include unadjusted percentages.

Relationships between chewing rate, occlusion, cephalometric anatomy, muscle activity, and masticatory performance.

OBJECTIVE: Mastication consists of rhythmic jaw openings and closings. Recent studies suggest that muscle mechanical properties determine the rhythmic rate; however, speed-accuracy tradeoffs may also play a role. This study evaluated how variation in chewing rate affected chewing performance, how masticatory muscle activity varied with chewing rate, and whether morphology and demographics contributed to performance. DESIGN: Chewing performance and muscle activity were sampled in 23 healthy, fully-dentate adults, who chewed a standardized test food to a metronome set at 0.5, 0.75, 1, 2 and 3 times their 'natural' chewing rates. Subjects produced ten chews per trial, and five trials for each of the five rates. Surface electromyographic (EMG) activity was sampled from masseter and temporalis muscles bilaterally. Demographic, occlusal, and cephalometric data were also obtained. RESULTS: Chewing performance, defined by median particle size, was inversely related to chewing rate; however, performance was not remarkably improved at rates slower than the natural chewing rate. Above the natural chewing rate, variability in EMG bursts diminished, suggesting a reduction in muscle activity modulation at fast rates. Occlusal contacts and most morphological features appeared to play a limited or no role in performance. CONCLUSIONS: Results support the hypothesis that the 'natural' chewing rate is selected to be as fast as possible while providing sufficient time to allow EMG modulation for improved performance. The interplay between EMG modulation and individual variation in skeletal morphology is likely critical for optimal chewing performance.

Improving the Safety and Effectiveness of Medical Device Therapy in Women.

When not enough women are included in many clinical trials, an information gap on medical device safety and effectiveness exists, which can make it difficult to detect sex-specific results. In this article we discuss potential reasons for the underrepresentation of women and the regulatory research conducted by the U.S. Food and Drug Administration (FDA) used in supporting regulatory decisions. We demonstrate that important differences in cardiovascular device performance between women and men exist. Furthermore, concrete steps are outlined on the possible ways these sex-specific results can be detected and how a recent FDA Action Plan and Guidance Document aim at encouraging female participation in clinical trials and the appropriate analysis thereof.

Toward Sex-Specific Guidelines for Cardiac Resynchronization Therapy?

An important treatment for patients with heart failure is cardiac resynchronization therapy (CRT). Even though only 20% of women were included in clinical trials for CRT, a benefit has been shown in recent studies for subgroups of women compared to their male counterparts. Given this low inclusion rate of women in clinical studies, professional society guideline-based CRT recommendations, such as those by the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS), may not truly represent the best treatment for women, especially since most of the reports that showed this greater benefit in women were published after the latest guidelines. Despite having research and multiple publications regarding sex-specific heart failure outcomes and response to CRT, the ACCF/AHA/HRS guidelines have not yet been updated to account for the recent information regarding the differences in benefit for women and men with similar patient characteristics. This review discusses the physiology behind CRT, sex-specific characteristics of heart failure, and cardiac electrophysiology and summarizes the current sex-specific literature to encourage consideration of CRT guidelines for women and men separately.

Sex differences in device therapy for heart failure: utilization, outcomes, and adverse events.

BACKGROUND: Multiple studies of heart failure patients demonstrated significant improvement in exercise capacity, quality of life, cardiac left ventricular function, and survival from cardiac resynchronization therapy (CRT), but the underenrollment of women in these studies is notable. Etiological and pathophysiological differences may result in different outcomes in response to this treatment by sex. The observed disproportionate representation of women suggests that many women with heart failure either do not meet current clinical criteria to receive CRT in trials or are not properly recruited and maintained in these studies. METHODS: We performed a systematic literature review through May 2014 of clinical trials and registries of CRT use that stratified outcomes by sex or reported percent women included. One-hundred eighty-three studies contained sex-specific information. RESULTS: Ninety percent of the studies evaluated included ≤ 35% women. Fifty-six articles included effectiveness data that reported response with regard to specific outcome parameters. When compared with men, women exhibited more dramatic improvement in specific parameters. In the studies reporting hazard ratios for hospitalization or death, women generally had greater benefit from CRT. CONCLUSIONS: Our review confirms women are markedly underrepresented in CRT trials, and when a CRT device is implanted, women have a therapeutic response that is equivalent to or better than in men, while there is no difference in adverse events reported by sex.

Improving the percentage of electronic discharge summaries completed within 24 hours of discharge.

EDSs are an important part of patient care and medical communication. The GWH has a financially motivated target stating that 95% of EDS are to be completed within 24 hours of patient discharge. On review of a six-week pre-intervention period, the medical ward mean weekly EDS completion rate within 24 hours was 74.3%. EDSs form a significant part of junior doctor workload. We found that on a medical ward the mean completion time for one EDS was 18.25 minutes. In January 2014, 387 EDSs were written between four medical wards. This equates to 29.25 hours per week of junior doctor time spent completing EDSs on the four main medical wards. Our aim was to improve the percentage of EDSs completed within 24 hours of discharge from medical wards in the GWH. We proposed and implemented two interventions: 1) Five day EDS summary 2) Protected EDS hour. The five day EDS summary was implemented on wards 1 and 2. The protected EDS hour on ward 3. Ward 1: mean pre-intervention EDS completion rate: 81.1% (six months pre-intervention). This increased by 7.9% to 89% (four week mean EDS completion rate post-intervention) Ward 2: mean pre-intervention EDS completion rate: 75.2%. This increased by 11.6% to 86.8% Ward 3: mean pre-intervention EDS completion rate: 71%. This increased by 4.5% to 75.5% Control ward: mean pre-intervention EDS completion rate: 85.1%. This increased by 5.1% to 90.2% Our results show the five day EDS summary led to a mean 9.75% improvement and the protected EDS hour a mean 4.5% improvement in EDS completion rates. A 5.1% increase was seen on the control ward suggesting confounding factors in this data which are most likely the trust EDS working group, junior doctor experience and EDS project publicity.

Lethal fighting in nematodes is dependent on developmental pathway: male-male fighting in the entomopathogenic nematode Steinernema longicaudum.

Aggressive encounters occur between competitors (particularly males) throughout the animal kingdom, and in some species can result in severe injury and death. Here we describe for the first time lethal interactions between male nematodes and provide evidence that the expression of this behaviour is developmentally controlled. Males of the entomopathogenic nematode Steinernema longicaudum coil around each other, resulting in injuries, paralysis and frequently death. The probability of death occurring between pairs of males was affected by the developmental pathway followed, being much greater among males that had passed through the infective juvenile (IJ, or dauer) stage than among males that had not. Post-IJ males are found only in newly colonised hosts, typically with few competing males present. Killing those few competitors may secure valuable resources (both females and a host cadaver for nourishment of offspring). Non-IJ males develop in subsequent generations within a host cadaver, where the presence of many closely related male competitors increases the risk:benefit ratio of fighting. Thus, passage through the IJ stage primes males for enhanced aggression in circumstances where this is more likely to result in increased reproductive success. Fighting occurred between males developing in mixed-sex social groups, indicating that it is an evolved trait and not an abnormal response to absence of females. This is supported by finding high mortality of males, but not of females, across a range of population densities in insect cadavers. We propose that these nematodes, with their relatively simple organization, may be a useful model for studies of aggression.

Interference competition in entomopathogenic nematodes: male Steinernema kill members of their own and other species.

There is evidence of competition within and between helminth species, but the mechanisms involved are not well described. In interference competition, organisms prevent each other from using the contested resource through direct negative interactions, either chemical or physical. Steinernema spp. are entomopathogenic nematodes; they enter a living insect host which they kill and consume with the aid of symbiotic bacteria. Several studies have demonstrated intra- and interspecific competition in Steinernema, mediated by a scramble for resources and by incompatibility of the bacterial symbiont. Here we describe a mechanism by which male Steinernema may compete directly for resources, both food (host) and females, by physically injuring or killing members of another species as well as males of their own species. A series of experiments was conducted in hanging drops of insect haemolymph. Males of each of four species (Steinernemalongicaudum, Steinernemacarpocapsae, Steinernemakraussei and Steinernemafeltiae), representing three of the five phylogenetic clades of the genus, killed each other. Within 48h, up to 86% of pairs included at least one dead male, compared with negligible mortality in single male controls. There was evidence of intraspecific difference: one strain of S. feltiae (4CFMO) killed while another (UK76) did not. Males also killed both females and males of other Steinernema spp. There was evidence of a hierarchy of killing, with highest mortality due to S. longicaudum followed by S. carpocapsae, S. kraussei and S. feltiae. Wax moth larvae were co-infected with members of two Steinernema spp. to confirm that killing also takes place in the natural environment of an insect cadaver. When insects were co-infected with one infective juvenile of each species, S. longicaudum males killed both S. feltiae UK76 and Steinernema hermaphroditum. Wax moths co-infected with larger, equal numbers of S. longicaudum and S. feltiae UK76 produced mainly S. longicaudum progeny, as expected based on hanging drop experiments.

Cardiac resynchronization therapy in women: US Food and Drug Administration meta-analysis of patient-level data.

IMPORTANCE: Women were underrepresented in cardiac resynchronization therapy (CRT) trials for heart failure (making up about 20% of enrollees). Combining individual patient data from multiple clinical trials would enable assessment of CRT benefit in women. OBJECTIVE: To evaluate whether women with left bundle branch block (LBBB) benefit from CRT-defibrillators (CRT-D) at a shorter QRS duration than men with LBBB do. DESIGN, SETTING, AND PARTICIPANTS: Individual patient data were pooled from 3 CRT-D vs implantable cardioverter defibrillator (ICD) trials (4076 patients) enrolling predominantly patients with New York Heart Association (NYHA) class II heart failure and follow-up to 3 years. The effect of CRT-D compared with ICD on outcomes was assessed using random effects Cox proportional hazards. MAIN OUTCOMES AND MEASURES: Time to heart failure event or death (primary) and death alone (secondary). RESULTS: Women benefited from CRT-D more than men. The main difference occurred in patients with LBBB and a QRS of 130 to 149 milliseconds. In this group, women had a 76% reduction in heart failure or death (absolute CRT-D to ICD difference, 23%; hazard ratio [HR], 0.24, [95% CI, 0.11-0.53]; P < .001) and a 76% reduction in death alone (absolute difference 9%; HR, 0.24, [95% CI, 0.06-0.89]; P = .03), while there was no significant benefit in men for heart failure or death (absolute difference 4%; HR, 0.85 [95% CI, 0.60-1.21]; P = .38) or death alone (absolute difference 2%; HR, 0.86 [95% CI, 0.49-1.52]; P = .60). Neither women nor men with LBBB benefited from CRT-D at QRS shorter than 130 milliseconds, while both sexes with LBBB benefited at QRS of 150 milliseconds or longer. CONCLUSIONS AND RELEVANCE: In this population of patients with primarily mild heart failure, women with LBBB benefited from CRT-D at a shorter QRS duration than men with LBBB. This is important because recent guidelines limit the class I indication for CRT-D to patients with LBBB and QRS of 150 milliseconds or longer. While guidelines do give a class IIa indication to patients with LBBB and a QRS of 120 to 149 milliseconds, the present findings are important to communicate because women are less likely to receive CRT-D than men are. This study exemplifies the potential public health and regulatory science value of combining data from multiple clinical trials submitted to the FDA.

Sex-based differences in outcomes after percutaneous coronary intervention for acute myocardial infarction: a report from TRANSLATE-ACS.

BACKGROUND: Data regarding sex-based outcomes after percutaneous coronary intervention (PCI) for myocardial infarction are mixed. We sought to examine whether sex differences in outcomes exist in contemporary practice. METHODS AND RESULTS: We examined acute myocardial infarction patients undergoing PCI between April 2010 and October 2012 at 210 US hospitals participating in the Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events after Acute Coronary Syndrome (TRANSLATE-ACS) observational study. Outcomes included 1-year risk of major adverse cardiac events and bleeding according to Global Utilization of Strategies To Open Occluded Arteries (GUSTO) and Bleeding Academic Research Consortium (BARC) definitions. Among 6218 patients, 27.5% (n=1712) were female. Compared with men, women were older, had more comorbidities, and had lower functional status. Use of multivessel PCI and drug-eluting stents was similar between sexes, while women received less prasugrel. Unadjusted cumulative incidence of 1-year major adverse cardiac events was higher for women than for men (15.7% versus 13.6%, P=0.02), but female sex was no longer associated with higher incidence of major adverse cardiac events after multivariable adjustment (hazard ratio 0.98, 95% CI 0.83 to 1.15). Female sex was associated with higher risks of post-PCI GUSTO bleeding (9.1% versus 5.7%, P<0.0001) and postdischarge BARC bleeding (39.6% versus 27.9%, P<0.0001). Differences persisted after adjustment (GUSTO: hazard ratio 1.32, 95% CI 1.06 to 1.64; BARC: incidence rate ratio 1.42, 95% CI 1.27 to 1.56). CONCLUSIONS: Female and male myocardial infarction patients undergoing PCI differ regarding demographic, clinical, and treatment profiles. These differences appear to explain the higher observed major adverse cardiac event rate but not higher adjusted bleeding risk for women versus men.

Gender- and race-based utilization and outcomes of pulmonary artery catheterization in the setting of full-time intensivist staffing.

BACKGROUND: Little is known regarding gender- or race-based differences in critical care. We investigated whether gender or race was associated with pulmonary artery catheter (PAC) utilization or with in-hospital death among patients with a PAC. A particular focus was patients with cardiogenic shock (CS), in whom guidelines recommend PAC use. METHODS: This was a retrospective cohort analysis from the coronary care unit of a large tertiary-care hospital staffed with full-time cardiac intensivists. RESULTS: We analyzed 8845 consecutive adult patients, of whom 42.1% were women and 40.8% were black. PAC use rates were 11.3% in women and 11.5% in men (P = 0.79), and 11.3% in blacks and 11.5% in whites (P = 0.76). In CS patients, PAC use rates in women and men were 50.3% and 49.1% (P = 0.85) and in blacks and whites were 43.7% and 53.3% (P = 0.05). There was no independent association between gender or race and PAC use overall or in those with CS. Neither gender nor race was a predictor of in-hospital death in patients undergoing PAC. CONCLUSIONS: PAC use and in-hospital death were determined not by gender or race but by disease severity. Full-time intensivist staffing and the presence of definitive guidelines may reduce gender- and race-based treatment disparities.

Solutions for disparities for women with heart disease.

Cardiovascular disease (CVD) mortality and morbidity is a major burden on the US and global population. Observed differences in prevalence, incidence, outcomes, and risk factors suggest a possible sex difference in etiology and pathophysiology of CVD. Disparate rates of referral and diagnosis may be attributable to differences in symptoms, presentation, and diagnostic accuracy. Many common procedural, pharmaceutical, and medical device therapies have been associated with worse outcomes in women compared to men. Awareness campaigns and efforts to improve female inclusion in clinical trials are contributing to improvements in CVD healthcare delivery for women, but much remains unknown about the biological basis for the differences described above, such as the role of estrogen, life-cycle changes (puberty, menstrual cycle, pregnancy, menopause), and possible chromosomal or genetic mechanisms. This is where translational research is uniquely poised to make immense contributions to resolving disparities in the quality of care and outcomes for women with CVD.

Sex ratios and sex-biased infection behaviour in the entomopathogenic nematode genus Steinernema.

In experimentally infected insects, the sex ratio of first generation nematodes of five species of Steinernema was female-biased (male proportion 0.35-0.47). There was a similar female bias when the worms developed in vitro (0.37-0.44), indicating that the bias in these species is not due to a lower rate of infection by male infective juveniles (IJs). Experimental conditions influenced the proportion of males establishing in insects, indicating that male and female IJs differ in their behaviour. However, there was no evidence that males are the colonising sex in any species, contrary to what has previously been proposed. Time of emergence from the host in which the nematodes had developed influenced sex ratios in experimental infections. In three species (Steinernema longicaudum, Steinernema glaseri and Steinernema kraussei), early emerged nematodes had a higher proportion of males than those that emerged later, with the reverse trend for Steinernema carpocapsae and Steinernema feltiae. In a more detailed in vitro study of S. longicaudum, the proportion of males was similar whether or not the nematodes passed through the developmentally arrested IJ stage, indicating that the female bias is not due to failure of males to exit this stage. The sex ratio in vitro was independent of survival rate from juvenile to adult, and was female-biased even when all juveniles developed, indicating that the bias is not explained by failure of males to develop to adults. The female-biased sex ratio characteristic of Steinernema populations appears to be present from at least the early juvenile stage. We hypothesise that the observed female bias is the population optimal sex ratio, a response to cycles of local mate competition experienced by nematodes reproducing within insect hosts interspersed with periods of outbreeding with less closely related worms following dispersal.

FDA's perspectives on cardiovascular devices.

The Food and Drug Administration (FDA) decision process for approving or clearing medical devices is often determined by a review of robust clinical data and extensive preclinical testing of the device. The mission statement for the Center for Devices and Radiological Health (CDRH) is to review the information provided by manufacturers so that it can promote and protect the health of the public by ensuring the safety and effectiveness of medical devices deemed appropriate for human use (Food, Drug & Cosmetic Act, Section 903(b)(1, 2(C)), December 31, 2004; accessed December 17, 2008 http://www.fda.gov/opacom/laws/fdcact/fdctoc.htm). For high-risk devices, such as ventricular assist devices (VADs), mechanical heart valves, stents, cardiac resynchronization therapy (CRT) devices, pacemakers, and defibrillators, the determination is based on FDA's review of extensive preclinical bench and animal testing followed by use of the device in a clinical trial in humans. These clinical trials allow the manufacturer to evaluate a device in the intended use population. FDA reviews the data from the clinical trial to determine if the device performed as predicted and the clinical benefits outweigh the risks. This article reviews the regulatory framework for different marketing applications related to cardiovascular devices and describes the process of obtaining approval to study a cardiovascular device in a U.S. clinical trial.