Composite outcome measures in high-impact critical care randomised controlled trials: a systematic review.

BACKGROUND: The use of composite outcome measures (COM) in clinical trials is increasing. Whilst their use is associated with benefits, several limitations have been highlighted and there is limited literature exploring their use within critical care. The primary aim of this study was to evaluate the use of COM in high-impact critical care trials, and compare study parameters (including sample size, statistical significance, and consistency of effect estimates) in trials using composite versus non-composite outcomes. METHODS: A systematic review of 16 high-impact journals was conducted. Randomised controlled trials published between 2012 and 2022 reporting a patient important outcome and involving critical care patients, were included. RESULTS: 8271 trials were screened, and 194 included. 39.1% of all trials used a COM and this increased over time. Of those using a COM, only 52.6% explicitly described the outcome as composite. The median number of components was 2 (IQR 2-3). Trials using a COM recruited fewer participants (409 (198.8-851.5) vs 584 (300-1566, p = 0.004), and their use was not associated with increased rates of statistical significance (19.7% vs 17.8%, p = 0.380). Predicted effect sizes were overestimated in all but 6 trials. For studies using a COM the effect estimates were consistent across all components in 43.4% of trials. 93% of COM included components that were not patient important. CONCLUSIONS: COM are increasingly used in critical care trials; however effect estimates are frequently inconsistent across COM components confounding outcome interpretations. The use of COM was associated with smaller sample sizes, and no increased likelihood of statistically significant results. Many of the limitations inherent to the use of COM are relevant to critical care research.

Endothelin-1 as a novel target for the prevention of metabolic dysfunction with intermittent hypoxia in male participants.

We examined the effect of intermittent hypoxia (IH, a hallmark feature of sleep apnea) on adipose tissue lipolysis and the role of endothelin-1 (ET-1) in this response. We hypothesized that IH can increase ET-1 secretion and plasma free fatty acid (FFA) concentrations. We further hypothesized that inhibition of ET-1 receptor activation with bosentan could prevent any IH-mediated increase in FFA. To test this hypothesis, 16 healthy male participants (32 ± 5 yr, 26 ± 2 kg/m2) were exposed to 30 min of IH in the absence (control) and presence of bosentan (62.5 mg oral twice daily for 3 days prior). Arterial blood samples for ET-1, epinephrine, and FFA concentrations, as well as abdominal subcutaneous adipose tissue biopsies (to assess transcription of cellular receptors/proteins involved in lipolysis), were collected. Additional proof-of-concept studies were conducted in vitro using primary differentiated human white preadipocytes (HWPs). We show that IH increased circulating ET-1, epinephrine, and FFA (P < 0.05). Bosentan treatment reduced plasma epinephrine concentrations and blunted IH-mediated increases in FFA (P < 0.01). In adipose tissue, bosentan had no effect on cellular receptors and proteins involved in lipolysis (P > 0.05). ET-1 treatment did not directly induce lipolysis in differentiated HWP. In conclusion, IH increases plasma ET-1 and FFA concentrations. Inhibition of ET-1 receptors with bosentan attenuates the FFA increase in response to IH. Based on a lack of a direct effect of ET-1 in HWP, we speculate the effect of bosentan on circulating FFA in vivo may be secondary to its ability to reduce sympathoadrenal tone.

Competency Assessment in Focused Cardiac Ultrasound-Can the Use of Sequential Testing Help Tailor Training Requirements?

Varying numbers of scans are required by different professional bodies before focused cardiac ultrasound (FCU) competence is assumed. It has been suggested that innovation in the assessment of FCU competence is needed and that competency assessment needs to be more individualized. We report our experience of how the use of sequential testing may help personalize the assessment of FCU competence. DESIGN: This was a planned exploratory reanalysis of previously prospectively collected data. FCU was performed sequentially by an intensive care trainee and expert on the same patient. Assessment of left ventricular (LV) function by the trainee and expert was compared. Sequential testing methods were used in the analysis of this data to see if they could be used to help in the assessment of competence. Each trainee had completed a 38-hour teaching program and a logbook of 30 scans prior to enrollment. SETTING: Tertiary Australian not for profit private academic hospital. MEASUREMENTS AND MAIN RESULTS: Two hundred seventy paired echocardiograms were completed by seven trainees. For trainees to achieve greater than 90% accuracy in correctly assessing LV function when compared with an expert, a variable number of scans were required. This ranged from 13 to 25 (95% CI, 13-25) scans. Over the study period, the ability to correctly identify LV function was maintained, and it appeared there was no degradation in skill. CONCLUSIONS: Using the Sequential Probability Ratio Test demonstrates a variable number of scans were required to show greater than 90% accuracy in the assessment of LV function. As such, the use of sequential testing could help individualize competency assessments in FCU. Additionally, our data suggests that over a 6-month period, echocardiographic skill is maintained without any formal teaching or feedback. Further work assessing the utility of this method based on larger samples is required.

Carotid body size measured by computed tomographic angiography in individuals born prematurely.

PURPOSE: We tested the hypothesis that the carotid bodies would be smaller in individuals born prematurely or exposed to perinatal oxygen therapy when compared individuals born full term that did not receive oxygen therapy. METHODS: A retrospective chart review was conducted on patients who underwent head/neck computed tomography angiography (CTA) at the Mayo Clinic between 10 and 40 years of age (n = 2503). Patients were identified as premature ( < 38 weeks) or receiving perinatal oxygen therapy by physician completion or billing codes (n = 16 premature and n = 7 receiving oxygen). Widest axial measurements of the carotid body images captured during the CTA were performed. RESULTS: Carotid body visualization was possible in 43% of patients and 52% of age, sex, and body mass index (BMI)-matched controls but only 17% of juvenile preterm subjects (p = .07). Of the carotid bodies that could be visualized, widest axial measurements of the carotid bodies in individuals born prematurely (n = 7, 34 ±â€¯4 weeks gestation, birth weight: 2460 ±â€¯454 g; average size: 2.5 ±â€¯0.2 cm) or individuals exposed to perinatal oxygen therapy (n = 3, 38 ±â€¯2 weeks gestation, Average size: 2.2 ±â€¯0.1 cm) were not different when compared to controls (2.3 ±â€¯0.2 cm and 2.3 ±â€¯0.2 cm, respectively, p > 0.05). CONCLUSIONS: Carotid body size, as measured using CTA, is not smaller in adults born prematurely or exposed to perinatal oxygen therapy when compared to sex, age, and BMI-matched controls. However, carotid body visualization was lower in juvenile premature patients. The decreased ability to visualize the carotid bodies in these individuals may be a result of their prematurity.

Effect of acute hypoxemia on cerebral blood flow velocity control during lower body negative pressure.

The ability to maintain adequate cerebral blood flow and oxygenation determines tolerance to central hypovolemia. We tested the hypothesis that acute hypoxemia during simulated blood loss in humans would cause impairments in cerebral blood flow control. Ten healthy subjects (32 ± 6 years, BMI 27 ± 2 kg·m-2 ) were exposed to stepwise lower body negative pressure (LBNP, 5 min at 0, -15, -30, and -45 mmHg) during both normoxia and hypoxia (Fi O2  = 0.12-0.15 O2 titrated to an SaO2 of ~85%). Physiological responses during both protocols were expressed as absolute changes from baseline, one subject was excluded from analysis due to presyncope during the first stage of LBNP during hypoxia. LBNP induced greater reductions in mean arterial pressure during hypoxia versus normoxia (MAP, at -45 mmHg: -20 ± 3 vs. -5 ± 3 mmHg, P < 0.01). Despite differences in MAP, middle cerebral artery velocity responses (MCAv) were similar between protocols (P = 0.41) due to increased cerebrovascular conductance index (CVCi) during hypoxia (main effect, P = 0.04). Low frequency MAP (at -45 mmHg: 17 ± 5 vs. 0 ± 5 mmHg2 , P = 0.01) and MCAv (at -45 mmHg: 4 ± 2 vs. -1 ± 1 cm·s-2 , P = 0.04) spectral power density, as well as low frequency MAP-mean MCAv transfer function gain (at -30 mmHg: 0.09 ± 0.06 vs. -0.07 ± 0.06 cm·s-1 ·mmHg-1 , P = 0.04) increased more during hypoxia versus normoxia. Contrary to our hypothesis, these findings support the notion that cerebral blood flow control is not impaired during exposure to acute hypoxia and progressive central hypovolemia despite lower MAP as a result of compensated increases in cerebral conductance and flow variability.

Impact of sleep disordered breathing on carotid body size.

We tested the hypotheses that: (1) carotid body size can be measured by computed tomographic angiography (CTA) with high inter-observer agreement, and (2) patients with sleep apnea exhibit larger carotid bodies than those without sleep apnea. A chart review was conducted from patients who underwent neck CTA and polysomnography at the Mayo Clinic between January 2000 and February 2015. Widest axial measurements of the carotid bodies, performed independently by two radiologists, were possible in 81% of patients. Intra-class correlation coefficients ranged from 0.93 to 0.95 (Right carotid body: 0.93; Left: 0.94; Average: 0.95). Widest axial measurements of the carotid bodies were greater in patients with sleep apnea (n=32) compared to controls (n=46, P-value range 0.02-0.04). After adjusting for age, no differences in carotid body size were observed between the patient groups (P-value range 0.45-0.59). We conclude carotid body size can be detected by CTA with high inter-observer agreement; however, carotid body size is not increased in patients with sleep apnea.

Transglutaminase activity is decreased in large arteries from hypertensive rats compared with normotensive controls.

Transglutaminases (TGs) catalyze the formation of covalent cross-links between glutamine residues and amine groups. This cross-linking activity has been implicated in arterial remodeling. Because hypertension is characterized by arterial remodeling, we hypothesized that TG activity, expression, and functionality would be increased in the aorta, but not in the vena cava (which does not undergo remodeling), from hypertensive rats relative to normotensive rats. Spontaneously hypertensive stroke-prone rats (SHRSP) and DOCA-salt rats as well as their respective normotensive Wistar-Kyoto or Sprague-Dawley counterparts were used. Immunohistochemistry and Western blot analysis measured the presence and expression of TG1 and TG2, in situ activity assays quantified active TGs, and isometric contractility was used to measure TG functionality. Contrary to our hypothesis, the activity (52% DOCA-salt vs. control rats and 56% SHRSP vs. control rats, P < 0.05), expression (TG1: 54% DOCA-salt vs. control rats, P > 0.05, and TG2: 77% DOCA-salt vs. control rats, P < 0.05), and functionality of TG1 and TG2 were decreased in the aorta, but not in the vena cava, from hypertensive rats. Mass spectrometry identified proteins uniquely amidated by TGs in the aorta that play roles in cytoskeletal regulation, redox regulation, and DNA/RNA/protein synthesis and regulation and in the vena cava that play roles in cytoskeletal regulation, coagulation regulation, and cell metabolism. Consistent with the idea that growing cells lose TG2 expression, vascular smooth muscle cells placed in culture lost TG2 expression. We conclude that the expression, activity, and functionality of TG1 and TG2 are decreased in the aorta, but not in the vena cava, from hypertensive rats compared with control rats.

Laparoscopic appendicectomy in pregnancy: a systematic review of the published evidence.

UNLABELLED: Surgical intervention for acute appendicitis during pregnancy carries significant risk to both mother and foetus. The safety of Laparoscopic Appendicectomy in pregnancy has been a matter of debate among clinicians. We have critically reviewed the available published evidence in regards with this debate. CONCLUSION: There is no strong current evidence as to the preferred modality of appendicectomy; open or laparoscopic, during pregnancy from the prospect of foetal or maternal safety. However, low grade evidence shows that laparoscopic appendicectomy during pregnancy might be associated with higher rates of foetal loss.

The many faces of moral distress among clinicians.

This narrative symposium illuminates the problem of clinician moral distress. NIB editorial staff and narrative symposium editors, Cynda Rushton, PhD, RN, FAAN and Renee Boss, MD, MHS, developed a call for stories, which was sent to several list serves and posted on Narrative Inquiry in Bioethics' website. The request for personal stories from inter-professional healthcare providers asked them to: identify specific clinical situations that give rise to moral distress; discuss the sources of this distress; reflect on how they experienced moral distress-physically, psychologically, socially, or spiritually; assess how they managed their situations; and offer suggestions for avoiding future problems of a similar nature. Twelve stories are found in the print version of the journal and an additional eight supplemental stories are published online only through Project MUSE. The clinicians describe a wide range of experiences with patients, other clinicians, and their own professional and personal identities. Embedded in each of the narratives are deeply felt emotions that accompany their experiences of moral distress. Katherine Brown-Saltzman (a nurse), Alisa Carse (a philosopher), Zhanna Bagdasarov and Shane Connelly (industrial-organizational psychologists), and Nancy Berlinger (a bioethicist) provided commentaries.

Bronchogenic cysts as a cause of infantile stridor: case report and literature review.

INTRODUCTION: Cystic lesions related to the upper airway are an unusual cause of infantile stridor. Such a lesion may exert a mass effect, with subsequent airway compromise. CASE REPORT: A six-month-old boy was transferred to our unit with a right-sided, level IV neck lump and a three-month history of chronic cough and, latterly, inspiratory stridor. Computed tomography revealed a large, unilocular, cystic, cervicothoracic lesion causing marked compression of the trachea. Airway endoscopy subsequently revealed the larynx to be displaced to the left, with severe external compression of the trachea from just below the subglottic level to immediately above the carina. The mediastinal lesion was excised via an external approach. The histological diagnosis was a bronchogenic cyst. CONCLUSION: Bronchogenic cysts are a rare cause of infantile stridor, and should be considered in the differential diagnosis of cystic cervical and mediastinal masses. Surgical excision is the treatment of choice.

Ileocaecal valve: how important is it?

PURPOSE: Our aim was to investigate the importance of the ileocaecal valve and its reconstruction in patients that are not suffering from short bowel syndrome and Crohn's disease. METHODS: Casenotes of 99 children with hemicolectomy and 24 children with terminal ileal resection were reviewed and sorted into three groups. Group 1: ileocaecal valve resection (limited hemicolectomy), Group 2: hemicolectomy, Group 3: terminal ileal resection between 10 and 25 cm. Patients with Crohn's, short bowel syndrome and incomplete follow-up were excluded. RESULTS: Chronic diarrhoea was documented in 7/26 cases (27%) in Group 1, 6/23 patients (26%) in Group 2, and none of the 13 patients had diarrhoea in Group 3. Pearson Chi-square test showed significant difference between Group 1 and Group 3 (p = 0.038) and between Group 2 and Group 3 (p = 0.043). But there was no significant difference between Group 1 and Group 2 (p = 0.947). CONCLUSION: Chronic diarrhoea is a significant complication after limited hemicolectomy not only in Crohn's disease and short bowel syndrome. This is likely to originate from the loss of the ileocaecal valve itself rather than the loss of the ileal or colonic segment. Our results justify attempts to reconstruct the ileocaecal valve.

Diversity, distribution and biogeography of testate amoebae in China: implications for ecological studies in Asia.

Testate amoebae are a group of shelled protozoa that occur in high density populations in wet environments. More than 1900 testate amoebae species or subspecies have been reported in published literature over the last 200 years, from many regions of the world. Testate amoebae are classified as Lobosea or Filosea respectively, according to the presence of lobose or filiform pseudopodia. Testate amoebae have proved an interesting group of indicator organisms in palaeoenvironmental studies and have also been used as bioindicators of human impact on ecosystems. Until recently, the testate amoebae of China were unknown to most western scientists, but our knowledge has improved greatly over the past 20 years. This paper summarizes the testate amoebae research in China along with relevant data from other countries in Asia, and provides the necessary context for future research.

Is there a size limit for cosmopolitan distribution in free-living microorganisms? A biogeographical analysis of testate amoebae from polar areas.

A long-standing debate in microbial ecology is the extent to which free-living microorganisms exhibit cosmopolitan distributions. We use a comparison of testate amoebae communities in cold "polar" locations (Arctic, Antarctic, and Tibet) to investigate how a microorganism's size affects its probability of having a cosmopolitan distribution. We show that the probability a given taxa being reported in all three locations increases as testate size decreases. Likewise, excluding those testates found only in Tibet, very small testates (<20 microm) are more likely to occur in both the Arctic and Antarctic than in either of these poles alone. Attempting to correct for phylogeny reduces the number of statistically significant relationships--both because of decreased sample size and potentially real phylogenetic patterns, although some size-dependent effects were still apparent. In particular, taxa found in both the Arctic and Antarctic poles were significantly smaller than congeneric taxa found only in Tibet. This pattern may in part be due to habitat effects, with the Tibetan samples being more likely to have come from aquatic sites which may be more suitable for larger taxa. Overall, our analysis suggests that, at least within testate amoebae, a cosmopolitan distribution becomes increasingly common as median taxon size decreases.

Conservative management of bilateral Sertoli cell tumors of the testicle in association with the Carney complex: a case report.

Large cell calcifying Sertoli cell tumor of the testicle is a rare, hormonally active sex cord-stromal tumor seen in patients with Carney complex. When such tumors occur bilaterally, treatment options for preserving fertility and addressing the secondary effects of excess hormone production must be considered. The availability of specific antiestrogen drugs means that bilateral orchiectomy for this benign tumor may no longer be warranted. Testicular-sparing surgery and advances in reproductive technology may also improve the overall prognosis for fertility. Gynecomastia in prepubescent boys can be emotionally very distressing. Approximately two thirds of teenaged boys will develop some degree of breast enlargement that spontaneously regresses as testosterone levels rise (Ill Med J 1938;73:113). In all cases, a thorough history and physical examination are required to exclude nonphysiologic causes such as drugs, pulmonary disease, chronic liver disease, exogenous estrogens, and estrogen-producing tumors (Seashore J. Disorders of the breast. In: Rowe MI, O'Neill JA, Grosfeld JL et al, editors. Pediatric surgery, 5th ed. St Louis (MO): Mosby Year Book, 1998). We report on a child who presented with a 2-year history of gynecomastia with associated bilateral testicular swellings and discuss a novel treatment strategy for managing bilateral testicular tumors in the context of the Carney complex.

A genomic view of the sea urchin nervous system.

The sequencing of the Strongylocentrotus purpuratus genome provides a unique opportunity to investigate the function and evolution of neural genes. The neurobiology of sea urchins is of particular interest because they have a close phylogenetic relationship with chordates, yet a distinctive pentaradiate body plan and unusual neural organization. Orthologues of transcription factors that regulate neurogenesis in other animals have been identified and several are expressed in neurogenic domains before gastrulation indicating that they may operate near the top of a conserved neural gene regulatory network. A family of genes encoding voltage-gated ion channels is present but, surprisingly, genes encoding gap junction proteins (connexins and pannexins) appear to be absent. Genes required for synapse formation and function have been identified and genes for synthesis and transport of neurotransmitters are present. There is a large family of G-protein-coupled receptors, including 874 rhodopsin-type receptors, 28 metabotropic glutamate-like receptors and a remarkably expanded group of 161 secretin receptor-like proteins. Absence of cannabinoid, lysophospholipid and melanocortin receptors indicates that this group may be unique to chordates. There are at least 37 putative G-protein-coupled peptide receptors and precursors for several neuropeptides and peptide hormones have been identified, including SALMFamides, NGFFFamide, a vasotocin-like peptide, glycoprotein hormones and insulin/insulin-like growth factors. Identification of a neurotrophin-like gene and Trk receptor in sea urchin indicates that this neural signaling system is not unique to chordates. Several hundred chemoreceptor genes have been predicted using several approaches, a number similar to that for other animals. Intriguingly, genes encoding homologues of rhodopsin, Pax6 and several other key mammalian retinal transcription factors are expressed in tube feet, suggesting tube feet function as photosensory organs. Analysis of the sea urchin genome presents a unique perspective on the evolutionary history of deuterostome nervous systems and reveals new approaches to investigate the development and neurobiology of sea urchins.

Asymmetric reduction of alpha, beta-unsaturated ketone to (R) allylic alcohol by Candida chilensis.

A pilot scale whole cell process was developed for the enantioselective 1,2-reduction of prochiral alpha,beta-unsaturated ketone to (R) allylic alcohol using Candida chilensis. Initial development showed high enantiomeric excess (EE > 95%) but low product yield (10%). Process development, using a combination of statistically designed screening and optimization experiments, improved the desired alcohol yield to 90%. The fermentation growth stage, particularly medium composition and growth pH, had a significant impact on the bioconversion while process characterization identified diverse challenges including the presence of multiple enzymes, substrate/product toxicity, and biphasic cellular morphology. Manipulating the fermentation media allowed control of the whole cell morphology to a predominantly unicellular broth, away from the viscous pseudohyphae, which were detrimental to the bioconversion. The activity of a competing enzyme, which produced the undesired saturated ketone and (R) saturated alcohol, was minimized to < or =5% by controlling the reaction pH, temperature, substrate concentration, and biomass level. Despite the toxicity effects limiting the volumetric productivity, a reproducible and scaleable process was demonstrated at pilot scale with high enantioselectivity (EE > 95%) and overall yield greater than 80%. This was the preferred route compared to a partially purified process using ultra centrifugation, which led to improved volumetric productivity but reduced yield (g/day). The whole cell approach proved to be a valuable alternative to chemical reduction routes, as an intermediate step for the asymmetric synthesis of an integrin receptor antagonist for the inhibition of bone resorption and treatment of osteoporosis.

The fusiform face area is not sufficient for face recognition: evidence from a patient with dense prosopagnosia and no occipital face area.

We tested functional activation for faces in patient D.F., who following acquired brain damage has a profound deficit in object recognition based on form (visual form agnosia) and also prosopagnosia that is undocumented to date. Functional imaging demonstrated that like our control observers, D.F. shows significantly more activation when passively viewing face compared to scene images in an area that is consistent with the fusiform face area (FFA) (p < 0.01). Control observers also show occipital face area (OFA) activation; however, whereas D.F.'s lesions appear to overlap the OFA bilaterally. We asked, given that D.F. shows FFA activation for faces, to what extent is she able to recognize faces? D.F. demonstrated a severe impairment in higher level face processing--she could not recognize face identity, gender or emotional expression. In contrast, she performed relatively normally on many face categorization tasks. D.F. can differentiate faces from non-faces given sufficient texture information and processing time, and she can do this is independent of color and illumination information. D.F. can use configural information for categorizing faces when they are presented in an upright but not a sideways orientation and given that she also cannot discriminate half-faces she may rely on a spatially symmetric feature arrangement. Faces appear to be a unique category, which she can classify even when she has no advance knowledge that she will be shown face images. Together, these imaging and behavioral data support the importance of the integrity of a complex network of regions for face identification, including more than just the FFA--in particular the OFA, a region believed to be associated with low-level processing.

Recognizing partially visible objects.

In two experiments we measured object recognition performance as a function of delay. In Experiment 1 we presented half of an image of an object, and then the other half after a variable delay. Objects were subdivided into top versus bottom halves, left versus right halves, or vertical strips. In Experiment 2 we separated the low (LSF) and high spatial frequency (HSF) components of an image, and presented one component followed by the other after a variable delay. For both experiments, performance was worse with a 105ms delay between the presentations of the object components than when the two components were presented simultaneously. These results are consistent with predictions made by models that combine information at a relatively early stage in processing. In addition, the results revealed that object recognition performance is significantly better when the LSF sub-image preceded the HSF sub-image than when the HSF sub-image preceded the LSF sub-image, consistent with previous work suggesting that LSF information is processed prior to HSF in object recognition.