Exploring the relationship of sleep, cognition, and cortisol in sickle cell disease

Background: Neurocognitive impairment is common in people with Sickle Cell Disease (SCD) and evidence is accumulating that sleep disturbances play a role. The interaction between cortisol and sleep in the general population is associated with cognition as well as general wellbeing but there are few data in SCD. We aimed to understand the relationship between cortisol and sleep in individuals with SCD and explored associations with cognition. Methods: Forty-five participants of black heritage (SCD: N = 27, 9–29 years, 16 females; Controls: N = 18, 11–25 years, 13 females) were recruited from the community between 2018 - 2020. Participants completed standardized questionnaires about their sleep behaviour and wore actigraphy MotionWatch8 for 7 nights to assess nocturnal sleep patterns. Salivary cortisol samples were taken on wakening and 3 times after 14:00. Cognition was assessed using the Wechsler Intelligence Scales for children and adults. Results: People with SCD took longer to fall asleep and experienced greater wake bouts, mobile minutes and fragmented sleep compared to controls. Although non-significant, people with SCD experienced lower morning cortisol, with a flattened diurnal cortisol ratio compared to controls. Interestingly, SCD participants, but not controls, with low diurnal variation scored lowest on processing speed (PSI) and perceptual reasoning index (PRI). A moderator analysis revealed that the effect of morning cortisol and diurnal cortisol ratio on PRI by group health (i.e., SCD and healthy controls) depended on sleep quality. Discussion: Sleep and cortisol may play a crucial role in the expression of cognitive difficulties seen in SCD. This should be considered for the development of interventions to optimise cognitive functioning and sleep. This, in turn, could positively impact on secretion of cortisol and general health in SCD

The open future, bivalence and assertion

It is highly intuitive that the future is open and the past is closed—whereas it is unsettled whether there will be a fourth world war, it is settled that there was a first. Recently, it has become increasingly popular to claim that the intuitive openness of the future implies that contingent statements about the future, such as ‘there will be a sea battle tomorrow,’ are non-bivalent (neither true nor false). In this paper, we argue that the non-bivalence of future contingents is at odds with our pre-theoretic intuitions about the openness of the future. These are revealed by our pragmatic judgments concerning the correctness and incorrectness of assertions of future contingents. We argue that the pragmatic data together with a plausible account of assertion shows that in many cases we take future contingents to be true (or to be false), though we take the future to be open in relevant respects. It follows that appeals to intuition to support the non-bivalence of future contingents is untenable. Intuition favours bivalence

Further insights from structural mass spectrometry into endocytosis adaptor protein assemblies

As a fundament in many biologically relevant processes, endocytosis in its different guises has been arousing interest for decades and still does so. This is true for the actual transport and its initiation alike. In clathrin-mediated endocytosis, a comparatively well understood endocytic pathway, a set of adaptor proteins bind specific lipids in the plasma membrane, subsequently assemble and thus form a crucial bridge from clathrin to actin for the ongoing process. These adaptor proteins are highly interesting themselves and the subject of this manuscript. Using many of the instruments that are available now in the mass spectrometry toolbox, we added some facets to the picture of how these minimal assemblies may look, how they form, and what influences the structure. Especially, lipids in the adaptor protein complexes result in reduced charging of a normal sized complex due to their specific binding position. The results further support our structural model of a double ring structure with interfacial lipids

Dialetheism in Action: A New Strategy for Solving the Equal Validity Paradox

This paper starts from the Equal Validity Paradox, a paradoxical argument connected to the so-called phenomenon of faultless disagreement. It is argued that there are at least six strategies for solving the paradox. After presenting the first five strategies and their main problems, the paper focuses on the sixth strategy which rejects the assumption that every proposition cannot be both true a false. Dialetheism is the natural candidate for developing strategy six. After presenting strategy six in detail, we formulate a normative problem for the dialetheist and offer a tentative solution to it. We then elaborate further considerations connecting strategy six to pluralism about truth and logic. Even if strategy six is a hard path to take, its scrutiny highlights some important points on truth, logic and the norms for acceptance and rejection

Editor's Choice - Infective Native Aortic Aneurysms: A Delphi Consensus Document on Terminology, Definition, Classification, Diagnosis, and Reporting Standards.

There is no consensus regarding the terminology, definition, classification, diagnostic criteria, and algorithm, or reporting standards for the disease of infective native aortic aneurysm (INAA), previously known as mycotic aneurysm. The aim of this study was to establish this by performing a consensus study. The Delphi methodology was used. Thirty-seven international experts were invited via mail to participate. Four two week Delphi rounds were performed, using an online questionnaire, initially with 22 statements and nine reporting items. The panellists rated the statements on a five point Likert scale. Comments on statements were analysed, statements revised, and results presented in iterative rounds. Consensus was defined as ≥ 75% of the panel selecting "strongly agree" or "agree" on the Likert scale, and consensus on the final assessment was defined as Cronbach's alpha coefficient > .80. All 38 panellists completed all four rounds, resulting in 100% participation and agreement that this study was necessary, and the term INAA was agreed to be optimal. Three more statements were added based on the results and comments of the panel, resulting in a final 25 statements and nine reporting items. All 25 statements reached an agreement of ≥ 87%, and all nine reporting items reached an agreement of 100%. The Cronbach's alpha increased for each consecutive round (round 1 = .84, round 2 = .87, round 3 = .90, and round 4 = .92). Thus, consensus was reached for all statements and reporting items. This Delphi study established the first consensus document on INAA regarding terminology, definition, classification, diagnostic criteria, and algorithm, as well as reporting standards. The results of this study create essential conditions for scientific research on this disease. The presented consensus will need future amendments in accordance with newly acquired knowledge

Comparison of single- and multistage strategies during fenestrated-branched endovascular aortic repair of thoracoabdominal aortic aneurysms

Objective: The aim of this study was to compare outcomes of single or multistage approach during fenestrated-branched endovascular aortic repair (FB-EVAR) of extensive thoracoabdominal aortic aneurysms (TAAAs). Methods: We reviewed the clinical data of consecutive patients treated by FB-EVAR for extent I to III TAAAs in 24 centers (2006-2021). All patients received a single brand manufactured patient-specific or off-the-shelf fenestrated-branched stent grafts. Staging strategies included proximal thoracic aortic repair, minimally invasive segmental artery coil embolization, temporary aneurysm sac perfusion and combinations of these techniques. Endpoints were analyzed for elective repair in patients who had a single- or multistage approach before and after propensity score adjustment for baseline differences, including the composite 30-day/in-hospital mortality and/or permanent paraplegia, major adverse event, patient survival, and freedom from aortic-related mortality. Results: A total of 1947 patients (65% male; mean age, 71 ± 8 years) underwent FB-EVAR of 155 extent I (10%), 729 extent II (46%), and 713 extent III TAAAs (44%). A single-stage approach was used in 939 patients (48%) and a multistage approach in 1008 patients (52%). A multistage approach was more frequently used in patients undergoing elective compared with non-elective repair (55% vs 35%; P < .001). Staging strategies were proximal thoracic aortic repair in 743 patients (74%), temporary aneurysm sac perfusion in 128 (13%), minimally invasive segmental artery coil embolization in 10 (1%), and combinations in 127 (12%). Among patients undergoing elective repair (n = 1597), the composite endpoint of 30-day/in-hospital mortality and/or permanent paraplegia rate occurred in 14% of single-stage and 6% of multistage approach patients (P < .001). After adjustment with a propensity score, multistage approach was associated with lower rates of 30-day/in-hospital mortality and/or permanent paraplegia (odds ratio, 0.466; 95% confidence interval, 0.271-0.801; P = .006) and higher patient survival at 1 year (86.9±1.3% vs 79.6±1.7%) and 3 years (72.7±2.1% vs 64.2±2.3%; adjusted hazard ratio, 0.714; 95% confidence interval, 0.528-0.966; P = .029), compared with a single stage approach. Conclusions: Staging elective FB-EVAR of extent I to III TAAAs was associated with decreased risk of mortality and/or permanent paraplegia at 30 days or within hospital stay, and with higher patient survival at 1 and 3 years

Exome reanalysis and proteomic profiling identified TRIP4 as a novel cause of cerebellar hypoplasia and spinal muscular atrophy (PCH1)

TRIP4 is one of the subunits of the transcriptional coregulator ASC-1, a ribonucleoprotein complex that participates in transcriptional coactivation and RNA processing events. Recessive variants in the TRIP4 gene have been associated with spinal muscular atrophy with bone fractures as well as a severe form of congenital muscular dystrophy. Here we present the diagnostic journey of a patient with cerebellar hypoplasia and spinal muscular atrophy (PCH1) and congenital bone fractures. Initial exome sequencing analysis revealed no candidate variants. Reanalysis of the exome data by inclusion in the Solve-RD project resulted in the identification of a homozygous stop-gain variant in the TRIP4 gene, previously reported as disease-causing. This highlights the importance of analysis reiteration and improved and updated bioinformatic pipelines. Proteomic profile of the patient’s fibroblasts showed altered RNA-processing and impaired exosome activity supporting the pathogenicity of the detected variant. In addition, we identified a novel genetic form of PCH1, further strengthening the link of this characteristic phenotype with altered RNA metabolism

Aorto-bronchial and aorto-pulmonary fistulation after thoracic endovascular aortic repair: an analysis from the European Registry of Endovascular Aortic Repair Complications.

OBJECTIVES: To learn upon incidence, underlying mechanisms and effectiveness of treatment strategies in patients with central airway and pulmonary parenchymal aorto-bronchial fistulation after thoracic endovascular aortic repair (TEVAR). METHODS: Analysis of an international multicentre registry (European Registry of Endovascular Aortic Repair Complications) between 2001 and 2012 with a total caseload of 4680 TEVAR procedures (14 centres). RESULTS: Twenty-six patients with a median age of 70 years (interquartile range: 60-77) (35% female) were identified. The incidence of either central airway (aorto-bronchial) or pulmonary parenchymal (aorto-pulmonary) fistulation (ABPF) in the entire cohort after TEVAR in the study period was 0.56% (central airway 58%, peripheral parenchymal 42%). Atherosclerotic aneurysm formation was the leading indication for TEVAR in 15 patients (58%). The incidence of primary endoleaks after initial TEVAR was n = 10 (38%), of these 80% were either type I or type III endoleaks. Fourteen patients (54%) developed central left bronchial tree lesions, 11 patients (42%) pulmonary parenchymal lesions and 1 patient (4%) developed a tracheal lesion. The recognized mechanism of ABPF was external compression of the bronchial tree in 13 patients (50%), the majority being due to endoleak formation, further ischaemia due to extensive coverage of bronchial feeding arteries in 3 patients (12%). Inflammation and graft erosion accounted for 4 patients (30%) each. Cumulative survival during the entire study period was 39%. Among deaths, 71% were attributed to ABPF. There was no difference in survival in patients having either central airway or pulmonary parenchymal ABPF (33 vs 45%, log-rank P = 0.55). Survival with a radical surgical approach was significantly better when compared with any other treatment strategy in terms of overall survival (63 vs 32% and 63 vs 21% at 1 and 2 years, respectively), as well as in terms of fistula-related survival (63 vs 43% and 63 vs 43% at 1 and 2 years, respectively). CONCLUSIONS: ABPF is a rare but highly lethal complication after TEVAR. The leading mechanism behind ABPF seems to be a continuing external compression of either the bronchial tree or left upper lobe parenchyma. In this setting, persisting or newly developing endoleak formation seems to play a crucial role. Prognosis does not differ in patients with central airway or pulmonary parenchymal fistulation. Radical bronchial or pulmonary parenchymal repair in combination with stent graft removal and aortic reconstruction seems to be the most durable treatment strategy

Impact of early enteral versus parenteral nutrition on mortality in patients requiring mechanical ventilation and catecholamines: study protocol for a randomized controlled trial (NUTRIREA-2)

BACKGROUND: Nutritional support is crucial to the management of patients receiving invasive mechanical ventilation (IMV) and the most commonly prescribed treatment in intensive care units (ICUs). International guidelines consistently indicate that enteral nutrition (EN) should be preferred over parenteral nutrition (PN) whenever possible and started as early as possible. However, no adequately designed study has evaluated whether a specific nutritional modality is associated with decreased mortality. The primary goal of this trial is to assess the hypothesis that early first-line EN, as compared to early first-line PN, decreases day 28 all-cause mortality in patients receiving IMV and vasoactive drugs for shock. METHODS/DESIGN: The NUTRIREA-2 study is a multicenter, open-label, parallel-group, randomized controlled trial comparing early PN versus early EN in critically ill patients requiring IMV for an expected duration of at least 48 hours, combined with vasoactive drugs, for shock. Patients will be allocated at random to first-line PN for at least 72 hours or to first-line EN. In both groups, nutritional support will be started within 24 hours after IMV initiation. Calorie targets will be 20 to 25 kcal/kg/day during the first week, then 25 to 30 kcal/kg/day thereafter. Patients receiving PN may be switched to EN after at least 72 hours in the event of shock resolution (no vasoactive drugs for 24 consecutive hours and arterial lactic acid level below 2 mmol/L). On day 7, all patients receiving PN and having no contraindications to EN will be switched to EN. In both groups, supplemental PN may be added to EN after day 7 in patients with persistent intolerance to EN and inadequate calorie intake. We plan to recruit 2,854 patients at 44 participating ICUs. DISCUSSION: The NUTRIREA-2 study is the first large randomized controlled trial designed to assess the hypothesis that early EN improves survival compared to early PN in ICU patients. Enrollment started on 22 March 2013 and is expected to end in November 2015. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01802099 (registered 27 February 2013)