Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Perioperative patient safety indicators-A Delphi study.

AIM: To identify, define and achieve consensus on perioperative patient safety indicators within a Swedish context. DESIGN: A modified Delphi method. METHODS: A purposeful sample of 22 experts, all experienced operating room nurse specialists, was recruited for this study. A questionnaire was constructed incorporating statements derived from a preceding study. The experts were asked to rate the importance of each statement concerning patient safety during the perioperative phase. The data collection occurred through an online survey platform between November 2022 and April 2023. The CREDES checklist guided the reporting of this study. RESULTS: The three-round Delphi study resulted in consensus on 73 statements out of 103, encompassing 74% process indicators and 26% structure indicators. Key areas of consensus included the use of the Surgical Safety Checklist and optimizing the operating room environment. CONCLUSION: Consensus was reached on perioperative safety indicators, underscoring the intricate challenges involved in ensuring patient safety in the operating room. It emphasizes the important integration of both structure and process indicators for comprehensive safety assessment during surgical procedures. Recognizing the difficulty in measuring factors like teamwork and communication, essential for patient safety, the study offers practical guidance. It underlines a balanced approach and specific consensus areas applicable in clinical practice to enhance perioperative patient safety. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: This study provides concrete practice guidance and establishes a structured framework for evaluating perioperative care processes. It emphasizes the critical role of professionals having the necessary skills and being present during surgical procedures. Additionally, the study underscores the paramount importance of effective communication and teamwork within the operating room team, substantively contributing to overall patient safety enhancement. IMPACT: The study focused on addressing the challenge of ensuring patient safety in operating rooms, acknowledging the persistent complications related to surgery despite global efforts to eliminate avoidable harm in healthcare. Consensus was reached on 73 crucial indicators for perioperative patient safety, emphasizing a balanced approach integrating both process and structure indicators for a comprehensive assessment of safety during surgical procedures. The study has a broad impact on professionals and healthcare systems, providing concrete guidance for practice and offering a structured process for evaluating perioperative care. REPORTING METHOD: The study is reported informed by 'Guidance on Conducting and REporting DElphi Studies (CREDES) in palliative care: Recommendations derived from a methodological systematic review'. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

Effects of an advanced first aid course or real-time video communication with ambulance personnel on layperson first response for building-site severe injury events: a simulation study.

BACKGROUND: The risk of high-energy trauma injuries on construction sites is relatively high. A delayed response time could affect outcomes after severe injury. This study assessed if an advanced first aid course for first aid response for laypersons (employees or apprentices) in the construction industry or real-time video communication and support with ambulance personnel, or neither, together with access to an advanced medical kit, would have an effect on immediate layperson vital responses in a severe injury scenario. METHOD: This was a controlled simulation study. Employees or apprentices at a construction site were recruited and randomly allocated into a group with video support or not, and advanced first aid course or not, and where one group had both. The primary outcomes were correct behavior to recognize and manage an occluded airway and correct behavior to stop life-threatening bleeding from a lower extremity injury. Secondary outcomes included head-to-toe assessment performed, placement of a pelvic sling, and application of remote vital signs monitors. RESULTS: Ninety participants were included in 10 groups of 3 for each of 4 exposures. One group was tested first as a baseline group, and then later after having done the training course. Live video support was effective in controlling bleeding. A first aid course given beforehand did not seem to be as effective on controlling bleeding. Video support and the first aid course previously given improved the ability of bystanders to manage the airway, the combination of the two being no better than each of the interventions taken in isolation. Course exposure and video support together were not superior to the course by itself or video by itself, except regarding placing the biosensors on the injured after video support. Secondary results showed an association between video support and completing a head-to-toe assessment. Both interventions were associated with applying a pelvic sling. CONCLUSION: These findings show that laypersons, here construction industry employees, can be supported to achieve good performance as first responders in a major injury scenario. Prior training, but especially live video support without prior training, improves layperson performance in this setting.

Longer work experience and age associated with safety attitudes in operating room nurses: an online cross-sectional study.

BACKGROUND: Patient safety is fundamental when providing care in the operating room. Still, adverse events and errors are a challenge for patient safety worldwide. To avoid preventable patient harm, organisations need a positive safety culture, the measurable component of which is known as the safety climate. To best improve the safety climate the current attitudes to safety must first be understood. AIM: To explore operating room nurses' safety attitudes and their views on how to improve patient safety in operating rooms. METHOD: A cross-sectional study using the Swedish-translated version of the Safety Attitudes Questionnaire, Operating Room version. Data were collected using an online survey platform. RESULTS: 358 operating room nurses completed the questionnaire. The results show that the older age group rated their working conditions and management support as better than the younger age groups. The older age group also rated their stress recognition as lower compared with the younger age groups. The same pattern was seen in terms of work experience, with more-experienced respondents showing a higher mean score for the factor working conditions and a lower mean score for the factor stress recognition as compared with their less-experienced colleagues. When comparing hospital types, county hospital employees had higher factor scores for safety climate, job satisfaction and working conditions than university hospital employees. The respondents' most recurring recommendations for improving patient safety were 'Having better and clearer communication' followed by 'Having enough time to do things the way they should be done'. CONCLUSION: More focus on safety with increasing age and experience was observed in this cohort. Need for improvements is reported for patient safety in operating rooms, mainly when it comes to communication and workload. To improve and develop patient safety in the operating room, the organisational safety climate needs to be actively managed and developed. One step in actively managing the safety climate may be efforts to retain experienced operating room nurses.

Cerebral Blood Flow Assessed with Phase-contrast Magnetic Resonance Imaging during Blood Pressure Changes with Noradrenaline and Labetalol: A Trial in Healthy Volunteers.

BACKGROUND: Adequate cerebral perfusion is central during general anesthesia. However, perfusion is not readily measured bedside. Clinicians currently rely mainly on mean arterial pressure (MAP) as a surrogate, even though the relationship between blood pressure and cerebral blood flow is not well understood. The aim of this study was to apply phase-contrast magnetic resonance imaging to characterize blood flow responses in healthy volunteers to commonly used pharmacologic agents that increase or decrease arterial blood pressure. METHODS: Eighteen healthy volunteers aged 30 to 50 yr were investigated with phase-contrast magnetic resonance imaging. Intra-arterial blood pressure monitoring was used. First, intravenous noradrenaline was administered to a target MAP of 20% above baseline. After a wash-out period, intravenous labetalol was given to a target MAP of 15% below baseline. Cerebral blood flow was measured using phase-contrast magnetic resonance imaging and defined as the sum of flow in the internal carotid arteries and vertebral arteries. Cardiac output (CO) was defined as the flow in the ascending aorta. RESULTS: Baseline median cerebral blood flow was 772 ml/min (interquartile range, 674 to 871), and CO was 5,874 ml/min (5,199 to 6,355). The median dose of noradrenaline was 0.17 µg · kg-1 · h-1 (0.14 to 0.22). During noradrenaline infusion, cerebral blood flow decreased to 705 ml/min (606 to 748; P = 0.001), and CO decreased to 4,995 ml/min (4,705 to 5,635; P = 0.01). A median dose of labetalol was 120 mg (118 to 150). After labetalol boluses, cerebral blood flow was unchanged at 769 ml/min (734 to 900; P = 0.68). CO increased to 6,413 ml/min (6,056 to 7,464; P = 0.03). CONCLUSIONS: In healthy, awake subjects, increasing MAP using intravenous noradrenaline decreased cerebral blood flow and CO. These data do not support inducing hypertension with noradrenaline to increase cerebral blood flow. Cerebral blood flow was unchanged when decreasing MAP using labetalol.

Organ aging signatures in the plasma proteome track health and disease.

Animal studies show aging varies between individuals as well as between organs within an individual1-4, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20-50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer's disease (AD) progression independently from and as strongly as plasma pTau-181 (ref. 5), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.

APOE4/4 is linked to damaging lipid droplets in Alzheimer's microglia.

Several genetic risk factors for Alzheimer's Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aß (fAß) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

Preoperative anxiety level is not associated with postoperative negative behavioral changes in premedicated children.

BACKGROUND: Anesthesia preinduction anxiety in children can according to some studies lead to long-term anxiety and negative behavioral changes (NBC), while other studies have not found this effect. This secondary analysis from a recent premedication trial comparing clonidine and midazolam aimed to test the relation between preoperative anxiety assessed with modified Yale Preoperative Anxiety Scale (mYPAS) and postoperative NBCs assessed with Post Hospital Behavior Questionnaire (PHBQ), regardless of premedication type. METHODS: This is a planned secondary analysis from a published premedication comparison trial in an outpatient surgery cohort, children aged 2-7 years. Participant and preoperative factors, particularly preoperative anxiety as mYPAS scores, were assessed for association with development of postoperative NBCs. RESULTS: Fifty-four of the 115 participants had high preinduction anxiety (mYPAS >30), and 19 of 115 developed >3 postoperative NBCs 1 week after surgery. There was no association between preinduction anxiety level as mYPAS scores and the development of postoperative NBCs at 1 week after surgery (10 of 19 had both, p = .62) nor after 4- or 26-weeks post-surgery. Only lower age was associated with development of NBCs postoperatively. CONCLUSIONS: Based on the findings from this cohort, high preinduction anxiety does not appear to be associated with NBCs postoperatively in children premedicated with clonidine or midazolam.

Left atrial contraction strain during a Valsalva manoeuvre: A study in healthy humans.

BACKGROUND: Cardiac mechanics are influenced by loading conditions as well as sympathetic tone. Left atrial (LA) contractile function assessed by two-dimensional (2D) strain has been described in the setting of controlled preload alterations; however, studies show conflicting findings about change or direction of change. We hypothesized that the controlled preload reduction and the sympathetic nervous system activation that occurs during a standardized Valsalva manoeuvre would bring about a change in LA contraction strain. METHODS: Healthy young adults of both sexes were recruited. Transthoracic echocardiographic ultrasound images were collected before and during a Valsalva manoeuvre. Standard imaging windows for LA strain assessment were used and the images were copied and stored for later offline analysis. These were assessed for adequate atrial wall visualization in 2D strain assessment. Paired comparisons were carried out using Student's T test. RESULT: Thirty-eight participants were included and there were 22 complete studies with paired pre- and during Valsalva manoeuvre. LA contraction strain at baseline was 10.5 ± 2.8% (standard deviation) and during the Valsalva manoeuvre 10.6 ± 4.6%, p = 0.86. CONCLUSION: The Valsalva manoeuvre, a combination of preload reduction and sympathetic nervous system activation, seems not to be associated with a change in LA contraction strain in healthy young individuals. LA contraction strain should be interpreted in the context of both atrial loading conditions and prevailing autonomic nervous system activity.

Surface microdialysis measures local tissue metabolism after Ivor Lewis esophagectomy; an attempt to predict anastomotic defect.

Anastomotic defect (AD) after esophagectomy can lead to severe complications with need for surgical or endoscopic intervention. Early detection enables early treatment and can limit the consequences of the AD. As of today, there are limited methods to predict AD. In this study, we have used microdialysis (MD) to measure local metabolism at the intrathoracic anastomosis. Feasibility and possible diagnostic use were investigated. Sixty patients planned for Ivor Lewis esophagectomy were enrolled. After construction of the anastomosis, surface MD (S-MD) probes were attached to the outer surface of the esophageal remnant and the gastric conduit in close vicinity of the anastomosis and left in place for 7 postoperative days (PODs). Continuous sampling of local tissue concentrations of metabolic substances (glucose, lactate, and pyruvate) was performed postoperatively. Outcome, defined as AD or not according to Esophagectomy Complications Consensus Group definitions, was recorded at discharge or at first postoperative follow up. Difference in concentrations of metabolic substances was analyzed retrospectively between the two groups by means of artificial neural network technique. S-MD probes can be attached and removed from the gastric tube reconstruction without any adverse events. Deviating metabolite concentrations on POD 1 were associated with later development of AD. In subjects who developed AD, no difference in metabolic concentrations between the esophageal and the gastric probe was recorded. The technical failure rate of the MD probes/procedure was high. S-MD can be used in a clinical setting after Ivor Lewis esophagectomy. Deviation in local tissue metabolism on POD 1 seems to be associated with development of AD. Further development of MD probes and procedure is required to reduce technical failure.

Young CSF restores oligodendrogenesis and memory in aged mice via Fgf17.

Recent understanding of how the systemic environment shapes the brain throughout life has led to numerous intervention strategies to slow brain ageing1-3. Cerebrospinal fluid (CSF) makes up the immediate environment of brain cells, providing them with nourishing compounds4,5. We discovered that infusing young CSF directly into aged brains improves memory function. Unbiased transcriptome analysis of the hippocampus identified oligodendrocytes to be most responsive to this rejuvenated CSF environment. We further showed that young CSF boosts oligodendrocyte progenitor cell (OPC) proliferation and differentiation in the aged hippocampus and in primary OPC cultures. Using SLAMseq to metabolically label nascent mRNA, we identified serum response factor (SRF), a transcription factor that drives actin cytoskeleton rearrangement, as a mediator of OPC proliferation following exposure to young CSF. With age, SRF expression decreases in hippocampal OPCs, and the pathway is induced by acute injection with young CSF. We screened for potential SRF activators in CSF and found that fibroblast growth factor 17 (Fgf17) infusion is sufficient to induce OPC proliferation and long-term memory consolidation in aged mice while Fgf17 blockade impairs cognition in young mice. These findings demonstrate the rejuvenating power of young CSF and identify Fgf17 as a key target to restore oligodendrocyte function in the ageing brain.

Plasma and bronchoalveolar lavage fluid oxylipin levels in experimental porcine lung injury.

Inflammatory signaling pathways involving eicosanoids and other regulatory lipid mediators are a subject of intensive study, and a role for these in acute lung injury is not yet well understood. We hypothesized that oxylipin release from lung injury could be detected in bronchoalveolar lavage fluid and in plasma. In a porcine model of surfactant depletion, ventilation with hyperinflation was assessed. Bronchoalveolar lavage and plasma samples were analyzed for 37 different fatty acid metabolites (oxylipins). Over time, hyperinflation altered concentrations of 4 oxylipins in plasma (TXB2, PGE2, 15-HETE and 11-HETE), and 9 oxylipins in bronchoalveolar lavage fluid (PGF2α, PGE2, PGD2, 12,13-DiHOME, 11,12-DiHETrE, 13-HODE, 9-HODE, 15-HETE, 11-HETE). Acute lung injury caused by high tidal volume ventilation in this porcine model was associated with rapid changes in some elements of the oxylipin profile, detectable in lavage fluid, and plasma. These oxylipins may be relevant in the pathogenesis of acute lung injury by hyperinflation.

Left atrial contraction strain and controlled preload alterations, a study in healthy individuals.

BACKGROUND: In order to assess left atrial contractile function in disturbed circulatory conditions, it is necessary to have a clear understanding of how it behaves in a normal resting state with changes in loading conditions. However, currently the understanding of this relationship is incomplete. We hypothesize that in healthy individuals, left atrial contraction strain and its peak strain rate are increased or decreased by increasing or decreasing preload, respectively. METHODS: Controlled maneuvers used to change preload included continuous positive airway pressure by mask (CPAP 20 cmH2O) for preload decrease, and passive leg raise (15 degrees angle) for preload increase. Cardiac ultrasound 4-chamber views of the left atria and left ventricle were acquired at baseline and during maneuver. Acquired images were post processed and analyzed offline. Comparisons were made using paired t-test and means with 95% confidence interval. RESULTS: There were 38 participants, complete results were obtained from 23 in the CPAP maneuver and 27 in the passive leg raise maneuver. For the CPAP group, left atrial contraction strain was 11.6% (10.1 to 13.1) at baseline and 12.8% (11.0 to 14.6) during the maneuver (p = 0.16). Left atrial contraction peak strain rate was - 1.7 s- 1 (- 1.8 to - 1.5) at baseline and - 1.8 s- 1 (- 2.0 to - 1.6) during the maneuver (p = 0.29). For the passive leg raise-group, left atrial contraction strain was 10.1% (9.0 to 11.2) at baseline and 10.8% (9.4 to 12.3) during the maneuver (p = 0.28). Left atrial contraction peak strain rate was - 1.5 s- 1 (- 1.6 to - 1.4) at baseline and - 1.6 s- 1 (- 1.8 to - 1.5) during the maneuver (p = 0.29). Left atrial area, an indicator of preload, increased significantly during passive leg raise and decreased during CPAP. CONCLUSION: In healthy individuals, left atrial contraction strain and its peak strain rate seem to be preload-independent. TRIAL REGISTRATION: The study was 2018-02-19 registered at clinicaltrials.gov ( NCT03436030 ).

Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration.

SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for breaking down biomolecules and recycling their constitutive parts. In this work, we find that the antiinflammatory and neuroprotective compound, discovered via a phenotypic screen, imparts its beneficial effects by targeting the lysosome and restoring its function. This is established using a genome-wide CRISPRi target identification screen and then confirmed using a variety of lysosome-targeted studies. The resulting small molecule from this study represents a potential treatment for neurodegenerative diseases as well as a research tool for the study of lysosomes in disease.

Respiratory and circulatory insufficiency during emergent long-distance critical care interhospital transports to tertiary care in a sparsely populated region: a retrospective analysis of late mortality risk.

OBJECTIVES: To test if impaired oxygenation or major haemodynamic instability at the time of emergency intensive care transport, from a smaller admitting hospital to a tertiary care centre, are predictors of long-term mortality. DESIGN: Retrospective observational study. Impaired oxygenation was defined as oxyhaemoglobin %-inspired oxygen fraction ratio (S/F ratio)<100. Major haemodynamic instability was defined as a need for treatment with norepinephrine infusion to sustain mean arterial pressure (MAP) at or above 60 mm Hg or having a mean MAP <60. Logistic regression was used to assess mortality risk with impaired oxygenation or major haemodynamic instability. SETTING: Sparsely populated Northern Sweden. A fixed-wing interhospital air ambulance system for critical care serving 900 000 inhabitants. PARTICIPANTS: Intensive care cases transported in fixed-wing air ambulance from outlying hospitals to a regional tertiary care centre during 2000-2016 for adults (16 years old or older). 2142 cases were included. PRIMARY AND SECONDARY OUTCOME MEASURES: All-cause mortality at 3 months after transport was the primary outcome, and secondary outcomes were all-cause mortality at 1 and 7 days, 1, 6 and 12 months. RESULTS: S/F ratio <100 was associated with increased mortality risk compared with S/F>300 at all time-points, with adjusted OR 6.3 (2.5 to 15.5, p<0.001) at 3 months. Major haemodynamic instability during intensive care unit (ICU) transport was associated with increased adjusted OR of all-cause mortality at 3 months with OR 2.5 (1.8 to 3.5, p<0.001). CONCLUSION: Major impairment of oxygenation and/or major haemodynamic instability at the time of ICU transport to get to urgent tertiary intervention is strongly associated with increased mortality risk at 3 months in this cohort. These findings support the conclusion that these conditions are markers for many fold increase in risk for death notable already at 3 months after transport for patients with these conditions.