Evaluation of the quality of COVID-19 guidance documents in anaesthesia using the Appraisal of Guidelines for Research and Evaluation II instrument.

BACKGROUND: Guidance documents are a valuable resource to clinicians to guide evidenced-based decision making. The quality of guidelines in anaesthesia and across other specialties has been demonstrated to be poor. COVID-19 presented an urgent need for immediate guidance for anaesthetists as frontline clinicians. The aim of this study was to evaluate the quality of COVID-19 guidance documents using the internationally validated Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. METHODS: A search was conducted in Ovid EMBASE and Ovid MEDLINE to identify all COVID-19 anaesthesia guidance documents from 2020-2021. Thirty-eight guidance documents were selected for analysis by 4 independent appraisers using the AGREE II instrument, across its 6 domains and 23 items. A scoring threshold for high quality was agreed by the working group via consensus. RESULTS: Overall, the body of COVID-19 guidance documents achieved poor scores using AGREE II. Only 5% of documents met the high-quality criteria. Markers of quality included international and multi-institutional collaboration. Document title ('guideline' vs 'consensus statement'/ 'recommendations') did not yield any differences in domain scores and overall quality ratings. Compared with recent general anaesthesia guidelines, COVID-19 guidelines performed significantly worse. CONCLUSIONS: COVID-19 guidance documents published during the first two years of the pandemic lacked rigour and appropriate quality. This raises concern about their trustworthiness for use in clinical practice. Enhanced systems are required to ensure the integrity of rapidly formulated guidance.

Control of osteocyte dendrite formation by Sp7 and its target gene osteocrin.

Some osteoblasts embed within bone matrix, change shape, and become dendrite-bearing osteocytes. The circuitry that drives dendrite formation during "osteocytogenesis" is poorly understood. Here we show that deletion of Sp7 in osteoblasts and osteocytes causes defects in osteocyte dendrites. Profiling of Sp7 target genes and binding sites reveals unexpected repurposing of this transcription factor to drive dendrite formation. Osteocrin is a Sp7 target gene that promotes osteocyte dendrite formation and rescues defects in Sp7-deficient mice. Single-cell RNA-sequencing demonstrates defects in osteocyte maturation in the absence of Sp7. Sp7-dependent osteocyte gene networks are associated with human skeletal diseases. Moreover, humans with a SP7R316C mutation show defective osteocyte morphology. Sp7-dependent genes that mark osteocytes are enriched in neurons, highlighting shared features between osteocytic and neuronal connectivity. These findings reveal a role for Sp7 and its target gene Osteocrin in osteocytogenesis, revealing that pathways that control osteocyte development influence human bone diseases.

Variation in Patient-Reported Advance Care Preferences in the Preoperative Setting.

BACKGROUND: High-quality shared decision-making for patients undergoing elective surgical procedures includes eliciting patient goals and treatment preferences. This is particularly important, should complications occur and life-sustaining therapies be considered. Our objective was to determine the preoperative care preferences of older higher-risk patients undergoing elective procedures and to determine any factors associated with a preference for limitations to life-sustaining treatments. METHODS: Cross-sectional survey conducted between May and December 2018. Patients ≥55 years of age presenting for a preprocedural evaluation in a high-risk anesthesia clinic were queried on their desire for life-sustaining treatments (cardiopulmonary resuscitation, mechanical ventilation, dialysis, and artificial nutrition) as well as tolerance for declines in health states (physical disability, cognitive disability, and daily severe pain). RESULTS: One hundred patients completed the survey. The median patient age was 68. Most patients were Caucasian (87%) and had an American Society of Anesthesiologists (ASA) score of III (88%). The majority of patients (89%) desired cardiopulmonary resuscitation. However, most patients would not accept mechanical ventilation, dialysis, or artificial nutrition for an indefinite period of time. Similarly, most patients (67%-81%) indicated they would not desire treatments to sustain life in the event of permanent physical disability, cognitive disability, or daily severe pain. CONCLUSIONS: Among older, higher-risk patients presenting for elective procedures, most patients chose limitations to life-sustaining treatments. This work highlights the need for an in-depth goals of care discussion and establishment of advance care preferences before a procedure or operative intervention.

Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.

Concordance in advance care preferences among high-risk surgical patients and surrogate health care decision makers in the perioperative setting.

BACKGROUND: Earlier studies have demonstrated poor concordance between patients' advance care preferences and those endorsed by their surrogate health care decision makers in a medical setting. This study aimed to determine concordance in the perioperative setting among high-risk patients and to identify areas for improvement. METHODS: This was a prospective cohort study set in a preoperative clinic for high-risk patients. Patients (>55 y) and their surrogates (dyads) were eligible for participation. Dyads were surveyed on the patient's desire for advance care preferences (cardiopulmonary resuscitation, mechanical ventilation, hemodialysis, artificial nutrition) and tolerance for physical disability, cognitive disability, and chronic pain. Concordance was defined as the surrogate correctly predicting patient preferences. Patients and surrogates were resurveyed for concordance 30 to 60 d after the index procedure. RESULTS: A total of 100 dyads (200 subjects) completed the survey. Median patient age was 68 y. Most patients were white (87%) and had an American Society of Anesthesiologists score of III (88%). The majority of dyads (59%) reported prior conversations about advance care preferences. Concordance specifically for cardiopulmonary resuscitation was 84%. In all other domains, <60% of dyads achieved concordance. Prior conversations regarding advance care preferences did not improve concordance in univariable or multivariable analysis. In postoperative surveys, substantial improvement was found in all domains except mechanical ventilation and cardiopulmonary resuscitation. CONCLUSION: In all domains except cardiopulmonary resuscitation, concordance was <60% in the preoperative setting and was not improved among dyads who reported prior conversations regarding advance care preferences. Discordance may limit patient autonomy by prolonging undesired interventions or terminating desired interventions prematurely.

Nonbacterial Thrombotic Endocarditis Due to Primary Gallbladder Malignancy with Recurrent Stroke Despite Anticoagulation: Case Report and Literature Review.

Nonbacterial thrombotic endocarditis (NBTE) associated with malignancy is rare; its infrequency and similarity to other diagnoses make it a significant diagnostic challenge. A 63-year-old woman on rivaroxaban for prior deep vein thrombosis presented with left upper extremity weakness and left facial droop with imaging demonstrating multiple strokes. Echocardiograms revealed mitral and aortic valve vegetations. The patient was switched to apixaban and started on vancomycin and ceftriaxone for presumed culture-negative endocarditis. Despite continuing apixaban, her hospital course was complicated by new acute embolic infarcts. Workup confirmed non-mucinous metastatic biliary adenocarcinoma. The patient was placed on a heparin drip then switched to low molecular weight heparin without further embolic events and was discharged to a rehabilitation facility in stable condition with plans for chemotherapy as an outpatient. These clinical, imaging, and histologic findings were consistent with a rare case of NBTE associated with primary non-mucinous gallbladder malignancy complicated by recurrent strokes in which direct oral anticoagulants did not provide adequate anticoagulation.

SIKs control osteocyte responses to parathyroid hormone.

Parathyroid hormone (PTH) activates receptors on osteocytes to orchestrate bone formation and resorption. Here we show that PTH inhibition of SOST (sclerostin), a WNT antagonist, requires HDAC4 and HDAC5, whereas PTH stimulation of RANKL, a stimulator of bone resorption, requires CRTC2. Salt inducible kinases (SIKs) control subcellular localization of HDAC4/5 and CRTC2. PTH regulates both HDAC4/5 and CRTC2 localization via phosphorylation and inhibition of SIK2. Like PTH, new small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation of HDAC4/5 and CRTC2. SIK inhibition mimics many of the effects of PTH in osteocytes as assessed by RNA-seq in cultured osteocytes and following in vivo administration. Once daily treatment with the small molecule SIK inhibitor YKL-05-099 increases bone formation and bone mass. Therefore, a major arm of PTH signalling in osteocytes involves SIK inhibition, and small molecule SIK inhibitors may be applied therapeutically to mimic skeletal effects of PTH.