bluuebunny/crossref_metadata_2025 huggingface dataset:
Accomplishment of instrumental activities of daily living and its relationship with cognitive functions in adults with myotonic dystrophy type 1 childhood phenotype: an exploratory study
Authors: Tremblay Marjolaine , Muslemani Samar , Côté Isabelle , Gagnon Cynthia , Fortin Julie , Gallais Benjamin
Published: April 2021

Background

The childhood phenotype of myotonic dystrophy type 1 (DM1) involves impaired cognitive functioning starting in infancy, which may compromise later on their ability to carry out instrumental activities of daily living (IADLs) necessary for living independently. The current study aims to document the ability to perform IADLs among adults with the childhood phenotype of DM1 and to explore its links to cognitive functioning.

Methods

This cross-sectional exploratory study was conducted among 11 individuals living with DM1. IADLs related to money management, home management & transportation and health & safety activities were assessed by the Independent Living Scale (ILS). Neuropsychological tests assessed participants’ intellectual abilities and executive functioning. Associations were investigated using Spearman’s rho correlation.

Results

Important difficulties were found in all three categories of IADLs, mostly in money management in which only 2/11 participants were scored as independent. 8/11 participants showed low to very low intellectual functioning and limit to impaired executive functioning. Apathy was also a common feature as 5/11 participants showed clinical level of apathy. A lower IQ was associated with greater difficulty in the home management & transportation subtest of the ILS.

Conclusions

Adults with the childhood phenotype of DM1 demonstrate relative dependence in regard to the following IADLs: money management and home management & transportation. Level of dependence is, at least partially, associated with cognitive impairments. The work relates to results from an exploratory study; thus, studies must be pursued to describe in more details difficulties experienced by this population.
Early outcomes and predictors of patient satisfaction after TKA: a prospective study of 200 cases with a contemporary cemented rotating platform implant design
Authors: van Loon Corné , Baas Niels , Huey Verdonna , Lesko James , Meermans Geert , Vergroesen Diederik
Published: April 2021

Purpose

The purpose of the study was to identify the earliest time point where subjects realized the greatest clinical improvement after TKA, and the time when post-operative scores became superior to pre-operative scores. Post-hoc exploratory analyses were conducted to investigate predictors of early post-operative outcomes and patient satisfaction.

Methods

Six investigators across 4 sites in the Netherlands prospectively implanted 200 subjects with a contemporary cemented rotating platform device. Patient Reported Outcome Measurements (PROMs) KOOS-PS, PKIP, and EQ-5D were collected pre-operatively and post-operatively through 2-years. PROMs change from pre-operative baseline were summarized, along with radiographic outcomes and adverse events (AEs). Pre-operative patient characteristics were explored for correlation with patient outcomes, and patient satisfaction for correlation with KOOS-PS.

Results

Follow-up compliance was 99% at 6-months, and 95.5% at 2-years. The percentage with higher KOOS-PS compared to baseline was 81.3% at 6-months. KOOS-PS, PKIP, and PKIP subscore means were all better at 6-weeks versus baseline. Gender, BMI, hypertension, and pre-operative KOOS-PS were weakly correlated with 6-week KOOS-PS (multivariate R-squared = 14.1%), but only pre-operative KOOS-PS demonstrated correlation with post-operative KOOS-PS at 6-months or later (R-squared < 5% at 6-months and 2 years). Satisfaction was moderately correlated with concurrent KOOS-PS at each post-operative time point, with (R-squared = 35.3% at 6-months, and 37.5% at 2 years).

Conclusion

The greatest mean clinical improvement occurred within the first 6-weeks. Although some pre-operative factors were correlated with higher early post-operative KOOS-PS outcomes, these advantages disappeared by 6-months aside from weak correlation with pre-operative KOOS-PS. Post-operative KOOS-PS was moderately correlated with concurrent post-operative satisfaction. These results may be used for pre-operative counseling and management of patient’s postoperative expectations.

Trial registration

Clinicaltrials.gov, NCT02339610. Registered 15 January 2015.
Anti-VEGF therapy prevents Müller intracellular edema by decreasing VEGF-A in diabetic retinopathy
Authors: Wang Tianqin , Zhang Chaoyang , Xie Hai , Jiang Mengmeng , Tian Haibin , Lu Lixia , Xu Guo-Tong , Liu Lin , Zhang Jingfa
Published: April 2021

Background

Although vascular endothelial growth factor A (VEGF-A) is known to play a key role in causing retinal edema, whether and how VEGF-A induces intracellular edema in the retina still remains unclear.

Methods

Sprague-Dawley rats were rendered diabetic with intraperitoneal injection of streptozotocin. Intravitreal injection of ranibizumab was performed 8 weeks after diabetes onset. rMC-1 cells (rat Müller cell line) were treated with glyoxal for 24 h with or without ranibizumab. The expression levels of inwardly rectifying K+ channel 4.1 (Kir4.1), aquaporin 4 (AQP4), Dystrophin 71 (Dp71), VEGF-A, glutamine synthetase (GS) and sodium-potassium-ATPase (Na+-K+-ATPase) were examined using Western blot. VEGF-A in the supernatant of the cell culture was detected with ELISA. The intracellular potassium and sodium levels were detected with specific indicators.

Results

Compared with normal control, protein expressions of Kir4.1 and AQP4 were down-regulated significantly in diabetic rat retinas, which were prevented by ranibizumab. The above changes were recapitulated in vitro. Similarly, the intracellular potassium level in glyoxal-treated rMC-1 cells was increased, while the intracellular sodium level and Na+-K+-ATPase protein level remained unchanged, compared with control. However, ranibizumab treatment decreased intracellular sodium, but not potassium.

Conclusion

Ranibizumab protected Müller cells from diabetic intracellular edema through the up-regulation of Kir4.1 and AQP4 by directly binding VEGF-A. It also caused a reduction in intracellular osmotic pressure.
Complete atrio-ventricular block with coronary artery spasm due to direct laryngoscopy in a pediatric patient with laryngeal papillomatosis: a case report
Authors: Matsushita Katsuyuki , Arai Risa , Nakayama Tetsuzo , Nakagaki Toshiaki , Kandabashi Tadashi , Yamaura Ken
Published: April 2021

Background

Coronary artery spasm has rarely been reported in pediatric patients. Previous studies have reported comorbidities and risk factors for coronary artery spasms. We present the case of a complete atrio-ventricular (AV) block that occurred in the absence of other risk factors immediately after direct laryngoscopy.

Case presentation

A 2-year-old girl developed severe coronary artery spasm after direct laryngoscopy for elective laryngeal papillomatosis resection. Immediately after the initiation of laryngoscopy, complete AV block and ST elevation on lead II of the electrocardiogram were observed. These findings indicated that the complete AV block was caused by a right coronary artery spasm.

Conclusion

Coronary artery spasm resulting in lethal arrhythmia rarely occurs in healthy pediatric patients. To the best of our knowledge, this is the first pediatric case of a severe coronary artery spasm resulting in a complete AV block due to direct laryngoscopy in a healthy patient.
Identification of metabolism genes related to hepatocarcinogenesis and progression in type 2 diabetes mellitus via co-expression networks analysis
Authors: Bi Yiming , Yin Bei , Fan Guanjie
Published: April 2021

Background

Type 2 Diabetes Mellitus (T2DM) is an independent risk factor of hepatocellular carcinoma (HCC). However, the related genes and modules to hepatocarcinogenesis and progression in T2DM remain unclear.

Methods

The microarray data from Gene Expression Omnibus (GEO) were analyzed to screen differentially expressed genes (DEGs) of T2DM and HCC dataset. Then, weighted gene co-expression network analysis (WGCNA) was performed on these DEGs to detect the modules and genes, respectively. Common genes in modules with clinical interests of T2DM and HCC were obtained and annotated via GOSemSim package and Metascape. Genes related to late-stage HCC and high glycated haemoglobin (HbA1c) were also identified. These genes were validated by UALCAN analysis and univariate cox regression based on The Cancer Genome Atlas (TCGA). Finally, another two independent datasets were applied to confirm the results of our study.

Results

A total of 1288 and 1559 DEGs of T2DM and HCC were screened, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment revealed several shared pathways in two diseases, such as pathways in cancer and metabolism. A total of 37 common genes correlated with T2DM and HCC were then identified with WGCNA. Furthermore, 12 genes from modules associated with late-stage HCC and high HbA1c were regarded as hub genes. Among these genes, 8 genes associated with tumor invasion and metastasis were validated by UALCAN analysis. Moreover, downregulations of ACAT1, SLC2A2, PCK1 and ABAT were significantly associated with poorer prognosis in HCC patients with elevated HbA1c. Additionally, the expressions of PCK1 and ABAT were raised in HepG2 cells pre-treated with metformin and phenformin.

Conclusions

The present study confirmed several metabolic genes related to hyperglycemia and malignant tumor, which may provide not only new insights into the pathogenesis of hepatocarcinogenesis and progression in T2DM, but also novel therapeutic targets for T2DM patients with HCC in the future.
In vitro antifungal activity of endophytic bacteria isolated from date palm (Phoenix doctylifera L.) against fungal pathogens causing leaf spot of date palm
Authors: Al-Nadabi H. H. , Al-Buraiki N. S. , Al-Nabhani A. A. , Maharachchikumbura S. N. , Velazhahan R. , Al-Sadi A. M.
Published: April 2021

Background

Date palm ((Phoenix doctylifera L.) suffers from several fungal diseases. The endophytic microorganisms present in higher plants generally offer protection to their host plants against invading phytopathogenic fungi and bacteria. In the present study, endophytic bacteria associated with date palm leaves were isolated and their in vitro antagonistic potential against fungal pathogens causing leaf spots in date palm was demonstrated.

Results

Endophytic bacteria were isolated from date palm leaves of 3 different cultivars viz., Nighal, Khalas and Khinaizi and evaluated for their inhibitory activity against leaf spot pathogens of date palm viz., Fusarium solani, Alternaria sp., Nigrospora sp., Thieloviopsis sp., Curvularia subpapendrofii and Tilletiopsis minor using an in vitro dual culture assay. Of the 24 endophytic bacterial strains tested, the endophytes designated B1, B7, B8 and B9 obtained from cv. Nighal showed inhibitory activities (more than 55% mycelial growth inhibition) against F. solani and Alternaria sp. None of the bacterial endophytes inhibited the growth of other fungal pathogens tested. These antagonistic bacterial strains were identified as Pantoea septica on the basis of 16S rRNA gene sequence analysis. The hyphae of F. solani and Alternaria sp. exhibited morphological abnormalities such as shrinkage and disintegration when grown in the presence of antagonistic bacterial endophytes. The cell-free culture filtrates of the bacterial endophytes caused inhibition of mycelial growth and induced leakage of electrolytes from the mycelia of F. solani and Alternaria sp. This is the first study that describes inhibition of the date palm pathogens F. solani and Alternaria sp. by P. septica.

Conclusion

Endophytic Pantoea septica strains isolated from date palm leaves inhibited the mycelial growth of F. solani and Alternaria sp. and induced morphological changes in their mycelia. The culture filtrates of these bacterial strains also inhibited the mycelial growth and caused leakage of electrolytes from the mycelia of F. solani and Alternaria sp. These promising bacterial strains can be exploited as biocontrol agents to control F. solani and Alternaria sp.-induced leaf spot diseases of date palm.
Development of screening criteria for microplastic particles in air and atmospheric deposition: critical review and applicability towards assessing human exposure
Authors: Wright Stephanie L. , Gouin Todd , Koelmans Albert A. , Scheuermann Lisa
Published: April 2021

Over the last several years there has been an increase in studies reporting the presence of microplastic particles (MPs) in both indoor and outdoor air. Data reported reflect a variety of different types of air samples, which have helped to demonstrate the ubiquity of MPs in the atmosphere and their potential contribution to atmospheric particulate matter (PM). The relative quality of the data reporting on MPs in air has not been evaluated, but represents an important step towards improving our overall understanding of the human health implications in relation to inhalation exposure to MPs. Adopting recent approaches that have been proposed to assess the quality of data for those studies reporting concentrations in biota and water samples, we identify a suite of criteria used to screen studies reporting MPs in air for the purposes of evaluating their usefulness in assessing human exposure. Here we review and summarize data from 27 studies reporting MPs in various types of air samples and evaluate each of the studies against 11 separate criteria representing four main categories (sampling; contamination mitigation; sample purification / handling; characterization and application towards assessing human exposure). On average, studies scored 48.6% (range 18.2–81.8%) of the maximum score. Only one study received a positive score for all criteria, implying that there remains a need for future studies to consider strengthening implementation and reporting of QA/QC protocol. The most urgent areas requiring attention relate to the need for studies to avoid and verify background contamination and to strengthen the quantification of method recovery efficiencies. The majority of studies report data for particulates > 10 μm. Due to the associations between exposure to particles < 10 μm and human health effects, we recommend that prioritization efforts that develop standard protocols, based on existing air sampling methods capable of characterizing MPs < 10 μm are progressed.
Nonrepeatability effects on time-lapse 4D seismic full-waveform inversion for ocean-bottom node data
Authors: Zhou Wei , Lumley David
Published: April 2021

Full-waveform inversion (FWI) can be applied to time-lapse (4D) seismic data for subsurface reservoir monitoring. However, nonrepeatability (NR) issues can contaminate the data and cause artifacts in the estimation of 4D rock and fluid property changes. Therefore, evaluating and studying the NR effects on the 4D data and FWI results can help, for instance, discriminate inversion artifacts from true changes and guide seismic survey design and processing workflows. Using realistic reservoir models, data, and field measurements of NR, we find the effects of NR source-receiver position and seawater velocity changes on the data and the 4D FWI results. We show that ignoring these NR effects in the inversion can cause strong artifacts in the estimated velocity change models and thus should be addressed before or during inversion. The NR source-receiver positioning issue can be successfully addressed by 4D FWI, whereas the NR water velocity issue requires measurements or estimations of water velocities. Furthermore, we compare the accuracy and robustness of the parallel, double-difference, and central-difference 4D FWI methods to realistic NR ocean-bottom node data in a quantitative way. Parallel 4D FWI fails to capture geomechanical changes and also overestimates the aquifer layer changes with NR data. Double-difference 4D FWI is capable of recovering the geomechanical changes, but it is also sensitive to NR noises, generating more artifacts in the overburden. By averaging the forward and reverse bootstrap 4D estimates, central-difference 4D FWI is more robust to NR noises and also produces the most accurate 4D estimates.
Conditional stochastic inversion of common-offset ground-penetrating radar reflection data
Authors: Xu Zhiwei , Irving James , Liu Yu , Zhu Peimin , Holliger Klaus
Published: April 2021

We have developed a stochastic inversion procedure for common-offset ground-penetrating radar (GPR) reflection measurements. Stochastic realizations of subsurface properties that offer an acceptable fit to GPR data are generated via simulated annealing optimization. The realizations are conditioned to borehole porosity measurements available along the GPR profile or equivalent measurements of another petrophysical property that can be related to the dielectric permittivity, as well as to geostatistical parameters derived from the borehole logs and the processed GPR image. Validation of our inversion procedure is performed on a pertinent synthetic data set and indicates that our method is capable of reliably recovering strongly heterogeneous porosity structures associated with surficial alluvial aquifers. This finding is largely corroborated through application of the methodology to field measurements from the Boise Hydrogeophysical Research Site near Boise, Idaho, USA.
Vector elastic deconvolution migration with dual wavefield decomposition
Authors: Chi Benxin , Gao Kai , Huang Lianjie
Published: April 2021

Elastic-wave imaging using multicomponent data can provide more useful subsurface information than acoustic-wave imaging, but it is usually algorithmically challenging. We have developed a vector elastic deconvolution migration method for high-resolution imaging of subsurface structures in isotropic and anisotropic elastic media. Our new method uses a vector deconvolution imaging condition based on dual wavefield decomposition, including an explicit directional wavefield separation using the Hilbert transform and a P/S vector wavefield decomposition using the low-rank decomposition method. Using three elastic models, we numerically determine that our new method produces notably higher resolution and more amplitude-balanced elastic images compared with a crosscorrelation-based vector elastic reverse time migration method.
Internal multiple elimination: Can we trust an acoustic approximation?
Authors: Reinicke Christian , Dukalski Marcin , Wapenaar Kees
Published: April 2021

Correct handling of strong elastic internal multiples remains a challenge for seismic imaging. Methods aimed at eliminating them are currently limited by monotonicity violations, a lack of a-priori knowledge about mode conversions, or unavailability of multicomponent sources and receivers for not only particle velocities but also the traction vector. Most of these challenges vanish in acoustic media such that Marchenko-equation-based methods are able, in theory, to remove multiples exactly (within a certain wavenumber-frequency band). In practice, however, when applied to (elastic) field data, mode conversions are unaccounted for. Aiming to support a recently published marine field data study, we build a representative synthetic model. For this setting, we demonstrate that mode conversions can have a substantial impact on the recovered multiple-free reflection response. Nevertheless, the images are significantly improved by acoustic multiple elimination. Moreover, after migration the imprint of elastic effects is considerably weaker and unlikely to alter the seismic interpretation.
Soluble Alpha Klotho in Acromegaly: Comparison With Traditional Markers of Disease Activity
Authors: Schweizer Júnia R O L , Schilbach Katharina , Haenelt Michael , Giannetti Alexandre V , Bizzi Mariana F , Soares Beatriz S , Paulino Eduardo , Schopohl Jochen , Störmann Sylvère , Ribeiro-Oliveira Antônio , Bidlingmaier Martin
Published: April 2021

Context

Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking.

Objective

To evaluate the potential of sαKL to aid classification of disease activity.

Methods

This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed.

Results

sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P <0.0001). High concentrations before treatment (A, median, interquartile range: 4.04 × upper limit of normal [2.26-8.08]) dropped to normal after treatment in controlled and in most discordant patients. A cutoff of 1548 pg/mL for sαKL discriminated controlled (B1, C1) and uncontrolled (B3, C3) patients with 97.8% (88.4%-99.9%) sensitivity and 100% (77.1%-100%) specificity. sαKL was below the cutoff in 84% of the discordant subjects. In the remaining 16%, elevated sαKL and IGF-I persisted, despite normal random GH. Sex, age, body mass index, and markers of bone and calcium metabolism did not significantly affect sαKL concentrations.

Conclusion

Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information.
SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases
Authors: Hoong Caroline W S , Chua Marvin W J
Published: April 2021

Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce glycosuria, reduce insulin levels, and promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF1, and modulate the closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favor a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signaling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms, including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors, such as PCG-1α, mitochondrial transcription factor A (TFAM), and nuclear factor E2-related factor (NRF)-2, that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared with other calorie restriction mimetics such as metformin, rapamycin, resveratrol, and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of aging-related diseases, due to their regulation of multiple longevity pathways that closely resembles that achieved by calorie restriction and their established efficacy in reducing cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-aging therapeutics.
Estrogen Regulation of the Molecular Phenotype and Active Translatome of AVPV Kisspeptin Neurons
Authors: Stephens Shannon B Z , Kauffman Alexander S
Published: April 2021

In females, ovarian estradiol (E2) exerts both negative and positive feedback regulation on the neural circuits governing reproductive hormone secretion, but the cellular and molecular mechanisms underlying this remain poorly understood. In rodents, estrogen receptor α–expressing kisspeptin neurons in the hypothalamic anteroventral periventricular region (AVPV) are prime candidates to mediate E2 positive feedback induction of preovulatory gonadotropin-releasing hormone and luteinizing hormone (LH) surges. E2 stimulates AVPV Kiss1 expression, but the full extent of estrogen effects in these neurons is unknown; whether E2 stimulates or inhibits other genes in AVPV Kiss1 cells has not been determined. Indeed, understanding of the function(s) of AVPV kisspeptin cells is limited, in part, by minimal knowledge of their overall molecular phenotype, as only a few genes are currently known to be co-expressed in AVPV Kiss1 cells. To provide a more detailed profiling of co-expressed genes in AVPV Kiss1 cells, including receptors and other signaling factors, and test how these genes respond to E2, we selectively isolated actively translated mRNAs from AVPV Kiss1 cells of female mice and performed RNA sequencing (RNA-seq). This identified >13 000 mRNAs co-expressed in AVPV Kiss1 cells, including multiple receptor and ligand transcripts positively or negatively regulated by E2. We also performed RNAscope to validate co-expression of several transcripts identified by RNA-seq, including Pdyn (prodynorphin), Penk (proenkephalin), Vgf (VGF), and Cartpt (CART), in female AVPV Kiss1 cells. Given the important role of AVPV kisspeptin cells in positive feedback, E2 effects on identified genes may relate to the LH surge mechanism and/or other physiological processes involving these cells.
Hormone Therapy in Menopause: Concepts, Controversies, and Approach to Treatment
Authors: Flores Valerie A , Pal Lubna , Manson JoAnn E
Published: April 2021

Hormone therapy (HT) is an effective treatment for menopausal symptoms, including vasomotor symptoms and genitourinary syndrome of menopause. Randomized trials also demonstrate positive effects on bone health, and age-stratified analyses indicate more favorable effects on coronary heart disease and all-cause mortality in younger women (close proximity to menopause) than in women more than a decade past menopause. In the absence of contraindications or other major comorbidities, recently menopausal women with moderate or severe symptoms are appropriate candidates for HT. The Women’s Health Initiative (WHI) hormone therapy trials—estrogen and progestin trial and the estrogen-alone trial—clarified the benefits and risks of HT, including how the results differed by age. A key lesson from the WHI trials, which was unfortunately lost in the posttrial cacophony, was that the risk:benefit ratio and safety profile of HT differed markedly by clinical characteristics of the participants, especially age, time since menopause, and comorbidity status. In the present review of the WHI and other recent HT trials, we aim to provide readers with an improved understanding of the importance of the timing of HT initiation, type and route of administration, and of patient-specific considerations that should be weighed when prescribing HT.
An Approach to Nonsuppressed Testosterone in Transgender Women Receiving Gender-Affirming Feminizing Hormonal Therapy
Authors: Maheshwari Arvind , Nippoldt Todd , Davidge-Pitts Caroline
Published: April 2021

Nonsuppressed levels of testosterone are seen in up to a quarter of transgender women on gender-affirming feminizing hormonal treatment. Multiple factors contribute to this situation, including patient, medication, laboratory, and organ-specific concerns. We propose a stepwise approach to determine the etiology of nonsuppressed levels of testosterone in transgender women. This may lead to an appropriate feminizing hormonal therapy regimen and diagnosis of manageable medical conditions.
The PRKAR1B p.R115K Variant is Associated with Lipoprotein Profile in African American Youth with Metabolic Challenges
Authors: Bloyd Michelle , Settas Nikolaos , Faucz Fabio Rueda , Sinaii Ninet , Bathon Kerstin , Iben James , Coon Steven , Caprio Sonia , Stratakis Constantine A , London Edra
Published: April 2021

Context

High childhood obesity rates coincide with increased incidence of nonalcoholic fatty liver disease (NAFLD) and other comorbidities. Understanding the genetics of susceptibility to obesity and its comorbidities could guide intervention. The cyclic adenosine monophosphate (cAMP)–dependent protein kinase (PKA) signaling pathway regulates energy balance, glucose homeostasis, and lipid metabolism.

Objective

We hypothesized that PKA-related gene variants may be associated with obesity or associated metabolic conditions.

Methods

We included 457 youths from the Yale Obesity Clinic into the Pathogenesis of Youth-Onset Diabetes cohort (NCT01967849); a variety of clinical tests were performed to characterize NAFLD. Exon sequencing of 54 PKA pathway genes was performed. Variants were confirmed by Sanger sequencing. Clinical data were analyzed, correcting for NAFLD status and body mass index z-score with adjustments for multiple comparisons. Fluorescence resonance energy transfer (FRET) and PKA enzymatic assays were performed in HEK293 cells transfected with the PRKAR1B p.R115K construct. In silico structural analysis for this variant was done.

Results

We identified the variant PRKAR1B p.R115K in 4 unrelated, African American patients. Analyses compared this variant group to other African American patients in the cohort. PRKAR1B p.R115K was associated with favorable circulating lipoprotein levels. Analysis of FRET and PKA enzymatic assay showed stronger interaction between the R1β mutant and PKA catalytic subunit Cα and decreased basal PKA activity compared with the wildtype (P < .0001). Structural analysis revealed that p.R115K may hinder conformational changes resulting from cAMP binding at cAMP binding domain A.

Conclusion

Data suggest PRKAR1B p.R115K affects cAMP signaling and may favorably modulate lipoprotein profile in African American youth, protecting them from some adverse metabolic outcomes.
Airway Management in Surgical Patients With Obstructive Sleep Apnea
Authors: Seet Edwin , Nagappa Mahesh , Wong David T.
Published: April 2021

Obstructive sleep apnea (OSA) is the most common sleep-related breathing disorder, and the difficult airway is perhaps the anesthesiologists’ quintessential concern. OSA and the difficult airway share certain similar anatomical, morphological, and physiological features. Individual studies and systematic reviews of retrospective, case-control, and large database studies have shown a likely association between patients with OSA and the difficult airway; OSA patients have a 3- to 4-fold higher risk of difficult intubation, difficult mask ventilation, or a combination of both. The presence of OSA should initiate proactive perioperative management in anticipation of a difficult airway. Prudent intraoperative management comprises the use of regional anesthesia where possible and considering an awake intubation technique where there is the presence of notable difficult airway predictors and risk of rapid desaturation following induction of general anesthesia. Familiarity with difficult airway algorithms, cautious extubation, and appropriate postoperative monitoring of patients with OSA are necessary to mitigate perioperative risks.
Sleep Loss in the Hospitalized Patient and Its Influence on Recovery From Illness and Operation
Authors: Hillman David R.
Published: April 2021

Adequate sleep is essential to health and well-being. Adverse effects of sleep loss are evident acutely and are cumulative in their effect. These include impairment of cognition, psychomotor function, and mood, as well as cardiovascular, metabolic, and immune dysfunction including proinflammatory effects and increased catabolic propensity. Such effects are counterproductive to recovery from illness and operation, yet hospitalization challenges sleep through the anxieties, discomforts, and sleep environmental challenges faced by patients, the inadequate attention given to the needs of patients with preexisting sleep disorders, and the lack of priority these issues receive from hospital staff and their leaders. Mitigation of the adverse effects of noise, light, uncomfortable bedding, intrusive observations, anxiety, and pain together with attention to specific sleep needs and monitoring of sleep quality are steps that would help address the issue and potentially improve patient outcomes.
Obesity and Obesity Hypoventilation, Sleep Hypoventilation, and Postoperative Respiratory Failure
Authors: Kaw Roop , Wong Jean , Mokhlesi Babak
Published: April 2021

Obesity hypoventilation syndrome (OHS) is considered as a diagnosis in obese patients (body mass index [BMI] ≥30 kg/m2) who also have sleep-disordered breathing and awake diurnal hypercapnia in the absence of other causes of hypoventilation. Patients with OHS have a higher burden of medical comorbidities as compared to those with obstructive sleep apnea (OSA). This places patients with OHS at higher risk for adverse postoperative events. Obese patients and those with OSA undergoing elective noncardiac surgery are not routinely screened for OHS. Screening for OHS would require additional preoperative evaluation of morbidly obese patients with severe OSA and suspicion of hypoventilation or resting hypoxemia. Cautious selection of the type of anesthesia, use of apneic oxygenation with high-flow nasal cannula during laryngoscopy, better monitoring in the postanesthesia care unit (PACU) can help minimize adverse perioperative events. Among other risk-reduction strategies are proper patient positioning, especially during intubation and extubation, multimodal analgesia, and cautious use of postoperative supplemental oxygen.
Effect of Inadequate Sleep on Clinician Performance
Authors: Saadat Haleh
Published: April 2021

The negative impacts of sleep deprivation and fatigue have long been recognized. Numerous studies have documented the ill effects of impaired alertness associated with the disruption of the sleep-wake cycle; these include an increased incidence of human error–related accidents, increased morbidity and mortality, and an overall decrement in social, financial, and human productivity. While there are multiple studies on the impact of sleep deprivation and fatigue in resident physicians, far fewer have examined the effects on attending physicians, and only a handful addresses the accumulated effects of chronic sleep disturbances on acute sleep loss during a night call-shift. Moreover, the rapid and unprecedented spread of coronavirus disease 2019 (COVID-19) pandemic significantly increased the level of anxiety and stress on the physical, psychological, and the economic well-being of the entire world, with heightened effect on frontline clinicians. Additional studies are necessary to evaluate the emotional and physical toll of the pandemic in clinicians, and its impact on sleep health, general well-being, and performance.
Chronic Opioid Use and Central Sleep Apnea, Where Are We Now and Where To Go? A State of the Art Review
Authors: Wang David , Yee Brendon J. , Grunstein Ronald R. , Chung Frances
Published: April 2021

Opioids are commonly used for pain management, perioperative procedures, and addiction treatment. There is a current opioid epidemic in North America that is paralleled by a marked increase in related deaths. Since 2000, chronic opioid users have been recognized to have significant central sleep apnea (CSA). After heart failure–related Cheyne-Stokes breathing (CSB), opioid-induced CSA is now the second most commonly seen CSA. It occurs in around 24% of chronic opioid users, typically after opioids have been used for more than 2 months, and usually corresponds in magnitude to opioid dose/plasma concentration. Opioid-induced CSA events often mix with episodes of ataxic breathing.

The pathophysiology of opioid-induced CSA is based on dysfunction in respiratory rhythm generation and ventilatory chemoreflexes. Opioids have a paradoxical effect on different brain regions, which result in irregular respiratory rhythm. Regarding ventilatory chemoreflexes, chronic opioid use induces hypoxia that appears to stimulate an augmented hypoxic ventilatory response (high loop gain) and cause a narrow CO2 reserve, a combination that promotes respiratory instability.

To date, no direct evidence has shown any major clinical consequence from CSA in chronic opioid users. A line of evidence suggested increased morbidity and mortality in overall chronic opioid users. CSA in chronic opioid users is likely to be a compensatory mechanism to avoid opioid injury and is potentially beneficial. The current treatments of CSA in chronic opioid users mainly focus on continuous positive airway pressure (CPAP) and adaptive servo-ventilation (ASV) or adding oxygen. ASV is more effective in reducing CSA events than CPAP. However, a recent ASV trial suggested an increased all-cause and cardiovascular mortality with the removal of CSA/CSB in cardiac failure patients. A major reason could be counteracting of a compensatory mechanism. No similar trial has been conducted for chronic opioid-related CSA. Future studies should focus on (1) investigating the phenotypes and genotypes of opioid-induced CSA that may have different clinical outcomes; (2) determining if CSA in chronic opioid users is beneficial or detrimental; and (3) assessing clinical consequences on different treatment options on opioid-induced CSA.
Perioperative Management of the Patient With Obstructive Sleep Apnea: A Narrative Review
Authors: Cozowicz Crispiana , Memtsoudis Stavros G.
Published: April 2021

The prevalence of obstructive sleep apnea (OSA) has reached 1 billion people worldwide, implying significant risk for the perioperative setting as patients are vulnerable to cardiopulmonary complications, critical care requirement, and unexpected death. This review summarizes main aspects and considerations for the perioperative management of OSA, a condition of public health concern. Critical determinants of perioperative risk include OSA-related changes in upper airway anatomy with augmented collapsibility, diminished capability of upper airway dilator muscles to respond to airway obstruction, disparities in hypoxemia and hypercarbia arousal thresholds, and instability of ventilatory control. Preoperative OSA screening to identify patients at increased risk has therefore been implemented in many institutions. Experts recommend that in the absence of severe symptoms or additional compounding health risks, patients may nevertheless proceed to surgery, while heightened awareness and the adjustment of postoperative care is required. Perioperative caregivers should anticipate difficult airway management in OSA and be prepared for airway complications. Anesthetic and sedative drug agents worsen upper airway collapsibility and depress central respiratory activity, while the risk for postoperative respiratory compromise is further increased with the utilization of neuromuscular blockade. Consistently, opioid analgesia has proven to be complex in OSA, as patients are particularly prone to opioid-induced respiratory depression. Moreover, basic features of OSA, including intermittent hypoxemia and repetitive sleep fragmentation, gradually precipitate a higher sensitivity to opioid analgesic potency along with an increased perception of pain. Hence, regional anesthesia by blockade of neural pathways directly at the site of surgical trauma as well as multimodal analgesia by facilitating additive and synergistic analgesic effects are both strongly supported in the literature as interventions that may reduce perioperative complication risk. Health care institutions are increasingly allocating resources, including those of postoperative enhanced monitoring, in an effort to increase patient safety. The implementation of evidence-based perioperative management strategies is however burdened by the rising prevalence of OSA, the large heterogeneity in disease severity, and the lack of evidence on the efficacy of costly perioperative measures. Screening and monitoring algorithms, as well as reliable risk predictors, are urgently needed to identify OSA patients that are truly in need of extended postoperative surveillance and care. The perioperative community is therefore challenged to develop feasible pathways and measures that can confer increased patient safety and prevent complications in patients with OSA.
Perioperative Continuous Positive Airway Pressure Therapy: A Review With the Emphasis on Randomized Controlled Trials and Obstructive Sleep Apnea
Authors: Jonsson Fagerlund M. , Franklin K. A.
Published: April 2021

The perioperative use of continuous positive airway pressure (CPAP) therapy has increased substantially in recent years, particularly in relationship to the treatment of patients with known or suspected obstructive sleep apnea (OSA). OSA is common in the surgical population and is reported as an independent risk factor for postoperative complications, intensive care unit admission, and increased length of hospital stay. A large proportion of OSA patients are undiagnosed at the time of surgery and can therefore not be optimized preoperatively. Nowadays, golden standard treatment of moderate to severe OSA is nightly CPAP at home, often with an autotitration mode. Unfortunately, there are only a handful of randomized clinical trials investigating the effect of preoperative and/or postoperative CPAP treatment in OSA patients, so the perioperative guidelines are based on a combination of randomized clinical trials, observational studies, case studies, and expert opinions. In this review, we have summarized the current evidence regarding the use of perioperative CPAP therapy with an emphasis on patients with OSA. We identified 21 randomized, controlled trials that investigated the effect of CPAP on postoperative physiology and complications in surgical patients. Our review reveals evidence, suggesting that CPAP after surgery improves oxygenation and reduces the need for reintubation and mechanical ventilation after surgery. It is also evident that CPAP reduces apnea and hypopnea frequency and related hypoxemia after surgery. Poor adherence to CPAP in the perioperative setting is a limiting factor in assessing its potential to optimize postoperative cardiorespiratory outcomes. Studies of postoperative outcomes in patients who have previously been prescribed CPAP for OSA and are therefore familiar with its use could help to address this shortcoming, but they are unfortunately lacking. This shortcoming should be addressed in future studies. Furthermore, many of the studies of the postoperative effect of CPAP in OSA patents are small, and therefore, single-center studies and larger randomized, controlled multicenter studies are warranted.
Environmental and Occupational Considerations of Anesthesia: A Narrative Review and Update
Authors: Varughese Shane , Ahmed Raza
Published: April 2021

With an estimated worldwide volume of 266 million surgeries in 2015, the call for general inhalation anesthesia is considerable. However, widely used volatile anesthetics such as N2O and the highly fluorinated gases sevoflurane, desflurane, and isoflurane are greenhouse gases, ozone-depleting agents, or both. Because these agents undergo minimal metabolism in the body during clinical use and are primarily (≥95%) eliminated unchanged via exhalation, waste anesthetic gases (WAGs) in operating rooms and postanesthesia care units can pose a challenge for overall elimination and occupational exposure. The chemical properties and global warming impacts of these gases vary, with atmospheric lifetimes of 1−5 years for sevoflurane, 3−6 years for isoflurane, 9−21 years for desflurane, and 114 years for N2O. Additionally, the use of N2O as a carrier gas for the inhalation anesthetics and as a supplement to intravenous (IV) anesthetics further contributes to these impacts. At the same time, unscavenged WAGs can result in chronic occupational exposure of health care workers to potential associated adverse health effects. Few adverse effects associated with WAGs have been documented, however, when workplace exposure limits are implemented. Specific measures that can help reduce occupational exposure and the environmental impact of inhaled anesthetics include efficient ventilation and scavenging systems, regular monitoring of airborne concentrations of waste gases to remain below recommended limits, ensuring that anesthesia equipment is well maintained, avoiding desflurane and N2O if possible, and minimizing fresh gas flow rates (eg, use of low-flow anesthesia). One alternative to volatile anesthetics may be total intravenous anesthesia (TIVA). While TIVA is not associated with the risks of occupational exposure or atmospheric pollution that are inherent to volatile anesthetic gases, clinical considerations should be weighed in the choice of agent. Appropriate procedures for the disposal of IV anesthetics must be followed to minimize any potential for negative environmental effects. Overall, although their contributions are relatively low compared with those of other human-produced substances, inhaled anesthetics are intrinsically potent greenhouse gases and pose a risk to operating-room personnel if not properly managed and scavenged. Factors to reduce waste and minimize the future impact of these substances should be considered.
Propofol for Induction and Maintenance of Anesthesia in Patients With Brugada Syndrome: A Single-Center, 25-Year, Retrospective Cohort Analysis
Authors: Flamée Panagiotis , Viaene Kea , Tosi Maurizio , Nogueira Carvalho Hugo , de Asmundis Carlo , Forget Patrice , Poelaert Jan
Published: April 2021

BACKGROUND:

Propofol administration in patients with Brugada syndrome (BrS) is still a matter of debate. Despite lacking evidence for its feared arrhythmogenicity, up to date, expert cardiologists recommend avoiding propofol. The main aim of this study is to assess the occurrence of malignant arrhythmias or defibrillations in patients with BrS, during and 30 days after propofol administration. The secondary aim is to investigate the occurrence of adverse events during propofol administration and hospitalization, as the 30-day readmission and 30-day mortality rate.

METHODS:

We performed a retrospective cohort study on patients with BrS who received propofol anytime from January 1, 1996 to September 30, 2020. Anesthesia was induced by propofol in both groups. In the total intravenous anesthesia (TIVA) group, anesthesia was maintained by propofol, while in the BOLUS group, volatile anesthesia was provided. The individual anesthetic charts and the full electronic medical records up to 30 postprocedural days were scrutinized.

RESULTS:

One hundred thirty-five BrS patients who underwent a total of 304 procedures were analyzed. The TIVA group included 27 patients for 33 procedures, and the BOLUS group included 108 patients for 271 procedures. In the TIVA group, the median time of propofol infusion was 60 minutes (interquartile range [IQR] = 30–180). The estimated plasma or effect-site concentration ranged between 1.0 and 6.0 µg·mL−
1 for target-controlled infusion (TCI). The infusion rate for manually driven TIVA varied between 0.8 and 10.0 mg·kg−
1·h−
1. In the BOLUS group, the mean propofol dose per kilogram total body weight was 2.4 ± 0.9 mg·kg−
1. No malignant arrhythmias or defibrillations were registered in both groups. The estimated 95% confidence interval (CI) of the risk for malignant arrhythmias in the BOLUS and TIVA groups was 0-0.011 and 0-0.091, respectively.

CONCLUSIONS:

The analysis of 304 anesthetic procedures in BrS patients, who received propofol, either as a TIVA or as a bolus during induction of volatile-based anesthesia, revealed no evidence of malignant arrhythmias or defibrillations. The present data do not support an increased risk with propofol-based TIVA compared to propofol-induced volatile anesthesia. Prospective studies are needed to investigate the electrophysiologic effects of propofol in BrS patents.