The CRTC1-SIK1 pathway regulates entrainment of the circadian clock.

Retinal photoreceptors entrain the circadian system to the solar day. This photic resetting involves cAMP response element binding protein (CREB)-mediated upregulation of Per genes within individual cells of the suprachiasmatic nuclei (SCN). Our detailed understanding of this pathway is poor, and it remains unclear why entrainment to a new time zone takes several days. By analyzing the light-regulated transcriptome of the SCN, we have identified a key role for salt inducible kinase 1 (SIK1) and CREB-regulated transcription coactivator 1 (CRTC1) in clock re-setting. An entrainment stimulus causes CRTC1 to coactivate CREB, inducing the expression of Per1 and Sik1. SIK1 then inhibits further shifts of the clock by phosphorylation and deactivation of CRTC1. Knockdown of Sik1 within the SCN results in increased behavioral phase shifts and rapid re-entrainment following experimental jet lag. Thus SIK1 provides negative feedback, acting to suppress the effects of light on the clock. This pathway provides a potential target for the regulation of circadian rhythms.

Neuraxial Anesthesia in Patients With Aortic Stenosis: A Systematic Review.

Neuraxial anesthesia (NA) has been contraindicated in patients with aortic stenosis (AS) due to concerns of sympathetic blockade and hemodynamic instability. These considerations are based on precautionary expert recommendations, supported by expected physiologic effects, but in the absence of any published scientific evidence. In light of the increasing elderly population and the prevalence of AS, this systematic review compiles available literature on NA in patients with AS to address the understanding of the anesthetic practice and safety in this population. Using a systematic approach, PubMed, Embase, and Web of Science were searched for studies of patients with AS who exclusively received NA. Primary outcomes included intraoperative and postoperative complications. Of 1,433 citations, 61 met full-text inclusion criteria, including 3,228 patients undergoing noncardiac (n = 3,146, 97.5%), obstetric (n = 69, 2.1%), and cardiac (n = 13, 0.4%) procedures. Significant data heterogeneity (local anesthetic dosing, intraoperative interventions, and measured outcomes) prevented formal metanalysis, but descriptive data are presented. Spinal block (n = 2,856, 88.5%) and epidural anesthesia (n = 397, 12.3%) were administered most frequently. Hypotension requiring vasopressors was the most common intraoperative complication-noncardiac (n = 16, 9.9%), obstetric (n = 6, 13.0%), and cardiac (n = 1, 7.7%)-with resolution in all patients and no reported intraoperative cardiovascular collapse or mortality. The relative risk of different AS severities remains unclear, and optimal medication dosing remains elusive. The authors' data suggested that NA may not be contraindicated in carefully selected patients with AS. The authors' results should inform the design of future prospective studies comparing NA and general anesthesia in patients with AS.

Hypoattenuated Leaflet Thickening: A Comprehensive Review of Contemporary Data.

Nearly one-third of patients who undergo surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) develop hypoattenuated leaflet thickening (HALT) within a year. HALT typically represents subclinical leaflet thrombosis in asymptomatic patients, and as a result it often is detected incidentally. However, HALT also may worsen in severity, resulting in leaflet immobility and/or valve deterioration. The clinical significance of HALT is a topic of ongoing debate, and currently there is no consensus on the screening and management of HALT in patients following TAVR or SAVR. This review provides a comprehensive evaluation of the available evidence on risk factors, preventative measures, treatment, and prognosis for this growing patient cohort.

Are Proud Tibial Cone Constructs an Effective Alternative to Those That are Fully Seated in Revision Total Knee Arthroplasty?

BACKGROUND: This study compared the clinical, radiographic, and patient-reported outcomes between patients treated with the traditional fully seated tibial cone construct and those with the novel proud tibial cone construct in revision total knee arthroplasty (rTKA). METHODS: This was a retrospective study of 56 adult patients who had a minimum 2-year follow-up and underwent rTKA with either the fully seated (n = 18 knees) or proud (n = 42 knees) tibial cone construct between 2010 and 2020. The electronic medical record was reviewed for demographic, clinical, and radiographic data. Knee Injury and Osteoarthritis Outcome Scores (KOOS) were collected. RESULTS: All patients had improved mechanical alignment postoperatively regardless of surgical technique. All patients showed good evidence of osseointegration without loss of fixation at the latest follow-up. There were no significant differences in the complication rate or re-revision rate between the groups. KOOS Function in Sport and Recreation (Sport/Rec) scores were significantly higher for patients treated with the fully seated construct (mean 57 [range, 20 to 95] versus 38 [range, 0 to 75], P = .04); however, no significant differences were present for the other KOOS subscales or KOOS Jr. CONCLUSION: The proud tibial cone construct may be an effective alternative to the fully seated construct in the setting of severe bone loss in rTKA. The proud construct avoids a proximal tibial cut, and thus is a bone-preserving technique that provides good fixation, reduces operative time, prevents potential iatrogenic injuries, decreases the need for tibial augments, saves costs, and improves the ease of restoring joint height.

Advancing Data Science Among the Federal Public Health Workforce: The Data Science Upskilling Program, Centers for Disease Control and Prevention.

CONTEXT: Data can guide decision-making to improve the health of communities, but potential for use can only be realized if public health professionals have data science skills. However, not enough public health professionals possess the quantitative data skills to meet growing data science needs, including at the Centers for Disease Control and Prevention (CDC). PROGRAM: The Data Science Upskilling (DSU) program increases data science literacy among staff and fellows working and training at CDC. The DSU program was established in 2019 as a team-based, project-driven, on-the-job applied upskilling program. Learners, within interdisciplinary teams, use curated learning resources to advance their CDC projects. The program has rapidly expanded from upskilling 13 teams of 31 learners during 2019-2020 to upskilling 36 teams of 143 learners during 2022-2023. EVALUATION: All 2022-2023 cohort respondents to the end-of-project survey reported the program increased their data science knowledge. In addition, 90% agreed DSU improved their data science skills, 93% agreed it improved their confidence making data science decisions, and 96% agreed it improved their ability to perform data science work that benefits CDC. DISCUSSION: DSU is an innovative, inclusive, and successful approach to improving data science literacy at CDC. DSU may serve as an upskilling model for other organizations.

Decreasing Alertness Modulates Perceptual Decision-Making.

The ability to make decisions based on external information, prior knowledge, and evidence is a crucial aspect of cognition and may determine the success and survival of an organism. Despite extensive work on decision-making mechanisms/models, understanding the effects of alertness on neural and cognitive processes remain limited. Here we use EEG and behavioral modeling to characterize cognitive and neural dynamics of perceptual decision-making in awake/low alertness periods in humans (14 male, 18 female) and characterize the compensatory mechanisms as alertness decreases. Well-rested human participants, changing between full-wakefulness and low alertness, performed an auditory tone-localization task, and its behavioral dynamics were quantified with psychophysics, signal detection theory, and drift-diffusion modeling, revealing slower reaction times, inattention to the left side of space, and a lower rate of evidence accumulation in periods of low alertness. Unconstrained multivariate pattern analysis (decoding) showed a ∼280 ms delayed onset driven by low alertness of the neural signatures differentiating between left and right decision, with a spatial reconfiguration from centroparietal to lateral frontal regions 150-360 ms. To understand the neural compensatory mechanisms with decreasing alertness, we connected the evidence-accumulation behavioral parameter to the neural activity, showing in the early periods (125-325 ms) a shift in the associated patterns from right parietal regions in awake, to right frontoparietal during low alertness. This change in the neurobehavioral dynamics for central accumulation-related cognitive processes defines a clear reconfiguration of the brain networks' regions and dynamics needed for the implementation of decision-making, revealing mechanisms of resilience of cognition when challenged by decreased alertness.SIGNIFICANCE STATEMENT Most living organisms make multiple daily decisions, and these require a degree of evidence from both the environment and the internal milieu. Such decisions are usually studied under sequential sampling models and involve making a behavioral choice based on sensory encoding, central accumulation, and motor implementation processes. Since there is little research on how decreasing alertness affects such cognitive processes, this study has looked at the cognitive and neural dynamics of perceptual decision-making in people while fully awake and in drowsy periods. Using computational modeling of behavior and neural dynamics on human participants performing an auditory tone-localization task, we reveal how low alertness modulates evidence accumulation-related processes and its corresponding compensatory neural signatures.

Diastolic Left Main Coronary Artery Flow Reversal.

In patients undergoing percutaneous cardiac interventions, perioperative transesophageal echocardiography is used routinely, often revealing an unusual pathology that was not previously detected with transthoracic echocardiography. In this e-challenge, the authors present a patient undergoing percutaneous transcatheter aortic valve replacement, with preprocedural transesophageal echocardiography revealing an abnormal color Doppler signal near the left main coronary artery during diastole.

Gastrointestinal Complications After Transesophageal Echocardiography for Mitral Valve Transcatheter Edge-to-Edge Repair: Insights From a Large Contemporary Cohort.

OBJECTIVES: Transesophageal echocardiography-related complications (TEE-RC) are higher in structural heart interventions than in traditional operative settings. In mitral valve transcatheter edge-to-edge repair (MV-TEER), the incidence of TEE-RC may be higher than in other structural interventions. However, existing reports are limited and robust data evaluating TEE safety in this patient population are lacking. The authors sought to describe the incidence and risk factors of upper gastrointestinal injuries after TEE in patients undergoing MV-TEER. DESIGN: A retrospective observational study. SETTING: A single tertiary academic hospital. PARTICIPANTS: A total of 442 consecutive patients who underwent MV-TEER, specifically with MitraClip, between December 2015 and March 2022. INTERVENTIONS: Transesophageal echocardiography was performed intraoperatively to guide all MV-TEERs. MEASUREMENTS AND MAIN RESULTS: The study's primary goal was to investigate an association between TEE procedure duration and TEE-RC risk. The contribution of demographic risk factors and intraprocedural characteristics also was investigated. Transesophageal echocardiography-RCs were observed in 17 out of 442 patients (3.8%). Dysphagia was the most common TEE-RC (n = 9/17, 53%), followed by new gastroesophageal reflux (n = 6/17, 35%) and odynophagia (n = 3/17, 18%). There were no esophageal perforations or upper gastrointestinal bleeds. History of dysphagia was the only variable associated with TEE-RCs (p = 0.008; n = 9 [2.1%] v n = 3 [18%]), with a relative risk of 8.67 (95% CI 2.57, 29.16). The TEE procedure duration was not statistically different between the 2 groups (46 minutes [39-64] in TEE-RCs v 49 minutes [36-77] in no complications). CONCLUSION: In patients undergoing MV-TEER, TEE-RCs are uncommon, and major complications are rare. The authors' outcomes reflect those of a high-volume referral center with TEEs performed by cardiac anesthesiologists.

Patient fibroblast circadian rhythms predict lithium sensitivity in bipolar disorder.

Bipolar disorder is a chronic neuropsychiatric condition associated with mood instability, where patients present significant sleep and circadian rhythm abnormalities. Currently, the pathophysiology of bipolar disorder remains elusive, but treatment with lithium continues as the benchmark pharmacotherapy, functioning as a potent mood stabilizer in most, but not all patients. Lithium is well documented to induce period lengthening and amplitude enhancement of the circadian clock. Based on this, we sought to investigate whether lithium differentially impacts circadian rhythms in bipolar patient cell lines and crucially if lithium's effect on the clock is fundamental to its mood-stabilizing effects. We analyzed the circadian rhythms of bipolar patient-derived fibroblasts (n = 39) and their responses to lithium and three further chronomodulators. Here we show, relative to controls (n = 23), patients exhibited a wider distribution of circadian period (p < 0.05), and that patients with longer periods were medicated with a wider range of drugs, suggesting lower effectiveness of lithium. In agreement, patient fibroblasts with longer periods displayed muted circadian responses to lithium as well as to other chronomodulators that phenocopy lithium. These results show that lithium differentially impacts the circadian system in a patient-specific manner and its effect is dependent on the patient's circadian phenotype. We also found that lithium-induced behavioral changes in mice were phenocopied by modulation of the circadian system with drugs that target the clock, and that a dysfunctional clock ablates this response. Thus, chronomodulatory compounds offer a promising route to a novel treatment paradigm. These findings, upon larger-scale validation, could facilitate the implementation of a personalized approach for mood stabilization.

Aortic Valve Repair Using HAART 300 Geometric Annuloplasty Ring: A Review and Echocardiographic Case Series.

Aortic valve repair (AVr) aims to preserve the native aortic leaflets and restore normal valve function. In doing so, AVr is a more technically challenging approach than traditional aortic valve replacement. Some of the complexity of repair techniques can be attributed to the unique structure of the functional aortic annulus (FAA), which, unlike the well-defined mitral annulus, is comprised of virtual and functional components. Though stabilizing the ventriculo-aortic junction (VAJ), a component of the FAA, is considered beneficial for patients with chronic aortic insufficiency (AI), the ideal AVr technique remains a subject of much debate. The existing AVr techniques do not completely stabilize the VAJ which may increase susceptibility to recurrent AI due to VAJ dilation. An emerging new technique showing promise for the treatment of both isolated and complex AI is AVr using HAART 300TM geometric annuloplasty ring (GAR). The GAR is implanted below the valve leaflets in the left ventricular outflow tract (LVOT), providing stability and creating a neo-annulus. As with other AVr subtypes, this procedure has a learning curve. There are unique surgical and echocardiographic aspects of AVr with GAR, including the appearance of the LVOT, the aortic valve leaflets, and their motion which cardiac anesthesiologists and echocardiographers must be familiar with. In this work, using an eight-patient echocardiographic case series, we provide an overview of this novel AVr technique, including some unique aspects of device sizing, patient selection, expected post-repair echocardiographic features, and a review of outcomes data.

Procedural, Short-Term, and Intermediate-Term Outcomes in Propensity-Matched Patients With Severe Mitral Valve Regurgitation Undergoing Urgent Versus Elective MitraClip Percutaneous Mitral Valve Repair.

OBJECTIVE: The study authors sought to compare outcomes in patients with severe mitral valve regurgitation (MR) undergoing urgent, as compared to elective, mitral valve repair employing MitraClip. They hypothesized that, compared to elective cases, MitraClip procedures performed for urgent indications would be associated with increased intraoperative and postoperative complications but have similar long-term outcomes. DESIGN: A retrospective chart review with 3:1 propensity score matching of elective-to-urgent cases. SETTING: A single, large-volume tertiary care academic medical center. PARTICIPANTS: All consecutive patients with severe MR who underwent elective or urgent MitraClip procedures between December 15, 2015, and October 26, 2020. INTERVENTIONS: MR repair with MitraClip. MEASUREMENTS AND MAIN RESULTS: As expected, patients in the urgent MitraClip group required a higher level of preprocedural care, and there were significant differences in baseline demographic and clinical variables as compared to the elective group. To reduce baseline characteristics heterogeneity, propensity matching was performed for age, left ventricular systolic dysfunction, congestive heart failure, chronic obstructive pulmonary disease, and smoking histories, using the nearest-neighbor matching with a caliper of 0.2 and with replacement. The final study cohort included 89 urgent and 252 matched elective cases, with a suitable alignment between the treatment groups. Propensity-matched urgent MitraClip patients experienced a longer hospital length of stay (p < 0.001), increased intensive care unit admissions (19% v 4%, p < 0.001) and mechanical ventilation (6.7% v 1.6%, p = 0.023), postprocedural atrial fibrillation (11% v 4.4%, p = 0.036), pericardial effusion (10% v 2.4%, p = 0.005), and acute kidney injury (7.9% v 2%, p = 0.016). Furthermore, patients in the urgent cohort incurred significantly higher 30-day cardiovascular mortality (6.7% v 2%, p = 0.039), increased 30-day (16% v 5.6%, p = 0.006), and 1-year (33% v 20%, p = 0.021) readmission rates. However, there were no statistically significant differences in 30-day and 1-year overall and 1-year cardiovascular mortality. CONCLUSIONS: Urgent MitraClip repairs can be performed successfully, when needed, in critically ill patients with severe MR. Despite the procedural success, patients undergoing urgent MitraClip repair remain at high risk for adverse outcomes in the short- and intermediate-term and incur increased cardiovascular mortality and morbidity. Further efforts are required to develop strategies to optimize short and intermediate outcomes in this vulnerable group of patients.

Incidence and effectiveness of manipulation under anaesthesia for stiffness following primary total knee arthroplasty.

Background: There are various modalities of cor- rection of stiffness following total knee arthro-plasty. Manipulation under anaesthesia (MUA) is generally indicated for people who fail to achieve their pre operative range of motion at 12 weeks. The purpose of this study was to determine: (1) the effect of MUA on Flexion arc (2) the influence of timing of MUA from index procedure and of diabetes mellitus on final flexion achieved. Methods: We retrospectively evaluated patients who underwent manipulation following total knee arthroplasty at our institution between January 2016 to December 2018. For the purpose of analysis, we have divided the patients into two groups. Those who underwent manipulation within 12 weeks and later than 12 weeks. We have also compared the effect of MUA between diabetic and non-diabetic patients. All were operated with posterior stabilised (PS) prosthesis by a single senior arthroplasty surgeon. The final flexion achieved during their last clinical follow-up were recorded and compared with the pre MUA flexion. Results: The incidence of MUA after TKA at our institute during this period is about 1.14 %. There was a significant statistical difference between the pre and post manipulation flexion, with p value <0.01. There was no significant statistical difference between those who were manipulated before 12 weeks and after 12 weeks in improving the Flexion of the operated knees. We have found that both the diabetic and non diabetic group had comparable flexion after the manipulation in our study. Conclusion: Manipulation after anaesthesia is a safe first intervention to improve post operative stiffness and gain additional range of motion following TKA in patients who develop stiffness. It can be done even after 12 weeks of surgery with reasonably good gain in range of motion.

Outcomes of COVID-19 in hospitalized solid organ transplant recipients compared to a matched cohort of non-transplant patients at a national healthcare system in the United States.

Data describing outcomes of solid organ transplant (SOT) recipients with coronavirus disease 2019 (COVID-19) are variable, and the association between SOT status and mortality remains unclear. In this study, we compare clinical outcomes of SOT recipients hospitalized with COVID-19 between March 10, and September 1, 2020, to a matched cohort of non-SOT recipients at a national healthcare system in the United States (US). From a population of 43 461 hospitalized COVID-19-positive patients, we created a coarsened exact matched cohort of 4035 patients including 128 SOT recipients and 3907 weighted matched non-SOT controls. Multiple logistic regression was used to evaluate association between SOT status and clinical outcomes. Among the 4035 patients, median age was 60 years, 61.7% were male, 21.9% were Black/African American, and 50.8% identified as Hispanic/Latino ethnicity. Patients with a history of SOT were more likely to die within the study period when compared to matched non-SOT recipients (21.9% and 14.9%, respectively; odds ratio [OR] 1.93; 95% confidence interval [CI]: 1.18-3.15). Moreover, SOT status was associated with increased odds of receiving invasive mechanical ventilation (OR [95% CI]: 2.34 [1.51-3.65]), developing acute kidney injury (OR [95% CI]: 2.41 [1.59-3.65]), and receiving vasopressor support during hospitalization (OR [95% CI]: 2.14 [1.31-3.48]).

Outcomes of Transfemoral Transcatheter Aortic Valve Replacement Performed With General Anesthesia Using a Supraglottic Airway Versus Monitored Anesthesia Care.

OBJECTIVE: Compare general anesthesia with a supraglottic airway versus monitored anesthesia care for transfemoral transcatheter aortic valve replacement (TF-TAVR) in patients with aortic stenosis. The authors hypothesized that the supraglottic airway group would have similar operating room and procedure times, postanesthesia care unit (PACU) and hospital stays, and similar rates of intraprocedural and postprocedural complications compared with the monitored anesthesia care group. STUDY DESIGN: Retrospective chart review with 1:1 propensity score matching of supraglottic airway to monitored anesthesia care patients. SETTING: Tertiary care academic medical center. PARTICIPANTS: TF-TAVR patients between 2017 and 2019. INTERVENTIONS: Supraglottic airway or monitored anesthesia care. MEASUREMENTS AND MAIN RESULTS: One hundred forty-eight supraglottic airway patients were matched with 148 monitored anesthesia care patients. Monitored anesthesia care patients had slightly shorter operating room (p < 0.001) and procedure times (p = 0.015). No difference was observed in hospital length of stay (p = 0.34). Fewer patients in the supraglottic airway group required a PACU stay >2 hours (p < 0.001). Use of intraprocedural vasopressors (p < 0.001) and fentanyl dosage (p < 0.001) was higher in the supraglottic airway group. No differences were observed in postoperative complications or procedural success rates. CONCLUSIONS: In this, the first study to compare these 2 modalities, supraglottic airway use was demonstrated to be a safe, feasible alternative to monitored anesthesia care during TF-TAVR and did not increase organ-specific morbidity, 30-day mortality, hospital length of stay, or PACU length of stay. Even though supraglottic airway was associated with slight increases in procedure and operating room times, these were not clinically significant.

Soft X-ray absorption of thin films detected using substrate luminescence: a performance analysis.

X-ray absorption spectroscopy of thin films is central to a broad range of scientific fields, and is typically detected using indirect techniques. X-ray excited optical luminescence (XEOL) from the sample's substrate is one such detection method, in which the luminescence signal acts as an effective transmission measurement through the film. This detection method has several advantages that make it versatile compared with others, in particular for insulating samples or when a probing depth larger than 10 nm is required. In this work a systematic performance analysis of this method is presented with the aim of providing guidelines for its advantages and pitfalls, enabling a wider use of this method by the thin film community. The efficiency of XEOL is compared and quantified from a range of commonly used substrates. These measurements demonstrate the equivalence between XEOL and X-ray transmission measurements for thin films. Moreover, the applicability of XEOL to magnetic studies is shown by employing XMCD sum rules with XEOL-generated data. Lastly, it is demonstrated that above a certain thickness XEOL shows a saturation-like effect, which can be modelled and corrected for.

The genetics of circadian rhythms, sleep and health.

Circadian rhythms are 24-h rhythms in physiology and behaviour generated by molecular clocks, which serve to coordinate internal time with the external world. The circadian system is a master regulator of nearly all physiology and its disruption has major consequences on health. Sleep and circadian rhythm disruption (SCRD) is a ubiquitous feature in today's 24/7 society, and studies on shift-workers have shown that SCRD can lead not only to cognitive impairment, but also metabolic syndrome and psychiatric illness including depression (1,2). Mouse models of clock mutants recapitulate these deficits, implicating mechanistic and causal links between SCRD and disease pathophysiology (3-5). Importantly, treating clock disruption reverses and attenuates these adverse health states in animal models (6,7), thus establishing the circadian system as a novel therapeutic target. Significantly, circadian and clock-controlled gene mutations have recently been identified by Genome-Wide Association Studies (GWAS) in the aetiology of sleep, mental health and metabolic disorders. This review will focus upon the genetics of circadian rhythms in sleep and health.

Consensus Perioperative Management Best Practices for Patients on Transdermal Fentanyl Patches Undergoing Surgery.

PURPOSE OF REVIEW: The administration of a transdermal fentanyl patch can be complicated with different pharmacokinetics than other fentanyl preparations. RECENT FINDINGS: The medical condition and baseline opioid requirements must all be carefully considered when dosing a fentanyl patch. An advantage of the fentanyl patch is its ability to bypass the gastrointestinal tract and in many patients, provide effective analgesia with minimal side effects. Fentanyl patches must be carefully administered since morbidity and/or mortality can result from the following: Giving higher doses than a patient needs, combining the medication with potent sedatives, or heating a fentanyl patch. The use of a transdermal fentanyl patch for the treatment of acute postoperative pain is not recommended and any patient undergoing a surgical procedure should have the fentanyl patch removed preoperatively. The current manuscript discusses the history of fentanyl and the fentanyl patch, as well as perioperative considerations, contraindications, current clinical efficacy, and clinical adversities related to the transdermal fentanyl patch. Regarding the heating of a transdermal fentanyl patch, which significantly increases blood levels of fentanyl, it is of the utmost importance that the patch be removed prior to surgery.