Discordant skeletal muscle gene and protein responses to exercise.

The ability of skeletal muscle to adapt to repeated contractile stimuli is one of the most intriguing aspects of physiology. The molecular bases underpinning these adaptations involve increased protein activity and/or expression, mediated by an array of pre- and post-transcriptional processes, as well as translational and post-translational control. A longstanding dogma assumes a direct relationship between exercise-induced increases in mRNA levels and subsequent changes in the abundance of the proteins they encode. Drawing on the results of recent studies, we dissect and question the common assumption of a direct relationship between changes in the skeletal muscle transcriptome and proteome induced by repeated muscle contractions (e.g., exercise).

Cyanocyclopentadiene-Annulated Polycyclic Aromatic Radical Anions: Predicted Negative Ion Photoelectron Spectra and Singlet-Triplet Energies of Cyanoindene and Cyanofluorene Radical Anions.

Isomer-specific negative ion photoelectron spectra (NIPES) of cyanoindene (C9H7CN) and cyanofluorene (C14H9N), acquired through the computation of Franck-Condon (FC) factors that utilize harmonic vibrational frequencies and normal mode vectors derived from density functional theory (DFT) at the B3LYP/aug-cc-pVQZ and 6-311++G(2d,2p) basis sets, are reported. The adiabatic electron affinity (EA) values of the ground singlet (S0) and the lowest lying triplet (T1) states are used to predict site-specific S0-T1 energies (ΔEST). The vibrational spectra of the S0 and T1 states are typified by ring distortion and ring C-C stretching vibrational progressions. Among all the S0 isomers in C9H7CN, the 2-cyanoindene (2-C9H7CN) is found to be the most stable at an EA of 0.716 eV, with the least stable isomer being the 1-C9H7CN at an EA of 0.208 eV. In C14H9N, the most stable S0 isomer, 2-cyanofluorene (2-C14H9N), has an EA of 0.781 eV. The least stable S0 isomer in C14H9N is the 9-C14H9N, with an EA of 0.364 eV. The FC calculations are designed to mimic simulations that would be performed to aid in the analysis of experimental spectra obtained in NIPE spectroscopic techniques. The vibrational spectra, adiabatic EAs, and ΔEST values reported in this study are intended to act as a guide for future gas-phase ion spectroscopic experiments and astronomical searches, especially with regard to the hitherto largely unexplored C14H9N isomers.

Cyanonaphthalene and cyanonaphthyl radicals: Vibrational structures via computed negative ion photoelectron spectra and thermochemistry of 1- and 2-cyanonaphthalene.

A double harmonic oscillator model is applied to compute the negative ion photoelectron spectra (NIPES) of the 1- and 2-cyanonaphthalene (CNN) radical anions. The computed Franck-Condon factors utilize optimized structures and harmonic vibrational frequencies obtained using density functional theory with the B3LYP 6-311++G (2d,2p) basis set while considering the mode-mixing Duschinsky effects. To test the accuracy of our model, the NIPES of α and ß naphthyl radical anions were computed, and a strong agreement between the slow electron velocity-map ion imaging spectra and the predicted spectra was found. The adiabatic electron affinities (EAs) of the ground singlet states (S0) in 1-CNN and 2-CNN are 0.856 and 0.798 eV, respectively. The origin of the lowest-lying triplet (T1) states in 1-CNN and 2-CNN is found to be 3.226 and 3.266 eV, resulting in singlet-triplet energy splittings (ΔEST) of 2.370 and 2.468 eV, respectively. Both the NIPES for electron detachment to the S0 and T1 states exhibit well-resolved vibrational features, allowing for the assignment of several vibrational fundamental frequencies. Following deprotonation, several isomers are formed, with the most stable deprotonated radical anions in 1-CNN and 2-CNN, corresponding to the removal of the most acidic proton, with EAs of 2.062 and 2.16 eV. The rich spectroscopic and thermochemical data obtained in the current study make the CNN radical anions and their deprotonated species interesting systems for investigation in gas-phase, negative-ion experiments.

Peri-operative decisions about cardiopulmonary resuscitation among adults as reported to the 7th National Audit Project of the Royal College of Anaesthetists.

Current guidance recommends that, in most circumstances, cardiopulmonary resuscitation should be attempted when cardiac arrest occurs during anaesthesia, and when a patient has a pre-existing 'do not attempt cardiopulmonary resuscitation' recommendation, this should be suspended. How this guidance is translated into everyday clinical practice in the UK is currently unknown. Here, as part of the 7th National Audit Project of the Royal College of Anaesthetists, we have: assessed the rates of pre-operative 'do not attempt cardiopulmonary resuscitation' recommendations via an activity survey of all cases undertaken by anaesthetists over four days in each participating site; and analysed our one-year case registry of peri-operative cardiac arrests to understand the rates of cardiac arrest in patients who had 'do not attempt cardiopulmonary resuscitation' decisions pre-operatively. In the activity survey, among 20,717 adults (aged > 18 y) undergoing surgery, 595 (3%) had a 'do not attempt cardiopulmonary resuscitation' recommendation pre-operatively, of which less than a third (175, 29%) were suspended. Of the 881 peri-operative cardiac arrest reports, 54 (6%) patients had a 'do not attempt cardiopulmonary resuscitation' recommendation made pre-operatively and of these 38 (70%) had a clinical frailty scale score ≥ 5. Just under half (25, 46%) of these 'do not attempt cardiopulmonary resuscitation' recommendations were formally suspended at the time of anaesthesia and surgery. One in five of these patients with a 'do not attempt cardiopulmonary resuscitation' recommendation who had a cardiac arrest survived to leave hospital and of the seven patients with documented modified Rankin Scale scores before and after cardiac arrest, four remained the same and three had worse scores. Very few patients who had a pre-existing 'do not attempt cardiopulmonary resuscitation' recommendation had a peri-operative cardiac arrest, and when cardiac arrest did occur, return of spontaneous circulation was achieved in 57%, although > 50% of these patients subsequently died before discharge from hospital.

A quantitative evaluation of aerosol generation during cardiopulmonary resuscitation.

It is unclear if cardiopulmonary resuscitation is an aerosol-generating procedure and whether this poses a risk of airborne disease transmission to healthcare workers and bystanders. Use of airborne transmission precautions during cardiopulmonary resuscitation may confer rescuer protection but risks patient harm due to delays in commencing treatment. To quantify the risk of respiratory aerosol generation during cardiopulmonary resuscitation in humans, we conducted an aerosol monitoring study during out-of-hospital cardiac arrests. Exhaled aerosol was recorded using an optical particle sizer spectrometer connected to the breathing system. Aerosol produced during resuscitation was compared with that produced by control participants under general anaesthesia ventilated with an equivalent respiratory pattern to cardiopulmonary resuscitation. A porcine cardiac arrest model was used to determine the independent contributions of ventilatory breaths, chest compressions and external cardiac defibrillation to aerosol generation. Time-series analysis of participants with cardiac arrest (n = 18) demonstrated a repeating waveform of respiratory aerosol that mapped to specific components of resuscitation. Very high peak aerosol concentrations were generated during ventilation of participants with cardiac arrest with median (IQR [range]) 17,926 (5546-59,209 [1523-242,648]) particles.l-1 , which were 24-fold greater than in control participants under general anaesthesia (744 (309-2106 [23-9099]) particles.l-1 , p < 0.001, n = 16). A substantial rise in aerosol also occurred with cardiac defibrillation and chest compressions. In a complimentary porcine model of cardiac arrest, aerosol recordings showed a strikingly similar profile to the human data. Time-averaged aerosol concentrations during ventilation were approximately 270-fold higher than before cardiac arrest (19,410 (2307-41,017 [104-136,025]) vs. 72 (41-136 [23-268]) particles.l-1 , p = 0.008). The porcine model also confirmed that both defibrillation and chest compressions generate high concentrations of aerosol independent of, but synergistic with, ventilation. In conclusion, multiple components of cardiopulmonary resuscitation generate high concentrations of respiratory aerosol. We recommend that airborne transmission precautions are warranted in the setting of high-risk pathogens, until the airway is secured with an airway device and breathing system with a filter.

Peri-operative cardiac arrest: epidemiology and clinical features of patients analysed in the 7th National Audit Project of the Royal College of Anaesthetists.

The 7th National Audit Project of the Royal College of Anaesthetists studied peri-operative cardiac arrest in the UK, a topic of importance to patients, anaesthetists and surgeons. Here we report the results of the 12-month registry, from 16 June 2021 to 15 June 2022, focusing on epidemiology and clinical features. We reviewed 881 cases of peri-operative cardiac arrest, giving an incidence of 3 in 10,000 anaesthetics (95%CI 3.0-3.5 per 10,000). Incidence varied with patient and surgical factors. Compared with denominator survey activity, patients with cardiac arrest: included more males (56% vs. 42%); were older (median (IQR) age 60.5 (40.5-80.5) vs. 50.5 (30.5-70.5) y), although the age distribution was bimodal, with infants and patients aged > 66 y overrepresented; and were notably more comorbid (73% ASA physical status 3-5 vs. 27% ASA physical status 1-2). The surgical case-mix included more weekend (14% vs. 11%), out-of-hours (19% vs. 10%), non-elective (65% vs. 30%) and major/complex cases (60% vs. 28%). Cardiac arrest was most prevalent in orthopaedic trauma (12%), lower gastrointestinal surgery (10%), cardiac surgery (9%), vascular surgery (8%) and interventional cardiology (6%). Specialities with the highest proportion of cases relative to denominator activity were: cardiac surgery (9% vs. 1%); cardiology (8% vs. 1%); and vascular surgery (8% vs. 2%). The most common causes of cardiac arrest were: major haemorrhage (17%); bradyarrhythmia (9%); and cardiac ischaemia (7%). Patient factors were judged a key cause of cardiac arrest in 82% of cases, anaesthesia in 40% and surgery in 35%.

The incidence of potentially serious complications during non-obstetric anaesthetic practice in the United Kingdom: an analysis from the 7th National Audit Project (NAP7) activity survey.

Complications and critical incidents arising during anaesthesia due to patient, surgical or anaesthetic factors, may cause harm themselves or progress to more severe events, including cardiac arrest or death. As part of the 7th National Audit Project of the Royal College of Anaesthetists, we studied a prospective national cohort of unselected patients. Anaesthetists recorded anonymous details of all cases undertaken over 4 days at their site through an online survey. Of 416 hospital sites invited to participate, 352 (85%) completed the survey. Among 24,172 cases, 1922 discrete potentially serious complications were reported during 1337 (6%) cases. Obstetric cases had a high reported major haemorrhage rate and were excluded from further analysis. Of 20,996 non-obstetric cases, 1705 complications were reported during 1150 (5%) cases. Circulatory events accounted for most complications (616, 36%), followed by airway (418, 25%), metabolic (264, 15%), breathing (259, 15%), and neurological (41, 2%) events. A single complication was reported in 851 (4%) cases, two complications in 166 (1%) cases and three or more complications in 133 (1%) cases. In non-obstetric elective surgery, all complications were 'uncommon' (10-100 per 10,000 cases). Emergency (urgent and immediate priority) surgery accounted for 3454 (16%) of non-obstetric cases but 714 (42%) of complications with severe hypotension, major haemorrhage, severe arrhythmias, septic shock, significant acidosis and electrolyte disturbances all being 'common' (100-1000 per 10,000 cases). Based on univariate analysis, complications were associated with: younger age; higher ASA physical status; male sex; increased frailty; urgency and extent of surgery; day of the week; and time of day. These data represent the rates of potentially serious complications during routine anaesthesia care and may be valuable for risk assessment and patient consent.

Peri-operative cardiac arrest: management and outcomes of patients analysed in the 7th National Audit Project of the Royal College of Anaesthetists.

The 7th National Audit Project of the Royal College of Anaesthetists studied peri-operative cardiac arrest in the UK, a topic of importance to patients, anaesthetists and surgeons. We report the results of the 12-month registry phase, from 16 June 2021 to 15 June 2022, focusing on management and outcomes. Among 881 cases of peri-operative cardiac arrest, the initial rhythm was non-shockable in 723 (82%) cases, most commonly pulseless electrical activity. There were 665 (75%) patients who survived the initial event and 384 (52%) who survived to hospital discharge. A favourable functional outcome (based on modified Rankin Scale score) was reported for 249 (88%) survivors. Outcomes varied according to arrest rhythm. The highest rates of survival were seen for bradycardic cardiac arrests with 111 (86%) patients surviving the initial event and 77 (60%) patients surviving the hospital episode. The lowest survival rates were seen for patients with pulseless electrical activity, with 312 (68%) surviving the initial episode and 156 (34%) surviving to hospital discharge. Survival to hospital discharge was worse in patients at the extremes of age with 76 (40%) patients aged > 75 y and 9 (45%) neonates surviving. Hospital survival was also associated with surgical priority, with 175 (88%) elective patients and 176 (37%) non-elective patients surviving to discharge. Outcomes varied with the cause of cardiac arrest, with lower initial survival rates for pulmonary embolism (5, 31%) and bone cement implantation syndrome (9, 45%), and hospital survival of < 25% for pulmonary embolism (0), septic shock (13, 24%) and significant hyperkalaemia (1, 20%). Overall care was rated good in 464 (53%) cases, and 18 (2%) cases had overall care rated as poor. Poor care elements were present in a further 245 (28%) cases. Care before cardiac arrest was the phase most frequently rated as poor (92, 11%) with elements of poor care identified in another 186 (21%) cases. These results describe the management and outcomes of peri-operative cardiac arrest in UK practice for the first time.

Scalp incision technique for decompressive hemicraniectomy: comparative systematic review and meta-analysis of the reverse question mark versus alternative retroauricular and Kempe incision techniques.

Decompressive hemicraniectomy (DHC) is a critical procedure used to alleviate elevated intracranial pressure (ICP) in emergent situations. It is typically performed to create space for the swelling brain and to prevent dangerous and potentially fatal increases in ICP. DHC is indicated for pathologies ranging from MCA stroke to traumatic subarachnoid hemorrhage-essentially any cause of refractory brain swelling and elevated ICPs. Scalp incisions for opening and closing the soft tissues during DHC are crucial to achieve optimal outcomes by promoting proper wound healing and minimizing surgical site infections (SSIs). Though the reverse question mark (RQM) scalp incision has gained significant traction within neurosurgical practice, alternatives-including the retroauricular (RA) and Kempe incisions-have been proposed. As choice of technique can impact postoperative outcomes and complications, we sought to compare outcomes associated with different scalp incision techniques used during DHC. We queried three databases according to PRISMA guidelines in order to identify studies comparing outcomes between the RQM versus "alternative" scalp incision techniques for DHC. Our primary outcome of interest in the present study was postoperative wound infection rates according to scalp incision type. Secondary outcomes included estimated blood loss (EBL) and operative duration. We identified seven studies eligible for inclusion in the formal meta-analysis. The traditional RQM technique shortened operative times by 36.56 min, on average. Additionally, mean EBL was significantly lower when the RQM scalp incision was used. Postoperatively, there was no significant association between DHC incision type and mean intensive care unit (ICU) length of stay (LOS), nor was there a significant difference in predisposition to developing wound complications or infections between the RQM and retroauricular/Kempe incision cohorts. Superficial temporal artery (STA) preservation and reoperation rates were collected but could not be analyzed due to insufficient number of studies reporting these outcomes. Our meta-analysis suggests that there is no significant difference between scalp incision techniques as they relate to surgical site infection and wound complications. At present, it appears that outcomes following DHC can be improved by ensuring that the bone flap is large enough to enable sufficient cerebral expansion and decompression of the temporal lobe, the latter of which is of particular importance. Although previous studies have suggested that there are several advantages to performing alternative scalp incision techniques during DHC, the present study (which is to our knowledge the first to meta-analyze the literature on outcomes in DHC by scalp incision type) does not support these findings. As such, further investigations in the form of prospective trials with high statistical power are merited.

Minimally invasive keyhole craniotomies for microsurgical clipping of cerebral aneurysms: comparative meta-analysis of the mini-pterional and supraorbital keyhole approaches.

OBJECTIVE: Axel Perneczky is responsible for conceptualizing the "keyhole" philosophy as a new paradigm of minimal invasiveness within cranial neurosurgery. Keyhole neurosurgery aims to limit approach-related traumatization and minimize brain retraction while still enabling the neurosurgeon to achieve operative goals. The supraorbital keyhole craniotomy (SOKC) and minipterional (pterional keyhole, PKC) approaches have become mainstays for clipping intracranial aneurysms. While studies have compared these approaches to the traditional pterional craniotomy for clipping cerebral aneurysms, head-to-head comparisons of these workhorse keyhole approaches remain limited. METHODS: The authors queried three databases per PRISMA guidelines to identify all studies comparing the SOKC to the PKC for microsurgical clipping of cerebral aneurysms. Of 148 unique studies returned on initial query, a total of 5 studies published between 2013 and 2019 met inclusion criteria. Where applicable, quantitative meta-analysis was performed via the Mantel-Haenszel method using Review Manager v5.4 (Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Risk of bias (ROB) was assessed using the Cochrane ROBINS-I tool, and all studies were assigned a Level of Evidence (I-V). RESULTS: Across all five studies, the mean age ranged from 53.0 to 57.5 years old, and the cohort consisted of more females (n = 403, 60.6%) than males. The proportion of patients presenting with ruptured aneurysmal SAH was comparable between the SOKC and PKC cohorts (p = 0.43). Clipping rate [defined as the rate of successful aneurysm clip deployment with successful intraoperative occlusion] (OR 1.52 [0.49, 4.71], I2 = 0%, p = 0.47), final occlusion rates (OR 1.27 [0.37, 4.32], p = 0.70), and operative durations (SMD 0.33 [-0.83. 1.49], I2 = 97%, p = 0.58) were comparable regardless of approach used. Furthermore, rates of intraoperative rupture (OR 1.51 [0.64, 3.55], I2 = 0, p = 0.34), postoperative hemorrhage (OR 1.49 [0.74, 3.01], I2 = 0, p = 0.26), postoperative vasospasm (OR 0.94 [0.49, 1.80], I2 = 63, p = 0.86), and postoperative infection (OR 0.70 [0.16, 2.99], I2 = 0%, p = 0.63) were equivocal across SOKC and PKC cohorts. CONCLUSION: The PKC and SOKC approaches appear to afford comparable outcomes when used for open microsurgical clipping of cerebral aneurysms in select patients with both ruptured and unruptured aneurysms. Both are associated with excellent clipping and occlusion rates, minimal perioperative complication profiles, and favorable postoperative neurologic outcomes. Further investigations are merited so clinicians can further parse out the indications and contraindications for each keyhole approach.

Assessing views and attitudes toward the use of extended reality and its implications in neurosurgical education: a survey of neurosurgical trainees.

OBJECTIVE: Extended reality (XR) systems, including augmented reality (AR), virtual reality (VR), and mixed reality, have rapidly emerged as new technologies capable of changing the way neurosurgeons prepare for cases. Thus, the authors sought to evaluate the perspectives of neurosurgical trainees on the integration of these technologies into neurosurgical education. METHODS: A 20-question cross-sectional survey was administered to neurosurgical residents and fellows to evaluate perceptions of the use of XR in neurosurgical training. Respondents evaluated each statement using a modified Likert scale (1-5). RESULTS: One hundred sixteen responses were recorded, with 59.5% of participants completing more than 90% of the questions. Approximately 59% of participants reported having institutional access to XR technologies. The majority of XR users (72%) believed it was effective for simulating surgical situations, compared with only 41% for those who did not have access to XR. Most respondents (61%) agreed that XR could become a standard in neurosurgical education and a cost-effective training tool (60%). Creating patient-specific anatomical XR models was considered relatively easy by 56% of respondents. Those with XR access reported finding it easier to create intraoperative models (58%) than those without access. A significant percentage (79%) agreed on the need for technical skill training outside the operating room (OR), especially among those without XR access (82%). There was general agreement (60%) regarding the specific need for XR. XR was perceived as effectively simulating stress in the OR. Regarding clinical outcomes, 61% believed XR improved efficiency and safety and 48% agreed it enhanced resection margins. Major barriers to XR integration included lack of ample training hours and/or time to use XR amid daily clinical obligations (63%). CONCLUSIONS: The data presented in this study indicate that there is broad agreement among neurosurgical trainees that XR holds potential as a training modality in neurosurgical education. Moreover, trainees who have access to XR technologies tend to hold more positive perceptions regarding the benefits of XR in their training. This finding suggests that the availability of XR resources can positively influence trainees' attitudes and beliefs regarding the utility of these technologies in their education and training.

Phosphoproteomics reveals conserved exercise-stimulated signaling and AMPK regulation of store-operated calcium entry.

Exercise stimulates cellular and physiological adaptations that are associated with widespread health benefits. To uncover conserved protein phosphorylation events underlying this adaptive response, we performed mass spectrometry-based phosphoproteomic analyses of skeletal muscle from two widely used rodent models: treadmill running in mice and in situ muscle contraction in rats. We overlaid these phosphoproteomic signatures with cycling in humans to identify common cross-species phosphosite responses, as well as unique model-specific regulation. We identified > 22,000 phosphosites, revealing orthologous protein phosphorylation and overlapping signaling pathways regulated by exercise. This included two conserved phosphosites on stromal interaction molecule 1 (STIM1), which we validate as AMPK substrates. Furthermore, we demonstrate that AMPK-mediated phosphorylation of STIM1 negatively regulates store-operated calcium entry, and this is beneficial for exercise in Drosophila. This integrated cross-species resource of exercise-regulated signaling in human, mouse, and rat skeletal muscle has uncovered conserved networks and unraveled crosstalk between AMPK and intracellular calcium flux.

Health Care Utilization and Costs in Systemic Therapies for Metastatic Melanoma from 2016 to 2020.

BACKGROUND: Widespread implementation of immune checkpoint inhibitors (ICI) and targeted therapies for metastatic melanoma has led to a decline in melanoma-related mortality but increased healthcare costs. We aimed to determine how healthcare utilization varied by systemic, non-adjuvant melanoma treatment from 2016 to 2020. PATIENTS AND METHODS: Adults with presumed stage IV metastatic melanoma receiving systemic therapy from 2016 to 2020 were identified in Optum, a nationwide commercial claims database. Treatment groups were nivolumab, pembrolizumab, ipilimumab+nivolumab (combination-ICI), or BRAF+MEK inhibitor (BRAFi+MEKi) therapy. Outcomes included hospitalizations, days hospitalized, emergency room (ER) visits, outpatient visits, and healthcare costs per patient per month (pppm). Multivariable regression models were used to analyze whether cost and utilization outcomes varied by treatment group, with nivolumab as reference. RESULTS: Among 2018 adult patients with metastatic melanoma identified, mean (SD) age was 67 (15) years. From 2016 to 2020, nivolumab surpassed pembrolizumab as the most prescribed systemic melanoma therapy while combination-ICI and BRAFi+MEKi therapies remained stable. Relative to nivolumab, all other therapies were associated with increased total healthcare costs (combination-ICI: ß = $47 600 pppm, 95%CI $42 200-$53 100; BRAFi+MEKi: ß = $3810, 95%CI $365-$7260; pembrolizumab: ß = $6450, 95%CI $4420-$8480). Combination-ICI and BRAFi+MEKi therapies were associated with more inpatient hospital days. CONCLUSIONS: Amid the evolving landscape of systemic therapy for advanced melanoma, nivolumab monotherapy emerged as the most used and least costly systemic treatment from 2016 to 2020. Its sharp increase in use in 2018 and lower costs relative to pembrolizumab may in part be due to earlier adoption of less frequent dosing intervals.

mTOR-dependent loss of PON1 secretion and antiphospholipid autoantibody production underlie autoimmunity-mediated cirrhosis in transaldolase deficiency.

Transaldolase deficiency predisposes to chronic liver disease progressing from cirrhosis to hepatocellular carcinoma (HCC). Transition from cirrhosis to hepatocarcinogenesis depends on mitochondrial oxidative stress, as controlled by cytosolic aldose metabolism through the pentose phosphate pathway (PPP). Progression to HCC is critically dependent on NADPH depletion and polyol buildup by aldose reductase (AR), while this enzyme protects from carbon trapping in the PPP and growth restriction in TAL deficiency. Although AR inactivation blocked susceptibility to hepatocarcinogenesis, it enhanced growth restriction, carbon trapping in the non-oxidative branch of the PPP and failed to reverse the depletion of glucose 6-phosphate (G6P) and liver cirrhosis. Here, we show that inactivation of the TAL-AR axis results in metabolic stress characterized by reduced mitophagy, enhanced overall autophagy, activation of the mechanistic target of rapamycin (mTOR), diminished glycosylation and secretion of paraoxonase 1 (PON1), production of antiphospholipid autoantibodies (aPL), loss of CD161+ NK cells, and expansion of CD38+ Ito cells, which are responsive to treatment with rapamycin in vivo. The present study thus identifies glycosylation and secretion of PON1 and aPL production as mTOR-dependent regulatory checkpoints of autoimmunity underlying liver cirrhosis in TAL deficiency.

Assessing survival outcomes and complication profiles following surgical excision and radiotherapy as interventions for skull base chordoma: a systematic review of operative margins and surgical approaches.

INTRODUCTION: Despite their precarious behavioral classification (benign and low grade on histopathology yet behaviorally malignant), great strides have been taken to improve prognostication and treatment paradigms for patients with skull base chordoma. With respect to surgical techniques, lateral transcranial (TC) approaches have traditionally been used, however endoscopic endonasal approaches (EEA) have been advocated for midline lesions. Nonetheless, due to the rarity of this pathology (0.2% of all intracranial neoplasms), investigations within the literature remain limited to small retrospective series. Furthermore, radiotherapeutic treatments investigated to date have proven largely ineffective. METHODS: Accordingly, we performed a systematic review in order to profile surgical and survival outcomes for skull base chordoma. Fixed and random-effect meta-analyses were performed for categorical variables including GTR, STR, 5-year OS, 10-year OS, 5-year PFS, and 10-year PFS. Additionally, we pooled eligible studies for formal meta-analysis to compare outcomes by surgical approach (lateral versus midline). Statistical analyses were performed using R Studio 'metafor' package or Cochrane Review Manager. Furthermore, meta-analysis of pooled mortality rates and sub-analyses of operative margin and surgical complications were used to compare midline versus lateral approaches via the Mantel-Haenszel method. We considered all p-values < 0.05 to be statistically significant. RESULTS: Following the systematic search and screen, 55 studies published between 1993 and 2022 reporting data for 2453 patients remained eligible for analysis. Sex distribution was comparable between males and females, with a slight predominance of male-identifying patients (0.5625 [95% CI: 0.5418; 0.3909]). Average age at diagnosis was 42.4 ± 12.5 years, while average age of treatment initiation was 43.0 ± 10.6 years. Overall, I2 value indicated notable heterogeneity across the 55 studies [I2 = 56.3% (95%CI: 44.0%; 65.9%)]. With respect to operative margins, the rate of GTR was 0.3323 [95% CI: 0.2824; 0.3909], I2 = 91.9% [95% CI: 90.2%; 93.4%], while the rate of STR was significantly higher at 0.5167 [95% CI: 0.4596; 0.5808], I2 = 93.1% [95% CI: 91.6%; 94.4%]. The most common complication was CSF leak (5.4%). In terms of survival outcomes, 5-year OS rate was 0.7113 [95% CI: 0.6685; 0.7568], I2 = 91.9% [95% CI: 90.0%; 93.5%]. 10-year OS rate was 0.4957 [95% CI: 0.4230; 0.5809], I2 = 92.3% [95% CI: 89.2%; 94.4%], which was comparable to the 5-year PFS rate of 0.5054 [95% CI: 0.4394; 0.5813], I2 = 84.2% [95% CI: 77.6%; 88.8%] and 10-yr PFS rate of 0.4949 [95% CI: 0.4075; 0.6010], I2 = 14.9% [95% CI: 0.0%; 87.0%]. There were 55 reported deaths for a perioperative mortality rate of 2.5%. The relative risk for mortality in the midline group versus the lateral approach group did not indicate any substantial difference in survival according to laterality of approach (-0.93 [95% CI: -1.03, -0.97], I2 = 95%, (p < 0.001). CONCLUSION: Overall, these results indicate good 5-year survival outcomes for patients with skull base chordoma; however, 10-year prognosis for skull base chordoma remains poor due to its radiotherapeutic resistance and high recurrence rate. Furthermore, mortality rates among patients undergoing midline versus lateral skull base approaches appear to be equivocal.

Generation Z and the Radiology Workforce: Ready or Not, Here I Come.

In 2023, the radiology community will experience the beginning of a generational change by matching its first class of Generation Z residents. To best welcome and embrace the changing face of the radiology workforce, this Viewpoint highlights the values that this next generation will bring, how radiologists can improve the way they teach the next generation, and the positive impact that Generation Z will have on the specialty and the way radiologists care for patients.

Periphyton Phosphorus Uptake in Response to Dynamic Concentrations in Streams: Assimilation and Changes to Intracellular Speciation.

Effective modeling and management of phosphorus (P) losses from landscapes to receiving waterbodies requires an adequate understanding of P retention and remobilization along the terrestrial-aquatic continuum. Within aquatic ecosystems, the stream periphyton can transiently store bioavailable P through uptake and incorporation into biomass during subscouring and baseflow conditions. However, the capacity of stream periphyton to respond to dynamic P concentrations, which are ubiquitous in streams, is largely unknown. Our study used artificial streams to impose short periods (48 h) of high SRP concentration on stream periphyton acclimated to P scarcity. We examined periphyton P content and speciation through nuclear magnetic resonance spectroscopy to elucidate the intracellular storage and transformation of P taken up across a gradient of transiently elevated SRP availabilities. Our study demonstrates that the stream periphyton not only takes up significant quantities of P following a 48-h high P pulse but also sustains supplemental growth over extended periods of time (10 days), following the reestablishment of P scarcity by efficiently assimilating P stored as polyphosphates into functional biomass (i.e., phospho-monoesters and phospho-diesters). Although P uptake and intracellular storage approached an upper limit across the experimentally imposed SRP pulse gradient, our findings demonstrate the previously underappreciated extent to which the periphyton can modulate the timing and magnitude of P delivery from streams. Further elucidating these intricacies in the transient storage potential of periphyton highlights opportunities to enhance the predictive capacity of watershed nutrient models and potentially improve watershed P management.

Comparison of clinicopathologic features, survival, and demographics in sebaceous carcinoma patients with and without Muir-Torre syndrome.

BACKGROUND: Visceral malignancies in patients with Lynch syndrome behave less aggressively than in those without Lynch syndrome. The behavior of sebaceous carcinoma (SC) in Muir-Torre syndrome (MTS), a variant of Lynch syndrome, is incompletely investigated. OBJECTIVE: To investigate features and survival of SC patients with and without MTS. METHODS: Retrospective cohort study in the Surveillance, Epidemiology, and End Results 17 database from 2000 to 2019 of patients with SC. Patients were classified as MTS or non-MTS cases based on a threshold score of 2 on the Mayo MTS risk score. RESULTS: We identified 105 (2.8%) MTS cases and 3677 (97.2%) non-MTS cases. On univariate analysis, MTS patients were younger, had a higher proportion of tumors outside the head/neck, and had fewer high-grade tumors. On Kaplan-Meier analysis, MTS patients trended toward having better SC-specific survival. On multivariate Cox proportional hazards analysis adjusting for other covariates, MTS status was an independent predictor of worse overall survival. However, there was no association between MTS status and SC-specific survival. LIMITATIONS: Given relatively high disease-specific survival in SC, our study may have been underpowered to detect a difference on Kaplan-Meier analysis. CONCLUSIONS: Our study suggests SC does not behave more aggressively in patients with MTS.

Predicted Negative Ion Photoelectron Spectra of 1-, 2-, and 9-Cyanoanthracene Radical Anions and Computed Thermochemical Values of the Three Cyanoanthracene Isomers.

In this work, the negative ion photoelectron spectra of 1-, 2-, and 9-cyanoanthracene (anthracenecarbonitrile, ACN) radical anions, obtained via the calculation of Franck-Condon (FC) factors based on a harmonic oscillator model, are reported. The FC calculations utilize harmonic vibrational frequencies and normal mode vectors derived from density functional theory using the B3LYP/6-311++G (2d,2p) basis set. The removal of an electron from the doublet anion allows for the computation of the negative ion photoelectron spectra that represents the neutral ground singlet state (So) and the lowest triplet state (T1) in each of the three ACN molecules. The respective adiabatic electron affinity (EA) values for the So state in 1-, 2-, and 9-ACN isomers are calculated to be 1.353, 1.360, and 1.423 eV. The calculated EA of the 9-cyanoanthracene singlet isomer is in close agreement with the previously reported experimental value of 1.27 ± 0.1 eV. Calculations show that the T1 states in 1-, 2-, and 9-ACN are located 1.656, 1.663, and 1.599 eV above the So state. The calculated T1 negative ion spectra exhibit intense vibrational origins and weak FC activity beyond the origins, indicating little change in geometry following electron detachment from the doublet anionic state. Upon deprotonation, the EA values of the radical isomers increase by ∼400-700 meV, resulting in neutral deprotonated radicals with EAs between 1.740 and 2.220 eV. The calculated site-specific gas-phase acidity values of ACN isomers indicate that ACN molecules are more acidic than benzonitrile.

Acute Mania and Psychosis in the Context of Primary Adrenal Insufficiency: A Systematic Review of the Literature.

BACKGROUND: Given the sparse nature of acute mania or psychosis in primary adrenal insufficiency (PAI), physicians may not be aware of the association of these two entities. OBJECTIVE: To conduct a systematic review of the literature for the purpose of identifying all studies reporting mania and/or psychosis in individuals with PAI. METHOD: We conducted a systematic review according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines using the PubMed, Embase, and Web of Science databases from June 22, 1970 to June 22, 2021, for the purpose of identifying all studies reporting instances of mania or psychosis associated with PAI. RESULTS: We identified nine case reports featuring nine patients (M age = 43.3 years, male = 44.4%) over eight countries that fit our inclusion/exclusion criteria. Eight (89%) of the patients had experienced psychosis. Manic and/or psychotic symptom resolution was achieved in 100% of the cases, of which steroid replacement therapy was efficacious in seven (78%) cases and was sufficient in six (67%). CONCLUSION: Acute mania and psychosis in the context of PAI is a very rare presentation of an already uncommon disease. Resolution of acute psychiatric change is reliably achieved with the correction of underlying adrenal insufficiency.