Post-intensive care syndrome and health-related quality of life in long-term survivors of cardiac arrest: a prospective cohort study.

Patients discharged from intensive care are at risk for post-intensive care syndrome (PICS), which consists of physical, psychological, and/or neurological impairments. This study aimed to analyze PICS at 24 months follow-up, to identify potential risk factors for PICS, and to assess health-related quality of life in a long-term cohort of adult cardiac arrest survivors. This prospective cohort study included adult cardiac arrest survivors admitted to the intensive care unit of a Swiss tertiary academic medical center. The primary endpoint was the prevalence of PICS at 24 months follow-up, defined as impairments in physical (measured through the European Quality of Life 5-Dimensions-3-Levels instrument [EQ-5D-3L]), neurological (defined as Cerebral Performance Category Score > 2 or Modified Rankin Score > 3), and psychological (based on the Hospital Anxiety and Depression Scale and the Impact of Event Scale-Revised) domains. Among 107 cardiac arrest survivors that completed the 2-year follow-up, 46 patients (43.0%) had symptoms of PICS, with 41 patients (38.7%) experiencing symptoms in the physical domain, 16 patients (15.4%) in the psychological domain, and 3 patients (2.8%) in the neurological domain. Key predictors for PICS in multivariate analyses were female sex (adjusted odds ratio [aOR] 3.17, 95% CI 1.08 to 9.3), duration of no-flow interval during cardiac arrest (minutes) (aOR 1.17, 95% CI 1.02 to 1.33), post-discharge job-loss (aOR 31.25, 95% CI 3.63 to 268.83), need for ongoing psychological support (aOR 3.64, 95% CI 1.29 to 10.29) or psychopharmacologic treatment (aOR 9.49, 95% CI 1.9 to 47.3), and EQ-visual analogue scale (points) (aOR 0.88, 95% CI 0.84 to 0.93). More than one-third of cardiac arrest survivors experience symptoms of PICS 2 years after resuscitation, with the highest impairment observed in the physical and psychological domains. However, long-term survivors of cardiac arrest report intact health-related quality of life when compared to the general population. Future research should focus on appropriate prevention, screening, and treatment strategies for PICS in cardiac arrest patients.

Does Single Dose Epinephrine Improve Outcomes for Patients with Out-of-Hospital Cardiac Arrest and Bystander CPR or a Shockable Rhythm?

Background: A single dose epinephrine protocol (SDEP) for out-of-hospital cardiac arrest (OHCA) achieves similar survival to hospital discharge (SHD) rates as a multidose epinephrine protocol (MDEP). However, it is unknown if a SDEP improves SHD rates among patients with a shockable rhythm or those receiving bystander cardiopulmonary resuscitation (CPR).Methods: This pre-post study, spanning 11/01/2016-10/29/2019 at 5 North Carolina EMS systems, compared pre-implementation MDEP and post-implementation SDEP in patients ≥18 years old with non-traumatic OHCA. Data on initial rhythm type, performance of bystander CPR, and the primary outcome of SHD were sourced from the Cardiac Arrest Registry to Enhance Survival. We compared SDEP vs MDEP performance in each rhythm (shockable and non-shockable) and CPR (bystander CPR or no bystander CPR) subgroup using Generalized Estimating Equations to account for clustering among EMS systems and to adjust for age, sex, race, witnessed arrest, arrest location, AED availability, EMS response interval, and presence of a shockable rhythm or receiving bystander CPR. The interaction of SDEP implementation with rhythm type and bystander CPR was evaluated.Results: Of 1690 patients accrued (899 MDEP, 791 SDEP), 19.2% (324/1690) had shockable rhythms and 38.9% (658/1690) received bystander CPR. After adjusting for confounders, SHD was increased after SDEP implementation among patients with bystander CPR (aOR 1.61, 95%CI 1.03-2.53). However, SHD was similar in the SDEP cohort vs MDEP cohort among patients without bystander CPR (aOR 0.81, 95%CI 0.60-1.09), with a shockable rhythm (aOR 0.96, 95%CI 0.48-1.91), and with a non-shockable rhythm (aOR 1.26, 95%CI 0.89-1.77). In the adjusted model, the interaction between SDEP implementation and bystander CPR was significant for SHD (p = 0.002).Conclusion: Adjusting for confounders, the SDEP increased SHD in patients who received bystander CPR and there was a significant interaction between SDEP and bystander CPR. Single dose epinephrine protocol and MDEP had similar SHD rates regardless of rhythm type.

Oral corticosteroid dosage and tapeduration at onset in myelin oligodendrocyte glycoprotein antibody-associated disease influences time to first relapse.

BACKGROUND: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure. METHODS: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy. RESULTS: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p=0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p=0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p=0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect. CONCLUSIONS: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse.

Clinicopathological profile and management challenges of congenital encephaloceles in a tertiary hospital in southwest Nigeria.

PURPOSE: A congenital encephalocele is the herniation of intracranial contents through skull defects of various sizes. Depending on the site, content, and size, it is associated with significant morbidity and mortality in children. There is a paucity of recent and comprehensive local clinical data regarding this anomaly. Understanding the peculiarities, clinical-pathologic profiles, and management challenges will help prevent and effectively manage congenital encephalocele to improve outcomes. METHODS: This was a retrospective study of all cases of congenital encephalocele managed between July 2000 and December 2023 at a tertiary hospital in the southwest region of Nigeria. Relevant demographic, clinicopathological, and management data were retrieved and analysed. RESULTS: There were 31 females and 11 males. Their ages ranged from 3 hours to 24 years. Sixteen (35.3%) were delivered in a non-health facility. Birth asphyxia was reported in 5 babies. Few mothers (4.8%) used preconception folic acid. Anaemia (n = 5) and sepsis (n = 4) were the common preoperative morbidities. All patients had definitive surgery, with 18 operated on within the first month of life. Cerebrospinal fluid (CSF) leak was the most common postoperative complication and was significantly observed in the sincipital group (p = 0.018). Thirty-one patients (73.8%) presented for follow-up after surgery, and the mean follow-up duration was 26.6 weeks. Mortality was recorded in a patient (2.4%) due to Klebsiella meningitis. CONCLUSION: Congenital encephaloceles are relatively common in our setting. Therefore, there is a need to address the associated poor maternal and neonatal health conditions. Early surgery can be performed with a favourable outcome.

Contrasting magma chemistry in the Candelaria IOCG district caused by changing tectonic regimes.

Iron oxide-copper-gold (IOCG) deposits are a vital source of copper and critical elements for emerging clean technologies. Andean-type IOCG deposits form in continental arcs undergoing extension, and they have a temporal relationship with magmatism although they do not exhibit a close spatial relation with the causative intrusions. The processes required to form IOCG deposits and their potential connections to iron oxide-apatite (IOA)-type mineralization remain poorly constrained, as well as the characteristics of magmatism linked to both deposit types. Here we combine zircon U-Pb geochronology with zircon trace element geochemistry of intrusive rocks associated with the Candelaria deposit, one of the world's largest IOCG deposits, to unravel distinctive signatures diagnostic of magmatic fertility. Our results reveal a marked transition in the geochemistry of intrusions in the Candelaria district, characterized by changes in the redox state, water content and temperature of magmas over time. The oldest magmatic stage (~ 128-125 Ma), prior to the formation of the Candelaria deposit, was characterized by zircon Eu/Eu* ratios of 0.20-0.42, and redox conditions of ΔFMQ - 0.4 to + 1.0. The earliest magmatic stage related to the formation of Fe-rich mineralization at Candelaria (118-115 Ma) exhibits low zircon Eu/Eu* ratios (0.09-0.18), low oxygen fugacity values (ΔFMQ ~- 1.8 to + 0.2) and relatively high crystallization temperatures. In contrast, the youngest stage at ~ 111-108 Ma shows higher zircon Eu/Eu* (~ 0.37-0.69), higher oxygen fugacity values (ΔFMQ ~ + 0.4 to + 1.3) and a decrease in crystallization temperatures, conditions that are favorable for the transport and precipitation of sulfur and chalcophile elements. We conclude that Candelaria was formed through two distinct ore-forming stages: the first associated with a reduced, high temperature, water-poor magma developed under a low tectonic stress, followed by a more oxidized, water-rich, and low temperature magmatic event related to a compressional regime. The first event led to Fe-rich and S-poor IOA-type mineralization, while the second event with geochemical signatures similar to those of porphyry copper systems, generated the Cu- and S-rich mineralization. This late stage overprinted preexisting IOA mineralization resulting in the formation of the giant Candelaria IOCG deposit.

Experimental Demonstration of Reservoir Computing with Self-Assembled Percolating Networks of Nanoparticles.

The complex self-assembled network of neurons and synapses that comprises the biological brain enables natural information processing with remarkable efficiency. Percolating networks of nanoparticles (PNNs) are complex self-assembled nanoscale systems that have been shown to possess many promising brain-like attributes and which are therefore appealing systems for neuromorphic computation. Here experiments are performed that show that PNNs can be utilized as physical reservoirs within a nanoelectronic reservoir computing framework and demonstrate successful computation for several benchmark tasks (chaotic time series prediction, nonlinear transformation, and memory capacity). For each task, relevant literature results are compiled and it is shown that the performance of the PNNs compares favorably to that previously reported from nanoelectronic reservoirs. It is then demonstrated experimentally that PNNs can be used for spoken digit recognition with state-of-the-art accuracy. Finally, a parallel reservoir architecture is emulated, which increases the dimensionality and richness of the reservoir outputs and results in further improvements in performance across all tasks.

Iron alloys of volatile elements in the deep Earth's interior.

Investigations into the compositional model of the Earth, particularly the atypical concentrations of volatile elements within the silicate portion of the early Earth, have attracted significant interest due to their pivotal role in elucidating the planet's evolution and dynamics. To understand the behavior of such volatile elements, an established 'volatility trend' has been used to explain the observed depletion of certain volatile elements. However, elements such as Se and Br remain notably over-depleted in the silicate Earth. Here we show the results from first-principles simulations that explore the potential for these elements to integrate into hcp-Fe through the formation of substitutional alloys, long presumed to be predominant constituents of the Earth's core. Based on our findings, the thermodynamic stability of these alloys suggests that these volatile elements might indeed be partially sequestered within the Earth's core. We suggest potential reservoirs for volatile elements within the deep Earth, augmenting our understanding of the deep Earth's composition.

Modular slot-die coater for in situ grazing-incidence x-ray scattering experiments on thin films.

Multimodal in situ experiments during slot-die coating of thin films pioneer the way to kinetic studies on thin-film formation. They establish a powerful tool to understand and optimize the formation and properties of thin-film devices, e.g., solar cells, sensors, or LED films. Thin-film research benefits from time-resolved grazing-incidence wide- and small-angle x-ray scattering (GIWAXS/GISAXS) with a sub-second resolution to reveal the evolution of crystal structure, texture, and morphology during the deposition process. Simultaneously investigating optical properties by in situ photoluminescence measurements complements in-depth kinetic studies focusing on a comprehensive understanding of the triangular interdependency of processing, structure, and function for a roll-to-roll compatible, scalable thin-film deposition process. Here, we introduce a modular slot-die coater specially designed for in situ GIWAXS/GISAXS measurements and applicable to various ink systems. With a design for quick assembly, the slot-die coater permits the reproducible and comparable fabrication of thin films in the lab and at the synchrotron using the very same hardware components, as demonstrated in this work by experiments performed at Deutsches Elektronen-Synchrotron (DESY). Simultaneous to GIWAXS/GISAXS, photoluminescence measurements probe optoelectronic properties in situ during thin-film formation. An environmental chamber allows to control the atmosphere inside the coater. Modular construction and lightweight design make the coater mobile, easy to transport, quickly extendable, and adaptable to new beamline environments.

Testing the Resilience, Physiological Plasticity and Mechanisms Underlying Upper Temperature Limits of Antarctic Marine Ectotherms.

Antarctic marine ectotherms live in the constant cold and are characterised by limited resilience to elevated temperature. Here we tested three of the central paradigms underlying this resilience. Firstly, we assessed the ability of eight species, from seven classes representing a range of functional groups, to survive, for 100 to 303 days, at temperatures 0 to 4 °C above previously calculated long-term temperature limits. Survivors were then tested for acclimation responses to acute warming and acclimatisation, in the field, was tested in the seastar Odontaster validus collected in different years, seasons and locations within Antarctica. Finally, we tested the importance of oxygen limitation in controlling upper thermal limits. We found that four of 11 species studied were able to survive for more than 245 days (245-303 days) at higher than previously recorded temperatures, between 6 and 10 °C. Only survivors of the anemone Urticinopsis antarctica did not acclimate CTmax and there was no evidence of acclimatisation in O. validus. We found species-specific effects of mild hyperoxia (30% oxygen) on survival duration, which was extended (two species), not changed (four species) or reduced (one species), re-enforcing that oxygen limitation is not universal in dictating thermal survival thresholds. Thermal sensitivity is clearly the product of multiple ecological and physiological capacities, and this diversity of response needs further investigation and interpretation to improve our ability to predict future patterns of biodiversity.

Exome sequencing identifies HELB as a novel susceptibility gene for non-mucinous, non-high-grade-serous epithelial ovarian cancer.

Rare, germline loss-of-function variants in a handful of genes that encode DNA repair proteins have been shown to be associated with epithelial ovarian cancer with a stronger association for the high-grade serous hiostotype. The aim of this study was to collate exome sequencing data from multiple epithelial ovarian cancer case cohorts and controls in order to systematically evaluate the role of coding, loss-of-function variants across the genome in epithelial ovarian cancer risk. We assembled exome data for a total of 2,573 non-mucinous cases (1,876 high-grade serous and 697 non-high grade serous) and 13,925 controls. Harmonised variant calling and quality control filtering was applied across the different data sets. We carried out a gene-by-gene simple burden test for association of rare loss-of-function variants (minor allele frequency < 0.1%) with all non-mucinous ovarian cancer, high grade serous ovarian cancer and non-high grade serous ovarian cancer using logistic regression adjusted for the top four principal components to account for cryptic population structure and genetic ancestry. Seven of the top 10 associated genes were associations of the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2 (false discovery probability < 0.1). A further four genes (HELB, OR2T35, NBN and MYO1A) had a false discovery rate of less than 0.1. Of these, HELB was most strongly associated with the non-high grade serous histotype (P = 1.3×10-6, FDR = 9.1×10-4). Further support for this association comes from the observation that loss of function variants in this gene are also associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

Inferring COVID-19 testing and vaccination behavior from New Jersey testing data.

Characterizing the relationship between disease testing behaviors and infectious disease dynamics is of great importance for public health. Tests for both current and past infection can influence disease-related behaviors at the individual level, while population-level knowledge of an epidemic's course may feed back to affect one's likelihood of taking a test. The COVID-19 pandemic has generated testing data on an unprecedented scale for tests detecting both current infection (PCR, antigen) and past infection (serology); this opens the way to characterizing the complex relationship between testing behavior and infection dynamics. Leveraging a rich database of individualized COVID-19 testing histories in New Jersey, we analyze the behavioral relationships between PCR and serology tests, infection, and vaccination. We quantify interactions between individuals' test-taking tendencies and their past testing and infection histories, finding that PCR tests were disproportionately taken by people currently infected, and serology tests were disproportionately taken by people with past infection or vaccination. The effects of previous positive test results on testing behavior are less consistent, as individuals with past PCR positives were more likely to take subsequent PCR and serology tests at some periods of the epidemic time course and less likely at others. Lastly, we fit a model to the titer values collected from serology tests to infer vaccination trends, finding a marked decrease in vaccination rates among individuals who had previously received a positive PCR test. These results exemplify the utility of individualized testing histories in uncovering hidden behavioral variables affecting testing and vaccination.

The Monocle Sign on 18F-FDG PET Indicates Contralateral Peripheral Facial Nerve Palsy.

BACKGROUND: The aim of our study was to retrospectively analyze FDG PET/CT data in patients with facial nerve palsy (FNP) for the presence of the monocle sign. PATIENTS AND METHODS: A total of 85 patients with unilateral FNP were included into our study, thereof 73 with peripheral FNP and 12 with central FNP. FDG uptake (SUVmax, SUVmean, total lesion glycolysis) was measured in both orbicularis oculi muscles (OOMs). FDG uptake of paretic and nonparetic muscles was compared in patients with FNP (Wilcoxon test and Mann-Whitney U test) and was also compared with FDG uptake in 33 patients without FNP (Mann-Whitney U test). SUVmax ratios of OOM were compared. A receiver operating characteristic curve and Youden Index were used to determine the optimal cutoff SUVmax ratio for the prevalence of contralateral peripheral FNP. RESULTS: The SUVmax ratio of OOM was significantly higher in patients with peripheral FNP compared with patients with central FNP and those without FNP (1.70 ± 0.94 vs 1.16 ± 0.09 vs 1.18 ± 0.21, respectively; P < 0.001). The SUVmax ratio of OOM yielded an area under the curve (AUC) of 0.719 (95% confidence interval, 0.630-0.809), with an optimal cutoff of 1.41, yielding a specificity of 94.4% and a sensitivity of 44.1% for identifying contralateral peripheral FNP. One hundred percent specificity is achieved using a cutoff of 1.91 (sensitivity, 29.4%). CONCLUSIONS: Asymmetrically increased FDG uptake of the OOM (the "monocle sign") indicates contralateral peripheral FNP. A nearly 2-fold higher SUVmax represents a practically useful cutoff.

Is rapid acute coronary syndrome evaluation with high-sensitivity cardiac troponin less costly? An economic evaluation.

Objective: Protocols to evaluate for myocardial infarction (MI) using high-sensitivity cardiac troponin (hs-cTn) have the potential to drive costs upward due to the added sensitivity. We performed an economic evaluation of an accelerated protocol (AP) to evaluate for MI using hs-cTn to identify changes in costs of treatment and length of stay compared with conventional testing. Methods: We performed a planned secondary economic analysis of a large, cluster randomized trial across nine emergency departments (EDs) from July 2020 to April 2021. Patients were included if they were 18 years or older with clinical suspicion for MI. In the AP, patients could be discharged without further testing at 0 h if they had a hs-cTnI < 4 ng/L and at 1 h if the initial value were 4 ng/L and the 1-h value ≤7 ng/L. Patients in the standard of care (SC) protocol used conventional cTn testing at 0 and 3 h. The primary outcome was the total cost of treatment, and the secondary outcome was ED length of stay. Results: Among 32,450 included patients, an AP had no significant differences in cost (+$89, CI: -$714, $893 hospital cost, +$362, CI: -$414, $1138 health system cost) or ED length of stay (+46, CI: -28, 120 min) compared with the SC protocol. In lower acuity, free-standing EDs, patients under the AP experienced shorter length of stay (-37 min, CI: -62, 12 min) and reduced health system cost (-$112, CI: -$250, $25). Conclusion: Overall, the implementation of AP using hs-cTn does not result in higher costs.

Risk factors for infection and outcomes in infants with neonatal encephalopathy: a cohort study.

BACKGROUND: To determine the association between early infection risk factors and short-term outcomes in infants with neonatal encephalopathy following perinatal asphyxia (NE). METHODS: A retrospective population-based cohort study utilizing the National Neonatal Research Database that included infants with NE admitted to neonatal units in England and Wales, Jan 2008-Feb 2018. EXPOSURE: one or more of rupture of membranes >18 h, maternal group B streptococcus colonization, chorioamnionitis, maternal pyrexia or antepartum antibiotics. PRIMARY OUTCOME: death or nasogastric feeds/nil by mouth (NG/NBM) at discharge. SECONDARY OUTCOMES: organ dysfunction; length of stay; intraventricular hemorrhage; antiseizure medications use. RESULTS: 998 (13.7%) out of 7265 NE infants had exposure to early infection risk factors. Primary outcome (20.3% vs. 23.1%, OR 0.87 (95% CI 0.71-1.08), p = 0.22), death (12.8% vs. 14.0%, p = 0.32) and NG/NBM (17.4% vs. 19.9%. p = 0.07) did not differ between the exposed and unexposed group. Time to full sucking feeds (OR 0.81 (0.69-0.95)), duration (OR 0.82 (0.71-0.95)) and the number of antiseizure medications (OR 0.84 (0.72-0.98)) were lower in exposed than unexposed infants after adjusting for confounders. Therapeutic hypothermia did not alter the results. CONCLUSIONS: Infants with NE exposed to risk factors for early-onset infection did not have worse short-term adverse outcomes. IMPACT: Risk factors for early-onset neonatal infection, including rupture of membranes >18 h, maternal group B streptococcus colonization, chorioamnionitis, maternal pyrexia or antepartum antibiotics, were not associated with death or short-term morbidity after cooling for NE. Despite exposure to risk factors for early-onset neonatal infection, infants with NE reached oral feeds earlier and needed fewer anti-seizure medications for a shorter duration than infants with NE but without such risk factors. This study supports current provision of therapeutic hypothermia for infants with NE and any risk factors for early-onset neonatal infection.

Aging-related defects in macrophage function are driven by MYC and USF1 transcriptional programs.

Macrophages are central innate immune cells whose function declines with age. The molecular mechanisms underlying age-related changes remain poorly understood, particularly in human macrophages. We report a substantial reduction in phagocytosis, migration, and chemotaxis in human monocyte-derived macrophages (MDMs) from older (>50 years old) compared with younger (18-30 years old) donors, alongside downregulation of transcription factors MYC and USF1. In MDMs from young donors, knockdown of MYC or USF1 decreases phagocytosis and chemotaxis and alters the expression of associated genes, alongside adhesion and extracellular matrix remodeling. A concordant dysregulation of MYC and USF1 target genes is also seen in MDMs from older donors. Furthermore, older age and loss of either MYC or USF1 in MDMs leads to an increased cell size, altered morphology, and reduced actin content. Together, these results define MYC and USF1 as key drivers of MDM age-related functional decline and identify downstream targets to improve macrophage function in aging.

Achieving the Fundamental Quantum Limit of Linear Waveform Estimation.

Sensing a classical signal using a linear quantum device is a pervasive application of quantum-enhanced measurement. The fundamental precision limits of linear waveform estimation, however, are not fully understood. In certain cases, there is an unexplained gap between the known waveform-estimation quantum Cramér-Rao bound and the optimal sensitivity from quadrature measurement of the outgoing mode from the device. We resolve this gap by establishing the fundamental precision limit, the waveform-estimation Holevo Cramér-Rao bound, and how to achieve it using a nonstationary measurement. We apply our results to detuned gravitational-wave interferometry to accelerate the search for postmerger remnants from binary neutron-star mergers. If we have an unequal weighting between estimating the signal's power and phase, then we propose how to further improve the signal-to-noise ratio by a factor of sqrt[2] using this nonstationary measurement.

Oncologic outcome with versus without target volume compartmentalization in postoperative radiotherapy for oral cavity squamous cell carcinoma.

Background and purpose: The volume treated with postoperative radiation therapy (PORT) in patients with oral cavity squamous cell carcinoma (OCSCC) is a mediator of toxicity affecting quality of life. Current guidelines only allow for very limited reduction of PORT volumes. This study investigated the safety and efficacy of de-intensified PORT for patients with OCSCC by refined compartmentalization of the treatment volume. Materials and methods: This retrospective cohort study identified 103 OCSCC patients treated surgically from 2014 to 2019 with a loco-regional risk profile qualifying for PORT according to guidelines. PORT was administered only to the at-risk compartment and according to a refined compartmentalization concept (CC). Oncological outcome of this CC cohort was compared to a historical cohort (HC) of 98 patients treated before the CC was implemented. Results: Median follow-up time was 4.5 and 4.8 years in the CC and HC cohorts, respectively. In the CC cohort, a total of 72 of 103 patients (70%) had a pathological risk profile that allowed for further compartmentalization and, hence, received a reduced treatment volume or omission of PORT altogether. Loco-regional control at 3 and 5 years was 77% and 73% in the CC cohort versus 78% and 73% in the HC (p = 0.93), progression-free survival was 72% and 64% versus75% and 68% (p = 0.58), respectively. Similarly, no statistically significant difference was seen in other outcome measures. Conclusions: De-intensified PORT limiting the treatment volume to the at-risk compartment or avoiding PORT altogether for low-risk patients with OCSCC does not seem to compromise disease control in this retrospective comparison. Based on these hypothesis-generating findings, a prospective study is being planned.

Molecular analysis using SalvGlandDx improves risk of malignancy estimation and diagnosis of salivary gland cytopathology: An exploratory multicenter study.

BACKGROUND: Diagnosis of salivary gland neoplasms is challenging, especially on cytological specimens acquired by fine-needle aspiration. The recently implemented standardized Milan system for reporting salivary gland cytopathology provides an estimated risk of malignancy (ROM); yet, for two of the categories, the diagnosis of the lesion remains unclear. However, a precise diagnosis is desirable for optimal patient management, including planning of surgery and imaging procedures. METHODS: Cytological specimens (n = 106) were subjected to molecular analysis using the SalvGlandDx panel. The risk of malignancy was calculated for each detected alteration based on the diagnosis of the resection specimen. By taking into account the molecular alterations, their associated ROM, the clinical and cytological features, and the current literature, the Milan category was evaluated. RESULTS: Of n = 63 technically valid cases, 76% revealed a molecular alteration. A total of 94% of these molecularly altered cases could be assigned to a different Milan category when additionally taking molecular results into account. In only 2% of the salivary gland neoplasms of uncertain malignant potential, in which a molecular alteration was detected, the classification remained salivary gland neoplasms of uncertain malignant potential. CONCLUSION: Molecular analysis of cytological specimens provides a benefit in classifying salivary gland neoplasms on fine-needle aspiration. It can improve the ROM estimation and thus help to assign cases of formerly unknown malignant potential to clearly benign or malignant categories.

Accelerated magnetocardiography in the evaluation of patients with suspected cardiac ischemia: The MAGNETO trial.

Background: Diagnosing ischemia in emergency department (ED) patients with suspected acute coronary syndrome (sACS) is challenging with equivocal disposition of intermediate risk patients. Objective: Compare sensitivity and specificity of magnetocardiography (MCG) versus standard of care (SOC) stress testing in diagnosing myocardial ischemia. Methods: Multicenter, prospective, observational cohort study. ED patients with sACS and HEART score ≥ 3 underwent 90 s noninvasive MCG to detect myocardial ischemia. Results were blinded to the patient's clinicians. MCGs were read independently by 3 physicians blinded to clinical data. Myocardial ischemia was ≥70 % epicardial coronary artery stenosis, revascularization within 30 days, or 30-day major adverse cardiac events (MACE). Time to first test (TTT) and patient satisfaction for MCG and SOC were compared. Results: Of enrolled patients (N = 390) (mean age 59 ± 12 years, 45 % female), 99 (25 %) underwent a non-invasive stress test: 42 (14 %) diagnosed with ischemia. MCG sensitivity was 66.7 % (50.5-80.4 %, 95 % CI) and specificity 57.1 % (50.0-63.3 %, 95 % CI) for detecting coronary ischemia. Noninvasive stress testing (stress echo, nuclear stress, and exercise stress) had the same sensitivity 66.7 % (95 % CI 29.9 % to 92.5 %) and a specificity of 89.9 % (95 % CI 81.7-95.3 %). Mean TTT was shorter for MCG, 3.18 h (SD 1.91) vs. SOC stress testing 22.71 (SD 15.23), p < 0.0001. Mean patient experience was MCG 4.7 versus 3.0 SOC stress testing (p < 0.0001). Conclusion: MCG provides similar sensitivity and lower specificity as non-invasive stress testing in ED sACS patients. Time to test is shorter for MCG with higher patient satisfaction scores.

AMP-activated protein kinase can be allosterically activated by ADP but AMP remains the key activating ligand.

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status. When activated by increases in ADP:ATP and/or AMP:ATP ratios (signalling energy deficit), AMPK acts to restore energy balance. Binding of AMP to one or more of three CBS repeats (CBS1, CBS3, CBS4) on the AMPK-γ subunit activates the kinase complex by three complementary mechanisms: (i) promoting α-subunit Thr172 phosphorylation by the upstream kinase LKB1; (ii) protecting against Thr172 dephosphorylation; (iii) allosteric activation. Surprisingly, binding of ADP has been reported to mimic the first two effects, but not the third. We now show that at physiologically relevant concentrations of Mg.ATP2- (above those used in the standard assay) ADP binding does cause allosteric activation. However, ADP causes only a modest activation because (unlike AMP), at concentrations just above those where activation becomes evident, ADP starts to cause competitive inhibition at the catalytic site. Our results cast doubt on the physiological relevance of the effects of ADP and suggest that AMP is the primary activator in vivo. We have also made mutations to hydrophobic residues involved in binding adenine nucleotides at each of the three γ subunit CBS repeats of the human α2ß2γ1 complex and examined their effects on regulation by AMP and ADP. Mutation of the CBS3 site has the largest effects on all three mechanisms of AMP activation, especially at lower ATP concentrations, while mutation of CBS4 reduces the sensitivity to AMP. All three sites appear to be required for allosteric activation by ADP.