Lipoprotein(a), C-Reactive Protein, and Cardiovascular Risk in Primary and Secondary Prevention Populations.

Importance: Elevated lipoprotein(a) (Lp[a]) is a putative causal risk factor for atherosclerotic cardiovascular disease (ASCVD). There are conflicting data as to whether Lp(a) may increase cardiovascular risk only in the presence of concomitant inflammation. Objective: To investigate whether Lp(a) is associated with cardiovascular risk independent of high-sensitivity C-reactive protein (hs-CRP) in both primary and secondary prevention populations. Design, Setting, and Participants: This cohort study uses data from 3 distinct cohorts, 1 population-based cohort and 2 randomized clinical trials. Participants included individuals from the UK Biobank (data from 2006-2010) without prevalent ASCVD, participants in the FOURIER (TIMI 59) trial (data from 2013-2017) who had baseline Lp(a) and hs-CRP data, and participants in the SAVOR-TIMI 53 trial (data from 2010-2013) who had prevalent ASCVD and baseline values for Lp(a) and hs-CRP. The data analysis took place from November 2022 to November 2023. Exposure: Baseline plasma Lp(a), considered either as a continuous variable or dichotomized at 125 nmol/L. Main Outcomes and Measures: Risk of major adverse cardiovascular events (MACE) (composite of cardiovascular death, myocardial infarction [MI], or ischemic stroke), the individual MACE components, and peripheral artery disease (PAD). Results: Among 357 220 individuals in the UK Biobank without prevalent ASCVD, 232 699 (65%) had low hs-CRP (<2 mg/L), and 124 521 (35%) had high hs-CRP (≥2 mg/L) values. In a Cox proportional hazard model adjusted for ASCVD risk factors, higher Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP value for MACE (hs-CRP ≥2 mg/L: hazard ratio [HR] per 50-nmol/L higher Lp[a], 1.05; 95% CI, 1.04-1.07; P < .001; for hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.04-1.07; P < .001; P = .80 for interaction), as well as MI, ischemic stroke, and PAD individually. Among 34 020 individuals in the FOURIER and SAVOR trials with baseline cardiometabolic disease, there were 17 643 (52%) with low and 16 377 (48%) with high baseline hs-CRP values. In Cox proportional hazard models using aggregated data from FOURIER and SAVOR, higher baseline Lp(a) was associated with increased cardiovascular risk regardless of baseline hs-CRP for MACE (hs-CRP ≥2 mg/L: HR per 50-nmol/L higher Lp[a], 1.02; 95% CI, 1.00-1.05; P = .04; hs-CRP <2 mg/L: HR, 1.05; 95% CI, 1.02-1.08; P < .001; P = .16 for interaction), MI, and PAD. Conclusions and Relevance: In this study, higher levels of Lp(a) were associated with MACE, MI, and PAD in both primary and secondary prevention populations regardless of baseline hs-CRP value.

Novel Polygenic Risk Score and Established Clinical Risk Factors for Risk Estimation of Aortic Stenosis.

Importance: Polygenic risk scores (PRSs) have proven to be as strong as or stronger than established clinical risk factors for many cardiovascular phenotypes. Whether this is true for aortic stenosis remains unknown. Objective: To develop a novel aortic stenosis PRS and compare its aortic stenosis risk estimation to established clinical risk factors. Design, Setting, and Participants: This was a longitudinal cohort study using data from the Million Veteran Program (MVP; 2011-2020), UK Biobank (2006-2010), and 6 Thrombolysis in Myocardial Infarction (TIMI) trials, including DECLARE-TIMI 58 (2013-2018), FOURIER (TIMI 59; 2013-2017), PEGASUS-TIMI 54 (2010-2014), SAVOR-TIMI 53 (2010-2013), SOLID-TIMI 52 (2009-2014), and ENGAGE AF-TIMI 48 (2008-2013), which were a mix of population-based and randomized clinical trials. Individuals from UK Biobank and the MVP meeting a previously validated case/control definition for aortic stenosis were included. All individuals from TIMI trials were included unless they had a documented preexisting aortic valve replacement. Analysis took place from January 2022 to December 2023. Exposures: PRS for aortic stenosis (developed using data from MVP and validated in UK Biobank) and other previously validated cardiovascular PRSs, defined either as a continuous variable or as low (bottom 20%), intermediate, and high (top 20%), and clinical risk factors. Main Outcomes: Aortic stenosis (defined using International Classification of Diseases or Current Procedural Terminology codes in UK Biobank and MVP or safety event data in the TIMI trials). Results: The median (IQR) age in MVP was 67 (57-73) years, and 135 140 of 147 104 participants (92%) were male. The median (IQR) age in the TIMI trials was 66 (54-78) years, and 45 524 of 59 866 participants (71%) were male. The best aortic stenosis PRS incorporated 5 170 041 single-nucleotide variants and was associated with aortic stenosis in both the MVP testing sample (odds ratio, 1.41; 95% CI, 1.37-1.45 per 1 SD PRS; P = 4.6 × 10-116) and TIMI trials (hazard ratio, 1.44; 95% CI, 1.27-1.62 per 1 SD PRS; P = 3.2 × 10-9). Among genetic and clinical risk factors, the aortic stenosis PRS performed comparably to most risk factors besides age, and within a given age range, the combination of clinical and genetic risk factors was additive, providing a 3- to 4-fold increased gradient of risk of aortic stenosis. However, the addition of the aortic stenosis PRS to a model including clinical risk factors only improved risk discrimination of aortic stenosis by 0.01 to 0.02 (C index in MVP: 0.78 with clinical risk factors, 0.79 with risk factors and aortic stenosis PRS; C index in TIMI: 0.71 with clinical risk factors, 0.73 with risk factors and aortic stenosis PRS). Conclusions: This study developed and validated 1 of the first aortic stenosis PRSs. While aortic stenosis genetic risk was independent from clinical risk factors and performed comparably to all other risk factors besides age, genetic risk resulted in only a small improvement in overall aortic stenosis risk discrimination beyond age and clinical risk factors. This work sets the stage for further development of an aortic stenosis PRS.

Chromosome evolution screens recapitulate tissue-specific tumor aneuploidy patterns.

Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer.

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

[The end of dialysis: the weariness to carry on]. / Médecin et patient face à l'arrêt de la dialyse : la fatigue de continuer.

Voluntary cessation of hemodialysis is a common cause of death in dialysis patients, often occurring related to an alteration in their quality of life. At the same time, psychiatric disorders such as depression or anxiety are common and often underestimated among these patients, that accentuate the suffering and complicate compliance with dialysis. In this paper some psychopathological conditions will be addressed, as well as the question of the patient's ambivalence towards dialysis and the clinical and ethical dilemma of caregivers: respect the patient's choice to stop treatment or keep them alive at all costs? A multidisciplinary approach, including palliative care, is essential to support the reflection and make balanced decisions while respecting patient autonomy.

L'arrêt volontaire de l'hémodialyse est une cause fréquente de décès chez les patients dialysés, survenant souvent en lien avec une détérioration de leur qualité de vie. Parallèlement, les conditions psychiatriques comme la dépression ou l'anxiété sont répandues et souvent sous-estimées chez ces patients, en accentuant la souffrance et en compliquant la compliance à la dialyse. Dans cet article, sont abordées certaines conditions psychopathologiques, ainsi que la question de l'ambivalence du patient face à la dialyse et le dilemme clinique et éthique des soignants: respecter le choix du patient d'arrêter le traitement ou le maintenir en vie à tout prix? Une approche pluridisciplinaire, incluant également les soins palliatifs, est essentielle pour accompagner la réflexion et prendre des décisions pondérées dans le respect de l'autonomie des patients.

Pre- and post-treatment in flexor tendon tenolysis: An observational study.

BACKGROUND: Glide deficit of the distal flexors' tendons following primary repair in zone 1-3 are very common. Adhesions of tendons have multi factorial origins and are closely related to the healing of the affected tissues. The surgical practice used to resolve these complications is tenolysis. PURPOSE: The purpose of this study was to identify and compare the Visual Analog Scale (VAS) relate to pain and Total Active Motion (TAM) of adult patients of both sexes undergoing tenolysis surgery. The results will then be compared to existing research to confirm their significance. STUDY DESIGN: Case-series. METHODS: Retrospective data for TAM and pain VAS were extracted from the medical records for 63 patients (73 fingers) who underwent flexor tenolysis between 2017 and 2019. Data were compared pre-operatively and 3 months after surgery. All patients underwent pre- and post-surgery therapy by hand therapists. RESULTS: The sample presented very encouraging improvements, except in the VAS and active range of motion (AROM) of thumb where some patients maintained the same assessment. The fingers reported statistically significant results, whereas the thumb group did not meet significant criteria. Overall, TAM improved from 134.6° to 196.7 and VAS decreased from 2.7 to 1.2. DISCUSSION: According to the results and the data change between pre- and post-treatment, the sample demonstrated improvements in all areas examined, reporting statistically significant results for the fingers with an improvement of TAM of 62.1° with a percentage value (%TAM) of 75.6%. CONCLUSIONS: A specific treatment for this type of surgery is required for the patients so they can return to their daily and working activities. This article can be used as a starting point for further studies.

[Borderline psychiatric disorder in the general hospital : specificity and clinical challenges]. / Personnalité borderline à l'hôpital général : spécificités et défis cliniques.

Borderline personality disorder (BPD) is a psychiatric condition frequently encountered at the general hospital. This article will focus on the multiple presentation of this mental illness in the aforementioned setting, such as chronic somatic disease, multiple physical complaints as well as chronic pain, all of which that could severely alter the life quality. In this context, especially if there is an unsatisfied need for reinsurance, risk taking behavior (self-harm or harming others) may arise, as well as significant rise of medical costs through multiple medical consultations, longer average lengths of stay and additional complementary examinations. Through a variety of recommendations and a better understanding of BPD, a therapeutic link can be established to facilitate management.

Le trouble de la personnalité borderline (TPB) est une condition psychopathologique fréquente à l'hôpital général. Dans cet article, nous abordons le spectre des présentations cliniques intrahospitalières, dont les pathologies somatiques chroniques, les plaintes physiques multiples et les douleurs chroniques. L'ensemble de ces conditions impactent lourdement la qualité de vie des patients atteints d'un TPB. Lorsque les besoins de réassurance ne sont pas satisfaits, peuvent apparaître des comportements auto et hétéro-agressifs, ainsi qu'une augmentation des coûts médicaux, via une hausse des consultations, des durées de séjour à l'hôpital somatique et des examens complémentaires. Grâce à diverses recommandations et à une meilleure connaissance du TPB, un lien thérapeutique facilitant la prise en charge peut être établi.

XEN 45 Gel Stent Implantation in Open Angle Glaucoma: 5-Year Results of a Prospective Study.

PRCIS: XEN 45 Gel Stent is safe and effective for 3 years. The study results provide useful insight into the outcome of XEN 45 Gel Stent surgery over 5 years in daily clinical practice. PURPOSE: To evaluate 5-year outcomes of XEN 45 gel stent implantation (XEN) in patients with open angle glaucoma. METHODS: This is a prospective, single-center, interventional study. XEN implantation either alone (XEN) or combined with phacoemulsification (Phaco + XEN) was performed on 170 consecutive eyes (126 patients) with uncontrolled intraocular pressure (IOP) or disease progression despite medical treatment. "Complete" surgical success at 60 months was defined as unmedicated IOP ≤15 mm Hg and a relative IOP reduction ≥20% from medicated baseline, while "qualified" success allowed fewer ocular hypotensive medications than at baseline. Other definitions of success with various IOP targets were also analyzed. Secondary outcomes included mean IOP and IOP-lowering medication changes and rates of reoperations. RESULTS: Mean age was 78.1±9.2 years, and 70.3% were female. Mean medicated IOP decreased from 19.8±7.7 mm Hg [19.6±7.1 (XEN) vs. 19.8±7.0 mm Hg (Phaco+XEN)] at baseline to 12.6±3.1 mm Hg [12.5± 3.1 (XEN) vs. 12.6±3.1 (Phaco+XEN)] at 5 years (-37.0%; P < 0.001). Medications decreased from 2.0±1.3 [2.0±1.3 (XEN) vs. 2.0±1.3 (Phaco+XEN)] to 0.8±1.1 [0.8±1.1 (XEN) vs. 0.8±1.1 (Phaco + XEN)] (-60%; P <0.001). Needling was performed in 84 eyes (49%), and 19.4% underwent a secondary surgical intervention. Complete success at 3 years was a strong predictor of success at 5 years (odds ratio: 3.06, P <0.01), while needling was associated with higher rates of failure (odds ratio: 3.6, P <0.01). CONCLUSIONS: At 5 years, XEN gel stent implantation was a safe procedure and achieved clinically meaningful IOP and medication reduction. Success at 3 years is a predictor of success at 5 years. Needling correlates with higher failure rates.

Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention.

Importance: The clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established. Objective: To investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk. Design, Setting, and Participants: This was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022. Exposures: Polygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), or high risk (≥20%). Main Outcomes and Measures: Myocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death). Results: A total of 330 201 patients (median [IQR] age, 57 [40-74] years; 189 107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age <50 years: hazard ratio [HR] per 1 SD of PRS, 1.72; 95% CI, 1.56-1.89; age 50-60 years: HR, 1.46; 95% CI, 1.38-1.53; age >60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction <.001). In patients younger than 50 years, those with high PRS had a 3- to 4-fold increased associated risk of MI compared with those in the low PRS category. A significant interaction between CAD PRS and age was replicated in Biobank Japan. When CAD PRS testing was added to the clinical ASCVD risk score in individuals younger than 50 years, 591 of 4373 patients (20%) with borderline risk were risk stratified into intermediate risk, warranting initiation of statin therapy and 3198 of 7477 patients (20%) with both borderline or intermediate risk were stratified as low risk, thus not warranting therapy. Conclusions and Relevance: Results of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.

Respiratory Intensive Care Unit management and efficacy during the COVID-19 outbreak in Naples, Italy.

The World Health Organization declared the Coronavirus Diseases 2019 (COVID-19) outbreak a global pandemic on March 11, 2020. COVID-19 had an impact on over 500 million people worldwide. According to the American Thoracic Society criteria, the respiratory spectrum of this disease ranges from mild illness to severe pneumonia, with the latter occurring in a not insignificant 15% of patients. A rapid increase in the incidence of COVID-19 pneumonia cases has been observed all over the world, resulting in a saturation of the Intensive Care Unit's capacity (ICUs). Because of this impressive outbreak, the ICU beds and invasive mechanical ventilators reached their capacity. Non-invasive supportive care has become an important option for keeping respiratory conditions under control. As a result, proper healthcare resource management was required to ensure adequate patient care. Respiratory Intensive Care Units (RICUs) have become a useful resource for managing complex patients due to a shortage of ICU capacity. This highlighted the importance of RICUs, where patients with moderate to severe respiratory failure can be treated with non-invasive respiratory support rather than being admitted to the ICU. The clinical outcomes and baseline characteristics of patients admitted to the RICU of Cotugno Hospital, a tertiary referral center in Naples (Italy), from January 2021 to October 2021 are described in this report.

Conjugated Polymers for Microwave Applications: Untethered Sensing Platforms and Multifunctional Devices.

In the past two decades, organic electronic materials have enabled and accelerated a large and diverse set of technologies, from energy-harvesting devices and electromechanical actuators, to flexible and printed (opto)electronic circuitry. Among organic (semi)conductors, organic mixed ion-electronic conductors (OMIECs) are now at the center of renewed interest in organic electronics, as they are key drivers of recent developments in the fields of bioelectronics, energy storage, and neuromorphic computing. However, due to the relatively slow switching dynamics of organic electronics, their application in microwave technology, until recently, has been overlooked. Nonetheless, other unique properties of OMIECs, such as their substantial electrochemical tunability, charge-modulation range, and processability, make this field of use ripe with opportunities. In this work, the use of a series of solution-processed intrinsic OMIECs is demonstrated to actively tune the properties of metamaterial-inspired microwave devices, including an untethered bioelectrochemical sensing platform that requires no external power, and a tunable resonating structure with independent amplitude- and frequency-modulation. These devices showcase the considerable potential of OMIEC-based metadevices in autonomous bioelectronics and reconfigurable microwave optics.

The keystone flap: A multi-centric experience in elderly patients treatment.

Soft tissue reconstruction in elderly patients must be rapid and reliable. The keystone island flap (KF) offers an effective solution, with low complication rates and quick recovery. This multi-centric study aims to show authors' experience with KFs in treating soft tissue defects of trunk and limbs. Patients with soft tissue defects suitable for KF reconstruction were recruited from March 2019 to December 2019. Active inflammation and previous surgeries in the same region were considered exclusion criteria. Complications that occurred during follow-up were recorded, and their incidence pattern was assessed with the Fisher test. Seventy-two patients with mean age of 76.2 years old were selected. They presented lesions in torso (46; 63.9%) or in upper (4; 5.6%) or lower (22; 30.6%) limb regions. Fifteen (20.8%) wounds were non-oncologic lesions, and the others were oncologic lesions, mostly non-melanoma skin cancers. KF type I was carried out in 42 (58.3%) cases, KF type II-A in 13 (18%) cases, double opposed type III KF in 16 (22.2%) patients, and 1 (1.4%) case required partial flap's undermining (IV KF). Mean post-operative recovery period was 4.3 days (range, 1-9 days). Post-surgical complications occurred in 15 (20.8%) cases, 7 (9.7%) of them were considered major complications. No statistically significant difference in complications' incidence, nor among different surgical sites nor among KF types, was registered. Reconstructive surgeons have to adapt their work to elderly patients. The KF allows rapid operative times, low morbidity rates, and short post-operative recovery time, thus appearing as a feasible solution.

Bilateral Nonpenetrating Deep Sclerectomy: Difference in Outcomes Between First- and Second-Operated Eyes at 24 Months.

BACKGROUND/AIM: The aim of this study was to assess the difference in outcome between the first-operated and the second-operated eyes after nonpenetrating deep sclerectomy (DS), and to identify potential success predictors for the second eye. METHODS: This single-surgeon, retrospective study analyzed the outcomes of all bilateral nonsimultaneous DS with at least 24 months of follow-up. Its main outcome measure was surgical success, defined as unmedicated intraocular pressure (IOP) ≤15 mm Hg associated with a relative reduction ≥20%. RESULTS: In all, 104 eyes of 52 patients who underwent bilateral (standalone or combined) DS, within a mean of 344.3±526.3 days of each other, were analyzed. Postoperatively, the mean medicated IOP decreased from 20.7±7.9 (first-operated eyes) and 19.3±6.6 mm Hg (second-operated eyes) at baseline (P=0.107) to 13.8±4.8 [(-33.3%; P<0.001) first-operated eyes) and 12.7±3.8 mm Hg [(-34.2%; P<0.001) second-operated eyes] after 2 years (P=0.619). Postoperative IOP and treatment reduction, respectively, showed fair (r=0.53) and good (r=0.71) levels of correlation between fellow eyes. The rates of complete success were comparable between first-operated and second-operated eyes (32.7% and 40.4%, respectively; P=0.364). At 2 years, among patients whose first-operated eyes were considered a success, 82.4% of surgeries in second eyes were successful (P=0.001). The odds ratio of a second-operated eye experiencing complete success were 6.32 (P=0.011) if the first-operated eye experienced complete success. CONCLUSIONS: The present study demonstrated a strong association between first-operated and second-operated eyes after DS, in terms of surgical outcomes and IOP reduction. In effect, surgical success in the first-operated eye increases the odds of success in the second eye by 6-fold.

Association of Apolipoprotein B-Containing Lipoproteins and Risk of Myocardial Infarction in Individuals With and Without Atherosclerosis: Distinguishing Between Particle Concentration, Type, and Content.

IMPORTANCE: Lipid management typically focuses on levels of low-density lipoprotein cholesterol (LDL-C) and, to a lesser extent, triglycerides (TG). However, animal models and genetic studies suggest that the atherogenic particle subpopulations (LDL and very-low-density lipoprotein [VLDL]) are both important and that the number of particles is more predictive of cardiac events than their lipid content. OBJECTIVE: To determine whether common measures of cholesterol concentration, TG concentration, or their ratio are associated with cardiovascular risk beyond the number of apolipoprotein B (apoB)-containing lipoproteins. DESIGN, SETTING, AND PARTICIPANTS: This prospective cohort analysis included individuals from the population-based UK Biobank and from 2 large international clinical trials, FOURIER and IMPROVE-IT. The median (IQR) follow-up was 11.1 (10.4-11.8) years in UK Biobank and 2.5 (2.0-4.7) years in the clinical trials. Two populations were studied in this analysis: 389 529 individuals in the primary prevention group who were not taking lipid-lowering therapy and 40 430 patients with established atherosclerosis who were receiving statin treatment. EXPOSURES: ApoB, non-high-density lipoprotein cholesterol (HDL-C), LDL-C, and TG. MAIN OUTCOME AND MEASURES: The primary study outcome was incident myocardial infarction (MI). RESULTS: Of the 389 529 individuals in the primary prevention group, 224 097 (58%) were female, and the median (IQR) age was 56.0 (49.5-62.5) years. Of the 40 430 patients with established atherosclerosis, 9647 (24%) were female, and the median (IQR) age was 63 (56.2-69.0) years. In the primary prevention cohort, apoB, non-HDL-C, and TG each individually were associated with incident MI. However, when assessed together, only apoB was associated (adjusted hazard ratio [aHR] per 1 SD, 1.27; 95% CI, 1.15-1.40; P < .001). Similarly, only apoB was associated with MI in the secondary prevention cohort. Adjusting for apoB, there was no association between the ratio of TG to LDL-C (a surrogate for the ratio of TG-rich lipoproteins to LDL) and risk of MI, implying that for a given concentration of apoB-containing lipoproteins, the relative proportions of particle subpopulations may no longer be a predictor of risk. CONCLUSIONS AND RELEVANCE: In this cohort study, risk of MI was best captured by the number of apoB-containing lipoproteins, independent from lipid content (cholesterol or TG) or type of lipoprotein (LDL or TG-rich). This suggests that apoB may be the primary driver of atherosclerosis and that lowering the concentration of all apoB-containing lipoproteins should be the focus of therapeutic strategies.

Computational analysis of cancer genome sequencing data.

Distilling biologically meaningful information from cancer genome sequencing data requires comprehensive identification of somatic alterations using rigorous computational methods. As the amount and complexity of sequencing data have increased, so has the number of tools for analysing them. Here, we describe the main steps involved in the bioinformatic analysis of cancer genomes, review key algorithmic developments and highlight popular tools and emerging technologies. These tools include those that identify point mutations, copy number alterations, structural variations and mutational signatures in cancer genomes. We also discuss issues in experimental design, the strengths and limitations of sequencing modalities and methodological challenges for the future.

Blood gas analyses in hyperbaric and underwater environments: a systematic review.

Pulmonary gas exchange during diving or in a dry hyperbaric environment is affected by increased breathing gas density and possibly water immersion. During free diving, there is also the effect of apnea. Few studies have published blood gas data in underwater or hyperbaric environments: this review summarizes the available literature and was used to test the hypothesis that arterial Po2 under hyperbaric conditions can be predicted from blood gas measurement at 1 atmosphere assuming a constant arterial/alveolar Po2 ratio (a:A). A systematic search was performed on traditional sources including arterial blood gases obtained on humans in hyperbaric or underwater environments. The a:A was calculated at 1 atmosphere absolute (ATA). For each condition, predicted arterial partial pressure of oxygen ([Formula: see text]) at pressure was calculated using the 1 ATA a:A, and the measured [Formula: see text] was plotted against the predicted value with Spearman correlation coefficients. Of 3,640 records reviewed, 30 studies were included: 25 were reports describing values obtained in hyperbaric chambers, and the remaining were collected while underwater. Increased inspired O2 at pressure resulted in increased [Formula: see text], although underlying lung disease in patients treated with hyperbaric oxygen attenuated the rise. [Formula: see text] generally increased only slightly. In breath-hold divers, hyperoxemia generally occurred at maximum depth, with hypoxemia after surfacing. The a:A adequately predicted the [Formula: see text] under various conditions: dry (r = 0.993, P < 0.0001), rest versus exercise (r = 0.999, P < 0.0001), and breathing mixtures (r = 0.995, P < 0.0001). In conclusion, pulmonary oxygenation under hyperbaric conditions can be reliably and accurately predicted from 1 ATA a:A measurements.

Caracterización colorimétrica del proceso termogravimétrico de la deshidroxilación de caolín hidrotermal y de toba / Colorimetric characterization of thermogravimetric process for dehydroxilation of hydrothermal and tuff kaolins

El metacaolín es el producto obtenido de la calcinación del caolín. La alta actividad puzolánica del metacaolín permite su utilización como un material sustituto del cemento en el concreto. Esta y otras propiedades fisicoquímicas se ven afectadas por las condiciones de procesamiento del caolín. Por lo tanto, este estudio tuvo como objetivo caracterizar los cambios del color y densidad de dos tipos de caolín (toba triturada e hidrotermal) por medio de un análisis termogravimétrico del proceso de calcinación. Para la evaluación de la densidad se empleó la norma ASTM C188, mientras que la valoración de los cambios de color utilizó un espectrofotómetro C I E - L* a * b* en conjunto con la norma UNE 80117. Asimismo, la pérdida de peso y la densidad se correlacionaron con las coordenadas de color mediante una regresión polinomial. Los resultados demostraron que la deshidroxi-lación de los caolines ocurrió entre 400 ºC y 650 ºC, caracterizándose por un máximo en el delta E* de 12.9 y 4.3 para el caolín hidrotermal y de toba, respectivamente. Además, el caolín de toba triturada presentó la máxima luminosidad (L* = 92.84) de todos los tratamientos a los 21 ºC. Este valor disminuyó 11.75% al incrementar la temperatura hasta 450 ºC. A partir de esta temperatura,L* incrementó linealmente hasta alcanzar un valor final de 87.3 a 900 ºC. La regresión polinomial obtenida explica en un 93% y 92% la variación del peso en función de los parámetros C I E - L* a * b* para el caolín de toba triturada e hidrotermal, respectivamente.

Metakaolin is a product of kaolin's calcination. The high pozzolanic activity of metakaolin allows its usage as supplementary cementitious material in concrete. This property and other physicochemical properties are affected by metakaolin's manufacturing conditions. Therefore, this study aims to characterize the changes in color and density of two types of kaolin (tuff and hydrothermal) through a thermogravimetric analysis of the calcina-tion process. Evaluation of density used ASTM C188, while the assessment of color changes used a CIE-L*a*b* spectrophotometer in conjunction with normative UNE 80117. In addition, weight loss and density were correlated with the color coordinates using polynomial regression. The results showed that kaolin dehydroxylation occurred at 450ºC and 650ºC, characterized by a maximum in delta E * of 12.9 and 4.3 for hydrothermal and tuff kaolin, respectively. In addition, the tuff kaolin presented the maximum luminosity (L * = 92.84) of all the treatments at 21ºC. This value decreased 11.75% during the temperature increment up to 450ºC. From this temperature, L * increased linearly until reaching a final value of 87.3 at 900ºC. The polynomial regression explained 93% and 92% of the weight variation as a function of the CIE-L*a*b* parameters for tuff and hydrothermal kaolin, respectively.

The origins and genetic interactions of KRAS mutations are allele- and tissue-specific.

Mutational activation of KRAS promotes the initiation and progression of cancers, especially in the colorectum, pancreas, lung, and blood plasma, with varying prevalence of specific activating missense mutations. Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear. Here, we analyze 13,492 samples from these four tumor types to examine allele- and tissue-specific genetic properties associated with oncogenic KRAS mutations. The prevalence of known mutagenic mechanisms partially explains the observed spectrum of KRAS activating mutations. However, there are substantial differences between the observed and predicted frequencies for many alleles, suggesting that biological selection underlies the tissue-specific frequencies of mutant alleles. Consistent with experimental studies that have identified distinct signaling properties associated with each mutant form of KRAS, our genetic analysis reveals that each KRAS allele is associated with a distinct tissue-specific comutation network. Moreover, we identify tissue-specific genetic dependencies associated with specific mutant KRAS alleles. Overall, this analysis demonstrates that the genetic interactions of oncogenic KRAS mutations are allele- and tissue-specific, underscoring the complexity that drives their clinical consequences.

Organizational aspects of pediatric anesthesia and surgery between two waves of Covid-19.

BACKGROUND: The initial wave of the Covid-19 pandemic has hit Italy, and Lombardy in particular, with violence, forcing to reshape all hospitals' activities; this happened even in pediatric hospitals, although the young population seemed initially spared from the disease. "Vittore Buzzi" Children's Hospital, which is a pediatric/maternal hospital located in Milan (Lombardy Region), had to stop elective procedures-with the exception of urgent/emergent ones-between February and May 2020 to leave space and resources to adults' care. We describe the challenges of reshaping the hospital's identity and structure, and restarting pediatric surgery and anesthesia, from May on, in the most hit area of the world, with the purpose to avoid and contain infections. Both patients and caregivers admitted to hospital have been tested for Sars-CoV-2 in every case. METHODS: Observational cohort study via review of clinical charts of patients undergoing surgery between 16th May and 30th September 2020, together with SARS-CoV -2 RT-PCR testing outcomes, and comparison to same period surgeries in 2019. RESULTS: An increase of approximately 70% in pediatric surgeries (OR 1.68 [1.33-2.13], P < .001) and a higher increase in the number of surgeries were reported (OR 1.75 (1.43-2.15), P < .001). Considering only urgent procedures, a significant difference in the distribution of the type of surgery was observed (Chi-squared P-value < .001). Sars-CoV-2-positive patients have been 0.8% of total number; 14% of these was discovered through caregiver's positivity. CONCLUSION: We describe our pathway for safe pediatric surgery and anesthesia and the importance of testing both patient and caregiver.