Opening of the Mitochondrial Permeability Transition Pore Causes Depletion of Mitochondrial and Cytosolic NAD+and Is a Causative Event in the Death of Myocytes in Postischemic Reperfusion of the Heart

The opening of the mitochondrial permeability transition pore (PTP) has been suggested to play a key role in various forms of cell death, but direct evidence in intact tissues is still lacking. We found that in the rat heart, 92% of NAD(+) glycohydrolase activity is associated with mitochondria. This activity was not modified by the addition of Triton X-100, although it was abolished by mild treatment with the protease Nagarse, a condition that did not affect the energy-linked properties of mitochondria. The addition of Ca(2+) to isolated rat heart mitochondria resulted in a profound decrease in their NAD(+) content, which followed mitochondrial swelling. Cyclosporin A(CsA), a PTP inhibitor, completely prevented NAD(+) depletion but had no effect on the glycohydrolase activity. Thus, in isolated mitochondria PTP opening makes NAD(+) available for its enzymatic hydrolysis. Perfused rat hearts subjected to global ischemia for 30 min displayed a 30% decrease in tissue NAD(+) content, which was not modified by extending the duration of ischemia. Reperfusion resulted in a more severe reduction of both total and mitochondrial contents of NAD(+), which could be measured in the coronary effluent together with lactate dehydrogenase. The addition of 0.2 microm CsA or of its analogue MeVal-4-Cs (which does not inhibit calcineurin) maintained higher NAD(+) contents, especially in mitochondria, and significantly protected the heart from reperfusion damage, as shown by the reduction in lactate dehydrogenase release. Thus, upon reperfusion after prolonged ischemia, PTP opening in the heart can be documented as a CsA-sensitive release of NAD(+), which is then partly degraded by glycohydrolase and partly released when sarcolemmal integrity is compromised. These results demonstrate that PTP opening is a causative event in reperfusion damage of the heart

Selective Hydrogenations and Dechlorinations in Water Mediated by Anionic Surfactant Stabilized Pd Nanoparticles

We report a facile, inexpensive and green method for the preparation of Pd nanoparticles in aqueous medium stabilized by anionic sulfonated surfactants sodium 1-dodecanesulfonate 1a, sodium dodecylbenzenesulfonate 1b, dioctyl sulfosuccinate sodium salt 1c and poly(ethylene glycol) 4-nonylphenyl-3-sulfopropyl ether potassium salt 1d simply obtained by stirring aqueous solutions of Pd(OAc)2 with the commercial anionic surfactants further treated under hydrogen atmosphere for variable times. The aqueous Pd nanoparticles solutions were tested in the selective hydrogenation reactions of aryl-alcohols, -aldehydes and -ketones leading to complete conversion to the deoxygenated products even in the absence of strong Brønsted acids in the reduction of aromatic aldehydes and ketones, in the controlled semi-hydrogenation of alkynes leading to alkenes and in the efficient hydro-dechlorination of aromatic substrates. In all cases the micellar media were crucial to stabilize the metal nanoparticles, to dissolve substrates, to steer product selectivity and to enable recycling. What is interesting is also that a benchmark catalyst like Pd/C can be often surpassed in activity and/or selectivity in the reactions tested by simply switching to the appropriate commercially available surfactant, thereby providing an easy to use, flexible and practical catalytic system capable of efficiently addressing a variety of synthetically significant hydrogenation reactions

Intranasal ketamine for procedural sedation and analgesia in children: A systematic review

Background Ketamine is commonly used for procedural sedation and analgesia (PSA) in children. Evidence suggests it can be administered intranasally (IN). We sought to review the evidence for IN ketamine for PSA in children. Methods We performed a systematic review of randomized trials of IN ketamine in PSA that reported any sedation-related outcome in children 0 to 19 years. Trials were identified through electronic searches of MEDLINE (1946±2016), EMBASE (1947±2016), Google Scholar (2016), CINAHL (1981±2016), The Cochrane Library (2016), Web of Science (2016), Scopus (2016), clinical trial registries, and conference proceedings (2000±2016) without language restrictions. The methodological qualities of studies and the overall quality of evidence were evaluated using the Cochrane Collaboration\u27s Risk of Bias tool, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system, respectively. Results The review included 7 studies (n = 264) of children ranging from 0 to 14 years. Heterogeneity in study design precluded meta-analysis. Most studies were associated with a low or unclear risk of bias and outcome-specific ratings for quality of evidence were low or very low. In four of seven studies, IN ketamine provided superior sedation to comparators and resulted in adequate sedation for 148/175 (85%) of participants. Vomiting was the most common adverse effect; reported by 9/91 (10%) of participants. Conclusions IN ketamine administration is well tolerated and without serious adverse effects. Although most participants were deemed adequately sedated with IN ketamine, effectiveness of sedation with respect to superiority over comparators was inconsistent, precluding a recommendation for PSA in children

Myocardial infarction with nonobstructive coronary arteries: from pathophysiology to therapeutic strategies

: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a heterogeneous group of clinical entities characterized by clinical evidence of acute myocardial infarction (AMI) with normal or near-normal coronary arteries on coronary angiography (stenosis < 50%) and without an over the alternative diagnosis for the acute presentation. Its prevalence ranges from 6% to 11% among all patients with AMI, with a predominance of young, nonwhite females with fewer traditional risks than those with an obstructive coronary artery disease (MI-CAD). MINOCA can be due to either epicardial causes such as rupture or fissuring of unstable nonobstructive atherosclerotic plaque, coronary artery spasm, spontaneous coronary dissection and cardioembolism in-situ or microvascular causes. Besides, also type-2 AMI due to supply-demand mismatch and Takotsubo syndrome must be considered as a possible MINOCA cause. Because of the complex etiology and a limited amount of evidence, there is still some confusion around the management and treatment of these patients. Therefore, the key focus of this condition is to identify the underlying individual mechanisms to achieve patient-specific treatments. Clinical history, electrocardiogram, echocardiography, and coronary angiography represent the first-level diagnostic investigations, but coronary imaging with intravascular ultrasound and optical coherent tomography, coronary physiology testing, and cardiac magnetic resonance imaging offer additional information to understand the underlying cause of MINOCA. Although the prognosis is slightly better compared with MI-CAD patients, MINOCA is not always benign and depends on the etiopathology. This review analyzes all possible pathophysiological mechanisms that could lead to MINOCA and provides the most specific and appropriate therapeutic approach in each scenario

Sex-Related Disparities in Cardiac Masses: Clinical Features and Outcomes

Background. Cardiac masses (CM) represent a heterogeneous clinical scenario, and sex-related differences of these patients remain to be established. Purpose: To evaluate sex-related disparities in CMs regarding clinical presentation and outcomes. Material and Methods. The study cohort included 321 consecutive patients with CM enrolled in our Centre between 2004 and 2022. A definitive diagnosis was achieved by histological examination or, in the case of cardiac thrombi, with radiological evidence of thrombus resolution after anticoagulant treatment. All-cause mortality at follow-up was evaluated. Multivariable regression analysis assessed the potential prognostic disparities between men and women. Results. Out of 321 patients with CM, 172 (54%) were female. Women were more frequently younger (p = 0.02) than men. Regarding CM histotypes, females were affected by benign masses more frequently (with cardiac myxoma above all), while metastatic tumours were more common in men (p < 0.001). At presentation, peripheral embolism occurred predominantly in women (p = 0.03). Echocardiographic features such as greater dimension, irregular margin, infiltration, sessile mass and immobility were far more common in men. Despite a better overall survival in women, no sex-related differences were observed in the prognosis of benign or malignant masses. In fact, in multivariate analyses, sex was not independently associated with all-cause death. Conversely, age, smoking habit, malignant tumours and peripheral embolism were independent predictors of mortality. Conclusions. In a large cohort of cardiac masses, a significant sex-related difference in histotype prevalence was found: Benign CMs affected female patients more frequently, while malignant tumours affected predominantly men. Despite better overall survival in women, sex did not influence prognosis in benign and malignant masses

Cardiac Magnetic Resonance to Predict Cardiac Mass Malignancy: The CMR Mass Score

Background: Multimodality imaging is currently suggested for the noninvasive diagnosis of cardiac masses. The identification of cardiac masses' malignant nature is essential to guide proper treatment. We aimed to develop a cardiac magnetic resonance (CMR)-derived model including mass localization, morphology, and tissue characterization to predict malignancy (with histology as gold standard), to compare its accuracy versus the diagnostic echocardiographic mass score, and to evaluate its prognostic ability. Methods: Observational cohort study of 167 consecutive patients undergoing comprehensive echocardiogram and CMR within 1-month time interval for suspected cardiac mass. A definitive diagnosis was achieved by histological examination or, in the case of cardiac thrombi, by histology or radiological resolution after adequate anticoagulation treatment. Logistic regression was performed to assess CMR-derived independent predictors of malignancy, which were included in a predictive model to derive the CMR mass score. Kaplan-Meier curves and Cox regression were used to investigate the prognostic ability of predictors. Results: In CMR, mass morphological features (non-left localization, sessile, polylobate, inhomogeneity, infiltration, and pericardial effusion) and mass tissue characterization features (first-pass perfusion and heterogeneity enhancement) were independent predictors of malignancy. The CMR mass score (range, 0-8 and cutoff, ≥5), including sessile appearance, polylobate shape, infiltration, pericardial effusion, first-pass contrast perfusion, and heterogeneity enhancement, showed excellent accuracy in predicting malignancy (areas under the curve, 0.976 [95% CI, 0.96-0.99]), significantly higher than diagnostic echocardiographic mass score (areas under the curve, 0.932; P=0.040). The agreement between the diagnostic echocardiographic mass and CMR mass scores was good (κ=0.66). A CMR mass score of ≥5 predicted a higher risk of all-cause death (P<0.001; hazard ratio, 5.70) at follow-up. Conclusions: A CMR-derived model, including mass morphology and tissue characterization, showed excellent accuracy, superior to echocardiography, in predicting cardiac masses malignancy, with prognostic implications

Search of the Orion spur for continuous gravitational waves using a loosely coherent algorithm on data from LIGO interferometers

We report results of a wideband search for periodic gravitational waves from isolated neutron stars within the Orion spur towards both the inner and outer regions of our Galaxy. As gravitational waves interact very weakly with matter, the search is unimpeded by dust and concentrations of stars. One search disk (A) is 6.87° in diameter and centered on 20h10m54.71s+33°33′25.29′′, and the other (B) is 7.45° in diameter and centered on 8h35m20.61s-46°49′25.151′′. We explored the frequency range of 50-1500 Hz and frequency derivative from 0 to -5×10-9 Hz/s. A multistage, loosely coherent search program allowed probing more deeply than before in these two regions, while increasing coherence length with every stage. Rigorous follow-up parameters have winnowed the initial coincidence set to only 70 candidates, to be examined manually. None of those 70 candidates proved to be consistent with an isolated gravitational-wave emitter, and 95% confidence level upper limits were placed on continuous-wave strain amplitudes. Near 169 Hz we achieve our lowest 95% C.L. upper limit on the worst-case linearly polarized strain amplitude h0 of 6.3×10-25, while at the high end of our frequency range we achieve a worst-case upper limit of 3.4×10-24 for all polarizations and sky locations. © 2016 American Physical Society

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Searching for stochastic gravitational waves using data from the two colocated LIGO Hanford detectors

Searches for a stochastic gravitational-wave background (SGWB) using terrestrial detectors typically involve cross-correlating data from pairs of detectors. The sensitivity of such cross-correlation analyses depends, among other things, on the separation between the two detectors: the smaller the separation, the better the sensitivity. Hence, a colocated detector pair is more sensitive to a gravitational-wave background than a noncolocated detector pair. However, colocated detectors are also expected to suffer from correlated noise from instrumental and environmental effects that could contaminate the measurement of the background. Hence, methods to identify and mitigate the effects of correlated noise are necessary to achieve the potential increase in sensitivity of colocated detectors. Here we report on the first SGWB analysis using the two LIGO Hanford detectors and address the complications arising from correlated environmental noise. We apply correlated noise identification and mitigation techniques to data taken by the two LIGO Hanford detectors, H1 and H2, during LIGO’s fifth science run. At low frequencies, 40–460 Hz, we are unable to sufficiently mitigate the correlated noise to a level where we may confidently measure or bound the stochastic gravitational-wave signal. However, at high frequencies, 460–1000 Hz, these techniques are sufficient to set a 95% confidence level upper limit on the gravitational-wave energy density of Ω(f) < 7.7 × 10[superscript -4](f/900  Hz)[superscript 3], which improves on the previous upper limit by a factor of ~180. In doing so, we demonstrate techniques that will be useful for future searches using advanced detectors, where correlated noise (e.g., from global magnetic fields) may affect even widely separated detectors.National Science Foundation (U.S.)United States. National Aeronautics and Space AdministrationCarnegie TrustDavid & Lucile Packard FoundationAlfred P. Sloan Foundatio