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We present the most distant detection of cosmic voids (z ∼ 2.3) and the first detection of three-dimensional voids in the Lyα forest. We used a 3D tomographic map of the absorption with an effective comoving spatial resolution of 2.5 h -1 Mpc and a volume of 3.15 105 h -3 Mpc3, which was reconstructed from moderate-resolution Keck I/LRIS spectra of 240 background Lyman-break galaxies and quasars in a 0.16 deg2 footprint in the COSMOS field. Voids were detected using a spherical overdensity finder calibrated from hydrodynamical simulations of the intergalactic medium (IGM). This allows us to identify voids in the IGM corresponding to voids in the underlying matter density field, yielding a consistent volume fraction of voids in both data (19.5%) and simulations (18.2%). We fit excursion set models to the void radius function and compare the radially averaged stacked profiles of large voids (r > 5 h -1 Mpc) to stacked voids in mock observations and the simulated density field. Comparing with 432 coeval galaxies with spectroscopic redshifts in the same volume as the tomographic map, we find that the tomography-identified voids are underdense in galaxies by 5.95σ compared to random cells.

Using moderate-resolution optical spectra from 58 background Lyman-break galaxies and quasars at z ∼ 2.3-3 within a 11′.5 × 13′.5 area of the COSMOS field (∼1200 deg-2 projected area density or ∼2.4 h-1 Mpc mean transverse separation), we reconstruct a 3D tomographic map of the foreground Lyα forest absorption at 2.2 < z < 2.5 with an effective smoothing scale of ∈3D ≈ 2.5 h-1 Mpc comoving. Comparing with 61 coeval galaxies with spectroscopic redshifts in the same volume, we find that the galaxy positions are clearly biased toward regions with enhanced intergalactic medium (IGM) absorption in the tomographic map. We find an extended IGM overdensity with deep absorption troughs at z = 2.45 associated with a recently discovered galaxy protocluster at the same redshift. Based on simulations matched to our data, we estimate the enclosed dark matter mass within this IGM overdensity to be Mdm (z= 2.45) = (1.1 ± 0.6) ×1014 h-1 M⊙, and argue based on this mass and absorption strength that it will form at least one z ∼ 0 galaxy cluster with M(z = 0) = (3 ± 1.5) ×1014 h-1 M⊙, although its elongated nature suggests that it will likely collapse into two separate clusters. We also point out a compact overdensity of six MOSDEF galaxies at z = 2.30 within a r ∼ 1 h-1 Mpc radius and Δz ∼ 0.006, which does not appear to have a large associated IGM overdensity. These results demonstrate the potential of Lyα forest tomography on larger volumes to study galaxy properties as a function of environment, as well as revealing the large-scale IGM overdensities associated with protoclusters or other features of large-scale structure.

We present a new method of finding cosmic voids using tomographic maps of Lyα forest flux. We identify cosmological voids with radii of 2-12 h-1 Mpc in a large N-body simulation at z=2.5, and characterize the signal of the high-redshift voids in density and Lyα forest flux. The void properties are similar to what has been found at lower redshifts, but they are smaller and have steeper radial density profiles. Similarly towhat has been found for low-redshift voids, the radial velocity profiles have little scatter and agree very well with the linear theory prediction. We run the same void finder on an ideal Lyα flux field and tomographic reconstructions at various spatial samplings. We compare the tomographic map void catalogues to the density void catalogue and find good agreement even with modest-sized voids (r > 6 h-1 Mpc). Using our simple void-finding method, the configuration of the ongoing COSMOS Lyman Alpha Mapping And Tomography Observations (CLAMATO) survey covering 1 deg2 would provide a sample of about 100 high-redshift voids. We also provide void-finding forecasts for larger area surveys, and discuss how these void samples can be used to test modified gravity models, study high-redshift void galaxies, and to make an Alcock-Paczynski measurement. To aid future work in this area, we provide public access to our simulation products, catalogues, and sample tomographic flux maps.

We study the statistics of the Lyα forest in a flat Λ cold dark matter cosmology with the N-body + Eulerian hydrodynamics code NYX.We produce a suite of simulations, covering the observationally relevant redshift range 2 ≤ z ≤ 4. We find that a grid resolution of 20 h-1 kpc is required to produce 1 per cent convergence of Lyα forest flux statistics, up to k = 10 h-1 Mpc. In addition to establishing resolution requirements, we study the effects of missing modes in these simulations, and find that box sizes of L > 40h-1 Mpc are needed to suppress numerical errors to a sub-per cent level. Our optically thin simulations with the ionizing background prescription of Haardt & Madau reproduce an intergalactic medium density-temperature relation with T0 ≈ 104 K and γ ≈ 1.55 at z = 2, with a mean transmitted flux close to the observed values. When using the ionizing background prescription of Faucher-Giguère et al., the mean flux is 10-15 per cent below observed values at z = 2, and a factor of 2 too small at z = 4. We show the effects of the common practice of rescaling optical depths to the observed mean flux and how it affects convergence rates. We also investigate the practice of 'splicing' results from a number of different simulations to estimate the 1D flux power spectrum and show it is accurate at the 10 per cent level. Finally, we find that collisional heating of the gas from dark matter particles is negligible in modern cosmological simulations.

We present a new method of finding protoclusters using tomographic maps of Ly α forest flux. We review our method of creating tomographic flux maps and discuss our new highperformance implementation, which makes large reconstructions computationally feasible. Using a large N-body simulation, we illustrate how protoclusters create large-scale flux decrements, roughly 10 h-1 Mpc across, and how we can use this signal to find them in flux maps. We test the performance of our protocluster finding method by running it on the ideal, noiseless map and tomographic reconstructions from mock surveys, and comparing to the halo catalogue. Using the noiseless map, we find protocluster candidates with about 90 per cent purity, and recover about 75 per cent of the protoclusters that form massive clusters (>3 × 1014 h-1M⊙). We construct mock surveys similar to the ongoing COSMOS Lyman-Alpha Mapping And Tomography Observations survey. While the existing data have an average sightline separation of 2.3 h-1 Mpc, we test separations of 2-6 h-1 Mpc to see what can be tolerated for our application. Using reconstructed maps from small separation mock surveys, the protocluster candidate purity and completeness are very close to what was found in the noiseless case. As the sightline separation increases, the purity and completeness decrease, although they remain much higher than we initially expected. We extended our test cases to mock surveys with an average separation of 15 h-1 Mpc, meant to reproduce high source density areas of the Baryon Oscillation Spectroscopic Survey. We find that even with such a large sightline separation, the method can still be used to find some of the largest protoclusters.

Complex regional pain syndrome (CRPS) is a debilitating chronic pain condition that, although exceedingly rare, carries a significant burden for the affected patient population. The complex and ambiguous pathophysiology of this condition further complicates clinical management and therapeutic interventions. Furthermore, being a diagnosis of exclusion requires a diligent workup to ensure an accurate diagnosis and subsequent targeted management. The development of the Budapest diagnostic criteria helped to consolidate existing definitions of CRPS but extensive work remains in identifying the underlying pathways. Currently, two distinct types are identified by the presence (CRPS type 1) or absence (CRPS type 2) of neuronal injury. Current management directed at this disease is broad and growing, ranging from non-invasive modalities such as physical and psychological therapy to more invasive techniques such as dorsal root ganglion stimulation and potentially amputation. Ideal therapeutic interventions are multimodal in nature to address the likely multifactorial pathological development of CRPS. Regardless, a significant need remains for continued studies to elucidate the pathways involved in developing CRPS as well as more robust clinical trials for various treatment modalities.

A straightforward route to 1,4-dihydropyrrolo[3,2- b ]pyrroles comprised of two electron-withdrawing quinoline or tetrazolo[1,5- a ]quinoline scaffolds has been developed. The versatile multicomponent reaction affording 1,4-dihydropyrrolo[3,2- b ]pyrroles combined with intramolecular direct arylation enables assembly of these products in just three steps from anilines with overall yields exceeding 30%. The planarized, ladder-type heteroacenes possess up to 14 conjugated rings. These nominally quadrupolar materials exhibit efficient fluorescence with wavelengths spanning most of the visible spectrum from green-yellow for the dyes possessing biaryl bridges and orange-red for the fully fused systems. In many cases, the fluorescence quantum yields are large, the solvatofluorochromic effects are strong, and the fluorescence is maintained even in crystalline state. Analysis of the electronic structure of these molecular architectures using quantum chemical methods suggests that the character and position of the flanking heterocycle determine the shape of HOMO and LUMO and their extension to N -aryl substituents, influencing the values of molar absorption coefficient. An experimental study of the two-photon absorption (2PA) properties has revealed that it occurs in the 700-800 nm range with apparent deviation from the Laporte parity selection rule, which may be attributed to Hertzberg-Teller contribution to vibronically allowed 2PA transition.

Administering sugammadex to reverse neuromuscular blockade can cause marked bradycardia and rarely asystole. In this case, a rapid onset, biphasic heart rate response; slowing then speeding, after administering sugammadex was noted while at steady state, 1.3% end-tidal sevoflurane. On review of the electrocardiogram (ECG), the heart rate slowing coincided with the onset of a second-degree, Mobitz type I block that lasted 45 seconds. No other events, drugs, or stimuli coincided with the event. The acute onset and transient nature of the atrioventricular block without evidence of ischemia implies a brief parasympathetic effect on the atrioventricular node after sugammadex administration., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 International Anesthesia Research Society.)

Chronic pain is a debilitating condition with a growing prevalence both in the USA and globally. The complex nature of this condition necessitates a multimodal approach to pain management that extends beyond the established pharmaceutical interventions currently employed. A variety of devices comprising both invasive and noninvasive approaches are available to patients, serving as adjuvants to existing regimens. The benefits of these interventions are notable for their lack of addiction potential, potential for patient autonomy regarding self-administration, minimal to no drug interaction, and overall relative safety. However, there remains a need for further research and more robust clinical trials to assess the true efficacy of these interventions and elucidate if there is an underlying physiological mechanism to their benefit in treating chronic pain or if their effect is predominantly placebo in nature. Regardless, the field of device-based intervention and treatment remains an evolving field with much promise for the future chronic pain management., (© 2022. The Author(s).)

The Laporte rule dictates that one- and two-photon absorption spectra of inversion-symmetric molecules should display alternatively forbidden electronic transitions; however, for organic fluorophores, drawing clear distinction between the symmetric- and non-inversion symmetric two-photon spectra is often obscured due to prevalent vibronic interactions. We take advantage of consecutive single- and double-protonation to break and then reconstitute inversion symmetry in a nominally symmetric diketopyrrolopyrrole, causing large changes in two-photon absorption. By performing detailed one- and two-photon titration experiments, with supporting quantum-chemical model calculations, we explain how certain low-frequency vibrational modes may lead to apparent deviations from the strict Laporte rule. As a result, the system may be indeed considered as an on-off-on inversion symmetry switch, opening new avenues for two-photon sensing applications., (© 2022 Wiley-VCH GmbH.)

Purpose of Review: Migraines are prevalent and cause significant morbidity, decline in quality of life and healthcare costs universally. Treatment options are varied, but efficacy is limited. This review centers on Eptinezumab-jjmr, a humanized monoclonal specific to CGRP for the prevention of migraines in adults. Herein presented are the science and mechanism of action, indication and clinical evidence for use., Recent Findings: Migraines are severe, recurrent headaches, which are either episodic or chronic in nature. The pain is severe, often accompanied by co-morbid symptoms, such as photophobia, phonophobia, nausea and emesis, and is limiting in nature. It is a prevalent disorder that causes significant, worldwide disability, morbidity, suffering, and costs.The pathophysiology of migraines is actively studied, though recent research points to an initiating event causing migraine generation, that is then propagated by other brain regions, a significant one being the trigeminocervical complex. This is driven by biochemical transmitters, chiefly CGRP. This discovery led to the development of CGRP-targeting drugs, including gepants (small molecular antagonists) and anti-CGRP antibodies, such as Eptinezumab-jjmr.Traditional therapy includes preventative and abortive treatment; however, adherence with preventative treatment has been historically poor, and certain types of abortive therapy carry risks and side effects that preclude them from a large patient population. Moreover, traditional therapy often falls short in migraine therapy. CGRP antagonist, including Eptinezumab, aims to cover the gaps in migraine therapy. We present here evidence to support the safe and effective use of Eptinezumab for the prevention of migraines., Summary: Migraines are a prevalent primary headache disorder causing significant morbidity worldwide. Traditional abortive and preventative treatments fall short for many patients. Eptinezumab is part of new generation of CGRP-targeting medications and has shown significant evidence to support its use for the prevention of migraines. Further research is required to properly compare eptinezumab with existing pharmacotherapy and update guidelines on the appropriate combinations of therapies that are not available and the correct patient selection for each., Competing Interests: None of the authors report any conflicts of interest.

Monoamine oxidase inhibitors (MAOI) are a class of drugs that were originally developed for the treatment of depression but have since been expanded to be used in management of affective and neurological disorders, as well as stroke and aging-related neurocognitive changes. Ranging from irreversible to reversible and selective to non-selective, these drugs target the monoamine oxidase (MAO) enzyme and prevent the oxidative deamination of various monoamines and catecholamines such as serotonin and dopamine, respectively. Tyramine is a potent releaser of norepinephrine (NE) and is found in high concentrations in foods such as aged cheeses and meats. Under normal conditions, NE is unable to accumulate to toxic levels due to the presence of MAO-A, an enzyme that degrades neurotransmitters, including NE. When MAO-A is inhibited, the capacity to handle tyramine intake from the diet is significantly reduced causing the brain to be vulnerable to overstimulation of postsynaptic adrenergic receptors with as little as 8-10 mg of tyramine ingested and can result in life-threatening blood pressure elevations. In addition to adverse reactions with certain foods, both older and newer MAOIs can negatively interact with both sympathomimetic and serotonergic drugs. In general, patients on a MAOI want to avoid two types of medications: those that can elevate blood pressure via sympathomimetic actions (e.g., phenylephrine and oxymetazoline) and those that can increase serotonin levels via 5-HT reuptake inhibition (e.g., dextromethorphan, chlorpheniramine, and brompheniramine). Illicit drugs that stimulate the central nervous system such as ecstasy (MDMA, 3,4-methylenedioxymethamphetamine) act as serotonin releasers. Patient involvement is also crucial to ensure any interaction within the healthcare setting includes making other providers aware of a MAOI prescription as well as avoiding certain OTC medications that can interact adversely with MAOIs.

Buprenorphine, a novel long-acting analgesic, was developed with the intention of two purposes: analgesia and opioid use disorder. Regarding its pharmacodynamics, it is a partial agonist at mu receptors, an inverse agonist at kappa receptors, and an antagonist at delta receptors. For the purpose of analgesia, three formulations of buprenorphine were developed: IV/IM injectable formulation (Buprenex®), transdermal patch formulation (Butrans®), and buccal film formulation (Belbuca®). Related to opioid dependence, the formulations developed were subcutaneous extended release (Sublocade®), subdermal implant (Probuphine®), and sublingual tablets (Subutex®). Lastly, in order to avoid misuse of buprenorphine for opioid dependence, two combination formulations paired with naloxone were developed: film formulation (Suboxone®) and tablet formulation (Zubsolv®). In this review, we present details of each formulation along with their similarities and differences between each other and clinical considerations., Competing Interests: None.

Lipophilic fluorophores are widely implemented in nonlinear microscopy; however, few existing membrane-specific probes combine the high brightness of two-photon excited fluorescence (2PEF) with pH sensitivity. Herein we describe four novel two-photon excited fluorophores, based on a coumarin 151 core structure, where lipophilicity is induced by a covalently attached phosphazene moiety. Changing the environmental acidity using trifluoromethanesulfonic (triflic) acid leads to profound changes in the linear fluorescence and 2PEF characteristics, due to chromophores' switching between neutral- and protonated forms. We characterize this dependence by measuring the two-photon absorption (2PA) spectra over the region λ 2PA =550-1000 nm, observing 2PA cross sections of σ 2PA =10-20 GM, with an associated 2PEF brightness of 10-13 GM, in neutral solutions of both acetonitrile and n-octanol. Although quantum chemical modelling and NMR measurements show that, at high chromophore concentrations, protonation may be accompanied by a dimerization process, these dimers likely do not form at the lower concentrations used in optical spectroscopy., (© 2021 Wiley-VCH GmbH.)

Preoperative laboratory testing is often necessary and can be invaluable for diagnosis, assessment, and treatment. However, performing routine laboratory tests for patients who are considered otherwise healthy is not usually beneficial and is costly. It is estimated that $18 billion (U.S.) is spent annually on preoperative testing, although how much is wasteful remains unknown. Ideally, a targeted and comprehensive patient history and physical exam should largely determine whether preprocedure laboratory studies should be obtained. Healthcare providers, primarily anesthesiologists, should remain cost-conscious when ordering specific laboratory or imaging tests prior to surgery based on available literature. We review the overall evidence and key points from the Choosing Wisely guidelines, the identification of potential wasteful practices, possible harms of testing, and key clinical findings associated with preoperative laboratory testing., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Ltd.)

The management principles of non-obstetric surgery during pregnancy are important concepts for all health care providers to be cognizant of. The goals of non-obstetric surgery are to ensure maternal safety, maintain the pregnancy, and ensure fetal well-being. In this regard, organogenesis occurs roughly between days 7-57 and thus, certain medications have a higher incidence of fetal teratogenicity in this first trimester. Some examples of common surgeries performed urgently or emergently include appendectomies, ovarian detorsions, bowel obstruction, trauma, and cholecystectomies. The choice of anesthetic technique and the selection of appropriate anesthetic drugs should be guided by indication for surgery, the nature of the surgery, and the site of the surgical procedure. Many of the concerns for any patients undergoing urgent or emergent surgery must be considered by anesthesia providers along with steps to ensure the fetus has the best outcome., Competing Interests: Declaration of Competing Interest None., (Published by Elsevier Ltd.)

Purpose of Review: Pain is multifactorial and complex, often with a genetic component. Pharmacogenomics is a relative new field, which allows for the development of a truly unique and personalized therapeutic approach in the treatment of pain., Recent Findings: Until recently, drug mechanisms in humans were determined by testing that drug in a population and calculating response averages. However, some patients will inevitably fall outside of those averages, and it is nearly impossible to predict who those outliers might be. Pharmacogenetics considers a patient's unique genetic information and allows for anticipation of that individual's response to medication. Pharmacogenomic testing is steadily making progress in the management of pain by being able to identify individual differences in the perception of pain and susceptibility and sensitivity to drugs based on genetic markers. This has a huge potential to increase efficacy and reduce the incidence of iatrogenic drug dependence and addiction. The streamlining of relevant polymorphisms of genes encoding receptors, transporters, and drug-metabolizing enzymes influencing the pain phenotype can be an important guide to develop safe new strategies and approaches to personalized pain management. Additionally, some challenges still prevail and preclude adoption of pharmacogenomic testing universally. These include lack of knowledge about pharmacogenomic testing, inadequate standardization of the process of data handling, questionable benefits about the clinical and financial aspects of pharmacogenomic testing-guided therapy, discrepancies in clinical evidence supporting these tests, and doubtful reimbursement of the tests by health insurance agencies.

The time-dependent localization of the metal-to-ligand charge transfer (MLCT) excited states of ruthenium(II) complexes containing 2,2'-bipyridine (bpy) and 1,10-phenanthroline (phen) ligands was studied by femtosecond transient absorption spectroscopy. Time-resolved anisotropy measurements indicate that the excited state hops randomly among the three ligands of each complex by subpicosecond interligand electron transfer (ILET). Although the bpy- and phen-localized (3)MLCT states have similar energies and steady-state emission spectra, pronounced differences in their excited-state absorption spectra make it possible to observe changes in excited state populations using magic angle transient absorption measurements. Analysis of the magic angle signals shows that the excited electron is equally likely to be found on any of the three ligands approximately 1 ps after excitation, but this statistical distribution subsequently evolves to a Boltzmann distribution with a time constant of approximately 10 ps. The apparent contradiction between ultrafast ILET revealed by time-dependent anisotropy measurements and the slower ILET seen in magic angle measurements on the tens of picoseconds time scale is explained by a model in which the underlying rates depend dynamically on excess vibrational energy. The insight that ILET can occur over multiple time scales reconciles contradictory literature observations and may lead to improved photosensitizer performance.

Perioperative pain is still a major problem, and new pharmacological means should be explored to mitigate such pain. Adenosine is an ubiquitous endogenous substance; when exogenously administered, it provides a number of salutary effects including neuromodulation, antinociception, and cytoprotective actions. The aim of this study was to characterize the perioperative antinociceptive-analgesic effects of intraoperative adenosine infusion and determine the duration of actions in the postoperative period, and compare them to those of remifentanil in patients undergoing major surgical procedures in a double-blind study.Sixty-two patients were randomly assigned to one of the two treatments. After standard induction of anesthesia, the lungs were mechanically ventilated. Anesthesia was maintained with a constant alveolar concentration of inhaled anesthetics (3% desflurane and 65% nitrous oxide in oxygen). A variable-rate of intravenous infusion of adenosine (50-500 microg kg(-1) x min(-1)) or remifentanil (0.05-0.5 microg kg(-1) x min(-1)) was initiated 5 min before the skin incision and was titrated to maintain systolic blood pressure and heart rate within 20% of baseline values during surgery. Postoperative evaluations included the level of sedation, degree of pain severity, opioid analgesic (fentanyl, morphine) consumption, and cardiorespiratory variables for 48 h. Intraoperative inhibition of the cardiovascular responses to surgical stimulation could be equally achieved by adenosine or remifentanil, and both could maintain excellent hemodynamic stability. Postoperatively, however, there were striking differences: (1). initial pain score was reduced by 60% (P<0.001) in the adenosine group compared to the remifentanil group and it remained lower throughout the 48 h recovery period; (2). postoperative morphine requirements during the first 0.25, 2 and 48 h were consistently lower in the adenosine group as compared to the remifentanil group (78, 71 and 42%, P<0.001, respectively); (3). adenosine patients remained significantly less sedated at all evaluations; (4) the end-tidal and arterial carbon dioxide values in the remifentanil group were significantly higher when patients were admitted to the postanesthesia care unit. No adverse effect of adenosine was observed at any time. Intraoperative adenosine infusion provided a salutary recovery from anesthesia associated with a pronounced and sustained postoperative pain relief. Compared to remifentanil, adenosine significantly reduced the opioid requirements and minimized the side effects including protracted sedation, cardiorespiratory instability, nausea, and vomiting in the postoperative recovery period.