Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

BACKGROUND: Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels. METHODS: In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group. RESULTS: A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P = 0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug. CONCLUSIONS: Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.).

Integrated information theory (IIT) 4.0: Formulating the properties of phenomenal existence in physical terms.

This paper presents Integrated Information Theory (IIT) 4.0. IIT aims to account for the properties of experience in physical (operational) terms. It identifies the essential properties of experience (axioms), infers the necessary and sufficient properties that its substrate must satisfy (postulates), and expresses them in mathematical terms. In principle, the postulates can be applied to any system of units in a state to determine whether it is conscious, to what degree, and in what way. IIT offers a parsimonious explanation of empirical evidence, makes testable predictions concerning both the presence and the quality of experience, and permits inferences and extrapolations. IIT 4.0 incorporates several developments of the past ten years, including a more accurate formulation of the axioms as postulates and mathematical expressions, the introduction of a unique measure of intrinsic information that is consistent with the postulates, and an explicit assessment of causal relations. By fully unfolding a system's irreducible cause-effect power, the distinctions and relations specified by a substrate can account for the quality of experience.

Three tRNA nuclear exporters in S. cerevisiae: parallel pathways, preferences, and precision.

tRNAs that are transcribed in the nucleus are exported to the cytoplasm to perform their iterative essential function in translation. However, the complex set of tRNA post-transcriptional processing and subcellular trafficking steps are not completely understood. In particular, proteins involved in tRNA nuclear export remain unknown since the canonical tRNA nuclear exportin, Los1/Exportin-t, is unessential in all tested organisms. We previously reported that budding yeast Mex67-Mtr2, a mRNA nuclear exporter, co-functions with Los1 in tRNA nuclear export. Here we employed in vivo co-purification of tRNAs with endogenously expressed nuclear exporters to document that Crm1 also is a bona fide tRNA nuclear exporter. We document that Los1, Mex67-Mtr2 and Crm1 possess individual tRNA preferences for forming nuclear export complexes with members of the 10 families of intron-containing pre-tRNAs. Remarkably, Mex67-Mtr2, but not Los1 or Crm1, is error-prone, delivering tRNAs to the cytoplasm prior to 5' leader removal. tRNA retrograde nuclear import functions to monitor the aberrant leader-containing spliced tRNAs, returning them to the nucleus where they are degraded by 3' to 5' exonucleases. Overall, our work identifies a new tRNA nuclear exporter, uncovers exporter preferences for specific tRNA families, and documents contribution of tRNA nuclear import to tRNA quality control.

Therapy With Allogeneic Severe Acute Respiratory Syndrome Coronavirus-2-Specific T Cells for Persistent Coronavirus Disease 2019 in Immunocompromised Patients.

We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study.

A majority of trauma-related deep venous thromboses resolve prior to discharge.

Post-traumatic DVTs present unique challenges in patient populations with specific high-risk injury patterns. Duplex ultrasound (US) can be used to assess evolution of DVTs and may guide treatment for high-risk patients. We hypothesized that many DVTs resolve during the initial admission. Weekly duplex US are ordered on all trauma inpatients regardless of prior DVT at our facility. We reviewed US and outcomes data on all patients with lower extremity DVTs at our Level I trauma center from January 2012-December 2021. 392 patients were diagnosed with lower extremity DVT by US. 261 (67%) patients received follow-up US with a mean time to repeat US of 6 days. Of these, 91 (35%) patients experienced DVT resolution prior to the first follow-up US, and 141 (54%) patients experienced resolution prior to discharge. Mean time to resolution was 10 days. Over 50% of DVTs resolve before discharge and are detected by US. Further studies and post-discharge follow-up are needed to determine if patients with resolved DVTs can be managed without therapeutic anticoagulation.

System Integrated Information.

Integrated information theory (IIT) starts from consciousness itself and identifies a set of properties (axioms) that are true of every conceivable experience. The axioms are translated into a set of postulates about the substrate of consciousness (called a complex), which are then used to formulate a mathematical framework for assessing both the quality and quantity of experience. The explanatory identity proposed by IIT is that an experience is identical to the cause-effect structure unfolded from a maximally irreducible substrate (a Φ-structure). In this work we introduce a definition for the integrated information of a system (φs) that is based on the existence, intrinsicality, information, and integration postulates of IIT. We explore how notions of determinism, degeneracy, and fault lines in the connectivity impact system-integrated information. We then demonstrate how the proposed measure identifies complexes as systems, the φs of which is greater than the φs of any overlapping candidate systems.

Increase in NREM sleep slow waves following injections of sodium oxybate in the mouse cerebral cortex and the role of somatostatin-positive interneurons.

The systemic administration of sodium oxybate (SXB), the sodium salt of gamma-hydroxybutyric acid, promotes slow wave activity (SWA, 0.5-4 Hz EEG power) and increases non-rapid eye movement (NREM) sleep. These effects are mediated by the widely expressed GABAb receptors, and thus, the brain areas targeted by SXB remain unclear. Because slow waves are mainly a cortical phenomenon, we tested here whether systemic SXB promotes SWA by acting directly on the cortex. Moreover, because somatostatin (SOM) + cortical interneurons play a key role in SWA generation, we also assessed their contribution to the effects of SXB. In adult SOM-Cre mice, the injection of SXB in left secondary motor cortex increased SWA during NREM sleep in the first 30 min post-injection (11 mice: either sex). SWA, the amplitude and frequency of the slow waves, and the frequency of the OFF periods increased ipsilaterally and contralaterally to the SXB injection in frontal and parietal cortex. All these changes disappeared when the intracortical injection of SXB was preceded by the chemogenetic inhibition of the SOM+ cells. Thus, SXB may promote the slow waves of NREM sleep, at least in part, by acting directly on the cortex, and this effect involves GABAergic SOM+ interneurons. Our working hypothesis is that SXB potentiates the ability of these cells to inhibit all other cortical cell types via a GABAb mechanism, thus promoting the transition from ON to OFF periods during NREM sleep.

ALVR109, an off-the-shelf partially HLA matched SARS-CoV-2-specific T cell therapy, to treat refractory severe COVID-19 pneumonia in a heart transplant patient: Case report.

An unvaccinated adult male heart transplant recipient patient with recalcitrant COVID-19 due to SARS-CoV-2 delta variant with rising nasopharyngeal quantitative viral load was successfully treated with ALVR109, an off-the-shelf SARS-CoV-2-specific T cell therapy. Background immunosuppression included 0.1 mg/kg prednisone, tacrolimus, and mycophenolate mofetil 1 gm twice daily for historical antibody-mediated rejection. Prior therapies included remdesivir, corticosteroids, and tocilizumab, with requirement for high-flow nasal oxygen. Lack of clinical improvement and acutely rising nasopharyngeal viral RNA more than 3 weeks into illness prompted the request of ALVR109 through an emergency IND. The day following the first ALVR109 infusion, the patient's nasopharyngeal SARS-CoV-2 RNA declined from 7.43 to 5.02 log10 RNA copies/ml. On post-infusion day 4, the patient transitioned to low-flow oxygen. Two subsequent infusions of ALVR109 were administered 10 and 26 days after the first; nasopharyngeal SARS-CoV-2 RNA became undetectable on Day 11, and he was discharged the following day on low-flow oxygen 5 weeks after the initial diagnosis of COVID-19. The clinical and virologic improvements observed in this patient following administration of ALVR109 suggest a potential benefit that warrants further exploration in clinical trials.

Left ventricular outflow tract to left atrial fistula: A rare long-term complication of the commando procedure.

The commando procedure involves aortic and mitral valve replacement with complete reconstruction of the aorto-mitral curtain. It is often a surgical treatment for invasive infective endocarditis with abscess, or less commonly for radiation-induced heart disease with extensive calcification extending from the aortic valve onto the anterior mitral leaflet. Prosthetic valve endocarditis is a known long-term complication of this surgery; however, reports of other long-term outcomes are limited. We report the case of a 59-year-old male who developed a non-infectious left ventricular outflow tract to left atrial fistula, incidentally found 5 years after undergoing a commando procedure for radiation-induced heart disease.

Delayed union, non-union and mal-union in 442 dogs.

OBJECTIVES: (1) To estimate the prevalence of delayed union, non-union and mal-union in canine fractures; (2) to describe fracture, demographic, and treatment characteristics for these outcomes; (3) to identify risk factors for delayed or non-union. STUDY DESIGN: Retrospective study. SAMPLE POPULATION: Four hundred and forty two dogs (461 fractures). METHODS: A review was conducted of clinical records and radiographs from 2 teaching hospitals. "Union," "delayed union," "non-union" and "mal-union" were defined, and fracture, demographic, treatment, and outcome variables described. Differences in proportions or medians between "union," "delayed union" and "non-union" were tested using χ2 and Mann-Whitney U-tests for categorical and continuous variables respectively. Potential explanatory variables for "delayed or non-union" were tested using logistic regression to identify risk factors. RESULTS: Median radiographic follow up was 53 days (14-282). Delayed union occurred in 13.9% of fractures (64/461), non-union in 4.6% (21/461), and mal-union in 0.7% (3/461). Risk factors for delayed or non-union were age (OR 1.21, 95% CI 1.12-1.31); comminuted fracture (OR 4.24, 95% CI 2.4-7.5); treatment with bone graft (all types) (OR 3.32, 95% CI 1.3-8.5); surgical site infection (OR 3.24, 95% CI 1.17-8.97), and major implant failure (OR 12.94, 95% CI 5.06-33.1). CONCLUSION: Older dogs, dogs with comminuted fractures, surgical site infection, or major implant failure were at increased odds of delayed or non-union. Radius and ulna fractures in toy breed dogs were not at increased odds of delayed or non-union. CLINICAL SIGNIFICANCE: The identified risk factors should inform fracture planning and prognosticating. The prognosis for radial fractures in toy breeds appears better than historically believed.

IIT, half masked and half disfigured.

The target article misrepresents the foundations of integrated information theory (IIT) and ignores many essential publications. It, thus, falls to this lead commentary to outline the axioms and postulates of IIT and correct major misconceptions. The commentary also explains why IIT starts from phenomenology and why it predicts that only select physical substrates can support consciousness. Finally, it highlights that IIT's account of experience - a cause-effect structure quantified by integrated information - has nothing to do with "information transfer."

Correlation of echocardiographic probability of pulmonary hypertension with maternal outcomes in pregnant women with elevated right ventricular systolic pressure.

INTRODUCTION: The use of echocardiography to evaluate the probability for pulmonary hypertension (PH) in pregnant women has not been reported or correlated with outcomes. We hypothesized that in women with elevated right ventricular systolic pressure (RVSP) on echocardiography first identified during pregnancy, those with low probability for PH would have fewer major adverse cardiac events (MACE). METHODS: We performed a retrospective cohort study of pregnant women with RVSP >35 mm Hg on echocardiogram first identified during pregnancy. Women were classified as intermediate-high probability for PH (HP) or low probability for PH (LP) based on simplified European Society of Cardiology echocardiographic criteria. Maternal cardiac, obstetric, and fetal outcomes were assessed. RESULTS: A total of 77 women met inclusion criteria (mean age 30 ± 5 years), with 45 (58%) classified as HP and 32 (42%) as LP. There were 21 (27%) women who experienced MACE, more commonly in the HP cohort (HP 18 (40%) women vs. LP 3 (9%) women, P = .01). The echocardiographic criteria for intermediate-high probability of PH identified women at risk for MACE with 85% sensitivity and 52% specificity. The negative predictive value for MACE in women meeting low echocardiographic probability for PH criteria was 91%. CONCLUSIONS: In women with elevated RVSP on echocardiography first identified during pregnancy, those with low echocardiographic PH probability are at significantly lower risk for MACE during pregnancy, though the risk is not eliminated. This may be useful to risk stratify pregnant women with suspected PH, guiding tertiary care referral and invasive catheterization.

Mechanism Integrated Information.

The Integrated Information Theory (IIT) of consciousness starts from essential phenomenological properties, which are then translated into postulates that any physical system must satisfy in order to specify the physical substrate of consciousness. We recently introduced an information measure (Barbosa et al., 2020) that captures three postulates of IIT-existence, intrinsicality and information-and is unique. Here we show that the new measure also satisfies the remaining postulates of IIT-integration and exclusion-and create the framework that identifies maximally irreducible mechanisms. These mechanisms can then form maximally irreducible systems, which in turn will specify the physical substrate of conscious experience.

Sleep Deprivation by Exposure to Novel Objects Increases Synapse Density and Axon-Spine Interface in the Hippocampal CA1 Region of Adolescent Mice.

Sleep has been hypothesized to rebalance overall synaptic strength after ongoing learning during waking leads to net synaptic potentiation. If so, because synaptic strength and size are correlated, synapses on average should be larger after wake and smaller after sleep. This prediction was recently confirmed in mouse cerebral cortex using serial block-face electron microscopy (SBEM). However, whether these findings extend to other brain regions is unknown. Moreover, sleep deprivation by gentle handling was reported to produce hippocampal spine loss, raising the question of whether synapse size and number are differentially affected by sleep and waking. Here we applied SBEM to measure axon-spine interface (ASI), the contact area between pre-synapse and post-synapse, and synapse density in CA1 stratum radiatum. Adolescent YFP-H mice were studied after 6-8 h of sleep (S = 6), spontaneous wake at night (W = 4) or wake enforced during the day by novelty exposure (EW = 4; males/females balanced). In each animal ≥425 ASIs were measured and synaptic vesicles were counted in ~100 synapses/mouse. Reconstructed dendrites included many small, nonperforated synapses and fewer large, perforated synapses. Relative to S, ASI sizes in perforated synapses shifted toward higher values after W and more so after EW. ASI sizes in nonperforated synapses grew after EW relative to S and W, and so did their density. ASI size correlated with presynaptic vesicle number but the proportion of readily available vesicles decreased after EW, suggesting presynaptic fatigue. Thus, CA1 synapses undergo changes consistent with sleep-dependent synaptic renormalization and their number increases after extended wake.SIGNIFICANCE STATEMENT Sleep benefits learning, memory consolidation, and the integration of new with old memories, but the underlying mechanisms remain highly debated. One hypothesis suggests that sleep's cognitive benefits stem from its ability to renormalize total synaptic strength, after ongoing learning during wake leads to net synaptic potentiation. Supporting evidence for this hypothesis mainly comes from the cerebral cortex, including the observation that cortical synapses are larger after wake and smaller after sleep. Using serial electron microscopy, we find here that sleep/wake synaptic changes consistent with sleep-dependent synaptic renormalization also occur in the CA1 region. Thus, the role of sleep in maintaining synaptic homeostasis may extend to the hippocampus, a key area for learning and synaptic plasticity.

Focal adhesion kinase and osmotic responses in ionocytes of Fundulus heteroclitus, a euryhaline teleost fish.

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) anion channels are the regulated exit pathway in Cl- secretion by teleost salt secreting ionocytes of the gill and opercular epithelia of euryhaline teleosts. By confocal light immunocytochemistry using regular and phospho-antibodies directed against conserved sites, we found that killifish CFTR (kfCFTR) and the tyrosine kinase Focal Adhesion Kinase (FAK) phosphorylated at Y407 (FAKpY407) and FAKpY397 are colocalized at the apical membrane and in subjacent membrane vesicles of ionocytes. Hypotonic shock and the α-2 adrenergic agonist clonidine rapidly and reversibly inhibit Cl- secretion by isolated opercular epithelia, simultaneous with dephosphorylation of FAKpY407 and increased FAKpY397, located in the apical membrane of ionocytes in the opercular epithelium. FAKpY407 is re-phosphorylated at the apical membrane of ionocytes and Cl- secretion rapidly restored by hypertonic shock, detectable at 2 min., maximum at 5 min and still elevated at 30 min. In isolated opercular epithelia, the FAK phosphorylation inhibitor Y15 and p38MAP kinase inhibitor SB203580 significantly blunted the recovery of short-circuit current (Isc, equal to Cl- secretion rate) after hypertonic shock. The cSRC inhibitor saracatinib dephosphorylated FAKpY861 seen near tight junctions of pavement cells, and reduced the increase in epithelial resistance normally seen with clonidine inhibition of ion transport, while FAKpY397 was unaffected. The results show rapid osmosensitive responses in teleost fish ionocytes involve phosphorylation of CFTR by FAKpY407, an opposing role for FAKpY397 and a possible role for FAKpY861 in tight junction dynamics.

Emergency Ambulatory Management of Low-Risk Febrile Neutropenia: Multinational Association for Supportive Care in Cancer Fits-Real-World Experience From a UK Cancer Center.

BACKGROUND: Emergency patient presentations with febrile neutropenia are a heterogeneous group. A small minority of these patients proceed to develop significant medical complications. Risk stratification using scores, such as the Multinational Association for Supportive Care in Cancer score, have been advocated to identify patients who are at low risk of adverse outcome suitable for treatment on an ambulatory care pathway. OBJECTIVES: We sought to report the experience of 100 patients presenting acutely with neutropenic fever managed in an emergency ambulatory fashion. METHODS: Patients presenting as an emergency with low-risk febrile neutropenia managed in an ambulatory setting between January 2017 and February 2019 at a tertiary cancer hospital in England were prospectively studied. Patients with a fever >38.0°C and an absolute neutrophil count <1.0 × 109/L were included. All patients with a Multinational Association for Supportive Care in Cancer score ≥21 and a National Early Warning Score ≤3 were potentially eligible for the pathway. Complications were classified as serious if the patient developed persistent hypotension, respiratory failure, intensive care unit admission, altered mental status, disseminated intravascular coagulation, renal failure requiring renal replacement therapy, electrocardiogram changes requiring antidysrhythmic treatment, and 30-day mortality. RESULTS: One hundred patients with low-risk febrile neutropenia consecutively managed in an emergency ambulatory fashion were prospectively analyzed. Eighty-one patients were female and the median age was 51 y (range 17-79 y). No patients developed serious complications. Eight (8% [95% confidence interval 4.1-15.0%]) patients had a 7-day readmission. CONCLUSION: Outpatient ambulatory care for emergency patients with low-risk febrile neutropenia can be delivered in a safe and effective fashion. Collaboration between acute care physicians and oncologists is required to develop local models based on national guidelines to facilitate individualised care for emergency oncology patients.

Synthesis of purines and adenines containing the hexafluoroisopropyl group.

Several new derivatives of adenine, purine, and theophylline containing the (CF3)2CH group connected to a nitrogen atom of the imidazole ring were prepared by the reaction of 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane (1) with the corresponding substrates, resulting in the selective alkylation of one of the nitrogen atoms of the imidazole ring. The reaction proceeds under mild conditions in a polar solvent, giving the alkylated products in 47-78% yield. While for purine and 4- and 5-azabenzimidazole, the reaction led to a mixture of two isomers, the reaction of adenine and the corresponding 2-fluoro derivative was regioselective, resulting in the formation of only one isomer in each case. The alkylation of theophylline led to the formation of a new derivative of caffeine.

Pharmacokinetic Interactions between the Hepatitis C Virus Inhibitors Elbasvir and Grazoprevir and HIV Protease Inhibitors Ritonavir, Atazanavir, Lopinavir, and Darunavir in Healthy Volunteers.

The combination of the hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor elbasvir and the NS3/4A protease inhibitor grazoprevir is a potent, once-daily therapy indicated for the treatment of chronic HCV infection in individuals coinfected with human immunodeficiency virus (HIV). We explored the pharmacokinetic interactions of elbasvir and grazoprevir with ritonavir and ritonavir-boosted HIV protease inhibitors in three phase 1 trials. Drug-drug interaction trials with healthy participants were conducted to evaluate the effect of ritonavir on the pharmacokinetics of grazoprevir (n = 10) and the potential two-way pharmacokinetic interactions of elbasvir (n = 30) or grazoprevir (n = 39) when coadministered with ritonavir-boosted atazanavir, lopinavir, or darunavir. Coadministration of ritonavir with grazoprevir increased grazoprevir exposure; the geometric mean ratio (GMR) for grazoprevir plus ritonavir versus grazoprevir alone area under the concentration-time curve from 0 to 24 h (AUC0-24) was 1.91 (90% confidence interval [CI]; 1.31 to 2.79). Grazoprevir exposure was markedly increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for grazoprevir AUC0-24 of 10.58 (90% CI, 7.78 to 14.39), 12.86 (90% CI, 10.25 to 16.13), and 7.50 (90% CI, 5.92 to 9.51), respectively. Elbasvir exposure was increased with coadministration of atazanavir-ritonavir, lopinavir-ritonavir, and darunavir-ritonavir, with GMRs for elbasvir AUC0-24 of 4.76 (90% CI, 4.07 to 5.56), 3.71 (90% CI, 3.05 to 4.53), and 1.66 (90% CI, 1.35 to 2.05), respectively. Grazoprevir and elbasvir had little effect on atazanavir, lopinavir, and darunavir pharmacokinetics. Coadministration of elbasvir-grazoprevir with atazanavir-ritonavir, lopinavir-ritonavir, or darunavir-ritonavir is contraindicated, owing to an increase in grazoprevir exposure. Therefore, HIV treatment regimens without HIV protease inhibitors should be considered for HCV/HIV-coinfected individuals who are being treated with elbasvir-grazoprevir.

Assessment of drug interaction potential between the HCV direct-acting antiviral agents elbasvir/grazoprevir and the HIV integrase inhibitors raltegravir and dolutegravir.

BACKGROUND: Elbasvir/grazoprevir is a once-daily fixed-dose combination therapy for the treatment of chronic HCV infection, including HCV/HIV coinfection. OBJECTIVES: To evaluate the pharmacokinetic interaction of elbasvir and grazoprevir with raltegravir or dolutegravir. METHODS: Three open-label trials in healthy adult participants were conducted. In the raltegravir trials, participants received a single dose of raltegravir 400 mg, a single dose of elbasvir 50 mg or grazoprevir 200 mg, and raltegravir with either elbasvir or grazoprevir. In the dolutegravir trial, participants received a single dose of dolutegravir 50 mg alone or co-administered with once-daily elbasvir 50 mg and grazoprevir 200 mg. RESULTS: The raltegravir AUC0-∞ geometric mean ratio (GMR) (90% CI) was 1.02 (0.81-1.27) with elbasvir and 1.43 (0.89-2.30) with grazoprevir. Dolutegravir AUC0-∞ GMR (90% CI) was 1.16 (1.00-1.34) with elbasvir and grazoprevir. The elbasvir AUC0-∞ GMR (90% CI) was 0.81 (0.57-1.17) with raltegravir and 0.98 (0.93-1.04) with dolutegravir. The grazoprevir AUC0-24 GMR (90% CI) was 0.89 (0.72-1.09) with raltegravir and 0.81 (0.67-0.97) with dolutegravir. CONCLUSIONS: Elbasvir or grazoprevir co-administered with raltegravir or dolutegravir resulted in no clinically meaningful drug-drug interactions and was generally well tolerated. These results support the assertion that no dose adjustments for elbasvir, grazoprevir, raltegravir or dolutegravir are needed for co-administration in HCV/HIV-coinfected people.

Black-boxing and cause-effect power.

Reductionism assumes that causation in the physical world occurs at the micro level, excluding the emergence of macro-level causation. We challenge this reductionist assumption by employing a principled, well-defined measure of intrinsic cause-effect power-integrated information (Φ), and showing that, according to this measure, it is possible for a macro level to "beat" the micro level. Simple systems were evaluated for Φ across different spatial and temporal scales by systematically considering all possible black boxes. These are macro elements that consist of one or more micro elements over one or more micro updates. Cause-effect power was evaluated based on the inputs and outputs of the black boxes, ignoring the internal micro elements that support their input-output function. We show how black-box elements can have more common inputs and outputs than the corresponding micro elements, revealing the emergence of high-order mechanisms and joint constraints that are not apparent at the micro level. As a consequence, a macro, black-box system can have higher Φ than its micro constituents by having more mechanisms (higher composition) that are more interconnected (higher integration). We also show that, for a given micro system, one can identify local maxima of Φ across several spatiotemporal scales. The framework is demonstrated on a simple biological system, the Boolean network model of the fission-yeast cell-cycle, for which we identify stable local maxima during the course of its simulated biological function. These local maxima correspond to macro levels of organization at which emergent cause-effect properties of physical systems come into focus, and provide a natural vantage point for scientific inquiries.