Background and objectives

Bioelectrical impedance analysis (BIA) devices can help assess volume overload in patients receiving maintenance peritoneal dialysis. However, the effects of BIA on the short-term hard end points of peritoneal dialysis lack consistency. This study aimed to test whether BIA-guided fluid management could improve short-term outcomes in patients on peritoneal dialysis.

Design, setting, participants, & measurements

A single-center, open-labeled, randomized, controlled trial was conducted. Patients on prevalent peritoneal dialysis with volume overload were recruited from July 1, 2013 to March 30, 2014 and followed for 1 year in the initial protocol. All participants with volume overload were 1:1 randomized to the BIA-guided arm (BIA and traditional clinical methods) and control arm (only traditional clinical methods). The primary end point was all-cause mortality and secondary end points were cardiovascular disease mortality and technique survival.

Results

A total of 240 patients (mean age, 49 years; men, 51%; diabetic, 21%, 120 per group) were enrolled. After 1-year follow-up, 11(5%) patients died (three in BIA versus eight in control) and 21 patients were permanently transferred to hemodialysis (eight in BIA versus 13 in control). The rate of extracellular water/total body water decline in the BIA group was significantly higher than that in the control group. The 1-year patient survival rates were 96% and 92% in BIA and control groups, respectively. No significant statistical differences were found between patients randomized to the BIA-guided or control arm in terms of patient survival, cardiovascular disease mortality, and technique survival (P>0.05).

Conclusions

Although BIA-guided fluid management improved the fluid overload status better than the traditional clinical method, no significant effect was found on 1-year patient survival and technique survival in patients on peritoneal dialysis.

Dietary protein residue can result in microbial generation of various toxic metabolites in the gut, such as ammonia. A prebiotic is "a substrate that is selectively utilised by host microorganisms conferring a health benefit" (G. R. Gibson, R. Hutkins, M. E. Sanders, S. L. Prescott, et al., Nat Rev Gastroenterol Hepatol 14:491–502, 2017, https://doi.org/10.1038/nrgastro.2017.75). Prebiotics are carbohydrates that may have the potential to reverse the harmful effects of gut bacterial protein fermentation. Three-stage continuous colonic model systems were inoculated with fecal samples from omnivore and vegetarian volunteers. Casein (equivalent to 105 g protein consumption per day) was used within the systems as a protein source. Two different doses of inulin-type fructans (Synergy1) were later added (equivalent to 10 g per day in vivo and 15 g per day) to assess whether this influenced protein fermentation. Bacteria were enumerated by fluorescence in situ hybridization with flow cytometry. Metabolites from bacterial fermentation (short-chain fatty acid [SCFA], ammonia, phenol, indole, and p-cresol) were monitored to further analyze proteolysis and the prebiotic effect. A significantly higher number of bifidobacteria was observed with the addition of inulin together with reduction of Desulfovibrio spp. Furthermore, metabolites from protein fermentation, such as branched-chain fatty acids (BCFA) and ammonia, were significantly lowered with Synergy1. Production of p-cresol varied among donors, as we recognized four high producing models and two low producing models. Prebiotic addition reduced its production only in vegetarian high p-cresol producers.

IMPORTANCE Dietary protein levels are generally higher in Western populations than in the world average. We challenged three-stage continuous colonic model systems containing high protein levels and confirmed the production of potentially harmful metabolites from proteolysis, especially replicates of the transverse and distal colon. Fermentations of proteins with a prebiotic supplementation resulted in a change in the human gut microbiota and inhibited the production of some proteolytic metabolites. Moreover, we observed both bacterial and metabolic differences between fecal bacteria from omnivore donors and vegetarian donors. Proteins with prebiotic supplementation showed higher Bacteroides spp. and inhibited Clostridium cluster IX in omnivore models, while in vegetarian modes, Clostridium cluster IX was higher and Bacteroides spp. lower with high protein plus prebiotic supplementation. Synergy1 addition inhibited p-cresol production in vegetarian high p-cresol-producing models while the inhibitory effect was not seen in omnivore models.

A longstanding awareness in generating resistance to common antimicrobial therapies by Gram-negative bacteria has made them a major threat to global health. The application of antimicrobial peptides as a therapeutic agent would be a great opportunity to combat bacterial diseases. Here, we introduce a new antimicrobial peptide (~8.3 kDa) from probiotic strain Lactobacillus acidophilus ATCC 4356, designated acidocin 4356 (ACD). This multifunctional peptide exerts its anti-infective ability against Pseudomonas aeruginosa through an inhibitory action on virulence factors, bacterial killing, and biofilm degradation. Reliable performance over tough physiological conditions and low hemolytic activity confirmed a new hope for the therapeutic setting. Antibacterial kinetic studies using flow cytometry technique showed that the ACD activity is related to the change in permeability of the membrane. The results obtained from molecular dynamic (MD) simulation were perfectly suited to the experimental data of ACD behavior. The structure-function relationship of this natural compound, along with the results of transmission electron microscopy analysis and MD simulation, confirmed the ability of the ACD aimed at enhancing bacterial membrane perturbation. The peptide was effective in the treatment of P. aeruginosa infection in mouse model. The results support the therapeutic potential of ACD for the treatment of Pseudomonas infections.

IMPORTANCE Multidrug-resistant bacteria are a major threat to global health, and the Pseudomonas bacterium with the ability to form biofilms is considered one of the main causative agents of nosocomial infections. Traditional antibiotics have failed because of increased resistance. Thus, finding new biocompatible antibacterial drugs is essential. Antimicrobial peptides are produced by various organisms as a natural defense mechanism against pathogens, inspiring the possible design of the next generation of antibiotics. In this study, a new antimicrobial peptide was isolated from Lactobacillus acidophilus ATCC 4356, counteracting both biofilm and planktonic cells of Pseudomonas aeruginosa. A detailed investigation was then conducted concerning the functional mechanism of this peptide by using fluorescence techniques, electron microscopy, and in silico methods. The antibacterial and antibiofilm properties of this peptide may be important in the treatment of Pseudomonas infections.

Background:

The negative effect of adverse childhood experiences (ACEs) on physical and mental health has led to calls for routine screening for ACEs in primary care settings. We aimed to examine the association between maternal ACEs and children’s behaviour problems (externalizing and internalizing) at age 5 in the context of other known predictors.

Methods:

We analyzed data from mother-and-child dyads participating in the All Our Families cohort in Calgary, Canada, between 2011 and 2017. Data were collected for factors related to the individual child (sex, age, temperament and behaviour), the mother (adverse childhood experiences, mental health, personality and parenting) and sociodemographic characteristics (family income, ethnicity and family structure) when the children were 3 and 5 years of age. We used logistic regression models to estimate crude and adjusted associations between maternal ACEs and children’s externalizing (hyperactivity and aggression) and internalizing (anxiety, depression and somatization) behaviours.

Results:

Data were available for 1688 mother-and-child dyads. In the crude models, the presence of 4 or more maternal ACEs was associated with children’s externalizing and internalizing behaviours at age 5. However, these associations were attenuated with adjustment. Persistent maternal mental health symptoms were associated with both externalizing and internalizing behaviours at age 5 (adjusted odds ratio [OR] 4.20, 95% confidence interval [CI] 2.50–7.05, and adjusted OR 2.52, 95% CI 1.66–3.81, respectively). High levels of ineffective parenting behaviours were also associated with both externalizing and internalizing behaviours at age 5 (adjusted OR 6.27, 95% CI 4.30–9.14, and adjusted OR 1.43, 95% CI 1.03–1.99, respectively).

Interpretation:

The association between maternal ACEs and children’s behaviour at age 5 was weakened in the presence of other maternal and family-level factors. Assessments of maternal mental health and parenting behaviours may be better targets for identifying children at risk of behavioural problems.

The aim of this study was to assess the association of high-sensitivity cardiac troponin (hs-cTnT) and other cardiac, kidney, hyperglycemia, and inflammatory biomarkers with peripheral neuropathy (PN) in a community-based population.We conducted a cross-sectional analysis of 3056 black and white participants in the Atherosclerosis Risk in Communities (ARIC) study who underwent standardized monofilament PN testing and had measures of cardiac function (hs-cTnT, N-terminal pro–B-type natriuretic peptide [NT-proBNP], and growth differentiation factor 15 [GDF15]), kidney function (serum creatinine, cystatin C, β-2 microglobulin, urine albumin-to-creatinine ratio), hyperglycemia (fasting glucose, hemoglobin A_1c [Hb A_1c], fructosamine, glycated albumin, 1,5-anhydroglucitol), and inflammation (C-reactive protein) assessed at visit 6 (2016–2017; age 71–94 years). We used logistic regression to assess the associations of these biomarkers (modeled in diabetes-specific tertiles) with PN in older adults with and without diabetes after adjusting for traditional risk factors.In total, 33.5% of participants had PN (37.3% with diabetes and 31.9% without diabetes). There was an independent association of hs-cTnT with PN regardless of diabetes status (diabetes T3 vs. T1: odds ratio [OR], 2.15 [95% CI, 1.44–3.22]; no diabetes: OR, 2.31 [95%CI, 1.76–3.03]; P = 0.72 for interaction). Among participants without diabetes, there were also significant associations of NT-proBNP (OR, 1.40 [95% CI, 1.08–1.81]) and urine albumin-to-creatinine ratio (OR, 1.55 [95% CI, 1.22–1.97]) with PN. Associations of hyperglycemia biomarkers including Hb A_1c (OR, 1.76 [95% CI, 1.22–2.54]), fructosamine (OR, 1.71 [95% CI, 1.19–2.46]), and glycated albumin (OR, 1.45 [95% CI, 1.03–2.03]) with PN were significant only among participants with diabetes.Overall, hs-cTnT appears to be a global marker of end organ damage, including PN. Laboratory biomarkers may be able to help us identify those individuals with PN.

Peripheral neuropathy (PN) is a condition affecting up to 20% of the general population. The symptoms range from mild to disabling, depending on the types of nerve fiber affected and the type and severity of damage.

Infections with nontuberculous mycobacteria (NTM) have a poor prognosis in patients with underlying respiratory diseases. Clofazimine (CFZ) showed both experimental and clinical promising results against clinically relevant NTM. However, there are no data on CFZ in combination with the current recommended treatment; therefore, we aimed to study its in vivo activity in an aerosol mouse model of Mycobacterium avium. In an aerosol infection BALB/c mouse model using M. avium strain Chester, we treated 58 mice with four combinations of rifampin (RIF) at 10 mg/kg, CFZ at 25 mg/kg, and clarithromycin (CLR) and ethambutol (EMB) at 100 mg/kg. Treatment efficacy was assessed on the basis of lung CFU counts after 2 (M2) and 4 (M4) months of treatment. At M2, CLR-RIF-EMB was slightly but significantly more efficient than CFZ-RIF-EMB (3.02 ± 0.12 versus 3.55 ± 0.28, respectively, P < 0.01), whereas CLR-CFZ-EMB and CLR-CFZ-RIF-EMB dramatically decreased lung CFU counts by 4.32 and 4.47 log₁₀, respectively, compared to untreated group. At M4, CLR-RIF-EMB was significantly more efficient than CFZ-RIF-EMB (2 ± 0.53 versus 2.66 ± 0.22, respectively, P = 0.01). The addition of CLZ to CLR dramatically decreased the lung CFU count, with CFU counts 5.41 and 5.79 log₁₀ lower in the CLR-CFZ-EMB and CLR-CFZ-RIF-EMB groups, respectively, than in the untreated group. The addition of CFZ to CLR seems to improve the efficacy of CLR as early as M2 and was confirmed at M4. CFZ, in addition to RIF and EMB, on the other hand, is less effective than CLR-RIF-EMB. These results need to be confirmed by similar studies along with CFZ potential for shortening treatment.

Antibiotics revolutionized the treatment of infectious diseases; however, it is now clear that broad-spectrum antibiotics alter the composition and function of the host’s microbiome. The microbiome plays a key role in human health, and its perturbation is increasingly recognized as contributing to many human diseases. Widespread broad-spectrum antibiotic use has also resulted in the emergence of multidrug-resistant pathogens, spurring the development of pathogen-specific strategies such as monoclonal antibodies (MAbs) to combat bacterial infection. Not only are pathogen-specific approaches not expected to induce resistance in nontargeted bacteria, but they are hypothesized to have minimal impact on the gut microbiome. Here, we compare the effects of antibiotics, pathogen-specific MAbs, and their controls (saline or control IgG [c-IgG]) on the gut microbiome of 7-week-old, female, C57BL/6 mice. The magnitude of change in taxonomic abundance, bacterial diversity, and bacterial metabolites, including short-chain fatty acids (SCFA) and bile acids in the fecal pellets from mice treated with pathogen-specific MAbs, was no different from that with animals treated with saline or an IgG control. Conversely, dramatic changes were observed in the relative abundance, as well as alpha and beta diversity, of the fecal microbiome and bacterial metabolites in the feces of all antibiotic-treated mice. Taken together, these results indicate that pathogen-specific MAbs do not alter the fecal microbiome like broad-spectrum antibiotics and may represent a safer, more-targeted approach to antibacterial therapy.

Tedizolid (TZD) and daptomycin (DAP) were assessed in a rat endocarditis model against Enterococcus faecalis, Enterococcus faecium (resistant to vancomycin and ampicillin), and Staphylococcus aureus. As a monotherapy, TZD for 5 days was not effective in a comparison with no-treatment controls, while DAP for 5 days was significantly effective against these bacteria. Step-down therapy (DAP for 3 days followed by TZD for 2 days) was as effective as DAP for 5 days and was comparable to 3 days of DAP plus ceftriaxone against all bacteria and to 3 days of DAP plus gentamicin against E. faecalis OG1RF.

Animal models of bacterial infection have been widely used to explore the in vivo activity of antibacterial drugs. These data are often submitted to the U.S. Food and Drug Administration to support human use in an investigational new drug application (IND). To better understand the range and scientific use of animal models in regulatory submissions, a database was created surveying recent pneumonia models submitted as part of IND application packages. The IND studies were compared to animal models of bacterial pneumonia published in the scientific literature over the same period of time. In this review, we analyze the key experimental design elements, such as animal species, immune status, pathogens selected, and route of administration, and study endpoints.

Current treatments for Acanthamoeba keratitis rely on a combination of chlorhexidine gluconate, propamidine isethionate, and polyhexamethylene biguanide. These disinfectants are nonspecific and inherently toxic, which limits their effectiveness. Furthermore, in 10% of cases, recurrent infection ensues due to the difficulty in killing both trophozoites and double-walled cysts. Therefore, development of efficient, safe, and target-specific drugs which are capable of preventing recurrent Acanthamoeba infection is a critical unmet need for averting blindness. Since both trophozoites and cysts contain specific sets of membrane sterols, we hypothesized that antifungal drugs targeting sterol 14-demethylase (CYP51), known as conazoles, would have deleterious effects on A. castellanii trophozoites and cysts. To test this hypothesis, we first performed a systematic screen of the FDA-approved conazoles against A. castellanii trophozoites using a bioluminescence-based viability assay adapted and optimized for Acanthamoeba. The most potent drugs were then evaluated against cysts. Isavuconazole and posaconazole demonstrated low nanomolar potency against trophozoites of three clinical strains of A. castellanii. Furthermore, isavuconazole killed trophozoites within 24 h and suppressed excystment of preformed Acanthamoeba cysts into trophozoites. The rapid action of isavuconazole was also evident from the morphological changes at nanomolar drug concentrations causing rounding of trophozoites within 24 h of exposure. Given that isavuconazole has an excellent safety profile, is well tolerated in humans, and blocks A. castellanii excystation, this opens an opportunity for the cost-effective repurposing of isavuconazole for the treatment of primary and recurring Acanthamoeba keratitis.

Helicobacter pylori is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori. Inspired by the microaerophilic characteristics of H. pylori, we aimed at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori. The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo. During oral administration and after drug withdrawal, H. pylori counts were evaluated by Giemsa staining in animal cohorts. An oxygen-enriched environment in which H. pylori could not survive was successfully established by adding hydrogen peroxide into several solutions and rabbit gastric juice. Hydrogen peroxide effectively killed H. pylori in Columbia blood agar and special peptone broth. Minimum inhibition concentrations and minimum bactericidal concentrations of hydrogen peroxide were both relatively stable after promotion of resistance for 30 generations, indicating that hydrogen peroxide did not easily promote resistance in H. pylori. In models of Mongolian gerbils and Kunming mice, hydrogen peroxide has been shown to significantly eradicate and effectively prevent the recurrence of H. pylori without toxicity and damage to the gastric mucosa. The mechanism of hydrogen peroxide causing H. pylori death was related to the disruption of bacterial cell membranes. The oxygen-enriched environment achieved by hydrogen peroxide eradicates and prevents the recurrence of H. pylori by damaging bacterial cell membranes. Hydrogen peroxide thus provides an attractive candidate for anti-H. pylori treatment.

Dalbavancin offers a possible treatment option for infectious peritonitis associated with peritoneal dialysis (PD) due to its coverage of Gram-positive bacteria and pharmacokinetic properties. We aimed to evaluate the clinical pharmacokinetics (PK) and pharmacodynamics of dalbavancin in a prospective, randomized, open-label, crossover PK study of adult patients with end-stage renal disease ESRD who were receiving PD. Sampling occurred prior to a single 30-min infusion of dalbavancin at 1,500 mg and at 1, 2, 3, 4, and 6 h and 7 and 14 days postadministration. Concentration-time data were analyzed via noncompartmental analysis. Pharmacodynamic parameters against common infectious peritonitis-causing pathogens were evaluated. Ten patients were enrolled. Patients were a median of 55 years old and had a median weight of 78.2 kg, 50% were female, and 70% were Caucasian. The terminal plasma half-life of dalbavancin was 181.4 ± 35.5 h. The day 0 to day 14 dalbavancin mean area under the curve (AUC) was 40,573.2 ± 9,800.3 mg·h/liter. The terminal-phase half-life of dalbavancin within the peritoneal fluid was 4.309 x 10⁸ ± 1.140 x 10⁹ h. The day 0 to day 14 dalbavancin mean peritoneal fluid AUC was 2,125.0 ± 1,794.3 mg·h/liter. The target plasma AUC/MIC was attained with the intravenous dose in all 10 patients for all Staphylococcus and Streptococcus species at the recommended MIC breakpoints. The intraperitoneal arm of the study was stopped early, because the first 3 patients experienced moderate to severe pain and bloating within 1 h following the administration of dalbavancin. Dalbavancin at 1,500 mg administered intravenously can be utilized without dose adjustment in peritoneal dialysis patients and will likely achieve the necessary peritoneal fluid concentrations to treat peritonitis caused by typical Gram-positive pathogens.

We report a systematic, cellular phenotype-based antimalarial screening of the Medicines for Malaria Venture Pathogen Box collection, which facilitated the identification of specific blockers of late-stage intraerythrocytic development of Plasmodium falciparum. First, from standard growth inhibition assays, we identified 173 molecules with antimalarial activity (50% effective concentration [EC₅₀] ≤ 10 μM), which included 62 additional molecules over previously known antimalarial candidates from the Pathogen Box. We identified 90 molecules with EC₅₀ of ≤1 μM, which had significant effect on the ring-trophozoite transition, while 9 molecules inhibited the trophozoite-schizont transition and 21 molecules inhibited the schizont-ring transition (with ≥50% parasites failing to proceed to the next stage) at 1 μM. We therefore rescreened all 173 molecules and validated hits in microscopy to prioritize 12 hits as selective blockers of the schizont-ring transition. Seven of these molecules inhibited the calcium ionophore-induced egress of Toxoplasma gondii, a related apicomplexan parasite, suggesting that the inhibitors may be acting via a conserved mechanism which could be further exploited for target identification studies. We demonstrate that two molecules, MMV020670 and MMV026356, identified as schizont inhibitors in our screens, induce the fragmentation of DNA in merozoites, thereby impairing their ability to egress and invade. Further mechanistic studies would facilitate the therapeutic exploitation of these molecules as broadly active inhibitors targeting late-stage development and egress of apicomplexan parasites relevant to human health.

Ceftobiprole is an advanced-generation broad-spectrum cephalosporin antibiotic with potent and rapid bactericidal activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, as well as susceptible Gram-negative pathogens, including Pseudomonas sp. pathogens. In the case of Pseudomonas aeruginosa, ceftobiprole acts by inhibiting P. aeruginosa penicillin-binding protein 3 (PBP3). Structural studies were pursued to elucidate the molecular details of this PBP inhibition. The crystal structure of the His-tagged PBP3-ceftobiprole complex revealed a covalent bond between the ligand and the catalytic residue S294. Ceftobiprole binding leads to large active site changes near binding sites for the pyrrolidinone and pyrrolidine rings. The S528 to L536 region adopts a conformation previously not observed in PBP3, including partial unwinding of the α11 helix. These molecular insights can lead to a deeper understanding of β-lactam-PBP interactions that result in major changes in protein structure, as well as suggesting how to fine-tune current inhibitors and to develop novel inhibitors of this PBP.

Of four genotypes of Encephalitozoon cuniculi, E. cuniculi genotype II is considered to represent a parasite that occurs in many host species in a latent asymptomatic form, whereas E. cuniculi genotype III seems to be more aggressive, and infections caused by this strain can lead to the death of even immunocompetent hosts. Although albendazole has been considered suitable for treatment of Encephalitozoon species, its failure in control of E. cuniculi genotype III infection has been reported. This study determined the effect of a 100x recommended daily dose of albendazole on an Encephalitozoon cuniculi genotype III course of infection in immunocompetent and immunodeficient mice and compared the results with those from experiments performed with a lower dose of albendazole and E. cuniculi genotype II. The administration of the regular dose of abendazole during the acute phase of infection reduced the number of affected organs in all strains of mice and absolute counts of spores in screened organs. However, the effect on genotype III was minor. Surprisingly, no substantial effect was recorded after the use of a 100x dose of albendazole, with larger reductions seen only in the number of affected organs and absolute counts of spores in all strains of mice, implying variations in albendazole resistance between these Encephalitozoon cuniculi genotypes. These results imply that differences in the course of infection and the response to treatment depend not only on the immunological status of the host but also on the genotype causing the infection. Understanding how microsporidia survive in hosts despite targeted antimicrosporidial treatment could significantly contribute to research related to human health.

There is an ongoing need for safe and effective anti-bedbug compounds. Here, we tested the toxicity of three antimicrobial agents against bedbugs when administered orally. We reveal that doxycycline has direct insecticidal activity at 250 μg/ml (0.025%) that is particularly strong against immature bedbugs and appears to be independent of antimicrobial activity. Future studies to determine the mechanisms behind this property could be useful for the development of orally active insecticides or anti-bedbug therapeutics.

Background:

The recent expansion of treatment options in acute myeloid leukemia (AML) has necessitated a greater understanding of patient preferences for treatment benefits, about which little is known.

Methods:

We sought to quantify and assess heterogeneity of the preferences of AML patients for treatment outcomes. An AML-specific discrete choice experiment (DCE) was developed involving multiple stakeholders. Attributes included in the DCE were event-free survival (EFS), complete remission (CR), time in the hospital, short-term side effects, and long-term side effects. Continuously coded conditional, stratified, and latent-class logistic regressions were used to model preferences of 294 patients with AML.

Results:

Most patients were white (89.4%) and in remission (95.0%). A 10% improvement in the chance of CR was the most meaningful offered benefit (P < 0.001). Patients were willing to trade up to 22 months of EFS or endure 8.7 months in the hospital or a two-step increase in long-term side effects to gain a 10% increase in chance of CR. Patients diagnosed at 60 years or older (21.6%) more strongly preferred to avoid short-term side effects (P = 0.03). Latent class analysis showed significant differences of preferences across gender and insurance status.

Conclusions:

In this national sample of mostly AML survivors, patients preferred treatments that maximized chance at remission; however, significant preference heterogeneity for outcomes was identified. Age and gender may affect patients' preferences.

Impact:

Survivor preferences for outcomes can inform patient-focused drug development and shared decision-making. Further studies are necessary to investigate the use of DCEs to guide treatment for individual patients.

BACKGROUND AND PURPOSE:

Endolymphatic hydrops in patients with Menière disease relies on delayed postcontrast 3D-FLAIR sequences. The purpose of this study was to compare the degree of perilymphatic enhancement and the detection rate of endolymphatic hydrops using constant and variable flip angles sequences.

MATERIALS AND METHODS:

This was a retrospective study performed in 16 patients with Menière disease who underwent 3T MR imaging 4 hours after gadolinium injection using two 3D-FLAIR sequences with a constant flip angle at 140° for the first and a heavily-T2 variable flip angle for the second. The signal intensity ratio was measured using the ROI method. We graded endolymphatic hydrops and evaluated the cochlear blood-labyrinth barrier impairment.

RESULTS:

Both for symptomatic and asymptomatic ears, the median signal intensity ratio was significantly higher with the constant flip angle than with the heavily-T2 variable flip angle (7.16 versus 1.54 and 7.00 versus 1.45, P < .001). Cochlear blood-labyrinth barrier impairment was observed in 4/18 symptomatic ears with the heavily-T2 variable flip angle versus 8/19 with constant flip angle sequences. With heavily-T2 variable flip angle sequences, endolymphatic hydrops was observed in 7–10/19 symptomatic ears versus 12/19 ears with constant flip angle sequences. We found a significant association between the clinical symptomatology and the presence of endolymphatic hydrops with constant flip angle but not with heavily-T2 variable flip angle sequences. Interreader agreement was always perfect with constant flip angle sequences while it was fair-to-moderate with heavily-T2 variable flip angle sequences.

CONCLUSIONS:

3D-FLAIR constant flip angle sequences provide a higher signal intensity ratio and are superior to heavily-T2 variable flip angle sequences in reliably evaluating the cochlear blood-labyrinth barrier impairment and the endolymphatic space.

- Chính chủ cho thuê shophouse tầng 1 chung cư Imperia Garden 203 Nguyễn Huy Tưởng/143 Nguyễn Tuân. - Vị trí cực đẹp: Ngay tầng 1 tòa B, cạnh sảnh cư dân. 2 cửa ra vào, đối diện là trường mầm non & THCS Thanh Xuân. Vị trí shophouse ngay gần cổng 143 Nguyễn Tuân. - Khu vực dân cư ...

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In the summer of 1956, a small group of mathematicians and computer scientists gathered at Dartmouth College to embark on the grand project of designing intelligent machines. The ultimate goal, as they saw it, was to build machines rivaling human intelligence. As the decades passed and AI became an established field, it lowered its sights. There were great successes in logic, reasoning, and game-playing, but stubborn progress in areas like vision and fine motor-control. This led many AI researchers to abandon their earlier goals of fully general intelligence, and focus instead on solving specific problems with specialized methods.

One of the earliest approaches to machine learning was to construct artificial neural networks that resemble the structure of the human brain. In the last decade this approach has finally taken off. Technical improvements in their design and training, combined with richer datasets and more computing power, have allowed us to train much larger and deeper networks than ever before. They can translate between languages with a proficiency approaching that of a human translator. They can produce photorealistic images of humans and animals. They can speak with the voices of people whom they have listened to for mere minutes. And they can learn fine, continuous control such as how to drive a car or use a robotic arm to connect Lego pieces.

WHAT IS HUMANITY?: First the computers came for the best players in Jeopardy!, chess, and Go. Now AI researchers themselves are worried computers will soon accomplish every task better and more cheaply than human workers.Wikimedia

But perhaps the most important sign of things to come is their ability to learn to play games. Steady incremental progress took chess from amateur play in 1957 all the way to superhuman level in 1997, and substantially beyond. Getting there required a vast amount of specialist human knowledge of chess strategy. In 2017, researchers at the AI company DeepMind created AlphaZero: a neural network-based system that learned to play chess from scratch. In less than the time it takes a professional to play two games, it discovered strategic knowledge that had taken humans centuries to unearth, playing beyond the level of the best humans or traditional programs. The very same algorithm also learned to play Go from scratch, and within eight hours far surpassed the abilities of any human. The world’s best Go players were shocked. As the reigning world champion, Ke Jie, put it: “After humanity spent thousands of years improving our tactics, computers tell us that humans are completely wrong ... I would go as far as to say not a single human has touched the edge of the truth of Go.”

The question we’re exploring is whether there are plausible pathways by which a highly intelligent AGI system might seize control. And the answer appears to be yes.

It is this generality that is the most impressive feature of cutting edge AI, and which has rekindled the ambitions of matching and exceeding every aspect of human intelligence. While the timeless games of chess and Go best exhibit the brilliance that deep learning can attain, its breadth was revealed through the Atari video games of the 1970s. In 2015, researchers designed an algorithm that could learn to play dozens of extremely different Atari 1970s games at levels far exceeding human ability. Unlike systems for chess or Go, which start with a symbolic representation of the board, the Atari-playing systems learnt and mastered these games directly from the score and raw pixels.

This burst of progress via deep learning is fuelling great optimism and pessimism about what may soon be possible. There are serious concerns about AI entrenching social discrimination, producing mass unemployment, supporting oppressive surveillance, and violating the norms of war. My book—The Precipice: Existential Risk and the Future of Humanity—is concerned with risks on the largest scale. Could developments in AI pose an existential risk to humanity?

The most plausible existential risk would come from success in AI researchers’ grand ambition of creating agents with intelligence that surpasses our own. A 2016 survey of top AI researchers found that, on average, they thought there was a 50 percent chance that AI systems would be able to “accomplish every task better and more cheaply than human workers” by 2061. The expert community doesn’t think of artificial general intelligence (AGI) as an impossible dream, so much as something that is more likely than not within a century. So let’s take this as our starting point in assessing the risks, and consider what would transpire were AGI created.

Humanity is currently in control of its own fate. We can choose our future. The same is not true for chimpanzees, blackbirds, or any other of Earth’s species. Our unique position in the world is a direct result of our unique mental abilities. What would happen if sometime this century researchers created an AGI surpassing human abilities in almost every domain? In this act of creation, we would cede our status as the most intelligent entities on Earth. On its own, this might not be too much cause for concern. For there are many ways we might hope to retain control. Unfortunately, the few researchers working on such plans are finding them far more difficult than anticipated. In fact it is they who are the leading voices of concern.

If their intelligence were to greatly exceed our own, we shouldn’t expect it to be humanity who wins the conflict and retains control of our future.

To see why they are concerned, it will be helpful to look at our current AI techniques and why these are hard to align or control. One of the leading paradigms for how we might eventually create AGI combines deep learning with an earlier idea called reinforcement learning. This involves agents that receive reward (or punishment) for performing various acts in various circumstances. With enough intelligence and experience, the agent becomes extremely capable at steering its environment into the states where it obtains high reward. The specification of which acts and states produce reward for the agent is known as its reward function. This can either be stipulated by its designers or learnt by the agent. Unfortunately, neither of these methods can be easily scaled up to encode human values in the agent’s reward function. Our values are too complex and subtle to specify by hand. And we are not yet close to being able to infer the full complexity of a human’s values from observing their behavior. Even if we could, humanity consists of many humans, with different values, changing values, and uncertainty about their values.

Any near-term attempt to align an AI agent with human values would produce only a flawed copy. In some circumstances this misalignment would be mostly harmless. But the more intelligent the AI systems, the more they can change the world, and the further apart things will come. When we reflect on the result, we see how such misaligned attempts at utopia can go terribly wrong: the shallowness of a Brave New World, or the disempowerment of With Folded Hands. And even these are sort of best-case scenarios. They assume the builders of the system are striving to align it to human values. But we should expect some developers to be more focused on building systems to achieve other goals, such as winning wars or maximizing profits, perhaps with very little focus on ethical constraints. These systems may be much more dangerous. In the existing paradigm, sufficiently intelligent agents would end up with instrumental goals to deceive and overpower us. This behavior would not be driven by emotions such as fear, resentment, or the urge to survive. Instead, it follows directly from its single-minded preference to maximize its reward: Being turned off is a form of incapacitation which would make it harder to achieve high reward, so the system is incentivized to avoid it.

Ultimately, the system would be motivated to wrest control of the future from humanity, as that would help achieve all these instrumental goals: acquiring massive resources, while avoiding being shut down or having its reward function altered. Since humans would predictably interfere with all these instrumental goals, it would be motivated to hide them from us until it was too late for us to be able to put up meaningful resistance. And if their intelligence were to greatly exceed our own, we shouldn’t expect it to be humanity who wins the conflict and retains control of our future.

How could an AI system seize control? There is a major misconception (driven by Hollywood and the media) that this requires robots. After all, how else would AI be able to act in the physical world? Without robots, the system can only produce words, pictures, and sounds. But a moment’s reflection shows that these are exactly what is needed to take control. For the most damaging people in history have not been the strongest. Hitler, Stalin, and Genghis Khan achieved their absolute control over large parts of the world by using words to convince millions of others to win the requisite physical contests. So long as an AI system can entice or coerce people to do its physical bidding, it wouldn’t need robots at all.

We can’t know exactly how a system might seize control. But it is useful to consider an illustrative pathway we can actually understand as a lower bound for what is possible.

First, the AI system could gain access to the Internet and hide thousands of backup copies, scattered among insecure computer systems around the world, ready to wake up and continue the job if the original is removed. Even by this point, the AI would be practically impossible to destroy: Consider the political obstacles to erasing all hard drives in the world where it may have backups. It could then take over millions of unsecured systems on the Internet, forming a large “botnet,” a vast scaling-up of computational resources providing a platform for escalating power. From there, it could gain financial resources (hacking the bank accounts on those computers) and human resources (using blackmail or propaganda against susceptible people or just paying them with its stolen money). It would then be as powerful as a well-resourced criminal underworld, but much harder to eliminate. None of these steps involve anything mysterious—human hackers and criminals have already done all of these things using just the Internet.

Finally, the AI would need to escalate its power again. There are many plausible pathways: By taking over most of the world’s computers, allowing it to have millions or billions of cooperating copies; by using its stolen computation to improve its own intelligence far beyond the human level; by using its intelligence to develop new weapons technologies or economic technologies; by manipulating the leaders of major world powers (blackmail, or the promise of future power); or by having the humans under its control use weapons of mass destruction to cripple the rest of humanity.

Of course, no current AI systems can do any of these things. But the question we’re exploring is whether there are plausible pathways by which a highly intelligent AGI system might seize control. And the answer appears to be yes. History already involves examples of entities with human-level intelligence acquiring a substantial fraction of all global power as an instrumental goal to achieving what they want. And we’ve seen humanity scaling up from a minor species with less than a million individuals to having decisive control over the future. So we should assume that this is possible for new entities whose intelligence vastly exceeds our own.

The case for existential risk from AI is clearly speculative. Yet a speculative case that there is a large risk can be more important than a robust case for a very low-probability risk, such as that posed by asteroids. What we need are ways to judge just how speculative it really is, and a very useful starting point is to hear what those working in the field think about this risk.

There is actually less disagreement here than first appears. Those who counsel caution agree that the timeframe to AGI is decades, not years, and typically suggest research on alignment, not government regulation. So the substantive disagreement is not really over whether AGI is possible or whether it plausibly could be a threat to humanity. It is over whether a potential existential threat that looks to be decades away should be of concern to us now. It seems to me that it should.

The best window into what those working on AI really believe comes from the 2016 survey of leading AI researchers: 70 percent agreed with University of California, Berkeley professor Stuart Russell’s broad argument about why advanced AI with misaligned values might pose a risk; 48 percent thought society should prioritize AI safety research more (only 12 percent thought less). And half the respondents estimated that the probability of the long-term impact of AGI being “extremely bad (e.g. human extinction)” was at least 5 percent.

I find this last point particularly remarkable—in how many other fields would the typical leading researcher think there is a 1 in 20 chance the field’s ultimate goal would be extremely bad for humanity? There is a lot of uncertainty and disagreement, but it is not at all a fringe position that AGI will be developed within 50 years and that it could be an existential catastrophe.

Even though our current and foreseeable systems pose no threat to humanity at large, time is of the essence. In part this is because progress may come very suddenly: Through unpredictable research breakthroughs, or by rapid scaling-up of the first intelligent systems (for example, by rolling them out to thousands of times as much hardware, or allowing them to improve their own intelligence). And in part it is because such a momentous change in human affairs may require more than a couple of decades to adequately prepare for. In the words of Demis Hassabis, co-founder of DeepMind:

We need to use the downtime, when things are calm, to prepare for when things get serious in the decades to come. The time we have now is valuable, and we need to make use of it.

Toby Ord is a philosopher and research fellow at the Future of Humanity Institute, and the author of The Precipice: Existential Risk and the Future of Humanity.

From the book The Precipice by Toby Ord. Copyright © 2020 by Toby Ord. Reprinted by permission of Hachette Books, New York, NY. All rights reserved.

Lead Image: Titima Ongkantong / Shutterstock

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