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Inputs delivered to different sensory organs provide us with complementary speech information about the environment. The goal of this study was to establish which multisensory characteristics can facilitate speech recognition in noise. The major finding is that the tracking of temporal cues of visual/tactile speech synced with auditory speech can play a key role in speech-in-noise performance. This suggests that multisensory interactions are fundamentally important for speech recognition ability in noisy environments, and they require salient temporal cues. The amplitude envelope, serving as a reliable temporal cue source, can be applied through different sensory modalities when speech recognition is compromised.

RATIONALE AND OBJECTIVE: The safety of intensive blood pressure (BP) targets is controversial for persons with chronic kidney disease (CKD). We studied the effects of hypertension treatment on cerebral perfusion and structure in those with and without CKD. STUDY DESIGN: Neuroimaging substudy of a randomized trial. SETTING & PARTICIPANTS: A subset of participants in the Systolic Blood Pressure Intervention Trial who underwent brain MRI studies. Presence of baseline CKD was assessed by estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR). INTERVENTION: Participants were randomly assigned to intensive (systolic BP 30 mg/g (N=151), the effects of intensive versus standard BP treatment on change in global cerebral blood flow, WMLs and total brain volume were 1.91 ml/100g/min (95% CI −3.01, 6.82), 0.003 cm(3) (asinh transformed, 95% CI −0.13, 0.13), and −7.0 cm(3) (95% CI −13.3, −0.3), respectively. The overall treatment effects on cerebral blood flow and total brain volume were not modified by baseline eGFR or UACR; however the effect on WMLs was attenuated in participants with albuminuria (interaction p-value 0.04). LIMITATIONS: Measurement variability due to multi-site design. CONCLUSIONS: Among hypertensive adults with primarily early kidney disease, intensive versus standard blood pressure treatment did not appear to have a detrimental effect on brain perfusion or structure. The findings support the safety of intensive blood pressure treatment targets on brain health in persons with early kidney disease. FUNDING: The Systolic Blood Pressure Intervention Trial was funded by the National Institutes of Health (including the National Heart, Lung, and Blood Institute, the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, and the National Institute of Neurological Disorders and Stroke), and this substudy was funded by the National Institutes of Diabetes and Digestive and Kidney Diseases. TRIAL REGISTRATION: SPRINT was registered at ClinicalTrials.gov with the study number NCT01206062.

Background: Previous studies suggest that wide area circumferential pulmonary vein ablation (WACA) is more effective than segmental pulmonary vein ablation (SPVA) for pulmonary vein isolation (PVI) for treatment of atrial fibrillation. Whether this is true in patients (pts) with very short duration paroxysmal atrial fibrillation (PAF) is unknown. Objective: To compare WACA to SPVA in pts with PAF lasting

INTRODUCTION: Radiofrequency catheter ablation is a common treatment for atrial fibrillation (AF), during which thermal esophageal injury may rarely occur and lead to an atrio-esophageal fistula. Therefore, we studied the utility of the Circa S-Cath™ multi-sensor luminal esophageal temperature (LET) probe to prevent esophageal thermal injury. METHODS AND RESULTS: Thirty-six patients, enrolled prospectively, underwent circumferential or segmental pulmonary vein isolation for treatment of AF. A maximum ablation electrode temperature of 42ºC was programmed for automatic power delivery cutoff. In addition, energy delivery was manually discontinued when the maximum LET on any sensor of the probe rose abruptly (i.e. ˃0.2ºC) or exceeded 39º C. Esophagoscopy was performed immediately after ablation in 18 patients (with the temperature probe still in place) and at approximately 24 hours after ablation in 18 patients. Esophageal lesions were classified as likely traumatic or thermally related. Of the 36 patients enrolled in the study, 21 had persistent and 15 had paroxysmal AF, average LVEF 57±16% and CHA2DS2VASc score 1.6±1.2 (range 0-4). Average maximum LET was 37.8±1.4ºC, power delivery 31.1±8 watts and ablation electrode temperature 36.4±4.1ºC. Average maximum contact force was 44.5±20.5 grams where measured. Only 1 patient (

The inputs delivered to different sensory organs provide us with complementary information about the environment. Our recent study demonstrated that presenting abstract visual information of speech envelopes substantially improves speech perception ability in normal-hearing (NH), listeners [Yuan et al., J. Acoust. Soc. Am. (2020)]. The purpose of this study was to expand this audiovisual speech perception to the tactile domain. Twenty adults participated in sentence recognition threshold measurements in four different sensory modalities (AO: auditory-only; AV: auditory-visual; AT: audio-tactile; and AVT: audio-visual-tactile). The target sentence [CRM speech corpus, Bolia et al., J. Acoust. Soc. Am . (2000)] level was fixed at 60 dBA, and the masker (speech-shaped noise) levels were adaptively varied to find masked thresholds. The amplitudes of both visual and vibrotactile stimuli were temporally synchronized and non-synchronized with the target speech envelope for comparison. Results show that temporally coherent multi-modal stimulation (AV, AT, and AVT) significantly improves speech perception ability when compared to audio-only (AO) stimulation. These multisensory speech perception benefits were reduced when the cross-modal temporal coherence characteristics were eliminated. These findings suggest that multisensory interactions are fundamentally important for speech perception ability in NH listeners. The outcome of this multisensory speech processing highly depends on temporal coherence characteristics between multi-modal sensory inputs.

Many enveloped viruses such as HIV have evolved to transmit by two infection modes: cell-free infection and cell-to-cell spread. Cell-to-cell spread is highly efficient as it involves directed viral transmission from the infected to the uninfected cell. In contrast, cell-free infection relies on chance encounters between the virion and cell. Despite the higher efficiency of cell-to-cell spread, there is substantial transmission by cell-free infection in conjunction with cell-to-cell spread. A possible reason is that cell-free infection offers a selective advantage by increasing sensitivity to factors interfering with infection, hence accelerating evolution of resistance relative to cell-to-cell spread alone. Here we investigated whether a combination of cell-free infection and cell-to-cell spread confers a selective advantage in experimental evolution to an antiretroviral drug. We maintained HIV infection using coculture of infected with uninfected cells in the face of moderate inhibition by the reverse transcriptase inhibitor efavirenz. We tested the effect on the rate of drug resistance evolution of replacing one coculture infection cycle with an infection cycle involving cell-free infection only, and observed earlier evolution of drug resistance mutations to efavirenz. When we increased selective pressure by adding a second reverse transcriptase inhibitor, emtricitabine, infection with the cell-free step consistently evolved multidrug resistance to both drugs and was able to replicate. In contrast, infection without a cell-free step mostly failed to evolve multidrug resistance. Therefore, HIV cell-to-cell spread decreases the ability of HIV to rapidly evolve resistance to inhibitors, which is conferred by cell-free infection.Author summaryCell-to-cell spread of HIV differs from cell-free, diffusion-based HIV infection in that viral transmission is directed from the infected to the uninfected cell through cellular interactions. Cell-to-cell spread has been recognized as a highly efficient infection mode that is able to surmount inhibition by antibodies and antiretroviral drugs. However, the effect of HIV cell-to-cell spread on the rate of evolution of viral resistance to infection inhibitors has not been studied. Here we used experimental evolution to investigate the effect of cell-to-cell spread versus cell-free infection on the emergence of drug resistance mutations to one or a combination of antiretroviral drugs. We found that replacing one infection cycle in experimental evolution with cell-free infection, where the filtered supernatant from infected cells, but not the cellular fraction, is used as the viral source, results in more rapid evolution of resistance. The consequences are that multidrug resistance consistently evolves with a cell-free viral cycle, but not when infection is solely by coculture of infected and uninfected cells. A possible consequence is that in environments where HIV cell-to-cell spread may predominate and some residual viral replication occurs in the face of ART, the emergence of drug resistance mutations would be delayed.

INTRODUCTION AND OBJECTIVE:New Zealand is an ethnically diverse country with a large number of Maori and Pacific Islanders (PI). Inferior health outcomes for Maori and PI continue to persist. Our o...

Background Radiofrequency (RF) technology has improved detection of retained surgical sponges with a reported 100% sensitivity and specificity. However, the potential for interactions of the RF signals emitted by the detection system with cardiac implantable electronic devices (CIEDs) or temporary pacemakers may limit its use in those patients with these devices. This study investigated whether RF detection technology causes interference or clinically significant changes in the programmed settings of implanted pacemakers and defibrillators or temporary epicardial pacemakers. Methods Fifty patients who were scheduled either for CIED removal or placement of a temporary epicardial pacemaker (at the time of open heart surgery) were recruited for this study. Device settings and measurements from separate interrogations before and after scanning with the RF detection system were compared. For the temporary pacemakers, we observed for any changes in hemodynamics or signs of pacing interference. Results Twenty (40%) pacemakers, 20 (40%) implantable cardioverter defibrillators, and 10 (20%) temporary pacemakers were analyzed in this study. During scanning, no signal interference was detected in any permanent device, and there were no significant changes in programmed settings after scanning with the RF detection system. However, pacing inhibition was detected with temporary pacing systems when programmed to a synchronous mode (DDD). Conclusions RF detection technology can be safely used to scan for retained surgical sponges in patients with permanent CIEDs and temporary pacemakers set to asynchronous mode.

HIV has been reported to be cytotoxic in vitro and in lymph node infection models. Using a computational approach, we found that partial inhibition of transmissions of multiple virions per cell could lead to increased numbers of live infected cells. If the number of viral DNA copies remains above one after inhibition, then eliminating the surplus viral copies reduces cell death. Using a cell line, we observed increased numbers of live infected cells when infection was partially inhibited with the antiretroviral efavirenz or neutralizing antibody. We then used efavirenz at concentrations reported in lymph nodes to inhibit lymph node infection by partially resistant HIV mutants. We observed more live infected lymph node cells, but with fewer HIV DNA copies per cell, relative to no drug. Hence, counterintuitively, limited attenuation of HIV transmission per cell may increase live infected cell numbers in environments where the force of infection is high., eLife digest The HIVvirus infects cells of the immune system. Once inside, it hijacks the cellular molecular machineries to make more copies of itself, which are then transmitted to new host cells. HIV eventually kills most cells it infects, either in the steps leading to the infection of the cell, or after the cell is already producing virus. HIV can spread between cells in two ways, known as cell-free or cell-to-cell. In the first, individual viruses are released from infected cells and move randomly through the body in the hope of finding new cells to infect. In the second, infected cells interact directly with uninfected cells. The second method is often much more successful at infecting new cells since they are exposed to multiple virus particles. HIV infections can be controlled by using combinations of antiretroviral drugs, such as efavirenz, to prevent the virus from making more of itself. With a high enough dose, the drugs can in theory completely stop HIV infections, unless the virus becomes resistant to treatment. However, some patients continue to use these drugs even after the virus they are infected with develops resistance. It is not clear what effect taking ineffective, or partially effective, drugs has on how HIV progresses. Using efavirenz, Jackson, Hunter et al. partially limited the spread of HIV between human cells grown in the laboratory. The experiments mirrored the situation where a partially resistant HIV strain spreads through the body. The results show that the success of cell-free infection is reduced as drug dose increases. Yet paradoxically, in cell-to-cell infection, the presence of drug caused more cells to become infected. This can be explained by the fact that, in cell-to-cell spread, each cell is exposed to multiple copies of the virus. The drug dose reduced the number of viral copies per cell without stopping the virus from infecting completely. The reduced number of viral copies per cell made it more likely that infected cells would survive the infection long enough to produce virus particles themselves. Viruses that can kill cells, such as HIV, must balance the need to make more of themselves against the speed that they kill their host cell to maximize the number of infected cells. If transmission between cells is too effective and too many virus particles are delivered to the new cell, the virus may not manage to infect new hosts before killing the old ones. These findings highlight this delicate balance. They also indicate a potential issue in using drugs to treat partially resistant virus strains. Without care, these treatments could increase the number of infected cells in the body, potentially worsening the effects of living with HIV.

Radiofrequency catheter ablation (RFCA) of the cavo-tricuspid isthmus (CTI) is a common treatment for atrial flutter (AFL). However, achieving bi-directional CTI conduction block may be difficult, partly due to catheter instability. To evaluate the safety and efficacy of the Amigo® Remote Catheter System (RCS) compared to manual catheter manipulation, during CTI ablation for AFL. Fifty patients (pts) were prospectively randomized to robotically (25 pts) versus manually (25 pts) controlled catheter manipulation during CTI ablation, using a force-contact sensing, irrigated ablation catheter. The primary outcome was recurrence of CTI conduction after a 30-min waiting period. Secondary outcomes included total ablation, procedure, and fluoroscopy times, contact force measurement, and catheter stability. Recurrence of CTI conduction 30 min after ablation was less with robotically (0/25) versus manually (6/25) controlled ablation (p = 0.023). Total ablation and procedure times to achieve persistent CTI block (6.7 ± 3 vs. 7.4 ± 2.5 min and 14.9 ± 7.5 vs. 15.2 ± 7 min, respectively) were not significantly different (p = 0.35 and p = 0.91, respectively). There was a non-significant trend toward a greater force time integral (FTI in gm/s) with robotically versus manually controlled CTI ablation (571 ± 278 vs. 471 ± 179, p = 0.13). Fluoroscopy time was longer with robotically versus manually controlled CTI ablation (6.8 ± 4.4 min vs. 3.8 ± 2.3 min, p = 0.0027). There were no complications in either group. Robotically controlled CTI ablation resulted in fewer acute recurrences of CTI conduction compared to manually controlled CTI ablation, and a trend toward higher FTI. The longer fluoroscopy time during robotically controlled ablation was likely due to a steep learning curve. Clinicaltrials.gov Identifier: NCT02467179

A hallmark of pulmonary tuberculosis is the formation of macrophage-rich granulomas. These may restrict Mycobacterium tuberculosis (Mtb) growth, or progress to central necrosis and cavitation, facilitating pathogen growth. To determine factors leading to Mtb proliferation and host cell death, we used live cell imaging to track Mtb infection outcomes in individual primary human macrophages. Internalization of Mtb aggregates caused macrophage death, and phagocytosis of large aggregates was more cytotoxic than multiple small aggregates containing similar numbers of bacilli. Macrophage death did not result in clearance of Mtb. Rather, it led to accelerated intracellular Mtb growth regardless of prior activation or macrophage type. In contrast, bacillary replication was controlled in live phagocytes. Mtb grew as a clump in dead cells, and macrophages which internalized dead infected cells were very likely to die themselves, leading to a cell death cascade. This demonstrates how pathogen virulence can be achieved through numbers and aggregation states. DOI: http://dx.doi.org/10.7554/eLife.22028.001, eLife digest Every year, around two million people worldwide die from tuberculosis, a disease caused by the bacterium Mycobacterium tuberculosis (Mtb). The bacteria generally infect the lungs. In response, the immune system forms structures called granulomas that attempt to control and isolate the infecting pathogens. Granulomas consist of immune cells known as macrophages, which engulf the M. tuberculosis bacteria and isolate them in a cellular compartment where the bacteria either cannot grow or are killed. However, if a large number of macrophages in a granuloma die, the granuloma’s core liquefies and the structure is coughed up into the airways, from where M. tuberculosis bacteria are transmitted to other people. But how do the bacteria manage to cause the extensive death of the cells that are supposed to control the infection? By imaging M. tuberculosis in human macrophages using time-lapse microscopy, Mahamed et al. reveal that the bacteria break down macrophage control by serially killing macrophages. M. tuberculosis cells first clump together and ‘gang up’ on a macrophage, which engulfs the clump and dies because the bacteria overwhelm it. This does not kill the bacteria, and they rapidly grow inside the dead macrophage. The dead cell is then cleaned up by another macrophage. However, the increasing number of bacteria inside the dead macrophage means that the new macrophage is even more likely to die than the first one. Hence, the bacteria use dead macrophages as fuel to grow on and as bait to attract the next immune cell. Overall, Mahamed et al. show that once a clump of M. tuberculosis initiates death of a single macrophage, it may lead to serial killing of other macrophages and a loss of control over the infection. An important next step will be to understand how the initial clump of bacteria is allowed to form. DOI: http://dx.doi.org/10.7554/eLife.22028.002

In 2015, individuals sentenced to death in the United States were housed in varying degrees of isolation. Many people were kept apart from others in profoundly isolating conditions, while others were housed with each other or with the general prison population. Given the growing awareness of the debilitating effects of long-term isolation, the placement of death-sentenced prisoners on what is colloquially known as “death row” has become the subject of discussion, controversy, and litigation. This Report, written under the auspices of the Arthur Liman Public Interest Program at Yale Law School, examines the legal parameters of death row housing to learn whether correctional administrators have discretion in deciding how to house death-sentenced individuals and to document the choices made in three jurisdictions where death-sentenced prisoners are not kept in isolation. Part I details the statutes, regulations, and policies that govern the housing of those sentenced to death and reviews prior research on the housing conditions of death-sentenced prisoners. Part II presents an overview of decisions in three states, North Carolina, Missouri, and Colorado, where correctional administrators enable death-sentenced prisoners to have meaningful opportunities to interact with others. Given the discretion that correctional officials have over housing arrangements, these states provide models to house capital-sentenced prisoners without placing them in solitary confinement.

Abstract The contact history of the languages of the Eastern and Western Torres Strait has been claimed (e.g. by Dixon 2002, Wurm 1972, and others) to have been sufficiently intense as to obscure the genetic relationship of the Western Torres Strait language. Some have argued that it is an Australian (Pama-Nyungan) language, though with considerable influence from the Papuan language Meryam Mir (the Eastern Torres Strait language). Others have claimed that the Western Torres language is, in fact, a genetically Papuan language, though with substantial Australian substrate or adstrate influence. Much has been made of phonological structures which have been viewed as unusual for Australian languages. In this paper we examine the evidence for contact claims in the region. We review aspects of the phonology, morphology, syntax and lexicon of the Eastern and Western Torres Strait languages with an eye to identifying areal influence. This larger data pool shows that the case for intense contact has been vastly overstated. Beyond some phonological features and some loan words, there is no linguistic evidence for intense contact; moreover, the phonological features adduced to be evidence of contact are also found to be not specifically Papuan, but part of a wider set of features in Australian languages.

To measure the prevalence of exposure to potentially modifiable risk factors in the homes of children hospitalised in Wellington.Parents/caregivers of all children admitted to Wellington Public Hospital during a two-week period in July 2012 completed a standardised questionnaire in a face-to-face interview. The questionnaire collected sociodemographic, health and housing condition data.We interviewed parents/caregivers of 106 children, of whom 72% were aged 0-4 years. Respiratory conditions were the most common cause of admission. One third of parents noticed dampness and mould in their house, 50% stated that their house was colder than they preferred during the past month, 20% lived in uninsulated houses, 20% lived in overcrowded houses, and 38% were exposed to second hand smoke (SHS). Compared to New Zealand European (NZE) children, the odds ratios (OR) for Pacific children living in cold and overcrowded houses and being exposed to SHS were 14.0 (95%CI 3.0-66.0), 10.8 (95%CI 2.6-44.1) and 16.0 (95%CI 4.8-55.5) respectively. OR for Maori children living in cold and overcrowded houses and being exposed to SHS were 3.0 (95%CI 1.0-9.0), 6.8 (95%CI 1.6-30.1) and 8.0 (95%CI 2.5-28.6) respectively, compared to NZE children. The OR for children from deprived neighbourhoods (NZDep2006 areas 7-10) living in cold and overcrowded houses and being exposed to SHS were 4.1 (95%CI 1.8-9.6), 5.7 (95%CI 1.9-17.0) and 4.1 (95%CI 1.6-9.6) respectively.Among children admitted to Wellington Hospital there is a high prevalence of exposure to cold, damp and overcrowded houses and many children are exposed to SHS. Maori and Pacific children and children living in socioeconomically deprived areas are more likely than others to be exposed to these potential risk factors for childhood hospitalisation. This audit of child admissions could be repeated to provide surveillance of modifiable risk factors. A shortened version of the questionnaire could be used to screen children to identify those with harmful exposures in their home environment, provided suitable intervention programmes can be established.

1.1 Cathepsins Cathepsins, originally identified as lysosomal proteases, play a fundamental role in intracellular protein turnover in lysosomes. However, several cathepsins and variants of cathepsins can also be found on the cell membrane, in the cytosol, nucleus, mitochondria, and extracellular space. These cathepsins are involved in a variety of important physiological and pathological processes [reviewed in: (Brix et al., 2008; Frlan and Gobec, 2006; Lutgens et al., 2007; Mohamed and Sloane, 2006; Nomura and Katunuma, 2005; Obermajer et al., 2008; Reiser et al., 2010; Stoka et al., 2005; Turk et al., 2001; Vasiljeva et al., 2007; Victor and Sloane, 2007)]. Cathepsins are classified mechanistically into groups which include serine (cathepsins A and G), aspartic (cathepsins D and E), and cysteine cathepsins (cathepsins B, C, F, H, L, K, O, S, V, W, and X). This classification is based on the nucleophilic residues present on their active sites responsible for proteolytic cleavage (Rawlings et al., 2006; Turk et al., 2001). Cathepsins are synthesized as zymogens composed of a signal peptide, a propeptide, and mature protein of distinct length and substrate specificity for individual cathepsins (Rawlings et al., 2006). The signal peptide is cleaved in the Endoplasmic Reticulum and the pro-protein is activated by proteolytic removal of the N-terminal pro-peptide either by autocatalysis in acidic environments, or by other proteases. The pro-peptide region of the cathepsin plays multiple roles. It can act as an inhibitor to block access to the active site that regulates cathepsin activity. In addition the propeptide can act as an intramolecular chaperone that assists in protein folding, or as a trafficking signal that targets the protein to its destination (Turk et al., 2002). Cathepsins exhibit a broad range of functions and tissue expression (Brix et al., 2008; Turk et al., 2001). Some of the cathepsins are ubiquitously expressed and others are tissue or cell-type specific. Cathepsins have been shown to be involved in the process of tumor invasion and metastasis (Bialas and Kafarski, 2009; Lindeman et al., 2004; Nomura and Katunuma, 2005; Obermajer