Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study.

BACKGROUND: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. METHODS: We used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions. FINDINGS: IPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor. INTERPRETATION: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.

Chronic Lung Injury after COVID-19 Pneumonia: Clinical, Radiologic, and Histopathologic Perspectives.

With the COVID-19 pandemic having lasted more than 3 years, concerns are growing about prolonged symptoms and respiratory complications in COVID-19 survivors, collectively termed post-COVID-19 condition (PCC). Up to 50% of patients have residual symptoms and physiologic impairment, particularly dyspnea and reduced diffusion capacity. Studies have also shown that 24%-54% of patients hospitalized during the 1st year of the pandemic exhibit radiologic abnormalities, such as ground-glass opacity, reticular opacity, bronchial dilatation, and air trapping, when imaged more than 1 year after infection. In patients with persistent respiratory symptoms but normal results at chest CT, dual-energy contrast-enhanced CT, xenon 129 MRI, and low-field-strength MRI were reported to show abnormal ventilation and/or perfusion, suggesting that some lung injury may not be detectable with standard CT. Histologic patterns in post-COVID-19 lung disease include fibrosis, organizing pneumonia, and vascular abnormality, indicating that different pathologic mechanisms may contribute to PCC. Therefore, a comprehensive imaging approach is necessary to evaluate and diagnose patients with persistent post-COVID-19 symptoms. This review will focus on the long-term findings of clinical and radiologic abnormalities and describe histopathologic perspectives. It also addresses advanced imaging techniques and deep learning approaches that can be applied to COVID-19 survivors. This field remains an active area of research, and further follow-up studies are warranted for a better understanding of the chronic stage of the disease and developing a multidisciplinary approach for patient management.

Virtual Patient and Family Engagement Strategies in Critical Care: A Scoping Review.

Background: Family engagement in care is increasingly recognized as an essential component of optimal critical care delivery. However, family engagement strategies have traditionally involved in-person family participation. Virtual approaches to family engagement may overcome barriers to family participation in care. The objective of this study was to perform a scoping review of virtual family engagement strategies in the intensive care unit (ICU). Methods: Studies were included if they involved a virtual engagement strategy with family members of an ICU patient and reported either (1) outcomes, (2) user perspectives, and/or (3) barriers or facilitators to virtual engagement in the ICU. Study types included primary research studies and review articles. Study selection followed the Joanna Briggs Institute Methodology for Scoping Reviews guidelines without any cultural, ethnic, gender, or specific language restrictions. The source of evidence included Ovid MEDLINE, PubMed, CINAHL, and Cochrane Library databases from inception to November 17, 2023. Google scholar was searched on December 1, 2023. Data were extracted on virtual engagement strategy used, outcomes (patient-centered, family-centered, and clinical), perspectives (patient, family, and health care professional [HCP]), and reported barriers or facilitators to virtual engagement in the ICU. Results were categorized into adult or pediatric/neonatal ICU setting. Results: Virtual engagement strategies identified were virtual visitation, virtual rounding, and virtual meetings. Family and HCPs were generally supportive of virtual visitation and rounding strategies. Overall, virtual strategies were associated with improved patient, family, and HCP outcomes. There were a few randomized interventional studies evaluating the effectiveness of virtual engagement strategies. Family, HCP, technological, and institutional barriers to the implementation and conduct of virtual engagement strategies were reported. Conclusions: Virtual family engagement strategies are associated with improved outcomes for patients, family, and HCPs. Identified barriers to virtual family engagement should be addressed. Future studies are needed to evaluate the effectiveness of virtual family engagement strategies in a more rigorous manner.

Pirfenidone in fibrotic hypersensitivity pneumonitis: a double-blind, randomised clinical trial of efficacy and safety.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients. METHODS: We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety. RESULTS: After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events. CONCLUSIONS: The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP. TRIAL REGISTRATION MUMBER: NCT02958917.

Interstitial lung disease progression after genomic usual interstitial pneumonia testing.

BACKGROUND: A genomic classifier for usual interstitial pneumonia (gUIP) has been shown to predict histological UIP with high specificity, increasing diagnostic confidence for idiopathic pulmonary fibrosis (IPF). Whether those with positive gUIP classification exhibit a progressive, IPF-like phenotype remains unknown. METHODS: A pooled, retrospective analysis of patients who underwent clinically indicated diagnostic bronchoscopy with gUIP testing at seven academic medical centres across the USA was performed. We assessed the association between gUIP classification and 18-month progression-free survival (PFS) using Cox proportional hazards regression. PFS was defined as the time from gUIP testing to death from any cause, lung transplant, ≥10% relative decline in forced vital capacity (FVC) or censoring at the time of last available FVC measure. Longitudinal change in FVC was then compared between gUIP classification groups using a joint regression model. RESULTS: Of 238 consecutive patients who underwent gUIP testing, 192 had available follow-up data and were included in the analysis, including 104 with positive gUIP classification and 88 with negative classification. In multivariable analysis, positive gUIP classification was associated with reduced PFS (hazard ratio 1.58, 95% CI 0.86-2.92; p=0.14), but this did not reach statistical significance. Mean annual change in FVC was -101.8 mL (95% CI -142.7- -60.9 mL; p<0.001) for those with positive gUIP classification and -73.2 mL (95% CI -115.2- -31.1 mL; p<0.001) for those with negative classification (difference 28.7 mL, 95% CI -83.2-25.9 mL; p=0.30). CONCLUSIONS: gUIP classification was not associated with differential rates of PFS or longitudinal FVC decline in a multicentre interstitial lung disease cohort undergoing bronchoscopy as part of the diagnostic evaluation.

Myositis-associated interstitial lung disease.

PURPOSE OF REVIEW: In idiopathic inflammatory myopathies (IIMs), interstitial lung disease (ILD) is common and the autoantibody profile, made up of myositis-specific and myositis-associated (MSA and MAA) antibodies, can predict the clinical phenotype and progression over time. This review will focus on the characteristics and management of antisynthetase syndrome related ILD and anti-MDA5 positive ILD, which are the most clinically relevant subtypes. RECENT FINDINGS: The prevalence of ILD in IIM has been estimated in Asia, North America and Europe at 50, 23 and 26%, respectively, and is increasing. In antisynthetase syndrome related ILD, the clinical presentation, progression and prognosis varies among anti-ARS antibodies. ILD is more common and severe in patients with anti-PL-7/anti-PL-12 antibodies when compared with anti Jo-1 patients. The prevalence of anti-MDA5 antibodies is higher in Asians (11-60%) than in whites (7-16%). Sixty-six percent of antisynthetase syndrome patients had 'chronic ILD' compared with the more rapidly progressive ILD (RP-ILD) seen in 69% of patients with anti-MDA5 antibodies. SUMMARY: ILD is most common in the antisynthetase subtype of IIM and can be a chronic indolent or RP- ILD. The MSA and MAAs are associated with different clinical phenotypes of ILD. Treatments typically involve combinations of corticosteroids and other immunosuppressants.

Surgical versus non-surgical interventions for displaced intra-articular calcaneal fractures.

BACKGROUND: Fractures of the calcaneus (heel bone) comprise up to 2% of all fractures. These fractures are mostly caused by a fall from a height, and are common in younger adults. Treatment can be surgical or non-surgical; however, there is clinical uncertainty over optimal management. This is an update of a Cochrane Review first published in 2013. OBJECTIVES: To assess the effects (benefits and harms) of surgical versus conservative treatment of displaced intra-articular calcaneal fractures. SEARCH METHODS: We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, CENTRAL, MEDLINE, Embase, and clinical trials registers in November 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs comparing surgical versus non-surgical management of displaced intra-articular calcaneal fractures in skeletally mature adults (older than 14 years of age). For surgical treatment, we included closed manipulation with percutaneous wire fixation, open reduction with internal fixation (ORIF) with or without bone graft, or primary arthrodesis. For non-surgical treatment, we included ice, elevation and rest, or plaster cast or splint immobilisation. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We collected data for the following outcomes: function in the short term (within three months of injury) or long term (more than three months after injury), chronic pain, health-related quality of life (HRQoL) and ability to return to normal activities, as well as complications which may or may not have led to an unplanned return to theatre. MAIN RESULTS: We included 10 RCTs and two quasi-RCTs with 1097 participants. Sample sizes in studies ranged from 29 to 424 participants. Most participants were male (86%), and the mean age in studies ranged from 28 to 52 years. In the surgical groups, participants were mostly managed with ORIF with plates, screws, or wires; one study used only minimally invasive techniques. Participants in the non-surgical groups were managed with a plaster cast, removable splint or a bandage, or with rest, elevation, and sometimes ice. Risk of performance bias was unavoidably high in all studies as it was not possible to blind participants and personnel to treatment; in addition, some studies were at high or unclear risk of other types of bias (including high risk of selection bias for quasi-RCTs, high risk of attrition bias, and unclear risk of selective reporting bias). We downgraded the certainty of all the evidence for serious risk of bias. We also downgraded the certainty of the evidence for imprecision for all outcomes (except for complications requiring return to theatre for subtalar arthrodesis) because the evidence was derived from few participants. We downgraded the evidence for subtalar arthrodesis for inconsistency because the pooled data included high levels of statistical heterogeneity. We found that surgical management may improve function at six to 24 months after injury when measured using the American Orthopaedic Foot and Ankle Society (AOFAS) score (mean difference (MD) 6.58, 95% confidence interval (CI) 1.04 to 12.12; 5 studies, 319 participants; low-certainty evidence). We are not aware of a published minimal clinically important difference (MCID) for the AOFAS score for this type of fracture. Previously published MCIDs for other foot conditions range from 2.0 to 7.9. No studies reported short-term function within three months of injury. Surgical management may reduce the number of people with chronic pain up to 24 months after injury (risk ratio (RR) 0.56, 95% CI 0.37 to 0.84; 4 studies, 175 participants; low-certainty evidence); this equates to 295 per 1000 fewer people with pain after surgical management (95% CI 107 to 422 per 1000). Surgical management may also lead to improved physical HRQoL (MD 6.49, 95% CI 2.49 to 10.48; 2 studies, 192 participants; low-certainty evidence). This outcome was measured using the physical component score of the 36-Item Short Form Health Survey. We used a change in effect of 5% to indicate a clinically important difference for this scoring system and thus judged that the difference in HRQoL between people treated surgically or non-surgically includes both clinically relevant and not relevant changes for those treated surgically. There may be little or no difference in the number of people who returned to work within 24 months (RR 1.26, 95% CI 0.94 to 1.68; 5 studies, 250 participants; low-certainty evidence) or who require secondary surgery for subtalar arthrodesis (RR 0.38, 95% CI 0.09 to 1.53; 3 studies, 657 participants; low-certainty evidence). For other complications requiring return to theatre in people treated surgically, we found low-certainty evidence for amputation (2.4%; 1 study, 42 participants), implant removal (3.4%; 3 studies, 321 participants), deep infection (5.3%; 1 study, 206 participants), and wound debridement (2.7%; 1 study, 73 participants). We found low-certainty evidence that 14% of participants who were treated surgically (7 studies, 847 participants) had superficial site infection. AUTHORS' CONCLUSIONS: Our confidence in the evidence is limited. Although pooled evidence indicated that surgical treatment may lead to improved functional outcome but with an increased risk of unplanned second operations, we judged the evidence to be of low certainty as it was often derived from few participants in studies that were not sufficiently robust in design. We found no evidence of a difference between treatment options in the number of people who needed late reconstruction surgery for subtalar arthritis, although the estimate included the possibility of important harms and benefits. Large, well-conducted studies that attempt to minimise detection bias and that measure functional outcomes using calcaneal-specific measurement tools would increase the confidence in these findings. Given that minimally invasive surgical procedures are already becoming more prevalent in practice, research is urgently needed to determine whether these newer surgical techniques offer better outcomes with regard to function, pain, quality of life, and postoperative complications for intra-articular displaced calcaneal fractures.

Family engagement in care for medical trainees and early career clinicians.

Engaging family members in care improves person- and family-centered outcomes. Many healthcare professionals have limited awareness of the role and potential benefit of family engagement in care. This review describes the rationale for engaging families in care, and opportunities to engage family in various clinical care settings during training and early career practice.

The attitudes and practices of physicians caring for patients with rheumatoid arthritis-associated interstitial lung disease: an international survey.

OBJECTIVES: This study sought to determine the level of understanding and opinion among rheumatologist and pulmonologists regarding risk factors, diagnostic approach and treatment of RA-associated interstitial lung disease (RA-ILD). METHODS: We conducted an international electronic survey of rheumatologists and pulmonologists utilizing two separate Redcap-based surveys with questions on the epidemiology, workup and management of RA-ILD as well as ILD screening questions using case-based scenarios directed at rheumatologists. The survey also collected demographic data on participants including their practice setting, years in practice and country of practice. RESULTS: We received a total of 616 responses (354 rheumatologists and 262 pulmonologists) from six continents. There were significant differences in responses between pulmonologists and rheumatologists in estimated prevalence and mortality, risk factors for the development of ILD in RA and medications that are effective or should be avoided. Rheumatologists were much less likely to consider assessment for ILD in high risk, asymptomatic patients compared with high-risk patients with either symptoms or exam findings suggestive of ILD. CONCLUSION: Our study brought to light the variability in disease assessment and clinical practice among providers caring for patients with RA-ILD and indicate that greater education is needed to optimize clinical decision making in the risk assessment, screening and treatment of RA-ILD. Research questions that address appropriate screening and treatment strategies for RA-ILD will be valuable for rheumatologists given their central role in the overall health and lung health of patients with RA.

Gain control of saccadic eye movements is probabilistic.

Saccades are rapid eye movements that orient the visual axis toward objects of interest to allow their processing by the central, high-acuity retina. Our ability to collect visual information efficiently relies on saccadic accuracy, which is limited by a combination of uncertainty in the location of the target and motor noise. It has been observed that saccades have a systematic tendency to fall short of their intended targets, and it has been suggested that this bias originates from a cost function that overly penalizes hypermetric errors. Here, we tested this hypothesis by systematically manipulating the positional uncertainty of saccadic targets. We found that increasing uncertainty produced not only a larger spread of the saccadic endpoints but also more hypometric errors and a systematic bias toward the average of target locations in a given block, revealing that prior knowledge was integrated into saccadic planning. Moreover, by examining how variability and bias covaried across conditions, we estimated the asymmetry of the cost function and found that it was related to individual differences in the additional time needed to program secondary saccades for correcting hypermetric errors, relative to hypometric ones. Taken together, these findings reveal that the saccadic system uses a probabilistic-Bayesian control strategy to compensate for uncertainty in a statistically principled way and to minimize the expected cost of saccadic errors.

CT of Post-Acute Lung Complications of COVID-19.

The acute course of COVID-19 is variable and ranges from asymptomatic infection to fulminant respiratory failure. Patients recovering from COVID-19 can have persistent symptoms and CT abnormalities of variable severity. At 3 months after acute infection, a subset of patients will have CT abnormalities that include ground-glass opacity (GGO) and subpleural bands with concomitant pulmonary function abnormalities. At 6 months after acute infection, some patients have persistent CT changes to include the resolution of GGOs seen in the early recovery phase and the persistence or development of changes suggestive of fibrosis, such as reticulation with or without parenchymal distortion. The etiology of lung disease after COVID-19 may be a sequela of prolonged mechanical ventilation, COVID-19-induced acute respiratory distress syndrome (ARDS), or direct injury from the virus. Predictors of lung disease after COVID-19 include need for intensive care unit admission, mechanical ventilation, higher inflammatory markers, longer hospital stay, and a diagnosis of ARDS. Treatments of lung disease after COVID-19 are being investigated, including the potential of antifibrotic agents for prevention of lung fibrosis after COVID-19. Future research is needed to determine the long-term persistence of lung disease after COVID-19, its impact on patients, and methods to either prevent or treat it. © RSNA, 2021.

Methotrexate and rheumatoid arthritis associated interstitial lung disease.

QUESTION ADDRESSED BY THE STUDY: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD. METHODS: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. RESULTS: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001). ANSWER TO THE QUESTION: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients.

Pelvic dimensions on preoperative imaging can identify poor-quality resections after laparoscopic low anterior resection for mid- and low rectal cancer.

BACKGROUND: High-quality surgery is essential for optimal oncologic outcomes in rectal cancer, but total mesorectal excision (TME) can be difficult for mid- and low rectal cancers. Preoperative identification of patients at risk for difficult TME may change the operative approach. The objective of this study was to determine if MRI pelvimetry can predict poor-quality surgery in patients undergoing laparoscopic low anterior resection (LAR) for mid- and low rectal cancer. METHODS: All patients undergoing laparoscopic LAR for rectal cancer ≤ 9 cm from the anal verge at a single tertiary care referral center from 2011 to 2017 were retrospectively reviewed. Pelvic dimensions were measured from preoperative staging MRI on sagittal and axial views. Pelvimetry variables were all dichotomized based on median values. Exploratory factor analysis then identified the most relevant variables for regression analysis. The primary outcome was poor-quality resection, defined as an incomplete mesorectal grade, or involved circumferential (CRM) or distal (DRM) resection margins. RESULTS: There were 92 patients included in this study, of which 70% were male, the mean BMI was 26.0 kg/m2, and the mean tumor height was 6.6 cm. Preoperative (chemo)radiotherapy was administered in 70%, and the pathologic T-stage was T3/T4 in 41%. The overall incidence of poor-quality resection was 17%, including 13% incomplete TME, 7% involved CRM, and 1% involved DRM. Factor analysis identified S1-pubic symphysis and the angle between S1 and S5-bottom of symphysis (angle ABD) as relevant variables. After adjusting for pathologic T-stage, BMI, and tumor height, a S1-S5-bottom of symphysis angle > 74.3° (OR 6.19, 95% CI 1.18-32.37) independently predicted poor-quality resection. CONCLUSIONS: MRI pelvimetry can identify patients at risk for a poor-quality resection after laparoscopic proctectomy for mid- and low rectal cancer. These patients may benefit from the selective use of more advanced access methods to improve surgical resection quality.

Models for discriminating image blur from loss of contrast.

Observers can discriminate between blurry and low-contrast images (Morgan, 2017). Wang and Simoncelli (2004) demonstrated that a code for blur is inherent to the phase relationships between localized pattern detectors of different scales. To test whether human observers actually use local phase coherence when discriminating between image blur and loss of contrast, we compared phase-scrambled chessboards with unscrambled chessboards. Although both stimuli had identical amplitude spectra, local phase coherence was disrupted by phase-scrambling. Human observers were required to concurrently detect and identify (as contrast or blur) image manipulations in the 2 × 2 forced-choice paradigm (Nachmias & Weber, 1975; Watson & Robson, 1981) traditionally considered to be a litmus test for "labelled lines" (i.e. detection mechanisms that can be distinguished on the basis of their preferred stimuli). Phase scrambling reduced some observers' ability to discriminate between blur and a reduction in contrast. However, none of our observers produced data consistent with Watson and Robson's most stringent test for labeled lines, regardless whether phases were scrambled or not. Models of performance fit significantly better when (a) the blur detector also responded to contrast modulations, (b) the contrast detector also responded to blur modulations, or (c) noise in the two detectors was anticorrelated.

A perceptual bias for man-made objects in humans.

Ambiguous images are widely recognized as a valuable tool for probing human perception. Perceptual biases that arise when people make judgements about ambiguous images reveal their expectations about the environment. While perceptual biases in early visual processing have been well established, their existence in higher-level vision has been explored only for faces, which may be processed differently from other objects. Here we developed a new, highly versatile method of creating ambiguous hybrid images comprising two component objects belonging to distinct categories. We used these hybrids to measure perceptual biases in object classification and found that images of man-made (manufactured) objects dominated those of naturally occurring (non-man-made) ones in hybrids. This dominance generalized to a broad range of object categories, persisted when the horizontal and vertical elements that dominate man-made objects were removed and increased with the real-world size of the manufactured object. Our findings show for the first time that people have perceptual biases to see man-made objects and suggest that extended exposure to manufactured environments in our urban-living participants has changed the way that they see the world.

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels.

Cardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG.

Calculation Efficiencies for Mean Numerosity.

Relative numerosity is traditionally studied using texture pairs. Observers must decide which member of each pair has the greater total number of texture elements. In the present experiment, textures were segregated into nonoverlapping "sectors" containing between zero and four elements, and our observers were asked to select the texture containing the greater average number of texture elements (per sector). If observers were more sensitive to total numerosity than average numerosity, their performance (quantified by the just-noticeable Weber fraction) should have been better when the two textures occupied the same number of sectors than when they occupied unequal numbers of sectors. However, we recorded Weber fractions between 11% and 13% for all observers in all conditions. This performance was comparable with an otherwise-ideal observer whose decisions were based on between three and five sectors in each texture. We conjecture that traditional numerosity discriminations are based on similarly small numbers of element clusters.

Robust averaging protects decisions from noise in neural computations.

An ideal observer will give equivalent weight to sources of information that are equally reliable. However, when averaging visual information, human observers tend to downweight or discount features that are relatively outlying or deviant ('robust averaging'). Why humans adopt an integration policy that discards important decision information remains unknown. Here, observers were asked to judge the average tilt in a circular array of high-contrast gratings, relative to an orientation boundary defined by a central reference grating. Observers showed robust averaging of orientation, but the extent to which they did so was a positive predictor of their overall performance. Using computational simulations, we show that although robust averaging is suboptimal for a perfect integrator, it paradoxically enhances performance in the presence of "late" noise, i.e. which corrupts decisions during integration. In other words, robust decision strategies increase the brain's resilience to noise arising in neural computations during decision-making.

Improvement of contrast sensitivity with practice is not compatible with a sensory threshold account.

In forced-choice detection, incorrect responses are routinely ascribed to internal noise, because experienced psychophysical observers do not act as if they have a sensory threshold, below which all perceived intensities would be identical. To determine whether inexperienced observers have sensory thresholds, we examined psychometric functions (percent correct versus log contrast) for detection and detection in full-screen, dynamic visual noise. Over five days, neither type of psychometric function changed shape, but both shifted leftwards, indicating increased sensitivity. These results are not consistent with a lowered sensory threshold, which would decrease psychometric slope. Our results can be understood within the context of Dosher and Lu's "stochastic" perceptual template model [Vis. Res.40, 1269 (2000)], augmented to allow intrinsic uncertainty. Specifically, our results are consistent with a combination of reduced internal additive noise and improved filtering of external noise.

Predictors of mortality in rheumatoid arthritis-associated interstitial lung disease.

Interstitial lung disease (ILD) is a common pulmonary manifestation of rheumatoid arthritis. There is lack of clarity around predictors of mortality and disease behaviour over time in these patients.We identified rheumatoid arthritis-related interstitial lung disease (RA-ILD) patients evaluated at National Jewish Health (Denver, CO, USA) from 1995 to 2013 whose baseline high-resolution computed tomography (HRCT) scans showed either a nonspecific interstitial pneumonia (NSIP) or a "definite" or "possible" usual interstitial pneumonia (UIP) pattern. We used univariate, multivariate and longitudinal analytical methods to identify clinical predictors of mortality and to model disease behaviour over time.The cohort included 137 subjects; 108 had UIP on HRCT (RA-UIP) and 29 had NSIP on HRCT (RA-NSIP). Those with RA-UIP had a shorter survival time than those with RA-NSIP (log rank p=0.02). In a model controlling for age, sex, smoking and HRCT pattern, a lower baseline % predicted forced vital capacity (FVC % pred) (HR 1.46; p<0.0001) and a 10% decline in FVC % pred from baseline to any time during follow up (HR 2.57; p<0.0001) were independently associated with an increased risk of death.Data from this study suggest that in RA-ILD, disease progression and survival differ between subgroups defined by HRCT pattern; however, when controlling for potentially influential variables, pulmonary physiology, but not HRCT pattern, independently predicts mortality.