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ObjectivesProlonged survival of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on environmental surfaces and personal protective equipment may lead to these surfaces transmitting this pathogen to others. We sought to determine the effectiveness of a pulsed-xenon ultraviolet (PX-UV) disinfection system in reducing the load of SARS-CoV-2 on hard surfaces and N95 respirators.MethodsChamber slides and N95 respirator material were directly inoculated with SARS-CoV-2 and were exposed to different durations of PX-UV.ResultsFor hard surfaces, disinfection for 1, 2, and 5 minutes resulted in 3.53 log10, >4.54 log10, and >4.12 log10 reductions in viral load, respectively. For N95 respirators, disinfection for 5 minutes resulted in >4.79 log10 reduction in viral load. PX-UV significantly reduced SARS-CoV-2 on hard surfaces and N95 respirators.ConclusionWith the potential to rapidly disinfectant environmental surfaces and N95 respirators, PX-UV devices are a promising technology to reduce environmental and personal protective equipment bioburden and to enhance both healthcare worker and patient safety by reducing the risk of exposure to SARS-CoV-2.

Psychosis rates in autism spectrum disorder (ASD) are 5-35% higher than in the general population. The overlap in sensory and attentional processing abnormalities highlights the possibility of related neurobiological substrates. Previous research has shown that several electroencephalography (EEG)-derived event-related potential (ERP) components that are abnormal in schizophrenia, including P300, are also abnormal in individuals at Clinical High Risk (CHR) for psychosis and predict conversion to psychosis. Yet, it is unclear whether P300 is similarly sensitive to psychosis risk in help-seeking CHR individuals with ASD history. In this exploratory study, we leveraged data from the North American Prodrome Longitudinal Study (NAPLS2) to probe for the first time EEG markers of longitudinal psychosis profiles in ASD. Specifically, we investigated the P300 ERP component and its sensitivity to psychosis conversion across CHR groups with (ASD+) and without (ASD-) comorbid ASD. Baseline EEG data were analyzed from 304 CHR patients (14 ASD+; 290 ASD-) from the NAPLS2 cohort who were followed longitudinally over two years. We examined P300 amplitude to infrequent Target (10%; P3b) and Novel distractor (10%; P3a) stimuli from visual and auditory oddball tasks. Whereas P300 amplitude attenuation is typically characteristic of CHR and predictive of conversion to psychosis in non-ASD sample, in our sample, history of ASD moderated this relationship such that, in CHR/ASD+ individuals, enhanced - rather than attenuated - visual P300 (regardless of stimulus type) was associated with psychosis conversion. This pattern was also seen for auditory P3b amplitude to Target stimuli. Though drawn from a small sample of CHR individuals with ASD, these preliminary results point to a paradoxical effect, wherein those with both CHR and ASD history who go on to develop psychosis have a unique pattern of enhanced neural response during attention orienting to both visual and target stimuli. Such a pattern stands out from the usual finding of P300 amplitude reductions predicting psychosis in non-ASD CHR populations and warrants follow up in larger scale, targeted, longitudinal studies of those with ASD at clinical high risk for psychosis.

Abstract: Background: Clinical outcomes vary among young people with the psychosis risk syndrome (PRS), with approximately 20% of individuals progressing to a psychotic disorder over 2–3 years and 30% achieving clinical remission. The identification of neurophysiological abnormalities associated with schizophrenia that predate and predict psychosis onset may enhance the accuracy of clinical outcome prediction in the PRS and help elucidate the pathogenic mechanisms of psychosis onset. Auditory P300 event-related potential (ERP) component amplitude reductions are well established in schizophrenia and reflect early attention-mediated information processing deficits. Recent studies employing auditory oddball tasks have shown that P300 amplitude deficits in PRS individuals are associated with later clinical outcomes, including both conversion to full-blown psychosis and remission from the at-risk state. The present study examined whether these effects extend to P300 in the visual modality using visual oddball task data collected as part of the North American Prodrome Longitudinal Study. Specifically, we evaluated whether visual P300 amplitudes are reduced in the PRS and predict future clinical outcomes. Methods: 540 individuals meeting PRS criteria and 229 healthy individuals completed baseline EEG recording during a visual oddball task. Visual P300 subcomponents were measured in response to two stimulus types: (1) infrequent target stimuli, reflecting top-down allocation of attention (target P3b), and (2) infrequent non-target novel distractor stimuli, reflecting bottom-up orienting of attention (novelty P3a). P300 amplitudes of PRS participants who converted to psychosis (n=70) were compared with those of PRS non-converters who were followed clinically for 24 months and continued to be symptomatic (n=131) or fully remitted from the PRS (n=87). Results: Group comparison effects did not differ by stimulus type. Visual P300 amplitudes were not significantly reduced in the PRS group relative to healthy individuals (p=.25). However, baseline target P3b and novelty P3a amplitudes were reduced in PRS individuals who later converted to psychosis relative to all PRS non-converters, including those who remitted (p=.006, d=.44) and those who remained symptomatic (p=.015, d=.37), as well as healthy individuals (p=.001, d=.44). Baseline P300 amplitudes were similar among healthy controls, PRS remitters, and PRS individuals who remained symptomatic (ps>.45). Moreover, visual P300 amplitudes differentiated future psychosis converters after accounting for PRS symptom severity. Finally, both target P3b and novelty P3a amplitudes predicted the time to psychosis onset in PRS participants (p=.03 and p=.02, respectively), such that more deficient P300 amplitudes were associated with shorter time to conversion. Discussion: Baseline visual P300 amplitudes were reduced in future PRS converters relative to non-converters, with effect sizes comparable to those reported in previous auditory P300 studies of the PRS. Results implicate visual P300 as a neurophysiological vulnerability marker that predicts clinical outcomes among PRS individuals, including future transition to psychosis. Accordingly, together with prior auditory P300 studies, results suggest that P300 may have the potential to contribute to personalized early intervention in the PRS by distinguishing individuals with the greatest risk for psychotic illness, who require the most aggressive treatment, from those who may need minimal intervention.

Abstract Background Individuals with autism spectrum disorders (ASD) have symptoms, including social and sensory deficits, and neurobiological alterations that overlap with schizophrenia. Though there is evidence of high rates of psychosis symptoms in ASD, little is known about psychosis prodrome in ASD, or about predictors of psychosis conversion in this population. In this study, we leverage data from clinical high risk (CHR) patients from the NAPLS2 consortium to examine: a) baseline differences in psychosis symptoms and social functioning, b) relative risk of conversion, and c) whether neural response to sensory stimuli yields differential predictors of conversion in CHR individuals with and without ASD (CHR/ASD+; CHR/ASD-). Methods Clinical, electrophysiological, and 24-month follow-up data were available for 305 individuals (14 CHR/ASD+; 291 CHR/ASD-). We examined baseline differences on the SOPS, GFS, and TASIT. Conversion risk was computed with the Cannon conversion calculator, and conversion was defined as SOPS>6 at 2-year outcome. P300 event-related potentials (ERP) were extracted from ongoing EEG collected at baseline in response to Target and Novel auditory and visual stimuli, each presented on 10% of trials within streams of 80% standard stimuli in the same modality. Results In line with our expectations, CHR/ASD+ had worse functioning than CHR/ASD- on the GF-Social scale (t=-4.2, p

Abstract Background: Reductions in the auditory P300 event-related potential (ERP) component are well established in schizophrenia and reflect early attention-mediated auditory processing deficits. Two subcomponents of P300 are evident depending on oddball task conditions; P3b is elicited by infrequent target stimuli and reflects top-down attention allocation, whereas P3a is elicited by infrequent non-target novel distractor stimuli and reflects bottom-up orienting of attention. The present study examined whether auditory P300 abnormalities precede illness onset and are associated with future clinical status by assessing both target P3b and novel P3a in individuals at clinical high risk for psychosis (CHR) and healthy controls (HC) collected as part of the North American Prodrome Longitudinal Study. Methods: CHR (n = 552) and HC (n = 235) participants completed baseline EEG recording during an auditory oddball task. CHR participants were further categorized by clinical status after 24 months of study participation (n = 298) and included a subgroup who transitioned to psychosis (CHR-Transition; n = 73), a subgroup who did not transition but remained symptomatic (CHR-Symptomatic; n = 135), and a subgroup who did not transition and was in symptom remission (CHR-Remission; n = 90). Results: CHR participants had reduced target P3b and novel P3a amplitudes relative to HC (Ps < .001). There was also an effect of 24-month clinical status group on both P3b and P3a amplitudes (P < .001 and P = .006, respectively). Planned contrasts revealed that compared to HC, CHR participants had smaller target P3b amplitudes at baseline (P < .001). In addition, CHR-Transition participants had attenuated P3b amplitudes at baseline relative to all CHR participants who did not transition to psychosis (P = .037). Furthermore, both CHR-Transition and CHR-Symptomatic had smaller P3b amplitudes than both HC (Ps < .001) and CHR-Remission (P = .003 and P = .005, respectively), while P3b of CHR-Remission did not differ from HC at baseline (P > .05). In contrast, although CHR participants also had smaller novel P3a amplitudes than HC at baseline (P < .001), P3a did not differentiate CHR-Transition participants from CHR participants who did not transition within 24 months (P > .05). Despite CHR-Transition and CHR-Symptomatic having smaller P3a amplitudes than HC (P = .028 and P = .002, respectively), they did not differ from CHR-Remission (Ps > .05) at baseline. Moreover, target P3b predicted the time to psychosis onset in CHR participants over and above novel P3a amplitude (P = .024). Conclusion: Both target P3b and novel P3a are reduced in individuals identified to be at risk for developing a psychotic disorder, and P3b in particular appears sensitive to future transition to psychosis. Given this association with clinical outcomes, results implicate target P3b as a neurophysiological vulnerability marker for psychosis.

Abstract Background: Recent studies have recognized that signs of functional disability in schizophrenia are evident in early phases of the disorder, and, as a result, can potentially serve as vulnerability markers of future illness. However, functional measures in the psychosis prodrome have focused exclusively on real-world accomplishment (ie, achievement), rather than on the skills required to carry-out a particular real-world function (ie, capacity). From this perspective capacity provides the foundation for what can actually be achieved. This is comparable to the comparison between IQ (capacity) vs grades at school (achievement). In one of the first reports of its kind, we introduced the Map task, a laboratory-based measure specifically designed to assess a young person’s basic capacity to carry-out age-appropriate skills that lead to independent community living (McLaughlin et al., 2016). Poor performance on the Map task was found to be predictive of conversion to psychosis, suggesting that functional capacity in the prodrome may represent a basic biologically-based vulnerability factor. Given that diminished functional capacity is often a key barrier to good functional outcomes in patients with schizophrenia, the current study sought to next evaluate whether deficits in capacity can also predict social and role (ie, academic) functioning in the prodrome. Methods: The Map task was administered to 609 subjects at Clinical High-Risk (CHR) for psychosis and 242 Healthy Controls (HCs) participating in the North American Prodrome Longitudinal Study (NAPLS2). Subjects were required to efficiently complete a set of specified errands in a fictional town. Results: Individuals with poor role functioning at study outcome had a lower Map efficiency score than those with good role outcome. In addition, the Map efficiency score predicted role functioning at outcome (OR = −0.971, 95% CI = 0.946 to 0.997; P = .027), even after accounting for conversion status, baseline IQ, and baseline role functioning). In contrast, the Map Efficiency score did not predict social outcome (OR = 0.989, 95% CI = 0.964–1.015; P = .416), supporting previous findings that social and role functioning are 2 distinct functional domains, with different developmental courses, with each having potential to provide predictors of long-term prognosis. Conclusion: Our findings support the notion that functional capacity may well represent a distinct vulnerability factor related to the multi-faceted long-term disability typically associated with schizophrenia. Poor performance on the Map task was significantly associated with impaired role functioning at study outcome, even after controlling for the contribution of conversion and intellectual performance. Thus, deficits in both role “capacity” and role “achievement” are present before the onset of the illness, and are not an artifact of psychosis onset or intellectual impairments.

Abstract Background: Social functioning deficits are present prior to the onset of psychosis and predict psychosis conversion in high-risk youth (Cornblatt et al, 2015; Cannon et al, 2008). In addition, past research from the Recognition and Prevention (RAP) Program found that social skill deficits are lifelong traits related to poor functional outcome in general (Cornblatt et al, 2015; Carrion et al, 2013). This poster reassesses the implications of social skill deficits as a developmental trait by examining change in social functioning. Methods: Subjects include 88 clinical high risk (CHR) participants enrolled in Phase 1 of the RAP Program and 347 CHR participants enrolled in the North American Prodrome Longitudinal Study 2 (NAPLS2). Social functioning deficits were assessed with the Global Functioning: Social (GF:S) scale, an interview measure of social interactions rated from 1–10 with higher scores indicating better functioning (Cornblatt et al, 2007). Associations between GF:S scores and baseline demographics, SIPS attenuated positive and negative symptoms, and Axis I diagnoses were examined. Conversion to psychosis and functional outcome were assessed at follow up (RAP = 3 years, NAPLS2 = 2 years). CHR participants were divided according to whether their GF:S score improved, did not change, or declined over follow up. GF:S scores were also dichotomized into Good (GF:S ≥ 7) vs Poor (GF:S ≤ 6) functioning at baseline and follow up. Results: For the RAP sample, there were no significant differences between groups on demographic variables or SIPS symptoms. The Improver and No Change groups were significantly more likely to be diagnosed with Social Phobia compared to Decliners (Ps < .01). Similar results were found in the larger NAPLS2 sample for demographic variables, SIPS symptoms, and Axis I diagnoses (all ns). Significantly more Decliners in both samples converted to psychosis (RAP 32%, NAPLS2 36%) compared to the Improvers (RAP 10.5%, NAPLS2 10%; Ps ≤ .03). Decliners were also more likely to convert than the No Change (8%) group (RAP, P = .03; NAPLS, trend). In addition, No Change subjects were more likely to have poor functioning at baseline and outcome (RAP 72%, NAPLS2 51%). Conclusion: As expected, CHRs with decline in social functioning are at greatest risk for psychosis. In contrast, CHRs who improve over time are likely not at risk for either psychosis or functional disability. The remaining subjects display stable poor functioning, but are less likely to develop psychosis, suggesting their risk is for long term functional disability. Only one clinical variable, Social Phobia, differentiated groups, indicating that social anxiety is more likely found in false positives. These findings have two major implications: (1) stable social skill deficits appear to relate to long-term disability and (2) change in adolescence is predictive of psychosis.

Abstract Background: The vast majority of studies of neuropsychological (NP) functioning in Clinical High Risk (CHR) cohorts have examined group averages, possibly concealing a range of subgroups ranging from very impaired to high functioning. Our objective was to assess NP profiles and to explore associations with conversion to psychosis, functional and diagnostic outcome. Methods: Data were acquired from individuals (mean age 18.4, SD = 4.6) participating in the longitudinal North American Prodrome Longitudinal Study-I (NAPLS-I), a multi-site consortium following individuals at CHR for developing psychosis for up to 2½ years. By applying the Hierarchical Clustering Ward’s method including 8 different neuropsychological tests, we clustered data of 166 CHR individuals, 49 persons with a family history of psychosis without prodromal symptoms, and 109 healthy controls. We then tested whether cluster profiles with more severe NP impairments were associated with higher conversion rates, lower social and role functioning scores, and/or more chronic diagnostic outcomes compared to the lesser-impaired profiles. To examine clinical utility, analyses were repeated after data were clustered based on clinical decision rules that were established by clinical experts in the field. Results: Four distinctive profile clusters best described the level of NP performance in our CHR cohort: Severely Impaired (n = 33); Clearly Abnormal (n = 82); Borderline (n = 145) and Normal (n = 64). The Severely Impaired cluster largely distinguished itself from the rest of the clusters by larger deviations on processing speed and memory tasks. We found compelling differences in outcome between cluster profiles. Importantly, those assigned to the most impaired profile had a conversion rate of 42.4%, had a 40% chance of developing a diagnosis in the schizophrenia spectrum (as compared to 24.4% in the Clearly impaired, 7.4 % in the Borderline impaired and 2.9% in the Normal functioning group), and had significantly worse social (P < .001) and role (P < .001) functioning scores at baseline and 12-month follow-up. Similar results were obtained when data were clustered following clinical decision rules. Conclusion: Despite extensive neuropsychological investigations within CHR cohorts, this is one of the first studies to investigate NP clustering profiles as a contributor to heterogeneity in outcome. Our results indicate that the four NP profiles vary substantially in their outcome, underscoring the relevance of cognitive functioning in the prediction of illness progression. Our findings may tentatively suggest that individualized cognitive profiling should be explored in clinical settings, and my point to important directions for personalized treatment.

In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics.

Adenoviruses are DNA viruses that infect a number of vertebrate hosts and are associated with both sporadic and epidemic disease in humans. We previously identified a novel adenovirus, titi monkey adenovirus (TMAdV), as the cause of a fulminant pneumonia outbreak in a colony of titi monkeys (Callicebus cupreus) at a national primate center in 2009. Serological evidence of infection by TMAdV was also found in a human researcher at the facility and household family member, raising concerns for potential cross-species transmission of the virus. Here we present experimental evidence of cross-species TMAdV infection in common marmosets (Callithrix jacchus). Nasal inoculation of a cell cultured-adapted TMAdV strain into three marmosets produced an acute, mild respiratory illness characterized by low-grade fever, reduced activity, anorexia, and sneezing. An increase in virus-specific neutralization antibody titers accompanied the development of clinical signs. Although serially collected nasal swabs were positive for TMAdV for at least 8 days, all 3 infected marmosets spontaneously recovered by day 12 post-inoculation, and persistence of the virus in tissues could not be established. Thus, the pathogenesis of experimental inoculation of TMAdV in common marmosets resembled the mild, self-limiting respiratory infection typically seen in immunocompetent human hosts rather than the rapidly progressive, fatal pneumonia observed in 19 of 23 titi monkeys during the prior 2009 outbreak. These findings further establish the potential for adenovirus cross-species transmission and provide the basis for development of a monkey model useful for assessing the zoonotic potential of adenoviruses.