Duration of untreated prodromal symptoms in individuals at clinical high risk for psychosis; analysis of onset of prodromal symptoms, and the effect of duration on outcomes in clinical high-risk populations.

Introduction: It is believed that people affected by schizophrenia, who have a long gap between the onset of psychotic symptoms, and the start of treatment have worse outcomes, both in the short and long-term. This is called the duration of untreated psychosis hypothesis An area where there is limited current research is the effect of the duration of prodromal symptoms in people at clinical high risk for psychosis (CHR-P). These prodromal symptoms are reported in a majority of those who transition to psychosis, suggesting that they may be significant for later outcomes. This study focuses on the timing of the relative onset of attenuated psychotic symptoms (APS) and basic symptoms (BS); on the reported duration of BS and APS, from participants at CHR-P; and the effects of these on functional outcomes, and on cognition. There is a specific hypothesis that APS are a consequence of BS, implying that BS should commence before APS. Methods: Participants were recruited as part of the Youth mental health, risk and Resilience (YouR) study. This is a community-based study, carried out among people aged 16 to 35 in Glasgow and Edinburgh, analyzing emerging psychotic symptoms. Data from 134 CHR-P participants were analyzed for the duration of APS and BS and these were related to global assessment of functioning (GAF), role functioning and social functioning. Two measures of cognition were collected during baseline assessments. An analysis was conducted to compare duration of APS and BS symptoms, and to assess the effect of duration on GAF scores, role functioning, social functioning and cognition measures. Results: There was no significant relationship between BS onset and APS, and in a significant percentage of the sample (n = 24, 37.5%) the reported APS onset was prior to BS onset. Only CHR-P individuals with long BS showed some evidence for the hypothesized relationship of BS preceding APS (n = 13, p = 0.04). Duration of APS and BS showed no significant effects on cognition, except for small effects on motor speed and verbal fluency. Duration of prodromal symptoms also did not show any significant effects on any of the measures of functioning. Discussion: The current study did not support the hypothesis that BS precedes the emergence of APS in individuals who are CHR-P. This could have significant implications for current conceptions of APS and BS in the prodromal period. A number of factors have been previously reported to effect recall of duration of prodromal symptoms, including years of education and age at onset of symptoms. No evidence was found of between group differences. These findings produce two key questions; how accurate is the hypothesis that APS are a secondary consequence of BS, and are there between group differences previously not considered which may affect the difference in reported symptoms. Areas for future research on this topic are discussed. The implications of the negative findings for functioning and cognition are compared to current research into duration of untreated psychosis. The differences in the finding are theorized to be linked to two key hypotheses in psychosis; the critical period of psychosis and the neurodevelopmental theory of psychosis. Both these theories have time dependent components, but current research using duration of prodromal symptoms is limited. Potential implications of this study as preliminary evidence for them are discussed. Finally, this study reported significantly longer duration of prodromal symptoms in a non-help seeking sample, compared to previous findings conducted on clinical samples. The implications of these findings and suggestion for future research are discussed

Duration of basic and attenuated-psychotic symptoms in individuals at clinical high risk for psychosis: pattern of symptom onset and effects of duration on functioning and cognition

Introduction: Duration of risk symptoms (DUR) in people at clinical high risk for psychosis (CHR-P) has been related to poorer clinical outcomes, such as reduced functioning, but it is currently unclear how different symptoms emerge as well as their link with cognitive deficits. To address these questions, we examined the duration of basic symptoms (BS) and attenuated psychotic symptoms (APS) in a sample of CHR-P participants to test the hypothesis that BS precede the manifestation of APS. As a secondary objective, we investigated the relationship between DUR, functioning and neuropsychological deficits. Methods: Data from 134 CHR-P participants were assessed with the Comprehensive Assessment of At-Risk Mental State and the Schizophrenia Proneness Interview, Adult Version. Global, role and social functioning and neurocognition were assessed and compared to a sample of healthy controls (n = 57). Results: In CHR-P participants who reported both APS and BS, onset of BS and APS was not significantly related. When divided into short and long BS duration (</> 8 years), CHR-P participants with a longer duration of BS showed evidence for an onset of BS preceding APS (n = 8, p = 0.003). However, in the short BS duration group, APS showed evidence of preceding BS (n = 56, p = 0.020). Finally, there were no significant effects of DUR on cognition or functioning measures. Conclusion: The present findings do not support the view that APS constitute a secondary phenomenon to BS. Moreover, our data could also not confirm that DUR has a significant effect on functioning and cognitive deficits. These findings are discussed in the context of current theories regarding emerging psychosis and the importance of DUR

Investigating the effectiveness of three school based interventions for preventing psychotic experiences over a year period – a secondary data analysis study of a randomized control trial

INTRODUCTION: Psychotic experiences (PEs) are associated with increased risk of later mental disorders and so could be valuable in prevention studies. However, to date few intervention studies have examined PEs. Given this lack of evidence, in the current study a secondary data analysis was conducted on a clustered-randomized control trial (RCT) of 3 school based interventions to reduce suicidal behaviour, to investigate if these may reduce rates of PEs, and prevent PE, at 3-month and 1-year follow-up. METHODS: The Irish site of the Saving and Empowering Young Lives in Europe study, trial registration (DRKS00000214), a cluster-RCT designed to examine the effect of school-based interventions on suicidal thoughts and behaviour. Seventeen schools (n = 1096) were randomly assigned to one of three intervention arms or a control arm. The interventions included a teacher training (gate-keeper) intervention, an interactive educational (universal-education) intervention, and a screening and integrated referral (selective-indicative) intervention. The primary outcome of this secondary data-analysis was reduction in point-prevalence of PEs at 12 months. A second analysis excluding those with PEs at baseline was conducted to examine prevention of PEs. Additional analysis was conducted of change in depression and anxiety scores (comparing those with/without PEs) in each arm of the intervention. Statistical analyses were conducted using mixed-effects modelling. RESULTS: At 12-months, the screening and referral intervention was associated with a significant reduction in PEs (OR:0.12,95%CI[0.02–0.62]) compared to the control arm. The teacher training and education intervention did not show this effect. Prevention was also observed only in the screening and referral arm (OR:0.30,95%CI[0.09–0.97]). Participants with PEs showed higher levels of depression and anxiety symptoms, compared to those without, and different responses to the screening and referral intervention & universal-education intervention. CONCLUSIONS: This study provides the first evidence for a school based intervention that reduce & prevent PEs in adolescence. This intervention is a combination of a school-based screening for psychopathology and subsequent referral intervention significantly reduced PEs in adolescents. Although further research is needed, our findings point to the effectiveness of school-based programmes for prevention of future mental health problems. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12889-023-15107-x

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Viral coinfections in hospitalized coronavirus disease 2019 patients recruited to the international severe acute respiratory and emerging infections consortium WHO clinical characterisation protocol UK study

Background We conducted this study to assess the prevalence of viral coinfection in a well characterized cohort of hospitalized coronavirus disease 2019 (COVID-19) patients and to investigate the impact of coinfection on disease severity. Methods Multiplex real-time polymerase chain reaction testing for endemic respiratory viruses was performed on upper respiratory tract samples from 1002 patients with COVID-19, aged <1 year to 102 years old, recruited to the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK study. Comprehensive demographic, clinical, and outcome data were collected prospectively up to 28 days post discharge. Results A coinfecting virus was detected in 20 (2.0%) participants. Multivariable analysis revealed no significant risk factors for coinfection, although this may be due to rarity of coinfection. Likewise, ordinal logistic regression analysis did not demonstrate a significant association between coinfection and increased disease severity. Conclusions Viral coinfection was rare among hospitalized COVID-19 patients in the United Kingdom during the first 18 months of the pandemic. With unbiased prospective sampling, we found no evidence of an association between viral coinfection and disease severity. Public health interventions disrupted normal seasonal transmission of respiratory viruses; relaxation of these measures mean it will be important to monitor the prevalence and impact of respiratory viral coinfections going forward