Category: Statistics

Shock. 2022 May 1;57(5):672-679. doi: 10.1097/SHK.0000000000001923.

ABSTRACT

PURPOSE: The development of targeted biological therapies for coronavirus disease 2019 (COVID-19) requires reliable biomarkers that could help indicate how patients are responding. The hyperactivation of inflammasomes by the SARS-CoV2 virus is hypothesized to contribute to a more severe course of the COVID-19 disease. Therefore, we aimed to evaluate the prognostic value of several inflammasome-related cytokines and proteins upon admission to the intensive care unit (ICU).

PATIENTS AND METHODS: We performed a prospective cohort study. Plasma samples were obtained from 45 critically ill COVID-19 patients and 10 patients without any signs of infection (traumatic brain injury [TBI]) on admission to the ICU. Concentrations of IL-1a, IL-1β, IL-18, IL-1RA, galectin-1, apoptosis-associated speck-like proteins, LDH, ferritin, and gasdermin D were analyzed. A cell-free caspase-1 plasma assay was done by inhibitor-based immunoprecipitation followed by a Western Blot. Demographic and clinical characteristics were recorded.

RESULTS: Inhospital mortality in COVID-19 patients was 62%. Galectin-1 was 1.8-fold lower in COVID-19 than in TBI patients (17101.84 pg/mL vs. 30764.20 pg/mL, P = 0.007), but other inflammasome-related biomarkers had similar concentrations. Patients with a Sequential Organ Failure Assessment (SOFA) score of > 9 on admission who were at high risk of death had significantly higher galectin-1 but lower IL-1RA in comparison with low-risk patients (25551.3 pg/mL vs. 16302.7 pg/mL, P = 0.014; 14.5 pg/mL vs. 39.4pg/mL, P = 0.04, respectively). Statistically significant correlations were observed between: IL-1a and platelets (r = -0.37), IL-1 β and platelets (r = -0.36), ferritin and INR (r = 0.39). Activated caspase-1 p35, whose presence was related to higher fibrinogen and lower D-dimers, was detected in 12 out of 22 COVID-19 patients and in none of the TBI patients. Moreover, densitometric analysis showed a significantly higher amount of p35 in patients with a SOFA score > 9.

CONCLUSION: We found that the systemic markers of activation of inflammasomes in critically ill COVID-19 patients were not directly related to outcome. Therefore, potential interventions aimed at the inflammasome pathway in this group of patients may be of limited effectiveness and should be biomarker-guided.

PMID:35583911 | DOI:10.1097/SHK.0000000000001923

JAMA Psychiatry. 2022 May 18. doi: 10.1001/jamapsychiatry.2022.1163. Online ahead of print.

ABSTRACT

IMPORTANCE: Approaches are needed to stratify individuals in early psychosis stages beyond positive symptom severity to investigate specificity related to affective and normative variation and to validate solutions with premorbid, longitudinal, and genetic risk measures.

OBJECTIVE: To use machine learning techniques to cluster, compare, and combine subgroup solutions using clinical and brain structural imaging data from early psychosis and depression stages.

DESIGN, SETTING, AND PARTICIPANTS: A multisite, naturalistic, longitudinal cohort study (10 sites in 5 European countries; including major follow-up intervals at 9 and 18 months) with a referred patient sample of those with clinical high risk for psychosis (CHR-P), recent-onset psychosis (ROP), recent-onset depression (ROD), and healthy controls were recruited between February 1, 2014, to July 1, 2019. Data were analyzed between January 2020 and January 2022.

MAIN OUTCOMES AND MEASURES: A nonnegative matrix factorization technique separately decomposed clinical (287 variables) and parcellated brain structural volume (204 gray, white, and cerebrospinal fluid regions) data across CHR-P, ROP, ROD, and healthy controls study groups. Stability criteria determined cluster number using nested cross-validation. Validation targets were compared across subgroup solutions (premorbid, longitudinal, and schizophrenia polygenic risk scores). Multiclass supervised machine learning produced a transferable solution to the validation sample.

RESULTS: There were a total of 749 individuals in the discovery group and 610 individuals in the validation group. Individuals included those with CHR-P (n = 287), ROP (n = 323), ROD (n = 285), and healthy controls (n = 464), The mean (SD) age was 25.1 (5.9) years, and 702 (51.7%) were female. A clinical 4-dimensional solution separated individuals based on positive symptoms, negative symptoms, depression, and functioning, demonstrating associations with all validation targets. Brain clustering revealed a subgroup with distributed brain volume reductions associated with negative symptoms, reduced performance IQ, and increased schizophrenia polygenic risk scores. Multilevel results distinguished between normative and illness-related brain differences. Subgroup results were largely validated in the external sample.

CONCLUSIONS AND RELEVANCE: The results of this longitudinal cohort study provide stratifications beyond the expression of positive symptoms that cut across illness stages and diagnoses. Clinical results suggest the importance of negative symptoms, depression, and functioning. Brain results suggest substantial overlap across illness stages and normative variation, which may highlight a vulnerability signature independent from specific presentations. Premorbid, longitudinal, and genetic risk validation suggested clinical importance of the subgroups to preventive treatments.

PMID:35583903 | DOI:10.1001/jamapsychiatry.2022.1163

JAMA Psychiatry. 2022 May 18. doi: 10.1001/jamapsychiatry.2022.1142. Online ahead of print.

ABSTRACT

IMPORTANCE: Schizophrenia is associated with major cognitive deficits and has been conceptualized as both a neurodevelopmental and a neurodegenerative disorder. However, when deficits develop and how they change over the course of illness is uncertain.

OBJECTIVE: To trace cognition from elementary school to old age to test neurodevelopmental and neurodegenerative theories of psychotic disorders.

DESIGN, SETTING, AND PARTICIPANTS: Data were taken from the Suffolk County Mental Health Project, a first-admission longitudinal cohort study of individuals with psychotic disorders. Participants were recruited from all 12 inpatient psychiatric facilities in Suffolk County, New York. This analysis concerns the 428 participants with at least 2 estimates of general cognitive ability. Data were collected between September 1989 and October 2019, and data were analyzed from January 2020 to October 2021.

EXPOSURES: Psychiatric hospitalization for psychosis.

MAIN OUTCOMES AND MEASURES: Preadmission cognitive scores were extracted from school and medical records. Postonset cognitive scores were based on neuropsychological testing at 6-month, 24-month, 20-year, and 25-year follow-ups.

RESULTS: Of the 428 included individuals (212 with schizophrenia and 216 with other psychotic disorders), 254 (59.6%) were male, and the mean (SD) age at psychosis onset was 27 (9) years. Three phases of cognitive change were observed: normative, declining, and deteriorating. In the first phase, cognition was stable. Fourteen years before psychosis onset, those with schizophrenia began to experience cognitive decline at a rate of 0.35 intelligence quotient (IQ) points per year (95% CI, 0.29-0.42; P < .001), a significantly faster decline than those with other psychotic disorders (0.15 IQ points per year; 95% CI, 0.08-0.22, P < .001). At 22 years after onset, both groups declined at a rate of 0.59 IQ points per year (95% CI, 0.25-0.94; P < .001).

CONCLUSIONS AND RELEVANCE: In this cohort study, cognitive trajectories in schizophrenia were consistent with both a neurodevelopmental and neurodegenerative pattern, resulting in a loss of 16 IQ points over the period of observation. Cognitive decline began long prior to psychosis onset, suggesting the window for primary prevention is earlier than previously thought. A window for secondary prevention emerges in the third decade of illness, when cognitive declines accelerate in individuals with schizophrenia and other psychotic disorders.

PMID:35583896 | DOI:10.1001/jamapsychiatry.2022.1142

Transl Vis Sci Technol. 2022 May 2;11(5):20. doi: 10.1167/tvst.11.5.20.

ABSTRACT

PURPOSE: To determine the sensitivity of optical coherence tomography (OCT) and standard automated perimetry (SAP) for detecting glaucomatous progression in the superior and inferior hemiretina.

METHODS: We calculated contrast-to-noise ratios (CNRs) for OCT retinal nerve fiber layer (RNFL) thickness of hemiretinas and for SAP mean total deviation (MTD) of the corresponding hemifields from longitudinal data (205 eyes, 125 participants). The glaucoma stage for each hemiretina was based on the corresponding hemifield’s MTD. Contrast was defined as the difference of the parameter between two consecutive glaucoma stages, whereas noise was the measurement variability of the parameter in those stages. The higher the CNR of a parameter, the more sensitive it is to detecting progression in the transition between successive stages.

RESULTS: There were no statistically significant differences for the RNFL CNR and MTD CNR between superior and inferior hemiretinas. As the glaucoma stage of the opposite hemiretina worsened, the MTD CNR in the transition from moderate to advanced glaucoma significantly increased. The RNFL CNR in the transition from mild to moderate glaucoma significantly decreased in case of advanced glaucoma in the opposite hemiretina.

CONCLUSIONS: Similar to full retinas, detecting conversion to glaucoma in hemiretinas is more sensitive with OCT than SAP, whereas with more advanced disease, SAP is more sensitive for detecting progression. More importantly, the sensitivity for detecting progression in one hemiretina with either technique depends on the glaucoma severity in the opposite hemiretina.

TRANSLATIONAL RELEVANCE: Monitoring glaucomatous progression with either OCT or SAP partly depends on the glaucoma severity in the opposite hemiretina.

PMID:35583886 | DOI:10.1167/tvst.11.5.20

Neurol Sci. 2022 May 18. doi: 10.1007/s10072-022-06150-4. Online ahead of print.

ABSTRACT

Slowness of information processing (SIP) is frequently reported after traumatic brain injury (TBI). Previous studies point toward a pivotal role of white matter damage on speed of information processing. However, little is known about the more comprehensive and ecological assessment of SIP in TBI. Here, we combined an ecological assessment of SIP with the use of tract-based spatial statistics (TBSS) on individuals’ fractional anisotropy (FA) maps. Twenty-six moderate-to-severe patients with TBI (21 males and 5 females) participated in this study: 10 individuals were classified as not having SIP (SIP-) and 16 were classified as having SIP (SIP +). SIP + showed lower FA in bilateral anterior thalamic radiation, corticospinal tract, cingulum, and forceps, as well as in bilateral inferior fronto-occipital, inferior and superior longitudinal fasciculi and uncinate fasciculus. Overall, this result is consistent with and expands previous reports on information processing speed to a more comprehensive and ecological perspective on SIP in TBI.

PMID:35583841 | DOI:10.1007/s10072-022-06150-4

Transbound Emerg Dis. 2022 May 18. doi: 10.1111/tbed.14599. Online ahead of print.

ABSTRACT

Lumpy skin disease (LSD) is an economically important transboundary disease affecting cattle, causing large economic losses such as decreased production and trade restrictions. LSD has been a historically neglected disease since it previously caused disease limited to the African continent. Currently, the epidemiology of lumpy skin disease virus is based on how the disease is transmitted in tropical and subtropical climates. The understanding of its epidemiology in hemiboreal climates is not well understood and needs urgent attention to expand the current knowledge. In this paper, the epidemiological findings on LSD in Russia over a 6-year period are summarized and discussed. A total of 471 outbreaks were identified spanning over a 9000 km range. The outbreaks of lumpy skin disease occur primarily in small holder farms (backyard) compared to commercial farms between mid-May through mid-November including weather conditions with snow and freezing temperatures that preclude vector activity. Mortality and morbidity varied across the six years ranged from 1.19 to 61.8% and 0 to 50% respectively with a tendency to decline from 2015 to 2020. The geographic pattern of spread was assessed by means of directionality, indicated a northward movement from 2015 to 2016, with a consequent East turn in 2017 through Siberia to the Far East by 2020. All cases occurred along the border with Kazakhstan. Mathematical modelling showed that the disease tended to form statistically verified annual spatio-temporal clusters in 2016 – 2018, whereas in 2019 and 2020 such segregation was not evident. The trend of spread was mainly either from south to north or from south to a north-east direction. This article is protected by copyright. All rights reserved.

PMID:35583857 | DOI:10.1111/tbed.14599

J Cancer Res Clin Oncol. 2022 May 18. doi: 10.1007/s00432-022-04048-4. Online ahead of print.

ABSTRACT

PURPOSE: Mesenchymal-epithelial transition (MET) amplification is one of the mechanisms accounting for the resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung cancer patients, as well as the poor prognosis. Fluorescence in situ hybridization (FISH) is the most widely used method for MET amplification detection. However, it is inapplicable when tissue samples were unavailable. Herein, we assessed the value of droplet digital PCR (ddPCR) in MET copy number gain (CNG) detection in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKIs.

MATERIALS AND METHODS: A total of 103 cancer tissues and the paired peripheral blood samples from NSCLC patients were collected for MET CNG detection using ddPCR. In parallel, MET amplification in tissue samples was verified by FISH. Also, the relationships between MET CNG and EGFR T790M, as well as the EGFR-TKI resistance were also evaluated using Chi-square or Fisher’s exact tests.

RESULT: The concordance rate of ddPCR and FISH in detecting MET CNG in tissue samples was 100% (102/102), and it was 94.17% (97/103) for ddPCR method in detecting the MET CNG among peripheral blood and tissue samples. No statistical difference was observed between MET amplification and EGFR T790M (p = 0.65), while MET amplification rate was significantly increased in patients with resistance to third generations of EGFR-TKIs as compared with patients with resistance to first/second EGFR-TKIs (p < 0.05).

CONCLUSIONS: ddPCR is an alternative method to detect MET CNG in both tissues and peripheral blood samples, which is of worthy in clinical promotion.

PMID:35583827 | DOI:10.1007/s00432-022-04048-4

Histopathology. 2022 May 18. doi: 10.1111/his.14698. Online ahead of print.

ABSTRACT

AIMS: Intraductal tubulopapillary neoplasm (ITPN) of the pancreas is a recently recognized pancreatic tumor entity. Here, we aimed to determine the most important features with a systematic review coupled with an integrated statistical approach.

METHODS AND RESULTS: PubMed, SCOPUS and Embase were searched for studies reporting data on pancreatic ITPN. The clinicopathological, immunohistochemical, and molecular data were summarized. Then, a comprehensive survival analysis and a comparative analysis of the molecular alterations of ITPN with those of pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) from reference cohorts (including the International Cancer Genome Consortium- ICGC dataset and The Cancer Genome Atlas- TCGA program) were conducted. The core findings of 128 patients were as follows – 1) Clinicopathological parameters: pancreatic head is the most common site; presence of an associated adenocarcinoma was reported in 60% of cases, but with rare nodal metastasis. 2) Immunohistochemistry: MUC1 (>90%) and MUC6 (70%) were the most frequently expressed mucins. ITPN lacked the intestinal marker MUC2; unlike IPMN, it did not express MUC5AC. 3) Molecular landscape: Compared with PDAC/IPMN, the classic pancreatic drivers KRAS, TP53, CDKN2A, SMAD4, GNAS, and RNF43 were less altered in ITPN (p<0.001), whereas MCL amplifications, FGFR2 fusions, and PI3KCA mutations were commonly altered (p<0.001). 4) Survival analysis: ITPN with a “pure” branch duct involvement showed the lowest risk of recurrence.

CONCLUSIONS: ITPN is a distinct pancreatic neoplasm with specific clinicopathological and molecular characteristics. Its recognition is fundamental for its clinical/prognostic implications and for the enrichment of potential targets for precision oncology.

PMID:35583805 | DOI:10.1111/his.14698

J Neurooncol. 2022 May 18. doi: 10.1007/s11060-022-04011-w. Online ahead of print.

ABSTRACT

PURPOSE: In-field high-grade glioma (HGG) recurrence is a common challenge with limited treatment options, including re-irradiation. The radiotracer 3,4-dihydroxy-6-[18F]-fluoro-L-phenylalanine (¹⁸F-DOPA) crosses the blood brain barrier and demonstrates high uptake in tumor, but low uptake in normal tissue. This study investigated whether ¹⁸F-DOPA positron emission tomography (PET) and MRI guided re-irradiation for recurrent HGG may improve progression free survival (PFS).

METHODS: Adults with recurrent or progressive HGG previously treated with radiation were eligible. The primary endpoint was a 20% improvement from the historical control PFS at 3 months (PFS3) of 20% with systemic therapy alone. Re-RT dose was 35 Gy in 10 fractions. The target volume was MRI T1 contrast-enhancement defined tumor plus ¹⁸F-DOPA PET defined tumor.

RESULTS: Twenty patients completed treatment per protocol. Diagnosis was most commonly glioblastoma, IDH-wildtype (60%). MRI-defined volumes were expanded by a median 43% (0-436%) by utilizing ¹⁸F-DOPA PET. PFS3 was 85% (95% CI 63.2-95.8%), meeting the primary endpoint of PFS3 ≥ 40%. With 9.7 months median follow-up, 17 (85%) had progressed and 15 (75%) had died. Median OS from re-RT was 8.8 months. Failure following re-RT was within both the MRI and PET tumor volumes in 75%, MRI only in 13%, PET only in 0%, and neither in 13%. Four (20%) patients experienced grade 3 toxicity, including CNS necrosis (n = 2, both asymptomatic with bevacizumab initiation for radiographic findings), seizures (n = 1), fatigue (n = 1), and nausea (n = 1). No grade 4-5 toxicities were observed.

CONCLUSION: ¹⁸F-DOPA PET-guided re-irradiation for progressive high-grade glioma appears safe and promising for further investigation.

PMID:35583721 | DOI:10.1007/s11060-022-04011-w

Int Arch Occup Environ Health. 2022 May 18. doi: 10.1007/s00420-022-01876-2. Online ahead of print.

ABSTRACT

PURPOSE: Occupational exposure limits (OEL) for nitrogen oxides (NO, NO₂) and diesel exhaust (EC-DPM) were reassessed by the German authorities in 2016/2017. We performed a clinical cross-sectional study among salt and potash underground workers exposed to these substances at relatively high levels to examine possible indicators of acute effects on workers’ health.

METHODS: We measured post- versus pre-shift differences in cardiovascular, inflammatory, immune, and respiratory effect biomarkers and assessed their associations with personal exposures measured during the same shift. We also compared post- versus pre-shift differences in biomarker levels between exposure groups defined based on work site and job type.

RESULTS: None of the above-ground workers exceeded the OEL for NO₂ and only 5% exceeded the OEL for EC-DPM exposure. Among underground workers, 33% of miners and 7% underground maintenance workers exceeded the OEL for NO₂; the OEL for EC-DPM was exceeded by 56% of miners and 17% of maintenance workers. Some effect biomarkers (thrombocytes, neutrophils, MPO, TNF-α, IgE, FeNO) showed statistically significant differences between pre- versus post-shift measurements; however, there were no consistent associations between pre- and post-shift differences and exposure group or personal exposure measurements during the shift.

CONCLUSIONS: We did not find evidence of associations between workplace exposure to NO, NO₂ or EC-DPM and clinically relevant indicators of acute cardiovascular, inflammatory and immune, or respiratory effects among salt and potash underground workers in Germany.

PMID:35583687 | DOI:10.1007/s00420-022-01876-2