Bias assessment and correction for Levin's population attributable fraction in the presence of confounding.

In 1953, Morton Levin introduced a simple approach to estimating population attributable fractions (PAF) depending only on risk factor prevalence and relative risk. This formula and its extensions are still in widespread use today, particularly to estimate PAF in populations where individual data is unavailable. Unfortunately, Levin's approach is known to be asymptotically biased for the PAF when the risk factor-disease relationship is confounded even if relative risks that are correctly adjusted for confounding are used in the estimator. Here we describe a simple re-expression of Miettinen's estimand that depends on the causal relative risk, the unadjusted relative risk and the population risk factor prevalence. While this re-expression is not new, it has been underappreciated in the literature, and the associated estimator may be useful in estimating PAF in populations when individual data is unavailable provided estimated adjusted and unadjusted relative risks can be transported to the population of interest. Using the re-expressed estimand, we develop novel analytic formulae for the relative and absolute asymptotic bias in Levin's formula, solidifying earlier work by Darrow and Steenland that used simulations to investigate this bias. We extend all results to settings with non-binary valued risk factors and continuous exposures and discuss the utility of these results in estimating PAF in practice.

Alterations in Aquaporin-4-IgG Serostatus in 986 Patients: A Laboratory-Based Longitudinal Analysis.

OBJECTIVE: This study was undertaken to investigate factors associated with aquaporin-4 (AQP4)-IgG serostatus change using a large serological database. METHODS: This retrospective study utilizes Mayo Clinic Neuroimmunology Laboratory data from 2007 to 2021. We included all patients with ≥2 AQP4-IgG tests (by cell-based assay). The frequency and clinical factors associated with serostatus change were evaluated. Multivariable logistic regression analysis examined whether age, sex, or initial titer was associated with serostatus change. RESULTS: There were 933 patients who had ≥2 AQP4-IgG tests with an initial positive result. Of those, 830 (89%) remained seropositive and 103 (11%) seroreverted to negative. Median interval to seroreversion was 1.2 years (interquartile range [IQR] = 0.4-3.5). Of those with sustained seropositivity, titers were stable in 92%. Seroreversion was associated with age ≤ 20 years (odds ratio [OR] = 2.25; 95% confidence interval [CI] = 1.09-4.63; p = 0.028) and low initial titer of ≤1:100 (OR = 11.44, 95% CI = 3.17-41.26, p < 0.001), and 5 had clinical attacks despite seroreversion. Among 62 retested after seroreversion, 50% returned to seropositive (median = 224 days, IQR = 160-371). An initial negative AQP4-IgG test occurred in 9,308 patients. Of those, 99% remained seronegative and 53 (0.3%) seroconverted at a median interval of 0.76 years (IQR = 0.37-1.68). INTERPRETATION: AQP4-IgG seropositivity usually persists over time with little change in titer. Seroreversion to negative is uncommon (11%) and associated with lower titers and younger age. Seroreversion was often transient, and attacks occasionally occurred despite prior seroreversion, suggesting it may not reliably reflect disease activity. Seroconversion to positive is rare (<1%), limiting the utility of repeat testing in seronegative patients unless clinical suspicion is high. ANN NEUROL 2023;94:727-735.

Population attributable fraction of hypertension for dementia: global, regional, and national estimates for 186 countries.

Background: Quantifying the proportion of dementia attributable to highly prevalent modifiable risk factors, such as hypertension, is important in informing effective dementia prevention strategies. We aim to quantify the population attributable fraction (PAF) of hypertension for dementia (the proportion of dementia cases that would not occur if hypertension was eliminated) at global, regional, and national levels. Methods: In this study, we searched international and governmental websites for global, regional, and national data reporting population hypertension (according to 10-year age categories) and dementia prevalence. MEDLINE was searched for studies reporting the risk of dementia from age at hypertension diagnosis from database inception to December 31, 2022. Longitudinal observational studies with >500 participants reporting hazard ratios by age at hypertension diagnosis for risk of future all-cause dementia were eligible for inclusion. Studies excluded had cross-sectional methodology, specific vascular dementia or 'cognitive impairment' outcomes, and no age-specific metrics of association reported. The PAF of hypertension for dementia was calculated globally and for each country and region worldwide. Findings: Data from the Global Burden of Disease, United Nations Population Prospectus, NCD Risk Factor Collaboration, UK Biobank, and Atherosclerosis Risk in Communities Study were obtained. 186 countries reported dementia and hypertension prevalence data. The global PAF of hypertension for dementia was 15.8% [95% Credible Interval (CI), 8.8%-22.7%]. Latin America and the Caribbean (18.0% [95% CI, 9.4%-26.6%]), and Europe (17.2% [95% CI, 9.6%-24.7%]) had the highest PAF of hypertension for dementia. Hypertension diagnosed between the ages of 30-44 had the highest age-specific global attributable fraction for dementia (8.4% [95% CI, 3.4%-13.5%]), followed by ages 45-54 (2.92% [ 95% CI, 0.96%-4.88%]), 55-64 (2.59% [95% CI, 1.15%-4.03%]) and 65-74 (1.82% [95% CI, -2.31%-5.96%]). Interpretation: The population attributable risk of hypertension for dementia is 15.8%, suggesting that optimal detection and treatment, particularly at midlife, has the potential to markedly reduce the global burden of dementia. Funding: Wellcome Trust; Health Research Board of Ireland; Alzheimer's Association.

Primary CNS EBV-positive post-transplant lymphoproliferative disorder with polymorphic and classic Hodgkin lymphoma features: A case report and literature review.

Post-transplant lymphoproliferative disorders (PTLD) are typically Epstein-Barr virus (EBV)-associated lymphoid or plasmacytic proliferations that occur when immunosuppressed after transplantation. Only 2 cases of primary central nervous system (PCNS) classic Hodgkin lymphoma PTLD and 1 case of PCNS Hodgkin lymphoma-like PTLD have been previously reported. A 59-year-old male presented with malaise, headaches, and dizziness; neuroimaging revealed a 1.7-cm right cerebellar mass and a 0.6-cm right frontal mass. Microscopic examination demonstrated a perivascular and parenchymal polymorphous infiltrate composed of lymphocytes (CD3-positive T cells and CD20-positive B cells), plasma cells, and macrophages. Focally, macrophages had a spindled morphology with a fascicular arrangement amounting to poorly formed granulomata. Mitoses were seen. Scattered large atypical cells were visualized with irregular hyperchromatic nuclei, reminiscent of lacunar cells, mononuclear Hodgkin and binucleate Reed-Sternberg (RS) cells. EBV in situ highlighted a significant number of small lymphoid cells as well as many large atypical forms. Large atypical cells were seen to co-express CD15 and CD30. To our knowledge, this is the first such case with hybrid polymorphic PTLD and classic Hodgkin lymphoma features and the first such case to arise following liver transplantation. This case highlights the histological and immunophenotypic spectrum of these lymphoid proliferations and the resulting challenges in diagnosis and definitive subtyping.

Comparison of verbal and computerised months backwards tests in a hospitalized older population.

BACKGROUND: Delirium is extremely prevalent, yet underdiagnosed, in older patients and is associated with prolonged length of hospital stay and higher mortality rates. Impaired attention is the cardinal deficit in delirium and is a required feature in diagnostic criteria. The verbal months backwards test (MBT) is the most sensitive bedside test of attention, however, hospital staff occasionally have difficulty with its administration and interpretation. We hypothesise that the MBT on an electronic tablet may be easier and more consistent to use for both experienced and unexperienced medical professionals and, if the diagnostic efficacy was similar, aid delirium diagnosis. AIM: We aim to investigate the correlation of the verbal MBT with a computerised MBT application. METHODS: Participants recruited (age > 65, n = 75) were allocated to different cohorts (Dementia and Delirium (DMDL), Dementia (DM), Delirium (DL), No Neurocognitive Disorder (NNCD)) and were administered both the verbal and electronic versions. RESULTS: Correlation between measurements were: overall Spearman's rho = 0.772 (p < 0.0001); DMDL rho = 0.666 (p < 0.0001); DL rho = 0.778 (p = 0.039); DM rho = 0.378 (p = 0.203); NNCD rho = 0.143 (p = 0.559). DISCUSSION: Overall, and for the delirious subset, statistically significant agreement was present. Poor inter-test correlation existed in the groups without delirium (DM, NNCD). CONCLUSIONS: The MBTc correlates well with the MBTv in patients who are clinically suspected to have delirium but has poor correlation in patients without delirium. Visuospatial cognition and psychomotor deficits in a dementia cohort and mechanical factors (such as tremor, poor fingernail hygiene and visual impairment) in a group with no neurocognitive disorder may limit the utility of the MBTc in a hospitalised older population.

Prone positioning improves oxygenation and lung recruitment in patients with SARS-CoV-2 acute respiratory distress syndrome; a single centre cohort study of 20 consecutive patients.

OBJECTIVE: We aimed to characterize the effects of prone positioning on respiratory mechanics and oxygenation in invasively ventilated patients with SARS-CoV-2 ARDS. RESULTS: This was a prospective cohort study in the Intensive Care Unit (ICU) of a tertiary referral centre. We included 20 consecutive, invasively ventilated patients with laboratory confirmed SARS-CoV-2 related ARDS who underwent prone positioning in ICU as part of their management. The main outcome was the effect of prone positioning on gas exchange and respiratory mechanics. There was a median improvement in the PaO2/FiO2 ratio of 132 in the prone position compared to the supine position (IQR 67-228). We observed lower PaO2/FiO2 ratios in those with low (< median) baseline respiratory system static compliance, compared to those with higher (> median) static compliance (P < 0.05). There was no significant difference in respiratory system static compliance with prone positioning. Prone positioning was effective in improving oxygenation in SARS-CoV-2 ARDS. Furthermore, poor respiratory system static compliance was common and was associated with disease severity. Improvements in oxygenation were partly due to lung recruitment. Prone positioning should be considered in patients with SARS-CoV-2 ARDS.

Induction of Rhodobacter capsulatus Gene Transfer Agent Gene Expression Is a Bistable Stochastic Process Repressed by an Extracellular Calcium-Binding RTX Protein Homologue.

Bacteriophage-like gene transfer agents (GTAs) have been discovered in both of the prokaryotic branches of the three-domain phylogenetic tree of life. The production of a GTA (RcGTA) by the phototrophic alphaproteobacterium Rhodobacter capsulatus is regulated by quorum sensing and a phosphorelay homologous to systems in other species that control essential functions such as the initiation of chromosome replication and cell division. In wild-type strains, RcGTA is produced in <3% of cells in laboratory cultures. Mutants of R. capsulatus that exhibit greatly elevated production of RcGTA were created decades ago by chemical mutagenesis, but the nature and molecular consequences of the mutation were unknown. We show that the number of cells in a population that go on to express RcGTA genes is controlled by a stochastic process, in contrast to a genetic process. We used transposon mutagenesis along with a fluorescent protein reporter system and genome sequence data to identify a gene, rcc00280, that encodes an RTX family calcium-binding protein homologue. The Rc280 protein acts as an extracellular repressor of RcGTA gene expression by decreasing the percentage of cells that induce the production of RcGTA.IMPORTANCE GTAs catalyze horizontal gene transfer (HGT), which is important for genomic evolution because the majority of genes found in bacterial genomes have undergone HGT at some point in their evolution. Therefore, it is important to determine how the production of GTAs is regulated to understand the factors that modulate the frequency of gene transfer and thereby specify the tempo of evolution. This work describes a new type of genetic regulation in which an extracellular calcium-binding protein homologue represses the induction of the Rhodobacter capsulatus GTA, RcGTA.

Genome-wide identification and characterization of small RNAs in Rhodobacter capsulatus and identification of small RNAs affected by loss of the response regulator CtrA.

Small non-coding RNAs (sRNAs) are involved in the control of numerous cellular processes through various regulatory mechanisms, and in the past decade many studies have identified sRNAs in a multitude of bacterial species using RNA sequencing (RNA-seq). Here, we present the first genome-wide analysis of sRNA sequencing data in Rhodobacter capsulatus, a purple nonsulfur photosynthetic alphaproteobacterium. Using a recently developed bioinformatics approach, sRNA-Detect, we detected 422 putative sRNAs from R. capsulatus RNA-seq data. Based on their sequence similarity to sRNAs in a sRNA collection, consisting of published putative sRNAs from 23 additional bacterial species, and RNA databases, the sequences of 124 putative sRNAs were conserved in at least one other bacterial species; and, 19 putative sRNAs were assigned a predicted function. We bioinformatically characterized all putative sRNAs and applied machine learning approaches to calculate the probability of a nucleotide sequence to be a bona fide sRNA. The resulting quantitative model was able to correctly classify 95.2% of sequences in a validation set. We found that putative cis-targets for antisense and partially overlapping sRNAs were enriched with protein-coding genes involved in primary metabolic processes, photosynthesis, compound binding, and with genes forming part of macromolecular complexes. We performed differential expression analysis to compare the wild type strain to a mutant lacking the response regulator CtrA, an important regulator of gene expression in R. capsulatus, and identified 18 putative sRNAs with differing levels in the two strains. Finally, we validated the existence and expression patterns of four novel sRNAs by Northern blot analysis.

DETECTION OF BACTERIAL SMALL TRANSCRIPTS FROM RNA-SEQ DATA: A COMPARATIVE ASSESSMENT.

Small non-coding RNAs (sRNAs) are regulatory RNA molecules that have been identified in a multitude of bacterial species and shown to control numerous cellular processes through various regulatory mechanisms. In the last decade, next generation RNA sequencing (RNA-seq) has been used for the genome-wide detection of bacterial sRNAs. Here we describe sRNA-Detect, a novel approach to identify expressed small transcripts from prokaryotic RNA-seq data. Using RNA-seq data from three bacterial species and two sequencing platforms, we performed a comparative assessment of five computational approaches for the detection of small transcripts. We demonstrate that sRNA-Detect improves upon current standalone computational approaches for identifying novel small transcripts in bacteria.

Nitrogen status modulates the expression of RNA-binding proteins in cyanobacteria.

Biochemical responses to cold and osmotic stresses overlap because each decreases the availability of free water. Since RNA-binding proteins are known to accumulate following cold stress and play key roles in regulating transcription termination, the effect of osmotic stress on expression of RNA-binding proteins was examined. The transcript levels of four genes encoding RNA-binding proteins (rbpA, rbpB, rbpC and rbpD) were monitored in Anabaena sp. PCC 7120 cultures supplemented with ammonium ions or growing under nitrogen-fixing conditions. Steady-state transcript levels of all four genes increased transiently in response to a temperature shift from 30 to 20 degrees C under both nitrogen regimes. Osmotic stress also enhanced rbpB, rbpC and rbpD gene expression in ammonium grown cultures. In the absence of a combined nitrogen source, osmotic stress repressed the short-term induction of rbp gene expression. The accumulation of RNA-binding proteins did not follow transcript levels, but remained high 24 h after stress initiation. It is concluded that nitrogen nutrition modulates the stress-responsive regulation of RNA-binding proteins in cyanobacteria, providing a potential mechanism to integrate environmental and developmental signals.