Cognitive and physical declines and falls in older people with and without mild cognitive impairment: a 7-year longitudinal study.

OBJECTIVES: We examined longitudinal changes in cognitive and physical function and associations between change in function and falls in people with and without mild cognitive impairment (MCI). DESIGN: Prospective cohort study with assessments every 2 years (for up to 6 years). SETTING: Community, Sydney, Australia. PARTICIPANTS: Four hundred and eighty one people were classified into three groups: those with MCI at baseline and MCI or dementia at follow-up assessments (n = 92); those who fluctuated between cognitively normal and MCI throughout follow-up (cognitively fluctuating) (n = 157), and those who were cognitively normal at baseline and all reassessments (n = 232). MEASUREMENTS: Cognitive and physical function measured over 2-6 years follow-up. Falls in the year following participants' final assessment. RESULTS: In summary, 27.4%, 38.5%, and 34.1% of participants completed 2, 4, and 6 years follow-up of cognitive and physical performance, respectively. The MCI and cognitive fluctuating groups demonstrated cognitive decline, whereas the cognitively normal group did not. The MCI group had worse physical function than the cognitively normal group at baseline but decline over time in physical performance was similar across all groups. Decline in global cognitive function and sensorimotor performance were associated with multiple falls in the cognitively normal group and decline in mobility (timed-up-and-go test) was associated with multiple falls across the whole sample. CONCLUSIONS: Cognitive declines were not associated with falls in people with MCI and fluctuating cognition. Declines in physical function were similar between groups and decline in mobility was associated with falls in the whole sample. As exercise has multiple health benefits including maintaining physical function, it should be recommended for all older people. Programs aimed at mitigating cognitive decline should be encouraged in people with MCI.

The impact of COVID-19 and associated lockdowns on traumatic spinal cord injury incidence: a population based study.

STUDY DESIGN: Natural experiment OBJECTIVES: To determine whether COVID-19 restrictions were associated with changes in the incidence of traumatic spinal cord injury (TSCI) in Scotland. SETTING: The Queen Elizabeth National Spinal Injuries Unit (QENSIU), the sole provider of treatment for TSCI in Scotland. METHODS: Time series analysis of all admissions for TSCI between 1st January 2015 and 31st August 2022. RESULTS: Over the 8-year study period, 745 patients were admitted to the QENSIU with a TSCI. Interrupted time series analysis showed that level 3 and 4 COVID-19 lockdown restrictions (the most severe levels) were associated with lower incidence of TSCI (RR 0.63, CI% CI 0.47, 0.82, p < 0.001). The associations were stronger in people aged over 45 (additive interaction p = 0.001), males (additive interaction p = 0.01) and non-tetraplegia (additive interaction p = 0.002). The incidence of TSCI due to deliberate self-harm was higher (0.41 versus 0.23 per month) during restrictions. CONCLUSIONS: Overall, TSCI incidence reduced in Scotland when lockdowns were implemented, presumably due to lower engagement in risky activities. The increase in TSCI due to deliberate self-harm may reflect increased mental health problems and social isolation and should be anticipated and targeted in future pandemics. The change in incidence during the COVID-19 pandemic may have an economic impact and see a temporary reduction in the burden on health and social care. The results of this study will be useful for resource planning in future pandemics.

Sex Differences in the Serum Proteomic Profile During Acute Low Back Pain-A Preliminary Study of the Relationship to Future Low Back Pain.

The molecular processes driving the transition from acute to chronic low back pain (LBP) remain poorly understood and are likely to be sexually dimorphic. This study aimed to explore sex differences in the serum proteomic profile of people experiencing an acute LBP episode and determine if serum protein concentrations were associated with three-month outcome. Serum samples were collected through venepuncture from 30 female and 29 male participants experiencing an acute LBP episode. Serum samples underwent trypsin digestion and fractionation using hydrophobic interaction chromatography and were then analysed using mass-spectrometry. Mass-spectrometry spectra were searched in the Swissprot database for protein identification. Sex differences in protein abundance changes were evident upon inspection of fold changes. Multivariable data analysis identified 21 serum proteins during the acute episode that correctly classified 93% of males and 23 serum proteins that correctly classified 90% of females with ongoing LBP at 3 months. Pathway analysis suggested the differentially expressed proteins during acute LBP were frequently involved in immune, inflammatory, complement, or coagulation responses. This data provides preliminary evidence that biological processes during an acute LBP episode may contribute to the resolution, or persistence, of LBP symptoms at 3 months, however, these processes differ between males and females. PERSPECTIVE: Differential expression of serum proteins was observed between male and female participants during an acute LBP episode. This preliminary work provides a foundation for future research targeting distinct immune system processes in males and females that may interfere with the transition from acute to chronic LBP.

Systemic pro- and anti-inflammatory profiles in acute non-specific low back pain: An exploratory longitudinal study of the relationship to six-month outcome.

OBJECTIVES: Pro-inflammatory molecules are thought to underpin the development of chronic low back pain (LBP). Although research has begun to explore the association between pro-inflammatory molecules in acute LBP and long-term outcome, no study has explored the role of anti-inflammatory molecules. We aimed to explore whether levels of systemic pro- and anti-inflammatory molecules 1) changed over a period of six months from the onset of acute LBP; 2) differed between people who were recovered (N = 11) and unrecovered (N = 24) from their episode of LBP at six months; 3) baseline psychological factors were related to inflammatory molecule serum concentrations at baseline, three and six months. METHODS: We retrospectively included participants with acute LBP included from a larger prospective trial and examined blood samples for the measurement of pro- and anti-inflammatory molecules and measures of pain, disability, and psychological factors at baseline, three and six months. RESULTS: The serum concentrations of pro- and anti-inflammatory molecules did not differ over time when compared between participants who recovered and those who did not recover at six-month follow-up. At three months, the unrecovered group had higher interleukin (IL)-8 and IL-10 serum concentrations than the recovered group. Baseline psychological factors were not related to inflammatory molecules at any time point. DISCUSSION: This exploratory study showed that levels of systemic inflammatory molecules did not change over the course of LBP, irrespective of whether people were recovered or unrecovered at six months. There was no relationship between acute-stage psychological factors and systemic inflammatory molecules. Further investigation is needed to elucidate the contribution of pro- and anti-inflammatory molecules to long-term LBP outcome.

Network analysis reveals a major role for 14q32 cluster miRNAs in determining transcriptional differences between IGHV-mutated and unmutated CLL.

Chronic lymphocytic leukaemia (CLL) cells can express unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain (IGHV) genes with differing clinical behaviours, variable B cell receptor (BCR) signalling capacity and distinct transcriptional profiles. As it remains unclear how these differences reflect the tumour cells' innate pre/post germinal centre origin or their BCR signalling competence, we applied mRNA/miRNA sequencing to 38 CLL cases categorised into three subsets by IGHV mutational status and BCR signalling capacity. We identified 492 mRNAs and 38 miRNAs differentially expressed between U-CLL and M-CLL, but only 9 mRNAs and 0 miRNAs associated with BCR competence within M-CLL. Of the IGHV-associated miRNAs, (14/38 (37%)) derived from chr14q32 clusters where all miRNAs were co-expressed with the MEG3 lncRNA from a cancer associated imprinted locus. Integrative analysis of miRNA/mRNA data revealed pronounced regulatory potential for the 14q32 miRNAs, potentially accounting for up to 25% of the IGHV-related transcriptome signature. GAB1, a positive regulator of BCR signalling, was potentially regulated by five 14q32 miRNAs and we confirmed that two of these (miR-409-3p and miR-411-3p) significantly repressed activity of the GAB1 3'UTR. Our analysis demonstrates a potential key role of the 14q32 miRNA locus in the regulation of CLL-related gene regulation.

Higher systolic blood pressure in early-mid adulthood is associated with poorer cognitive performance in those with a dominantly inherited Alzheimer's disease mutation but not in non-carriers. Results from the DIAN study.

BACKGROUND: The Dominantly Inherited Alzheimer Network (DIAN) is a longitudinal observational study that collects data on cognition, blood pressure (BP), and other variables from autosomal-dominant Alzheimer's disease mutation carriers (MCs) and non-carrier (NC) family members in early to mid-adulthood, providing a unique opportunity to evaluate BP and cognition relationships in these populations. METHOD: We examined cross-sectional and longitudinal relationships between systolic and diastolic BP and cognition in DIAN MC and NC. RESULTS: Data were available from 528 participants, who had a mean age of 38 (SD = 11) and were 42% male and 61% MCs, at a median follow-up of 2 years. Linear-multilevel models found only cross-sectional associations in the MC group between higher systolic BP and poorer performance on language (ß = -0.181 [-0.318, -0.044]), episodic memory (-0.212 [-0.375, -0.049]), and a composite cognitive measure (-0.146 [-0.276, -0.015]). In NCs, the relationship was cross-sectional only and present for language alone. DISCUSSION: Higher systolic BP was cross-sectionally but not longitudinally associated with poorer cognition, particularly in MCs. BP may influence cognition gradually, but further longitudinal research is needed.

Repeatability of brain phase-based magnetic resonance electric properties tomography methods and effect of compressed SENSE and RF shimming.

Magnetic resonance electrical properties tomography (MREPT) is an emerging imaging modality to noninvasively measure tissue conductivity and permittivity. Implementation of MREPT in the clinic requires repeatable measurements at a short scan time and an appropriate protocol. The aim of this study was to investigate the repeatability of conductivity measurements using phase-based MREPT and the effects of compressed SENSE (CS), and RF shimming on the precision of conductivity measurements. Conductivity measurements using turbo spin echo (TSE) and three-dimensional balanced fast field echo (bFFE) with CS factors were repeatable. Conductivity measurement using bFFE phase showed smaller mean and variance that those measured by TSE. The conductivity measurements using bFFE showed minimal deviation with CS factors up to 8, with deviation increasing at CS factors > 8. Subcortical structures produced less consistent measurements than cortical parcellations at higher CS factors. RF shimming using full slice coverage 2D dual refocusing echo acquisition mode (DREAM) and full coverage 3D dual TR approaches further improved measurement precision. BFFE is a more optimal sequence than TSE for phase-based MREPT in brain. Depending on the area of the brain being measured, the scan can be safely accelerated with compressed SENSE without sacrifice of precision, offering the potential to employ MREPT in clinical research and applications. RF shimming with better field mapping further improves precision of the conductivity measures.

Human assumed central sensitization in people with acute non-specific low back pain: A cross-sectional study of the association with brain-derived neurotrophic factor, clinical, psychological and demographic factors.

BACKGROUND: Early evidence suggests human assumed central sensitization (HACS) is present in some people with acute low back pain (LBP). Factors influencing individual variation in HACS during acute LBP have not been fully explored. We aimed to examine the evidence for HACS in acute LBP and the contribution of brain-derived neurotrophic factor (BDNF), clinical, psychological and demographic factors to HACS. METHODS: Participants with acute LBP (<6 weeks after pain onset, N = 118) and pain-free controls (N = 57) from a longitudinal trial were included. Quantitative sensory testing including pressure and heat pain thresholds and conditioned pain modulation, BDNF serum concentration and genotype and questionnaires were assessed. RESULTS: There were no signs of HACS during acute LBP at group level when compared with controls. Sensory measures did not differ when compared between controls and LBP participants with different BDNF genotypes. Two LBP subgroups with distinct sensory profiles were identified. Although one subgroup (N = 60) demonstrated features of HACS including pressure/heat pain hypersensitivity at a remote site and deficient conditioned pain modulation, pain severity and disability did not differ between the two subgroups. Variation in sensory measures (~33%) was partially explained by BDNF genotype, sex, age and psychological factors. CONCLUSIONS: This study confirms that HACS is present in some people with acute LBP, but this was not associated with pain or disability. Further, no relationship was observed between BDNF and HACS in acute LBP. More research is needed to understand factors contributing to individual variation in sensory measures in LBP. SIGNIFICANCE: Human assumed central sensitization (HACS) is present in acute low back pain (LBP) but factors contributing to individual variation are not fully explored. This study investigated the relationship between factors such as brain derived neurotrophic factor (BDNF) and HACS in acute LBP. Our findings indicate that HACS was present in specific LBP subgroups but BDNF was unrelated to HACS. Combinations of BDNF genotype, demographic and psychological factors explained a small proportion of the variation in sensory measures during acute LBP.

Cortical function and sensorimotor plasticity are prognostic factors associated with future low back pain after an acute episode: the Understanding persistent Pain Where it ResiDes prospective cohort study.

ABSTRACT: Predicting the development of chronic low back pain (LBP) at the time of an acute episode remains challenging. The Understanding persistent Pain Where it ResiDes study aimed to identify neurobiological and psychological risk factors for chronic LBP. Individuals with acute LBP (N = 120) participated in a prospective cohort study with 6-month follow-up. Candidate predictors were selected from the neurobiological (eg, sensorimotor cortical excitability assessed by sensory and motor-evoked potentials and brain-derived neurotrophic factor genotype), psychological (eg, depression and anxiety), symptom-related (eg, LBP history), and demographic domains. Analyses involved multivariable linear regression models with pain intensity or disability degree as continuous variables. Secondary analyses involved a multivariable logistic model with the presence of LBP at 6 months (thresholding pain intensity and disability degree) as a dichotomous variable. Lower sensory cortex and corticomotor excitability, higher baseline pain intensity, higher depression, stress, and pain catastrophizing were the strongest predictors ( R2 = 0.47) of pain intensity at 6 months. Older age and higher pain catastrophizing were the strongest predictors ( R2 = 0.30) of disability at 6 months. When the LBP outcome was dichotomised, sensory cortex and corticomotor excitability, brain-derived neurotrophic factor genotype, depression and anxiety, LBP history and baseline pain intensity, discriminated between those who did and did not report LBP at 6 months (C-statistic 0.91). This study identifies novel risk factors for the development of future LBP. Neurobiological risk factors, when added to a multivariable linear regression model, explained a further 15% of the variance in the 6-month pain intensity.

Blood pressure lowering and prevention of dementia: an individual patient data meta-analysis.

AIMS: Observational studies indicate U-shaped associations of blood pressure (BP) and incident dementia in older age, but randomized controlled trials of BP-lowering treatment show mixed results on this outcome in hypertensive patients. A pooled individual participant data analysis of five seminal randomized double-blind placebo-controlled trials was undertaken to better define the effects of BP-lowering treatment for the prevention of dementia. METHODS AND RESULTS: Multilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia. The total sample included 28 008 individuals recruited from 20 countries. After a median follow-up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval: 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4 mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk. CONCLUSION: The first single-stage individual patient data meta-analysis from randomized double-blind placebo-controlled clinical trials provides evidence to support benefits of antihypertensive treatment in late-mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well-controlled hypertension and of antihypertensive treatment commenced earlier in the life-course to reduce the long-term risk of dementia. CLASSIFICATION OF EVIDENCE: Class I evidence in favour of antihypertensive treatment reducing risk of incident dementia compared with placebo.

The relationship between mandibular advancement, tongue movement, and treatment outcome in obstructive sleep apnea.

STUDY OBJECTIVES: To characterize how mandibular advancement enlarges the upper airway via posterior tongue advancement in people with obstructive sleep apnea (OSA) and whether this is associated with mandibular advancement splint (MAS) treatment outcome. METHODS: One-hundred and one untreated people with OSA underwent a 3T magnetic resonance (MRI) scan. Dynamic mid-sagittal posterior tongue and mandible movements during passive jaw advancement were measured with tagged MRI. Upper airway cross-sectional areas were measured with the mandible in a neutral position and advanced to 70% of maximum advancement. Treatment outcome was determined after a minimum of 9 weeks of therapy. RESULTS: Seventy-one participants completed the study: 33 were responders (AHI<5 or AHI≤10 events/hr with >50% AHI reduction), 11 were partial responders (>50% AHI reduction but AHI>10 events/hr), and 27 nonresponders (AHI reduction<50% and AHI≥10 events/hr). Responders had the greatest naso- and oropharyngeal tongue anterior movement (0.40 ± 0.08 and 0.47 ± 0.13 mm, respectively) and oropharyngeal cross-sectional area enlargement (6.41 ± 2.12%) per millimeter of mandibular advancement. A multivariate model that included tongue movement and percentage of airway enlargement per millimeter of mandibular advancement along with baseline AHI correctly classified 69.2% (5-fold cross-validated 62.5%, n = 39) of participants in response categories when the jaw was advanced in the range that would usually be regarded as sufficient for clinical efficacy (> 4 mm). In comparison, a model using only baseline AHI correctly classified 50.0% of patients (5-fold cross-validated 52.5%, n = 40). CONCLUSIONS: Tongue advancement and upper airway enlargement with mandibular advancement in conjunction with baseline AHI improve treatment response categorization to a satisfactory level (69.2%, 5-fold cross-validated 62.5%).

Identifying individual-based injury patterns in multi-trauma road users by using an association rule mining method.

In many road crashes the human body is exposed to high forces, commonly resulting in multiple injuries. This study of linked road crash data aimed to identify co-occurring injuries in multiple injured road users by using a novel application of a data mining technique commonly used in Market Basket Analysis. We expected that some injuries are statistically associated with each other and form Individual-Based Injury Patterns (IBIPs) and further that specific road users are associated with certain IBIPs. First, a new injury taxonomy was developed through a four-step process to allow the use of injury data recorded from either of the two major dictionaries used to document anatomical injury. Then data from the Swedish Traffic Accident Data Acquisition, which includes crash circumstances from the police and injury information from hospitals, was analysed for the years 2011 to 2017. The injury data was analysed using the Apriori algorithm to identify statistical association between injuries (IBIP). Each IBIP were then used as the outcome variable in logistic regression modelling to identify associations between specific road user types and IBIPs. A total of 48,544 individuals were included in the analysis of which 36,480 (75.1%) had a single injury category recorded and 12,064 (24.9%) were considered multiply injured. The data mining analysis identified 77 IBIPs in the multiply injured sample and 16 of these were associated with only one road user type. IBIPs and their relation to road user type are one step on the journey towards developing a tool to better understand and quantify injury severity and thereby improve the evidence-base supporting prioritisation of road safety countermeasures.

Effectiveness of Computer-Based Auditory Training for Adult Cochlear Implant Users: A Randomized Crossover Study.

The aim of this study was to assess whether a computer-based speech-in-noise auditory training (AT) program would lead to short- and long-term changes in trained and untrained measures of listening, cognition, and quality of life. A secondary aim was to assess whether directly training the underlying cognitive abilities required for speech perception in noise, using a computer-based visual training (VT) program without the auditory component, would elicit comparable outcomes as the AT program. A randomized crossover study with repeated measures was conducted with 26 adult cochlear implant users. Participants completed either 6 weeks of speech perception in noise training followed by 6 weeks of masked text recognition training, or vice versa. Outcome measures were administered twice before each training program, as well as twice after the completion of each program. The test battery was designed to evaluate whether training led to improvements in listening abilities, cognitive abilities, or quality of life. Mixed-effects models were conducted to analyze whether changes occurred on the trained tasks and on untrained outcome measures after training. Statistically significant improvements were shown for verbal recognition performance during both training programs, in particular for consonants in words, and during the first 2 weeks of training. This on-task learning, however, did not lead to clear improvements in outcomes measured beyond the training programs. This suggests that experienced cochlear implant users may not show transfer of on-task learning to untrained tasks after computer-based auditory and visual training programs such as the ones used in this study.

The Emotional Dysregulation Questionnaire: Development and comparative analysis.

OBJECTIVES: A widely used measure of emotion dysregulation, the Difficulties in Emotion Regulation Scale (DERS), may insufficiently cover a number of potentially important aspects of emotional dysregulation. A new measure of emotional dysregulation, the Emotional Dysregulation Questionnaire (EDQ) was therefore developed based upon an eight-factor model of the construct. DESIGN AND METHOD: The DERS and the EDQ were administered to a community sample (N = 362; 183 female, 179 male), along with a number of measures of psychopathology associated with emotional dysregulation. The capacity of the EDQ and the DERS to account for the emotional dysregulation associated with these different types of psychopathology was then compared. RESULTS: In several of the psychopathologies examined, the EDQ could account for more variation than the DERS, suggesting that it more comprehensively assessed the emotion regulation deficits associated with these issues. CONCLUSIONS: Results suggest the EDQ possesses several advantages relative to the DERS, allowing for a more comprehensive and accurate assessment of emotional dysregulation. PRACTITIONER POINTS: Emotional dysregulation is a common component of many psychological disorders. The Difficulties in Emotion Regulation Scale is one of the primary self-report measures used to asses these difficulties, however, concerns exist that it may not comprehensively assess the construct of emotional dysregulation. A new self-report measure of comparable length, the Emotional Dysregulation Questionnaire has been developed, with this new measure possessing several advantages relative to the DERS with regard to the assessment of emotional dysregulation. The use of this measure in clinical practice may more accurately identify the emotion regulation deficits present in clients.

Cluster Analyses Reveals Subgroups of Children With Suspected Auditory Processing Disorders.

BACKGROUND: Some children appear to not hear well in class despite normal hearing sensitivity. These children may be referred for auditory processing disorder (APD) assessment but can also have attention, language, and/or reading disorders. Despite presenting with similar concerns regarding hearing difficulties in difficult listening conditions, the overall profile of deficits can vary in children with suspected or confirmed APD. The current study used cluster analysis to determine whether subprofiles of difficulties could be identified within a cohort of children presenting for auditory processing assessment. METHODS: Ninety school-aged children (7-13 years old) with suspected APDs were included in a cluster analysis. All children had their reading, language, cognition and auditory processing assessed. Parents also completed the Children's Auditory Performance Scale (CHAPS). Cluster analysis was based on tasks where age-norms were available, including word reading (Castles and Coltheart irregular and non-words test), phonological awareness (Queensland University Inventory of Literacy), language [Comprehensive Language of Assessment-4, Comprehensive Assessment of Spoken Language (CASL)], sustained attention (Continuous Performance Test), working memory (digits forward and backward), and auditory processing [Frequency Pattern Test (FPT), Dichotic Digits Test (DDT)]. Hierarchical cluster analysis was undertaken to determine the optimal number of clusters for the data, followed by a k-means cluster analysis. RESULTS: Hierarchical cluster analysis suggested a four-group solution. The four subgroups can be summarized as follows: children with (1) global deficits, n = 35; (2) poor auditory processing with good word reading and phonological awareness skills, n = 22; (3) poor auditory processing with poor attention and memory but good language skills, n = 15; and (4) poor auditory processing and attention with good memory skills, n = 18. CONCLUSION: The cluster analysis identified distinct subgroups of children. These subgroups display the variation in areas of difficulty observed across different studies in the literature (e.g., not every child with APD has an attention deficit), highlighting the heterogeneous nature of APD and the need to assess a range of skills in children with suspected APD. It would be valuable for future studies to independently verify these subgroups and to determine whether interventions can be optimized based on these subgroups.

AltHapAlignR: improved accuracy of RNA-seq analyses through the use of alternative haplotypes.

Motivation: Reliance on mapping to a single reference haplotype currently limits accurate estimation of allele or haplotype-specific expression using RNA-sequencing, notably in highly polymorphic regions such as the major histocompatibility complex. Results: We present AltHapAlignR, a method incorporating alternate reference haplotypes to generate gene- and haplotype-level estimates of transcript abundance for any genomic region where such information is available. We validate using simulated and experimental data to quantify input allelic ratios for major histocompatibility complex haplotypes, demonstrating significantly improved correlation with ground truth estimates of gene counts compared to standard single reference mapping. We apply AltHapAlignR to RNA-seq data from 462 individuals, showing how significant underestimation of expression of the majority of classical human leukocyte antigen genes using conventional mapping can be corrected using AltHapAlignR to allow more accurate quantification of gene expression for individual alleles and haplotypes. Availability and implementation: Source code freely available at https://github.com/jknightlab/AltHapAlignR. Supplementary information: Supplementary data are available at Bioinformatics online.

Synergistic cooperation and crosstalk between MYD88L265P and mutations that dysregulate CD79B and surface IgM.

CD79B and MYD88 mutations are frequently and simultaneously detected in B cell malignancies. It is not known if these mutations cooperate or how crosstalk occurs. Here we analyze the consequences of CD79B and MYD88L265P mutations individually and combined in normal activated mouse B lymphocytes. CD79B mutations alone increased surface IgM but did not enhance B cell survival, proliferation, or altered NF-κB responsive markers. Conversely, B cells expressing MYD88L265P decreased surface IgM coupled with accumulation of endoglycosidase H-sensitive IgM intracellularly, resembling the trafficking block in anergic B cells repeatedly stimulated by self-antigen. Mutation or overexpression of CD79B counteracted the effect of MYD88L265P In B cells chronically stimulated by self-antigen, CD79B and MYD88L265P mutations in combination, but not individually, blocked peripheral deletion and triggered differentiation into autoantibody secreting plasmablasts. These results reveal that CD79B and surface IgM constitute a rate-limiting checkpoint against B cell dysregulation by MYD88L265P and provide an explanation for the co-occurrence of MYD88 and CD79B mutations in lymphomas.

High resolution HLA haplotyping by imputation for a British population bioresource.

This study aimed to establish the occurrence and frequency of HLA alleles and haplotypes for a healthy British Caucasian population bioresource from Oxfordshire. We present the results of imputation from HLA SNP genotyping data using SNP2HLA for 5553 individuals from Oxford Biobank, defining one- and two-field alleles together with amino acid polymorphisms. We show that this achieves a high level of accuracy with validation using sequence-specific primer amplification PCR. We define six- and eight-locus HLA haplotypes for this population by Bayesian methods implemented using PHASE. We determine patterns of linkage disequilibrium and recombination for these individuals involving classical HLA loci and show how analysis within a haplotype block structure may be more tractable for imputed data. Our findings contribute to knowledge of HLA diversity in healthy populations and further validate future large-scale use of HLA imputation as an informative approach in population bioresources.

Shared and Distinct Aspects of the Sepsis Transcriptomic Response to Fecal Peritonitis and Pneumonia.

RATIONALE: Heterogeneity in the septic response has hindered efforts to understand pathophysiology and develop targeted therapies. Source of infection, with different causative organisms and temporal changes, might influence this heterogeneity. OBJECTIVES: To investigate individual and temporal variations in the transcriptomic response to sepsis due to fecal peritonitis, and to compare these with the same parameters in community-acquired pneumonia. METHODS: We performed genome-wide gene expression profiling in peripheral blood leukocytes of adult patients admitted to intensive care with sepsis due to fecal peritonitis (n = 117) or community-acquired pneumonia (n = 126), and of control subjects without sepsis (n = 10). MEASUREMENTS AND MAIN RESULTS: A substantial portion of the transcribed genome (18%) was differentially expressed compared with that of control subjects, independent of source of infection, with eukaryotic initiation factor 2 signaling being the most enriched canonical pathway. We identified two sepsis response signature (SRS) subgroups in fecal peritonitis associated with early mortality (P = 0.01; hazard ratio, 4.78). We defined gene sets predictive of SRS group, and serial sampling demonstrated that subgroup membership is dynamic during intensive care unit admission. We found that SRS is the major predictor of transcriptomic variation; a small number of genes (n = 263) were differentially regulated according to the source of infection, enriched for IFN signaling and antigen presentation. We define temporal changes in gene expression from disease onset involving phagosome formation as well as natural killer cell and IL-3 signaling. CONCLUSIONS: The majority of the sepsis transcriptomic response is independent of the source of infection and includes signatures reflecting immune response state and prognosis. A modest number of genes show evidence of specificity. Our findings highlight opportunities for patient stratification and precision medicine in sepsis.