Increased peritoneal B1-like cells during acute phase of human septic peritonitis.

Sepsis is a life-threatening condition caused by dysregulated host responses to infection. Myeloid cell accumulation and lymphocyte decline are widely recognized phenomena in septic patients. However, the fate of specific immune cells remains unclear. Here, we report the results of a human explorative study of patients with septic peritonitis and patients undergoing abdominal surgery without sepsis. We analyzed pairwise peritoneal fluid and peripheral blood taken 24 h after surgery to characterize immediate immune cell changes. Our results show that myeloid cell expansion and lymphocyte loss occur in all patients undergoing open abdominal surgery, indicating that these changes are not specific to sepsis. However, B1-like lymphocytes were specifically increased in the peritoneal fluid of septic patients, correlating positively with sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation II (APACHE-II) clinical severity scores. In support of this notion, we identified an accumulation of peritoneal B1b lymphocytes in septic mice.

Long-read sequencing for brain tumors.

Brain tumors and genomics have a long-standing history given that glioblastoma was the first cancer studied by the cancer genome atlas. The numerous and continuous advances through the decades in sequencing technologies have aided in the advanced molecular characterization of brain tumors for diagnosis, prognosis, and treatment. Since the implementation of molecular biomarkers by the WHO CNS in 2016, the genomics of brain tumors has been integrated into diagnostic criteria. Long-read sequencing, also known as third generation sequencing, is an emerging technique that allows for the sequencing of longer DNA segments leading to improved detection of structural variants and epigenetics. These capabilities are opening a way for better characterization of brain tumors. Here, we present a comprehensive summary of the state of the art of third-generation sequencing in the application for brain tumor diagnosis, prognosis, and treatment. We discuss the advantages and potential new implementations of long-read sequencing into clinical paradigms for neuro-oncology patients.

Risk and Protective Factors for Injury in Adult Front- and Rear-Seated Motor Vehicle Occupants in New York State.

Although seatbelt use is known to reduce motor vehicle occupant crash injury and death, rear-seated adult occupants are less likely to use restraints. This study examines risk and protective factors associated with injury severity in front- and rear-seated adults involved in a motor vehicle crash in New York State. The Crash Outcome Data Evaluation System (CODES) (2016-2017) was used to examine injury severity in front- and rear-seated occupants aged 18 years or older (N = 958,704) involved in a motor vehicle crash. CODES uses probabilistic linkage of New York State hospitalization, emergency department, and police and motorist crash reports. Multivariable logistic regression models with MI analyze employed SAS 9.4. Odds ratios are reported as OR with 95% CI. The mortality rate was approximately 1.5 times higher for rear-seated than front-seated occupants (136.60 vs. 92.45 per 100,000), with rear-seated occupants more frequently unrestrained than front-seated occupants (15.28% vs. 1.70%, p < 0.0001). In adjusted analyses that did not include restraint status, serious injury/death was higher in rear-seated compared to front-seated occupants (OR:1.272, 1.146-1.412), but lower once restraint use was added (OR: 0.851, 0.771-0.939). Unrestrained rear-seated occupants exhibited higher serious injury/death than restrained front-seated occupants. Unrestrained teens aged 18-19 years old exhibit mortality per 100,000 occupants that is more similar to that of the oldest two age groups than to other young and middle-aged adults. Speeding, a drinking driver, and older vehicles were among the independent predictors of serious injury/death. Unrestrained rear-seated adult occupants exhibit higher severe injury/death than restrained front-seated occupants. When restrained, rear-seated occupants are less likely to be seriously injured than restrained front-seated occupants.

Type-I interferon shapes peritoneal immunity in cirrhosis and drives caspase-5-mediated progranulin release upon infection.

BACKGROUND & AIMS: Gut bacterial translocation contributes to immune dysfunction and spontaneous bacterial peritonitis (SBP) in cirrhosis. We hypothesized that exposure of peritoneal macrophages (PMs) to bacterial DNA results in type-I interferon (IFN) production, shaping subsequent immune responses, inflammasome activation, and the release of damage-associated molecular patterns (DAMPs). METHODS: PMs from patients with cirrhosis were stimulated with E. coli single-stranded DNA (ssDNA), lipopolysaccharide LPS, and IFN or infected with E. coli, S. aureus, and Group B streptococcus in vitro. Cytokine release, inflammasome activation, and DAMP release were quantified by quantitative-PCR, ELISA, western blots, and reporter cells employing primary PMs, monocytes, and caspase-deficient THP-1 macrophages. Serum progranulin concentration was correlated with transplant-free survival in 77 patients with SBP. RESULTS: E. coli ssDNA induced strong type-I IFN activity in PMs and monocytes, priming them for enhanced LPS-mediated tumor necrosis factor production without toll-like receptor 4 tolerance induction. During in vitro macrophage bacterial infection, type-I IFN release aligned with upregulated expression of IFN-regulatory factors (IRF)1/2 and guanylate binding proteins (GBP)2/5. PMs upregulated inflammasome-associated proteins and type-I IFN upon E. coli ssDNA exposure and released interleukin-1ß upon bacterial infection. Proteomic screen in mouse macrophages revealed progranulin as being caspase-11-dependent during E. coli infection. PMs and THP-1 macrophages released significant amounts of progranulin when infected with S. aureus or E. coli via gasdermin-D in a type-I IFN and caspase-5-dependent manner. During SBP, PMs upregulated IRF1, GBP2/5 and caspase-5 and higher serum progranulin concentrations were indicative of lower 90-day transplant-free survival after SBP. CONCLUSIONS: Type-I IFN shapes peritoneal immune responses and regulates caspase-5-mediated progranulin release during SBP. IMPACT AND IMPLICATIONS: Patients with cirrhosis exhibit impaired immune responses and increased susceptibility to bacterial infections. This study reveals that type-I interferon responses, triggered by pathogen-associated molecular patterns, are crucial in regulating macrophage activation and priming them for inflammatory responses. Additionally, we elucidate the mechanisms by which type-I interferons promote the release of progranulin from macrophages during spontaneous bacterial peritonitis. Our findings enhance understanding of how bacterial translocation affects immune responses, identify novel biomarkers for inflammasome activation during infections, and point to potential therapeutic targets.

Larger putamen in individuals at risk and with manifest bipolar disorder.

BACKGROUND: Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. METHODS: In 410 male and female participants aged 17-35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. RESULTS: Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. CONCLUSIONS: Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

Hormesis as an adaptive response to infection.

Hormesis is a phenomenon whereby low-level stress can improve cellular, organ, or organismal fitness in response to a subsequent similar or other stress insult. Whereas hormesis is thought to contribute to the fitness benefits arising from symbiotic host-microbe interactions, the putative benefits of hormesis in host-pathogen interactions have yet to be explored. Hormetic responses have nonetheless been reported in experimental models of infection, a common feature of which is regulation of host mitochondrial function. We propose that these mitohormetic responses could be harnessed therapeutically to limit the severity of infectious diseases.

Lithium-discontinuation-induced treatment refractoriness revisited.

BACKGROUND: Lithium is effective in the long-term treatment of bipolar disorder. Concerns have been raised about non-responsiveness after discontinuation and resuming previously effective lithium prophylaxis. We reviewed the available literature on this so-called lithium-discontinuation-induced treatment refractoriness (LDITR). RESULTS: We found 11 case reports and six cohort studies including 403 patients addressing LDITR, and one nation-wide register study providing some additional data on LDITR. Pooling all cohort studies, the percentages of non-responders during re-treatment with lithium ranged from 3.6 to 27.7%, with an average of 17.3%. Non-responsiveness was associated with longer duration of lithium treatment before discontinuation, longer duration of bipolar disorder before start of lithium, faster tapering off lithium, and longer duration of discontinuation. CONCLUSIONS: There may be a subgroup in whom lithium discontinuation-induced treatment refractoriness exists. However, the vast majority of people respond when lithium is restarted. Moreover, it may be necessary to continue lithium beyond the first relapses to restore long-term prophylactic efficacy.

An app-based ecological momentary assessment of undergraduate student mental Health during the COVID-19 pandemic in Canada (Smart Healthy Campus Version 2.0): Longitudinal study.

This paper presents results from the Smart Healthy Campus 2.0 study/smartphone app, developed and used to collect mental health-related lifestyle data from 86 Canadian undergraduates January-August 2021. Objectives of the study were to 1) address the absence of longitudinal mental health overview and lifestyle-related data from Canadian undergraduate students, and 2) to identify associations between these self-reported mental health overviews (questionnaires) and lifestyle-related measures (from smartphone digital measures). This was a longitudinal repeat measures study conducted over 40 weeks. A 9-item mental health questionnaire was accessible once daily in the app. Two variants of this mental health questionnaire existed; the first was a weekly variant, available each Monday or until a participant responded during the week. The second was a daily variant available after the weekly variant. 6518 digital measure samples and 1722 questionnaire responses were collected. Mixed models were fit for responses to the two questionnaire variants and 12 phone digital measures (e.g. GPS, step counts). The daily questionnaire had positive associations with floors walked, installed apps, and campus proximity, while having negative associations with uptime, and daily calendar events. Daily depression had a positive association with uptime. Daily resilience appeared to have a slight positive association with campus proximity. The weekly questionnaire variant had positive associations with device idling and installed apps, and negative associations with floors walked, calendar events, and campus proximity. Physical activity, weekly, had a negative association with uptime, and a positive association with calendar events and device idling. These lifestyle indicators that associated with student mental health during the COVID-19 pandemic suggest directions for new mental health-related interventions (digital or otherwise) and further efforts in mental health surveillance under comparable circumstances.

Medical comorbidities in bipolar disorder (BIPCOM): clinical validation of risk factors and biomarkers to improve prevention and treatment. Study protocol.

BACKGROUND: BIPCOM aims to (1) identify medical comorbidities in people with bipolar disorder (BD); (2) examine risk factors and clinical profiles of Medical Comorbidities (MC) in this clinical group, with a special focus on Metabolic Syndrome (MetS); (3) develop a Clinical Support Tool (CST) for the personalized management of BD and medical comorbidities. METHODS: The BIPCOM project aims to investigate MC, specifically MetS, in individuals with BD using various approaches. Initially, prevalence rates, characteristics, genetic and non-genetic risk factors, and the natural progression of MetS among individuals with BD will be assessed by analysing Nordic registers, biobanks, and existing patient datasets from 11 European recruiting centres across 5 countries. Subsequently, a clinical study involving 400 participants from these sites will be conducted to examine the clinical profiles and incidence of specific MetS risk factors over 1 year. Baseline assessments, 1-year follow-ups, biomarker analyses, and physical activity measurements with wearable biosensors, and focus groups will be performed. Using this comprehensive data, a CST will be developed to enhance the prevention, early detection, and personalized treatment of MC in BD, by incorporating clinical, biological, sex and genetic information. This protocol will highlight the study's methodology. DISCUSSION: BIPCOM's data collection will pave the way for tailored treatment and prevention approaches for individuals with BD. This approach has the potential to generate significant healthcare savings by preventing complications, hospitalizations, and emergency visits related to comorbidities and cardiovascular risks in BD. BIPCOM's data collection will enhance BD patient care through personalized strategies, resulting in improved quality of life and reduced costly interventions. The findings of the study will contribute to a better understanding of the relationship between medical comorbidities and BD, enabling accurate prediction and effective management of MetS and cardiovascular diseases. TRIAL REGISTRATION: ISRCTN68010602 at https://www.isrctn.com/ISRCTN68010602 . Registration date: 18/04/2023.

Targeted rescue of synaptic plasticity improves cognitive decline in sepsis-associated encephalopathy.

Sepsis-associated encephalopathy (SAE) is a frequent complication of severe systemic infection resulting in delirium, premature death, and long-term cognitive impairment. We closely mimicked SAE in a murine peritoneal contamination and infection (PCI) model. We found long-lasting synaptic pathology in the hippocampus including defective long-term synaptic plasticity, reduction of mature neuronal dendritic spines, and severely affected excitatory neurotransmission. Genes related to synaptic signaling, including the gene for activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) and members of the transcription-regulatory EGR gene family, were downregulated. At the protein level, ARC expression and mitogen-activated protein kinase signaling in the brain were affected. For targeted rescue we used adeno-associated virus-mediated overexpression of ARC in the hippocampus in vivo. This recovered defective synaptic plasticity and improved memory dysfunction. Using the enriched environment paradigm as a non-invasive rescue intervention, we found improvement of defective long-term potentiation, memory, and anxiety. The beneficial effects of an enriched environment were accompanied by an increase in brain-derived neurotrophic factor (BDNF) and ARC expression in the hippocampus, suggesting that activation of the BDNF-TrkB pathway leads to restoration of the PCI-induced reduction of ARC. Collectively, our findings identify synaptic pathomechanisms underlying SAE and provide a conceptual approach to target SAE-induced synaptic dysfunction with potential therapeutic applications to patients with SAE.

Computed tomography in patients with sepsis presenting to the emergency department: exploring its role in light of patient outcomes.

OBJECTIVES: This study aimed to explore the role of CT in septic patients presenting to the emergency department (ED). MATERIALS AND METHODS: We performed a retrospective secondary analysis of 192 septic patients from a prospective observational study, i.e., the "LIFE POC" study. Sepsis was diagnosed in accordance with the Sepsis-3 definition. Clinical and radiological data were collected from the hospital administration and radiological systems. Information on mortality and morbidity was collected. Time-to-CT between CT scan and sepsis diagnosis (ttCTsd) was calculated. Diagnostic accuracy was assessed with the final sepsis source as reference standard. The reference standard was established through the treating team of the patient based on all available clinical, imaging, and microbiological data. RESULTS: Sixty-two of 192 patients underwent a CT examination for sepsis focus detection. The final septic source was identified by CT in 69.4% (n = 43). CT detected septic foci with 81.1% sensitivity (95% CI, 68.0-90.6%) and 55.6% specificity (95% CI, 21.2-86.3%). Patients with short versus long ttCTsd did not differ in terms of mortality (16.1%, n = 5 vs 9.7, n = 3; p = 0.449), length of hospital stay (median 16 d, IQR 9 d 12 h-23 d 18 h vs median 13 d, IQR 10 d 00 h-24 d 00 h; p = 0.863), or duration of intensive care (median 3d 12 h, IQR 2 d 6 h-7 d 18 h vs median 5d, IQR 2 d-11 d; p = 0.800). CONCLUSIONS: Our findings show a high sensitivity of CT in ED patients with sepsis, confirming its relevance in guiding treatment decisions. The low specificity suggests that a negative CT requires further ancillary diagnostic tests for focus detection. The timing of CT did not affect morbidity or mortality outcomes. CLINICAL RELEVANCE STATEMENT: In patients with sepsis who present to the ED, CT can be used to identify infectious foci on the basis of clinical suspicion, but should not be used as a rule-out test. Scientific evidence for the optimal timing of CT beyond clinical decision-making is currently missing, as potential mortality benefits are clouded by differences in clinical severity at the time of ED presentation. KEY POINTS: • In patients with sepsis who present to the ED, CT for focus identification has a high sensitivity and can thereby be valuable for patient management. • As the specificity is considerably lower, a thorough microbiological assessment is important in these cases. • The timing of CT did not affect morbidity and mortality outcomes in this study, which might be due to variability in clinical severity at the time of ED presentation.

Epirubicin for the Treatment of Sepsis and Septic Shock (EPOS-1): study protocol for a randomised, placebo-controlled phase IIa dose-escalation trial.

INTRODUCTION: Sepsis remains the major cause of death among hospitalised patients in intensive care. While targeting sepsis-causing pathogens with source control or antimicrobials has had a dramatic impact on morbidity and mortality of sepsis patients, this strategy remains insufficient for about one-third of the affected individuals who succumb. Pharmacological targeting of mechanisms that reduce sepsis-defining organ dysfunction may be beneficial. When given at low doses, the anthracycline epirubicin promotes tissue damage control and lessens the severity of sepsis independently of the host-pathogen load by conferring disease tolerance to infection. Since epirubicin at higher doses can be myelotoxic, a first dose-response trial is necessary to assess the potential harm of this drug in this new indication. METHODS AND ANALYSIS: Epirubicin for the Treatment of Sepsis and Septic Shock-1 is a randomised, double-blind, placebo-controlled phase 2 dose-escalation phase IIa clinical trial to assess the safety of epirubicin as an adjunctive in patients with sepsis. The primary endpoint is the 14-day myelotoxicity. Secondary and explorative outcomes include 30-day and 90-day mortality, organ dysfunction, pharmacokinetic/pharmacodynamic (PK/PD) and cytokine release. Patients will be randomised in three consecutive phases. For each study phase, patients are randomised to one of the two study arms (epirubicin or placebo) in a 4:1 ratio. Approximately 45 patients will be recruited. Patients in the epirubicin group will receive a single dose of epirubicin (3.75, 7.5 or 15 mg/m2 depending on the study phase. After each study phase, a data and safety monitoring board will recommend continuation or premature stopping of the trial. The primary analyses for each dose level will report the proportion of myelotoxicity together with a 95% CI. A potential dose-toxicity association will be analysed using a logistic regression model with dose as a covariate. All further analyses will be descriptive. ETHICS AND DISSEMINATION: The protocol is approved by the German Federal Institute for Drugs and Medical Devices. The results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05033808.

Predicting state level suicide fatalities in the united states with realtime data and machine learning.

Digital trace data and machine learning techniques are increasingly being adopted to predict suicide-related outcomes at the individual level; however, there is also considerable public health need for timely data about suicide trends at the population level. Although significant geographic variation in suicide rates exist by state within the United States, national systems for reporting state suicide trends typically lag by one or more years. We developed and validated a deep learning based approach to utilize real-time, state-level online (Mental Health America web-based depression screenings; Google and YouTube Search Trends), social media (Twitter), and health administrative data (National Syndromic Surveillance Program emergency department visits) to estimate weekly suicide counts in four participating states. Specifically, per state, we built a long short-term memory (LSTM) neural network model to combine signals from the real-time data sources and compared predicted values of suicide deaths from our model to observed values in the same state. Our LSTM model produced accurate estimates of state-specific suicide rates in all four states (percentage error in suicide rate of -2.768% for Utah, -2.823% for Louisiana, -3.449% for New York, and -5.323% for Colorado). Furthermore, our deep learning based approach outperformed current gold-standard baseline autoregressive models that use historical death data alone. We demonstrate an approach to incorporate signals from multiple proxy real-time data sources that can potentially provide more timely estimates of suicide trends at the state level. Timely suicide data at the state level has the potential to improve suicide prevention planning and response tailored to the needs of specific geographic communities.

RNA sequencing of formalin fixed paraffin-embedded heart tissue provides transcriptomic information about chemotherapy-induced cardiotoxicity.

Gene expression of formalin-fixed paraffin-embedded (FFPE) tissue may serve for molecular studies on cardiovascular diseases. Chemotherapeutics, such as doxorubicin (DOX) may cause heart injury, but the mechanisms of these side effects of DOX are not well understood. This study aimed to investigate whether DOX-induced gene expression in archival FFPE heart tissue in experimental rats would correlate with the gene expression in fresh-frozen heart tissue by applying RNA sequencing technology. The results showed RNA from FFPE samples was degraded, resulting in a lower number of uniquely mapped reads. However, DOX-induced differentially expressed genes in FFPE were related to molecular mechanisms of DOX-induced cardiotoxicity, such as inflammation, calcium binding, endothelial dysfunction, senescence, and cardiac hypertrophy signaling. Our data suggest that, despite the limitations, RNA sequencing of archival FFPE heart tissue supports utilizing FFPE tissues from retrospective studies on cardiovascular disorders, including DOX-induced cardiotoxicity.

Biomarkers Improve Diagnostics of Sepsis in Adult Patients With Suspected Organ Dysfunction Based on the Quick Sepsis-Related Organ Failure Assessment (qSOFA) Score in the Emergency Department.

OBJECTIVES: Consensus regarding biomarkers for detection of infection-related organ dysfunction in the emergency department is lacking. We aimed to identify and validate biomarkers that could improve risk prediction for overt or incipient organ dysfunction when added to quick Sepsis-related Organ Failure Assessment (qSOFA) as a screening tool. DESIGN: In a large prospective multicenter cohort of adult patients presenting to the emergency department with a qSOFA score greater than or equal to 1, admission plasma levels of C-reactive protein, procalcitonin, adrenomedullin (either bioavailable adrenomedullin or midregional fragment of proadrenomedullin), proenkephalin, and dipeptidyl peptidase 3 were assessed. Least absolute shrinkage and selection operator regression was applied to assess the impact of these biomarkers alone or in combination to detect the primary endpoint of prediction of sepsis within 96 hours of admission. SETTING: Three tertiary emergency departments at German University Hospitals (Jena University Hospital and two sites of the Charité University Hospital, Berlin). PATIENTS: One thousand four hundred seventy-seven adult patients presenting with suspected organ dysfunction based on qSOFA score greater than or equal to 1. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The cohort was of moderate severity with 81% presenting with qSOFA = 1; 29.2% of these patients developed sepsis. Procalcitonin outperformed all other biomarkers regarding the primary endpoint (area under the curve for receiver operating characteristic [AUC-ROC], 0.86 [0.79-0.93]). Adding other biomarkers failed to further improve the AUC-ROC for the primary endpoint; however, they improved the model regarding several secondary endpoints, such as mortality, need for vasopressors, or dialysis. Addition of procalcitonin with a cutoff level of 0.25 ng/mL improved net (re)classification by 35.2% compared with qSOFA alone, with positive and negative predictive values of 60.7% and 88.7%, respectively. CONCLUSIONS: Biomarkers of infection and organ dysfunction, most notably procalcitonin, substantially improve early prediction of sepsis with added value to qSOFA alone as a simple screening tool on emergency department admission.

Implications of Online Self-Diagnosis in Psychiatry.

Online self-diagnosis of psychiatric disorders by the general public is increasing. The reasons for the increase include the expansion of Internet technologies and the use of social media, the rapid growth of direct-to-consumer e-commerce in healthcare, and the increased emphasis on patient involvement in decision making. The publicity given to artificial intelligence (AI) has also contributed to the increased use of online screening tools by the general public. This paper aims to review factors contributing to the expansion of online self-diagnosis by the general public, and discuss both the risks and benefits of online self-diagnosis of psychiatric disorders. A narrative review was performed with examples obtained from the scientific literature and commercial articles written for the general public. Online self-diagnosis of psychiatric disorders is growing rapidly. Some people with a positive result on a screening tool will seek professional help. However, there are many potential risks for patients who self-diagnose, including an incorrect or dangerous diagnosis, increased patient anxiety about the diagnosis, obtaining unfiltered advice on social media, using the self-diagnosis to self-treat, including online purchase of medications without a prescription, and technical issues including the loss of privacy. Physicians need to be aware of the increase in self-diagnosis by the general public and the potential risks, both medical and technical. Psychiatrists must recognize that the general public is often unaware of the challenging medical and technical issues involved in the diagnosis of a mental disorder, and be ready to treat patients who have already obtained an online self-diagnosis.

Reframing sepsis immunobiology for translation: towards informative subtyping and targeted immunomodulatory therapies.

Sepsis is a common and deadly condition. Within the current model of sepsis immunobiology, the framing of dysregulated host immune responses into proinflammatory and immunosuppressive responses for the testing of novel treatments has not resulted in successful immunomodulatory therapies. Thus, the recent focus has been to parse observable heterogeneity into subtypes of sepsis to enable personalised immunomodulation. In this Personal View, we highlight that many fundamental immunological concepts such as resistance, disease tolerance, resilience, resolution, and repair are not incorporated into the current sepsis immunobiology model. The focus for addressing heterogeneity in sepsis should be broadened beyond subtyping to encompass the identification of deterministic molecular networks or dominant mechanisms. We explicitly reframe the dysregulated host immune responses in sepsis as altered homoeostasis with pathological disruption of immune-driven resistance, disease tolerance, resilience, and resolution mechanisms. Our proposal highlights opportunities to identify novel treatment targets and could enable successful immunomodulation in the future.

White and gray matter alterations in bipolar I and bipolar II disorder subtypes compared with healthy controls - exploring associations with disease course and polygenic risk.

Patients with bipolar disorder (BD) show alterations in both gray matter volume (GMV) and white matter (WM) integrity compared with healthy controls (HC). However, it remains unclear whether the phenotypically distinct BD subtypes (BD-I and BD-II) also exhibit brain structural differences. This study investigated GMV and WM differences between HC, BD-I, and BD-II, along with clinical and genetic associations. N = 73 BD-I, n = 63 BD-II patients and n = 136 matched HC were included. Using voxel-based morphometry and tract-based spatial statistics, main effects of group in GMV and fractional anisotropy (FA) were analyzed. Associations between clinical and genetic features and GMV or FA were calculated using regression models. For FA but not GMV, we found significant differences between groups. BD-I patients showed lower FA compared with BD-II patients (ptfce-FWE = 0.006), primarily in the anterior corpus callosum. Compared with HC, BD-I patients exhibited lower FA in widespread clusters (ptfce-FWE < 0.001), including almost all major projection, association, and commissural fiber tracts. BD-II patients also demonstrated lower FA compared with HC, although less pronounced (ptfce-FWE = 0.049). The results remained unchanged after controlling for clinical and genetic features, for which no independent associations with FA or GMV emerged. Our findings suggest that, at a neurobiological level, BD subtypes may reflect distinct degrees of disease expression, with increasing WM microstructure disruption from BD-II to BD-I. This differential magnitude of microstructural alterations was not clearly linked to clinical and genetic variables. These findings should be considered when discussing the classification of BD subtypes within the spectrum of affective disorders.