Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients.

OBJECTIVE: Gut microbiome composition is associated with multiple diseases, but relatively little is known about its relationship with long-term outcome measures. While gut dysbiosis has been linked to mortality risk in the general population, the relationship with overall survival in specific diseases has not been extensively studied. In the current study, we present results from an in-depth analysis of the relationship between gut dysbiosis and all-cause and cause-specific mortality in the setting of solid organ transplant recipients (SOTR). DESIGN: We analysed 1337 metagenomes derived from faecal samples of 766 kidney, 334 liver, 170 lung and 67 heart transplant recipients part of the TransplantLines Biobank and Cohort-a prospective cohort study including extensive phenotype data with 6.5 years of follow-up. To analyze gut dysbiosis, we included an additional 8208 metagenomes from the general population of the same geographical area (northern Netherlands). Multivariable Cox regression and a machine learning algorithm were used to analyse the association between multiple indicators of gut dysbiosis, including individual species abundances, and all-cause and cause-specific mortality. RESULTS: We identified two patterns representing overall microbiome community variation that were associated with both all-cause and cause-specific mortality. The gut microbiome distance between each transplantation recipient to the average of the general population was associated with all-cause mortality and death from infection, malignancy and cardiovascular disease. A multivariable Cox regression on individual species abundances identified 23 bacterial species that were associated with all-cause mortality, and by applying a machine learning algorithm, we identified a balance (a type of log-ratio) consisting of 19 out of the 23 species that were associated with all-cause mortality. CONCLUSION: Gut dysbiosis is consistently associated with mortality in SOTR. Our results support the observations that gut dysbiosis is associated with long-term survival. Since our data do not allow us to infer causality, more preclinical research is needed to understand mechanisms before we can determine whether gut microbiome-directed therapies may be designed to improve long-term outcomes.

SGIP1 binding to the α-helical H9 domain of cannabinoid receptor 1 promotes axonal surface expression.

Endocannabinoid signalling mediated by cannabinoid receptor 1 (CB1R, also known as CNR1) is critical for homeostatic neuromodulation of both excitatory and inhibitory synapses. This requires highly polarised axonal surface expression of CB1R, but how this is achieved remains unclear. We previously reported that the α-helical H9 domain in the intracellular C terminus of CB1R contributes to axonal surface expression by an unknown mechanism. Here, we show in rat primary neuronal cultures that the H9 domain binds to the endocytic adaptor protein SGIP1 to promote CB1R expression in the axonal membrane. Overexpression of SGIP1 increases CB1R axonal surface localisation but has no effect on CB1R lacking the H9 domain (CB1RΔH9). Conversely, SGIP1 knockdown reduces axonal surface expression of CB1R but does not affect CB1RΔH9. Furthermore, SGIP1 knockdown diminishes CB1R-mediated inhibition of presynaptic Ca2+ influx in response to neuronal activity. Taken together, these data advance mechanistic understanding of endocannabinoid signalling by demonstrating that SGIP1 interaction with the H9 domain underpins axonal CB1R surface expression to regulate presynaptic responsiveness.

Organic fertilization reduces nitrous oxide emission by altering nitrogen cycling microbial guilds favouring complete denitrification at soil aggregate scale.

Agricultural management practices can induce changes in soil aggregation structure that alter the microbial nitrous oxide (N2O) production and reduction processes occurring at the microscale, leading to large-scale consequences for N2O emissions. However, the mechanistic understanding of how organic fertilization affects these context-dependent small-scale N2O emissions and associated key nitrogen (N) cycling microbial communities is lacking. Here, denitrification gas (N2O, N2) and potential denitrification capacity N2O/(N2O + N2) were assessed by automated gas chromatography in different soil aggregates (>2 mm, 2-0.25 and <0.25 mm), while associated microbial communities were assessed by sequencing and qPCR of N2O-producing (nirK and nirS) and reducing (nosZ clade I and II) genes. The results indicated that organic fertilization reduced N2O emissions by enhancing the conversion of N2O to N2 in all aggregate sizes. Moreover, potential N2O production and reduction hotspots occurred in smaller soil aggregates, with the degree depending on organic fertilizer type and application rate. Further, significantly higher abundance and diversity of nosZ clades relative to nirK and nirS revealed complete denitrification promoted through selection of denitrifying communities at microscales favouring N2O reduction. Communities associated with high and low emission treatments form modules with specific sequence types which may be diagnostic of emission levels. Taken together, these findings suggest that organic fertilizers reduced N2O emissions through influencing soil factors and patterns of niche partitioning between N2O-producing and reducing communities within soil aggregates, and selection for communities that overall are more likely to consume than emit N2O. These findings are helpful in strengthening the ability to predict N2O emissions from agricultural soils under organic fertilization as well as contributing to the development of net-zero carbon strategies for sustainable agriculture.

Implementing enhanced extracorporeal membrane oxygenation for CPR (ECPR) in the emergency department.

Refractory out-of-hospital cardiac arrest (OHCA) has a very poor prognosis, with survival rates at around 10%. Extracorporeal membrane oxygenation (ECMO) for patients in refractory arrest, known as ECPR, aims to provide perfusion to the patient whilst the underlying cause of arrest can be addressed. ECPR use has increased substantially, with varying survival rates to hospital discharge. The best outcomes for ECPR occur when the time from cardiac arrest to implementation of ECPR is minimised. To reduce this time, systems must be in place to identify the correct patient, expedite transfer to hospital, facilitate rapid cannulation and ECMO circuit flows. We describe the process of activation of ECPR, patient selection, and the steps that emergency department clinicians can utilise to facilitate timely cannulation to ensure the best outcomes for patients in refractory cardiac arrest. With these processes in place our survival to hospital discharge for OHCA patients is 35%, with most patients having a good neurological function.

The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for the Mitigation of Complications of Neurostimulation.

INTRODUCTION: The International Neuromodulation Society convened a multispecialty group of physicians based on expertise and international representation to establish evidence-based guidance on the mitigation of neuromodulation complications. This Neurostimulation Appropriateness Consensus Committee (NACC)® project intends to update evidence-based guidance and offer expert opinion that will improve efficacy and safety. MATERIALS AND METHODS: Authors were chosen on the basis of their clinical expertise, familiarity with the peer-reviewed literature, research productivity, and contributions to the neuromodulation literature. Section leaders supervised literature searches of MEDLINE, BioMed Central, Current Contents Connect, Embase, International Pharmaceutical Abstracts, Web of Science, Google Scholar, and PubMed from 2017 (when NACC last published guidelines) to October 2023. Identified studies were graded using the United States Preventive Services Task Force criteria for evidence and certainty of net benefit. Recommendations are based on the strength of evidence or consensus when evidence was scant. RESULTS: The NACC examined the published literature and established evidence- and consensus-based recommendations to guide best practices. Additional guidance will occur as new evidence is developed in future iterations of this process. CONCLUSIONS: The NACC recommends best practices regarding the mitigation of complications associated with neurostimulation to improve safety and efficacy. The evidence- and consensus-based recommendations should be used as a guide to assist decision-making when clinically appropriate.

Comparison of open and endovascular left subclavian artery revascularization for zone 2 thoracic endovascular aortic repair.

OBJECTIVE: In patients undergoing elective thoracic endovascular aortic repair (TEVAR) and left subclavian artery (LSA) coverage, routine preoperative LSA revascularization is recommended. However, in the current endovascular era, the optimal surgical approach is debated. We compared baseline characteristics, procedural details, and perioperative outcomes of patients undergoing open or endovascular LSA revascularization in the setting of TEVAR. METHODS: Adult patients undergoing TEVAR with zone 2 proximal landing and LSA revascularization between 2013-2023 were identified in the Vascular Quality Initiative. We excluded patients with traumatic aortic injury, aortic thrombus, or ruptured presentations, and stratified based on revascularization type (open vs. any endovascular). Open LSA revascularization included surgical bypass or transposition. Endovascular LSA revascularization included single-branch, fenestration, or parallel stent grafting. Primary outcomes were stroke, spinal cord ischemia, and perioperative mortality (Pearson's χ2-test). Multivariable logistic regression was used to evaluate associations between revascularization type and primary outcomes. Secondarily, we studied other in-hospital complications and 5-year mortality (Kaplan-Meier, multivariable Cox-regression). Sensitivity analysis was performed in patients undergoing concomitant LSA revascularization to TEVAR. RESULTS: Of 2,489 patients, 1,842 (74%) underwent open and 647 (26%) received endovascular LSA revascularization. Demographics and comorbidities were similar between open and endovascular cohorts. Compared with open, endovascular revascularization had shorter procedure times (median 135 vs. 174min, p<.001), longer fluoroscopy time (median 23 vs. 16min, p<.001), lower estimated blood loss (median 100 vs. 123ml, p<.001), and less preoperative spinal drain use (40% vs. 49%, p<.001). Patients undergoing endovascular revascularization were more likely to present urgently (24% vs. 19%) or emergently (7.4% vs. 3.4%) (p<.001). Compared with open, endovascular patients experienced lower stroke rates (2.6% vs. 4.8%, p=.026; aOR 0.50[95%C.I., 0.25-0.90]), but had comparable spinal cord ischemia (2.9% vs. 3.5%, p=.60; 0.64[0.31-1.22]) and perioperative mortality (3.1% vs. 3.3%, p=.94; 0.71[0.34-1.37]). Compared with open, endovascular LSA revascularization had lower rates of overall composite in-hospital complications (20% vs. 27%, p<.001; 0.64[0.49-0.83]) and shorter overall hospital stay (7 vs. 8 days, p<.001). After adjustment, 5-year mortality was similar among groups (aHR 0.85[0.64-1.13]). Sensitivity analysis supported the primary analysis with similar outcomes. CONCLUSIONS: In patients undergoing TEVAR starting in zone 2, endovascular LSA revascularization had lower rates of postoperative stroke and overall composite in-hospital complications, but similar spinal cord ischemia, perioperative and 5-year mortality rates compared with open LSA revascularization. Future comparative studies are needed to evaluate the mid- to long-term safety of endovascular LSA revascularization and assess differences between specific endovascular techniques.

Caloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice.

Introduction: Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardio-metabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure and its endocrine profile in the context of aging. Methods: Young and aged male C57Bl6J mice were subjected to CR for 8 weeks and were compared to age-matched littermates with free food access. We assessed bone microstructure and BMAT by micro-CT, bone fatty acid and transcriptomic profiles, and bone healing. Results: CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice. Discussion: Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Outcomes of carotid revascularization stratified by procedure in eGFR<30 and dialysis patients.

OBJECTIVE: Renal failure is a predictor of adverse outcomes in carotid revascularization. There has been debate regarding the benefit of revascularization in patients with severe CKD or on dialysis. METHODS: VQI patients undergoing TCAR, tfCAS, or CEA between 2016 and 2023 with eGFR <30 ml/min/1.73m2 or on dialysis were included. Patients were divided into cohorts based on procedure. Additional analyses were performed for patients on dialysis only and by symptomatology. Primary outcomes were perioperative stroke/death/MI (SDM). Secondary outcomes included perioperative death, stroke, MI, CNI and stroke/death. Inverse probability of treatment weighting (IPW) was performed based on treatment assignment to TCAR, tfCAS, and CEA patients and adjusted for demographics, comorbidities, and pre-op symptoms. Chi-square and multivariable logistic regression analysis were used to evaluate the association of procedure with perioperative outcomes in the weighted cohort. Five-year survival was evaluated using Kaplan-Meier and weighted Cox regression. RESULTS: In the weighted cohort, 13,851 patients with eGFR of <30 (2,506 on dialysis) underwent TCAR (3,639, dialysis 704), tfCAS (1,975, 393) or CEA (8,237, 1,409) during the study period. Compared with TCAR, CEA had higher odds of stroke/death/MI (2.8% vs 3.6%, aOR 1.27 [1.00,1.61], p=.049), and MI (0.7% vs 1.5%, aOR 2.00 [1.31,3.05], p=.001)... Compared to TCAR, rates of SDM (2.8%vs5.8%), stroke (1.2%vs2.6%), death (0.9%vs2,4%)were all higher for tfCAS. In asymptomatic patients CEA patients had higher odds of MI (0.7% vs 1.3%, aOR 1.85[1.15, 2.97]p=.011) and CNI (0.3% vs 1.9%, aOR 7.23[3.28, 15.9] p<.001). Like the primary analysis, asymptomatic tfCAS patients demonstrated higher odds of death, and stroke/death. Symptomatic CEA patients demonstrated no difference in stroke, death or stroke/death. While tfCAS patients demonstrated higher odds of death, stroke, MI, stroke/death, and SDM. In both groups, 5-year survival was similar for TCAR and CEA (eGFR <30: 75.1% vs 74.2%, aHR1.06, p=.3) and lower for tfCAS (eGFR <30: 75.1% vs 70.4%, aHR1.44, p<.001) CONCLUSION: CEA and TCAR had similar odds of stroke and death and are both a reasonable choice in this population; however, TCAR may be better in patients with increased risk of MI. Additionally, tfCAS patients were more likely to have worse outcomes after weighting for symptom status. Finally, while patients with reduced eGFR have worse outcomes than their healthy peers, this analysis shows that the majority of patients survive long enough to benefit from the potential stroke risk reduction provided by all revascularization procedures.

Early-phase amyloid PET reproduces metabolic signatures of cognitive decline in Parkinson's disease.

INTRODUCTION: Recent work suggests that amyloid beta (Aß) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase 18F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD. METHODS: One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aß PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion. RESULTS: Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions. DISCUSSION: EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment. Highlights: Images taken at amyloid beta (Aß) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aß burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.

Effects of maternal calcium supplementation on offspring blood pressure and growth in childhood and adolescence in a population with a low-calcium intake: follow-up study of a randomized controlled trial.

BACKGROUND: The World Health Organization recommends calcium supplementation (1500-2000 mg/d) during pregnancy for women with a low-calcium intake. OBJECTIVES: The purpose of this study was to investigate whether pregnancy calcium supplementation affects offspring blood pressure and growth in The Gambia where calcium intakes are low (300-400 mg/d). METHODS: Follow-up of offspring born during a randomized controlled trial of pregnancy calcium supplementation (ISRCTN96502494, 1996-2000) in which mothers were randomly assigned to 1500 mg Ca/d (Ca) or placebo (P) from 20 wk pregnancy to delivery. Offspring were enrolled at age 3 y in studies where blood pressure and anthropometry were measured under standardized conditions at approximately 2-yearly intervals. Mean blood pressure and growth curves were fitted for females and males separately, using the longitudinal SuperImposition by Translation and Rotation (SITAR) mixed effects model. This generates 3 individual-specific random effects: size, timing, and intensity, reflecting differences in size, age at peak velocity, and peak velocity through puberty relative to the mean curve, respectively. RESULTS: Five hundred twenty-three singleton infants were born during the trial (maternal group assignment: Ca/P = 259/264). Four hundred ninety-one were enrolled as children (females: F-Ca/F-P = 122/129 and males: M-Ca/M-P = 119/121) and measured regularly from 3.0 y to mean age 18.4 y; 90% were measured on ≥8 occasions. SITAR revealed differences in the systolic blood pressure and height curves between pregnancy supplement groups in females, but not in males. F-Ca had lower systolic blood pressure than F-P at all ages (size = -2.1 ± SE 0.8 mmHg; P = 0.005) and lower peak height velocity (intensity = -2.9 ± SE 1.1%, P = 0.009). No significant pregnancy supplement effects were seen for other measures. CONCLUSIONS: This study showed, in female offspring, that pregnancy calcium supplementation may lower systolic blood pressure and slow linear growth in childhood and adolescence, adding to evidence of offspring sexual dimorphism in responses to maternal supplementation. Further research is warranted on the long-term and intergenerational effects of antenatal supplementations. This trial was registered at ISRCTN Registry as ISRCTN96502494.

Creatine homeostasis and the kidney: comparison between kidney transplant recipients and healthy controls.

Creatine is a natural nitrogenous organic acid that is integral to energy metabolism and crucial for proper cell functioning. The kidneys are involved in the first step of creatine production. With kidney transplantation being the gold-standard treatment for end-stage kidney disease, kidney transplant recipients (KTR) may be at risk of impaired creatine synthesis. We aimed to compare creatine homeostasis between KTR and controls. Plasma and urine concentrations of arginine, glycine, guanidinoacetate, creatine and creatinine were measured in 553 KTR and 168 healthy controls. Creatine intake was assessed using food frequency questionnaires. Iothalamate-measured GFR data were available in subsets of 157 KTR and 167 controls. KTR and controls had comparable body weight, height and creatine intake (all P > 0.05). However, the total creatine pool was 14% lower in KTR as compared to controls (651 ± 178 vs. 753 ± 239 mmol, P < 0.001). The endogenous creatine synthesis rate was 22% lower in KTR as compared to controls (7.8 ± 3.0 vs. 10.0 ± 4.1 mmol per day, P < 0.001). Despite lower GFR, the plasma guanidinoacetate and creatine concentrations were 21% and 41% lower in KTR as compared to controls (both P < 0.001). Urinary excretion of guanidinoacetate and creatine were 66% and 59% lower in KTR as compared to controls (both P < 0.001). In KTR, but not in controls, a higher measured GFR was associated with a higher endogenous creatine synthesis rate (std. beta: 0.21, 95% CI: 0.08; 0.33; P = 0.002), as well as a higher total creatine pool (std. beta: 0.22, 95% CI: 0.11; 0.33; P < 0.001). These associations were fully mediated (93% and 95%; P < 0.001) by urinary guanidinoacetate excretion which is consistent with production of the creatine precursor guanidinoacetate as rate-limiting factor. Our findings highlight that KTR have a disturbed creatine homeostasis as compared to controls. Given the direct relationship of measured GFR with endogenous creatine synthesis rate and the total creatine pool, creatine supplementation might be beneficial in KTR with low kidney function.Trial registration ID: NCT02811835.Trial registration URL: https://clinicaltrials.gov/ct2/show/NCT02811835 .

Identifying proteomic risk factors for overall, aggressive, and early onset prostate cancer using Mendelian Randomisation and tumour spatial transcriptomics.

BACKGROUND: Understanding the role of circulating proteins in prostate cancer risk can reveal key biological pathways and identify novel targets for cancer prevention. METHODS: We investigated the association of 2002 genetically predicted circulating protein levels with risk of prostate cancer overall, and of aggressive and early onset disease, using cis-pQTL Mendelian randomisation (MR) and colocalisation. Findings for proteins with support from both MR, after correction for multiple-testing, and colocalisation were replicated using two independent cancer GWAS, one of European and one of African ancestry. Proteins with evidence of prostate-specific tissue expression were additionally investigated using spatial transcriptomic data in prostate tumour tissue to assess their role in tumour aggressiveness. Finally, we mapped risk proteins to drug and ongoing clinical trials targets. FINDINGS: We identified 20 proteins genetically linked to prostate cancer risk (14 for overall [8 specific], 7 for aggressive [3 specific], and 8 for early onset disease [2 specific]), of which the majority replicated where data were available. Among these were proteins associated with aggressive disease, such as PPA2 [Odds Ratio (OR) per 1 SD increment = 2.13, 95% CI: 1.54-2.93], PYY [OR = 1.87, 95% CI: 1.43-2.44] and PRSS3 [OR = 0.80, 95% CI: 0.73-0.89], and those associated with early onset disease, including EHPB1 [OR = 2.89, 95% CI: 1.99-4.21], POGLUT3 [OR = 0.76, 95% CI: 0.67-0.86] and TPM3 [OR = 0.47, 95% CI: 0.34-0.64]. We confirmed an inverse association of MSMB with prostate cancer overall [OR = 0.81, 95% CI: 0.80-0.82], and also found an inverse association with both aggressive [OR = 0.84, 95% CI: 0.82-0.86] and early onset disease [OR = 0.71, 95% CI: 0.68-0.74]. Using spatial transcriptomics data, we identified MSMB as the genome-wide top-most predictive gene to distinguish benign regions from high grade cancer regions that comparatively had five-fold lower MSMB expression. Additionally, ten proteins that were associated with prostate cancer risk also mapped to existing therapeutic interventions. INTERPRETATION: Our findings emphasise the importance of proteomics for improving our understanding of prostate cancer aetiology and of opportunities for novel therapeutic interventions. Additionally, we demonstrate the added benefit of in-depth functional analyses to triangulate the role of risk proteins in the clinical aggressiveness of prostate tumours. Using these integrated methods, we identify a subset of risk proteins associated with aggressive and early onset disease as priorities for investigation for the future prevention and treatment of prostate cancer. FUNDING: This work was supported by Cancer Research UK (grant no. C8221/A29017).

The Neurostimulation Appropriateness Consensus Committee (NACC)®: Recommendations for Spinal Cord Stimulation Long-term Outcome Optimization and Salvage Therapy.

INTRODUCTION: The International Neuromodulation Society (INS) has recognized a need to establish best practices for optimizing implantable devices and salvage when ideal outcomes are not realized. This group has established the Neurostimulation Appropriateness Consensus Committee (NACC)® to offer guidance on matters needed for both our members and the broader community of those affected by neuromodulation devices. MATERIALS AND METHODS: The executive committee of the INS nominated faculty for this NACC® publication on the basis of expertise, publications, and career work on the issue. In addition, the faculty was chosen in consideration of diversity and inclusion of different career paths and demographic categories. Once chosen, the faculty was asked to grade current evidence and along with expert opinion create consensus recommendations to address the lapses in information on this topic. RESULTS: The NACC® group established informative and authoritative recommendations on the salvage and optimization of care for those with indwelling devices. The recommendations are based on evidence and expert opinion and will be expected to evolve as new data are generated for each topic. CONCLUSIONS: NACC® guidance should be considered for any patient with less-than-optimal outcomes with a stimulation device implanted for treating chronic pain. Consideration should be given to these consensus points to salvage a potentially failed device before explant.

Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus.

Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form of paired helical filaments is a major hallmark of Alzheimer's disease. Subcellular localization of ptau at various stages of disease progression is likely to be informative of the cellular mechanisms involving its spread. Here, we found that the density of ptau within several distinct rostral thalamic nuclei in post-mortem human tissue (n = 25 cases) increased with the disease stage, with the anterodorsal nucleus (ADn) consistently being the most affected. In the ADn, ptau-positive elements were present already in the pre-cortical (Braak 0) stage. Tau pathology preferentially affected the calretinin-expressing subpopulation of glutamatergic neurons in the ADn. At the subcellular level, we detected ptau immunoreactivity in ADn cell bodies, dendrites, and in a specialized type of presynaptic terminal that expresses vesicular glutamate transporter 2 (vGLUT2) and likely originates from the mammillary body. The ptau-containing terminals displayed signs of degeneration, including endosomal/lysosomal organelles. In contrast, corticothalamic axon terminals lacked ptau. The data demonstrate the involvement of a specific cell population in ADn at the onset of the disease. The presence of ptau in subcortical glutamatergic presynaptic terminals supports hypotheses about the transsynaptic spread of tau selectively affecting specialized axonal pathways.

Evaluation of the clinical assessment scale for autoimmune encephalitis (CASE) in a retrospective cohort and a systematic review.

BACKGROUND: Autoimmune encephalitis (AE) poses significant challenges in clinical management, requiring effective monitoring tools for therapeutic success and relapse detection. This study aims to assess the Clinical Assessment Scale in Autoimmune Encephalitis (CASE) as compared to the modified Rankin scale (mRS) in evaluating AE patients and to determine the real-world adoption of the CASE score. METHODS: A retrospective cohort study was conducted on 20 AE patients, assessing clinical data including symptomatology, diagnostic findings, and therapeutic regimens. Furthermore, we performed a systematic review on the test performance criteria and the real-world use of the CASE score. RESULTS: The CASE score showed a higher sensitivity in detecting clinical changes compared to the mRS, with a significant correlation between the two scales throughout the disease course (r = 0.85, p < 0.01). A systematic review of 150 articles revealed widespread adoption of the CASE score, especially in Asian populations, demonstrating high reliability and internal consistency. DISCUSSION: Despite limitations such as retrospective design and small sample size, our findings underscore the CASE score's utility in both clinical practice and research settings. The CASE score emerges as a valuable tool for monitoring AE patients, offering improved sensitivity over existing scales like the mRS. Further validation studies in diverse populations are warranted to establish its broader applicability and inform future therapeutic interventions.

Altered brain perfusion and oxygen levels relate to sleepiness and attention in post-COVID syndrome.

OBJECTIVE: Persisting neurological symptoms after COVID-19 affect up to 10% of patients and can manifest in fatigue and cognitive complaints. Based on recent evidence, we evaluated whether cerebral hemodynamic changes contribute to post-COVID syndrome (PCS). METHODS: Using resting-state functional magnetic resonance imaging, we investigated brain perfusion and oxygen level estimates in 47 patients (44.4 ± 11.6 years; F:M = 38:9) and 47 individually matched healthy control participants. Group differences were calculated using two-sample t-tests. Multivariable linear regression was used for associations of each regional perfusion and oxygen level measure with cognition and sleepiness measures. Exploratory hazard ratios were calculated for each brain metric with clinical measures. RESULTS: Patients presented with high levels of fatigue (79%) and daytime sleepiness (45%). We found widespread decreased brain oxygen levels, most evident in the white matter (false discovery rate adjusted-p-value (p-FDR) = 0.038) and cortical grey matter (p-FDR = 0.015). Brain perfusion did not differ between patients and healthy participants. However, delayed patient caudate nucleus perfusion was associated with better executive function (p-FDR = 0.008). Delayed perfusion in the cortical grey matter and hippocampus were associated with a reduced risk of daytime sleepiness (hazard ratio (HR) = 0.07, p = 0.037 and HR = 0.06, p = 0.034). Decreased putamen oxygen levels were associated with a reduced risk of poor cognitive outcome (HR = 0.22, p = 0.019). Meanwhile, lower thalamic oxygen levels were associated with a higher risk of cognitive fatigue (HR = 6.29, p = 0.017). INTERPRETATION: Our findings of lower regional brain blood oxygen levels suggest increased cerebral metabolism in PCS, which potentially holds a compensatory function. These hemodynamic changes were related to symptom severity, possibly representing metabolic adaptations.

A host-microbial metabolite interaction gut-on-a-chip model of the adult human intestine demonstrates beneficial effects upon inulin treatment of gut microbiome.

Background: The gut and its microbiome have a major impact on many aspects of health and are therefore also an attractive target for drug- or food-based therapies. Here, we report on the added value of combining a microbiome screening model, the i-screen, with fresh intestinal tissue explants in a microfluidic gut-on-a-chip model, the Intestinal Explant Barrier Chip (IEBC). Methods: Adult human gut microbiome (fecal pool of 6 healthy donors) was cultured anaerobically in the i-screen platform for 24 h, without and with exposure to 4 mg/mL inulin. The i-screen cell-free culture supernatant was subsequently applied to the luminal side of adult human colon tissue explants (n = 3 donors), fixed in the IEBC, for 24 h and effects were evaluated. Results: The supplementation of the media with inulin promoted the growth of Anaerostipes, Bifidobacterium, Blautia, and Collinsella in the in vitro i-screen, and triggered an elevated production of butyrate by the microbiota. Human colon tissue exposed to inulin-treated i-screen cell-free culture supernatant or control i-screen cell-free culture supernatant with added short-chain fatty acids (SCFAs) showed improved tissue barrier integrity measured by a 28.2%-34.2% reduction in FITC-dextran 4000 (FD4) leakage and 1.3 times lower transport of antipyrine. Furthermore, the release of pro-inflammatory cytokines IL-1ß, IL-6, IL-8, and TNF-α was reduced under these circumstances. Gene expression profiles confirmed these findings, but showed more profound effects for inulin-treated supernatant compared to SCFA-supplemented supernatant. Conclusion: The combination of i-screen and IEBC facilitates the study of complex intestinal processes such as host-microbial metabolite interaction and gut health.

First-Principles Modeling of the Absorption Spectrum of Crystal Violet in Solution: The Importance of Environmentally Driven Symmetry Breaking.

Theoretical spectroscopy plays a crucial role in understanding the properties of the materials and molecules. One of the most promising methods for computing optical spectra of chromophores embedded in complex environments from the first principles is the cumulant approach, where both (generally anharmonic) vibrational degrees of freedom and environmental interactions are explicitly accounted for. In this work, we verify the capabilities of the cumulant approach in describing the effect of complex environmental interactions on linear absorption spectra by studying Crystal Violet (CV) in different solvents. The experimental absorption spectrum of CV strongly depends on the nature of the solvent, indicating strong coupling to the condensed-phase environment. We demonstrate that these changes in absorption line shape are driven by an increased splitting between absorption bands of two low-lying excited states that is caused by a breaking of the D3 symmetry of the molecule and that in polar solvents, this symmetry breaking is mainly driven by electrostatic interactions with the condensed-phase environment rather than distortion of the structure of the molecule, in contrast with conclusions reached in a number of previous studies. Our results reveal the importance of explicitly including a counterion in the calculations in nonpolar solvents due to electrostatic interactions between CV and the ion. In polar solvents, these interactions are strongly reduced due to solvent screening effects, thus minimizing the symmetry breaking. Computed spectra in methanol are found to be in reasonable agreement with the experiment, demonstrating the strengths of the outlined approach in modeling strong environmental interactions.

A systematic review and meta-analysis of the dietary fiber menu provision and consumption for older adults living in residential care facilities.

BACKGROUND: Older adults living in residential care facilities are commonly given laxatives to treat constipation; however, these may not always provide full relief, and side effects include diarrhea. Dietary fiber effectively prevents constipation, and international guidelines recommend 25 g/d for optimal laxation. Older adults in residential care rely on the facility menu to provide their nutritional requirements, including adequate dietary fiber. Little is known about how much dietary fiber is provided and consumed. OBJECTIVES: We aimed to determine the provision and consumption of dietary fiber for older adults living in residential care facilities. METHODS: We systematically searched available literature for studies reporting the analysis of residential care menus and meals consumed by residents aged over 65 y. A meta-analysis was performed on the studies that provided the mean amount of dietary fiber provided and consumed by residents. A random effect model was applied due to the heterogeneity of study methodologies. RESULTS: The literature search yielded 4406 publications, but only 28 studies were eligible for our meta-analysis. The study sample comprised 4817 residents. The mean amount of fiber provided to residents was 21.4 g/d [standard error (SE): 1.2; 95% confidence interval: 18.8, 24.2 g/d], the mean amount of fiber consumed by residents was 15.8 g/d (SE: 0.6; 95% confidence interval: 14.7, 16.9 g/d). CONCLUSIONS: Older adults living in care facilities are provided with dietary fiber below the recommended guidelines. Compounding this is that residents consume much less than what is provided and do not meet the recommendations for dietary fiber consumption. There is scope to improve dietary fiber provision, promote consumption to residents to aid laxation, and potentially reduce laxative use and the unwanted side effects of diarrhea. This trial was registered at PROSPERO as CRD42023427265.