High-fat diet, microbiome-gut-brain axis signaling, and anxiety-like behavior in male rats.

Obesity, associated with the intake of a high-fat diet (HFD), and anxiety are common among those living in modern urban societies. Recent studies suggest a role of microbiome-gut-brain axis signaling, including a role for brain serotonergic systems in the relationship between HFD and anxiety. Evidence suggests the gut microbiome and the serotonergic brain system together may play an important role in this response. Here we conducted a nine-week HFD protocol in male rats, followed by an analysis of the gut microbiome diversity and community composition, brainstem serotonergic gene expression (tph2, htr1a, and slc6a4), and anxiety-related defensive behavioral responses. We show that HFD intake decreased alpha diversity and altered the community composition of the gut microbiome in association with obesity, increased brainstem tph2, htr1a and slc6a4 mRNA expression, including in the caudal part of the dorsomedial dorsal raphe nucleus (cDRD), a subregion previously associated with stress- and anxiety-related behavioral responses, and, finally, increased anxiety-related defensive behavioral responses. The HFD increased the Firmicutes/Bacteroidetes ratio relative to control diet, as well as higher relative abundances of Blautia, and decreases in Prevotella. We found that tph2, htr1a and slc6a4 mRNA expression were increased in subregions of the dorsal raphe nucleus in the HFD, relative to control diet. Specific bacterial taxa were associated with increased serotonergic gene expression in the cDRD. Thus, we propose that HFD-induced obesity is associated with altered microbiome-gut-serotonergic brain axis signaling, leading to increased anxiety-related defensive behavioral responses in rats.

Reduced temporal muscle thickness predicts shorter survival in patients undergoing chronic subdural haematoma drainage.

BACKGROUND: Chronic subdural haematoma (CSDH) drainage is a common neurosurgical procedure. CSDHs cause excess mortality, which is exacerbated by frailty. Sarcopenia contributes to frailty - its key component, low muscle mass, can be assessed using cross-sectional imaging. We aimed to examine the prognostic role of temporal muscle thickness (TMT) measured from preoperative computed tomography head scans among patients undergoing surgical CSDH drainage. METHODS: We retrospectively identified all patients who underwent CSDH drainage within 1 year of February 2019. We measured their mean TMT from preoperative computed tomography scans, tested the reliability of these measurements, and evaluated their prognostic value for postoperative survival. RESULTS: One hundred and eighty-eight (122, 65% males) patients (median age 78 years, IQR 70-85 years) were included. Thirty-four (18%) patients died within 2 years, and 51 (27%) died at a median follow-up of 39 months (IQR 34-42 months). Intra- and inter-observer reliability of TMT measurements was good-to-excellent (ICC 0.85-0.97, P < 0.05). TMT decreased with age (Pearson's r = -0.38, P < 0.001). Females had lower TMT than males (P < 0.001). The optimal TMT cut-off values for predicting two-year survival were 4.475 mm for males and 3.125 mm for females. TMT below these cut-offs was associated with shorter survival in both univariate (HR 3.24, 95% CI 1.85-5.67) and multivariate (HR 1.86, 95% CI 1.02-3.36) analyses adjusted for age, ASA grade and bleed size. The effect of TMT on mortality was not mediated by age. CONCLUSIONS: In patients with CSDH, TMT measurements from preoperative imaging were reliable and contained prognostic information supplemental to previously known predictors of poor outcomes.

Global Proteomic Analysis Reveals Alterations in Differentially Expressed Proteins between Cardiopathic Lamin A/C Mutations.

Lamin A/C (LMNA) is an important component of nuclear lamina. Mutations cause arrhythmia, heart failure, and sudden cardiac death. While LMNA-associated cardiomyopathy typically has an aggressive course that responds poorly to conventional heart failure therapies, there is variability in severity and age of penetrance between and even within specific mutations, which is poorly understood at the cellular level. Further, this heterogeneity has not previously been captured to mimic the heterozygous state, nor have the hundreds of clinical LMNA mutations been represented. Herein, we have overexpressed cardiopathic LMNA variants in HEK cells and utilized state-of-the-art quantitative proteomics to compare the global proteomic profiles of (1) aggregating Q353 K alone, (2) Q353 K coexpressed with WT, (3) aggregating N195 K coexpressed with WT, and (4) nonaggregating E317 K coexpressed with WT to help capture some of the heterogeneity between mutations. We analyzed each data set to obtain the differentially expressed proteins (DEPs) and applied gene ontology (GO) and KEGG pathway analyses. We found a range of 162 to 324 DEPs from over 6000 total protein IDs with differences in GO terms, KEGG pathways, and DEPs important in cardiac function, further highlighting the complexity of cardiac laminopathies. Pathways disrupted by LMNA mutations were validated with redox, autophagy, and apoptosis functional assays in both HEK 293 cells and in induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) for LMNA N195 K. These proteomic profiles expand our repertoire for mutation-specific downstream cellular effects that may become useful as druggable targets for personalized medicine approach for cardiac laminopathies.

Use and performance of the evolut FX transcatheter aortic valve system.

BACKGROUND: The next generation supra-annular, self-expanding Evolut FX transcatheter aortic valve (TAV) system was designed to improve catheter deliverability, provide stable and symmetric valve deployment, and assess commissural alignment during the procedure. The impact of these modifications has not been clinically evaluated. METHODS: Procedural information was collected by survey in 2 Stages: Stage I comprised 23 centers with extensive experience with Evolut TAV systems, and Stage II comprised an additional 46 centers with a broad range of balloon- and self-expanding system experience. Operators were to compare the experience with the Evolut FX to the predicate Evolut PRO+ system. RESULTS: There were 285 cases during Stage I from June 24 to August 12, 2022, and 254 cases during Stage II from August 15 to September 11, 2022. Overall, the cusp overlap technique was used in 88.6 %, and commissural alignment was achieved in 96.1 % of these cases. Compared to implanter's previous experience with the Evolut PRO+ system, less resistance was noted with the Evolut FX system: in 83.0 % of cases during vascular insertion, in 84.7 % of cases while tracking through the vasculature, in 84.4 % of cases while traversing over the arch, and 76.1 % of cases in advancing across the valve. Better symmetry of valve depth was observed in 423 of 525 cases (80.6 %). CONCLUSION: Evolut FX system design modifications translated into improvements in catheter deliverability, deployment symmetry and stability, and commissural alignment as assessed by experienced self-expanding and balloon expandable operators.

Metabologenomic characterization uncovers a clinically aggressive IDH mutant glioma subtype.

Mutations in the pivotal metabolic isocitrate dehydrogenase (IDH) enzymes are recognized to drive the molecular footprint of diffuse gliomas, and patients with IDH mutant gliomas have overall favorable outcomes compared to patients with IDH wild-type tumors. However, survival still varies widely among patients with IDH mutated tumors. Here, we aimed to characterize molecular signatures that explain the range of IDH mutant gliomas. By integrating matched epigenome-wide methylome, transcriptome, and global metabolome data in 154 patients with gliomas, we identified a group of IDH mutant gliomas with globally altered metabolism that resembled IDH wild-type tumors. IDH-mutant gliomas with altered metabolism have significantly shorter overall survival from their IDH mutant counterparts that is not fully accounted for by recognized molecular prognostic markers of CDKN2A/B loss and glioma CpG Island Methylator Phenotype (GCIMP) status. IDH-mutant tumors with dysregulated metabolism harbored distinct epigenetic alterations that converged to drive proliferative and stem-like transcriptional profiles, providing a window to target novel dependencies in gliomas.

Visualization of Cerebral Pressure Autoregulatory Insults in Traumatic Brain Injury.

OBJECTIVES: The first aim was to investigate the combined effect of insult intensity and duration of the pressure reactivity index (PRx) and deviation from the autoregulatory cerebral perfusion pressure target (∆CPPopt = actual CPP - optimal CPP [CPPopt]) on outcome in traumatic brain injury. The second aim was to determine if PRx influenced the association between intracranial pressure (ICP), CPP, and ∆CPPopt with outcome. DESIGN: Observational cohort study. SETTING: Neurocritical care unit, Cambridge, United Kingdom. PATIENTS: Five hundred fifty-three traumatic brain injury patients with ICP and arterial blood pressure monitoring and 6-month outcome data (Glasgow Outcome Scale [GOS]). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The insult intensity (mm Hg or PRx coefficient) and duration (minutes) of ICP, PRx, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In these plots, there was a transition from favorable to unfavorable outcome when PRx remained positive for 30 minutes and this was also the case for shorter durations when the intensity was higher. In a similar plot of ∆CPPopt, there was a gradual transition from favorable to unfavorable outcome when ∆CPPopt went below -5 mm Hg for 30-minute episodes of time and for shorter durations for more negative ∆CPPopt. Furthermore, the percentage of monitoring time with certain combinations of PRx with ICP, CPP, and ∆CPPopt were correlated with GOS and visualized in heatmaps. In the combined PRx/ICP heatmap, ICP above 20 mm Hg together with PRx above 0 correlated with unfavorable outcome. In a PRx/CPP heatmap, CPP below 70 mm Hg together with PRx above 0.2-0.4 correlated with unfavorable outcome. In the PRx-/∆CPPopt heatmap, ∆CPPopt below 0 together with PRx above 0.2-0.4 correlated with unfavorable outcome. CONCLUSIONS: Higher intensities for longer durations of positive PRx and negative ∆CPPopt correlated with worse outcome. Elevated ICP, low CPP, and negative ∆CPPopt were particularly associated with worse outcomes when the cerebral pressure autoregulation was concurrently impaired.

Reinterventions After CoreValve/Evolut Transcatheter or Surgical Aortic Valve Replacement for Treatment of Severe Aortic Stenosis.

BACKGROUND: Data on valve reintervention after transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) are limited. OBJECTIVES: The authors compared the 5-year incidence of valve reintervention after self-expanding CoreValve/Evolut TAVR vs SAVR. METHODS: Pooled data from CoreValve and Evolut R/PRO (Medtronic) randomized trials and single-arm studies encompassed 5,925 TAVR (4,478 CoreValve and 1,447 Evolut R/PRO) and 1,832 SAVR patients. Reinterventions were categorized by indication, timing, and treatment. The cumulative incidence of reintervention was compared between TAVR vs SAVR, Evolut vs CoreValve, and Evolut vs SAVR. RESULTS: There were 99 reinterventions (80 TAVR and 19 SAVR). The cumulative incidence of reintervention through 5 years was higher with TAVR vs SAVR (2.2% vs 1.5%; P = 0.017), with differences observed early (≤1 year; adjusted subdistribution HR: 3.50; 95% CI: 1.53-8.02) but not from >1 to 5 years (adjusted subdistribution HR: 1.05; 95% CI: 0.48-2.28). The most common reason for reintervention was paravalvular regurgitation after TAVR and endocarditis after SAVR. Evolut had a significantly lower incidence of reintervention than CoreValve (0.9% vs 1.6%; P = 0.006) at 5 years with differences observed early (adjusted subdistribution HR: 0.30; 95% CI: 0.12-0.73) but not from >1 to 5 years (adjusted subdistribution HR: 0.61; 95% CI: 0.21-1.74). The 5-year incidence of reintervention was similar for Evolut vs SAVR (0.9% vs 1.5%; P = 0.41). CONCLUSIONS: A low incidence of reintervention was observed for CoreValve/Evolut R/PRO and SAVR through 5 years. Reintervention occurred most often at ≤1 year for TAVR and >1 year for SAVR. Most early reinterventions were with the first-generation CoreValve and managed percutaneously. Reinterventions were more common following CoreValve TAVR compared with Evolut TAVR or SAVR.

The Arctic Plant Aboveground Biomass Synthesis Dataset.

Plant biomass is a fundamental ecosystem attribute that is sensitive to rapid climatic changes occurring in the Arctic. Nevertheless, measuring plant biomass in the Arctic is logistically challenging and resource intensive. Lack of accessible field data hinders efforts to understand the amount, composition, distribution, and changes in plant biomass in these northern ecosystems. Here, we present The Arctic plant aboveground biomass synthesis dataset, which includes field measurements of lichen, bryophyte, herb, shrub, and/or tree aboveground biomass (g m-2) on 2,327 sample plots from 636 field sites in seven countries. We created the synthesis dataset by assembling and harmonizing 32 individual datasets. Aboveground biomass was primarily quantified by harvesting sample plots during mid- to late-summer, though tree and often tall shrub biomass were quantified using surveys and allometric models. Each biomass measurement is associated with metadata including sample date, location, method, data source, and other information. This unique dataset can be leveraged to monitor, map, and model plant biomass across the rapidly warming Arctic.

Differences in methylation profiles between long-term survivors and short-term survivors of IDH-wild-type glioblastoma.

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

Horse to human: Streptococcus equi septicemia presenting as endogenous endophthalmitis.

Purpose: To present a rarely reported systemic infection with streptococcus equi subspecies zooepidemicus (streptococcus equi), transmitted from a horse, and to describe successful treatment when complicated by endogenous endophthalmitis. Observations: We diagnosed suspected streptococcus equi septicemia presenting as loss of vision in the right eye of an otherwise healthy polo player/horse trainer. He received immediate intravenous antibiotics and three vitrectomies with two intravitreal antibiotic injections during the first week, to cure infection and subsequent retinal detachment. Blood and initial vitreous cultures rapidly grew streptococcus equi. The septicemia was quickly controlled by systemic antibiotics without developing commonly seen and often fatal meningitis. The right eye recovered 20/30 visual acuity three months post infection. Conclusions: Presentation of this rare septicemia as endogenous endophthalmitis illustrates the potentially lifesaving role of early diagnosis by the ophthalmologist. Immediate and recurrent vitrectomy in conjunction with intravitreal and systemic antibiotic therapy resulted in recovery of near normal vision, whereas less timely and interventional treatments have failed heretofore.

A low-tech, low-cost method to capture point-source ammonia emissions and their potential use as a nitrogen fertiliser.

Rising global energy prices have led to increased costs of nitrogen (N) fertilisers for farmers, but N pollution (losses) from agricultural activities can account for over 50% of the nitrogen applied. This study assesses the feasibility of a low-cost and low-tech method of NH3 emission capture from an agricultural point source (chicken manure) using a water column bubbling technique, and its application as a fertiliser to several plant types. Solutions of i) nitric acid (HNO3), ii) calcium nitrate (Ca(NO3)2), iii) a mixture of Ca(NO3)2 and HNO3 and iv) deionised H2O were used to scrub NH3 from air pumped from a storage container containing chicken manure. We conclude that NH3 can be captured from manure using low-tech methods, and that solutions of common fertiliser compounds such as ammonium nitrate and calcium ammonium nitrate can be replicated by binding captured NH3 to solutions of nitrate. Our results suggest that dissolved calcium nitrate is just as effective at scrubbing NH3 from the atmosphere as nitric acid at low concentrations, but could do so at a near neutral pH. For use on common silage grass for livestock feed, all of the captured ammonium solutions significantly increased yields, including the ammonium only solution. However, the aquatic plants (Taxiphyllum Barbieri and Salvinia auriculata) did not respond favourably to a high ratio of NH4+ in solution, and in the case of Salvinia auriculata, the plant was significantly damaged by the ammonium only solution. In conclusion, we highlight that the capture and utilisation of NH3 emissions from point sources is possible using very basic apparatus and that if used correctly, this captured nitrogen can be stored and applied to crops in a variety of forms which could reduce reliance and cost of mineral fertiliser use.

Routine Extubation in the Operating Room After Isolated Coronary Artery Bypass.

BACKGROUND: The benefits of fast-track extubation in the intensive care unit (ICU) after cardiac surgery are well established. Although extubation in the operating room (OR) is safe in carefully selected patients, widespread use of this strategy in cardiac surgery remains unproven. This study was designed to evaluate perioperative outcomes with OR vs ICU extubation in patients undergoing nonemergency, isolated coronary artery bypass grafting (CABG). METHODS: The Society of Thoracic Surgeons (STS) data for all single-center patients who underwent nonemergency isolated CABG over a 6-year interval were analyzed. Perioperative morbidity and mortality with ICU vs OR extubation were compared. RESULTS: Between January 1, 2017 and December 31, 2022, 1397 patients underwent nonemergency, isolated CABG; 891 (63.8%) of these patients were extubated in the ICU, and 506 (36.2%) were extubated in the OR. Propensity matching resulted in 414 pairs. In the propensity-matched cohort, there were no differences between the 2 groups in incidence of reintubation, reoperation for bleeding, total operative time, stroke or transient ischemic attack, renal failure, or 30-day mortality. OR-extubated patients had shorter ICU hours (14 hours vs 20 hours; P < .0001), shorter postoperative hospital length of stay (3 days vs 5 days; P < .0001), a greater likelihood of being discharged directly to home (97.3% vs 89.9%; P < .0001), and a lower 30-day readmission rate (1.7% vs 4.1%; P = .04). CONCLUSIONS: Routine extubation in the OR is a feasible and safe strategy for a broad spectrum of patients after nonemergency CABG, with no increase in perioperative morbidity or mortality. Wider adoption of routine OR extubation for nonemergency CABG is indicated.

Technical considerations and long-term results of endovascular venous stenting to control venous hypertension from meningiomas invading intracranial venous sinuses.

OBJECTIVE: Meningiomas invading the intracranial venous sinuses may cause intracranial venous hypertension, papilledema, and visual compromise. Sinus resection and graft reconstructions, however, add significant complexity to tumor surgery, with the potential for increased morbidity. In this study, the authors explored whether venous sinus stenting might provide an alternative means of controlling venous hypertension that would be sustainable over the long term. METHODS: The authors performed a retrospective review of all 16 patients with intracranial meningiomas who underwent stenting at their institution for venous sinus compromise. At presentation, all had headache and 9 had papilledema. Thirteen patients had 1 meningioma and 3 had 2 or more. Three patients had had previous tumor resection and radiotherapy. One patient had been treated with a lumboperitoneal shunt and radiotherapy. The median length of clinical follow-up was 8 years (range 4 months-18 years). RESULTS: Venous sinus narrowing was often not confined to the site of meningioma, and bilateral transverse sinus narrowing, reminiscent of that seen in idiopathic intracranial hypertension, was present in 7 patients with sagittal sinus meningiomas. Eleven patients had stents placed solely across sinus narrowing caused by meningioma. Five patients had additional stents placed at other sites of venous narrowing at the same time: in one of these patients, a stent was placed across a defect in the sagittal sinus caused by previous surgery, and in the 4 other patients, stents were placed across nontumor narrowings of the transverse sinuses. In 1 patient, the jugular vein was also stented. Nine patients developed symptomatic in-stent restenosis at the meningioma site. Eight had further stenting procedures with variable success in restoring the in-stent lumen. The remaining patient, with a late partial relapse, is being reinvestigated. Papilledema resolved in all patients after stenting. Six patients experienced prolonged and very substantial relief of all symptoms. Five patients had persistent headache despite restoration of the sinus lumen. Five had persistent symptoms associated with resistant in-stent stenosis. There were no significant complications from any of the diagnostic or therapeutic procedures. CONCLUSIONS: In patients who are symptomatic with meningiomas obstructing the venous sinuses, successful stenting of the affected segment can give a good outcome, especially in terms of relieving papilledema. However, further procedures are often necessary to maintain stent patency, other areas of venous compromise frequently coexist, and some patients remain symptomatic despite apparently successful treatment of the index lesion. Long-term surveillance is a requirement.

Associations of inflammation-related proteome with demographic and clinical characteristics of people with HIV in South Africa.

PURPOSE: Elevated levels of inflammation associated with human immunodeficiency virus (HIV) infection are one of the primary causes for the burden of age-related diseases among people with HIV (PWH). Circulating proteins can be used to investigate pathways to inflammation among PWH. EXPERIMENTAL DESIGN: We profiled 73 inflammation-related protein markers and assessed their associations with chronological age, sex, and CD4+ cell count among 87 black South African PWH before antiretroviral therapy (ART). RESULTS: We identified 1, 1, and 14 inflammatory proteins significantly associated with sex, CD4+ cell count, and age respectively. Twelve out of 14 age-associated proteins have been reported to be associated with age in the general population, and 4 have previously shown significant associations with age for PWH. Furthermore, many of the age-associated proteins such as CST5, CCL23, SLAMF1, MMP-1, MCP-1, and CDCP1 have been linked to chronic diseases such as cardiovascular disease and neurocognitive decline in the general population. We also found a synergistic interaction between male and older age accounting for excessive expression of CST5. CONCLUSIONS AND CLINICAL RELEVANCE: We found that advanced age may lead to the elevation of multiple inflammatory proteins among PWH. We also demonstrated the potential utility of proteomics for evaluating and characterizing the inflammatory status of PWH.

1-Year Outcomes of Transcatheter Edge-to-Edge Repair in Anatomically Complex Degenerative Mitral Regurgitation Patients.

BACKGROUND: Favorable 6-month outcomes from the CLASP IID Registry (Edwards PASCAL transcatheter valve repair system pivotal clinical trial) demonstrated that mitral valve transcatheter edge-to-edge repair with the PASCAL transcatheter valve repair system is safe and beneficial for treating prohibitive surgical risk degenerative mitral regurgitation (DMR) patients with complex mitral valve anatomy. OBJECTIVES: The authors sought to assess 1-year safety, echocardiographic and clinical outcomes from the CLASP IID Registry. METHODS: Patients with 3+ or 4+ DMR who were at prohibitive surgical risk, had complex mitral valve anatomy based on the MitraClip Instructions for Use, and deemed suitable for treatment with the PASCAL system were enrolled prospectively. Safety, clinical, echocardiographic, functional, and quality-of-life outcomes were assessed at 1 year. Study oversight included a central screening committee, echocardiographic core laboratory, and clinical events committee. RESULTS: Ninety-eight patients were enrolled. One-year Kaplan-Meier (KM) estimates of freedom from composite major adverse events, all-cause mortality, and heart failure hospitalization were 83.5%, 89.3%, and 91.5%, respectively. Significant mitral regurgitation (MR) reduction was achieved at 1 year (P < 0.001 vs baseline) including 93.2% at MR ≤2+ and 57.6% at MR ≤1+ with improvements in related echocardiographic measures. NYHA functional class and Kansas City Cardiomyopathy Questionnaire score also improved significantly (P < 0.001 vs baseline). CONCLUSIONS: At 1 year, treatment with the PASCAL system demonstrated safety and significant MR reduction, with continued improvement in clinical, echocardiographic, functional, and quality-of-life outcomes, illustrating the value of the PASCAL system in the treatment of prohibitive surgical risk patients with 3+ or 4+ DMR and complex mitral valve anatomy.

Brain tissue oxygen monitoring in traumatic brain injury-part II: isolated and combined insults in relation to outcome.

BACKGROUND: The primary aim was to explore the concept of isolated and combined threshold-insults for brain tissue oxygenation (pbtO2) in relation to outcome in traumatic brain injury (TBI). METHODS: A total of 239 TBI patients with data on clinical outcome (GOS) and intracranial pressure (ICP) and pbtO2 monitoring for at least 12 h, who had been treated at the neurocritical care unit, Addenbrooke's Hospital, Cambridge, UK, between 2002 and 2022 were included. Outcome was dichotomised into favourable/unfavourable (GOS 4-5/1-3) and survival/mortality (GOS 2-5/1). PbtO2 was studied over the entire monitoring period. Thresholds were analysed in relation to outcome based on median and mean values, percentage of time and dose per hour below critical values and visualised as the combined insult intensity and duration. RESULTS: Median pbtO2 was slightly, but not significantly, associated with outcome. A pbtO2 threshold at 25 and 20 mmHg, respectively, yielded the highest x2 when dichotomised for favourable/unfavourable outcome and mortality/survival in chi-square analyses. A higher dose and higher percentage of time spent with pbtO2 below 25 mmHg as well as lower thresholds were associated with unfavourable outcome, but not mortality. In a combined insult intensity and duration analysis, there was a transition from favourable towards unfavourable outcome when pbtO2 went below 25-30 mmHg for 30 min and similar transitions occurred for shorter durations when the intensity was higher. Although these insults were rare, pbtO2 under 15 mmHg was more strongly associated with unfavourable outcome if, concurrently, ICP was above 20 mmHg, cerebral perfusion pressure below 60 mmHg, or pressure reactivity index above 0.30 than if these variables were not deranged. In a multiple logistic regression, a higher percentage of monitoring time with pbtO2 < 15 mmHg was associated with a higher rate of unfavourable outcome. CONCLUSIONS: Low pbtO2, under 25 mmHg and particularly below 15 mmHg, for longer durations and in combination with disturbances in global cerebral physiological variables were associated with poor outcome and may indicate detrimental ischaemic hypoxia. Prospective trials are needed to determine if pbtO2-directed therapy is beneficial, at what individualised pbtO2 threshold therapies are warranted, and how this may depend on the presence/absence of concurrent cerebral physiological disturbances.

Results of Surgical Treatment of Aneurysmal Subarachnoid Hemorrhage in a Single Institution Over 12 Years.

OBJECTIVE: For patients with aneurysmal subarachnoid hemorrhage (aSAH) in whom endovascular treatment is not the optimal treatment strategy, microsurgical clipping remains a viable option. We examined changes in morbidity and outcome over time in patients treated surgically and in relation to surgeon volume and experience. METHODS: All patients who underwent microsurgery for aSAH from 2007 to 2019 at our institution were included. We compared technical complication rates and surgical outcomes between experienced (≥50 independent cases) and inexperienced (<50 independent cases) surgeons and between high-volume (≥20 cases/year) and low-volume (<20 cases/year) surgeons. RESULTS: Most of the 1,003 aneurysms (970 patients, median age 56 years) were in the middle cerebral (41.4%), anterior communicating (27.6%), and posterior communicating (17.5%) arteries; 46.5% were <7 mm. The technical complication rate was 7%, resulting in postoperative infarct in 4.9% of patients. Nineteen patients (2%) died within 30 days of admission. There were no significant changes in rates of technical complication, postoperative infarct, or mortality over the study period. There were no differences in postoperative infarction and technical complication rates between experienced and inexperienced surgeons (P = 0.28 and P = 0.05, respectively), but there were differences when comparing high-volume and low-volume surgeons (P = 0.03 and P < 0.001, respectively). The independent predictors of postoperative infarctions were aneurysm size (P = 0.001), intraoperative large-vessel injury (P < 0.001), and low surgeon volume (P = 0.03). CONCLUSIONS: We present real-world data on surgical morbidity and outcomes after aSAH. We demonstrated a relationship between surgeon volume and outcome for surgical treatment of aSAH, which supports the benefit of subspecialization in cerebrovascular surgery.

Use of a jumbo plate in dogs greater than 50 kg following tibial plateau leveling osteotomy does not prevent increase in tibial plateau angle through convalescence.

OBJECTIVE: To investigate the use of a locking 3.5/4.0-mm jumbo tibial plateau leveling osteotomy (TPLO) plate in maintaining the postoperative tibial plateau angle (TPA) in giant-breed dogs weighing > 50 kg and to report the associated complications. ANIMALS: Canine patients weighing > 50 kg that underwent TPLO stabilized with a locking 3.5/4.0-mm jumbo TPLO plate between January 2017 and May 2022. METHODS: Retrospective case series retrieving postoperative outcomes from the medical records. Healing scores and TPAs were calculated using postoperative and recheck radiographs. Owner-perceived outcomes were obtained via questionnaire. RESULTS: 24 stifles in 22 dogs were included. Postoperative complications were recorded in 11 of 24 cases (45.8%) inclusive of 1 minor, 1 catastrophic, and 9 major complications. A statistically significant increase in TPA over the convalescent period was found. Grade 4 healing was present in 18 of 24 (75%) stifles, while the remainder were scored as grade 3. CLINICAL RELEVANCE: The use of a locking 3.5/4.0-mm jumbo TPLO plate did not prevent a statistically significant increase in TPA through convalescence. This procedure displayed an unacceptably high complication rate when compared with contemporary literature of TPLO. Despite a high complication rate in this patient population, most complications were successfully managed with medical and/or surgical treatment, and high mean and median healing scores were achieved at the radiographic recheck. Additionally, owner-perceived long-term outcomes were excellent.

Supplemental findings of the 2021 National Blood Collection and Utilization Survey.

BACKGROUND: The Department of Health and Human Services' National Blood Collection and Utilization Survey (NBCUS) has been conducted biennially since 1997. Data are used to estimate national blood collection and use. Supplemental data from the 2021 NBCUS not presented elsewhere are presented here. METHODS: Data on survey participation, donor characteristics, blood component cost, transfusion-associated adverse reactions, and implementation of blood safety measures, including pathogen-reduction of platelets, during 2021, were analyzed. Comparisons are made to 2019 survey data where available (2013-2019 for survey participation). RESULTS: During 2021, there were 11,507,000 successful blood donations in the United States, a 4.8% increase from 2019. Persons aged 45-64 years accounted for 42% of all successful blood donations. Donations by persons aged 65 years and older increased by 40.7%, while donations among minorities and donors aged <25 years decreased. From 2019 to 2021, the median price hospitals paid per unit of leukoreduced red blood cells, leukoreduced and pathogen-reduced apheresis platelets, and fresh frozen plasma increased. The largest increase in price per unit of blood component in 2021 was for leukoreduced apheresis platelets, which increased by ~$51. Between 2019 and 2021, the proportion of transfusing facilities reporting use of pathogen-reduced platelets increased, from 13% to 60%. Transfusion-related adverse reactions declined slightly between 2019 and 2021, although the rate of transfusion-transmitted bacterial infections remained unchanged. CONCLUSION: During 2021, blood donations increased nationally, although donations from those aged <25 years and minorities declined. The prices hospitals paid for most blood products increased, as did the use of pathogen-reduced platelets.

Targeted Polymersome Delivery of a Stapled Peptide for Drugging the Tumor Protein p53:BCL-2-Family Axis in Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) remains a formidable diagnosis in need of new treatment paradigms. In this work, we elucidated an opportunity for therapeutic synergy in DLBCL by reactivating tumor protein p53 with a stapled peptide, ATSP-7041, thereby priming cells for apoptosis and enhancing their sensitivity to BCL-2 family modulation with a BH3-mimetic, ABT-263 (navitoclax). While this combination was highly effective at activating apoptosis in DLBCL in vitro, it was highly toxic in vivo, resulting in a prohibitively narrow therapeutic window. We, therefore, developed a targeted nanomedicine delivery platform to maintain the therapeutic potency of this combination while minimizing its toxicity via packaging and targeted delivery of a stapled peptide. We developed a CD19-targeted polymersome using block copolymers of poly(ethylene glycol) disulfide linked to poly(propylene sulfide) (PEG-SS-PPS) for ATSP-7041 delivery into DLBCL cells. Intracellular delivery was optimized in vitro and validated in vivo by using an aggressive human DLBCL xenograft model. Targeted delivery of ATSP-7041 unlocked the ability to systemically cotreat with ABT-263, resulting in delayed tumor growth, prolonged survival, and no overt toxicity. This work demonstrates a proof-of-concept for antigen-specific targeting of polymersome nanomedicines, targeted delivery of a stapled peptide in vivo, and synergistic dual intrinsic apoptotic therapy against DLBCL via direct p53 reactivation and BCL-2 family modulation.