Neurosurgical Management of Patients with Alpha-Gal Syndrome.

Alpha-gal syndrome (AGS) is an immunoglobulin E-mediated hypersensitivity to galatcose-alpha-1,3-galactose (alpha-gal), a carbohydrate compound present in nonprimate mammalian products. Initial exposure to alpha-gal most often occurs through a tick bite, most commonly the lone star tick in the United States. Repeated exposure to alpha-gal may elicit severe allergic reactions, including anaphylaxis. The allergy restricts dietary intake and may significantly impact perioperative risk, as many medications, anesthetics, and intraoperative surgical products utilize bovine or porcine-derived agents, including those containing magnesium stearate, glycerol, and gelatin. Here, we review the perineurosurgical care of two individuals with AGS and highlight pertinent clinical practices and perioperative management of these patients.

PET/CT-Based Absorbed Dose Maps in 90Y Selective Internal Radiation Therapy Correlate with Spatial Changes in Liver Function Derived from Dynamic MRI.

Functional liver parenchyma can be damaged from treatment of liver malignancies with 90Y selective internal radiation therapy (SIRT). Evaluating functional parenchymal changes and developing an absorbed dose (AD)-toxicity model can assist the clinical management of patients receiving SIRT. We aimed to determine whether there is a correlation between 90Y PET AD voxel maps and spatial changes in the nontumoral liver (NTL) function derived from dynamic gadoxetic acid-enhanced MRI before and after SIRT. Methods: Dynamic gadoxetic acid-enhanced MRI scans were acquired before and after treatment for 11 patients undergoing 90Y SIRT. Gadoxetic acid uptake rate (k1) maps that directly quantify spatial liver parenchymal function were generated from MRI data. Voxel-based AD maps, derived from the 90Y PET/CT scans, were binned according to AD. Pre- and post-SIRT k1 maps were coregistered to the AD map. Absolute and percentage k1 loss in each bin was calculated as a measure of loss of liver function, and Spearman correlation coefficients between k1 loss and AD were evaluated for each patient. Average k1 loss over the patients was fit to a 3-parameter logistic function based on AD. Patients were further stratified into subgroups based on lesion type, baseline albumin-bilirubin scores and alanine transaminase levels, dose-volume effect, and number of SIRT treatments. Results: Significant positive correlations (ρ = 0.53-0.99, P < 0.001) between both absolute and percentage k1 loss and AD were observed in most patients (8/11). The average k1 loss over 9 patients also exhibited a significant strong correlation with AD (ρ ≥ 0.92, P < 0.001). The average percentage k1 loss of patients across AD bins was 28%, with a logistic function model demonstrating about a 25% k1 loss at about 100 Gy. Analysis between patient subgroups demonstrated that k1 loss was greater among patients with hepatocellular carcinoma, higher alanine transaminase levels, larger fractional volumes of NTL receiving an AD of 70 Gy or more, and sequential SIRT treatments. Conclusion: Novel application of multimodality imaging demonstrated a correlation between 90Y SIRT AD and spatial functional liver parenchymal degradation, indicating that a higher AD is associated with a larger loss of local hepatocyte function. With the developed response models, PET-derived AD maps can potentially be used prospectively to identify localized damage in liver and to enhance treatment strategies.

Real-world comprehensive genomic and immune profiling reveals distinct age- and sex-based genomic and immune landscapes in tumors of patients with non-small cell lung cancer.

Introduction: Younger patients with non-small cell lung cancer (NSCLC) (<50 years) represent a significant patient population with distinct clinicopathological features and enriched targetable genomic alterations compared to older patients. However, previous studies of younger NSCLC suffer from inconsistent findings, few studies have incorporated sex into their analyses, and studies targeting age-related differences in the tumor immune microenvironment are lacking. Methods: We performed a retrospective analysis of 8,230 patients with NSCLC, comparing genomic alterations and immunogenic markers of younger and older patients while also considering differences between male and female patients. We defined older patients as those ≥65 years and used a 5-year sliding threshold from <45 to <65 years to define various groups of younger patients. Additionally, in an independent cohort of patients with NSCLC, we use our observations to inform testing of the combinatorial effect of age and sex on survival of patients given immunotherapy with or without chemotherapy. Results: We observed distinct genomic and immune microenvironment profiles for tumors of younger patients compared to tumors of older patients. Younger patient tumors were enriched in clinically relevant genomic alterations and had gene expression patterns indicative of reduced immune system activation, which was most evident when analyzing male patients. Further, we found younger male patients treated with immunotherapy alone had significantly worse survival compared to male patients ≥65 years, while the addition of chemotherapy reduced this disparity. Contrarily, we found younger female patients had significantly better survival compared to female patients ≥65 years when treated with immunotherapy plus chemotherapy, while treatment with immunotherapy alone resulted in similar outcomes. Discussion: These results show the value of comprehensive genomic and immune profiling (CGIP) for informing clinical treatment of younger patients with NSCLC and provides support for broader coverage of CGIP for younger patients with advanced NSCLC.

Multi-color dual wavelength vat photopolymerization 3D printing via spatially controlled acidity.

Dual wavelength vat photopolymerization (DW-VP) has emerged as a powerful approach to create multimaterial objects. However, only a limited range of properties have been showcased. In this work, we report the 3D printing (3DP) of multi-color objects from a single resin vat using DW-VP. This was accomplished by concurrently curing resin with visible light and modulating local resin color with 365-nm ultraviolet (UV) light. The key advance was to use a photoacid generator (PAG) in combination with pH responsive dyes in the 3DP resins. The specific color is dictated by the extent of reaction, or local acidity in our case, and controlled by the light dosage and pattern of UV light applied. Multi-color object formation was implemented in two-step processes involving first 3DP to set the object structure, followed by UV exposure, as well as single processes that leveraged DW-VP to create a broad range of vibrant colors and patterns.

Iterative methods for Navier-Stokes inverse problems.

Even when the partial differential equation underlying a physical process can be evolved forward in time, the retrospective (backward in time) inverse problem often has its own challenges and applications. Direct adjoint looping (DAL) is the defacto approach for solving retrospective inverse problems, but it has not been applied to deterministic retrospective Navier-Stokes inverse problems in 2D or 3D. In this paper, we demonstrate that DAL is ill-suited for solving retrospective 2D Navier-Stokes inverse problems. Alongside DAL, we study two other iterative methods: simple backward integration (SBI) and the quasireversible method (QRM). As far as we know, our iterative SBI approach is novel, while iterative QRM has previously been used. Using these three iterative methods, we solve two retrospective inverse problems: 1D Korteweg-de Vries-Burgers (decaying nonlinear wave) and 2D Navier-Stokes (unstratified Kelvin-Helmholtz vortex). In both cases, SBI and QRM reproduce the target final states more accurately and in fewer iterations than DAL. We attribute this performance gap to additional terms present in SBI and QRM's respective backward integrations which are absent in DAL.

Intricacies of Human-AI Interaction in Dynamic Decision-Making for Precision Oncology: A Case Study in Response-Adaptive Radiotherapy.

Background: Adaptive treatment strategies that can dynamically react to individual cancer progression can provide effective personalized care. Longitudinal multi-omics information, paired with an artificially intelligent clinical decision support system (AI-CDSS) can assist clinicians in determining optimal therapeutic options and treatment adaptations. However, AI-CDSS is not perfectly accurate, as such, clinicians' over/under reliance on AI may lead to unintended consequences, ultimately failing to develop optimal strategies. To investigate such collaborative decision-making process, we conducted a Human-AI interaction case study on response-adaptive radiotherapy (RT). Methods: We designed and conducted a two-phase study for two disease sites and two treatment modalities-adaptive RT for non-small cell lung cancer (NSCLC) and adaptive stereotactic body RT for hepatocellular carcinoma (HCC)-in which clinicians were asked to consider mid-treatment modification of the dose per fraction for a number of retrospective cancer patients without AI-support (Unassisted Phase) and with AI-assistance (AI-assisted Phase). The AI-CDSS graphically presented trade-offs in tumor control and the likelihood of toxicity to organs at risk, provided an optimal recommendation, and associated model uncertainties. In addition, we asked for clinicians' decision confidence level and trust level in individual AI recommendations and encouraged them to provide written remarks. We enrolled 13 evaluators (radiation oncology physicians and residents) from two medical institutions located in two different states, out of which, 4 evaluators volunteered in both NSCLC and HCC studies, resulting in a total of 17 completed evaluations (9 NSCLC, and 8 HCC). To limit the evaluation time to under an hour, we selected 8 treated patients for NSCLC and 9 for HCC, resulting in a total of 144 sets of evaluations (72 from NSCLC and 72 from HCC). Evaluation for each patient consisted of 8 required inputs and 2 optional remarks, resulting in up to a total of 1440 data points. Results: AI-assistance did not homogeneously influence all experts and clinical decisions. From NSCLC cohort, 41 (57%) decisions and from HCC cohort, 34 (47%) decisions were adjusted after AI assistance. Two evaluations (12%) from the NSCLC cohort had zero decision adjustments, while the remaining 15 (88%) evaluations resulted in at least two decision adjustments. Decision adjustment level positively correlated with dissimilarity in decision-making with AI [NSCLC: ρ = 0.53 ( p < 0.001); HCC: ρ = 0.60 ( p < 0.001)] indicating that evaluators adjusted their decision closer towards AI recommendation. Agreement with AI-recommendation positively correlated with AI Trust Level [NSCLC: ρ = 0.59 ( p < 0.001); HCC: ρ = 0.7 ( p < 0.001)] indicating that evaluators followed AI's recommendation if they agreed with that recommendation. The correlation between decision confidence changes and decision adjustment level showed an opposite trend [NSCLC: ρ = -0.24 ( p = 0.045), HCC: ρ = 0.28 ( p = 0.017)] reflecting the difference in behavior due to underlying differences in disease type and treatment modality. Decision confidence positively correlated with the closeness of decisions to the standard of care (NSCLC: 2 Gy/fx; HCC: 10 Gy/fx) indicating that evaluators were generally more confident in prescribing dose fractionations more similar to those used in standard clinical practice. Inter-evaluator agreement increased with AI-assistance indicating that AI-assistance can decrease inter-physician variability. The majority of decisions were adjusted to achieve higher tumor control in NSCLC and lower normal tissue complications in HCC. Analysis of evaluators' remarks indicated concerns for organs at risk and RT outcome estimates as important decision-making factors. Conclusions: Human-AI interaction depends on the complex interrelationship between expert's prior knowledge and preferences, patient's state, disease site, treatment modality, model transparency, and AI's learned behavior and biases. The collaborative decision-making process can be summarized as follows: (i) some clinicians may not believe in an AI system, completely disregarding its recommendation, (ii) some clinicians may believe in the AI system but will critically analyze its recommendations on a case-by-case basis; (iii) when a clinician finds that the AI recommendation indicates the possibility for better outcomes they will adjust their decisions accordingly; and (iv) When a clinician finds that the AI recommendation indicate a worse possible outcome they will disregard it and seek their own alternative approach.

Immunologic Factors Associated with Differential Response to Neoadjuvant Chemoimmunotherapy in Triple-Negative Breast Cancer.

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors.

Sexual Activity in Adults with Pediatric-Onset Spinal Cord Injury: Injury, Demographic, and Lifestyle Factors.

Background: Sexual development is a complex process of understanding oneself as a sexual being. Youth with spinal cord injury (SCI) navigate the typical phases of sexual development along with the physical and psychological sequelae of an SCI. As youth with SCI progress from adolescence to emerging adulthood, sexual activity-physical intimacy and sexual intercourse-is an important milestone. Objectives: The aims of the study were to (1) describe frequency of physical intimacy among adults with pediatric-onset SCI and (2) identify injury, demographic, and lifestyle factors that predict frequency of physical intimacy. Methods: Adults with pediatric-onset SCI who were former patients within a North American pediatric hospital system (N = 277) completed a structured telephone interview that included medical and sociodemographic information and standardized measures of psychological functioning. Participants rated physical intimacy and sexual intercourse frequency on a 5-point Likert scale, with a response of monthly, weekly, or daily classified as regular frequency and never or yearly as irregular frequency. Bivariate and multivariate analyses were conducted with physical intimacy frequency as the primary outcome. Results: Of the participants, 55% engaged in physical intimacy and 49% engaged in sexual intercourse with regular frequency. In logistic regression analyses, living independently of parents, being married, and higher perceived social integration increased likelihood of regular frequency of physical intimacy. Injury severity and secondary medical complications were not significant independent predictors of frequency of physical intimacy. Conclusion: Half of adults with pediatric-onset SCI engage in regular physical intimacy; this is below the estimates for the general population. Psychosocial factors are stronger contributors to physical intimacy frequency than SCI-related factors. Health care providers and researchers should focus on barriers to social integration and development of social relationships as factors that influence physical intimacy in this population.

Excitation of optically trapped single particles using femtosecond pulses.

Excitation from optically trapped particles is examined through laser-induced breakdown spectroscopy following interactions with mJ-level fs pulses. Optical emissions from sub-ng ablation of precisely positioned cupric oxide microparticles are used as a method to spatially resolve laser-particle interactions resulting in excitation. External focusing lenses are often used to change the dynamics of nonlinear self-focusing of fs pulses to form laser filaments or, alternatively, to form very intense air plasmas. Given the significant implications external focusing has on laser propagation and plasma conditions, single-particle emissions are studied with focusing lenses ranging from 50 to 300 mm. It is shown that, while single particles are less excited at longer focal lengths due to limited energy transfer through laser-particle interactions, the cooler plasma results in a lower thermal background to reveal resolved single-shot emission peaks. By developing an understanding in the fundamental interaction that occurs between single particles and fs pulses and filaments, practical improvements can be made for atmospheric remote sensing of low-concentration aerosols.

Reducing False-Positives Due to Urinary Stagnation in the Prostatic Urethra on 18 F-DCFPyL PSMA PET/CT With MRI.

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeting PET radiotracers reveal physiologic uptake in the urinary system, potentially misrepresenting activity in the prostatic urethra as an intraprostatic lesion. This study examined the correlation between midline 18 F-DCFPyL activity in the prostate and hyperintensity on T2-weighted (T2W) MRI as an indication of retained urine in the prostatic urethra. PATIENTS AND METHODS: Eighty-five patients who underwent both 18 F-DCFPyL PSMA PET/CT and prostate MRI between July 2017 and September 2023 were retrospectively analyzed for midline radiotracer activity and retained urine on postvoid T2W MRIs. Fisher's exact tests and unpaired t tests were used to compare residual urine presence and prostatic urethra measurements between patients with and without midline radiotracer activity. The influence of anatomical factors including prostate volume and urethral curvature on urinary stagnation was also explored. RESULTS: Midline activity on PSMA PET imaging was seen in 14 patients included in the case group, whereas the remaining 71 with no midline activity constituted the control group. A total of 71.4% (10/14) and 29.6% (21/71) of patients in the case and control groups had urethral hyperintensity on T2W MRI, respectively ( P < 0.01). Patients in the case group had significantly larger mean urethral dimensions, larger prostate volumes, and higher incidence of severe urethral curvature compared with the controls. CONCLUSIONS: Stagnated urine within the prostatic urethra is a potential confounding factor on PSMA PET scans. Integrating PET imaging with T2W MRI can mitigate false-positive calls, especially as PSMA PET/CT continues to gain traction in diagnosing localized prostate cancer.

Evaluation of Oral Amoxicillin/Clavulanate for Urinary Tract Infections Caused by Ceftriaxone Non-Susceptible Enterobacterales.

Urinary tract infections (UTIs) are one of the most common infections and are frequently caused by Gram-negative organisms. The rise of resistant isolates has prompted evaluation of alternative therapies, including amoxicillin-clavulanate which has potent activity against Ambler class A enzymes. This study sought to evaluate clinical outcomes of patients with ceftriaxone non-susceptible UTIs receiving amoxicillin-clavulanate or standard of care (SOC). This was a single-center, retrospective, cohort study of adult patients with urinary tract infections caused by a ceftriaxone non-susceptible pathogen who received amoxicillin-clavulanate or SOC. The primary outcome was clinical failure at 90 days. Secondary outcomes included time to failure, isolation of a resistant organism, and hospital length of stay. Fifty-nine patients met study inclusion: 26 received amoxicillin/clavulanate and 33 received SOC. Amoxicillin-clavulanate recipients did not have higher failure rates compared to SOC recipients. For patients requiring hospital admission, hospital length of stay was numerically shorter with amoxicillin-clavulanate. The frequency of amoxicillin-clavulanate and carbapenem-resistant organisms did not differ significantly between groups. Amoxicillin-clavulanate may be a useful alternative therapy for the treatment of ceftriaxone non-susceptible Enterobacterales UTIs.

How a positive fluid balance develops in acute kidney injury: A binational, observational study.

PURPOSE: A positive fluid balance (FB) is associated with harm in intensive care unit (ICU) patients with acute kidney injury (AKI). We aimed to understand how a positive balance develops in such patients. METHODS: Multinational, retrospective cohort study of critically ill patients with AKI not requiring renal replacement therapy. RESULTS: AKI occurred at a median of two days after admission in 7894 (17.3%) patients. Cumulative FB became progressively positive, peaking on day three despite only 848 (10.7%) patients receiving fluid resuscitation in the ICU. In those three days, persistent crystalloid use (median:60.0 mL/h; IQR 28.9-89.2), nutritional intake (median:18.2 mL/h; IQR 0.0-45.9) and limited urine output (UO) (median:70.8 mL/h; IQR 49.0-96.7) contributed to a positive FB. Although UO increased each day, it failed to match input, with only 797 (10.1%) patients receiving diuretics in ICU. After adjustment, a positive FB four days after AKI diagnosis was associated with an increased risk of hospital mortality (OR 1.12;95% confidence intervals 1.05-1.19;p-value <0.001). CONCLUSION: Among ICU patients with AKI, cumulative FB increased after diagnosis and was associated with an increased risk of mortality. Continued crystalloid administration, increased nutritional intake, limited UO, and minimal use of diuretics all contributed to positive FB. KEY POINTS: Question How does a positive fluid balance develop in critically ill patients with acute kidney injury? Findings Cumulative FB increased after AKI diagnosis and was secondary to persistent crystalloid fluid administration, increasing nutritional fluid intake, and insufficient urine output. Despite the absence of resuscitation fluid and an increasing cumulative FB, there was persistently low diuretics use, ongoing crystalloid use, and a progressive escalation of nutritional fluid therapy. Meaning Current management results in fluid accumulation after diagnosis of AKI, as a result of ongoing crystalloid administration, increasing nutritional fluid, limited urine output and minimal diuretic use.

Improved optic nerve visualization and treatment planning through a dedicated optic nerve MRI protocol.

OBJECTIVE: This study describes an innovative optic nerve MRI protocol for better delineating optic nerve anatomy from neighboring pathology. METHODS: Twenty-two patients undergoing MRI examination of the optic nerve with the dedicated protocol were identified and included for analysis of imaging, surgical strategy, and outcomes. T2-weighted and fat-suppressed T1-weighted gadolinium-enhanced images were acquired perpendicular and parallel to the long axis of the optic nerve to achieve en face and in-line views along the course of the nerve. RESULTS: Dedicated optic nerve MRI sequences provided enhanced visualization of the nerve, CSF within the nerve sheath, and local pathology. Optic nerve sequences leveraged the "CSF ring" within the optic nerve sheath to create contrast between pathology and normal tissue, highlighting areas of compression. Tumor was readily tracked along the longitudinal axis of the nerve by images obtained parallel to the nerve. The findings augmented treatment planning. CONCLUSIONS: The authors present a dedicated optic nerve MRI protocol that is simple to use and affords improved cross-sectional and longitudinal visualization of the nerve, surrounding CSF, and pathology. This improved visualization enhances radiological evaluation and treatment planning for optic nerve lesions.

Endoscopic precaruncular medial transorbital and endonasal multiport approaches to the contralateral skull base: a clinicoanatomical study.

OBJECTIVE: Minimally invasive endoscopic endonasal multiport approaches create additional visualization angles to treat skull base pathologies. The sublabial contralateral transmaxillary (CTM) approach and superior eyelid lateral transorbital approach, frequently used nowadays, have been referred to as the "third port" when used alongside the endoscopic endonasal approach (EEA). The endoscopic precaruncular contralateral medial transorbital (cMTO) corridor, on the other hand, is an underrecognized but unique port that has been used to repair CSF rhinorrhea originating from the lateral sphenoid sinus recess. However, no anatomical feasibility studies or clinical experience exists to assess its benefits and demonstrate its potential role in multiport endoscopic access to the other contralateral skull base areas. In this study, the authors explored the application and potential utility of multiport EEA combined with the endoscopic cMTO approach (EEA/cMTO) to three target areas of the contralateral skull base: lateral recess of sphenoid sinus (LRSS), petrous apex (PA) and petroclival region, and retrocarotid clinoidocavernous space (CCS). METHODS: Ten cadaveric specimens (20 sides) were dissected bilaterally under stereotactic navigation guidance to access contralateral LRSS via EEA/cMTO. The PA and petroclival region and retrocarotid CCS were exposed via EEA alone, EEA/cMTO, and EEA combined with the sublabial CTM approach (EEA/CTM). Qualitative and quantitative assessments, including working distance and visualization angle to the PA, were recorded. Clinical application of EEA/cMTO is demonstrated in a lateral sphenoid sinus CSF leak repair. RESULTS: During the qualitative assessment, multiport EEA/cMTO provides superior visualization from a high vantage point and better instrument maneuverability than multiport EEA/CTM for the PA and retrocarotid CCS, while maintaining a similar lateral trajectory. The cMTO approach has significantly shorter working distances to all three target areas compared with the CTM approach and EEA. The mean distances to the LRSS, PA, and retrocarotid CCS were 50.69 ± 4.28 mm (p < 0.05), 67.11 ± 5.05 mm (p < 0.001), and 50.32 ± 3.6 mm (p < 0.001), respectively. The mean visualization angles to the PA obtained by multiport EEA/cMTO and EEA/CTM were 28.4° ± 3.27° and 24.42° ± 5.02° (p < 0.005), respectively. CONCLUSIONS: Multiport EEA/cMTO to the contralateral LRSS offers the advantage of preserving the pterygopalatine fossa contents and the vidian nerve, which are frequently sacrificed during a transpterygoid approach. This approach also offers superior visualization and better instrument maneuverability compared with EEA/CTM for targeting the petroclival region and retrocarotid CCS.

Last Glacial Maximum pattern effects reduce climate sensitivity estimates.

Here, we show that the Last Glacial Maximum (LGM) provides a stronger constraint on equilibrium climate sensitivity (ECS), the global warming from increasing greenhouse gases, after accounting for temperature patterns. Feedbacks governing ECS depend on spatial patterns of surface temperature ("pattern effects"); hence, using the LGM to constrain future warming requires quantifying how temperature patterns produce different feedbacks during LGM cooling versus modern-day warming. Combining data assimilation reconstructions with atmospheric models, we show that the climate is more sensitive to LGM forcing because ice sheets amplify extratropical cooling where feedbacks are destabilizing. Accounting for LGM pattern effects yields a median modern-day ECS of 2.4°C, 66% range 1.7° to 3.5°C (1.4° to 5.0°C, 5 to 95%), from LGM evidence alone. Combining the LGM with other lines of evidence, the best estimate becomes 2.9°C, 66% range 2.4° to 3.5°C (2.1° to 4.1°C, 5 to 95%), substantially narrowing uncertainty compared to recent assessments.