Occipital condyle fracture in the pediatric population: A management algorithm and systematic review.

Purpose: This study aims to develop an accessible stepwise management algorithm for pediatric presentations of occipital condyle fractures (OCFs) based on a systematic review of the published literature regarding diagnostic evaluation, treatment, and outcomes. Methods: A systematic review of the literature was conducted on PubMed to locate English language studies reporting on the management of pediatric OCFs. Data extraction of clinical presentation, management strategies, imaging, and treatment outcome was performed. Results: A total of 15 studies reporting on 38 patients aged 18 years and younger presenting with OCFs were identified. Loss of consciousness (LOC), depressed level of consciousness, neck pain, decreased neck range of motion (ROM), and cranial nerve injury were the most common presenting symptoms. Diagnostic imaging included radiographs, computed tomography (CT) scans, magnetic resonance imaging (MRI), and functional radiographs to assess cervical stability. Treatment options varied and included soft collar, hard collar, and halo vest. All studies resulted in a complete healing of the OCF, with resolution of associated pain. Conclusion: The proposed treatment algorithm suggests a framework for the management of pediatric OCFs based on the available evidence (levels of evidence: 3, 4). This review of the literature indicated that a stepwise approach should be utilized in the management of isolated pediatric OCFs.

Clinical utility of C-reactive protein-to-albumin ratio in the management of patients with inflammatory bowel disease.

Background and Aim: C-reactive protein (CRP)-to-albumin ratio (CAR) is a novel score with prognostic value in inflammatory conditions. This study assessed the performance of CAR as an objective marker of disease activity and prediction of subtherapeutic infliximab trough levels in patients with inflammatory bowel disease (IBD). Methods: A retrospective study was conducted on three different patient cohorts with IBD: patients who had (i) fecal calprotectin (FC) measurements; (ii) Mayo Endoscopic Scores; and (iii) infliximab trough levels available. The relative performances of CAR, albumin, and CRP were compared in predicting disease activity (based on FC or Mayo Endoscopic Score) and infliximab trough levels. Results: In both the FC (n = 289) and endoscopy (n = 65) cohorts, albumin and CAR correlated with objective disease activity. CAR (area under the curve [AUC] 0.70) was only marginally better at detecting active disease, measured by FC, compared to CRP (AUC 0.68). A CAR >0.15 was able to detect Mayo 3 disease (AUC 0.83, sensitivity 81%, specificity 89%). Albumin (r = 0.38) and CAR (r = -0.42) correlated with infliximab trough levels (n = 204). The optimal CAR for detecting subtherapeutic infliximab trough levels was >0.08 (AUC 0.70, sensitivity 66%, specificity 64%). Both albumin and CAR were independent predictors of subtherapeutic infliximab trough levels but correlated poorly with infliximab trough levels longitudinally in the same patient. Conclusion: CAR was only a modest discriminator of subtherapeutic infliximab levels and offers little more than CRP in detecting active disease. CAR has potential to detect severe Mayo 3 disease and could be calculated in patients admitted with suspected acute severe ulcerative colitis.

Discontinuation of medication treatment for opioid use disorder after a successful course: The discontinuation phase of the CTN-0100 (RDD) trial.

INTRODUCTION AND BACKGROUND: Buprenorphine, and extended-release naltrexone, are effective in decreasing opioid use, morbidity and mortality. The available evidence suggests that these medications should be used for long term treatment; however, patients often ask how long they need to be on medication, and whether it would be safe to discontinue. There are sparse data to guide us. The CTN-0100 trial will address this gap in our knowledge by studying participants who have decided to discontinue buprenorphine and extended-release naltrexone for OUD. RESEARCH DESIGN AND METHODS: The trial is a multicenter, randomized, non-blinded study. Participants are stable adult volunteers, on sublingual buprenorphine, extended-release buprenorphine, or extended-release naltrexone, expressing an interest in discontinuing medication. Participants on buprenorphine must be stable for at least 1 year and participants on extended-release naltrexone must be stable for at least 6 months. Participants are engaged in the study for up to 96 weeks, including a flexible taper period, and are then transitioned to follow-up within the trial. All participants are randomly assigned to the study Medical Management (MM) or to MM plus Connections (CHESS health) digital smartphone application aimed at recovery and abstinence (MMD). Sublingual Buprenorphine participants are also randomized (2 × 2 design) to a taper using either sublingual or extended-release buprenorphine. DISCUSSION/CONCLUSION: It is hoped that this trial will provide a rich source of data on management of patients discontinuing medication for opioid use disorder (MOUD) to inform future research and practice. The trial will shed light on which strategies are most likely to lead to long-term success (absence of relapse), and what participant characteristics distinguish those who can safely discontinue MOUD from those who remain at risk of relapse should they discontinue. CLINICALTRIALS: gov Identifier: NCT04464980.

Branched chemically modified poly(A) tails enhance the translation capacity of mRNA.

Although messenger RNA (mRNA) has proved effective as a vaccine, its potential as a general therapeutic modality is limited by its instability and low translation capacity. To increase the duration and level of protein expression from mRNA, we designed and synthesized topologically and chemically modified mRNAs with multiple synthetic poly(A) tails. Here we demonstrate that the optimized multitailed mRNA yielded ~4.7-19.5-fold higher luminescence signals than the control mRNA from 24 to 72 h post transfection in cellulo and 14 days detectable signal versus <7 days signal from the control in vivo. We further achieve efficient multiplexed genome editing of the clinically relevant genes Pcsk9 and Angptl3 in mouse liver at a minimal mRNA dosage. Taken together, these results provide a generalizable approach to synthesize capped branched mRNA with markedly enhanced translation capacity.

Early Results With the New Active Bone-Conduction Hearing Implant: A Systematic Review and Meta-Analysis.

OBJECTIVE: The bone conduction implant (BCI) 602 is a new transcutaneous BCI with smaller dimensions. However, limited patient numbers restrict the statistical power and generalizability of the current studies. The present systematic review and meta-analysis summarize early audiological and medical outcomes of adult and pediatric patients implanted with the BCI 602 due to mixed or conductive hearing loss. DATA SOURCE: Following the Preferred Reporting items for Systematic Reviews and Meta-analyses guidelines, 108 studies were reviewed, and 6 (5.6%) were included in the meta-analysis. REVIEW METHOD: The data on study and patient characteristics, surgical outcomes, and audiological test results were extracted from each article. Meta-analysis employed the fixed-effect and random-effects models to analyze the mean differences (MDs) between pre- and postoperative performances. RESULTS: In total, 116 patients were evaluated, including 64 (55%) adult and 52 (45%) pediatric patients. No intraoperative adverse events were reported, while postoperative complications were reported in 2 (3.1%) adult and 2 (3.8%) pediatric patients. Studies consistently showed significant improvements in audiological outcomes, quality of life, and sound localization in the aided condition. In the meta-analysis, we observed a significant difference in the unaided compared to the aided condition in sound field thresholds (n = 112; MD, -27.05 dB; P < 0.01), signal-to-noise ratio (n = 96; MD, -6.35 dB; P < 0.01), and word recognition scores (n = 96; MD, 68.89%; P < 0.01). CONCLUSION: The implantation of the BCI 602 was associated with minimal surgical complications and excellent audiological outcomes for both the pediatric and the adult cohort. Therefore, our analysis indicates a high level of safety and reliability. Further research should focus on direct comparisons with other BCIs and long-term functional outcomes.

Telehealth Potential in Pediatric Orthopaedics and Sports Medicine Care is Comparable to In-Person Care But Disparities Remain.

BACKGROUND: Understanding the challenges and potential of telehealth visits (THVs) in a large population can inform future practice and policy discussion for pediatric orthopaedic and sports medicine (OSM) care. We comprehensively assess telehealth challenges and potential in a large pediatric OSM population based on access, visit completion, patient satisfaction, and technological challenges. METHODS: Demographics, address, insurance, visit information, patient feedback, experience with video visits, and technical challenges of all 2019 to 2020 visits at our hospital were assessed (3,278,006 visits). We evaluated the differences in rate of telehealth utilization, rate of patient adherence, disparities in care access and patient satisfaction, and technological issues. RESULTS: Compared with in-person prepandemic visits, THVs had lower ratios of non-White patients (by 5.8%; P<0.001), Hispanic patients (by 2.8%; P<0.001) and patients with public insurance (by 1.8%; P<0.001), and a higher mean distance between the patient's residence and clinic (by 18.8 miles; P<0.001). There were minimal differences in median household income (average $2297 less in THV; P<0.001) and social vulnerability index (average 0.01 points lower in THV; P<0.001) between groups. THVs had comparable patient satisfaction to in-person visits. Non-White patients, Hispanics, and those with public insurance had lower ratings for both in-person visits and THVs and had more technical difficulties during their THV. CONCLUSIONS: Telehealth is a viable method of care for a range of pediatric OSM conditions, providing a similar quality of care as in-person visits with a greater geographic reach. However, in its current format, reduced disparities were not observed in pediatric OSM THVs. LEVEL OF EVIDENCE: Level III.

EvoAI enables extreme compression and reconstruction of the protein sequence space.

Designing proteins with improved functions requires a deep understanding of how sequence and function are related, a vast space that is hard to explore. The ability to efficiently compress this space by identifying functionally important features is extremely valuable. Here, we first establish a method called EvoScan to comprehensively segment and scan the high-fitness sequence space to obtain anchor points that capture its essential features, especially in high dimensions. Our approach is compatible with any biomolecular function that can be coupled to a transcriptional output. We then develop deep learning and large language models to accurately reconstruct the space from these anchors, allowing computational prediction of novel, highly fit sequences without prior homology-derived or structural information. We apply this hybrid experimental-computational method, which we call EvoAI, to a repressor protein and find that only 82 anchors are sufficient to compress the high-fitness sequence space with a compression ratio of 1048. The extreme compressibility of the space informs both applied biomolecular design and understanding of natural evolution.

Comparative effectiveness of stereotactic, subdural, or hybrid intracranial EEG monitoring in epilepsy surgery.

OBJECTIVE: Surgical intervention can be curative or palliative for drug-resistant focal epilepsy. However, if the seizure onset zone (SOZ) cannot be adequately localized via noninvasive tests, intracranial EEG (iEEG) recordings are often carried out to develop surgical plans in appropriate candidates. Stereotactic EEG (SEEG), subdural EEG (SDE), and SDE with depth electrodes (hybrid) are major tools used for investigation, but there is no class 1 or 2 evidence comparing the effectiveness of these modalities. METHODS: The authors identified an institutional cohort of patients who underwent iEEG monitoring between 2001 and 2022. Demographic data, preoperative clinical features, iEEG intervention, and follow-up data were identified. Primary study endpoints included the following: 1) likelihood of SOZ localization; 2) likelihood of surgical treatment after iEEG; 3) seizure outcomes; and 4) complications. RESULTS: A total of 329 patients were identified (176 in the SEEG, 60 in the SDE, and 93 in the hybrid cohort) who were followed for a median of 5.4 (IQR 6.8) years. Baseline characteristics, including demographics, mean age at epilepsy diagnosis, mean age at iEEG investigation, number of preoperative antiseizure medications, and preoperative seizure frequency, were not statistically different across the 3 cohorts. Patients in the SEEG cohort were more likely to have their SOZ localized than were the patients in the SDE group (OR 2.3) and were less likely to undergo subsequent resection (OR 0.3) or to have complications (OR 0.4), although there was no statistical difference with respect to likelihood of undergoing any subsequent neurosurgical treatment, or with respect to favorable seizure outcomes. Patients in the hybrid cohort were more likely to have SOZ localized than were patients in the SDE group (OR 3.1), but were more likely to undergo resection (OR 4.9) or any neurosurgical treatment (OR 2.5) compared to patients in the SEEG group. Patients in the hybrid cohort had better seizure outcomes compared to the SDE (OR 2.3) but not to the SEEG group. CONCLUSIONS: Patients in the SEEG group were more likely to have their SOZ localized and patients in the SDE group were more likely to undergo resection, but they did not differ with respect to seizure outcomes.

Continuous evolution of compact protein degradation tags regulated by selective molecular glues.

Conditional protein degradation tags (degrons) are usually >100 amino acids long or are triggered by small molecules with substantial off-target effects, thwarting their use as specific modulators of endogenous protein levels. We developed a phage-assisted continuous evolution platform for molecular glue complexes (MG-PACE) and evolved a 36-amino acid zinc finger (ZF) degron (SD40) that binds the ubiquitin ligase substrate receptor cereblon in complex with PT-179, an orthogonal thalidomide derivative. Endogenous proteins tagged in-frame with SD40 using prime editing are degraded by otherwise inert PT-179. Cryo-electron microscopy structures of SD40 in complex with ligand-bound cereblon revealed mechanistic insights into the molecular basis of SD40's activity and specificity. Our efforts establish a system for continuous evolution of molecular glue complexes and provide ZF tags that overcome shortcomings associated with existing degrons.

Peritoneal Tumor DNA as a Prognostic Biomarker in Gastric Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Gastric cancers commonly spread to the peritoneum. Its presence significantly alters patient prognosis and treatment-intent; however, current methods of peritoneal staging are inaccurate. Peritoneal tumor DNA (ptDNA) is tumor-derived DNA detectable in peritoneal lavage fluid. ptDNA positivity may indicate peritoneal micrometastasis and may be more sensitive than cytology in staging the peritoneum. In this meta-analysis, we evaluated the prognostic potential of ptDNA in gastric cancer. METHODS: PubMed, Embase, Scopus, and Web of Science databases were searched using PRISMA guidelines. Studies published between January 1, 1990, and April 30, 2023, containing quantitative data relating to ptDNA in gastric cancer were meta-analyzed. RESULTS: Six studies were analyzed. Of the total 757 patients with gastric adenocarcinoma, 318 (42.0%) were stage I, 311 (41.0%) were stage II/III, 116 (15.3%) were stage IV, and 22 (2.9%) were undetermined. Overall, ptDNA detected cytology-positive cases with a sensitivity and specificity of 85.2% (95% CI, 66.5 to 100.0) and 91.5% (95% CI, 86.5 to 96.6), respectively. Additionally, ptDNA was detected in 54 (8.5%) of 634 cytology-negative patients. The presence of ptDNA negatively correlated with pathological stage I (relative risk [RR], 0.29 [95% CI, 0.13 to 0.66]) and positively correlated with pathological stage IV (RR, 8.61 [95% CI, 1.86 to 39.89]) disease. Importantly, ptDNA positivity predicted an increased risk of peritoneal-specific metastasis (RR, 13.81 [95% CI, 8.11 to 23.53]) and reduced 3-year progression-free (RR, 5.37 [95% CI, 1.39 to 20.74]) and overall (hazard ratio, 4.13 [95% CI, 1.51 to 11.32]) survival. CONCLUSION: ptDNA carries valuable prognostic information and can detect peritoneal micrometastases in patients with gastric cancer. Its clinical utility in peritoneal staging for gastric cancer deserves further investigation.

High-throughput evaluation of genetic variants with prime editing sensor libraries.

Tumor genomes often harbor a complex spectrum of single nucleotide alterations and chromosomal rearrangements that can perturb protein function. Prime editing has been applied to install and evaluate genetic variants, but previous approaches have been limited by the variable efficiency of prime editing guide RNAs. Here we present a high-throughput prime editing sensor strategy that couples prime editing guide RNAs with synthetic versions of their cognate target sites to quantitatively assess the functional impact of endogenous genetic variants. We screen over 1,000 endogenous cancer-associated variants of TP53-the most frequently mutated gene in cancer-to identify alleles that impact p53 function in mechanistically diverse ways. We find that certain endogenous TP53 variants, particularly those in the p53 oligomerization domain, display opposite phenotypes in exogenous overexpression systems. Our results emphasize the physiological importance of gene dosage in shaping native protein stoichiometry and protein-protein interactions, and establish a framework for studying genetic variants in their endogenous sequence context at scale.

Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference.

TadA-derived cytosine base editors (TadCBEs) enable programmable C•G-to-T•A editing while retaining the small size, high on-target activity, and low off-target activity of TadA deaminases. Existing TadCBEs, however, exhibit residual A•T-to-G•C editing at certain positions and lower editing efficiencies at some sequence contexts and with non-SpCas9 targeting domains. To address these limitations, we use phage-assisted evolution to evolve CBE6s from a TadA-mediated dual cytosine and adenine base editor, discovering mutations at N46 and Y73 in TadA that prevent A•T-to-G•C editing and improve C•G-to-T•A editing with expanded sequence-context compatibility, respectively. In E. coli, CBE6 variants offer high C•G-to-T•A editing and no detected A•T-to-G•C editing in any sequence context. In human cells, CBE6 variants exhibit broad Cas domain compatibility and retain low off-target editing despite exceeding BE4max and previous TadCBEs in on-target editing efficiency. Finally, we show that the high selectivity of CBE6 variants is well-suited for therapeutically relevant stop codon installation without creating unwanted missense mutations from residual A•T-to-G•C editing.

Vagal sparing gastrectomy: A systematic review and meta-analysis.

Radical gastrectomy is associated with significant functional complications. In appropriate patients may be amenable to less invasive resection aimed at preserving the vagal trunks. The aim of this systematic review and meta-analysis is to assess the functional consequences and oncological safety of vagal sparing gastrectomy (VSG) compared to conventional non-vagal sparing gastrectomy (CG). A systematic review of four databases was undertaken for studies published between 1/11990 and 15/122021, comparing patients who underwent VSG to CG. We meta-analysed the following outcomes: operative time, blood loss, nodal yield, days to flatus, body weight changes, as well as the incidence of post-operative cholelithiasis, diarrhoea, delayed gastric emptying, and dumping syndrome. Thirty studies were included in the meta-analysis with a selection of studies qualitatively analysed. VSG was associated with a lower rate of cholelithiasis (OR 0.25, 95% CI 0.15-0.41, p<0.010) and early dumping syndrome (OR 0.42, 95% CI 0.21 - 0.86; p=0.02), less blood loss (MD -51 ml, 95% CI -89.11 to -12.81 ml, p=0.009), less long term weight loss (MD 2.03%, 95% CI 0.31-3.76%, p=0.02) and a faster time to flatus (MD -0.42 days, 95% CI -0.48 - 0.36, p<0.001). There was no significant difference in nodal harvest, overall survival, and all other endpoints. VSG significantly reduces the incidence of post-operative cholelithiasis and dumping syndrome, decreases weight loss and facilitates an earlier return of gut motility. Although technically more challenging, VSG should be considered for prophylactic surgery.

A Novel Design-Thinking, Hospital Innovation Core Certificate Curriculum for Radiologists and Trainees: Creation, Implementation, and Multiyear Results.

RATIONALE AND OBJECTIVES: Innovation is a crucial skill for physicians and researchers, yet traditional medical education does not provide instruction or experience to cultivate an innovative mindset. This study evaluates the effectiveness of a novel course implemented in an academic radiology department training program over a 5-year period designed to educate future radiologists on the fundamentals of medical innovation. MATERIALS AND METHODS: A pre- and post-course survey and examination were administered to residents who participated in the innovation course (MESH Core) from 2018 to 2022. Respondents were first evaluated on their subjective comfort level, understanding, and beliefs on innovation-related topics using a 5-point Likert-scale survey. Respondents were also administered a 21-question multiple-choice exam to test their objective knowledge of innovation-related topics. RESULTS: Thirty-eight residents participated in the survey (response rate 95%). Resident understanding, comfort and belief regarding innovation-related topics improved significantly (P < .0001) on all nine Likert-scale questions after the course. After the course, a significant majority of residents either agreed or strongly agreed that technological innovation should be a core competency for the residency curriculum, and that a workshop to prototype their ideas would be beneficial. Performance on the course exam showed significant improvement (48% vs 86%, P < .0001). The overall course experience was rated 5 out of 5 by all participants. CONCLUSION: MESH Core demonstrates long-term success in educating future radiologists on the basic concepts of medical technological innovation. Years later, residents used the knowledge and experience gained from MESH Core to successfully pursue their own inventions and innovative projects. This innovation model may serve as an approach for other institutions to implement training in this domain.

Association between polyunsaturated fatty acids in adipose tissue and mortality of colorectal cancer patients.

INTRODUCTION: Nutritional intake and dysregulation of fatty acid metabolism play a role in the progression of various tumors, but the consumption of fatty acids is difficult to assess accurately with dietary questionnaires. Biomarkers can objectively assess intake, storage and bioavailability. OBJECTIVE: We studied the association between the polyunsaturated fatty acid (PUFA) composition of abdominal subcutaneous adipose tissue (good indicator of dietary intake over 2-3 years) and all-cause mortality. METHODS: In the multicenter AGARIC study, samples from 203 patients with colorectal cancer (CRC) undergoing curative surgery, were harvested from subcutaneous adipose tissue, which were then analyzed for PUFA composition. RESULTS: After a median follow-up of 45 months, 76 patients died. These patients were more often men (72.4% versus 57.5%, P = 0.04), diabetic (32.9% versus 13.4%, P = 0.001), old (median: 74.5 versus 66.6 years, P < 0.001) and with high alcohol consumption (47.4% versus 30.7%, P = 0.005). An increased risk of death was observed with higher levels of 20:2 ω-6 (hazard ratiotertile3 vstertile1 (HRT3vsT1) 2.12; 95% confidence interval (CI) 1.01-4.42; p-trend = 0.04), 22:4 ω-6 (HRT3vsT1 = 3.52; 95% CI = 1.51-8.17; p-trend = 0.005), and 22:5 ω-6 (HRT3vsT1 = 3.50; 95% CI = 1.56-7.87; p-trend = 0.002). Conversely, the risk of death seemed lower when higher concentrations of 18:3 ω-6 (HRT3vsT1 = 0.52; 95% CI = 0.27-0.99; p-trend = 0.04) and the essential fatty acid, α-linolenic acid 18:3 ω-3 (HRT3vsT1 = 0.47; 95% CI = 0.24-0.93; p-trend = 0.03) were observed. CONCLUSION: The risk of death was increased in CRC patients with higher concentrations of certain ω-6 PUFAs and lower concentrations of α-linolenic acid in their subcutaneous adipose tissue. These results reflect dietary habits and altered fatty acid metabolism. Our exploratory results warrant confirmation in larger studies with further exploration of the mechanisms involved.

Development of the 12-Item Facial Complaints Evaluation Scale (FaCES-12).

OBJECTIVES: Chronic rhinosinusitis and related rhinologic disorders are common in routine otolaryngologic practice. Common presenting symptoms include nasal obstruction, facial pain, facial pressure, headache, and a subjective feeling of the face feeling "swollen," a perceptual distortion. No validated scale exists to assess facial pain in addition to perceptual distortion or headache. The objective was to develop a novel scale for assessment of facial symptoms experienced by patients presenting for rhinologic evaluation. METHODS: This was a prospective validation cross-sectional study. A patient questionnaire, the 12-item Facial Complaints Evaluation Scale (FaCES-12), was created to evaluate facial symptoms based on clinical experience and the literature, including severity and timing of facial pain, facial pressure, facial perceptual swelling, and headache. Each item was assessed utilizing an 11-point Likert scale ranging from 0 to 10 in severity. Data was collected prospectively from 210 patients in 1 private and 2 academic otolaryngologic practices from August to December 2019 along with the PROMIS Pain Intensity Scale 3a and 22-Item Sino-nasal Outcome Test. Construct validity was determined using Pearson correlation and exploratory factor analysis. Internal consistency and test-retest reliability were assessed by calculating Cronbach's alpha and assessing test-retest scores. RESULTS: A new 12-item scale named FaCES-12 was developed. FaCES-12 demonstrated high reliability with a Cronbach's alpha of .94 and high test-retest reliability (r = .90). The scale revealed very strong correlation with the PROMIS Pain Intensity Scale 3a (r = .81) and moderate correlation with the Sino-nasal Outcome Test (r = .48). Exploratory factor analysis demonstrated the scale contained interrelated variables that measured unique components of facial sensations. CONCLUSION: The FaCES-12 is a valid and reliable instrument for use in the evaluation of facial symptoms. Further research into the application of this scale is warranted.

Disrupting CD38-driven T cell dysfunction restores sensitivity to cancer immunotherapy.

A central problem in cancer immunotherapy with immune checkpoint blockade (ICB) is the development of resistance, which affects 50% of patients with metastatic melanoma1,2. T cell exhaustion, resulting from chronic antigen exposure in the tumour microenvironment, is a major driver of ICB resistance3. Here, we show that CD38, an ecto-enzyme involved in nicotinamide adenine dinucleotide (NAD+) catabolism, is highly expressed in exhausted CD8+ T cells in melanoma and is associated with ICB resistance. Tumour-derived CD38hiCD8+ T cells are dysfunctional, characterised by impaired proliferative capacity, effector function, and dysregulated mitochondrial bioenergetics. Genetic and pharmacological blockade of CD38 in murine and patient-derived organotypic tumour models (MDOTS/PDOTS) enhanced tumour immunity and overcame ICB resistance. Mechanistically, disrupting CD38 activity in T cells restored cellular NAD+ pools, improved mitochondrial function, increased proliferation, augmented effector function, and restored ICB sensitivity. Taken together, these data demonstrate a role for the CD38-NAD+ axis in promoting T cell exhaustion and ICB resistance, and establish the efficacy of CD38 directed therapeutic strategies to overcome ICB resistance using clinically relevant, patient-derived 3D tumour models.

Quantifying Perioperative Risks for Antireflux and Hiatus Hernia Surgery: A Multicenter Cohort Study of 4301 Patients.

OBJECTIVE: Using a comprehensive Australian cohort, we quantified the incidence and determined the independent predictors of intraoperative and postoperative complications associated with antireflux and hiatus hernia surgeries. In addition, we performed an in-depth analysis to understand the complication profiles associated with each independent risk factor. BACKGROUND: Predicting perioperative risks for fundoplication and hiatus hernia repair will inform treatment decision-making, hospital resource allocation, and benchmarking. However, available risk calculators do not account for hernia anatomy or technical aspects of surgery in estimating perioperative risk. METHODS: Retrospective analysis of all elective antireflux and hiatus hernia surgeries in 36 Australian hospitals over 10 years. Hierarchical multivariate logistic regression analyses were performed to determine the independent predictors of intraoperative and postoperative complications accounting for patient, surgical, anatomic, and perioperative factors. RESULTS: A total of 4301 surgeries were analyzed. Of these, 1569 (36.5%) were large/giant hernias and 292 (6.8%) were revisional procedures. The incidence rates of intraoperative and postoperative complications were 12.6% and 13.3%, respectively. The Charlson Comorbidity Index, hernia size, revisional surgery, and baseline anticoagulant usage independently predicted both intraoperative and postoperative complications. These risk factors were associated with their own complication profiles. Finally, using risk matrices, we visualized the cumulative impact of these 4 risk factors on the development of intraoperative, overall postoperative, and major postoperative complications. CONCLUSIONS: This study has improved our understanding of perioperative morbidity associated with antireflux and hiatus hernia surgery. Our findings group patients along a spectrum of perioperative risks that inform care at an individual and institutional level.