Development and validation of AI-assisted transcriptomic signatures to personalize adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

Preoperative CT imaging as a tool to predict incisional hernia outcomes following abdominal wall reconstruction: A retrospective cohort analysis.

INTRODUCTION: Ventral wall hernia often causes significant morbidity and requires complex abdominal wall reconstruction (AWR). This study aims to determine whether subcutaneous abdominal fat thickness (AFT) measured with preoperative CT scans could predict postoperative outcomes in patients undergoing AWR. METHODS: A retrospective cohort study was conducted on all patients who underwent AWR at our institution between 2009 and 2021, with a minimum follow-up of 12 months. Using preoperative CT scans, AFT was measured at the xiphoid process, umbilicus, and pubic tubercle, as well as the hernia dimensions. Demographic, operative, and surgical outcome data were also collected and analyzed using statistical tests. RESULTS: The results showed that 9 of 101 patients (8.9%) experienced hernia recurrence. Smoking was associated with an increased risk of hernia recurrence (p < 0.001) with a predictive odds ratio (OR) of 18.27 (p = 0.041). Increased AFT at the xiphoid (p = 0.005), umbilicus (p < 0.001), and pubic tubercle (p < 0.001) were also associated with hernia recurrence and risk of infection. Only AFT at the pubic tubercle reached significance in the regression model predicting recurrence (OR=1.10; p = 0.030) and infection (OR=1.04; p = 0.021). A cut-off value of 67 mm was associated with a positive predictive value of 42.14% (sensitivity of 67% and specificity of 91%). Hernia defect area was not associated with risk of recurrence or infection. CONCLUSIONS: Smoking and increased AFT at the pubic tubercle are significant predictive factors for recurrence and infection in patients undergoing AWR, and preoperative optimization should focus on reducing these factors.

Prediction of underlying atrial fibrillation in patients with a cryptogenic stroke: results from the NOR-FIB Study.

BACKGROUND: Atrial fibrillation (AF) detection and treatment are key elements to reduce recurrence risk in cryptogenic stroke (CS) with underlying arrhythmia. The purpose of the present study was to assess the predictors of AF in CS and the utility of existing AF-predicting scores in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study. METHOD: The NOR-FIB study was an international prospective observational multicenter study designed to detect and quantify AF in CS and cryptogenic transient ischaemic attack (TIA) patients monitored by the insertable cardiac monitor (ICM), and to identify AF-predicting biomarkers. The utility of the following AF-predicting scores was tested: AS5F, Brown ESUS-AF, CHA2DS2-VASc, CHASE-LESS, HATCH, HAVOC, STAF and SURF. RESULTS: In univariate analyses increasing age, hypertension, left ventricle hypertrophy, dyslipidaemia, antiarrhythmic drugs usage, valvular heart disease, and neuroimaging findings of stroke due to intracranial vessel occlusions and previous ischemic lesions were associated with a higher likelihood of detected AF. In multivariate analysis, age was the only independent predictor of AF. All the AF-predicting scores showed significantly higher score levels for AF than non-AF patients. The STAF and the SURF scores provided the highest sensitivity and negative predictive values, while the AS5F and SURF reached an area under the receiver operating curve (AUC) > 0.7. CONCLUSION: Clinical risk scores may guide a personalized evaluation approach in CS patients. Increasing awareness of the usage of available AF-predicting scores may optimize the arrhythmia detection pathway in stroke units.

Atrial fibrillation in cryptogenic stroke and TIA patients in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study: Main results.

Introduction: Secondary stroke prevention depends on proper identification of the underlying etiology and initiation of optimal treatment after the index event. The aim of the NOR-FIB study was to detect and quantify underlying atrial fibrillation (AF) in patients with cryptogenic stroke (CS) or transient ischaemic attack (TIA) using insertable cardiac monitor (ICM), to optimise secondary prevention, and to test the feasibility of ICM usage for stroke physicians. Patients and methods: Prospective observational international multicenter real-life study of CS and TIA patients monitored for 12 months with ICM (Reveal LINQ) for AF detection. Results: ICM insertion was performed in 91.5% by stroke physicians, within median 9 days after index event. Paroxysmal AF was diagnosed in 74 out of 259 patients (28.6%), detected early after ICM insertion (mean 48 ± 52 days) in 86.5% of patients. AF patients were older (72.6 vs 62.2; p < 0.001), had higher pre-stroke CHA2DS2-VASc score (median 3 vs 2; p < 0.001) and admission NIHSS (median 2 vs 1; p = 0.001); and more often hypertension (p = 0.045) and dyslipidaemia (p = 0.005) than non-AF patients. The arrhythmia was recurrent in 91.9% and asymptomatic in 93.2%. At 12-month follow-up anticoagulants usage was 97.3%. Discussion and conclusions: ICM was an effective tool for diagnosing underlying AF, capturing AF in 29% of the CS and TIA patients. AF was asymptomatic in most cases and would mainly have gone undiagnosed without ICM. The insertion and use of ICM was feasible for stroke physicians in stroke units.

Evaluation of catch-up growth in severe pediatric Hashimoto's hypothyroidism.

BACKGROUND: We aimed to evaluate catch-up growth in children with severe Hashimoto's hypothyroidism (HH) after thyroid hormone replacement therapy (HRT). METHODS: A multicenter retrospective study was conducted including children referred for growth slowdown that led to the diagnosis of HH between 1998 and 2017. RESULTS: A total of 29 patients were included, with a median age of 9.7 years (13-172 months). Median height at diagnosis was -2.7 [-4.6; -0.1] standard deviation score (SDS), with a height loss of 2.5 [0.7; 5.4] SDS compared to height before growth deflection (p<0.0001). At diagnosis, the median TSH level was 819.5 mIU/L [100; 1844], the median FT4 level was 0 pmol/L [undetectable; 5.4], and the median anti-thyroperoxidase antibody level was 1601 UI/L [47; 25,500]. In the 20 patients treated only with HRT, there were significant differences between height at diagnosis and height at 1 year (n = 19, p<0.0001), 2 years (n = 13, p = 0.0005), 3 years (n = 9, p = 0.0039), 4 years (n = 10, p = 0.0078), and 5 years (n = 10, p = 0.0018) of treatment but not in the case of final height (n = 6, p = 0.0625). Median final height was -1.4 [-2.7; 1,5] SDS (n = 6), with a significant difference between height loss at diagnosis and total catch-up growth (p = 0.003). The other nine patients were also given growth hormone (GH). They were smaller at diagnosis (p = 0.01); however, there was no difference in final height between those two groups (p = 0.68). CONCLUSION: Severe HH can lead to a major height deficit, and catch-up growth seems to be insufficient after treatment with HRT alone. In the most severe cases, administration of GH may enhance this catch-up.

Underlying causes of cryptogenic stroke and TIA in the nordic atrial fibrillation and stroke (NOR-FIB) study - the importance of comprehensive clinical evaluation.

BACKGROUND: Cryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management. METHODS: Prospective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis. RESULTS: After 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA2DS2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091). CONCLUSION: Cryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.

The impact of donor consent mechanism on organ procurement organization performance in the United States.

BACKGROUND: Lack of donor organ availability represents a major limitation to the success of solid organ transplantation. The Scientific Registry of Transplant Recipients (SRTR) publishes performance reports of organ procurement organizations (OPO) in the United States, but does not stratify by the mechanism of donor consent, namely first-person authorization (organ donor registry) and next-of-kin authorization. This study aimed to report the trends in deceased organ donation in the United States and assess the regional differences in OPO performance after accounting for the different mechanisms of donor consent. METHODS: The SRTR database was queried for all eligible deaths (2008-2019) which were then stratified based on the mechanism of donor authorization. Multivariable logistic regression was performed to assess the probability of organ donation across OPOs based on specific donor consent mechanisms. Eligible deaths were divided into 3 cohorts based on the probability to donate. Consent rates at the OPO level were calculated for each cohort. RESULTS: Organ donor registration among adult eligible deaths in the U.S. increased over time (2008: 10% vs 2019: 39%, p < 0.001), coincident with a decline in next-of-kin authorization rates (2008: 70% vs 2019: 64%, p < 0.001). At the OPO level, the increased organ donor registration was associated with lower next-of-kin authorization rates. Among eligible deaths with medium- and low-probability of donation, recruitment was highly variable across OPO's, ranging from 36% to 75% in the medium-probability group (median 54%, IQR 50%-59%) and 8% and 73% in the low-probability group (median 30%, IQR 17%-38%). CONCLUSION: Significant variability exists across OPOs in the consent of potentially persuadable donors after adjusting for population demographic differences and the mechanism of consent. Current metrics may not truly reflect OPO performance as they do not account for consent mechanism. There is further opportunity for improvement in deceased organ donation through targeted initiatives across OPOs, modeled after regions with the best performance.

Minimally Invasive Coronary Artery Bypass Grafting in a Patient With Chronic Tracheostoma: Alternative to Reduce Sternal Wound Complication Risk.

Patients with chronic tracheostoma present a challenge when they require coronary bypass surgery due to an elevated risk of sternal wound infections (SWI). Minimally invasive coronary artery bypass grafting (MICS CABG) is a robust technique that allows complete surgical revascularization while mitigating the risks of sternal complications and functional decline associated with sternotomy. In such patients at elevated risk for SWI, MICS CABG may represent a viable revascularization strategy to avoid sternotomy. Here, we present a case of a frail, comorbid patient with a chronic tracheostomy and symptomatic multivessel coronary artery disease not amenable to percutaneous therapy referred for MICS CABG.

Incidence and associated factors of cetuximab-induced hypersensitivity infusion reactions in 1392 cancer patients treated in four French areas: a possible association with Lyme disease?

BACKGROUND: Previous studies have observed an increased incidence of Cetuximab-induced hypersensitivity infusion reactions (CI-IRs) in the southeastern states of the USA. Tick's bites were suspected of generating cross-reactions between cetuximab and alpha-gal. This study aims was to describe the incidence and associated risk factors of CI-IRs, in the French areas chosen according to their Lyme disease incidence. PATIENTS AND METHODS: A retrospective chart review was conducted on patients that received cetuximab infusion from January 2010 to June 2019 in 4 French areas with different Lyme disease incidence rates. RESULTS: Of 1392 patients, 117 (8.4%) experienced a CI-IR, including 68 severe (grade 3 or 4) reactions (4.9%). This CI-IR incidence was significantly higher in the Lyme disease high-risk area than in the other areas (13.2% versus 7.1%, 8.1% and 6.4%; P = 0.016). Sex (P = 0.53), premedication (P = 0.91), primary cancer location (P = 0.46) and chemotherapy regimen type (P = 0.78) had no impact on CI-IR incidence in the overall population. In the head and neck squamous cell carcinoma (HNSCC) patient subgroup, CI-IRs were significantly more frequent in the high-risk area (16.4% versus 6.7%, 7.1% and 7.0%; P = 0.0015). CONCLUSION: This study suggests that patients treated in the French area with the highest incidence of Lyme disease are at a higher risk of CI-IRs.

Technology implementation in care practices for community-dwelling older adults with mild cognitive decline: Perspectives of professional caregivers in Quebec and Brussels.

Objective: As worldwide population aging is accelerating, innovative technologies are being developed to support independent living among community-dwelling older adults with mild cognitive decline. However, the successful implementation of these interventions is often challenging. Until now, literature on implementation issues related to the specific context of older adults with mild cognitive decline is lacking and the few studies available do not focus specifically on the perspective of professional caregivers. Yet the perspective of these caregivers is important as they can be considered a key facilitator for technology implementation among this population. Therefore, this study was the first to examine technology implementation among community-dwelling older adults with mild cognitive decline from the broader perspective of professional caregivers. Methods: In this qualitative study, two focus groups consisting of a heterogeneous pool of professional caregivers were conducted: one in Quebec (Canada, n = 6) and one in Brussels (Belgium, n = 8). Braun and Clarke' method for thematic analysis, guided by a qualitative descriptive approach was applied to inductively identify themes from the data. Results: We identified factors influencing technology implementation in older adults with mild cognitive decline on three levels: an individual level (e.g., characteristics of older adults with mild cognitive decline and professional caregivers' attitude), an organizational level (e.g., lack of training among professional caregivers) and a level referring to the broader context (e.g., ethical considerations). Conclusions: This study contributes to the research gap in knowledge on the needs of professional caregivers to facilitate technology implementation among the population of older adults with cognitive decline. Future directions for research, practice, and policy are given, more specifically to improve knowledge among caregivers and on the development of decision support to retrieve safe and effective technologies that suit patient-centered care.

The Hunga Tonga-Hunga Ha'apai Hydration of the Stratosphere.

Following the 15 January 2022 Hunga Tonga-Hunga Ha'apai eruption, several trace gases measured by the Aura Microwave Limb Sounder (MLS) displayed anomalous stratospheric values. Trajectories and radiance simulations confirm that the H2O, SO2, and HCl enhancements were injected by the eruption. In comparison with those from previous eruptions, the SO2 and HCl mass injections were unexceptional, although they reached higher altitudes. In contrast, the H2O injection was unprecedented in both magnitude (far exceeding any previous values in the 17-year MLS record) and altitude (penetrating into the mesosphere). We estimate the mass of H2O injected into the stratosphere to be 146 ± 5 Tg, or ∼10% of the stratospheric burden. It may take several years for the H2O plume to dissipate. This eruption could impact climate not through surface cooling due to sulfate aerosols, but rather through surface warming due to the radiative forcing from the excess stratospheric H2O.

Bullous haemorrhagic dermatitis induced by heparins and other anticoagulants: 94 cases from French pharmacovigilance centres and a literature review.

BACKGROUND: Bullous haemorrhagic dermatitis (BHD) is an uncommon and highly particular side effect of various forms of heparins. METHODS: To better characterise the disease, we collected all cases from French Pharmacovigilance centres recorded over a 20-year period (37 cases) and performed a Medline literature search up to June 2020 (57 cases). RESULTS: In all, 94 patients were identified (male/female ratio: 2.2) of mean age 73.5±12.1 years (31-94). Patients were treated with enoxaparin (n=66), unfractionated heparin (n=11), fondaparinux (n=10), tinzaparin (n=4), bemiparin (n=1), reviparin (n=1), dalteparin (n=1), and 4 with other anticoagulants: warfarin (n=3) and rivaroxaban (n=1). All cases presented with 1 to more than 100 haemorrhagic vesicles and bullae, distant from the injection sites, located mainly on the lower (75%) or upper limbs (69%). The lesions were asymptomatic, except in 5 patients who had pruritic or painful lesions. The interval between treatment initiation and BHD ranged from 6 hours to 30 days (mean: 8.4±7 days). Biopsy (n=53) showed intraepidermal or subcorneal cavity with red cells (n=39) or junctional blisters (n=10), with eosinophilic infiltrate only rarely. Direct immuno-fluorescence was negative in 19/20 cases and indirect immunofluorescence was negative in 8/8. The outcome was favourable in all cases, including in 12 patients for whom heparin was maintained. A 93-year-old patient died of compressive haematomas unrelated to BHD. We found 5 cases similar to BHD due to other anticoagulants. DISCUSSION: This is the largest comprehensive series of this adverse effect due to heparins or, more rarely, to other anticoagulants. Dermatologists must be aware of BHD, since this benign side effect does not necessarily require interruption of treatment. It is rare, considering the large-scale prescription of heparins, and occurs mainly in male patients aged over 70. Although the presentation is highly typical, the physiopathology is difficult to understand, as coagulation parameters are usually normal. Aging, skin fragility or mechanical factors might play a role.

An Integrated Clinical and Genetic Prediction Model for Tacrolimus Levels in Pediatric Solid Organ Transplant Recipients.

BACKGROUND: There are challenges in achieving and maintaining therapeutic tacrolimus levels after solid organ transplantation (SOT). The purpose of this genome-wide association study was to generate an integrated clinical and genetic prediction model for tacrolimus levels in pediatric SOT. METHODS: In a multicenter prospective observational cohort study (2015-2018), children <18 years old at their first SOT receiving tacrolimus as maintenance immunosuppression were included (455 as discovery cohort; 322 as validation cohort). Genotyping was performed using a genome-wide single nucleotide polymorphism (SNP) array and analyzed for association with tacrolimus trough levels during 1-y follow-up. RESULTS: Genome-wide association study adjusted for clinical factors identified 25 SNPs associated with tacrolimus levels; 8 were significant at a genome-wide level (P < 1.025 × 10-7). Nineteen SNPs were replicated in the validation cohort. After removing SNPs in strong linkage disequilibrium, 14 SNPs remained independently associated with tacrolimus levels. Both traditional and machine learning approaches selected organ type, age at transplant, rs776746, rs12333983, and rs12957142 SNPs as the top predictor variables for dose-adjusted 36- to 48-h posttacrolimus initiation (T1) levels. There was a significant interaction between age and organ type with rs776476*1 SNP (P < 0.05). The combined clinical and genetic model had lower prediction error and explained 30% of the variation in dose-adjusted T1 levels compared with 18% by the clinical and 12% by the genetic only model. CONCLUSIONS: Our study highlights the importance of incorporating age, organ type, and genotype in predicting tacrolimus levels and lays the groundwork for developing an individualized age and organ-specific genotype-guided tacrolimus dosing algorithm.

Checklist for follow-up of adolescents with chronic illness. A monitoring tool to help prepare the transition from pediatric to adult care.

Adolescence can be a particularly challenging period for individuals with a chronic illness. To help the specialized healthcare teams, an expert panel drafted a checklist of topics to be addressed throughout adolescence that are often not covered in subspecialty clinic visits such as peers, coping, adherence, understanding of illness, sexuality, etc., since these topics apply to youth with special healthcare needs. Each member of the specialized team can discuss one of the themes according to their role with the adolescent as a doctor, educator, nurse, dietician, etc. The coherence of the team enables a comprehensive approach and will facilitate the transition to adult medical care.

Waitlist and Post-Heart Transplant Outcomes for Children with Kawasaki Disease in the United States.

We evaluated waitlist and post-heart transplant outcomes for children with Kawasaki disease and found that over 3 decades the number of patients requiring heart transplantation in the US is low. Also, patients with Kawasaki disease have similar waitlist and post-transplant outcomes compared with patients with dilated cardiomyopathy.

Determination of the optimal dose of ephedrine in the treatment of arterial hypotension due to general anesthesia in neonates and infants below 6 months old: the ephedrine study protocol for a randomized, open-label, controlled, dose escalation trial.

BACKGROUND: Arterial hypotension induced by general anesthesia is commonly identified as a risk factor of morbidity, especially neurological, after cardiac or noncardiac surgery in adults and children. Intraoperative hypotension is observed with sevoflurane anesthesia in children, in particular in neonates, infants younger than 6 months, and preterm babies. Ephedrine is commonly used to treat intraoperative hypotension. It is an attractive therapeutic, due to its dual action on receptors alpha and beta and its possible peripheral intravenous infusion. There are few data in the literature on the use of ephedrine in the context of pediatric anesthesia. The actual recommended dose of ephedrine (0.1 to 0.2 mg/Kg) frequently leads to a therapeutic failure in neonates and infants up to 6 months of age. The use of higher doses would probably lead to a better correction of hypotension in this population. The objective of our project is to determine the optimal dose of ephedrine for the treatment of hypotension after induction of general anesthesia with sevoflurane, in neonates and infants up to 6 months of age. METHODS: The ephedrine study is a prospective, randomized, open-label, controlled, dose-escalation trial. The dose escalation consists of 6 successive cohorts of 20 subjects. The doses studied are 0.6, 0.8, 1, 1.2, and 1.4 mg/kg. The dose chosen as the reference is 0.1 mg/kg, the actual recommended dose. Neonates and infants younger than 6 months, males and females, including preterm babies who undergo a surgery with general anesthesia inducted with sevoflurane were eligible. Parents of the subject were informed. Then, the subjects were randomized if presenting a decrease in mean blood pressure superior to 20% of their initial mean blood pressure (before induction of anesthesia), despite a vascular filling with sodium chloride 0.9%. The primary outcome is the success of the therapy defined as an mBP superior to 80% of the baseline mBP (prior to anesthesia) within 10 min post ephedrine administration. The subjects were followed-up for 3 days postanesthesia. DISCUSSION: This study is the first randomized, controlled trial intending to determine the optimal dose of ephedrine to treat hypotension in neonates and infants below 6 months old. TRIAL REGISTRATION: ClinicalTrials.gov NCT02384876 . Registered on March 2015.