Extended observation of reduced methamphetamine use with combined naltrexone plus bupropion in the ADAPT-2 trial.

BACKGROUND AND AIMS: A 12-week placebo-controlled, sequential parallel Accelerated Development of Additive Pharmacotherapy Treatment for Methamphetamine Use Disorder (ADAPT-2) trial evaluated the effects of extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN) on methamphetamine (MA) use over two stages. This study reports on the previously unpublished stage 2 MA use in participants randomized at stage 1 to receive NTX + BUPN through both stages compared with those assigned to placebo. DESIGN: This is a secondary analysis of the US National Institute on Drug Abuse (NIDA) ADAPT-2 network trial. SETTING: The parent ADAPT-2 trial was carried out across multiple NIDA Clinical Trials Network (CTN) sites in the United States. PARTICIPANTS: This analysis includes 403 people with MA use disorder who participated in the ADAPT-2 CTN trial. INTERVENTION AND COMPARATOR: NTX + BUPN was compared with placebo over the course of the trial. MEASUREMENT: MA use was measured by urine drug screens conducted twice weekly for 12 weeks, then once in week 13 and once in week 16 post-treatment follow-up. FINDINGS: Participants on NTX + BUPN in stage 1 showed an additional 9.2% increase [95% confidence interval (CI), 0.09%-17.9%, P = 0.038] during stage 2 in their probability of testing negative for MA, with a total increase of 27.1% (95% CI, 13.2%-41.1%, P < 0.001) over the full 12 weeks of treatment. In contrast, participants on placebo in both stages increased in probability of testing MA-negative by a total of 11.4% (95% CI, 4.1%-18.6%, P = 0.002) over all 12 weeks. The 12-week increase among participants on NTX + BUPN was significantly greater-by 15.8% (95% CI, 4.5%-27.0%, P = 0.006)-than the increase among those on placebo. CONCLUSION: For people with methamphetamine (MA) use disorder receiving treatment with extended-release injectable naltrexone plus extended-release oral bupropion (NTX + BUPN), continued treatment with NTX + BUPN after 6 weeks is associated with additional reductions in MA use up to 12 weeks.

Immunotherapy for hepatocellular carcinoma: the next evolution in expanding access to liver transplantation.

Immunotherapy has revolutionized treatment of advanced hepatocellular carcinoma (HCC). In addition, several phase III trials of immunotherapy in early- to intermediate-stage HCC in combination with surgical or locoregional therapies have recently reported positive results, and multiple other phase III trials in the same patient population are currently in process. As the application of immunotherapy is shifting to include patients with earlier stages of HCC, one looming question now emerges: What is the role of immunotherapy in the pre-liver transplant population? Liver transplantation is a potentially curative therapy for HCC and confers the additional advantage of restoring a normal, healthy liver. In pre-transplant patients, immunotherapy may improve downstaging success and tumour control at the cost of some immunologic risks. These include immune-related toxicities, which are particularly relevant in a uniquely vulnerable population with chronic liver disease, and the possibility of acute rejection after transplantation. Ultimately, the goal of immunotherapy in this population will be to effectively expand access to liver transplantation while preserving pre- and post-transplant outcomes. In this review, we discuss the mechanisms supporting combination immunotherapy, summarize key recent clinical data from major immunotherapy trials, and explore how immunotherapy can be applied in the neoadjuvant setting prior to liver transplantation in selected high-risk patients.

Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.

BACKGROUND: Patients with inflammatory bowel disease (IBD) exhibit considerable interindividual variability in medication response, highlighting the need for precision medicine approaches to optimize and tailor treatment. Pharmacogenetics (PGx) offers the ability to individualize dosing by examining genetic factors underlying the metabolism of medications such as thiopurines. Pharmacogenetic testing can identify individuals who may be at risk for thiopurine dose-dependent adverse reactions including myelosuppression. We aimed to evaluate PGx variation in genes supported by clinical guidelines that inform dosing of thiopurines and characterize differences in the distribution of actionable PGx variation among diverse ancestral groups. METHODS: Pharmacogenetic variation in TPMT and NUDT15 was captured by genome-wide genotyping of 1083 pediatric IBD patients from a diverse Canadian cohort. Genetic ancestry was inferred using principal component analysis. The proportion of PGx variation and associated metabolizer status phenotypes was compared across 5 genetic ancestral groups within the cohort (Admixed American, African, East Asian, European, and South Asian) and to prior global estimates from corresponding populations. RESULTS: Collectively, 11% of the cohort was categorized as intermediate or poor metabolizers of thiopurines, which would warrant a significant dose reduction or selection of alternate therapy. Clinically actionable variation in TPMT was more prevalent in participants of European and Admixed American/Latino ancestry (8.7% and 7.5%, respectively), whereas variation in NUDT15 was more prevalent in participants of East Asian and Admixed American/Latino ancestry (16% and 15% respectively). CONCLUSIONS: These findings demonstrate the considerable interpopulation variability in PGx variation underlying thiopurine metabolism, which should be factored into testing diverse patient populations.

In a large, pediatric inflammatory bowel disease cohort comprised of 5 genetic ancestry groups, we evaluated the distribution of loss-of-function pharmacogenetic variants in TPMT and NUDT15 and predicted phenotypes (impact on thiopurine metabolism).

Patient-focused drug development in primary sclerosing cholangitis: Insights on patient priorities and involvement in clinical trials.

BACKGROUND: According to the new AASLD Practice Guidance, all patients with primary sclerosing cholangitis (PSC) should be considered for participation in clinical trials. However, PSC's rarity has posed challenges to characterizing patient interest in trial participation and identifying predictors of patient willingness to participate in drug trials. METHODS: PSC Partners Seeking a Cure developed the "Our Voices" survey to inform the development of the Externally-Led Patient-Focused Drug Development Forum, an FDA initiative to capture patient experiences and perspectives on drug development. RESULTS: Of 797 survey respondents from over 30 countries, 536 (67%) identified slowing disease progression as the most important outcome. Eighty-nine percent identified their hepatologist/gastroenterologist as someone they would approach for advice about trials. Although 61% reported being willing to participate in drug trials, only 26% had ever been asked to participate. Notable barriers to trial involvement included unknown long-term risks (71%), long travel times to the study center (32%), and a liver biopsy requirement (27%). On multivariable logistic regression, pruritus (OR 1.62, 95% CI: 1.09-2.40, p = 0.017) was positively associated with willingness to participate in disease-modifying therapy trials, while jaundice (OR 0.34, 95% CI: 0.19-0.61, p < 0.001) and inflammatory bowel disease (OR 0.64, 95% CI: 0.42-0.98, p = 0.038) were negatively associated. Pruritus (OR 2.25, 95% CI: 1.50-3.39, p < 0.001) was also independently associated with willingness to participate in symptom treatment trials. CONCLUSIONS: Most patients with PSC report interest in participating in clinical trials, but few have been asked to participate. Referral of patients with PSC by their hepatologist/gastroenterologist to clinical trials and patient education on trial participation are vital to closing the gap between trial interest and participation. Pruritus may serve as a key indicator of patient interest in trial participation.

Frailty is a predictor of immediate postoperative complications following surgical management of knee dislocations.

PURPOSE: To assess the utility of frailty in predicting outcomes following surgical intervention for KDs. METHODS: The NIS database was queried for non-congenital knee dislocations from 2015 to 2019 that underwent ligament repair or surgical reduction. Patients were assigned frailty scores using the mFI-11, and outcomes were compared. Multivariate regression and ROC curve analysis were used to assess the independent association of obesity, frailty, VI, and age with adverse outcomes. RESULTS: A total of 3797 patients who underwent surgical management were included. Frailty was associated with extended LOS (OR 1.353, 95% CI 1.212-1.510, p < 0.001), adverse discharge (OR 1.716, 95% CI 1.515-1.946, p < 0.001), and complications (OR 1.449, 95% CI 1.352-1.553, p < 0.001). Severely frailty was associated with extended LOS (OR 1.838, 95% CI 1.611-2.097, p < 0.001), adverse discharge (OR 2.756, 95% CI 2.394-3.171, p < 0.001), and complications (OR 1.603, 95% CI 1.453-1.768, p < 0.001). Additionally, VI was a risk factor for extended LOS (OR 7.647 (6.442-9.076) p < 0.001), complications (OR 2.065 (1.810-2.341) p < 0.001), and adverse discharge (OR 1.825 (1.606-2.075), p < 0.001). Obesity was a risk factor for extended LOS (OR 1.599 (1.470-1.739), p < 0.001) and complications (OR 1.235 (1.108-1.377), p < 0.001). AUC analysis showed that frailty was the most accurate predictor of all outcomes when compared to VI, obesity, and age. CONCLUSIONS: Frailty is superior to age and obesity, and comparable to VI, at predicting adverse outcomes following surgical management of KDs. These findings suggest that frailty assessment might play a role in risk stratification and preoperative planning for KD patients that require surgical intervention.

Review article: Contemporary management of gastrointestinal, pancreatic and hepatic toxicities of immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are effective oncologic agents which frequently cause immune-related adverse events (irAEs) which can impact multiple organ systems. Onco-Gastroenterology is a novel and emerging subspecialty within gastroenterology focused on cancer treatment-related complications. Gastroenterologists must be prepared to identify and manage diverse immune-mediated toxicities including enterocolitis, hepatitis, pancreatitis and other ICI-induced toxicities. AIM: To provide a narrative review of the epidemiology, diagnostic evaluation and management of checkpoint inhibitor-induced gastrointestinal and hepatic toxicities. METHODS: We searched Cochrane and PubMed databases for articles published through August 2023. RESULTS: Gastrointestinal and hepatic irAEs include most commonly enterocolitis and hepatitis, but also pancreatitis, oesophagitis, gastritis, motility disorders (gastroparesis) and other rarer toxicities. Guidelines from the National Comprehensive Cancer Network, American Society of Clinical Oncology and European Society for Medical Oncology, in combination with emerging cohort and clinical trial data, offer strategies for management of ICI toxicities. Evaluation of irAEs severity by formal classification and clinical stability, and a thorough workup for alternative etiologies which may clinically mimic irAEs underlie initial management. Treatments include corticosteroids, biologics and other immunosuppressive agents plus supportive care; decisions on dosing, timing and choice of steroid adjuncts and potential for subsequent checkpoint inhibitor dosing are nuanced and toxicity-specific. CONCLUSIONS: Expanding clinical trial and cohort data have clarified the epidemiology and clinical characteristics of gastrointestinal, pancreatic and hepatic toxicities of ICIs. Guidelines, though valuable, remain based principally on retrospective cohort data. Quality prospective, controlled studies may refine algorithms for treatment and potential immunotherapy rechallenge.

TRAF3 loss-of-function reveals the noncanonical NF-κB pathway as a therapeutic target in diffuse large B cell lymphoma.

Here, we report recurrent focal deletions of the chr14q32.31-32 locus, including TRAF3, a negative regulator of NF-κB signaling, in de novo diffuse large B cell lymphoma (DLBCL) (24/324 cases). Integrative analysis revealed an association between TRAF3 copy number loss with accumulation of NIK, the central noncanonical (NC) NF-κB kinase, and increased NC NF-κB pathway activity. Accordingly, TRAF3 genetic ablation in isogenic DLBCL model systems caused upregulation of NIK and enhanced NC NF-κB downstream signaling. Knockdown or pharmacological inhibition of NIK in TRAF3-deficient cells differentially impaired their proliferation and survival, suggesting an acquired onco-addiction to NC NF-κB. TRAF3 ablation also led to exacerbated secretion of the immunosuppressive cytokine IL-10. Coculturing of TRAF3-deficient DLBCL cells with CD8+ T cells impaired the induction of Granzyme B and interferon (IFN) γ, which were restored following neutralization of IL-10. Our findings corroborate a direct relationship between TRAF3 genetic alterations and NC NF-κB activation, and highlight NIK as a potential therapeutic target in a defined subset of DLBCL.

Specific Gravity Improves Identification of Clinically Significant Quantitative Proteinuria from the Dipstick Urinalysis.

BACKGROUND: CKD is often underdiagnosed during early stages when GFR is preserved due to underutilization of testing for quantitative urine albumin-to-creatinine ratio (UACR) or protein-to-creatinine ratio (UPCR). Semi-quantitative dipstick proteinuria (DSP) on urinalysis is widely obtained but not accurate for identifying clinically significant proteinuria. METHODS: We identified all patients with a urinalysis and UACR or UPCR obtained on the same day at a tertiary referral center. The accuracy of DSP alone or in combination with specific gravity against a gold-standard of UACR ≥30 mg/g or UPCR ≥0.15 g/g, characterizing clinically significant proteinuria, was evaluated using logistic regression. Models were internally validated using 10-fold cross validation. The specific gravity for each DSP above which significant proteinuria is unlikely was determined. RESULTS: Of 11,229 patients, clinically significant proteinuria was present in 4,073 (36%). The area under the receiver operating characteristic curve (95% confidence interval) was 0.77 (0.76, 0.77) using DSP alone and 0.82 (0.82, 0.83) in combination with specific gravity (P<0.001), yielding a specificity of 0.93 (standard error, SE=0.02) and positive likelihood ratio of 9.52 (SE=0.85). The optimal specific gravity cut-offs to identify significant proteinuria were ≤1.0012, 1.0238, and 1.0442, for DSP of trace, 30, and 100 mg/dL. At any specific gravity, a DSP ≥300 mg/dL was extremely likely to represent significant proteinuria. CONCLUSION: Adding specific gravity to DSP improves recognition of clinically significant proteinuria and can be easily used to identify patients with early-stage CKD who may not have otherwise received a quantified proteinuria measurement for both clinical and research purposes.

Evaluating the management trends for priapism and assessing the risk of priapism after in-office intracavernosal injections: a cross-sectional analysis.

We describe the management trends of patients suffering from any priapism and evaluate the risks of developing priapism after intracavernosal injections (ICI) performed in office. We queried TriNetX for two separate male adult cohorts - those presenting with any priapism based on International Classification of Disease code, N48.3 (priapism) and those who underwent ICI in office based on Current Procedural Terminology code, 54235 (injection of corpora cavernosa with pharmacologic agent[s]). We evaluated treatment options for these patients after any priapism and described demographic risks for developing priapism after ICI performed in office. There were 17,545 priapism encounters and 26,104 usages of ICI in the office. Most common treatment for any priapism was corporal irrigation/injection of medications (11.3%). Patients presenting with priapism after ICI were younger (age > 65 years, OR 0.44 [95% CI 0.38-0.51], p < 0.01) and had a higher prevalence of mood disorders (20% vs 14%), behavioral disorders (7% vs 2%) and sickle cell disease (6% vs <1%). They were less likely to have diabetes (14% vs 22%), hypertension (33% vs 40%), prostate cancer (13% vs 25%) or have taken sildenafil or tadalafil (29-30% vs 35-38%). For patients administering ICI, proper screening and counseling of priapism is important to reduce complications.

Evaluation of 1D convolutional neural network in estimation of mango dry matter content.

This study empirically validates prior claims regarding the superior performance of a Convolutional Neural Network (CNN) model for estimating mango Dry Matter Content (DMC) using Near Infrared (NIR) spectroscopy. The Partial Least Squares (PLS), Artificial Neural Network (ANN), and CNN models employed in the previous publications were compared on an equal footing, i.e., employing the same training and test data, with consideration of the effect of other practices employed in those studies, i.e., outlier removal, training set partitioning, sample ordering, and spectral pretreatment and augmentation. A new benchmark RMSEP of 0.77 %FW was achieved, being statistically significant (P<0.05) different than the previously published best RMSEP for the same independent test set. This CNN model was also shown to be more robust when tested on a new season of fruit than optimised ANN and PLS models, with RMSEPs of 1.18, 2.62, and 1.87, and bias of 0.16, 2.36 and 1.56 %FW, respectively. The combination of model type and data augmentation was important, with the CNN model only slightly outperforming the ANN model when using only a second derivative pretreatment. This requirement highlights the need for chemometric input to model development. The quantification of the sensitivity of neural network model training to use of differing seeds for pseudo-random sequence generation is also recommended. The standard deviation in RMSEP of 50 ANN and CNN models trained with differing random seeds was 0.03 and 0.02 %FW, respectively.

Diagnostic utility of prolonged ambulatory video-electroencephalography monitoring.

OBJECTIVES: Ambulatory video-electroencephalography (video-EEG) represents a low-cost, convenient and accessible alternative to inpatient video-EEG monitoring, however few studies have examined their diagnostic yield. In this large-scale retrospective study conducted in Australia, we evaluated the efficacy of prolonged ambulatory video-EEG recordings in capturing diagnostic events and resolving the referring question. METHODS: Sequential adult and paediatric ambulatory video-EEG reports from April 2020 to June 2021 were reviewed retrospectively. Data collection included patient demographics, clinical information, and details of events and EEG abnormalities. Clinical utility was assessed by examining i) time to first diagnostic event, and ii) ability to resolve the referring questions - seizure localisation, quantification, classification, and differentiation (differentiating seizures from non-epileptic events). RESULTS: Of the 600 reports analysed, 49 % captured at least one event, and 45 % captured interictal abnormalities (epileptiform or non-epileptiform). Seizures, probable psychogenic events (mostly non-convulsive), and other non-epileptic events occurred in 13 %, 23 % and 21 % of recordings respectively, with overlap. Unreported events were captured in 53 (9 %) recordings, and unreported seizures represented more than half of all seizures captured (51 %, 392/773). Nine percent of events were missing clinical, video or electrographic data. A diagnostic event occurred in 244 (41 %) recordings, of which 14 % were captured between the fifth and eighth day of recording. Reported event frequency ≥ 1/week was the only significant predictor of diagnostic event capture. In recordings with both seizures and psychogenic events, unrecognized seizures were frequent, and seizures may be missed if recording is terminated early. The referring question was resolved in 85 % of reports with at least one event, and 53 % of all reports. Specifically, this represented 46 % of reports (235/512) for differentiation of events, and 75 % of reports (27/36) for classification of seizures. CONCLUSION: Ambulatory video-EEG recordings are of high diagnostic value in capturing clinically relevant events and resolving the referring clinical questions.

Outcomes of High-Grade Immune Checkpoint Inhibitor Hepatitis in Hospitalized and Nonhospitalized Patients.

BACKGROUND & AIMS: Guidelines recommend hospitalization for severe immune checkpoint inhibitor (ICI) hepatitis. We compared patient outcomes in the inpatient versus outpatient settings. METHODS: We conducted a multicenter, retrospective cohort study of 294 ICI-treated patients who developed grade 3-4 ICI hepatitis. The primary outcome was time to alanine aminotransferase (ALT) normalization (≤40); secondary outcomes included time to ALT ≤100 U/L and time to death. To account for confounding by indication, inverse probability of treatment weighting was applied to perform Cox regression. A sensitivity analysis was performed excluding patients with grade 4 hepatitis. RESULTS: One hundred and sixty-six patients (56.5%) were hospitalized for a median of 6 (interquartile range, 3-11) days. On inverse probability of treatment weighting Cox regression, hospitalization was not associated with time to ALT normalization (hazard ratio [HR], 1.11; 95% confidence interval [CI], 0.86-1.43; P = .436) or time to ALT ≤100 U/L (HR, 1.11; 95% CI, 0.86-1.43; P = .420). In the sensitivity analysis limited to patients with grade 3 hepatitis, hospitalization was also not associated with time to ALT normalization (HR, 1.11; 95% CI, 0.83-1.50; P = .474) or time to ALT ≤100 U/L (HR, 1.19; 95% CI, 0.90-1.58; P = .225). In a subgroup analysis of 152 patients with melanoma, hospitalization was not associated with reduced risk of all-cause death (HR, 0.93; 95% CI, 0.53-1.64; P = .798). Notably, despite their Common Terminology Criteria for Adverse Events classification of high-grade hepatitis, 94% of patients had "mild" liver injury based on International Drug-Induced Liver Injury Criteria. CONCLUSIONS: Hospitalization of patients with high-grade ICI hepatitis was not associated with faster hepatitis resolution and did not affect mortality. Routine hospitalization may not be necessary in all patients with high-grade ICI hepatitis and Common Terminology Criteria for Adverse Events criteria may overestimate severity of liver injury.

Respiratory dysfunction in degenerative cervical myelopathy: A systematic review.

INTRODUCTION: Degenerative cervical myelopathy is a condition of symptomatic cervical spinal cord compression secondary to a range of degenerative spinal pathology. Respiratory symptoms such as shortness of breath are not uncommonly reported by people with DCM and respiratory dysfunction has been described in several DCM studies. The objective of this review was therefore to systematically synthesise the current evidence on the relationship between DCM and respiratory function. METHODS: The review was registered on PROSPERO and adhered to PRISMA guidelines. Ovid MEDLINE and Embase were searched from inception to 14th March 2023. DCM studies reporting on any measure or outcome relating to respiratory function or disease were eligible. Reference lists of included studies and relevant reviews articles were hand searched. Title, abstract and full text screening, risk of bias and GRADE assessments were completed in duplicate. A quantitative synthesis is presented. RESULTS: Of 1991 studies identified by literature searching, 13 met inclusion criteria: 3 cohort studies, 5 case-control studies, 1 case series and 4 case studies. Forced vital capacity (FVC), peak expiratory flow rate (PEFR) and maximal voluntary ventilation (MVV) were reported to be lower in DCM patients than controls; there was inconsistency in comparisons of forced expiratory volume in 1 s (FEV1). There was conflicting evidence on whether surgical decompression was associated with improvements in respiratory parameters and on the relationship between level of spinal cord compression and respiratory dysfunction. CONCLUSION: DCM may be associated with respiratory dysfunction. However, consistency and quality of evidence is currently low. Further work should characterise respiratory dysfunction in DCM patients more rigorously and investigate putative mechanisms such as disruption to cervical nerve roots responsible for diaphragmatic innervation and damage to descending spinal projections from brainstem respiratory centres.

A machine learning algorithm predicting risk of dilating VUR among infants with hydronephrosis using UTD classification.

BACKGROUNDS: Urinary Tract Dilation (UTD) classification has been designed to be a more objective grading system to evaluate antenatal and post-natal UTD. Due to unclear association between UTD classifications to specific anomalies such as vesico-ureteral reflux (VUR), management recommendations tend to be subjective. OBJECTIVE: We sought to develop a model to reliably predict VUR from early post-natal ultrasound. STUDY DESIGN: Radiology records from single institution were reviewed to identify infants aged 0-90 days undergoing early ultrasound for antenatal UTD. Medical records were reviewed to confirm diagnosis of VUR. Primary outcome defined as dilating (≥Gr3) VUR. Exclusion criteria include major congenital urologic anomalies (bilateral renal agenesis, horseshoe kidney, cross fused ectopia, exstrophy) as well as patients without VCUG. Data were split into training/testing sets by 4:1 ratio. Machine learning (ML) algorithm hyperparameters were tuned by the validation set. RESULTS: In total, 280 patients (540 renal units) were included in the study (73 % male). Median (IQR) age at ultrasound was 27 (18-38) days. 66 renal units were found to have ≥ grade 3 VUR. The final model included gender, ureteral dilation, parenchymal appearance, parenchymal thickness, central calyceal dilation. The model predicted VUR with AUC at 0.81(0.73-0.88) on out-of-sample testing data. Model is shown in the figure. DISCUSSION: We developed a ML model that can predict dilating VUR among patients with hydronephrosis in early ultrasound. The study is limited by the retrospective and single institutional nature of data source. This is one of the first studies demonstrating high performance for future diagnosis prediction in early hydronephrosis cohort. CONCLUSIONS: By predicting dilating VUR, our predictive model using machine learning algorithm provides promising performance to facilitate individualized management of children with prenatal hydronephrosis, and identify those most likely to benefit from VCUG. This would allow more selective use of this test, increasing the yield while also minimizing overutilization.

Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest for salvage mandibular reconstruction: Case and technique.

In the era of free flap reconstruction, mandibular defects are routinely reconstructed with osseous free flaps, and non-free flap bony reconstruction options are limited. A patient with T4N0 mandibular squamous cell carcinoma underwent resection with fibula free flap reconstruction of a parasymphyseal to angle defect. After free flap failure due to venous congestion, the flap was explanted. He declined additional free flap reconstruction and elected to proceed with pedicled osteomyocutaneous pectoralis major with rib. In this case presentation, we discuss the technical details of harvest of this flap using the 6th rib. The pedicled osteomyocutaneous pectoralis major flap with osseous rib harvest, which is infrequently described in the literature, remains a viable option for bony reconstruction, particularly in the salvage setting.

Exploring the dynamics of the 2022 mpox outbreak in Canada.

The 2022 mpox outbreak predominantly impacted gay, bisexual, and other men who have sex with men (gbMSM). Two models were developed to support situational awareness and management decisions in Canada. A compartmental model characterized epidemic drivers at national/provincial levels, while an agent-based model (ABM) assessed municipal-level impacts of vaccination. The models were parameterized and calibrated using empirical case and vaccination data between 2022 and 2023. The compartmental model explored: (1) the epidemic trajectory through community transmission, (2) the potential for transmission among non-gbMSM, and (3) impacts of vaccination and the proportion of gbMSM contributing to disease transmission. The ABM incorporated sexual-contact data and modeled: (1) effects of vaccine uptake on disease dynamics, and (2) impacts of case importation on outbreak resurgence. The calibrated, compartmental model followed the trajectory of the epidemic, which peaked in July 2022, and died out in December 2022. Most cases occurred among gbMSM, and epidemic trajectories were not consistent with sustained transmission among non-gbMSM. The ABM suggested that unprioritized vaccination strategies could increase the outbreak size by 47%, and that consistent importation (≥5 cases per 10 000) is necessary for outbreak resurgence. These models can inform time-sensitive situational awareness and policy decisions for similar future outbreaks.

Late-life shift in caloric intake affects fly metabolism and longevity.

The prevalence of obesity is increasing in older adults and contributes to age-related decline. Caloric restriction (CR) alleviates obesity phenotypes and delays the onset of age-related changes. However, how late in life organisms benefit from switching from a high-(H) to a low-calorie (L) diet is unclear. We transferred male flies from a H to a L (HL) diet or vice versa (LH) at different times during life. Both shifts immediately change fly rate of aging even when applied late in life. HL shift rapidly reduces fly mortality rate to briefly lower rate than in flies on a constant L diet, and extends lifespan. Transcriptomic analysis uncovers that flies aged on H diet have acquired increased stress response, which may have temporal advantage over flies aged on L diet and leads to rapid decrease in mortality rate after HL switch. Conversely, a LH shift increases mortality rate, which is temporarily higher than in flies aged on a H diet, and shortens lifespan. Unexpectedly, more abundant transcriptomic changes accompanied LH shift, including increase in ribosome biogenesis, stress response and growth. These changes reflect protection from sudden release of ROS, energy storage, and use of energy to growth, which all likely contribute to higher mortality rate. As the beneficial effects of CR on physiology and lifespan are conserved across many organisms, our study provides framework to study underlying mechanisms of CR interventions that counteract the detrimental effects of H diets and reduce rate of aging even when initiated later in life.