An intermediate Rb-E2F activity state safeguards proliferation commitment.

Tissue repair, immune defence and cancer progression rely on a vital cellular decision between quiescence and proliferation1,2. Mammalian cells proliferate by triggering a positive feedback mechanism3,4. The transcription factor E2F activates cyclin-dependent kinase 2 (CDK2), which in turn phosphorylates and inactivates the E2F inhibitor protein retinoblastoma (Rb). This action further increases E2F activity to express genes needed for proliferation. Given that positive feedback can inadvertently amplify small signals, understanding how cells keep this positive feedback in check remains a puzzle. Here we measured E2F and CDK2 signal changes in single cells and found that the positive feedback mechanism engages only late in G1 phase. Cells spend variable and often extended times in a reversible state of intermediate E2F activity before committing to proliferate. This intermediate E2F activity is proportional to the amount of phosphorylation of a conserved T373 residue in Rb that is mediated by CDK2 or CDK4/CDK6. Such T373-phosphorylated Rb remains bound on chromatin but dissociates from it once Rb is hyperphosphorylated at many sites, which fully activates E2F. The preferential initial phosphorylation of T373 can be explained by its relatively slower rate of dephosphorylation. Together, our study identifies a primed state of intermediate E2F activation whereby cells sense external and internal signals and decide whether to reverse and exit to quiescence or trigger the positive feedback mechanism that initiates cell proliferation.

Acute Effects of Coffee Consumption on Health among Ambulatory Adults.

BACKGROUND: Coffee is one of the most commonly consumed beverages in the world, but the acute health effects of coffee consumption remain uncertain. METHODS: We conducted a prospective, randomized, case-crossover trial to examine the effects of caffeinated coffee on cardiac ectopy and arrhythmias, daily step counts, sleep minutes, and serum glucose levels. A total of 100 adults were fitted with a continuously recording electrocardiogram device, a wrist-worn accelerometer, and a continuous glucose monitor. Participants downloaded a smartphone application to collect geolocation data. We used daily text messages, sent over a period of 14 days, to randomly instruct participants to consume caffeinated coffee or avoid caffeine. The primary outcome was the mean number of daily premature atrial contractions. Adherence to the randomization assignment was assessed with the use of real-time indicators recorded by the participants, daily surveys, reimbursements for date-stamped receipts for coffee purchases, and virtual monitoring (geofencing) of coffee-shop visits. RESULTS: The mean (±SD) age of the participants was 39±13 years; 51% were women, and 51% were non-Hispanic White. Adherence to the random assignments was assessed to be high. The consumption of caffeinated coffee was associated with 58 daily premature atrial contractions as compared with 53 daily events on days when caffeine was avoided (rate ratio, 1.09; 95% confidence interval [CI], 0.98 to 1.20; P = 0.10). The consumption of caffeinated coffee as compared with no caffeine consumption was associated with 154 and 102 daily premature ventricular contractions, respectively (rate ratio, 1.51; 95% CI, 1.18 to 1.94); 10,646 and 9665 daily steps (mean difference, 1058; 95% CI, 441 to 1675); 397 and 432 minutes of nightly sleep (mean difference, 36; 95% CI, 25 to 47); and serum glucose levels of 95 mg per deciliter and 96 mg per deciliter (mean difference, -0.41; 95% CI, -5.42 to 4.60). CONCLUSIONS: In this randomized trial, the consumption of caffeinated coffee did not result in significantly more daily premature atrial contractions than the avoidance of caffeine. (Funded by the University of California, San Francisco, and the National Institutes of Health; CRAVE ClinicalTrials.gov number, NCT03671759.).

Surrogate endpoints in clinical trials of p16-positive squamous cell carcinoma of the oropharynx: an individual patient data meta-analysis.

BACKGROUND: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy. METHODS: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r2 greater than 0·7 was used as criteria for clinically relevant surrogacy. FINDINGS: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r2 0·83), and progression-free survival (Kendall's τ 0·88 and r2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r2 0·88), distant metastasis-free survival (r2 0·96), and progression-free survival (r2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival. INTERPRETATION: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints. FUNDING: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan.

Achieving Consensus: Severity-Graded Definitions of Fontan-Associated Complications to Characterize Fontan Circulatory Failure.

BACKGROUND: Fontan physiology leads to chronic changes in other organ systems that may affect long-term survival and the success of heart transplantation. Inadequate assessment and treatment of the extra-cardiac effects of Fontan may contribute to poor outcomes. Severity-graded/ordinal consensus definitions of Fontan complications are lacking, which limits understanding of how Fontan-specific morbidity affects patients' outcomes. METHODS AND RESULTS: A panel of Fontan patient and physiology experts, including pediatric, adult congenital, heart failure, and critical-care cardiology as well as pediatric nephrology, hepatology and psychology, convened to develop definitions of Fontan complications. Definitions were created by using a severity-graded ordinal scale: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, disabling or life threatening. Following definition creation, a second panel of 21 experts in Fontan circulatory failure used a modified Delphi methodology to modify and vote on definitions until consensus (> 90% agreement without recommended further modification) was reached on final definitions. After 3 rounds of modifications and voting, consensus agreement was achieved on all Fontan-specific definitions. The defined complications and morbidities of Fontan include: anatomic Fontan pathway obstruction, cyanosis, systemic venous abnormalities resulting from venous insufficiency, atrial arrhythmia, ventricular arrhythmia, bradycardia, chronic pleural effusions, chronic ascites, protein-losing enteropathy, plastic bronchitis, hemoptysis and pulmonary hemorrhage, sleep apnea, Fontan-associated liver disease, portal and hepatic variceal disease, acute kidney injury affecting clinical treatment, polycythemia, thrombotic disease, recurrent or severe bacterial infection, skin atrophy, adrenal insufficiency, physical impact of previous stroke, mood/behavior disorder, and neurodevelopmental disorder. CONCLUSION: Consensus and severity-graded definitions of Fontan-specific cardiac and extra-cardiac complications were achieved and are available for use in research. They will allow future robust analyses of Fontan patient outcomes.

Reducing donor acceptance practice variation - Learnings from a discussion forum.

PURPOSE: Although waitlist mortality is unacceptably high, nearly half of donor heart offers are rejected by pediatric heart transplant centers. The Advanced Cardiac Therapy Improving Outcome Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a multi-institutional donor decision discussion forum (DDDF) aimed at assessing donor acceptance practices and reducing practice variation. METHODS: A 1-h-long virtual DDDF for providers across North America, the United Kingdom, and Brazil was held monthly. Each session typically included two case presentations posing a real-world donor decision challenge. Attendees were polled before the presenting center's decision was revealed. Group discussion followed, including a review of relevant literature and PHTS data. Metrics of participation, participant agreement with presenting center decisions, and impact on future decision-making were collected and analyzed. RESULTS: Over 2 years, 41 cases were discussed. Approximately 50 clinicians attended each call. Risk factors influencing decision-making included donor quality (10), size discrepancy (8), and COVID-19 (8). Donor characteristics influenced 63% of decisions, recipient factors 35%. Participants agreed with the decision made by the presenting center only 49% of the time. Post-presentation discussion resulted in 25% of participants changing their original decision. Survey conducted reported that 50% respondents changed their donor acceptance practices. CONCLUSION: DDDF identified significant variation in pediatric donor decision-making among centers. DDDF may be an effective format to reduce practice variation, provide education to decision-makers, and ultimately increase donor utilization.

An integrated program to expand donor utilization in pediatric heart transplantation: Case report of successful transplant with multiple donor risk factors.

BACKGROUND: Pediatric heart transplantation (HT) continues to be limited by the shortage of donor organs, distance constraints, and the number of potential donor offers that are declined due to the presence of multiple risk factors. METHODS: We report a case of successful pediatric HT in which multiple risk factors were mitigated through a combination of innovative donor utilization improvement strategies. RESULTS: An 11-year-old, 25-kilogram child with cardiomyopathy and pulmonary hypertension, on chronic milrinone therapy and anticoagulated with apixaban, was transplanted with a heart from a Hepatitis C virus positive donor and an increased donor-to-recipient weight ratio. Due to extended geographic distance, an extracorporeal heart preservation system (TransMedics™ OCS Heart) was used for procurement. No significant bleeding was observed post-operatively, and she was discharged by post-operative day 15 with normal biventricular systolic function. Post-transplant Hepatitis C virus seroconversion was successfully treated. CONCLUSIONS: Heart transplantation in donors with multiple risk factor can be achieved with an integrative team approach and should be taken into consideration when evaluating marginal donors in order to expand the current limited donor pool in pediatric patients.

Mechanical Ventilation and Outcomes of Children Who Undergo Ventricular Assist Device Placement: 2014-2020 Linked Analysis From the Advanced Cardiac Therapies Improving Outcomes Network and Pediatric Cardiac Critical Care Consortium Registries.

OBJECTIVES: Placement of a ventricular assist device (VAD) improves outcomes in children with advanced heart failure, but adverse events remain important consequences. Preoperative mechanical ventilation (MV) increases mortality, but it is unknown what impact prolonged postoperative MV has. DESIGN: Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Cardiac Critical Care Consortium (PC 4 ) registries were used to identify and link children with initial VAD placement admitted to the cardiac ICU (CICU) from August 2014 to July 2020. Demographics, cardiac diagnosis, preoperative and postoperative CICU courses, and outcomes were compiled. Univariable and multivariable statistics assessed association of patient factors with prolonged postoperative MV. Multivariable logistic regression sought independent associations with outcomes. SETTING: Thirty-five pediatric CICUs across the United States and Canada. PATIENTS: Children on VADs included in both registries. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred forty-eight ACTION subjects were linked to a matching patient in PC 4 . Median (interquartile) age 7.7 years (1.5-15.5 yr), weight 21.3 kg (9.1-58 kg), and 56% male. Primary diagnosis was congenital heart disease (CHD) in 35%. Pre-VAD explanatory variables independently associated with prolonged postoperative MV included: age (incidence rate ratio [IRR], 0.95; 95% CI, 0.93-0.96; p < 0.01); preoperative MV within 48 hours (IRR, 2.76; 95% CI, 1.59-4.79; p < 0.01), 2-7 days (IRR, 1.82; 95% CI, 1.15-2.89; p = 0.011), and greater than 7 days before VAD implant (IRR, 2.35; 95% CI, 1.62-3.4; p < 0.01); and CHD (IRR, 1.96; 95% CI, 1.48-2.59; p < 0.01). Each additional day of postoperative MV was associated with greater odds of mortality (odds ratio [OR], 1.09 per day; p < 0.01) in the full cohort. We identified an associated greater odds of mortality in the 102 patients with intracorporeal devices (OR, 1.24; 95% CI, 1.04-1.48; p = 0.014), but not paracorporeal devices (77 patients; OR, 1.04; 95% CI, 0.99-1.09; p = 0.115). CONCLUSIONS: Prolonged MV after VAD placement is associated with greater odds of mortality in intracorporeal devices, which may indicate inadequacy of cardiopulmonary support in this group. This linkage provides a platform for future analyses in this population.

Addressing Food Insecurity Through Community Empowerment in a Staten Island (Richmond County) Neighborhood in New York City.

This study investigated community empowerment as a means of addressing food insecurity amongst underserved neighborhoods by increasing available and affordable food choices through Clementine Collective stands in Staten Island, New York (Richmond County), one of the 5 Boroughs of New York City. Given the growing complexity of food insecurity, inclusive and equitable action must be taken that incorporates the voices, perspectives and needs of those most impacted. Through methods of community engagement and empowerment, the Clementine Collective collaborates with local community residents to introduce sustainable solutions that address food insecurity. A survey (N = 132) was administered to customers of a Clementine Collective stand, located in Staten Island, that assessed customers' food habits and attitudes towards their food environment and solutions. The stand was placed in a local meat market grocery store. Descriptive statistics suggested that residents recognized gaps in their food environment and were empowered to advocate for solutions. Engaging residents from their food environment to advocate for local solutions, such as at community bodegas, or small grocery stores, may be an effective method of addressing food insecurity.

Successful implementation of telehealth visits in the paediatric heart failure and heart transplant population.

The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) and Pediatric Heart Transplant Society (PHTS) convened a working group at the beginning of 2020 during the COVID-19 pandemic, with the aim of using telehealth as an alternative medium to provide quality care to a high-acuity paediatric population receiving advanced cardiac therapies. An algorithm was developed to determine appropriateness, educational handouts were developed for both patients and providers, and post-visit surveys were collected. Telehealth was found to be a viable modality for health care delivery in the paediatric heart failure and transplant population and has promising application in the continuity of follow-up, medication titration, and patient education/counselling domains.

Differences in Quality of Life in Children Across the Spectrum of Congenital Heart Disease.

OBJECTIVE: To create complexity groups based upon a patient's cardiac medical history and to test for group differences in health-related quality of life (HRQOL). METHODS: Patients 8-18 years with congenital heart disease (CHD) and parent-proxies from the Pediatric Cardiac Quality of Life Inventory (PCQLI) Testing Study were included. Outcome variables included PCQLI Total, Disease Impact, and Psychosocial Impact scores. Using a patient's medical history (cardiac, neurologic, psychological, and cognitive diagnosis), latent class analysis (LCA) was used to create CHD complexity groups. Covariates included demographics and burden of illness (number of: school weeks missed, physician visits in the past year, and daily medications). Generalized estimation equations tested for differences in burden of illness and patient and parent-proxy PCQLI scores. RESULTS: Using 1482 CHD patients (60% male; 84% white; age 12.3 ± 3.0 years), latent class analysis (LCA) estimates showed 4 distinct CHD complexity groups (Mild, Moderate 1, Moderate 2, and Severe). Increasing CHD complexity was associated with increased risk of learning disorders, seizures, mental health problems, and history of stroke. Greater CHD complexity was associated with greater burden of illness (P < .01) and lower patient- and parent-reported PCQLI scores (P < .001). CONCLUSIONS: LCA identified 4 congenital heart disease (CHD) complexity groupings. Increasing CHD complexity was associated with higher burden of illness and worse patient- and parent-reported HRQOL.

Impact of Cancer Care Regionalization on Patient Volume.

BACKGROUND: Cancer centers are regionalizing care to expand patient access, but the effects on patient volume are unknown. This study aimed to compare patient volumes before and after the establishment of head and neck regional care centers (HNRCCs). METHODS: This study analyzed 35,394 unique new patient visits at MD Anderson Cancer Center (MDACC) before and after the creation of HNRCCs. Univariate regression estimated the rate of increase in new patient appointments. Geospatial analysis evaluated patient origin and distribution. RESULTS: The mean new patients per year in 2006-2011 versus 2012-2017 was 2735 ± 156 patients versus 3155 ± 207 patients, including 464 ± 78 patients at HNRCCs, reflecting a 38.4 % increase in overall patient volumes. The rate of increase in new patient appointments did not differ significantly before and after HNRCCs (121.9 vs 95.8 patients/year; P = 0.519). The patients from counties near HNRCCs, showed a 210.8 % increase in appointments overall, 33.8 % of which were at an HNRCC. At the main campus exclusively, the shift in regional patients to HNRCCs coincided with a lower rate of increase in patients from the MDACC service area (33.7 vs. 11.0 patients/year; P = 0.035), but the trend was toward a greater increase in out-of-state patients (25.7 vs. 40.3 patients/year; P = 0.299). CONCLUSIONS: The creation of HNRCCs coincided with stable increases in new patient volume, and a sizeable minority of patients sought care at regional centers. Regional patients shifted to the HNRCCs, and out-of-state patient volume increased at the main campus, optimizing access for both local and out-of-state patients.

Primary Care for Veterans Experiencing Homelessness: a Narrative Review of the Homeless Patient Aligned Care Team (HPACT) Model.

In 2011, the U.S. Department of Veterans Health (VA) implemented a homeless-tailored primary care medical home model called the Homeless Patient Aligned Care Teams (HPACTs). The impact of HPACTs on health and healthcare outcomes of veterans experiencing homelessness has not been adequately synthesized. This narrative review summarized peer-reviewed studies published in databases Ovid MEDLINE, Ovid EMBASE, and APA PsycInfo from 1946 to February 2022. Only original research studies that reported outcomes of the HPACT model were included in the review. Of 575 studies that were initially identified and screened, 26 studies met inclusion criteria and were included in this review. Included studies were categorized into studies that described the following: (1) early HPACT pilot implementation; (2) HPACT's association with service quality and utilization; and (3) specialized HPACT programs. Together, studies in this review suggest HPACT is associated with reductions in emergency department utilization and improvements in primary care utilization, engagement, and positive patient experiences; however, the methodological rigor of the included studies was low, and thus, these findings should only be considered preliminary. There is a need for randomized controlled trials assessing the impact of the PACT model on key outcomes of interest, as well as to determine whether the model is a viable way to manage healthcare for persons experiencing homelessness outside of the VA system.

Increased risk of infections in pediatric Fontan patients after heart transplantation.

BACKGROUND: Infectious complications are a major cause of morbidity and mortality after HT. Fontan patients may be more susceptible to post-HT infections. METHODS: This was a single-center, retrospective cohort analysis of pediatric patients undergoing HT for FF physiology or DCM, who underwent induction with ATG. The primary endpoint was an infection in the first 180 days post-HT, defined as positive (1) blood/urine/respiratory culture; (2) viral PCR; (3) skin or wound infection; and/or (4) culture-negative infection if ≥5 days of antibiotics were completed. Secondary endpoints included (1) cell counts after ATG; (2) PTLD; and (3) rejection (≥Grade 2R ACR or pAMR2) in the first 180 days post-HT. RESULTS: A total of 59 patients (26 FF, 33 DCM) underwent HT at 14.7 (IQR 10.6, 19.5) and 11.7 (IQR 1.4, 13.6) years of age, respectively. The median total ATG received was 7.4 (IQR 4.9, 7.7) vs 7.5 (IQR 7.3, 7.6) mg/kg (p = NS) for FF and DCM patients, respectively. Twenty-three patients (39%) developed an infection 180 days post-HT, with a higher rate of infection in FF patients (54% vs 27%, p = .03). Adjusted for pre-transplant absolute lymphocyte count, FF patients had a higher risk of infection at 30 days post-HT (OR 7.62, 95% CI 1.13-51.48, p = .04). There was no difference in the incidence of PTLD (12% vs 0%; p = .08) or rejection (12% vs 21%; p = .49). CONCLUSION: Compared to DCM patients, FF patients have a higher risk of infection. Modifications to induction therapy for FF patients should be considered.

Patient and parent-reported outcomes in paediatric ventricular assist device support: a multi-center ACTION learning network feasibility and pilot experience.

BACKGROUND: Patient- and proxy-reported outcomes (PROs) are an important indicator of healthcare quality and can be used to inform treatment. Despite the widescale use of PROs in adult cardiology, they are underutilised in paediatric cardiac care. This study describes a six-center feasibility and pilot experience implementing PROs in the paediatric and young adult ventricular assist device population. METHODS: The Advanced Cardiac Therapies Improving Outcomes Network (ACTION) is a collaborative learning network comprised of 55 centres focused on improving clinical outcomes and the patient/family experience for children with heart failure and those supported by ventricular assist devices. The development of ACTION's PRO programme via engagement with patient and parent stakeholders is described. Pilot feasibility, patient/parent and clinician feedback, and initial PRO findings of patients and families receiving paediatric ventricular assist support across six centres are detailed. RESULTS: Thirty of the thirty-five eligible patients (85.7%) were enrolled in the PRO programme during the pilot study period. Clinicians and participating patients/parents reported positive experiences with the PRO pilot programme. The most common symptoms reported by patients/parents in the first month post-implant period included limitations in activities, dressing change distress, and post-operative pain. Poor sleep, dressing change distress, sadness, and fatigue were the most common symptoms endorsed >30 days post-implant. Parental sadness and worry were notable throughout the entirety of the post-implant experience. CONCLUSIONS: This multi-center ACTION learning network-based PRO programme demonstrated initial success in this six-center pilot study experience and yields important next steps for larger-scale PRO collection, research, and clinical intervention.

Major Adverse Dystrophinopathy Events (MADE) Score as Marker of Cumulative Morbidity and Risk for Mortality in Boys with Duchenne Muscular Dystrophy.

Background: Overlapping symptoms from cardiomyopathy, respiratory insufficiency, and skeletal myopathy confound assessment of heart failure in Duchenne Muscular Dystrophy. We developed an ordinal scale of multiorgan clinical variables that reflect cumulative disease burden-the Major Adverse Dystrophinopathy Event (MADE) Score. We hypothesized that a higher MADE score would be associated with increased mortality in boys with Duchenne Muscular Dystrophy. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study dataset was utilized for validation. Methods: Duchenne Natural History Study variables were selected based on clinical relevance to prespecified domains: Cardiac, Pulmonary, Myopathy, Nutrition. Severity points (0-4) were assigned and summed for study visits. MADE score for cohorts defined by age, ambulatory status, and survival were compared at enrollment and longitudinally.Associations between MADE score and mortality were examined. Results: Duchenne Natural History Study enrolled 440 males, 12.6 ±6.1 years old, with 3,559 visits over 4.6 ±2.8 years, 45 deaths. MADE score increased with age and nonambulatory status. Mean MADE score per visit was 19 ±10 for those who died vs. 9.8 ±9.3 in survivors p=0.03. Baseline MADE score >12 predicted mortality independent of age (78% sensitivity, CPE.70). Rising MADE score trajectory was associated with mortality in models adjusted for enrollment age, follow-up time, and ambulatory status, all p<.001. Conclusion: A multiorgan severity score, MADE, was developed to track cumulative morbidities that impact heart failure in Duchenne muscular dystrophy. MADE score predicted Duchenne Natural History Study mortality. MADE score can be used for serial heart failure assessment in males and may serve as an endpoint for Duchenne muscular dystrophy clinical research.

Allergic reactions to coronavirus disease 2019 vaccines and addressing vaccine hesitancy: Northwell Health experience.

BACKGROUND: Allergic and nonallergic adverse reactions have been reported with global coronavirus disease 2019 (COVID-19) vaccination. It was previously hypothesized that polyethylene glycol (PEG) may be responsible for anaphylactic reactions to messenger RNA (mRNA) COVID-19 vaccines. OBJECTIVE: To report the workflow established at our institution, types, and frequency of adverse reactions to mRNA COVID-19 vaccines in patients presenting for allergy evaluation. METHODS: A COVID-19 vaccine adverse reaction registry was established. We used PEG prick skin testing, followed by PEG challenges in selected cases, to ensure PEG tolerance and encourage completion of COVID-19 vaccination series. RESULTS: A total of 113 patients were included. Most vaccine reactions (86.7%) occurred in women. Anaphylaxis occurred only in women, all of which had a history of allergic disease and two-thirds had asthma. Anaphylaxis rate was 40.6 cases per million. None of the anaphylactic cases developed hypotension, required intubation, or required hospital admission. Systemic allergic symptoms, not fulfilling anaphylaxis criteria, were significantly more common in Pfizer-BioNTech than Moderna-vaccinated patients (P = .02). We observed a higher incidence of dermatologic nonurticarial reactions in men (P = .004). Among first-dose reactors, 86.7% received and tolerated the second dose. We observed a high rate of false-positive intradermal skin test results and frequent subjective symptoms with oral PEG challenge. CONCLUSION: Intradermal PEG testing has limited utility in evaluating anaphylaxis to mRNA vaccines. Most severe postvaccination allergic symptoms are not caused by hypersensitivity to PEG. Most people with reaction to the initial mRNA vaccine can be safely revaccinated. Patients with anaphylaxis to COVID-19 vaccines benefit from physician-observed vaccination.

The influence of radiation dose on taste impairment in a prospective observational study cohort of oropharyngeal cancer patients.

BACKGROUND: To analyze the influence of radiation dose on late radiation-associated taste impairment in oropharyngeal cancer (OPC) patients treated with intensity-modulated radiotherapy (IMRT) using the taste bud bearing tongue mucosa as organ at risk. MATERIAL AND METHODS: This study is part of an ongoing, prospective observational study. Cancer-free OPC survivors with at least 24 months from IMRT were included in this analysis. Scores for taste impairment and dry mouth were extracted from the MD Anderson Symptom Inventory Head and Neck module (MDASI-HN) with scores of ≥5 considered as moderate-to-severe symptoms. The mean dose, minimum and maximum dose to the taste bud bearing tongue mucosa, the ipsi- and contralateral parotid and submandibular glands were extracted and analyzed for correlation with moderate-to-severe taste impairment. RESULTS: One hundred sixteen T1-4 OPC patients were included (81% males, median age: 55). The primary tumor was in the tonsil in 92 cases (79%) and in the base of tongue in 21 cases (18%). Patients were treated with 64.2-72.0 Gy; 37 patients (32%) received concurrent chemotherapy and 22 (19%) concurrent targeted therapy. After a median of 58 months from RT (IQR: 43-68) 38 patients (33%) suffered from moderate-to-severe long-term radiation-associated taste impairment. No dose volume parameter of the taste bud bearing tongue mucosa and the salivary glands was significantly associated with moderate-to-severe taste impairment for the whole patient cohort. For patients without concurrent chemotherapy, the minimum and mean dose to the ipsilateral parotid gland, and the maximum dose to the submandibular gland was significantly associated with late taste impairment (all p < 0.05). A significant correlation was found between taste impairment and dry mouth (p < 0.001). CONCLUSION: The dose to the ipsilateral parotid gland seems to play an important role in the development of late taste impairment. The influence of dose to the taste bud bearing tongue mucosa remains unclear and needs further investigation.

Clinical approach to mechanical circulatory support in the transplant patient from the Pediatric Heart Transplant Society.

The use of mechanical circulatory support (MCS) for pediatric patients who have undergone heart transplant has grown rapidly in the past decade. This includes support in the immediate post-transplant period and "rescue" therapy for patient later in their transplant course. Extracorporeal membrane oxygenation (ECMO) remains a standard modality of support for intraoperative concerns and for acute decompensation in the immediate post-transplant period. However, both pulsatile and continuous flow ventricular assist devices (VADs) have been used with increasing success in transplant patients for longer durations of support. Centers participating in the Pediatric Heart Transplant Society (PHTS) were queried to provide their internal protocols and rationale for mechanical circulatory support following heart transplant. These protocols coupled with evidence-based literature were used to provide the following description of clinical approaches to MCS in the transplant patient highlighting areas of both broad consensus and significant practice variation.

Decreased Risk of Strokes in Children with Ventricular Assist Devices Within ACTION.

We sought to characterize strokes in children with ventricular assist devices. Of 407 patients in the ACTION registry (4/1/18-5/3/2021), 45 (11%) experienced 52 strokes (45 ischemic and 7 hemorrhagic). Median time to stroke was 23.5 days and 19/52 (37%) occurred ≤ 10 days. Stroke rate was 0.09 and 0.63 strokes per patient-year for implantable continuous and paracorporeal devices, respectively. Patients with stroke were younger, more likely to have congenital heart disease and have been on extracorporeal membrane oxygenation at time of VAD. Based on these data, ACTION is now focused on decreasing strokes in these higher-risk patients with particular attention to the peri-implant period.

Outcomes of patients with oropharyngeal squamous cell carcinoma treated with induction chemotherapy followed by concurrent chemoradiation compared with those treated with concurrent chemoradiation.

BACKGROUND: Induction chemotherapy (IC) has been associated with a decreased risk of distant metastasis in locally advanced head and neck squamous cell carcinoma. However, its role in the treatment of oropharyngeal squamous cell carcinoma (OPSCC) is not well established. METHODS: The outcomes of patients with OPSCC treated with IC followed by concurrent chemoradiation (CRT) were compared with the outcomes of those treated with CRT alone. The primary outcome was overall survival (OS), and the secondary end points were the times to locoregional and distant recurrence. RESULTS: In an existing database, 585 patients met the inclusion criteria: 137 received IC plus CRT, and 448 received CRT. Most patients were positive for human papillomavirus (HPV; 90.9%). Patients receiving IC were more likely to present with a higher T stage, a higher N stage, and low neck disease. The 3-year OS rate was significantly lower in patients receiving IC (75.7%) versus CRT alone (92.9%). In a multicovariate analysis, receipt of IC (adjusted hazard ratio [aHR], 3.4; P < .001), HPV tumor status (aHR, 0.36; P = .002), and receipt of concurrent cetuximab (aHR, 2.7; P = .002) were independently associated with OS. The risk of distant metastasis was also significantly higher in IC patients (aHR, 2.8; P = .001), whereas an HPV-positive tumor status (aHR, 0.44; P = .032) and completion of therapy (aHR, 0.51; P = .034) were associated with a lower risk of distant metastasis. In HPV-positive patients, IC remained associated with distant metastatic progression (aHR, 2.6; P = .004) but not OS. CONCLUSIONS: In contrast to prior studies, IC was independently associated with worse OS and a higher risk of distant metastasis in patients with OPSCC. Future studies are needed to validate these findings.